2 research outputs found
Kiloscale Buchwald–Hartwig Amination: Optimized Coupling of Base-Sensitive 6‑Bromoisoquinoline-1-carbonitrile with (<i>S</i>)‑3-Amino-2-methylpropan-1-ol
This
work describes the optimization and scale-up of a Buchwald–Hartwig
amination reaction for the preparation of a pharmaceutical intermediate.
This C–N bond formation is challenged by the use of a chiral
primary amine, which both adds cost and favors formation of biaryl
byproducts. In order to develop a scalable process, a number of factors
had to be investigated including catalyst selection and stoichiometry
of the chiral amine. These all needed to be optimized while maintaining
low palladium levels in the isolated product. The reaction was found
to be most effective using PdÂ(dba)<sub>2</sub> with BINAP and Cs<sub>2</sub>CO<sub>3</sub> in THF. When executed on 2.5 kg scale, these
conditions provided 2.06 kg of the desired product in 80% yield with
only 73 ppm residual palladium. To date, this process has been successfully
executed to produce more than 12 kg of compound <b>(</b><i><b>S</b></i><b>)-3</b>
Introduction of a Crystalline, Shelf-Stable Reagent for the Synthesis of Sulfur(VI) Fluorides
The design, synthesis,
and application of [4-(acetylamino)Âphenyl]Âimidodisulfuryl
difluoride (AISF), a shelf-stable, crystalline reagent for the synthesis
of sulfurÂ(VI) fluorides, is described. The utility of AISF is demonstrated
in the synthesis of a diverse array of aryl fluorosulfates and sulfamoyl
fluorides under mild conditions. Additionally, a single-step preparation
of AISF was developed that installed the bisÂ(fluorosulfonyl)Âimide
group on acetanilide utilizing an oxidative C–H functionalization
protocol