Methods for stereoselective reduction

• US 9,238,672 B2
• Filed: 05/02/2014
• Issued: 01/19/2016
• Est. Priority Date: 12/27/2007
• Status: Active Grant

• Current Assignee: Royalty Security, LLC
• Original Assignee: Infinity Pharmaceuticals, Inc.
• Inventors: Austad, Brian C., Lescarbeau, Andre, Yu, Lin-Chen
• Primary Examiner(s): Kosar, Andrew D
• Assistant Examiner(s): COVINGTON, RAYMOND K
• Application Number:
  US14/268,952
• Publication Number:
  US 20140357868A1
• Time in Patent Office: 627 Days
• Field of Search: 546/17
• US Class Current: 1/1
• 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: