Understanding the Alkylation of a Phenol by 1-(3-Chloropropyl)pyrrolidine: Evidence for the Intermediacy of an Azetidinium Ion.

The final synthetic step in the synthesis of cediranib, AZD2171, 1, is the alkylation of a phenol with an alkyl halide to generate an ether. Our need to understand and control the formation of synthetic impurities generated in this step of the synthesis led us to investigate the kinetics and mechanism of the alkylation of indolphenol, 2, 4-[(4-fluoro-2-methyl-1 H-indol-5-yl)oxy]-6-methoxyquinazolin-7-ol, by chloropyrrolidine, 3, 1-(3-chloropropyl)pyrrolidine. Studies in 1-methyl-2-pyrrolidinone (NMP) established that the active alkylating agent is the azetidinium ion, 4, 4-azoniaspiro[3.4]octane, formed via a slow intramolecular cyclization reaction of chloropyrrolidine, 3. The azetidinium ion was isolated as its tetraphenylborate salt from water by heating 3 in the presence of aqueous potassium tetraphenyl borate, and its competence as an intermediate was demonstrated by its fast reaction with 2 to yield cediranib, 1.