Process for the preparation of brexpiprazole and intermediates thereof

Patent metadata

Field	Value
Publication number	US-10358440-B2
Application number	US-201916274352-A
Country	US
Kind code	B2
Filing date	Feb 13, 2019
Priority date	May 3, 2016
Publication date	Jul 23, 2019
Grant date	Jul 23, 2019

Abstract

The present invention relates to Brexpiprazole having a purity of about 99.5% or more by area percentage of HPLC, having total impurities not more than 0.5% relative to brexpiprazole as measured by area percentage of HPLC, and having less than 0.1% 1-(benzo[b]thiophen-4-yl)piperazine or a salt thereof relative to brexpiprazole by area percentage of HPLC. The present invention also provides a composition comprising brexpiprazole having 1-(benzo[b]thiophen-4-yl)-piperazine or a salt thereof in an amount less than about 0.1% relative to brexpiprazole by area percentage of HPLC and process for the preparation of brexpiprazole.

First claim

We claim:

1. A process for the preparation of brexpiprazole, the process comprising the steps of:
(a) reacting compound 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride of Formula (V) with 1,4-dibromobutane to obtain a spiro compound of Formula (III); and

(b) reacting the spiro compound of Formula (III) with a compound 7-hydroxy-quinolin-2(1H)-one of Formula (II),

to obtain the brexpiprazole.

2. The process according to claim 1 , wherein the brexpiprazole obtained in step (b) is crystallized from one or more solvents.

3. The process according to claim 2 , wherein the solvent comprises one or more of water, methanol, ethanol, isopropanol, butanol, acetone, methyl ethyl ketone, methyl isobutylketone, ethyl acetate, isopropyl acetate, butyl acetate, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-methyl acetamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone-(DMI), and acetonitrile, toluene, or a mixture thereof.

4. The process according to claim 1 , wherein the brexpiprazole obtained in step (b) is crystallized from toluene.

5. An intermediate compound of Formula (III),

for the preparation of brexpiprazole.

6. The process according to claim 2 , wherein the brexpiprazole has one or more of impurities 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)-1-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butyl)quinolin-2(1H)-one (impurity-S); 2,7-bis(4-(4-(benzo[b]thiophen-4-yl) piperazin-1-yl)butoxy)quinoline (impurity-T); and 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)-1,2-dihydro-quinoline (impurity-U) from 0.0% to 0.05%, relative to brexpiprazole by area percentage of HPLC.

7. The process according to claim 1 , wherein the brexpiprazole has 1-(benzo[b]thiophen-4-yl)-piperazine, or a salt thereof in an amount less than about 0.1% relative to brexpiprazole by area percentage of HPLC.

8. The process according to claim 1 , wherein the brexpiprazole has a purity of 99.9% or more by area percentage of HPLC.

Assignees

• Cadila Healthcare Ltd

Inventors

• Desai Sanjay Jagdish
• Parihar Jayprakash Ajitsingh
• Shah Alpesh Pravinchandra

Classifications

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• C07D487/10

  Spiro-condensed systems · CPC title

• C07D333/54

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

• C07D247/02

  having the nitrogen atoms in positions 1 and 3 · CPC title

• C07D409/12

  linked by a chain containing hetero atoms as chain links · CPC title