New process

Abstract

The present invention provides an improved process for the preparation of the anti-migraine drug, (R)-5-(2-benzenesulphonylethyl)-3-N-methylpyrrolidin-2-ylmethyl)-1H-indole (eletriptan), available commercially as the hydrobromide salt, and an intermediate and dimer-free products obtained from such process.

1 . A process for the preparation of a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       which comprises hydrolysis of a compound of formula (II)  
       
         
           
           
               
               
           
         
       
     
     
         2 . A process according to  claim 1  which is carried out under basic conditions.  
     
     
         3 . A process according to  claim 2  wherein said hydrolysis is performed using potassium carbonate in methanol/water.  
     
     
         4 . A process according to  claim 1  wherein the compound of formula (II) is obtained by catalytic reduction of a compound of formula (III)  
       
         
           
           
               
               
           
         
       
     
     
         5 . A process according to  claim 4  wherein said reduction is carried out using hydrogen or a hydrogen source in the presence of a suitable catalyst.  
     
     
         6 . A process according to  claim 5  wherein said reduction is carried out using hydrogen at a pressure of from 1 to 15 atmospheres.  
     
     
         7 . A process according to  claim 5  wherein said reduction is carried out using a hydrogen source which is ammonium formate or formic acid.  
     
     
         8 . A process according to according to  claim 4  wherein said catalyst is palladium on carbon, Raney nickel, platinum oxide, rhodium, or ruthenium.  
     
     
         9 . A process according to  claim 8  wherein said catalyst is 5% w/w palladium on carbon.  
     
     
         10 . A process according to  claim 4  wherein the catalytic reduction is carried out in the presence of an acid.  
     
     
         11 . A process according to  claim 10  wherein said acid is methanesulphonic acid, acetic acid, or trifluoroacetic acid.  
     
     
         12 . A process according to  claim 4  wherein the compound of formula (II) obtained by catalytic reduction is slurried with cold aqueous tetrahydrofuran before hydrolysis to the compound of formula (I).  
     
     
         13 . A process according to  claim 4  wherein the compound of formula (III) is obtained by treating a compound of formula (IV)  
       
         
           
           
               
               
           
         
       
       with phenyl vinyl sulphone in the presence of a palladium catalyst, a triarylphosphine and a base.  
     
     
         14 . A process according to  claim 13  wherein the compound of formula (IV) is obtained by N-acetylating (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole.  
     
     
         15 . A process according to  claim 1  wherein the compound of formula (I) so obtained is converted to a pharmaceutically acceptable acid addition salt by treatment with an appropriate acid.  
     
     
         16 . A process according to  claim 15  wherein said conversion is carried out in situ without isolation of the compound of formula (I).  
     
     
         17 . A process according to  claim 15  wherein the acid is hydrobromic acid and the resulting salt is the hydrobromide.  
     
     
         18 . The compound of formula (II):  
       
         
           
           
               
               
           
         
       
     
     
         19 . Eletriptan which is substantially free of  
       
         
           
           
               
               
           
         
       
     
     
         20 . A pharmaceutically acceptable acid addition salt of eletriptan which is substantially free of  
       
         
           
           
               
               
           
         
       
     
     
         21 . A pharmaceutically acceptable acid addition salt of eletriptan according to  claim 20  which is the hydrobromide.  
     
     
         22 . A pharmaceutical composition comprising eletriptan or a pharmaceutically acceptable acid addition salt thereof which is substantially free of  
       
         
           
           
               
               
           
         
       
       and a suitable carrier or excipient.  
     
     
         23 . A composition according to  claim 22  wherein said pharmaceutically acceptable acid addition salt is the hydrobromide.