We report the discovery and optimization of an amine-promoted Friedel–Crafts alkylation of cinnamaldehyde with 4-hydroxymethyl phenol. This reaction has been used successfully on commercial scale (200 kg) in the context of the manufacture of fesoterodine, a muscarinic antagonist used for the treatment of overactive bladder. Reductive aminations of diisopropylamine and lactol 4 are also discussed, as well as the resolution of the racemic amine
rac
-2 into its enantiomerically pure form.
Three catalysts were used to promote an imidazolide coupling.
These catalysts were 2-hydroxypyridine (HOPy), endo-N-hydroxy-5-norbornene-2,3-dicarboximide (HONB) (both reported for the first time to catalyse this type of reaction), and
1-hydroxybenzotriazole (HOBt). The thermal safety, cost, and
catalytic effectiveness of these three catalysts are compared. In
addition, kinetic modelling using the Dynochem software was
used to optimise the HOBt- and HOPy-catalysed reactions. By
use of this simulation method, the optimal reaction conditions,
such as catalyst quantity, reaction time, and reaction temperature were predicted. Subsequent experiments confirmed that
the predictions were accurate.
A regioselective Heck cross-coupling strategy is presented
for
the large-scale preparation of the thromboxane receptor antagonist
3-{3-[2-(4-chlorobenzenesulfonamido)ethyl]-5-(4-fluorobenzyl)phenyl}propionic acid (1).
Commercially available
3-bromo-5-iodobenzoic acid was first converted to the
corresponding acid chloride, and this was then condensed with
4-fluorobenzene via a Friedel−Crafts acylation reaction to
give
3-bromo-5-iodophenyl 4-fluorophenyl ketone.
Regioselective
cross-coupling with ethyl acrylate and then
N-vinylphthalimide,
each under phosphine-free Heck conditions, led to
formation
of ethyl
3-[3-(4-fluorobenzoyl)-5-(2-phthalimidovinyl)phenyl]propenoate. Reduction of the benzophenone moiety and
saturation of the olefin double bonds, followed by
phthalimide
ring cleavage, then gave ethyl
3-[3-(2-aminoethyl)-5-(4-fluorobenzyl)phenyl]propionate monocitrate salt. This was
converted to the sulfonamido-substituted arylpropionic acid 1
via
a two-step one-pot procedure in which sulfonamide
formation
was achieved via condensation with 4-chlorobenzenesulfonyl
chloride, followed by ethyl ester saponification. The
route
described avoids hazards identified with the original
medicinal
chemistry based synthesis and allows bulk quantities of
drug
substance to be produced for toxicological and clinical
trials.
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