Abstract: Orteronel (TAK-700) is a small-molecule CYP17A1 inhibitor and a clinical candidate drug mainly used for the treatment of malignant tumors, including prostate cancer, breast cancer and ovarian cancer, and it is still in the clinical trial stage. 5,6-Dihydropyrrolo[1,2-C]imidazol-5-one is an essential key intermediate for the synthesis of Orteronel. The original synthetic route adopts highly toxic methanesulfonyl chloride and extremely flammable lithium aluminum hydride. These hazardous reagents adversely affect the purity of active pharmaceutical ingredients and bring challenges to the quality control of final products. In this work, an improved synthetic route was designed. Commercially available (1H-imidazol-4-yl) methanol hydrochloride was selected as the starting material. The target intermediate was synthesized through six continuous reaction steps, including trityl protection of imidazole amino group, oxidation of hydroxymethyl group to aldehyde, nucleophilic addition of vinylmagnesium bromide, oxidation of allylic alcohol to ketone, hydrogen bromide addition to carbon-carbon double bond, and alkaline cyclization. The optimized process exhibits mild reaction conditions and moderate total yield. The chemical structures of all synthetic products were fully confirmed by ¹H NMR, ¹³C NMR, mass spectrometry (MS) and infrared spectroscopy (IR).

Key words: CYP17A1 inhibitor, 5,6?dihydropyrrolo[1,2?C]imidazol?5?one, 4?hydroxymethylimidazole hydrochloride, key pharmaceutical intermediate, structural identification