An
efficient four-step synthesis of 1 is described
in which utilization of ReactIR was key to efficient processing and
reaction monitoring. Key chemical steps included (i) nucleophilic
aromatic substitution, iron reduction of aromatic nitro group to aniline,
(ii) decarboxylation, and (iii) ester formation.
A practical synthesis of 4-amino-2-(trifluoromethyl)-nicotinic acid is described. 2-(Trifluoromethyl)pyridine was lithiated using lithium 2,2,6,6-tetramethylpiperidide (LTMP) in the presence of 1,3-dimethyl-2-imidazolidinone (DMI) and followed by CO 2 quench to give the C-3 carboxylation product. Subsequent directed C-4 lithiation of carboxylation product afforded 4-iodo-2-(trifluoromethyl)nicotinic acid, which was coupled with tert-butyl carbamate under Pd-catalyzed conditions and followed by Boc deprotection to yield the title product in four steps and 50% overall yield.
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