A new pathway via intermediate 4-amino-3-fluorophenol for the synthesis of regorafenib

Abstract

A practical synthetic route to regorafenib, in which the target compound was obtained via a 10-step synthesis starting from 2-picolinic acid, 4-chloro-3-(trifluoromethyl)aniline, and 3-fluorophenol, is reported. Crucial to the strategy is the preparation of 4-amino-3-fluorophenol via Fries and Beckman rearrangements using an economical and practical protocol. The main advantages of the route include inexpensive starting materials and an acceptable overall yield. A scale-up experiment was carried out to provide regorafenib with 99.96% purity in 46.5% total yield.

Graphical Abstract

Keywords:

• Regorafenib
• Fries rearrangement
• Beckman rearrangement
• Optimization

Acknowledgments

We thank the ACS ChemWorx Authoring Services ([email protected]) for its linguistic assistance during the preparation of this manuscript.

Additional information

Funding

This work was financially supported by the Liaoning Provincial Natural Science Foundation of China [No. 201602707].