Safe and Sustainable\nIndustrial-Scale Production of\nAnhydrous Diazomethane via a Fully DCS/SIS-Controlled Continuous Flow\nSystem: Synthesis of α‑Haloketones

Anhydrous diazomethane in nitrogen (12% v/v, moisture\nat <0.5\ng/m<sup>3</sup>) has been safely manufactured via a fully automation\ncontrolled continuous microchannel reactor on a 1500 kg per month\nscale while the maximum accumulation of diazomethane was less than\n20 g. Treatment of <i>N</i>-methyl-<i>N</i>-nitroso-<i>p</i>-toluenesulfonamide (MNTS, diazald) with KOH generated\ndiazomethane <i>in situ</i>, which was isolated by a custom-designed\ngas–liquid distributor. Subsequently, the afforded anhydrous\ndiazomethane was used to synthesize α-haloketones, which serve\nas key intermediates for anti-HIV and antihypertensive drugs such\nas Atazanavir and Nebivolol. The entire process from TsCl to α-haloketones\nhad been continuously operated at the ABAChem manufacturing site for\nmore than 6 months, affording a total of 5000 kg of pure diazomethane\nand 15,000 kg of α-haloketones smoothly without any safety issues.\nThe microchannel flow reactor and gas–liquid distributor were\ndesigned specifically for the process and equipped with a fully distributed\ncontrol system and safety instrumented system (DCS/SIS) to ensure\nsafety, quality, and efficiency. The wastewater and solvent had been\nrecycled and reused, while the process mass intensity for the six\nchemical synthesis steps from TsCl to the corresponding α-haloketones\nwas significantly reduced from 200 to 300 to 40–60. This production\nprotocol paves a safer, sustainable, and expedient access to industrial-scale\nsynthesis of α-haloketones and other intermediates useful for\nproduction of pharmaceutical and agrochemical substances involving\ndiazomethane.