3-{{2-[N-(4-氰基苯基)亚氨基]氯甲基}-1-甲基苯并咪唑-5-基-(N-苄基甲酰氨基)}丙酸乙酯的合成及晶体结构  

Synthesis and crystal structure of ethyl 3-(N-benzyl-2-(chloro((4-cyanophenyl)imino)methyl)-1-methyl-1Hbenzo[d]imidazole-5-carboxamido)propanoate

作　　者：王悦秋[1] 王昌 马远东 梁大伟[1] WANG Yue-qiu;WANG Chang;MA Yuan-dong;LIANG Da-wei(School of Pharmacy&Medical Laboratory Science,Ya'an Polytechnic College,Ya'an 625100,China;Key Laboratory of Structure-based Drug Design&Discovery of Ministry of Education,Shenyang Pharmaceutical University,Shenyang 110016,China)

机构地区：[1]雅安职业技术学院药学与检验学院,四川雅安625100 [2]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：《精细与专用化学品》2025年第4期23-26,共4页Fine and Specialty Chemicals

基　　金：雅安市科技创新创业苗子工程重点项目(YKZ20211307);雅安市应用技术研究与开发项目(21KJJH0080)。

摘　　要：以2-{[(4-氰基苯基)氨基]甲基}-1-甲基苯并咪唑-5-甲酸(化合物2)为原料,经二氯亚砜氯代反应和进一步与3-(苄基氨基)丙酸乙酯反应,得到一种结构新颖的抗凝药物达比加群酯衍生物———3-{{2-[N-(4-氰基苯基)亚氨基]氯甲基}-1-甲基苯并咪唑-5-基-(N-苄基甲酰氨基)}丙酸乙酯(化合物1),优化并确定氯代反应的适宜条件为:n(化合物2)∶n(二氯亚砜)>1∶6,回流反应4h,化合物1的收率为77%(以化合物2为基准)。通过质谱、核磁和X-射线单晶衍射对化合物1的晶体结构进行检测,确定化合物1的晶体结构属于单斜晶系,P21/n空间群,晶胞参数a=14.2949(5)Å,b=11.1250(4)Å,c=21.2110(8)Å,α=90°,β=104.396(4)°,γ=90°,体积V=3267.3(2)Å^(3),单个晶胞中所含分子数Z=4,单个晶胞密度D_(c)=1.075g/cm^(3),衍射线波长μ=1.303mm^(-1),单胞中电子数目F(000)=1108.0。The synthesis and crystal structure of a novel dabigratran etexilate derivative,ethyl 3-(N-benzyl-2-(chloro((4-cyanophenyl)imino)methyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamido)propanoate(compound 1)was reported.The target compound was obtained by chlorination using 2-(((4-cyanophenyl)amino)methyl)-1-(methyl-)-1H-benzo[d]imidazole-5-carboxylic acid(compound 2)as the starting material,and compound 2 further reacted with ethyl 3-(benzylamino)propionate.The optimal conditions for the chlorination reaction were optimized and determined as follows:n(compound 2):n(SOCl_(2))>1:6,the reaction was heated to reflux for 4h and the yield was 77%(based on compound 2).The structure of the compound 1 was characterized by MS,NMR and X-ray single crystal diffraction.It was confirmed that the crystal structure belongs to the monoclinic system,P21/n space group,cell parameters a=14.2949(5)Å,b=11.1250(4)Å,c=21.2110(8)Å,α=90°,β=104.396(4)°,γ=90°,;VolumeV=3267.3(2)Å^(3),number of molecules in single cell Z=4,single cell density D_(c)=1.075g/cm^(3),diffraction wavelengthμ=1.303 mm=1,number of electrons in single cell F(000)=1108.0.

关 键 词：凝血酶抑制剂 氯代反应 工艺优化 晶体结构 

分 类 号：TQ463[化学工程—制药化工]