Intermediate compound for synthesizing pharmaceutical agent and production method thereof

Abstract

The present invention relates to a production method of an optically active morpholine compound represented by the formula 10, which includes the following steps: wherein each symbol is as defined in the specification. The present invention also relates to a production method of an compound represented by the formula 55, which includes the following steps: wherein each symbol is as defined in the specification. According to the production method of the present invention, an optically active 2-aryl-substituted morpholine compound and 3-oxo-3-(pyrimidin-4-yl)propionate, which are important as starting materials for synthesizing 2-(2-arylmorpholin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one having a tau protein kinase 1 inhibitory activity and useful as a therapeutic drug for Alzheimer's disease and the like, can be produced in a high yield by an industrially advantageous method.

1 . A production method of an optically active compound represented by the formula (I), 
       
         
           
           
               
               
           
         
       
       wherein R is an aryl optionally having substituent(s) or a heteroaryl optionally having substituent(s), and a carbon atom marked with * is an asymmetric carbon atom; which comprises Step (1) or (2):
 Step (1) synthesizing an optically active compound represented by the formula 5, which comprises the following steps: 
 
       
         
           
           
               
               
           
         
       
       wherein R is an aryl optionally having substituent(s) or a heteroaryl optionally having substituent(s), X 1  is a halogen, and R 1  is a C 1 -C 6  alkyl, an aralkyl optionally having substituent(s) or a C 2 -C 6  alkenyl
 reacting a compound of the formula 1 with a borane or a complex thereof in a solvent in the presence of (S)-2-methyl-CBS-oxazaborolidine to give a compound of the formula 2, 
 reacting the compound of the formula 2 with a base in a solvent to give a compound of the formula 3, and 
 reacting the compound of the formula 3 with an amine of the formula 4 to give the compound of the formula 5; or 
 Step (2) synthesizing an optically active compound represented by the formula 25, which comprises the following steps: 
 
       
         
           
           
               
               
           
         
       
       wherein R is an aryl optionally having substituent(s) or a heteroaryl optionally having substituent(s), X 1  is a halogen, and R 1  is a C 1 -C 6  alkyl, an aralkyl optionally having substituent(s) or a C 2 -C 6  alkenyl;
 reacting a compound of the formula 21 with a borane or a complex thereof in a solvent in the presence of (R)-2-methyl-CBS-oxazaborolidine to give a compound of the formula 22, 
 reacting the compound of the formula 22 with a base in a solvent to give a compound of the formula 23, and 
 reacting the compound of the formula 23 with an amine of the formula 24 to give the compound of the formula 25. 
 
     
     
         2 . A production method of an optically active compound represented by the formula (I), 
       
         
           
           
               
               
           
         
       
       wherein R is an aryl optionally having substituent(s) or a heteroaryl optionally having substituent(s), and a carbon atom marked with * is an asymmetric carbon atom; which comprises the use of a compound of any one of Groups (1), (2), (3) and (4):
 Group (1) an optically active compound represented by the formula 11: 
 
       
         
           
           
               
               
           
         
       
       wherein R is an aryl optionally having substituent(s) or a heteroaryl optionally having substituent(s), R 1  is a C 1 -C 6  alkyl, an aralkyl optionally having substituent(s) or a C 2 -C 6  alkenyl, and R 10  is a hydrogen atom or a group represented by the formula: —CO—CH 2 —X 2  (wherein X 2  is a halogen), or a salt thereof;
 Group (2) the compound of Group (1), wherein R is a phenyl having 1 to 3 substituents selected from halogen, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy, substituted C 1 -C 6  alkoxy, nitro, aralkyloxy, C 1 -C 6  alkylsulfonyloxy, arylsulfonyloxy and C 1 -C 6  alkyl-substituted arylsulfonyloxy, or a salt thereof; 
 Group (3) an optically active compound represented by the formula 31: 
 
       
         
           
           
               
               
           
         
       
       wherein R is an aryl optionally having substituent(s) or a heteroaryl optionally having substituent(s), R 1  is a C 1 -C 6  alkyl, an aralkyl optionally having substituent(s) or a C 2 -C 6  alkenyl, and R 10  is a hydrogen atom or a group represented by the formula: —CO—CH 2 —X 2  (wherein X 2  is a halogen), or a salt thereof; or
 Group (4) the compound of Group (3), wherein R is a phenyl having 1 to 3 substituents selected from halogen, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy, substituted C 1 -C 6  alkoxy, nitro, aralkyloxy, C 1 -C 6  alkylsulfonyloxy, arylsulfonyloxy and C 1 -C 6  alkyl-substituted arylsulfonyloxy, or a salt thereof.