A new, practical, and convergent synthetic route of gedatolisib, an antitumor agent, is developed on a hectogram scale which avoids the Pd coupling method. The key step is adopting 6-(4-nitrophenyl)-1,3,5-triazine-2,4-diamine and 2,2′-dichlorodiethyl ether to prepare the key 4,4′-(6-(4-nitrophenyl)-1,3,5-triazine-2,4-diyl)dimorpholine in 77% yield and 98.8% purity. Gedatolisib is obtained in 48.6% yield over five simple steps and 99.3% purity (HPLC). Purification methods of the intermediates and the final product involved in the route are given.
off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.46 (brs, 2H), 1.89 (brs, 2H), 2.29 (s, 6H), 2.94 (brs, 2H), 3.76 (m, 8H), 3.89 (m, 8H), 7.09 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 8.28 (s, 1H), 8.31 (d, J = 8.6 Hz, 2H), 8.48 (s, 1H). ESI-MS (m/z) 615.9 (M + H). HPLC conditions: Column: Agilent Eclipse XDB-C18 (250 mm × 4.6 mm × 5 μm); Detection: 254 nm; Flow rate: 0.8 mL/min; Temperature: 30 °C; Injection load: 1 μL; Solvent: MeOH; Concentration: 0.5 mg/mL; Run time: 20 min; Mobile phase A: water; Mobile phase B: MeOH/TEA = 100:0.1; Gradient program: time (min): 20; % of mobile phase A: 10; % of mobile phase B: 90; tR = 2.598 min, purity: 99.34%
- Zhao, X.; Tan, Q.; Zhang, Z.; Zhao, Y. Med. Chem. Res. 2014, 23, 5188– 5196 DOI: 10.1007/s00044-014-1084-z
- Khafizova, G.; Potoski, J. R. PCT Int. Appl. WO 2010096619, 2010.
- Venkatesan, A. M.; Chen, Z.; Dehnhardt, C. M.; Dos Santos, O.; Delos Santos, E. G.; Zask, A.; Verheijen, J. C.; Kaplan, J. A.; Richard, D. J.; Ayral-Kaloustian, S.; Mansour, T. S.; Gopalsamy, A.; Curran, K. J.; Shi, M. PCT Int. Appl. WO 2009143317, 2009.
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