AZD6738 is currently
being tested in multiple phase I/II trials
for the treatment of cancer. Its structure, comprising a pyrimidine
core decorated with a chiral morpholine, a cyclopropyl sulfoximine,
and an azaindole, make it a challenging molecule to synthesize on
a large scale. We describe the evolution of the chemical processes,
following the manufacture of AZD6738 from the initial scale-up through
to multikilos on plant scale. During this evolution, we developed
a biocatalytic process to install the sulfoxide with high enantioselectivity,
followed by introduction of the cyclopropyl group first in batch,
then in a continuous flow plate reactor, and finally through a series
of continuous stirred tank reactors. The final plant scale process
to form AZD6738 was operated on 46 kg scale with an overall yield
of 18%. We discuss the impurities formed throughout the process and
highlight the limitations of this route for further scale-up.
Flow chemistry has been more frequently used in the development and manufacture of pharmaceuticals due to the progression of equipment and the availability of manufacturing facilities. This important tool for manufacture enables chemistries which were previously inefficient, hazardous, or not viable on scale in batch. Described herein is how continuous flow has been used to overcome issues with respect to the handling of hazardous materials in batch. The manufacturing step described is a Curtius reaction using diphenylphosphoryl azide (DPPA) as the azide precursor in the formation of a purinone at high temperatures with inline infrared monitoring.
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