Synthesis 2019; 51(13): 2660-2664
DOI: 10.1055/s-0037-1610706
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© Georg Thieme Verlag Stuttgart · New York

New Synthetic Route to Tucatinib

Lingfeng Yin
,
Yongjun Mao*
College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road, Shanghai 201620, P. R. of China   Email: [email protected]
,
Yaowei Liu
,
Lehao Bu
,
Long Zhang
,
Wenxin Chen
› Author Affiliations
Further Information

Publication History

Received: 13 January 2019

Accepted after revision: 01 April 2019

Publication Date:
16 April 2019 (online)


Abstract

A new and improved synthetic route to tucatinib is described that involves three key intermediates. The first of these, 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline, was prepared on a 100 g scale in 33% yield over five steps and 99% purity. Next, N 4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)quinazoline-4,6-diamine was isolated in 67% yield over three steps and >99% purity. Then, 4,4-dimethyl-2-(methylthio)-4,5-dihydrooxazole trifluoromethanesulfonate was prepared under mild conditions in 67% yield over two steps. Finally, tucatinib was obtained in 17% yield over nine steps and in >99% purity (HPLC). Purification methods used to isolate the product and the intermediates involved in the route are also reported.

 
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