Improved Synthesis of the Nav1.7 Inhibitor GDC-0276
via a Highly Regioselective SNAr Reaction
Posted on 2019-08-16 - 20:03
The
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.
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Stumpf, Andreas; Cheng, Zhigang Ken; Beaudry, Danial; Angelaud, Remy; Gosselin, Francis (2019). Improved Synthesis of the Nav1.7 Inhibitor GDC-0276
via a Highly Regioselective SNAr Reaction. ACS Publications. Collection. https://doi.org/10.1021/acs.oprd.9b00082
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AUTHORS (5)
AS
Andreas Stumpf
ZC
Zhigang Ken Cheng
DB
Danial Beaudry
RA
Remy Angelaud
FG
Francis Gosselin