op9b00082_si_001.pdf (4.73 MB)
Improved Synthesis of the Nav1.7 Inhibitor GDC-0276 via a Highly Regioselective SNAr Reaction
journal contribution
posted on 2019-08-16, 20:03 authored by Andreas Stumpf, Zhigang Ken Cheng, Danial Beaudry, Remy Angelaud, Francis GosselinThe
development of a redesigned and improved second-generation
synthesis of the Nav1.7 inhibitor GDC-0276 based on experience gained
from a fit-for-purpose first-generation synthesis will be described. The first-generation synthesis
proceeded via a regioselective SNAr reaction on the advanced
starting material t-butyl 5-chloro-2,4-difluorobenzoate
with 1-adamantanemethanol. In the newly developed second-generation
synthesis, the much improved regioselective SNAr reaction
was performed on the readily available starting material 1-chloro-2,4-difluorobenzene,
followed by installation of the carboxylate group by electrophilic
aromatic bromination and a palladium-catalyzed alkoxycarbonylation.
A subsequent Suzuki–Miyaura cross-coupling reaction was then
telescoped directly into a phase-transfer-catalyzed ester hydrolysis.
Amidation of the resulting acid intermediate with 1-azetidine sulfamide
in turn provided GDC-0276 in high overall yield and purity on a 100
kg scale.