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.
The copper-catalyzed racemization of a complex, quaternary
center
of a key intermediate on route to lanabecestat has been identified.
Optimization and mechanistic understanding were achieved through the
use of an efficient, combined kinetic-multiple linear regression approach
to experimental design and modeling. The use of a definitive screening
design with mechanistically relevant factors and a mixture of fitted
kinetic descriptors and empirical measurements facilitated the generation
of a model that accurately predicted complex reaction time course
behavior. The synergistic model was used to minimize the formation
of dimer byproducts, determine optimal conditions for batch operation,
and highlight superheated conditions that could be accessed in flow,
leading to a further increase in yield which was predicted by the
original model.
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