Document Detail

Efficient synthesis of novel NK1 receptor antagonists: selective 1,4-addition of grignard reagents to 6-chloronicotinic acid derivatives.
MedLine Citation:
PMID:  16496986     Owner:  NLM     Status:  MEDLINE    
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.
Fabienne Hoffmann-Emery; Hans Hilpert; Michelangelo Scalone; Pius Waldmeier
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  The Journal of organic chemistry     Volume:  71     ISSN:  0022-3263     ISO Abbreviation:  J. Org. Chem.     Publication Date:  2006 Mar 
Date Detail:
Created Date:  2006-02-24     Completed Date:  2007-01-12     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985193R     Medline TA:  J Org Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2000-8     Citation Subset:  IM    
F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Safety & Technical Sciences, Synthesis & Process Research, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
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MeSH Terms
Nicotinic Acids / chemistry*
Propionic Acids / chemical synthesis,  chemistry*
Pyridines / chemical synthesis*,  pharmacology
Receptors, Neurokinin-1 / antagonists & inhibitors*
Reg. No./Substance:
0/Nicotinic Acids; 0/Propionic Acids; 0/Pyridines; 0/Receptors, Neurokinin-1; 0/befetupitant; 0/netupitant; 5326-23-8/6-chloronicotinic acid

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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