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

Autor:	Andrew R. Phillips, Brian G. Cox, Ian Michael Mcfarlane, Lai C. Chan, Ian W. Ashworth
Rok vydání:	2018
Předmět:	chemistry.chemical_classification Aqueous solution Tetraphenylborate 010405 organic chemistry Organic Chemistry Ether Alkylation 010402 general chemistry 01 natural sciences Medicinal chemistry Pyrrolidine 0104 chemical sciences chemistry.chemical_compound chemistry Phenol Alkyl Octane
Zdroj:	The Journal of Organic Chemistry. 84:4754-4762
ISSN:	1520-6904 0022-3263
DOI:	10.1021/acs.joc.8b02458
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::21b0f7e791038d9319176d988b4031e9 https://doi.org/10.1021/acs.joc.8b02458 Zobrazit plný text záznamu