Development of a Scalable Synthesis of a VEGFR Inhibitor

Abstract

Process development and salt selection for a novel ­VEGFR inhibitor are described. The overall convergent synthesis involved coupling of three key fragments, 2-chloronicotinoyl chloride, 4-isopropyl-3-methylaniline and 7-aminoisoquinoline. A cost-effective and scalable synthesis of 7-aminoisoquinoline was also achieved. A transition-metal-free S_NAr process enabled the final C–N coupling to afford the target molecule. A phosphate form of the drug substance with improved physical properties was selected for further development and the corresponding crystallization process was subsequently developed. Overall, a robust six-step route was developed and demonstrated on multikilogram scales affording the target compound in >30% yield and high purity (>99%).

Key words

amination - oxidation - amides - VEGFR inhibitor - 7-aminoisoqinoline

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