The Design, Synthesis and Preliminary Pharmacokinetic Evaluation of d3-Poziotinib Hydrochloride

• Published in: Biological & pharmaceutical bulletin Vol. 42; no. 6; pp. 873 - 876
• Main Authors: Ma, Shuchao, Wang, Linan, Ouyang, Ben, Bai, Xinfa, Ji, Qinglin, Yao, Lei
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01-06-2019; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: d3-poziotinib; Hydrochloric acid; metabolic closure; Pharmacokinetics; Piperidine; poziotinib; Substitution reactions; d3-poziotinib; poziotinib; metabolic closure
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b19-00153

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 (SN2) 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 (t1/2 = 4.6 h) than poziotinib (t1/2 = 3.5 h).