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Efficient synthesis of novel NK1 receptor antagonists: selective 1,4-addition of grignard reagents to 6-chloronicotinic acid derivatives.

作者信息

Hoffmann-Emery Fabienne, Hilpert Hans, Scalone Michelangelo, Waldmeier Pius

机构信息

F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Safety & Technical Sciences, Synthesis & Process Research, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.

出版信息

J Org Chem. 2006 Mar 3;71(5):2000-8. doi: 10.1021/jo0523666.

DOI:10.1021/jo0523666
PMID:16496986
Abstract

A new efficient synthesis of two novel classes of NK1 receptor antagonists, among them befetupitant and netupitant, starting from 6-chloronicotinic acid is described. The introduction of the o-tolyl substituent at C4 of the pyridine ring was achieved by a one-pot selective 1,4-Grignard addition/oxidation sequence to 6-chloronicotinic acid or a derivative of it. The scope of this addition/oxidation sequence was examined. It was also shown that the carboxylic function can be converted to a methyl amino group by a Hofmann rearrangement followed by reduction. Furthermore, a new high-yielding synthesis of 2-(3,5-bistrifluoromethylphenyl)-2-methyl propionic acid based on the carbonylation of the tertiary alcohol obtained by Grignard addition of 3,5-bis(trifluoromethyl)bromobenzene to acetone was established.

摘要

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J Org Chem. 2006 Mar 3;71(5):2000-8. doi: 10.1021/jo0523666.
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