Continuous Process to Safely Manufacture an Aryldiazoacetate and Its Direct Use in a Dirhodium-Catalyzed Enantioselective Cyclopropanation

• Stephen P. Lathrop^a, Laurie B. Mlinar^a, Onkar N. Manjrekar^a, Yong Zhou^a, Kaid C. Harper^a, Eric R. Sacia^a, Molly Higgins^a, Andrew R. Bogdan^b, Zhe Wang^a, Steven M. Richter^a, Wei Gong^c, Eric A. Voight^c, Jeremy Henle^a, Moiz Diwan^a, Jeffrey M. Kallemeyn^a, Jack C. Sharland^d, Bo Wei^d, and Huw M. L. Davies^d

• ^aProcess Research and Development, AbbVie Inc., North Chicago, Illinois 60064, United States
• ^bAdvanced Chemistry Technologies, AbbVie Inc., North Chicago, Illinois 60064, United States
• ^cDrug Discovery Science & Technology, AbbVie Inc., North Chicago, Illinois 60064, United States
• ^dDepartment of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States

We report the development and demonstration of a continuous-flow process for the safe formation, extraction, and drying of aryldiazoacetate 2, which enables direct use in a fed-batch dirhodium-catalyzed enantioselective cyclopropanation reaction to provide cyclopropane 4. Designing this process with safety as a primary objective, we identified the appropriate arylsulfonyl hydrazone starting material and organic soluble base to facilitate a Bamford–Stevens diazo-generating flow process at 30 °C, well below the thermal onset temperature (Tonset = 57 °C), while also minimizing accumulation of the highly energetic diazo intermediate (ΔHD = −729 J/g). The Bamford–Stevens reaction byproducts are efficiently removed via a continuous aqueous extraction utilizing a liquid–liquid hydrophobic membrane separator. Continuous molecular sieve drying of the organic layer was demonstrated to maintain water levels <100 ppm in the final aryldiazoacetate solution, thereby ensuring acceptable reactivity, selectivity, and purity in the water sensitive cyclopropanation reaction. The full process was successfully executed on a 100 g scale, setting the foundation for the wider application of this and related chemistries on a kilogram scale.

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