芳基乙内酰脲衍生物RU58841合成工艺  

Synthesis Process of Arylhydantoin Derivative RU58841

作　　者：李泽坤 魏立梁 王芳芳 田雨 苏玲玲 张玲 LI Zekun;WEI Liliang;WANG Fangfang;TIAN Yu;SU Lingling;ZHANG Ling(Shandong Minghua New Material Co.,Ltd.,Jinan 250000,China;Gansu Institute of Chemical Industry Co.,Ltd.,Lanzhou 730000,China)

机构地区：[1]山东明化新材料有限公司,山东济南250000 [2]甘肃省化工研究院有限责任公司,甘肃兰州730000

出　　处：《合成化学》2025年第3期184-189,共6页Chinese Journal of Synthetic Chemistry

基　　金：中美合作开发[3+2]环加成关键技术在芳基乙内酰脲衍生物合成中的应用项目(20YF3WA001)。

摘　　要：4-[3-(4-羟基丁基)-4,4-二甲基-2,5-二氧代-1-咪唑烷基]-2-(三氟甲基)苯腈(RU58841)作为一种局部活性非甾体类抗雄激素,在临床上用于治疗痤疮及雄性脱发。研究发现,此化合物可以通过三步反应得到。首先,4-溴-1-丁醇与2-氨基异丁酸甲酯盐酸盐反应得到2-((4-羟基丁基)氨基)-2-甲基丙酸甲酯,然后以4-氨基-2-(三氟甲基)苯甲腈为起始原料,采用固体二(三氯甲基)碳酸酯替代光气反应合成3-三氟甲基-4-氰基苯异氰酸酯,最后与2-((4-羟基丁基)氨基)-2-甲基丙酸甲酯进行环加成反应合成了RU58841。通过筛选反应中所需要的溶剂及碱,确定在最佳反应条件下的总收率为50.75%,HPLC检测纯度为98.2%。相比于传统方法,该法缩短了反应路线,使得总收率提高了15%以上,并且未用到氰化物,可以更方便、更安全地合成RU58841。RU58841 as a locally active non-steroidal antiandrogen,it is clinically used to treat acne and androgenetic alopecia.Studies have found that this compound can be obtained by a three-step reaction,Firstly,4-bromo-1-butanol was reacted with methyl 2-aminoisobutyrate hydrochloride to obtain methyl 2-((4-hydroxybutyl)amino)-2-methylpropanoate,and then 4-amino-2-(trifluoromethyl)benzonitrile was used as the starting material,and solid triphosgene was used to substitute phosgene to synthesize 3-trifluoromethyl-4-cyanophenyl isocyanate,and finally with methyl 2-((4-hydroxybutyl)amino)-2-methylpropanoate which was passed by cycloaddition reaction to prepare RU58841,and the total yield under the optimal reaction conditions was determined to be 50.75%and the HPLC detection purity was 98.2%by screening the solvent and base required in the reaction.Compared with the traditional method,this method shortens the reaction route,increases the total yield by more than 15%,and does not use cyanide,which can make it more convenient and safer to prepare RU58841.

关 键 词：非甾体类抗雄激素 4-[3-(4-羟基丁基)-4 4-二甲基-2 5-二氧代-1-咪唑烷基]-2-(三氟甲基)苯腈 固体二(三氯甲基)碳酸酯 3-三氟甲基-4-氰基苯异氰酸酯 环加成反应 

分 类 号：TQ460.1[化学工程—制药化工]