An asymmetric hydrogenation process for the α-isopropyl
dihydrocinnamic acid derivative 2, an intermediate for the renin
inhibitor aliskiren (4), has been developed using a rhodium
catalyst ligated with a chiral monodentate phosphoramidite and
a nonchiral phosphine. Whereas catalysts based on two equivalents of monodentate phosphoramidites gave promising results,
the rate of hydrogenation and ee of the product could be
improved spectacularly by the addition of monodentate nonchiral triarylphosphines to these catalysts. This remarkable
mixed-ligand catalyst has been identified using high-throughput
experimentation. With the best catalysts turnover numbers
>5000 mol mol-1, turnover frequencies >1000 mol mol-1 h-1,
and ee's up to 95% have been achieved.
Mandelate racemase (EC 5.1.2.2) is one of the few biochemically well-characterized racemases. The remarkable stability of this cofactor-independent enzyme and its broad substrate tolerance make it an ideal candidate for the racemization of non-natural a-hydroxycarboxylic acids under physiological reaction conditions to be applied in deracemization protocols in connection with a kinetic resolution step. This review summarizes all aspects of mandelate racemase relevant for the application of this enzyme in preparative-scale biotransformations with special emphasis on its substrate tolerance. Collection and evaluation of substrate structure-activity data led to a set of general guidelines, which were used as basis for the construction of a general substrate model, which allows a quick estimation of the expected activity for a given substrate.
Within
this paper, we present the design, development, and scale-up
of a process for a continuous Matteson reaction to produce a key intermediate
toward the β-lactamase inhibitor vaborbactam. This includes
the successful implementation of the continuous concept at a multiton
production scale for the API at Patheon, part of Thermo Fisher Scientific.
The first-generation continuous flow production with its discontinuous
downstream processing was further developed to a fully continuous
production through installation of a continuous loop reactor. This
enabled increased productivity and energy efficiency, eliminated volume
and time bottlenecks, and reduced waste.
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