Process for making hydroxylated cyclopentylpyrimidine compounds

Patent metadata

Field	Value
Publication number	US-9676730-B2
Application number	US-201615204715-A
Country	US
Kind code	B2
Filing date	Jul 7, 2016
Priority date	May 17, 2012
Publication date	Jun 13, 2017
Grant date	Jun 13, 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 process comprising cyclizing a compound of formula II:

or a salt thereof, to form a compound of formula I

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 C 1-12 alkyl, substituted or unsubstituted C 2-12 alkenyl, substituted or unsubstituted C 2-12 alkynyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted 3 to 12 membered 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; and
M is Li or Mg.

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:

wherein R 3 is bromo or iodo; to form the compound of formula I or a salt thereof.

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

or a salt thereof, with a compound

or a salt thereof, wherein Lv is a leaving group, and each R 3 is independently iodo or bromo, to form the compound of formula III or a salt thereof.

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

or a salt thereof, wherein R 4 is —Cl or —OH, to form the compound of formula IV or a salt thereof.

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 R 1 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 R 1 is a Boc group.

10. The process of claim 1 , wherein R 2 is —COOR a or —CONR a R b .

11. The process of claim 1 , wherein R 2 is —C(O)N(R a )OR c .

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

13. The process of claim 2 , wherein R 3 is iodo.

14. The process of claim 3 , wherein Lv is hydrogen and R 1 is an amino protecting group.

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

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

• C07D239/30

  Halogen atoms or nitro radicals · CPC title

• C07D403/04

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