Regorafenib monohydrate

Regorafenib monohydrate (BAY 73-4506) is an orally active and potent multi-targeted receptor tyrosine kinase inhibitor with potent anti-tumour and anti-angiogenic activity. It is approved for the treatment of metastatic colorectal cancer, advanced gastrointestinal mesenchymal stromal tumours and hepatocellular carcinoma.

Regorafenib was approved by the U.S. Food and Drug Administration (FDA) in September 2012 for the treatment of metastatic colorectal cancer in patients who have previously undergone fluoropyrimidine-, oxaliplatin-, and irinotecan-based therapies. The FDA expanded the approved use of the drug to include patients with advanced gastrointestinal stromal tumors (GIST) that cannot be surgically removed and no longer respond to imatinib and sunitinib, two other drugs approved for treatment of GIST. Regorafenib, marketed under the trade name Stivarga®, was discovered and developed by Bayer Pharmaceuticals and marketed jointly with Onyx Pharmaceuticals. The active metabolites of the drug inhibit multiple targets within a variety of kinase families including those in the RET, VEGF, FGFR, PTK, and Abl pathways.

Among several published synthesis, the most likely process scale synthesis will be highlighted from the two published syntheses, and this is described in the scheme. Commercially available picolinic acid (148) was heated with thionyl chloride to provide the crude intermediate 4-chloro-2- pyridyl acid chloride which was subsequently reacted with aqueous methyl amine in toluene to give 4- chloro-2-methylcarboxamide as its hydrochloride salt 149 in quantitative yield after treatment with acetyl chloride in toluene and ethanol. The hydrochloride salt was free based with sodium hydroxide and then immediately reacted with imine 150 (formed upon exposure to 4-amino-3-fluorophenol (153) in refluxing 3-methyl 2-butanone) in base to provide diaryl ether 151 in 84% yield. Reaction of amine 151 with the commercially available isocyanate 152 ultimately delivered regorafenib hydrate (XXIII) in 83% yield.