抗帕金森性精神病药物哌马色林的合成

Synthesis of Pimavanserin for Parkinson’s Psychosis

以对羟基苯乙酸为原料,经酯化、烷基化、酯水解、酰化、霍夫曼重排、水解和酰化反应合成了N-(4-异丁氧基苄基)氨基甲酸苯酯(9);再以对氟苄氨和N-甲基-4-哌啶酮为原料经过还原胺化生成4-(4-氟苄基氨基)-1-甲基哌啶(10);最后中间体(9)和中间体(10)经氨解反应合成哌马色林,总收率为50.2%,其结构经1H NMR和13C NMR确证。

Phenyl[4-(2-methylpropoxy)benzyl]carbamate(9)was synthesized by seven-steps reactions of esterification,alkylation,hydrolysis,acylation,Hofmann rearrangement,hydrolysis,and acylation using 4-hydroxyphenylacetic acid as the starting material;then 4-(4-fluorobenzylamino)-1-methylpiperidine(10)was obtained by Borch reduction using 4-fluorobenzylamine and N-methyl-4-piperidinone as the starting materials;finally the resulting product(9)underwent an ammonolysis reaction with 4-(4-fluorobenzylamino)-1-methyl piperidine(10)to give the final product of Pimavanserin with the total yield of 50.2%.The structure of Pimavanserin was confirmed by 1H NMR and 13C NMR.