Enzymatic transformation of a prostaglandin (bimatoprost) intermediate

• US 7,611,886 B2
• Filed: 03/06/2006
• Issued: 11/03/2009
• Est. Priority Date: 03/04/2005
• Status: Expired due to Fees

• Current Assignee: Teva Pharmaceuticals USA, Inc. (Teva Pharmaceutical Industries Limited)
• Original Assignee: Teva Pharmaceutical Industries Limited
• Inventors: Effenberger, Reinhard, Fishman, Ayelet
• Primary Examiner(s): Saucier; Sandra
• Assistant Examiner(s): HANLEY, SUSAN MARIE
• Application Number:
  US11/369,518
• Publication Number:
  US 20060247453A1
• Time in Patent Office: 1,338 Days
• Field of Search: None
• US Class Current: 435/280
• CPC Class Codes: C12P 31/00 Preparation of compounds containing a five-membered ring having two side-chains in ortho position to each other, and having at least one oxygen atom directly bound to the ring in ortho position to one of the side-chains, one side-chain containing, not directly bound to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having at least one oxygen atom bound in gamma-position to the ring, e.g. prostaglandins
• CPC Class Codes: C12P 41/004 by esterification of alcohol- or thiol groups in the enantiomers or the inverse reaction

Abstract

A method for the selective enzymatic acetylation of a bimatoprost intermediate is provided.

Claims

1. A process for the selective conversion of the (R)-epimer substrate in a mixture comprising either:

(a) (S)-I, (1S,5R,6R,7R)-6-[(3S)-3-hydroxy-5-phenyl-1-pentenyl]-7-[(4-benzoyl)oxy]-2-oxabicyclo[3,3,0]octan-3-one and (R)-I, (1S,5R,6R,7R)-6-[(3R)-3-hydroxy-5-phenyl-1-pentenyl]-7-[(4-benzoyl)oxy]-2-oxabicyclo[3,3,0]octan-3-one, or

(b) (S)-III, (1S,5R,6R,7R)-6-[(3R)-3-acetoxy-5-phenyl-1-pentenyl]-7-[(4-benzoyl)oxy]-2-oxabicyclo[3,3,0]octan-3-one and (R)-III, (1S,5R,6R,7R)-6-[(3R)-3-acetoxy-5-phenyl-1-pentenyl]-7-[(4-benzoyl)oxy]-2-oxabicyclo[3,3,0]octan-3-one,

wherein, for (a), the mixture is combined with an acetylating agent in the presence of a lipase to form an acetylation reaction mixture, wherein the (R)-I substrate is selectively converted to (R)-III, and, for (b), the mixture is combined with a C_1-6 alcohol in the presence of a lipase to form an alcoholysis reaction mixture, wherein the (R)-III substrate is selectively converted to (R)-I; and

recovering the (S)-I substrate from 1(a) or recovering the (S)-III substrate from 1(b).

2. The process of claim 1, wherein the reaction mixture further comprises a solvent.

3. The process of claim 2, wherein the solvent is C₂ to C₈ linear, branched, or cyclic ether, C₂ to C₈ ketone, chlorinated C₁ to C₄ hydrocarbons, and tri(C₁-C₆ alkyl)silyl groups.

4. The process of claim 3, wherein the solvent is selected from the group consisting of methyl tert-butyl ether (MTBE), diisopropyl ether, methyl ethyl ketone, dichloromethane, tetrachloromethane, acetone, methyl isobutyl ketone (MIBK), and THF.

5. The process of claim 4, wherein the solvent is MTBE or methyl ethyl ketone.

6. The process of claim 2, wherein the substrate is present in the solvent in an amount of from about 0.1 to about 20 weight/volume percent.

7. The process of claim 6, wherein the substrate is present in the solvent in about 0.1 to about 3 weight/volume percent.

8. The process of claim 1, wherein the (S)-I and (R)-I or (R)-III and (S)-III are in any ratio up to the solubility limit.

9. The process of claim 1, wherein the lipase is immobilized or crude.

10. The process of claim 1, wherein the lipase is selected from the group consisting of microbial, mammalian, and plant lipases.

11. The process of claim 10, wherein the lipase is isolated from at least one of Candida antarctica, Pseudomonas sp., Pseudomonas cepacia, Alcaligenes sp., Pseudomonas stutzeri, Candida antarctica, Candida rugosa, Aspergillus niger, and Mucor meihei.

12. The process of claim 11, wherein the lipase is isolated from Pseudomonas cepacia lipase, Pseudomonas stutzeri lipase or Alcaligenes sp lipase.

13. The process of claim 1, wherein the acetylation or alcoholysis reaction mixture is stirred for a period of time of from about 10 to about 250 hours.

14. The process of claim 13, wherein the acetylation reaction mixture is stirred for a period of time of from about 24 to about 60 hours.

15. The process of claim 14, wherein the acetylation reaction mixture is stirred for a period of time of from about 24 to about 52 hours.

16. The process of claim 13, wherein the alcoholysis reaction mixture is stirred for a period of time of from about 24 to about 250 hours.

17. The process of claim 16, wherein the alcoholysis reaction mixture is stirred for a period of time of from about 90 to about 160 hours.

18. The process of claim 1, wherein the acetylation or alcoholysis reaction mixture is stirred at a temperature of from about 10°

C. to about 70°

C.

19. The process of claim 18, wherein the acetylation or alcoholysis reaction mixture is stirred at a temperature of from about 25°

C. to about 55°

C.

20. The process of claim 1, wherein the acetylating agent is a C₂-C₆ alkyl acetate, C₂-C₆ alkenyl acetate or C₅-C₈ benzoyl acetate.

21. The process of claim 20, wherein the acetylating agent is selected from the group consisting of vinyl acetate, ethyl acetate, butyl acetate, vinyl butyrate and vinyl propionate.

22. The process of claim 1, wherein the C_1-6 alcohol is a C_2-5 alcohol.

23. The process of claim 22, wherein the C_1-6 alcohol is ethanol or butanol.

24. The process of claim 1, wherein the acetylating agent or C_1-6 alcohol and the substrate are present in a mole ratio of acetylating agent or alcohol to substrate of at least about 1:

1.

25. The process of claim 24, wherein the acetylating agent or C_1-6 alcohol and the substrate are present in a mole ratio of acetylating agent or alcohol to substrate of from about 2:

1 to about 3;

1.

26. The process of claim 1, wherein the mixture in (a) further comprises reduced (R)-I, wherein both (R)-I and reduced (R)-I are selectively acetylated.

27. The process of claim 26, wherein the recovery of the (S)-I substrate or the (S)-III substrate is by chromatographic separation.

28. The process of claim 1, wherein the (R)-epimer is in reduced form.

29. The process of claim 1, wherein the (S)-I or (S)-III is in reduced form.

30. A process for the preparation of bimatoprost, comprising:

a. selectively converting the (R)-I, (1S,5R,6R,7R)-6-[(3R)-3-hydroxy-5-phenyl-1-pentenyl]-7-[(4-benzoyl)oxy]-2-oxabicyclo[3,3,0]octan-3-one to (R)-III, (1S,5R,6R,7R)-6-[(3R)-3-acetoxy-5-phenyl-1-pentenyl]-7-[(4-benzoyl)oxy]-2-oxabicyclo[3,3,0]octan-3-one according to claim 1(a);

b. recovering (S)-I; and

c. converting (S)-I into bimatoprost.

31. A process for the preparation of bimatoprost, comprising:

a. selectively converting (R)-III, (1S,5R,6R,7R)-6-[(3S)-3-acetoxy-5-phenyl-1-pentenyl]-7-[(4-benzoyl)oxy]-2-oxabicyclo[3,3,0]octan-3-one to (R)-I, (1S,5R,6R,7R)-6-[(3R)-3-hydroxy-5-phenyl-1-pentenyl]-7-[(4-benzoyl)oxy]-2-oxabicyclo[3,3,0]octan-3-one according to claim 1(b);

b. recovering (S)-III;

c. converting (S)-III into (S)-I; and

d. converting (S)-I into bimatoprost.