posted on 2014-12-19, 00:00authored byJeffrey B. Sperry, Kristin
E. Price Wiglesworth, Ian Edmonds, Phillip Fiore, David C. Boyles, David B. Damon, Roberta L. Dorow, Eugene L. Piatnitski
Chekler, Jonathan Langille, Jotham
W. Coe
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 Pd(dba)2 with BINAP and Cs2CO3 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 (S)-3.