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:
 synthesizing a compound represented by the formula 55, which comprises the following steps: 
 
       
         
           
           
               
               
           
         
       
       wherein R a  and R b  are the same or different and each is a C 1-6  alkyl,
 reacting orotic acid of the formula 51 with an alkylating agent in a solvent in the presence of a base to give a compound of the formula 52, 
 heating the compound of the formula 52 under reflux with a chlorinating agent to give a compound of formula 53, 
 dechlorinating the compound of the formula 53 in the presence of a base to give a compound of the formula 54, and 
 reacting the compound of the formula 54 with acetate in the presence of a base to give the compound of the formula 55.