The Application of a Continuous Grignard Reaction in the Preparation of Fluconazole

The application of continuous methods in the synthesis of active pharmaceutical ingredients continues to receive significant attention in the academic as well as the industrial research communities. One of the major advantages of continuous methods is the ability to safely access kinetic synthons as...

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Bibliographic Details
Published in:European journal of organic chemistry 2017-12, Vol.2017 (44), p.6495-6498
Main Authors: Korwar, Sudha, Amir, Somi, Tosso, Perrer N., Desai, Bimbisar K., Kong, Caleb J., Fadnis, Swara, Telang, Nakul S., Ahmad, Saeed, Roper, Thomas D., Gupton, B. Frank
Format: Article
Language:English
Subjects:
Aromatic compounds
Continuous
Continuous flow
Flow
Fluconazole
Fungicides
Grignard reactions
Industrial research
Reagents
Synthesis
Turbo Grignard
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Summary:The application of continuous methods in the synthesis of active pharmaceutical ingredients continues to receive significant attention in the academic as well as the industrial research communities. One of the major advantages of continuous methods is the ability to safely access kinetic synthons as well as highly reactive reagents that are typically unavailable through traditional batch methods. In this work, we report the high‐yielding, clean formation of an aryl‐turbo Grignard and its selective addition to a highly‐enolizable 1,3‐dichloroacetone, for the continuous synthesis of a key intermediate for fluconazole, a widely‐prescribed anti‐fungal agent. In addition, process optimization of the final API was also carried out to arrive at a semi‐continuous method to this essential medicine. This work describes the semi‐continuous synthesis of the anti‐fungal agent fluconazole by high‐yielding and clean formation of an aryl‐turbo Grignard followed by its selective addition to 1,3‐dichloroacetone in a continuous operation to form the precursor to the API.
ISSN:1434-193X
1099-0690
DOI:10.1002/ejoc.201701002