α-(N-SULPHONAMIDO)ACETAMIDE DERIVATIVES AS β - AMYLOID INHIBITORS

The present invention provides novel α- (N-sulfonamido) acetamide compounds having medicinal and bioavailable properties, their pharmaceutical compositions and a method of use. More specifically, the invention relates to α- (N-arylsulfonamido) acetamides. These compounds are unique in that they inhibit the production of β-amyloid peptide (β-ΑΡ), thereby preventing the accumulation of amyloid protein deposits in the brain. More specifically, the present invention relates to the treatment of Alzheimer's disease (AD).

BASIS OF THE INVENTION

Alzheimer's disease is a progressive, neurodegenerative disease characterized by impaired memory and cognitive dysfunction. AD is pathologically characterized by accumulation of senile (neurite) plaques, neurofibril entanglement, amyloid deposition in nerve tissues and vessels, loss of synapses, and neuronal death. It is the most common form of dementia and today represents the third leading cause of death, after cardiovascular diseases and cancer. The cost of Alzheimer's disease is enormous (it exceeds $ 100 billion a year in the United States) and includes the suffering of patients, their families, and the loss of productivity of patients and those who care for them. As life expectancy increases, so does the number of AD cases. It is estimated that, if prevention and treatment methods are not found, by 2020. more than 10 million Americans have AD. It is estimated that today AD affects 10% of the population over the age of 65, and up to 50% over the age of 85. Currently, there are no ways to effectively prevent AD or eliminate the underlying clinical symptoms and pathophysiological changes (for a review, see Selkoe, DJ Ann. Rev. Cell. Biol. 1994.10: 373-403).

51155Β

There are many theories related to the etiology and pathogenesis of AD. These theories are either based on analogies with other diseases and conditions (c <g. Slow virus theory and aluminum theory) or are based on pathological observations (eg cholinergic. Amyloid or entanglement theory). By genetic analysis, it is potentially possible to distinguish between competing theories. Identification of mutations in p-amyloid precursor protein (β-ΑΡΡ) in individuals prone to early-onset forms of AD as well as related diseases. strongly supports amyloidogenic theories.

Histopathological examinations of brain tissue obtained by autopsy or neurosurgical samples of individuals affected by the disease reveal the appearance of amyloid plaques and the entanglement of neurofibrils in the cerebral cortex of these patients. Similar changes have been observed in patients with trisomy 21 (Down syndrome). Biochemical and immunological studies suggest that the dominant protein component of amyloid plaques is a protein of approximately

4.2 kilodaltons (kD), from about 39 to 4.3 amino acids. This protein is designated Αβ. βamyloid peptide. and sometimes β / Λ4; here it is designated as Αβ. In addition to deposition in amyloid plaques, Aβ is also found in the walls of meningeal and parenchymal arterioles, small arteries. capillaries and, sometimes. venula. An increasing body of evidence gathered over the last decade reveals that the Aβ internal polypeptide is derived from an integrated membrane protein type 1, called β-amyloid precursor protein (APP), (Selkoe, D. Phvsiol. Rev. 2001- 81. 741-766; Wolfc, MJ Med. Chem. 2001. 44, 2039-2060). Many cells in vivo and in culture, originating from different animals and from humans. normally produced βΑΡΡ. Several proteolytic fragments of APP are formed by the action of proteinases designated as secretases. A subset of these proteolytic fragments, called β-amyloid peptide (Αβ), contains 39 to 43 amino acids and is generated by the combined action of β-secretase and γ-secretase. β-secretase is a membrane-bound aspartyl protease whose activity forms the N-terminus of the Aβ peptide. The C-terminus of the Aβ peptide is formed by v-secretase, a clearly oligomemic complex that includes presemlin-1 and / or presenilin-2. Presenilin-1 and presenilin-2 are polytopic proteins that cross the membrane and may contain catalytic components of γ-secretase (Seiffert. D; Bradley. .1. Et al. BioL Chem. 2000, 275. 3408634091).

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Multiple pieces of evidence together strongly suggest that reducing Aβ levels in the brain prevents the onset and progression of AD. First. Αβ is the main component of parenchymal plaques observed in all AD patients and amyloid deposits in the cerebral vasculature observed in 90% of AD patients (reviewed in: Selkoe. D. Phvsiol. Rev. 2001, 81, 741766; Wolfe, MJ Med. C.hem . 2001,44, 2039-2060). These plaques are formed from clusters of soluble Aβ whose levels in the brain are highly correlated with the strength of AD neurodegeneration (McLean, C „Cliemv. R. et cd., Am ?. Neurol. 1999. 46, 860-866). Another. mutations in three genes (APP, PS-1, or PS-2) that increase Αβ cause familial AD (familial Alzheimer's disease. FAĐ), where the occurrence of AD is accelerated for at least a decade. Mutations that increase Aβ include trisomy 21, which causes Down syndrome. Third. transgenic mice expressing one or more mutant FAD genes have elevated levels of Aβ, form parenchymal plaques and cerebral vascular deposits containing Aβ, exhibit memory deficits (Chapman, P „White, G., et al., Nature Neurosci. 1999, 2. 271-276), and neurodegeneration is enhanced in mice that also overexpress mutant tau (Lcvvis. .1., Dickson. D., e! Al. Science 2001, 293. 1487-1491), Fourth, Αβ is toxic to cells in culture (Dahlgren. K., Manelli, A .. el al. J. Biol. Chem. 2002. 277, 32046-32053), induces neurofibril entanglement in mice with mutant tau (Gotz. J. Chen. F., et al. Science 2001. 293, 1491-1495) and interferes with long-term potentiation. veiovatnom component of memory (Walsh, D .. Klvubin, I .. el al. Nature 2002, 416, 535-539, and references cited therein). Take it together. these data suggest that excess Αβ production and / or decreased Λβ clearance cause AD. It follows that reducing brain Αβ levels by inhibiting γ-secretase would prevent the occurrence and progression of AD.

In addition to AD, increased production and / or decreased β β leads to cerebral amyloid angiopathy. CAA) (review given in Thal, D „Gherbremedin. E, et al., J Neuropalh. Ehr. Neuro. 2002, 61. 282-293). In these patients, vascular amyloid deposits cause degeneration of blood vessel walls and aneurysms that may be responsible for 10-15% of hemorrhagic strokes in elderly patients. As with AD, mutations in the gene encoding Aβ lead to an early-onset form of CAA. designated as cerebral hemorrhage with Dutch-type amyloidosis. and mice expressing this mutated protein develop CAA similar to that in patients.

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It has been hypothesized that inhibiting Aβ production will prevent and reduce neurological degeneration, by reducing neurotoxicity and. in general. mediation in pathology associated with the production of Αβ. Treatment methods would focus on the formation of Αβ via enzymes involved in the proteolytic processing of β-amyloid precursor protein. Compounds that inhibit β- or γ-secretase activity. directly or indirectly, could control Aβ production. Preferably, compounds that are specifically directed to γ-secretases. could control the production of Αβ. Such inhibition of β- or γ-secretase could reduce the production of Αβ, which could reduce or prevent neurological diseases associated with the Αβ protein.

Smith et al. in International Application WO 00/50391, published August 31, 2000, disclose a series of sulfonamide compounds that can modulate the production of amyloidβ proteins as agents for the treatment of various diseases. in particular Alzheimer's disease and other diseases associated with amyloid deposition. Japanese Patent No. 11343279, published December 14, 1999, discloses a list of sulfonamide derivatives that are TNFα inhibitors useful in the treatment of autoimmune diseases.

There is nothing in these references that could be construed as discovering or proposing novel compounds of the present invention and their use to inhibit Αβ production.

BRIEF DESCRIPTION OF THE INVENTION

A series of α- (N-sulfonamido) -acetamide derivatives was synthesized. These compounds specifically inhibit the production of β-amyloid peptide (βΑΡ) from β-amyloid precursor protein (β-ΑΡΡ). The pharmacological action of these compounds makes them useful for treating conditions responsive to β-iciju inhibition in a patient; e. g. Alzheimer's disease (AD) and Down's syndrome. Treatment in which these compounds are administered to patients suffering from or susceptible to these conditions involves the reduction of β-ΑΡ available for accumulation and deposition in the brain of these patients.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes the compounds of Formula I. their pharmaceutical formulations, and their use in inhibiting the production of β-ΑΡ in patients suffering from.

51155 Β or are susceptible to AD or other diseases resulting from the accumulation (β-ΑΡ in brain tissue. Compounds of Formula I which include their non-toxic pharmaceutically acceptable salts and / or hydrates have the following formula and meanings:

R²

<img file="RS51155B_D0001.tif" />

where:

R¹ is selected from the group consisting of (a) linear or branched chain C 1-6 alkyl or C 1-6 alkenyl optionally substituted with substituents selected from the group consisting of hydroxy, C 1-6 alkyl.₄ alkoxy, C 1₄alkylthio, and halogen;

R is hydrogen;

R² is selected from the group consisting of (a) lineami or garnet-chain C- ₆ alkyl or C₃Alkyl optionally substituted with substituents selected from the group consisting of halogen, Cualkoxy, and NR⁴R⁵;

(b) C 1-6 cycloalkylmethyl optionally substituted with substituents selected from the group consisting of amino, (C 1-4 alkyl) NH-, di_!4alkyl) N-, C1-6 ₄alkylC (= O) NH-, and C1-6. ₄alkylOC (= O) NH-;

(c) linear or branched chain C 1-6 alkyl-C (= O) -A;

(d) -B-naphthyl;

(e) (E) -Y

Z

D and E are each independently a direct link. linear or garnet-chain Ci_₆alkyl, C₂. ₆alkenyl, or C1-7cycloalkyl;

Z is selected from the group consisting of hydrogen, C1-4alkyl, C1.₄alkoxy, halogen, cyano, hydroxy, -OCHF₂, -OCF₃, -CF₃, and -CHF₂;

<img file="RS51155B_D0002.tif" />

51155 Β

X and Υ are each independently selected from the group consisting of hydrogen, hydroxy. halogcn. (halogcn)₃C-, (halogen)₂CH-. Ci.₄alkylS-. C1-4alkylS (O) -, C1.₄alkylSO₂, nitro, F₃S-, and cyano; -OR₆: - \ RR. -NR⁷C (= O) R^S: -NR⁷C (= O) OR^S; -NHSO2C,. 4a) keel; -N (SO 2 C 1-4 alkyl) 2; -C (^ O) W wherein W is selected from the group consisting of hydroxyL C 1-4 alkyl, C 1-4 alkoxy, phenoxy, and -NR⁴R 1 -OS (= O) S; .4a1k | 1; -phenyl wherein said phenyl is optionally substituted with cyano, halogen, C 1-6.₄alkoxy. Ci.₄alkylS-. CH₃C (= O). C |.₄alkylS (O) -, or C].₄alkylSO₂-; and a heterocyclic group wherein said heterocyclic group is selected from the group consisting of furanyl, thiofuranyl. pyrrolyl, imidazolyl, pyrazolyl. triazolyl, tetrazolyl. pyridiniI, pyrimidinyl, oxadiazolyl, oxazolyl, isoxazolyl. thiadiazolyl. and thiazoles 1, wherein said heterocyclic group is optionally substituted with substituents selected from the group consisting of cyano. halogcn. C |.₄alkyl. (halogen) C |₄a! kil. in CChCuaikil:

(f) -B- (heterocycle), wherein said heterocycle is selected from the group consisting of furanyl. thiofuranyl, pyrrolyl. imidazolyl, pyrazolyl, triazolyl. tetrazolyl, pyridinyl. pyrimidinyl, oxadiazolyl, oxazolyl, isoxazolyl. thiadiazolyl and thiazolyl, wherein said heterocycle is optionally substituted with substituents selected from the group consisting of cyano. halogen, (C |.₄alkyl), CO 2 C 1-6 alkyl. amino, (C_f. ₄alkyl) NII-, di (C1-₄alkyl) N-. inorfolin-4-yl. thiomorpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl. piperazin-1-yk and 4- (C1._f-, alkyl) piperazin-1-yl;

(g) -B- (piperidin-4-yl). gdc is said piperidin-4-yl optionally substituted with substituents selected from the group consisting of linear or granatochal C 1-4.₆alkyl, SNJS (= O) GepJ1, phenyl and phenylmethyl where C is mentioned_l4, alkyl and said phenyl optionally substituted with substituents selected from the group consisting of cyano. halogen, benzimidazol-2-yl. pyridyl and tetrahydrofuran-2-yk ί -C (= O) W 'where W' is selected from the group consisting of C_t.₄alkoxy. R⁹, and -NR⁴R \

A is hydroxy. C1-4alco.si or NR''R^?;

B is linear or garnet-chain C !.₆a) kN or C₃._halkenyl;

R 1 is phenyl or pyridyl optionally substituted with substituents selected from the group consisting of halogen, hydroxy. C |.₄alkoxy. C1.₄alkyl, (halogen)₃C-.

51155 ) (Halogen) iCH- and halogenCll · -:

R⁴ and R³ are each independently hydrogen. linear or garnet-chain Sm, a1kI. C 1-6 alkenyl. C₃.

₆alkynyl C1-8cycloalkyl, C1-6₃.7cycloalkylmethyl. Ci-₄alkoxy. phenyl, benzyl, pyridyl. piperidin-4-yl, indan-1-yl, indan-2-yl. tetrahydrofuran-3-yl. or pyrrolidin-3-yl: wherein each is optionally substituted with substituents selected from the group consisting of hydroxy. cyano, halogen, (halogen)₃C-, (halogen) -OH-. halogenCH; -. hydroxymethyl, benzyloxymethyl. phenyl. pyridyl, C 1-6 alkyl. Ci.₄alkoxy, (halogen)₃CO-, (halogen)₂-CH-O-, Cj.₄alkylthio. amino, (Ci.₄alkyl) NH-, di (C1-6)₄alkyl) N-. morpholin-4-yl, thiomorpholin-4-yl. pyrrolidin-1-yl piperidin-1-yl, piperazin-1-yl, 4- (C 1-4 alkyl) piperazin-

1-yl, 4-phenylpiperazin-1-yl, 4-benzylpiperazin-1-yl. 4-pyridylpiperazin-1-yl, SO₂Н. CO₂C |.₄alkyl, N, NNHC, alkyl. and C (= O) N_walkyl)₂:

R⁴ and R^? together may be morpholin-4-yl. thiomorpholin-4-yl. pyrrolidin-1-yl. 1,2.3.4 tetrahydroisoquinolin-2-yl, decahydroquinolin-1-yl. piperidin-1-yl. piperazin-1-yl, [1.4] oxazepan-4-yl, azetidin-1-yl, 2,3-dihydro-1H-isoindol-2-yl, or 2,3-dihydro-1H-indol-

1-yl; wherein each is optionally substituted with substituents selected from the group consisting of hydroxy, cyano, halogen. (haiogen)₃C-. (halogen)₂-CI 1-. halogenCl 1₂-, phenyl, pyridyl, benzyl, C 1.₆alkyl, C1-6cycloalkyl. Cualkoxy. C |.

₄alkylthio. amino, (C 1-6 alkylDNH-, di (C 1-4).₄alkyl) N-, CO41. CO₂C_ualkyl.

C (= O) NHC_Malkyl, and C (= O) N_{! 4}alkyl)₂:

R⁶ jc linear or garnet-chain C |.₆alkyl. C 1-6 alkenyl, benzyl, iii phenyl wherein each is optionally substituted with substituents selected from the group consisting of halogen. Ci_₄alkyl, C 1.₄alkoxy, amino, (Ci.₄alkyl) NH-, di (C1.₄alkyl) N-, (C 1. ₄alkyl) (phenyl) N-. morpholin-4-yl, thiomorpholin-4-yl. pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, and 4- (C1-4alkyl) piperazin-1-yl

R 1 is hydrogen, linear or garnet-chain C 1.₆aikil;

R^s is a linear or garnet-chain C |.₍, alkyl. C 1-7 cycloalkyl, phenyl. pyridyl. or furanyl; wherein each is optionally substituted with substituents selected from the group consisting of halogen. C].₄alkyl, C,.₄alkoxy. (C'i.₄alkyl) NH-, di (C1-8).₄alkyl) N-, morpholin-4-yl. thiomorpholin-4-yl, pyrrolidin-1-yl piperidin-1-yl. piperazin-1-yl. and 4- {C1.₍, alkyl) piperazine8

51155 Β

R⁹ is a linear or garnet-chain C1-6alkyl, Sz.₆alkyl, benzyl, phenyl, oxazolyl or pyridyl; wherein each is optionally substituted with substituents selected from the group consisting of haiogen, (halogenFC-, (halogenHCH-, halogenCHr.₄alkyl C1-6alkoxy, amino, (C1-6₄alkyl) NH-, di (C1-6)₄alkyl) N-, morpholin-4-yl, thiomorpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl and 4- (C1-4).₆alkyl) piperazin-1-yl; or a non-toxic pharmaceutically acceptable salt thereof.

The present invention also provides a process for the manufacture of a medicament for treating or ameliorating diseases associated with (3-amyloid peptide, in particular Alzheimer's disease), comprising administering together with a conventional adjuvant, carrier or diluent a therapeutically effective amount of a compound of formula I or a non-toxic pharmaceutically acceptable salts, solvates or hydrates.

The term C 1-6 alkyl as used herein and in the claims (unless otherwise indicated by the context) means a linear or branched chain alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, N-butyl, pentyl, 3-methylbutyl, hexyl and the like. The term C 1-4 alkenyl as used herein and in the claims (unless otherwise indicated by the context) means a linear or branched chain alkenyl group such as ethenyl. vinyl), propenyl, allyl, butenyl, 3methylbutenyl, pentenyl, hexenyl, and the like. Unless otherwise specified, the term halogen as used herein and in the claims includes bronze, chlorine, iodine and fluorine, while the term halide includes bromide, chloride and iodide anion.

The term C 1-6 cycloalkyl denotes a carbon cyclic ring system such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term C |.₄haloalkyl means linear or garnet-chain C1.₄an alkyl group containing from 1 to 3 halogen atoms such as trifluoromethyl, fluoroethyl, 1,2-dichloroethyl, trichloromethyl and the like.

The term C2-5alkylene denotes a linear or branched-chain alkylene group such as methylene, ethylene, propylene, methylethylene. butylene, methylpropylene, pentylene. methylbutylene and ethylpropylene.

As the compounds of the present invention possess an asymmetric carbon atom, the present invention includes racemates as well as individual enantiomeric forms of the compounds of Formula 1 as described herein and in the claims. Using a single label as (R) or (S)

51155 Β is intended to denote mainly one stereoisomer. Mixtures of isomers can be separated into individual isomers by methods known in the art, such as fractional crystallization, adsorption chromalography or other suitable separation processes. The resulting racemates can be separated into antipodes in a conventional manner after the introduction of suitable co-forming groups, eg by forming a mixture of diastereoisomeric salts with optically active co-forming agents. by separating the mixture into diastereomeric salts and converting the separated salts into free compounds. Possible enantiomeric forms can also be separated by fractionation via high pressure chiral liquid chromatography columns.

The term non-toxic pharmaceutically acceptable salt as used herein and in the claims. includes non-toxic base-addition salts. Suitable salts include opels derived from organic and inorganic acids such as, without limitation. hydrochloric acid. hydrobromic acid. phosphoric acid. sulfuric acid. niethanesulfonic acid, acetic acid, tartaric acid. lactic acid. sulfinic acid. citric acid, maleic acid, fumaric acid. sorbic acid. aconitic acid. salicylic acid, phthalic acid and the like.

In the process of the present invention. the term 'therapeutically effective amount' means the total amount of each active component of the procedure that is sufficient to demonstrate a significant benefit to the patient. for the treatment of acute conditions characterized by inhibition of β-amyloid peptide production. When applied to a single active ingredient, applied alone, the term refers only to that ingredient. When applied to a combination. the term refers to the combined amounts of active ingredients that result in a therapeutic effect. either to be applied in combination. serial or simultaneous. Terms treat. treatment, method of treatment. as used herein and in the claims to mean the prevention or alleviation of β-amyloid peptide-related diseases.

General Reaction Schemes

General procedures used for the synthesis of compounds of Formula I are described in Reaction Schemes 1-23. Reasonable variations of the described procedures are apparent to one skilled in the art. are within the scope of the present invention.

51155 Β

Reaction scheme 1

<img file="RS51155B_D0003.tif" />

II Ш 1

The starting (α-amino) acetamides of Formula P are used in racetin or enanlioinc pure form and are commercially available or prepared from commercially available (amino) acids according to methods well known in the literature (general reference for amide preparation: RC Larock). Ccnnprehensive Organic Transformations, VCH Publishers, New, York, 1989. pp. 972-976: see also Reaction Scheme 18 for the conversion of an acid of Formula XLVH1 to an amide of Formula H1JH). The compound of Formula II is treated with a suitable base and a sulfonylating reagent such as sulfonyl chloride in an aprotic solvent such as CHiCF at room temperature to form (α-sulfonamido) acetamide of Formula III. Suitable bases include tricylamine and pyridine.

In one process for the conversion of a compound of Formula 111 into a sulfonamide of Formula 1. the compound of Formula 111 is treated with a suitable base and alkylating agent in an aprotic solvent with or without heating. Suitable bases for this reaction include potassium carbonate and cesium carbonate. Alkylating agents include alkyl halides (eg alkyl chloride, alkyl bromide or alkyl iodide) and alkyl sulfonates (tosylates, mesylates, trifluoromethanesulfonates). Preferred solvents include DMF and acetoniyl. The temperature range for the reaction is typically 20 ° C to 100 ° C.

An alternative method for converting a compound of Formula III to a compound of Formula I involves treating a compound of Formula 11! triphenylphosphine, dialkyl azodicarboxylate, and alcohol in an inert solvent with or without heating.

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Reaction scheme 1-solid support

<img file="RS51155B_D0004.tif" />

IV V 1

Compounds of Formula I may also be prepared using a solid phase methodology. For example. The FMOC-protected Rink-amide resin was treated with piperidine in DMF to effect removal of the FMOC group. The resin is then coupled with an amino-protected (amino) acid in the presence of a coupling agent of 1-hydroxybenzotriazole and dialkylcarbodiimide in an inert solvent such as DMF with or without heating. Deprotection of the amino group affords the polymer-bound amine of Formula IV. In the case of FMOC-protected amino acids. deprotection can be performed by treatment with piperidine in DMF.

Reaction of a compound of Formula IV with a suitable base such as pyridine and a sulfonylating agent such as a sulfonyl chloride in an inert solvent provides a resin-bound sulfonamide of Formula V. Alkylation of a compound of Formula V with an alkyl halide (c 1, alkyl chloride, alkyl or alkyl iodide) or alkyl sulfonate (e.g. mesylate. tosylate. or trifluoromethanesulfonate) takes place in the presence of a base in an inert solvent at room temperature. The preferred base is 2 - [- butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine. Separation from the resin gives a sulfonamide of Formula 1. In the case of Rink-amide resin, the separation is preferably carried out using trifluoroacetic acid in an inert solvent such as SN? S1₂.

Reaction scheme 2 o

<img file="RS51155B_D0005.tif" />

(i

OR²

<img file="RS51155B_D0006.tif" />

VI

<img file="RS51155B_D0007.tif" />

The compounds of Formula I may also be prepared as shown in Reaction Scheme 2. Reductive alkylation of an amine of Formula I to provide an amine of Formula VI

51155Β is achieved by treatment with an aldehyde and a hydride reducing agent in the presence of an acid catalyst with iii without heating. The preferred reducing agent is sodium cyanoborohydride. The preferred acid catalyst is Levvis acid as ZnCl2. The reaction solvent is preferably methanol. The anion of Formula VI is then treated with a sulfonylating agent such as sulfonium chloride in the presence of an amine such as triethylamine. This reaction takes place in an inert solvent such as CIFCl? with or without heating to give a product of Formula I. The reaction is typically carried out at room temperature.

Reaction scheme 3

<td>linker-LG</td><td>linker-NR⁴^</td>

<td>Jt!^Ng Art</td><td>HNR⁴R^s P. A _R³ ---_:X R &lt;0 G</td>

<td>VII</td><td>VI »</td>

where linker = linear-chain III garnet C 1-6 alkyl or C₃alkenyl; LG = outgoing group

The preparation of a compound of Formula VIII is performed as shown in Reaction Scheme 3 by reacting a compound of Formula VII with an amine in the presence of an acid scavenger such as triethylamine in an inert solvent such as CFFCF with or without heating. The compound of Formula VII is prepared according to the sequence shown in Reaction Scheme 1 or Reaction Scheme 2.

51155 Β

Reaction scheme 4

<img file="RS51155B_D0008.tif" />

<img file="RS51155B_D0009.tif" />

Compounds of Formula XI and XII are prepared as shown in Reaction Scheme 4. Reduction of the nitro group of a compound of Formula IX (prepared according to the sequence shown in Reaction Scheme 1 or 2) with hydrogen gas under pressure in the presence of a palladium catalyst, acid. and in a solvent such as methanol, gives an aniline derivative of Formula X. Monomethylation of a compound of Formula X to give a compound of Formula XI is carried out by reaction with 1.1 equivalent of methyl halide iii methyl sulfonate, for example dimethyl sulfate, in the presence of a base such as triethylamine and in an inert solvent such as DMF. The monomethylation reaction typically takes place at a temperature between 20^cC and 40 ° C. The preparation of dimethylaniline of Formula XII is carried out by treating the aniline of Formula X with excess methyl halide. e.g. methyl iodide or methyl sulfonate in the presence of a base. for example. cesium carbonate. in a solvent such as DMF, with or without heating.

51155 Β

Reaction scheme 5 ο

<img file="RS51155B_D0010.tif" />

Ο

<img file="RS51155B_D0011.tif" />

_v„_ki SNSM.1VD

<img file="RS51155B_D0012.tif" />

XII!

,. , ΟΗ ćpkeg

<img file="RS51155B_D0013.tif" />

<img file="RS51155B_D0014.tif" />

XV where linker = linear-chain or branched C 1-6 alkyl

Reaction Scheme 5 shows the synthesis of esters of Formula XIII, Fonnula XIV acids. and the amide of Formula XV. Reaction of a compound of Formula III with a haloalkylcarboxylate ester, for example, t-butyl bromoacetate, in the presence of a base such as potassium carbonate and in an inert solvent such as DMF affords an ester of Formula XIII. Deprotection of cstra is performed by methods known to those skilled in the art (ref. TW Greene and PGM Wuts, Protecting Groups in Organic Synthesis, Wiley Intrrscience. New York, 1999. pp. 373-442). For example, for / -butyl esters. cleavage to the acid of Formula XIV is performed by treating with trifluoroacetic acid in a solvent such as SNJSk. The conversion of the acid to the amide of Formula XV takes place using a conventional amide-coupling procedure well known to those skilled in the art (ref. RC Larock. Comprehensive Organic Transformations. VCH Publishers, New York. 1989. pp. 972-976). In a preferred procedure, the acid of Formula XIV is treated with a primary or secondary amine in the presence of hydroxybenzotriazole and 1,3-dicyclohexylcarbodiimide in an aprotic solvent such as

CH₂C1₂ or DMF.

51155 Β

Reaction scheme 6

<img file="RS51155B_D0015.tif" />

<img file="RS51155B_D0016.tif" />

<img file="RS51155B_D0017.tif" />

Preparation of acids

Formula XVII and amide

Formula XVIII is shown in

Reaction Scheme 6. The conversion of an ester of Formula XVI (prepared as shown in Reaction Schemes 1 or 2) to an acid of Formula XVII was performed using standard ester cleavage conditions well known to those skilled in the art (ref. TW Greene and PGM Wuts, Protecting Groups in Organic Synthesis, Wiley Interscience, New York, 1999. pp. 373-442). In the case of the methyl ester of Formula XVI, treatment with aqueous sodium hydroxide in a solvent such as methanol or a methanol / THF mixture at 20 ° C to 40 ° C gives the acid of formula XVII. The conversion of an acid of Formula XVII to an amide of Formula XVIII is achieved using general amine coupling procedures well known to those skilled in the art (ref. RC Larock, Compressive Organic Transformations. VCII Publishers, Ncw, York. 1989, pp. 972-976). In a preferred method, the acid of Formula XVII is treated with a primary or secondary amine in the presence of 1-hydroxybenzotriazole and a carbodiimide, for example I- (3-dimethylaminopropyl) -3-ethylcarbodiimide. in a solvent such as DMF or CFFCF. A base such as diisopropylethylamine can be added as an acid scavenger.

51155 Β

<img file="RS51155B_D0018.tif" />

Synthesis of piperidine derivatives of Formula XIX, XX. XXI. HHP, and HHS are described in Reaction Scheme 7. Reaction of a compound of Formula E with a N-prolected piperidine substituted with a 4-haloalkyl or 4-sulfonyloxyalkyl group, such as 4- (toluenesulfonyloxymethyl) 1- (Abutoxycarbonyl) piperidine. in the presence of a base such as cesium carbonate in a solvent such as DMF. with or without heating. gives carbamal Formulc XIX. The cleavage of the carbamainc group in the compound of formula XIX takes place under standard conditions well known to those skilled in the art (ref. T. \ V. Greene and PGM Wuts, Prolecting Groups in Organic Synthesis, Wiley Interscience. New York, 1999. pp. 503-550 ) to give the piperidine of formula XX. In the case of (Abutoxycarbonyl) piperidine derivative, the deprotection is performed by treating with trifluoroacetic acid in SNJSE.

The conversion of a piperidine of Formula XX to an amide of Formula XXI takes place using amide-coupling procedures well known to those skilled in the art (ref. RC Larock. Comprehensive Organic Transformations, VCH Publishers. New, York. 1989, pp. 972976). In the preferred procedure. the piperidine of Formula XX sc is treated with an acyl chloride in the presence of an amine such as tricylamine and an inert solvent such as CH 2 Cl 2? with or without heating.

51155Β

Alternatively, the piperidine of Formula XX may be coupled with an acid in the presence of a coupling agent of hydroxybenzotriazole and carbodiimide to give an amide of formula XXI. The preparation of the urea of ​​Formula XXII is achieved by treating the amine of Formula XX with an isocyanate and a base such as triethylamine in a solvent as CH₂Cl ·. with or without heating. Alkylation of the piperidine of Formula XX affords the N-substituted piperidine of Formula XXIII. In a typical procedure, the piperidine is treated with an alkyl halide or alkyl sulfonate in the presence of a base such as tricylamine in a solvent such as Ci FCk

Reaction scheme 8

<img file="RS51155B_D0019.tif" />

XXIV

PG = alcohol protective group D is different from the bond

XXVI

<img file="RS51155B_D0020.tif" />

Alcohols of Formula XXV and amines of Formula XXVI are synthesized according to the order shown in Reaction Scheme 8. Protected alcohol of Formula XXIV is prepared according to the procedure shown in Reaction Schemes I or 2. Deprotection of alcohol under conditions suitable for the selected protecting group (ref. TW Greene and PG , Protecting Groups in Organic Synthesis Chapter 2) gives the alcohol of Formula XXV. For example, when the protecting group is a tetrahydropyranyl residue, the alcohol is released by treating the compound of Formula XXIV with toluenesulfonic acid in a solvent such as methanol. The alcohol of Formula XXV is converted to the leaving group (cg halide or sulfonate) and then treated with a primary or secondary amine to give the amine of Formula XXVI. On the printer. the alcohol may be converted to the mesylate derivative by reaction with methanesulfonyl chloride and a base such as triethylamine in SNJSk The next reaction of the mesylate with a primary or secondary amine in the presence of a base such as triethylainine in a solvent such as SNJSR gives an amine of Formula XXVI.

51155 Β

Reaction scheme 9

<img file="RS51155B_D0021.tif" />

XXVII

<img file="RS51155B_D0022.tif" />

<img file="RS51155B_D0023.tif" />

χχνίίϊ

Aniids of Formula XXVIII are prepared from amines of Formula XXVII as shown in Reaction Scheme 9. Amines of Formula XXVI! where D is a direct bond. are prepared as in Reaction Schemes I or 4. Amines of Formula XXVII where D is different from the direct bond are prepared as in Reaction Scheme 8. The conversion of amines of Forniula XXVII to amides of Formula XXVIII takes place using amide coupling conditions well known to those skilled in the art. (ref '. RC Larock, Comprehensive Organic Transformations, VCH Publishers. New. York. 1989, pp. 972-976). For example. reaction of an ainine of Formula XXVII with an acid chloride in the presence of a base such as triethylamine in a solvent such as CFFCF affords the amide of Formula XXVIII. The conversion of the amine of Formula XXVII to carbamate derivatives can be accomplished using conditions well known to those skilled in the art (ref. TW Grcene and PGM Wuts. Protecting Groups in Organic Synthesis. P 503-550). The preparation of sulfonamide amine derivatives of Formula XXVII can be more readily accomplished using methods such as those described for the conversion of an intermediate of Formula II to a sulfonamide of Formula 111.

Reaction scheme 10

51155 Β

<img file="RS51155B_D0024.tif" />

XXIX

<img file="RS51155B_D0025.tif" />

XXX

The synthesis of the pyridinesyl derivatives of Formula XXX is performed as shown in Reaction Scheme 10. The chloropyridine derivative of Formula XXIX is prepared using the chemistry described in Reaction steps 1 or 2. Treatment of a compound of Formula XXIX with a primary or secondary amine in a solvent such as TH C to 10 ° C. with the use of sealed pressure vessels as appropriate. gives aminopyridine of Formula XXX.

Reaction scheme 11

<img file="RS51155B_D0026.tif" />

<img file="RS51155B_D0027.tif" />

XXXII

The amine-substituted phenolic ethers of Formula XXXII are prepared from (O-alkyl) phenols as shown in Reaction Scheme 11. The starting allyl ethers of Formula XXXI are prepared as shown in Reaction Schemes 1 or 2. Treatment of the compounds of Formula XXXI with osmium tetroxide and trimethylamine-N-oxide in a solvent such as acetone. followed by treatment with sodium periodate gives an intermediate aldehyde which is typically used without purification. Reaction of the crude aldehyde with a primary or secondary amine and a reducing agent such as sodium triacetoxyborohydride in a solvent such as ethanol with or without heating gives an amine of Formula HHHP.

51155 Β

Reaction scheme 12 h₂n

<img file="RS51155B_D0028.tif" />

ΧΧΧ1Ι1

<img file="RS51155B_D0029.tif" />

XXXIV

The conversion of an ester of Formula XXXIII to a tertiary alcohol of Formula XXXIV takes place as shown in Reaction Scheme 12. The reaction of an ester of Formula XXXIII with an excess of methyl organometallic reagent in excess such as methyl magnesium bromide in a solvent such as THF at 0 ° C to 25 ° C gives alcohol forinule XXXIV.

<img file="RS51155B_D0030.tif" />

XXXV

<img file="RS51155B_D0031.tif" />

<img file="RS51155B_D0032.tif" />

MN

The preparation of 1,3,4-oxadiazole of Formula XXXVI takes place as shown in Reaction Scheme 13 using methods well known to those skilled in the art (rcf. Joule. J. L .. Mills. K .. Smith, GF I leterocyclic Chemistry, 3rd ed „Chapman &amp; Hall: London. 1995: 452-456 and references cited therein). For example. the ester of Formula XXXV is treated with hydrazine in methanol with heating to reflux. The resulting acylhydrazide intermediate is used without purification in a sequential reaction with alkylacetamide in pyridine with reflux heating to give the oxadiazole of Formula XXXVI.

Reaction scheme 14

51155 Β

<img file="RS51155B_D0033.tif" />

XVII

<img file="RS51155B_D0034.tif" />

XXXVII

The synthesis of 1,2,4-oxadiazole of Formula XXXVII is accomplished as shown in Reaction Scheme 14, using methods well known to those skilled in the art (rcf. Joulc, JA, Mills, K .. Smith. GF Heterocyclic Chemistry. 3rd ed „ Chapman &amp; Hall: London. 1995; 452-456 and references cited therein). For example, treatment of an acid of Formula XVII with hydroxybenzotriazole, carbodiimide and acetamidoxime- (N-hydroxyethanimidamide) in the presence of a base such as triethylamine provides an intermediate which is heated in refluxing pyridine to give the oxadiazole of Formula XXXVII.

Reaction scheme 15

<img file="RS51155B_D0035.tif" />

XXXVIII

<img file="RS51155B_D0036.tif" />

XXXIX

<img file="RS51155B_D0037.tif" />

N-0

1,2,4-Oxadiazole of Formula XXXIX is prepared from the nitrile of Formula XXXVIII (Reaction Scheme 15) using methods well known to those skilled in the art (ref. Joule, .1. A., Mills, K. Smith, GF Hcterocyclic Chemistry. 3rd ed .. Chapman &amp; Hall: London. 1995; 452-456 and references cited therein). For example. Reaction of the nyryl of Formula XXXVIII with a hydroxylamine in a solvent such as ethanol at reflux temperatures affords the intermediate N-hydroxyamidine which is then treated with acetyl chloride in

51155 Β the presence of a base such as triethylamine in a solvent such as ClhCl? to give 1,2,4-oxadiazole of Formula XXXIX.

Reaction scheme 16

<img file="RS51155B_D0038.tif" />

XL xu

Reaction Scheme 16 shows the transformation of an amide of Formula XI. in ketone Fonnule XLl. The amide of formula XL. which is prepared as shown in Reaction Scheme 6. is treated with a methyl organometallic reagent such as methyl magnesium bromide in a solvent such as THF to give a ketone of Formula XL1. The reaction temperature range is from -20 ° C to 25 ° C.

Reaction scheme 17

<img file="RS51155B_D0039.tif" />

<img file="RS51155B_D0040.tif" />

<img file="RS51155B_D0041.tif" />

xui xun β-amino-amides of Formula H1L11 are prepared from acrylamides of Formula XLI1 as shown in Reaction Scheme 17. For example, acrylamides of Formula XLII. which is prepared as described in Reaction Scheme 9. is irradiated with a primary or secondary amine in a solvent such as jetoluene to give the β-amino-amide of Formula XL1II.

51155 Β

Reaction scheme 18

<img file="RS51155B_D0042.tif" />

<img file="RS51155B_D0043.tif" />

The preparation of a sulfonamide intermediate of Formula XL1X (single enantiomer of a compound of Formula III) is shown in Reaction Scheme 18. Reaction of the α-anion of an intermediate of Formula XLIV (ref. Josien, H „Martin. A .. Chassaing. G. Tetrahedron Lett. 1991. 32, 6547 ) with an alkylating agent such as alkyl halide (eg alkyl chloride, alkyl bromide or alkyl iodide) or alkyl sulfonate (eg alkyl mesylate, alkyl tosylate, i) and alkyltrifluoromethanesulfonate) giving an intermediate of Formula X. The α-anion of the compound of Formula XLIV is formed by treatment with a strong base such as alkyl-lithium (eg n-BuLi) or dialkylamide (eg Hthium-diisopropylamide) in a solvent such as THF with or without a solvent such as HMPA. The reaction temperature is lipically between -78 ° C and 25 ° C. Removal of the benzhydrylidene protecting group of the compound of Formula XLV is performed under conditions well known to those skilled in the art (ref. TW Greene and PGM Wuts. Protecting Groups in Organic Synthesis, pp. 587-588). For example, a compound of Formula XLV is treated with an acid such as HCl in water in a co-agent such as THF to effect hydrolysis of the benzhydrylidene protecting group. The resulting amine of Formula XLV1 is treated with a sulfonylating agent as described for Reaction Scheme I to give a sulfonamide of Formula XLV11. Hydrolysis of the acylsulfonanide of Formula XLVI1 to give the acid of Formula

51155 Β

XLVIII is carried out by treatment with a hydroxide ion. for example in the form of lithium hydroxide. in the presence of additives such as lithium bromide and tetrabutylamine bromide. The acid of Formula XLVII1 is converted to the amide of Formula XL1X under conditions well known to those skilled in the art (general ref. For amide preparation: RC Larock, Comprehensive Organic Transformations. VCH Publishers, New, York, 1989. pp. 972976). For example, the reaction of a compound of Formula XLVIII with ammonium chloride in the presence of 1-hydroxybenzotriazole, a carbodiimide reagent. and amine bases such as diisopropylethylamine give the amide of Formula XLIX. This reaction proceeds lipidically in a polar solvent such as DMF and at a reaction temperature of 0 ° C to 40 ° C. The amide of Formula XL1X is converted to the compound of Formula I by the method described in Reaction Scheme 1.

<img file="RS51155B_D0044.tif" />

Reaction Scheme 19 illustrates a process for the synthesis of an α-substituted (Nsulfonamido) acetamide intermediate of Formula III starting from an activated glycine derivative of Formula L. The reaction of a compound of Formula L (ref. Haufe, G. Laue. K. W „Triller, MU, Takeuchi Y., Shibata, N. Tetrahedron 1998, 54. pp. 5929-5938; Kroger. S., Haufe, G. Amino Acids 1997, F2- P · 363-372) with an alkylating agent such as an alkyl halide (eg alkyl chloride, alkyl bromide or alkyl iodide) or alkyl sulfonate (eg alkyl mesylate, alkyl tosylate. or alkyl trifluoromethanesulfonate) in the presence of a base such as potassium carbonate and an additive such as tetrabutylammonium bromide and in an inert solvent such as acetonitrile at a reaction temperature between 25 ° C and 70 ° C to give the compounds of Formula L1. Removal of the benzhydrylidene protecting group takes place under conditions well known to those skilled in the art.

51155 Ref (ref '. Τ. W. Greene and PGM Wuts. Protecting Groups in Organic Synthesis. Wiley Interscience, New York. 1999, pp. 587-588). For example, a solution of a compound of Formula U in a solvent such as diethyl ether is treated with an aqueous acid solution (eg aqueous HCl), typically at a reaction temperature between 0 ° C and 30 ° C. to obtain the amino-cstar Formulc Lll. The conversion of the ester of Formula LII to the amide of Formula II takes place using a procedure well known to those skilled in the art. For example, when a compound of Formula LII is an ethyl ester, hydrolysis of the ester is accomplished by treating the ether solution with an acid such as HCl. typically by heating the reaction mixture in a refluxing solvent. The resulting acid intermediate is then converted to the methyl ester of Formula III by transformation to the acid chloride under standard conditions. (eg treatment with thionyl chloride and methanol). followed by reaction with aqueous ammonia in a solvent such as toluene (ref. RC Larock, Comprehensive Organic Transformalions. VCH Publishers. New. York, 1989, pp. 972976). The amine of Formula II is converted to the compounds of Formula I as described in Reaction Scheme 1.

Reaction scheme 20

<img file="RS51155B_D0045.tif" />

<img file="RS51155B_D0046.tif" />

Ull LIV

<img file="RS51155B_D0047.tif" />

The preparation of the compound of Formula LVII is shown in Reaction Scheme 20. Alkene

The LIH is prepared as described in Reaction Scheme 18 from intermediates of Formula XL1V and 1-bromo-2-methyl-2-propene. Treatment of the alkene of Formula LIII 11F-pyridinones in the solvent as

51155 TH that THF at a reaction temperature between 0 ° C and 25 ° C gives a fluoroalkyl compound of Formula LIV. The conversion of a compound of Formula LIV to an amide of Formula LV is performed as described in Reaction Scheme 18. The transformation of an amide of Formula LV to a compound of Formula LVj proceeds as described in Reaction Scheme 1.

Reaction scheme 21

<img file="RS51155B_D0048.tif" />

n

I,

N ..

s

O 0

<img file="RS51155B_D0049.tif" />

<img file="RS51155B_D0050.tif" />

Reaction scheme 1

LVll

<img file="RS51155B_D0051.tif" />

<img file="RS51155B_D0052.tif" />

<img file="RS51155B_D0053.tif" />

in short they are zane na

Syntheses of compounds of Formula LXI1 and Formula

Reaction Scheme 21. Ethyl 2-amino-4-methyl-4-pentenoal (prepared as in Reaction Scheme 19 from ethyl ester (benzhydrylideneamino) acetic acid and 1-bromo-2-methyl-2-propene) is treated with a sulfonylating agent such as a sulfonyl chloride in the presence of a base such as triethylamine in an inert solvent such as SNJSE to give an ester of Formula LVII. Reaction of the ester of Formula LV11 with HF-pyridine in a solvent such as THF and at a reaction temperature between 0 ° C and 25 ° C gives a mixture of fluoroalkyl derivatives of Formula LVIil and a lactone of Formula L1X. These products are separated and further individually participate in the reactions that follow.

The ester of Formula LVIII is hydrolyzed to the acid of Formula LX using procedures well known to those skilled in the art (ref. TW Greene and PGM Wuts, Protecting Groups in Organic Synthesis. Wilev Inierscience. New York, 1999. pp. 373

51155 Β

442). For example, treatment of an ester of Formula LVIII with aqueous sodium hydroxide in a solvent such as methanol affords the acid of Form LX. The acid of Formula LX is converted to the amide of Formula LXI using the procedure described in Reaction Scheme 18 to prepare an amide of Formula XLIX. Preparation of the amide of Formula LXII from the compound of Formula LXI is accomplished as described in Reaction Scheme 1.

For the lactone of Formula LIX. treatment with aqueous ammonia gives the amide Formulc LXUI. This reaction typically takes place by heating in a sealed tube. The reaction temperature is between 40 ° C and 80 ° C. Further conversion of the intermediate Forniule LXiii to the sLilfonamide of Formula LX1V is continued as described in Reaction Scheme 1.

Reaction scheme 22

<img file="RS51155B_D0054.tif" />

<img file="RS51155B_D0055.tif" />

The synthetic sequence for the preparation of difluoroalkyl amide of Formula LXIX is shown in Reaction Scheme 22. A compound of Formula L is treated with 4-bromo-1-butane in the presence of a base such as potassium carbonate in the presence of a tetraalkylammonium halide salt such as tetrabutyl a solvent such as CH₃CN at a temperature of 20 ° C to 70^oC, Removal of the benzhydrylidene protecting group as described in Reaction Scheme 19 affords an intermediate amine which is then treated with a sulfonylating reagent such as a sulfonyl chloride to give an ester of Formula LXV. Alkylation of the sulfonamide nitrogen is performed using the procedure described in Reaction Scheme 1 to give a compound of Formula LXVi. The conversion of an alkene of Formula LXV1 to an aldehyde of Formula LXVII is accomplished by reacting the alkene with osmium tetroxide and trimethylamine-N-oxide in a solvent such as acetone. followed by sodium periodate treatment. The reaction temperature is typically 20 ° C to 40 ° C. Aldehyde reaction

51155Β

Formula LXVI1 with a fluorinating agent such as DAST in a solvent such as SNJSR provides a difluoroalkyl derivative of Formula LXVIH. The compound of Formula I.XVIII is converted to the amide of Formula LXIX by hydrolysis of the ester to an acid using a base such as sodium hydroxide in a solvent such as methanol. The intermediate acid is converted to the amide using conditions well known to those skilled in the art (ref. RC Larock. Comprehensive Organic Transformations. VCII Publishers, Nevv, York, 1989. pp. 972976). For example, the reaction of an acid with ammonium chloride in the presence of hydroxybenzotriazole and a carbodiimide reagent and an amine base such as diisopropylethylamine affords the amide of Formula LXIX. This reaction typically takes place in a polar solvent such as DMF and at a reaction temperature of 0 ° C to 40 ° C.

Reaction scheme 23

<img file="RS51155B_D0056.tif" />

<img file="RS51155B_D0057.tif" />

<img file="RS51155B_D0058.tif" />

<img file="RS51155B_D0059.tif" />

<img file="RS51155B_D0060.tif" />

The LXXI α-amino-amide of Formula LXXI is prepared using the reaction shown in Reaction Scheme 23. The amide of Formula LXX is prepared as described in Reaction Scheme

9. Trituration of the compound of Formula LXX with a secondary or tertiary amine in a solvent such as THF at a reaction temperature between 20 ° C and 40 ° C affords the amine of Formula LXX1.

51155 Β

<img file="RS51155B_D0061.tif" />

Preferably, the present invention includes compounds of Formula Ia or pharmaceutically acceptable salts thereof

R²

JLa, r³

H₂N Αχ X

QO where:

R¹ is selected from the group consisting of (a) linear or branched chain C 1-6 alkyl and C 1-6 alkenyl optionally substituted with substituents selected from the group consisting of hydroxy, C 1-4 alkoxy, C 1-6. 4aiki! Thio, and halogen;

R² is selected from the group consisting of (a) linear or garnet-fanned C1.₆alkyl or C 1-6 alkylN optionally substituted with substituents selected from the group consisting of halogen, C 1-8.₄alkoxy, and NR⁴R⁵;

(b) C. ₇cycloalkylmethyl optionally substituted with substituents selected from the group consisting of amino, (C 1-6 alkyl) NH-, di (C_{t 4}alkyl) N-, S_ma1kIS (= O) №1-, and C_t. ₄alkylOC (= O) NH-;

(c) linear or garnetted chain C 1-6 alkyl-C (= O) -A;

(d) -B-naphthyl;

51155Β (e)

<img file="RS51155B_D0062.tif" />

ζ

D and Ε are each independently a direct bond, linear or garnet-chain Ci__Galkyl, C2-6alkenyl, or C1-6cycloalkyl;

Z is selected from the group consisting of hydrogen, Ci₄alkyl. Ci.₄alkoxy, halogen, cyano, hydroxy, -OCHF ;. -OCF ;. -CF₃. and -CHF₂;

X and Y are each independently selected from the group consisting of hydrogen, hydroxy. halogen. (halogen)₃C-. (halogen)₂CH-, Ci_₄alkylS-. C |.₄alkylS (O) -. C |.₄alkylS ()₂-. nitro, F₃S-, and cyano;

-OR₆;

-NR⁴R⁵;

-NR⁷C (= O) R⁸;

-NR⁷C (= O) OR⁸:

-NHSO₂C \₄alkyl;

-N (SO₂C_walkyl)₂;

-C (= O) W where W is selected from the group consisting of hydroxy, C1-₄alkyl. C_!4alkoxy, phenoxy, and -NR⁴R 1 -OC (= O) C 1-4 alkyl;

-phenyl wherein said phenyl is optionally substituted with cyano, halogen, C₄alkoxy. C_N4alkylS-. CH_?C (= O), C 1-6 alkylSfO) -, or C 1-7.₄alkylSO₂-; and a heterocyclic group wherein said heterocyclic group is selected from the group consisting of furanyl, thiofuranyl. pyrrolyl. imidazolyl. pyrazolyl. triaz.olyl, tetrazolyl. pyridinyl, pyrimidinyl, oxadiazolyl, oxazolyl, isoxazolic thiadiazolyl, and thiazolyl. wherein said heterocyclic group is optionally substituted with substituents selected from the group consisting of cyano. halogen, C 1-4 alkyl.

(halogen) CY₄alkyl. and CO₂C].₄alkyl:

(f) -B- (heterocycle). wherein said heterocycle is selected from the group consisting of furanyl. thiofuranyl. pyrrolyl, imidazolyl. pyrazolyl, triazolyl. tetrazolyl, pyridinyl. pyrimidine.

51155 Β oxadiazolyl, oxazolyl, isoxazolyl. thiadiazolyl and liazolyl, wherein said heterocycle is optionally substituted with substituents selected from the group consisting of cyano, halogen. C |.₄alkyl, CO₂C |.₄alkyl, amino. (C |.₄alkyl) NH-, di (C1.₄alkyl) N-, morpholin-4-yl. thiomorpholin-4-yl. pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, and 4- (C₁.₆alkyl) piperazin-1-yl:

(g) -B- (piperidin-4-yl), wherein said piperidin-4-yl is optionally substituted with substituents selected from the group consisting of linear or branched chain C 1-6 alkyl. ClBC (= O) phenyl, phenyl and phenylmethyl wherein C 1 is mentioned.₆alkyl and said phenyl optionally substituted with substituents selected from the group consisting of cyano, halogen, benzimidazol-2-yl. pyridyl and tetrahydrofuran-2-yl: and -C (= O) W 'wherein W' is selected from the group consisting of C1.₄alkoxy, R⁴, and -NR⁴R⁵;

A is hydroxy, C 1.₄alkoxy or NR⁴R ”;

B is linear or garnetted chain C 1-6 alkyl or C₃.₍, alkenyl;

R 1 is phenyl or pyridyl optionally substituted with substituents selected from the group consisting of halogen. hydroxy. Ci_₄alkoxy, C_Malkyl, (halogen)₃C-, (halogen)₂CH- and halogenCFB-:

R⁴ and R 1 are each independently hydrogen, linear or branched chain C 1-6 alkyl, C 1-6 alkyl₃.6alkenyl, C₃.

₆alkynyl. C₃.₇cycloalkyl, C₃.₇cycloalkylmethyl, C 1₄alkoxy, phenyl, benzyl. pyridyl. piperidin-4-yl, indan-1-N, indan-2-yl. tetrahydrofuran-3-yl. or pyrrolidin-3-yl; wherein each is optionally substituted with substituents selected from the group consisting of hydroxy. cyano. halogen, (halogens)₃C-, (halogen)₂CH-. halogcnCIB-. hydroxymethyl, benzyloxymethyl, phenyl, pyridines). Cualkil. C |.₄alkoxy, (halogen)₃CO-, (halogen)₂-CH-0-. C |.₄alkylthio, amino. (C |.₄alkyl) MH-. di (Ci.₄alkyl) N-, morpholin-4-yl, thiomorpholin-4-yl, pyrrolidin-1-yl. piperidin-1-yl. piperazin-1-yl, 4- (C1 H2.₆alkyl) piperazin-1-yl, 4-phenylpiperazin-1-yl. 4-benzylpiperazin-1-yl. 4-pyridylpiperazin-1-yl, S'O₂11, CO₂C |.₄alkyl C (= O) NHC_Malkyl, and C (= O) N (C_Malkyl)_?;

R⁴ and R^? together they may be morpholin-4-yl. thiomorpholin-4-yl. pyrrolidin-1-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl. decahydroquinolin-1-yl, piperidin-1-yl, piperazin-1-yl. [1,4] oxazepan-4-yl. azetidin-1-yl, 2,3-dihydro-1H-isoindol-2-yl. or 2,3-dihydro-1H-indol-1-yl; wherein each is optionally substituted with substituents selected from

51155 Β a group containing hydroxy. cyano, halogen. (halogen); C-, (halogen)₂-CH-. halogenCIF-. phenyl. pyridyl. benzii. C 1-4 alkyl, C 1-4 cycloalkyl, C 1-4 alkoxy, C 1-4 alkylthio amino.₄alkyl) NH-, di (C1-8).₄alkyl) N-. CO₂H. CO₂C |.₄alkyl, C (= O) NHC].₄alkyl, and C (= O) N₍.₄alkyl)₂;

R⁶ is a linear or branched chain C 1-6 alkyl, C 1-6 alkenyl, benzyl, or phenyl wherein each is optionally substituted with substituents selected from the group consisting of halogen, C 1-6.₄alkyl. Ci_₄alkoxy, amino. (Ci_₄alkyl) NH-, di (C1.₄alkyl) N-, (S / ₄alkyl) (phenyl) N-, morpholin-4-yl. thiomorpholin-4-yl, pyrrolidin-1-yl. piperidin-1-yl, piperazin-1-yl. and 4- (C1-6alkyl) piperazin-1-yl:

R⁷ is hydrogen. linear iii garnet-chain CGalkyl:

R^s jc lineami or garnet-chain Cj.₀alkyl. C 1-6 cycloalkyl, phenyl, pyridyl, or furanyl; wherein each is optionally substituted with substituents selected from. halogen-containing group, Ci.₄alkyl. C | „₄alkoxy. (Ci_₄alkyl) NH-, di (C1-8).₄alkyl) N-, morpholin-4-yl. thiomorpholin-4-yl, pyrrolidin-1-yl. piperidin-1-yl. piperazin-1-yl. and 4- (C 1-6 alkyl) piperazin1-yl:

R is linear or garnet-chain C1.₆alkyl, C1-4.₆alkenyl. benzyl, phenyl, oxazolyl or pyridyl; wherein each is optionally substituted with substituents selected from halogen-containing gnipes, (halogen)₃C-. (halogen)₂CH-. halogenCl I₂-. C].₄alkyl. C_t. ₄alkoxy, amino, (Cr₄alkyl) NH-. di (C 1-4 alkyl) N-, morpholin-4-yl. thiomorpholin-4-yl. pyrrolidin-1-yl, piperidin-1-yl piperazin-1-yl, and 4- (Ci.₆alkyl) piperazin-1-yk or a non-toxic pharmaceutically acceptable salt thereof.

In another preferred embodiment, the invention includes compounds of Formula Ia or a pharmaceutically acceptable salt thereof wherein R? phenyl optionally substituted with substituents selected from the group consisting of halogen, hydroxy. Ci_₄alkoxy, Ci.₄alkyl. (halogen)₃C-, (halogen)₂CH-, and halogenCFF-.

In another preferred embodiment, the invention includes compounds of Formula Ia or a pharmaceutically acceptable salt thereof, wherein R "

<img file="RS51155B_D0063.tif" />

51155 Β

METHOD OF BIOLOGICAL TESTING

The compounds of Formula (I) are expected to possess γ-secretase inhibiting activity. Detection of γ-secretase activity requires tests that can reliably, accurately and purposefully detect cleavage products by γ-secretase, especially Αβ. The activity of a compound of the present invention in inhibiting γ-scretase is demonstrated using assays for that activity, for example, using the assays described below. The compounds encompassed by the present invention have been shown to inhibit γ-secretase activity. as determined by using tests for that activity.

The compounds of the present invention should also be useful as standards and reagents in determining the ability of a potential pharmaceutical to inhibit Aβ production, which would be provided by commercial kits comprising a compound of the invention.

In vitro binding assay to identify γ-secretase inhibitors

Competitive binding assays can be used to identify molecules that inhibit the binding of radiolabeled γ-secretase inhibitors and thus inhibit γ-secretase activity. For example. '' HJ-Compound A can be used for membrane binding membranes from THP-1 cells (Seiffert, D. Bradley, J. et al. J. Biol. Chem. 2000, 275, 34086-34091). Compound A is (2R, 3S) N1 - [(3S) -hexahydro-1- (3-phenoxybenzyl) -2-oxo1H-azepin-3-yl] -2- (2-methylpropyl) -3- (propyl) -butanediamide, the synthesis of which is described in U.S. Pat. No. 6,631,408 (December 18, 2001); PCT Publication WO 00/28331; PCT Publication WO 00/07995; and Sciffcrt, D., Bradley. .1. ei aL J. Biol. Chem. 2000, 275, 34086-34091.

<img file="RS51155B_D0064.tif" />

For sheep tests. TllP-1 cells were grown in spinner cultures in RPM1 1640 with Lglutamine and 10 μΜ β-mercaptoeianol to a density of 5. \ 10^? cell / ml. Cells were harvested by centrifugation, cell pellets were rapidly frozen in dry ice / ethanol and stored at -70 ° C.

51155 Β to use. Pellets from about 2 h 10ⁿ THP-1 cells were homogenized using a Brinkman Polytron set to 6.10 seconds. The homogenate was centrifuged at 48,000 h g.

min. and the resulting pellet is washed by repeated homogenization and centrifugation. The final cell pellet was resuspended in buffer to give a prolein concentration of approximately 0.5 mg / ml. Assays were initiated by adding 150 μΐ of membrane suspension to 150 μΐ of assay buffer containing 0.064 pCi of radioligand and various concentrations of unlabeled compounds. Binding tests were performed in duplicate on 96-well polypropylene plates, in a final volume of 0.3 ml containing 50 mM Hepes. pH 7.0. and 5% dimethyl sulfoxide. Nonspecific binding was defined using incubations with 300 nM of compound A (Seiffert. D., Bradley, .1. El al „Biol. Chem. 2000, 275. 34086-34091). After incubation at 23 ° C. For 1.3 h, the bound ligand was separated from the free radioligand by filtration through GFF glass fiber filters pre-moistened with 0.3% ethyleneimine polymer solution. The fillers are washed three times with 0.3 ml of ice-cold phosphate buffered saline, pH 7.0. containing 0.1% Triton H-100. Filter-related radioactivity is measured by scintillation counting. IC50 values ​​are then determined and used to calculate K, values ​​using Chcng-Prusoft correction for IC values_Jn. Compounds are considered active γ-secretase inhibitors if K, values ​​less than 10 μΜ.

Examples of the results obtained when the compounds of the invention are exposed to the test described above are shown in Table 1. In the table. inhibitory concentration (IC50) less than or equal to 50 pM is represented by +++; between 50 nM and 500 nM with between 500 nM and 10000 nM with +,

TABLE 1: Examples of activities in the iri in vitro binding assay

<td>EXAMPLE</td><td>ACTIVITY ASSESSMENT *</td>

<td> 96</td><td> +++</td>

<td> 123</td><td> +++</td>

<td> 159</td><td> +++</td>

<td> 315</td><td> ++</td>

<td> 341</td><td>Ή *</td>

<td> 357</td><td> ++</td>

51155 Β

<td>EXAMPLE</td><td>ACTIVITY ASSESSMENT</td>

<td> 362</td><td> +++</td>

<td> 365</td><td> +++</td>

<td> 366</td><td> +++</td>

<td> 367</td><td> + '</td>

<td> 376</td><td> ++</td>

<td> 379</td><td> +++</td>

<td> 385</td><td>jr I g ^ t g</td>

<td> 389</td><td> 4++</td>

<td> 394</td><td> +++</td>

<td> 403</td><td> ++</td>

<td> 405</td><td> +++</td>

<td> 408</td><td> +</td>

<td> 409</td><td> ++</td>

<td> 437</td><td> +++</td>

<td> 441</td><td> +++</td>

<td> 443</td><td> ++</td>

<td> 445</td><td> +++</td>

<td> 447</td><td> +++</td>

<td> 450</td><td></td>

<td> 451</td><td> +</td>

<td> 452</td><td> ++</td>

<td> 457</td><td> ++</td>

<td> 464</td><td> +</td>

<td> 474</td><td> !’ 1 !</td>

<td> 476</td><td> +14</td>

<td> 479</td><td> ++</td>

<td> 486</td><td> +++</td>

51155 Β ^a Activity based on IC 50 values:

+++ = &lt;50 n M ++ = 50-500 nM + =&gt; 500 nMi &lt;10,000 nM

In vitro assay for the identification of γ-secretase inhibitors based on the inhibition of Aβ formation from a membrane preparation

An isolated membrane fraction containing functionally active γ-secretase and βAPP substrates can generate γ-secretase cleavage products, including Αβ (Roberts, SB, llcndrick. .1. P., Vinitskv. A .. Lewis, M., Smith. I ). W „Pak. R. PCT Publication WO 01/0175435; Swordsman. K ... Bone. M., Fuchs. M. Patent Application No. DE 99-19941039; Shearman. M .. Beher. D. ei a! .. Biochemistry. 2000, 39, 8698-8704; Zhang, L .. Song. L el al .. Biochemistry, 2001, 40, 5049-5055). An isolated membrane fraction can be prepared from a cell line of human origin. e.g. HcLa and 114 which were transfected with wild-type or mutant forms of β-ΑΡΡ or human alkaline phosphatase - β-ΑΡΡ fusion construct. and stably express high levels of γ-secretase substrates. Endogenous γ-secretase present in the isolation of membranes prepared at 04 ° C cleaves β-ΑΡΡ subslrate when the membranes are transferred from 0-4 ° C to 37 ° C. Detection of cleavage products including Aβ can be monitored by standard techniques such as immunoprecipitation (Citron. M .. Diehl, 1. S. e1 al .. Proc. Nail. Acad. Sci. USA. 1996, 93. 13170-13175), western blot (Klatki, HW. Ambramowski. D. et al. J. Biol. Chem. 1996, 271. 28655-28659), enzyme-linked immunosorbent lest (ELISA) as shown by Seubert, P .. Vigo-Pclfrcy , C. el al., Naiure. 1992 359, 325-327, or by a preferred procedure using a time-decreasing fluorescence of a homogeneous sample containing membranes and Aβ (Roberts. SB, Hendrick, .1. P. Vinitsky, L. Lewis. M. Smith, DW. Pack. R. PCT Publication WO 01/0175435: Shearman. M .. Beher. D. el al .. Biochemistiy. 2000. 39, 8698-8704). Aβ present in a homogenous membrane-containing sample can be detected by time-decreasing fluorescence with two antibodies recognizing different Aβ epitopes. One of the antibodies recognizes an epitope that is present on Aβ but not present on precursor fragments; desirable. the antibody binds the carboxyl-terminus Αβ

51155 Β generated by γ-secretase cleavage. The second antibody binds to any other cytopite present on Aβ. For example, antibodies that bind the N-terminal region (eg 26D6-B2-B3) are known.^{J &lt;} SIBIA Neurosciences. La Jolla. CA) or bind the C-terminal end (eg 983.2 antibody Biosolutions, Newark. DE) of the Aβ peptide. Antibodies are labeled with a pair of fluorescent adducts that transmit fluorescent energy when the adducts are brought in close proximity as a result of binding to the N- and C-terminal ends or regions of Αβ. [Fluorescence residue indicates the absence of cleavage products. resulting from γsecretase inhibition. The isolated membrane assay can be used to identify agents that are candidates for inhibitors of γ-secretase activity in Aβ cleavage and production.

For a typical membrane-based assay, 45 pg of membrane protein per reservoir is required, in a 96 or 384 reservoir format. Membranes in neural buffer were combined with the test compound and switched from 0-4 to 37 ° C. Tesla agents may typically consist of synthetic compounds. secondary metabolites from bacterial or fungal fermentation extracts, or plant extracts or marine samples. All synthetic agents are initially tested in doses in the range of 10-100 μΜ or, in the case of excipients, at a dilution sufficient to minimize toxicity. Incubation of the membranes with the test medium is continued for approximately 90 minutes. when fluorescently labeled antibodies are added to each Aβ quantification tank. Delection of time-decreasing fluorescence and quantification of Aβ have been described elsewhere (Roberts, SB, Hendrick. JP, Vinitsky. A „Levvis. M .. Smith. DW. Pak, R. PCT Publication WO 01/0175435: Shearman, M .. Bchcr, D. et al .. Biochemistry. 2000, 39. 8698-8704). The results are obtained by analyzing the plates on a plate fluorescence reader and comparing them with falsely treated membranes and samples to which known amounts of Aβ were added to construct a standard concentration curve. A compound with a positive effect is one that inhibits Αβ relative to the control sample by at least 50% at the initial test concentration. If the compound is found to be active then a dose response experiment is performed to determine the lowest dose necessary to exhibit inhibition of Aβ production. .flicts are considered active γ-secretase inhibitors if K, values ​​are less than 10 μΜ.

Examples of the results obtained when the compounds of the invention are subjected to the test described above are shown in Table 2. In the table. inhibitory concentration (IC₅₍₎) less than or equal to 50

51155 Β ηΜ is represented by +++; between 50 nM and 500 nM with ++. between 500 nM and 10000 nM with

-Mr.

Table 2: Examples of activities in an in vitro test based on inhibition of Aβ formation from membrane preparations

<td>EXAMPLE</td><td>ACTIVITY ASSESSMENT</td>

<td> 1</td><td>4 — H-</td>

<td> 2</td><td> +++</td>

<td> 3</td><td> +4+</td>

<td> 4</td><td>4 H '</td>

<td> 5</td><td> +++</td>

<td>b</td><td> +++</td>

<td> 7</td><td> +++</td>

<td> 8</td><td> +++</td>

<td> 9</td><td> +++</td>

<td> 10</td><td> +++</td>

<td> 11</td><td> +++</td>

<td> 12</td><td> +++</td>

<td> 13</td><td> +++</td>

<td> 14</td><td> +++</td>

<td> 15</td><td> +++</td>

<td> 16</td><td> +++</td>

<td> 17</td><td>Η 1-</td>

51155 Β

<td>EXAMPLE</td><td>ACTIVITY ASSESSMENTp</td>

<td> 18</td><td>-Η-</td>

<td> 19</td><td> 4+</td>

<td> 20</td><td> ++</td>

<td> 21</td><td> +++</td>

<td> 22</td><td> +++</td>

<td> 23</td><td> +++</td>

<td> 24</td><td> +++</td>

<td> 25</td><td> +++</td>

<td> 26</td><td> +++</td>

<td> 27</td><td> ++</td>

<td> 28</td><td> ++</td>

<td> •29</td><td> +++</td>

<td> 30</td><td> ++</td>

<td> 31</td><td> ++</td>

<td> 32</td><td> +++</td>

<td> 33</td><td>, .i&gt; 1. TT Τ '</td>

<td> 34</td><td> +++</td>

<td> 35</td><td> ++</td>

<td> 36</td><td> ++</td>

<td> 37</td><td> +++</td>

<td> 38</td><td> +++</td>

<td> 39</td><td> +++</td>

<td> 40</td><td> +++</td>

<td> 41</td><td> +++</td>

<td> 42 - </td><td> +++</td>

<td> 43</td><td>Ή +</td>

<td> 44</td><td> +++</td>

<td> 45</td><td> +++</td>

51155 Β

<td>EXAMPLE</td><td>ACTIVITY ASSESSMENT *</td>

<td> 46</td><td> +++</td>

<td> 47</td><td> +++</td>

<td> 48</td><td> +++</td>

<td> 49</td><td> ++</td>

<td> 50</td><td> +++</td>

<td> 51</td><td> +++</td>

<td> 52</td><td> +++</td>

<td> 59</td><td> ++</td>

<td> 61</td><td> +++</td>

<td> 83</td><td>₊ .</td>

<td> 85</td><td> 4*</td>

<td> 87</td><td> +++</td>

<td> 89</td><td> +++</td>

<td> 95</td><td> +++</td>

<td> 103</td><td> +++</td>

<td> 113</td><td> ++</td>

<td> 122</td><td> 4-</td>

<td> 133</td><td>_Jf4+</td>

<td> 153</td><td> ++</td>

^a IC-based activity₅₀ values:

+++ = &lt;50 nM ++ = 50-500 nM + =&gt; 500 nMi &lt;10,000 nM

51155 Β ln v / tro assays for identification of γ-secretase inhibitors based on inhibition of Aβ formation in cells in culture

Human cell lines in culture. as UEK293 and H4 cells. which express APP and γ-secretase activity or transfected derived cell lines that overexpress wild-type APP, mutant APP. or APP fusion proteins secrete into the culture medium Αβ peptides that can be quantified as previously shown (Dovev, II., John. V. et al., J. Neurochem. 2001, 76. 173-181). incubation of these cells in culture with γ-secretase inhibitors reduces the production of Αβ peptides. For example, H4 cells stably transfected to overexpress HPLAP-APP fusion protein, described above. grow. as above, are separated and adjusted to 2 h I0³ cell / ml 100 μΐ of the resulting suspension was then added to each 96-well plate reservoir. After 4 h, the medium was removed and replaced with 100 μΐ scrum-free medium containing various dilutions of the test compound. The plates were then incubated for 18 h at 37 ° C and a 100 μl aliquot of tissue culture supernatant was taken to determine Aβ levels using a time-decreasing fluorescence of a homogeneous sample as described above. Alternatively. other methods described above can be used to determine Aβ. The degree of inhibition of Aβ is used to calculate the IC50 values ​​for the test compound.

The compounds of the present invention are considered active when tested by the above assay if the IC50 value for the test compound is less than 50 μΜ.

Examples of the results obtained when the compounds of the invention were subjected to the test described above are shown in Table 3. In the table. inhibitory concentration (IC50) less than or equal to 50 nM is represented by +++: between 50 nM and 500 nM with ++. between 500 nM and 50000 nM with +.

TABLE 3: Examples of in vitro test activities based on inhibition of Aβ formation in kaituri eejjja

<td>EXAMPLE</td><td>ACTIVITY ASSESSMENT</td>

<td> 1</td><td> +++</td>

<td> 5</td><td>+ -H-</td>

<td> 19</td><td>-n-</td>

<td> 26</td><td> +++</td>

51155 Β

<td>EXAMPLE</td><td>ASSESSMENT OF ACTIVITY</td>

<td> 38</td><td> +++</td>

<td> 41</td><td> +++</td>

<td> 51</td><td> +++</td>

<td> 55</td><td> +++</td>

<td> 61</td><td> +++</td>

<td> 72</td><td> +4+</td>

<td> 80</td><td> +++</td>

<td> 89</td><td> +++</td>

<td> 96</td><td> 44-+</td>

<td> 101</td><td> +++</td>

<td> 123</td><td> +4+</td>

<td> 127</td><td> ++</td>

<td> 143</td><td> +4+</td>

<td> 147</td><td> 4+</td>

<td> 158</td><td> +4+</td>

<td> ' 171</td><td> 4+</td>

<td> 193</td><td> +4+</td>

<td> 203</td><td></td>

<td> 205</td><td></td>

<td> 207</td><td> +++</td>

<td> 245</td><td> +++</td>

<td> 246</td><td> +++</td>

<td> 249</td><td>-Η *</td>

<td> 254</td><td> +++</td>

<td> 256</td><td> +++</td>

<td> 260</td><td> +++</td>

<td> 272</td><td> 4-++</td>

<td> 280</td><td> ++</td>

51155 Β

<td>EXAMPLE</td><td>ACTIVITY ASSESSMENT *</td>

<td> 282</td><td> +++</td>

<td> 288</td><td> +4-</td>

<td> 301</td><td>-H-</td>

<td> 302</td><td>+++ ι</td>

<td> 321</td><td> 4+</td>

<td> 322</td><td> +++</td>

<td> 329</td><td> +++</td>

<td> 330</td><td> ++</td>

<td> 331</td><td> +</td>

<td> 340</td><td> +++</td>

<td> 341</td><td> ++</td>

<td> 342</td><td> 4+4-</td>

<td> 349</td><td> ·+++</td>

<td> 352</td><td> ++</td>

<td> 358</td><td> ++</td>

<td> 359</td><td> +++</td>

<td> 366</td><td> +++</td>

<td> 367</td><td> +</td>

<td> 378</td><td> +++</td>

<td> 383</td><td> +++</td>

<td> 394</td><td> +++</td>

<td> 403</td><td> 4+</td>

<td> 416</td><td> +++</td>

<td> 418</td><td> +++</td>

<td> 424</td><td> +++</td>

<td> 433</td><td> +++</td>

<td> 434</td><td> 4+¼</td>

<td> 439</td><td>Ή l ·</td>

51155 Β

<td>EXAMPLE</td><td>ACTIVITY ASSESSMENT *</td>

<td> 442</td><td> +++</td>

<td> 472</td><td> +++</td>

<td> 481</td><td></td>

<td> 492</td><td> 44-</td>

<td> 495</td><td>-H- +</td>

<td> 497</td><td> +++</td>

^a Activity based on IC50 values:

+++ = &lt;50 nM ++ -50-500 pM + =&gt; 500 nM i &lt;10,000 ηΜ

The compounds of the present invention have been shown to have an IR₅₀ a value less than 10 μΜ in one or all of the above tests. So. Fornnile I compounds or pharmaceutical compositions thereof are useful for treating, alleviating or eliminating diseases or other disorders associated with β-amyloid peptide inhibition.

In addition to APP cleavage, γ-secretase cleaves other substrates, including the Notch family of transmembrane receptors (review given in: Selkoe, D. Physiol. Rev. 2001, 81, 741-766; Wolfe. M. .7. Med. Chem. 2001, 44, 2039-2060): LDL receptor-bound proteins (Mau, P „Reddv, K.. K. Herz. .1. .1. Biol. Cheni. 2002, 277, 18736-18743): ErbB-4 (Ni. CY, Murphv, M, P .. Golde, TE. Carpenter, G. Science 2001,294. 2179-2181); E-cadherin (Marambaud, P., Shioi, .1., Et al., EMBO J. 2002, 21. 1948-1956); and CD44 (Okamoto. L „Kavvano, Y-, et al. J ('ell Biol. 2001. 155, 755-762). If inhibition of nc-APP substrate cleavage causes undesirable effects in humans. then γ-secretase inhibitors would be desired inhibited APP cleavage preferentially over unwanted substrates Notch cleavage can be monitored by measuring the amount of cleavage product or indirectly by measuring the effect of the cleaved product on transcription (Mizutani. T .. Taniguchi, Y. et al. Proc. Nall. Acad. Sci. USA 2004,98, 9026-9031).

51155 Β

7/7 in vivo assays to determine the reduction of Αβ by γ-secretase inhibitors

In vivo assays are available to demonstrate inhibition of γ-secretase activity. In these tests, animals such as mice. which express normal levels of APP and γ-secretase or are engineered to express higher levels of APP and thus Αβ can be used to demonstrate the usefulness of γ-secretase inhibitors (Dovev, H .. John, V. et al.,, J. Neurochem 2001, 76, and 73-181). In these assays, γ-secretase inhibitors are administered to animals and Aβ levels are monitored in multiple compartments, such as plasma, cerebrospinal fluid, and brain extracts, using the procedures described previously. For example, in Tg2576 mice overexpressing human APP, γ-secretase inhibitors are administered orally in doses that will lead to a measurable decrease in Aβ. typically less than 100 mg / kg. Three hours after dosing. plasma, brain and CSF are taken, frozen in liquid nitrogen. and storage at -80 ° C until analysis. For Αβ detection, plasma was diluted 15-fold in PBS with 0.1% Chaps while CSF was diluted 15-fold in 1% Cliaps with protease inhibitors (5 pg / ml leupeptin, 30 pg / ml aprotinin, I mM phenylmethylsulfonyl fluoride, I μΜ pepstatin ). Brains were homogenized in 1% Chaps with protease inhibitors using 24 ml solution / g brain tissue. The homogenates were then centrifuged at 100,000 h g, 1 h, at 4 ° C. The resulting supernatants were diluted 10-fold in 1% Chaps-II with protease inhibitors. Plasma, CSF, and brain lysate levels of Aβ are measured using time-decreasing fluorescence of a homogeneous sample or some of the other methods previously described.

An γ-secretase inhibitor is considered active in one of the above in vivo assays if it reduces the Aβ bar by 50% at a dose of 100 mg / kg.

Thus, the compounds of Formula I or pharmaceutical compositions thereof are useful for treating, alleviating or eliminating staining or other disorders associated with β-amyloid peptide inhibition.

In another aspect, the present invention encompasses pharmaceutical compositions comprising at least one compound of Formula I in combination with a pharmaceutical adjuvant, carrier or diluent.

In another aspect, the present invention relates to a method of treating or preventing diseases responsive to inhibition of a β-amyloid peptide in a mammal.

51155 Β necessary, which comprises administering to the treated mammal a therapeutically effective amount of a compound of Formula I or a non-toxic pharmaceutically acceptable salt, solvate or hydrate thereof.

In another form. the present invention relates to a method of treating Alzheimer's disease and Down syndrome in a mammal in need thereof, comprising administering to said mammal a therapeutically effective amount of a compound of Formula 1 or a non-toxic pharmaceutically acceptable salt thereof. solvate iii hydrate.

For use in therapy, the pharmacologically active compounds of Formula I will normally be administered as pharmaceutical compositions comprising as essential active ingredient at least one such compound in association with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically acceptable adjuvants and excipients using standard and common techniques.

Pharmaceutical compositions include suitable dosage forms for oral, parenteral (including subcutaneous, intramuscular, intradermal and intravenous), bronchial or nasal administration. Thus, if a solid carrier is used, the preparation can be tableted. placed in hard gelatin capsules in the form of powder or peyet. or in the form of a trochee or lozenge. The solid carrier may contain conventional excipients such as binders, support agents, tableting lubricants, disintegrants, wetting agents and the like. The tablets may, if desired, be film-coated by conventional techniques. If a liquid carrier is used. the preparation may be in the form of a syrup. emusions, soft gelatin capsules. sieryl vehicle for injection, aqueous or non-aqueous liquid suspension, or may be a dry product for reconstitution with water or another suitable vehicle, prior to use. Liquid preparations may contain conventional additives such as suspending agents. emulsifying agents, binders, non-aqueous vehicles (including edible oils), preservatives, as well as odor improvers and / or coloring agents. For parenteral administration, the vehicle normally includes sterile water, at least in large part, although saline solutions, glucose solutions and the like may be used. Injectable suspensions may also be employed, in which case conventional suspending agents may be employed. Conventional preservatives, buffering agents and syrups may also be added to the parent dosage forms. The pharmaceutical compositions are prepared by conventional techniques suitable for the desired

51155 Β a preparation containing appropriate quantities of the active ingredient, that is. compounds of Formula I according to the invention. See, on priirier, Remington's Pharmaccutical Scicnccs. Mack Publishing Sotrapu. Easton, PA. 17th edition, 1985.

The dosage of the compounds of Formula I to achieve a therapeutic effect depends not only on factors such as age. the weight and sex of the patient and the mode of administration, but also the degree of desired inhibition of β-ΑΡ and the potency of the particular compound used for the particular disease in question. It is also to be understood that the treatment and dosing of a particular compound may be performed in unit dosage forms and that these unit dosage forms can be adjusted by one skilled in the art to reflect the relative level of activity. The decision on the particular dosage form to be used (and the number of times to be administered daily) is at the discretion of the physician, and may be varied by titration of the dosage of the present invention according to the particular circumstances. to produce the desired therapeutic effect.

A suitable dose of a compound of Formula 1 or a pharmaceutical composition thereof for a mammal. including man. suffering from, or likely to suffer from any condition associated with the production of β-ΛΡ, as described herein, is typically from about 0.05 mg / kg to about 10 mg / kg per day and preferably about 0.1 to 2 mg / kg when administered parenterally. For oral administration, the dose may be in the range of about 1 to about 75 mg / kg and preferably 0.1 to 10 mg / kg of body weight. The active ingredient will preferably be administered in equal doses of one to four times a day. However. small doses are usually administered and the dosage is gradually increased until the optimal dose is determined for the host being treated. In accordance with good clinical practice, it is desirable to administer these compounds at a concentration level that will produce an effective anti-amyloid effect without causing any harm or adverse side effects. However, it is understood that the amount of compound actually administered will be determined by a physician. in the light of relevant circumstances including the condition to be treated. selection of compounds to be applied, selected route of administration, age. severity, and the response of the individual patient, as well as the severity of the patient's symptoms.

The following examples are provided by way of illustration and should not be construed as limiting the invention in any way. since within the spirit of the invention ninogc variations are possible.

51155 Β

DESCRIPTION OF SPECIFIC SPECIES

In the following examples, all temperatures are expressed in degrees Celsius. Melting points were determined on a Thomas Scictive Unimelt capillary melting point apparatus and were uncorrected. Proton magnetic resonance (^!1 H NMR) spectra were recorded on a Bruker Avance 300, Bruker Avance 400, or Brukcr Avance 500 spectrometer. All spectra were determined in the indicated solvents. chemical shifts are reported in b units downstream of the internal standard trimethylsilane (TMS) and the interprolon coupling constants are expressed in hertz (Hz). Separation patterns are labeled as follows: s. singlet; d, depth; t, triplel: q, quartet; m, multiplet; no. wide peak; dd, doublet doublet; br d, wide doublet; dt, triplet double: no s. wide singlet; dq. doublet of the quartet. Infrared (IR) spectra were determined, using potassium bromide (KBr) or sodium chloride film, on a Jaco FT / IR-410 or Perkin Elmer 2000 FT-IR spectrometer of 4000 cm -1.¹ to 400 cnf ', calibrated to absorb the 1601 cnT polystyrene film¹ and are expressed in reciprocal centimeters (cm '¹). Optical rotations were determined on a Rudolph Scientific Autopol IV polarimeter in said solvents; concentrations are given in mg / ml. Low-resolution mass spectra (MS) and apparent molecular (Μ1Γ)¹ or (MH)⁺ were determined on a Finnegan SSQ7000. High-resolution mass spectra were determined on a Finnegan MLT900. Liquid chromatography (LC) / mass spectra were performed on a Shimadzu LC associated with Water Micromass ZQ.

The following abbreviations were used: DMF (dimethylformanide); THF (tetrahydrofuran; DMSO (dimethylsulfoxide). Leu (leucine); TFA (trifluoroacetic acid): DAST [(diethylamino) sulfur trinuoride]. · HPLC (liquid chromatography under high pressure); rt (room temperature); ).

Example Reaction Scheme 1

<img file="RS51155B_D0065.tif" />

51155 Β

(2R) -2- (4-Chlorobenzenesulfonylamino) -4-inethylpentanoic acid amide:

To a solution of (D) -leucinamide hydrochloride (0.25 g, 1.5 mmol), and E1N (0.43 mL, 3.0 mmol) 11 CH 2 Cl 2 (150 mL) was added 4-chlorobenzenesulfonyl chloride (380 mg, 1.8 mmol). The grated solution was stirred at rt for 18 h. The reaction was then diluted with CIECE (200 mL) and washed with NJO, 0.5N IlCl, brine. and dried over MgSO 4 to give the title compound (410 mg) as a white solid in 90% yield. MS (ESI), (M + H) 305.2: 1 H NMR (DMSO-d 6) δ 7.77 (d. 2H, δ = 8.7). 7.62 (d, 2H, .7 = 8.7), 6.90 (br s, 1H). 3.67 (m. 111),

1.54 (m, 1 H), 1.31 (m, 2 H), 0.81 (d, ZN. 7 = 7.0), 0.71 (d. ZN, 7 = 7.0).

Procedure A for the conversion of III to I:

<img file="RS51155B_D0066.tif" />

(2R) -2- (N- (4-chlorobenzenesulfonyl) -N- (4-methoxybenzyl) amino] -4-methylpentanoic acid amide) (Example 1):

(2R) -2- (4-Chlorobenzenesulfonylamino) -4-methylpentanoic acid amide (300 mg, and mmol). K2CO3 (170 mg, 1.2 mmol), and 4-inethoxybenzyl chloride (170 mg, 1.1 mmol) in DMF (25 mL) were heated at 60 ° C for 18 h. The reaction was then diluted with EtOAc (150 mL) and washed with H₂Oh, salt water, dried over MgSO₄ and concentrates to give a crude white waxy substance. Further purification by flash chromatography (Si ()₂, 25% EtOAc / hexanes) gave the title compound (297 mg) as a white solid in 70% yield. [α] D + + 44.2 (c 1.00, MeOH): MS (ESI), (MH) &amp; lt; + &amp; gt ;: 422.9; Ϊ́ ΐ NMR (CDCl 3) δ 7.63 (d, 211. .7 = 7.0). 7.42 (d, 2H, 7 = 7.0), 7.25 (d, 2H, .7 = 8.0), 6.79 (d, 2H, 7 = 8.0). 6.25 (No. p. 111). 5.35 (br. 1H). 4.36 (dd, 2H, 7 = 50.15), 4.26 (t, 1H, 7 = 7.2), 3.78 (s, 311), 1.83 (m, 1H). 1.18 - 1.34 (m, 2H), 0.75 (d, ZN, 7 = 7.0). 0.67 (d, 311.7 = 7.0): IR (KBr) 3480, 2959. 1693, 1674. 1514, 1333, 1158 cm -1.

Procedure B for the conversion of III to I:

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<img file="RS51155B_D0067.tif" />

Methyl 6-dimethylaminonicotinate

A solution of methyl 6-chloronicotinate (4.0 g, 23 mmol) in dimethylamine / MeOH (2M, 80 mL, 160 mmol) in a pressure vessel was stirred at 95 ° C. 2 h. cool to cape and concentrate. The residue was dissolved in EtOAc (250 mL), washed with water (2 x 150 mL). sushi prcko Na₂SO₄, and concentrated to give the title compound as a tan solid (4.1 g, 98%). MS (ESI), (MH)⁺Stk #: 181.24; 1 H NMR (CDCl 3) δ 8.79 (s, 1H), 7.99 (d, 1H,&gt; 9.2). 6.45 (d, 1 H).

./=9.2),3.85 (s. ZN). 3.15 (s, 6H).

<img file="RS51155B_D0068.tif" />

2-dimethylamino-5-hydroxymethylpyridine:

A solution of methyl 6-dimethylaminonicotinate (4.14 g, 23.0 mmol) in anhydrous ether (80 mL) at 0 ° C was treated with lithium aluminum hydridoin (1M ether, 20 mL, 20 mmol). The mixture was stirred at rt for 0.5 h, cooled again to 0 ° C and slowly quenched for an hour. aq. NaHCO₃ (10 ml). The resulting mixture was stirred at rt. 0.5 h, filtered and washed with elrom. The combined filtrates were dried over Na₂SC&gt; 4 and concentrated to give the title compound as a beige waxy solid (3.5 g, 100%). MS (ESI). (M + H).: 153.4; 'N \ MR (CDCl₃) b 8.06 (d, 1H, ./ = 2.4),

7.47 (dd, 1 H, 7-2.4, 8.8), 6.45 (d, 1 H,&gt; 8.8). 4.50 (s, 2 H), 3.06 (s, 6 H). 1.98 (br s, 1 H).

<img file="RS51155B_D0069.tif" />

<img file="RS51155B_D0070.tif" />

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(2 H) -2- [N- (4-chlorobenzenesullonyl) -N- (2-dimethylaminopyridin-5-yl) amino] -4-fluoro-4-methylpentanoic acid amide TFA salt (Example 459):

In a stranded solution of (2R) -2 - [(4-lilorobenzenesulfonylamino) -4-fluoro-4-methylpentanoic acid amide (prepared as in Reaction Scheme 20 or from γfluoro-D-Leu-OH methyl ester, Papageorgiu et al. Bioorg. &amp; Med. Chem. Lett. 1994. Vol. 4, pp 267272; 0.060 g, 0.18 mmol), 2-dimethylamino-5-hydroxymethylpyridine (71 mg, 0.46 mmol). triphenylphosphine (122 mg, 0.464 mmol) in OESE (9.5 mL) was added dropwise to diisopropyl azodicarboxylate (75 μ], 0.46 mmol). The resulting pale yellow solution was stirred at rt for 2 h and concentrated in vacuo. The residue was dissolved in methanol and purified by reverse phase preparative HPLC (YMC S5, ODS. MeOH-water-TFA) to give the title compound as a benium (90 mg, 85%). MS (ESI). (M + H)⁺Stk #: 457.2; 1 H NMR (CDCl 3) δ 8.11 (s, 1H), 7.95 (d. 1H. .7 = 9.6), 7.77 (d. 2H. ./=6.8), 7.51 (d, 2H. .7 = 6.8). ), 6.76 (d, 211, .7 = 9.6), 6.34 (s, 1H), 6.02 (s, 1H). 4.58 (br d. 1H. .7 = 8.4), 4.46 (d. 1H. .7 = 16.0), 4.06 (d. 1H.&gt; 16), 3.29 (s, 6H), 2.50 (m. 1H), 1.39 (rn. 1H). 1.25 (d. ZN, .7 = 22.0), 1.17 (d, ZN,&gt; 22.0)

Example of Reaction Scheme 1- solid support

<img file="RS51155B_D0071.tif" />

<img file="RS51155B_D0072.tif" />

Polymer-bonded D-Leu-NH3: FMOC-protected Rink amide resin (30 g, 0.61 mmol / g, 18 mmol) was treated with piperidine / DMF solution (250 mL). The mixture was shaken on rt for 24 h, occluded, washed with DMF (5x200 ml), SNJSE (5x200 ml) and dried under vacuum. The resin was then treated with FMOC-D-Leu-OH (22 g, 62 irnol). N-hydroxybenzotriazole hydrate (2.5 g, 18 mmol), 1,3-diisopropylcarhodiimidorn (9.8 mL, 62 mmol), and DMF (250 mL). The mixture was stirred for 20 h, drained, washed with DMF (4x200 ml), DMF-water (1: 1). 3x200 ml), DMF (3x200 ml), MeOH (3x200 ml). CIFCl · (3x200 ml) and dried. Completion of the reaction and loading of the resin-bound FMOC-D-Leu-NIl · (0.56 mmol / g) was determined by treating 52 mg of the resin with 10% (v / v) TFA / CI-FCb (2 ml) to obtain II mg FMOC-D-Leu-NFl ·. Resin-bonded

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FMOC-D-Leu-NH, was deprotected with 20% (v / v) piperidine / DMF solution (250 mL) to give polymer-bound D-Leu-Nl I? (20 g).

<img file="RS51155B_D0073.tif" />

(R) -2- (4-Chlorobenzenesulfonylamino) -4-methylpentanoic acid polymer-linked amide:

The above polymer-bound D-Leu-NIF (20 g) was treated with CH₂C1₂ (150 mL), pyridine (100 mL) and 4-chlorophenylsulfonyl chloride (20.0 g, 94.8 mmol). The mixture was shaken for 24 h, drained, washed with DMF (4x200ml), CFFCF (4x200ml) and concentrated to give the polymer-bound amide (R) -2- (4-chlorobenzenesulfonylamino) -4-methylpentanoic acid as a yellow resin (22 g ). The completion of the reaction and the filling of the resin (0.57 mmol / g) were determined by treating 50 mg of the resin with 10% (v / v) TFA / CH 2 Cl 2 (2 ml) to give 8.7 mg of amide (R) -2- (4-chlorobenzenesulfonyl atnino) -4-methylpentanoic acid.

<img file="RS51155B_D0074.tif" />

(2R) -2- [N- (4-chlorobenzenesulfonyl) -N- (4-methylbenzyl) amino [-4-methylpenic acid ”(2)?

To a mixture of polymer-linked amide (2A) -2- [N- (4-chlorobenzenesulfonyl) amino] -4-methylpentanoic acid (loading 0.45 mmol / g. 50.0 mg, 0.0225 mmol), 4-methylbenzyl bromide (44 mg, 0.24 mmol) and DMF (1.5 mL) was added 2- [tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diaza-phosphorine (0.10 mL, 0.34 mmol). The resulting mixture was triturated at rt for 2 days, then drained and washed with DMF (4x2 ml), MeOH (4x2 ml) and CHbCF (4x2 ml).

Srnola was then treated with 10% (v / v) TFA / CH₂C1₂. The mixture was shaken for 1 h, filtered and washed with CH2Cl2 (2x0.5 ml). The combined filtrates were concentrated in vacuo to give the title compound 11 as a beige solid (7.7 mg, 100%, HPLC purity&gt; 95%). IIRMS (ESI). (MH) &amp; lt; + &amp; gt; for CAolkfSCIN.O; Calcd: 407.1206, Found: 407.1201; 'N

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NMR (CDCl 3)₃) b 7.64 (d. 2Η. ./=8.0), 7.44 (d, 2N. ./=8.0), 7.22 (d, 211., / = 8.0). 7.08 (d. 211. .7 = 8.0), 6.29 (brs. 1H). 5.34 (No. p. III). 4.53 (d. III., 7 = 15.2), 4.34 (d, 111,, 7 = 15.2), 4.27 (t, 1H, .7 = 7.2), 2.32 (s, 311). 1.84 (m, 1 H). 1.30 (m, 1 H). 1.21 (m, 1 H). 0.75 (d, ZN., 7 = 6.8). 0.67 (d, 314 ../= 6.8): IR (KBr) 3467, 3367, 2956, 2869. 1694, 1670. 1340. 1160 cm -1¹.

Principle for Reaction Scheme 2

<img file="RS51155B_D0075.tif" />

(2R) -2- (4-Methoxybenzylamino) -4-methylpentanoic acid amide:

D-leucinamide hydrochloride solution (2.8 g, 16.8 mmol). and p-anisaldchide (2.29 g.

16.8 mmol) in methanol (150 mL) was treated with anhydrous ZnCP (538 mg, 5 lnrnol). The resulting suspension was then treated with NaCNBlh (1.05 g, 16.8 mmol) in portions and heated at reflux for 3 h. The reaction was cooled to rt. quenched with saturated NaHCCE, (3 mL). dilute with EtOAc (500 mL). and rinse with salt water. Concentration gave the crude benzyl amine as a white waxy substance. which was further used without purification (3.57 g. 84%). MS (ESI), (M + H +: 251.4; 1 H NMR (CDCl 3)₃) b 7.20 (d. 2H., / = 6.6). 7.10 (br s, 2 H). 6.88 (d, 2H, .7 = 8.4), 5.30 (br s, 1H), 3.80 (s, 314), 3.63 (dd, 2H,, / = 4.5, 12), 1.44-1.65 (m. ZN ), 0.95 (d, 314,, 7 = 6.3), 0.80 (d, ZN. ./=6.3).

OMe

<img file="RS51155B_D0076.tif" />

<img file="RS51155B_D0077.tif" />

(2R) -2- [N- (4-chlorobenzenesulfonyl) -N- (4-nitroxybenzyl) amino] -4-methylpentanoic acid amide (Example 1):

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(2R) -2- [N- (4-Methoxybenzyl) amino] -4-methylpentanoic acid amide (3.57 g, 14.3 mmol) was dissolved in SN₂S1₂ (100 ml) and treated with Et₃N (4.2 mL, 29 mmol) and 4-chlorobenzenesulfonyl chloride (3.6 g, 17 mmol) at rt, 18 h. The solvents were removed and taken up in EtOAc (500 mL). The organic solution was washed with NJO, brine, dried over M0SO4, and concentrated. The resulting material was then further purified by flash chromatography (SiCl 3% MeON / SN₂S1₂) to give the title compound (2.4 g) as a slightly colored solid in 40% yield. MS (ESI). (MH) &amp; lt; + &amp; gt ;: 422.9; 1 H NMR (CDCl 3) δ 7.63 (d. 2H, 7 = 7.0). 7.42 (d. 2H. .7 = 7.0). 7.25 (d, 2 H, 1 = 8.0). 6.79 (d, 2 H, δ = 8.0). 6.25 (br s, 1H), 5.35 (br s, 1 H). 4.36 (dd, 2H, 7 = 5.0. 15), 4.26 (t. 1H. 7 = 7.2). 3.78 (s. 311), 1.83 (m. 1H). 1.18-1.34 (m, 2 H), 0.75 (d. 311, 7 = 7.0), 0.67 (d, ZN. 7 = 7.0): IR (KBr) 3480, 2959, 1693, 1674, 1514, 1333, 1158 cm -1. '.

Example of Reaction Scheme 3

<img file="RS51155B_D0078.tif" />

(2A) -2- (N- (4-morpholinohexyl) -N- (4-chlorobenzenesulfonyl) amino] -4-methylpentanoic acid amide (Example 25):

(1? A) -2- [N- (4-Bramoliexyl) -N- (4-chlorobenzenesulfonyl) amino] -4-methylpenlanoic acid amide solution (Example 24: prepared as described in Reaction Scheme 1: 0.20 g, 0.44 mmol) . Et₃N (0.25 mL, 1.7 mmol), and morpholine (150 mg, 1.7 mmol) in CH₂C1₂ (2 ml) was stirred at rt for 18 h. The reaction was then concentrated to give a crude white wax which was purified by flash chromatography (Si (X 85% EtOAc / 5% hexanes / 10% MeOH) to give the title compound (112 mg) as a white solid with 54% MS (ESI), (M + H)⁺Stk #: 474.4; 1 H NMR (DMSO - &lt;/₆) b 7.82 (d, 2H. 7 = 8.0). 7.64 (d, 2 H, 7 = 8.0). 7.42 (no. 114). 6.99 (s, 1H), 4.25 (m, 1H), 3.51-3.60 (br, s, 4H).

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3.18-3.41 (m, 2Η), 2.25-2.35 (br s. 4H). 2.27 (m, 2 H). 1.15-1.62 (m, 9 H). 0.80 (d, 6H, / = 6.0).

Example of Reaction Scheme 4

<img file="RS51155B_D0079.tif" />

(2R) -2- (N- (4-chlorobenzenesulfonyl) -N- (4-aminobenzyl) amino] -4-methylpentanoic acid amide) (Example 48):

(2R) - (2- (N- (4-chlorobenzenesulfonyl)) - [1- (4-nitrobenzyl) amino] -4-methylpentanoic acid amide (Compound of Example 24; prepared as described in Reaction Scheme 1;

2.8 g, 6.6 mmol) was suspended with 10% Pd / C (1 g) and conc. HCl (1 mL) in MeOH (100 mL) and placed under a hydrogen atmosphere at 40 psi. I h. The suspension was filtered through Celite and then concentrated to give the title compound as a yellow-brown solid (2.4 g, 88% yield). MS (ESI). (M + H)⁺: 410.1: 1 N NMR (CDCl 3)₃) b 7.80 (d. 2H. ./=8.5). 7.63 (d, 2H. 7 = 8.5), 7.52 (br s. 1H), 7.46 (d. 1H, .7 = 8.0), 7.26 (d, 1H, ./=8.0), 7.02 (br s. 1H) , 4.70 (dd. 2H. ./=50, 18), 4.30-4.41 (m, 1H). 3.67 (br. S. 2H), 1.28-1.33 (m. ZN). 0.86 (d. ZN, 7 = 7.0).

0.57 (d, 311.7 = 7.0).

<img file="RS51155B_D0080.tif" />

(2R) -2- (N- (4-chlorobenzenesulfonyl) -N- (4-methylaminobenzyl) amino] -4-methylpentanoic acid amide) (Example 51):

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(2R) -2- [N- (4-Chlorobetizensulfonyl) -N- (4-aminobenzyl) amino] -4-methyl-pentanoic acid amide solution (Example 48. 400 mg. 1 mmol), El₃N (0.16 mL, 1.1 mmol). dimethylsulfate (139 mg, 1.1 mmol) in 25 mL of toluene, stirred at rt for 18 h. The reaction was concentrated, then taken up in EiOAc and washed with H₂Oh, salt water, dried over K₂CO₃ and concentrates to give a crude mixture of starting material and product. The material was further purified by flash chromatography (SiO₂, 35% EtOAc / hexanes) to give the title compound, 195 mg, 46% yield. MS (ESI). (M + H)⁺Stk #: 424.1; 1 H NMR (CDCl 3)₃) b 7.65 (d. 2H,&gt; 8.0), 7.58 (d, 2H.&gt; 8.2), 7.47 (d, 211. .7 = 8.0). 7.31 (d, 2H.&gt; 8.5). 6.24 (br. 1H). 5.16 (br s, 1 H), 4.50 (dd, 211,&gt; 50, 17). 4.27 (t, 1H,&gt; 10), 2.44 (s, 311), 1.74-1.83 (m, 111), 1.25-1.33 (m, 1H), 0.93-1.01 (m, 1H), 0.74 (d. ZN. &gt; 7.0), 0.63 (d, 311,&gt; 7.0).

<img file="RS51155B_D0081.tif" />

(2R) -2-N- (4-chlorobenzenesulfonyl) -N- (4-dimethylaminobenzyl) amino] -4-yl] ethylpentanoic acid amide (Example 65):

(2R) -2 - ['N- (4-chlorobenzenesulfonyl) -N- (4-aminobenzyl) amino] -4-methyl-pentanoic acid amide (Example 48, 0.10 g, 0.22 mmol) was dissolved in DMF 5 ml). Iodomethane (62 mg, 0.44 mmol) was added to this solution. and cesium carbonate (220 mg, 0.66 mmol). The reaction was then stirred at 40 ° C for 18 h. The reaction was poured into EtOAc and water. The organic part is collected. dried over MgSO₄, and concentrates in an oily residue. The residue was further purified (Biotagc 40S, charged in CH 2 Cl 2)₂CI₂, eluted in 25% EtOAc / hexanes) to give a yellow powder (15 mg, 16%). MS (ESI). (M + H)⁺Stk #: 438.1; 1 H NMR (DMSO-&gt; δ 7.74 (dd. 2H.&gt; 1.9. 6.7), 7.54 (dd, 2H,&gt; 1.9. 6.8), 7.43 (s. 1H), 7.16 (d.2H.&gt; 8.6). 7.01 (s, 1H), 6.61 (d, 2H,&gt; 8.8), 4.59 (q, 2H,&gt; 16.25), 4.34 (dd, 1H,&gt; 5.0, 9.3), 2.85 (s, 6H), 1.27-1.47 (m. ZN). 0.80 (d. 311, .7 = 5.9). 0.52 (d, 3ΙΟ6.1).

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Example for Reaction Scheme 5

<img file="RS51155B_D0082.tif" />

N - [(R) -1-carbamoyl-3-methyl-butyl] -N- (4-chlorobenzenesulfonyl) amino) acetic acid tert-butyl ester (Primcr 46):

(2R) -2- (4-Chlorobenzenesulfonylamino) -4-methylpentanoic acid amide (3.00 g, 9.87 mmol) was dissolved in DMF (50 mL). Potassium carbonate (6.0 g, 39 nimol) and bromoacetic acid tert-butyl ester (6.0 g, 39 mmol) were added to the solution. The solution was heated at 70 ° C for 3 h. The reaction was quenched with EtOAc; saturated NaHCO₃. The organic layer was washed with brine, dried over MgSO 4₄, and concentrates. The crude oil was further purified on Biotage 40M (packed in CHiCE, eluted in 25% ElOAc / hexanes) to give a white powder (1.2 g, 35%). MS (ESI), (M + H)⁺: 446.3: 1 N NMR (CDCl 3)₃) b 7.76 (2 2H,&gt; 8.0). 7.52 (d, 2H, 7 = 8.0).

6.61 (br. S. 1H), 5.45 (s, 1H), 4.15-4.18 (m. 1H), 3.09-3.24 (m, 2H). 2.50-2. 58 (m, 4H). 2.31-2.39 (m, 2H), 1.92-1.99 (m, 1H), 1.15-1.59 (m, 8H), 1.00-1.04 (m, 711). 0.71-0.74 (m. 611).

<img file="RS51155B_D0083.tif" />

N - [(1R) -1-carbamoyl-3-methyl-butyl] -Nⁱ- (4-chlorobenzenesulfonyl) aminoacetic acid (Example 59):

Trifluoroacetic acid (15 ml) was added to a solution of [N - [(1R) -1-carbamoyl-3-methyl-butyl] -N- (4-chlorobenzenesulfonyl) amino} acetic acid tert-butyl ester (0.50 g. 1.2 mmol) in S11₂C1₂ (15 ml). The reaction was stirred at rl for 4 h. The reaction was then concentrated to a solid (0.40 g, 92%), which was used without further purification. MS (ESI). (M + H) &amp; lt; + &amp; gt ;: 363.1; 1 H NMR (DMSO-t /₆) b 7.90 (dd. 2H. 7 = 2.0. 6.8). 7.65 (dd, 2H, 7 = 2.0, 6.8), 7.60 (s).

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1Η), 7.06 (p. 1 Η), 4.32 (d. 111.7 = 18). 4.12 (1. 1 Η. .7-8.0). 4.02 (d. IH ../= I8), 1.55-1.65 (m. III). 1.35-1.45 (m, 2H), 0.78 (d, ZN. 7 = 6.1), 0.73 (d. ZN, 7 = 6.1).

<img file="RS51155B_D0084.tif" />

<img file="RS51155B_D0085.tif" />

(2R) -2- [N- (4-chlorobenzenesulfonyl) -N- (cyclopropylcarbanioylmethyl) amino] -4-methylpentanoic acid amide (Example 88):

To a solution of {N - [(1R) -1-carbamoyl-3-methyl-butyl] -N- (4-chlorobenzenesulfonyl) amino [acetic acid) (Example 59. 175 mg, 0.480 mmol). cyclopropylamine (41 μL, 0.58 mmol) in CH 2 Cl 2 (3 mL) was added 1-hydroxybenzotriazole (47 μg, 0.72 mmol). and 1.3 dicyclohexylcarbodiimide (144 mg. 0.720 mmol). The reaction was stirred at rt for 18 h. and then poured into an EtOAc / water mixture. The organic layer was separated. dried over MgSO₄, and concentrates into a clear oil residue. The residue was further purified by Biotage 40C (eluted in 40% EtOAc in hexanes) to give a white solid (54 mg, 29%). MS (ESI). (M + H) &amp; lt; - &amp; gt ;; 402.2 ; 1 H NMR (CDCl 3 500 MHz) δ 7.85 (dd. 211. .7-1.9. 8.9). 7.50 (dd. 211, .7 = 2.0, 8.7), 7.40 (br s, 1H), 6.55 (brs, 1H), 6.30 (brs, 1H), 4.23 (dd. 111..7 = 2.9, 8.9). 3.92 (d, 114, .7 = 17), 3.83 (d, 1H, 7 = 17), 2.68-2.73 (m, 1H), 1.75-1.83 (m, 1H). 1.50-1.57 (m, 111), 1.40-1.49 (m, 1H). 0.88 (d, ZN, .7 = 6.4), 0.87 (d. ZN. , 7 = 6.7), 0.80 (d. 211.7'7.0), 0.51 (t. 2H, .7 = 4.0).

Example of Reaction Scheme 6

<img file="RS51155B_D0086.tif" />

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4 - {[N - ((R) -1-Carbamoyl-3-methyl-butyl) -N- (4-chlorobenzenesulfonyl) amino] -methylbenzoic acid (Example 89)

A solution of the compound of Example 61, 4 - {[N - ((R) -1-carbamoyl-3-methylbutyl) -N- (4-chlorobenzenesulfonyl) amino] -methyl} benzoic acid [methyl ester. 354 mg, 0.782 mmol] was dissolved in methanol (4 mL). A solution of 5N NaOH (1 ml) was added, followed by an amount of TH1 · '(1 ml) sufficient to achieve homogeneity. After 1 h, an additional aliquot of 5N NaOH (1 mL) was added, and stirring was continued for 2.5 h. The solution is acidified to pH = 2. with IN IICl and extracted with CHCl3 (2x). The combined organic layers were dried and concentrated to give a white solid (343 mg, 100%) MS (ESI), (M + H)⁺Stk #: 439.17; 1 H NMR (CDCl 3, 300 () b 7.91 (d. 2H, .7 = 8.2). 7.81-7.84 (m. ZN). 7.56 (d, 2H, ./=8.6), 7.49 (d, 2H,, 7 = 8.2). 6.55 (no. S. 1H). 5.10 (d. 1H, ./=15.4). 4.23 (dd, 1H. 7 = 4.6. 9.7), 4.05 (d. 111.7 = 15.4). 2.04-2.14 (m, 1H), 1.20-1.31 (m, 1H), 0.80-0.89 (m, 1H). 0.74 (d. ZN. 7 = 6.6). 0.68 (d. ZN. 7 = 6.6).

<img file="RS51155B_D0087.tif" />

(2R) -2- {N- (4-chlorobenzenesulfonyl) -N- [4- (morpholine-4-carbonyl) -benzyl] amino} -4-methyl-pentanoic acid amide (Primer10);

To a solution of 4- {fN - ((1A) -1-carbamoyl-3-methyl-butyl) -N- (4-chlorobenzenesulfonyl) amino] methyl} benzoic acid (50.0 mg, 0.114 mmol) in DMF (0.3 ml) was cooled. at 0 °. added morpholine (12.9 mg, 0.148 mmol), followed by 1-hydroxybenzotriazole (18.5 mg. 0.137 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (26.2 mg. 0.137 mmol), and / / PnNEt (26 μΐ 0.15 mmol). After 2 h, the solution was warmed to rt. After 4 h. the solution is poured into 10% aq. citric acid and extracted with EtOAc (2x). The combined organic layers were washed sequentially with water for an hour. aq. NaHCO₃. then dried (MgSO₄) and concentrate. Flash column chromatography (SiO 2: 40 to 100% EtOAc / hexanes) afforded the title compound as a white solid (46.0 mg, 79%). MS (ESI). (M + H) &amp; lt; + &amp; gt ;: 508.22;^l1 H NMR (CDCl 3, 300 () b 7.68 (d, 2H, 7 = 8.6). 7.29-7.47 (m. 614). 6.38 (br s, 114). 5.75 (No. p. 114). 4.65 (d.

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Η, ./-16.0), 4.42 (d. 1Η. ./-16.0), 4.32 (0 111. ./-7.5). 3.30-3. 85 (br m, 8H). 1.69-1.78 (m,

1H). 1.28-1. 37 (m, 1H), 1.08-1.14 (m, 1 H). 0.76 (d, ZN. .7 = 6.5). 0.63 (d. ZN. ./=6.6).

Example of Reaction Scheme 7

<img file="RS51155B_D0088.tif" />

(fcr) -butyl ester 4-_t^frN - ((R) -1-Carbamoyl-3-methyl-butyl) -N- (4-chlorobenzenesulfonyl) aminomethyl} -piperidine-1-carboxylic acid (Example 92):

To a solution of (2R) -2- (4-chlorobenzenesulionilamino) -4-inethylpentanoic acid amide (4.2 g, 14 mmol) in DMF (50 mL). cesium carbonate (13.6 g, 417 mmol) was added. To this reaction was added 4- (toluene-4-sulfonyloxymethyl) -piperidine-1-carboxylic acid tert-butyl ester (ref: Gilissen. C .. Bormans. G .. Ge Groot, T „Verbruggen, AJ Labeled Cmpd. Radiopharm. 1999, 42. 1289; 10.4 g, 282 mmol). The reaction was stirred at 70 ° C for 18 h. The reaction was then quenched for an hour. aq. NaHCO₃ and extracted with EtOAc. The organic layer was collected, washed with brine, dried over MgSO 4₄. and concentrated to a clear oil. The oil was then purified on Biotage 40C (eluted with 30% EtOAc in hexanes) to give a white solid (3.0 g, 44%). MS (ESI), (M + H)⁴: 502.1: 1 H NMR (DMSO4, 500 500) b 7.86 (dd, 2H, ./=2.0, 6.8), 7.65 (dd, 2H, .7-2.0. 6.8), 7.37 (br s. 1H). 7.07 (no. 1H). 4.19 (0 1H, ./=7.6). 3.92 (br s, 2 H), 3.35 (dd, 1 H, 7-15, 6.8), 3.05 (dd, 1 H, .7 = 15, 8.1). 1.85 (br s, 111), 1.50-1.70 (m, 4H), 1.38 (s, 9H), 1.10-1.20 (m, 1H), 0.80-1.00 (m, 311). 0.82 (d, 6H, .7 = 7.6).

<img file="RS51155B_D0089.tif" />

51155 Β

(2R) -2- [N- (4-chlorobenzenesulfonyl) -N- (piperidin-4-ylmethyl) amino] -4-inethyl-pentanoic acid amide (Example 126):

In 4 - {[N - ((1H) -1-carbamoyl-3-methyl-bulyl) -N- (4-chlorobenzenesulfonyl) amino] -rnetyl} -piperidine-1-carboxylic acid solution / e-butyl ester 92, 2.6 grams.

5.2 mmol) in SNJSE (25 ml) was added trifluoroacetic acid (10 ml). The reaction was stirred at rt for 1 h and then concentrated to give a white solid (1.6 grams. 84%). %). MS (ESI), (MH): 402.15; 1 H NMR (DMSO-A 500 () b 7.87 (d, 2H. ./=8.5), 7.66 (d. 2H, 7 = 8.6), 7.41 (s, 1H). 7.04 (s, 1H). 4.17 (ι. 1H. 7 = 7.3), 3.40-3.50 (m, 111). 3.20-3.25 (m, 1H). 3.03-3.10 (m, III), 2.65-2.80 (m, 2H). 1.85-2. 00 (m, 1H). 1.20-1. 85 (m, 2H), 1.45-1.60 (m, 1H), 1.30-1.40 (m, 1H), 1.10-1.30 (m, 4H). 0.75-0.90 (м. 1H), 0.82 (d, ZN, 7 = 7.3), 0.80 (d, ZN, 7 = 7.0).

<img file="RS51155B_D0090.tif" />

(2R) -2- {N- (4-Chlorobenzenesulfonyl) -N- [1- (pyridine-4-carbonyl) -piperidin-4-ylmethylamino} -4-methyl-pentanoic acid amide (Example 278):

To a solution of amide (2H) -2- [N] (4-chlorobenzenesulfonyl) -N- (piperidin-4-ylmethyl) amino] -

4-methyl-pentanoic acid (Prirner 126, 0.10 g. 0.22 mmol) and Et₃N (0.06 mL, 0.5 mmol) in SNgSE (3.0 mL) was added isonicotinoyl chloride hydrochloride (56 mg. 0.32 mmol). The reaction was stirred at rt 18 h and poured into EtOAc for one hour. aq. NaHCO₃. The organic solution was separated and washed with brine. dried over MgSO₄ and concentrated to an oily residue. The residue was purified on Biotage 10Μ (eluted with 80% EtOAc / hexanes) to give a white solid (36 mg, 30%). MS (ESI). (M + H 0: 509.20: 1 H NMR (CDCl 3, 500 500) b 8.66 (br s, 2H), 7.80 (d, 1H, 7 = 8.6), 7.73 (d, 2H, 7 = 8.5), 7.51 (d .2H, 7 = 7.6 (7.41 (br s. 1H), 6.64 (br s. 1H), 5.35 (br s. 1H). 4.70 (br s. 1H), 4.10 (br s. 1H). 3.71) br s 1H (3. s) 1.02 (dd, 2H, 7 = 4.8, 16), 2.70-2.85 (br s, 1H), 1.50-2.09 (m, 5H), 1.18-133 (m , 4H), 0.73 (d, ZN. 7 = 6.7). 0.68 (d. ZN. 7 = 6.5).

51155Β

<img file="RS51155B_D0091.tif" />

Phenethylamide 4-ylN - ((1R) -1-carbamoyl-3-methyl-butyl) -N^:- (4-chlorobenzenesulfonyl) amino] methyl] -piperidine-1-carboxylic acid (Example 256):

To a solution of amide (2R) -2- [N- (4-chlorobenzenesulfonyl) -N- (piperidin-4-ylmethyl) amino] -

4-methyl-pentanoic acid (Example 126, 0.10 g. 0.22 inmol) and Et₃N (32 μΐ, 0.25 mmol) in SNJSE was added (2-isocyanato-ethyl) -benzene (0.040 mL, 0.30 mmol). The reaction was stirred at rt for 18 h. and then pour in an hour. aq. NaHCO₃ and extracted with EtOAc. The organic layer was washed with brine. dried over MgSO₄, and concentrates in an oily residue. The residue was further purified on a Biotage system (eluted with 75% EtOAc / hexanes) to give the desired product as a white solid (67 mg, 52%). MS (ESI), (M + H) &amp; lt; + &amp; gt ;: 549.00; 1 H NMR (CDCl 3)₃, 500 MHz) b 7.71 (d, 2H. .7 = 8.6). 7.71 (d, 2H, .7 = 8.9). 7.15-7. 35 (m, 5H). 6.64 (s, 1H). 5.86 (s, 1H), 4.15 (dd, 1H, 7 = 5.2, 9.5). 3.88 (d, 1H, .7 = 13). 3.76 (d, 1H, .7 = 13). 3.46 (t, 211.7 = 6.7), 3.21-3.29 (m, 1H), 2.97 (dd, 1H, .7 = 4.6, 14), 2.65-2.85 (m, 4H), 1.75-1.95 (m, 3H). ), 1.00-1.30 (m, 5H). 0.75-0.80 (m, 1 H), 0.72 (d. ZN, 7 = 6.7). 0.67 (d. ZN. 7 = 6.7).

<img file="RS51155B_D0092.tif" />

51155 Β

(2R) -2- (N- (4-Chlorobenzenesulfonyl) -N- {1- [2- (4-cyanophenyl-2-oxo-ethyl-piperidin-4-ylmethyl} -amino) -4-methyl-pentanoic acid amide ” Example 286):

In (2R) -2- [N- (4-chlorobenzenesulfonyl) -N- (piperidin-4-ylmethyl) amino] amide solution

4-methyl-pentanoic acid (Example 126, 0.050 g. 0.12 mmol) and Et₃N (0.040 mL, 0.30 mmol) in SN 2 SE (2.0 mL) was added 4- (2-chloroacetyl) -benzonitrile (55 mg, 0.30 mmol). The reaction was stirred at rt for 18 h and then concentrated to a residue. The residue was purified by 11a Biotage system (eluted with 80% EtOAc / hexanes) to give 29 mg (48%) of the desired product as a white solid. MS (ESI). (M + N /: 545.16; 11 NMR (CDCl 3)₃, 500 MHz) b 7.72 (d. 2H, ./ 8.5). 7.50-7.65 (m, 2 H), 7.50 (d, 211,&gt; 7.0). 7.35-7. 45 (m, 2H), 6.67 (s, 1H). 5.32 (s, 1H), 4.14 (dd, 114, .7 = 5.0. 9.0), 3.52 (br, s, 1H), 3.28 (t, 1H, .7 = 14), 2.97 (dd, 1H,&gt; 3.5, 14),

2.82 (brs, 1H), 1.00-2.00 (m, 10Η), 0.71 (d, 311,&gt; 6.5), 0.66 (d, ZN., 7 = 6.5).

Example of reaction scheme 8

<img file="RS51155B_D0093.tif" />

(2R) -2- {N- (4-Chlorobenzenesulfonyl) -N- [4- (tetrahydro-pyran-2-yloxymethyl-benzyl] amino] -4-methyl-pentanoic acid amide:

(2R) -2- (4-Chlorobenzenesulfonylamino) -4-methylpentanoic acid amide (6.35 g. 196 mmol), Cs₂CO₃ (5.62 g, 196 mmol). ί 2 - ((4-bi-methylmethyl) benzyl] oxy) tetrahydropyran (5.62 g. 196 mmol) in acetonitrile (200 ml) was heated at reflux for 1 h. The reaction was filtered hot. by suction through Celite. The filtrate was significantly reduced to a white foam (9.5 g, 96%). Rela is used as such in the following reaction. MS (ESI), (M + H)⁺Stk #: 510.9; 1 H NMR (CDCl 3)₃) b 7.83 (d. 211, .7 = 8.0), 7.75 (d. 214., 7 = 8.0). 7.39 (d, 2 H,&gt; 8.0). 7.24 (d, 2H,&gt; 8.0). 6.25 (br s, 1 H). 5.35 (br s, 1 H), 4.82 (d, 1 H,, 7)_ab= l 2). 4.65 (m, 1 H). 4.52 (d. 1H,, 7_ab= 12). 4.30 (d. 1H., 7_ab= 16). 4.20 (d, 1H, .7_ab= 16), 3.74 (m, 2H), 3.46 (m, 111), 1.89 (m, III), 1.66 (m, 614), 0.97 (d, 311).

&gt; 7.0), 0.94 (d. 311..7 = 7.0).

51155 Β

<img file="RS51155B_D0094.tif" />

(2R) -2- (N- (4-chlorobenzenesulfonyl) -N- (4-hydroxymethyl) -benzylamino] -4-tripentyl pentanoic acid amide) (Example 95):

To a solution of (2R) -2- [N- (4-chlorobenzenesulfonyl) -N- [4- (tetrahydropyran-2-yloxymethyl) benzylamino] -4-methyl-pentanoic acid amide (9.5 g, 186 mmol) in methanol (200 ml) , a catalytic amount of p-toluenesulfonic acid is added. The mixture was stirred overnight at rt. The solvent was removed in vacuo. The resulting foam was dissolved in CIFCF (100 mL), washed with 1N NaOH, FFO, brine, and dried over MgSCH. The filtrate solvent was removed in vacuo. The resulting foam was crystallized from hot hexane to give the product as a white solid (7.7 g) in 92% yield. MS (ESI). (M + H)¹ 425.17, ^!1 H NMR (CDCl 3)₃) b 7.68 (d, 2H, ./=7.0). 7.46 (d, 2H, ./=7.0), 7.33 (d, 2H.

5.35 (br s, 111), 4.67 (br s, 211). 4.59 (d, 1 H,_ab= 16), 4.37 (d, 1H ../)_ab= 16). 4.26 (t, 1 H, 7.0),

1.86-1. 80 (m, 2H), 1.34-1.28 (m, 111). 1.16-1.10 (m. Lll). 0.96 (d, 311. .7 = 7.0), 0.93 (d, 311.

.7=7.0).

<img file="RS51155B_D0095.tif" />

4-N- (1R) -1-Carbamoyl-3-methyl-butyl) -N- (4-chlorobenzenesulfonyl) -aminol-methyl. methanesulfonic acid ester -benzyl:

To a stirred solution of (2A) -2- [N- (4-chloro-benzenesulfonyl) -N- (4-hydroxymethylbenzyl) amino] -4-methyl-pentanoic acid amide (1.5 g, 3.5 mmol) in CFECF (15 mL) cooled to 0 ° C, Et₃N (0.74 mL, 5.3 mmol). A solution of methanesulfonyl chloride (0.29 mL, 3.5 mmol) in 5 mL of CI ECF was added dropwise and the reaction was allowed to stir at 0 ° C for 1 h. Reactionary

51155 Β Dilute the mixture with 25 ml of CH₂C1₂, washed rapidly with 1N HCl, brine, and dried by conducting the organic phase through a cotton plug. The solvent was removed in vacuo to give the title compound in quantitative yield. The resulting foam is used as such in subsequent reactions. MS (ESI), (M-95)⁺ 409.15, Ϊ1 NMR (CDCl 3)₃) b 7.70 (d, 2H. .7 = 8.0). 7.48 (d, 2H, 7 = 8.0), 7.41 (d, 2H, .7 = 8.0), 7.38 (7, 2H, .7 = 8.0), 6.27 (br s. 1H), 5.32 (br s, 1H) . 5.24 (s, 2H), 4.64 (d, 1H, 7)_ab= 16), 4.43 (d. 1H. 7_ab= 16). 4.33 (m, 1H, .7 = 6). 2.90 (s. ZN). 1.90 (m, 1 H), 1.60 (m, 2 H), 0.96 (d, ZN, 7 = 7.0). 0.91 (d. 3I I. 7 = 7.0).

<img file="RS51155B_D0096.tif" />

<img file="RS51155B_D0097.tif" />

(2R) -2- (N- (4-Chlorobenzenesulfonyl) -N- (4-dimethylaminomethyl-benzyl) amino] -4-methylpentanoic acid amide) (Example 110):

LJ Mixed 4 - {[N - ((R?) - 1-carbamoyl-3-methyl-butyl) -N- (4-chlorobenzenesulfonyl) amino] -methyl} -benzyl-ester methanesulfonic acid solution (150 mg, 0.298 mmol) ) in (3 ml) CH₂CI₂ at 0 ° C add 1 equivalent of Et₃N. followed by dimethylamine (0.3 ml, 2M in THF). The reaction was stirred overnight at rt. The mixture was diluted with CH₂CI₂. wash with H₂O. salt water, dried over MgSO₄ and concentrates to give an amber glassy substance. Purification by flash chromatography (Si ()₂, 1 ()% MeO11 / CII₂C1₂) gave the title compound (95 mg), in 71% yield. MS (ESI). (M + H)¹ 452.23. 1 H NMR (CDCl 3)₃) b 7.94 (d, 211. 7 = 8.0), 7.74 (d, 2H, 7 = 8.0), 7.63 (d. 2H.&gt; 8.0). 7.38 (d, 2H, 7 = 8.0). 6.23 (br s, 1 H). 5.35 (br s, 1 H), 4.22 (d. 1 H, 7_{; ib}= l6). 4.14 (d, 1H, 7_ab= 16). 3.28-3.23 (m, ZN). 2.17 (br. P. 6H), 1.95 (m. 1 Η). 1.55 (m, 2 H). 0.96 (d. ZN. 7 = 7.0), 0.93 (d, ZN., 7 = 7.0).

Example of Reaction Scheme 9

51155 Β

<img file="RS51155B_D0098.tif" />

(2A) -2- [N- (4-Acetylaminobenzyl) -N- (4-chlorobenzenesulfonin-aminol-4-methylpentanoic acid amide) (Primcr 163):

Solution of the compound of Example 48 [(2R) -2- [N- (4-chlorobenzenesulfonyl) -N- (4-aminobenzyl) amino] -4-methyl-pentanoic acid (250 mg. 0.60 mmol)] and Et₃N (120 mg, 1.2 mmol) in S1ESE (20 mL) was treated with acetyl chloride (56 mg, 0.72 mmol). After stirring for 18 h. the reaction was concentrated, chromatographed using flash chromatography on silica gel (1% methanol / SNJSE) to give the title compound (110 mg, 41%). MS (ESI). (MH) &amp; lt; + &amp; gt; 422.9, 1 HNMR (CDCl3.0 b 7.67 (d, 2H, 7 = 8.0), 7.28-7.46 (m, 6H), 7.12 (br s, 1H), 6.24 (br s, 1H), 5.19 (br s. 1H), 4.48 (dd, 2IL, 7 = 50, 15), 4.27 (t, 1H. .7 = 7.0), 2.18 (s, ZN), 1.80-2.01 (m, 1H), 1.12 -1.32 (m, 2 H), 0.75 (d. ZN. , 7 = 7.0), 0.67 (d, ZN, .7 = 7.0).

<img file="RS51155B_D0099.tif" />

<img file="RS51155B_D0100.tif" />

o

J ^ / NMe₂

(2R) -2- [N- (4-Chlorobenzenesulfonyl) -N- (4 - [([(2-dimethylamino-acetyl)) -methyl-amino] methyl-benzyl) -amino] -4-methyl-pentane amide acid (Example 272):

(2R) -2- [N- (4-Chlorobenzenesulfonyl) -N- (4-methylaminomethyl-benzyl) -amino] -4-methyl-pentanoic acid amide (75 mg, 0.17 mmol), (α-dimethylamino) acetic acid (18) mg.

0.17 mmol). 1-hydroxybenzotriazole (24 mg, 0.17 mmol). and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (33 mg, 0.17 mmol) were combined in 3 mL of SNCl and stirred overnight. The reaction mixture was diluted with 5 mL of CI ECP and washed with 1N NaOH and brine. The organic phase was dried by filtration through a pad and the solvent was removed in vacuo.

51155 Β

Purification by preparative 1IPLC gave the title compound (61 mg) in 68% yield. MS (ESI), (M + NG 523.4. 1 H NMR (CDCl 3) δ 8.02 (d, 2H. .7 = 8.0). 7.71 (d. 2H. .7 = 8.0). 7.37 (d, 2H,, / = 8.0), 7.28 (d. 2H., / = 8.0), 6.23 (br. S. 111). 5.51 (br. S, 1H), 4.46 (s. 2H), 4.70 (d. 1H. J)_ab= 16), 4.33 (d. 111, Jab = 16), 3.25 (t. II I. ./=6.0), 2.69 (s. ZN), 2.63 (s, 2H), 2.20 (s. 6H), 1.95 (m, 1 H), 1.60 (m, 214), 0.98 (d, 311, / 7.0). 0.94 (d, ZN. ./=7.0).

<img file="RS51155B_D0101.tif" />

(2R) -2- [N- (4-chlorobenzenesulfonyl) -N- (2-dimethylaminopyridin-5-ylmethyl) amino] -4-methylpentanoic acid amide TFA salt: (Example 254):

(2R) -2- (N-4-Chlorobenzenesulfonyl) -N- (2-chloropyridin-5-ylmethyl) amino] -4-methylpentanoic acid amide solution (prepared according to Reaction Scheme 1.18 mg, 41 mmol) in dimethylamine / THF (2M, 20 mL, 40 mmol) was stirred at 95 ° C. 30 h, in court under pressure. Five ml of the reaction mixture (25% of the total reaction volume) was purified by reverse phase preparative HPLC (YMC S5. ODS, MeOH-water-1'FA) to give the title compound as a white foam (17 mg, 30% yield). (IRMS). (MH) &amp; lt; - &amp; gt; for C20H26SCIN4O5 calc .: 437.1426. found: 437.1420: 1 N NMR (CDCl 3) δ 8.04 (s. 1H), 8.03 (d. 1H. .7 = 9.8).

7.76 (d. 211, ./=7.6), 7.54 (d, 211. ./=7.6), 6.83 (d. 1H, ./=9.8), 6.62 (br s. 1H), 6.40 (br s. 1H) ), 4.64 (d, 111, ./=15.9). 4.29 (m, 1 H). 4.18 (d. 1H. ./=15.9), 3.30 (s, 6H), 1.84 (ιη. 1H). 1.29 (m, 1H), 0.93 (m, 111), 0.77 (d. 311,, / = 6.5). 0.72 (d. ZN. ./=6.5).

Example of Reaction Scheme 11

51155 Β

<img file="RS51155B_D0102.tif" />

(2R) -2- [N- (4-Allyloxy-3-fluorobenzyl) -N- (4-chlorobenzenesullonyl) amino] -4-methyl-pentanoic acid amide:

To a solution of amide (2R) -2- (4-chlorobenzenesulfonylamino) -4-methyl-pentanoic acid (1.00 g. 3.29 mmol), and CS2CO3 (1.29 g. 3.95 mmol) in DMF (25 ml) was added 1 - allyloxy-4-bromomethyl-2-fluorobenzene (ref: Graham. Sarnuel. L. e / al. F.ur. Pat. Appl. (1992): FP 487270: 0.88 g, 3.67 mmol). The resulting solution was stirred at rt for 18 h. The reaction was then diluted with 9: 1 EtOAc: hexanes (350 mL) and washed with IEO (4x200 mL). salt water and dried over Na₂SO₄, to give the title compound (393 mg) as a white solid in 26% yield. MS (ESI), (M + -N / 469.1. 1 H NMR (CDCl 3)₃) b 7.66 (d, 2H. 7 = 8.1), 7.45 (d. 211.

Δ = 8.1), 7.11 (d, 1H, 7 = 12.0), 6.98 (m, 1 H). 6.84 (t, 1 H, J = 8.0). 6.22 (br s, 1 H). 6.04 (m.

211). 5.42 (m, 111), 5.16 (br s, 1H), 4.59 (m, 2H). 4.40 (m. ZN). 1.83 (m, 1 H). 1.32 (m, 1 H).

1.14 (m, 1 H), 0.76 (d. ZN, 7 = 7.0), 0.68 (d. 311.7 = 7.0).

<img file="RS51155B_D0103.tif" />

(2R) -2- {N- (4-Chlorobenzenesulfonyl) -N-13-fluoro-4- (2-morpholin-4-yl-ethoxy) -benzyl] amino} -4-methyl-penlanic acid amide (Example 427) ):

Mixture of allyloxy intermediate (0.39 g, 0.84 mmol), bitter, osmium tetraoxide (0.01 g, 0.04 mmol). and trimethylamine-N-oxide (0.140 g, 1.81 mmol) was dissolved in acetone (10 mL) and stirred for 4 h at rt. The solution was concentrated in vacuo and redissolved in 1.5: 1 dioxane: H₂O (15 ml). Sodium periodate (0.22 g, 1.0 mmol) was added and the solution was stirred at rt for 18 h. Reaction

51155 (Was then diluted with EtOAc (200 mL) and washed with (₂θ · salt water, dried over Na₂SO₄ and concentrates to give (2R) - {N- (4-chlorobenzenesulfonyl) -N- [3-fluoro-4- (2-oxo-ethoxy) benzyl] -amino} -4-methyl-pentanoic acid amide as a crude solid beige substances. This crude material was introduced to the next step without further purification. (2A) -2- {N- (4-Chlorobenzenesulfonyl) -N- [3-fluoro-4- (2-oxo-ethoxy) -benzyl] -amino) -4-methyl-pentanoic acid amide (0.16 g, 0.34 mmol) and morpholine (0.090 g, 1.0 mmol) were dissolved in EtOH (5 mL) and heated to 80 ° C for approximately 15 min. The oil bath was removed and sodium triacetoxyborohydride (0.290 g, 1.36 mmol) was added and the paste was stirred at rt for 16 h. The solution is concentrated to dryness, taken up in brine. extracted with EtOAC (2x100 mL), dried over NaoSO 4, and concentrated in vacuo to give a crude orange residue. Further purification Prep. HPLC (20x100 mm YMC S5 ODS C-18 column, 25 ml / min. 0-100% MsON / NJO 0.1% TFA 15 min) gave the TFA salt of the title compound (69.5 mg) as a pale yellow solid with 31% yield. [a]_D +23 (c. 6.4. CIFCF): LCMS (M + II) * 542.25, 1 H NMR (CDCl 3) δ 7.71 (d, 2H, .7 = 8.0), 7.50 (d. 2H, 7 = 8.0) , 7.16 (d, 1H, 7 = 12.0), 7.05 (d, 1H, 7 = 8.0), 6.87 (t. 114,. / = 8.0), 6.38 (br s, 111), 5.91 (br s, 111) , 4.41 (ABq. 2H, 7 = 16, 7 ^ = 176).

4.45 (m, 2H), 4.27 (m, 1H, 7 = 8.0), 4.03 (m, 4H), 3.70 (m, 2H), 3.51 (m, 2H). 3.10 (m, 2 H),

1.83 (m, 111), 1.29 (m, 111), 1.05 (m, 1H). 0.75 (d, ZN, 7 = 8.0), 0.68 (d, ZN, 7 = 8.0).

Example of Reaction Scheme 12

<img file="RS51155B_D0104.tif" />

(2R) -2-N- (4-Chlorobenzenesulfonyl) -N- [4- (1-hydroxy-1-methyl-ethyl) -benzyl] -amino] -4-methyl-pentanoic acid amide (Example 287):

Solution of the compound of Example 61 [4 - {[N - ((1R) -1-carbamoyl-3-methylbutyl) -N- (4-chlorobenzenesulfonyl) amino] -methyl} -benzoic acid methyl ester, 101 mg, 0.221 mmol] cool to 0^sS 'in THF (2 ml). Methyl magnesium bromide solution (I.4M in toluene / THF,

51155 Β

0.50 ml. 0.71 mmol) was added dropwise. The dark yellow solution was stirred at 0C. and after 30 min. more methyl magnesium bromide solution (0.25 mL, 0.353 mmol) was added. After 1 h. the solution is allowed to warm to rt. After 3.5 h, the reaction was quenched by the addition of one hour. aq. N1CS1. and the mixture was extracted with EtOAc (2x). The combined organic layers were dried (Na₂SO₄) and concentrate. Flash column chromatography (SiO₂. 20 to 100% EtOAc / hexanes gave the title compound as a white foam (62 mg, 62%). MS (ESI), (M + H)⁺ 453.16, 114 NMR (CDCl 3)₃, 300 MHz) b 7.61 (d, 2H. 7 = 8.7), 7.40 (d, 2H,, / = 8.7), 7.37 (d. 2H. ./=8.4), 7.26 (d, 2H, 7 = 8.4) , 6.28 (brs, 1Η), 5.25 (br s. 1H), 4.49 (d. 114.7 = 15.9), 4.41 (d, 1H, 7 = 15.9), 4.33 (t, 111.7 = 6.6). 1.73-1. 80 (m, 1H). 1.55 (s, 6H). 1.28-1. 35 (m, 1H). 1.20-1.25 (m, 111) .0.77 (d, 314.7 = 6.5), 0.66 (d, 3H, 7 = 6.6).

Example of Reaction Scheme 13

<img file="RS51155B_D0105.tif" />

(2R) -2- {N- (4-Chlorobenzenesulfonyl) - [4- (5-methyl- [1.3.4] oxadiazol-2-yl) -benzyl] amino} -4-methyl-pentanoic acid amide (Primcr 436):

Step 1: Solution of the compound of Example 61 [4 - {[N - ((1H) -1-Carbamoyl-3-methyl-butyl) -N- (4-chlorobenzenesulfonyl) amino] -methyl} -benzoic acid methyl ester. 0.500g, 1.10 rnniol] was diluted with methanol (10 mL) and hydrazine (2 mL) was added. The starting material slowly dissolves over 5 min. After 30 min. the solution is heated to reflux. After 10 p.m. the solution is cooled to rt. Water (15 nil) was added. and white precipitates are formed. The mixture was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated to give the corresponding acyl hydrazide as a white beet, which was further introduced into the cyclization step without purification.

51155 Β

Step 2: The crude acyl hydrazide (0.150 g, 0.331 mmol) was dissolved in pyridine (2.2 mL) and ethyl acetimidate hydrochloride (60 mg 0.364 mmol) was added. The mixture was heated at reflux for 1.25 h. The solution was cooled to rt and concentrated to remove pyridine. The residue was taken up in EtOAc, and washed sequentially. water, 1N HCl (2x), sat. aq. NaHCO₃, and salt water. The solution was dried (MgSO 4)₄) and concentrates. Flash chromatography and columns (SiO₂. 50 to 100% EtOAc / hexanes) gave the title compound as a white solid (138 mg, 88% over 2 steps). [a]_D +11.1 (c, 7.0 mg / ml. CHCl 3)₃); MS (ESI), (M + H)⁺ 477.22. 1 H NMR (CDCl 3)₃, 300 MHz) b 7.94 (dd, 2H,&gt; 1.8, 8.4). 7.69 (dd, 2H. ./=1.8. 8.7), 7.45-7.50 (m, 4H), 6.23 (br s, 1H), 5.19 (br s, 1H), 4.65 (d. 1H, ./=15.9) . 4.46 (d. 111 ../= 15.9), 4.31 (dd. 111,. / = 6.6. 7.8),

2.61 (s, 3 H), 1.75-1.85 (m, 1 H), 1.28-1.35 (m, 114). 1.08-1.15 (m, 1H), 0.76 (d, 3H,&gt; 6.6), 0.64 (d. 311.&gt; 6.6).

Example of Reaction Scheme 14

<img file="RS51155B_D0106.tif" />

(2R) -2- {N- (4-Chlorobenzenesulfonyl) -N- [4- (3-methyl- [1,2,4] oxadiazol-5-yl) -benzyl] amino} -4-methyl-pentanoic acid amide (Example 437):

Step 1: To a solution of the compound of Example 89 [4 - {[N - ((R?) - 1-carbamoyl-3-methylbutyl) -N- (4-chlorobenzenesulfonyl) -amino] -methyl} -benzoic acid. 520 mg. 1.2 mmol] in DMF (2.4 ml) and SNJSE (7.1 ml) at rt. add 1-hydroxybenzotriazole (192 mg, 1.42 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (272 mg, 1.42 mmol), and / or₂NEt (0.31 mL, 1.8 mmol). N-hydroxyacetamide (105 mg, 1.42 mmol) was also added. After 9 p.m. the starting material is visible by adding additional portions of all reagents periodically to further the reaction. After 3 d. the mixture was concentrated and partitioned between sat. aq.

51155 Β

NaHCO₃ and EtOAc (2x). The combined organic layers were washed with brine, dried (MgSO 4)₄) and concentrated to a yellow oil, which was used in the next step without purification.

Step 2: The crude aceiamidoxime was dissolved in toluene (10 mL) and the solution was heated at reflux. After 1 h, pyridine (2 mL) was added and heating was continued for another 15 h. The mixture was concentrated and diluted with EtOAc. The organic phase was washed successively with water, 1N HCl (2x), hour. aq. NaHCO 3, and brine, then dried (MgSO 4)₄) and concentrates. Flash column chromatography (SiO₂. 10 to 40% ElOAc / hexanes) gave the title compound as a pale yellow solid (238 mg, 42% in two steps). [«] '[)^] 9.30 (c, 5.93, CHCl 3); MS (ESI). (M + H)⁺477.18, 1 H NMR (CDCl 3)₃, 300 MHz) &lt;5 8.04 (d. 211. ./=8.4). 7.70 (dd, 2H, ./=1.8. 8.4), 7.45-

7.52 (m, 4H), 6.23 (br s, 1H), 5.19 (br s, 1H). 4.67 (d, 1H, 7 = 16.2), 4.47 (d, 1H, 7 = 15.9),

4.31 (t, 1 H, 7 = 7.2), 2.47 (s, ZN), 1.75-1.85 (m, 1H). 1.28-1. 35 (m, 1H), 1.08-1.15 (m, 1H), 0.76 (d, 311.7 = 6.6), 0.64 (d, ZN, 7 = 6.6).

Example of Reaction Scheme 15

<img file="RS51155B_D0107.tif" />

<img file="RS51155B_D0108.tif" />

(2R) -2- (N- (4-Chlorobenzenesulfonyl) -N- [4- (5-methyl- [1.2.4] oxadiazol-3-yl) -benzyl] amino) -4-methyl-pentane amide acids (Example 465):

A solution of the compound from. Example 6 [(27R) -2- [N- (4-chlorobenzenesulfonyl) -N- (4-cyanobenzyl) amino] -4-methyl-pentanoic acid [(0.20 g. 0.47 mmol)] in ethanol (6 inl) was treated hydroxylamine (50% solution in water. 0.050 ml. 0.71 mmol). The reaction was heated at 80 ° C for 18 h. Concentration of the reaction to a residue and recrysialization from EtOAc / hexanes gave a white solid (136 mg, 51%). This solid (0.18 mmol) was then dissolved in chloroform and treated with Et₃N (0.030 mL, 0.24 mmol) and acetyl chloride (0.020 mL, 0.18 mmol). The reaction was stirred at rt for 2 h, and then poured into EhOAs and brine. Organic

51155 Β The layer separates. dried over MgSO₄ and concentrate to the residue. The residue was taken up in toluene and heated at reflux for 24 h. The reaction was concentrated in residue and purified on a Biotage system (elution in 1: 1 EtOAc / hexanes) to give the desired product as a white solid (35 mg, 39% yield). MS (ESI). (M + NG 477.13, 1 H NMR (CDCl 3. 500 MHz) δ 7.98 (d, 2H. 7 = 8.2), 7.68 (d, 2H, 7 = 8.9). 7.45 (d, 4H. 7 = 8.5). 6.21 (s. 1H). 5.19 (s. 1H). 4.62 (d. 111. 7 = 15), 4.48 (d, 1H. 7 = 16). 4.31 (t, 111.7 = 7.0). 2.65 (s. ZN), 1.75-1.85 (m. 111), 1.20-1.35 (m, 4H), 1.10-1.17 (m, 1H). 0.85-0.90 (m, 1 H), 0.75 (d, 311.7 = 6.7), 0.64 (d, ZN, 7 = 6.4).

Example of Reaction Scheme 16

<img file="RS51155B_D0109.tif" />

(2R) -2- [N- (4-Acetylbenzyl) -N- (4-chlorobenzenesulfonyl) amide |^,Iino] -4-ylmethyl-pentanoic acid (Example 273):

Solution of the compound of Example 251 (4- {N - ((1S) -1-carbamoyl-3-methyl-butyl) -N- (4-chlorobenzenesulfonyl) -amino] -methyl) -N-methoxy-N-methyl-benzamide. 0.100 g, 0.207 mmol] was cooled to 0 ° C in TIIF (2.1 mL). A solution of methyl magnesium bromide (1.4Μ in toluene / THF ', 0.178 mL, 0.249 minol) was added dropwise. The resulting solution was stirred at 0 ° C. 3 h, when more solution of methyl magnesium bromide (0.178 mL, 0.249 mmol) was added. After another 30 min. a formal portion of MeMgBr solution (0.3 ml) was added. After a final 15 min, the reaction was quenched by the addition of an hour. aq. NH 3 Cl and 1N HCl. and the mixture was extracted with EtOAc (2x). The combined organic layers were washed with a watch. aq. NaHCO3,;, and salt water, dried (Na₂SO₄) and concentrate. Flash column chromatography (SiO₂. 20 to 60% EtOAc / hexanes) gave the desired compound as an off-white foam (79 mg, 87%). [a]^2j_D &lt;20.4 (c, 7.57. CHCl 3): MS (ESI), (M + NG 437.13. 1 N NMR (CDCl 3. 300 MHz) δ 7.87 (d, 211, 7 = 8.4) .7.67 (dd. 211. 7 = 1.8, 8.7), 7.42-7.46 (m, 411), 6.21 (br s. 1H), 5.28 (br s, 1H), 4.64 (d. 1H, 7 = 15.9),

51155 Β

4.45 (d, 1 Η,, / = 15.9). 4.31 (t, 1Η.&gt; 6.6), 2.58 (s, ZN). 1.73-1.80 (m, 1H). 1.25-1.35 (m,

1H). 1.05-1. 14 (m, 1H). 0.74 (d, 311,&gt; 6.5), 0.65 (d, 3H,&gt; 6.6).

Example of Reaction Scheme 17

<img file="RS51155B_D0110.tif" />

(2R) -2-N- (4-Chlorobenzenesulfonyl) -N- [4- (3-piperidin-1-yl-propionylamino) -benzyl] amino} -4-methyl-pentanoic acid amide (Example 274):

To a solution of N- (4 - {[N - ((15) -1-carbamoyl-3-methyl-butyl) -N- (4-chlorobenzenesulfonyl) amino] -methyl] -phenyl) -acrylamide (0.10 g. 0.22 mmol ) in toluene (5 mL) was added piperidine (20 mg, 0.24 mmol). The mixture was heated at mild reflux for 1 h and then the solvent was removed in vacuo. Purification by flash chromatography (SiCK 10% MeOH / SNJSE) gave the title compound (105 mg), in 86% yield. MS (ESI). (M + H) 449.16. 1 H NMR (CDCl 3, 400 MHz) δ 7.69 (d, 211,&gt; 8.0), 7.63 (d, 2H. ./=8.0). 7.38 (d, 2H,&gt; 8.0). 7.23 (d, 2 H). &gt; 8.0), 6.25 (no. P. 111), 5.35 (no. S, III). 4.75 (d, 1H,&gt; = 16). 4.38 (d. 1H.&gt;, = 16). 3.25 (m. III.&gt; 6.0), 2.65 (t, 2H,&gt; 6.0). 2.56-2.44 (m, 6H), 1.95 (m, 1H), 1.68-1.45 (m, 8H), 0.98 (d, ZN,&gt; 7.0). 0.94 (d. 3H.&gt; 7.0).

Example of Reaction Scheme 18

<img file="RS51155B_D0111.tif" />

51155 N- (2R) -2- (Benzhydrylidene-amino) -1- (1H) -10'-10'-dimethyl-N'-dioxo-S-Mia-T-azatricyclo-1 5.2.1.0¹³] dec-4'-yl} -4-fluorobutan-1-one:

To a solution of N-2- (benzhydrylidene-amino) -1- (13), (53) -10 ', 10'-dimethyl-3', 3'-dioxo-thia-4'-aza-tricyclo- [5.2 .1.0 '³] dec-4'-ylJ-ethanone (ref. Josien, H „Martin, L., Chassaing, G. Tetrahedron Lett, 1991, 32, 6547; 30.0 g, 68 mmol) in NMRA (60 mL) and THF (300 ml), cooled to -78 ° C, n-BuLi (1.6Μ in hexane. 42.4 ml. 68 mmol) was added dropwise, maintaining below -65 ° C. The reaction was allowed to reach rt, when a solution of 1-bromo-3-fluoroethane was added dropwise to rt. After 18 h, the reaction was poured over IBO / 1 HOAc (200 mL / 2 mL), diluted with EtOAc, and the organic layers were washed with saturated NH 4.₄C1. with salt water, dried over MgSO₄, and concentrate. The resulting orange oil was further purified by chromatography on silica gel (25% EtOAc / hexanes) to give a white solid which was recrystallized from 15% EtOAc / hexanes to give the desired material (24.3 g, 70%). MS (ESI), (M + H)⁴ 483.27. 1 H NMR (CDCl 3) δ 7.66 (d, 2H, .7 = 7.2), 7.13-7.44 (m, 8H). 4.82 - 4.83 (m, 2H). 4.39-4.81 (m, 211), 3.84-3.87 (m, 1H). 3.28 (ABq. 2H, .7 = 18, 10), 2.33-2.41 (m. 2H). 2.02-2.04 (m, 2H), 1.84-1.87 (m, 2H). 1.32-1. 39 (m, 2H), 1.10 (s, 3H). 0.91 (s, 3 H).

<img file="RS51155B_D0112.tif" />

(2R) -2-Amino-1- (13). (53) -10 '. 10'-dinethyl-3'.3'-dioxo-3'X⁶-tia-4^,-aza-tricycle [5.2.1.0¹Dec-4'-1H--4-fluorobutan-1-one:

(2R) -2- (Benzhydrylidene-amino) -1- (rS), (5'3) -10 ', 10'-dimethyl-3', 3'-dioxo3'I solution⁶-thia-4'-aza-tricyclo- [5.2.1.0¹°] dec-4'-yl J-4-fluorobutan-1-one (20.0 g, 41.0 mmol) and THF (400 mL) were treated with 1N HCl (200 mL). After 3 h. the reaction was diluted with H₂O and extracted with Et₂A. The aqueous phase is then neutralized by the addition of 0.5N NaOH. The base fa / .a is then extracted with CH₂C1₂. dried over MgSO₄ and concentrated to give a white solid (11.9 g. 90%). 11 NMR (CDCl 3) δ 4.56-4.71 (m, 2H). 4.23-4.31 (m, 1 H), 3.40-3.49 (m, 311). 3.11 (d. 2H. .7 = 4.4), 1.17-2.23 (m. 8H). 1.13 (s. ZN). 0.93-1.12 (m. ZN).

51155 Β

<img file="RS51155B_D0113.tif" />

(2R) -2- (4-chlorobenzenesulfonylamino) -1-1 (1) 9), (5) 9) -1 () ', 1H-dimethyl-3'.3^l-dioxo-3^lk⁶-thia-4'aza-tricyclo- [5.2.1.0^{l 3}1dec-4'-yl} -4-fluorohutan-1-one:

To a solution of (2R) -2-amino-1 - {(1) 9). (5) 9) -10) 10'-dimethyl-3 ', 3'-dioxo-3'Z⁶-thia-4'-azatricyclo- [5.2.1.O^l,;&gt;1-Chlorobenzenesulfonyl chloride (9.1 g) was added to dec-4'-yl} -4-fluorobutan-1-one (12 g, 36 mmol) and Et? N (10.4 ml, 72.0 mmol) in CIECF (350 ml). , 43 mmol) in one serving. After 6 p.m. the reaction was concentrated and the resulting residue was taken up in EtOAc and washed with NJO. salt water, dried over MgSO₄. and concentrates. The material was then further purified by chromatography on silica gel (30% EtOAc / hexanes) to give the title compound (16.0 g, 92%) as a white waxy substance. 1 H NMR (CDCl 3) δ 7.79 (d, 2H, 7 = 8.0), 7.43 (d, 211, 7 = 8.0), 5.69 (br d, 8.0), 4.42.4.77 (m, 4H). 3.71-3.72 (m, 1 H), 3.10 (ABq. 2H, 7 = 9. 4.4). 2.11-2.29 (m, 2 H), 1.33-1.99 (m, 6 H), 1.04 (s, ZN). 0.91 (s, ZN).

<img file="RS51155B_D0114.tif" />

(2L) -2- (4-chlorobenzenesulfonylamino) -4-fluorobutanoic acid:

In solution (2R) -2- (4-chlorobenzenesulfonylamino) -1 - {(I) 9), (5) 9) -10 '. 10'-dimethyl-3'.Z'dioxo-S ^ '- thia-N'-aza-tricyclo-N, N-fluorobutan-1-one (16 g, 32 mmol) in acetonitrile 200 ml) which mixes rapidly. LiBr (13.9 g, 16 mmol) was added. tetrabutylammonium bromide (4.13 g, 12.8 mmol), and LiOH (5.45 g, 0.130 mol). After 4.5 h, the reaction was concentrated to half volume. then dilute with H₂O and extracted with CH₂Cl₂The aqueous layer was acidified with 1N HCl and extracted with F.tOAc. The EtOAc extracts were combined, dried over MgSO 4₄, and concentrated to give a white solid of which 9.4 g was directly transferred to the next step. 1 H NMR (DMSO-T 3) δ 8.39 (d, 1H, ./=9.0), 7.76 (d, 211,

51155 Β&gt; 6.8), 7.64 (d, 2Η,, 7 = 6.8). 7.00 (No. p. 111). 4.29-4. 48 (m, 2H). 3.80-3. 88 (m, 1H), 1.66

1.96 (m, 2H).

<img file="RS51155B_D0115.tif" />

(2R) -2- (4-Chlorobenzenesulfonylamino) -4-fluorobutanoic acid amide:

To a solution of (2R) -2- (4-chlorobenzenesulfonylamino) -4-fluorobutanoic acid (9.0 g, 31 mmol) in DMF (250 mL) was added one after the other I-hydroxybenzotriazole hydrate (6.2 g, 46 mmol) . LH-diisopropylethylamine (23 ml. 124 mmol), ammonium chloride (3.34 g. 62 mmol). and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (8.8 g, 46 mmol). pod Ž The resulting solution was mixed on a cape for 18 h. The solution was poured over ice water (500 ml) and the solid was filtered off and dried. The material was then precipitated from 10% EtOAc / hexanes to give a pure white solid (4.5 g) in 50% yield. [α] ρ -21.0 (c, 1.00, DMF); MS (ESI). (ΜΗ) 293.01; 1 H NMR (DMSO-d 6) δ 8.12 (d, 1H. ./=8.8) .7.77 (d, 211.&gt; 7.0), 7.62 (d, 2H. ./=7.0), 7.38 (brs, 1H), 7.03 (brs, 1 H), 4.22-4.47 (m, 2H), 3.71-3.85 (rn, 1H), 1.65-1.92 (m, 2H).

<img file="RS51155B_D0116.tif" />

(2 / O-2 - [(4-chlorobenzenesulfonyl) - (4-cyanobenzyl) -amino] -4-fluorobiothyramide (Primeg 360): (2A) -2- (4-chlorobenzenesulfonylamino) -4-fluorobutyramide (20 mg, 0.7 mmol) was converted to the title compound according to Reaction Scheme 1, method A to give the title compound (208 mg) in 73% yield, MS (ESI). (MH) + 407.99; [ss] o +39.13 (c , 1.00, McOH) 1 H NMR (CDCl 3)₃) b 7.72 (d, 2H. ./=8.4). 7.58 (d. 2H, ./=8.4), 7.50 (d. 211. ./=8.4), 7.45 (d. 2H., / = 8.4), 6.29 (br s. 1H), 5.21 (br s. 111 ). 4.19-4. 67 (m, 5H). 2.17-2. 28 (m, 1H). 1.49-1.61 (m. 111).

51155Β

Example of Reaction Scheme 19

<img file="RS51155B_D0117.tif" />

(III) 2- (4-Chlorobenzenesulfonylamino) -6-fluoro-hexanoic acid amide:

A mixture of ethyl ester (benzhydridine-amino) acetic acid (8.6 g, 32 mmol), 4-bromo-1-fluorobutane (10.0 g, 64.5 mmol). K₂CO₃ (13.4 g, 96.9 mmol). tetrabutylammonium bromide (2.1 g. 6.5 mmol), and acetonitrile (300 ml) were heated at reflux for 72 h. The reaction was cooled to rt and filtered through a sintered glass funnel. The filtrate was concentrated in vacuo. The residue was dissolved in diethyl ether (250 ml) and a white solid precipitated. The solid was removed by vacuum filtration. A solution of 1N 11 Cl (100 mL) was added to the filtrate, which contained the crude product (2- (benzhydrylideneamino) -6-fluoroohexanoic acid ethyl ester). The resulting biphasic mixture was stirred vigorously for 3 h. The mixture was transferred to a separatory funnel. The aqueous layer was collected. The organic layer was extracted with 1N HCl (30 mL). The combined organic layers were washed with 200 mL of diethyl ether. Concentrated HCl (10.8 mL) was added to the aqueous portion and the resulting solution was heated at reflux for 6 h. The reaction mixture was cooled to rt and concentrated in vacuo. Toluene was added to the residue, and the mixture was reconcentrated at z7 vacuo to give 2-amino-6-fluoro-hexanoic acid hydrochloride as a white solid. The crude amino acid salt is used without purification or characterization. 2-Amino-6-fluorohexanoic acid hydrochloride (32.3 mmol) was theoretically suspended in anhydrous methanol (300 ml) and cooled to 0 ° C. Thionyl chloride (10.3 mL, 129 mmol) was added slowly over 5 min. The resilient solution was allowed to warm to rt and stirred for 18 h. The reaction mixture was concentrated in vacuo to give methyl 2-amino-6-fluorohexanoic acid hydrochloride. Toluene (100 ml) and 28% ammonia in water (75 ml) were added to the crude amino ester. The resulting biphasic mixture was stirred vigorously at rt for 24 h. The reaction mixture was concentrated in vacuo. The residual solid was suspended in toluene (200 ml) and reconcentrated in vacuo to give the (II) 6-fluorohexanoic acid amide as a white solid.

51155 Β substance. The crude amino acid amide was dissolved in anhydrous DMF (50 mL) and CIFCF (350 mL) and reacted with 4-chlorobenzenesulfonyl chloride (82 g, 32.3 mmol) and Et₃N (13.5 mL, 96.9 mmol). After 2 h, a second portion of 4-chlorobenzenesulfonyl chloride (1.70 g, 8.1 mmol) was added. After an additional 18 h, the resulting mixture was poured into 1N HCl (500 mL). The organic layer was collected and washed with water (2x500 ml). Hexane (600 ml) was added to the organic layer. A white precipitate formed. The solid was collected by vacuum friction, washed with cold ethanol (50 ml) and dried in vacuo to give 4.95 g (48% yield, 6 steps) of (111) 2- (4-chlorobenzenesulfonylamino) -6-fluorohexanoic acid amide. LCMS (M + Na)¹ 345.2; 1 H NMR (400 MHz, DMSO-d 6)₆) b 7.99 (d, 1H. .7 = 8.8), 7.77 (d, 2H., 7 = 8.8). 7.62 (d, 2 H, .7 = 8.8). 7.29 (s, 1 H). 6.95 (s, 1H). 4.34 (dt, 2H, .7_d= 47.5. .7 = 6.1). 3.65 (dt, 1H, 7_d=5.6, 7₍= 8.6), 1.60-1.39 (m, 4H), 1.36-1.15 (m, 2H); Anal. calc. for C 1 H 2₆C1FN₂Oh₃S: C. 44.65; H, 4.99; N. 8.67. Found: C, 44.61; H, 5.08; N. 8.75.

<img file="RS51155B_D0118.tif" />

2 - [(4-H] Orobenzenesulfonyl) - (4-cyanobenzyl) -amino] -6-fluoro-hexanoic acid amide (Example 333):

The 2- (4-chlorobenzenesulfonylamino) -6-fluoro-hexanoic acid amide (0.500 g, 1.55 mmol) was converted to the title compound (360 ng. 50% yield) as in Reaction Scheme 1. procedure L. LCMS (M + Na)⁴ 459.9; 1 H NMR (400 MHz, DMSO-d 6) δ 7.82 (d, 2H, ./=8.8), 7.79 (d, 2H, 7 = 8.5). 7.63 (d, 2 H, 7 = 8.8). 7.58 (d, 2H, .7 = 8.3), 7.52 (s, 1H), 7.09 (s, 1H), 4.82 (ABq, 2H, Δν-37.2, J_ab= l 7.6), 4.34 (dd. lH. 7 = 8.0. 6.6). 4.25 (dt, 2H, J_d=47.2. 7_t= 5.7). 1.58 (m, 1H), 1.49-1.12 (m, 5H): Anal. calc. for C₂₀H_2lClFN₃Oh₃S: C, 54.85; H. 4.83; N, 9.59. Found: C. 54.92; H, 4.76; N. 9.54.

51155 Β

Example of reaction scheme 20

<img file="RS51155B_D0119.tif" />

(2A) -2- (4-chlorobenzenesulfonylamino) -1 - {(1) S). (5) S) -1O ', 10'-dimethyl-3',3'-dioxo-3'X⁶-thia-4'aza-tricyclo- [5.2.1.0^l?| dec-4^l-yl] -4-fluoro-4-methyl-pyrrian-1-one:

In solution (2S) -2- (4-chlorobenzenesulfonylamino) -1 - {(1) 8), (5) 8) -10 '. 10'-dimethyl-3 ', 3'dioxo-3'X⁶-thia-4'-aza-tricyclo- [5.2.I.0^l?'Jdcc-4'-yl} -4-methyl-4-penten-1-one [500 mg, 1 mmol, prepared according to Reaction Scheme 18 of N-2- (benzhydrylidene-amino) -1 {(1) 8) . (5) 8) -10 ', 10'-dimethyl-3', 3'-dioxo-37H-thia-4'-aza-tricyclo- [5.2.1,0^L&gt;] dec-4'-yl} -ethanone (ref. Josien, H „Martin, A„ Chassaing. G. Tetrahedron Lett. 1991, 32, 6547) and 1-bromo-2-methyl-2-propene] in THF [5 ml ) at 0 ° C was added hydrofluoric acid-pyridine (10 ml). The reaction mixture was allowed to warm to rt and stirred for 18 h. The reaction contents were carefully added to saturated aqueous NaHCO 3₃ (300ml). The aqueous mixture was extracted with EtOAc (3 x 100 mL). The combined organic sieves were washed sequentially with 1N HCl (200 mL) and brine (100 mL). The organic layer was dried over MgSO 4₄. filtered and concentrated in vacuo to give 490 mg (94%) of the title compound as a white solid. 1 H NMR (400 MHz, DMSO-40 b 7.83 (d, 2H, ./=8.8), 7.45 (d, 2H, ./=8.8), 5.37 (d, 1H, ./-8.1), 4.65) (m .1H), 3.64 (t, 1H. .7 = 6.4), 3.43 (ABq, 2H. Δν = 5.4, /_ab= l3.7). 2.19-1. 83 (m, 7H), 1.41-1.3Ι (m, 8H). 1.04 (s, ZN). 0.94 (s. ZN).

<img file="RS51155B_D0120.tif" />

(2R) -2- (4-Chlorobenzenesulfonylamino) -4-fluoro-4-methyl-pentanoic acid amide (2R) -2- (4-chlorobenzenesulfonylamino) -1 - {(1) S). ) S) -110'10-dimethyl-3 ', 3'-dioxo-3'k⁶thia-4'-aza-tricyclo- [5.2.1.0 ' ^?] dec-4'-yl) -4-fluoro-4-methyl-pentan-1-one was converted to the title compound in two steps as in Reaction Scheme 18 (165 mg. 55% yield): LCMS (M + Na ) '345.1; 1 H NMR (500 MHz, DMSO-δ₆) δ 8.I0 (d. 1H. ./=9.2), 7.77 (d. 2H. ./=8.5),

51155 Β

7.62 (d, 2Η, .7 = 8.9). 7.34 (s, 1 N). 6.92 (s, 111). 3.85 (m, 1 H). 1.89 (m, 1 H). 1.74 (m, 1 H).

1.31 (d, ZN, .7 = 21.7), 1.29 (d, ZN. .7 = 21.9).

Example of Reaction Scheme 21

<img file="RS51155B_D0121.tif" />

Ethyl -2- (4-chlorobenzenesulfonylamino) -4-phenyl-4-pentenoate:

A solution of ethyl 2-amino-4-methyl-4-pentenoate (2.84 g, 18.1 mmol) prepared as in Reaction Scheme 19 from ethyl acetate (benzhydrylideneamino) acetic acid and 1-bromo-2-methyl-

2-propene) in CIECE (250 mL) reacted with 4-chlorobenzenesulfonyl chloride (4.20 g, 19.9 mmol) and E1₃N (3.78 mL, 27.2 mmol). After 4 h. the resulting mixture was poured into 1N aqueous HCl (500 mL) and extracted with EtOAc (3 x 150 mL). The organic layer was washed with brine (50 mL), dried₄), filtered and concentrated in vacuo. The crude concentrate was purified using silica gel column chromatography (10: 1 to 5: 1 gradient hexanes / EtOAc) to give 3.04 g (25% yield over 3 steps) of ethyl 2- (4-chlorobenzenesulfonylamino) -4- methyl 4-penthenoate: LCMS (M + Na)⁺ 354.2: ^f1 H NMR (400 MHz, CDCl 3) 7.77 (d, 2H, .7 = 9.1), 7.46 (d, 2H, .7 = 8.8), 5.07 (d, 1H, .7 = 9.0). 4.84 (s, 1 H). 4.73 (s, 114), 4.05 (m, 111), 3.95 (q, 214, .7 = 7.1). 2.40 (m, 2H), 1.66 (s, 3H). 1.13 (t, ZN. .7 = 7.1).

<img file="RS51155B_D0122.tif" />

<img file="RS51155B_D0123.tif" />

2- (4-Chlorobenzenesulfonylamino) -4-fluoro-4-methyl-pentanoic acid ethyl ester and 4-chloro-N (5.5-dimethyl-2-oxo-tetrahydro-furan-3-yl) -benzenesulfonainide:

Hydrogen fluoride, pyridine (10 mL) was added to 11 solutions of allyl 2- (4-chloro-benzenesulfonylamino) -4-methyl-4-pentenoate (1.0 g, 3.0 mmol) in THF (15 mL). cooled to 0 °. The reaction mixture was allowed to warm to rt. After 5 h, another portion of hydrogen fluoride · pyridine was added. The mixture was stirred for 24 h, and then a third portion of the hydrogen fluoride-pyridine portions was added.

51155 Β (10 ml). After a total of 53 h, the reaction was quenched with ice cubes (20 mL). The crude mixture was poured into ice water (500 ml) and extracted with CFFCF (2x200 rnl). The combined organic layers were washed with a watch. aq. NaHCO; (100 ml) and concentrated in vcictto. The crude concentrate was purified using silica gel column chromatography (10: 1 to 5: 1 gradient, hexanes / EtOAc) to give 0.395 g (37% yield) of ethyl 2- (4-chlorobenzenesulfonylamino) -4-fluoro-4-methyl. -pentanoate and 0.425 g (46% yield) of 4-chloro-N- (5,5-dimethyl-2-oxo-tetrahydrofuran-3-yl-benzenesulfonamide) Data for ethyl 2- (4-chlorobenzenesulfonylamino) -4-fluoro -4-methyl pentanoate: LCMS (M + Na)⁺ 374.1: 1 H NMR (500 MHz, CDCl 3)₃) 7.78 (d, 211.7 = 8.9).

7.47 (d, 2H, 7 = 8.5), 5.19 (d, 111, 7 = 7.9), 4.08 (m, 1H), 3.93 (m, 2H), 2.09-1.94 (m, 211),

1.42 (d, ZN, 7 = 21.6), 1.37 (d, 311, 7 = 21.6), 1.12 (t. ZN, 7 = 7.0). Data for 4-chloro-A '- (5,5-dimethyl-2-oxo-tetrahydro-furan-3-yl-benzenesulfonamide: LCMS (M + Na)' 326.0; 1 H NMR (400 MHz, DMSO-δ) 8.41 d, 1H, 7 = 9.1), 7.86 (d, 2H, 7 = 8.6), 7.67 (d, 2H, 7 = 8.8), 4.57 (m, 1H), 2.22 (dd, 1H, 7 = 12.4, 9.0). 1.72 (t, 1H, 7 = 12.0), 1.33 (s, ZN), 1.31 (s, ZN).

<img file="RS51155B_D0124.tif" />

2- (4-Chlorobenzenesulfonylamino) -4-fluoro-4-methyl-pentanoic acid anide:

A solution of 2- (4-chlorobenzenesulfonylamino) -4-fluoro-4-methyl-penic acid ethyl ester (457 mg, 1.30 mmol) in MeOH (20 yryl) was treated with 10 sa NaOH (780 μΙ, 7.8 mmol) at rt 18 h. The crude reaction mixture was concentrated in vacuo. The residue was treated with water (50 mL) and 1N HCl (20 mL). The aqueous solution was extracted with EtOAc (3x100 mi). The combined organic layers were washed with brine (50 mL) and dried over MgSO 4₄, filtered and concentrated in vacuo to give a white solid containing 2- (4-chlorobenzenesulfonylamino) -4-fluoro-

4-methyl-pentanoic acid. A mixture of crude solids. 1-hydroxybenzotriazole (263 mg. 1.95 mmol), diisopropylethylamine (670 mg, 5.2 mmol), ammonium chloride (140 nig, 2.6 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (373 mg, 1.95 mmol) ). and DMF (20 mL) was stirred at rt for 24 h. The crude mixture is poured into water (500 ml). The aqueous solution was extracted with EtOAc / hexane (90:10, 3 x 150 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO 4.₄, filter and concentrate in vacno. Raw

51155 Concentration was purified using silica gel column chromatography (95: 5, chloroform / McOH) to give 0.426 g (100% yield) of the title compound: LCMS (M + Na)⁺ 345.3; 1 H NMR (400 MHz, DMSO-d 6 d d 8.10 (d, 1H, / = 9.2), 7.77 (d, 2H,, / = 8.5),

7.62 (d, 2U, ./=8.9), 7.34 (s, 1H), 6.92 (p. 114). 3.85 (m, 1 H). 1.89 (m, 1 H). 1.74 (m, 1 H).

1.31 (d. ZN, ./=21.7), 1.29 (d.3H. ./=21.9).

<img file="RS51155B_D0125.tif" />

2 - [(4-Chlorobenzenesulfonyl) - (4-cyanobenzyl) -amino] -4-fluoro-4-methyl-pentanoic acid amide (Example 357):

2- (4-Chiorobenzenesulfonylamino) -4-fluoro-4-nethyl-pentanoic acid amide was converted to the title compound according to Reaction Scheme 1, Method A. LCMS (M + Na) 4460.2; 1 H NMR (400 MHz. DMSO-d 6)_rt) b 7.83 (d, 2H. ./=8.5), 7.75 (d, 2H. ./-8.3), 7.68 (s, 1H), 7.64 (d, 2H. ./=8.6), 7.49 (d. 2H) ,, / = 8.1). 7.20 (s, 1H), 4.67 (ABq, 2H, Δν = 28.3, ./_jb= 17.3).

4.54 (dd, 1H, ./=9.3, 3.2), 2.23 (m, 1H), 1.42 (m, 1H), 1.25 (d. ZN. 7 = 21.6), 1.21 (d. ZN. 7 = 21.7).

CN

<img file="RS51155B_D0126.tif" />

2 - [(4-Chlorobenzenesulfonyl] -4-cyanobenzyl) -anilino] -4-hydroxy-4-ylmethyl-pentanoic acid amide (Example 443):

A sealed vial with a mixture of 4-chloro-N- (5.5-dimethyl-2-oxo-tetrahydro-furan-3-yl) benzenesulfonamide (0.20 g. 0.66 mniol) and 28% ammonia in water (3 ml) was heated in a microwave reactor at 80 ° C, 40 min. The reaction mixture was cooled to rt and concentrated to dryness in vacuo to give a white solid containing 2- (4) amide.

51155 Β Chlorobenzenesulfonylamino) -4-hydroxy-4-methyl-pentanoic acid. The crude solid was converted to the title compound (98 mg. 34% yield) as in Reaction Scheme 1, Method A: LCMS (M + Naf 458.2; 1 H NMR (400 MHz, DMSO-d 6) b 7.84 (d, 2H) , J = 8.6),

7.76 (d, 2H, ./=8.3), 7.62 (d, 2H, / = 8.8), 7.51 (d, 2H,. = 8.3), 7.40 (s, 1H), 7.11 (s, 1H), 4.63 (ABq, 2H, Δν = 5.9,, /_ab= l 7.6). 4.56 (dd. 1H. ./=8.3, 2.5), 4.54 (s. 1H). 1.95 (dd, 1H. ./=13.7. 8.6), 1.26 (dd, 1H, ./13.6. 2.4). 1.04 (p. 314). 0.99 (s. ZN). Anal calculation. for C₂₀H₂₂ClNl₃Oh₄S: C, 55.10; H, 5.08; N. 9.64. Found: C. 54.96; H, 5.14; N, 9.58.

<img file="RS51155B_D0127.tif" />

2- (4-Chlorobenzenesulfonylamino) -5-hexenoic acid ethyl ester:

Mixture of ethyl ester (benzhydrylidene-amino) acetic acid (20 g, 74.8 mmol), 4-bromo-1-butene (10.1 g, 74.8 mmol), K? CO₃ (31.0 g, 224 mmol), tetrabutylammonium bromide (2.41 g, 7.48 mmol), and acetonitrile (150 mL) were heated at reflux for 6 h. The reaction was cooled to rt and filtered through a sintered glass funnel. The filtrate was concentrated in vacuo. The residue was dissolved in diethyl ether (250 ml) and a white solid precipitated. The solid was removed by vacuum filtration. A solution of 1N HCl (150 mL) was added to the filtrate containing the crude product ethyl ester (2- (benzhydrylidene-amino) -hex-5-enoic acid). The resulting biphasic mixture was stirred vigorously for 18 h. The mixture was transferred to a separatory funnel. The aqueous layer was collected and concentrated in vacuo. The residue was dissolved in toluene (2x200 ml) and reconcentrated. The crude amino ester was dissolved in CH₂CI₂ and reacted with 4-chlorobenzenesulfonyl chloride (15.8 g, 74.8 mmol) and Et₃N (31.2 mL, 224 mmol). After 6 p.m. the resulting mixture was poured into 1N HCl (500 mL). The organic layer was collected and washed sequentially with 1N HCl (500 mL) and brine (500 mL). The organic layer was dried over MgSO 4₄. filtered and concentrated in vactio. The crude concentrate was purified using silica gel column chromatography (5: 1, hexanes / EtOAc) to give 5.57 g (23% yield over 3 steps) of the title compound: LCMS (M + Na)⁺ 354.0; 1 H NMR (400 MHz, DMSO-d 6 8.47 (d, 1H, ./=8.8), 7.76 (d, 211,

51155 Β&gt; 8.8), 7.66 (d, 2Η, ./=8.8), 5.69 (m. 1H), 4.95-4.88 (m. 211), 3.86 (q, 2H., / = 7.1), 3.76 (m.

IX). 1.98 (m, 2 H), 1.71-1.54 (m, 2 H), 1.03 (m. 311.&gt; 7.1).

CN

<img file="RS51155B_D0128.tif" />

2 - ((4-Chlorobenzenesulfonyl)) - (4-cyanobenzyl) -amino] -hex-5-enoic acid ethyl ester:

2 - [(4-Chlorobenzenesulfonyl) - (4-cyanobenzyl) -amino] -hex-5-enoic acid ethyl ester was prepared in the same manner as in Reaction Scheme 1. starting from 2- (4-chlorobenzenesulfonylamino) ethyl ester. -hex-5-enoic acid. 2 - ((4-Chlorobenzenesulfonyl) -) (4-cyanobenzyl) -amino] -hex-5-enoic acid ethyl ester was isolated as a crude yellow solid (1.14 g) and used in the next step without further purification. 1 H NMR (CDCl 3)₃) b 7.71 (d, 2H,&gt; 8.0). 7.61 (d, 2 H,&gt; 8.0). 7.53 (d, 2H,&gt; 8.0), 7.46 (d, 2H,&gt; 8.0). 5.54 (m, 2 H). 4.90 (m, 211), 4.74 (d, 1H,&gt; 16.0), 4.48 (m, 2H), 3.90 (m, 1H). 1.95 (m, 2 H), 1.81 (m, 1 H),

1.48 (m, 1 H). 1.11 (t, 3H&gt; 8.0).

<img file="RS51155B_D0129.tif" />

2 - [(4-Chlorobenzenesulfonyl) - (4-cyanobenzyl) -amino] -5-oxo-pentanoic acid ethyl ester:

Mixture of (4-chlorobenzenesulfonyl) - (4-cyanobenzyl) -amino] -hex-5-enoic acid ethyl ester (1.14 g, 2.56 mmol). osmium tetraoxide (0.030 g, 0.13 mmol), and trimethylamine oxide (0.41 g, 5.5 mmol) were dissolved in acetone (50 mL) and stirred for 4 h at rt. Upon completion. the solution was concentrated in vacuo and redissolved in 1.5: 1 dioxane: H₂O (50 ml). To this solution was added sodium periodate (0.66 g, 3.07 mmol) and stirred at rt for 18 h. The reaction was then diluted with EtOAc (500 mL) and washed with H₂Oh, salt water. dries over Na₂SO₄ and concentrates giving

51155 Β Crude colorless oil. Further purification by flash chromatography (SiO₂, 5 to 75% EtOAc / hexanes) gave 2 - [(4-chlorobenzenesulfonyl) - (4-cyanobenzyl) -amino] -5-oxopentanoic acid ethyl ester (0.26 g) as a colorless oil in 23% yield. 1 N NMR (CDCl 3) δ 9.57 (s, 1H), 7.69 (d, 2H, .7 = 8.0), 7.51 (m, 6H), 5.99 (ABq, 2H, Δν = 16, ./_ab= I 68), 4.47 (m, 111), 3.89 (m, 2H), 2.53 (m, 1H), 2.32 (m, 1H), 2.11 (m, 1H), 1.61 (m, 1H), 1.06 (t , ZN, .7 = 8.0).

<img file="RS51155B_D0130.tif" />

2 - [(4-Chlorobenzenesulfonyl) - (4-cyanobenzyl) -amino] -5,5-di fluoro-pentanoic acid ethyl ester:

2 - [(4-Chlorobenzenesulfonyl) - (4-cyanobenzyl) -amino] -5-oxo-pentanoic acid ethyl ester (0.05 g, 0.11 mmol) was slowly added to a solution of DAST (0.020 ml. 0.11 mmol) in SNJSE 2 ml) at rt and stirred for 16 h. The reaction was diluted with SNJSE (20 mL) and extracted with H₂O (2x25 ml). The combined organic layers were washed with H₂O. salt water, dried over Na₂SO4 and concentrated to give 2 - [(4-chloro-benzenesulfonyl) - (4-cyanobenzyl) -amino] -5,5-difluoro-pentanoic acid ethyl ester as a crude yellow residue (61 mg). This crude residue was taken to the next step without further purification.

<img file="RS51155B_D0131.tif" />

2 - [(4-Chlorobenzenesulfonyl) - (4-cyanobenzyl) -amino] -5,5-difluoro-pentanoic acid amide (Example 377):

51155 Β

The crude 2 - [(4-chlorobenzenesulfonyl) - (4-cyanobenzyl) -amino] -5,5-difluoropentanoic acid 1-ester (0.061 g, 0.13 mmol) was dissolved in MeOH (2 mL). To this mixture was added 10Ν NaOH (0.052 mL, 0.52 mmol) and the resulting solution was stirred at rt for 16 h. The reaction was diluted with NJO (25 mL). acidifies with 1N HCl. and extracted with CH2Cl2 (4x100 mL). The combined organic layers were dried over Na₂SO₄ and concentrated in vacuo to give the carboxylic acid residue as a crude colorless oil. The carboxylic acid intermediate was then dissolved in DMF (10 mL) and mixed with 1-hydroxybenzotriazole (0.030 g, 0.20 mmol), zPnNEt (0.090 mL, 0.52 mmol), NH 4 Cl (0.01 g, 0.26 mmol). 1- (3dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.04 g. 0.20 mmol) and stirred at rt 72

h. The reaction was diluted with EtOAc (150 mL) and washed with FEO (4x50 mL). The organic layer was dried over Na2SO₄ and concentrated in vacuo to give a crude off-white solid. Further purification by flash chromatography (SiO₂. 5 to 85% EtOAc / hexanes) gave the title compound (10.7 mg) as a white solid in 19% yield. LCMS (M + Na) ~ 464.01; 1 H NMR (CDCl 3) δ 7.69 (d, 2H,&gt; 8.3). 7.60 (d, 2H,&gt; 8.3), 7.49 (m, 411). 6.18 (br s, 1H),

5.67 (tt, 1H,&gt; 56, 4.0), 5.22 (br s. 1H), 4.52 (ABq. 2H, Δν = 16, »00), 4.34 (m, 1H), 2.03 (m, IFI), 1.68 m, 1H), 1.38 (m, 1H). 0.86 (m, 1H).

Example of Reaction Scheme 23

<img file="RS51155B_D0132.tif" />

(2R) -2- [4- (2-Bromo-acetylamino) -benzyl] - (4-chlorobenzenesulfonyl) -amino] -4-methylpentanoic acid amide

To a solution of (2R) -2 - [(4-aminobenzyl) - (4-chlorobenzenesulfonyl) -amino] -4-methylpentanoic acid amide (248 mg, 0.56 mmol) and Et₃N (1 76 mg, 1.74 mmol) in CH₂C1₂ (3 mL) was added bromoacetyl chloride (105 mg. 0.67 mmol). The reaction mixture was stirred overnight at rt. The reaction mixture was diluted with SNJSV (5 mL), washed with ΓΝ HCl, brine. and sushi

51155 Β by passing through a cotton plug. The solvent was removed in vacuo. Purification by flash chromatography (SiO₂, 10% acetone / CH₂CI₂) gave the title compound (124 mg) in 42% yield. MS (ESI), (M + N)⁺ 531.86. ^!1 H NMR (CDCl 3)₃, 400 MHz) b 8.78 (br s, NH). 7.95 (d, 2 H, ./=8.0). 7.82 (d, 211.7 = 8.0), 7.42 (d, 2H, 7 = 8.0), 7.33 (d, 2H, 7 = 8.0), 6.20 (br s, 1H), 5.20 (br s, 1H), 4.30 (s, 211), 4.22 (d, 1H, 7)_ab= 16). 4.14 (d, 1H, 7_ab= 16). 3.25 (t, 1H, 7 = 6.0), 1.95 (m, 1H), 1.60 (m, 2H). 0.98 (d, ZN. 7 = 7.0), 0.94 (d, ZN, 7 = 7.0).

<img file="RS51155B_D0133.tif" />

(2R) -2-i (4-ChlorobenzenesulfonylH4- (2-dimethylamino-acetylamino) -benzyl] -amino} -4-methyl-pentanoic acid amide) (Example 308):

To a solution of (2R) -2 - [[4- (2-bromo-acetylamino) -benzyl] - (4-chlorobenzenesulfonyl) amino] -4-methyl-pentanoic acid amide (CH (41 mg. 0.77 mmol) in CH₂CI₂ (2 m!) Was added in excess 2.0M dimethylamine in THF. The reaction mixture was stirred overnight. The solvent was removed in vacuo. Purification by flash chromatography (SiO₂. 10% McOH / Cl 1₂S1₂) gave the title compound (24 mg) in 63% yield. MS (ESI). (M + H) &amp; lt; + &amp; gt; 495.14, 1 H NMR (CDCl3. 400 MHz) δ 8.85 (s, 1H). 8.02 (d, 2 H, 7 = 8.0). 7.75 (d, 2H, 7 = 8.0). 7.38 (d, 2 H, 7 = 8.0), 7.29 (d, 2 H, 7 = 8.0). 6.23 (br s, 111), 5.39 (br s, 1 H). 4.62 (m, 4H), 3.25 (m, 1H, 7 = 6.0). 2.95 (s, 6 H), 1.95 (m, 1 H). 1.60 (m, 2 H), 0.98 (d. ZN. 7-7.0). 0.94 (d. ZN. 7 = 7.0).

51155 Β

Starting materials

The following α-amino-amides are commercially available or are obtained by standard methods from commercially available amino acids:

<td>A / JnH., h₂n γ</td><td>1¼ h₂n γ</td><td></td><td>N₂N '</td>

<td></td><td>X</td><td></td><td></td>

<td> 0</td><td> 0</td><td>⁰ ™</td><td>Ο</td>

<td></td><td></td><td>h_{! n}7&gt;</td><td></td>

<td></td><td></td><td>V</td><td></td>

<td> 0</td><td> 0</td><td> 0</td><td></td>

<td>JH&gt; n₂h₂n</td><td></td><td>h₂n γ</td><td></td>

<td>V</td><td>s</td><td>% l</td><td></td>

5.5,5-Trifluoro-2-aminopentanoic acid amide and 6,6,6-trifluoro-2-aminohexanoic acid amide are prepared according to: Ojima. L., Kato. K .. Nakahashi, KJ Org. Chem. 1989. 54. 4511.

The benzyl bromide used in the synthesis of the compounds of Examples 100 and 155 was prepared according to Ishihara, Y, Fujisawa, Y., Furuyama. N. PCT Int. Appl. WO 9846590; Senanayake. CH, Fang, QK, Wilkinson. SH PCT Int. Appl. WO 9833789.

The aldehydes required for the synthesis of Example 91. 248. 249, 289, 290 and 300 (see Reaction Scheme 2) were prepared as shown for 4- (piperidin-1-yl) benzaldehyde. A suspension of 4-fluorobenzaldehyde (0.48 mL, 4 mmol), K.2CO3 (522 mg, 4 mmol), piperidine (340 mg, 4 mmol) in DMSO (5 mL) was heated in a sealed tube at 150 ° C for 18 h, after of which the reaction is concentrated and purified by chromatography on silica gel (ClhCl ·. then 2% MeOH / SNJSE) to give 4- (piperidin-1-yl) benzaldelide, 748 mg, 98% yield.

The aldehydes used in the 11 syntheses of the compounds of Examples 317. 318 and 320 were prepared as shown for 4- (piperidin-1-yl) -3-fluorobenzaldehyde. Suspension 4.3

51155 Β difluorobenzaldehyde (500 mg. 3.5 minol). K₂CO₃ (483 mg, 3.5 inmol), piperidine (298 mg.

3.5 mmol) in DMSO (5 mL) was heated in a sealed tube at 130 ° C for 18 h. The reaction mixture was allowed to cool to rt. is concentrated and purified by chromatography on silica gel (CH₂C1₂, then 2% MeOH / CH₂CI₂) giving 4- (piperidin-1-yl) -3-fluorobenzaldehyde. 740 mg, 99% yield.

The benzyl chloride used to prepare the compounds of Examples 433, 474, 480 and 500 was prepared according to the following procedure. In a solution of 2 - [(4-chloromethyl) phenyl] propan-2-ol (769 mg, 4.16 mmol) (ref: Sgeagu, X. Mehrsheikh-Mohammadi. Mc. E., McDonald, S., 1. Org. Chem. 1987, 52. 3254) in SNJS1₂ (14 mL) at -78 ° C was added DAST (0.72 mL, 5.4 mmol). After 1.5 h, the solution was quenched with water and quenched at rt. The mixture is extracted with CH₂Cl · (Zh). The combined organic layers were dried (Na₂SO₄) and concentrate. Flash column chromatography (SiO₂, 0 to 5% EtOAc / hexanes) gave the chloride as a pale yellow liquid (512 mg. 66%). 1 H NMR (CDCl 3)₃, 300 MHz) b 7.30-7.48 (m, 4H). 4.58 (s, 2 H), 1.70 (s, ZN), 1.63 (s, ZN).

Preparation of 4-bromomethyl-benzoic acid 2-trimethylsilyanyl-ethyl ester. used in the synthesis of Example 470 was described by Graffner-Nordberg. M., Sjoedin, K .. Tunek, A., Hallberg, A. Chem. Pharm. Bull. 1998, 46. 591.

Conditions for chromatographic separation of enantiomeric mixtures

Condition 1: Example 345 is isolated using the following procedure. 4.6x250 mm. 10 μΜ, Chiracel, OJkolona. 1.0 ml / min, 85% hexane / EtOH 0.1% DEA, locomotive 20 min.

Lislov 2: Example 346 is isolated using the following procedure. 4.6x250 mm. 10 μΜ, Chiralpak AD column, 1.0 ml / min. 80% hexane / EtOH 0.15% DEA. during 20 min.

Condition 3: Example 347 was isolated using the following procedure. 4.6x250 mm, 10 μΜ, Chiralpak AD column, 1.0 ml / min. 65% hexane / IPA 0.1% DEA, over 18 min.

Condition 4: Examples 365 and 366 are isolated using the following procedure. 4.6x250 mm, 10 μΜ, Chiralpak AD column, 1.0 ml / min. 75% hexane / EtOH 0.15% DEA, over 25 min.

Lislov 5: Examples 408 and 409 are isolated using the following procedure. 4.6x250 mm. 10 μΜ, Chiracel OD column, 1.0 ml / min. 90% hexane / EtOH 0.15% DEA. during 36 min.

51155 Β

TABLE 4

<img file="RS51155B_D0134.tif" />

51155 Β

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<td> 1</td><td>Axis account</td><td> 423.2</td><td> 420.13</td><td>4 γΟ «SG</td>

<td>Ret./ Procedure</td><td>&lt; yes «5 &amp; d 2 VI O SC</td><td>1.71 Procedure Α ι [</td><td>1.45 Procedure A</td><td>1.58 Procedure Α</td>

<td>Calculate. MM</td><td> 429.37</td><td>CO Ολ sch gč Μ *</td><td>n 0 * r</td><td> 412.91</td>

<td>Appearance</td><td>white solid</td><td>white solid i</td><td>white solid substance</td><td>white solid</td>

<td>Reactionary scheme</td><td> -</td><td>h »« 4</td><td> «—1</td><td>V “i</td>

<td></td><td>0 P</td><td>o P</td><td>In p</td><td>0 Υ</td>

<td></td><td> 5 ^5</td><td>0 V</td><td> 2* □</td><td>IL ·</td>

<td>p £</td><td>^f&gt;</td><td>Ύ</td><td></td><td></td>

<td>A- x&gt;</td><td></td><td>«L</td><td>XG&gt;</td><td>r *</td>

51155 Β

<img file="RS51155B_D0135.tif" />

<img file="RS51155B_D0136.tif" />

51155 Β

<img file="RS51155B_D0137.tif" />

<img file="RS51155B_D0138.tif" />

<img file="RS51155B_D0139.tif" />

<img file="RS51155B_D0140.tif" />

<img file="RS51155B_D0141.tif" />

51155 Β

<img file="RS51155B_D0142.tif" />

<img file="RS51155B_D0143.tif" />

<img file="RS51155B_D0144.tif" />

<img file="RS51155B_D0145.tif" />

51155 Β

<td>NMR data</td><td>^M S? H · * St d s r- m -t oo · 'Ch d ά · η n -7 ο ° - π ^Ν. и Β đ с 2 V '-' S '| m 5? uS - ^: 2 Η? «” ΜΒΒ »Γτ5“? 8Β · ο 2G * OčhS ^ G)</td><td>O »&lt;N • 'Ώ C? G * &amp; 2 3 ~ Ξ 3 8 - £ 2- 4 S d ^_a-3 «z7 37.0 ^^ 4 04 ^ 3 υ ° ο? Η ρ ¢ 5 ^ g d - Τ S «• mD s d 7 Jd ~ £ β 5 ^ 8 £ · “.? £ πί '·</td><td>£ Ξ 7ς? 4 7 « S «'η. η Ρ § '“SiŠAS 7 4&gt; Γ ~ j. G4 -, 2.00 ο χ cg £ η Ά “3 I i Γ- t&gt; - Ώ“ Ί ΟΧ Ώ. . _-Ϊ́ΐνΐΐ&gt; 2 ^ 5 · ** Α V ►X ® Μ χο ο οο • ο c? 9 ”Μ * Ί RP Τ - ζΑ Κ II II _ χ · „. ž 4^κ. ± (? D m ί? Š 6 3? ± «* β G · 2 &lt;ΐ^Μ. d S D rf- ° Ρ335ο3ώΰ</td>

<td> 1</td><td> 423.2</td><td> 423.2</td><td>MS ι / Ί V) 'd'</td>

<td>Time ret./ Procedure</td><td>1.68 Procedure B 1</td><td>ffl -1 cho ο * -ϊ z U5 Ο sc</td><td>1.94 Procedure Β</td>

<td>'U 1—1 ez&gt; n SNS</td><td> 422.52</td><td> 422.52</td><td> 455.02</td>

<td>Appearance</td><td>pale yellow oil</td><td>1 pale yellow oil</td><td>clear oil</td>

<td>Reactionary scheme</td><td> -</td><td> -</td><td>gp</td>

<td>P4</td><td>0 £ P</td><td>α £ P</td><td>□ R</td>

<td>Bi</td><td>f ε u. o</td><td>ο s Ux Ο</td><td> 0</td>

<td> ~(4</td><td>Ύ</td><td></td><td></td>

<td>uu fu x&gt;</td><td>o &lt;s</td><td> &lt;4</td><td>N em</td>

51155 Β

<img file="RS51155B_D0146.tif" />

<img file="RS51155B_D0147.tif" />

<img file="RS51155B_D0148.tif" />

<img file="RS51155B_D0149.tif" />

51155 Β

<td>Ο 03 Ο ο £ Χ</td><td>s š 1-. X π o 5rn u. E η S °° 'S'_S35 = A ° PK ^ čđi «αα“ ± ss # čr ϊ □ Z-1- θ 'i ».1 _D« l ή 2 ® ® 5 £ 9 2</td><td>SC o g * f &lt;tn Ό 'V ό © nm O \ 04 ζρ Γ- t ® O D s- £ fssj «! ·? 'O O O &lt;L f * | i- &lt;Hoo QQ ~ SO · cd c II ό. o. U4 * - »&lt;» mm r ~&gt; ΜΜ &lt;&gt; жс®сг £ п ** СЧ Г £ м * 00 _г D * q Ό i *</td><td>Z¹ г ~ τι SR -x ° «e 5-00 Оч - -ч- * ^ Л ^ т¹ii o S n ώ · - »К · 'Ώ._ΜΌ £ v&gt; £ c mm ο „- 2 .4 ° 5 04 ΒΑ Β? Ϊ *! Ό Ό_ΜΟ * Ε D N3 T? 00 * 3 - X ' Λ ϊ X °° .og ~ Λ (4 Ό «9 ⁰⁴ Ο&gt; 5 L *. ^ ΤΓο ο. ₽4 Τ X Β χ * - 41 § 4 “1 η X Β Ό Ί, &amp; X —'X Μ “Χ ± /? Χ D Ό · * Ό νΓ te · · * đ b '· κϋ · -D ΓΠ Ο' «-« *</td><td>. &lt;=&gt; ο2 ^&gt; ττ οο X S »χ = g g-ς / δ-Λ £, 55 χ χ G, X tf 8 Κ _ X JZ -S g 's Ρ &gt; · V) 00 fT&gt; ΟΊ &lt;ο 'Č χ 2 d 2' R č r- G ** · S? and O ^ rn _{L L} tn 0O un tj ν''ν '^ ϊ— ° i S · QXX ΒχΊδ Ο ο ο h; 5xo' -'θά «i.g3Ks pd II II - °.» II 5 h h w d w h rsl Csi θ 'CO ! _ □ ™ ° 1 еч о ес 2J. ffl * σ đ · · · tz -X &lt;&gt; Ό TG * m &lt;—f</td>

<td>S</td><td>Ο Ο \</td><td>CN 40 Ч'Т</td><td>G- « 0С СЧ</td><td> 485.0</td>

<td>Ret./ Procedure</td><td>1.21 Procedure Α</td><td>1.08 Procedure A</td><td>1.51 Procedure Α</td><td>1.89 Procedure Α</td>

<td>'В 1— сЗ&gt;^N 2</td><td> 490.13</td><td> 446.01</td><td> 428.91</td><td> 484.59</td>

<td>Appearance</td><td>clear oil</td><td>bistro uljc</td><td>--------------------------------------------------- ------------------- -----------------------------, white solid</td><td>white solid</td>

<td>Reactionary scheme</td><td>m</td><td> &lt;*)</td><td>Μ</td><td> -</td>

<td></td><td>u 9</td><td>u 9</td><td>ο Ρ</td><td>m U. at 9</td>

<td>vj</td><td>o no</td><td>0 ^ g⁴</td><td>X U. ο</td><td></td>

<td>G4</td><td>Ύ</td><td>Ύ</td><td>^!&gt;</td><td>Ύ</td>

<td>U and CU X)</td><td>ГгЧ</td><td>00 &lt;s</td><td>ο СЧ</td><td>om</td>

51155 Β

<img file="RS51155B_D0150.tif" />

<img file="RS51155B_D0151.tif" />

<img file="RS51155B_D0152.tif" />

<img file="RS51155B_D0153.tif" />

<img file="RS51155B_D0154.tif" />

100

51155Β

<td>03 Ό Ο Λ</td><td>\ έ&gt; n D D D „g-1„ Č.P ~ 0 ^ 0 v E E ffi * 4 N «č-uh-h č_&gt; oo m *. gq o W_w. Ε &lt;7 &lt;7 ο Γ0 Γ- Λ τ 'ζ; ό Α ο ο «, ΜΌ'Ύη-'Ο NS _g --5 H md s «U Ν'S8 D 'O 5? 0S§xSWi- $ gijSTssa «? ^^ '^ aGE — g-J—: tz Pč «Ž 1 — č m' S θ '* 7 I' T M r * Č ^ 31č&gt; f * S gl SČ A o S-</td><td>$ + + r «l 3 J. K p $ ο »Č G« J · - m ° *, - &lt;. γ-, z ί «5 jt ** *“ I Ό Q Ε c £, 60 hl χη Ε &lt;&gt; Ε χ ε&gt; ss 5 «ν” didT ^ Sl ® ш3еМ-ш £ -о</td><td>L O&gt; oj K Π, ο Ο i-) «Ί sl · ^g: rj Α S ^ 5 «5 δ ^ 4. fig 'η S.¹°. uj 'tfl ο " ^M cf ' ^Ν - 7&gt; * ° &lt;Ί. ~ ί -μG oo - S 3 &lt;p '° 2.Zl „. U θ sE- oo čg 0 θ Τ / ΐ'ΓΊοο.-στ. —'-. Vk D -ί n K N g D 4 D? G ® · S Z- V · α · ο</td>

<td>ι</td><td>ri ri 40</td><td>p 00</td><td> 429.1</td>

<td>Ret./ Procedure</td><td>1.31 Procedure A</td><td>1.25 Procedure A</td><td>1.5 Procedure Α</td>

<td>N g</td><td>oo Oi</td><td> 418.0</td><td> 428.91</td>

<td>Appearance</td><td>clear oil 1</td><td>clear oil</td><td>yellow-brown solid</td>

<td>Reactionary scheme</td><td>m</td><td></td><td></td>

<td></td><td>υ</td><td>G P</td><td>Ђ P</td>

<td> 04</td><td>ο</td><td> . \ 2—</td><td>\ u- O ^ 5</td>

<td>s4</td><td>? -y</td><td>Ύ -</td><td>n</td>

<td>u</td><td>m en</td><td>40 ΓΊ</td><td>br * -&gt;</td>

101

51155 Β

<td>υ CQ tz 0 &amp;</td><td>đ * Ο sch οχ νΐ ι Ο ~ Οχ σ »Ο γ&gt; ζ- &lt;ο 0 m D g» 40 -1 - - and¹ ε V *} D - ϊ&gt; ρΓ ρμ Λ ^no^ '· - &lt; «= - = - ^ 'V · π C2^Ђ? FS °. . h5-5? s35</td><td>_l - &amp; 0X r- ^. -d * eč č a do £ - G- N -M £ g □ h a a + _e* χ · &lt;a m i-S²- ^. «JO ^⁴. Χΐ + η — '40 &gt;? b_i-&gt; 2 ά ο &gt; 1 r- -1 T = * Λ - S m? ° '' Ζ X ϊ ~ - ® t; - Ž z «. ^ s + gs. рJГХ.Жв-jј g z№- F 3 3 ΐ V&gt; -1 O S</td><td>s4 « D ~ 1 ο £ “2 £ V Ί P 41 Τ. • SgS 'S S-ooslOč ^ Js - ^^ oKJ 3 -.-. * i s. QS I X I D (S a rf® UN and η η ig 33 ° DD D ^ .m-ooo D gw hj&gt; ί i'8 *? 7 a and 3333 «D - -3</td>

<td>+ ϊ 2</td><td>sch Η -F</td><td>eč m · o f</td><td>Φ un φ</td>

<td>Weather Tet./ Procedure</td><td>c 4 rM sL o v-</td><td>&lt; r- s Rč W 3 «-» ΪΛ Ο cu</td><td>&lt; »L l. HO d »-D Č-» 1L Ο Ι-ι</td>

<td>ea 5 α N 5</td><td>45 F oi P * -f</td><td>οο Φ 8 φ</td><td>σχ φ GP &lt;η φ</td>

<td>Appearance</td><td>white solid</td><td>white solid</td><td>white solid</td>

<td>Ο υ ^ S Ο S pi «»</td><td>f-4</td><td></td><td>r — 1</td>

<td>Β5</td><td>l H. fi</td><td>u. , P</td><td>p c_ υ fi</td>

<td>Ρ &lt;</td><td>\ u. Oh</td><td>^z\ u</td><td>^Ζ\ u</td>

<td>* ρί</td><td>n</td><td>Ύ</td><td>. Ύ</td>

<td>Ρ- X)</td><td>oo m</td><td>οχ m</td><td>ο φ</td>

102

51155 Β

<td>ο T5 Ο α</td><td>2 £ v ~&gt; I Ο £ ϊ D - = r Ά Ή d sS ί '·· b% ΑίΑ 32.22. onSp °. o-S'S-'n'IT Q d d d S * -t. LZ d? eG S 0 o sch ο · η κΤ D D ο © ^ 00000000 ^: ^ 2 ^^ 12ρί II II ι 1 Μ 9 ΐ ί Ο 'e --1 - -. SS Α Β4 · s χ μ d jg κ * S 'ι Κ £ ®3®®-2S®5Slq. d Ό Ό Ό τ&gt; w J + - J g4 3³,</td><td>- * ef m £ ~ 2 o °! -. . ° £ - «Ας5 G- O m - 04 Ui * T * 't *' Жи ^ РСшСс. «Ob®5 34% s'S ^ S'S »⁰- 6 ® ® £ -SS'Sig £ · 'v * = pAisfe ^ ešvb ^ h ^ MZva ДđđмјпјК · тј тј С-ч&gt; О Т * ц \ | G9 O «/</td><td>W&gt; θ '» ЧТ сч η&gt; λ η N £ сбп! 2з? &lt;rn Η _ r \ l ^ sdc? Ε «ο. * Σ I - = = 'ο *« ϋχ r-2 * 3 μ * F m n j Ε g '4 (Ο «1 = Ο 3 &lt; / -st ^ «ο FT 00 SL ο - .® = c C ο 1 U 'ti'N' ^ Μ - U «ΟΜΜΊόΝχί 000 ^ 1 /) 0, ^ 3 27 h? 4? Σ2 γΊ · * “'t ρίΙΙΙΌ · _ _. t ^ Ζ? Ϊ S ί 4 4 ο&gt; “izz ^ ££ 22</td>

<td> 1</td><td>04 Ο © ^ ·</td><td>sch Tt * t</td><td>Γ * Ί Ο ΤΓ 'and'</td>

<td>Time ret./ Procedure</td><td>&lt; -3 € Π CL vq d * “* Ώ Oh</td><td>&lt; -t Ul o Ach</td><td>&lt;ο «'!. 25 α&gt; ο CU</td>

<td>&gt; ό _ b «Μ N * 5 μ — t ^ -ί</td><td>Mrs. W&gt; O \ 05 m</td><td>o. n &lt;± HG</td><td>Ό ο 'χΤ</td>

<td>Τ3 Q .ο N ί-Η</td><td>rt CJ eg 2 rt K^. &lt;l č w CU w&gt; z X&gt; K&gt; sl</td><td> 2_Usl -, -, • Μ «mN -C z</td><td>ο ♦ 3 ο cn .—, • &lt;· * Λ □</td>

<td>Reactionary scheme</td><td></td><td>m</td><td>ΓΊ</td>

<td></td><td></td><td>υ fi</td><td>Ο 0 4</td>

<td>e4</td><td>z (~ 7</td><td>ϋ</td><td> 0</td>

<td>Yes</td><td>Ύ</td><td>Α</td><td>Ύ</td>

<td>In 1m 'SC JD</td><td></td><td>sM</td><td>m</td>

103

51155 Β

<img file="RS51155B_D0155.tif" />

<img file="RS51155B_D0156.tif" />

<img file="RS51155B_D0157.tif" />

<img file="RS51155B_D0158.tif" />

<img file="RS51155B_D0159.tif" />

ul ui

CU J =&gt;

<img file="RS51155B_D0160.tif" />

104

51155 Β

<td>NMR data ..</td><td>&lt;5 ® £ « s η. S O Ž E i ® '“ϊ. Ί S io, 2 Ϊ / 2fe t- n g ». - -α р- ο о .l £ 5 'n-: Č -' ΐ? -TLl ·⁰® ± ° q i d m S ΰ g D £ O o 2- »5S ο ?? Q&gt; “» Ό * 7 * t £ Ž 'Ό sw i 1 Ϊ ž5 «2 * £; *“ «$ ί Zg &lt;ZdD« 63</td><td>n Ш Ч 0 в&gt; I 3 D ° i D f 7 «D-d £ i £ o &lt;č S gg č 2 00 Ί3« G ⁰⁰ M ° lz »O --S J t⁴. μ g 5 Α. 6VbM £ i ® ~ 7 °° m ® 'Č r &lt;n P t χ £ Ό «Ί T 3 lz - Sl 't- -t 4 - °</td><td>G -Č- Π. Ό Ρ £ Ε 90 - u ^ 3 £ U 00 JD Ό * - Μ •&gt; ΙΛ ΤΊ ι Γ- w * 2 Α Ο \ 'Γ £ Q d d tj εΓγ- I 4o3r- =, V, - ο '00 00 f- SC ~ - i? Λ ^ η £ Α W4 -r £ i- '“i Ά &lt;N α Στ D Ό TZ CO' '-J Π Ό \ _z s— G * H SC S. Č-ι * ·</td>

<td> *5 2</td><td> 440.2</td><td>Ο 4-</td><td> 432</td>

<td>Ret./ Procedure</td><td>1.69 Procedure A</td><td>1.26 Procedure Α</td><td>1.19 Procedure A</td>

<td>Calculate. MM</td><td>cn Oh Gί G * b</td><td> 409.94</td><td>c \ c \ m TG</td>

<td>Appearance</td><td>yellow solid</td><td>yellow-brown solid</td><td>yellow-brown foam</td>

<td>Reactionary scheme</td><td> ¥-»</td><td>tg</td><td>m</td>

<td>k</td><td> □</td><td>b F</td><td>u .0</td>

<td></td><td>□ z</td><td>Ν X 2 ^ Ч&gt;</td><td> 0 1</td>

<td>~ d</td><td> 0-</td><td>Α</td><td> 0-</td>

<td>CU -O</td><td>r * • 4 ·</td><td>00 'e</td><td>o • * r</td>

105

51155 Β

<td>NMR data</td><td>Mrs._l£ £ 4 -b⁴» ž ί &lt;STS⁴»05 G? G * ~ · r- »” _gP / 4 - £ D kG „“ S «eo&gt; + 23» I ^v «S Gfgr -S ^ S Q ffl II \ O. v&gt; VI Ž C ο '-i. -. ° C?^N o ag “li + di; еđ У ^MG! L .11 S »rf e —G S *« K Č&gt; * », B ft «2 £« u · 7- Ά</td><td>O -&gt; A? 'n' · -¹ Z? G n-ί • θ θ '&gt; 4 d U ° O. £ κ · τ. j K Ч И г β, η V4 Ρ5 r-h. ► · m 43 J- ”S · IZ v&gt; Č- gP &lt;l t&gt; - - '&lt;O 0 ο ή b # g H ^ Z ^ ISOSOMH ^^ m ^ giAAi.Si S4 ž ^ SSSs'sJšS 43 ТЗ 45 * 43 и II 3 2 Ό 17 * чЗ * · ~~&gt; '__ · ι-ч ГЧ · - · ч ^ /</td><td>2J sch ® v&gt; VO .. pJ-4 oo ίΖϊ⁴ ^ 1 _р 1 ® so 'Ί č £? » nč Kf * kG _ GP QQ ® sć l k S o ™ t i ^G1 L. n kO uG O - - 2+ ° (o S 7? ^ ° 1 ^Μ “S U 77 + 'S'lA V 77 Dаgгп ^ -Ак Ο Π £ · ® 4 &amp; ς&gt; д Α ”£ 7τ®3Ϊ 9 D. τΓ -&gt;. »£ i S * 4 &amp; Μ Α hH 35 *. · Η4 Ο - ♦ ± f G 2ί ο + «^ R + S ^ A sč = 3</td>

<td>Μ + Η *</td><td> 437.1</td><td>rH &lt;s Xf</td><td>Ο Ch -šf</td>

<td>Time ret./ Procedure</td><td>1.58 Procedure A 1</td><td>1.21 Procedure A</td><td>1.79 Procedure A</td>

<td>= ό N 5 l — t &amp;</td><td> 436.51</td><td>г &lt;3ч н гЧ m ·</td><td>o 05 OO 'f</td>

<td>Appearance</td><td>white Solid 1 1 i</td><td>yellow-brown Solid! substance</td><td>white Solid</td>

<td>go 5</td><td> «-4</td><td>4f</td><td> -</td>

<td></td><td>u. ?</td><td>ϋ fi</td><td>fi</td>

<td>p4</td><td>/ o i</td><td>\ ΞΧ</td><td>u? o</td>

<td>p &lt;</td><td></td><td>Ύ</td><td></td>

<td>&gt; - &lt;u Pn X&gt;</td><td>o ¥ Ί</td><td></td><td>СЧ «ΖΊ</td>

106

51155 Β

<img file="RS51155B_D0161.tif" />

107

51155 Β

<td>NMR data</td><td>“Č c? ό £ i 5 U · ”! rt. and? ho ^ t · '* q ČG VO g-č « U2S⁴o '+^NNo7 ° ry · _LGO_G - _ Ο Λ ' 8 I χί'Άσί 'Ί «d . Ο * g-č © Ο_l „SP ! ss 41 “” and ash and S ^rt -! ° Ί Ό κ R °! η - П -4 ~ ГЧтЛСЧГ4 ^ ФФ</td><td>S -m £ C ¹- ®- сч „~ -е '-ζ - G * * “&gt; S: gm 'O _l TZ II 5.32^1/1 «» S · ^ r &lt;η Λ δ ή '/. T - 7 «S t- ο C3 e? 2. &lt;*&gt; Poo '^' ^ 't'S'C' ZS £ ® £ da II . Ϊ sl&gt; l g ^ _ m 5 v S ί h D - S =^sA * · P &lt;-&gt; _ MS G * • n 2 ⁰⁴ KR ^ Zi mS - o</td><td>o&gt;,, -; ° l · -W II nif t- s ώ&gt; -&gt; «to C4„ · w 00 'n'tJ''b 7 + 4 ESS D °&gt; Ο Ό &lt;4 S „- © _2 - oo ^M D 'l. X hj - e l = .11 JL -tč 4 = 00 --- 'D S- S. - чJЧ с and Č s π δ τ S g ^m &lt;*&gt; - Ά ® η ιι. ^l Ό m α — v ΒΛ ζ &lt;Χ '-'α . ΟΟ - 'GM „Ιφ / «-, ·» · MS ο « Đ Μ σι © g d - S- II -4- co Om</td>

<td>ιΧι £</td><td>458.2 L</td><td>Mrs. o, en</td><td> 363.1</td>

<td>Ret./ Procedure</td><td>2.16 Procedure C</td><td>1.51 Procedure A</td><td>1.28 Procedure Α</td>

<td>NW 5 c N 2</td><td> 458.07 _</td><td>68Ό6Ε</td><td> 362.83</td>

<td>Appearance</td><td>brown oil i__</td><td>colorless oil</td><td>white solid</td>

<td>Reactionary scheme</td><td>m</td><td>vn</td><td>u-)</td>

<td></td><td>P</td><td>o F</td><td>o</td>

<td>pS</td><td>o</td><td>/ o g</td><td>o</td>

<td></td><td>Ύ</td><td></td><td></td>

<td>* -ί u * SC £&gt;</td><td>G ' VI</td><td>oo</td><td>σ \ un</td>

108

51155 Β

<td>Q Cđ 75 g</td><td>- - »ŠđS ac n.-Eđ '-' gN ^ j &lt;N ® ZL S ć - = - ° II ; o&gt; l 5 n -r - n κιί u-3§ £££ 3 45 TZ Č m wS σ&gt; “Μ Ά Ο tg II Sč S II« 4 - Q Č = n 0^I. »Ν 'Og-d ^ z d N« D and fnf _Μ-πΤ nk</td><td>H-0 &gt; W _r S SC Ό · - &lt;jč g, 0 co ό X \ z 11 si u r. ·? C) 0 1 - m 3 1 «°° - · - · 3 ^G1 hs l k ¹¹</td><td>_- D. , _ς τί i? d £ 3z§_s-g « D ££ k GT X «G Ή \ o _, O υ α. * ° Ά 'Τ II BSiR'Sga w&gt; 7&gt; D ⁰⁰Z 2 ^m 2 ° - š T u-7 ”1 n d r D r 43 n m</td>

<td></td><td> 409.1</td><td> 453.08</td><td>o m 7G</td>

<td>Ret./ Procedure</td><td>1.82 min Procedure B</td><td>1.85 min Procedure A</td><td>1.81 min Procedure Β</td>

<td>Wi GO&gt; m s N 2</td><td> 408.95</td><td>452.96 I</td><td> 430.95</td>

<td>Appearance</td><td>white solid</td><td>white solid</td><td>white solid</td>

<td>Reactionary scheme</td><td>1-solid substrate</td><td>1-Procedure. A</td><td>1 -solid substrate</td>

<td></td><td>D 0 no</td><td>fi</td><td>X</td>

<td></td><td>đ&gt; 2</td><td>/ o '\ = o o</td><td></td>

<td>e4</td><td>Ύ</td><td></td><td>Ύ</td>

<td>Fh U « RčL</td><td>oo</td><td>v — 4</td><td>sch ko</td>

109

51155Β

<td>NMR data</td><td>'T sb »π«% 5 £ T UooJL ^ ln ..— Q “!^H . * 1 · * »• o'n 'U t * i ΰ * j * -Х 5. С 'С'— оо оо г&gt; с ев'? s ® S «? S- ^. s ° ± g =? r- 00 -_e? č £ T “HI</td><td>Tt. who un * z-5 · * · O „ ^m ž ¢ 4 „ шС .- ^ С2 С ^K. »D« g d «5 Γ-γ« M г ^ дг-лшс 'Οθίκϊ * 7 сđ 1? · ° хIл § ffl i, D ^a. ^ D d gŠ'A £ -tf</td><td>.o-dS- ^ S g G «g1d n ° ii ® ° \ £ “&gt; i “g ττ γ * 2 ⁴⁰ α - &lt;ν ζ-ι £ β · Ο © Τ ΙΤϊ Brl σι ί °° ν_σ· G 2 V 1? 2^w. ο * β 8) _γ η ”b J Ο \</td>

<td> 2</td><td>c * O «—1 Fč?</td><td>395.11 M + Na</td><td> 438.1</td>

<td>Time ret./ Pcstupak</td><td>2.04 min Procedure B i</td><td>1.82 min Procedure B</td><td>1.39 Procedure A</td>

<td>&lt;5 s§ NS * t — 4 &lt;4</td><td> 471.02 !</td><td> 372.92</td><td> 437.99</td>

<td>Appearance</td><td>pale yellow solid 1</td><td>pale pink. solid</td><td>white solid</td>

<td>Reactionary scheme</td><td>1-Solid substrate</td><td>1-solid substrate</td><td>'F</td>

<td></td><td>t&gt; P</td><td>fi</td><td>u P</td>

<td></td><td>o o</td><td> 1</td><td>\ z—</td>

<td></td><td>Ύ '</td><td>. Ύ</td><td></td>

<td>Pr. no.</td><td>SL Ό</td><td>tg o</td><td>»N Ό</td>

110

51155 Β

<img file="RS51155B_D0162.tif" />

<img file="RS51155B_D0163.tif" />

<img file="RS51155B_D0164.tif" />

<img file="RS51155B_D0165.tif" />

<img file="RS51155B_D0166.tif" />

<img file="RS51155B_D0167.tif" />

<img file="RS51155B_D0168.tif" />

<img file="RS51155B_D0169.tif" />

0-Χ

<img file="RS51155B_D0170.tif" />

111

51155Β

<td>NMR data</td><td> ε r- S! 55 SG. ^ · Οο \ o “? * Π, -ζ oo _ · r— t &lt;CN II t—, - o. O s' »Ll cA &lt;? s K * Β · đs vo • μ · 'j co. _G n OW 'T S5 - o tS4 gch - D r J? » r- «l -. O rfdi-đL M '-'. G 'Π ΐαί S' -'n, - D r- ⁴⁰U · ® II „&gt; n5 JO ¹у W СЧ р- · гП .. У. S g *&gt; p ^ SJ · ЖОК - «Д Z. tn CS DQ i Ά h &lt;p 27¹ b * S- \ O n gč OC,</td><td>hR η s «* N ^³. Μ &lt;*} * J * GT T n E g. ji A o&gt; g ^ D j E^. VI - '-⁴ . SL 3t &lt;kS Q ^1/1 5S- ® ⁰ D Ή 7? ΰ&gt; ίΠΑ ~ 5§ ο ° 3 l &lt;-, - - Mrf N ιλ Γ _Λ ζ · *. 5? ώ η »D &lt;&gt; Μ Μ &gt; r &lt;'n' Si S Ό Ρ 8 R D R «# Sr- Ort</td><td>o W _l l d * m t * * ζ. Ε -4, Ν _Λ „Ν_ζ^m D 4? h- g sp t T5 A_w- sč P r; W -⁷ - θ ', - «© r- l! &lt;-&gt; tz g4&gt; „ VnS ^ Ss 1 Β ο Α -4 D W CM -Π &lt;Ν. . Ζ ~ 4 Α Ο * ± đ Ο S Đ Ђ Β \. Μ D , ζ-cho λ ⁰⁰ τ? Š N &lt;Γ, _rj Ch CA N Z * S4 »- · J2 SC v- / a ϊίϊ 2 ^ 1</td><td>rA 00 j Ο n 'kG X £ Ξ l KG L2 a em V mr * οδ⁵^⁷⁰· Ί? Γγ S —'® ° 5 * Os * Sj δΑζΛ ^ ζ * L pi ν 'μ · 5 · * Ε - NS ® 3 S vT ^ _i-2 22d -&gt; —Ϊ Γ * Č-Ζ «&lt;-«&gt; ​​- &lt;· -¹ ►-»</td>

<td></td><td> 423.14</td><td> 467.03</td><td> 388.0</td><td> 482.06</td>

<td>Ret./ Procedure</td><td>1.56 min Procedure A</td><td>I 1.77niin Procedure Β</td><td>1.80min Procedure Β</td><td>l-79min Procedure Β 1 ..... —........</td>

<td>Calculate. MM</td><td>00 hG ri</td><td> 466.89</td><td>o&gt; 00 of α \ m</td><td> 482.01</td>

<td>Appearance</td><td>white solid</td><td>white solid</td><td>white waxy substance</td><td>white solid</td>

<td>Reactionary scheme</td><td>\ o</td><td>1-Procedure.A</td><td>1-Procedure.A</td><td>1-Procedure.A</td>

<td></td><td>u. P</td><td>υ</td><td>υ?</td><td>0 P</td>

<td>Pi</td><td>t o \ = o (/</td><td>uu C.-U u- \ /</td><td>u.</td><td>'LU^g 0</td>

<td>~ sha</td><td></td><td>? -y_</td><td>£ -y_</td><td>* λ_</td>

<td>SC</td><td>who</td><td>0 G'-</td><td>r *</td><td>see</td>

112

51155 Β

<td>NMR data</td><td> -4. ¹r- t · ο 3 w X n? 1 Ό i _ G- OO &lt;, g »'- * &gt; 3 ^ _i «= L _m ef = « ⁰⁰ L_4 Λ _ ΟΧ ίΠ ϊ&gt; Ш С ii ° Ч дг 1 F 2 2.S o t- 2. r- * A _k n «. k ». η</td><td>oš d ° i 2 S II 3 2χ2 o 7 &lt;, - rn Ώ fn = 1 *; α J »&gt; TT - &lt;d sE. Q «Ί 3 CN OO &lt;l ^ J. g □ 7 ч / &lt;-ч&gt;. · Fl * “&lt;» ^ Sb-OC'sHO. b ~ ° o _ Ξ - h · h ό g ί ο «w 'r« co ₄</td><td>Γ- С п - &lt;Н »м ш ¹⁰ I ~ - 'C- = CS χ ”ν · ^« ofio' o cf S οό μ 'Ώ C)' ί 'ιι sl ο &lt;λ 2j “7 3 χ&gt; 3 ο ​​gm« -σι m r- &lt;(-. g4 oo vo X \ j, Jqx * i V 7 - q υ &lt;č «c &lt;0 £ Q II oo D D _m ς-ζ 2- ,, ~ _w V&gt; 1D ν— » С »ι ί-» - __τ α: д * г сч 1 Ζ τ '*' Ί »- &lt;b * Ό * i * τ · 2 ε ° i ~ Sr5 h? U3 xr C G4</td>

<td></td><td>427.09 I</td><td> 437.09 | 1 1 1</td><td>m ο A Ο e</td>

<td>Ret./ Procedure</td><td>MP g- o ° 5 ri sl ο cu</td><td>1.88 min Procedure A</td><td>1.63 min Procedure A</td>

<td>Calculate. MM</td><td>ο Сч 'Ο gč 'ύ *</td><td> 436.92</td><td> 403.89</td>

<td>Appearance</td><td>pale yellow solid 1 !!</td><td>colorless uljc</td><td>white solid</td>

<td>Reactionary scheme</td><td>l-Postup.A</td><td>&lt;d 3 • m w O o.</td><td>----------------- η 1-Procedure.A</td>

<td>Pi</td><td>ϋ fi</td><td>6 fi</td><td>Q 'fi</td>

<td></td><td>\ c. o</td><td>/ o \ = o / Č</td><td>z / o</td>

<td>rj</td><td></td><td> 0 .</td><td> 0</td>

<td> 0-</td><td>m</td><td>xr g-</td><td>Ό r *</td>

113

51155 Β

<td>NMR data</td><td>r- - &lt;n - ZJ s π r&gt; o, -č- m S 9&gt; 9 d.-Ί 1 &lt;4 &lt;* »Ч еч оо мл« - рđ r&gt; *** ΜΊ * T _U * Fj -lί A ο © ϊ 5. ν) o ,. 51 I S ta β-tСШ «! Μ З м ч- о \ оо&gt; л са Ч «м ^Ν Ί Ά * Č? · S * o ίο 'F II r®</td><td>-I .® Ž Ο. - Е.^Ν, S - ° I Β 2 «3-00 sS. 0 0 ο 1 &lt;η 5 D Ρ *. Η »* Τ5 -2 Ο L-Č Γ- D νο D «Ο Ν. »Η Ν ~ 'I tj Ο ι Λ · »ο £ »&amp; 2 SS s? ^ Kd ^ dZZd</td><td>• m £ m ° i S n-g 57 ^m »Đ - a &lt;af? _Ε-ϊϊ t &lt;ffi * Ά '-' »- _ „C? Ν Λ η ΓΠ ό 15 ώ &lt;ч τΥ Ђ · Ο Ν Μ Μ -X ς ^ '- χ Π ή Ε ± 3 ο - · Β Ο &lt;l i 4 · _ _ο γ £ 4 'S'S Ν »-⁴ΒΤ ^ ϊίίΐ D [ν&gt; l Η</td><td>.jfi-f _i i .s E? S »0,. · M 00 - · * II Zoo * 'tg? _Ε* Ί. A ts ^ .h r-. &lt;3ⁱ”NP fn _j.O *? d ichzB, 3 8 S * GDg * K0 ^ gg&gt; -m—</td>

<td>+ d ž</td><td> 447.05</td><td>Ν 40 of tg</td><td>4đ · S Ο ζ τ-4 -] -</td><td>'đ' you ®? 4- 92</td>

<td>Ret./ Procedure</td><td>2.04 min Procedure A</td><td>1.51min Procedure B</td><td>S &amp; 4 3 οο * - · • V5 *** Ο cu</td><td>1.89 Procedure B</td>

<td>Calculate. MM</td><td>oo DO \ ό t</td><td> 405.91</td><td> 408.95</td><td> 408.95</td>

<td>Appearance</td><td>white solid</td><td>ίβ ο s4 * К С. 0 ^ 3 Ό Ό &lt;Λ</td><td>white foam</td><td>colorless syrup</td>

<td>Reactionary scheme</td><td>1-Procedure. A</td><td>1-Procedure.A</td><td>1-solid substrate</td><td>1 -solid substrate</td>

<td> ¢4</td><td>0 F</td><td>υ</td><td>υ p</td><td>0 P</td>

<td></td><td>u_ C.L — u. (7</td><td>—-Z. 0</td><td> «</td><td>9 l.</td>

<td>Ίχ &lt;</td><td>V</td><td></td><td>Ύ</td><td></td>

<td>uu</td><td>ke&gt; r-</td><td>r * ·</td><td>00 r-</td><td>O \</td>

114

51155 Β

<img file="RS51155B_D0171.tif" />

<img file="RS51155B_D0172.tif" />

<img file="RS51155B_D0173.tif" />

115

51155 Β

<img file="RS51155B_D0174.tif" />

<img file="RS51155B_D0175.tif" />

116

Reactionary _Izgi_ed Expression. Vremeret./_{шн +} NMR data

<img file="RS51155B_D0176.tif" />

<img file="RS51155B_D0177.tif" />

117

51155 Β

<td>Ο Ο a</td><td>°° s m h v: Z? - P - g t&gt; - SO g • đ ha __ “ ^t~ 1 Gh? ο, Ό Ό ►— O oo - £ · r, U1- A, ram . I Š O._s . • i&gt; r i 'Ρ - σΧ 1 || ®SN® 2 m o _s . - &lt;m „5 ώ m. E · σ E Sj 1 I W © =. in g * gč g i as «? L, ZNN g * · w&gt; X_ž m «—- ~ g Č Č ž WX? Ε'Έ'Γ'- ό m * - * &lt;h</td><td>&lt;Α οοί&gt; - “ff σ D = - π JP X 3 · £, · ° £ ST 'η ^Ν.δ »·²ο ° Ό ^C. “1 _Ν' ^Γ&gt; Q λ η Ck ιγ) ο · - - * «; · Ρ sč X ρ Γ х «ш оД η η, Β-^{10 Ν} J 3 - - &lt;₽r Ο&gt; 5J «SX ο ο⁰⁰ l © S ° ® ΚΝΟΙ'ΙτιΓ'Ι.Αμ</td><td>t ** --- 2¹* n N s— * m O z ° -1 »» u k KJ 2-G.N Ό e.⁰'« S £ 5 R ⁱ “ _I ο ls ?: 'Ч ^^ - рш · | Г | ° ^ -5зо * iGrn 5 - 1Λ «© ¹¹Ο ιι II oSf обчУ.з · ^ έδ! ''. '!⁵'³’?⁰Z «5. ^š “ -г-гчОС ^ сч - - м</td>

<td>S</td><td> 423.05</td><td> 450.2</td><td> 502.1</td>

<td>Ret./ Procedure</td><td>1.41 πώι Procedure Α i</td><td>1.62min Procedure Β</td><td>1.72 Procedure A</td>

<td>Expression. ΜΜ</td><td> 422.89</td><td> 450.0</td><td> 502.08</td>

<td>Appearance</td><td>white solid i</td><td>yellow-brown solid</td><td>white solid</td>

<td>Reactionary scheme</td><td>MZ</td><td>SC '</td><td>G '</td>

<td></td><td>υ Γ</td><td>o</td><td>o 0 X</td>

<td>'al</td><td>X ο s = ° (/</td><td> 0</td><td>4- o ) = a?</td>

<td>P4</td><td></td><td></td><td></td>

<td>uu CU -D</td><td>ο Ο \</td><td>CA</td><td>Mrs. C *</td>

118

51155 Β

<td>NMR data</td><td>O ”š i D tn '-j · s ι »” D d _m- o 5 k, _ -u ^mp E D _ &lt;$ e Y £ G • «'SS'f» “Υ q so S m - t3 8 egggvSs. ₽5 „*_l jc? S 72- S &lt;2 · ► «* ° * - · D Z mv ~&gt; m^MO 'JZ G- u d II F 00 S chg iSsS— -i</td><td>'and oo &lt;-X «3 ν S - ^BOZ? . η 3 * ΐ Ο 'Č Ό Ο&gt; 0 ° ΥΥν, Π? * S ι ϊ «® S a S · ~&gt; d · θ, d * 3 * β °. —R n S S 3b- S &lt;? - &lt;o Z ka Alb- W4 _ž c \ UN η D ιη - oq čz- mm čz</td><td> -^k'- E £ □ 0 g ® ^' '.' N '-' S &lt;=&gt; 'eČ ^ / GtzDO · £ 7 «2 2 5 ® * O I-k Ifl \ fi 8 ι - 2 * .—,. D0, 2 «J, \ 0 Ο D? S &lt;1 ο * η, ® -&gt; 0 sč t—- D g—,_n II 8 ^ 7-52 ^ 2 ί5 ~ &lt;Μ * · SD Α ^ 5³e&gt; * 1 S I ϊ &lt;l V4 ψ ž Ό (J. P · oo - g ιΧ »/ -S D«. “Θ '§ II S® D« J £ D a «£ T« γιγ'Η, ,η, 'τμ s- /</td>

<td>BS + s</td><td> 478.1</td><td> 531.2</td><td> 425.17</td>

<td>Time ret./ Procedure</td><td>1.60 Procedure A</td><td>1.59 Posiupak A</td><td>1.49 min Procedure A</td>

<td>Calculate. MM</td><td> 478.01</td><td> 530.20</td><td>04 • ч · 'ГЧ е</td>

<td>Appearance</td><td>white solid</td><td>white solid</td><td>white solid</td>

<td>Reactionary scheme</td><td>1G&gt;</td><td>V4</td><td> 00</td>

<td></td><td> 5</td><td>w</td><td>o 0 no</td>

<td></td><td>Sđ</td><td> 0 °=&lt; 0 3</td><td>X o</td>

<td></td><td>Ύ</td><td>? “Y_ /</td><td>Ύ '</td>

<td>Μ Μ Sm X)</td><td>GL CN</td><td> 04</td><td>Ή 04</td>

119

51155 Β

<td>cž η Ο (λ</td><td>Ч &lt;н&gt; ^l I 7? . π ° o 'SASSsbΓ ^ η3₂° * o - &lt;O Ž V5 Q i— » &lt;- 'O'G &lt;N „. Afl L \ R « Do »ο II. tj N 8 Ο ° ο 'S 2 6 ”&amp; αγ® t = Ρ ο II 2 ώ 3. η S ~ 12 2 = Α ^ · 2 d β 't Τ Τ ° i ® - Γ * tN Γ * L * ϋ »» »“ $ ΓΟ · —1 gm GO</td><td>&lt;- ~ s c S £ ο «ι.^Ν. g jgN &amp; z ^ boI J? Ό 0F w&gt; T * “** r ·« * -ζ «, Ο 3 fi. D α ”Α ζΑ Γ-. _Μ- 00 d Μ ί¹⁴ η «I. Ε N Μ • Ί¹ — ^Μ ° Qm ρ 6 's - ° Α ^ α 0 ”£ = ιι -5-: ® γ» - «? 4 4 ° ^Μ&lt;&gt; Γ * W3 4-&gt; · “·· s - ^ * Ο</td><td>_ -3 · - p oo S £ 5 and 4 sch D “E” a-;^e.3 8 at ⁰¹ Ό * ĆZ &gt; · ~ · Fe 'G- * 3 6 firj II Ρ ^Μ. ο 5 ο *. Λ »=&gt; 9 Yes Ο FgA⁴¹!! - Τ ° 85 «2 ^ £ ε 4&gt; Ό - * 9 6 2 Ζ СЧ ГЧ - &lt;5 _ Ο ΤΓ i zZ š £ 'SS 5</td>

<td>fe 4 * 2</td><td> 453.1</td><td> 418.11</td><td> 461.05</td>

<td>Ret./ Procedure</td><td>1.75 min Procedure A</td><td>1.53 mm Procedure A</td><td>1.76 mm Procedure Α</td>

<td>»0 N 2</td><td> 452.96</td><td> 417.92</td><td> 460.91</td>

<td>Appearance</td><td>white solid</td><td>white solid</td><td>white solid</td>

<td>Reactionary scheme</td><td>1-Procedure.A</td><td>1-Procedure.A</td><td>1 -Postup.A</td>

<td> ₽4</td><td>u</td><td>o P</td><td> 0</td>

<td>rt</td><td>« JS Oh Q Q t)</td><td>/ Gh</td><td>u. 110 - IL o</td>

<td>p4</td><td></td><td>no</td><td>• no</td>

<td>| X</td><td>cho □ 4</td><td>of CA.</td><td>QQ 04</td>

120

51155 Β

<td>NMR data</td><td>L r- r- οό „° =. , · ε 1 μ ί ¢ 7A С А '··' οϋ * 5 ό еч ⁿ Λ. - g · —-rn 3 11 «*&gt; RN OS ⁴⁵ o S d *? 0 Sr γ * ί _ O __g m * „đ II D 1? ή N i »1 W -_rSlG š _- -f - IČ d rf *« Ί * Sr &lt;»iS oo o</td><td>-, Ό to σ^- κ m&gt; «- '-τ' WITH." O &lt;xd i i СЧ 5 ° “° όϊ2 * ₽'d ® r &lt;ffl ® 3 cs čE-m / - &lt;'m'¹ č HG m _h 'Μ, N ev 2 υ Ά -Ά A ΐ ί _j 0 · γο b θ '^-*¹ m 'k? ^ i A ^ .ia ·: ^ * dh “b“ 2-Ti-: T2 2G CM 1— »rM fn ΓΏ&gt;“ l O</td><td>in, II »Oo &amp; □^Ο-ίίΊ®Χ®^πE K I H I. -ο 'm'⁴- '- · &lt;- · r— 3 S ”tz * qg G ΙχβχΧ Dz! S £ g · ®s3s- £ --o4 =</td>

<td>s</td><td> 451.06</td><td>MS SA O M ~)</td><td> 508.22</td>

<td>Ret./ Procedure</td><td>1.63 min Procedure A</td><td>1.94 min Procedure A</td><td>1.48 min Procedure A</td>

<td>Calculator mm</td><td> 450.94</td><td>Ό O CN © Ό</td><td> 508.04</td>

<td>Appearance</td><td>white solid i 1</td><td>white solid</td><td>white solid</td>

<td>Reactionary scheme</td><td>1-Procedure.A</td><td>&lt;d = » 4- »sl Ο Lj</td><td>o</td>

<td></td><td>L&gt; i⁵</td><td> □ ?</td><td>U</td>

<td>tt!</td><td>/ o \ = oo</td><td>š Oh o o ί</td><td>o \ = o o</td>

<td></td><td>no</td><td>Ύ</td><td>Ύ</td>

<td>uu</td><td>Och S *</td><td>o o</td><td>1 “(o 4—4</td>

121

51155 Β

<img file="RS51155B_D0178.tif" />

<img file="RS51155B_D0179.tif" />

pđ

<img file="RS51155B_D0180.tif" />

<img file="RS51155B_D0181.tif" />

o

<img file="RS51155B_D0182.tif" />

<img file="RS51155B_D0183.tif" />

122

51155 Β

<td>cS 43 P.</td><td>V1 03 . VJ 00 v&gt; GJ S KA p d 2S r &lt;43. ~ g O S.ME'aSš-; s? 33 - W tz v d JD μ §ώ ^ 5 »&lt;bi_a- Ο &lt;Ο c + S 'Č G' -ί '“' Š ' £ - · &lt;=. » and L t 1 + “LRJ З &lt;ч оо - © ^c σ&gt; _&gt; *&gt; D +) · Ό 2 oGVtJ 2G * čH * Ό θ 'r-1 CS č- * · λ— ”</td><td>MS, 4-Γ * ° d «5 j&gt; g- ~ O hg £ s„ · rb Č oo 00 \ VI .. § * n S. d II □ l Υ Wo “7&gt; Κ ^ * ό sL« OčO ^ ij m ί- * o Z? ® Š O - * N 7 Tf · X 'ζ! *&gt; ο4 Β Β &lt;&lt; ν&gt;, ο · &lt;ι ·¹ cs rf-i ο § -ο tz Κ 'Β. F&gt; η οο X m ^ m: «z: -s: ^ zz</td><td> .2⁴ vv • ο A vf gč * č&gt; oe C2- - &lt;m m »- II - 2 &lt;Ί X 40 Γ4 S GJ &gt; - US Α οη «Ί ό Ο s-o CS _Λ 1 * 1 ΠΊ „з-о-г ^ л ^ г ^ Шо-Ж s ® r- »© fi OI t5 Ч ·· 'i Z * oj V »S Os Ό ϊ Ϊ ^y. 7 ϊ * ”in D o un D mo</td>

<td>1zJ ± 2</td><td>σ&gt; СЧ Гο 40</td><td> 554.19</td><td>'BC vi + £ S</td>

<td>Ret./ Procedure</td><td>&lt; β ο. ο Β Γ * - SD - &lt;&amp; Ρ- (</td><td>1.75 min Procedure Α</td><td>1.60min Procedure B</td>

<td>Calculate. MM</td><td> 607.17</td><td>and 554.11</td><td> 456.97</td>

<td>Appearance</td><td>white solid</td><td>white solid</td><td>a transparent waxy substance</td>

<td>Reactionary scheme</td><td> 40</td><td>4o</td><td>1-Method A</td>

<td></td><td>Ο</td><td>Q F</td><td>u P</td>

<td></td><td>Α ° = κ ° 0</td><td>o \ —Z F</td><td>\ u. p \ /</td>

<td>P4</td><td>Ύ</td><td>Ύ</td><td></td>

<td>uu CL &lt;HJ</td><td>ιτ&gt; ο τ— &lt;</td><td>4Q O</td><td> 107</td>

123

51155 Β

<img file="RS51155B_D0184.tif" />

7.9).

C,

<img file="RS51155B_D0185.tif" />

<img file="RS51155B_D0186.tif" />

<img file="RS51155B_D0187.tif" />

124

51155 Β

<td>cž HJ</td><td>1 jr. 'H 1 O, o ”G 'Ά ο ύίΣ ° ϊ rfS &lt;? D h * «P sč g e'7 2 -0 θ / -. ——- χ '«n. © &lt;s S oo -7 jA „'Οέέϊόχ |&gt; οϊϊ ° Ε⁵® 9 2-2 32 ^ -11 s-tf / Z &lt;SC / - &lt;js 7j * iZ) c * i r⁴ . £&gt; q \ * -&gt; - * 11 сч ^ о</td><td>g- m -RT CN _l " qs G ~), q v o D G- Oc? vo 2 cO Ol £ N. 00 'Ό -. = »- τί 2“. N II _i“. “Ό u · Οχ G I 3 (^ 22-⁴ s c5 “: ardj⁵. e- - s. « GJ cs) ~ G ~. ° Ϊ 11 P ⁹⁹ 'L&gt; _g .J m m oD gt- - o .4 |⁵.i⁵AS2gS J2; and eSI «</td><td>0 ± h · D -¹ - "η," “. - 5 · - o xb g&gt; ® s 3 n ₇ X - NX Ο l _: _ sSd!%; &lt;£ '»4 gn ~ 7 c O - o II * ori °° - ⁱ“^m *&gt; £ 2 »2 _5&gt; -okh-ČAHn Q ^m -g Ή S rf R —- , 2όο®ο5 5 X v l »“? i Β ο ο ж ~ 1- Λ 2^m χη ό μ 3 č ιι χ ρ = ” ^{m 43}- Ο — οχο</td>

<td>ž</td><td>o rc&gt; QO 'T</td><td>ΓΊ G * οό hG</td><td>\ ρ гч οο νγ</td>

<td>Vrcme ret./ Procedure</td><td>1.52 min Procedure A</td><td>&lt; Β r, N 3 Ώΐϊ .-. Q ίΧ.</td><td>1.62 min Procedure Α</td>

<td>”Ύ s |</td><td>m O \ 00 чг</td><td>Ό Ch A gi chg</td><td>SC ρ οό W ~ t</td>

<td>Look</td><td>3С «tu υ X (X</td><td>white oily Solid substance</td><td>white solid</td>

<td>g .2 CJ g £ ω RČ HL</td><td>tn</td><td>17Ί</td><td>ιη</td>

<td>a £</td><td>□ 0 h</td><td>o 0 h /</td><td> 4</td>

<td>'Hi</td><td>u. o “/ IZ r</td><td>4- xz 0</td><td>9 ΧΖ 9</td>

<td> ¢4</td><td> &gt;</td><td>Ύ</td><td>Ύ</td>

<td>uu SCH5</td><td></td><td>v&gt; 4</td><td>τ-1 ι — 1</td>

125

51155 Β

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3

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O \ CN kg »f

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Ο ιη Gφ

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u &lt;U Cu Λ

126

51155Β

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<td>4- + s</td><td>461.1 i</td><td>+ З 'Сđ 2 ач 4- &lt;η</td><td>* 'l' &lt;Z&gt; 5 GP + o * 5 ¹⁰</td>

<td>Time ret./ Procedure</td><td>š ® § * ho D _J ⁱo 0-</td><td>1.84 min Procedure F</td><td>2.08 min Procedure F</td>

<td>Expression. MM</td><td>О \ Γ · ζ Сћ ΜΊ</td><td>Ό e&gt; A n * t</td><td>h? o o 00 'T</td>

<td>Appearance</td><td>bcla solid</td><td>yellow solid</td><td>white solid</td>

<td>Reactionary scheme</td><td>1-Procedure.A</td><td>1-Procedure.A</td><td>1-Procedure.A</td>

<td></td><td>b P</td><td>o . P</td><td>p</td>

<td>'it</td><td>š</td><td>z α</td><td>g »c_ υ</td>

<td>p5</td><td>and--</td><td>$ „&gt; P \ + - ω \</td><td>&gt; Rl,</td>

<td>In 1-1 CL. jO</td><td>Οθ</td><td>Ch fl</td><td>© MS! ”</td>

127

51155 Β

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ΓΊ

128

51155 Β

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jzn, 7 = 7.0).

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129

51155 Β

<td>NMR data</td><td>£ o 2 3, t? «S . m _ -O D ®. NN 11 -&gt; 2: 2-40 o tz * n ν®π · ο &lt;&gt; ? ^^s.54 ^ S? © gp p '- &lt;' n * ***. A *** Pj oo · _.Β ί w -r § «N £ .5.8 AD 3 Z ~ ο om ψ * e -2 · n V D -ΓΜΓ'ΉΜ'Η ^ '-' ΌΟ</td><td>tS D ύ! 5 N p- S24- НпјС-ш 7 ^ 2-23 С. II &lt;l · gL - '⁰⁴ &lt;§Έ? 42 ZI5 • * a®4 m ^^ ·⁵· ® 4-n- .4.43 S 'i? Σ Ϊ3§dZ§ ® Ρ3 ►&gt; Ό Α _% «-&lt; *-« „ » 4* - ⁰⁰ ll II -Ό 6 j-BTf χ-'Ώ 'ig g κγ G G4&gt; AJ Č · N- »</td><td>£? D u &lt;o (s i-&gt; O &lt;i · ® 0χΓ; H. tn oč&gt; l for ® ^ 4s? 2n Γ! η | .η ^ Α. Ш ° g z S 4 | U. «D; | l ^ 20..3 ^ 2: 4 ^ rg-fbz « J2 „f⁴·· * “* n v&gt; 60 d I &lt;Ώ u.-! »H a 2 II (S [N H-, (Y | č_l o</td>

<td> 1</td><td> 480.25</td><td> 504.25</td><td> 583.40</td>

<td>Ret./ Procedure</td><td>&lt; i _a5 - (Λ »· * ο Rn</td><td>1.32 min Procedure A</td><td>1.26 myths Procedure Α</td>

<td>iS§ s * 5 1—1 &amp;</td><td> 480.07</td><td> 504.1</td><td> 583.2</td>

<td>Appearance</td><td>white solid</td><td>white solid</td><td>white solid</td>

<td>Reactionary scheme</td><td> 00</td><td>co</td><td> 00</td>

<td></td><td>S</td><td>u P</td><td>□ .P</td>

<td></td><td></td><td>= .. { '- z</td><td>p 2—. o —ss č / Č r \</td>

<td>here</td><td>Ύ</td><td></td><td></td>

<td>№ X</td><td>b</td><td> 128</td><td>04 G&gt; J t— ·</td>

130

51155 Β

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ϋ

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<img file="RS51155B_D0215.tif" />

<img file="RS51155B_D0216.tif" />

<img file="RS51155B_D0217.tif" />

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СЧ м

131

51155Β

<td>NMR data</td><td>* tG Tj⁴ i ~ 7 * O £ as h · ° X p £ o K oo £ c'33 -i? . 00 _- 40 d 3 3® ® JB Ž co D - &lt;η - JJ „ -4 n ii $ ~ XSEE: tz t&gt; □ • o-gjzatdvv.čzd 'ioK * ζ? ° 4Lhhiz o i-&gt; sč «-1 * -¹ - 'k d' j 2 A3gS &lt;4 «&gt;« c / 2S - NO⁴· N, o · r— f-4 »&gt; i r-m gč r- &lt;μ-&gt;</td><td>X m ® 3 h * 'h' X is -53r- °? Ό 00 .®ΧΧ®Μ to čHg II Ρ4 Ο \ »~ · 3 d 3 £ 3 Ί 3 ιϊ i ^ g-d ^.-.- EZž '' ·· D -i 3 - ® ¹³¹ ® F \ »N Η ζ-č \ D · - 'ο ϋ §2-3 = + ® ^ ε2 • ί IΕ ^s 4 _i- χ - ° дВЧТ Л ^ -иТ - гч Г⁴·&gt; -&gt; «ο ·» '' - »*** *“&gt;</td>

<td> 1</td><td> 540,34</td><td>\ 0 gf</td>

<td>Ret./ Procedure</td><td>1.28 min Procedure Α</td><td>1.31 min Procedure Α</td>

<td>&gt; 0 «S N</td><td>cn ο φ νπ</td><td>φ ο 4&gt; Gφ</td>

<td>Izglcd</td><td>vitreous substance amber color</td><td>white solid</td>

<td>Reactionary scheme</td><td> 00</td><td> 00</td>

<td>si</td><td>u P</td><td>the fi</td>

<td>Bi</td><td>\ / “- z 3 / \</td><td> 3 ( \</td>

<td> 74</td><td></td><td>Ύ</td>

<td>* 4 n P - C&gt;</td><td>ΓΩ n ₽4</td><td>φ γΊ</td>

132

51155 Β

<td>NMR data</td><td>for- + '° £ gš_M-Ax Q 5 η X »Η, · -ΐ ΐι § D Ό &lt;g \ 11 ^, ο'Ν-ιΟ ^ Ss ^ '. ^ SA-shssh®. D dA f Μ-ζ- S c? d T § i * G * J G *&gt; - »_O s ^ z» - »» - * t- «► — j ©</td><td>čI. . 'TG-L ^ gE' Rt ~ - 3ϊ4 © χη® ® O G- -υ 2-S * Q -ο “3 χ5 Β 2.1? - SQ &lt;t 3 I&gt; ο ° S ° 2 ° ® κ 5 ^ « r © Ό d μ Ο Ί · © ΓΠ 3 00 - ώ. 00 rf 00 _Τ § ιι + ado ed -SS-d 2 Ζ&gt; ο τ -. ». - * · D 4 »Π Š Η ° ί Š jr'tsb ^ in ^ rncseS '- ^^ oo</td>

<td> 4- 2</td><td> 532.32</td><td> 537,34</td>

<td>Time ret./ Procedure</td><td>1.34 min Procedure A</td><td>and 1.24 tnin Procedure Α</td>

<td></td><td> 532.14</td><td> 537.17</td>

<td>Appearance</td><td>white solid</td><td>white solid</td>

<td>Reactionary scheme</td><td> 00</td><td>oo</td>

<td></td><td> 0</td><td>u 0 X</td>

<td>U</td><td>\ z— J β \</td><td>o -3 0</td>

<td>Bi</td><td>Fy_</td><td>Ύ</td>

<td>* - m X)</td><td>Ή tn «—0</td><td>V0 ΓΊ ——</td>

133

51155 Β

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<img file="RS51155B_D0223.tif" />

<img file="RS51155B_D0224.tif" />

<img file="RS51155B_D0225.tif" />

<img file="RS51155B_D0226.tif" />

134

51155 Β

<img file="RS51155B_D0227.tif" />

135

51155 Β

<td>Q tJ Ο P,</td><td>S -. - 2^l.d “« ^ 2. ^ 2 zd Q ^ u-&gt; T3-S «n.tn S -o - - · D * 1 g&gt; _- / -&gt; tfp {t * · * “* o © 11 gs&gt; 1o.o17 .- &lt;! £ 3o2^gg'□ w L -Μ g / ζ * t SCh rn V &lt;* 4 „4 05 * L d D 't “Π Β? 3</td><td>* O \ «, 3 43 - “J” 7 ϊ »l« g - °. - ~ Γ * Ο ts. - »-r · s * l ж гп с. »* &lt;4-i rl Ό * m .N Q o, »-» X _S rJ § X «O g? II - 3 - 3 Β a / A^m Ά i-G'T? 5? 2? 2d ^ §hh§h§2L&gt; tG S \ οθ l l oo X⁴ oo S? 't *' Š. II кГ рри И Ж И Д Д? Р&gt; Д Ж СА еч Д д γό</td><td>* VN _l77 ώ h - · ® rn o &lt;m. _- m Ό. 00 - och Q- C DJ Dj - t- u zn w 2 / n ~ *&gt; 2g-2® 1? g 3S glZZ = $ (jCNt-D! g t- O \ SL ® Q »tt i—“&gt; —o oO 04 Z-arv 2.2-3 i „• so» „- · = g sf § Ο! What is it? 2 š Β κ 'ίο'Ξ'δ D - Ο gč · * g «« 5 ^Μ Λ © I i - 43 ^Ν c «, · 43 * 5 π Ό L S j- lJ and Ž_iдчТ -Mt'Alj ^ im - ο&gt; ~&gt;</td>

<td> 1</td><td>• tf CN 03 QC</td><td>C) &lt;C g&gt; j βη</td><td>r— &lt;oi oi 05 hG</td>

<td>Time ret. Procedure</td><td>1.28 min Procedure A</td><td>&lt; Β Ίζ ^α ο &lt; GČ □ GČ £ - U5 - * ο 0-1</td><td>1.31 min Procedure A</td>

<td>Calculate. MM</td><td>W) © SC co</td><td>5 MS i / 5</td><td>05 o oi 05 'sS'</td>

<td>Appearance</td><td>white solid</td><td>transparent glassy substance</td><td>white solid</td>

<td>Reactionary scheme</td><td>O0</td><td>O0</td><td> 00</td>

<td></td><td>Q 0 h</td><td>α fi</td><td>b X</td>

<td>'pA</td><td>X oi / \</td><td>X O m 0 \</td><td>Q \</td>

<td></td><td>Ύ</td><td></td><td></td>

<td>SC -O</td><td>m Xf</td><td> 5 »</td><td>• l</td>

136

51155 Β

<td>Ο «J Ό 0 Ρ.</td><td>sl o? 3 gmhomgpg- 'o. «J ο -5_Μ· R &lt;i^m. r- II tc S «-h *? Α - 1 QO * z? -^σ - Q? E '³ 'ί? ϋ- ^ ξτξ? Α ^ § X. · · Ί 3С N | - P I) З ».ЕС | к го CN д» -С -С - ® š L s§ i a § k o »» d - X. · »m Μ · —γ * 1 /“) is S4Τ and „-T ΕΚ? ν r &lt;Α .5 3 Α &lt;u * l ο</td><td>L 77 ~ sar * _l . * zz G ** - U 75 D * X m SC Vb Μ_s- _ε-^Λzk ThsT SSa N N&gt; D ΐ D = οι, -1 «t &amp; Q Ό * ό - *« 1 - Ч 'Ч * Ί το ν' Ž- ^ ZztLik ^ »« Λ * oo. * D „m · - &lt;zj 1l2-§d§hi «δ, ε, Ε, .^β&amp;Α &amp; Α £ 3μ - ο</td>

<td>ΐ 2</td><td> 564.24</td><td> -----------------------------------------------------------------------------------------------------------------------------------------------------------------------1 582.41</td>

<td>Time ret / Procedure</td><td>1.33 min Procedure Α</td><td>1.46 πώι Procedure Α</td>

<td>Calculate. ΜΜ</td><td> 564.15</td><td> 582.21</td>

<td>Appearance</td><td>white solid</td><td>white solid</td>

<td>Reactionary scheme</td><td>co</td><td>oo</td>

<td></td><td>ω 0 no</td><td>P P</td>

<td>p4</td><td>\ 2 o A '- z</td><td>P b</td>

<td>~ 0A</td><td>^ ~ U ~</td><td>Ύ</td>

<td>U n 'SmH)</td><td>\ D • &lt;r ψ- *</td><td>g · V m</td>

137

51155 Β

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<img file="RS51155B_D0229.tif" />

<img file="RS51155B_D0230.tif" />

138

51155 Β

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<img file="RS51155B_D0233.tif" />

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em rn ο ιη

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CS 'e «ο

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Ό ο

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un

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&gt;

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<img file="RS51155B_D0252.tif" />

139

51155 Β

<td>NMR data</td><td>X - 11 a k £ -S z- &lt;«&gt; °° Sj c-tc °&gt; - ffc, .G-. -^{1 w} II ** «S Ό - JX 2J _ς &lt;&gt; οι K v ^ .gs- '. 2 X «. .1 7 - K «P ' OC ^ž l l | ΐ &lt;J · m i o S? OtG ¹¹ go Ο h |₍ • '-' a dA wr ^ _s [f&gt; ίη £ 2 «2 ^m I® -r °! Ч «П С⁵ S 1! - II S ol - - Ό</td><td>Α tz K _, - D J Ό. t- r · »p · 3 N 2 tg * O '-' Ο sf hf т— О -е л ћ&gt; _m g- -ϋ D « 'sč Λ' i '- X - ^. - ο-_Ό -ο s? rK1 8 W - '8 oj &lt;d δ “·³.Β §§ g 9 43 .a 44 a £ β · £ d εκ 'ii ΕκΊ? ϊΤ Jt · 'fsj &lt;2r »- &lt;gč · * Χ &lt;n n g4 tn Η</td><td>Oh CO p o nm • m \ o ώ Εαό © „D ?. d.1 =! oq -ο Ο ~ ^ · so * ΰ &lt;** 7? Α rD® ϊ ^ 5 «· κ _Η \ Ο μΕ &lt;e · * G4 D Ό gp rq „* ξ -Ο R - Γ * σ ο -t i - 0 * 3 ·. '-'j * ο λ &lt;g Π οο οι ο 2 d £. -ο ο- Κ ~</td>

<td> 2</td><td>Ο m ϊ &lt; ν&gt;</td><td> 495.1</td><td>υ-ϊ g9</td>

<td>Ret./ Procedure</td><td>1.53 πΰπ Procedure Α</td><td>1.88 min Procedure Α '</td><td>1.57 min Procedure Β</td>

<td>CTJ&gt; N * 5</td><td> 516.18</td><td> 495.04</td><td> 434.07</td>

<td>Appearance</td><td>white solid</td><td>white solid</td><td>white Solid substance</td>

<td>Reactionary scheme</td><td>υ ~ ι</td><td>1-Procedure.A</td><td>1-Procedure. A</td>

<td></td><td>Q</td><td>Q 0 X</td><td>b 0 X</td>

<td></td><td>5 ο ) t = O r— 2 e</td><td>š o o = 4 € / V</td><td>u_ Oh</td>

<td>ffi</td><td></td><td></td><td> $.....\</td>

<td>U in CL. -D</td><td> 154</td><td>and Ή</td><td>čs » »- &lt;</td>

140

51155 Β

<td>NMR data</td><td>m O ”K 23 '' s: a · i «d np § в&gt; сч р · &lt;г £, -; £? · &lt;Shso 7 s: A li FG I ~ _l Oh S 2 Z IL Vn ΠΊ A ^w х ~ ч „д °« + Ш И 00 r- TG OC-— -&gt;</td><td>- “i 'II ε' ·&gt; Ш * о »Г? ! / *&gt; * - ' Ч- &lt;Гз Д _ΐΟ_ι ΙΓ) ΓΊ νΡ4 ^ 4οξ 8T1a7§ £ d S ^ 4, ^ e.^med ^ d , NNN Ο r- &lt; _lS -Γ ° X 'C Č? S St'- Srn - &lt;&lt;5 i- crs &lt;O gč ΓΊ d &lt;η - οό τί * cb 'gL 50</td><td>. S5. a S 00 D D Z = · 'o © acm -_o m _or- 7 &lt;đ £ 'r'® 4 Ν' , λ II · 50 · - 50 i 44. »η, Ό - p đsssi-ssi 8đg7S3 ^ 3 D ”SO ® ^Δ iČV rf rn Č 7 ° i-daZAo β. _ g 4.T V » £ M «£. U¹ 2 b 1D ^ § £ 3</td>

<td> 1 2</td><td> 478.1</td><td> 531.2</td><td> 1 425.17</td>

<td>Ret./ Procedure</td><td>1.60 Procedure A</td><td>1.59 Procedure A</td><td>1.49 min Procedure A</td>

<td>Calculate. MM</td><td> 478.01</td><td> 530.20</td><td> | 424.95</td>

<td>Appearance</td><td>white solid</td><td>white solid</td><td>white solid</td>

<td>Reactionary scheme</td><td>&lt;n</td><td>* n</td><td> 00</td>

<td>Ίύ</td><td>o</td><td>o .0</td><td>&lt;5 fi</td>

<td> ¢4</td><td>Cz</td><td> °=( 0</td><td>X o</td>

<td></td><td></td><td></td><td></td>

<td>uu C - D</td><td>m Pts</td><td>o%</td><td>V4 o</td>

141

51155 Β

<td>ο</td><td>γ? Ξ £ Μ * Ο 9 * 3 ^ 2. ! Β ^_χβ§ 'SA-gSg ^ Ss® σ &lt;4 ^ 7® r- 1m CQ η ° ® · Ό D ϊλ Ο ι -^η * · Η DG ® », ο ϊ - L 4J S ®“ 'Č 16 D BzE ^ -Zo d ΖώΊ, ηΗ .22 - * - Si =! »Č ^ JT72^pvb and⁴ r-- ech 6- «ϋ D&gt; -» m »-μ τ-ι ro</td><td>F f ό Ν JŠ-® « And gT 'is? đ ° § ~ o rJČg n o «? A0AA R. · · »-&gt; 'о сч Β 1 'Ч г -4 х' -7 р г ЖБф? o_-S - ® &amp; Z sč g- r- m - &lt;&lt; _ ίη i 't 7 «ί 5» {f Α Ζ * č_&gt; ζ- * · ΜΊ »—1 Č&gt; w &lt;4— * Ο</td><td>_Λ Ο DQ g * · ο Α,. *, ' f- ® £ Π I¹⁰ Ε I D Ζ ° - S'S! - ^ s? b Š! lⁱ "?" E O S 2 II Ε ° i ο 'ί ο Č D -Β ο j?¹?. = κ ✓ — ч * Ό _ &lt;«- · гЧ ΰ · II - II £ Ζ S εΓ- ΑΑ | κβρ Α &lt;Ν (Μ * - &lt;5 „Ο · * Τ Ž * t3 Π3 Ε 2 2</td>

<td> 1</td><td> 453.1</td><td> 418.11</td><td> 461.05</td>

<td>Ret./ Procedure</td><td>1.75 min Procedure A i.</td><td>1.53 min Procedure Α</td><td>1.76 rain Procedure Α</td>

<td></td><td> 452.96 1</td><td> 417.92</td><td> 460.91</td>

<td>Appearance</td><td>white solid</td><td>white solid</td><td>white solid</td>

<td>C5 α ο ο _ «g</td><td>α -S 4L o ₽ut ♦ - ·</td><td>1-Procedure.A</td><td>1-Procedure.A</td>

<td>Yes</td><td>p P</td><td>u P</td><td>5 0 Tue.</td>

<td> ₽4</td><td>© 2 Oh O o kl</td><td>z . Gh</td><td>u. U- \ LL (/</td>

<td>β!</td><td>Α</td><td>Α</td><td> a</td>

<td>U u Λ χ&gt;</td><td>kO Οχ</td><td>r- * Οχ</td><td>GO SL</td>

142

51155 Β

<td>Q e «Ό Ο α</td><td> &amp; « ^ro· ¹_n d "£ 1 - sch h G" «3. i '. (d ® - S'S js s g CN O- * «GJ OD g '-ή S II n ™ O £ ⁴⁵ O «Τ'® ·· © υ p? '* d-p ± ° g AS E®3 ^ d £ QuO m oo · £ w&gt; 22 Č g ​​~~ - »iM® E R + ι **** ί — s ϊ-n» sč m «π ss. o 's D -! A D 2 Jg * r-, and v-1 r-1 ο Ο O</td><td>_ 7. Ό co / - &lt; cr _l m 1— Zb / j 3 » ® doDd &lt;, 3 3 »®®8» G_. · G ** ”®đs £ s'Yo. • RP LLj lL. **. θ 'ж / «с r- ττ 2 XX £ Ο&gt; 7. «S £ D _-D Z · Q &lt;? E4 a “«, Α^GJ 3 g- 3 ,, · D XX ΟΟ ζ-h m Π Z ** s ΜΊ ώ ΓΠ</td><td>&lt;n, I »{CJ 00 οο A “S sam V 7 Ό 'Z'⁴- '- g 3 5 “tfn * 5 · ** s- * r- Λ -g bl ^ Z β °° _j ° § £: čdώz ^ &amp; SsST gSsso ^ - ia * a © 4 ^ ? šSđše ”5?</td>

<td>Μ + Η *</td><td>© o r— &lt;WJ *</td><td>04 in G? kP</td><td> 508.22</td>

<td>Ret./ Procedure</td><td>1.63 min Procedure A</td><td>1.94 min Procedure A</td><td>1.48 min Procedure A</td>

<td>Calculate. ΜΜ</td><td> 450.94</td><td>Ό O SL o Mb</td><td>0 00 0 * n</td>

<td>Appearance</td><td>white solid 1</td><td>white solid</td><td>white solid</td>

<td>Reactionary scheme</td><td>1-Procedure.A</td><td>1-Procedure. A</td><td>Ό</td>

<td></td><td> □ 0</td><td> □</td><td> &lt;5 ?</td>

<td></td><td>/ o \ = o (7</td><td>š o 0 in X</td><td>0 \ = of /</td>

<td></td><td>no</td><td></td><td>X</td>

<td></td><td>sh O \</td><td> 0 0</td><td>t-4 Oh</td>

143

51155 Β

<td>υ «β • ο ο Β.</td><td>£ r? 8 ® x “© X .čJ £ II о С г &lt;ο .2—1 II _rt TG w n -D | -g? o «« g = ® , СЧ Γ * В δνι ^ ονο 1 ο 1 Ζ ο η &lt;- ^ Tt ko m οο &lt;-ζ „ , b&gt; * N · ^ 1! H ri n Η</td><td>, - Ч цс,. g- m „« l ii «-ΖΐΗ, -ίζΧ« άχ- » S'E'lV® · 3^si2 &lt;&gt; 3 cfs ·⁵^ 5 oc b. = tS. oo ·⁰ i .; 5 *. β D and P = *? Γ Γ * · ι / Ί ♦ “- &lt;σ&gt; π Ο r- &lt;ο II ^η.Ν f ». Π3-2 * 5-D SP g5&gt; j č- ιο S · ”s-, 4 m D + Q G- ^ &lt;G&gt; II t-; N - - « 'T' · '* »· ς? Χ' P * v&gt; g _s- ч X - &lt;*&gt; ό 'εΤ Ί' Ρ § Се- 2- ^ д © Hsč &lt;m »m ° 1 ^m ω αο -. □ 1 Ρ- 00 Μ -φ r- rfoo ο ν&gt; ŽF \ £&gt; &amp; II Οτ-ί ^ νο</td><td>ЧЧ р? g 5? ~ 00 72 ° 1 Ο— / ¾. Η'Μ'Λ 'Ό Γ- ⁰⁰ ο П С * Ο - sd © »π / L U and? ΓΛ^β® = 2 2 χ ^sΞΙ -ο Γ '³ »&amp; * 2 &amp; g * G JG ^ ooa ^ DOd «. = £ Ο D ifl Ο Q, -Α u £ ό; _c»^« ug d ć - £ - · 7 2 1η we «κΟον-Τ-νηΓ * / - ^». D Z o gđ u-ζ Οι „rn / - &lt;_ ~ «» ^ Χ'Ώ-τίΧ'ηΧ sX</td>

<td>ΐ 2</td><td> 492.23</td><td>CS 1G)</td><td> 535.28</td>

<td>Time ret./ Procedure</td><td>1.39 min Procedure Α</td><td>1.32 min Procedure Α</td><td>1.22 min Procedure A</td>

<td>Expression. ΜΜ</td><td> 491.59</td><td>Mr. ΙΟ * η</td><td>Ό \ o 'Φ gP</td>

<td>Appearance</td><td>white solid 1.</td><td>colorless oil</td><td>white solid</td>

<td>Reactionary scheme</td><td>SD</td><td>Ό</td><td></td>

<td></td><td>U.</td><td>β X</td><td>u. .0</td>

<td>ai</td><td>0 V = o (/</td><td>Ο Ί } χζ \ = ο Ο</td><td>0 xz?</td>

<td></td><td></td><td></td><td>Ύ</td>

<td>Rč x&gt;</td><td>o - ₄</td><td>Ο</td><td>TfO</td>

144

Reaction Time Ret./

<img file="RS51155B_D0253.tif" />

<img file="RS51155B_D0254.tif" />

<img file="RS51155B_D0255.tif" />

145

<img file="RS51155B_D0256.tif" />

Reaction j _ice Calculate. Ret./ NMR time. scheme data^e MM Procedure 1 H NMR (CDCl 3) δ 7.67 (d, 2H,

<img file="RS51155B_D0257.tif" />

<img file="RS51155B_D0258.tif" />

146

51155 Β

<td>NMR data</td><td>&lt; -Γ -L Μ g S Υ-3 Υ Ά U r &lt;? ** ο - JL ϋ .. η ν ο ίΐί -κ Λ Λ ^ο · &lt;W 4. Ο Ο &lt;Λ ♦ nt „ Κ 'n c? \ Η ν., Rt · S £ 3 З— СЧ &lt;-&gt; „* А сЛ p -r ° š and K Ή °° W ZoJ S * ΐι Μ «ο</td><td>γ * ~ m η. TJ- μ; ο! ι&gt; «ί Ε £ I * 2 3 3 ' ^s- z · £ » 5 D D 3 t ~ -&gt; η §Β --- Υ «^ Ι θ^Ν.Α 3p.8^s. «TZ&gt; X r-n Gn g ⁰⁴ X -j Ог ~ - ο | 3 £ 3 «^ 23⁴°. ć -Μ - S Ζ! L MS 05 _l1L X .'ί τ *! Ί U¹ λ Κ Κ F? &lt;η ® £, 22. £ d S &amp; ιι</td><td>&lt;&gt; * ίΤ .-, »00 _{i w}* «3 1 w ο - S r⁷ «G 3 b tn * D m« O dj d - t g ASA ° С ^ 'ш * r р &lt;3.-2-С · п? 1L 00, - g DO * “* S® '? Ss? 2 Ί® » ^At ° Λ J -OkA®! Č?_V· I ° pb -: ^ 7^гчМ! l Q^MU · - □ i m τ ^ - Πγ °° ® £ .2'Υ¹'* σχ G- £ H? 3 ~ β Μ ό Ξ °) “2 § ® 2z D W So ο Ζ - t- ~. ·, - Ο.-Ί «3 · * II κ R g °°. = * 'Ρ Γ Zg- 3 - Ο Ό</td>

<td>+ S</td><td> 488.20</td><td>m ech «ί</td><td> 458.26</td>

<td>Ret./ Procedure</td><td>1.52 πώι Procedure Α</td><td>1.52 min Procedure A</td><td>1 1.62 min Procedure Α</td>

<td>Calculate. MM</td><td> 487.93</td><td>Ό 04 A č — 1 'tf</td><td> 458.02</td>

<td>Appearance</td><td>“§ Ο ο X &amp;</td><td>white oily solid</td><td>white solid</td>

<td>Reactionary scheme</td><td>m</td><td></td><td>»L</td>

<td></td><td>Ο γ</td><td>ϋ 0 No.</td><td></td>

<td></td><td>№. Ο IU 2 χζ G</td><td>xz g</td><td>q ΧΖ Γ</td>

<td></td><td>Ύ</td><td></td><td>$ -γ</td>

<td>Pr. no.</td><td>• MS ♦ -4</td><td>m fl «t Ή</td><td>'Φ u-N ^ N</td>

147

51155 Β

<td>NMR data</td><td>S0-, a &gt; Z_h= »·« A »n-gfs. )&gt; l 'l! P - s * S * ffi - “- 7“ g ~ a ^- ? l r- β'Β b ° 1 Φ 'τ co m z-τι xfN (r S - “XX &lt;&gt;' - r ~ d-® * 00 ... m η t · »- &lt;p Q sč +&gt; £ * · »4 D r- Ξ- P I „- n-g S s? w ii II ГЧ w ffi &lt;NX I&gt; © c £ * tz,. r * ύ ,, 5&gt; _? Ό N ό σ 'i · σ ·' trj z M O. № G-. NX ® «« • “IČČH®! ® II £ 3-G- 'N G ~ Ί · - n - · ~ ί</td><td>£ and £. £ Τ, βΰί g · _ -g t '“' rn '-' rfv'-js.m g E »K N g ® ⁴⁰Ώ CS d XGH 7 u? - v - '~&gt; R Kk rt o 7 - ts. ^ “Λ U 3 i ο Ο— _m R ιι ± Jo -ί 5 τΓ 5? R11 KTT'S Ο. _Μ· Ό 1L „&gt;. ν&gt; 00 ,, ΐ Μ ΤΟ,⁰⁰ ►_, · i ₄ X “ć _. · Ε ^ 7 ° - ^ Ζ -σ ',, -s .β®Χ Τ S 7 S¹⁰ -ί Π 7 Β ϊ - S g ^ - ιι 3 η - &lt;· - · π</td><td>CC U 03 G4 * ° V »tj 43 L-Γ GP m⁰⁰ . C- * iS 'V -^Λ 40 40 f *. tfi f *. * &lt;✓ — h n C'OO -S. Β_Μ-Ώ π ο £ 4 G) ~ D £ 5 FT Ο -. - —— * - r \ | &lt; U '3 ν: Ο r'- u ~ i 1 Q =⁴ -g f 4 T d oo 5 - UL S ιι '-'T d o . VI 04 k. «L u-, 3 mZ »1 r- · - X ^ -. O u d Ξ7 ETf ζ- ^ £ G s 5 - ZS r- -⁴ 8 si&gt; GP Ό O &lt;?</td>

<td></td><td>sch ech sb w&gt; zg</td><td>GΑ GČ ο GČ Xt</td><td>40 cs ή f * HJ ·</td>

<td>Weather rct./ Procedure</td><td> &lt; ^s Q &lt; 3 3 • cn - Fr. CU</td><td>&lt;ο Λ Λ λ 3 &lt;Č. S - &lt;ο a.</td><td>c Ig5 “* - * ^ • (L - * O fU</td>

<td>.. ce 5 u ζ!</td><td>No? SL ¢ 4 kn</td><td>gb Č6 ΟΧ • ČG</td><td>f vS rXt</td>

<td>Appearance</td><td>Sv QG «2, 2 2 S.«&gt; 3 JZ ČJ &lt;n</td><td>JS Η υ ω 40 CU</td><td>t § l sh</td>

<td>sg 'o</td><td>tn</td><td>Ό</td><td>V ~)</td>

<td></td><td>P</td><td>υ Ρ</td><td>A</td>

<td>Chi</td><td>q xz f ·</td><td>/ ο ^ = 0</td><td>0.&gt; G</td>

<td>vj</td><td></td><td>Ύ</td><td></td>

<td>n 'Rn -O</td><td>т&gt; &lt;—т</td><td>5— · ί ~ 4</td><td>g * VX</td>

148

51155 Β

<td>hedgehog Φ sh</td><td>45 «s5. ΰ ϋ · β „ί 7 77 p „P - S σ, * Sr- ts&gt; Ύ - O || · * 35 j g- g d m D -4 ® * - · to gč KP _ - P £? £ υ «T Ύ- 'ο γ вт 'Μ Ч . -—ЧСЧ⁴⁰ m Μ * - = 4 ξ $ »S τί5? d 'jj- χ ® £ r Ss g' G * D b- Ο 4 τ- &lt;· ς&gt;</td><td>m £ 2 - .A&gt; n ° 7 &lt;-. * &lt;i 4 t- p -c? α v t-e A *^A . - ί 'Ч СС иг ^ з⁰⁴« ^Q.S&gt; 9 Ό “L 2 &lt;4&gt;? o ° '- 2 t * »”. 1 5 O = »0 N Hg S «K? tfS-r g 4^N&gt; A_?·? ό 2 s'S (jv3-3 / ζ CS Tt · O \ z-ζ _ хј _г «“ 'Ί Ч С и γ3γ ^ η · 4 * ν0</td><td>C'J ta ^ 00 l m M v- r- Ά Y. \ o oo and SE? □ Ά ® Qa · -® E S ^ S ^ Ss' g β W © d Ό S D O b; S -SČ r- &lt;, -Χ Τ 'ΓΊ ζ-ί - —Γ Ε * 33 ® 3 / · ** Ι-? SC 6Ί</td>

<td> + ¥ 2</td><td>40 τ</td><td>+ Ζ- “ч еđ Οχ Ϊ5 Οχ 4- m</td><td>+ 'Z' ο 5 6 ± ° g, · '·'</td>

<td>Time ret./ Procedure</td><td>1.62min Procedure Β</td><td>1.84 min Procedure F</td><td>h^α a gO 2 o £ : &lt;l SC Q CL</td>

<td>Calculate. MM</td><td> 459.79</td><td> 437.06</td><td>40 Ο . □ ο</td>

<td>Appearance</td><td>white solid</td><td>yellow solid</td><td>white solid</td>

<td>Reactionary scheme</td><td>1-Procedure.A</td><td>1-Procedure.A</td><td>1-Procedure.A</td>

<td></td><td>o P</td><td>o P</td><td>5 P</td>

<td></td><td>l</td><td>to</td><td></td>

<td>pi</td><td>iv</td><td>'--- (P \</td><td>^...... V. \</td>

<td>i- &lt;U CU X</td><td>0Q</td><td> 04</td><td>o ech</td>

149

51155 Β

<img file="RS51155B_D0259.tif" />

<img file="RS51155B_D0260.tif" />

cs ΟΙ

<img file="RS51155B_D0261.tif" />

<img file="RS51155B_D0262.tif" />

150

51155 Β

<img file="RS51155B_D0263.tif" />

<img file="RS51155B_D0264.tif" />

MS

<img file="RS51155B_D0265.tif" />

<img file="RS51155B_D0266.tif" />

151

51155 Β

<td>CO Ό Ο Ρ.</td><td>• * &lt;&gt; TJ N. »T &lt;u * Jj NO w S Ό O yes -¹ T5 D Ο A G ~ U u “—-S - ll 3 = 0 ^ 3. 0 45 ^ - 4. 8ŠS £? £££ * O m l »- · n ® sp 5 W - Deso '· 2&gt; ^ .SS&gt; S z3. &lt;Ao w I n ₇ I 'lg O; D °! • M —J ^ -j. Ό ©</td><td>• tf 7? . - 'H 35 i S n J aom'—' č- i -&gt; 00 - 'L Rp ^ -L r. f ό ro &lt;&gt; o D D 'O-.vA S Π Ο A m * ό ii d: Ro_i- с ^ .пш β ^ .ΊΓΪΓ ? gxp h ^ Č _G O SČ O 5Ώ 'T? S T Sg £ ŠS D &lt;- = § i d ”ΊΡ u-3 'ig £ ίΎ G 1Ν&gt; D Λ * t -&gt;</td><td>r- ο от »2 t- οΞ ^{10 η} 11 m C \ ΙΛ zd zz S Q TJ rf XM ^M 0 &lt;j -3 D l _v- °. £ f K _M-oo P S, ie · «· * '' st 'm JL ? d ££ 20H.d | d šg? ćs «: hz§ a m p j 'i« a 2 ϊ r N b L H fC Ć-Φ Η</td>

<td> % 2</td><td> 480.25</td><td>υ-&gt; гч • чГ о * n</td><td> 583.40</td>

<td>Time ret./ Procedure</td><td>1.34 min Procedure A</td><td>1.32 min Procedure A</td><td>1.26 min Procedure A</td>

<td>Calculate. MM</td><td> 480.07</td><td> 504.1</td><td> 583.2</td>

<td>Appearance</td><td>white solid</td><td>white solid</td><td>white solid</td>

<td>Reactionary scheme</td><td>oo</td><td>DO</td><td>QO</td>

<td>a4</td><td>o P</td><td>u P</td><td>Q fi</td>

<td>rS</td><td></td><td>=, ( &lt;- z</td><td>P 0 s ό (</td>

<td>Pi</td><td>Ύ</td><td>Ύ</td><td>Ύ</td>

<td>U n *</td><td> 127</td><td>GO account</td><td>CA account</td>

152

51155 Β

<img file="RS51155B_D0267.tif" />

<img file="RS51155B_D0268.tif" />

<img file="RS51155B_D0269.tif" />

153

51155 Β

<td>NMR data</td><td>- jz 3- С'СЖКБ _l AX tn -g - ί * ι _l F “? -ίώ «ί gG eG-g-gt--: p eč r- _-Ο © o&gt; r- * - · D-O ^ zuei *! *!?! h o 7 - ° g SGmnJč 2 'κί · * “» ⁿ css ® ^ S II 5 ⁴ 3 ^{G |} E * 7 7 5 f * “» θ'— · H _l „* * Č § χ 8 T g £ «ίκ + ΐ μ! Γ * fsj η-, Ο τ- ^ &lt;Ν -¹ -&gt;</td><td> ’2^Ν. «Ϊ ^ Ε_Μ.ίί ZMPsu £ &lt;~ - '“^|r \ * - * N t- «-Α ⁱ OS Eq-, S- ° X _, - Z _m-® .45 O ^ -sč 3n j? II D ι?⁴ Ό di Ζ »m II Ο d X ž «U ·!» £ «- a ϊ - sČ Γ '* · · -» * £ ·&gt;^ι_~ * * “* *“ Ι</td>

<td>ΐ 2</td><td>HJm Ο • * r ΜΊ</td><td> 1 476.17</td>

<td>Ret./ Procedure</td><td>I 1.28 πύη Procedure Α</td><td>1.31 shsh Procedure Α</td>

<td>Calculate. MM</td><td> 1 540.13</td><td> 476.04</td>

<td>Appearance</td><td>vitreous substance amber color</td><td>white solid</td>

<td>Reactionary scheme</td><td> 00</td><td> 00</td>

<td>oi</td><td>ο 0</td><td>o fi</td>

<td>p4</td><td>p * / * —Ζ β \</td><td>d / \</td>

<td>ćx &lt;</td><td>Ύ</td><td>Ύ</td>

<td>ЦУ -Ђ</td><td>ro mr ~ 4</td><td>tG m</td>

154

51155 Β

<td rowspan="4">Ο Ό Ο Λ</td><td rowspan="4">S Ο, 4&gt; Γ ~ to υ Q Ο Chi * bT κ ο ο • 5Γ</td><td rowspan="4">5? »Ό οθ Α μ SC SC \ ο Γ * ' this is ΟΟ Α κ СЧ</td><td rowspan="4">κ CN Μ c⁴* » tS q » £ tJ 4_ / G ' G0 S '</td><td rowspan="4">w ο tr ιη o 5 u * l SL r- gč kb 'ν' q ob d</td><td rowspan="4">C 5 S č- m š =⁴⁵ .η N 7 * ⁰⁵ · II gm, a&gt; -&gt; «l * -č Τ '.- -4 T Ξ-ΓΛ1 tGzZ ijS = AS g! Č Gi? A «h S k '- + ti_ž гч * + · σ С е? J0 '-' &lt;- '</td><td rowspan="4">fi Ч- * * л оа 1 ( 1 Ή Ch T — 4 (tn Č »· ' V4 G4 g4 f cd »£»</td><td rowspan="4">® m • Jč ^ &lt; F ίΓ Mrs. κη 1 r * \ q - + &gt; t * «4</td><td colspan="2" rowspan="3">'ν' π φ τ ► “» I (ν 'm Β τΓ®</td><td colspan="2" rowspan="2">• 0 ν '№ G4 Ο οό Λ 5? ® ο &lt;Ν</td><td rowspan="4">7.41-7.36 (m, 4Η), 6.57 (s, br, W),</td><td colspan="2">- Α z—&gt; «-&gt; 7+ N» -ZjM D σι ° Ό \ D 00 «- + pj 0 »11 'l · - *</td><td rowspan="4">k ΠΊ U1 rc CN 'T? ž ο ΟΟ II &lt;- »W 'Z' cr • č »&lt; un gč</td><td rowspan="4">o © =&gt; r- d £ ® sč m o ¹⁰§ = l -4 © rf oo “·» OH. °°. £ - + 45</td><td rowspan="4">£ φ &gt; II »-&gt; K m • ο Č-i- -z · ο&gt; ο</td>

<td rowspan="3">S O \ p m- з — Ч с uT - □ w č— ' F V)</td><td rowspan="3">L £ k ® ζ-- · 3m « H &lt;NH NNX .00 G5 ij η - d 'lo ^ zJ r-Tr-i (Μ</td>

<td rowspan="2">8 ϊ ο ο 'S' Κ</td><td rowspan="2">Π3 4-ζ -Φ Ό 1q Μ φ CO »-&gt; MS</td>

<td>S · «' ΟΟ © S Ο and 00 Α</td><td>Γ ** Α S SO • S 4μΧ w-&gt; SL ο</td>

<td> 1</td><td colspan="9">ГЧ м MS m Ui</td><td colspan="8">τΤ GS S mm</td>

<td></td><td></td><td></td><td></td><td></td><td> &lt;</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> &lt;</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>i ^</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>and 3</td><td></td><td></td><td></td>

<td>Ο CU Η 5 ο V)</td><td></td><td></td><td></td><td></td><td>ⁿ α -4- z τ; o</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Γ4 £: &lt;Λ ο</td><td></td><td></td><td></td>

<td>&gt; SC</td><td></td><td></td><td></td><td></td><td>lj</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>'tf'</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>-ό.</td><td></td><td></td><td></td><td></td><td>gč ΓΊ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>m</td><td></td><td></td><td></td>

<td>N?</td><td></td><td></td><td></td><td></td><td>Ό</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> »—&lt; &lt;4</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>stf</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>oS</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>α</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>e</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>ss</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>cđ CC</td><td></td><td></td><td></td>

<td>υ</td><td></td><td></td><td></td><td></td><td rowspan="2">L £ &amp; Q&gt; 3</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>D “a</td><td></td><td></td><td></td>

<td>ZD</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Q&gt; D</td><td></td><td></td><td></td>

<td>N ♦ - &lt;</td><td></td><td></td><td></td><td></td><td>Α) ϋ z</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>X) »U &lt;l</td><td></td><td></td><td></td>

<td>Λ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>α</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>ο</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>υ</td><td></td><td></td><td></td><td></td><td>OO</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>oo</td><td></td><td></td><td></td>

<td>SS hl</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>b</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>U</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>&lt;n</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>who</td><td></td><td></td><td></td><td></td><td>P</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>r</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>\ z—</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>(j 'Z.-f</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td> '0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>$ -z</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>d</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td> \</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>c</td><td></td><td></td><td></td>

<td>Yes</td><td colspan="9">Ύ</td><td colspan="8">Α</td>

<td></td><td></td><td></td><td></td><td></td><td>* l</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>H £ 3</td><td></td><td></td><td></td>

<td>UU</td><td></td><td></td><td></td><td></td><td>en</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>co</td><td></td><td></td><td></td>

<td>Och χ&gt;</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> —«4</td><td></td><td></td><td></td>

155

51155 Β

<td>·· “&lt;u ee 45 Ο a</td><td>_ * ®0 h δ'Υ-Υό. VljbrD . ao _ * D 4? n-G sl ZC «gG 1 3g 2 5 «η A ei« - 'S D5 Č “5 3 l ^σ: U 4 ^ _m”45 ς? § 4 θ '° CJ τ: Τ '-? Ev η D i Η o O' -'US a + ¥ ^ -¹ and? ϋ - K 4 &lt;P. _m- -g Λ .ο ο -ο V&gt; - ^^ 49 09 "Ji D U" r {^ SS -'- S ' 2 D 2, § s From D ~ S-§ i SS 9 f &amp; ζ-⁸«D V D 9 Τ 'F n D ό S-. gch 45 ο A</td><td>_w At 40 rf ~ zG £ 3. * L Ξ Κ w 'tf · γί N ο Μ' r- '®'x .O A-lHgS -rno ΰ 5 О + + - - · Е 9 Ш Q Оо С f'ATS'šl'v ^mo © ig&gt; ί “» (N _1l 'Μ - · ΟΧ IAS'SMKS ^ B d D “·&gt; 1? U .rf 8 Κ TN Gč Α Λ Ć&gt; O (N n,</td><td>_{l /}-&gt; чг α 45 N * 'Τ 40 '' * D iS wT «F t-ί&gt; -n gO O G4 X— '-r ** · r- v 2, · η £ ifK tgH ¹⁰ 4 N 4 Č&gt; ° 4, &lt; 0 442 -sG ~ © 4 Q -σ &lt;&gt; .— ЧкХЕ &amp; ^ г ^ Б'4- ^ 4¹ . · OT hj z * \ - .U a ϊ Υ-o SX | a2 - ^ «Dg4h |</td>

<td>ΐϊ 4s</td><td> 509.33</td><td> 494.27</td><td> 494.26</td>

<td>Time ret./ Procedure</td><td>1.32 tnin Procedure Α</td><td>1.37 min Procedure Α</td><td>1.33 ιηίιι Procedure Α</td>

<td>Calculate. MM</td><td> 509.12</td><td> 494.1</td><td>xr Ch L-</td>

<td>Looks like</td><td>white solid subsalt</td><td>transparent glassy substance</td><td>white solid</td>

<td>Reactionary scheme</td><td>oo</td><td>co</td><td>oo</td>

<td>v!</td><td>6 F</td><td>υ F</td><td>Q 0 no</td>

<td> 74</td><td>\ z— $ —Z</td><td>f A —Z β</td><td>\ —2 β</td>

<td> 74</td><td>i — y__</td><td>Ύ</td><td> ?—</td>

<td>&gt; 4 U P- X)</td><td> 137</td><td>oo m</td><td> 139</td>

156

51155 Β

<img file="RS51155B_D0270.tif" />

<img file="RS51155B_D0271.tif" />

<img file="RS51155B_D0272.tif" />

157

51155 Β

<td>NMR data</td><td>, * 7&gt; -Г &lt;—з »-&gt; о, -, Д Q ^N ιλ · ύ \ - Ж «η Q tz Η '-Έ ^Μ Π Fpz-i JO JZ N - ^m§ d gČ = _a~ SS F⁴ fsi r ·. l /&gt; k-G Π) * - · »-1« Ή Ο</td><td>- /&gt; C7 \ S-tg «£ 2 U-4 D w ča · jt&gt; „„ ro CS \ 0 Ό «-O -43- * 4&gt; ° 1 «3 ^w „* L vp 'G m &amp; Ό £ ^ ® ^ k- ~ £ A4 &gt; O _m- -. g gč g O z- »s&gt; -» eq, © čf 00. &lt;t * ? $ i f ~ T 1 D5-§a a§q§® D j— * d &lt;*} υ n * tz ιι D u D D ** R5g ^ Dhz ^ DsčD &lt;čg *&gt;</td><td>Λ / -H sp Ό N _lHDDl &lt;j .X 'Z i - &lt;l E * Μ&gt; ”εΐ $ 3 Ό Ί. r- 9 r r -J nđt M -S - 5-S &lt;J GČ G- D igficnCA® Q trt - * H ®0 Γ'Ί ££ m% N.zd &lt;o ~ m X o i £ O 23 A ob '-' h Lč ® A g. u ό S g 11 § £ _i-čj k ΐΓ-M «d g 2^N-S * ^ S = -3-2⁴| AS§axqS3§ adčT '^ - ggl' ^ °&gt; '1G 1? £ g ~: D l SK - o D</td>

<td>b: s</td><td> 482.24</td><td> 512.25</td><td> 492.21</td>

<td>Ret. Time, Procedure</td><td>1.28 mta Procedure Α</td><td>1.22 min 'Poslupak A'</td><td>1.31 min Procedure Α</td>

<td>'. k ·</td><td> 482.05</td><td>t ^ o oi I— &lt;vi</td><td> 492.09</td>

<td>Appearance</td><td>white solid</td><td>And a transparent glassy substance</td><td>white solid</td>

<td>Reactionary scheme</td><td> 00</td><td>oo</td><td> 00</td>

<td>r4</td><td>u 0 no</td><td>ϋ 0</td><td>A</td>

<td></td><td>XO ( &gt; —X 8 / \</td><td>t ο аJ A-g 0 \</td><td>Q \</td>

<td>~ S4</td><td>Ύ</td><td></td><td>Ύ</td>

<td>h and Ck X)</td><td>m 3</td><td> 3</td><td>»N 3</td>

158

51155 Β

<td>Rt rt Ό Ο a.</td><td>= - ® i i » 04 O sč * - * ”N Ό co G * 1 4 ST ® S m 4 2 4 2? □ «ra 'L ^ p-404 Q -O ».- &lt;= c-off is't? k \ 5! = 2o ^ .G_ o _i- = ^ $ 4 _- S ° Č 2j t ~ - co = - _, - 41 4 E - J ot '®. 1 7 &lt;S ^ ί¹ J χΐ g ^ 4 ^rt· M = ^ S ° i 5 - * «Ϊ^β.0 I ^ iZj « ± »· £ χ; μΟ4Ο“ .- Τ Σ · 35εχ5^{3γ, 3}4, = g^K_M4S * 4-x^K.in m · * ^ld d¹ 32 sg » ? gch N D 8 3 D 3 &lt;D He O</td><td>• an _ © _ -č; n '***^Z »P» - «t⁴· Ca * -rf · _{l š} Η 04 Ο *** - «D X η ^ 0.4 ^ and 3 ³ i- '7 ί m ^{Ν a} ' *&gt; 4oo®S4 ^ 9 d d-u 35 4 - »t a ZZd □ 4 ^ D5, d α 15 ό - · m. = τ 'β Π —- » □ λ 44 ^sa Γ 'Γ · 2 3 2:45 4' Ν'Χ'ί &lt;? ° | 4Τ ^ 4ν ^ ®44 °. » 3 »_ D“&gt; / 5 ν; 3 *. ff β χ 1 DZ®d§dao4U, For 2.g-2: Dh '^_,= g &lt;^{00kO, l}дачт ^ тг</td>

<td> 2</td><td> 564.24</td><td> 582.41</td>

<td>Ret./ Procedure</td><td>1.33 min Procedure A</td><td>1 1.46 gšp Procedure Α</td>

<td>Calculate. MM</td><td> 564.15</td><td>and 582.21</td>

<td>Appearance</td><td>white solid</td><td>white solid</td>

<td>Reactionary scheme</td><td>co</td><td> 90</td>

<td></td><td>p</td><td>Ο 0</td>

<td></td><td>X 2 О đ ° 0 \</td><td>П đ</td>

<td></td><td></td><td>Ύ</td>

<td></td><td>40 Chf (G ^</td><td>g * tg r- ·</td>

159

S^Ci° n »* · NMK data

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<img file="RS51155B_D0274.tif" />

160

51155Β

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ο ΰ

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ο

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<img file="RS51155B_D0280.tif" />

161

51155 Β

<td>NMR data</td><td>X “- 11 m «fa 2 jn f? - _&gt; «, °° d vaA - *« η c? 2- ο 2- -o I Ε Ε · β «Η _» - · 1 C * 3 · “« (* - ►Μ r 1 CN ^t~ * · 0? · * ** π u β -e ^ .7 2 □ m ΙΟ Ώ αο -_ »· · · έ® 2h Ό CS ί-Η «5 R Ćh 40 Ν Μ F * &amp; II Α II &amp; οί ~</td><td>X tgd _-d SN «a -&gt; ^κ «· £ t-.« · „·« £ = Γε £!? 3 ai'-p-Sođ / -. c Ο β Ρ 6 W Α S CQ &lt;ffl 5 Α. Κ Α ο u ο τΐ u Ό 8ρκ ^ 5 · «Μ.Ι ​​# δ.Ι.Ι.ί ef 5 Ρδ 5 Pp £ £ S ν '4 d gp® D h .A čFF κ £ ε £ ^ ££ · Π n-f, ►&gt; v— &lt;eč Ό m n N rc n m&gt; -&gt;</td><td>ο pO X η F 't? &lt;m ο Ό s £ “®» Ά s? * Ί t&gt; σΐ 5 m ® 1 ίΓ ο Λ ό * · ⁴³ c_g ο d ^W 3 Μ * SW D \ Ο GL SC „. * 5 rA Π S . Γ-&gt; i&gt; sSs ^ g II * - ·· - t * 4 d OH. Β ⁿ α oo sč (-, 2 I * '2 ® ff'^NO &gt; 5 - Α d .rf K -s Ε Τ r S bs Μ Η * ώ Α</td>

<td>ΐ 2</td><td> 517.30</td><td> 495.1</td><td>and</td>

<td>Ret./ Procedure</td><td>1.53 πώι Procedure Α</td><td>1.88 min Postupak Αί</td><td>1.57 mia Procedure Β</td>

<td>co&gt; μ-ta N 'J * - (im</td><td>0Ο G— &lt;ο «Μ ιη</td><td> 495.04</td><td> 434.07</td>

<td>Appearance</td><td>white solid</td><td>white solid</td><td>white Solid substanceE</td>

<td>§ o ž&gt; Sž</td><td>«Η</td><td>1-Procedure.A</td><td>1-Procedure. A</td>

<td> ¢5</td><td> 9</td><td>Q V</td><td>0 'A</td>

<td></td><td>) 1 ο ) c = G</td><td>wo ο = 4 o U</td><td>u? o</td>

<td>d!</td><td></td><td></td><td></td>

<td>Qm X</td><td>'d »L</td><td>&lt;L »M</td><td>Ό v&gt; • ^ - «</td>

162

51155 Β

<td>NMR data</td><td>₍l oc T. R _i- η »г- &lt;f D č Ί ^r 3 U 1 c ·&gt; r? t - 3 oo x 5-7 S 3 -3 -3 ° 2 h? cf 1- · 0 G&gt; '—4 D ® JL * 0 ^g:. ΰ^{N n} n S,⁰⁰ X rr G * S § d a ^ S-iS ^ Z G «(N G- O 00 40 h · «5 5 3 3 * Π \ X &lt;G⁴· ► “&gt; F Φ '“¹</td><td>4 = r- „\ · * X č&gt; G1 D 3% D ο D-ο- 'ir, j gmmr— S 5; Č &lt;? «W Č_hеч т&gt; и 00. p £ Q rjT ®O - sČ S * Ο ° 1 Φ Ό * g ^ Ί3 đ 7 Ch ™ j4 · 0Q r- J * »j 00 I b 5® I SS⁴_ fS '^ r' s «&gt; HO &lt;-&gt;</td><td>(l * ® S? Α,. -ο - ffi 0 00; Σζ - pz O · km «00 _r _g 4 -. Εΐζ.ϊϊϊΜ- « Θ _g “« D Α 1 4L! g Sr- - ~ £ 40 0 ​​40 0 ​​00, -č Β 'ϋ' ΓΟ * -rl 11¹⁰ č © ~ Λ Η οο * τΓ σ? π m Ε τΓ &lt;5 .? sčf ^ -, \ oof1L40 Κ + - Ό .. Ό m γί b ι | 1 Χ'2. ^ D 7/7 0 D Χ'ΟΧ ^. &amp; Χ - чзЗг ^ οο р-, η цн - - м</td>

<td> 2</td><td>+ g? ~! 5 pcs X CA. S rn</td><td> 478.17</td><td> 496.21</td>

<td>Ret./ Procedure</td><td>1.32 tnin Procedure B</td><td>1.53 min Procedure A</td><td>1.50 min Procedure Α</td>

<td>&gt; 0 w N 5</td><td> 391.08</td><td> 478.01 1</td><td> 496.03</td>

<td>Appearance</td><td>white solid</td><td>white solid</td><td>white solid</td>

<td>Reactionary šcma</td><td>1-Procedure.A</td><td>Ό</td><td> 40</td>

<td> ¢4</td><td>Q fi</td><td>Q 0 X</td><td> &lt;5</td>

<td></td><td>z α</td><td>ΙΣ &gt; 0</td><td>\ 0 from \ = O f /</td>

<td></td><td></td><td>Ύ</td><td>Ύ</td>

<td>»4 U</td><td>ί-ν V)</td><td>UP TO 1L</td><td>sl m</td>

163

51155Β

<td>Ο cđ Ό Ο SH</td><td>- -fcj 'Š' еч „χο 5 7 л ha ха Ρ '» ι ^p Λ s χ 2 ¹a&gt; ' ⁱ J 4 ST ^ 7 S d2 · «-&gt; S3 εΓ7 ~ 7 b ^ dRL» £ T £&gt; ~ ; G- 3 i D -e n Ez 7 ° υ? 7HR 72) 7® Π · 5 S Ό _ d m rn. · «SoT · 2,; Ο ii N W -oP iT ^ -ϊ II gi Ο · * II O - 1 i £ 2-e7D μ - ® d 2 &lt;Č -ΟχΧΟΟχ - Ό ό 2 _- © Λ *. V&gt; D Η S Ε χ ® ocj r * * η ** · ** g9 m</td><td>* 0 · Τ4 “3 -6&gt; _? ο &lt;ν &lt;&gt; 4 χ; Κ «- £ · ° ο Μ'2 £ 7 ° ioE t 72 Κ S S g Τ '· «· $ e “7 d 4 ° TLd rfS'nshi r&gt;. D fj »m · 7? l&gt; G9 Ή 1 G? Ο ι /). gč w «oo, 11 SA ° - S * ®5G-3 · | and T 7? £ Hg® ŽS7J3 7?&gt; &lt;N? τ 'ΐ I. · # ϊ “! đ ϊ ί⁵ Α k e Λ D - &lt;=&gt; D</td><td> 7§⁴³«S® li'S 'Ε ~«; ”Κ-Dd £ .b Λ - · S» G · ^Ν ° ο ¹ α rO SG t- ·. m „m. сJ п -х-ч zV ^ g £ 3 ° □ 1 gt ° 1L h D Q t s $ 4 Τ'ς57 o m&gt; Š -? Z ® d &lt;- 'Κ. -. CsOj -ч * &lt;. D ^ · gsgS-.sssg = 6-ϊ2 · ί ^ 5Ϊ -ir * r- · nČ v © Or «» - «ο · -&gt;</td>

<td>⁺¥ 2</td><td>00 ech ιη U3</td><td>Mrs. CN</td><td>Α ο ΙΓ)</td>

<td>Ret./ Procedure</td><td>&lt;• 13&gt; 5 &amp; m 3 77 »4 Ο Ρ.</td><td>m | 3 £ § kP-AJ • tfl ~ o CU</td><td>(Đ 1 s l &amp; Ή w -ί ^wΟ Rč</td>

<td>Calculate. ΜΜ</td><td>ν% ι: ♦ 4-4 &lt;Λ Ό</td><td>Ό e&gt; • чг σ \ т?</td><td>«• 4 Ο Ά ο * η</td>

<td>Appearance</td><td>white solid</td><td>rt υ C ¢ 0 l c7 (Λ ws -η C C g&gt; 23 -Ο ij sl</td><td>S «β £ S G L ι w Ο £ £ 4- »M Cl | 3&gt; 3 ”N '□ ιη</td>

<td>cd VS On nl</td><td>Ο</td><td>Ο \</td><td>Ch</td>

<td>pđ</td><td>α?</td><td>Ρ</td><td>o P</td>

<td>pi</td><td>tf š ζ χζ \ = ο ο S</td><td>ζχ</td><td>° A zz * ^ 5</td>

<td>pi</td><td>^ U</td><td>$ -y</td><td>$ —U</td>

<td>CU £)</td><td>ο 4?</td><td>τ-Μ \ £&gt;</td><td>&lt;ч \ о</td>

164

51155 Β

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χ ο

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ρ4 ι- &lt;»-! CU X

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Ο σ3 α&gt; X Ό

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οο

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165

51155 Β

<td>NMR data</td><td>O CN - G- 'T G ^ om ^. jg -f .4 / “ShS'kS š'S'g'S '« 34 «^ © 4 iZb 4 (JO | G ~ Lj' L · JČJ II u D · εί C? 't ® l 4 -osh ΰ, Λ κ-ω s: 4 · Η · ζ ~ $^σ_Μ- 'Ω Α i'JJ -'- οΌ -ς ш2иР55^si + 4 §kd4p S J'sgg's g ^ 4S «Ζ« * ^τ—'μ VI »_ V5 i D 4 ϊ u · ЧJ- 'ί 9 Β ό ~</td><td>sj in « ZjZn- - *. «£ -s »Ο ο Λ - ϊ 3 ιι S-4&gt; S Μ Ε ® ο \ «z 7.G. ® ™ ρ- ρ SSI 07 22.4 «S-Β υ 4.43 ^ 0 = 7 £ s Q · ο ^ τ ·. “&gt; Τ ® 4 Ο '-'Lj k u-mί Ή 7 =&gt; = 72 ο 4s χ Μ sl 00 m'RAm' U-OOOS ° D D ⁴⁵ Π&gt;! „&lt;Ο SS βί 54 ^ 4 ^ D - - z N- »tr! 'T ». —G. Ο SP Τ w. II u · «(J Λ⁴ CN Γ- ι- »J3 Ο * - · * - ·</td>

<td>Nč</td><td> 506.31</td><td>Ο ΓΊ κ © Ο</td>

<td>Time ret./ Procedure</td><td>1.41 min Procedure Α</td><td>1.42 min Procedure Α</td>

<td>Calculate. MM</td><td> 506.11 ... .:</td><td> 506.11</td>

<td>Appearance</td><td>transparent glassy substance</td><td>transparent glassy substance</td>

<td>Reactionary scheme</td><td> 00</td><td> 00</td>

<td>.</td><td>5 fi</td><td>5 fi</td>

<td>R²</td><td></td><td>\ Q</td>

<td></td><td> &gt;</td><td></td>

<td>U hGk &amp;</td><td>45 Ό</td><td>g * · 5 © «-«</td>

166

51155 Β

<img file="RS51155B_D0303.tif" />

<img file="RS51155B_D0304.tif" />

<img file="RS51155B_D0305.tif" />

167

51155Β

<img file="RS51155B_D0306.tif" />

| 3Η, J-7-ΟΗζ)

<img file="RS51155B_D0307.tif" />

<img file="RS51155B_D0308.tif" />

168

51155 Β

<td>NMR</td><td>&lt;2 c? h · t ~ - 11 oz ° š ΰ. _c-8 &amp; o ».II II, · &lt;7 d s ^m 11 « ® ^w- in S d 2S 25 2 24 ° - $ it. oo * * - * „2 o ε ι »® ® g * 7 ± ^w T r- &lt;n f73o n S «2 _i* $ D 00 \ J ~ ¹Hsč hg σ \ * f -F · * ·, —č „ m -g “i ® t &lt;χ č h E 2G¹ v-4 (-h. f- »« m «-t» i '©&gt;</td><td>MD X 42 m -ej- O © -a Č w Μ χρ g- ο- D 11 Ό - Č ·· G; 41 s ». &gt; · Is S? οο ® &amp; $ ΧΟ X ΙΛ, N ο Ε * 2 * 'Ο κ_&gt; U „S0 X ζ&gt; Γ- □ t- —hz ^1:0 N? the^ha1 1 M I Ά ž S tfs 2 »d D h d d d</td><td>2 -G . ~ £ -e xt Či £ e “5 D. £ 7 2 u m ® 3 £ · ° ΝΪ» rf'd '' - '2 to -a. ®^SXO Č oo 3 55- 2 θ '³ 9 ° · o £ G ^ £ &lt;&gt; Š rf® ⁴</td><td></td><td></td>

<td>s</td><td> 437.16</td><td>&lt;đ V »X ° 1 + - = r S2</td><td>M + Na 471.97</td><td> 479.02</td><td>449.02 M + Na</td>

<td>Ret./ Procedure</td><td>1.52 min Procedure A</td><td>1 2.13 min Procedure D !! 1___________________________________</td><td>1.94 min. Procedure D</td><td>1.86 Procedure Β</td><td>1.82 Procedure B</td>

<td>Calculate. MM</td><td> 436.92</td><td> 492.11</td><td> 1 449.12</td><td> 478.90</td><td>o O \ \ D rS tg</td>

<td>Appearance</td><td>white solid</td><td>whitish solid</td><td>| white solid substance</td><td></td><td></td>

<td>Reactionary scheme</td><td> 40</td><td>1-Procedure.A 1 i______________________________________________________________________________________________</td><td>1 1-Procedure.A</td><td>1-solid substrate</td><td>l-solid substrate</td>

<td></td><td>5 0 h</td><td>Q P</td><td>5 U '</td><td>u 2</td><td>o P</td>

<td>no</td><td>X o U = o o</td><td>\ LU</td><td>a: α</td><td>g » U. O rd</td><td> t</td>

<td> 74</td><td>no</td><td></td><td></td><td></td><td></td>

<td></td><td> 173</td><td> 174</td><td>• l t — t</td><td>40 G- 1— «</td><td>rbr4</td>

169

51155 Β

<td>Ο Ο Ο Cu</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td rowspan="2"> 505.07</td>

<td>ΐ 2</td><td> 496.06</td><td> 413.04</td><td>445.02 M + Na</td><td>523.04 M + Na</td><td> 414.05</td><td> 423.08</td><td> 467.06</td>

<td>Ret./ Procedure</td><td>1.81 Procedure B</td><td>1.72 Procedure B</td><td>1.86 Procedure B i</td><td>D -I ch - 2 V3 O 0h</td><td>m σι ΙΛ Oč _ · □ ”w fig Oh SC</td><td>1.88 Procedure B</td><td>1.60 Procedure B</td><td>1.89 Procedure B</td>

<td>'Q Μ N 2</td><td> 496.00</td><td>o &lt;5 \ ech 'ί ·</td><td> 423.00</td><td> 501.10</td><td>about fig m</td><td>O G&gt; rS &lt;N 'T</td><td> 467.00</td><td> 505.00</td>

<td>Appearance</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Reactionary scheme</td><td>1-solid substrate</td><td>l-solid substrate</td><td>NW l esh? with</td><td>1-solid substrate</td><td>l-ćvrsia 'substrate</td><td>l-solid substrate</td><td>1-solid substrate</td><td>1-solid substrate</td>

<td></td><td> 0</td><td></td><td>Q F</td><td>u</td><td>Q</td><td></td><td>o P</td><td>S fi</td>

<td>c!</td><td>α²</td><td>-F,</td><td>f</td><td></td><td>oz</td><td>V</td><td>no 0</td><td>-9 g</td>

<td>p {</td><td>Ύ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>u C cx &lt;X »</td><td>00 r- «</td><td>G \ r ·</td><td> 180</td><td> 00</td><td> 182</td><td>m oO v-4</td><td> 00</td><td>• l οο ч-Ч</td>

170

51155 Β

<td>СJ еј д ο With I</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>ΐ 2</td><td> 479.02</td><td> 505.06</td><td>450.90 M + Na</td><td> 423.09</td><td>C) SC</td><td> 487.04</td><td>459.05 M + Na</td><td>381.07 M + Na</td>

<td>Time ret./ Procedure</td><td>1.84 Procedure B</td><td>d 2 § tft o Ck</td><td>1.80 Procedure B</td><td>1.89 Procedure Β</td><td>1 1.92 Procedure Β</td><td>D sl g. - Β (L Ο ¢ +</td><td>1.95 Procedure Β</td><td>1.67 Procedure Β</td>

<td>Calculate. MM</td><td> 478.90</td><td> 505.00</td><td> 429.40</td><td>Ο φ GP СЧ</td><td> 1 425.00</td><td> 487.00</td><td> 437.00</td><td> 358.90</td>

<td>Appearance</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Reactionary šcma</td><td>1 -solid substrate</td><td>1-solid substrate</td><td>l-solid substrate</td><td>1 -solid substrate</td><td>--------------------------------------------------- -------------------------------------------------! 1 -solid substrate</td><td>1-solid substrate</td><td>1-solid substrate</td><td>1-solid substrate</td>

<td> 74</td><td></td><td>u 0</td><td>b 0</td><td>υ fi</td><td>Ρ</td><td>υ Ρ</td><td>Ο .0</td><td>op ·</td>

<td> 74</td><td></td><td>f ΐ '</td><td> 10</td><td>φ</td><td>and</td><td>Ρ</td><td>Ο</td><td> 0</td>

<td> 74</td><td></td><td></td><td>Ύ</td><td></td><td>Ύ</td><td>Ύ</td><td>Ύ</td><td></td>

<td>n 'u Rč L</td><td>ΟΟ</td><td>tΟΟ</td><td>οο ΟΟ , —4</td><td> 189</td><td>ο ΟΧ</td><td>S</td><td>СЧ σχ, —4</td><td>m σ \</td>

171

51155 Β

<td>NMR data</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>1 s</td><td> 472.9</td><td> 431.04</td><td> 400.98</td><td>m + 4 “« 3</td><td> 400.99</td><td>what about \</td><td>487.10 M + Na</td><td> 483.04</td>

<td>Ret./ Procedure</td><td>1.86 Procedure B</td><td>1.75 Procedure B</td><td>1.65 j Procedure Β</td><td>1.82 Procedure B</td><td>1.64 ProcedureB</td><td>1.95 Procedure B</td><td>2.05 Procedure B</td><td>1.72 Procedure B</td>

<td>Calculate. MM</td><td> 473.80</td><td> 430.9</td><td> 379.30</td><td> 421.00</td><td> 379.30</td><td> 495.00</td><td> 465.10</td><td> 483.00</td>

<td>Appearance</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Reactionary scheme</td><td>1-solid substrate</td><td>1 -solid substrate</td><td>1 -solid substrate 1</td><td>--------------------------------------------------- --------------------------------------------------- --------------------------------------------------- --------------------------------------------------- ,, 1 1-solid substrate</td><td>1 -solid substrate</td><td>1 -solid substrate</td><td>1-solid substrate</td><td>1-solid substrate</td>

<td>Bi</td><td>Q</td><td>in fi</td><td>b</td><td>3 p</td><td> 0</td><td>u P</td><td>b P</td><td>Q 0</td>

<td></td><td>u Ш ό</td><td>u. 0</td><td></td><td>t</td><td> .?</td><td>u? ω co 7</td><td> 0</td><td>MeO y ~^cofl</td>

<td>v4</td><td></td><td>A</td><td> 0-</td><td></td><td>A</td><td> 0-</td><td>A</td><td>A</td>

<td></td><td> 4-</td><td>»L Сћ</td><td>Ch</td><td> 197</td><td>□ o O \</td><td>O \ c * T -— &lt;</td><td> 200</td><td> 201</td>

172

51155 Β

<td>NMR data</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 1</td><td>486.96 M + Na</td><td> 431.04</td><td> 409.07</td><td> 463.04</td><td> 1 1 423.10</td><td> 492.91</td><td>цј · еј * 4 * l</td><td>S&gt; 3 =! Z m + 52</td>

<td>Ret./ Procedure</td><td>1.91 Procedure B</td><td>1.77 Procedure B</td><td>1.79 Procedure Β</td><td>1.81 Procedure B</td><td>i 00 L - s ίΛ Ο GU</td><td>1.88 Procedure B</td><td>1.78 Procedure B</td><td>1.58 Procedure B</td>

<td>Calculate. MM</td><td> 463.80</td><td> 430.90</td><td> 409.00</td><td> 462.90</td><td> 423.00</td><td>o oo 5h 4 ·</td><td> 409.00</td><td> 419.9</td>

<td>Appearance</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Reactionary scheme</td><td>l-solid substrate</td><td>CQ the D-</td><td>1-solid pad</td><td>l-solid substrate</td><td>1 -Solid substrate</td><td>1 -solid substrate</td><td>1-solid substrate</td><td>1-solid substrate</td>

<td></td><td>o 0</td><td>υ / Č no</td><td></td><td></td><td>u P</td><td>υ .0</td><td>p P</td><td>fi</td>

<td>pi</td><td>Cl Cl</td><td>d</td><td>v.</td><td></td><td></td><td> 0</td><td></td><td>z no</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> 202</td><td>© sč</td><td> 204</td><td> 205</td><td>Ό O Ms.</td><td>r * o Ol</td><td>□ oon</td><td>Ch O sch</td>

173

51155 Β

<td>NMR data</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 1</td><td>G * · 4 “\ D m</td><td> 481.02</td><td> 453.02 1 ..</td><td>ι 1 455.07</td><td>515.09 j</td><td>O \ rt £ oo 4-</td><td> 481.00</td><td> 403.12</td>

<td>Ret./l time Procedure</td><td>1.56 Procedure B</td><td>1.87. Procedure Β</td><td>1.76 Procedure B i</td><td>1.71 Procedure B</td><td>1.91 j Procedure B</td><td>1.82 Procedure B</td><td>1.80 Procedure B</td><td>1,600 Procedure B</td>

<td>Expression. MM</td><td> 344.90</td><td>ο Ο \ ό ΟΟ</td><td>430.90 i </td><td> |------------------------------------------------------------------------------------------------------------------------------------------------------------------------- 455.00</td><td> 515.00</td><td> 447.40</td><td> 480.90</td><td> 402.90</td>

<td>Appearance</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Reactionary scheme</td><td>1-solid substrate</td><td>1-solid substrate</td><td>1-solid substrate</td><td>1 -solid substrate</td><td>1-solid substrate</td><td>--------------------------------------------------- --------------------------------------------------- --------------------------------------------------- -----------------------------, 1-solid substrate</td><td>1-solid substrate</td><td>1-solid substrate</td>

<td>Bi</td><td>υ 0 no</td><td>δ 0 no</td><td>□ P</td><td>o P</td><td>u 0 no</td><td> 7</td><td>u P</td><td>b fi</td>

<td>Pd</td><td> 7</td><td>u.</td><td>v</td><td>you F ss V</td><td> 9</td><td></td><td>r? U_</td><td>\ o</td>

<td>»I</td><td></td><td>X</td><td></td><td></td><td>Ύ</td><td></td><td></td><td></td>

<td>»- &lt;u</td><td> 210</td><td>rt sč</td><td>n?</td><td>m G- * Mrs.</td><td> 1 214</td><td>CN</td><td> 216</td><td> 217</td>

174

51155 Β

<td>NMR data</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>t s</td><td> 429.04</td><td> 471.00</td><td>cn Q rn V)</td><td>503.00 M + Na</td><td>47 NW</td><td>mor ** i vn</td><td>V »q gP</td>

<td>Time ret./ Procedure</td><td>1.78 Procedure B</td><td>1.78 'Procedure B</td><td>1.75 Procedure B</td><td>1.85 Procedure B</td><td>1.87 Procedure B</td><td>1.62 Procedure B</td><td>1.63 Procedure B</td>

<td>&gt; - sg sj st — i &amp;</td><td> 429.40</td><td> 448.90</td><td> 430.90</td><td>Ο c \ ό QO • Cj ·</td><td>oo • cj</td><td> 453.00</td><td> 453.00</td>

<td>Appearance</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Reaction scheme</td><td>1-solid substrate</td><td>1-solid substrate</td><td>1 -solid substrate I</td><td>1 -solid substrate</td><td>1 -solid substrate</td><td>1-solid substrate</td><td>1-solid substrate</td>

<td>7ύ</td><td>fi</td><td>5 p</td><td></td><td>p '</td><td>U P</td><td>op</td><td>o P</td>

<td>Pi</td><td></td><td>u</td><td></td><td>rcf F</td><td> (?</td><td></td><td>oo ό</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Ί-ί Urt v. l</td><td> 218</td><td> 219</td><td>© gč ίΝ</td><td>cS C4</td><td> 222</td><td> 223</td><td> 224</td>

175

51155 Β

<img file="RS51155B_D0309.tif" />

176

51155 Β

<td>NMR data</td><td></td><td>Γ4 g !? HJ A o tO ° f? to * “* b ® θ 'G-» I JZ ~ w af š t Ύ L £ S -Ή t W i, -b? d.-So- _; E čo ' tf © h; D k -55 II 2 f- ~ »- 'o J 2 O HD '“' K II .rn □ G:. SC⁴ ₽ 4 JG 00 D P _rft&gt; ri'5'— ' 1 ifiS'tn Hn fsj - &lt;rt o \ r ~ h_i = ° n &lt;h yes - ч&gt; Г⁴· * - »xf Ό * gm</td><td>° o X uT m ® 4 M L ^G '4. 0 T = F7 «-&gt; Λ w d o S? »© _ § &amp; d₀ D - K 5 -V &lt;-s? ^ „^ E.m · D« ό, N S \ - tC »- &lt;t-« D Ό * - «psj gP g 5G to 5 O · * -4 * m X .Υ. v. ρ “! Ί p 8 S κ κ- · * G ± X gč —1.,. CO D'-g 2, * 1 “· C?</td><td></td><td></td><td></td>

<td>S</td><td>ca. % 00 + kD m</td><td>3 * Ο ? 9</td><td>'άΓ Ο 2 νΐ + ΟΟ</td><td> 530.99</td><td> 417.07</td><td> 467.06</td>

<td>Vrcme ret / Procedure</td><td>1.78 Procedure B</td><td>1.91 min Procedure F</td><td>2.13 rnin Procedure F</td><td>1.92 Procedure B</td><td>1.61 Procedure B</td><td>1.62 Procedure B</td>

<td>&lt;e 5 Н Ч! «—4 1 * 5</td><td> 447.40</td><td>419.11 I</td><td>o g4</td><td> 530.92</td><td> 416.93</td><td>ech Cs &lt;&gt; Ό 'G</td>

<td>Appearance</td><td></td><td>white solid</td><td>white solid</td><td>white solid</td><td>white solid</td><td>white solid</td>

<td>Reactionary scheme</td><td>1-solid substrate</td><td>1-Procedure.A</td><td>1-Procedure.A</td><td>1 -solid substrate</td><td>1-solid substrate</td><td>1 -solid substrate</td>

<td> 74</td><td> 7</td><td>b?</td><td>υ fi</td><td>5 fi</td><td>Q fi</td><td>α 0</td>

<td> 74</td><td></td><td>to</td><td>u? Oh</td><td>u. u- V</td><td>,. • no</td><td>X oo t</td>

<td> ₽4</td><td>Ί - ^ _</td><td>i ..... \</td><td> £11111\</td><td>Ύ</td><td></td><td></td>

<td>lj x&gt;</td><td> 233</td><td>чг м еч</td><td>GP SM</td><td>Ό г “&gt; СЧ</td><td> 237</td><td> 238</td>

177

51155Β

<td>ce τ5 Q (X</td><td></td><td></td><td>* 2 I) ώ Zg m _l &lt;s _ N N § K 3 · * r4 S - P 3 D zs 'ν' § ² ® ⁰¹9 «2 l &lt;Lz °. §D3§S®So £ H§ - Ν Г&gt; »-ι 2 '• s *“&gt;</td><td>* η-Γ Λ ζ — Ύ X) Ν .Λ 3 ~ Μ rs ® rfo J7S. . P4N-4.S oodZ 'r ^ f 3ί? Λ-Τ® 9§ “=“ Et- n ΐ7ς? = 2 * 3-2 ZH ^ h.E i Εΰ'S'oo ιΓ (J gč&gt; D \ o „ ί? ο ο Q č5 'd' c 'Z UČ o w zs U' G 'j-' -2 vo Ί⁴ S ± j 5 -o n »i / -jt * Y ο © c? - D Ž «C G * r-ι Z—«,, II Ο / - ^ · - »GJ. · Ν £ 5 φ D = ό ^Μ- ν 'Τ ο Κ L S °. 3 »35 4 jd3 ~ £ z Ε ± i-&gt; Ο _» —ι 'Ο Α * m · ζ &lt;«. * η m · οο dd *^,ui «v®! č7“ G “- rt« -&gt; n&gt; o</td>

<td>ΐΰ</td><td>оО еđ 92</td><td> 396.01</td><td>Ch sl oi sl w ~)</td><td> 648.43</td>

<td>Ret./ Procedure</td><td> 1.62</td><td> 1.13 .........</td><td>1.69 min Procedure Ai</td><td>1.88 gpt Procedure A</td>

<td>Calculate. MM</td><td> 379.13</td><td>os * l Ćh</td><td> 592.29</td><td> 648.4</td>

<td>Appearance</td><td>white solid</td><td>white solid</td><td>glassy substance amber color</td><td>vitreous substance amber color</td>

<td>Reactionary šcma</td><td>1-solid substrate</td><td>1 -solid substrate</td><td>oo</td><td>co</td>

<td> 74</td><td>o</td><td>Q 0</td><td>5 fl</td><td>o P</td>

<td></td><td> %</td><td></td><td>m V— z</td><td>) \ \ -zd</td>

<td>β.</td><td></td><td></td><td></td><td>^.&gt;</td>

<td>U μ. ' with x&gt;</td><td>Ch cn fS</td><td> 240</td><td>N</td><td> 242</td>

178

51155 Β

<img file="RS51155B_D0310.tif" />

<img file="RS51155B_D0311.tif" />

<img file="RS51155B_D0312.tif" />

179

51155 Β

<img file="RS51155B_D0313.tif" />

<img file="RS51155B_D0314.tif" />

<img file="RS51155B_D0315.tif" />

180

51155 Β

<td>υ Ο Ο SH</td><td>tn * • _l m O ♦ £ iZ i —Οι . 7 3 π £ * 'O'onOO ^ O ^ O'rnj-J &lt;2 D ιο D D h Αχ;⁰⁴f'SS'jš'a rf-SS &lt;a ™ g * ° m S £ - rO ° Č η m r-. £ Ο F? ^ OO NN &lt;&gt; „· СJ ^ г ^ гг § МјБц'пиБјајТ Е? o oo AN rf „-« n » οα 2 do ** 5 &lt;_r O _g&gt; -4 “ D 11 · II m Ή g 33 g 3 «</td><td>_ * * «· &lt;D N - _rt đ gč ώ * ® z 6ϊ £ ϊ§31 gx. D g 5 5 »i! Td A - · 00 ι— * to * X 3 * · b m - 3 О ^ - ^ ЛОгчспсЧ 8&gt; д ~ т ° в5 I -S οό. μ oN c&gt; | §§d d f d? β- £ · s' G¹ D gč o Ji4i— Ο ·</td><td>r. · Β '2 -⁰¹ _g l S - '^ Ό 1L X. 'đ ^ βΐο '^ ί ^ χί⁴'t- ”ι - m .. p; sg o -¹° v ·· ί? (2 D -® »h JZ-HD“ O^e v ~ dg-.R i »M f? £. » r, 5 Ξ^c© TJ- * o * _g - ^ Z SJS * 11 © ζ * Τ5 33 ⁱ i-S A * “* J m sch k&gt; fs u, cho m ι a: □ II ^r~ ^r: _e. . .d.E.L «' = 4 X 7 pK ι,. -Η ο._n§ sč II · * · «i - λ * e · Č oo - Ϊ? Ϊ7 ^ D 'Ώ &lt;Ί D X</td>

<td></td><td> 479.02</td><td>CN A</td><td>g * ο Q \ Γ * r</td>

<td>Weather rct./ Procedure</td><td>l.lSmin Procedure B</td><td>1.92min Procedure B</td><td>2.01 min Procedure B</td>

<td>Calculate. ΜΜ</td><td> 479.05</td><td>ΓΌ Ο SF:&gt; HG</td><td> -----------------------------------------------------------------------------------1 482.00</td>

<td>Appearance</td><td>yellow solid</td><td>yellow-brown solid</td><td>white solid</td>

<td>Reactionary scheme</td><td>sch</td><td>C4</td><td>ЧО</td>

<td>pi</td><td>u P</td><td>0 • no</td><td>Oh 0 p</td>

<td>PŽ</td><td>d</td><td>-f)^Z&gt; v</td><td>\ o / —G \ _o o</td>

<td>c!</td><td>ί-Λ_</td><td></td><td></td>

<td>X)</td><td>0 \ 'Z · G4</td><td>o »n gč</td><td>r-4 ι / Ί MS</td>

181

51155 Β

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<img file="RS51155B_D0317.tif" />

Bi

<img file="RS51155B_D0318.tif" />

s4

<img file="RS51155B_D0319.tif" />

<img file="RS51155B_D0320.tif" />

182

51155 Β

<img file="RS51155B_D0321.tif" />

<img file="RS51155B_D0322.tif" />

<img file="RS51155B_D0323.tif" />

183

51155 Β

<td>'S -3 α.</td><td>P? I§ c £ o Ο στ θ '- _r - 8, is it? M-D D - 2 C 2 G-; of «= -; 7« _ο· Čz ίΕ * 11 b '· gn „ _r5 2 ®! ά г? Pi o D «=&gt;! J D “1 g =_rf3 SrS43-T3Hb g6? 2§ «sx # | gS aTg-: SSS ^ Sj S «s“ »5 °» ® «- &lt;&gt; 35 D- g ° 5 M 'O 5 35 r Ον n - n</td><td>Ά r 1G4 ZN -? nJ .DD -X d-d- 'V ° £ ° z _m”&lt;D -¹ * £&gt; 'T | § &amp; 0 »· ί ^ '' !. Εί &lt;4ό '° § τ&gt;“ ί) 5 ³ η I '^l „- ^ - Д ојАЧо № \ © O · Gch Tf II O 1 · * z * \ 1— &lt;&gt; -n Ώ. = ® _ί ^ o D - °. P⁴³ 3 „- Q 2; Oj ^ oh ^ oo ^. 0? m Ά t »• 'O K tn O §D-3, «&gt;_m-čZ® £ 2-oZ m _j- S0 z? -Dg ^ D ^^ ZJI * &lt;Sr-i4iiTr ^ &lt;Ot4 ^ r4 ^</td>

<td>ϊ</td><td>^ G gP «Č &lt;L</td><td>сч ΠΊ 05 ”G VI</td>

<td>Ret./ Procedure</td><td>i 1.81 min Procedure A i</td><td>1.78 min Procedure Α</td>

<td>&gt; ό - u- rs N * 5</td><td>'T sč VD GCH w ~&gt;</td><td>Ms. CN 00 ΈΤ VI</td>

<td>Appearance</td><td>white solid substance</td><td>white solid</td>

<td>Reactionary scheme</td><td></td><td>Γ-</td>

<td>* n. Cđ</td><td>u p</td><td>G 0</td>

<td></td><td>Q zz ° č č</td><td>0 21 ° = &lt; no</td>

<td>Pi</td><td></td><td>Ύ</td>

<td>uu</td><td>GO v-&gt; SC</td><td>SL VI Msgr</td>

184

51155Β

<td>• tČ υ « • a ο η</td><td>- £ 5 «o« g? 3 " '0'X- ^ e? 3g?^:S^c'^|Sa'4 o G4 ^l w 1 © 0-3.0 II S m? _i3 ^ ζ q ;&gt; Μ &lt;2. 1η Ss 8 £ -_, -¹ 3 ® s? 9 ”S ZDs33 ~ 222s £ « 5 2- -o «ii = 1 β $ · s 2 5 ¹¹D - Ό GČ * “~ - Ο Ο, -ί - m ^ čndbgvio ^ dk</td><td>¢ 5 Ο - _ί _-,, .- q \ τ 'σ ° ο. Ε poo ^ vdffiriT »„ £ - D Α ο Ο 3. 2.2 v d ^ -h ^ pl «ρ ν 'Β -,.-'- Ί ί. С 7 - «Ш„ 2 *. .ο &lt;,. \ Γ \ «Λ Ο» 5 Ό * d · η -. _Μ· 5 7 Ο = 1 g 3 &lt;S HSI sc D 3 T O £ * 2 ο K TS ⁴⁰ s&gt; ° £ 2 B &lt;—'.- ςD ό 2, ο 2 r ^ _ΛΓ- οο Mg «χ α&gt; ~ Β, Ш ^ 7 £; 44ШС · ϋΐε ^ ϊκΐ3СС5С έΒ I _M* S ν .ΙηηΕ .'-'- ΝΓ-ΧΥ Μ 4 ° ϊ - ίη °! ^ Β¹¹- 3 Γ— Ό 3 II 3 - 'ГЧ</td>

<td>I</td><td> 589.25</td><td> 555.24</td>

<td>- ~ V υ &amp; 65 0J (Λ&gt; ο&gt; cu</td><td>1.90 min Procedure Α</td><td>1.86 min Procedure Α</td>

<td>Calculate. ΜΜ</td><td> 588.18</td><td> 554.14</td>

<td>Appearance</td><td>white solid</td><td>and white solid</td>

<td>Reactionary scheme</td><td></td><td>t * ·</td>

<td></td><td>Q 0 h</td><td>b 2</td>

<td>p4</td><td>au % zs ° = &lt; no</td><td>4 ΣΧ ° no no</td>

<td>~ f4</td><td>Α</td><td>? -u</td>

<td>Och-O</td><td>ο \ Ο MS</td><td>i 1 261</td>

185

51155 Β

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<img file="RS51155B_D0325.tif" />

186

51155 Β

<img file="RS51155B_D0326.tif" />

<img file="RS51155B_D0327.tif" />

<img file="RS51155B_D0328.tif" />

<img file="RS51155B_D0329.tif" />

<img file="RS51155B_D0330.tif" />

<img file="RS51155B_D0331.tif" />

<img file="RS51155B_D0332.tif" />

<img file="RS51155B_D0333.tif" />

w&gt; o GJ

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187

51155 Β

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<img file="RS51155B_D0336.tif" />

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г * · &lt;-η οο ο «ο

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«Β

Ό

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yes

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o hl

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O (

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Сч £) ао во сч в © &lt;с

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188

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<img file="RS51155B_D0356.tif" />

<img file="RS51155B_D0357.tif" />

<img file="RS51155B_D0358.tif" />

<img file="RS51155B_D0359.tif" />

<img file="RS51155B_D0360.tif" />

<img file="RS51155B_D0361.tif" />

<img file="RS51155B_D0362.tif" />

<img file="RS51155B_D0363.tif" />

<img file="RS51155B_D0364.tif" />

еч реч м

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189

51155Β

Ο 03 * 3 ο a

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4-*

Ο62 Ο &lt;Λ

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&lt;· | 3 «Ο, m 3

G-4 U CU

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Τ tH αχ Τ '

4Ί w ~&gt;

T- '

XЂ νη q cri ο W-&gt;

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S - * -&gt; Ρ 3 ο -'Ν CU

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Ρ &lt;§ * +

L fig

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ω&gt; Ν SH

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*₽$

<img file="RS51155B_D0375.tif" />

<img file="RS51155B_D0376.tif" />

<img file="RS51155B_D0377.tif" />

Yes

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<img file="RS51155B_D0379.tif" />

<img file="RS51155B_D0380.tif" />

U and X)

I Goi

190

51155 Β

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191

51155Β

<td>¢ ¢ 3 Ό Ο α</td><td>Oč * »č. &lt;A cn; D * 9 ​​-r G 11 S “Ό 9 _; · ς? κ3β-Μ- «η, b -“ S 5? Ό X- £ ± n 2 S ίί'σίσι w οο η · g ^ S ~ - ΟΟ □ £, 1 t&gt; ο O £ j * “« Γ O sfl F, - :. D 3 SW * 9 oi □ -e- «n_xStn t5 * «Ό in X - · § i * g®e ~ '£, © Zn « ⁱ g- m ? 2g.g ~ č-g5gjmo</td><td>Š _A £&gt; p. 2 years¹⁰ ό g ”gt 00 Ο, -ί D Ο G4. Z1 11 «” «O 7 N 45 -04 ^ 3 . \ Š 4G O -4- &lt;NK _ GS Ž 1 '_ 1 - ΟΟ Μ □ σ «- π 0 χ _„ s 9, 'P IJ t ± D E h g Ί3 Ό Ό CQ GP O «X l m ό (4 a 2 m d ° «S 2 S ^ 2 3 ® £ - 4 ^ 00 0 m 0 0,. ai 11 «Ι sm J w 00 j-, g u5. (Ό ώβ ^ · rtS ± 5 9-o0 ^ oslh4 = 1 © g&gt; D G9 &lt;C - &lt;'i' O- F</td><td>5l / ι ⁱ . * R ° = '3- ^ D -^s^ 2-®5: -po E ^ .o D N eo O °°. S 'S' n 5 P ®r^e -3s » £_I'2L -b-; £, £ g-D υσ? ό ~ »% έ-νέ ^ όο i! - * m ** ι⁴· T *&gt; P5 * 5 u ® O _o· „ S a £ = 1 ^ &lt;? S sč 00 »i - K -đ ® 8 k</td>

<td>ί-&gt; ΐ S</td><td>SP O g * n</td><td>mo © g ~ * TG</td><td>(* P F 00 o &lt;n</td>

<td>Time ret./ Procedure</td><td>um * § 3 V3 Oh Rč</td><td>ο •• z With 00 £ r ^ i GČ Ο &amp; n</td><td>0 .2 S l I Ο. ЧО □ η SM ο</td>

<td>hj sv&gt; M QNS * 4</td><td>rO O &lt;l</td><td>-3o o r-</td><td>Go μ5 © * η</td>

<td>Appearance</td><td>еđ у đ ® ž2 o. Έ)&gt; 3 HJ&gt; □ VI</td><td>«Cž ga *« · gZ sl ί · - n CU 3 X&gt;&gt; QV</td><td>Λ ω α «£ &amp; ω&gt; 3 -Ο&gt; Q 5Λ</td>

<td>with α .2 '3 -M w S 2 »05&gt;«</td><td>r ·</td><td>r-</td><td>G *</td>

<td> ₽4</td><td>b P</td><td> ,0‘</td><td> ,0</td>

<td></td><td>lu u. h?</td><td>L?</td><td>g Ρ</td>

<td></td><td>Ύ</td><td></td><td>^ ~ U ~</td>

<td>P. £&gt;</td><td>o 00 Ol</td><td>co rs</td><td>04 te n</td>

192

51155 Β

<td>NMR data</td><td>S ® « СЧ Ζΰ? &lt;⁴ P TN ”θ * b · ® £ rf *. Μ Ο Ο^1X5 £ SC £, ό ό 2, Β X (Α G &lt;χ 3 · a ιι E «8 ^“ 7 7- G- jjLJ u, _s . ΰ c?¹ 5 ° · »'S- - C? 8 I π «~ α a sč - ιι i! ° * S - - - Q 3¹ riZ® - З &lt;м о /А.ј· »- м G N 0CO I 4 / 4z</td><td>_S5®s £ L. L · n. - l - s = 4 a^sα ⁱ_i* 7 ^ 3 s n J1 _i* to a u. Ο &lt;O&gt; -U kGM - β-j! No? «Λ h Ο - 2 'β 2 ° ό® S * Č&gt; I gs O or ~ X -, -? G NH ΎΥ-Ά, -οό ή = 0 SE d 3η Off '«oo 77 Q oo s * gG« 2 θ p D ® d 'V χ'Υ «w . 41 сч&gt; -&gt; -&gt; ном. r ΟΙ —--, ·. * L XQ ιι ο Σ D 33om rn ο) Κ οό ΖΝηηΝΑ-ΐΑ. . « - Ό 'Τ ri G) N 0Η Ό</td><td>A «J“ Α, ® 1 . _ ', _ (O m · »J Ο ϊ II έίβχ ^ tO._kX^vYes_l.r3 ^ &lt;&gt; M *^,* «- r ± “„ -'joo £ -o. E 3&gt; 5 1 «Ο Β '-' ηχ SA «f * -n -S ·« o&gt; » .ρΎ-τ® I 74 “^ oa * · i« * - »« IS ¹⁴ ® 1 S Ξ. η. ο έ s Ζ 5 'l d ^m &gt; α ►r „« Κ '», 8 ~. 8 ** = 4 ° 4^r :.? -ĆS 33θΟ · - * τΤ · -4 Β G4 - &lt;Ο 4 ©</td>

<td></td><td> 517.19</td><td> 550.06</td><td> 540.98</td>

<td>Time ret./ Procedure</td><td>1.34 πώι Procedure Α</td><td>2.87 min Procedure C</td><td>I 2.76 ηιίη Procedure C</td>

<td>Calculate. MM</td><td> 517.09</td><td> 550.12</td><td> 541.50</td>

<td>Appearance</td><td>white solid</td><td>white solid</td><td>bcla solid</td>

<td>Reactionary scheme</td><td>g *</td><td>t'-</td><td>t * -</td>

<td>Yes</td><td>ϋ 0</td><td>u fi</td><td>Q5 0</td>

<td>hey</td><td> 0 0</td><td>\ o __ zg ?</td><td>no. 0</td>

<td> 8</td><td></td><td>'Ύ</td><td>Ύ</td>

<td>X)</td><td> 283</td><td> 284</td><td>\ l 00</td>

193

51155 Β

<img file="RS51155B_D0382.tif" />

<img file="RS51155B_D0383.tif" />

<img file="RS51155B_D0384.tif" />

194

51155 Β

<td>υ Χ3 Ο α</td><td>G⁴· KD M W t Α I «3 ⁰⁴ S. tsl 3- WJ, 00 D &lt;&gt; -753.3 'B'-ri'M 3 gč D ^σ; «&gt; * S 6 b / τ - 5 n °? z G 7 o х 31 * * c4 Тđ · р- &lt; _ž gč ' _l ' §5&gt; s3SSš2g; - Ζ 5 c, 5 m D ir, ^N om , ΓημΑΛ '-' ^ ΗΓΝ ^ '-' Ο</td><td>.pf Ο, 3 z t? s ž k a 2 £ ® nK ^^ S '-' ^ ooč 5 oo w *** o \ Oč u 3.00 ”m ti7 P S? '· * јС ^ АриС-Бш -ШС “-КЕС«! = 8i . z- &lt;o Č o - cs „_ 9 » ¹ - * J -⁰⁰ X | ZT— &lt;h Z—&gt; GP &lt;-&gt; „ d f ~! R D K g o.</td><td>Η Η —- Ч Е Α Gέγ g ^ ° ​​i - * ^ · * τ * * S&gt; 'P ® £ ® z / · * ““ Ά D5®§ Α ^ ϊΓ.ίΓϊ «X &lt;. v. ts p C · D ^. GJ_Ό m. K_N . I 3t ~ - - · Ξ · c Ζ rn 5 α 7 C «D --VS &lt;n r- D ό _. pS ^ j θ'ΑΑ ''¹-® S§ §5 k^ž S 'n' g ^ G ^ OoedJpd D op ur ^f. pO S Ο X ir · II o g *. II m Ν -Η Η</td>

<td>D1 + I</td><td> 493.2 !</td><td>CN 'CF Ό T</td><td> 522.1</td>

<td>Ret./ Procedure</td><td>«• gs E tx £ ³^woo №</td><td>1.16min Procedure B</td><td>1.52 πώι Procedure Ε</td>

<td>I Ν 2</td><td> 493.07 1</td><td> 464.03</td><td> 522.11</td>

<td>Appearance</td><td>yellow solid</td><td>yellow-brown solid</td><td>orange solid</td>

<td>Reactionary scheme</td><td>Mrs.</td><td>MS</td><td>V ~ 4</td>

<td> 74</td><td>o</td><td> 5 3</td><td>&lt;5 Ρ</td>

<td>ri</td><td>-z^zό</td><td>ο</td><td>Q Ο</td>

<td></td><td></td><td> 0\_</td><td>Λ * w</td>

<td>u ν; SC Λ</td><td> 289</td><td> 290</td><td>σχ Οί</td>

195

51155Β

<td>υ Ό Ο 0.</td><td>04 * ν '-Ό X -Jg d 'U h? D X i »n» uG J 1 m D m. gj • · - · d jJ -tg¹ “= £ -^g® «· Γzh -sgb gg ° SgP« S ^ 0^A. g k iT * n «3 2; ^ cx&gt; X) ^ Wjg-cnO M 00 oo sl T Ό F &lt;tl ΏΆο</td><td>OO - - Sgi &lt;® ^ ki &lt;&gt; “GN D G / D S ⁰⁴ tG £ ί ci 4 ϋ ”□ * κο * β - ΟΈ 'ϋ' 5 O ^ Om Οιη r * &lt;-&gt; * t m * _ f. t 'N to. Oh Z ST 43 £ 90 D _σνο· M oo - o m Μ- ί X P II 42 · + - II «D Η Η</td><td>in IZ cf _ ч&gt; «в'5 с. * -&gt; N - S l dJg ^ a U · - ΟΟ £ &lt;η SŽ «ο'ηοο-Ό'τίΧ £ □ 0 T ^ qo 1, - &lt;£ X. * ““&gt;&gt; Η- &lt;f * ·¹ Q ~ J G £ k® «3®^gaс3 ^ гЖл^{g_ |}'3'L © A &lt;-k TZ W _l &gt; - »(-u. 2!; 2X^HS +^N7 -ο &amp; D u? '-' o A _ž * ~ i and? ZgJib '« - V Ć- F&gt; V © D - ±&gt; - «m n i</td>

<td>S</td><td> 482.06</td><td>M + Na 532.03</td><td> 544.13</td>

<td>Ret./ Procedure</td><td>1.46 min Procedure E i</td><td>1.52 min Procedure E</td><td>1.78 min Procedure E</td>

<td>Appearance</td><td> 481.18</td><td> 509.21</td><td> 544.12</td>

<td>Izglcd</td><td>white solid i</td><td>white residue</td><td>light brown solid</td>

<td>Reactionary scheme</td><td>t-4</td><td>1-t «—1</td><td>• -Ч «- &lt;</td>

<td>i!</td><td>U P</td><td>U 0 XI</td><td>) ο Ρ</td>

<td></td><td>/ —Z &gt; o</td><td>v} o</td><td>š ο</td>

<td></td><td>Ύ</td><td>^ -y</td><td> ^”7~</td>

<td>U &lt;kJ CU jO</td><td>sČ Q&gt; sČ</td><td> 293</td><td> 294</td>

196

51155 Β

<td>C5 15 Ο &amp;</td><td>-st Ό . V&gt;. rt D N T 5 tG X ^M £ &lt; D. 3_i 2 N fj-Or-l D '-' 'r 2.40 -U-.ush W. »T, 00 P - ts E w đj S -σ Ε », ·? S'-SS č&gt; 3 τ —- -D ο ° ο 2 J2 ο ο 'Tj · | $ £ · | 1 ^ 3 ®tfsm £! 22</td><td>Ch r? • σρ «l 2 - &gt; 3 c - .I js ~ £ ο ^ -¹. E^mm3- 2.2 T v υ '' '(ž- rf I f K /' tf £ 4— '[tJ ^ N-o'O'jTsKfrj-g Ώ '-' ^, Λοο S 5 μ E h -Bgf g T QT_— '-&gt; n χ 5, -. you 0. . tn -t - = SUS - ° £ X s? »43 S .2 = - + - 5- 3S C =&gt; -U u * Ό NO Г * Р 2 /&gt; - Αιηη (Νθ * -&gt;</td><td>h - = d 5 -Μ.Ά3 - s- ς? - ® 't e “^ £ · oč «Ϊ-β ^ ϊΙΙλ - ° - § Μ 2 m ο Η sS * ηΑ ® Ο ΟΟ'ο 'πΰ N £ d g-2 wf II №ί^Ν.5 α i 7. _- m «7 z 5 2- m Τ '- D ® S ό'-' ο 2 o&gt; 2 § κ ν τ. D D Ζ θ 'JJ Ρ⁴ __r r- \ * · »4 a οό _i&lt;““ 5hvvv JG * II 5r-oAS-NHK</td>

<td> 1</td><td> 558,10</td><td> 508.07</td><td> 524.09</td>

<td>Ret./ Procedure</td><td>Μ f 3 w § * 45 - - w - To Father</td><td>1.49 min Procedure E</td><td>1.46 min Procedure E</td>

<td>Calculate. MM</td><td> 558,14</td><td> 508.08</td><td> 524.08</td>

<td>Appearance</td><td>white powder</td><td>iŠ -t-c&gt; SL 73 S -Oh</td><td>whitish solid</td>

<td>Reactionary scheme</td><td>Μ</td><td>t</td><td>T</td>

<td>Pi </td><td>p</td><td>υ u.</td><td>u b</td>

<td>rj</td><td> 0.</td><td>Q ( Ο</td><td>o? 0</td>

<td></td><td></td><td>t-y_</td><td></td>

<td>uu</td><td> 295</td><td>ko C * GČ</td><td> 297</td>

197

51155 Β

<img file="RS51155B_D0385.tif" />

<img file="RS51155B_D0386.tif" />

<img file="RS51155B_D0387.tif" />

<img file="RS51155B_D0388.tif" />

<img file="RS51155B_D0389.tif" />

Ρ $

<img file="RS51155B_D0390.tif" />

<img file="RS51155B_D0391.tif" />

<img file="RS51155B_D0392.tif" />

<img file="RS51155B_D0393.tif" />

Οχ Μ

198

51155 Β

S0 I ^1Z6'^ed š 'Postup ^ ^{M + H +} NMR data

<img file="RS51155B_D0394.tif" />

<img file="RS51155B_D0395.tif" />

199

51155 Β

<td>υ 43 Ο α</td><td>шг фи.о⁰⁰ &lt;5 * ći o ►t⁴· Ώ -T ^ i'zgSg'oS-S. Ξ ξ Α o d * 4'-^h3 ^{m 01} tL ^ tJi i 423 »—LZH ^ v — gdl A S Π co „· ® 5 'T OO N</td>

<td>S</td><td>• čG o s0 OH 'T</td>

<td>Time ret./ Procedure</td><td>1,357 Procedure Β</td>

<td>NS</td><td> 493.07</td>

<td>Izgied</td><td>brown solid</td>

<td>Reactionary scheme</td><td>o</td>

<td> 74</td><td> □</td>

<td> 74</td><td>Yk z β</td>

<td> 74</td><td>$ -y</td>

<td>uu CU</td><td>o gP</td>

<td>z ** 4 P 7? D a 0 S ¹¹ Y 4 ”. Ό «□ 4 3« - i -u-i + SŠ4 S4c? Š® « 4 73 D '-'Nrt σρ w&gt; t-Γ «_g. 5 O _m- oj 6, So • n VJ —-_w f; • г ^ в&gt;. £ J Ό S? p? 22 £ m _y r-ί 1P ** * § _i- »l C = ό« e; W '- * * 5G χ-&gt; · χ-χ g μ ν&gt; 4 - ο&gt; m _-Ό «θ'η 9 X S-U5 S - - ο</td><td>/ “X G * '* n i ► + ο, II 7 h &lt;n α «- D l č d _κ· “030 Μ» § tz vi j-J7 v&gt; m Jjj g - p O «L« o ^ m '^ OmcN' ^ 4 ^ 3 i £ 3 £ g O 5? '~ Ϊ7 a2 '*^od^:i⁰'γ “5 + ^m © ό p4 ~ _C* V5 Ό еч Γ- η \ В4 ς? Μ - · ° ¹⁴ fi Π X · 0 Γ 3 Ό 11 Ο m sč οο</td>

<td> 513,36</td><td> 487.019</td>

<td>1.03 ιηΐπ Procedure Α</td><td>1.43 min Procedure Α</td>

<td> 513</td><td>G * να 'dT</td>

<td>white solid substance</td><td>white solid</td>

<td></td><td></td>

<td>č5 p</td><td> 5 '?</td>

<td>0 s. P</td><td>\ 7Z - ^ = op</td>

<td>Ύ ·</td><td>Ύ</td>

<td> 305</td><td>Ό O m</td>

200

51155 Β

<img file="RS51155B_D0396.tif" />

m ο

τ τ τ

<img file="RS51155B_D0397.tif" />

ad N

1—4

<img file="RS51155B_D0398.tif" />

<img file="RS51155B_D0399.tif" />

<img file="RS51155B_D0400.tif" />

<img file="RS51155B_D0401.tif" />

<img file="RS51155B_D0402.tif" />

<img file="RS51155B_D0403.tif" />

<img file="RS51155B_D0404.tif" />

<img file="RS51155B_D0405.tif" />

<img file="RS51155B_D0406.tif" />

201

51155 Β

<td>Ο 3 * 3 ο α.</td><td>00 - (_ oP «.-3® in D - »oos5® ° o + H m- '”33 + cinf cn r-4 ™ m _ - - sč n' ΰ '^ Χ đ3 ž '/ iroč® 8 «' S'iT a v 43 - S 'Č ό43 §§Μ§42-κό쮧 + ⁴ τ- + »-&gt; ΧΟ + - * ►“ · »+ / f4</td><td>cSr ~ sG m _R Oh. GL 00 .X z^-*, * ~ П »2 ^ 28 ^ С К 2- а 7 х 7 ГЧ m Ч VI £ »T os V- 11 k- ^ v hs⁴».Ό» «Ο 3? ® S? K - -o tn h. and 3^m si dG- C ·. - xr S-S-νΊ X + -'Z-GO iflOjO Eοό E -e O υ ј в м ιΑ « , v&gt; “* n P r ··. no: 1A c5 “° ' S BbB '—'oi Z gč un D r ~ - m?. d -o +_i· *. č · o I</td><td>p »δ; NG ° S « 2.2-da &amp; © s ό * j «gč« η σχ m. ό 1 aZ £ § £ s doic .ς? 2&gt; \ · Ορ »- §ό S J χ -“ Αά ®_ | ®S5frn Ο Ζ sč νη VI ο Β X · sch E? τ £ ΐθ -Ι ©</td><td>Ρ i-zj μ * Β Ε χ (ć &lt;ί 6 &gt;&gt; *. ^ {c £ «efj ac? +„ - ΣΌΠςχ .όΛ S «= I 6 i + -S2 £ 8® 8 © Γ) Π £ 5 en ζ-3 rfS68 « 'S H + _1L · Sč 'aa «ν' 4. ^ 0 · S ΓΊ O cn 1I '^^ mV0v Z d ν, in p h t * i_M Ό. + sg h r ~. “&lt;&gt; C1 go Om ο</td>

<td> 2</td><td>UJ ech Ο * l »l</td><td>Ϊ2 04 Oh, T</td><td>Ό 04χ 04 ν&gt;</td><td>00 - &lt; gP</td>

<td>Ret./ Procedure</td><td>&lt;5 1 s and a * 3 vj r + Ο ίΧ</td><td>CJ with CA O 3 m - ♦ - * . sl СЧ Ο sc</td><td>υ 13 c _aΓ * · 3 SC ο &amp;</td><td>&lt; i -8 00 § * - · α SC</td>

<td>Calculate. ΜΜ</td><td>04 • «ό« L 1L</td><td>σχ q oi Οχ τ</td><td>ΜΊ —4 p.m. Γ4 ιη</td><td>G * 4 Η r * «l</td>

<td>Appearance</td><td>sZ £ 6 23 3 ο '-Ν Λ</td><td>&lt;x ¢ 3 cđ m CLf 2&gt; 3 X) Ό I</td><td>3 ο 3 Λ ® 4S2S. Ο&gt; 3 JD&gt; Ο ίΛ</td><td>3 £ Λ ± 5 4 ~ » 3 ia £ u Cl Ο&gt; z A5'U Λ</td>

<td>Reactionary scheme</td><td>Π MS</td><td>G-</td><td>G »</td><td></td>

<td> 74</td><td>ΰ Ρ</td><td>ϋ r</td><td>υ Ρ</td><td>u Ρ</td>

<td> 74</td><td>⁴ζ— ο \ - ζ ο ζχ Ρ</td><td>q P</td><td>5 4. Ρ</td><td>Λ ο = (ζ— 0ο Ρ</td>

<td> 74</td><td>Ύ</td><td>Ύ</td><td></td><td></td>

<td>cxx&gt;</td><td>Ο en</td><td>V— · · &lt;m</td><td>04 m</td><td>Γθ m</td>

202

51155 Β

<img file="RS51155B_D0407.tif" />

<img file="RS51155B_D0408.tif" />

<img file="RS51155B_D0409.tif" />

<img file="RS51155B_D0410.tif" />

<img file="RS51155B_D0411.tif" />

«Λ

203

51155 Β

<img file="RS51155B_D0412.tif" />

<img file="RS51155B_D0413.tif" />

sch

<img file="RS51155B_D0414.tif" />

<img file="RS51155B_D0415.tif" />

<img file="RS51155B_D0416.tif" />

<img file="RS51155B_D0417.tif" />

<img file="RS51155B_D0418.tif" />

204

51155Β

<img file="RS51155B_D0419.tif" />

<img file="RS51155B_D0420.tif" />

<img file="RS51155B_D0421.tif" />

<img file="RS51155B_D0422.tif" />

<img file="RS51155B_D0423.tif" />

<img file="RS51155B_D0424.tif" />

ui U

<img file="RS51155B_D0425.tif" />

sch sch m

205

51155 Β

<img file="RS51155B_D0426.tif" />

<img file="RS51155B_D0427.tif" />

206

51155Β

<img file="RS51155B_D0428.tif" />

<td>sO</td><td>ca.</td><td>L</td>

<td>Q</td><td>o</td><td>Q</td>

<td>e</td><td>α</td><td>d</td>

<td></td><td></td><td>ra = M</td>

<td>V}</td><td></td><td>sv tfl X</td>

<td>Pts</td><td>- &lt;U &lt;d.</td><td></td>

<td>d</td><td>o&gt; 3</td><td>g&gt; s</td>

<td>V3</td><td>X) Ό w</td><td>&gt; U i</td>

<img file="RS51155B_D0429.tif" />

<img file="RS51155B_D0430.tif" />

<img file="RS51155B_D0431.tif" />

207

51155 Β

<img file="RS51155B_D0432.tif" />

<img file="RS51155B_D0433.tif" />

<img file="RS51155B_D0434.tif" />

208

51155 Β

<img file="RS51155B_D0435.tif" />

<img file="RS51155B_D0436.tif" />

209

51155 Β

<img file="RS51155B_D0437.tif" />

Reactionary

<img file="RS51155B_D0438.tif" />

<img file="RS51155B_D0439.tif" />

210

51155 Β

<td>NMR data</td><td>r-Ά °&gt;! S “P5 £ AS^r~ ^Mrs. &lt;&lt;n · -⁶⁰ so-called U »° ® OO &lt;j4&gt; kH ~ S&gt; p + ~ 3 o S 3&gt; ^ 0-5 KSS'i'Ajs Q II * 4 Cj? h 55 ZH * &lt;&gt; s · 'SS ΣΓ' i * &lt;00 ^. Γ- &lt;N ** ^ ®'2 &lt;“253?</td><td>- “ 5 kP Ό * h '^' G / η tc 5 Ο approx. еч тз * Д ко ^ 3 * ^ 5 S ίς D ^ &lt;5 ^ β oo Ž V), -, 4_b ts «č t- a« η tj · g'S'f-vi ~ © - »7 T - * 7 I £ - «&gt; r ·; gcho“; £ | pn g 3 &lt;“» 2 QG + ^u! &lt;7?+ ⁴⁰7 .ο ν ~ ι · ο _, - - Τ 'Ap / lA | 5 ^ 27Dš +</td><td>^kj'-μ^ΝΧ ^ . Ό _ _ 73 «4« &lt;3 · * 4 ^ 1— ♦ 1&gt; ι-4 m Οχ cs CO - Π- _ &lt;«· * 8 I 'Ο Ό Ρ0δ * Μ ~ 3 £ L0 u ^Μ ^ - *? H 45 ~ ο fi 4 I ΟΆ 0, ι- '-'Μ a ρ £ / G&gt; C ζ-ί, §; S Ι- Ε, Κ Α οο -0 D 00 D 7 £ ί⁴ II - 4 · ο</td><td>. D w. J an. v-&gt;_a _ k a m ​​z π k Β • σ '3 sl D ¢ 4 jf Ϊ'ϊ “9 --ί &lt;1&gt; · ΑκΑ -Č T7. -'ί '^-1&lt;ο 'Č i £ 4 _ o «z9 ^ 'i' WO 8? G ~ - ί 3 ”g» D 7 oo 5 E^&amp;7g05X S | d§ £ ŽČ °? S k. 1.5? 04 N · μ. -g nC A * D&gt; A μ-Getch</td>

<td>S</td><td> 461.07</td><td>S 00 сч 'Τ</td><td> 503.02</td><td> 460.13</td>

<td>υ cu ES Ο mj&gt; &lt;£</td><td>1.74 πϋη Procedure A</td><td>&lt;• | Η £ 5 * 04 SS tž - ο 0-,</td><td>--------------------------------------------------- --------------------------------------------------- 1 1.99 min Procedure Ε</td><td>1.76 min Procedure E</td>

<td>'ό rt 5? i- (&lt;-4 M § 1-4</td><td> 460.88</td><td> 427.85</td><td> 502.87</td><td> 459.88</td>

<td>Appearance</td><td>white solid</td><td>white solid</td><td>white solid</td><td>white solid</td>

<td>Reactionary scheme</td><td>Ch «- &lt;</td><td>ooh</td><td>1-Procedure A, usl. sep. 1</td><td>1-Procedure A, usl. sep. 2</td>

<td>* oi</td><td> □ .0</td><td>ϋ 0</td><td>o 0</td><td>o fl</td>

<td>PS</td><td>/ o \ = o o</td><td>ο</td><td>U_ c. A</td><td>z 0</td>

<td> ₽&lt;</td><td>u.</td><td>υ_</td><td>? - \ 1 h -. + - m. u.</td><td>\ X u-</td>

<td>sI X 04 X)</td><td> 343</td><td> 344 .!</td><td> 345</td><td>46 m</td>

211

51155Β

<td>NMR data</td><td>SL N (&lt;qsu · No? oG Efž? &lt;+ c · G4d&gt; ® ^ C '· Gs. Si'Z.iS 5⁴· Ό'ΰ'ο and + 22-1-rS</td><td>ι- * C * 4? * o L · / · &lt;v—&gt; G⁴ o š oh .ο * ® - S.SC ° s Sb¹⁰δ'Β'ζ 2 E (ZJ Μ V s * ' * 5 * oo Λ «ΓG? ®2 igSish K O0 _R *-4</td><td> ~ ⁴⁰ Ο Κ&gt; sch VI .00 ΟΟ - S 5 Κ ^sT^M-h'p * S X Γ.χ S, - Εν 4r4 »J4 ^ sg ^ 4 ^⁴³.½ e, d = 8 6? S □ oo oo 'G? « ® d S d shsSs</td><td>u « . - ° _. ' Mr. ES ZDZ Ό n! 1 " '- • G' vi R g -. _ oo &lt;D “-Ž ® ^ iZ «= _a- D ^N „· O b D 0 ** - * _l CQ gč §b £ §.4 „£ - р * _ζ · ο 1 £ § С £ κ Ч? D ® ΐ 4 D -4 ΙΓ! &gt; - »- &lt;</td><td>_J * OO (yi D NN. tf jfsssi ~ a _g 4 V, -¹ m N II S, KJ Č- X - r ~ N D f- · ° ί - -z P «2 O«. Mk «_: oo * τ * ^ 4D4 £ · -Ν- 23 _- D -¹S - 3 ^Α μΓ S § * D -Ι - ΧΟ 2. XD * gm Ο WD? DeLDS</td>

<td>1 s</td><td>сч сч 00 m</td><td>ev TG ο «Α * Ί</td><td> £ £ + ? 2</td><td>Χ ρ νϊ ΟΟ 4ί-</td><td>ΓΊ ± 2?</td>

<td>Ret./ Procedure</td><td>W p^α α Г · 3 ЧО • (Ο Ο Ri</td><td>Μ • ρ ^κ and h · 3 G1 ο CL,</td><td> » ^k &amp; σ, 3 4 S - ο Rč</td><td>Μ 1 ^ ^c am z C \ • wo CL,</td><td>Ή ^κ &amp; 05 S rj · 01 'U5 r- * Q Ct</td>

<td>• ČJ -_±NS</td><td>SC Ο \ VI</td><td>τ-4 00 ο 00 4G</td><td>Thu ΟΧ e&gt; g- 'Č ·</td><td>oo 00 4t 00</td><td>SC Ch m TJ *</td>

<td>Appearance</td><td>eb g S Oj * - »GQ U3 η&gt; λ μ ά. 53 Q&gt; Β&gt; Ν&gt; »O £ Λ</td><td>_, _ ι ΧΛ ο 2 X CL</td><td>«._ &lt;hl -7 *« J Q &lt;m _D Ct</td><td>«J o C« J 5 «3 t $ £ fe On O&gt; 3 © Ό iz</td><td>0 3 £ 2 ca «“ ~ m μ. sh ω&gt; 3 JR · Ο w</td>

<td>o 'o a $ * 05 hl</td><td>s ·? «1 ο_ΰ0i.</td><td>fS- Η „ 52 ν Ο 3 Lj ^ * ί m</td><td>&lt;cl Β + -&gt; sl Ο cu i</td><td>sch ech</td><td>&lt;cL Β + - »sl Ο 'l ·</td>

<td>Yes</td><td>υ Ρ</td><td>υ 0 4</td><td>u P</td><td>υ 0 • No.</td><td>u P</td>

<td>α:</td><td>s (/ ηΛ-</td><td>lb U. V-UL (/</td><td>/ o \ s = O o</td><td>uu Ρ</td><td>• Z u</td>

<td> ₽4</td><td>Η V_u_</td><td>—IL</td><td>'a.</td><td>u</td><td>^s&gt; f u.</td>

<td>uu Rč X&gt;</td><td>r = V)</td><td>00 ЧГ ΓΊ</td><td>0h • S · cn</td><td>ο U1 m</td><td>v&gt; m</td>

212

51155 Β

<td>NMR data</td><td>δ £ z2₉722D 40 'and &lt;&lt; g- 'Υη ⁵«3 I« 3 N CS 9 -ί 2. D Ν ~ 2 4 Η „i ^ D 'L' 'Ο q &lt;&lt; vc ~ - t 2 ~ g E m I - Č ^ 2D 2 £ ~ n f4 n„ t $ 3 hd 2 3 3, z _i- d q 7 Č R Ο ί - X ”w _ i _f m r ®D'De £ D8</td><td>i - 5 2 £ ο ® d -g- ™ 2 -ϊ £ 2 P ο. ЗДЮ9 Ρ it ίη ZЗ г 5 Π Ώ _, _ gj ep g $ 3D · * £ d ψ m · «® E G D LGČ N X-</td><td>D 40 η-Τ rG N n J O -G 40 &lt;n S- - sch tn 40 * b TF “® d &gt; · Г &lt;Ή х. to £ 55 xr ° С ^ • 'Ne w -ο a s Sr4 2 d S¹c4 P ''¹ &amp; S JzzTZ i t m-i £ · G D ώ Μ 21</td><td>• ς} · г ла Str ^ S- - «1 p - k 2 v ”2 2 3 DGs? S. U = MS 3 'z' - - * 2 mm оСф '„-'Ч 2 3 eč Η- Q ¹⁴ - * I gs 1χ4Ε 15oo Ž -čZ · η Ν N „μ Τ 4 2 ί ? D r- \ 2-tn ο</td><td>&lt;Ν 3 С. * 40 CM bz ^ Ε $ § · Κχ *^ηS οό 3 ⁰⁰ Β X ι 9 Τ S-3 5 * g rf '* δ r2 3Β⁰⁵cO sč g * ~ £ ”* ο '-, s- R1 rn M J2 [2 / ^ ώη S e- - u · Tf 3 oo ώ Ζ. / ΝΝΪΙ &lt;&lt; оо х “Ч 3 2 7⁴ A r- 'S-η i- «</td>

<td> 2</td><td>2j t {* ΐ 5 ο X</td><td>40 40 40 • &lt;r</td><td>'t sč Tf</td><td>sČ SČ 04 00 Ή</td><td>gL CS uS o 4P</td>

<td>Time ret. Procedure</td><td>sz Ή ^s a 4 © © G · Č ~ &lt; · (L - o α</td><td>m §3 1 g · • ^ · © 'ΙΛ * “* Ο IX</td><td>š | z ! §&gt; v-1 © tv * Q α</td><td>ω i ^ 5 ^ r - • (Λ - ο CL,</td><td>X | ^s and sch © w - W3 _oCL.</td>

<td>Calculate. MM</td><td>0, Ο αΟ</td><td>Ο □ Ο 40 40 hG</td><td>o O \ t * i GJ</td><td>GM ρ Η 00 U-)</td><td>40 O uS Ćh</td>

<td>Ό t) ab N ) —I</td><td>03 of Β 3 3 £ £ ο&gt; 5S X »u SL</td><td>ce o s «s LZ £ α ο&gt; © X * Q &lt;L</td><td>03 uc ctj ez 1l -l X h Ο, ο&gt; 3 X 'Ο (Λ</td><td>υ D 5 S &lt;ύ sl μ * 4&gt; 7 Sh 3&gt; a&gt; Ν · Ο nj</td><td>Ct £ d «SOW« ts »- &lt;cu K&gt; 3 Λ υ ir</td>

<td>C o Q 2 S Nj HL</td><td>&lt;ά S SL Ο α</td><td> 00</td><td>οθ</td><td>»-Č</td><td></td>

<td> 74</td><td>ο</td><td>ΰ 9</td><td>υ Ρ</td><td>Q Ρ</td><td>W 0 h</td>

<td> 74</td><td>LU U- I</td><td>u. Χ-H-X (/</td><td> (/</td><td> 3 2</td><td>b</td>

<td> 74</td><td>Α</td><td>9-l_. X</td><td>^{? _ν}Λ X</td><td>4— \&gt; \ —Z_u U</td><td>\ b</td>

<td>U n αχ</td><td>MS no CA.</td><td>ro C) η</td><td>* 5? 4Ί γΊ</td><td>* η 40 r * i</td><td>40 4P Ms.</td>

213

51155Β

<img file="RS51155B_D0440.tif" />

<td>Ο</td><td>Ό</td><td></td>

<td></td><td></td><td>1 «is</td>

<td>α. 3</td><td>ο a , _4 S and</td><td>m d Β -: w</td>

<td>ο ,.</td><td>Ο</td><td>Ο α &lt;</td>

<img file="RS51155B_D0441.tif" />

υ

<img file="RS51155B_D0442.tif" />

<img file="RS51155B_D0443.tif" />

<img file="RS51155B_D0444.tif" />

<img file="RS51155B_D0445.tif" />

214

51155Β

<img file="RS51155B_D0446.tif" />

<img file="RS51155B_D0447.tif" />

215

51155 Β

<td>NMR data</td><td>-02 D E «S d _Λ es X * m £ ®3 OO oo ž «ο * ε, ίΰ ££ ~ 7 n _Lgl sč dH®: i t- ¢ - &lt;č ο - 2qS bcho ί ΓΥ * η *&gt; ΤΊ »» * Ό § £ «~ X sc Zo. °° Z.« - d «Β X Ή β X“ Γ'- LJ- —4 m Ο * -η</td><td>* G * P HF - '^ w from σχ ž 22 Ό \ o HG ¹⁴ oo _l t * _l-SZ co ο Ή Ε ο ¢ 4} *** »/ -Č ΟΟ &lt;** £ ηoZZ ^ b rsS ° £ Π γμ * ~ * '· *' ' X 1L - φ JG -Ο «DrjŠZ ^</td><td>oo h P £ S. £, XX ES * ^ eT-S - '-. O &lt;4 RČ Γ- ΟΟ J5 ^ .p. ^ oi f '·' »D ΓΊ ^ βΓ- * 3rd. Q Č &lt;PX iGSPP N 2 ό 5 Ε * ο Ε o QEx 4-H - &lt;s - r- -_as g- £ · « ** r. o in gs 40 ₽-4</td><td>d * 'E 5 b X * ^ -3- = r .'P £ ο ^ Ρ S? 33&gt; 5- ^ D ® cho L _lP® eG '! = £ 3 «Β X gsb ^; 8 s z 3 &amp; rv⁴ • Tl⁴ Ό «» G) SG 4 © «£ 3§l £</td>

<td> 1</td><td> 582.18 . .</td><td>595.19 i</td><td>he vS σ \ 1L</td><td> 546.20 .</td>

<td>Ret./ Procedure</td><td>1.47 πώι Procedure Ε</td><td>1.43 min Procedure E</td><td>1.42 niin | Procedure E</td><td>1.55 min Procedure Ε</td>

<td>Calculate. MM</td><td>C4 or 0Q</td><td>80 O vj Gh m</td><td> ------------------------------------------------------------------------------------1 1 595.06</td><td>Φ ο 80 Φ Ι / ~&gt;</td>

<td>Appearance</td><td>whitish solid</td><td>yellow solid</td><td>white solid</td><td>dark yellow solid</td>

<td>Reactionary scheme</td><td>11, usl. sep. 4</td><td>11, usl. sep. 4 _____________</td><td>11, usl. scp. 4</td><td>11, usl. sep. 4</td>

<td>p4</td><td>fi</td><td>Q fi</td><td>fi</td><td>Q P</td>

<td></td><td>0 b</td><td>b (b-</td><td>b </td><td>o</td>

<td>dogs</td><td>\ - £ —n- 4 tL</td><td>_? U. X --- 4 — u_ c.</td><td>C_</td><td>^ '- 7 u.</td>

<td></td><td>vx 8 © m</td><td>40 Ό m</td><td>40 GP</td><td> 368</td>

216

51155 Β

<img file="RS51155B_D0448.tif" />

<img file="RS51155B_D0449.tif" />

<img file="RS51155B_D0450.tif" />

ο r *

<img file="RS51155B_D0451.tif" />

rGP r ·

217

51155 Β

<img file="RS51155B_D0452.tif" />

<img file="RS51155B_D0453.tif" />

218

51155 Β

<td>NMR data</td><td>g® SL = 4 h х »&gt; .7 ° κέχ SL: ο - * ^ &lt;7 ^⁴° d Ϊ * «m WS</td><td>5? d lt s to rl l Ο cho £ sb s = -S U -g-35 η © 0 = I t&gt; ^{43 l} Сћ СЧ .Х ^ » »G *&gt; 'V' i = E ^ 'o» = - _u.4&gt; ΰ N II t- £ 04 Q r-,^1-1 no. &lt;N y, Corfu «3ql« V »&lt;4 * G&gt; 00 'tf. ps X * N r4 t — 1 z — h. s νί ts L a θ “££? and G⁴ (N [N D, m r₍ Oh</td><td>U) . Ч— 'x ^ 4 = 3χΝ - «ZerZ» S,^I 3 Ш = Л =; * т4 l η Oh ⁿ Č o S d U aJ N sm 'Č D = ® = ^ 0H nn ο. N · * e | 35d5o -&gt; D j Or-</td><td>h E £ N = - = X D N č R - ¥ 4 «'θ' D oo = - = = - .'t »&lt;N 3 =&gt; Ίο&gt; χ sČ χ;« ι © d СШС5J4®. G) μ m »n. l t⁴ А х&gt; ж гв Q ~ - е 'о add ^ Z-g ' NN □&gt; 1 · S -. m ό «Σ ~ 2-Zč&gt; t = ον χν χ d = ΆϊηD 53 00 Γ ~ ΥΊ &lt;</td><td>SK N = - = - “0 and Os₂ 1, r = P = HG 00 tM W-&gt; X r-, &lt;NX. OO · kJ - * *** ®3 | § £ 00 g * “&gt; E —7 r = oz - Q _ =. _v so 3-v k - = = . &lt;ί &lt;4 Ό Ό 40 Ri „- &lt;η Ό« L S S&gt; © 5 ”* Ζ 3 \ N Xr * χ Μ Α D Β 00&gt; * τ</td>

<td></td><td>ž® 4 · ** Sš</td><td>CN cS tn tg</td><td>'đ' © 04 Ο Xt</td><td> 464.99</td><td> 465.96</td>

<td>Time ret./ Procedure</td><td>1.65 min Procedure E</td><td>1.52рнм ProcedureB i 1__________ _</td><td>1.53mm Procedure Β</td><td>1.54min Procedure Β</td><td>I Η ? Η - ο a.</td>

<td>sS U &lt;HN 4ί 1 — I 1 * 4</td><td> 441.89</td><td> 450.92</td><td>Ο CT4 οα © 4đ *</td><td> 464.95</td><td> 465.94</td>

<td>Appearance</td><td>white solid</td><td>white solid</td><td>Λ Ο 3 C3 Β G. Τ ~ 1 Η Pts Q&gt; 3 X -Q &lt;L</td><td>white solid</td><td>white solid</td>

<td>Reactionary scheme</td><td></td><td> 60</td><td>00 t **</td><td>□ ο</td><td>co</td>

<td>li</td><td>u 0</td><td>u 0 no</td><td>and fi</td><td>ο P</td><td>o 0 • no</td>

<td>n</td><td>z υ / l Ντν</td><td></td><td> 2 ₂&lt;· ^xw -</td><td>= oz—^.</td><td>_z-^2</td>

<td>v4</td><td>LL</td><td></td><td></td><td>u.</td><td>IL</td>

<td>U * “Cu X</td><td>&gt; g * m</td><td>00 r * m</td><td>«35 ge &lt;i</td><td>Oh 09 m</td><td>CO</td>

219

51155 Β

<td>NMR data</td><td>and S? X Sn _Μ-ρ · I Č “Ί&gt; £&gt; = 5 -¹ 00 t- _i- ο and J, σ&gt; 'P = -'. 'Γ N &lt;h⁴⁵ D t- J. P m? ”Ai? g N Λ 7} · S μ - CN VD g -'f Zo X &lt;SA дЛЧИПб и⁴ i r- č · t «t</td><td>_® Τ - ο d £ 1 - S *. £ «££ · S '⁰.’⁰. * ZdZgč Ο θ '2 7 θ Ε&gt; [$ Η 2 · w § Α. X g »Μ SP« JzM</td><td>.Ι i £&gt; 2 £ SC X ₽ II S l η □&gt; χ ο С ° θ - &lt;1 ϊ С η »ч Η ¢ 4 ο D χ Μ ΟΟ -. tM η _ gAS č g ”⁴S $ “ίS R5 ^ * 1 I l 0Π ₽4 __. '“* Fit · Ό _ n СЧ_ldd £ sj? 5 £</td><td>&lt;h 5? ech. * ^ * · ~ * ·¹ &lt;·. ® «- Ž E z-p £ ®Gh ”“ 1 II - Д gгХ Т. s h k h &lt;6 5? ShSoil? S gG 5 &lt;J Zsg «? e'p'pz-BS- I ~ _S-X fj 2? D g- CP'T m ο</td><td>š £ bv »vGz i d 2. ž X II č θ '“? Сћ S 2-oS 5 c &lt;d -S-? ¹⁰ 2 · ^ s 12 g? , - --Ϊ £ £ p giT-đ £ o = § &lt;4 5 Β Λ® 1 ° - c: mm -&gt; oo -⁴ 00 $? 00 n? 11 D K II - · II D L 'i jr- D r— nč sč &lt;j -</td>

<td>'ϊ 2</td><td>r- ^ SC o W1</td><td>m Τ-4 sz Ή</td><td>00 Ϊ — I sm m V}</td><td>Τ) гч уС чГ Ό</td><td>Ο 04 'tf 4Ί</td>

<td>23 Q (L o</td><td>m 1z “O &lt;nN - s P-</td><td>, Ρ3 Ό 3 oС Β g CU</td><td>W -r^G α Ό 5 WITH • U) o CU</td><td>»Λ sč 2 «- · ο α</td><td>Μ^R &amp; m d m * - • en Q SC</td>

<td>l&gt; »Η S N * 5 * t— &lt;l</td><td>Mrs. Ch Ο W5</td><td>Γ * Ί 05 Ο Ο Ό</td><td>o S4 go V-)</td><td>U-) Ο uS • ^ g 5Α</td><td>gč Ο un</td>

<td>Appearance</td><td>Λ CJ α «β l 03 I 2 U-N V-č fi, ο&gt; 3 Χ&gt; 'Ο sl</td><td>Λ Ο α 03 D * 2g, ω&gt; 3 · Ο I)</td><td>ge u r: 03 i χ., Š ha «·“ “) &gt; ϊ «σ&gt; □ 5Λ Δ SW</td><td>± ј ocSS • rt L el “a&gt; zz CL 45&gt; a X) C Ό [D</td><td>NW 3 &gt; N Si</td>

<td>Reactionary scheme</td><td>&lt;ά Ζ3 Č- * υι Ο CU τ— &lt;</td><td>&lt;d Β SL Ο PC ί - 4</td><td>r- «ed</td><td>oo</td><td>Τ '· 4 QO ? -i</td>

<td></td><td>ρ</td><td>Ο .ρ</td><td>P?</td><td>o .0 I;</td><td>υ fi</td>

<td>r4</td><td></td><td>^ζΌ</td><td> 0 4'</td><td>\ 0 X rJ</td><td>o o</td>

<td>PS</td><td>ί-lu and.</td><td>£ ----- UU C.</td><td></td><td>^ Vu.</td><td></td>

<td>m * m SC Λ</td><td>04 00 m</td><td>m □ ο G5</td><td>TG 0Q m</td><td>V5 O0 m</td><td>50 OO m</td>

220

51155Β

<td>'q tZ ο Λ</td><td>D Μ Ο, ​​- L-I CN D «D i Τ C. SP «oitj CNG S «5S. 11 сч ζ-&gt; σ * χ f *&gt; £ D - £ d Ί · 4 °. .tEoi g * ί-G _ - d · « “=ⁿ°4_Ss 22 Ο χ9Ί C U-) d- «5 ό Qr- · χ -2 * -» S _lI ^{1 1} 33 - CA k Ч— /. D M ž G ^. 1- * _j &lt;·&gt; ♦ * / *&gt; rb nZ / *&gt;. ~ Eg a ι * i Ч 2 «jt⁴ K, P- D, (Č &lt;►- * Μ &lt;- &lt;</td><td>.'fS'S -N d m č g D o »r- &lt;α · * Гч Р - тг h k 2 3 't d rr *? NW r- E? 8 Šci _ go _r o n * π ίθ Λ μν4 * Ύ— * L. “,_l a ϊ n OC - ^σ: E d I O lf^{n 1}- Q- | £ „ Š ^s 5 «Oo ir, ^N /) Ш -п Оо «. r. &lt;s O E.d-7 fS m - ΖΓ ο_l η-, X— (_J VI С “* \ n d “D H g ® ® G D -n tg Č&gt; m</td><td> - ^s ® τ Α? AfŽ5-Υ.5 £ ί - Ε £ V ·, D ~ Γ * r? K '9 JZ S.ο οι -_ο3₽Χ— ώ r ι rn ЗЖ · “* ol . ol K οι. . Α g «Ί 4« 3 55 g&gt;</td><td>ο-ί οι _ VO Ί d d ot 1 ia ^ · « so «£ 27 = zk^k® O =? “With H 'ο l c »G οο 3 D '-'Ω ΰ ° 1 oi Ί θ Ξ * 6 9 Ύ \ Ο ^ΜΙ ^ -Εε Ž ά J5 Ύ η μ S »s 2</td>

<td>ΐΰ 4- S</td><td>Ο &lt;4 Γ * SC ν&gt;</td><td>čf T- * Cb v&gt; v&gt;</td><td>/ “4 5t« 3 Zl ·</td><td>Ο Γ · ^ r</td>

<td>Time ret.Z Procedure</td><td>Μ • f ^ «Sc so □ SČ Č · * &gt; [L - · o CU</td><td>wⁿ l tn S vp * -&gt; • M * “* Q CL</td><td>ffl p £ &amp; &lt;n .p _ · (L O Pts</td><td>ffl ρ ΟΟ w 5G 4Ξ * (Λ Ο CU</td>

<td>&gt; 0 u- Μ * 5 Η-1 * 5</td><td>ЧО Ο in KL</td><td>cho O b 40 V)</td><td>O \ oo Ι · * - sđ-</td><td>ο Ο \ Ο \ 40 • Φ</td>

<td>Appearance</td><td>orange, a solid substance</td><td>yellow-brown solid</td><td>yellow solid</td><td>white solid</td>

<td>Reactionary šcma</td><td>V-4 so »- &lt;</td><td>G “&lt;00 *</td><td> 00</td><td> 00</td>

<td> ?4</td><td>υ</td><td>ο Ο</td><td>u</td><td>5 fi</td>

<td>pi</td><td>b I</td><td>ο 7</td><td></td><td></td>

<td> ¢4</td><td>Α</td><td>Α^Ζ U.</td><td>k J — u_ kk</td><td>k U — c. uf</td>

<td>uu CU £ i</td><td>GQ cn</td><td>οο α&gt; m</td><td>S? Č OO m</td><td>ο Οϊ &lt;l</td>

221

51155 Β

<img file="RS51155B_D0454.tif" />

<img file="RS51155B_D0455.tif" />

<img file="RS51155B_D0456.tif" />

Сћ т * 4

SC sl o \

222

51155 Β

<img file="RS51155B_D0457.tif" />

<img file="RS51155B_D0458.tif" />

223

51155Β

<img file="RS51155B_D0459.tif" />

<img file="RS51155B_D0460.tif" />

<img file="RS51155B_D0461.tif" />

224

51155 Β

<td>NMR data</td><td>I44 'Ν' 72 MS _l in * S &lt;1 * &lt;4 £ &lt; 3,003f £ +: £ 7 r-D 7 £ · 7.^Λ d £ r * »t2 ± sf -G ^ L Ϊ £ T ££ - H G ^ (N T- / SČ »- '» - *</td><td>_ tG η - - d (SX ° 0 Οχ 41 .Ο - 'Ό X t- t = «Ds4«, o ho D ^m -HO D G 'I T _σ53 - &lt;š &lt;o l &lt;n- - £ E «o OT 00 -ho 'j' Q ^ 7 ® ^ θΧ D o ~ o n m - 7 ο a g ^ Dg-Asč ^ P'- · * - »</td><td>tf D . - Ш§ - -ех.7 хЗ *⁴⁰ °° SS 2i v D D σχ II - g Π sx -Ο „ho XG o _vx X .rfTŽ g⁴⁰!! -A'TS'SS D ® ~ ST u · ^ -® L · ® SSd8_x&amp; R \ «R £ r ~ 25 - 4 &amp; 7 ® 'RS⁰¹/ * 4! - * O&gt; * · 4 d m · ° m NN Α Ο § d «, i II s ± / te žssgpsžs': -</td>

<td>Ϊ</td><td> 542.21</td><td> 1 555.27</td><td> 532.18</td>

<td>Ret./ Procedure</td><td>1.51mm Procedure E</td><td>i 1.45min Procedure E</td><td>1.43min Procedure E</td>

<td>HJ - Sg s&gt;</td><td> 542.07</td><td> 555.12</td><td> 532.01</td>

<td>Appearance</td><td>pale yellow residue</td><td>light orange solid</td><td>pale yellow residue</td>

<td>Reactionary scheme</td><td> 20, 11</td><td>F —ΐ 3</td><td> 18,11</td>

<td></td><td>u P</td><td>o p</td><td>o P</td>

<td>f4</td><td>0 • / o</td><td>b and b</td><td>Q X 0</td>

<td></td><td>A</td><td>^f u.</td><td>u.</td>

<td>U ui CU</td><td>гч о тГ</td><td>403 ι</td><td>”Mr. F * = t ·</td>

225

51155 Β

<img file="RS51155B_D0462.tif" />

<img file="RS51155B_D0463.tif" />

<img file="RS51155B_D0464.tif" />

<img file="RS51155B_D0465.tif" />

<img file="RS51155B_D0466.tif" />

CL, »L Ο * 4 * ο

<img file="RS51155B_D0467.tif" />

<img file="RS51155B_D0468.tif" />

226 £ S^Zion MM^No.'M-NG NMR data:

<img file="RS51155B_D0469.tif" />

<img file="RS51155B_D0470.tif" />

<img file="RS51155B_D0471.tif" />

227

51155Β

<td>NMR data</td><td>. j * w · »» ·. «H &gt;. (N - · tG Β «3 τ5 -'L-gjoD © S * 0 ¥ ΧΊ1 - 5 JL 2 t- -&gt; 2 “ΓII -RS μ χ '* ο λ * -' . οο^Μ Υ Κ ® ίη ¢ 5 U? - · η 7 S ϋ '^ Ηζ., Ίν. R 7 ί Ο I S y, ji „t-zo d O lgpi-, Ο Β&gt; - t- Ч С7 * г z -δ- *? ._E К 7 Ж Д '“З 3 ​​р-ι с3 II оо - &lt;η Ύ</td><td>S ⁰⁵ CT ό - G &lt;II D ιι ν 'M b D g _- § 3 · C 3 ιι? 5 g ^ „ΧχτΚχδΚ Α«&gt; Ε S 2-Ш 8 U, u ο _η ® _s &lt;&lt; . / c ⁱh.n ° Α 'μ «ч * д * Ώ ^η ^ -Μ ^ ΙΛΗΟ) JG * \ 2 * ·&gt; ή --η μ »-</td><td>· -! 13 Co ε⁰⁰ 'ί? »« + -Α ^ μ, -ς .το Α ® t&gt; &amp; Τ Š ^^ - iS X ® ζ^Α.κ® F? X G 'ο Ό II, κ θ' χ Ο X. II - · + = - μ * &lt;G „- Ή ·« 2 μ g -J ° 0 CN »—ι« kU □ ο νο - -12 ο Η&gt; οο! Ϊ́ 2 ~ ο ο ¹⁴ ζ * Λ κδ'χ ^ ο. (2 ίΤ®</td>

<td> 4 5 2</td><td>m V — 4 r-</td><td> 481.22</td><td> 429.18</td>

<td>Ret./ Procedure</td><td>1.69 min Procedure B</td><td>1.41 π ± ι Procedure Β</td><td>1.34 Procedure Β</td>

<td>&lt;5 dz&gt; N g</td><td> 470.86</td><td> 480.95</td><td> 428.92</td>

<td>Appearance</td><td>white solid</td><td>white solid</td><td>white foam</td>

<td>Reaction scheme</td><td> 00</td><td>sL T “&lt; oo &lt;r ~ i</td><td> 18,10</td>

<td>pi</td><td> 6</td><td>υ fi</td><td>Q '?</td>

<td>ctf</td><td>n U. (J ^ 5</td><td>° Č ϊ = ζ Ο</td><td>\ ζ—</td>

<td> 01</td><td>u.</td><td>Ί U.</td><td></td>

<td>U ui SC JZ</td><td> 413</td><td>Μ *</td><td> 415</td>

228

51155Β

<img file="RS51155B_D0472.tif" />

<img file="RS51155B_D0473.tif" />

<img file="RS51155B_D0474.tif" />

<img file="RS51155B_D0475.tif" />

<img file="RS51155B_D0476.tif" />

ea

229

51155 Β

<img file="RS51155B_D0477.tif" />

<td> &lt;</td><td> &lt;</td>

<td>α</td><td>Ή ΟΟ 3</td>

<td>5 &lt;Λ</td><td> --¹ Ο</td>

<td>Š</td><td>a&gt;</td>

230

51155 Β

<td>NMR data</td><td>X -^w- 7 OXX t '» XS ® £ T * Kj XEX vZGTD P 36 ^ ”ν · 47 ° ο ό .s · ® χ - Τ q χ, 9 ® χ = □ s £ - *.? «®μ # χ® D Ά ^ -ΐ? 5 £? »® 'Β Ε- □ χ g S D D D / =! d T a 'Α: § Ε Α Τ X⁴ Α 04 40 &lt;ί / Ο - &lt;ο&gt; -&gt;</td><td>_ž vn © &lt;-Č V ~ 1 04 &lt;&lt; &lt;Ώ Α&gt; р &lt;* η T®v Ο.-F &lt;l χ „so i X S-7- -«, · ο S ^ SSjg « ^α.2Ά ^ Τ “&amp; &gt; g * 00 E o ^ D ^ dD M &lt;sgD —1 § ^ d ^ £ h ® SS Ϊ 55 m £</td><td>~ A - O J— «l O θ 'XX ® A ^m ,. X g- _ X «» ®δ · ζ® SP o · «β» ·&gt; * d w d - «&lt;=&gt; * s N m- SJ £ K . - 'г ~. «Η X ο 43 m χο 3 -„ goooo® &lt;ix-.g «2 ° r. »Ο ο s «s“ &lt;τϋΓκΰ Ζ Nr; γ N - Ο ν “Τ”. X Ε 2? 3&gt; D π 4- 3ο</td>

<td>• u »- &lt;</td><td>τΤ ο »-H σ \</td><td>i «</td><td>* ? Η έ =? ζ- &lt;</td>

<td>Vretne ret./ Procedure</td><td>1.84τηίπ Procedure Β</td><td>1.54 min Procedure F '</td><td>· | 3 »Ο04 3 £ «&gt; ο β.</td>

<td>'8 5 us N * 5</td><td>Μ αο ♦ Μ Pts</td><td>O \ o • 7G MS * F</td><td>04 and no</td>

<td>Appearance</td><td>yellow-brown solid</td><td>and bcla solid</td><td>I and white solid</td>

<td>vz CO Q Hί hl</td><td>1-Procedure.A</td><td>1-Procedure. A</td><td>&lt;ά 3 Ch-ί 16 Ο</td>

<td>P &lt;</td><td>Ο 9</td><td>o £</td><td>Ο Ρ</td>

<td>fti</td><td>L, U. ffl</td><td>n XU 0 o</td><td>η X υ 8</td>

<td>with</td><td>^ ~ y</td><td> £\</td><td>ί ..... \ _ ^</td>

<td>SC £ 3</td><td>O4 ol 'T</td><td>oi 'ST</td><td>04 p.m.</td>

231

51155 Β

<img file="RS51155B_D0478.tif" />

<img file="RS51155B_D0479.tif" />

<img file="RS51155B_D0480.tif" />

<img file="RS51155B_D0481.tif" />

<img file="RS51155B_D0482.tif" />

232

51155 Β

<td>υ . □ ο.</td><td>ŠTSS Ls £ K gS3 gs G⁴* &lt;N D 2 04 'T⁴ OOt-ch 'Z'OJ &lt;C _G Ο vS a! G ** b-_l you Ч&gt; 77 i - X sč * σ \ ađ M -'n 'Č j · «G ° ® r? ⁰⁹§ o SM dČA⁷ L. D ® S sz o _ o · Ό - nrt &lt;- &lt;rΑ r &lt;—h. d -— ' κΪτΤτττ ^ β'ίϊΤ</td><td>0-2, £ · II *. K Č 3 SO ^ K- 4; &lt;r Β - R Ν'i όΎ ^ -τί'Ο d &lt;Ν d g_ο z c 5 TZ = -O rt s 2nd '-' - ¹ Ο Κ^1,1 Τ ³ Τ 0,; G, A ° £ A £ e £. Ο II _ m _^σGu * I - - '¢ ,. ζ-h § wi ¹¹ U 7 Z C4 1G&gt;. About MS. h- - &lt;i X Ό “ j® £. \ o »-&gt; r-&gt; o -</td><td>D W «GG! g ”'Οι^. · &lt;T II fj XXC - - nJ- 'Ό tQ ⁶⁰ _g .1 * l *** ♦ 4? D ®.o J&gt; ° n ς? rfS'f ζ -ί 0 2 Ο N Č o «d ^^ da'MSož '? υς? «II o ^ .r- Č ~ S ' v ί k a. ~ d s t / © g * 1 Z gg (&lt;d- 0 - g D 3600 &lt;m ^ Λη ·_A G &lt;lc 1G | V, ο &lt;: _ &lt;l o. m.ČZ— slslm r g- °! 0? * Svj tg gl ech cs -S— &lt;0 t ^</td>

<td> 2</td><td>555.28 and</td><td> 545.36</td><td> 541.24</td>

<td>Time ret./ Procedure</td><td>1.41 min Procedure E ..........</td><td>1.84min Procedure C</td><td>1.43 πώι Procedure A</td>

<td>Calculate. ΜΜ</td><td> 555.12</td><td> 545.17</td><td> 541.16</td>

<td>Appearance</td><td>yellow solid</td><td>white solid</td><td>bcla solid</td>

<td>Reactionary scheme</td><td> -</td><td>r-</td><td>g-</td>

<td>p4</td><td>o fi</td><td>o .P</td><td>Ό</td>

<td>pi</td><td>b</td><td>o ^ = sO p</td><td>Q ^ = 0 p</td>

<td></td><td></td><td>Ύ -</td><td></td>

<td>** u Oi -O</td><td> 428</td><td>&lt;5s G&gt; J tu</td><td> 430</td>

51155 Β

<img file="RS51155B_D0483.tif" />

Ο ο.

<img file="RS51155B_D0484.tif" />

<td>HG</td><td>TJ V)</td><td>k r — i</td><td>cn m ·</td><td>d G &lt;</td><td>»Mrs.</td>

<td></td><td>cS \ ©</td><td>s</td><td>/ —X v ©</td><td>E [</td><td>cs</td>

<td>CN</td><td></td><td>r — 4</td><td>tn</td><td>m</td><td> -*</td>

<td>n</td><td>sch</td><td>7Ί</td><td>T * Č</td><td>co</td><td>i</td>

<td></td><td>r *</td><td></td><td>II</td><td> »—’</td><td>m</td>

• d

Go

N

<img file="RS51155B_D0485.tif" />

<img file="RS51155B_D0486.tif" />

<img file="RS51155B_D0487.tif" />

<img file="RS51155B_D0488.tif" />

<img file="RS51155B_D0489.tif" />

t— »ω&gt; X»&gt; о

<img file="RS51155B_D0490.tif" />

<img file="RS51155B_D0491.tif" />

oo sch

G · 'm · &lt;g

<img file="RS51155B_D0492.tif" />

. sl Q α.

'f' Z 'eđ x&gt;

(L u&gt;

<img file="RS51155B_D0493.tif" />

<img file="RS51155B_D0494.tif" />

&lt;η hG '' t

CQ

<img file="RS51155B_D0495.tif" />

m 3 - o fu ο ο urx b ~&gt;

sv oc «z p —-i» n 2&gt; -D&gt; U

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<td>&gt; Q _. SS N 5</td><td>CA O r- ' 't *</td><td>sch V-C 00 wn • 5G</td><td>O o&gt; CS • + t ^ r</td>

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<td>NMR data</td><td>_i ι-Γ N s- «-aS.fc5 пј г * 1 II “-Г “= K'S p -gGL ΟΝ ·&gt;. · - z&gt; Оч &amp; сгСшс ^ • г ^ јсС 'и® O t4 rd &lt;l _m S O⁴© Ž^g^ '“' ·» T &lt;'- X' T g «et OD Ό -ΐ § TS« 4 S 2.G-. £ H «“ i ^ 2®2 _ G4 ί— »· -</td><td> - £ ⁵ Ο - Μ Κ Ο g r- s Γζ V&gt;. oo - » G-. ! ' n -. «=. s. RoTrS'-o? '⁴ϋΗ E - K &lt;- *&gt; - · ν + * —a η About Nj -_ * o » ^M __ ©&gt; г + - ^. _ffi - ο * s ~ o 1? ώ 8 2 4 ?. «&gt; S” * z G § i XS 42 СЧ τ— · р-ζ * ^ «» СЧ</td><td>= Q0 V4 £ ® ~ 2 = CO ¹ D »-Č t-č r-&gt; -. »N II il._ca fjp7 + 1? 24? 52s «Ss O «. o vo »G * Q * * Z? 2 * “» -sG n TJ D u. G&gt; h -oc, ϋ'— Χ X d X 00 00 +4 7- —'ΌΆ a ο * \ p. - ©. p 2 ^^ 2452 · »&lt;n d aJi SS 2 dd G⁴ - N Ό 45 Ό</td>

<td>S</td><td> 515.31</td><td> 547.20</td><td> 447.13</td>

<td>^{1 1}ο Μ l υ ο. 62 υ and 5Ρ &gt; Λ</td><td>1.22 min Procedure A</td><td>1.26 min Procedure Α</td><td>1.01 Procedure B</td>

<td>Izrac. ΜΜ</td><td> 515.02</td><td> 547.03</td><td>© 43 TR Č ·</td>

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<td>Reactionary scheme</td><td> 00 00</td><td>O0</td><td>18, 1-Procedure. B</td>

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242

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243

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245

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<td>NMR data</td><td>„O„ 2&gt; Ϊ'κ'ϊ g «« D MS _ž 45 &lt;5- - 2 -tf 8 X ρ ο ό / 4 3 12 ο ο ^:&lt;and ^Μ = q S'ŠČS'r-g &gt; T * C Υ1. ΟΓ9 N Ό C = At ​​cc '- «m 4 NO - · O o &lt;A „ ® S'O in m gČ sč £ /</td><td>-ES » VO r- 05 D m 'O' »-« „* nn r &lt;4 &lt;Q 2³⁵ 5- + 3 t- · + -ί ό Ί D * oo co xt 11 0 N SC '—'oo, -⁴ O \ 1 Q II II o 2 2 rf 2 s 0.2 2 2 X * ?; 0 0. h ~ O £ _oV * and HN Q Ž Ό Ά- «- *&gt;, G9 z2 _ &lt;Ά n 2 7 đ £ ii £ d D = 333 = 2 ^ -5 «</td><td>- cn Ol O o 6Ί °) 2 'ri »ο A · £ č 11 t. II ° £ s 7 S g * « g Ό -α 2 -n G. § »ZI Q 5- * ίο D Ο r-ί 2 4- ^ - &lt;- &lt;2 c? X. £ λ «d ««% £ 3 - § š ⁴ ”X« £ αϊνχ&gt; 4 &lt;Χ ^ 2Σ «Ο» _Γ tg đ ° 0 F⁵ 2&gt; р4 Г4 32 Ρ &lt;чВ₽4</td>

<td> 5 2</td><td>535.18 i ........</td><td>gCh α ο Z 5 +</td><td> 429.04</td>

<td>Ret./ Procedure</td><td>1.72 min Procedure A</td><td>Q • h with ~ s __________ a, ....................</td><td>1.58 min Procedure D</td>

<td>Calculation, mm</td><td> 535.06</td><td>444.93 i</td><td> 428.87</td>

<td>Appearance</td><td>bistro uije</td><td>whitish foam</td><td>white solid</td>

<td>Reactionary scheme</td><td>r-</td><td>r ~ 4</td><td>in</td>

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249

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<td> 1</td><td>CR ο г7đ В</td><td>G »-M SZ r £ ⁰⁰ 4- 00 ~ -g</td><td>»N ot—</td>

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<td>NMR data</td><td>χ. II - GC D »« tf J -N 1 b Α 7 · ο Ο _ Ό - 'ΧΪ Η 7¹ 1 {52 ~ β ». Ο m b-, ~ &amp; r-Λ N _ «II -ο Ώ D Ε - ιι 8 3rd year ^m. χΚ s d »d 3] s? G. 8 ιι h |? &lt;m c? &lt;N «£ 33 2 .l α ⁸¹2-=- «17®£52212</td><td>, »C? || II £ 0 oo S u. * z »«&gt; r4 D PQ 'č - * “* L? ^M rM - » W CA - DG " ^wΦ 'ττ' b uč OČ G * g Ξ p in F &lt;N ζ-l pj *. - 'b' m * ' χ t G; 2 R CS XX aj] С 2х2. * «DD -? ^ X F 00 g-č · o λΓΠΟΟ, —č d _- Η N ¢ - «X“ 7 XX ΓΑ / ^ 'ΰ'Ή-ΐ' - 'Γ'ΊίΝ ^</td><td>\ ο cn&gt; II ° ο vj Ή rn * Sa-⁰ e * ά ο π χ «^₂ο χ έ X ο Ε. u, χχτ — ο - χ? πd «χ ^ Η 3. υ ^ χ« ^ oibcs D-ς «η gG * ~« m \ © O, H &amp; e ^ 5 2ηί bb ^ oomfMrć ^ lco 3 θ '* C? Η Η'Ι⁴· Ό ^ · Φ κ ίΜ U-4 d * 7 DI S * ^ h Ε - Γ-. οο Φ sč Om Ο</td>

<td>I</td><td>48834 I</td><td>T-Ch F F o m</td><td> 486.14</td>

<td>Ret./ Procedure</td><td>1.63 min Procedure D</td><td>1.40 gas Procedure A</td><td>1.27 min Procedure Β</td>

<td>Expression. MM</td><td> 487.96</td><td> 503.96</td><td> 485.97</td>

<td>Appearance</td><td>white solid</td><td>whitish solid</td><td>white solid</td>

<td>s 2 '3</td><td>Ό</td><td>Ό</td><td>Ό</td>

<td>Bi</td><td>Oh i⁵</td><td>α 9</td><td>Ο and⁵</td>

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