A process for preparation of pyrroles having hypolipidemic hypocholesteremic activities

Abstract

The present invention provides pyrroles having hypolipidemic hypocholesteremic activities. The invention provides saroglitazar and its pharmaceutically acceptable salts, hydrates, solvates, polymorphs or intermediates thereof. The invention also provides a process for the preparation of saroglitazar. The invention further provides intermediates as well process for preparation thereof.

We claim: 
     
         1 . A substantially amorphous form of saroglitazar magnesium of Formula (I). 
       
         
           
           
               
               
           
         
       
     
     
         2 . A substantially amorphous form of saroglitazar magnesium having a purity of at least about 98% by area percentage of HPLC and less than about 0.5% residual solvent. 
     
     
         3 . The substantially amorphous form of saroglitazar magnesium according to  claim 1  having less than about 25% of crystalline saroglitazar magnesium. 
     
     
         4 . The substantially amorphous form of saroglitazar magnesium according to  claim 1  having an X-ray powder diffraction pattern substantially the same as that shown in  FIG. 1  or by X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 4.5°, 7.9° and 9.0°±0.2° 2θ. 
     
     
         5 . A process for the preparation of saroglitazar magnesium of Formula (I), 
       
         
           
           
               
               
           
         
         the process comprising: 
         (a) reacting hydroxy compound (A) with a mesylate compound (A1) in one or more organic solvents in the presence of a base and a phase transfer catalyst to obtain alkoxy ester compound of Formula (II); 
       
       
         
           
           
               
               
           
         
         (b) hydrolyzing the alkoxy ester compound of Formula (II) with a base to obtain saroglitazar; and 
         (c) reacting the saroglitazar with a magnesium source to obtain saroglitazar magnesium of Formula (I). 
       
     
     
         6 . The process according to  claim 5 , 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; hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers selected from tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, and methyl tert-butyl ether; or mixtures thereof. 
     
     
         7 . The process according to  claim 5 , 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 hydride, potassium hydride, potassium tert-butoxide, and sodium pentoxide. 
     
     
         8 . The process according to  claim 5 , wherein the phase transfer catalyst comprises one or more of tetrabutyl ammonium bromide (TBAB), tetrabutyl ammonium iodide (TBAI), benzyl triethyl ammonium chloride (TEBAC), polyethylene Glycol (PEG-200, 400, 600, 800, 1000), crown ethers selected from 12-crown-4, 15-crown-5, 18-crown-6, dibenzo-18-crown-6, and diaza-18-crown-6. 
     
     
         9 . A process for the preparation of saroglitazar of Formula (IA) or its pharmaceutically acceptable salt, 
       
         
           
           
               
               
           
         
         the process comprising: 
         (a) reacting hydroxy compound (A) with a compound of Formula (A1′) in one or more organic solvents in the presence of a base and a phase transfer catalyst to obtain alkoxy ester compound of Formula (II), 
       
       
         
           
           
               
               
           
         
         wherein, R is mesylate, tosylate, or triflate; 
         (b) hydrolyzing the alkoxy ester compound of Formula (II) with a base to obtain saroglitazar; and 
         (c) optionally, converting the saroglitazar to its pharmaceutically acceptable salt. 
       
     
     
         10 . A process for the preparation of hydroxy compound of Formula (A), 
       
         
           
           
               
               
           
         
         the process comprising: 
         (a) reacting L-tyrosine (E) with cupric sulphate pentahydrate in the presence of a base to obtain copper complex of L-tyrosine; 
       
       
         
           
           
               
               
           
         
         (b) reacting the copper complex of L-tyrosine with benzyl halide in the presence of a base, followed by hydrolysis to obtain compound (D); 
       
       
         
           
           
               
               
           
         
         (c) diazotization of the compound (D) in the presence of sodium nitrite and an acid followed by hydrolysis with water to obtain compound (C); 
       
       
         
           
           
               
               
           
         
         (d) reacting the compound (C) with diethyl sulfate in one or more organic solvents in the presence of a base and a phase transfer catalyst to obtain compound (B); and 
       
       
         
           
           
               
               
           
         
         (e) deprotecting the compound (B) to obtain the hydroxy compound (A). 
       
     
     
         11 . The process according to  claim 10 , 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, and potassium hydride. 
     
     
         12 . The process according to  claim 10 , wherein the organic solvent comprises one or more of esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; hydrocarbons selected from toluene, xylene, ethyl benzene, heptane, hexane, and cyclohexane; and chlorinated solvents selected from methylene dichloride, ethylene dichloride, chlorobenzene, chloroform, and carbontetrachloride. 
     
     
         13 . A crystalline hydroxy compound of Formula (A). 
       
         
           
           
               
               
           
         
       
     
     
         14 . A crystalline hydroxy compound of Formula (A), 
       
         
           
           
               
               
           
         
         having an X-ray powder diffraction having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at about 7.0, 13.4, 13.9, 14.6, 15.3, 16.6, 19.0, 21.7, 22.1, 23.5, 24.4, 26.1, 26.8 and 29.5±0.2° 2θ. 
       
     
     
         15 . A process for the preparation of mesylate compound of Formula (A1), 
       
         
           
           
               
               
           
         
         the process comprising: 
         (a) reacting 2-bromo-1-(4-(methylthio)phenyl)ethanone (E1) with methyl acetoacetate in one or more organic solvents in the presence of a base to obtain compound (D1); 
       
       
         
           
           
               
               
           
         
         (b) hydrolyzing the compound (D1) with a base followed by decarboxylation to obtain compound (C1); 
       
       
         
           
           
               
               
           
         
         (c) reacting the compound (C1) with ethanolamine under Paal-Knorr conditions in the presence of an acid to obtain compound (B1); and 
       
       
         
           
           
               
               
           
         
         (d) reacting the compound (B1) with methane sulphonyl chloride in the presence of a base in one or more organic solvents to obtain the mesylate compound (A1). 
       
     
     
         16 . The process according to  claim 15 , wherein the organic solvent comprises one or more of esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; hydrocarbons selected from toluene, xylene, ethyl benzene, heptane, hexane, and cyclohexane; and chlorinated solvents selected from methylene dichloride, ethylene dichloride, chlorobenzene, chloroform, and carbontetrachloride. 
     
     
         17 . The process according to  claim 15 , 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, sodium methoxide, potassium tert-butoxide, and sodium pentoxide. 
     
     
         18 . The process according to  claim 15 , wherein the base in step (b) comprises one or more of inorganic bases selected from sodium hydroxide, potassium hydroxide, lithium hydroxide: sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate; and ammonia or its aqueous solution; and organic bases selected from methyl amine, ethyl amine, TEA, TBA, DIPA, DIPEA, pyridine, piperidine, morpholine, DBU, DABCO or DBN. 
     
     
         19 . A crystalline mesylate compound of Formula (A1), 
       
         
           
           
               
               
           
         
         having an x-ray powder diffraction having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at about 12.4, 15.0, 17.7 and 23.2±0.2° 2θ. 
       
     
     
         20 . Saroglitazar magnesium having a purity of at least about 98% by area percentage of HPLC. 
     
     
         21 . Saroglitazar magnesium having a chiral purity of at least about 98% by area percentage of HPLC. 
     
     
         22 : A pharmaceutical composition comprising substantially amorphous form of saroglitazar magnesium having a particle size distribution having (D 10 ) of about 10 μm or less, (D 50 ) of about 25 μm or less and (D 90 ) of about 100 μm or less together with one or more pharmaceutically acceptable carriers, excipients or diluents. 
     
     
         23 . A pharmaceutical composition comprising substantially amorphous form of saroglitazar magnesium together with one or more of pharmaceutically acceptable carriers, excipients or diluents.