奥氮平合成新工艺研究

Study on the novel process for synthesizing Olanzapine

研究了以硫、丙醛以及丙二腈为原料，经关环反应、还原反应、缩合反应制得奥氮平的新工艺．考察了反应试剂、缩合剂、反应物配比、反应温度等因素的影响，得到了最佳工艺组合：关环反应温度取20～25℃；缩合反应以氢氧化钾为缩合剂，用邻硝基氟苯替代邻硝基氯苯合成关键中间体2-（邻硝基苯胺基）-3-氰基-5-甲基噻吩；2-（2-硝基苯胺基）-3-氰基-5-甲基噻吩与二氯亚锡投料比1：4．0，还原关环产物与N-甲基哌嗪投料比1：8．0．在优化条件下，奥氮平总收率为38％．

A novel preparation process for Olanzapine starting from sulphur, propioaldehyde and malononitrile by ring-closure, reduction, condensation reactions was studied. The influence factors such as reactants, condensing agent, the molar ratio of reactants and the reaction temperature were investigated. The optimum process parameters were determined as follow., the temperature of ring-closure reaction was 20 ～ 25 ℃. The key intermediate 2-（2-nitrophenylamino）- thiophene-3-carbonitrile was synthesized by condensation of 2-amino-5-methylthiophene-3- carbonitrile and 2-fluoronitrobenzene in the presence of KOH~ 2-（ 2-nitroanilino ）-5- methylthiophene-3-carbonitrile ： SnCl2 = 1 ： 4.0. The product of reduction and ring-closure ; N- methyl-piperazine= 1 ： 8.0. The total yield of Olanzapine was improved to 38%.