Synthesis of chirally purified substituted benzothiazole diamines

Abstract

Methods for preparing chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamines such as, for example, (6R)2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole and purifying a dominant enantiomer of substituted 4,5,6,7-tetrahydro-benzothiazole diamines from entantiomerically enriched mixtures of substituted 4,5,6,7-tetrahydro-benzothiazole diamines are provided herein.

1 . A process for preparing a chirally purified substituted 4,5,6,7,-tetrahydro-benzothaizole diamine comprising:
 heating a solution comprising entantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine of general formula (I):   
       
         
           
           
               
               
           
         
         wherein: 
         R 1  represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl or alkynyl group each having 3 to 6 carbon atoms, an alkanoyl group having 1 to 6 carbon atoms, a phenyl alkyl or phenyl alkanoyl group having 1 to 3 carbon atoms in the alkyl part, whilst the above-mentioned phenyl nuclei may be substituted by 1 or 2 halogen atoms; 
         R 2  represents a hydrogen atom or an alkyl group with 1 to 4 carbon atoms; 
         R 3  represents a hydrogen atom, an alkyl group with 1 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms, an alkanoyl group having 1 to 7 carbon atoms, a phenyl alkyl or phenyl alkanoyl group having 1 to 3 carbon atoms in the alkyl part, whilst the phenyl nucleus may be substituted by fluorine, chlorine or bromine atoms, 
         R 4  represents a hydrogen atom, an alkyl group with 1 to 4 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms; and 
         at least one or R 1 , R 2 , R 3  or R 4  is a hydrogen in an organic solvent; and 
         an alkyl sulfonate or an alkyl halide in a solvent to form a reaction mixture; 
         reacting the reaction mixture; and 
         recovering a chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine. 
       
     
     
         2 - 28 . (canceled) 
     
     
         29 . Chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole prepared by a process comprising:
 heating a solution comprising entantiomerically enriched 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and a propyl halide or a propyl sulfonate to form a reaction mixture;   reacting the reaction mixture; and   recovering the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole.   
     
     
         30 - 52 . (canceled) 
     
     
         53 . A process for preparing a chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole comprising:
 heating a solution comprising 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole in an organic solvent;   adding to the heated solution propyl sulfonate or a propyl halide to form a reaction mixture; and   reacting the reaction mixture for up to about 12 hours.   
     
     
         54 - 79 . (canceled) 
     
     
         80 . A process for preparing chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole comprising:
 heating a solution comprising 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole;   adding a propyl halide or a propyl sulfonate to the heated solution slowly over from about 0.5 hours to about 2 hours to form a reaction mixture;   reacting the reaction mixture; and   recovering the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole.   
     
     
         81 - 101 . (canceled) 
     
     
         102 . Chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole prepared by a process comprising:
 heating a solution comprising 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole;   adding a propyl halide or a propyl sulfonate to the heated solution slowly over from about 0.5 hours to about 2 hours to form a reaction mixture;   reacting the reaction mixture; and   recovering the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole.   
     
     
         103 - 125 . (canceled) 
     
     
         126 . A process for preparing chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole comprising:
 dissolving entantiomerically enriched 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole in an organic solvent to form a solution;   heating the solution to from about 50° C. to about 125° C.;   adding an acid to the solution to form a reaction mixture; and   recovering the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole.   
     
     
         127 - 128 . (canceled) 
     
     
         129 . A chirally pure 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole prepared by a process of  claim 126 . 
     
     
         130 . A process for preparing chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole comprising:
 dissolving entantiomerically enriched 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole in an organic solvent to form a solution;   heating the solution to from about 50° C. to about 125° C.;   adding an achiral salt to the solution to form a reaction mixture; and   recovering the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole.   
     
     
         131 - 132 . (canceled) 
     
     
         133 . A chirally pure 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole prepared by a process of  claim 130 . 
     
     
         134 . A process for preparing a 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole dihydrochloride comprising:
 dissolving a 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole salt in an organic solvent to form a solution;   cooling the solution to a temperature of from about 0° C. to about 5° C.;   adding concentrated HCl and an organic solvent to the cooled solution; and   stirring the solution at a temperature of about 0° C. to about 5° C.