摘要：To establish a synthetic route to d3 -poziotinib hydrochloride. Treatment of 4-chloro-7-hydroxyquinazolin-6-yl pivalate ( 1 ) with d3 -methyliodide afforded the etherization product, which reacted with 3,4-dichloro-2-fluoroaniline to generate the key intermediate d3 -4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yl pivalate ( 3 ). Followed the de-protection reaction, the nucleophilic substitution ( S N 2) reaction with tert -butyl 4-(tosyloxy)piperidine-1-carboxylate ( TSP ), and the de-protection reaction of t -butoxycarbonyl (Boc) group, and the amide formation reaction with acrylyl chloride, d3 -poziotinib was obtained, which was converted to hydrochloride salt by treatment with concentrated hydrochloric acid (HCl). Starting from a known compound 4-chloro-7-hydroxyquinazolin-6-yl pivalate ( 1 ), after 7 steps transformation, d3 -poziotinib hydrochloride was obtained with a total yield of 9.02%. The structure of d3 -poziotinib hydrochloride was confirmed by 1H-NMR, 13C-NMR, and high resolution (HR)-MS. Meanwhile, the in vitro microsomal stability experiment showed that d3 -poziotinib had a longer half time ( t 1/2 = 4.6 h) than poziotinib ( t 1/2 = 3.5 h).
