Claims for Patent: 8,785,427

Summary for Patent: 8,785,427

Title:	Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
Abstract:	The present invention refers to a new enzymatic process for obtaining 17.alpha.-monoesters of cortexolone and/or its 9,11-dehydroderivatives starting from the corresponding 17.alpha.,21-diesters which comprises an enzymatic alcoholysis reaction. Furthermore, the present invention refers to new crystalline forms of cortexolone 17.alpha.-propionate and 9,11-dehydro-cortexolone 17.alpha.-butanoate.
Inventor(s):	Mauro; Ajani (Lainate, IT), Luigi; Moro (Lainate, IT)
Assignee:	Cosmo Dermatos Srl (Lainate (MI), IT)
Application Number:	12/671,932
Patent Claims:	1. A process for preparing cortexolone-17.alpha.-propionate in crystalline form III, said process comprising reacting a compound of formula II ##STR00006## with a compound of formula III R'OH (III) in an organic solvent in the presence of a lipase from Candida to give cortexolone-17.alpha.-propionate, wherein R is CH.sub.3--CH.sub.2 and R' is a linear aliphatic chain containing 1-10 carbon atoms and crystallizing said cortexolone-17.alpha.-propionate from a mixture of dichloromethane/n-hexane, or a mixture of acetone/n-hexane, or a mixture of ethanol/water, to give cortexolone-17.alpha.-propionate in crystalline form III. 2. The process according to claim 1 wherein R' is an aliphatic chain containing 1-8 carbon atoms. 3. The process according to claim 1 wherein the organic solvent is aprotic. 4. The process according to claim 3 wherein said solvent is selected from the group consisting of toluene, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, and combinations thereof. 5. The process according to claim 1 wherein said compound of formula II is present at an amount in the range of about 0.01 to 0.15 molar. 6. The process according to claim 5 wherein said compound of formula II is present at an amount of about 0.025 molar. 7. The process according to claim 1 wherein said compound of formula III is selected from the group consisting of methanol, ethanol, butanol, octanol, and combinations thereof. 8. The process according to claim 1 wherein said compound of formula III is present in an amount varying from about 0.5 to about 50 moles per mole of compound of formula (II). 9. The process according to claim 1 wherein said compound of formula III is present at 5 moles per mole of the compound of formula (II). 10. The process according to claim 1 wherein said lipase from Candida is Candida cylindracea or Candida antarctica of type B. 11. The process according to claim 1 wherein said lipase from Candida is present at an amount varying from about 100 to 1,000,000 U/mmol. 12. The process according to claim 11 wherein said lipase from Candida is present in an amount ranging from about 1,000 to 1,000,000 U/mmol when the lipase from Candida is Candida cylindracea, and from about 100 to 100,000 U/mmol when the lipase from Candida is Candida antarctica of type B. 13. The process according to claim 1 wherein the reaction takes place at a temperature in the range of about 10 to 48.degree. C. 14. The process of claim 1, wherein the cortexolone-17.alpha.-propionate is crystallized from the mixture of dichloromethane/n-hexane and is characterized by a DRX spectrum as represented in FIG. 7, a DSC spectrum as represented in FIG. 8 and an IR spectrum as represented in FIG. 9. 15. The process of claim 14, wherein the mixture of dichloromethane/n-hexane is in a ratio of about 1/30. 16. The process of claim 1, wherein the cortexolone-17.alpha.-propionate is crystallized from the mixture of acetone/n-hexane and is characterized by a DRX spectrum as represented in FIG. 10, a DSC spectrum as represented in FIG. 11 and an IR spectrum as represented in FIG. 12. 17. The process of claim 16, wherein the mixture of acetone/n-hexane is in a ratio of about 1/8. 18. The process of claim 1, wherein the cortexolone-17.alpha.-propionate is crystallized from the mixture of ethanol/water and is characterized by a DRX spectrum as represented in FIG. 13, a DSC spectrum as represented in FIG. 14 and an IR spectrum as represented in FIG. 15. 19. The process of claim 18, wherein the mixture of ethanol/water is in a ratio of about 1/2. 20. Crystalline form III of cortexolone-17.alpha.-propionate having a DRX spectrum as represented in FIG. 7 or 10 or 13 and a DSC spectrum as represented in FIG. 8 or 11 or 14 and an IR spectrum as represented in FIG. 9 or 12 or 15. 21. The crystalline form III of cortexolone-17.alpha.-propionate of claim 20, which is characterized by a DRX spectrum as represented in FIG. 7; and a DSC spectrum as represented in FIG. 8; and an IR spectrum as represented in FIG. 9. 22. The crystalline form III of cortexolone-17.alpha.-propionate of claim 20, which is characterized by a DRX spectrum as represented in FIG. 10, a DSC spectrum as represented in FIG. 11 and an IR spectrum as represented in FIG. 12. 23. The crystalline form III of cortexolone-17.alpha.-propionate of claim 20, which is characterized by a DRX spectrum as represented in FIG. 13, a DSC spectrum as represented in FIG. 14 and an IR spectrum as represented in FIG. 15. 24. A pharmaceutical composition comprising the crystalline form III of any one of claims 20, 21, 22, and 23, in association with at least one physiologically acceptable excipient. 25. The composition according to claim 24 wherein said composition is in the form of a tablet, capsule, powder, pellet, suspension, emulsion, solution, cream, gel, ointment, lotion, or paste. 26. The composition of claim 24, which is in the form of a solid, semi-solid or a paste. 27. The composition of claim 24, which is in the form of a solid. 28. The composition of claim 27, in the form of a tablet, capsule, powder, or pellet. 29. The composition of claim 24, which is in the form of an ointment.