Synthesis Of Atypical Antipsychotic Olanzapine And Its Derivatives

Olanzapine(zyprexa) is a novel atypical antipsychotic that belongs to the thienobenzodiazepine class, with rare extrapyramidal side effects of typical antipsychotics. This paper simply introduces mechanism of action, research advances of antipsychotics, the pharmacology and clinical evaluation of olazapine,and so on.On the basis of the comprehensive analysis and evaluation of the reported synthesis routes of olanzapine,two synthesis routes of olanzapine were designed. Olanzapine was synthesized using sublimed sulfur,propaldehyde and malononitrile as starting materials by Gewald aminothiophene synthesis,Ullmann reaction,reduction,cyclization,condensation,and so on(route 2), which is investigated in detail.Meanwhile,the synthesis route 1 using ethyl cyanoacetate as starting material was also investigated.The structure of olanzapine prepared by the two synthesis route was identified by Mass and ~1H NMR,and the melting point of was identical with the value in the literature.The total yield of the synthesis route 2 was 29.3%(the international patent:20.3%,the literature at home:29.0%),while the total yield of the synthesis route 1 was 20.0%( the international patent:20.1%).The reaction conditions of important intermediate (4) and (5) were investigated in detail.Compared with the yield level of literatures their yields increased obviously respectively.The influence of reaction solvent,reaction time and recrystallization solvent on yield of products was investigated.The optimum synthetics reaction conditions were obtained.According to the reference literatures about structure-activity relationship and metabolic process of olanzapine,8 olanzapine derivatives were designed and synthesized under the condition that the basic structure kept constant,6 of them were not reported.Their structures were identified by Mass and ~1H NMR.