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.
A definitive screening design (DSD) combined with reaction profiling was conducted using a flow reactor, in a short time frame, for the accurate estimation of kinetic parameters.
The
development of a continuous-flow Sonogashira cross-coupling
protocol using propyne gas for the synthesis of a key intermediate
in the manufacturing of a β-amyloid precursor protein cleaving
enzyme 1 (BACE1) inhibitor, currently undergoing late stage clinical
trials for a disease-modifying therapy of Alzheimer’s disease,
is described. Instead of the currently used batch manufacturing process
for this intermediate that utilizes TMS-propyne as reagent, we herein
demonstrate the safe utilization of propyne gas, as a cheaper and
more atom efficient reagent, using an intensified continuous-flow
protocol under homogeneous conditions. The flow process afforded the
target intermediate with a desired product selectivity of ∼91%
(vs the bis adduct) after a residence time of 10 min at 160 °C.
The continuous-flow process compares favorably with the batch process,
which uses TMS-propyne and requires overnight processing, TBAF as
an additive, and a significantly higher loading of Cu co-catalyst.
The intramolecular Diels−Alder reaction provides a useful synthetic methodology to build biologically active and synthetically useful isoindolone ring systems. An application of this methodology, providing an efficient manufacturing route to an mGluR2 positive allosteric modulator via a 1,5,7-substituted isoindolone, is reported herein.
An improved synthetic procedure for
the multistep synthesis of
aminoimidazole 6, a key intermediate in the preparation
of lanabecestat (AZD3293/LY3314814), is described. Under intensified
conditions (high temperature and elevated pressure), the overall processing
time and required amounts of reagents could be significantly reduced,
thus potentially minimizing manufacturing costs and improving the
sustainability footprint. Process integration of three sequential
steps starting from ketone intermediate 2 has been attempted
to set the stage for a potential multistep continuous manufacturing
route. The process consists of initial formation of imine 3 by treatment of ketone 2 with ammonia and Ti(iPrO)4, cyclocondensation of 3 with
thioamide 4 to form thiol 5, and aminolysis
using ammonia and Zn(OAc)2, allowing the target building
block 6 to be accessed in 47% overall yield.
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