Method for preparation of pitavastatin and its pharmaceutical acceptable salts thereof

Abstract

The present invention discloses a compound, which is alkali or alkaline earth metal salts of pitavastatin, wherein the alkali or earth metal comprise one or more of magnesium, zinc, potassium, strontium and barium.

1 . A compound, which is alkali or alkaline earth metal salts of pitavastatin, wherein the alkali or earth metal comprise one or more of magnesium, zinc, potassium, strontium and barium. 
     
     
         2 . The compound as claimed in  claim 1 , which is pitavastatinmagnesium. 
     
     
         3 . The compound as claimed in  claim 2 , wherein the compound is a hydrate. 
     
     
         4 . The compound as claimed in  claim 3 , wherein thecompound has water content in the range of from about 7% to about 12% wt/wt. 
     
     
         5 . The compound as claimed in  claim 2 , wherein the compound is crystalline. 
     
     
         6 . The compound as claimed in  claim 5 , wherein the crystalline form is characterized by an X-ray powder diffraction pattern having characteristics peaks expressed in degrees 2θ (±0.2° 2θ) at 10.1°, 13.2°, 19.3° and 27.2°±0.2°. 
     
     
         7 . The compound as claimed in  claim 6  having an x-ray powder diffraction pattern substantially same as that shown in  FIG. 1 . 
     
     
         8 . The compound as claimed in  claim 2 , wherein the compound is amorphous. 
     
     
         9 . The compound as claimed in  claim 8  having x-ray powder diffraction pattern substantially same that shown in  FIG. 2 . 
     
     
         10 . The compound as claimed in  claim 8 , wherein the compound has water content less than about 5% wt/wt. 
     
     
         11 . The compound as claimed in  claim 2  having a specific optical rotation of about +22.0 to +22.5 in 1% DMSO at 20±0.5° C. 
     
     
         12 . A pharmaceutical composition comprising pitavastatinmagnesium and one or more pharmaceutically acceptable carriers or excipients. 
     
     
         13 . The compound as claimed in  claim 2 , wherein the pitavastatinmagnesium is substantially pure having a purity greater than about 99% by area percentage of HPLC. 
     
     
         14 . The compound as claimed in  claim 2 , wherein the pitavastatinmagnesium is substantially pure having less than about 0.3% of diastereomeric impurity by area percentage of HPLC. 
     
     
         15 . A process for the preparation of pitavastatinmagnesium of Formula (1B), 
       
         
           
           
               
               
           
         
       
       the process comprising:
 (a) reacting phosphonium bromide compound of Formula-IV 
 
       
         
           
           
               
               
           
         
       
       with an aldehyde compound of Formula-III 
       
         
           
           
               
               
           
         
       
       in the presence of an alkali or alkaline earth metal base in one or more suitable polar aprotic solvents to provide (4R,6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-vinyl-2,2-dimethyl-1,3-dioxane-4-yl]acetic acid tertiary butyl ester compound of Formula-II; 
       
         
           
           
               
               
           
         
         (b) hydrolyzing the compound of Formula-II under acidic conditions to remove acetonideprotection to form a diol compound; 
         (c) treating the diol compound of step (b) in situ with an alkali metal hydroxide to form corresponding alkali metal salt of pitavastatin (I); 
       
       
         
           
           
               
               
           
         
       
       wherein, M is Na + , K + , Li + ;
 (d) treating alkali metal salt of pitavastatin (I) with a magnesium source to obtain pitavastatinmagnesium; and 
 (e) isolating the pitavastatinmagnesium. 
 
     
     
         16 . The process as claimed in  claim 15  (a), wherein the alkali or alkaline earth metal base comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, and the like. 
     
     
         17 . The process as claimed in  claim 15  (a), wherein the suitable polar aprotic solvent comprises one or more of dimethylformamide, dimethylsulfoxide, dimethylacetamide, tetrahydrofuran, N-methylpyrrolidone, or mixtures thereof. 
     
     
         18 . The process as claimed in  claim 15 , wherein the compound (II) can optionally be isolated by removal of the solvent. 
     
     
         19 . The process as claimed in  claim 15 , wherein the compound (II) can optionally be purified in suitable polar solvent like methanol, ethanol, isopropanol, acetone, DMF, ethyl acetate, butyl acetate, and the like. 
     
     
         20 . The process as claimed in  claim 15  (b), wherein the hydrolysis of compound (II) under acidic conditions can be done by selecting suitable acids from hydrochloric acid, acetic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. 
     
     
         21 . The process as claimed in  claim 15  (c), wherein the suitable alkali metal hydroxide comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like. 
     
     
         22 . The process as claimed in  claim 15  (c), wherein the alkali metal salt of pitavastatin is pitavastatinsodium. 
     
     
         23 . The process as claimed in  claim 15  (d), wherein the suitable magnesium source comprises one or more of magnesium chloride, magnesium methoxide, magnesium acetate and hydrates thereof. 
     
     
         24 . The process as claimed in  claim 15  (e), wherein the pitavastatin magnesium is isolated in a crystalline form. 
     
     
         25 . A compound (4R,6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-vinyl-2,2-dimethyl-1,3-dioxane-4-yl]acetic acid tertiary butyl ester of Formula (II) in crystalline form. 
     
     
         26 . The compound as claimed in  claim 25 , wherein the crystalline form is characterized by an X-ray powder diffraction pattern having characteristics peaks expressed in degrees 20 at 7.86°, 9.94°, 11.48°, 12.71°, 14.80°, 15.88°, 17.44°, 18.16°, 19.17°, 19.97°, 20.77°, 22.71°, 23.41°, 24.68°, 26.02°, 27.63° and 29.36°±0.2°. 
     
     
         27 . The compound as claimed in  claim 25 , wherein the crystalline form is characterized by an IR spectrum having peaks at about 2999, 2976, 1720, 1600, 1512, 1487, 1379, 1342, 1288, 1197, 1134, 1066, 1035, 931 and 842 cm − . 
     
     
         28 . The compound as claimed in  claim 25 , wherein the crystalline form is having DSC endotherm at about 116.04° C. 
     
     
         29 . An improved process for the preparation of (4R,6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-yl)-vinyl-2,2-dimethyl-1,3-dioxane-4-yl]acetic acid tertiary butyl ester of Formula (II), 
       
         
           
           
               
               
           
         
       
       the process comprising:
 (a) reacting phosphonium bromide compound of Formula-IV with an aldehyde compound of Formula-III in the presence of an alkali or alkaline earth metal base in one or more suitable polar aprotic solvents to provide an (4R,6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-vinyl-2,2-dimethyl-1,3-dioxane-4-yl]acetic acid tertiary butyl ester compound of Formula-II; 
 (b) treating compound of Formula-II with one or more suitable polar solvents to form a reaction mixture; 
 (c) heating the reaction mixture at an elevated temperature; 
 (d) cooling the reaction mixture to ambient temperature; and 
 (e) isolating the (4R,6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-vinyl-2,2-dimethyl-1,3-dioxane-4-yl]acetic acid tertiary butyl ester in crystalline form. 
 
     
     
         30 . The process as claimed in  claim 29 , wherein the suitable polar solvent comprises one or more of methanol, ethanol, isopropanol, acetone, DMF, ethyl acetate, butyl acetate, and the like. 
     
     
         31 . The process as claimed in  claim 29 , wherein the elevated temperature is from about 50° C. to about 100° C. 
     
     
         32 . The process as claimed in  claim 29 , wherein the ambient temperature is from about 0° C. to about 30° C. 
     
     
         33 . A process for the preparation of amorphous form of pitavastatinmagnesium, the process comprising:
 (a) providing a solution comprising pitavastatinmagnesium in a suitable organic solvent wherein the organic solvent is one or more of a chlorinated solvent, alcoholic solvent, ketonic solvent, esters solvent and mixtures thereof;   (b) removing the organic solvent to obtain a residue;   (c) adding a suitable anti-solvent to the residue; and   (d) recovering the amorphous form of the pitavastatinmagnesium.   
     
     
         34 . The process as claimed in  claim 33  (a), wherein the suitable organic solvent comprises one or more of methylene dichloride, ethylene dichloride, chlorobenzene, methanol, ethanol, isopropanol, butanol, acetone, methylethyl ketone, ethyl acetate, butyl acetate, isopropyl acetate, and mixtures thereof or mixture thereof with water. 
     
     
         35 . The process as claimed in  claim 33  (c), wherein the suitable anti-solvent comprises one or more of hexane, heptane, cyclohexane, toluene, xylene, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran, and the like. 
     
     
         36 . A process for the preparation of amorphous form of pitavastatinmagnesium, the process comprising:
 (a) providing a solution comprising pitavastatinmagnesium in a suitable organic solvent wherein the organic solvent is one or more of a chlorinated solvent, alcoholic solvent, ketonic solvent, esters solvent and mixtures thereof;   (b) heating reaction mixture at an elevated temperature followed by cooling to ambient temperature;   (c) adding a suitable anti-solvent to the solution; and   (d) recovering the amorphous form of the pitavastatinmagnesium.   
     
     
         37 . The process as claimed in  claim 36  (a), wherein the suitable organic solvent comprises one or more of methylene dichloride, ethylene dichloride, chlorobenzene, methanol, ethanol, isopropanol, butanol, acetone, methylethyl ketone, ethyl acetate, butyl acetate, isopropyl acetate, and mixtures thereof or mixture thereof with water. 
     
     
         38 . The process as claimed in  claim 36  (b), wherein the elevated temperature is from about 50° C. to about 100° C. 
     
     
         39 . The process as claimed in  claim 36  (b), wherein the ambient temperature is from about 15° C. to about 35° C. 
     
     
         40 . The process as claimed in  claim 36  (c), wherein the suitable anti-solvent comprises one or more of hexane, heptane, cyclohexane, toluene, xylene, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran, and the like. 
     
     
         41 . A process for the preparation of an amorphous form of pitavastatinmagnesium having water content less than 2% wt/wt, the process comprising:
 (a) providing pitavastatinmagnesium in crystalline form having water content in the range of about 8% to about 12% wt/wt;   (b) contacting the pitavastatinmagnesium with humid air in a fluidized bed drier, or maintaining the pitavastatinmagnesium at a temperature of from about 5 to about 60° C., under pressure of less than 30 mm/Hg for a period of from about 1 to 5 days; and   (c) recovering the pitavastatinmagnesium in the amorphous form having water content less than 2% wt/wt.   
     
     
         42 . The process as claimed in  claim 41 , wherein the humid air refers to a relative humidity of at least 30%. 
     
     
         43 . A process for the preparation of pitavastatinzinc of Formula (1C), 
       
         
           
           
               
               
           
         
         the process comprising: 
         (a) reacting phosphonium bromide compound of Formula-IV with an aldehyde compound of Formula-III in the presence of an alkali or alkaline earth metal base in a suitable polar aprotic solvent to provide (4R,6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-vinyl-2,2-dimethyl-1,3-dioxane-4-yl]acetic acid tertiary butyl ester compound of Formula-II; 
         (b) hydrolyzing the compound of Formula-II under acidic conditions to remove the acetonide protection to form a diol compound; 
         (c) treating the diol compound of step (b) in situ with an alkali metal hydroxide to form corresponding alkali metal salt of pitavastatin (I); 
         (d) treating the alkali metal salt of pitavastatin (I) with a zinc source to obtain pitavastatin zinc; and 
         (e) isolating the pitavastatin zinc. 
       
     
     
         44 . The process as claimed in  claim 43 , wherein the zinc source comprises one or more of zinc formate, zinc acetate, zinc propionate, zinc maleate, zinc fumarate, zinc tartrate, zinc lactate, zinc malate, zinc citrate, zinc ascorbate, zinc malonate, zinc oxalate, zinc glycolate, Zinc methanesulfonate, zinc ethanesulfonate, a salt of zinc with amino acid, zinc sulfate, zinc chloride, zinc carbonate or zinc nitrate. 
     
     
         45 . A process for the preparation of pitavastatinpotassium of Formula (1D), 
       
         
           
           
               
               
           
         
       
       the process comprising:
 (a) reacting phosphonium bromide compound of Formula-IV with an aldehyde compound of Formula-III in the presence of an alkali or alkaline earth metal base in a suitable polar aprotic solvent to provide an (4R,6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-vinyl-2,2-dimethyl-1,3-dioxane-4-yl]acetic acid tertiary butyl ester compound of Formula-II; 
 (b) hydrolyzing the compound of Formula-II by subjecting under the acidic conditions to remove the acetonideprotection to form a diol compound; and 
 (c) treating the diol compound of step (b) in situ with a potassium source to obtain pitavastatinpotassium. 
 
     
     
         46 . The process as claimed in  claim 45 , wherein the potassium source comprises one or more of potassium hydroxide, potassium carbonate, potassium bicarbonate, potassium acetate, potassium chloride, and the like.