Process to produce oxazolidinones

METHOD FOR THE PREPARATION OF OXAZOLIDINones

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is a process for preparing the pharmacologically active oxazolidinones and the various intermediates used in the process.

2. Description of the Invention

Various 5-acetamidomethyloxazolidinones are well known to those skilled in the art as pharmacologically useful antibacterial agents. Various methods of preparing these useful therapeutic agents are well known to those skilled in the art.

U.S. Patents 5,164,510, 5,182,403 and 5,225,565 disclose 5'-indolinyl-oxazolidinones, 3- (5'-indazolyl) -oxazolidinones and 3- (substituted with fused rings) phenyl-oxazolidinones, respectively, as useful antibacterial agents.

U.S. Patent Nos. 5,231,188 and 5,247,090 disclose various tricyclic oxazolidinones with [6.5.5] and [6.6.5] condensed rings as useful antibacterial agents.

International Publication No. WO 93/09103 discloses antibacterial mono- and dihalogenophenyloxazolidinones which are pharmaceutically active agents useful for their antibacterial activity.

Known methods for the preparation of oxazolidinones include condensation of the aromatic carbamate with a nitrogen-free triple carbon atom to give the oxazolidinone at the 5-position of the hydroxylmethyl substituted intermediate. The hydroxyl group can then be replaced by an acetamido group to obtain pharmacologically active 5-acetamidomethyloxazolidinones. Variations on this important two-step method have been extensively studied.

U.S. Patents 4,150,029; 4,250,318; 4,476,136; 4,340,606;

461 773 discloses the synthesis of 5-hydroxymethyloxazolidinones from amines (R-NHX_1Z wherein X₁ is H or p-toluenesulfonyl) and (R, S) -glycidol (C^#H2-OC^#H-CH 2 -OH in which ^#the carbon atoms indicated by are bonded together to form io cyclic epoxide). A mixture of enantiomers (represented by the formula R-NH-CH₂-CHOH-CH₂-OH) is separated by fractional crystallization of mandelic acid salts. The enantiomerically pure (R 1 -diol is then converted to the corresponding (R) -hydroxymethyl substituted oxazolidinone by condensation with di 15 ethyl carbonate in the presence of sodium methoxide. These 5 (R) -hydroxymethyl substituted oxazolidinones must be aminated in the next step.

J. Med. Chem., 32, 1673, 1989, Tetrahedron, 45, 1323, 1989 and

U.S. Patent No. 4,948,801 discloses a process for the preparation of oxazolidinones comprising reacting an isocyanate (RN = C = O) with (R) -glycidylbutyrate in the presence of a catalytic amount of lithium bromide tributylphosphine oxide complex to provide the corresponding (R) -butyryloxymethyl-oxy. The process is carried out at a temperature of 135-145 ° C. The butyrate ester is then hydrolyzed in the next step to give the corresponding (R) -hydroxymethyl substituted oxazolidinone. The (R) -hydroxymethyl-substituted oxazolidinone must then be aminated in the next step.

Reaction of the carbamate with butyl lithium, lithium diisopropylamide or lithium hexamethyldisilazide at -78 to -40 ° C, then with glycidyl butyrate at -78 ° C, followed by heating to 20 to

25th ° C to give 5 (R) -hydroxymethyl-substituted oxazolidinones, the ester of which is cleaved during the reaction, and the next step for 5 (R) -hydroxymethyl-substituted oxazolidinones from amiiEE 200000210Α is described in the following publications: theses: 206^th National Meeting of the American Chemical Society, Chicago, IL, August, 1993; American Chemical Society: Washington, DC, 1993; ORGN 089; J. Med Chem. 39, 673, 1996; J. Med Chem.

39, 680, 1996; International Publications: WO 93/09103,

WO 93/09103, WO 95/07271 and WO 93/23384; PCT Patent Applications: PCT / US95 / 12751 and PCT / US95 / 10992; theses: 35^th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, September, 1995; American Society for Microbiology: io Washington, DC, 1995; theses no. F208; theses: 35^th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, September, 1995; American Society for Microbiology: Washington, DC, 1995; theses no. F207; theses: 35^thInterscience Conference on Antimicrobial Agents and Chemo15 Therapy, San Francisco, CA, September 1995; American Society for Microbiology: Washington, DC, 1995; theses no. F206; theses: 35^th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, September, 1995; American Society for Microbiology: Washington, DC, 1995; theses no.

F227.

International Publication No. WO 95/07271 discloses ammonolysis of R, methylsulfonyloxymethyl substituted oxazolidinones.

U.S. Patent 4,476,136 discloses a process for converting 5-hydroxymethyl-substituted oxazolidinones to the corresponding 5 (5) -aminomethyl-substituted oxazolidinones (VII) which comprises treatment with methanesulfonyl chloride followed by potassium phthalimide and hydrazine.

J. Med. Chem., 32, 1673, 1989 and Tetrahedron, 45, 1323, 1989 disclose a method for converting 5 (R) -hydroxymethyl-substituted oxazolidinones to the corresponding 5 (S) -acetamidomethyl-substituted oxazolidinones, comprising treatment with methanesulfonyl chloride or tosyl chloride, followed by sodium metabis with hydrogen, then

EE 200000210 Α acetic anhydride or acetyl chloride to give the desired 5 (S) -acetamidomethyl-substituted oxazolidinone.

U.S. Patent Application 60 / 015,499 discloses a process for the preparation of 5 (S) -hydroxymethyl-substituted oxazolidinone intermediates useful in the preparation of pharmacologically active 5 (S) -acetamidomethyloxazolidinones. Further disclosed is a process for converting 5-hydroxymethyl substituted oxazolidinone intermediates to 5-aminomethyl substituted oxazolidinone intermediates which can be acylated to yield pharmacologically active 5 (S) -acetamidomethyl substituted oxazolidinones.

J. Med. Chem., 33, 2569, 1990 discloses condensation of an isocyanate with a racemic glycidyl azide to give a racemic

5-azidomethyl-substituted oxazolidinone. The next two steps are required to convert the racemic azidomethyl-substituted oxazolidinone to the racemic 5-acetamidomethyl-substituted oxazolidinone, which has an antibiotic effect. The present invention converts isocyanates into (S) -enantiomers of acetamidomethyl-substituted oxa20 solidinones, which have a stronger antibiotic activity than racemates in one step.

U.S. Patent No. 5,332,754 discloses (column 2, lines 14-34) that racemic oxazolidinone-CH₂-NH-Ac can be synthesized in one step by condensation of the carbamate with racemic glycidylacetamide in the presence of a base such as an amine, alkali metal hydroxide, alkali metal alkoxide and the like and the reaction is carried out by heating, preferably at 90 to 110 ° C (column 4, lines 44-56). Under these conditions, it is shown that there is a regrouping of the undesired product. The patent examples do not provide a yield or description of this method. In fact, there is no one-step method but a multi-step method known to those skilled in the art, which involves mesylation of the 5-hydroxymethyl substituted oxazolidinone followed by azide displacement, hydrogenation and amine acylation. See Examples 59-63 for details. The present invention differs in that the reaction between carbamate (IX) and epoxide (VIIIB)

EE 200000210 Α is carried out under conditions in which competing substitution for unwanted by-products is largely suppressed.

Tetrahedron Letters, 37, 7937-7940, 1996 discloses (S) -Glyc 5 -cidylacetamide (R² - -NHAc) synthesis line and method for condensation of carbamate with 1.1 equivalents of butyllithium (THF,

-78 ° C) followed by 2 equivalents of (S) -glycidylacetamide to give the corresponding (S) -acetamidomethyl-substituted oxazolidinone. The present invention is characterized in that the carbamate (IX) and (S) -glycidylacetamide reaction is carried out in the presence of a lithium alkoxide base, or the carbamate (IX) is reacted with (S) -chlorohydrinacetamide (VIHA) or (S) -chloroacetateacetamide (VIIIC), isocyanate (XIV) is reacted with (S) -chlorohydrinacetamide (VIIIA).

U.S. Patent 3,654,298 discloses the synthesis of 5-alkoxymethyl-3-aryl-substituted oxazolidinones by sodium ethoxide-induced cyclization of chlorocarbamates. The present invention is characterized in that in position 5 the substituent is an acylamino group.

SUMMARY OF THE INVENTION

The present invention provides (S) -Secondary alcohol of formula (VIIIA), (S) -epoxide of formula (VIIIB), (S) -ester of formula (VIIIC), (S) -protected alcohol of formula (IVA), (S) -Phthalimide alcohol of formula (IVC), (β-phthalimide epoxide of formula (IVD), glycidylamine (S) -imine of formula (IVB), (S) intermediate of formula (XV) and (S) -oxazolidinone phthalamide intermediate of formula (XVI)).

Also disclosed is a process for the preparation of an (S) -3-carbon amino alcohol of formula (V) comprising reacting 1. a non-nitrogenous compound of formula (I) with aqueous ammonia (II) in the presence of (S)-protected epoxide of formula (III); reacting the reaction mixture with an acid.

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Further disclosed is a process for the preparation of an (S) -3-carbon amino alcohol of formula (V) comprising reacting a phthalimide of formula (VI) with an (S) -protected epoxide of formula (III) in potassium phthalamide in DMF or DMAC to give (S) phthalimide alcohol IVC) and the product of Step 2 1 with aqueous acid.

Further disclosed is a process for the preparation of a secondary alcohol of formula (VIHA) which comprises: reacting a (S) -3-carbonate of 10 amino acids of formula (V) with an acylating agent and a tri (alkyl) amine.

Disclosed is (S) -oxazolidinone CH of formula (X)₂-NH-CO-R_N A process for the preparation which comprises reacting a carbamate of formula (IX) with an oxygen saturated amino reagent selected from: (S) -Secondary alcohol of formula (VIHA), (S) epoxide of formula (VIIIB) or (S) -ester of formula (VIIIC) , lithium cation and base with conjugated acid pK_g is greater than 8 in the presence.

Also disclosed is (S) -oxazolidinone-CH of formula (X)₂-NH-CO-R_NA process for the preparation which comprises: 1. reacting a carbamate of formula (IX) with a phthalimide alcohol of formula (IVC) or a phthalimide epoxide of formula (IVD), a lithium cation and a base having a conjugated acid pK_g is greater than 8 in the presence of an aqueous acid solution of the product of Step 2, Step 2, with an acid anhydride of formula O (COR_n)₂ or with an acid halide of formula R_N-CO-X₄, and a tri (alkyl) amine wherein the alkyl group is C1-C3₅-alkyl.

Further disclosed is (S) -R of formula (X)_twigring-CH₂-NH-CO-R_N A process for the preparation which comprises: reacting a carbamate of formula (IX) with a compound selected from: (S)-protected alcohol of formula (IVA) or (S) -3-carbon protected epoxide of formula (IVB) with a lithium cation and a conjugated acid pK_a is greater than 8, in the presence of (S) protected oxazolidinone of formula (XII), reaction of Step 2, reaction 200000210 A with an aqueous acid to give (S) -oxazolidinone free amine of formula (XIII) and reaction of Step 3 product with a reagent selected from the group consisting of: an acid anhydride of formula O (CO-R_N)₂ or an acid halide of formula

R_n-CO-X₄, wherein R_N is as defined above, and with a tri (alkyl) amine wherein the alkyl is C1-C3₅-alkyl; and R_twigis defined as above.

Further disclosed is (S) -R of formula (X)_twig-cycle-CH₂-NH10 CO-R_n A process for the preparation which comprises reacting a carbamate of formula (IX) with a lithium cation and a base having a conjugated acid pK_a is greater than 8 in the presence of an acylating agent of the formula O (CO-R) to give (S) -oxazolidinone free amine of formula (XIII) and 2 (S) -oxazolidinone free amine by acylation with an acylating reagent._n)₂ or an acid halide of formula R_N-CO-X₄, and tri (alkyl) amine wherein the alkyl group is a C 1 -C 6 alkyl group.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses both novel intermediates and methods for preparing commercially valuable oxazolidinone antibiotics (X). One new method is shown in Scheme D and involves the reaction of the carbamate (IX) with either (S) -secondary alcohol (VIHA) or (S) -epoxide (VIIIB) or (S) ester (VIIIC) to provide the corresponding pharmacologically active (S) - oxazolidinone-CH₂-CO-R₁ (X). Another method is pharmacologically active (S) -oxazolidinone-CH₂-CO-R₁ (X) is obtained in Scheme H and involves the reaction of the isocyanate (XIV) with (S) secondary alcohol (VIIIA) to afford the (S) intermediate (XV), which is then readily converted to the corresponding pharmacologically active (S) -oxazolidinone-CH₂-CO-R₁ (X).

Fragments containing the three carbon atoms of the (S) -secondary alcohol (VIHA), the (S) -epoxide (VIIIB) and the (S) -ester (VIIIC) and the nitrogen atom can be obtained in two different ways. This fragment yields two adjacent carbon atoms of the oxazolidinone ring, E 200000210, a carbon atom of a methylene group to which they are attached, as well as a nitrogen atom attached to a methylene group. These three carbon atoms and (S) -secondary alcohol (VIHA), (S) -epoxide (VIIIB) and (S) -ester (VIIIC) fragments containing these atoms are prepared according to the methods of Scheme C.

Scheme A discloses a process for the preparation of (S) -X-amino alcohol (V) having a (S) -3-carbon atom₂-epoxide (III) using non-mildew compound (I) and ammonia (II) as a source of nitrogen ion. (S) -X₂-epoxide (III) and other compounds of the invention means that (^#) atoms are bonded to each other to form a ring (epoxide). (S) X₂for epoxides (III) it is preferred that X₂ is Cl. (S) -X₂Epoxides (III) are either known to those skilled in the art or can be readily prepared from compounds known to those skilled in the art by methods known in the art. It is preferred that the nitrogen-free compound (I) is Χθ φ, more preferably Χθ φ. Non-nitrogenous Compound (I), Ammonia (II) and (S) -X₂The epoxide (III) reaction is carried out as described in Examples 1 and 14. It should be noted that when enantiomerically pure (S) -X is used₂-epoxide (III), the enantiomerically pure (S) -protected alcohol (IVA) is obtained. In the pharmacologically usable (S) -oxazolidinone 25 C 4 -CO 4 - (X) the absolute configuration of the carbon atom is S and it is therefore preferable to proceed with the enantiomerically pure (S) -X.₂-epoxide (III) to obtain the enantiomerically pure (S) protected alcohol (IVA), see Scheme A. In the schemes and claims, the superscript * such as -C * (a) (b) - indicates that the asymmetric carbon atom has the appropriate enantiomeric configuration (S) ) so that when this carbon atom changes to (S) -oxazolidinone-CH₂~ CO-R₁ (X) then this is the correct enantiomer. When any of the methods of the present invention are based on the optically pure (racemic) rather than enantiomerically pure form, it will be apparent to those skilled in the art that the products obtained are also optically pure (racemic) forms.

The (S)-protected alcohol (IVA) is then reacted with an acid to give the corresponding (S) -3-carbon amino alcohol (V). Neither the nature, the strength nor the amount of the acid is critical. It is preferred that the acid pK_g is less than 4. It doesn't matter if the acid is organic or inorganic. The amino alcohol of (S) -3-carbon is converted to a cation and the non-protic portion of the acid is anion. For example, when the mixture is acidified with sulfuric acid, the (S) -3-carbon amino alcohol (V) is obtained as the sulfate salt. The nature of the anion does not matter.

Scheme B discloses a method for obtaining the desired (S) -3-carbon amino alcohol (V) from the same (S) -X₂~ epoxide (III), but the nitrogen-containing compound (VI) is used. In this case, ammonia (II) is not required. In the final step of the process, when the product of the first step is reacted with an aqueous acid solution, it is preferred that the acid is hydrochloric, hydrobromic, hydroiodic, sulfuric or p-toluenesulfonic acid.

Scheme C discloses a method for converting (S) -3-carbon aminoalkyl alcohol (V) to the corresponding (S) -secondary alcohol (VIHA), (S) -epoxide (VIIIB) or (S) -ester (VIIIC) and (S) - to convert the secondary alcohol (VIIIA) to the corresponding (S) epoxide (VIIIB) and the (S) -ester (VIIIC). In order to convert the (S) -3-carbon amino alcohol (V) to the corresponding (S) secondary alcohol (VIHA), the 3-carbon amino alcohol (V) is reacted with a suitable acylating agent such as acyl halide or acyl anhydride under conditions known to those skilled in the art. 2. It is preferred that the acylating reagent is selected from: an acid30 hydride of formula O (CO-R_N)₂, wherein R_N is a C 1 -C 4 alkyl group, or an acid halide of formula R_N-CO-X₄, wherein X₄ is Cl or Br, and the alkyl group of the tri (alkyl) amine is C₁-C₅-alkyl. More preferably, R is_H N-alkyl and X₄ is Cl. More preferably, the acylating agent is acyl anhydride and preferably the acyl anhydride is acetic anhydride.

Alternatively, (S) -epoxide (VIIIB) may be obtained by reaction of (S) -ester (VIIIC) with a base such as sodium methoxide or potassium carbonate / methanol. Alternatively, the (S) -3-carbon amino alcohol (V) can be converted to the corresponding (S) -ester (VIIIC) by reaction with acetic anhydride in pyridine, see Example 3. (S) Epoxide (VIIIB) can be obtained from the corresponding (S) second alcohol (VIHA) ) with potassium tert-butoxide in THF at -20 ° C, see Example 11. In addition, the (S) -secondary alcohol (VIIIA) can be converted to the corresponding (S) -ester (VIIIC) by reaction with acylating agents as described above.

In the case of the (S) -ester (VIIIC), it is preferred that R_N is CO-CH₃.

In Scheme D, the method discloses a carbamate of formula R_oxg-NH-CO-OCH₂-X₁ (IX) by reaction with either (S) -secondary alcohol (VIHA), (S) -epoxide (VIIIB) or (S) -ester (VIIIC) to give the corresponding (S) -oxazolidinone-CH₂-CO-R₁ (X). Carbamates (IX) are known to those skilled in the art or can be readily prepared from known compounds by methods known in the art. Preferably X is₁ H.R._twig is a phenyl group substituted with one F20 atom and one substituted amino group. Substituted amino groups include 4- (benzyloxycarbonyl) -1-piperazinyl, 4-morpholinyl and 4-hydroxyacetylpiperazinyl. Preferably^Roxa 3-fluoro-4- [4- (benzyloxycarbonyl) -1-piperazinyl] phenyl or 3-fluoro-4- (4-morpholinyl) phenyl. The carbamate (IX) and the three carbon moiety (VIHA, VIIIB or VIIIC) are reacted with the reaction base. Its nature is not relevant as long as it is strong enough to deprotonate the carbamate (IX). The bases used are those having a conjugated acid ρΚθ greater than 8. Preferred bases are those selected from the following:

alkoxy compounds of one to seven carbon atoms, carbonate, methyl, sec-butyl and tert-butylcarbanions, tri (alkyl) amines in which the alkyl group has 1 to 4 carbon atoms, conjugate base of carbamate (II),

DBU,

EE 200000210 Α

DBN,

N-methylpiperidine,

N-methylmorpholine,

2,2,2-trichloroethoxide and

C1₃C-CH₂-O '.

More preferred are bases based on alkoxy of four or five carbon atoms. Preferably, the alcoholic bases having four and five carbon atoms are tert-amylate or tert-butoxide. Sodium or potassium bases in combination with a lithium salt (such as lithium chloride or lithium bromide) may be used to form the lithium cation and base in situ. The nature of the solvent is not important. The solvents used are cyclic ethers such as THF, amides such as DMF and DMAC, amines such as triethylamine, acetonitrile and alcohols such as tert-amyl alcohol and tert-butyl alcohol. As is known to those skilled in the art, the choice of solvent depends on the solubility of the carbamate (IX) and the three carbon atoms (VIIIA, VIIIB or VIIIC).

Scheme E illustrates the reaction of a carbamate (IX) with either (S) phthalimide alcohol (IVC) or (S) phthalimide epoxide (IVD) to give (S) -cyclic phthalimide (XI), which is then converted to the corresponding (S) -oxazolidinone-CH₂-NH-CO-R_H(X) which has a pharmaceutical effect.

Scheme F illustrates the reaction of a carbamate (IX) with either (S) protected alcohol (IVA) or glycidylamine (S) -amine (IVB) to give the corresponding (S) -oxazolidinone protected compound (XII), which is then converted to (S) -oxazolidinone to the amine (XIII), which is then acylated as described above to give (S) -oxazolidinone-CH 2 -NH-CO-R 1, (X) which has a pharmaceutical effect. These methods are the same as those disclosed in Schemes D and E, or are known to those skilled in the art.

Scheme G directly discloses the reaction of a carbamate (IX) directly with (S) a 3-carbon amino alcohol (V) to provide the (S) -oxazolidinone free amine (XIII), which is then acylated to give

EE 200000210 Α Azolidinone-CH₂-NH-CO-R_N (X) · These methods are carried out in Latvian as published above.

_t1 H discloses the reaction of technical isocyanate (XIV) with ecundial alcohol (VIHA) to give the (S) intermediate which is then converted to the (S) -oxazolidinone-CH₂-NH-CO-R_N see Examples 6, 8 and 9.

emil I discloses a reaction analogous to Scheme E, wherein the method of Scheme E employs a carbamate (IX) and the method of Scheme I employs isocyanate (XIV).

S) -oxazolidinone-CH₂-CO-amines (X) are known as antibiotic pharmaceuticals.

DEFINITIONS AND AGREEMENTS

The following definitions and explanations of terms are used throughout the document, both in the specification and in the claims.

I. AGREEMENTS FOR THE VARIOUS FORMULAS AND DEFINITIONS

The formulas of the various chemical compounds or molecular fragments disclosed in the specification and claims may contain variable substituents in addition to explicit structural features. These variable substituents are identified by a letter or a letter followed by a numeric underscore, such as Zf or RJ ', where i is an integer. These variable substituents are either monovalent or bivalent, i.e. they represent a group linked by one or two chemical bonds of the formula. An example is Z₁ a divalent variable when related to a formula as follows: CH₃-C (= Z₁) H. Groups R_i and R 1 are monovalent variable substituents when attached in the formula: CH₃-CH₂-C (R_i) (Rp -H.) When the chemical formulas are drawn in a linear fashion as described above, the variable substituents in parentheses are linked directly to the left atom preceding the substituents in parenthesis EE 200000210. with the immediately preceding left atom which is not enclosed in parentheses_;- as well as Rj bound to the preceding carbon atom. Also, in any given atomic numbering molecule, such as steroids, those carbon atoms are designated as Ct, where i is an integer corresponding to the number of carbon atoms. For example, C₆ refers to the sixth position or carbon atom number in the ste10 ring nucleus, as traditionally noted by those skilled in the art of steroid chemistry. Similarly, the term R represents₆ variable substituents (either monovalent or bivalent) C₆position.

Linearly written chemical formulas, or portions thereof, describe atoms in a straight chain. generally denotes the bond between two atoms in the chain. Thus, CH₃-O-CH₂-CH (Rj) -CH₃ is a 2-substituted-1-methoxypropane compound. Similarly, denotes a double bond, for example CH₂= C (R 1) -O-CH₃ and "= triple bond, for example HC = C-CH (R 1) -CH₂-CH₃. Carbonyl groups are also represented in one way: -CO- or -C (= O) -, the former being preferred for simplicity.

The chemical formulas of cyclic compounds or molecular fragments may be represented linearly. Thus, the 4-chloro-225 methylpyridine of the compound can be represented linearly as N^#= C (CH 3) -CH = CC 1 CH = C^#H, whereas the atoms marked with an asterisk (#) are linked together to form a ring. Similarly, the cyclic molecular moiety of 4- (ethyl) -1-piperazinyl may be represented as N^#(ch2) ₂-n (c₂h₅ ) -ch₂-c^#h₂ .

The rigid cyclic structure of any of the compounds provided herein determines the orientation of each substituent bonded to the carbon atom of the rigid cyclic compound relative to the ring plane. In saturated compounds containing two substituents -C (X on the carbon atom of the cyclic system)₁) (X₂) -, these two substituents can be either axial or equatorial with respect to the ring and become axial to equatorial. However, the positions of the two substituents on the ring and on each other remain fixed. Although the substituent may over time be located either in the plane of the cycle (equatorial position) or up or down in the plane of the cycle (axial position), one substituent is always above the other. In the chemical structural formulas of such compounds, the substituent (X.,) below is defined relative to the other substituent (X.₂), in the alpha (a) configuration, and is labeled with a dashed or dotted carbon atom, such as a --- or the corresponding substituent io above (X₂) with respect to the second substituent (X.,) is defined as in the beta (β) configuration and is dotted with a continuous carbon atom.

When the variable substituent is bivalent, the valence bonds can be reported together or separately, or both definitions of the variable may be used. For example, the variable R₁, bonded to a carbon atom as -C (= R_i) -, can be bivalent and is defined as an oxo or keto group (thus forming a carbonyl group (-CO-)) or is independently linked as two monovalent variable substituents aR, - j and β20 R, -._k· If the bivalent variable R_; is defined as consisting of two monovalent variable substituents, the convention is used that the bivalent variable is in the form aR_i . : 3-R.__k or some other variant of these. In this case both aR, · - and 3 “R, -._kbonded to a carbon atom to give the -Cia-R group. .) (β-R_i__k)-.

For example, if it is defined that the bivalent variable R₆, -C (= R₆) -, consists of two monovalent variable substituents, then the two monovalent variable substituents are aR₆_₁ : β-Κ₆_₂,

.... aR₆_₉ : 3-R₆.₁₀ etc., giving the group -C (aR₆,₁) (β-Ρ₆_₂) -, ....

-C (aR_{6 9}) (PR₆_₁₀) - etc. Similarly, the bivalent variable is R_1V

-C (= R₁₁) -, for two univalent variables aR_1v1 : β-Κ_η.₂.

For a ring substituent which does not have a distinction between the α and β orientations (eg due to the presence of a carbon-carbon double bond in the ring) and for a non-ring carbon substituent, the above convention is used, but the α and β designations are deleted.

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Just as a divalent variable can be defined as two different monovalent variable substituents, two separate monovalent variable substituents can be defined together as a divalent variable. For example, in the formula -C₁ (RJ HC₂(Rj) H- (C₁ and C₂ is defined arbitrarily when the first and second carbon atoms, respectively) can be R_; and Rj taken together to form 1. a second bond C₁ and C₂ or 2. a bivalent group such as a branch (-O-) and thus the formula would describe the epoxide. When Rj and Rj taken together form a more complex group, such as -XY-, then the group orientation is such that C in the above formula is linked to X and C₂ Yga. Thus, the designation ... Rj and Rj taken together to form the -CH group₂-CH₂O-CO -..., a lactone having a carbonyl group attached to C₂ga. The designation ... Rj and Rj taken together to form the group -CO-O15 CH₂-CH₂-, means a lactone to which the carbonyl group is attached

Cjga.

The content of carbon atoms in the variable substituent is indicated in one way or another. The first method uses a prefix like C, - C in the variable name₄, where both 1 and 4 are integers defining the minimum and maximum number of carbon atoms in the variable. The prefix is ​​separated from the variable by a hyphen. For example, C 1 -C 6 alkyl is an alkyl group having 1 to 4 carbon atoms (including its isomeric forms unless otherwise defined). If a single prefix is ​​given, it indicates the total carbon atoms in the specified variable. Thus, C₂-C₄alkoxycarbonyl describes CH₃- (CH₂)_n-O-CO-, wherein n is zero, one or two. Alternatively, the carbon atoms content is determined separately for each of the defined portions, denoted C 1 -C. round brackets and place it directly (not to insert a space) in front of the part defined in the definition. Under this selective arrangement, (C,₃) -alkoxycarbonyl has the same meaning as C₂-C₄-alkoxycarbonyl, since C_y-C₃ means only the carbon atoms in the alkoc35 group. Similarly, though both C₂-C₆alkoxyalkyl as well as (C 1 -C 3) alkoxy (C 1 -C 4)₃) -alkyl defines an alkoxyalkyl group containing from 2 to 6 carbon atoms, the two defiEn 200000210 ions are different since the above definition only refers to an alkoxy or alkyl moiety having 4 or 5 carbon atoms, while the latter definition limits both groups to 3 carbon atoms.

Where a complex (cyclic) substituent is claimed, the end of the name / designation (in parentheses) shall be indicated by the designation / designation of that substituent in one of the schemes showing the chemical structural formula for that substituent.

II. DEFINITIONS

All temperatures are in degrees Celsius.

TLC is thin layer chromatography.

HPLC is high performance liquid chromatography.

THF is tetrahydrofuran.

* indicates that the carbon atom is the enantiomeric carbon atom in the (S) configuration.

# indicates that the atoms marked with (#) are bonded to each other to form a ring.

The ring is defined in Scheme J as the oxazolidinone ring

2,5-disubstituted oxazolidinone.

DMF is dimethylformamide.

DMAC is dimethylacetamide.

Chromatography (column and flash chromatography) is a method of purification / isolation of the compounds (carrier, eluent). It will be understood that appropriate fractions are combined and concentrated to provide the desired compound (s).

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IP is infrared spectroscopy.

CMR is C-13 carbon magnetic resonance spectroscopy, chemical shifts are reported in ppm (5) relative to TMS.

NMR is nuclear (proton) magnetic resonance spectroscopy, chemical shifts are reported in ppm (δ) relative to TMS.

TMS is a trimethylsilyl group.

φ is phenyl (C₆H₅) .

[a]_D²⁵ is the rotation angle (specific optical rotation) of the polarized light with respect to the sodium D line (589A) at 25 ° C.

MS is mass spectrometry expressed in m / e, m / z or mass / charge. [M + H]⁺ is the positive ion of the parent compound plus the hydrogen atom. NO is the electron effect. CI is chemical ionization. FAB is fast atom bombardment20.

Pharmaceutically acceptable are those properties and / or substances which are acceptable to the patient from the pharmacological / toxicological point of view and from the physical / chemical point of view of the pharmaceutical chemical industry, taking into account the composition, dosage form, stability, patient acceptability and bioavailability.

When solvent pairs are used, the solvent ratio used is volume / volume (v / v).

When solubility of a solid in a solvent is used, the ratio of solid to solvent per unit volume / volume (w / v) is used.

EE 200000210 Α

EXAMPLES

Without further elaboration, those skilled in the art using the above descriptions may practically carry out the present invention in its entirety. The following detailed examples illustrate how to prepare the various compounds and / or carry out the various methods of the invention and are provided for purposes of illustration only and are not intended to limit in any way the above description. Those skilled in the art will readily recognize suitable variations of the methods both in terms of reagents, reaction conditions, and techniques.

PREPARATION

3-Fluoro-4-morpholinylaniline

To a mixture of morpholine (60.0 mL, 688 mmol, 4.34 eq) in THF (30 mL) is added 3,4-difluoronitrobenzene (25.196 g, 158.38 mmol) at -14 ° C. The mixture is allowed to warm to 10 ° C and then maintained at 10-13 ° C for 1 hour.

A mixture of citric acid monohydrate (75 g, 357 mmol, 2.25 eq.) In water (365 mL) is added with an exothermic rise to 28 ° C. The layers are separated and the aqueous layer is washed with toluene (95 mL). The organic layer is washed with water (315 mL) and concentrated under reduced pressure. Toluene (46 mL) and methanol (60 mL) are added followed by palladium on carbon (5%, 50% water, 3.1603 g, 0.7426 mmol, 0.00469 eq) and the mixture is sealed on a Parr shaker. Hydrogen pressure (40 psi) is used and shaking is continued for 42 minutes. The catalyst is then removed by filtration under reduced pressure and washed with toluene (60 mL). Heptane (150 mL) is added to the filtrate and the resulting suspension is concentrated under reduced pressure. Heptane (300 mL) is added, the precipitate is collected by filtration under reduced pressure, washed with heptane and dried to give the title compound. HPLC (stationary phase 4.6 x 250 mm Zorbax RX C-8 column, mobile phase at35 cetonitrile (650 mL), triethylamine (1.85 mL) and acetic acid (1.30 mL) and sufficient water to obtain 1000 mL , flow rate = 3.0 mL / min, UV detection at 254 nm, RT = 1.08

EE 200000210 Α min, & gt; 99.3% area), NMR (pyridine-D₅) 2.95-2.98, 3.80-3.83, 5.38, 6.68, 6.78 and 6.90 δ, CMR (Pyridine-D)₅) 52,43, 67,33,

103.31, 110.63, 121.29, 130.80, 146.23 and 157.72 δ.

PREPARATION

N-Carbomethoxy-3-fluoro-4-morpholinylaniline (IX)

To a mixture of morpholine (60.0 mL, 688 mmol, 4.38 eq) in THF (30 mL) is added 3,4-difluoronitrobenzene (Preparation 1, 24.967 g, 156.94 mmol) at -6 ° C. The mixture is allowed to warm to 10 ° C over 2 hours, then held at 10 ° C for 1/2 hour. A mixture of citric acid monohydrate (75 g, 357 mmol, 2.27 equiv.) In water (365 mL) is added with an exothermic rise to 28 ° C. The layers are separated and the aqueous layer is washed with toluene (95 mL). The organic layer is washed with water (315 mL), the aqueous layer is extracted with toluene (95 mL) and concentrated under reduced pressure. Toluene (76 mL) and methanol (60 mL) are added followed by palladium on carbon (5%, 50% water, 3.1370 g, 0.7371 mmol, 0.00470 eq) and the mixture is poured into a Parr shaker. Hydrogen pressure (40 psi) is used and shaking is continued for 4.5 hours. The catalyst is then removed by filtration under reduced pressure and washed with toluene (100 mL). The mixture is cooled to 2 ° C and a mixture of aqueous potassium carbonate (47%, 17.1 mL, 85 mmol, 0.54 equiv.) And water (150 mL) is added. Methyl chloroformate (16.4 mL, 212 mmol, 1.35 eq.) Is then added, maintaining the temperature between about 3 and 3.5 ° C. The resulting suspension is allowed to warm to 20-25 ° C and stirred for 17 hours. The solution is heated to 75 ° C, then cooled to 46 ° C, heptane (333 ml) is added, then the mixture is cooled to 0 ° C, the precipitate is collected by filtration under reduced pressure, washed with heptane (100 ml, cooled to 5 ° C), then with water (230 mL, cooled to 5 ° C) and dried to give the title compound. TLC (silica gel, methanol / methylene chloride, 5/95) R_f = 0.74 (one spot), NMR (CDCl₃) 3,03, 3,76, 3,86, 6,75, 6,87, 6,98, 7,27,

CMR (CDCl₃) 51,18, 52,42, 67,03, 107,81, 114,56, 119,00,

133,25, 135,77, 154,07, 155,70.

PREPARATION

3-Fluoro-4-morpholinylphenyl isocyanate (XIV)

To a mixture of phosgene (1.93 M in toluene, 63.4 mL, 122.4 mmol, 2.00 equiv.) In p-chlorotoluene (60 mL) is added 3-fluoro-4-morpholinylaniline (Preparation 1, 12.01 g, 61 mL) over 15 minutes. , 21 Io mmol) in methylene chloride (100 mL) keeping the temperature between -12 and 3 ° C. The substance is rinsed with methylene chloride (30 mL). The mixture is then warmed to atmospheric pressure to 130 ° C, with distillation of the methylene chloride, phosgene, toluene and gaseous hydrogen chloride in a caustic cleaner. The mixture is cooled to 25 ° C and filtered. The precipitate is washed with methylene chloride (3 x 15 mL). The filtrate is concentrated under reduced pressure. To the concentrated filtrate is added heptane (200 mL) and the resulting suspension is cooled to -32 ° C. The product is collected by filtration under reduced pressure, washed with heptane cooled to -30 ° C and dried under a stream of nitrogen to give the title compound. HPLC (stationary phase 4.6 x 250 mm Zorbax RX C-8 column, mobile phase acetonitrile (650 mL), triethylamine (1.85 mL) and acetic acid (1.30 mL) and sufficient water

1000 ml, flow rate = 3.0 ml / min, UV detection at 254 nm), RT = 1.08 min. Derivatized to N-carbomethoxy-3-fluoro-4-morpholinylaniline by dissolution in methanol, NMR (CDCl₃) 3.05, 3.86 and 6.78-6.89 δ, CMR (CDCl₃) 50,90,

66.89, 113.11, 119.15, 120.83, 124.67, 127.65, 138.06 and

155.40 δ, MS (EI), m / z (relative intensity) 222 (37) and

164 (100).

EXAMPLE 1 (S) -1-Amino-3-chloro-2-propanol hydrochloride (V)

To a mixture of benzaldehyde (I, 50.0 mL, 492 mmol, 1.012 eq), ethanol (163 mL) and aqueous ammonia (II, 29.8% w / w, mL, 787.4 mmol, 1.62 eq) is added at 18 ° C over 10 minutes (S) -epichlorohydrin (III, 44.978 g, 486.1 mmol, 98.9% enantiomeric excess, 99.3% chemical purity), accompanied by an exothermic rise to 22 ° C.

The reaction mixture is allowed to rise exothermically to 34 ° C over 1.5 hours, warmed to 42 ° C, stirred at 20-25 ° C for 20.5 hours, then warmed to 74 ° C and allowed to cool immediately. The mixture is concentrated under reduced pressure to give (S) -1-benzalimino-3-chloro-2-propanol (IVA). Water (382 mL) and hydrochloric acid (37.7% w / w, 76.2 mL, 938 mmol, 1.93 eq.) Are added to the concentrate and the mixture is stirred at 20-25 ° C for 2 hours. Toluene (150 mL) is added and the layers are separated. The organic layer is washed with water (15 mL) and the combined aqueous layers are washed with toluene (2 x 150 mL), each organic extract is extracted with water (15 mL). The combined aqueous extracts are concentrated under reduced pressure. Ethanol (200 mL) is added to the concentrate and the mixture is concentrated under reduced pressure. Ethanol (300 mL) is added to the concentrate and the mixture is brought to reflux. The mixture is cooled to -30 ° C and the precipitate is collected by filtration under reduced pressure, washed with ethanol (2 x 60 ml) cooled to -30 ° C and dried under a stream of nitrogen to give a white solid, m.p. = 132-141 ° C.₃OD) 2.96, 3.21, 3.57-3.64 and 25 4.03-4.09 δ, CMR (CD CDOD) 43.52, 46.91 and 68.72 δ, MS (CI, NH₃), m / z (relative intensity) 129 (24) and 127 (69), 112 (61),

110 (100), [a]²⁵D = 22 (c = 1.00, H₂0) .

EXAMPLE 2 A suspension of (S) -1-acetamido-2-hydroxy-3-chloropropane (VIIIA) (S) -1-amino-3-chloro-2-propanol hydrochloride (V, Example 1, 9.938 g, 68.059 mmol) in THF ( 80 ml) is added at -40 ° C triethylamine (10.5 ml, 75.3 mmol, 1.11 eq.) And the mixture is stirred at -40 ° C for 5 minutes. Acetic anhydride (6.78 mL,

71.86 mmol, 1.056 eq.) And the mixture is allowed to warm to 20-25 ° C over 1.5 h. The precipitate is removed by filtration under reduced pressure and washed with THF. The filtrate is treated with magnesium salt (5.69 g) which is removed by filtration under reduced pressure and washed with THF (2 x 60 ml). The filtrate is then concentrated under reduced pressure. The concentrate is purified by flash chromatography (silica gel, gradient elution with 75-100% ethyl acetate / cyclohexane) to give the title compound. NMR (CDCl₃) 2.03, 3.32, 3.50-3.57, 3.55, 3.91-4.13, 5.01 and

7.09 δ, CMR (CDCl₃) 23.00, 43.31, 46.52, 70.65 and 172.40 δ, MS 10 (CI, NH₃), m / z (relative intensity) 171 (41.6), 169 (100),

154 (22.4), 152 (48.1), [a]²⁵D = -7.44 (c = 1.00, H₂O).

EXAMPLE 3 (±) -1-Acetamido-2-acetoxy-3-chloropropane (VIIIC) (±) -1-Amino-3-chloro-2-propanol hydrochloride ((±) -V, Example 5, 5.0110 g) To a liquid suspension of 34.317 mmol) in pyridine (20 mL) is added acetic anhydride (13 mL) while maintaining the temperature between 20-50 ° C. The mixture is stirred at 20-25 ° C for 18 hours, then water (14 ml) is added with an exothermic rise to 65 ° C. The mixture is concentrated under reduced pressure and water (50 mL) is added. The pH is adjusted at 0 ° C with hydrochloric acid (37.7%, 1.467 g,

15.17 mmol, 0.442 eq.) To 0.89. The mixture is extracted with methylene chloride (4 x 50 mL), the extracts are dried over sodium sulfate and concentrated under reduced pressure. Ethyl acetate (20 mL) and heptane (20 mL) are added, the mixture is seeded, then heptane (40 mL) is added to the resulting suspension. The precipitate is collected by filtration under reduced pressure, washed with heptane and, after drying, the title compound is obtained, m.p. = 68.0-69.5 ° C, TLC (silica gel, ethyl acetate, iodine chamber) R_f = 0.39 (one spot), NMR 2.00, 2.21, 3.52, 3.62, 3.70, 5.10 and 6.33 δ, CMR

20.93, 23.10, 40.47, 43.53, 71.95, 170.45 and 170.71 <5, MS (CI,

NH₃), m / z (relative intensity) 213 (36), 211 (100), 196 (18) and 194 (53).

EE 200000210 Α

EXAMPLE 4 (S) -1-Phthalimido-3-chloro-2-propanol (S) - (IVC)

To a suspension of potassium metalimide (VI, 5.031 g, 27.161 mmol, 0.507 eq.) And phthalimide (VI, 11.836 g, 80.45 mmol, 1.5006 eq.) In DMF (32 mL) is added (S) -epichlorohydrin (III, 98.9%). enantiomeric purity, 99.3% chemical purity, 4.9605 g, 53.61 mmol) and the mixture is stirred at 50 ° C for 4.5 hours. The mixture is added to methylene chloride (50 mL) and water (50 mL) is added. The solid is removed by filtration under reduced pressure and washed with methylene chloride (20 mL). The filtrate layers are separated and the aqueous layer is washed with methylene chloride (50 mL). The combined organic layers are washed with water (50 mL) and the aqueous layer is extracted with methylene chloride (50 mL) after addition of water (25 mL). The combined organic layers are dried over sodium sulfate and saturated with hydrogen chloride gas at 6 ° C. Water (100 mL) is added and the layers are separated. The aqueous layer is washed with methylene chloride (2 x 50 mL) and the combined organic layers are dried over sodium sulfate. The organic layer is concentrated under reduced pressure and toluene (77 mL) is added. The mixture is concentrated under reduced pressure to a pure weight of 31 g and toluene (50 ml) and heptane (75 ml) are added. The solid is filtered and washed with toluene / heptane (1/1, 20 mL). The filtrate is concentrated under reduced pressure to 17 g pure, heptane (100 ml) is added and the mixture is concentrated under reduced pressure to 15 g pure. Heptane (100 mL) and methylene chloride (100 mL) are added and the mixture is concentrated under reduced pressure to a pure weight of 13.0 g. The solid is filtered and washed with heptane / methylene chloride (2/1, 3 x 15 mL). The filtrate is concentrated under reduced pressure to a net weight of 11 g and toluene (90 ml) is added followed by heptane (400 ml). The resulting slurry is then cooled to -20 ° C and the product is collected by filtration under reduced pressure, washed with heptane and dried to give a crude solid. Flash chromatography of the crude solid (silica gel, gradient elution with 15-45% ethyl acetate / cyclohexane) affords the title compound as an analytical sample. NMR 3.11, 3.62, 3.68, 3.87, 3.95, 4.14EE 200000210 Α

4.20, 7.70-7.76 and $ 7.82-7.88, CMR 41.61, 47.27, 69.68,

123.53, 131.83, 134.26 and 168.65 δ, MS (CI, NH₃), m / z (relative intensity) 259 (1.4), 257 (17), 242 (0.11), 240 (0.31), 221 (100), [a]²⁵0 = -33 (c = 0.712, CHCl 1)₃). Mosher esterder5 barrel NMR showed 96.2% enantiomeric purity of the product relative to the racemate mosher ester NMR.

EXAMPLE 5 (±) -1-Amino-3-chloro-2-propanol hydrochloride (±) - (V) (±) -1-Phthalimido-3-chloro-2-propanol (IVC, 40.0118 g, 166.98 mmol) a suspension of hydrochloric acid (37.5% w / w, 79 mL, 968 mmol, 5.80 eq.) and water (82 mL) is stirred at 109 ° C for 5 h. The mixture is cooled to 22 ° C, the precipitate is removed by filtration under reduced pressure and washed with water (40 ml). The filtrate is concentrated under reduced pressure to a net weight of 26 g and ethanol (100 ml) is added. The solution is heated to 75 ° C, then cooled to -12 ° C, and the resulting precipitate is collected by filtration under reduced pressure, washed with ethanol cooled to -12 ° C and dried to give the title compound, m.p. = 101-104 ° C. CD₃OD) 2.96, 3.21, 3.57-3.64 and 4.03-4.09 δ, CMR (CD₃OD)

43.54, 46.95 and 68.71 δ, MS (CI, NH₃), m / z (relative intensity) 129 (12), 127 (39), 112 (56), 110 (100).

EXAMPLE 6 (S) -N-Carbo- (1'-acetamido-3'-chloro-2'-propoxy) -3-fluoro-4-morpholinylaniline ((S) -XV) (S) -1-amino-3- To a suspension of chloro-2-propanol hydrochloride (V, Example 1, 0.6020 g, 4.12 mmol) and triethylamine (1.26 mL, 9.04 mmol, 2.19 eq.) in acetonitrile (70 mL) is added at -40 ° C. C acetyl chloride (0.3297 g, 4.20 mmol, 1.019 eq.). The mixture is then warmed to 3-6 ° C, stirred for a few hours, warmed to 22 ° C and 3-fluoro-4-morpholinylphenyl isocyanate (XIV, Preparation 3, 1.0152 g, 4.568 mmol, 1.108 eq.) Is added. The mixture is heated

EE 200000210 Α to 64 ° C, stir for 10 minutes then concentrate under reduced pressure to about 25 ml. Then added

3-Fluoro-4-morpholinylphenyl isocyanate (XIV, 0.0907 g, 0.408 mmol, 0.09887 eq.) And the mixture is stirred at 65 ° C for 17 h. Pentanol (1.34 mL, 12.33 mmol, 2.99 eq.) Is added and the mixture is stirred at 65 ° C for 1.7 h. Water (5 mL) is added and the mixture is cooled to -4 ° C. Water (38 mL) and heptane (30 mL) are added and the mixture is warmed to 15 ° C and stirred for 1 hour. The resulting precipitate is collected by filtration under reduced pressure, washed with heptane and water and dried to give a solid. The filtrate is concentrated under reduced pressure to a total volume of 50 ml and the precipitate is collected by filtration under reduced pressure, washed with water (10 ml) and heptane (10 ml) and dried to give a brown solid. A portion of the first solid (0.9404 g) and the second solid (0.4018 g) are dissolved at 76 ° C in acetonitrile (15 mL), then cooled to -10 ° C and the precipitate is collected by filtration under reduced pressure, washed to -10 ° C with chilled acetonitrile and dried to give the title compound, HPLC (stationary phase 4.6 x 250 mm Zorbax RX C-8 column, mobile phase acetonitrile (650 mL), triethylamine (1.85 ml) and acetic acid (1.30 ml) and sufficient water to make up to 1000 ml, flow rate = 3.0 ml / min, UV detection at 254 nm, 92.3% of the surface).

EXAMPLE 7 (S) -N-Carbo- (1'-acetamido-3'-chloro-2'-propoxy) -3-fluoro-4-morpholinylaniline ((S) -XV) (S) -1-acetamido-3- chloro-2-propanol (VIIIA, Example 2, 1.024 g, 6.754 mmol, 1.00 eq.) and 3-fluoro-4-morpholinylphenyl isocyanate (XIV, Preparation 3, 1.6756 g, 7.539 mmol,

A mixture of 1.12 eq. Of acetonitrile (25 mL) is stirred at 60 ° C for 46 h. The resulting suspension is cooled to temperature

-13 ° C, the precipitate is collected by filtration under reduced pressure, washed with acetonitrile (20 ml) cooled to -13 ° C and dried to give the title compound. NMR (DMSO-D 6) 1.83,

EE 200000210 Α

2.93, 3.2-3.5, 3.73, 3.78, 3.88, 4.99, 6.97, 7.20, 7.36, 8.07 and 9.80 δ, CMR (DMSO-D6) 22.42, 39.6, 44.71, 50.77, 66.15,

71.81, 106.49, 114.23, 119.21, 134.18, 134.59, 152.57, 154.65 and 169.67 S, MS (CI, NH₃), m / z (relative intensity) 376 (27.0), 374 (85.9), 339 (12.2), 338 (80.8), and 223 (17.2), [q]²⁵d = -4.08 (c = 0.930, DMF).

EXAMPLE 8 (S) -N - [[3-Fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide ((S) -X) (S) -N-Carbo To a suspension of (1'-acetamido-3'-chloro-2'-propoxy) -3-fluoro-4-morpholinylaniline ((S) -XV), Example 7, 0.3176 g, 0.850 mmol) in ethanol (4.6 mL) is added. temperature

65 A solution of sodium tert-butoxide (0.0854 g, 0.889 mmol, 1.05 equiv.) In ethanol (0.60 mL) and rinsed with ethanol (0.50 mL). The mixture is stirred for 28 minutes and cooled to 0 ° C. Citric acid monohydrate (0.1943 g,

0.925 mmol, 1.09 eq.) And the resulting suspension is concentrated under reduced pressure to a net weight of 1.30 g. Water (10 mL) and methylene chloride (10 mL) are added, the layers are separated, and the aqueous layer is washed with methylene chloride (2 x 10 mL). The combined organic layers are dried over sodium sulfate and concentrated under reduced pressure to a solid. The solid is dissolved in ethyl acetate (8.4 mL) at 70 ° C, the solution is cooled to 50 ° C, seeded, further cooled to -28 ° C, the precipitate is collected by filtration under reduced pressure, washed with ethyl acetate cooled to -30 ° C and dried, The title compound is obtained by HPLC (100.7% 99.9% w / w), NMR (CDCl₃) 2,04, 3,04, 3,65, 3,77,

3.86, 4.02, 4.74-4.82, 6.80, 6.91, 7.06 and 7.42 δ, CMR (CDCl₃)

22,99, 41,88, 47,64, 50,96, 66,94, 72,08, 107,55, 113,98,

118.83, 132.93, 136.55, 154.55, 155.44 and 171.40 δ, MS (EI), m / z (relative intensity) 337 (16.9), 293 (74.4). , 234 (37.5), 209 (100), [<*]²⁵D = -15.8 (c = 0.903, ethanol).

EE 200000210 Α

EXAMPLE 9 (S) -N - [[3-Fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (IV)

According to the method of Example 8, and without significant modification, the title compound, NMR 2.02, 3.04, 3.65, 3.77, 3.86, is obtained.

4.02, 4.74-4.82, 6.74, 6.91, 7.06 and 7.42 δ, CMR 23.02, 41.89, 47.65, 50.97, 66.87, 72.06, 107.48, 114.01, 118.76, 132.85,

136.48, 154.52, 155.38 and 171.34 δ, MS (CI, NH₃), m / z (ratio 10 intensity) 338 (100), 294 (86.8), [a]²⁵0 ⁼ -15.2 (c =

0.783, ethanol).

EXAMPLE 10 (±) - N - (2-Hydroxy-3-chloro) acetamide (VIIIA) (±) -1-Amino-3-chloro-2-propanol hydrochloride (V, Example 5, 47.71 g, 326.74) to a suspension of THF (381 mL) at -40 ° C is added triethylamine (36.496 g, 360.67 mmol, 1.104 eq.) followed by acetic anhydride (35.007 g, 342.90 mmol).

1.049 eq.) While maintaining the temperature <-30 ° C. The mixture is stirred at -30 ° C for 15 minutes, then allowed to warm to 20 ° C over 1 hour. The mixture is stirred at 20-25 ° C for 3 hours, then the precipitate is removed by suction filtration through a medium density frit and washed with THF (175 mL). The filtrate is concentrated under reduced pressure and toluene (195 mL) is added. The mixture is concentrated under reduced pressure and toluene (250 mL) is added. The mixture is concentrated under reduced pressure and toluene (250 ml), methanol (40 ml) and ethyl acetate (10 ml) are added. The mixture is cooled to -20 ° C, seeded, heptane (200 ml) is added at -3 ° C, the mixture is cooled to -33 ° C and the precipitate is collected by suction filtration, washed with heptane (100 ml) and dried. The resulting solid (44.818 g) is dissolved in toluene (250 mL) and methanol (120 mL) and concentrated under an alpha35 pressure. The mixture is cooled to -30 ° C, seeded and heptane (180 ml) is added, the precipitate is collected by vacuum filtration at -30 ° C, washed with heptane (100 ml) and a solid, m.p. = 50.1-, is obtained. 52.3 ° C. TLC (silica gel, methanol / methylene chloride (5/95), iodine chamber) R_f = 0.23 (one more polar spot was identified by NMR as 1.1% w / w t- ethyl ammonium acetate), NMR (CDCl₃) 2,03, 3,33,

3.54, 3.95, 4.73 and 6.93 δ, CMR (CDCl₃) 23,01, 43,32, 46,48,

70.72 and 172.37 S, MS (CI, NH₃), m / z (relative intensity) 154 (34), 152 (100).

EXAMPLE 11 To a solution of io (±) -glycidylacetamide (VIIIB) (±) -1-acetamido-3-chloro-2-propanol (V, Example 10, 10.344 g, 68.24 mmol) in THF (21 mL) is added at -40 A solution of potassium tert-butoxide in THF (1.0 M, 65 mL,

65 mmol, 0.95 eq.). The mixture is warmed to -20 ° C and stirred for 15 minutes, then cooled to -37 ° C and silica gel (18.5 g) is added. The solid is removed by vacuum filtration and washed with ethyl acetate (1000 mL). The filtrate is concentrated and the precipitate is removed by suction filtration. The filtrate is concentrated and heptane (50 mL) is added. The mixture is seeded, sonicated and the precipitate is collected by suction filtration, washed with heptane and dried under a stream of nitrogen to give the title compound, m.p. = 34.6-37.3 ° C, TLC (silica gel, methanol / methylene chloride (5/95), iodine chamber) R_f = 0.24, NMR 2.01, 2.59, 2.80, 3.103.13, 3.24-3.29, 3.7-3.9, 6.19 6, CMR 23.07, 40, 67, 45.19,

50.61 and 170.54 S.

EXAMPLE 12 (±) - N - [[3- (3-Fluoro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl] methyl] acetamide (X) (±) -Glycidyl Acetamide (VIIIB, Example 11, 0.1571) g, 1.365 mmol) in THF (1.63 mL) is added at -78 ° C

N-Carbomethoxy-3-fluoro-4-morpholinylaniline (IX, Preparation 2, 0.4358 g, 1.71 mmol, 1.26 eq) and lithium tert-butoxide (0.1267 g, 1.583 mmol, 1.16 eq). The reaction mixture is stirred

EE 200000210 Α at 0 to 11 ° C for 17.5 hours, after which HPLC shows (±) - N - [[3- (3-fluoro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl] methyl] acetamide 80 % yield (retention time = 0.97 min, method B, stationary phase: 4.6 x 250 mm Zorbax RX C-8 column, mobile phase: 650 ml acetonitrile, 1.85 ml triethylamine, 1.30 ml acetic acid and sufficient amount water to 1000 ml, flow rate = 3.0 ml / min, UV detection at 254 nm). The above compound is isolated in a manner known to those skilled in the art.

EXAMPLE 13 (S) -N - [[3- (3-Fluoro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl] methyl] acetamide (X)

Step A: (S) -N- (2-Hydroxy-3-chloro) acetamide (VIIIA)

According to the general method of Example 10, and without substantial modification, but starting from (S) -1-amino-3-chloro-2-propanol hydrochloride (V, Example 1), the title compound is obtained.

Step B: (S) -Glycidyl Acetamide (VIIIB)

According to the general method of Example 11, and without substantial modification, but starting from (S) -N- (2-hydroxy-3-chloro) acetamide (VIIIA, Step A), the title compound is obtained.

Step C: (S) -N - [[3- (3-Fluoro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl] methyl] acetamide (X)

According to the general method of Example 12, and without substantial modification, but starting from (S) -glycidylacetamide (VIIIB, Step B), the title compound is obtained.

EE 200000210 Α

EXAMPLE 14 (S) -1-Acetamido-2-acetoxy-3-chloropropane (VIIIC)

According to the general method of Example 3, and without substantial modification, but starting from (S) -1-amino-3-chloro-2-propanol hydrochloride (V, Example 1), the title compound is obtained.

EXAMPLE 15 (S) -1-Amino-3-chloro-2-propanol hydrochloride (S) - (V)

According to the general method of Example 5, and without substantial modification, but using (S) -1-phthalimido-3-chloro-2-propanol (S) - (IVC, Example 4), the title compound is obtained.

Scheme A

O ^ CH-Xq nh₃

X 2 -CH₂-C *^#H-CH₂-O^#

X₂-CH₂-C * H (OH) -CH₂-N = CH-X₀

<img file="EE200000210A_D0001.tif" />

(I) (II) (III) (IVA)

X₂-CH₂-C * H (OH) -CH₂-NH₃⁺

-O^#-CH2-C *^#H-CH 2 -N = CH-X₀ (V) (IVB)

Scheme B phthalimide

X ^ CHg-C ^ H-CH ^ O # C // o

X₂-CH₂-C * H (OH) -CH₂—Ν_χ

<img file="EE200000210A_D0002.tif" />

X 2 -CH₂-C * H (OH) -CH₂-NH₃⁺

<img file="EE200000210A_D0003.tif" />

(VI) (III) (IVC) (V) (IVD)

Scheme C

X 2 -CH₂-C * H (OH) -CH₂-NH3⁺ (V)

X 2 -CH₂-C * H (OH) -CH₂-NH-CO-R_n (VIIIA)

-O^#-CH2-C *^#H-CH 2 -NH-CO-R_n (VIIIB)

X 2 -CH₂-C * H (O-CO-R_n) -CH₂-NH-CO-R_n (VIIIC)

EE 200000210 Α

Scheme D ^Rok_you-NH ^c° -θ ^CH2 ^X1 (IX)

X₂-CH₂-C * H (OH) -CH₂-NH-CO-R_n or

-O^#-CH2-C *^#H-CH 2 -NH-CO-R_n or

X ^ CKg- ^ HCO-CO-R ^ -CH ^ NH-CO-RN (VIIIA) (VIIIB) (VIIIC)

R_twig-Cycle-CH₂-NH-CO-R, (X)

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Scheme Ε ^Ro_Yeah-^NH-^C0-°-^X·,

<img file="EE200000210A_D0004.tif" />

or

<img file="EE200000210A_D0005.tif" />

<img file="EE200000210A_D0006.tif" />

(IX)

CFC) (IVD) (XI) ^Rok_Sa^-Cycle“^CH2^_NH_CO_RN (X)

Scheme F

X₂-CH₂-C'H (OH) -CH₂-N = CH-X₀ or

-O^#-CH2-C *^#H-CH 2 -N = CH-X₀ +

^Rtwig^—NH-CO-O-CH3-X, (IVA) (IVB) (IX)

R_twig-cycle-CH₂-N = CH-X₀ (XII) ^Rok_you-cycle-CH₂-NH, (XIII) ^Rtwig "^cycle-CH₂-NH-CO-R_N (X)

Scheme G

X 1 -CH 2 CH (OH) -CH₂-NH₃⁺ (V) ^Roxa-NH-CO-O-CK₂-^X1 (IX) ^Roxa-ring-CH₂-NH₂ (XIII) ^Rtwig^-cycle_CH2^-NH_CO-RN (X)

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Scheme Η ^Rok_You-^{N = c}=^o (XIV)

X₂-CH₂-C * H (OH) -CH₂-NH-CO-R_n (VIIIA)

Rock-NH - ^ - OC ^ i C ^ - ^ lt-C ^ -Nn-CO-RN] (XV) ^Rox_a“^cycle_CH2^_NH~^CO_RN ®

Scheme I ^Roxa -N = C = 0

<img file="EE200000210A_D0007.tif" />

^Rtwig^_NH’^CO'^O'^C*^Ht‘^CH2'^X2^'^CH2

<img file="EE200000210A_D0008.tif" />

O

<img file="EE200000210A_D0009.tif" />

o (XIV) (IVC) (XV) (XI)

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Scheme J

The cycle is on

<img file="EE200000210A_D0010.tif" />

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