硫代乙内酰脲衍生物Ru59063的公斤级合成  

Kilogram-scale synthesis of thiohydantoin derivative Ru59063

作　　者：赵娅敏[1,2] 李泽坤 魏立梁 马瑜浩 刘荣 ZHAO Yamin;LI Zekun;WEI Liiang;MA Yuhao;LIU Rong(College of Chemical Engineering,Northwest Minzu University,Lanzhou 730000,Gansu,China;Key Laboratory of Utility of Environmental Friendly Composite Materials and Biomass in Universities of Gansu Province,Lanzhou 730000,Gansu,China;Gansu Chemical Industry Research Institute Co.,Ltd.,Lanzhou 730000,Gansu,China;Key Laboratory of Fine Chemicals of Gansu Province,Lanzhou 730020,Gansu,China)

机构地区：[1]西北民族大学化工学院,甘肃兰州730000 [2]甘肃省高校环境友好复合材料及生物质利用省级重点实验室,甘肃兰州730000 [3]甘肃省化工研究院有限责任公司,甘肃兰州730000 [4]甘肃省精细化工重点实验室,甘肃兰州730020

出　　处：《精细化工》2023年第12期2781-2784,共4页Fine Chemicals

基　　金：中央高校基本科研业务费专项资金项目(31920180003)。

摘　　要：对Ru59063的合成进行了改进。首先,4-氨基-2-(三氟甲基)苯甲腈(Ⅲ)与硫光气反应,制备了4-异硫氰基-2-(三氟甲基)苯腈(Ⅳ);然后,中间体Ⅳ与2-氨基异丁酸甲酯盐酸盐进行[3+2]环加成反应,合成了4-(2-硫代-4,4-二甲基-5-氧代咪唑烷-1-基)-2-三氟甲基苯腈(Ⅶ);化合物Ⅶ再与叔丁基-(4-氯丁氧基)-二甲基硅烷通过乌尔曼C—N偶联反应,得到了4-{3-[4-(叔丁基二甲基硅基)-羟基丁基]-4,4-二甲基-5-氧代-2-硫代咪唑烷-1-基}-2-(三氟甲基)苯甲腈(Ⅷ);最后,中间体Ⅷ进行羟基脱保护得到Ru59063,4步反应总收率为61.6%,HPLC纯度为98.2%。与传统方法相比,该法收率提高了4.7倍,并且未使用氰化物,可以更方便、更安全地制备了Ru59063。对2 kg 4-氨基-2-(三氟甲基)苯甲腈进行了放大实验,总收率可达到60.7%。The synthesis of Ru59063 was improved.Here,intermediate 4-isothiocyanato-2-(trifluoromethyl)benzonitrile(Ⅳ)was firstly prepared from 4-amino-2-(trifluoromethyl)benzonitrile(Ⅲ)and thiophosgene,which further reacted with methyl 2-aminoisobutyrate hydrochloride via[3+2]cycloaddition to obtain 4-[2-thio-4,4-dimethyl-5-oxomidazolidine-1-yl]-2-trifluoromethylbenzonitrile(Ⅶ).Then,4-{3-[4-(tert-butyldimethylsilane)-hydroxybutyl]-4,4-dimethyl-5-oxo-2-thiomidazole-1-yl}-2-(trifluoromethyl)benzonitrile(Ⅷ)was synthesized from Ullmann C—N coupling reaction of intermediateⅦand tert-butyl(4-chlorobutoxy)dimethylsilane.Finally,target product Ru59063 was obtained by hydroxy-deprotection of intermediateⅧ.The total yield and HPLC purity of 4-step reaction were 61.6%and 98.2%.An improvement of 4.7 times compared with conventional method.This method for Ru59063 preparation was easier and safer without use of cyanide.The total yield of Ru59063 was 60.7%in the scaled-up production using 2 kg 4-amino-2-(trifluoromethyl)benzonitrile as starting material.

关 键 词：Ru59063 硫光气 硫代乙内酰脲 [3+2]环加成 乌尔曼C—N偶联反应 精细化工中间体 

分 类 号：TQ460.1[化学工程—制药化工]