Transfer hydrogenation of cyclopamine analogs

• US 9,376,447 B2
• Filed: 09/14/2011
• Issued: 06/28/2016
• 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:
  US13/232,898
• Publication Number:
  US 20120065400A1
• Time in Patent Office: 1,749 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 according to claim 1, effective to form at least about 90% by weight of the compound of formula (II-a) relative to its α

- or (R)-isomer.

3. The process according to claim 1, wherein the ruthenium transfer-hydrogenation catalyst comprises a chiral ephedrine ligand.

4. The process according to claim 1, wherein the chiral amino alcohol ligand is selected from chiral 2-methylaminocyclohexanol, propranolol, 2-amino-1-indanol, and prolinol.

5. The process of claim 3, wherein the chiral amino alcohol ligand is (1S,2R)ephedrine, (1R,2S)ephedrine, (+)-(1S,2S)pseudoephedrine, or (31)-(1R,2R) pseudoephedrine.

6. The process according to claim 1, wherein Ar is hexamethylbenzene.

7. The process according to claim 6, wherein the ruthenium transfer-hydrogenation catalyst is generated by reaction of (hexamethylbenzene)ruthenium chloride dimer and a chiral amino alcohol selected from ephedrine, pseudoephedrine, 2-methylaminocyclohexanol, propranolol, 1-amino-2-indanol, and prolinol.

8. The process according to claim 1, wherein the reacting step is carried out in the presence of base.

9. The process according to claim 8, wherein the base is an alkoxide.

10. The process according to claim 1, further comprising a ruthenium transfer-hydrogenation catalyst of formula RuAr(chiral amino alcohol), wherein Ar and chiral amino alcohol are as defined in claim 1.

11. The process according to claim 2, wherein the ruthenium transfer-hydrogenation catalyst comprises one or more of RuHCl(mesitylene)[(1S,2R)-ephedrine] (10), RuHCl(hexamethylbenzene)[(1R,2S)-ephedrine] (12), RuHCl(hexamethylbenzene)[(1S, 2R)-ephedrine] (13), RuHCl(mesitylene)[(1R,2S)2-methylaminocyclohexanol] (64), RuHCl(hexamethylbenzene)[R-propranolol] (75), RuHCl(hexamethylbenzene)[1S,2R-cis-1-amino-2-indanol] (80), RuHCl(hexamethylbenzene)[(1S,2S)2-methylaminocyclohexanol] (82), RuHCl(hexamethylbenzene)[(1R,2S)2-methylaminocyclohexanol] (83), and RuHCl(hexamethylbenzene)[D-prolinol] (86).

12. The process according to claim 1, wherein the ruthenium transfer-hydrogenation catalyst is selected from RuHCl(mesitylene)[(1S, 2R)-ephedrine] (10), RuHCl(hexamethylbenzene)[(1S,2R)-ephedrine] (13), RuHCl(hexamethylbenzene)[(1R,2S)-ephedrine] (12), RuHCl(p-cymene)[(1S,2R)-ephedrine] (15), RuHCl(mesitylene)[(1R,2S)2-methylaminocyclohexanol] (64), RuHCl(hexamethylbenzene)[(1R,2S)2-methylaminocyclohexanol] (83), RuHCl(hexamethylbenzene)[(1S,2S)2-methylaminocyclohexanol] (82), RuHCl(hexamethylbenzene)[R-propranolol] (75), RuHCl(hexamethylbenzene)[S-propranolol] (74), RuHCl(hexamethylbenzene)[1R,2S-cis-1-amino-2-indanol] (81), RuHCl(hexamethylbenzene)[D-prolinol] (86), RuHCl(hexamethylbenzene)[1S,2R-cis-1-amino-2-indanol] (80), and RuHCl(hexamethylbenzene)[L-prolinol] (87).

13. The process according to claim 2,

where R¹ is selected from H, benzyl, and —

CO₂R¹⁶ where R¹⁶ is selected from t-butyl and benzyl.

14. The process of claim 13, wherein R¹ is —

CO₂R¹⁶ and R¹⁶ is t-butyl.

15. The process of claim 13 wherein R¹ is —

CO₂R¹⁶ and R¹⁶ is benzyl.

16. The process of claim 1, where the organic alcohol is isopropanol.

17. The process of claim 1, wherein the reacting step further includes a solvent.

18. The process of claim 17, where the solvent is an ether.

19. The process of claim 1, wherein the compound of formula (II-a) or a pharmaceutically acceptable form thereof is formed in enantiomeric excess of about 80% or more.