Synthesis 2019; 51(13): 2660-2664
DOI: 10.1055/s-0037-1610706
© 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)


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.

  • References

  • 1 Dinkel V, Anderson D, Winski S, Winkler J, Koch K, Lee PA. Cancer Res. 2014; 72: 852
  • 2 Lee P, Anderson D, Bouhana K, Garrus J, Napier C, Avrustkaya A, White A, Pheneger T, Winkler J. Cancer Res. 2014; 69: 5104
  • 3 Lyssikatos JP, Marmsater FP, Zhao Q, Greschuk JM. PCT Int. Appl WO 2007059257, 2007
  • 4 Tsou HR, Mamuya N, Johnson BD, Reich MF, Gruber BC, Ye F, Nilakantan R, Shen R, Discafani C, DeBlanc R. J. Med. Chem. 2001; 44: 2719
  • 5 Matsushima T, Shirotori S, Takahashi K, Kamada A, Wakasugi K, Sakaguchi T. US Pat. Appl. Publ US 20080319188, 2008
  • 6 Allen JR, Hitchcock SA, Turner WW. Jr, Liu B. PCT Int. Appl WO 2004094382, 2004