Process for the preparation of 6-chloro-2,3,4,9-tetrahydro-1h-carbazole-1-carboxamide and intermediates thereof

Abstract

The invention relates to a novel process for the preparation of rac-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (I) in pharmaceutically acceptable polymorphic form, through the conversion of a 3-bromo-2-oxo-cyclohexanecarboxylic acid alkyl ester into 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxylic acid alkyl ester, which in turn is processed to yield the final product.

1 . A process for the preparation of compound (I′-b) according to the following scheme: 
       
         
           
           
               
               
           
         
         wherein R is C 1 -C 6  linear, branched or cyclic alkyl chain and preferably ethyl, 
         said process being characterised in that the reaction between (I′-a) and 4-chloroaniline is performed under heating in a solvent which forms an azeotropic mixture with water. 
       
     
     
         2 . A process according to  claim 1 , wherein said solvent is selected from xylenes, chlorobenzene, cyclohexane, ethyl acetate, MTBE, toluene and preferably ethanol. 
     
     
         3 . A process according to  claim 1 , wherein the water ensuing from said reaction is removed by azeotropic distillation. 
     
     
         4 . A process according to  claim 1 , further comprising crystallization of compound (I′-b) from an apolar solvent. 
     
     
         5 . A process according to  claim 4 , wherein said apolar solvent is cyclohexane. 
     
     
         6 . A process for the preparation of compound (I) 
       
         
           
           
               
               
           
         
         comprising the conversion of compound (I′-a) into compound (I′-b) as defined in  claim 1 , followed by reaction of (I′-b) with ammonia. 
       
     
     
         7 . A process according to  claim 6 , wherein said reaction is carried out in a solvent selected from ethanol and methanol. 
     
     
         8 . A process according to  claim 6 , wherein compound (I) is further processed by:
 a) removing any unreacted ammonia from the reaction mixture;   b) precipitating compound (I) from the reaction mixture;   c) recrystallising the precipitate from a suitable solvent so as to obtain compound (I) in crystalline form A.   
     
     
         9 . A process according to  claim 8 , wherein step a) is performed by evaporation under reduced pressure and/or heating and/or sparging the reaction mixture with an inert gas. 
     
     
         10 . A process according to  claim 8 , wherein step b) is performed by addition of water to the reaction mixture. 
     
     
         11 . A process according to  claim 8 , wherein the solvent used in step c) is selected from ethyl acetate, water, methanol, ethanol and preferably isopropanol. 
     
     
         12 . A process according to  claim 8 , further comprising crystallizing the crude precipitate ensuing from step b) from a MEK/cyclohexane solvent mixture before performing step c). 
     
     
         13 . A process according to  claim 1 , wherein compound (I′-a) is obtained by reacting equimolar amounts of bromine and a compound of formula (I′-c), at 0-5° C. in DCM: 
       
         
           
           
               
               
           
         
       
     
     
         14 . A process according to  claim 1 , wherein compound (I-a′) is obtained by slow addition, under stirring, of gaseous bromine to a solvent-free equimolar amount of compound (I′-c), at 0-10° C.