135995-44-7Relevant 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.
body text, 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.
