Optimisation of Permanganate Oxidation and Suzuki−Miyaura Coupling Steps in the Synthesis of a Na_v1.8 Sodium Channel Modulator

Abstract

The development is described of a viable kilo-scale synthesis of the Na v 1.8 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 protodeboronation in the absence of sufficient active catalyst. In the final step, amidation of the ester with methylamine gave PF-1247324.

Design, preparation and application of conjugated microporous polymers

“…The Suzuki reaction is an arguably efficient method for aryl–aryl bond formation since initial reports in 1979 . The development of the Suzuki reaction has proceeded, including boronic acid and aryl chloride coupling, boronic acid and aryl bromide coupling, boronic acid and aryl iodide coupling, boronic acid and alkenyl triflate coupling, borane and aryl halide coupling, borane and alkyl halide coupling, boronic ester and aryl halide coupling, boronic ester and alkyl halide coupling, borate complexes, etc.…”

Synthesis and Late-Stage Functionalization of Complex Molecules through C–H Fluorination and Nucleophilic Aromatic Substitution

“…19 The medicinal chemistry route to this compound comprised six steps and occurred in less than 1% yield; an advanced intermediate was outsourced for the kilogram-scale synthesis of PF-1247324. 20 Our route to this compound began with the fluorination of methyl 5-bromopicolinate. The fluoropyridine intermediate contains two electrophilic sites for nucleophilic substitution: a methyl ester and a 2-fluoropyridine.…”

“…After aqueous workup, the crude reaction mixture was treated with ammonium hydroxide in DMSO to substitute an NH 2 group for the fluoride. Finally, the 3-bromopyridine was subjected to the reported Suzuki cross-coupling reaction conditions 20 to provide the title compound. By our route, the synthesis of PF-1247324 involving C–H fluorination was completed with just three total isolations in 51% overall yield, a major improvement in yield and step count over the published synthesis.…”

Discovery and Optimization of Selective Nav1.8 Modulator Series That Demonstrate Efficacy in Preclinical Models of Pain

“…Further synthesis details are available in the Supporting Information. 23 In conclusion, optimization of a biaryl lead has led to highly selective Na v 1.8 series. Three key compounds 3, 13, and 18 have also demonstrated good pharmacokinetics in preclinical species leading to low human CL projections.…”