Process for the preparation of brexpiprazole and intermediates thereof

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.

1 . Brexpiprazole having a purity of about 99.5% or more by area percentage of HPLC. 
     
     
         2 . The brexpiprazole according to  claim 1  having total impurities of not more than 0.5% relative to brexpiprazole as measured by area percentage of HPLC. 
     
     
         3 . The brexpiprazole according to  claim 1  having less than 0.1% 1-(benzo[b]thiophen-4-yl) piperazine or a salt thereof relative to brexpiprazole by area percentage of HPLC. 
     
     
         4 . The brexpiprazole according to  claim 1  substantially free from one: or more of
 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), relative to brexpiprazole by area percentage of HPLC. 
 
     
     
         5 . The brexpiprazole according to  claim 1 , which is crystallized from toluene. 
     
     
         6 . The brexpiprazole according to  claim 5 , which is substantially free from residual solvents. 
     
     
         7 . The brexpiprazole according to  claim 1 , comprising crystallizing brexpiprazole in one or more solvents. 
     
     
         8 . The brexpiprazole according to  claim 7  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, or a mixture thereof. 
     
     
         9 . 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. 
     
     
         10 . The composition according to  claim 9 , wherein brexpiprazole has a purity of about 99.5% or more and total impurities not more than 0.5%, by area percentage of HPLC. 
     
     
         11 . The brexpiprazole according to  claim 1 , having particle size d90 of about 100 μm or less. 
     
     
         12 . The brexpiprazole according to  claim 1 , which is anhydrous crystalline form of brexpiprazole characterized by an X-ray powder diffraction pattern comprising peaks expressed in degrees 2θ (±0.2° 2θ) at 12.2°, 14.4°, 17.4°, 19.1°, 20.2°, 21.3° and 23.2±0.2°2θ. 
     
     
         13 . A compound of of Formula (III), 
       
         
           
           
               
               
           
         
       
     
     
         14 . A process for preparing the brexpiprazole according to  claim 1  is comprising the steps:
 (a) reacting a 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. 
       
     
     
         15 . The process according to  claim 14 , wherein the brexpiprazole obtained in step (b) is crystallized from toluene. 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . A pharmaceutical composition comprising brexpiprazole according to  claim 1  together with one or more pharmaceutically acceptable carriers, excipients or diluents.