Continuous Flow Generation and Reactions of Anhydrous Diazomethane Using a Teflon AF-2400 Tube-in-Tube Reactor

Abstract

A continuous process for generation, separation, and reactions of anhydrous diazomethane in a tube-in-tube reactor was developed. The inner tube of the reactor is made of hydrophobic, gas-permeable Teflon AF-2400. The diazomethane is formed in the inner tube and then diffuses through the permeable membrane into the outer chamber and subsequently reacts in the solution carried within. This technique allows safe and scalable reactions with dry diazomethane to be performed on a laboratory scale.

Continuous‐Flow Technology—A Tool for the Safe Manufacturing of Active Pharmaceutical Ingredients

“…An analogous approach using acommercial tube-in-tube reactor allowed the laboratory-scale generation of anhydrous diazo- methane in mmol per hour quantities. [140] Thei nner tube of the device was made of hydrophobic, gas-permeable Te flon AF-2400 with an internal volume of 2mLa nd was enclosed within athick-walled impermeable outer tube (PTFE;3.2 mm outer diameter). Diazomethane was generated in the inner tube from amethanolic solution of Diazald and asolution of KOH, while the substrate solution was carried and reacted in the outer chamber.T wo equivalents of Diazald in the inner tube sufficed to obtain quantitative conversion for esterifications,c yclopropanations,a nd [2+ +3] cycloadditions,w ith throughputs of around 1.8 mmol h À1 .T he set-up was later extended to achieve the direct transformation of protected aamino acids to their corresponding a-chloro ketones in afully continuous,multistep reaction sequence (Scheme 37 a).…”

Integrated Micro‐Flow Synthesis Based on Photochemical Wolff Rearrangement

“…Explosive and toxic diazomethane was safely generated by treating Diazald with KOH. [44,45] The diazomethane-containing mixture was introduced into the inner tube of the tube-in-tube reactor. The inner tube (inner diameter 0.8 mm) was made of a hydrophobic, gas-permeable Teflon AF-2400 membrane.…”

Advances in steady-state continuous-flow purification by small-scale free-flow electrophoresis

“…(3) suitability for in-line monitoring of reaction efficiency [8]; (4) automation capabilities [9,10]; (5) safer handling of hazardous reactions [11]; and, (6) simple scale-up strategies for larger product quantities [12,13].…”