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

    • Stephen P. Lathropa, Laurie B. Mlinara, Onkar N. Manjrekara, Yong Zhoua, Kaid C. Harpera, Eric R. Saciaa, Molly Higginsa, Andrew R. Bogdanb, Zhe Wanga, Steven M. Richtera, Wei Gongc, Eric A. Voightc, Jeremy Henlea, Moiz Diwana, Jeffrey M. Kallemeyna, Jack C. Sharlandd, Bo Weid, and Huw M. L. Daviesd
    • 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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