his-gly-glu modified methotrexate, its synthesis, anti-metastatic activity and application
A technology of his-gly-glu and methotrexate, 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-Gly-Glu(OBzl)-OBzl(1)
[0017] Dissolve 1.00 g (5.72 mmol) Boc-Gly with 60 mL of anhydrous tetrahydrofuran to obtain No. 1 solution. 1.41 g (6.84 mmol) of dicyclohexylcarbodiimide and 0.77 g (5.71 mmol) of N-hydroxybenzotriazole in anhydrous tetrahydrofuran were added to No. 1 solution and stirred for 30 minutes. Add 1.90g (5.22mmol) HCl Glu(OBzl)-OBzl, adjust the pH of the reaction solution to 9 with N-methylmorpholine, remove the ice bath, stir well at room temperature for 19 hours, then TLC (dichloromethane / methanol) =30 / 1) shows that the reaction is complete and the reaction is terminated. The white solid dicyclohexyl urea in the reaction solution was filtered off, concentrated, and 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 ), 5% potassium bisulfate aqueous solution (30mL×3), saturated ...
Embodiment 2
[0018] Example 2 Preparation of Gly-Glu(OBzl)-OBzl(2)
[0019] 1.12 g (2.32 mmol) of compound (1) was dissolved in anhydrous ethyl acetate. Under stirring at 0°C, 20 mL of hydrogen chloride in ethyl acetate (4M) was added, and after stirring for 9 hours, TLC (dichloromethane / methanol=30 / 1) showed that the reaction was complete. Under the condition of a warm water bath, the reaction solution was repeatedly concentrated under reduced pressure, then dissolved with anhydrous ethyl acetate, concentrated (3 times), and then repeatedly washed with anhydrous ether to obtain 0.89 g (100%) of the target compound. It is a yellow viscous oil. ESI-MS(m / e):385[M+H] + .
Embodiment 3
[0020] Example 3 Preparation of Fmoc-His(Trt)-Gly-Glu(OBzl)-OBzl(3)
[0021] Using the method of Example 1, 1.50 g (67%) of the target compound was obtained as a colorless powder from 1.40 g (2.26 mmol) of Fmoc-His (Trt) and 0.89 g (2.32 mmol) of compound (2). ESI-MS(m / e):986[M+H] + , 1 H NMR (300MHz, DMSO-d 6 ):δ / ppm=8.44(d, J=7.5Hz, 1H), 8.34-8.28(m, 1H), 7.89(d, J=7.5Hz, 2H), 7.68(m, 2H), 7.36-7.28( m,25H),7.06-7.03(m,6H),6.73(s,1H),5.07(s,2H),5.03(s,2H),4.39-4.38(m,1H),4.28-4.14(m, 4H), 3.78-3.67(m, 2H), 2.89-2.73(m, 2H), 2.43-2.38(m, 2H), 2.06-2.00(m, 1H), 1.89-1.80(m, 1H).
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