Safe and Sustainable Industrial-Scale Production of Anhydrous Diazomethane via a Fully DCS/SIS-Controlled Continuous Flow System: Synthesis of α-Haloketones

Anhydrous diazomethane in nitrogen (12% v/v, moisture at <0.5 g/m 3 ) has been safely manufactured via a fully automation controlled continuous microchannel reactor on a 1500 kg per month scale while the maximum accumulation of diazomethane was less than 20 g. Treatment of N -methyl- N -nitroso- p -toluenesulfonamide (MNTS, diazald) with KOH generated diazomethane in situ, which was isolated by a custom-designed gas–liquid distributor. Subsequently, the afforded anhydrous diazomethane was used to synthesize α-haloketones, which serve as key intermediates for anti-HIV and antihypertensive drugs such as Atazanavir and Nebivolol. The entire process from TsCl to α-haloketones had been continuously operated at the ABAChem manufacturing site for more than 6 months, affording a total of 5000 kg of pure diazomethane and 15,000 kg of α-haloketones smoothly without any safety issues. The microchannel flow reactor and gas–liquid distributor were designed specifically for the process and equipped with a fully distributed control system and safety instrumented system (DCS/SIS) to ensure safety, quality, and efficiency. The wastewater and solvent had been recycled and reused, while the process mass intensity for the six chemical synthesis steps from TsCl to the corresponding α-haloketones was significantly reduced from 200 to 300 to 40–60. This production protocol paves a safer, sustainable, and expedient access to industrial-scale synthesis of α-haloketones and other intermediates useful for production of pharmaceutical and agrochemical substances involving diazomethane.