Transfer hydrogenation of cyclopamine analogs

• US 9,394,313 B2
• Filed: 09/14/2011
• Issued: 07/19/2016
• Est. Priority Date: 09/14/2010
• Status: Active Grant

• Current Assignee: Royalty Security, LLC
• Original Assignee: Infinity Pharmaceuticals, Inc.
• Inventors: Genov, Daniel G., Austad, Brian C., White, Brian H.
• Primary Examiner(s): DESAI, RITA J
• Application Number:
  US13/232,851
• Publication Number:
  US 20120065399A1
• Time in Patent Office: 1,770 Days
• Field of Search: 546/18
• US Class Current: 1/1
• CPC Class Codes: B01J 2231/643 of R2C=O or R2C=NR (R= C, H)
• CPC Class Codes: B01J 2531/821 Ruthenium
• CPC Class Codes: B01J 31/181 Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
• CPC Class Codes: B01J 31/2428 with more than one complexing phosphine-P atom
• CPC Class Codes: C07D 491/048 the oxygen-containing ring being five-membered
• CPC Class Codes: C07D 491/107 with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• CPC Class Codes: C07F 17/02 of metals of Groups 8, 9 or 10 of the Periodic System

Abstract

Provided herein is a process for the transfer-hydrogenation of ketone analogs of members of the jervine type of Veratrum alkaloids, such as cyclopamine. Also provided herein are novel ruthenium transfer-hydrogenation catalysts.

Claims

1. A process for preparing a compound of formula II-a:

2. The process of claim 1, wherein R¹ is benzyl or —

CO₂R¹⁶, and R¹⁶ is benzyl.

3. The process according to claim 1, wherein R^a and R^b are both methyl.

4. The process according to claim 1, wherein R^a and R^b are both hydrogen.

5. The process according to claim 1, wherein R^c is C₁-C₆ alkyl.

6. The process according to claim 5, wherein R^c is —

CH₂CH₃.

7. The process according to claim 1, wherein the ruthenium transfer-hydrogenation catalyst is generated from (hexamethylbenzene)ruthenium chloride dimer and an achiral amino alcohol having the formula,

8. The process according to claim 1, wherein the ruthenium transfer-hydrogenation catalyst is of the formula (iii-g):

9. The process according to claim 1, wherein the ruthenium transfer-hydrogenation catalyst is prepared from a catalyst precursor of formula (iii-i):

10. The process according to claim 9, wherein X_a is chloro.

11. The process according to claim 1, further comprising a ruthenium transfer-hydrogenation catalyst of formula (iii-k):

12. The process according to claim 1, wherein the ruthenium transfer-hydrogenation catalyst further comprises one or more ruthenium complexes selected from formulas (iii-i), and (iii-k):

13. The process of claim 1, wherein compound (II-a) is formed in greater than 99 percent diastereomeric excess.

14. The process of claim 1, wherein the reacting step is carried out in the presence of a base.

15. The process of claim 14, wherein the hydrogen donor is isopropanol.

16. The process of claim 15, wherein the reacting step further comprises a solvent.

17. The process of claim 16, wherein the solvent is an ether.

18. The process of claim 16, wherein the solvent is 2-methyltetrahydrofuran.

19. The process of claim 1, wherein R^a and R^b are both hydrogen and R^c is methyl.

20. The process of claim 1, wherein R^a and R^b are both methyl and R^c is selected from hydrogen, isopropyl and n-propyl.

21. The process of claim 20, wherein R^c is hydrogen.

22. The process of claim 20, wherein R^c is isopropyl.

23. The process of claim 20, wherein R^c is n-propyl.

24. The process of claim 8, wherein the reacting step is carried out in the presence of a base and further comprises a solvent, the hydrogen donor is isopropanol, and the solvent is 2-methyltetrahydrofuran.