Continuous Flow Intensification for the Synthesis of High-Purity Warfarin

API synthesis; flow synthesis; intensification; Michael addition; organocatalysis; warfarin; Anti-coagulant drugs; Blood clots; Continuous-flow; Flow synthesis; High purity; Intensification; Michael additions; Organocatalysis; Warfarin; Physical and Theoretical Chemistry; Organic Chemistry

Abstract :

[en] While racemic warfarin was initially commercialized as a rodenticide, it has become the most prescribed anticoagulant drug for prevention of blood clots and is part of the World Health Organization’s list of essential medicines. The synthesis of warfarin appears straightforward, consisting of a single Michael addition reaction. However, the reaction is notoriously slow, with reflux times on the scale of days frequently affording the product in little more than 40% yield. Herein we report a highly intensified synthesis of warfarin exploiting the assets of flow chemistry and organocatalysis. The selection of a suitable catalyst to increase the rate of the reaction was crucial to obtain high conversion and selectivity, resulting in the development of a continuous flow protocol that affords warfarin in 85% isolated yield within 15 min of residence time. The product can be obtained with >97% purity by simple precipitation in acid. The achieved throughput of 9.4 g h-1 with a space-time yield (STY) of 1570.67 g h-1 L-1 is orders of magnitude higher than those of previously published flow protocols. Not only is this protocol more environmentally favorable, but also the estimated cost of 0.07 cents per dose hints that the novel process may be more economically favorable than the patented industrial synthesis.

Research Center/Unit :

MolSys - Molecular Systems - ULiège
Center for Integrated Technology and Organic Synthesis

Disciplines :

Chemistry

Author, co-author :

Silva Brenes, Diana Vanessa ; Université de Liège - ULiège > Département de chimie (sciences) > Center for Integrated Technology and Organic Synthesis

Reyes-Vargas, Stephanie K.; Department of Chemistry, University of Puerto Rico, San Juan, United States

Duconge, Jorge ; Department of Pharmaceutical Sciences, University of Puerto Rico, San Juan, United States

Vlaar, Cornelis ; Department of Pharmaceutical Sciences, University of Puerto Rico, San Juan, United States

Stelzer, Torsten ; Department of Pharmaceutical Sciences, University of Puerto Rico, San Juan, United States ; Crystallization Design Institute, Molecular Sciences Research Center, University of Puerto Rico, San Juan, United States

Monbaliu, Jean-Christophe ; Université de Liège - ULiège > Molecular Systems (MolSys)

Language :

English

Title :

Continuous Flow Intensification for the Synthesis of High-Purity Warfarin

Publication date :

2023

Journal title :

Organic Process Research and Development

ISSN :

1083-6160

eISSN :

1520-586X

Publisher :

American Chemical Society

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://pubs.acs.org/doi/pdf/10.1021/acs.oprd.3c00338

Funders :

ULiège - Université de Liège
NASA - National Aeronautics and Space Administration
F.R.S.-FNRS - Fonds de la Recherche Scientifique

Funding text :

This work was funded by a NASA EPSCoR Grant (Personalized Medication System for Deep Space Missions, NASA Grant 80NSSC19M0148) and the University of Liège and the F.R.S.-FNRS (Incentive Grant for Scientific Research MIS F453020F to J.-C.M.M.).The authors acknowledge Dr. Aliou Mbodji (UPR) for the determination of the XRD analysis of 7 . The Rigaku XtaLAB SuperNova X-ray microdiffractometer was acquired through the support of the National Science Foundation under the Major Research Instrumentation Program (CHE-1626103).

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