Glu-Asp-Gly modified methotrexate, and synthesis, anti-metastasis activity and application of Glu-Asp-Gly modified methotrexate
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. 0 ℃ and stirring, 1.36g (6.60mmol) dicyclohexyl carbodiimide and 0.59g (4.40mmol) N-hydroxybenzotriazole anhydrous tetrahydrofuran solution was added to the No. 1 solution and stirred for 30 minutes. Subsequently, 1.10 g (3.26 mmol) 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 18 hours of thorough stirring at room temperature, TLC (dichloromethane / Methanol = 30 / 1) showed 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 successively with saturated aqueous sodium bicarbonate (30 mL×3) and saturated aqueous sodium chloride (30 mL×3). , washed with 5% potass...
Embodiment 2
[0018] Example 2 Preparation of Asp(OBzl)-Gly-OBzl(2)
[0019] Dissolve 1.34g (2.85mmol) Boc-Asp(OBzl)-Gly-OBzl(1) in anhydrous ethyl acetate, add 20mL 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 complete. Under the condition of warm water bath, the reaction solution was repeatedly concentrated under reduced pressure, and then the concentrate was dissolved with anhydrous ethyl acetate, and the reaction solution was repeatedly concentrated under reduced pressure (3 times). The reactant was washed repeatedly 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 target 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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