Process Development and Multikilogram Syntheses of XL228

Route scouting, process development, and multikilogram syntheses of an IGF-1R/Src/Bcr-Abl inihibitor are reported.

Tuesday, 31 March 2020

Route scouting, process development, and multikilogram syntheses of an IGF-1R/Src/Bcr-Abl inihibitor are reported. Key aspects of the developed route are a regioselective [ 3 + 2] isoxazole formation on a pyrimidine core and a selective SNAr addition of an aryl amine to a symmetrical dichloro substituted pyrimidine. The route contains six synthetic steps and was demonstrated twice on scale, delivering 4.6 and 11.2 kg (25% and 16% overall yield), for Phase I clinical studies.

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