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

Abstract

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.

Improvements to Enable the Large Scale Synthesis of 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833)

“…37 A significant effort was therefore put into the identification of a highly diastereoselective enolate oxidation procedure, one which could be carried out safely and which employed an inexpensive, readily available oxidizing agent. 38 Initial work using oxygen at −70 °C to oxidize the lithium enolate 13 gave a 4:1 ratio of diastereomers in favor of 14. However, the use of lithium t-butylperoxide (t-BuOOLi) afforded 14 with greater than 30:1 diastereoselectivity.…”

Green Organic Solvent-Free Oxidation of Alkylarenes with tert-Butyl Hydroperoxide Catalyzed by Water-Soluble Copper Complex

“…The above mentioned advantages of CuCl 2 /BQC coupled with those of 70% TBHP prompted us to investigate the catalytic activity of CuCl 2 / BQC/TBHP system for the oxidation of benzylic methylenes to the corresponding carbonyl moieties. It is important to note that aqueous TBHP (70% in water) is much safer to use compared to the explosive anhydrous TBHP that has serious safety problems regarding handling, storage and shipping [43]. In this paper we are pleased to report our results regarding this unprecedented, general, and highly efficient organic solvent-free catalytic oxidation of alkylarenes (Scheme 1).…”

Reactivity of Styrenes in Micelles: Safe, Selective, and Sustainable Functionalization with Azides and Carboxylic Acids

“…Recently, Reiser and co-workers have reported visible-light-accelerated oxyazidation of styrene derivatives using [Cu­(dap) 2 Cl] as the catalyst . However, all these reported methods have limitations, such as use of a metal catalyst, and/or require excessive amounts of metallic or corrosive oxidants or toxic organic solvents. , Organic azides and peroxides are also known to be explosive, especially in flammable organic solvents, further restricting their applications to large-scale reactions.…”