Reaction of the Grignard reagent prepared from 2-fluorobenzyl bromide (I) and Mg in ether with cyclopropyl cyanide (II) in the same solvent gives 1-cyclopropyl-2-(2-fluorophenyl)ethanone (III), which is brominated with Br2 in CCl4 to yield the a-bromoketone (IV). Condensation of ketone (IV) with 2,3,4,5,6,7-hexahydrothieno[3,2-c]pyridin-2-one hydrochloride (V) by means of K2CO3 in DMF affords the adduct (VI), which is finally treated with acetic anhydride and NaH in DMF.
Reaction of 2,3,4,5,6,7-hexahydrothieno[3,2-c]pyridin-2-one p-toluenesulfonate (VII) with TBDMS-Cl and TEA in dichloromethane gives the silylated enol ether (VIII), which is condensed with 1-cyclopropyl-2-chloro-2-(2-fluorophenyl)ethanone (IX) by means of TEA in the same solvent to provide the adduct (X). Finally, this compound is treated with TEA and DMAP and acetylated with Ac2O.
Protection of 4-piperidone (I) with trityl chloride and TEA gives 1-tritylpiperidin-4-one (II), which is condensed with ethyl 2-oxoacetate (III) by means of pyrrolidine in refluxing benzene to yield 3-(ethoxycarbonylmethylene)-1-tritylpiperidin-4-one (IV). The deprotection and simultaneous reduction of compound (IV) with NaBH4 in methanol affords the 4-hydroxypiperidine derivative (V), which is condensed with 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)ethanone (VI) by means of K2CO3 in DMF to provide the adduct (VII). Reaction of the OH group of (VII) with CBr4 and PPh3 in dichloromethane gives the 4-bromopiperidine derivative (VIII), which by reaction with potassium thioacetate (IX) in ethanol provides the 4-(acetylthio)piperidine derivative (X). Selective hydrolysis of compound (X) with HCl in ethanol yields the 4-sulfanylpiperidine derivative (XI), which is finally submitted to a new hydrolysis with HCl in acetic acid.