Methods for stereoselective reduction

Patent metadata

Field	Value
Publication number	US-9238672-B2
Application number	US-201414268952-A
Country	US
Kind code	B2
Filing date	May 2, 2014
Priority date	Dec 27, 2007
Publication date	Jan 19, 2016
Grant date	Jan 19, 2016

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.

First claim

What is claimed is:

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:

or a pharmaceutically acceptable salt thereof, wherein:
n is 0 or 1;
R 30 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, —OR 31 , —C(O)R 31 , —CO 2 R 31 , —SO 2 R 31 , —C(O)N(R 31 )(R 31 ), —[C(R) 2 ] q —R 31 , —[(W)—N(R)C(O)] q R 31 , —[(W)—C(O)] q R 31 , —[(W)—C(O)O] q R 31 , —[(W)—OC(O)] q R 3 , —[(W)—SO 2 ] q R 31 , —[(W)N(R 31 )SO 2 ] q R 31 , —[(W)—C( O)N(R 31 )] q R 31 , —[(W)—O] q R 31 , —[(W)—N(R)] q R 31 , —W—(NR 31 ) 3 + X − or —[(W)—S] q R 31 ;
W, at each occurrence, independently is an alkylene group;
q, at each occurrence, independently is 1, 2, 3, 4, 5, or 6;
X − is a halide;
R 31 , at each occurrence, independently is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or —[C(R) 2 ] p —R 32 ;
or any two occurrences of R 31 taken together with the atom to which they are bound form an optionally substituted 4-8 membered ring that contains 0-3 heteroatoms selected from N, O and S;
p is 0-6;
each R 32 is independently

hydroxyl, —N(R)COR, —N(R)C(O)OR, —N(R)SO 2 (R), —C(O)N(R) 2 , —OC(O)N(R)(R), —SO 2 N(R)(R), —N(R)(R), —COOR, —C(O)N(OH)(R), —OS(O) 2 OR, —S(O) 2 OR, —OP(O)(OR)(OR), —NP(O)(OR)(OR), or —P(O)(OR)(OR); and
each R is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl or aralkyl;

the method comprising treating a solution or suspension of compound of formula IV:

or a pharmaceutically acceptable salt thereof, in a solvent with hydrogen gas in the presence of a catalyst and a substituted pyridine.

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 R 30 is H.

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

Assignees

• Infinity Pharmaceuticals Inc

Inventors

• Austad Brian C
• Lescarbeau Andre
• Yu Lin-Chen

Classifications

• C07J5/0053

  not substituted in position 16 · CPC title

• C07J69/00

  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 title

• C07J9/00

  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 · CPC title

• C07J1/0011

  substituted in position 17 by a keto group · CPC title

• C07J65/00

  Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by contraction of two rings, each by one atom · CPC title