glu-asp-gly modified methotrexate, its synthesis, antimetastatic activity and application
A glu-asp-gly, methotrexate technology, applied in the field of biomedicine, can solve the problems of limiting the application and curative effect of methotrexate
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Embodiment 1
[0016] Example 1 Preparation of Boc-Asp(OBzl)-Gly-OBzl(1)
[0017] 1.42 g (4.40 mmol) of Boc-Asp (OBzl) was dissolved in 60 mL of anhydrous tetrahydrofuran to obtain No. 1 solution. Under stirring, 1.36 g (6.60 mmol) of dicyclohexylcarbodiimide and 0.59 g (4.40 mmol) of N-hydroxybenzotriazole in anhydrous tetrahydrofuran were added to No. 1 solution and stirred for 30 minutes at 0°C. Subsequently, 1.10 g (3.26 mmol) of Tos·Gly-OBzl was added, the pH of the reaction solution was adjusted to 8-9 with N-methylmorpholine, the ice bath was removed, and after stirring at room temperature for 18 hours, TLC (dichloromethane / Methanol = 30 / 1) showed that the reaction was complete. The colorless solid in the reaction solution was filtered off, the filtrate was concentrated, the residue was dissolved in 100 mL of ethyl acetate, and the solution was washed with saturated aqueous sodium bicarbonate solution (30 mL × 3) and saturated aqueous sodium chloride solution (30 mL × 3) in turn. ,...
Embodiment 2
[0018] Example 2 Preparation of Asp(OBzl)-Gly-OBzl(2)
[0019] Dissolve 1.34g (2.85mmol) of Boc-Asp(OBzl)-Gly-OBzl(1) with anhydrous ethyl acetate, add 20mL of hydrogen chloride in ethyl acetate solution (4M) under stirring at 0°C, and stir for 7 hours. TLC (dichloromethane / methanol=30 / 1) showed that the reaction was completed. Under the condition of a warm water bath, the reaction solution was repeatedly concentrated under reduced pressure, and then the concentrate was dissolved in anhydrous ethyl acetate, and the reaction solution was repeatedly concentrated under reduced pressure (3 times), The reactant was repeatedly triturated with anhydrous ether to obtain 1.05 g (100%) of the target compound as a yellow viscous oil. ESI-MS(m / e): 371[M+1] + .
Embodiment 3
[0020] Example 3 Preparation of Boc-Glu(OBzl)-Asp(OBzl)-Gly-OBzl(3)
[0021] Using the method of Example 1, 1.31 g (77%) of the title compound was obtained as a colorless powder from 0.83 g (2.47 mmol) of Boc-Glu (OBzl) and 1.05 g (2.84 mmol) of compound (2). ESI-MS(m / e): 690[M+H] + , 1H NMR (300MHz, DMSO-d 6 ): δ / ppm=8.32(t, J=5.7Hz, 1H), 8.24(d, J=8.1Hz, 1H), 7.39-7.30(m, 15H), 7.03(d, J=7.8Hz, 1H) ,5.10-5.06(m,6H),4.71(m,1H),3.90(m,3H),2.81(dd,J=8.4Hz,5.1Hz,2H),2.52(m,2H),1.83(m, 2H), 1.36 (s, 9H).
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