Continuous Flow Synthesis of Methyl Oximino Acetoacetate: Accessing Greener Purification Methods with Inline Liquid-Liquid Extraction and Membrane Separation Technology

    • René Lebl
    • Trevor Murray
    • Andrea Adamo
    • David Cantillo
    • C. Oliver Kappe
    • Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
    • Institute of Chemistry, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria
    • Zaiput Flow Technologies, 300 2nd Avenue, Waltham, Massachusetts 02451, United States

    A greener continuous flow procedure for the synthesis and purification of methyl oximino acetoacetate, a key intermediate for the generation of several heterocyclic scaffolds, has been established. The synthesis is based on the continuous flow generation of nitrous acid to effect the oximation reaction. Neat reactants and a nearly saturated aqueous NaNO2 solution have provided a methodology with a very low solvent consumption. The extraction of the oxime from the reaction mixture, a challenging process due to the presence of acetic acid in the solution, has been achieved by liquid–liquid extraction in a microreactor and a continuous multistage phase separation platform. Fine-tuning of the output pH by inline monitoring using a flow cell has enabled optimal extraction performance as well as the minimization of the acetic acid residue in the organic phase and the use of very low amounts of extraction solvents. An excellent value for the process mass intensity of 11.1 has been achieved. Moreover, the lack of acetic acid in the product avoids an additional and energy-consuming distillation step.

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