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An Efficient Synthesis of Ivacaftor
Author(s) -
Zhang Rui,
Han Guanyu,
Jiang Luobin,
Shen Yao,
Yang Rui,
Mao Yongjun,
Wang Hang
Publication year - 2017
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.2931
Subject(s) - chemistry , yield (engineering) , ivacaftor , dimethylformamide , electrophile , ring (chemistry) , condensation , high performance liquid chromatography , intramolecular force , organic chemistry , chromatography , combinatorial chemistry , catalysis , biochemistry , materials science , thermodynamics , physics , solvent , gene , cystic fibrosis transmembrane conductance regulator , metallurgy
New and practical synthetic route of ivacaftor is described on a grams scale. An electrophilic addition of two t‐ butyl groups to the aromatic ring is adopted to prepare 5‐amino‐2,4‐di‐ t‐ butylphenol in 61% yield over three steps with 98.1% purity (high‐performance liquid chromatography). An intramolecular cyclization of ethyl 3‐(2‐aminophenyl)‐3‐oxo‐propanoate with dimethylformamide‐dynamic mechanical analysis is used to prepare 4‐oxo‐1,4‐dihydroquinoline‐3‐carboxylic acid in 54% yield over four steps. Ivacaftor is obtained by condensation of the two parts in 71% yield with 99.1% purity (high‐performance liquid chromatography).
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