Scalable, Economical, and Practical Synthesis of 4-(Difluoromethyl)pyridin-2-amine, a Key Intermediate for Lipid Kinase Inhibitors

Article abstract of DOI:10.1021/acs.oprd.9b00312

A new, scalable, rapid, high yielding, and practical synthesis of 4-(difluoromethyl)pyridin-2-amine provides a key intermediate for the preparation of numerous protein kinase inhibitors and clinical candidates targeting phosphoinositide 3-kinase (PI3K) and the mechanistic target of rapamycin (mTOR) kinase. Starting from 2,2-difluoroacetic anhydride, an efficient five-step and two-pot procedure to prepare 4-(difluoromethyl)pyridin-2-amine (1) has been developed. Noteworthy aspects of this strategy include the avoidance of an amination process using a sealed vessel. Each step of the synthetic route has been optimized, and key intermediates have been isolated and characterized prior to the final two-pot procedure, which has been successfully applied for large-scale production.

Full text of DOI:10.1021/acs.oprd.9b00312

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Full Paper
A scalable, economical and practical synthesis of 4-
(difluoromethyl)pyridin-2-amine, a key intermediate for lipid kinase inhibitors
Denise Rageot, Florent Beaufils, Chiara Borsari, Alix Dall' Asen,
Markus Neuburger, Paul Hebeisen, and Matthias P. Wymann
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00312 • Publication Date (Web): 25 Sep 2019
Downloaded from pubs.acs.org on September 25, 2019
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Organic Process Research & Development
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A scalable, economical and practical synthesis of 4-
(difluoromethyl)pyridin-2-amine, a key intermediate
for lipid kinase inhibitors
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Denise Rageot,†$ Florent Beaufils,‡$ Chiara Borsari,†$ Alix Dall’Asen,‡ Markus
Neuburger,§ Paul Hebeisen,‡ Matthias P. Wymann†,*
†Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland;
‡PIQUR Therapeutics AG, Hochbergerstrasse 60, 4057 Basel, Switzerland;
§Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland
$Equal contribution: these authors contributed equally
*Correspondence to: matthias.wymann@unibas.ch;
Dept. Biomedicine, University of Basel, Mattenstrasse 28; 4058 Basel; Tel. +41 61 207 5046
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Table of Contents Graphic
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F
F
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O
O
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F
F
O
N
NH2
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F
F
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5 Steps - 2 Pots - 46% overall yield - 1.36 kg
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ABSTRACT
A new, scalable, rapid, high yielding and practical synthesis of 4-(difluoromethyl)pyridin-2-amine
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provides a key intermediate for the preparation of numerous protein kinase inhibitors and clinical candidates
targeting phosphoinositide 3-kinase (PI3K) and the mechanistic target of rapamycin (mTOR) kinase.
Starting from 2,2-difluoroacetic anhydride, an efficient five-step and two-pot procedure to prepare 4-
(difluoromethyl)pyridin-2-amine (1) has been developed. Noteworthy aspects of this strategy include the
avoidance of an amination process using a sealed vessel. Each step of the synthetic route has been
optimized, and key intermediates have been isolated and characterized prior to the final two-pot procedure,
which has been successfully applied for large scale production.
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KEYWORDS
Upscaling, 4-(difluoromethyl)pyridin-2-amine, pyridine ring closure, difluoroacetic acid
anhydride, telescope process, chromatography-free process.
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