One-pot synthesis of α-haloketones employing a membrane-based semibatch diazomethane generator

Silvia Garbarino; Javier Guerra; Peter Poechlauer; Bernhard Gutmann; C. Oliver Kappe

doi:10.1556/1846.2015.00046

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Journal of Flow Chemistry

Volume/Issue:: Volume 6: Issue 3

One-pot synthesis of α-haloketones employing a membrane-based semibatch diazomethane generator

Authors:

Silvia Garbarino

Silvia Garbarino University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, Austria
University of Genova, Via Dodecaneso 31, 16146 Genova, Italy

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Javier Guerra

Javier Guerra University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, Austria
Crystal Pharma SAU, Gadea Pharmaceutical Group-AMRI, Valladolid 47151, Spain

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Peter Poechlauer

Peter Poechlauer DPx Fine Chemicals Austria GmbH & Co KG, St. Peter-Strasse 25, 4020 Linz, Austria

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Bernhard Gutmann

Bernhard Gutmann University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, Austria

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bernhard.gutmann@uni-graz.at

, and

C. Oliver Kappe

C. Oliver Kappe University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, Austria

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oliver.kappe@uni-graz.at

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Pages:: 211–217

Online Publication Date:: Sep 2016

Publication Date:: 01 Sep 2016

Article Category:: Research Article

DOI:: https://doi.org/10.1556/1846.2015.00046

Keywords:: diazomethane; a-chloroketone; gas-permeable tubing; tube-in-flask reactor; Arndt—Eistert reaction

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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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Journal of Flow Chemistry A Journal of the Flow Chemistry Society

Print ISSN:: 2062-249X

Online ISSN:: 2063-0212

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Journal of Flow Chemistry
Language	English
Size	A4
Year of Foundation	2011
Volumes per Year	1
Issues per Year	4
Founder	Áramlásos Kémiai Tudományos Társaság
Founder's Address	H-1031 Budapest, Hungary Záhony utca 7.
Publisher	Akadémiai Kiadó Springer Nature Switzerland AG
Publisher's Address	H-1117 Budapest, Hungary 1516 Budapest, PO Box 245. CH-6330 Cham, Switzerland Gewerbestrasse 11
Responsible Publisher	Chief Executive Officer, Akadémiai Kiadó
ISSN	2062-249X (Print)
ISSN	2063-0212 (Online)