Synthesis of Tucatinib

Tucatinib was synthesised in a two-step reaction by an aniline fragment. The specific synthesis steps are as follows:

Step 1: Preparation of Tucatinib Aniline

An approach beginning from 2-methyl-4-nitrophenol (395) and 4- chloropyridin-2-amine (396) largely stemming from the original Array disclosures represents a likely scalable route. SNAr involving phenol 395 and chloropyridine 396 took place in the presence of base and at elevated temperature to furnish diaryl ether 397, which was then subjected to DMF-DMA and hydroxylamine hydrochloride to furnish the aryl formamidine 398. Cyclization occurred next resulting in the formation of triazolopyridine 399 upon treatment with TFAA. Reduction of the nitro group finished the preparation of aniline 400.

Step 2: Preparation of Tucatinib

Conversion of aniline 401 to formamidine 402 was facilitated by DMF-DMA, and this was followed by reduction of the nitro group, which spared the nitrile within 403. The reaction with the thiocarbonyl equivalent of 1,1′-thiocarbonyldiimidazole (TCDI) allowed for thiocarbonylative insertion between commercial 404 and the aniline to furnish thiourea 405. Subjection of aniline 400 to nitrile 405 in the presence of acid and mild heating led to an addition?cyclization sequence that delivered aminoquinazoline 406. Activation of the thiourea with tosyl chloride in aqueous base led to the formation of 2H-aminooxazolidine, finishing the synthesis of tucatinib in excellent yields.