Process development work to provide an efficient, robust, and cost-effective manufacturing route to avibactam, a β-lactamase inhibitor is presented herewith. Aspects of this optimization work include the counterintuitive introduction of a protecting group to effect a difficult urea formation and the use of controlled feed hydrogenation conditions to facilitate an elegant one pot debenzylation and sulfation reaction. Overall, the commercial process delivers avibactam in much improved yield with significant reduction in the environmental footprint.
ω-Transaminase enzyme chemistry
provides an excellent methodology
to build synthetically useful chiral amines from their corresponding
ketones. An application of this methodology, providing a long-term
commercial manufacturing route to a JAK2 kinase inhibitor, is reported
herein.
Screening of 60 transaminases using
three different amine donors
found that the ω-transaminase from Vibrio fluvialis together with (S)-α-methylbenzylamine to
be the most promising combination to deliver the desired (S)-1-(5-fluoropyrimidin-2-yl)-ethylamine (2) in almost quantitative conversion. The process was further improved
by the addition of immiscible organic solvents with toluene identified
as most suitable concerning the distribution of the reactants without
negatively impacting the performance of the biocatalyst. Further process
optimization using commercial enzyme preparations of V. fluvialis led to product/catalyst ratios of 15
g/g cell dry weight. This approach led to a process that provided
(S)-1-(5-fluoropyrimidin-2-yl)ethylamine (2) in 77% yield with 99.8% ee. In addition, a recombinant E. coli-based whole-cell biocatalyst was also designed
and applied to this process. The use of this low cost enzyme formulation
gave product of similar quality to that obtained using the commercial
formulation of V. fluvialis
. This process was further optimized and scaled-up to deliver
(S)-1-(5-fluoropyrimidin-2-yl)ethylamine (2)with a yield of 66% and an optical purity of 97.3% ee. These results
confirm the efficiency and competitiveness of the transaminase technology
for the production of chiral amines.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.