Process for preparing (cyclopentyl[d]pyrimidin-4-yl)piperazine compounds

Patent metadata

Field	Value
Publication number	US-10870626-B2
Application number	US-201916574933-A
Country	US
Kind code	B2
Filing date	Sep 18, 2019
Priority date	Sep 26, 2014
Publication date	Dec 22, 2020
Grant date	Dec 22, 2020

Abstract

The present disclosure relates to processes for preparing (cyclopentyl[d]pyrimidin-4-yl)piperazine compounds, and more particularly relates to processes for preparing (R)-4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d] pyrimidin-4-yl)piperazine and N-protected derivatives thereof, which may be used as an intermediate in the synthesis of Ipatasertib (i.e., (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). The present disclosure additionally relates to various compounds that are intermediates employed in these processes.

First claim

What is claimed is:

1. A process for preparing a compound of Formula V b :

or a salt thereof, the process comprising:
(i) contacting crotononitrile with malonate to form an isomeric mixture comprising a compound of Formula VI a and Formula VI b :

or a salt thereof;
(ii) separating the compound of Formula VI b , or a salt thereof, from the compound of Formula VI a , or a salt thereof via enzymatic resolution; and
(iii) cyclizing a compound of Formula VI b , or a salt thereof.

2. The process of claim 1 , wherein the cyclization is achieved by contacting the compound or salt of Formula VI b with a formamidine salt.

3. The process of claim 1 , wherein the enzymatic resolution is achieved by contacting the isomeric mixture comprising the compound of Formula VI a and Formula VI b , or salts thereof, with a nitrilase enzyme or a lipase enzyme.

4. The process of claim 3 , wherein the enzymatic resolution is achieved by contacting the isomeric mixture comprising the compound of Formula VI a and Formula VI b , or salts thereof, with a nitrilase enzyme.

5. The process of claim 3 , wherein the enzymatic resolution is achieved by contacting the isomeric mixture comprising the compound of Formula VI a and Formula VI b , or salts thereof, with a lipase enzyme.

6. The process of claim 1 , wherein the steps (ii) and (iii) are performed through-process.

7. The process of claim 1 , wherein step (ii) is performed at a pH of about 7.

8. The process of claim 1 , wherein step (ii) is performed at a pH of about 9.

Assignees

• Hoffmann La Roche
• Genentech Inc

Inventors

• Gosselin Francis
• Han Chong
• Iding Hans
• Reents Reinhard
• Savage Scott
• Wirz Beat

Classifications

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• C07D239/26 Primary

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D239/30

  Halogen atoms or nitro radicals · CPC title

• C07C253/30

  by reactions not involving the formation of cyano groups · CPC title

• C07C253/34

  Separation; Purification · CPC title