摘要
目的改进抗静脉血栓药利伐沙班的合成工艺。方法以苯乙醇胺为原料,先与氯乙酰氯反应成环后,经硝化、还原、酰化得到N-苄氧羰基-4-(3-吗啉酮)苯胺(5),中间体5与(S)-N-(2,3-环氧丙基)邻苯二甲酰亚胺环合、肼解得到4-{4-[(5S)-5-(氨基甲基)-2-氧代-1,3-唑烷-3-基]苯基}吗啉-3-酮(7),7与5-氯-2-噻吩甲酰氯反应得到利伐沙班。结果与结论目标化合物的结构经IR、1H-NMR和MS谱确证。改进后的工艺操作简单,生产成本低廉,利于工业化生产,7步反应的总收率由文献报道的29.5%提高至50.2%。
Rivaroxaban（1 ）, a new class of highly potent FXa inhibitors has been used for the treatment of thrombolic diseases. An improved preparation method was used to synthesize the target compound in this pa- per. Benzyl 4-（ 3-oxomorpholino ） phenylcarbamate （ 5 ） was synthesized by cyclization, nitration, reduction and acylation starting from 2-anilino ethanol. Compound 5 was subjected to cyclization with （S）-N-（ 2,3- epoxypropyl） phthalimide, hydrolysis with hydrazine hydrate and reaction with 5-chlorothiophene-2-carbonyl chloride to give rivaroxaban. The total yield was improved from 29. 5% to 50. 2%. The structure of rivaro- xaban and its intermediates were identified by 1H-NMR spectra. Compared with the synthetic process repor- ted in the literature, this synthetic route is simple and suitable for industrialized production owing to simple operation, high security and high yield.
出处
《中国药物化学杂志》
CAS
CSCD
2013年第1期26-29,共4页
Chinese Journal of Medicinal Chemistry
关键词
工艺改进
苯乙醇胺
利伐沙班
合成
process improvement
2-anilino ethanol
rivaroxaban
synthesis
