Process for making hydroxylated cyclopentylpyrimidine compounds

Patent metadata

Field	Value
Publication number	US-9309204-B2
Application number	US-201314401091-A
Country	US
Kind code	B2
Filing date	May 17, 2013
Priority date	May 17, 2012
Publication date	Apr 12, 2016
Grant date	Apr 12, 2016

Abstract

The invention provides new processes for making and purifying hydroxylated cyclopenta[d]pyrimidine compounds, which are useful for the treatment of diseases such as cancer as AKT protein kinase inhibitors, including the compound (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.

First claim

The invention claimed is:

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

wherein
R 1 is hydrogen or an amino protecting group;
R 2 is hydrogen or optionally substituted C 1 -C 12 alkyl; and
R 3 is halogen,

with carbon monoxide, a carbonylation catalyst and an alcohol of formula R 4 OH to form a compound of formula III, or a salt thereof:

wherein
R 4 is C 1 -C 6 alkyl.

2. The process of claim 1 , wherein the carbonylation catalyst comprises Pd(OAc) 2 .

3. The process of claim 1 , wherein R 1 is a Boc group.

4. The process of claim 1 , wherein R 2 is methyl or benzyl.

5. The process of claim 1 , wherein R 3 is Cl.

6. The process of claim 1 , wherein R 4 is isopropyl.

7. The process of claim 1 , further comprising (i) reacting the compound of formula III, or the salt thereof, with base to form an intermediate; and (ii) decarboxylating the intermediate to produce a compound of formula II or a salt thereof:

8. The process of claim 7 , wherein the base comprises potassium t-butoxide.

9. The process of claim 7 , wherein the decarboxylating further comprises a catalyst comprising Pd and hydrogen gas.

10. The process of claim 7 , further comprising reducing the compound of formula II, or the salt thereof, to form a compound of formula I, or a salt thereof:

11. The process of claim 10 , wherein the reducing comprises a catalyst comprising ruthenium and hydrogen gas.

12. The process of claim 1 , wherein the compound of formula IV or the salt thereof is a compound of formula IVa:

or a salt thereof, and the compound of formula III or the salt thereof is a compound of formula IIIa:

or a salf thereof.

13. The process of claim 12 , further comprising preparing the compound of formula IVa or the salt thereof by contacting a corresponding of formula XIII or a salt thereof:

with a compound of formula

to form the compound of formula IVa or the salt thereof:

wherein R 3 is Cl.

14. The process of claim 13 , further comprising preparing the compound of formula XIII or the salt thereof by chlorinating a corresponding compound of formula XII or a salt thereof:

to form the compound of formula XIII or the salt thereof.

15. The process of claim 14 , further comprising preparing the compound of formula XII or the salt thereof by reacting a compound of formula X or a salt thereof:

wherein R a and R b are independently C 1-12 alkyl, with formamidine to form the compound of formula XII or the salt thereof.

16. The process of claim 15 , further comprising preparing the compound of formula X or the salt thereof by contacting a corresponding compound of formula XI:

with a lipase to form the compound of formula X or the salt thereof.

Assignees

• Array Biopharma Inc
• Genentech Inc

Inventors

• Lane Jonathan W
• Remarchuk Travis
• Shakya Sagar
• Spencer Keith L
• Stengel Peter J

Classifications

• C07D239/42 Primary

  One nitrogen atom (nitro radicals C07D239/30) · CPC title

• C07D403/04

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

• C07D239/70 Primary

  condensed with carbocyclic rings or ring systems · CPC title

• C07D239/54

  as doubly bound oxygen atoms or as unsubstituted hydroxy radicals · CPC title

• C07D239/30

  Halogen atoms or nitro radicals · CPC title