Process for the preparation of 4-(8-chloro-5,6-dihydro-11h-benzo (5,6)-cyclohepta-(1,2b) -pyridin-11-ylidene)-1-piperidinecarboxylic acid ethyl ester (loratadine)

Abstract

A process and new oxazolinic intermediates for the preparation of 4-(8-chloro-5,6-dihydro-11H-benzo-[5,6]-clohepta-[1,2-b]-pyridin-11-ylide-ne)-1-piperidinecarboxylic acid ethyl ester (loratadine) is described. The process starts from 2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-3-methyl-pyridine, a new intermediate to obtain loratadine. 2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-3-methyl-pyridine is condensed with 3-chloro-benzyl-chloride and the resultant product is treated with Grignard reagent of 4-chloro-N-methyl-piperidine. [3-(2-(3-chloro-phenyl)-ethyl]-pyridin-2-yl-]-1-(methyl-piperidin-4-yl)-methanone is obtained for subsequent hydrolysis. Starting from this last compound it is possible to obtain loratadine with known methods.

1 . A process for synthesizing intermediate b), comprising:
 i) reacting compound 2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-3-methylpyridine, represented by formula I:   
       
         
           
           
               
               
           
         
         with 3-chlorobenzyl chloride, in the presence of a strong base, to give compound 3-[2-(3-chlorophenyl)ethyl]-2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)pyridine, represented by formula II: 
       
       
         
           
           
               
               
           
         
         ii) reacting said compound represented by formula II with Grignard reagent 4-chloro-N-methylpiperidine, in the presence of an inert solvent, to give compound [3-[2-(3-chlorophenyl)ethyl]-2-[4,4-dimethyl-2-(1-methyl-piperidin-4-yl)-oxazolidin-2-yl]pyridine, represented by formula III: 
       
       
         
           
           
               
               
           
         
         iii) hydrolyzing said compound represented by formula III to give said intermediate b): 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The process according to  claim 1 , wherein said reacting of said compound represented by formula I occurs in the presence of tetrahydrofuran and in the presence of lithium diisopropylamide. 
     
     
         3 . The process according to  claim 1 , wherein said reacting of said compound represented by formula I occurs at a temperature no greater that −5° C. 
     
     
         4 . Process according to  claim 1 , wherein said hydrolyzing is performed in acidic medium. 
     
     
         5 . A process for synthesizing intermediate c), comprising:
 i) reacting compound 2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-3-methylpyridine, represented by formula I   
       
         
           
           
               
               
           
         
         with 3-chlorobenzyl chloride, in the presence of a strong base, to give compound 3-[2-(3-chlorophenyl)ethyl]-2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)pyridine, represented by formula II, 
       
       
         
           
           
               
               
           
         
         ii) hydrolyzing an oxazoline group of said compound represented by formula II to give compound 3-[2-(3-chlorophenyl)ethyl]-2-pyridinecarboxylic acid, represented by formula IV, 
       
       
         
           
           
               
               
           
         
         iii) converting said compound represented by formula IV into a corresponding acid chloride compound to give a compound represented by formula IVa 
       
       
         
           
           
               
               
           
         
         iv) condensing said compound of formula IVa to give compound c) via a Friedel-Crafts reaction 
       
       
         
           
           
               
               
           
         
       
     
     
         6 . The process according to  claim 5 , wherein said reacting of said compound represented by formula I occurs in the presence of tetrahydrofuran and in the presence of lithium diisopropylamide. 
     
     
         7 . The process according to  claim 5 , wherein said converting of said compound represented by formula IV occurs in the presence of SOCl 2 . 
     
     
         8 . The process according to  claim 5 , wherein said converting of said compound represented by formula IV occurs at a temperature ranging from 55 to 60° C. 
     
     
         9 . The process according to  claim 5 , wherein said condensing occurs as a temperature ranging from −5 to 0° C. 
     
     
         10 . Process according to  claim 5 , wherein said hydrolyzing is performed in acidic medium. 
     
     
         11 . A compound selected from the group consisting of:
 i) 2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-3-methylpyridine, represented by formula I,   
       
         
           
           
               
               
           
         
         ii) 3-[2-(3-chlorophenyl)ethyl]-2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)pyridine, represented by formula II, 
       
       
         
           
           
               
               
           
         
         iii) 3-[2-(3-chlorophenyl)ethyl]-2-[4,4-dimethyl-2-(1-methyl-4-piperidyl)-2-oxazolidinyl]pyridine, represented by formula III,