1130115-44-4

Donafenib blocks the proliferation of tumor cells by inhibiting Raf kinase and VEGFR tyrosine kinase. The deuterated methyl group in donafenib improves the metabolic stability of the drug, resulting in a prolonged half-life, reduced systemic clearance, and increased systemic exposure. Donafenib has shown significantly improved overall survival compared to sorafenib in the treatment of patients with unresectable HCC, while having a favorable safety and tolerability profile.

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Labelled Sorafenib, a potent RAF kinase inhibitor. Antineoplastic.

The synthetic route began with the amidation of methyl formate 31.2 using chloromethane-d3-amine (31.1) as a deuterium source to afford CD3-amide 31.3 in high yield (98%). Aminophenol 31.4 was reacted with 31.2 in dimethyl sulfoxide via a SNAr displacement reaction to afford diaryl ether 31.5. Finally, aniline was reacted with isocyanate 31.6 to synthesize donafenib (31) from 31.3 in 79% yield.