Transfer hydrogenation of cyclopamine analogs

• US 9,879,025 B2
• Filed: 06/23/2016
• Issued: 01/30/2018
• 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:
  US15/191,371
• Publication Number:
  US 20170029433A1
• Time in Patent Office: 586 Days
• Field of Search: 546 18
• 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):

2. The process of claim 1, wherein the compound of formula (I) is a compound of formula (I-AA):

3. The process of claim 2 wherein the ring carbon atom that is directly attached to the hydroxyl group on the compound of formula (II-AA) has an (S) stereochemical configuration and R¹¹ is hydrogen in the β

-position.

4. The process of claim 1, wherein R^a and R^b are both —

CH₃ and R^c is —

CH₂CH₃.

5. The process according to claim 1, wherein the benzene ligand with R^h-R^m is selected from benzene, mesitylene, p-cymene, and hexamethylbenzene.

6. The process according to claim 5, wherein the ruthenium transfer-hydrogenation catalyst is generated from (hexamethylbenzene)ruthenium chloride dimer and an achiral amino alcohol.

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

8. The process according to claim 7, wherein the ruthenium transfer-hydrogenation catalyst is of the formula (iii-g):

9. The process of claim 1, wherein R^a and R^b are each methyl, R^c is ethyl, each of R^h, Rⁱ, R^j, R^k, R^l, and R^m is methyl, and X_a is Cl⁻

.

10. The process of claim 1, wherein the hydrogen donor is an organic alcohol.

11. The process of claim 10, wherein the reducing is carried out in an ether solvent.

12. The process of claim 11, wherein the reducing is carried out at a temperature of about 10°

C. to about 40°

C.

13. The process of claim 11, wherein the reducing is carried out in the presence of base.