阿哌沙班的合成工艺研究  

The process research of apixaban

作　　者：张乾坤 沈思思 张峻铭 郭奥锋 沙宇[1] ZHANG Qian-kun;SHEN Si-si;ZHANG Jun-ming;GUO Ao-feng;SHA Yu(Key Laboratory of Structure-Basod Drug Design and Discovery(Shenyang Pharmaceutical University),Ministry of Education,Shenyang 110016,China;Department of Pharmacy,General Hospital of Anshan Iron and Steel Group,Anshan 114000,China)

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 [2]鞍钢集团公司总医院药剂科,辽宁鞍山114000

出　　处：《中国药物化学杂志》2022年第3期199-203,共5页Chinese Journal of Medicinal Chemistry

摘　　要：目的研究阿哌沙班的合成工艺,以获得适合工业化生产的合成路线。方法以5,6-二氢-3-(4-吗啉基)-1-(4-硝基苯基)-2(1H)-吡啶酮和[(4-甲氧基苯基)肼基]氯乙酸乙酯为起始原料,依次经过[3+2]环合-消除、还原、酰胺化、环合、水解、与N,N′-羰基二咪唑(CDI)作用得活性酰胺中间体,再经氨水氨解得目标化合物阿哌沙班。结果与结论所得终产物阿哌沙班经HPLC检测纯度达到99.8%以上,总收率36.2%,且单一杂质的含量均低于0.1%,符合工业化生产的要求。通过X射线粉末衍射测试确证制备的阿哌沙班晶型为N-1晶型。Apixaban is increasingly available and will play a significant role in the prevention and treatment of thrombotic diseases in humans,from a market perspective,sales and market share of apixaban are increasing year by year,and it is of great economic value to develop a route capable of industrial production.It has been reported that 3-morpholine-1-(4-nitrophenyl)-5,6-dihydropyridine-2(1H)-one(1)was obtained from cyclopentanone oxime as raw material through three steps of rearrangement,dichlorosubstitution,condensation and nucleophilic substitution.Using p-methoxy-aniline as starting material,2-chloro-2-[2-(4-methoxy-phenyl)hydrazone]ethyl acetate was obtained by Japp-Klingmann reaction.The target compound was obtained by[3+2]cyclization,demorpholine,reduction,amidation,cyclization and aminolysis.The reaction route is long,a large amount of iron slag is generated by iron powder reduction and the environment is polluted,and the method of formamide ammonolysis to obtain the target compound under the catalysis of sodium methoxide is troublesome for post-processing and the product purity is poor.The route in the literature is improved:take 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridone and[(4-methoxyphenyl)hydrazine ethyl]chloroacetate as the starting material,followed by[3+2]cyclization-elimination,reduction,amidation,cyclization,and hydrolysis to obtain compound 6,compound 6 and 1,1′-carbonyldiimidazole(CDI)acts as an active amide intermediate,which is then subjected to ammonia hydrolysis to obtain the target compound apixaban.The purity of the final product apixaban was determined to be over 99.8%by HPLC,and the total yield of the route was 36.2%.And the single impurity content is less than 0.1%.This method is suitable for the preparation of apixaban in industrial production.An X-ray powder diffraction test was performed on the prepared apixaban,and the test results confirmed that the prepared apixaban crystal form was N-1 crystal form.

关 键 词：XA因子抑制剂 阿哌沙班 工艺优化 

分 类 号：R914[医药卫生—药物化学]