Acta Chimica Sinica ›› 2023, Vol. 81 ›› Issue (7): 697-702.DOI: 10.6023/A23040154 Previous Articles     Next Articles

Communication

含三氟甲基三氮嗪酪氨酸激酶抑制剂设计合成及生物活性研究

秦沛a, 马海b, 张发光a,*(), 马军安a,*()   

  1. a 天津大学理学院化学系 天津市分子光电科学重点实验室 天津 300072
    b 中国中医科学院中药研究所 北京 100700
  • 投稿日期:2023-04-20 发布日期:2023-06-15
  • 作者简介:
    庆祝《化学学报》创刊90周年.
  • 基金资助:
    国家自然科学基金(92156025); 国家自然科学基金(22271212); 国家自然科学基金(21961142015); 国家重点研发计划(2019YFA0905100)

Synthesis of 6-CF3-1,2,4-triazine-based Tyrosine Kinase Inhibitors and The Evaluation of Biological Activities

Pei Qina, Hai Mab, Fa-Guang Zhanga(), Jun-An Maa()   

  1. a Department of Chemistry, School of Science, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Tianjin University, Tianjin 300072
    b Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700
  • Received:2023-04-20 Published:2023-06-15
  • Contact: *E-mail: zhangfg1987@tju.edu.cn; majun_an68@tju.edu.cn
  • About author:
    Dedicated to the 90th anniversary of Acta Chimica Sinica.
  • Supported by:
    National Natural Science Foundation of China(92156025); National Natural Science Foundation of China(22271212); National Natural Science Foundation of China(21961142015); National Key Research and Development Program of China(2019YFA0905100)

Trifluoromethyl group has strong electron-withdrawing ability and stable C—F bond, and its introduction into organic molecules could often significantly modify the acidity, dipole moment, lipophilicity and metabolic stability of parent compounds. Therefore, the incorporation of trifluoromethyl group into bioactive molecules has become a common strategy for drug development. Trifluoromethylated arene moiety is the important unit of many drugs and related candidates, such as Nilotinib, Radotinib, Ponatinib, Regorafenib, Pexidartinib, Bimiralisi, and Defactinib. Therefore, it is of great interest to design new compounds containing trifluoromethyl group and explore their potential applications in the development of protein kinase inhibitors. Imatinib is the first-generation tyrosine kinase inhibitor and the first small molecule targeting anti-tumor drug that inspires the synthesis of a large number of excellent anti-tumor drugs. Therefore, in this study, we aimed to design new trifluoromethyl-containing tyrosine kinase inhibitors via combining the aniline-pyrimidine structure of Imatinib with 1,2,4-triazines. In particular, we developed a one-pot [3+3] cycloaddition sequence to construct a series of 3-ester-5-aryl-6- CF3-1,2,4-triazines in good yields. Subsequently, a series of new compounds containing the trifluoromethyl 1,2,4-triazine skeleton were obtained via a sequence of hydrolysis, chlorination, and amidation reactions. Finally, a preliminary evaluation of biological activity was conducted and a hit compound 4a was found with good activity in promoting apoptosis protein Caspase 9. A representative procedure for the synthesis of model product 4a is described as following: Starting from trifluoroethylamine (9.91 g, 100 mmol), tert-butyl nitrite (11.34 g, 110 mmol) and AcOH (1.2 g, 20 mmol) were used to generate trifluorodiazoethane in situ in tetrahydrofuran (THF, 20 mL) at 55 ℃ for 30 min. Then the CF3CHN2 solution was added to the mixture of glycine imine 1 (50 mmol), silver fluoride catalyst (0.64 g, 5 mmol) and cesium carbonate (20.36 g, 62.5 mmol) in THF (80 mL), and the reaction mixture reacted at 0 ℃ for 24 h to give the corresponding 6-CF3-tetrahydrotriazine 2. Afterwards, 2,3-dichloro-5,6-dicyanophenoquinone (DDQ) (2.72 g, 12 mmol) was used as oxidant for compound 2 (3 mmol) to produce the corresponding 3-ester-5-aryl-6-trifluoromethyl-1,2,4-triazine 3. The obtained trifluoromethyl-1,2,4-triazine 3 (3 mmol) was hydrolyzed under the promotion of lithium hydroxide (0.15 g, 3.6 mmol) in THF/H2O (5 mL THF, 10 mL H2O) at r.t. for 1 h to give the corresponding carboxylic acid. The carboxylic acid intermediate reacted with oxalyl chloride (0.31 mL, 3.6 mmol) under the catalysis of N,N-dimethylformamide (DMF, 1~2 drop) in CH2Cl2 at r.t. for 2 h to give the corresponding acyl chlorides. Finally, in a mixture of CH2Cl2 (5 mL) and DMF (2 mL), acyl chloride intermediates reacted with the corresponding aniline-pyrimidine intermediate (0.92 g, 3.3 mmol) to give the desired product 4.

Key words: trifluoromethyl group, triazines, kinase inhibitors, fluorine-containing drugs