PROCESS FOR STEREOSELECTIVE SYNTHESIS OF LAMIVUDINE

• US 20100063283A1
• Filed: 11/17/2009
• Published: 03/11/2010
• Est. Priority Date: 05/18/2007
• Status: Active Grant

• Current Assignee: Feng Lv, Jinliang Li
• Original Assignee: Shanghai Acebright Pharmaceuticals Co., Ltd.
• Inventors: LV, Feng, LI, Jinliang
• Granted Patent: US 8,304,540 B2
• Time in Patent Office: Days
• US Class Current: 544/317
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 327/04 Five-membered rings
• CPC Class Codes: C07D 411/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

A process for stereoselective synthesis of lamivudine, comprising (a) glycosylation of compounds of formula (I) and cytosine or protected cytosine, separating the resulting products by crystallization to afford intermediates of formula (II); (b) removing the protecting groups of intermediates of formula (II) to obtain lamivudine.

Claims

1. A process for stereoselective synthesis of Lamivudine, comprising the following steps:

(a) performing a glycosylation reaction between the compound of formula (I) and cytosine or protected cytosine, and separating the reaction product by recrystallization to obtain the intermediate of formula (II); and

(b) deprotecting the intermediate of formula (II) to obtain Lamivudine,

wherein the reaction scheme is as follows;

wherein R₁ is a hydroxyl protecting group containing a chiral center, L is a leaving group; and

R₂ is a hydrogen or an amino protecting group.

2. The process for stereoselective synthesis of Lamivudine according to claim 1, wherein the preparation method of the compound of formula (I) is as follows:

the chiral auxiliary menthol is acylated by triphosgene to give L-menthol chloroformate, which is reacted with 1,2-isopropylidene protected glycerol, and then hydrolyzed to deprotect 1,2-isopropylidene;

the resulting product is oxidized by sodium periodate, and condensed with 1,4-dihydroxy-2,5-dithiane to give an intermediate of formula (VIII) of high optical purity; and

a hydroxyl at position 5 of the intermediate of formula (VIII) is substituted by chlorine to give a compound of formula (III), which belongs to the compound of formula (I);

the reaction scheme is as follows;

wherein X is Cl or Br.

3. The process for stereoselective synthesis of Lamivudine according to claim 1, wherein the preparation method of the compound of formula (I) may also be as follows:

a chiral compound of formula (IX) reported in WO95/29174 is used as a starting material, and methyl etherificated at 5-hydroxy, and then reduced to give the intermediate of formula (X), and then a chiral auxiliary is introduced to the hydroxy at position 2 of the intermediate of formula (X) to obtain the compound of formula (I);

the reaction scheme is as follows;

4. The process for stereoselective synthesis of Lamivudine according to claim 3, wherein the said method for introducing a chiral auxiliary comprises esterificating the acyl compound containing the chiral auxiliary with the intermediate of formula (X).

5. The process for stereoselective synthesis of Lamivudine according to claim 4, wherein the acyl compounds containing the chiral auxiliary is one of L-menthol formylchloride, (S)-naproxenoyl and (R)-methyl mandeloyl chloride.

6. The process for stereoselective synthesis of Lamivudine according to claim 4, wherein the acyl compound containing the chiral auxiliary is L-menthol formylchloride.

7. The process for stereoselective synthesis of Lamivudine according to claim 3, wherein the intermediate of formula (IV) for chiral control resulted form the compound of formula (X) is transformed to a compound of formula (V), which then undergoes a glycosylation reaction with protected cytosine, and the reaction scheme is as follows:

8. The process for stereoselective synthesis of Lamivudine according to claim 1, wherein R₁ is L-mentholformyl.

9. The process for stereoselective synthesis of Lamivudine according to claim 1, wherein R₂ is hydrogen or acetyl.

10. The process for stereoselective synthesis of Lamivudine according to claim 1, wherein L is methoxy or halogen or acetate group.

11. The process for stereoselective synthesis of Lamivudine according to claim 1, wherein step (a) can be described as follows:

cytosine or 4-amino protected cytosine is reacted with hexamethyldisilazane to give silylated 4-amino protected cytosine;

which is then reacted with the compound of formula (I) at 10-80°

C. for 1-20 hours;

finally the resulting glycosylated product is separated by recrystallization to give 2R,5S-intermediate of formula (II) of high optical purity.

12. The process for stereoselective synthesis of Lamivudine according to claim 11, wherein the 4-amino protected cytosine is N⁴-acetylcytosine.

13. The process for stereoselective synthesis of Lamivudine according to claim 1, 8, 9, 10 or 11, wherein step (b) can be described as follows:

the intermediate of formula (II) from step (a) is hydrolyzed by a base, and forms a salt with an organic acid, then the salt precipitates from water and finally the water insoluble salt is neutralized by an organic base to give Lamivudine.

14. The process for stereoselective synthesis of Lamivudine according to claim 13, wherein organic acid is p-nitrobenzoic acid.

15. The process for stereoselective synthesis of Lamivudine according to claim 1, wherein the synthetic scheme is as follows: