Process for the preparation of substituted thiazolines and their intermediates

Abstract

Process for the preparation of substituted thiazolines of the formula (I) in which Ar is a phenyl, naphthyl, thienyl, pyridyl or quinolinyl radical which can optionally be substituted by one or more substituents from the group consisting of halogen, OH, benzyloxy, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, COOR 1 where R 1 is H or C 1 -C 4 -alkyl, by coupling of (S)-α-methylcysteine hydrochloride of the formula (II) with a nitrile of the formula (III) Ar—CN in which Ar is as defined above, or a corresponding C 1 -C 4 -alkyl imidate, in which (S)-α-methylcysteine hydrochloride of the formula (II) is reacted in a suitable solvent with a nitrile of the formula (III) or a corresponding C 1 -C 4 -alkyl imidate in the presence of a tertiary base at a pH of 6.5 to 10 at 50 ° C. up to the reflux temperature to give the corresponding thiazoline of the formula (I), and processes for the preparation of (S)-α-methylcysteine hydrochloride and its use for the preparation of thiazolines of the formula (I).

1 - 6 . (canceled)  
     
     
         7 . A process for the preparation of the (S)-α-methylcysteine hydrochloride of the formula (II)  
       
         
           
           
               
               
           
         
       
       which comprises 
 a) coupling an L-cysteine compound of the formula (IV)  
                     
 in which R 2  is H or C 1 -C 4 -alkyl, to optionally substituted nitriles of the formula (V)  
   Ar—CN  
 in which Ar is a phenyl, naphthyl, thienyl, pyridyl or quinolinyl radical which can optionally be substituted by one or more substituents from the group consisting of halogen, OH, benzyloxy, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, COOR 1  where R 1  is H or C 1 -C 4 -alkyl, where the OH groups can optionally be protected by a suitable protective group, or a corresponding C 1 -C 4 -alkyl imidate, in the presence of 0.9 to 1.3 mol of a tert-base per mole of L-cysteine compound in a C 1 -C 4 -alcohol, a mixture of two or more C 1 -C 4 -alcohols or a mixture of C 1 -C 4 -alcohol and a hydrocarbon to give a compound of the formula (VI)  
                     
 in which Ar and R 2  are as defined above,  
 which  
 b) if R 2  is H, is then converted into a C 1 -C 4 -ester, then  
 c) is methylated in an ether as solvent using 1 to 3 mol of a methylating reagent per mole of the compound of the formula (VI) and in the presence of 1 to 1.5 mol of a base per mole of the compound of the formula (VI) at a temperature of −80° C. to +40° C. to give the corresponding thiazoline of the formula (VII)  
                     
 in which Ar is as defined above and R 3  is C 1 -C 4 -alkyl,  
 whereupon  
 d) by means of basic hydrolysis, the corresponding thiazolinecarboxylic acid of the formula (VIII)  
                     
 in which Ar is as defined above, is obtained as a racemate, where, by the addition of the base, a two-phase reaction mixture is obtained, which is stirred at reflux temperature and then cooled, whereupon the aqueous phase is treated with HCl until a pH of between 1.5 and 4.5 is achieved, whereby the carboxylic acid racemate separates as an oil, which  
 e) is cleaved by addition of a chiral amine as cleavage base, the corresponding salt of the carboxylic acid is crystallized out and the corresponding chiral acid is released in a water-immiscible solvent which is resistant to HCl by addition of HCl until a pH of the aqueous phase of between 1 and 4 is achieved, separation of the organic phase and of the solvent or  
 f) instead of the resolution by means of cleavage bases, a lipase-catalyzed resolution of the compound of the formula (VII) to give the free acid is carried out, whereupon  
 b) g) following step e) or f), the (S)-thiazolinecarboxylic acid of the formula (VIII) obtained is dissolved in HCl, the solution is boiled at reflux temperature and cooled to 0 to 30° C., precipitated cleavage products are separated off, the acidic filtrate is optionally extracted for the complete removal of the cleavage products, whereupon the aqueous phase is either spray dried or completely or partially evaporated and, if not completely evaporated, the water is stripped off by azeotropic distillation by addition of a suitable solvent, whereupon (S)-2-methylcysteine.HCl is obtained in solution or as a suspension or, if appropriate for the precipitation of crystalline (S)-2-methylcysteine.HCl, an ether or a hydrocarbon is added to the remaining suspension or solution, whereupon a crystalline precipitate of (S)-2-methylcysteine.HCl is obtained.  
 
     
     
         8 . The process as claimed in  claim 7 , wherein the lipase employed is pig liver esterase, Candida rugosa lipase, Aspergillus species lipase, Aspergillus species protease, Bacillus species protease, subtilisin Carlsberg, Candida antarctica “A” lipase, Candida antarctica “B” lipase, ChiroCLEC TM-PC  (dry) or ChiroCLEC TM-PC  (slurry).  
     
     
         9 . A process for the preparation of the (S)-α-methylcysteine hydrochloride of the formula (II)  
       
         
           
           
               
               
           
         
       
       which comprises 
 a) reacting L-cysteine ethyl ester.HCl with 2 to 3 equivalents of acetone in a hydrocarbon as solvent or in acetone itself, if appropriate in the presence of a tert-amine, to give the corresponding acetonide, which  
 b) is dissolved in 2 to 3 equivalents of formic acid and treated with toluene or acetic anhydride, whereupon the reaction mixture is concentrated and partitioned between an ether, ester or suitable hydrocarbon and a sodium hydrogencarbonate, NaOH or KOH solution, the organic phase is azeotropically dried and freed of the solvent, whereupon  
 c) the N-formylated acetonide thus obtained, ethyl 3-formyl-2,2-dimethylthiazoline-4-carboxylate, is converted by deprotonation using 1 to 1.5 equivalents of lithium diisopropylamide and subsequent reaction with 1 to 2 equivalents of methylating agent into the racemic ethyl 3-formyl-2,2,4-trimethylthiazoline-4-carboxylate, whereupon  
 d) by means of selective ester hydrolysis using a lipase, 3-formyl-2,2,4-trimethylthiazoline-4-carboxylic acid is obtained, whereupon  
 e) an acidic hydrolysis by means of HCl is carried out, boiling at reflux temperature and cooling to 0 to 30° C., either spray drying the aqueous phase or completely or partially evaporating it and, if not completely evaporated, stripping off the water by means of azeotropic distillation by addition of a suitable solvent, whereupon (S)-2-methylcysteine.HCl is obtained in solution or as a suspension or, if appropriate for the precipitation of crystalline (S)-2-methyl-cysteine.HCl, an ether or a hydrocarbon is added to the remaining suspension or solution, whereupon a crystalline precipitate of (S)-2-methylcysteine.HCl is obtained.  
 
     
     
         10 - 11 . (canceled)