Study On Synthesis Of Nefiracetam, Etiracetam And Analogues

Cognitive dysfuntions occur in persons of all ages. They may result from disease, accident , developmental defects, or aging. The development of effective drugs for treatment of cognitive dysfuntions is one of the greatest challenges in the medicinal chemistry today. Piracetam -like drugs are important cognition enchancers. Nefiracetam, etiracetam and a series of 2-(2-oxo-l-pyrrolidinyl) acetamide and 2-(2-oxo-1- pyrrolidinyl) butyramide were synthesized in this paper:Nefiracetam was synthesized by N-acylation of 2,6-dimethylaniline with chloroacetylchloride and N-alkylation of 2-pyrrolidone. The N-acylation reaction was performed in the toluene in the presence of 10% NaCO3 solution, and the yield was 95.3%. The optimum process conditions of N-alkylation reaction were determined by orthogonal experiment as follows: the base was sodium hydride, the solvent was toluene, reaction time was 2 hours and the phrase transfer catalyst was TEBA, and the yield was 94.3%. The structure of nefiracetam was confirmed by IR, 1H NMR, 13C NMR and MS. This synthetic method was feasible and suitable for industry.Etiracetam was firstly synthesized from 2-pyrrolidone by N- alkylation reaction and aminolysis reaction in internal. The process conditions of synthesis of etiracetam were obtained as follows: in the presence of phrase transfer catalyst TEBA, the N-alkylation was performed for 6 hours at 75-80 in the toluene, the aminolysis was performed for 27 hours at 30 in the methanol, and the overall yield was 42.6% . Etiracetam was also synthesized by aminolysis at first and then N-alkylation. The aminolysis was performed for 6 hours at 5癈 in the methanol. The N-alkylation was performed for 4 hours in the THF. This process was better than the other listed above. The overall yield was 45.7%. The structure of etiracetam was confirmed by IR, 1H NMR and 13C NMR .An key intermediate of levetiracetam, (S)-4-methylthio-2-(2-oxo-1-pyrrolidinyl) butryamide, was firstly synthesized from L- methionine by acidification, esterification, aminolysis, N- acylation and cyclization. The structure of (S)-4-methylthio-2-(2-oxo-l -pyrrolidinyl) butryamide was confirmed by 1H NMR and 13C NMR.According to the relation between the structure and biological activity of compounds developed, a series of 2-(2-oxo-1-pyrrolidinyl) acetamide and 2-(2-oxo-l- pyrrolidinyl) butyramide, N-phenyl-2-(2-oxo-1-pyrrolidinyl) acetamide, N-(2-methylphenyl) -2-(2- oxo-1-pyrrolidinyl) acetamide, N-(2-methyl-6-ethylphenyl)- 2-(2-oxo-1-pyrrolidinyl) acetamide, N-( 1 -naphthyl)-2-(2-oxo-l-pyrrolidinyl) acetamide, N-(4-methoxyphenyl)- 2-(2-oxo-l-pyrrolidinyl) acetamide, and N-(2,6-dimethylphenyl)- 2-(2-oxo- 1-pyrrolidinyl) butyramide, were designed and synthesized. Four new compounds and two target compounds were obtained in high yield at experiment conditions. The structure of new compounds and target compounds was confirmed by IR, 1H NMR and 13C NMR.