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

Patent metadata

Field	Value
Publication number	US-10457648-B2
Application number	US-201515514188-A
Country	US
Kind code	B2
Filing date	Sep 25, 2015
Priority date	Sep 26, 2014
Publication date	Oct 29, 2019
Grant date	Oct 29, 2019

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 I:

or a salt thereof, the process comprising:
(a) cyclizing a compound of VI b :

or a salt thereof to form a compound of Formula (V);

wherein each X is hydroxyl;
(b) brominating the compound of Formula V or a salt thereof with a brominating agent to form a compound of Formula IV:

or a salt thereof, wherein Y is bromo;
(c) contacting the compound of Formula IV with a piperazine compound having the structure:

or a salt thereof, wherein Lv is a leaving group and R 1 is an amino protecting group to form a compound of Formula III:

or a salt thereof; and
(d) contacting the compound of Formula III with a metalating agent to form the compound of Formula I, or a salt thereof; wherein R 1 is hydrogen or an amino protecting group.

2. The process of claim 1 , wherein Lv is selected from hydrogen and a halogen, and R 1 is selected from acetyl, trifluoroacetyl, phthalimidyl, benzyl, triphenylmethyl, benzylidenyl, p-toluenesulfonyl, p-methoxybenzyl, tertbutyloxycarbonyl, 9-fluorenylmethyloxycarbonyl and carbobenzyloxy.

3. The process of claim 1 , wherein the brominating agent is selected from bromine, bromotrimethylsilane, phosphorus oxybromide, N-bromosuccinimide, and phosphorus tribromide.

4. The process of claim 1 , wherein distillation is used to remove volatile byproducts during the bromination reaction.

5. The process of claim 1 , wherein the process comprises contacting the compound or a salt thereof of Formula VI b with a formamidine salt to cyclize the compound of Formula VI b , or a salt thereof.

6. The process of claim 1 , wherein R 1 is selected from acetyl, trifluoroacetyl, phthalimidyl, benzyl, triphenylmethyl, benzylidenyl, p-toluenesulfonyl, p-methoxybenzyl, tertbutyloxycarbonyl, 9-fluorenylmethyl oxycarbonyl and carbobenzyloxy.

7. The process of claim 1 , wherein the metalating agent is an organometal compound.

8. The process of claim 7 , wherein the organometal compound is selected from isopropylmagnesium chloride, isopropylmagnesium chloride lithium chloride complex, sec-butylmagnesium chloride, n-butyllithium, sec-butyllithium, t-butyllithium, lithium tri-n-butylmagnesiate, lithium triisopropylmagnesiate, and lithium (isopropyl)(di-n-butyl)magnesiate.

9. The process of claim 1 , wherein R 1 is tertbutyloxycarbonyl.

10. The process of claim 1 , wherein Lv is hydrogen.

11. The process of claim 1 , wherein the metalating agent is an organomagnesium compound.

12. The process of claim 11 , wherein the organomagnesium compound is a C 1 -C 6 alkylmagnesium halide.

13. The process of claim 11 , wherein the organomagnesium compound is isopropylmagnesium chloride or sec-butylmagnesium chloride.

14. The process of claim 11 , wherein the organomagnesium compound is isopropylmagnesium chloride.

Assignees

• Hoffmann La Roche
• Genentech Inc

Inventors

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

Classifications

• C07D239/46

  Two or more oxygen, sulphur or nitrogen atoms · CPC title

• C07C253/30

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

• C12N9/78

  acting on carbon to nitrogen bonds other than peptide bonds (3.5) · CPC title

• C07D239/70 Primary

  condensed with carbocyclic rings or ring systems · CPC title

• C07D239/52

  Two oxygen atoms · CPC title