4-Piperidinone hydrochloride (I) was protected as the tert-butyl carbamate (II) using Boc2O and diisopropyl ethylamine. Condensation of (II) with 2-aminobenzyl alcohol (III) in boiling toluene, followed by reduction with sodium cyanoborohydride gave secondary amine (IV). Subsequent cyclization of (IV) in the presence of triphosgene and diisopropyl ethylamine produced the benzoxazinone (V), from which the Boc group was removed with HCl in EtOAc to yield intermediate (VI).
Regioselective Mitsunobu condensation of 2',4'-dihydroxyacetophenone (VII) with N-Boc-4-piperidinol (VIII) afforded ether (IX). The 2'-hydroxyl group of (IX) was then alkylated with 2,2,2-trifluoroethyl trifluoromethanesulfonate in the presence of Cs2CO3 to give (X). Oxidative rearrangement of the acetophenone (X) employing thallium trinitrate and trimethyl orthoformate generated the phenylacetic ester (XI), which was hydrolyzed to acid (XII) with NaOH in aqueous MeOH. Subsequent EDC-mediated coupling of (XII) with piperidine intermediate (VI) yielded amide (XIII). The N-Boc group of (XIII) was cleaved using HCl in EtOAc, and the secondary amine (XIV) was acylated with acetic anhydride in the presence of diisopropyl ethylamine to afford the target acetamide.