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-aminoi...

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Bibliographic Details
Published in:Synlett 2013-02, Vol.24 (3), p.301-304
Main Authors: Chen, Ying, Crockett, Richard D., Wang, Xin, Larsen, Robert D., Cui, Sheng, Faul, Margaret M.
Format: Article
Language:English
Subjects:
cluster
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Summary: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 N Ar 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%).
ISSN:0936-5214
1437-2096
DOI:10.1055/s-0032-1317554