Continuous Production of Anhydrous tert-Butyl Hydroperoxide in Nonane Using Membrane Pervaporation and Its Application in Flow Oxidation of a γ-Butyrolactam

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 1.5M 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.