342417-06-5Relevant articles and documents
Process for preparation of pyridine derivatives of NK-1 receptor antagonist
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Page/Page column 14, (2010/02/15)
The present invention provides a process for preparing a pyridine compound of the formula: wherein R1, R2, R3 and a are those defined herein.
Research and development of an efficient process for the construction of the 2,4,5-substituted pyridines of NK-1 receptor antagonists
Harrington, Peter J.,Johnston, Dave,Moorlag, Henk,Wong, Jim-Wah,Hodges, L. Mark,Harris, Les,McEwen, Gerald K.,Smallwood, Blair
, p. 1157 - 1166 (2012/12/23)
Roche has identified a 2,4,5-trisubstituted pyridine template for a new class of potent NK1 receptor antagonists. Previous strategies for construction of the pyridine core of these NK-1 receptor antagonists involved functionalization of a 2,5-disubstituted pyridine. We now report on construction of the pyridine core from commodity components. Shestopalov reported the synthesis of trans-4′-aryl-5′-cyano-1′,2′,3′, 4′-tetrahydro-6′-hydroxy-2′-oxo-1,3′-bipyridinium inner salts from 1-(2-amino-2-oxo-ethyl)pyridinium chloride, aromatic aldehydes, and ethyl cyanoacetate in the presence of a base. Reaction of these salts with phosphorus oxychloride affords 4-aryl-3-cyano-2,6-dichloropyridines. These are efficiently converted to nicotinamide precursors of the Roche NK-1 receptor antagonists by regioselective displacement of one chlorine by an amine, hydrogenolysis of the remaining chlorine, and nitrile hydrolysis.
Efficient synthesis of novel NK1 receptor antagonists: Selective 1,4-addition of Grignard reagents to 6-chloronicotinic acid derivatives
Hoffmann-Emery, Fabienne,Hilpert, Hans,Scalone, Michelangelo,Waldmeier, Pius
, p. 2000 - 2008 (2007/10/03)
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.
Process for preparation of pyridine derivatives
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Page/Page column 7, (2010/02/10)
The present invention relates to a process for the manufacture of compounds of formula wherein the substituents are as described herein which comprises the steps of a) reacting a compound of formula with a compound of formula to form a compound of formula b) converting the OH/═O function of compounds of formula XIV/XIVa into a leaving group P with a reagent containing a leaving group, selected from POCl3, PBr3, MeI and (F3CSO2)2O to form a compound of formula wherein P is halogen or trifluoromethanesulfonate; c) substituting R2 for the leaving group P by reacting compound XV with HR2 to form a compound of formula and d) hydrolyzing the nitrile function in an acidic medium selected from H2SO4, HCl and acetic acid, to form a compound of formula I The compounds of formula I are valuable intermediates for the manufacture of therapeutically active compounds which have NK-1 antagonist activity.
