The Use of Molecular Oxygen in Pharmaceutical Manufacturing: Is Flow the Way to Go?

Abstract

Molecular oxygen is arguably the greenest reagent available to the organic chemist. Most commonly, a diluted form of oxygen gas, consisting of less than 10 % O in N ("synthetic air"), is used in pharmaceutical and fine chemical batch manufacturing to effectively address safety concerns when handling molecular oxygen. Concentrations of O in N below 10 % are generally required to prevent the risk of combustions in the presence of flammable organic solvents ("limiting oxygen concentration"). Nonetheless, the use of pure oxygen is more efficient than using O diluted with N and can often provide enhanced reaction rates, resulting in significant improvements in product quality and process efficiency. This Concept takes into account recent studies to make the argument that, for liquid-phase aerobic oxidations, pure oxygen can indeed be handled safely on large scale by employing continuous-flow reactors, while also providing highly convincing synthetic and manufacturing benefits.

Catalytic Transformation of Biomass Derivatives to Value‐Added Chemicals and Fuels in Continuous Flow Microreactors

“…[259][260][261] The improved safety characteristics in microreactors allow the use of pure O 2 (even under explosive regimes), peroxides or other hazardous reagents, thus the reaction chemistry could be well tuned in a wide range for obtaining the enhanced reaction rate and yields of the target product. [285] Many chemicals derived from biomass oxidation may have applications in the synthesis of novel and existing pharmaceuticals and could therefore be industrially converted using microreactor technology. [285] Many chemicals derived from biomass oxidation may have applications in the synthesis of novel and existing pharmaceuticals and could therefore be industrially converted using microreactor technology.…”

Catalytic Aerobic Oxidation of C(sp3)−H Bonds

“…[19] While H 2 O 2 possesses its own unique reactivity patterns,o ften distinct from O 2 (epoxidations,Baeyer-Villiger oxidations), it can often also replace O 2 in many reactions as it is areduced form of O 2 .I ts availability in dilute aqueous solution limits usability,t hough stable adducts such as urea-H 2 O 2 can sometimes also be used. [21] Efficient and selective oxidation protocols,i nvolving (partial) O 2 atmosphere,a re now expected from academia to subsequently resolve the technical and safety aspects of the continuous production of fine chemicals intermediates applying these protocols. [20] With the introduction of flow chemistry in the fine chemicals industry,n ew solutions (dedicated low-volume reactors,m inimizing risk and guaranteeing productivity by numbering-up,e nhanced gas-liquid mass/heat transfer, easy pressurization limiting/omitting combustible headspace) for hitherto generally considered "unaccessible" chemistry such as aerobic oxidations arose.…”

Continuous Photo-Oxidation in a Vortex Reactor: Efficient Operations Using Air Drawn from the Laboratory

“…15,35−42 Such reactions are not often carried out on a large scale because the use of pure oxygen poses several risks. 43 A recent example 34 that highlights the dilemma in scaling chemistry involving oxygen is a photoreactor design in which reaction solutions are nebulized into an atmosphere of O 2 or air creating fine droplets that are then irradiated. The large surface area of the droplets result in highly efficient reactions because the interface between gas and liquid is increased while the small diameter of the droplets means that light can more easily penetrate the solution.…”