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Journal of Flow Chemistry
Authors: Silvia Garbarino, Javier Guerra, Peter Poechlauer, Bernhard Gutmann and C. Oliver Kappe

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 inhibitor via an α-chloroketone intermediate. The α-chloroketone can be synthesized in a multistep sequence from naturally occurring l-phenylalanine. Herein, we report a onepot 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 diazomethane was generated from in situ formed N-nitroso-N-methylurea within a gas-permeable tubing contained inside the flask. 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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Summary

The evaluation of several derivatization procedures for the gas chromatographic analysis of selected anticancer pharmaceuticals (cyclophosphamide, iphosphamide, flutamide, chlorambucil, and melphalan) in the presence of tricyclic antidepressants was carried out. Among the methods, concerning trimethylsilylation, tert-butyldimethylsilylation, and methylation, the most useful was methylation using (trimethylsilyl)diazomethane (TMSD), which is a safe alternative for the common reaction with diazomethane. Most of the anticancer drugs were unstable during derivatization using silylating agents, while antidepressants were stable in all tested conditions. Melphalan was the only compound, for which the results of all tested procedures were not satisfying. The TMSD-based procedure was validated, giving the results possibly suitable for the screening purposes in contaminated environmental samples.

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. Schlenk, H. and Gellerman, J. L. (1960): Esterification of fatty acid with diazomethane on a small scale. Anal. Chem. 32, 1412-1415. Esterification of fatty acid with diazomethane on a small scale

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for the generation of very reactive reagents [ 28 ]. Some of these reagents, such as diazomethane (CH 2 N 2 ), ethyl diazoacetate, carbon monoxide (CO), hydrogen cyanide (HCN), and isocyanides, are normally used only reluctantly or are entirely banned

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ketone was obtained on a 3-step continuous protocol affording the desired product in high yield and purity, where the key step was the diazomethane reaction using the tube-in-tube technology followed by acidic quench [ 10 ]. Scheme 3

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, called “generators,” are one of the strengths of flow chemistry, allowing for safe access to reagents which are usually avoided or even deemed “forbidden” such as diazomethane [ 10 ], chlorine [ 11 , 12 ], singlet oxygen [ 13 – 16 ], ozone [ 17 – 20

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