METHODS FOR STEREOSELECTIVE REDUCTION

• US 20110009442A1
• Filed: 12/24/2008
• Published: 01/13/2011
• Est. Priority Date: 12/27/2007
• Status: Active Grant

• Current Assignee: Royalty Security, LLC
• Original Assignee: Infinity Pharmaceuticals, Inc.
• Inventors: Lescarbeau, Andre, Yu, Lin-Chen, Austad, Brian C.
• Granted Patent: US 8,716,479 B2
• Time in Patent Office: Days
• US Class Current: 514/278
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07B 2200/09 Geometrical isomers
• CPC Class Codes: C07D 471/10 Spiro-condensed systems
• CPC Class Codes: C07D 491/22 in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07J 1/0011 substituted in position 17 by a keto group
• CPC Class Codes: C07J 21/00 Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
• CPC Class Codes: C07J 43/006 spiro-condensed
• CPC Class Codes: C07J 5/0053 not substituted in position 16
• CPC Class Codes: C07J 63/00 Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
• CPC Class Codes: C07J 65/00 Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by contraction of two rings, each by one atom
• CPC Class Codes: C07J 69/00 Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by contraction of only one ring by one atom and expansion of only one ring by one atom
• CPC Class Codes: C07J 7/009 by only one oxygen atom doubly bound
• CPC Class Codes: C07J 71/0005 Oxygen-containing hetero ring
• CPC Class Codes: C07J 9/00 Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

Abstract

The invention is directed to a method to reduce a C—C double bond of an enone of a steroidal compound to produce a mixture of β ketone product and α ketone product, comprising treating a solution or suspension of the steroidal compound in a solvent with hydrogen gas in the presence of a catalyst and a substituted pyridine.

Claims

1. A method of reducing the C—

C double bond of an enone of a steroidal compound to produce a mixture of β

ketone product and α

ketone product, the method comprising treating a solution or suspension of the steroidal compound in a solvent with hydrogen gas in the presence of a catalyst and a substituted pyridine.

2. The method of claim 1, wherein an excess of the β

ketone product is produced compared to the α

ketone product.

3. The method of claim 1, wherein the ratio of the β

ketone product to the α

ketone product is at least 2;

1.

4. The method of claim 1, wherein the ratio of the β

ketone product to the α

ketone product is at least 10;

1.

5. The method of claim 1, wherein the ratio of the β

ketone product to the α

ketone product is at least 20;

1.

6. The method of claim 1, wherein the ratio of the β

ketone product to the α

ketone product is at least 50;

1.

7. The method of claim 1, wherein the substituted pyridine is a 3-substituted pyridine.

8. The method of claim 7, wherein the 3-substituted pyridine is selected from 3-picoline, 3-methoxypyridine, 3-ethylpyridine, 3-n-butylpyridine, 3-isobutylpyridine, 3-hydroxypyridine, 3-aminopyridine, and 3-dimethylaminopyridine.

9. The method of claim 7, wherein the 3-substituted pyridine is 3-picoline.

10. The method of claim 1, wherein the catalyst is a palladium catalyst.

11. The method of claim 1, wherein the solvent comprises the substituted pyridine.

12. The method of claim 11, wherein the solvent comprises 3-picoline.

13. A method of making a mixture of compounds of formulae II and III:

14. The method of claim 13, wherein an excess of the compound of formula II is produced compared to the compound of formula III.

15. The method of claim 13, wherein the ratio of the compound of formula II to compound of formula III is at least 10:

1.

16. The method of claim 13, wherein the ratio of the compound of formula II to compound of formula III is at least 20:

1.

17. The method of claim 13, wherein the substituted pyridine is a 3-substituted pyridine.

18. The method of claim 17, wherein the 3-substituted pyridine is 3-picoline.

19. The method of claim 13, wherein the solvent comprises the substituted pyridine.

20. The method of claim 19, wherein the solvent comprises 3-picoline.

21. The method of claim 13, wherein the catalyst is a palladium catalyst.

22. The method of claim 13, wherein n is 1.

23. The method of claim 22, wherein R³⁰ is H.

24. The method of claim 13, wherein the compounds of formulae II and III have the following absolute chemistry:

25. A method of making a mixture of compounds V and VI:

26. The method of claim 25, wherein an excess of the compound of formula V is produced compared to the compound of formula VI.

27. The method of claim 25, wherein the ratio of the compound of formula V to compound of formula VI is at least 20:

1.

28. The method of claim 25, wherein the substituted pyridine is a 3-substituted pyridine.

29. The method of claim 28, wherein the 3-substituted pyridine is 3-picoline.

30. The method of claim 25, wherein the substituted pyridine is a 4-substituted pyridine.

31. The method of claim 30, wherein the 4-substituted pyridine is selected from 4-picoline and 4-methoxypyridine.

32. The method of claim 25, wherein the solvent comprises the substituted pyridine.

33. The method of claim 32, wherein the solvent comprises 3-picoline.

34. The method of claim 25, further comprising adding an aqueous solution of an acid and isolating the salt of compounds V and VI.

35. The method of claim 34, wherein the acid is selected from HCl, HBr, H₂SO₄, methanesulfonic acid, and citric acid.

36. A compound of formula IX:

37. The compound of claim 36, wherein X⁻

is citrate.

38. A mixture of compounds IX and X:

39. The mixture of claim 38, wherein X⁻

is citrate.

40. The mixture of claim 38, comprising an excess of compound IX compared to compound X.

41. The mixture of claim 38, wherein the ratio of the compound of formula IX to compound of formula X is at least 20:

1.

42. The mixture of claim 38, wherein the ratio of the compound of formula IX to compound of formula X is at least 50:

1.

43. A method of making a compound of formula XV:

44. The method of claim 43, wherein X⁻

is citrate.

45. The method of claim 43, wherein step (c) comprises:

(1) converting the alcohol to a leaving group to produce a compound of formula XVI;

46. The method of claim 43, wherein PG is benzyloxycarbonyl (Cbz) and the sulfonamide of formula XIV is deprotected by treatment with hydrogen gas in the presence of a catalyst to form the compound of formula XV.

47. The method of claim 43, wherein the compound of formula XV has the following absolute stereochemistry:

48. The method of claim 43, further comprising the step of treating the compound of formula XV with an acid to produce a compound of formula XIX:

49. The method of claim 48, wherein the acid comprises HCl and X⁻

is chloride.

50. A mixture comprising a compound of formula V, or a pharmaceutically acceptable salt thereof:

51. The mixture of claim 50, wherein the compound of formula 2c is present in less than 1%.