Method for preparing (2s,3r,4s)-4-hydroxyisoleucine and analogues thereof

Abstract

The invention concerns a method for preparing a-amino acids of general formula (2S-1) wherein: the group R1 represents a hydrogen atom, a group protecting the amino group or a group of formula —COOR2 wherein the group R2 represents a C1-C6 alkyl group, an aryl or aralkyl group. The invention also concerns a-amino acids of general formula (2S-1) wherein the group R1 represents a group protecting the amino group or a group of formula —COOR2 wherein the group R2 represents a C1-C6 alkyl group, an aryl or aralkyl group and their use as medicine.

1 . A method for synthesizing compounds of the following general formula (2S)-1:  
       
         
           
           
               
               
           
         
       
       in which the group R 1  represents a hydrogen atom, a group protecting the amine group or a group of formula —COOR 2  in which the group R 2  represents a C 1 -C 6  alkyl group, an aryl or aralkyl group 
 comprising the step a) of diastereo- and enantioselective reduction of the compound of the following formula 2:  
                     
 in order to obtain the compound of the following formula 3:  
                     
 with an enantiomeric excess of at least about 85%, preferably of at least about 90%, and a diastereomeric excess of at least about 90%, preferably of at least about 95%.  
 
     
     
         2 . The method as claimed in  claim 1 , characterized in that the diastereo- and enantioselective reduction is carried out using an enzyme.  
     
     
         3 . The method as claimed in  claim 2 , characterized in that a microorganism containing this enzyme, in particular  Geotrichum candidum,  is used.  
     
     
         4 . The method as claimed in any one of the preceding claims, characterized in that it comprises the additional steps of: 
 b) protection of the OH group of the alcohol of formula 3 with a group Y,    c) reduction of the group —COOEt to an alcohol, and    d) oxidation of the unprotected OH group obtained in    c) to obtain the aldehyde of the following general formula II:                          in which the group Y represents a group protecting the OH group.    
     
     
         5 . The method as claimed in  claim 4 , characterized in that it comprises an additional step e 1 ) of treatment of the compound of general formula II with a sulfinamide having the configuration (S)(+) in order to obtain the compound of the following general formula IV:  
       
         
           
           
               
               
           
         
       
       in which 
 the group Y represents a group protecting the OH group and the group R4 represents a C 1 -C 6  alkyl, aryl or aralkyl group.  
 
     
     
         6 . The method as claimed in  claim 5;  characterized in that it comprises an additional step f 1 ) of treatment of the compound of general formula IV in order to obtain the aminonitrile of the following general formula V:  
       
         
           
           
               
               
           
         
       
       in which 
 the group Y represents a group protecting the OH group and the group R4 represents a C 1 -C 6  alkyl, aryl or aralkyl group.  
 
     
     
         7 . The method as claimed in  claim 6 , characterized in that it comprises an additional step g 1 ) of treatment with an acid of the aminonitrile of general formula V in order to obtain the salt of the lactone of the following formula 9:  
       
         
           
           
               
               
           
         
       
     
     
         8 . The method as claimed in  claim 7 , characterized in that it comprises an additional step h 1 ) of alkaline hydrolysis of the salt of the lactone of formula 9 in order to obtain the compound of general formula (2S)-I in which the group R 1  represents a hydrogen atom.  
     
     
         9 . The method as claimed in  claim 4 , characterized in that it comprises an additional step e 2 ) of treatment of the compound of general formula II in order to obtain the aminonitrile of the following general formula III:  
       
         
           
           
               
               
           
         
       
       in which: 
 the group Y represents a group protecting the OH group and the group R 3  represents a group protecting the amine group.  
 
     
     
         10 . The method as claimed in  claim 9 , characterized in that it comprises an additional step f 2 ) of treatment with an acid of the aminonitrile of general formula III in order to obtain the lactone of the following general formula VI:  
       
         
           
           
               
               
           
         
       
       in which the group R 3  represents a hydrogen atom or a group protecting the amine group 
 followed, if necessary, by an additional step f 2.1 ) of treatment of the lactone of general formula VI in order to obtain the lactone of the following general formula VII:  
                     
 in which the group R 2  represents a C 1 -C 6  alkyl group, an aryl or aralkyl group.  
 
     
     
         11 . The method as claimed in  claim 10 , characterized in that it comprises an additional step g2) of diastereoselective hydrolysis of the lactone of general formula VI or VII in order to obtain the compound of general formula (2S)-I.  
     
     
         12 . The method as claimed in  claim 11 , in the case where the group R 3  represents the group protecting the amine group and the group R 1  represents a group protecting the amine group or a group of formula —COOR 2  in which the group R 2  represents a C 1 -C 6  alkyl group, an aryl or aralkyl group, characterized in that the diastereoselective hydrolysis consists in: 
 The alkaline hydrolysis of the lactone of general formula VI in which the group R 3  represents a group protecting the amine group or of general formula VII in order to obtain a mixture of diastereomers of the following general formula I:  
                     
  in which the group R 1  represents a group protecting the amine group or a group of formula —COOR 2  in which the group R 2  represents a C 1 -C 6  alkyl group, an aryl or aralkyl group,  
 The addition of an organic acid, preferably TFA, in the form of traces, and heating in order to recyclize the compound of the following general formula (2R)-I:  
                     
  in which the group R 1  represents a group protecting the amine group or a group of formula —COOR 2  in which the group R 2  represents a C 1 -C 6  alkyl group, an aryl or aralkyl group,  
 into a lactone of the following general formula (3R)-VIII:  
                     
  in which the group R 1  represents a group protecting the amine group or a group of formula —COOR 2  in which the group R 2  represents a C 1 -C 6  alkyl group, an aryl or aralkyl group,  
 The extraction, with an organic solvent, of the lactone of general formula (3R)-VIII in order to recover the compound of general formula (2S)-I in which the group R 1  represents a group protecting the amine group or a group of formula —COOR 2  in which the group R 2  represents a C 1 -C 6  alkyl group, an aryl or aralkyl group.  
 
     
     
         13 . The method as claimed in  claim 11 , characterized in that the diastereoselective hydrolysis consists in: 
 The diastereoselective enzymatic hydrolysis of the lactone of general formula (3R)-VI or (3R)-VII to give the compound of general formula (2R)-I,    The extraction with an organic solvent of the remaining nonhydrolyzed lactone of the following general formula (3S)-VIII:                           in which the group R 1  represents a hydrogen atom, a group protecting the amine group or a group of formula —COOR 2  in which the group R 2  represents a C 1 -C 6  alkyl group, an aryl or aralkyl group,    The nonselective enzymatic hydrolysis of the lactone of general formula (3S)-VIII in order to obtain the compound of general formula (2S)-I in which the group R 1  represents a hydrogen atom, a group protecting the amine group or a group of formula —COOR 2  in which the group R 2  represents a C 1 -C 6  alkyl group, an aryl or aralkyl group.    
     
     
         14 . The method as claimed in  claim 11 , in the case where the group R 3  represents the group protecting the amine group, characterized in that the diastereoselective hydrolysis consists in: 
 the crystallization, from an alcohol, of the lactone of general formula VI in an organic solvent so as to obtain the salt of the compound of formula (3S)-VIII in which the group R 1  represents a group protecting the amine group,    the catalytic hydrogenolysis of the salt of the compound of formula (3S)-VIII in which the group R 1  represents a group protecting the amine group so as to obtain the salt of the lactone of formula 9,    the alkaline hydrolysis of the salt of the lactone of formula 9 in order to obtain the compound of general formula (2S)-I in which the group R 1  represents a hydrogen atom.    
     
     
         15 . The method as claimed in any one of  claims 11  to  13  in the case where the group R 3  represents a group protecting the amine and the group R 1  represents a group protecting the amine group or a group of formula —COOR 2  in which the group R 2  represents a C 1 -C 6  alkyl group, an aryl or aralkyl group, characterized in that it comprises an additional step h 2 ) of catalytic hydrogenolysis of the compound of formula (2S)-I in which the group R 1  represents a group protecting the amine group or a group of formula —COOR 2  in which the group R 2  represents a C 1 -C 6  alkyl group, an aryl or aralkyl group in order to obtain the compound of general formula (2S)-I in which the group R 1  represents a hydrogen atom.  
     
     
         16 . The method as claimed in any one of claims  8 ,  11  to  15 , characterized in that it comprises an additional step of purifying the compound of general formula (2S)-I in which the group R 1  represents a hydrogen atom.  
     
     
         17 . The method as claimed in  claim 16 , characterized in that the purification step consists in neutralizing, with an organic acid, the compound of general formula (2S)-I in which the group R 1  represents a hydrogen atom and its crystallization from an alcohol in order to obtain the compound of general formula (2S)-I in which the group R 1  represents a hydrogen atom pure.  
     
     
         18 . A method of purifying the compound of general formula (2S)-I in which the group R 1  represents a hydrogen atom, characterized in that it consists in neutralizing, with an organic acid, the compound of general formula (2S)-I in which the group R 1  represents a hydrogen atom and its crystallization from an alcohol in order to obtain the compound of general formula (2S)-I in which the group R 1  represents a hydrogen atom pure.  
     
     
         19 . A method for synthesizing compounds of the following general formula (2S)-I:  
       
         
           
           
               
               
           
         
       
       in which the group R 1  represents a hydrogen atom, a group protecting the amine group or a group of formula —COOR 2  in which the group R 2  represents a C 1 -C 6  alkyl group, an aryl or aralkyl group by diastereoselective hydrolysis of the lactone of the following general formula VI or VII:  
       
         
           
           
               
               
           
         
       
       in which the group R 3  represents a hydrogen atom or a group protecting the amine group or the group R 2  represents a C 1 -C 6  alkyl group, an aryl or aralkyl group or by alkaline hydrolysis of the salt of the lactone of the following formula 9:  
       
         
           
           
               
               
           
         
       
     
     
         20 . The method as claimed in  claim 19 , in the case where the group R 1  represents a group protecting the amine group or a group of formula —COOR 2  in which the group R 2  represents a C 1 -C 6  alkyl group, an aryl or aralkyl group, characterized in that the diastereoselective hydrolysis consists in: 
 The alkaline hydrolysis of the lactone of general formula VII or VI in which R 3  represents a group protecting the amine group in order to obtain a mixture of diastereoisomers of the following general formula I:  
                     
  in which the group R 1  represents a group protecting the amine group or a group of formula —COOR 2  in which the group R 2  represents a C 1 -C 6  alkyl group, an aryl or aralkyl group,  
 The addition of an organic acid, preferably TFA, in the form of traces, and heating in order to recyclize the compound of the following general formula (2R)-I:  
                     
  in which the group R 1  represents a group protecting the amine group or a group of formula —COOR 2  in which the group R 2  represents a C 1 -C 6  alkyl group, an aryl or aralkyl group, into a lactone of the following general formula (3R)-VIII:  
                     
  in which the group R 1  represents a group protecting the amine group or a group of formula —COOR 2  in which the group R 2  represents a C 1 -C 6  alkyl group, an aryl or aralkyl group,  
 The extraction, with an organic solvent, of the lactone of general formula (3R)-VIII in order to recover the compound of general formula (2S)-I in which the group R 1  represents a group protecting the amine group or a group of formula —COOR 2  in which the group R 2  represents a C 1 -C 6  alkyl group, an aryl or aralkyl group.  
 
     
     
         21 . The method as claimed in  claim 19 , characterized in that the diastereoselective hydrolysis consists in: 
 The diastereoselective enzymatic hydrolysis of the lactone of general formula (3R)-VI or (3R)-VII to give the compound of general formula (2R)-I,    The extraction with an organic solvent of the remaining nonhydrolyzed lactone of the following general formula (3S)-VIII:                           in which the group R 1  represents a hydrogen atom, a group protecting the amine group or a group of formula —COOR 2  in which the group R 2  represents a C 1 -C 6  alkyl group, an aryl or aralkyl group,    The nonselective enzymatic hydrolysis of the lactone of general formula (3S)-VIII in order to obtain the compound of general formula (2S)-I.    
     
     
         22 . The method as claimed in  claim 19 , in the case where the group R 3  represents the group protecting the amine group, characterized in that the diastereoselective hydrolysis consists in: 
 the crystallization, from an alcohol, of the lactone of general formula VI in an organic solvent so as to obtain the salt of the compound of formula (3S)-VIII in which the group R 1  represents a group protecting the amine group,    the catalytic hydrogenolysis of the salt of the compound of formula (3S)-VIII in which the group R 1  represents a group protecting the amine group so as to obtain the salt of the lactone of formula 9,    the alkaline hydrolysis of the salt of the lactone of formula 9 in order to obtain the compound of general formula (2S)-I in which the group R 1  represents a hydrogen atom.    
     
     
         23 . The method as claimed in any one of  claims 19  to  21  in the case where the group R 1  represents a group protecting the amine group or a group of formula —COOR 2  in which the group R 2  represents a C 1 -C 6  alkyl group, an aryl or aralkyl group, characterized in that it comprises an additional step of catalytic hydrogenolysis of the compound of formula (2S)-I in which the group R 1  represents a group protecting the amine group or a group of formula —COOR 2  in which the group R 2  represents a C 1 -C 6  alkyl group, an aryl or aralkyl group in order to obtain the compound of general formula (2S)-I in which the group R 1  represents a hydrogen atom.  
     
     
         24 . The method as claimed in any one of  claims 19  to  22 , characterized in that the lactone of general formula VII is obtained by treating the lactone of general formula VI.  
     
     
         25 . The method as claimed in any one of claims  19  to  24 , characterized in that the lactone of general formula VI is obtained by treating, with an acid, the aminonitrile of the following general formula III:  
       
         
           
           
               
               
           
         
       
       in which: 
 the group Y represents a group protecting the OH group and the group R 3  represents a group protecting the amine group.  
 
     
     
         26 . The method as claimed in  claim 19 , characterized in that the lactone salt of formula 9 is obtained by treating, with an acid, the aminonitrile of the following general formula V:  
       
         
           
           
               
               
           
         
       
       in which: 
 the group Y represents a group protecting the OH group and the group R4 represents a C 1 -C 6  alkyl, aryl or aralkyl group.  
 
     
     
         27 . The method as claimed in  claim 25 , characterized in that the aminonitrile of general formula III is obtained by treating the aldehyde of the following general formula II:  
       
         
           
           
               
               
           
         
       
       in which the group Y represents a group protecting the OH group.  
     
     
         28 . The method as claimed in  claim 26 , characterized in [lacuna] the aminonitrile of general formula V is obtained by treating the compound of the following general formula IV:  
       
         
           
           
               
               
           
         
       
       in which: 
 the group Y represents a group protecting the OH group and the group R4 represents a C 1 -C 6  alkyl, aryl or aralkyl group.  
 
     
     
         29 . The method as claimed in  claim 28 , characterized in that the compound of general formula IV is obtained by treating the aldehyde of general formula II with a sulfinamide having the configuration (S)-(+).  
     
     
         30 . The method as claimed in either of claims  27  and  29 , characterized in that the aldehyde of general formula II is obtained by the steps of: 
 protection, with a group Y, of the OH group of the alcohol of the following formula 3:  
                     
 reduction of the —COOEt group to an alcohol and  
 oxidation of the unprotected OH group obtained in the preceding step.  
 
     
     
         31 . The method as claimed in  claim 30 , characterized in that the alcohol of formula 3 is obtained with an enantiomeric excess of at least about 85%, preferably of at least about 90%, and a diastereomeric excess of at least about 90%, preferably of at least about 95% by diastereo- and enantioselective reduction of the compound of the following formula 2:  
       
         
           
           
               
               
           
         
       
     
     
         32 . The method as claimed in  claim 31 , characterized in that the diastereo- and enantioselective reduction is carried out using an enzyme.  
     
     
         33 . The method as claimed in  claim 32 , characterized in that a microorganism containing this enzyme, in particular  Geotrichum candidum,  is used.  
     
     
         34 . A lactone of the following general formula VIII:  
       
         
           
           
               
               
           
         
       
       in which the group R 1  represents a group of formula —COOR 2  in which the group R 2  represents a C 1 -C 6  alkyl group, an aryl or aralkyl group in free form or in the form of salts.  
     
     
         35 . An aminonitrile of the following general formula III:  
       
         
           
           
               
               
           
         
       
       in which: 
 the group Y represents a group protecting the OH group and the group R 3  represents a group protecting the amine group.  
 
     
     
         36 . The aminonitrile as claimed in  claim 35 , characterized in that it is represented by the following general formula V:  
       
         
           
           
               
               
           
         
       
       in which: 
 the group Y represents a group protecting the OH group and the group R4 represents a C 1 -C 6  alkyl, aryl or aralkyl group.  
 
     
     
         37 . A compound of the following general formula general formula IV:  
       
         
           
           
               
               
           
         
       
       in which: 
 the group Y represents a group protecting the OH group and the group R4 represents a C 1 -C 6  alkyl, aryl or aralkyl group.  
 
     
     
         38 . A compound of the following general formula I:  
       
         
           
           
               
               
           
         
       
       in which the group R 1  represents a group of formula —COOR 2  in which the group R 2  represents a C 1 -C 6  alkyl group, an aryl or aralkyl group.  
     
     
         39 . The compound as claimed in  claim 38 , as a medicine.  
     
     
         40 . The compound as claimed in  claim 38 , as a medicine intended for the treatment of noninsulin-dependent diabetes mellitus.  
     
     
         41 . The use of the compound as claimed in  claim 38  for the manufacture of a medicine useful for treating noninsulin-dependent diabetes mellitus.