Process development and multikilogram syntheses of XL228 utilizing a regioselective isoxazole formation and a selective SNAr reaction to a pyrimidine core

NR Guz, H Leuser, E Goldman

Index: Guz, Nathan R.; Leuser, Helena; Goldman, Erick Organic Process Research and Development, 2013 , vol. 17, # 8 p. 1066 - 1073

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Citation Number: 5

Abstract

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 ...