Difenidol hydrochloride is synthesized in three steps. S1: Preparation of 1-(3-chloropropyl)hexahydropyridine: 1,3-Bromochloropropane reacts with hexahydropyridine at room temperature. Liquid base is then added. After layering, the oily layer is collected and dried to give the intermediate. S2: Preparation of ,-diphenyl-1-piperidinobutanol: After initiation with magnesium, a THF solution of intermediate N-(3-chloropropyl)piperidine is added dropwise, followed by a THF solution of benzophenone. After holding, the mixture is poured into ice-cold ammonium chloride solution for hydrolysis. Filtration and drying yield the product. S3: Preparation of ,-diphenyl-1-piperidinobutanol hydrochloride: The product from step 2 is dissolved in acetone. After decolorization, hydrochloric acid is added dropwise to form the salt. Gradient cooling induces crystallization. Filtration and drying give the final product.
