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1. (WO2010072742) PROCESSES AND INTERMEDIATES FOR PREPARING A MACROCYCLIC PROTEASE INHIBITOR OF HCV
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Claims

A process for preparing a compound of formula (VIII), starting from an cinchonidine salt (XXa), which is reacted with N-methyl-hexenamine (NMHA) (XIX) in an amide-forming reaction to yield the bicyclic lactone amide (XVIII), in which the lactone group is opened to yield the desired product (VIII), as illustrated in the scheme below, wherein R1 is Ci_4alkyl:



(XVIII)

2. The process of claim 1 wherein R1 is methyl.

3. The process of claims 1 or 2, wherein amide-forming reaction is conducted in the presence of an amide-coupling reagent in a reaction- inert solvent, optionally in the presence of a base.

4. The process of claim 3 wherein the solvent comprises halogenated hydrocarbons such as dichloromethane (DCM) or chloroform, ethers such as tetrahydrofuran (THF) or 2-methyltetrahydrofuran (MeTHF), alcohols such as methanol or ethanol, hydrocarbon solvents such as toluene or xylene, dipolar aprotic solvents such as DMF, DMA, acetonitrile, or mixtures thereof.

5. The process of claim 3 wherein the amide forming agent comprises agents such as

N-ethoxycarbonyl-2-ethoxy- 1 ,2-dihydroquinoline (EEDQ), N-isopropoxy- carbonyl-2-isopropoxy-l,2-dihydroquinoline (IIDQ), N,N,N ,Λ/"-tetramethyl-O- (7-azabenzotriazol-l-yl)uronium hexafluorophosphate (HATU), benzotriazol-1-yl- oxy-tris-pyrrolidino-phosphonium hexafluorophosphate, CDI, l-ethyl-3-(3-di- methylaminopropyl) carbodiimide (EDCI) or its hydrochloride, dicyclohexyl- carbodiimide (DCC), 1,3-diisopropylcarbodiimide, or O-benzotriazole-N,N,N',N'- tetramethyl-uronium-hexafluorophosphate (HBTU), optionally in the presence of a catalyst such as 1-hydroxybenzotriazole (HOBt) or 4-dimethylaminopyridine (DMAP).

6. The process of claim 3 wherein the optional base is a tertiary amine, such as triethylamine, N-methylmorpholine, N,N-diisopropylethylamine.

7. A process for preparing the cinchonidine salt (XXa), which is obtained from the racemic salt (XX) by crystallization:


8. The process of claim 7, wherein the racemic salt (XX) is obtained by contacting the bicyclic lactone carboxylic acid (XV) with cinchonidine:


(XV) (XX)

9. The process of claim 8, wherein a suspension of cinchonidine is added to a solution of (XV) at slightly elevated temperature and subsequently allowing the mixture to cool whereupon the desired product (XXa) crystallizes.

10. The process of claim 7 or 8, wherein (XV) is dissolved in a solvent selected from ester solvents such as ethyl acetate, and solvents for the cinchonidine supension include acetonitrile.

11. The process of claims 9 or 10, wherein the salt formation is done at a temperature of about 50 to about 700C, in particular at about 600C, and the mixture is allowed to cool to about room temperature, such as a temperature in the range from about 20 to about 25°C.

12. The process of claims 9 or 10, wherein the salt is further purified by recrystallization from an appropriate solvent or solvent mixture; or by re-slurrying in a solvent or solvent mixture.

13. The process of claim 12, wherein the solvent in the recrystallization is a

Ci_4alkanol, e.g. isopropanol, or in the re-slurrying the solvent or solvent mixture is an ethano I/water mixture such as a 5%/95% (w/w) water/ethanol mixture.

14. The cinchonidine salt of formula


(XXa)

15. The use of the chinochonidine salt (XXa) defined in claim 4, as an intermediate in the preparation of intermediate (VIII).