Process of making hydroxylated cyclopentapyrimidine compounds and salts thereof

• US 9,315,471 B2
• Filed: 05/17/2013
• Issued: 04/19/2016
• Est. Priority Date: 05/17/2012
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genetec Incorporated (Noritsu Koki Co., Ltd.)
• Inventors: Babu, Srinivasan, Gosselin, Francis, Ran, Yingqing, Remarchuk, Travis, Savage, Scott J., Stults, Jeffrey, Yajima, Herbert
• Primary Examiner(s): Murray, Jeffrey H
• Application Number:
  US14/401,089
• Publication Number:
  US 20150099880A1
• Time in Patent Office: 1,068 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: C07D 239/70 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C12P 17/165 Heterorings having nitrogen atoms as the only ring heteroatoms
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention provides new processes for making and purifying salts of hydroxylated cyclopentapyrimidine compounds, which are useful as AKT inhibitors used in the treatment of diseases such as cancer, including the monohydrochloride salt of (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one.

Claims

1. A process comprising contacting a compound of formula II or a salt thereof:

2. The process of claim 1, wherein said ketoreductase or alcohol dehydrogenase enzyme is selected from KRED-101, KRED-112, KRED-113, KRED-114, KRED-115, KRED-121, KRED-123, KRED-124, KRED-130, KRED-132, KRED-133, KRED-135, KRED-142, KRED-145, KRED-153, Codexis-134, Codexis-150, Codexis-168, Codexis-112, Codexis-102, Codexis-151, Codexis-123, Codexis-103, Codexis-119, Codexis-128, Codexis-136, Codexis-174, Codexis-105, Codexis-129, Codexis-137, Codexis-161, Codexis-176, Codexis-154, Codexis-106, Codexis-131, Codexis-155, Codexis-148, Codexis-165, Codexis-129, Codexis-108, Codexis-116, Codexis-125, Codexis-149, Codexis-111, DAICEL-E073, DAICEL-E087, BCC 111, C-LEcta-ADH-44s, DAICEL-E005, DAICEL-E077, C-LEcta-ADH-24 s, BCC 103, C-LEcta-ADH-14s, C-LEcta-ADH-16s, DAICEL-E007, DAICEL-E008, DAICEL-E080, DAICEL-E082, DAICEL-E052, BCC 101, C-LEcta-ADH-48s, BCC 109, EVO-1.1.211, DAICEL-E072, ADH-1, ADH-2, ADH-3, ADH-A, ADH-B, ADH-III and C-LEcta-ADH-50 s.

3. The process of claim 1, wherein said ketoreductase is KRED-101.

4. The process of claim 1, wherein said contacting step further comprises contacting a compound of formula II or a salt thereof with cofactor.

5. The process of claim 4, wherein said cofactor comprises one of NADP, NADH, NADPH or GDH.

6. The process of claim 4, wherein said cofactor comprises NADP and GDH.

7. The process of claim 1, further comprising reacting a compound of formula III or salt thereof wherein R¹ is an amino protecting group with acid to form a compound of formula Ma or salt thereof:

8. The process of claim 7, further comprising reacting a compound of formula Ma or salt thereof with a compound of formula IV or salt thereof under conditions that form a compound of formula I or salt thereof,

9. The process of claim 8, further comprising reacting a compound of formula I or salt thereof, wherein R² is amino protecting group, with acid to form a dihydrochloride salt of a compound of formula I, wherein R² is hydrogen.

10. The process of claim 9, further comprising contacting the dihydrochloride salt of compound of formula I with base to form a monohydrochloride salt of a compound of formula I, wherein R² is hydrogen.

11. The process of claim 10, wherein said base is a polymeric resin comprising a functionalized styrene divinylbenzene copolymer.

12. The process of claim 1, further comprising reacting a compound of formula III or salt thereof, wherein R₁ is hydrogen, with a compound of formula IV or salt thereof under conditions that form a compound of formula I or salt thereof,

13. The process of claim 12, further comprising reacting a compound of formula I or salt thereof, wherein R² is amino protecting group, with acid to form a dihydrochloride salt of a compound of formula I, wherein R² is hydrogen.

14. The process of claim 13, further comprising contacting the dihydrochloride salt of compound of formula I with base to form a monohydrochloride salt of a compound of formula I, wherein R² is hydrogen.

15. The process of claim 14, wherein said base is a polymeric resin comprising a functionalized styrene divinylbenzene.

16. The process of claim 1 comprising contacting a compound of formula II or a salt thereof with a ketoreductase enzyme.