Process for the preparation of an indole derivative

Abstract

A process for the preparation of methyl 2-(3-chloropropoxy)-indole-3-carboxylate, which comprises reacting a 3-chloro-3-carboxylate indole compound with 3-chloropropanol in the presence of an acid having a pKa of from 0 to 2.

1  and  2  (Cancelled)  
     
     
         3 . A process for preparing N-[(1- n butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide, i.e. the compound of Formula (I):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, which process comprises 
 (a) preparing methyl 2-(3-chloropropoxy)-indole-3-carboxylate, i.e. the compound of formula (B):  
                     
 by reacting a compound of formula (C)  
                     
 with 3-chloropropanol in the presence of an acid having a pKa of from 0 to 2; and  
 (b) using the resulting methyl 2-(3-chloropropoxy)-indole-3-carboxylate of formula (B) in the next stage in the synthesis of the N-[(1- n butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide or the pharmaceutically acceptable salt thereof.  
 
     
     
         4 . A process as claimed in  claim 3  wherein in step (a) the acid is trichloroacetic acid, dichloroacetic acid and/or trifluoroacetic acid.  
     
     
         5 . A process as claimed in  claim 3  wherein in step (a) the acid is trichloroacetic acid.  
     
     
         6 . A process as claimed in  claim 3  wherein the reaction in step (a) is effected in an organic solvent.  
     
     
         7 . A process as claimed in  claim 6  wherein in step (a) the organic solvent is dichloromethane or chloroform.  
     
     
         8 . A process as claimed in  claim 3  wherein the reaction in step (a) is effected in an organic solvent at a temperature in the range −20° C. to +10° C.  
     
     
         9 . A process as claimed in  claim 4  wherein the reaction in step (a) is effected in an organic solvent at a temperature in the range −20° C. to +10° C.  
     
     
         10 . A process as claimed in  claim 8  wherein in step (a) the organic solvent is dichloromethane or chloroform.  
     
     
         11 . A process as claimed in  claim 9  wherein in step (a) the organic solvent is dichloromethane or chloroform.  
     
     
         12 . A process as claimed in  claim 6  wherein the reaction in step (a) is effected using a catalytic amount of the acid.  
     
     
         13 . A process as claimed in  claim 8  wherein the reaction in step (a) is effected using a catalytic amount of the acid.  
     
     
         14 . A process as claimed in  claim 9  wherein the reaction in step (a) is effected using a catalytic amount of the acid.  
     
     
         15 . A process as claimed in  claim 11  wherein the reaction in step (a) is effected using a catalytic amount of the acid.  
     
     
         16 . A process as claimed in  claim 3  comprising, in step (b), cyclisation of the intermediate (B) (the methyl 2-(3-chloropropoxy)-indole-3-carboxylate) by treatment with base in a solvent to prepare a compound of formula (A):  
       
         
           
           
               
               
           
         
       
       wherein R is methyl, which compound of formula (A) is methyl 3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxylate.  
     
     
         17 . A process as claimed in  claim 16 , comprising, in step (b): reacting N-(1- n butyl-4-piperidyl)methylamine with the methyl 3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxylate of formula (A) to prepare the N-[(1- n butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide of formula (I); and 
 optionally preparing a pharmaceutically acceptable salt of the N-[(1- n butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide.    
     
     
         18 . A process as claimed in  claim 13  comprising, in step (b), cyclisation of the intermediate (B) (the methyl 2-(3-chloropropoxy)-indole-3-carboxylate) by treatment with base in a solvent to prepare a compound of formula (A):  
       
         
           
           
               
               
           
         
       
       wherein R is methyl, which compound of formula (A) is methyl 3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxylate.  
     
     
         19 . A process as claimed in  claim 18 , comprising, in step (b): reacting N-(1- n butyl-4-piperidyl)methylamine with the methyl 3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxylate of formula (A) to prepare the N-[(1- n butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide of formula (I); and 
 optionally preparing a pharmaceutically acceptable salt of the N-[(1- n butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide.    
     
     
         20 . A process as claimed in  claim 3 , wherein step (b) comprises preparing the hydrochloride salt of N-[(1- n butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide.  
     
     
         21 . A process as claimed in  claim 13 , wherein step (b) comprises preparing the hydrochloride salt of N-[(1- n butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide (SB-207266-A).  
     
     
         22 . A process as claimed in  claim 17 , wherein step (b) comprises preparing the hydrochloride salt of N-[(1- n butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide (SB-207266-A).  
     
     
         23 . A process as claimed in  claim 19 , wherein step (b) comprises preparing the hydrochloride salt of N-[(1- n butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide.