Efficient Synthesis of Novel NK1 Receptor Antagonists:  Selective 1,4-Addition of Grignard Reagents to 6-Chloronicotinic Acid Derivatives

• Published in: Journal of organic chemistry Vol. 71; no. 5; pp. 2000 - 2008
• Main Authors: Hoffmann-Emery, Fabienne, Hilpert, Hans, Scalone, Michelangelo, Waldmeier, Pius
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 03.03.2006; Amer Chemical Soc
• Subjects: Animals; Chemistry; Chemistry, Organic; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Humans; Neurokinin-1 Receptor Antagonists; Nicotinic Acids - chemistry; Organic chemistry; Physical Sciences; Preparations and properties; Propionates - chemical synthesis; Propionates - chemistry; Pyridines - chemical synthesis; Pyridines - pharmacology; Science & Technology; MONOMETHYLATION; SUBSTITUTION; HANTZSCH 1,4-DIHYDROPYRIDINES; CARBON-MONOXIDE; PRIMARY AMINES; SULFURIC-ACID; DIHYDROPYRIDINES; CARBOXYLATION; PYRIDINES; REGIOSELECTIVE ADDITION; Chemical rearrangement; Nitrogen heterocycle; Selectivity; Pyridine derivatives; Chemical reduction; Carbonylation; Grignard reagent; Amine; Carboxylic acid; Tertiary alcohol; Oxidation; Antagonist; Fluorine Organic compounds; Chemical synthesis; Acetone
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo0523666

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 C(4) 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.