Kilogram-scale synthesis of thiohydantoin derivative Ru59063

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 intermediate Ⅶ and tert-butyl(4-chlorobutoxy)dimethylsilane. Finally, target product Ru59063 was obtained by hydroxydeprotection of intermediate Ⅷ. 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. © 2023 Fine Chemicals. All rights reserved.