Processes for the synthesis of rocuronium bromide

Abstract

The invention encompasses processes for synthesizing 1-[17β-acetyloxy-3α-hydroxy-2β-(4-morpholinyl)-5α-androstan-16β-yl]-1-(2-propenyl)pyrrolidinium bromide (rocuronium bromide) and intermediates thereof.

1 . A process for the preparation of Compound VIII 
     
       
         
         
             
             
         
       
     
     comprising:
 (a) mixing Compound VII, 
 
     
       
         
         
             
             
         
       
        a polar organic solvent, and at least one acetylating reagent with at least one base to obtain a mixture; and 
       (b) isolating Compound VIII from the mixture. 
     
   
   
       2 . The process according to  claim 1 , wherein the isolated compound VIII contains an impurity selected from a group consisting of compound VII, compound IX, and mixtures thereof. 
     
       
         
         
             
             
         
       
     
   
   
       3 . The process according to  claim 1 , wherein compound VII is present in an amount of no more than about 1.7% area by HPLC. 
   
   
       4 . The process according to  claim 1 , wherein compound IX is present in an amount of no more than about 7% area by HPLC. 
     
       
         
         
             
             
         
       
     
   
   
       5 . The process according to  claim 1 , wherein Compound VII is obtained by the process comprising:
 (a) forming a suspension of Compound IV, morpholine, and at least one acid catalyst;   (b) stirring the suspension at a temperature of about 100° C. to about reflux for about 24 hours to about 48 hours; and   
     isolating Compound VII from the suspension. 
   
   
       6 . The process according to  claim 1 , wherein the polar organic solvent is a polar aprotic solvent selected from the group consisting of ketones, esters, ethers, amides, nitromethane, and halogenated hydrocarbons. 
   
   
       7 . The process according to  claim 6 , wherein the polar aprotic organic solvent is selected from the group consisting of C 3-6  ketones, C 4-6  esters, C 3-4  cyclic ethers, C 3-4  amides, and C 1-2  halogenated hydrocarbons. 
   
   
       8 . The process of  claim 6 , wherein the polar aprotic organic solvent is selected from the group consisting of acetone, methylisobutylketone, ethyl acetate, isobutyl acetate, tetrahydrofuran, N,N-dimethylformamide, dichloromethane, and dichloroethane. 
   
   
       9 . The process according to  claim 6 , wherein the polar aprotic organic solvent is dichloromethane. 
   
   
       10 . The process according to  claim 1 , wherein the acetylating reagent is selected from the group consisting of acetyl halide, halogenated ester, anhydride and ester. 
   
   
       11 . The process according to  claim 1 , wherein the acetylating reagent is selected from the group consisting of acetyl chloride, AcOCH 2 CCl 3 , AcOCH 2 CF 3 , mixed anhydrides, acetic anhydride, and isopropenyl acetate. 
   
   
       12 . The process according to  claim 1 , wherein the acetylating reagent is acetyl chloride or acetic anhydride. 
   
   
       13 . The process according to  claim 1 , wherein the base is an organic base. 
   
   
       14 . The process according to  claim 12 , wherein the organic base is selected from the group consisting of aliphatic amine and aromatic amine. 
   
   
       15 . The process according to  claim 13 , wherein the organic base is selected from the group consisting of triethylamine, diethylisopropylamine, tri-n-propylamine or tributylamine, and 4-dimethylaminopyridine. 
   
   
       16 . The process according to  claim 1 , wherein the base is an inorganic base. 
   
   
       17 . The process according to  claim 15 , wherein the inorganic base is selected from the group consisting of alkaline and aluminum bases. 
   
   
       18 . The process according to  claim 15 , wherein the inorganic base is selected from the group consisting of sodium carbonate, sodium bicarbonate, and aluminum oxide. 
   
   
       19 . The process according to  claim 1 , wherein the base is triethyl amine, pyridine or sodium carbonate. 
   
   
       20 . The process according to  claim 1 , wherein the mixture in step (a) is stirred at a temperature of about 0° C. to about 60° C. 
   
   
       21 . The process according to  claim 1 , wherein the mixture in step (a) is stirred for about 12 hours to about 22 hours. 
   
   
       22 . The process according to  claim 1 , further comprising purifying compound VIII by isolating compound VIII from the mixture and crystallizing the isolated compound VIII from a mixture of wet acetonitrile and dichloromethane. 
   
   
       23 . The process according to  claim 21 , wherein wet acetonitrile contains about 1% to about 5% of water by volume. 
   
   
       24 . The process according to  claim 21 , wherein the crystallized compound VIII contains an impurity selected from the group consisting of compound VII, compound IX and mixtures thereof. 
   
   
       25 . The process according to  claim 23 , wherein compound VII is present in an amount of no more than 0.3% area by HPLC. 
   
   
       26 . The process according to  claim 23 , wherein compound IX is present in an amount of no more than 1% area by HPLC.