Asymetric synthesis of (s)-(-)-6-chloro-4-cyclopropyl-3,4-dihydro-4-/(2-pyridyl)ethynyl/-2(1h)-quinazoline

Ovaj the subject of the u-ties of all the U.s. Serial br. 07/991,164, podnijetim 16. prosinca 1992, Merck predmetima 19043 s 19060.

Retrovirus labeled as a human imunodeficijentni virus (HIV) is a etiološki agens complex bolesti koja obuhvaća progresivnu destrukciju imunog of the system (the syndrome stečene imunodeficijencije; SIDA (francuski title on hiv / AIDS (acquired immune deficiency syndrome) (anglosaksonski name)) i degeneraciju centralnog i perifernog nervnog of the system. Ovaj virus ranije bio poznat kao LAV, HTLV-III, or ARV. Opća characterization of replication retrovirusa the reverzna transkripcija RNK-genome viral kodiranom reverznom transkriptazom to get the DNA copies of the HIV-sekvenci, zahtjevani stupanj u virusnoj replikaciji. Poznato je da su to one spojevi inhibitori reverzne transkriptaze i, to the su-efikasna means of a u tretiranju SIDE of the i similar bolesti, in the pr., kao što the azidotimidin or AZT.

Ovaj of the invention, the relationship of the poboljšani postupak for sintezu of SIDU antivirusnog of L-738, 372, koji is hiralni the slijedeće the chemical structure of, 10:

<img file="HRP940906A2_D0001.tif" />

Supstituirani hinazolin L-738,372 is izuzetno jak inhibitor HIV infection reverzne transkriptaze. Ova the activity of the spojeva ranks it korisnim x tretiranju you spriječavanju SIDE. Ovaj invention describes a poboljšanu sintezu ovog at the splice.

Ovaj invention describes novu reakciju acetilida we cikličnim N-aciliranim ketiminom. Postoji opći nedostatak ranije of the literature on the asimetričnoj adiciji acetilidnih nukleofila, naročito on the imin products, kao što this is just in case u ovom invention.

Jedine srodne hiralne acetilidne adicije su has been in the aldehide. Mukaiyama (Chemistry Letters, 447 (1979)), the objavio adiciju acetilida the aldehidne substrate, the u prisustvu diaminskog hiralnog modifikatora. Asimetričnu adiciju diak inilcink reagenasa the aldehide u malom enantiomemom the height of the opisao the Soai (Joumal of the Chemical Society, Perkin Transactions 1, 937 (1990)). Most recently, corey August is objavio asimetričnu adiciju acetilida the aldehide, kataliziranu pomoću hiralnih oksazaborolidina (Abstract (s, a 33-ći to the National Organic Chemistry Symposium, 13-17, 1993, Bozeman, Montana, Figure 21). U ovom invention, the substrate is reliable, u tome što the acelilid adiran of the cyclic N-acilirani ketimin prije care of the free aldehyde.

Tomioka /Tetrahedron Letters, 32, 3095 (1991); Tetrahedron Letters 3_lm 6681 (1990); Synthesis 541 (1990), and it is objavio hiralnu adiciju alkyl of i vinyl of litija (whether or not acetilida) in a relatively non-coated acilirane aldimine u prisustvu hiralnih amino-etara. The Amino ethers do not funkcioniraju efikasno u ovom postupku.

Upotreba alkaloida (uključujući cinhona alkaloida hinin i dihidrohinin u asimetričnoj synthesis, released from the side of H. Wyberg, the Asymmetric Catalvsis by the Alkaloids, u-E, L-Elie 1 (The Products). Topics and Stereochemistry, Vol. 16, Wiley and Sons, p. 87-129 i of the side Blaser s (Chemistry Reviews, 92, 935 (1992)). Nikakva ranija city of hiralnu adiciju acetilida to the cyclic ketimine nije published.

Ovaj of the invention, the relationship of the new postupak for asimetričnu sintezu at the splice 10, the through hiralne adicije of lithium 2-piridil acetilida N¹zaštićeni hinazolinon of the structure of 2,

<img file="HRP940906A2_D0002.tif" />

gdje R zaštitna group. The reaction of the copies of the below hiralnim modificirajućim utjecajem lithium alkoksida hinina you dihidrohinina i zatim uklanjanjem zaštitne material groups.

The new postupak prema ovom invention is presented to the slijedećom reakcijskom shemom:

<img file="HRP940906A2_D0003.tif" />

<img file="HRP940906A2_D0004.tif" />

<img file="HRP940906A2_D0005.tif" />

gdje R zaštitna group, a, and R is defined as -CH₂A s A

i) a phenyl nesupstituiran you supstituiran jednom ili higher than that puta sa, a, B, gdje has a, B, C_{M M M M}alkyl, (C_{M M M M}alkoksi, or halogen;

ii) naftil nesupstituiran you supstituiran jednom ili higher than that puta s-B; or iii) antril nesupstituiran you supstituiran jednom ili higher than that puta s-B.

Ovaj of the invention, the relationship of the postupak for dobijanje spojeva of the structural formula:

<img file="HRP940906A2_D0006.tif" />

R.

gdje R -CH)₂A s A

i) a phenyl nesupstituiran you supstituiran jednom ili higher than that puta sa, a, B, gdje B Ci_₄alkyl, Cj^alkoksi, or halogen;

ii) naftil nesupstituiran you supstituiran jednom ili higher than that puta s-B; or iii) antril nesupstituiran you supstituiran jednom ili higher than that puta s-B;

that postupak obuhvaća stupnjeve:

(a) the mješanje one equivalent of 2-etinilpiridina all the eye jednim terms hiralnog modifikatora odabranog of the hinina you dihidrohinina u otapalu koji sadrži etarsko otapalo odabran from THF, diethyl ether, 1,2-dimetoksietana, or dioksana a specified etarsko otapalo is opciono pomješano we toluolom, heksanima or other capture polarnim otapalima;

(b) the mješanje to the setting, in between the eye of -70° c to the eye at -20°C for two or higher ekvivalenata be n-butyl, litija on lithium heksametildisilazana;

(c) the mješanje to the setting, from 0.5 to 1.0 ekvivalenata spojeva of the structural formula________________

<img file="HRP940906A2_D0007.tif" />

in the eye of -50° c to 0°C, and

(c) a održavanje dobijene smjese in the eye of -40°C up to the eye as 0°C, 2-24 sata;

(d) what is the purpose of the dobija the formula I.

Važan intermedijar u postupku prema ovom the invention of the digital camera alkoksidna salt hiralnog modifikatora. Intermedijar is an formulom A slijedeće of the structure:

<img file="HRP940906A2_D0008.tif" />

Hinin R^=CH—CH₂

Dihidrohinin ^R1=^CH2'^CH₃

U jednoj building postupak obuhvaća treatment smjese hiralnog modifikatora kao što the hinin or dihidrohinin, i 2etinilpiridina 8, x etarskom otapalu kao što is THF, diethyl etar or 1,2-dimethoxyethane x smjesi we toluolom you heksanima, on the other, not polarnim otapalima in the eye of -70°C to the eye at -20°C for sa-n-butyl litijem on lithium heksametil-disilazanom, a zatim tretiranjem s-7 is in the eye of -50°C to 0°C, and the a zatim zagrijavanjem to the eye of -40°C to 0°C, i održavanjem at the toj the temperature of the eye

2-24 sati. The reaction of the copies at a concentration of alkina, the u power of 5 to 300 mM.

Manja polama otapala upotrcbljcna u a prema ovom invention, obuhvaćaju, or nisu ograničeni to, diethyl etar, benzol, n-heksan, n-octane, toluol i of the cyclohexane.

Halogen obuhvaća bromine, chlorine i, iodine.

Prijavioci su pronašli to adicija lithium acetilida 7 u prisustvu lithium alkoksida cinhona alkaloida protječe we asimetričnom indukcijom. Desired enantiomer is formira u is the height of the kada is a upotrebljen hinin, dihidrohinin, or cinhonidin. Pseudoenantiomemi spojevi hinidin i dihidrohinidin favoriziraju to the other enantiomer. Upotreba magnesium, or sodium umjesto litija it gives a lot nižu selection i give obrnuti smisao selectivity. Ees of the second test tipovi liganada gave the su a little, how hr is delivering uopće enantioselektivnost. A global analysis of the chemical prinosa there are generally nepromijenjena prisustvom liganada, i oni su jednoobrazno high. The parametoksibenzil zaštitu grupu (PMB) the results of the su sakupljeni x Table of Primjera 1.

U najpogodnijem postupku prema ovom the invention, the structural formula:

<img file="HRP940906A2_D0009.tif" />

dobija se postupkom koji obuhvaća stupnjeve:

(a) the mješanje x otapalu koji obuhvaća THF, the eye of one equivalent of 2-etinilpiridina all the eye jednim terms hiralnog modifikatora hinina;

(b) the hlađenje smjese up between the eye of -40°C, the i, the eye of -60°C;

(c) as dodavanje to the tome. the eye of the 2.0 ekvivalenata n-butyl, litija;

(d) (zagrijavanje reaction smjese to the eye of -25°C.;

(e) as dodavanje between the eye of the 0.5 to 1.0 ekvivalenata hinazolinona.

<img file="HRP940906A2_D0010.tif" />

f) mješanje dobijene smjese in the eye of -25°C and the eye 16 of the sati, the show is dobija the formula II.

Dobijanje polaznog material 7, the i uklanjanje zaštitne material groups hr detailed presentation of the u Primjerima koji slijede i run a u suglasnosti s slijedećom reakcijskom shemom.

NC^ ^ci BCI3, GaCI₃ toluol. 100°C

<img file="HRP940906A2_D0011.tif" />

<img file="HRP940906A2_D0012.tif" />

1) teuOK

THF, 25°C

2) HCI

<img file="HRP940906A2_D0013.tif" />

KOCN

AcOH-H₂On the

<img file="HRP940906A2_D0014.tif" />

H

R,-x, x=halogen, methanesulphonate trifluormetansulfonat—~

<img file="HRP940906A2_D0015.tif" />

<img file="HRP940906A2_D0016.tif" />

R

<img file="HRP940906A2_D0017.tif" />

<img file="HRP940906A2_D0018.tif" />

H

The 10 korisno u inhibiranju of the PEOPLE reverzne transkriptaze, sprječavanju you tretiranju infection human imunodeficijentnim virus (HIV) i tretiranju konzekventnih patoloških the status of kao što the SIDA. Treatment SIDE you sprječavanje or treatment of infection HlV-infection was defined so as to obuhvaća, or a da nije ograničeno only, treatment to the broad authority of the status of HIV infection; the SIDE, the ARC (SIDI srodan of the complex), i simptomatično i asimptomatično, i is the index ili potencijalno izlaganje HIV. The primjer, spojevi prema ovom the invention of su korisni u tretiranju infection HlV-infection poslije sumnje the prošlo izlaganje HIV, e.g., transfuzijom blood izmjenom tjelesnih tekućina, ujeda, as a result of accidental uboda iglom, or izlaganja blood pacijenta the flow of the operation.

A special preimućstvo at the splice 10 is in its where the inhibicija protiv aids-related reverzne transkriptaze rezistentne to the other of the antivirusna assets, kao što su 3-(/(a 4.7-diklor-l,3-benzoksazol-2-yl)methyl/-amino)-5-ethyl-6-methyl-pyridine-2(lH)-one; or 3/2-(l,3-benzoksazol-2-yl)ethyl/-5-ethyl-6-methyl-pyridine-2(lH)-one; or AZT.

The 10 također korisno u dobijanju i izvođenju the analysis of the pretraživanja for antivirusna at the splice. The primjer, it is korisno for low-mutanata enzima, a koji su a great asset to the pretraživanje snažnijih antivirusnih spojeva. Osim on the other hand, it is korisno u uspostavljanju you određivanju position of the vezivanja other antivirusnih sredstava of the PEOPLE reverznu transkriptazu, per pr., konkurentnom inhibicijom.

The following sources svrhe, the 10 men that primjeni oral, parenteralno (uključujući subkutane injections, thermal disinfection, intramuskulame, intrastemalne injections or infuzione techniques), inhalacionim answer, or rektalno (in formulacijama jediničnih box koje sadrže of the conventional non-toxic farmaceutski prihvatljive nosače, ađuvante i prenosioce.

The 10 men that primjeni the oral code of the people of the u power specifications of from 0.1 to 100 mg/kg tjelesne težine u podjeljenim dozama. Championship the dominion of the dose is 0.1 to 10 mg/kg tjelesne težine oral x podjeljenim dozama. The second championship the dominion of the dose is 0.1 to 20 mg/kg tjelesne težine oral x podjeljenim dozama. Međutim, it is clear that the specifičan level of the cans i frekvencija dosage for svakog određenog pacijenta men mjenjati i is that the if the zavisiti from različitih faktora uključujući activity specifičnog at the splice while it is upotrebljeno i metaboličke the stability of the i dužine djelovanja solid at the splice, the age tjelesne težine, općeg healthcare center poles, ishranjenosti, the way i weather primjene, brzine izlučivanja, smjese lijekova, ozbiljnosti određenog the situation, i domaćina koji podliježe therapy.

Polazni materijal

Pobijanje ketone 3

X dry trogrli of the balloon 50 to 1 šaržira the 10.6 i suhog toluola (KF &lt;100 pg/ml) sd hlađenje ice-MeOH. U ovu otopinu se dodaje pine triklorid u, the office of the gas (1.42 kg) držeći temperaturu ispod 7°C;

U trogrli of the balloon, snabdjeven we cijevi for uvođenje nitrogen, i zračnom mješalicom, dodaje the dry toluol (10.2 to 1, KF &lt; 100 pg/ml). U ovu otopinu se dodaje 2,214 kg of 4-chlorine-aniline. Smjesa the zagrijava to 55°C, what is the purpose of the dobija homogeneous otopina. Otopina to be cooled to about 10-20°C.

Otopina 4-kloranilina sc prebacuje u lijevak the ukapavanjc 10 1 i i dodaje se u otopinu pine trifluorida, održavajući temperaturu ispod 10°C, the sa kupaonom suhog no ice-acetone.

Suspension is mješa the sobnoj temperature for 30 minutes. U ovu suspenziju se dodaje 4-klorbutironitril (991 ml, 11 mol), u-jednom course, pod atmosferom of nitrogen.

Poslije 30 minutes mješanja u smjesu se dodaje gallium triklorid (2.324 kg) pod atmosferom of nitrogen. Created egzotermna the podiže the temperature of the smjese to the eye, of 40°C. Otopina the miješa at 100°C for 5 sati, the show is dobija dvofazna reaction mass smjesa (70-75% prinos). Otopina it is cooled to 40°C.

Ova otopina the razblaži we toluolom (3 in 1). i destiliranom lines (11 to 1). Odvoji the organic phase. the pH of the vodenog layer is about 0.2. The organic layer it is cleaned all destiliranom lines (11 to 1) in order to uklonio of 4-chloroaniline. The final organic layer (25 to 1), the sadržavao, 70 mg/ml of the product (1800 g; 72% of the prinos). Otopina to be concentrated under the smanjenim the pressure of what it is dobija 16, the 1, 113 mg/ml (0.5 M), otopina of the product (KF &lt; 170 pg/ml).

Pobijanje 4

U cilindričnu bocu from 50 to 1, snabdjevenu we termoelementom, cijevi for uvođenje them, i zračnom mješalicom, dodaje se otopina of the 4-chlorine-2-(4-chlorine-p-oksobutil)aniline x smjesi toluola i in THF (4.99 1 a, koji sadrži polazni materijal 1.2 kg of u-toluolu 3,75 1 THF 1.25 to 1), dry THF (8.95 1) in dry toluol (6.45 to 1. Ova otopina it is cooled down to 0-5°C., the U ovu otopinu se dodaje To the t-butoksid (672 g; 5.99 mol) under atmosferom of nitrogen. Smjesa the zagrija to room temperature (20-25°C). i miješa 1 satellite. Analizom pomoću HPLC method has been shown to polazni materijal ispod 0.5% A. Dodaje water (16 to 1) is an i sodium chloride (2.6 kg), i smjesa the miješa at 25°C for 20 minutes. The organic layer is vented i dried destilacijom, for what it is dobija otopina (7.3 to 1, and 81 v/v% toluola/ 19 v/v% THF) željenog ciklopropil ketone (976 g) 96.7% prinos). Having aniline to be converted into u.s. dollars according of the u odgovarajuću hidrokloridnu the salt of the slijedeći način. U cilindričnu bocu from 50 to 1, snabdjevenu we termoelementom, cijevi for uvođenje of nitrogen, i zračnom mješalicom, dodaje se otopina of the 4-chlorine-2-cikloprpilkarbonilanilina x toluolu'THF. Dodaje se još suhog toluola (13.2 1) i suhog THF (15.6). U ovu otopinu at 25°C dodaje klorovodična kiselina (2.55 M HC1 u, THF, 2.31 to 1), i smjesa be ostavi that old, at 25°C for 1 sat. Smjesa the tada cooled down to 05°C. i ostavi da old 1 satellite. Šarža the profiltrira i is cleaned it s-2-8.5 1 heksana. Tough supstanca to be dried u vacuum sušnici at 30-35°C, what is the purpose of the dobija 1.071 kg (93%) of hidrokloridne of salt.

Pobijanje 5

U cilindričnu bocu from 100 to 1, and the snabdjevenu we termoelementom, cijevi for uvođenje of nitrogen, i zračnom mješalicom, dodaje se octena kiselina (23.1 to 1). i cooled to 15°C. the U-obrocima se dodaje 4-chlorine-2-ciklopropilkarbonilanilin hydrochloride. U dobijenu smjesu at 15-20°C dodaje se otopina KOCN (2.52 M; 964.7 pa 4.73 to 1 of water). Dobija is a homogeneous otopina. Smjesa the miješa at 25°C for 1 sat. Dodaje the water 46.0 1) i smjesa be ostavi that old, at 25°C 1 sat, zatim to be cooled down to 05°C. Profiltriraju the firm supstance, whilst the s-2-a 20 to 1 water (5-10°C). i drought u vacuum sušnici at 30-35°C, what is the purpose of the dobija 926 g (93% of the prinos).

Pobijanje 7 (R = 4-metoksibenzil)

Nal (10.2 g, 68.03 mmola), the dried zagrijavanjem up to 80°C under high vacuum for 4 sata.

Hinazolinon of 5 (10 g, 45. 35 mmola), the dried azeotropno we toluolom i zatim se otopi u PMF (80 ml). Reaction mass of posuda is cooled to 0°C, the i i dodaje se LHMPS (55 ml, 55.0 mmola), održavajući temperaturu ispod +5°C; Poslije between 15 and 30 minutes, dodaje 4-metoksibenzil chloride for 6 and 8 ml, 59.0 mmola), a zatim Nal (10.2 g, 68.03 mmola). Tada se uklanja kupaona the hlađenje i ostavi is that the zagrije to room temperature. The reaction of the zagrijava of up to 60°C, i ostavi to the old, over the nights in the 60°C. S-about 2% of polaznog material (5) of the prisutnog, reaction mass of smjesa is cooled to room temperature, concentrated to be the u a vacuum, i is a condensed form of the ispere we acetonitrilom (2 x 50 ml). Acetonictirl (140 ml) of the tada dodaje u in concentrate, mg mješanje, a zatim se lagano dodaje water (70 ml). Pobijena smjesa be ostavi that miješa 10 minutes i the product is filtered. The cake is pere s acetonitrilom-line (75 ml, 2:1). i dried the u in the vacuum of what is to be dobija 7, 11.3 g (73%).

Pobijanje 7 (R = 9-antrilmetil)

X dry bulb all okruglim to the bottom of the 75 litara, snabdjeven we lijevkom for dodavanje from 5 to 1, and the termoelementom, cijevi for uvođenje nitrogen, šaržira is 8 to 1, the suhog THF. Air-x reakcijskoj posudi se potpuno conversion all three of the vacuum prečišćavanja s a nitrogen gas. Dodaje se uz miješanje 870 gram of 6-chlorine-4-ciklopropilhinazolin-2(lH)-it (96 weight %; 3,79 mol). U suspenziju se dodaje 2.30 1 suhog Ν,Ν-suction i još 8 1 suhog THF. U suspenziju the lagano dodaje otopina of lithium bis (trimetilsilil)amide catalyst u-tetrahydrofuran (1 M; 4.28 to 1), održavajući temperaturu batches ispod 27°C, the Mail is added to 900 mt otopine, reaction mass of smjesa it became homogeneous. U do vrijeme is to stop the adicija i of the reaction mass smjesa the miješa at 25°C for 5 minutes. Adicija the sc to be updated by održavajući temperaturu ispod 27°C, U is the flow adicijc, reaction mass of smjesa station ponovo heterogeneous. The mail is smjesa mješana for 30 minutes at sobnoj a temperature of (the eye 23°C), dodaju the sodium-jodid (743 g) 4,96 mol) n 9-klormetilantracen (965 g, 4.26 mol) (0.9 1 suhog tetrahidrofurana the upotrebljeno the ispiranje). Smjesa the miješa the sobnoj temperature for 24 sata. U reakcijsku smjesu se dodaje 20 1 prethodno ohlađene water (5°C) i 7 to 1 water to sobnoj temperature održavajući temperaturu batches ispod 22°C, Dobijena smjesa the miješa the sobnoj temperature for 3 sata. Taiog the sakupija filtracijom, is cleaned to be jedno of the other s 10 to 1 of water i i 2 x, 5 1 of methanol. Cheese materijal is suspendira ml methanol (13 to 1), on the sobnoj a temperature of 4 sata profiltrira it is, is cleaned it s-a 3 1 of methanol, i dried u vacuum sušnici at 35°C in sa čišćenjem of nitrogen, in what is dobija 1,44 kg sirovog of the product. Cheese product, suspendira s-butyl chloride (13 in 1) on the sobnoj a temperature of 5.5 sati, profiltrira is is cleaned the all 4, the 1-butyl chloride i s drought the u sušnici at 37°C under a kućnim vacuum ig ispiranje nitrogen gas x the flow of the nights, when the show is dobija 1.24 kg of the product. The product is miješa x 13 1 methanol sobnoj temperature for 6 sati i use the profiltriraju, whilst the s-4 1 of methanol, the i drought u sušnici at 37°C under a kućnim vacuum i ispiranjem nitrogen gas x the flow of the nights, when the show is dobija 1.21 kg (85% of the prinos) of the product.

Primjer 1

Cl

<img file="HRP940906A2_D0019.tif" />

<img file="HRP940906A2_D0020.tif" />

2-Etinilpiridm (76 μΐ, 77 mg, 0.75 mmola) i dihidrohinin (261 mg, 0.80 mmola), the otope of a u suhom tetrahydrofuran (5 ml) under atmosferom suhog of nitrogen. Otopina to be cooled down to -65°C, i may be treated to be ukapavanjem s -, or n-butyl-litijem (1.0 ml, 1.6 M in 5 otopine x heksanima, 1.6 mmola). Otopina the zatim zagrijava of up to -45°C, u is the flow period of 60 minutes. Dodaju the heksani (4 ml), a zatim to 1 ml of the dodatnog tetrahidrofurana. A robust hinazolinon of 7 (170 mg, 0.50 mmola), the tada dodaje, i dobijena suspension is zagrijava to -15°C. Poslije mješanja 3.5 sati at -15°c. the reaction mass smjesa se ugasi ml of 1 N HCI. Smjesa the raspodjeljuje between CH₂C1₂ i of 1 N HCI. If the layer to be packaged in a self-re-s-CH₂C1₂. Welded carbon slojevi to be dry over the MgSO₄ i otapalo the uparava under the smanjenim the pressure of what it is dobija bijela pjena (212 mg). The HPLC analysis of the 10 (Sumichiral OA 4700 column 4 x 250 mm; mobile phase 96:4:0.2 heksani/ethanol/trifluoroctena kiselina; brzina protoka

1.0 ml/min), pokazuje 9% of the preostalog 7 (18.8 min), 82.4% 9 (21.4 min), i, 7.8% second enantiomera at the splice of 9 (24.9 min) for an 83% ee x product 9.

Upotrebljavajući postupke suštinski kao što su is described in a u, the upper Primjeru, or sa različitim smjesama otapala i hiralnim 15 modifikatorima realiziraju, the results show a u slijedećoj the Table.

Table

The asymmetrical adiciia alkina, a review of

<img file="HRP940906A2_D0021.tif" />

<img file="HRP940906A2_D0022.tif" />

<img file="HRP940906A2_D0023.tif" />

<td>Odrednica</td><td>Ligand¹</td><td>ekviv.</td><td>Otapalo²</td><td>the temp. (°C)</td><td>Areas(%)</td>

<td> 1</td><td>Hinin</td><td> 1</td><td>THF</td><td> -20</td><td> 48</td>

<td> 2</td><td>Hidrohinin</td><td> 1</td><td>THF</td><td> -20</td><td> 64</td>

<td> 3</td><td>Hinidin</td><td> 1</td><td>THF</td><td> -20</td><td> -55</td>

<td> 4</td><td>Hidrohinidin</td><td> 1</td><td>THF</td><td> -15</td><td> -39</td>

<td> 5</td><td>Cinhonidin</td><td> 1</td><td>THF</td><td>-30 to-10 in</td><td> 26</td>

<td> 6</td><td>Hinin</td><td> 0.25</td><td>THF</td><td> -20</td><td> 17</td>

<td> 7</td><td>Hinin</td><td> 1.5</td><td>THF</td><td> -20</td><td> 41</td>

<td> 8</td><td>Hinin</td><td> 1</td><td>My₂On the</td><td> 20</td><td> 36</td>

<td> 9</td><td>Hinin</td><td> 1</td><td>Toluol</td><td> 20</td><td> 28</td>

<td> 10</td><td>Hidrohinin</td><td> 1</td><td>THF/te-tol (1:1)⁴</td><td> -15</td><td> 75</td>

<td> 11</td><td>Hidrohinin</td><td> 1</td><td>The te-tol/THF (5:1)</td><td> -15</td><td> 66</td>

<td> 12</td><td>Hidrohinin</td><td> 1</td><td>THF/Heks (6:4)</td><td> -15</td><td> 83</td>

<td> 13</td><td>Hinin (Mg)</td><td> 1</td><td>THF</td><td> 50</td><td> -12</td>

<td> 14</td><td>Hinin (To)</td><td> 1</td><td>THF/Heks (1:1)⁵</td><td> -20</td><td> -9</td>

<td> 15</td><td>Ephedrine</td><td> 1</td><td>THF</td><td> -25</td><td> 6</td>

<td> 16</td><td>N-Methyl-</td><td></td><td></td><td></td><td></td>

<td></td><td>prolinol</td><td> 1</td><td>THF</td><td> -20</td><td> 0</td>

<td> 17</td><td>Hidrohinin 4-methyl- 2-</td><td></td><td></td><td></td>

<td></td><td>hinolil etar 1</td><td>THF</td><td> -20</td><td> 0</td>

<td> 18</td><td>Spartein 1</td><td>THF</td><td> -15</td><td> 0</td>

'Added to the dovoljno of n-Buli (EtMgBr odrednica 13, Wa (reguş latory oversight of sudan)₂ odrednica 14) in order to deprotonizirao alkin i was koja ligand group.

²The reaction of su izvođene on a 75 mM x alkinu ukoliko nije drugačije to the foregoing.

³Deprotonizacija i adicija iraina pots at -75 to -45°C, a zatim se smjesa zagrijava up to the specified temperature.

⁴The same ee at 75 mM and i, and 38 mM).

⁵Reakcjja we nižim prinosom.

Primjer 2

<img file="HRP940906A2_D0024.tif" />

1)FHnin - F

2) of the (+)-CSA

Cilindrična posuda 50 1 snabdjevena sa kupaonom the hlađenje, linijom the ispiranje nitrogen, i lijevkom for dodavanje, ispere it is all dry THF s šaržira it is all dry THF (21.0 to 1. Otopina was dried to 23 of the (gg H20/'ml pumpanjem kroz kolonu 1 1 4A molecular sieves, the doc is nitrogen propušta u posudu. Dodaju the hinin (1278 g) i, 2-etinilpiridin (osušen screen vent cross, 372 ml). i otopina the šaržira ml of n-BuLi (4.55 To 1 1.72 M x heksanima) i otopina koja se miješa to be cooled to -52°. Adicija of n-BuLi to be the copies of u in the stream for 60 minutes, at what temperature to grow up to -38°C. Otopina the tada zagrijava of up to 25°C, u is the flow for 60 minutes. Dodaje se u jednom meal replacements, crisp hinazolinon (1080 g), a, i, dobijena suspension is miješa at -25° C. Poslije 14 sati suspension is zagrije to -20°C, Lagano se kroz lijevak for dodavanje dodaje 2 M M M M H H₂They ARE₄ (10 to 1), što izaziva zagrijavanje by up to 5°C, the Smjesa the razblažuje s-10 1 zasićene give otopine NaCl i prebacuje u cilindričnu posudu from 100 to 1, and the ispere the ht 6.6 to 1 THF. Dodaje the zasićena led otopina NaCl (10 to 1), smjesa the miješa, i zatim se ostavi that staloži i odvoje the slojevi. The organic layer was sadržavao 1146 g, 86.5% at 94% of the surface of the čistoće (220 nm) of the i, &gt; 97% ee. The organic layer is dried over MgSO₄ iprofiltrira. Zapremnina se smanjuje 15 1 vacuum destilacijom Otopina koja se miješa may be treated to be s - (+)- kamforsulfonskom kiselinom (611 g) to what dobija, the first is clear otopina, zatim crystallization poslije 10 minutes. Poslije 14 sati, a salt of the product is sakuplja filtracijom, pere se sa malom zapremninom THF i, it is dried at 37°C under a vacuum ig ispiranje nitrogen. Prinos THF solvata is a bio-1823 g + 88,6 masenih % of salt, 83.8% prinos. Čistoća was 99% of the surface area; the ee was &gt; 98%.

Uklanjanje zaštitine material groups

Pobijanie 10 (R = p-metoksibenzil)

A quantity of 70 mg (0.16 mmola) 9 may be treated to s-otopinom of 3.2 ml of trifluoroctene kiseline a 4.5 ml of methylene chloride for 96 sati under the argonom. Otapala the uparavaju i ostatak the raspodjeljuje between CHC1₃ i to 10% by weight/zap-controlled otopine NaHCO₃- The organic layer is dried over of The₂They ARE₄, out the i uparava and 38 mg of amorphous firm supstance (73%).

NMR (CPC1₃): δ 0.58-0.72 (m, IH), 0.73-0.90 (m, 2H), 0.91-1.04 (m, IH), 1.47-1.60 (m, IH), 5.85 (s, IH), 6.78 (d, J=8 Hz, IH), 7.15 (dd, J=8.2 Hz, IH), 7.20-7.28 (m, IH), 7.39 (d, J=8 Hz, IH), 7.25 (d, J=2HZ, IH), 7.63 (td, J=8 AND 2HZ, IH), 8.58 (d, J=4 Hz, IH), 9.13 (s, IH).

Pobijanje 10 (R = 9-antrilmetil)

<img file="HRP940906A2_D0025.tif" />

FW = 746.33 (C43H₄₀BET₃On the₅With the

<img file="HRP940906A2_D0026.tif" />

FW = 323.78 (C₁₈H₁₄BET₃On

Pobijanje 10 (R = 9-antrilmetil)

U trogli of the balloon all okruglim to the bottom of the 12 to 1 snabdjeven we cijevi for uvođenje nitrogen, termoelementom, slobodnom mješalicom, dodaje se anizol (1.8 to 1). i trifluoroctena kiselina (2 in 1). Smjesa are cooled to 12-13°C. U-ovu otopinu se dodaje salt of (+)-kamforsulfonske kiseline (1.7 kg), držeći temperaturu batches ispod 25°C, i ispiranjem we trifluoroctenom kiselinom (0.55 to 1).

Smjesa station of the homogeneous. Otopina the miješa the sobnoj a temperature of 23 sati. Polazni materijal should be that of the buddha ispod 1% određeno pomoću HPLC poslije 23 sati. Smjesa are talking the u a vacuum ispod 50°C (Ostatak the otapa u-ethyl acetatu (8.5 to 1). Otopina you may be treated all zasićenom vodenom otopinom natrijevog chloride (6.2 1), a zatim to be cooled to 13°C. the X smjesu se dodaje 10 weight % natrijevog hydroxide solution (eye is 6 to 1), the održavajući temperaturu ispod 30°C. the pH of the vodenog layer of the bio-8.5. The organic layer is vented, the i is cleaned the all zasićenom vodenom otopinom natrijevog chloride (3 to 1). The extract (12 to 1), the concentrated u vacuum i ostatak the otapa x metanolu (6.81). Dodaje water (140 ml) i smjesa the miješa the sobnoj temperature through the nights. Talog is profiltrira i is cleaned it is all of 98% methanol (3.4 to 1). Filtrate i otopina of the washing of the spajaju i podvrgavaju chromatography on a resin /AB 206; 171 resins, eluiranjem s-2 v/v % of water, the u metanolu/. The fractions of the koje sadrže 10 se spajaju, koncentriraju u in a vacuum, i otapaju u-ethyl acetatu (6.8 to 1). Otopina the miješa the sobnoj temperature through the nights. Dobijeni use the profiltriraju s peru se jedno by one, all by weight of ethyl acetatom (1 1) i 1:1 smjesom by weight of ethyl acetate, the i heksana (3 in 1). The crystals are dry at 40°C, u sušnici, for what it is dobija 545 g of 10 as ethyl acetate solvat. The crystals (540 g), suspendiraju u-lead (12 to 1). i zagrijavaju the his of up to about 100°C. to uklonilo the eye of a 4 to 1 water to destilacijom. Smjesa is cooled down to room temperature. Use the profiltriraju i, whilst the s-pipe (2 to 1). i osuše under the strujom of nitrogen, in what is dobija 532 g 10 (R = 9antrilmetil)monohydrate (78% of the prinos).