Abstract
The crucial structural motive in viral protease inhibitors such as atazanavir and darunavir is a chiral aminoalcohol structure. The structure is generally introduced during the synthesis of the protease inhibitorvia an α-chloroketone intermediate. The α-chloroketone can be synthesized in a multistep sequence from naturally occurring L-phenylalanine. Herein, we report a one- pot synthesis of an α-chloroketone starting from N-Boc-L-phenylalanine in a novel type of “tube-in-flask” semi-batch diazomethane generator. Activation of the amino acid to the mixed anhydride was carried out in the flask, while diazomethanewas generated from insituformed N-nitroso-N-methylurea within a gas-permeable tubing contained inside theflask. The diazomethane diffused through the gas-selective membrane into the flask, and reacted with the anhydride to the diazoketone (Arndt-Eistert reaction). The addition of aqueous hydrogen chloride provided the α-chloroketone and destroyed any excess of diazomethane. The desired product was isolated by extraction in excellent purity and yield (90%–96%).
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Garbarino, S., Guerra, J., Poechlauer, P. et al. One-Pot Synthesis of α-Haloketones Employing a Membrane-Based Semibatch Diazomethane Generator. J Flow Chem 6, 211–217 (2016). https://doi.org/10.1556/1846.2015.00046
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DOI: https://doi.org/10.1556/1846.2015.00046