875051-79-9Relevant articles and documents
Optimisation of permanganate oxidation and suzuki-miyaura coupling steps in the synthesis of a Nav1.8 Sodium channel modulator
Fray, M. Jonathan,Gillmore, Adam T.,Glossop, Melanie S.,McManus, David J.,Moses, Ian B.,Praquin, Celine F.B.,Reeves, Keith A.,Thompson, Lisa R.
experimental part, p. 263 - 271 (2010/04/28)
The development is described of a viable kilo-scale synthesis of the Nav1.8 sodium channel modulator, N-methyl-6-amino- 5-(2,3,5-trichlorophenyl)pyridine-2-carboxamide(PF-1247324) in five steps, starting from 6-amino-5-bromo-2-picoline, in 33% overall yield. Two key steps required significant optimisation to improve yield and reproducibility. Oxidation of 6-acetamido-5-bromo-2-methylpyridine by permanganate to give the corresponding carboxylic acid derivative was improved by adding potassium dihydrogen phosphate, which moderated the reaction mixture pH and doubled the yield. The potassium fluoride-promoted Suzuki-Miyaura coupling between 2,4,5-trichlorophenylboronic acid and methyl 6-amino-5-bromopyridine-2- carboxylate, catalysed by tri(tert-butyl)phosphinepalladium (0), proceeded reliably to completion at room temperature in high yield when water was added. Anhydrous reaction mixtures reacted much more slowly, and 'wet' mixtures led to significant proto- deboronation in the absence of sufficient active catalyst. In the final step, amidation of the ester with methylamine gave PF-1247324.
PYRIDINE DERIVATIVES
-
Page/Page column 47, (2008/06/13)
The present invention relates to compounds of the formula (I) and pharmaceutically acceptable salts and solvates thereof, to processes for the preparation of, intermediates used in the preparation of, and compositions containing such compounds and the uses of such compounds for the treatment of pain.
