PROCESS FOR PREPARATION OF 5H DIBENZO[a,d] CYCLOHEPTENE DERIVATIVES

Abstract

A process for preparation of protriptyline hydrochloride from 5-dihydrobenzocycloheptatriene of formula (1) by coupling with chloropropyl alcohol in the presence of excess n-butyl Lithium in tetrahydrofuran under inert atmosphere, followed by preparation of mesylate derivative of formula (3) and finally the nucleophilic displacement of the mesylate group by reacting methylamine solution in methanol to give protriptyline free base of the formula (4). Also the present process reveals the hydrochloride salt formation and purification of the same to give pure pharmaceutical grade protriptyline hydrochloride with impurities less than 0.1% w/w.

1 . A process of preparing 3-(5H-Dibenzo[a,d]cyclohepten-5-yl)-propan-1-ol comprising reacting 5-dihydro dibenzocycloheptatriene with chloro propyl alcohol in the presence of an excess of n-butyl lithium. 
     
     
         2 . The process of  claim 1  wherein the step of preparing 3-(5H-Dibenzo[a,d]cyclohepten-5-yl)-propan-1-ol comprises using 4 eq. of n-butyllithium and 1.05 eq. of 3-chloropropyl alcohol. 
     
     
         3 . A process of preparing a compound of formula (4) 
       
         
           
           
               
               
           
         
       
       comprising combining a compound of formula (3) 
       
         
           
           
               
               
           
         
       
       and methyl amine solution in a solvent selected from the group consisting of methanol, THF and water. 
     
     
         4 . The process in accordance with  claim 3  wherein a 2.0M solution of Methyl amine in methanol is employed. 
     
     
         5 . The process in accordance with  claim 3  wherein a 2.0M solution of Methyl amine in THF is employed. 
     
     
         6 . The process in accordance with  claim 3  wherein methyl amine in water is employed in a concentration of 15% or greater. 
     
     
         7 . The process in accordance with  claim 3  wherein a 15-30% solution of methyl amine solution in methanol is employed.