Process for making hydroxylated cyclopentylpyrimidine compounds

Patent metadata

Field	Value
Publication number	US-9790190-B2
Application number	US-201715593064-A
Country	US
Kind code	B2
Filing date	May 11, 2017
Priority date	May 17, 2012
Publication date	Oct 17, 2017
Grant date	Oct 17, 2017

Abstract

The invention provides processes for preparing a compound of formula I

and salts thereof, wherein R 1 is defined herein, and compounds and intermediates of said formula.

First claim

We claim:

1. A compound of formula II or formula III:

or

or a salt thereof, wherein:
R 1 is hydrogen or an amino protecting group;
R 2 is —CN, —COOR a or —CONR a R b ;
R a and R b are independently hydrogen, —OR c , 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; or
R a and R b are taken together with the atom to which they are attached to form a 3-7 membered heterocyclyl;
R c is independently hydrogen or optionally substituted C 1-12 alkyl;
M is Li or Mg; and
R 3 is bromo or iodo.

2. The compound of claim 1 , wherein R 2 —COOR a or —CONR a R b .

3. The compound of claim 1 , wherein R 2 is —COOH or —COOCH 3 .

4. The compound of claim 1 , wherein R 2 is —C(O)N(CH 3 )OCH 3 .

5. The compound of claim 1 , wherein R 3 is iodo.

6. The compound of claim 1 , wherein R 1 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:

or a salt thereof.

8. The compound of claim 7 , wherein R 1 is a Boc group, R 2 is —C(O)N(R a )OR c , and M is Mg.

9. The compound of claim 7 , wherein R 2 is —COOH or —COOCH 3 .

10. The compound of claim 7 , wherein R 2 is —C(O)N(CH 3 )OCH 3 .

11. The compound of claim 7 , wherein R 1 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:

or a salt thereof.

13. The compound of claim 12 , wherein R 1 is hydrogen or a Boc group, R 2 is —CONR a (OR c ), and R 3 is iodo.

14. The compound of claim 12 , wherein R 2 is —COOH or —COOCH 3 .

15. The compound of claim 12 , wherein R 2 is —C(O)N(CH 3 )OCH 3 .

16. The compound of claim 12 , wherein R 3 is iodo.

17. The compound of claim 12 , wherein R 1 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.

Assignees

• Array Biopharma Inc
• Genentech Inc

Inventors

• Askin David
• Han Chong
• Lane Jonathan W
• Remarchuk Travis
• Shakya Sagar
• Sowell C Gregory
• Spencer Keith L
• Stengel Peter J

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D239/70 Primary

  condensed with carbocyclic rings or ring systems · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D239/30

  Halogen atoms or nitro radicals · CPC title