Efficient synthesis of novel NK1 receptor antagonists: selective 1,4-addition of grignard reagents to 6-chloronicotinic acid derivatives.
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.
F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Safety & Technical Sciences, Synthesis & Process Research, Grenzacherstrasse 124, CH-4070 Basel, Switzerland. fabienne.horffmann-emery@roche.com
Fabienne
F
Hoffmann-Emery
Hans
H
Hilpert
Michelangelo
M
Scalone
Pius
P
Waldmeier
D000818:Animals; D006801:Humans; D064729:Neurokinin-1 Receptor Antagonists; D009539:Nicotinic Acids / Q000737:chemistry*; D011422:Propionates / Q000138:chemical synthesis / Q000737:chemistry*; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D010879:Piperazines; D044482:Benzeneacetamides
D064729:Neurokinin-1 Receptor Antagonists; D009539:Nicotinic Acids; D011422:Propionates; D011725:Pyridines; C508854:netupitant; D010879:Piperazines; D044482:Benzeneacetamides; C035953:6-chloronicotinic acid; C508855:befetupitant