盐酸左米那普仑的合成

Synthesis of Levomilnacipran Hydrochloride

以苯乙腈为起始原料,在氨基钠作用下与(R)-环氧氯丙烷反应后,经水解、分子内环合得(1S,5R)-1-苯基-3-氧杂二环[3,1,0]己烷-2-酮,在三氯化铝作用下与二乙胺反应得(1S,2R)-N,N-二乙基-2-羟甲基-1-苯基环丙烷-1-甲酰胺,再经氯代、盖布瑞尔反应、氨解,最后与盐酸成盐得盐酸左米那普仑,总收率25.5%(以苯乙腈计)。该工艺条件温和、操作简便,适合工业化生产。

Phenyl acetonitrile reacted with （R）-epichlorohydrin in the presence of sodium amide, followed by hydrolysis and intramolecular cyclization to provide （1S,5R）-1-phenyl-3-oxabicyclo[3.1.0]hexan-2-one, then it reacted with diethylamine in the presence of aluminium trichloride to give （1S,2R）-N,N-diethyl-2-（hydroxymethyl）-1-phenylcyclopropane-1-carboxamide, the latter was subjected to chlorination, Gabriel synthesis, ammonolysis and salification to prepare the target compound levomilnacipran hydrochloride with an overall yield of 25.5%. The process was suitable for industrial production in view of the mild condition and simple operation.