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 . Isolated 2α,3α-epoxy-16β-(1-pyrrolidinyl)-5α-androstan-17-one, compound VI. 
     
       
         
         
             
             
         
       
     
   
   
       2 . The compound according to  claim 1  characterized by data selected from: a  13 C-NMR spectrum having carbon chemical shifts at about 218.3, 69, 53.9, 52.2, 51.9, 50.8, 47.5, 46.9, 38.1, 36.2, 34.4, 33.8, 31.9, 30.6, 28.9, 28, 26.6, 23.2, 20, 13.9 and 12.9 ppm; a  13 C-NMR spectrum substantially as depicted in  FIG. 5 ; an  1 H-NMR spectrum having hydrogen chemical shifts at about 3.17-3.09, 2.92, 2.79, 2.64, 2.1, 1.95-0.66, 0.9 and 0.75 ppm; an  1 H-NMR spectrum substantially as depicted in  FIG. 4 ; a mass spectrum (FAB(+), m/z) having a peak of MH+ at about 358.2; a mass spectrum substantially as depicted in  FIG. 7 ; an IR spectrum having peaks at about 1736, 3452 and 1157 cm-1, and an IR spectrum substantially as depicted in  FIG. 8 . 
   
   
       3 . A crystalline 2α,3α-epoxy-16β-(1-pyrrolidinyl)-5α-androstan-17-one, compound VI. 
     
       
         
         
             
             
         
       
     
   
   
       4 . The crystalline 2α,3α-epoxy-16β-(1-pyrrolidinyl)-5α-androstan-17-one according to  claim 3  characterized by powder X-ray diffraction peaks at 10.3, 14.8, 17.5, 18.4 and 19 degrees two-theta, ±0.1 degrees two-theta. 
   
   
       5 . The crystalline 2α,3α-epoxy-16β-(1-pyrrolidinyl)-5α-androstan-17-one according to  claim 4  further characterized by data selected from a group consisting of: a powder X-ray diffraction peaks at about 10.9, 20.7, 22, 24.1, 25.9 and 27 degrees two-theta, ±0.1 degrees two-theta; a powder X-ray diffraction substantially as depicted in  FIG. 1 ; a weight loss of about 0.2% by weight, as determined by TGA analysis; a TGA curve substantially as depicted in  FIG. 3 ; a DSC having a first broad endothermic peak at about 35° C. to about 122° C., and a second endothermic peak at about 146° C.; a DSC curve substantially as depicted in  FIG. 2 , and by a melting point of about 155° C. 
   
   
       6 . A process for increasing the isomeric ratio of Compound VI to Compound VI-a 
     
       
         
         
             
             
         
       
     
     comprising:
 (a) combining a starting Compound VI containing about 10% to about 40% area by HPLC of Compound VI-a with a water miscible organic solvent to obtain a suspension; 
 (b) stirring the suspension at a temperature of about 60° C. to about 80° C. for a sufficient amount of time to obtain a solution; 
 (c) adding water to the solution to form a suspension; and 
 (d) isolating Compound VI from the mixture; 
 wherein the isolated Compound VI contains no more than about 3% area by HPLC of Compound VI-a. 
 
   
   
       7 . The process according to  claim 6 , wherein the starting compound VI contains about 15% to about 30% area by HPLC of compound VI-a. 
   
   
       8 . The process according to  claim 6 , wherein the isolated Compound VI contains less than 2% area by HPLC of Compound VI-a. 
   
   
       9 . The process according to  claim 6 , wherein the water miscible organic solvent is a C 1-4  alcohol. 
   
   
       10 . The process according to  claim 6 , wherein the C 1-4  alcohol is methanol, ethanol, propanol, isopropanol or butanol and mixtures thereof. 
   
   
       11 . The process according to  claim 6 , wherein the suspension in step b, is stirred at a temperature of about 50° C. to about 70° C. 
   
   
       12 . The process according to  claim 6 , wherein the water in step c is added drop-wise to the mixture. 
   
   
       13 . The process according to  claim 6 , wherein the water is added while maintaining the mixture at a temperature above 60° C. 
   
   
       14 . The process according to  claim 6 , wherein the water is added in an amount of about 3 to about 4 volumes of the volume of the water miscible organic solvent. 
   
   
       15 . The process according to  claim 6 , wherein the isolated compound of formula VI having less than about 3% area by HPLC of Compound VI-a is converted to Rocuronium bromide. 
   
   
       16 . The process according to  claim 6 , wherein the starting compound VI contains less than about 10% area by HPLC of compound VI-a, and the isolated compound VI contains less than about 2% area by HPLC of compound VI-a, less than about 1% area by HPLC of compound IV-b, and less than about 2% area by HPLC of compound IV-c. 
     
       
         
         
             
             
         
       
     
   
   
       17 . The process according to  claim 6 , wherein the water miscible organic solvent is a straight or branched C 1-5  alcohol. 
   
   
       18 . The process according to  claim 17 , wherein the C 1-5  alcohol is a C 1-3  alcohol. 
   
   
       19 . The process according to  claim 18 , wherein the said C 1-3  alcohol is methanol, ethanol or isopropanol.