Epimerization of analogs of vitamin D

• US 7,205,420 B2
• Filed: 06/11/2003
• Issued: 04/17/2007
• Est. Priority Date: 06/13/2002
• Status: Expired due to Fees

• Current Assignee: Teva Pharmaceuticals USA, Inc. (Teva Pharmaceutical Industries Limited)
• Original Assignee: Teva Pharmaceutical Industries Limited
• Inventors: Shapiro, Evgeny, Effenberger, Reinhard, Schwartz, Anchel, Maymon, Asher
• Primary Examiner(s): QAZI, SABIHA NAIM
• Application Number:
  US10/459,073
• Publication Number:
  US 20040054204A1
• Time in Patent Office: 1,406 Days
• Field of Search: 435/68.1, 552/653, 514/167
• US Class Current: 552/653
• CPC Class Codes: C07C 401/00 Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation

Abstract

Provided is a method of general applicability of epimerizing a vitamin-D analog having an asymmetric allylic carbon atom at the C-24 position. The method is of particular utility in making calcipotriene.

Claims

1. A method of epimerizing a C-24 epimer of a vitamin D analog having a hydroxyl substituent on an asymmetric allylic carbon at the 24 position comprising the steps of:

a) esterifying the hydroxyl group on the asymmetric allylic carbon atom at the 24 position with an esterifying agent,

b) contacting>

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a solution of the ester in a solvent with an epimerization-active solid, whereby the ester is epimerized, and

c) hydrolyzing the epimerized ester to obtain a mixture of C-24 epimers having a hydroxyl substituent on the asymmetric allylic carbon at position 24.

2. The method of claim 1 wherein the ester is an acetate.

3. The method of claim 2 wherein the hydroxyl group is esterified with an esterifying agent selected from acetic acid, acetyl chloride, and acetic anhydride.

4. The method of claim 2 wherein the acetate ester of the vitamin D analog can be represented by either of structure VI or IX

5. The method of claim 1 wherein the epimerization active solid is selected from the group consisting of silica gel, aluminum oxide, florisil, and zeolite.

6. The method of claim 5 wherein an amine or an inorganic base is combined with the epimerization-active solid.

7. The method of claim 6 wherein the inorganic base is potassium carbonate.

8. The method of claim 1 further comprising, after the contacting step, the steps of:

1) separating the solution of epimerized ester from the epimerization-active solid,

2) washing, at least once, the separated epimerization-active solid with a solvent that can be the same or different from the solvent in which the ester to be epimerized was contacted,

3) combining the washings with the separated solution of epimerized ester, and

4) removing solvent to obtain the epimerized ester.

9. The method of claim 1 wherein the contacting is at a temperature of about 35°

C.

10. A method of decreasing the diastereometric excess of a starting mixture of epimers of a vitamin D analog, which analog is represented by one or the other of structures IV or VII

11. The method of claim 10 wherein R₃ is cyclopropyl.

12. The method of claim 10 wherein R₁ and R₂ are t-butyl dimethylsilyl.

13. The method of claim 10 wherein the acetylating agent is selected from acetyl chloride and acetic anhydride.

14. The method of claim 10 wherein the acetylating is by enzyme-assisted acetylation with vinyl acetate.

15. The method of claim 10 wherein the epimerization-active solid is selected from the group consisting of silica gel, aluminum oxide, florisil, and zeolite.

16. The method of claim 15 wherein the epimerization-active solid is combined with an amine or an inorganic base.

17. The method of claim 16 wherein the inorganic base is potassium carbonate.

18. A method for making mixed epimers of a vitamin D analog having a hydroxyl substituent on an asymmetric allylic carbon atom at the C-24 position, starting from an individual C-24 OH epimer or a mixture of C-24 OH epimers having an initial diastereometric excess, comprising the steps of:

a) esterifying the hydroxyl group on the asymmetric allylic carbon atom at the C-24 position of the epimer or epimers with an esterifying agent,

b) contacting a solution of the ester in a solvent with an epimerization-active solid, whereby the ester is epimerized, and

c) hydrolyzing the epimerized ester to obtain a mixture of C-24 epimers having a hydroxyl substituent on the asymmetric allylic carbon at position 24, wherein the diastereometric excess of the mixture is less than the initial diastereometric excess.

19. The method of claim 18 wherein the epimerization-active solid is combined with an amine or an inorganic base.

20. The method of claim 19 wherein the inorganic base is potassium carbonate.

21. The method of claim 18 wherein the contacting is at a temperature of about 35°

C.

22. The method of claim 18 wherein the ester is in solution in a solvent selected from hexane, heptane, toluene, benzene, dihloromethane, ethyl acetate, and mixtures of these.

23. The method of claim 18 further comprising, after the contacting step, (b), the steps of:

1) separating the solution of epimerized ester from the epimerization-active solid,

2) washing, at least once, the separated epimerization-active solid with a solvent that can be the same or different from the solvent in which the ester to be epimerized was contacted,

3) combining the washings with the separated solution of epimerized ester, and

4) removing solvent to obtain the epimerized ester.

24. In a process for making calcipotriene, the steps of:

a) acetylating an alcohol selected from XI and XII, wherein R₁ and R₂ are independently H or a silyl hydroxyl protecting group,