Process for manufacture of L-DOPA ethyl ester

Abstract

A process for manufacturing a highly purified, stable, non-hygroscopic, crystalline composition of L-DOPA ethyl ester. The L-DOPA ethyl ester is an active ingredient in many pharmaceutical preparations for the treatment of patients suffering from Parkinson's Disease and related indications.

What is claimed:  
     
         1 . A process for preparing a composition comprising pharmaceutically acceptable, crystalline, non-hygroscopic L-DOPA ethyl ester as free base in an amount which is at least 95% by weight of the composition and L-DOPA in an amount which is less than 2% by weight of the composition, which process comprises: 
 (a) reacting L-DOPA with ethanol in the presence of thionyl chloride or an acid catalyst to produce a solution of crude L-DOPA ethyl ester salt;    (b) removing any residual volatiles from the solution of crude L-DOPA ethyl ester salt produced in step (a);    (c) diluting the solution from step (b) with water, and adding a cosolvent and a suitable antioxidant;    (d) adding a suitable base to the solution from step (c) under controlled conditions to precipitate a crude L-DOPA ethyl ester free base;    (e) drying the precipitated crude L-DOPA ethyl ester free base from step (d); and    (f) recrystallizing the dried, precipitated crude L-DOPA ethyl ester free base from step (e) in the presence of a suitable solvent containing an antioxidant at a temperature of less than 10° C. to produce the composition of pharmaceutically acceptable, crystalline, non-hygroscopic L-DOPA ethyl ester free base.    
     
     
         2 . The process of  claim 1 , wherein the acid catalyst of step (a) is hydrogen chloride or toluenesulfonic acid.  
     
     
         3 . The process of  claim 2 , wherein the acid catalyst of step (a) is hydrogen chloride.  
     
     
         4 . The process of  claim 1 , wherein the crude L-DOPA ethyl ester salt produced in step (a) is L-DOPA ethyl ester hydrochloride.  
     
     
         5 . The process of  claim 1 , wherein the removing of residual volatiles in step (b) is effected by vacuum distillation.  
     
     
         6 . The process of  claim 5 , wherein the residual volatiles removed in step (b) are ethanol and excess HCl.  
     
     
         7 . The process of  claim 1 , wherein the cosolvent of step (c) is toluene.  
     
     
         8 . The process of  claim 1 , wherein the suitable antioxidant of step (c) is selected from a group consisting of ascorbic acid, sodium sulfite, sodium metabisulfite, propyl gallate, and vitamin E.  
     
     
         9 . The process of  claim 8 , wherein the suitable antioxidant of step (c) is sodium metabisulfite.  
     
     
         10 . The process of  claim 1 , wherein the suitable base of step (d) is sodium hydroxide or ammonium hydroxide.  
     
     
         11 . The process of  claim 10 , wherein the suitable base of step (d) is sodium hydroxide.  
     
     
         12 . The process of  claim 1 , wherein the addition of a suitable base in step (d) effects an adjustment in the pH of the solution to a pH range between about 5.0 and about 9.0 to precipitate a crude L-DOPA ethyl ester base.  
     
     
         13 . The process of  claim 12 , wherein the addition of a suitable base in step (d) effects an adjustment in the pH of the solution to a pH range between 6.5 and 8.0 to precipitate a crude L-DOPA ethyl ester base.  
     
     
         14 . The process of  claim 1 , wherein the controlled conditions from step (d) are conditions in which addition of the base solution is slowly performed in a nitrogen atmosphere, and a trace amount of L-DOPA ethyl ester is added to induce formation of precipitate.  
     
     
         15 . The process of  claim 1 , wherein the drying of step (e) is effected by azeotropic distillation.  
     
     
         16 . The process of  claim 1 , wherein the suitable solvent of step (f) is selected from a group consisting of ethyl acetate, methylene chloride, and toluene.  
     
     
         17 . The process of  claim 16 , wherein the suitable solvent of step (f) is ethyl acetate.  
     
     
         18 . The process of  claim 1 , wherein the antioxidant of step (f) is selected from a group consisting of ascorbic acid, 2,6-Di-tert-butyl-4-methylphenol (BHT), butylated hydroxy anisol (BHA) propyl gallate, and vitamin E.  
     
     
         19 . The process of  claim 17 , wherein the antioxidant of step (f) is 2,6-Di-tert-butyl-4-methylphenol (BHT).  
     
     
         20 . A process for preparing a composition comprising pharmaceutically acceptable, crystalline, non-hygroscopic L-DOPA ethyl ester as free base in an amount which is at least 95% by weight of the composition and L-DOPA in an amount which is less than 2% by weight of the composition, which process comprises: 
 (a) reacting L-DOPA with ethanol in the presence of hydrogen chloride (HCl) to produce a solution of crude L-DOPA ethyl ester hydrochloride;    (b) removing ethanol and excess HCl from the solution of crude L-DOPA ethyl ester hydrochloride produced in step (a);    (c) diluting the solution from step (b) with water, toluene, and sodium metabisulfite;    (d) adding a suitable base to the solution from step (c) under controlled conditions to precipitate a crude L-DOPA ethyl ester free base;    (e) drying the precipitated crude L-DOPA ethyl ester free base from step (d); and    (f) recrystallizing the dried, precipitated crude L-DOPA ethyl ester free base from step (e) in the presence of a suitable solvent containing an antioxidant at a temperatures of less than 10° C. to produce the composition of pharmaceutically acceptable, crystalline, non-hygroscopic L-DOPA ethyl ester free base.    
     
     
         21 . The process of  claim 20 , wherein the amount of hydrogen chloride gas of step (a) is between 1-3 equivalents.  
     
     
         22 . The process of  claim 21 , wherein the hydrogen chloride gas of step (a) is between 1.75-2 equivalents.  
     
     
         23 . The process of  claim 20 , wherein the base solution in step (c) is sodium hydroxide solution or ammonium hydroxide.  
     
     
         24 . The process of  claim 23 , wherein the base solution in step (c) is sodium hydroxide solution.  
     
     
         25 . The process of  claim 20 , wherein the controlled conditions from step (d) are conditions in which addition of the sodium hydroxide solution is slowly performed in a nitrogen atmosphere, at a reaction temperature between 10-30° C. and a trace amount of L-DOPA ethyl ester is added to induce formation of precipitate.  
     
     
         26 . The process of  claim 25 , wherein reaction temperature is between 25-30° C.  
     
     
         27 . The process of  claim 20 , wherein the addition of a suitable base in step (d) effects an adjustment in the pH of the solution to a pH range between 6.5 and 8.0 to precipitate a crude L-DOPA ethyl ester base.  
     
     
         28 . The process of  claim 28 , wherein the addition of a suitable base in step (d) effects an adjustment in the pH of the solution to a pH range between 7.6 and 7.8 to precipitate a crude L-DOPA ethyl ester base.