BMS-986251,
a potent
and efficacious RORγt inverse agonist,
was synthesized starting from 6-iodotetralone using 13 chemical transformations
with only eight isolated intermediates. The synthesis involved a four-step
telescoped diastereoselective aza-Michael reaction-annulation sequence
followed by installation of the heptafluoro-iso-propyl
side chain and final amidation to furnish the desired API.
The development of a multi-kilogram-scale synthetic route to enantiomerically pure ((2S,3S,4S)-3-ethyl-4-fluoro-5oxopyrrolidin-2-yl)methyl methanesulfonate (BMT-415200) 1 is described in this work. In this sequence, a safe and robust process of nine linear steps with four isolations was implemented. The synthesis features highly diastereoselective hydrogenation of enones 12, diastereoselective reduction of ketone 13, and deoxyfluorination of the corresponding secondary alcohol 8 followed by C−H oxidation of 9 to lactam 10. The target compound 1 was prepared in 19% overall yield with >99% purity from commercially available di-tert-butyl (S)-4-oxopyrrolidine-1,2-dicarboxylate 7.
The
large-scale synthesis of ethyl 4-bromocyclohex-3-enecarboxyalate,
using a mild brominating reagent derived from triphenyl phosphite
and bromine, is reported. The development and comparison of both continuous
and batch processes are described. A modified addition sequence was
developed based on the knowledge garnered from flow-processing, resulting
in a safe and efficient process for the in situ generation of the
unstable active reagent and its immediate reaction with the ketone
in a batch mode process.
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