Process for making hydroxylated cyclopentylpyrimidine compounds

• US 9,676,730 B2
• Filed: 07/07/2016
• Issued: 06/13/2017
• 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., Shakya, Sagar, Sowell, C. Gregory, Stengel, Peter J., Spencer, Keith L., Remarchuk, Travis
• Primary Examiner(s): Murray, Jeffrey H
• Application Number:
  US15/204,715
• Publication Number:
  US 20160318877A1
• Time in Patent Office: 341 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 process comprising cyclizing a compound of formula II:

2. The process of claim 1, further comprising, contacting a compound of formula III, or a salt thereof, with a magnesium or lithium metalating agent:

3. The process of claim 2, further comprising contacting a compound of formula IV:

4. The process of claim 3, further comprising brominating or iodinating a compound of formula V:

5. The process of claim 1, wherein M is Mg.

6. The process of claim 2, wherein the metalating agent is an alkylmagnesium halide.

7. The process of claim 2, wherein the metalating agent is iPrMgCl.

8. The process of claim 1, wherein R¹ is —

C(O)OR^d, wherein R^d is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted heterocyclyl.

9. The process of claim 1, wherein R¹ is a Boc group.

10. The process of claim 1, wherein R² is —

COOR^a or —

CONR^aR^b.

11. The process of claim 1, wherein R² is —

C(O)N(R^a)OR^c.

12. The process of claim 1, wherein R² is —

C(O)N(CH₃)OCH₃.

13. The process of claim 2, wherein R³ is iodo.

14. The process of claim 3, wherein Lv is hydrogen and R¹ is an amino protecting group.

15. The process of claim 1, wherein R¹ is selected from acetyl, trifluoroacetyl, phthalimidyl, benzyl, triphenylmethyl, benzylidenyl, p-toluenesulfonyl, p-methoxybenzyl, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl and carbobenzyloxy.