Synlett 2013; 24(3): 301-304
DOI: 10.1055/s-0032-1317554
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© Georg Thieme Verlag Stuttgart · New York

Development of a Scalable Synthesis of a VEGFR Inhibitor

Ying Chen*
a   Chemical Process Research and Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA   Fax: +1(805)3754531   Email: ying@amgen.com   Email: scui@amgen.com   Email: mfaul@amgen.com
,
Richard D. Crockett
a   Chemical Process Research and Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA   Fax: +1(805)3754531   Email: ying@amgen.com   Email: scui@amgen.com   Email: mfaul@amgen.com
,
Xin Wang
b   Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA
,
Robert D. Larsen
c   Alcon Laboratories, Inc., 6201 South Freeway, Fort Worth, TX 76134, USA
,
Sheng Cui*
a   Chemical Process Research and Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA   Fax: +1(805)3754531   Email: ying@amgen.com   Email: scui@amgen.com   Email: mfaul@amgen.com
,
Margaret M. Faul*
a   Chemical Process Research and Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA   Fax: +1(805)3754531   Email: ying@amgen.com   Email: scui@amgen.com   Email: mfaul@amgen.com
› Author Affiliations
Further Information

Publication History

Received: 27 September 2012

Accepted after revision: 19 October 2012

Publication Date:
16 November 2012 (online)


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 SNAr 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%).

Supporting Information