3, 4, 5-trihydroxybenzoic acid derivative and preparation method and application thereof
A technology of trihydroxybenzoic acid and derivatives, applied in the field of anti-HIV drugs, derivatives and their preparation, 3,4,5-trihydroxybenzoic acid derivatives and their preparation fields
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Embodiment 1
[0034] Embodiment 1: Preparation of intermediate 4-(3,4,5-tris(benzyloxy)benzamido)piperidine-1-carboxylic acid tert-butyl ester (I-b)
[0035] Weigh 3,4,5-tribenzyloxybenzoic acid (2.0g, 4.5mmol) into a 250mL flask, add 50mL N,N-dimethylformamide (DMF) to dissolve, add 1 -(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 0.96g, 5.0mmol), 1-hydroxybenzotriazole (HOBT, 0.67g, 5.0mmol), three Ethylamine (1.3 mL, 10 mmol), stirred for 15 minutes, removed the ice bath, and stirred at room temperature for 1 hour. Finally, 1-Boc-4-aminopiperidine (1.1 g, 5.4 mmol) was added into the flask and reacted for 12 hours. After the reaction, add 100 mL of water, extract three times with ethyl acetate (3×50 mL), combine the organic phases, wash with dilute hydrochloric acid aqueous solution and saturated sodium bicarbonate solution for 2-3 times respectively, and finally wash with saturated sodium chloride solution. Take the organic phase, add appropriate amount of anhydrous...
Embodiment 2
[0037] Embodiment 2: Preparation of intermediate 3,4,5-tris(benzyloxy)-N-(piperidin-4-yl)benzamide (I-c)
[0038] Put the intermediate I-b in a 250 mL flask, gradually add 4 mol / L hydrochloric acid / ethyl acetate solution under stirring until the solution becomes clear, and react at room temperature for 2 hours. Evaporate the reaction solution to dryness to obtain a white solid, add 1 mol / L NaOH solution to adjust the pH to nearly neutral, and then filter to obtain a white solid I-c. Yield: 89.8%, mp: 169-170°C.
[0039] Spectral data: 1 H NMR (400MHz, DMSO-d 6 ,ppm)δ:8.18(d,J=7.8Hz,1H,NH),7.51-7.45(m,4H,Ph-H),7.44-7.38(m,4H,Ph-H),7.38-7.31(m ,6H,Ph-H),7.30-7.23(m,3H,Ph-H),5.17(s,4H,2×CH 2 ),4.99(s,2H,CH 2 ), 3.81(dt, J=7.8, 4.0Hz, 1H, CH), 2.96(dt, J=12.6, 3.3Hz, 2H, CH 2 ), 2.53(d, J=2.2Hz, 1H, CH), 2.47(d, J=2.4Hz, 1H, CH), 2.16(s, 1H, NH), 1.78-1.67(m, 2H, CH 2 ), 1.42 (qd, J=12.0, 4.1Hz, 2H, CH 2 ). 13 C NMR (100MHz, DMSO-d 6 , ppm) δ: 164.92 (C=O), 152.34 (2×C),...
Embodiment 3
[0040] Embodiment 3: General method for preparing intermediate I-d
[0041] Weigh intermediate I-c (0.10g, 0.19mmol, 1eq.) and join in 25mL flask, add 4mL dichloromethane to dissolve, add triethylamine (2eq.) and corresponding acid chloride substituent ( 1.2-1.5eq.), stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was evaporated to dryness, and ethyl acetate was added for ultrasonic filtration to obtain the crude intermediate directly or purified by column chromatography and then submitted to the next reaction. Take I-5 intermediate 3,4,5-tris(benzyloxy)-N-(1-(ethylsulfonyl)piperidin-4-yl)benzamide (I-d-5) as an example.
[0042] Weigh intermediate I-c (0.10g, 0.19mmol) into a 25mL flask, add 6mL of dichloromethane to dissolve, add triethylamine (53μL, 0.38mmol) and ethylsulfonyl chloride (30mg, 0.23mmol), stirred at room temperature for 12 hours. After the reaction, the reaction solution was evaporated to dryness to obtain ...
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