Cross-linked pyrrolobenzodiazepine*dimer (PBD) derivative and its conjugates
A technology of benzodiazepine dimer and bipyrrole, which is applied in the field of novel cross-linkable cytotoxic agents and can solve problems such as patient death
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Embodiment 1
[0399] Embodiment 1.1, the synthesis of 2-bis(2-(tert-butoxy)-2-oxyethyl)hydrazine-1,2-dicarboxylic acid di-tert-butyl ester
[0400]
[0401] To a solution of di-tert-butyl di-tert-butylhydrazine-1,2-dicarboxylate (8.01 g, 34.4 mmol) in DMF (150 mL) was added NaH (60%, 2.76 g, 68.8 mmol). After stirring at room temperature for 30 minutes, tert-butyl 2-bromoacetate (14.01 g, 72.1 mmol) was added. The mixture was stirred overnight, quenched by the addition of methanol (3 mL), concentrated, diluted with ethyl acetate (100 mL) and water (100 mL), separated, and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with MgSO 4 dried, filtered, concentrated, and passed through SiO 2 Purification by column chromatography (ethyl acetate / hexane 1:5 to 1:3) afforded the title compound (12.98 g, 82% yield) as a colorless oil. MS ESI m / z C 22 h 41 N 2 o 8 [M+H] + : The calculated value is 461.28, and the measured value is 461.4...
Embodiment 2
[0402] Example 2. Synthesis of 2,2'-(hydrazino-1,2-diyl)diacetic acid.
[0403]
[0404] 1, 4 - Add HCL (12M, 10mL) to dioxane (40mL). The mixture was stirred for 30 minutes, diluted with dioxane (20mL) and toluene (40mL), concentrated and mixed with dioxane (20mL) and toluene (40mL) Evaporation to dryness gave the crude product which was used in the next step without further purification (2.15 g, 103% yield, 93% purity). MS ESI m / z C 4 h 9 N 2 o 4 [M+H] + : The calculated value is 149.05, and the measured value is 149.40.
Embodiment 3
[0405] Example 3. 2,2'-(1,2-bis((benzyloxy)carbonyl)hydrazine-1,2-diyl)synthesis of diacetic acid
[0406]
[0407] To 2,2'-(hydrazine-1,2-diyl)diacetic acid (1.10 g, 7.43 mmol) in THF (200 mL) and NaH 2 PO 4 (0.1 M, 250 mL, pH 8.0) was added benzyl phosgene (5.01 g, 29.47 mmol) in 4 portions over two hours. The mixture was stirred for another 6 h, concentrated and purified on a silica gel column with 1% formic acid in H 2 O / CH 3 CN (1:9) eluted to give the title compound (2.26 g, 73% yield, 95% purity). MS ESI m / z C 20 h 21 N 2 o 8 [M+H] + : The calculated value is 417.12, and the measured value is 417.40.
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