Methylindole and aromatic amino acid modified 2,5-diketopiperazines, their synthesis, activity and application
A technology of diketopiperazine and indole, which is applied to 3R--6R-[4-Lys-amino-n-butyl]-2,5-diketopiperazine, and the application field of preparing anti-tumor metastases medicine, can Solve the problems of unsatisfactory clinical efficacy of tumor chemotherapy and no anti-tumor metastasis effect
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Embodiment 1
[0016] Embodiment 1 prepares D-Boc-Lys(Cbz)-Trp-OBzl
[0017] Suspend 7.7g (20mmol) D-Boc-Lys (Cbz) in 100mL of anhydrous tetrahydrofuran (THF), and add 2.7g (20mmol) 1-hydroxybenzotriazole ( HOBt) and 5.0 g (25 mmol) of dicyclohexylcarbodiimide (DCC), then stirred for 30 min. Afterwards, 8.0 g (25 mmol) D-Trp-OBzl was added. The reaction mixture was adjusted to pH 9 by adding N-methylmorpholine (NMM) dropwise. The reaction mixture was first stirred under ice bath for 1 h, and then stirred at room temperature for 12 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was dissolved in 150 mL of ethyl acetate solution. The obtained ethyl acetate solution was sequentially washed with 5% KHSO 4 Wash 3 times with aqueous solution and 3 times with saturated NaCl aqueous solution. Ethyl acetate layer with anhydrous Na 2 SO 4 Dry for 12h, filter, and concentrate the filtrate to dryness under reduced pressure. The obtained...
Embodiment 2
[0018] Embodiment 2 prepares D-Lys(Cbz)-D-Trp-OBzl
[0019] 3.8 g (5 mmol) of D-Boc-Lys(Cbz)-D-Trp-OBzl was slowly mixed with 52 mL of hydrogen chloride in ethyl acetate (4M) under ice bath and stirring. The resulting solution was stirred for 5 h in an ice bath. After that, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 50 mL of anhydrous ethyl acetate, and the resulting solution was concentrated under reduced pressure. This operation was repeated three times. The residue was washed well with anhydrous ether to obtain 3.41 g (93%) of the title compound as a yellow powder. ESI-MS(m / e):557[M+H] + .
Embodiment 3
[0020] Example 3 Preparation of 3R-(indole-3-methyl)-6R-(4-benzyloxycarbonylamino-n-butyl)-2,5-diketopiperazine (1)
[0021] 3.45 g (6.2 mmol) of D-Lys(Cbz)-D-Trp-OBzl were dissolved in 150 mL of ethyl acetate. The obtained solution was washed three times with 5% aqueous sodium bicarbonate solution, and then the ethyl acetate solution was stirred at room temperature for 12 h to fully separate out the colorless solid. 1.8 g (51%) of the title compound were filtered off. ESI-MS(m / e):449[M+H] + .
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