Development of a Scalable and Practical Synthesis of AB928, a Dual A2a/A2b Receptor Antagonist

AB928 is a potent and selective dual antagonist of the A2a and A2b receptors, which is currently in clinical trials. Here, we report the development of two scalable and practical syntheses of AB928. The first-generation synthesis was used to successfully obtain AB928 in excellent yield and purity to support our preclinical and initial clinical studies. Recently, we have developed a second-generation synthesis of AB928 featuring a palladium-free protocol to access 3-(2-amino-6-chloropyrimidin-4-yl)-2-methylbenzonitrile, a key intermediate in the AB928 synthesis. The new method is scalable, practical, and significantly more cost-effective.