Selective enzymatic esterification and solvolysis of epimeric vitamin D analog and separation of the epimers

• US 8,129,173 B2
• Filed: 01/09/2003
• Issued: 03/06/2012
• Est. Priority Date: 01/10/2002
• Status: Expired due to Fees

• Current Assignee: Teva Pharmaceuticals USA, Inc. (Teva Pharmaceutical Industries Limited)
• Original Assignee: Teva Pharmaceutical Industries Limited
• Inventors: Shapiro, Evgeny, Fishman, Ayelet, Effenberger, Reinhard, Maymon, Asher, Schwartz, Anchel
• Primary Examiner(s): Skowronek, Karlheinz R
• Assistant Examiner(s): Soroush, Ali
• Application Number:
  US10/339,226
• Publication Number:
  US 20030166226A1
• Time in Patent Office: 3,344 Days
• Field of Search: 552/653, 435/280, 514/167
• US Class Current: 435/280
• CPC Class Codes: C12P 41/004 by esterification of alcohol- or thiol groups in the enantiomers or the inverse reaction
• CPC Class Codes: C12P 7/18 polyhydric

Abstract

Provided is a method of selectively enzymatically esterifying or selectively enzymatically solvolyzing epimers of analogs of vitamin D having a stereogenic center at C-24 that has a free or esterified OH group. The metod can be used, for example, for separating mixed epimers of the vitamin D analog.

Claims

1. A method of selectively enzymatically esterifying the C-24 hydroxyl group of one epimer in a mixture of C-24 epimers of a compound of general formula III or IX:

2. The method of claim 1 wherein R₁ and R₂ are both H.

3. The method of claim 1 wherein the lipase is Alcaligenes sp lipase.

4. The method of claim 2 wherein the lipase is Pseudomonas sp. lipase.

5. The method of any one of claims 1-4 wherein the lipase is fixed.

6. The method of any one of claims 1-4 wherein the lipase is free.

7. The method of claim 1 or claim 3 wherein the mixed C-24 epimers are an epimeric mixture at C-24 of [1α

,3β

,5E,7E,20R]-1,3-bis(tert-butyldimethylsiloxy)-20-(3′

-cyclo-propyl -3′

(R,S)-hydroxy-1′

-propenyl)-9,10-secopregna-5,7,10(19) -triene.

8. The method of claim 7 wherein the C-24 OH epimer selectively esterified is [1α

,3β

,5E,7E,20R]-1,3-bis(tertbutyldimethylsiloxy)-20-(3′

-cyclopropyl-3′

(R)-hydroxy-1′

-propenyl)-9,10-secopregna-5,7,10(19)-triene.

9. The method of claim 1 or claim 3 wherein the mixed epimers are an epimeric mixture at C-24 of [1α

,3β

,5Z,7E,20R]-1,3-bis(tert-butyldimethylsiloxy)-20-(3′

-cyclo-propyl -3′

(R,S)-hydroxy-1′

-propenyl)-9,10-secopregna-5,7,10(19) -triene.

10. The method of claim 9 wherein the C-24 OH epimer selectively esterified is [1α

,3β

,5Z,7E,20R]-1,3-bis(tertbutyldimethylsiloxy)-20-(3′

-cyclopropyl-3′

(R)-hydroxy-1′

-propenyl)-9,10-secopregna-5,7,10(1-9)-triene.

11. The method of any one of claims 1-4 wherein the esterifying agent is selected from the group consisting of alkyl and vinyl esters of lower alkyl carboxylic acids having 2 to 6 carbon atoms.

12. The method of claim 11 wherein the esterifying agent is selected from the group consisting of ethyl acetate, vinyl acetate, and vinyl butyrate.

13. The method of any one of claims 1-4 wherein the organic solvent is a linear or branched alkane having up to 12 carbon atoms, a dialkyl ether, or an alkyl ester of an alkyl carboxylic acid.

14. The method of claim 12 wherein the solvent is selected from the group consisting of hexane, ethyl acetate, carbon tetrachloride and diisopropyl ether.

15. The method of claim 13 wherein the solvent is selected from the group consisting of hexane, ethyl acetate, carbon tetrachloride and diisopropyl ether.

16. A method of selectively enzymatically esterifying the C-24 hydroxyl group of one epimer in a mixture of C-24 epimers of a compound of general formula III or IX

17. The method of claim 16 wherein R₁ and R₂ are both —

H.

18. The method of claim 16 wherein the lipase is fixed.

19. The method of claim 16 wherein the lipase is free.

20. The method of claim 16 wherein the esterifying agent is selected from the group consisting of alkyl and vinyl esters of lower alkyl carboxylic acids having 2 to 6 carbon atoms.

21. The method of claim 20 wherein the esterifying agent is selected from the group consisting of ethyl acetate, vinyl acetate, and vinyl butyrate.

22. The method of claim 16 wherein the organic solvent is a linear or branched alkane having up to 12 carbon atoms, a dialkyl ether, or an alkyl ester of an alkyl carboxylic acid.

23. The method of claim 21 wherein the solvent is selected from the group consisting of hexane, ethyl acetate, carbon tetrachloride and diisopropyl ether.

24. The method of claim 22 wherein the solvent is selected from the group consisting of hexane, ethyl acetate, carbon tetrachloride and diisopropyl ether.