Scalable On-Demand Production of Purified Diazomethane Suitable for Sensitive Catalytic Reactions

Article
Continuous flow
Drug substance
Process development

In this article, we discuss how our team at Snapdragon Chemistry, in collaboration with Qpex Biopharma, Inc., designed and built a convenient development-scale reactor (0.44 mol/h) to prepare diazomethane from N-methyl-N-nitroso-p-toluenesulfonamide (MNTS) in ∼80% yield. Diazomethane (CH2N2) made with this reactor is extracted into nitrogen gas from the liquid reaction mixture, which effectively removes it from reagents and byproducts that may interfere in subsequent reactions. Vertically oriented tubular reactors were used to produce and consume diazomethane in situ.

Key features of this reactor include:

  • High productivity and correspondingly low reactor volume (reactor volume/liquid flow rate = 6.5 min)
  • Commercially available gas/liquid separator equipped with a selectively permeating hydrophilic membrane.
  • Reactor design keeps the inventory below 53 mg of CH2N2 during normal operation.

The reactor demonstration generated CH2N2 that was used in a connected continuous reactor. Our team evaluated esterification reactions and a continuous Pd-catalyzed cyclopropanation reaction with the reactor and were able to achieve high conversion with 1.5 and 4.1 equiv of MNTS precursor, respectively.

Read the entire article, “Scalable On-Demand Production of Purified Diazomethane Suitable for Sensitive Catalytic Reactions,” to learn more about this reactor and its practical application in diazomethane preparation.

View the full article (via ACS Publications)