Process for making hydroxylated cyclopentylpyrimidine compounds

• US 9,790,190 B2
• Filed: 05/11/2017
• Issued: 10/17/2017
• Est. Priority Date: 05/17/2012
• Status: Active Grant

• Current Assignee: Array Biopharma Incorporated (Pfizer Inc.), Genentech, Inc. (Roche Holding AG)
• Original Assignee: Array Biopharma Incorporated (Pfizer Inc.), Genentech, Inc. (Roche Holding AG)
• Inventors: Askin, David, Han, Chong, Lane, Jonathan W., Remarchuk, Travis, Shakya, Sagar, Sowell, C. Gregory, Spencer, Keith L., Stengel, Peter J.
• Primary Examiner(s): Murray, Jeffrey H
• Application Number:
  US15/593,064
• Publication Number:
  US 20170247337A1
• Time in Patent Office: 159 Days
• Field of Search: None
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 239/30 Halogen atoms or nitro radicals
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• 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: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention provides processes for preparing a compound of formula I

and salts thereof, wherein R¹ is defined herein, and compounds and intermediates of said formula.

Claims

1. A compound of formula II or formula III:

2. The compound of claim 1, wherein R² —

COOR^a or —

CONR^aR^b.

3. The compound of claim 1, wherein R² is —

COOH or —

COOCH₃.

4. The compound of claim 1, wherein R² is —

C(O)N(CH₃)OCH₃.

5. The compound of claim 1, wherein R³ is iodo.

6. The compound of claim 1, wherein R¹ is —

C(O)—

R^d or —

C(O)OR^d and R^d is C_1-6 alkyl or hydrogen, wherein said alkyl is optionally substituted by oxo, halo or phenyl.

7. The compound of claim 1 that is a compound of formula II:

8. The compound of claim 7, wherein R¹ is a Boc group, R² is —

C(O)N(R^a)OR^c, and M is Mg.

9. The compound of claim 7, wherein R² is —

COOH or —

COOCH₃.

10. The compound of claim 7, wherein R² is —

C(O)N(CH₃)OCH₃.

11. The compound of claim 7, wherein R¹ is —

C(O)—

R^d or —

C(O)OR^d and R^d is C_1-6 alkyl or hydrogen, wherein said alkyl is optionally substituted by oxo, halo or phenyl.

12. The compound of claim 1 that is a compound of formula III:

13. The compound of claim 12, wherein R¹ is hydrogen or a Boc group, R² is —

CONR^a(OR^c), and R³ is iodo.

14. The compound of claim 12, wherein R² is —

COOH or —

COOCH₃.

15. The compound of claim 12, wherein R² is —

C(O)N(CH₃)OCH₃.

16. The compound of claim 12, wherein R³ is iodo.

17. The compound of claim 12, wherein R¹ is —

C(O)—

R^d or —

C(O)OR^d and R^d is C_1-6 alkyl or hydrogen, wherein said alkyl is optionally substituted by oxo, halo or phenyl.

18. The compound of claim 1 that is (R)-tert-butyl 4-(6-iodo-5-(4-methoxy-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine-1-carboxylate or a salt thereof.

19. The compound of claim 1 that is (R)-tert-butyl 4-(6-iodo-5-(4-methoxy-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine-1-carboxylate.

20. The compound of claim 1 that is (R)-3-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-iodo-pyrimidin-5-yl)butanoic acid or a salt thereof.

21. The compound of claim 1 that is (R)-3-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-iodo-pyrimidin-5-yl)butanoic acid.

22. The compound of claim 1 that is (R)-tert-butyl 4-(6-iodo-5-(4-(methoxy(methyl)amino)-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine-1-carboxylate or a salt thereof.

23. The compound of claim 1 that is (R)-tert-butyl 4-(6-iodo-5-(4-(methoxy(methyl)amino)-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine-1-carboxylate.