半富马酸喹硫平的合成工艺研究  

Study on the synthesis of quetiapine hemifumarate

作　　者：胡金星[1] 张凯[1] 刘海城[1] 李旭[1] 钱萍[1] 张晓菁[1] 宫平[1] 

机构地区：[1]沈阳药科大学基于靶点的药物设计与研究教育部重点实验室,辽宁沈阳110016

出　　处：《中国药物化学杂志》2015年第3期194-198,共5页Chinese Journal of Medicinal Chemistry

摘　　要：目的改进半富马酸喹硫平的合成工艺。方法 2-氨基二苯硫醚与三光气反应得到2-异氰酸基二苯硫醚,然后在多聚磷酸的作用下进行环合反应得到10H-二苯并[b,f][1,4]硫氮杂艹卓-11-酮,经三氯氧磷氯代、与无水哌嗪缩合、烷基化,最后与富马酸成盐得到半富马酸喹硫平。结果与结论改进了半富马酸喹硫平的合成路线,并且优化其合成工艺。目标化合物的结构经1H-NMR、13C-NMR、MS谱确证。新合成路线原料廉价易得、操作简便,为半富马酸喹硫平的工艺放大奠定了一定基础。Quetiapine hemifumarate developed by AstraZeneca in Britain, one of effective atypical antipsy- chotic agent,is widely used in clinical. However, there exists some limitation, such as high cost of original material, enviromentally unfriendly substance phenyl chloroformate with under-utilization, and excess polyphosphoric acid during the cyclization process. Therefore, it is of great value in improving the synthesis process of quetiapine hemifumarate. Synthesis of quetiapine hemifumarate was optimized thoroughly based on references. Taking 2-nitroaniline as starting material, target compound was obtained after a series ofchemical reactions including reduction through a ＂one-pot＂ process, acetylation, diazotization, denitrifica- tion, cyclization, chlorination, condensation and alkylation. Finally, the target product quetiapine hemi- fumarate was gained through salification with fumaric acid. All of the key intermediates and quetiapine hemi- fumarate were confirmed by 1H-NMR, 13C-NMR and MS spectra. Their purity were determined by HPLC. The improved procedure can reduce the cost of pre-paration and environmental pollution, increase the yield, and make it more suitable for the industrial requirements.

关 键 词：半富马酸喹硫平 抗精神病药 合成 

分 类 号：R914[医药卫生—药物化学]