Process for (3r, 5r)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3, 5-dihydroxy-heptanoic acid hemi calcium salt

Abstract

The present invention relates to processes for the manufacture of (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino)carbonyl]-pyrrol- 1 -yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt.

1 . A method of making 3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino)carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt of Formula I, 
       
         
           
           
               
               
           
         
       
       pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, pro-drugs, stereoisomers, tautomeric forms, N-oxides and metabolites thereof, the method comprising:
 (a) reacting a compound of Formula II with a compound of Formula III, 
 
       
         
           
           
               
               
           
         
       
       to form a compound of Formula of IV (wherein R is alkyl, aryl or arylalkyl); 
       
         
           
           
               
               
           
         
         (b) reacting the compound of Formula IV with benzaldehyde to form a compound of Formula V; 
       
       
         
           
           
               
               
           
         
         (c) reacting the compound of Formula V with 4-fluorobenzaldehyde to form a compound of Formula VI; 
       
       
         
           
           
               
               
           
         
         (d) reacting the compound of Formula VI with a compound of Formula VII, 
       
       
         
           
           
               
               
           
         
       
       to form the compound of Formula VIII; 
       
         
           
           
               
               
           
         
         (e) deprotecting the compound of Formula VIII to form a compound of Formula IX; 
       
       
         
           
           
               
               
           
         
         (f) reducing the compound of Formula IX to form a compound of Formula X; 
       
       
         
           
           
               
               
           
         
         (g) deprotecting the compound of Formula X to form a compound of Formula XI; and 
       
       
         
           
           
               
               
           
         
         (h) converting the compound of Formula XI to compound of Formula I, 
         wherein any purification of products of the steps (a) to (h) is carried out without using column chromatography, and the reaction in step (h) involves a one-pot conversion of compound of Formula XI to the calcium salt of Formula I. 
       
     
     
         2 . The process according to  claim 1 , wherein step (a) involves reaction in toluene. 
     
     
         3 . The process according to  claim 1 , wherein step (c) involves triethylamine. 
     
     
         4 . The process according to  claim 1 , wherein the reaction of step (e) is carried out in one or more solvents selected from acetonitrile, propionitrile, dimethylsulfoxide, dimethylformamide and dimethoxyethane or methanol:tetrahydrofuran (1:3), in presence of sodium hydroxide, at temperatures ranging from about 50 to about 55° C. for about 4-5 hours, or at about 30° C. for about 8-10 hours. 
     
     
         5 . The process according to  claim 1 , wherein the step (f) is carried out at a temperatures ranging from about 40 to about 45° C. for about 5 hours. 
     
     
         6 . The process according to  claim 1 , wherein the reaction of step (g) is carried out in methanol:tetrahydrofuran:water (1:1:1). 
     
     
         7 . The process according to  claim 1 , wherein the reaction of step (h) is carried out in tetrahydrofuran:de-ionized water (1:1). 
     
     
         8 . The process according to  claim 1 , wherein the reaction of step (h) is carried out in ethanol:water (4:1) in presence of calcium hydroxide and a phase transfer catalyst selected from tetraalkylammonium halide, tetrabutylammonium hydrogen sulfate, tetrabutylammonium thiocyanate, tetrabutylammonium tetrafluoroborate, benzyltributylammonium chloride and tetraalkylphosphonium halide. 
     
     
         9 . The process according to  claim 1 , wherein the reaction of step (h) is carried out at a temperature ranging from about 30 to about 50° C. for about 2 to about 8 hours. 
     
     
         10 . The process according to  claim 1 , wherein the product of step (h) is amorphous.