Study On The Green Synthesis Process Of 4-methyl-3-oxo-N-phenylpentaneamide And Related Compounds

This thesis mainly explores the solvent-free amidation process of 4-methyl-3-oxo-N-phenylpentaneamide（1-18）and the separation,identification and source analysis of an unknown impurity.In addition,the green amidation process was applied to the synthesis of teriflunomide intermediates and achieved good results.The thesis mainly includes three parts.In the first part,the progress in the synthesis of amides is reviewed,and the important role of amides in organic synthesis is briefly introduced.Secondly,the synthetic routes of two drug intermediates 1-18 and 1-22 are reviewed.Intermediates 1-18 and 1-22 are amide compounds;finally,the synthetic routes of intermediates 1-18 and 1-22 were selected.In the second part,the analytical method,central control method and quality standard of intermediates 1-18 were established based on HPLC.Secondly,the process conditions such as catalyst,reaction temperature,reactant molar ratio and reaction time were optimized.Finally,the source of the new impurity 2-1 was analyzed,and its structure was confirmed by ¹H NMR,¹³C NMR,HRMS,¹H-¹H-COSY,DEPT,HMBC and HMQC.In the third part,the green solvent-free amidation reaction conditions of the synthesis1-18 were applied to the synthesis intermediate 1-22,and the green solvent-free synthesis process of the intermediate 1-22 was further optimized.Firstly,the analytical method,central control method and quality standard of the intermediate 1-22 were established by HPLC.Secondly,the process conditions such as catalyst,reaction temperature,reactant molar ratio and reaction time were optimized.For the synthesis of intermediates 1-18 and 1-22,the conventional solvents such as toluene and xylene with high toxicity coefficient are abandoned and the reaction raw materials are used as solvents.The post-treatment removes the water and hydrochloric acid treatment,dichloromethane treatment and recovery,and the subsequent treatment is direct vacuum concentration to the intermediates 1-18 and 1-22,and the raw materials can be recovered.After optimization,a mild,high-yield,high-purity,low-impurity,and green amidation reaction process conditions were constructed,which is a route suitable for industrial production.