This article details
the approach to large-scale production of
cyclobutane 2 by the continuous-flow [2 + 2] photocycloaddition
of maleic anhydride and ethylene, including (1) focused reaction optimization
and development of a robust isolation protocol, (2) the approach to
equipment design and process safety, and (3) the results of commissioning
tests and production runs delivering the target compound at throughputs
exceeding 5 kg/day.
Anhydrous tert-butyl
hydroperoxide (TBHP) is a
powerful oxidizing agent in many chemical transformations. Despite
the versatility in organic reactions, the use of anhydrous TBHP has
been greatly limited because of safety concerns over its shipping,
handling, and storage, particularly on production scale. Herein we
describe a membrane pervaporation method that allows the production
of the anhydrous TBHP solution in continuous manner. The system consists
of membrane modules in series that are made of perfluorinated polymer
with very high gas permeability, allowing it to remove water efficiently.
The pervaporation skid has been successfully implemented in production
by continuously generating anhydrous 1.5 M TBHP solution in nonane
at a rate of up to 100 mL·min–1 for more than
96 h, achieving the target of 0.15 wt % water. An integrated flow
oxidation of a γ-butyrolactam substrate provides an efficient
and diastereoselective synthesis of a key lactam intermediate for
the preparation of a drug candidate targeting interleukin-1 receptor
associated kinase 4 for the treatment of inflammation and oncology
diseases.
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