Polymorphic form of pyrrole derivative and intermediate thereof

Abstract

The present invention relates to Saroglitazar free acid of Formula (IA) or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable esters, stereoisomers, tautomers, analogs and derivatives thereof. The present invention also provides an amorphous form of saroglitazar free acid and processes of preparation thereof. The present invention also provides pharmaceutical composition comprising an amorphous form saroglitazar magnesium.

1 . Saroglitazar free acid of Formula (IA): 
       
         
           
           
               
               
           
         
       
     
     
         2 . (canceled) 
     
     
         3 . The saroglitazar free acid of Formula (IA) according to  claim 1 , wherein the saroglitazar free acid of Formula (IA) is in amorphous form. 
     
     
         4 . The saroglitazar free acid of Formula (IA) according to  claim 3 , wherein the amorphous form of saroglitazar free acid has an X-ray powder diffraction pattern substantially the same as that shown in  FIG. 5 . 
     
     
         5 - 18 . (canceled) 
     
     
         19 . A process for the preparation of saroglitazar free acid of Formula (IA): 
       
         
           
           
               
               
           
         
         the process comprising: 
         (a) reacting a hydroxy compound (A) with a mesylate compound (A1) in one or more suitable organic solvents in the presence of a base to obtain an alkoxy ester compound of Formula (II); 
       
       
         
           
           
               
               
           
         
         (b) hydrolyzing the alkoxy ester compound of Formula (II) with a base in one or more organic solvents to obtain a reaction mixture; 
         (c) acidifying the reaction mixture with an acid to obtain saroglitazar free acid (IA) in the reaction mixture; 
         (d) extracting the saroglitazar free acid (IA) in one or more organic solvents; and 
         (e) obtaining the saroglitazar free acid (IA) by removal of the solvents. 
       
     
     
         20 . The process according to  claim 19 , wherein the acid comprises one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, oxalic acid, acetic acid, and triflouroacetic acid. 
     
     
         21 . The process according to  claim 19 , wherein the organic solvent for extraction is methylene dichloride, dimethyl formamide, dimethyl acetamide, tetrahydrofuran, toluene, ethyl acetate, n-butyl acetate, methanol, acetone, chloroform, and 1,4-dioxane. 
     
     
         22 . The process according to  claim 19 , wherein the saroglitazar free acid (IA) is obtained by extracting with methylene dichloride; removing the solvent to obtain a residue; and treating the residue with an anti-solvent. 
     
     
         23 . The process according to  claim 22 , wherein the anti-solvent comprises one or more of hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers selected from tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, and methyl tertbutyl ether. 
     
     
         24 . A process for the preparation of saroglitazar free acid of Formula (IA) or its pharmaceutically acceptable salts thereof, 
       
         
           
           
               
               
           
         
         the process comprising:
 (a) providing a solution of saroglitazar magnesium of Formula (I) in one or more organic solvents; 
 (b) adding a base in the solution to obtain a reaction mixture; 
 (c) acidifying the reaction mixture with an acid to obtain saroglitazar free acid (IA) in the reaction mixture; 
 (d) extracting the saroglitazar free acid (IA) in one or more organic solvents; and 
 (e) obtaining the saroglitazar free acid (IA) by removal of the solvents. 
 
       
     
     
         25 . The process according to  claim 24 , wherein the organic solvent comprises one or more of alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; ketones selected from acetone, butanone, and methyl isobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene; or mixture thereof. 
     
     
         26 . The process according to  claim 24 , wherein the base comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydride, potassium tert-butoxide, and sodium pentoxide. 
     
     
         27 . The process according to  claim 24 , wherein the acid comprises one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, oxalic acid, acetic acid, and triflouroacetic acid. 
     
     
         28 . The process according to  claim 24 , wherein the organic solvent for extraction is methylene dichloride, dimethyl formamide, dimethyl acetamide, tetrahydrofuran, toluene, ethyl acetate, n-butyl acetate, methanol, acetone, chloroform, and 1,4-dioxane. 
     
     
         29 . The process according to  claim 24 , wherein the saroglitazar free acid (IA) is obtained by extracting with methylene dichloride; removing the solvent to obtain a residue; and treating the residue with an anti-solvent. 
     
     
         30 . The process according to  claim 29 , wherein the anti-solvent comprises one or more of hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers selected from tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, and methyl tertbutyl ether. 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . (canceled) 
     
     
         34 . Saroglitazar free acid of Formula (IA) according to  claim 1 , wherein the saroglitazar free acid has a purity of at least about 98% by area percentage of HPLC. 
     
     
         35 . Saroglitazar free acid of Formula (IA) according to  claim 1 , wherein the saroglitazar free acid has a chiral purity of at least about 98% by area percentage of HPLC. 
     
     
         36 . (canceled) 
     
     
         37 . A pharmaceutical composition comprising saroglitazar free acid of Formula (IA) according to  claim 1 , together with one or more pharmaceutically acceptable carriers, excipients or diluents. 
     
     
         38 . A pharmaceutical composition comprising saroglitazar free acid of Formula (IA) according to  claim 3 , together with one or more pharmaceutically acceptable carriers, excipients or diluents.