Tanshinol ligustrazine derivative and preparation method and application thereof
A Danshensu derivative and a technology for preparing medicine are applied in the field of pharmaceutical and medical applications in the composition containing the Danshensu derivative or its salt, and can solve the problems of prone to oxidation and decarboxylation reactions, unfavorable drug storage and storage, The mechanism of action is not comprehensive enough to achieve the effect of changing absorption performance, maintaining integrity and improving drug efficacy
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Embodiment 1
[0145] Embodiment 1, the synthesis of compound BnOH
[0146] Take a 25mL single-necked flask, weigh Danshensu (100mg, 0.505mmol), add 2mL of acetone to dissolve, stir at room temperature until uniform, then add anhydrous K 2 CO 3 (200mg, 1.45mmol), then added benzyl bromide (0.2mL, 1.67mmol), the reaction was refluxed at 65°C for 24h, and the reaction was monitored by TLC. After the reaction was completed, it was cooled to room temperature, acidified with 1N HCl, added saturated NaCl solution and Diluted with ethyl acetate, extracted 3 times with ethyl acetate (25mL×3), the organic phase was washed with Na 2 SO 4 Drying, spin-drying, and silica gel column separation (ethyl acetate:petroleum ether=1:2) gave the target compound (130 mg, yield 55.8%) as a solid. mp92-95℃; 1 H NMR (DMSO-d 6 ,500MHz)δ:2.88(dd,J=6.4,14.0Hz,1H,CH 2 ),3.30(dd,J=4.8,14.0Hz,1H,CH 2 ),4.10(m,1H,alcohol),4.41(m,1H,CH),5.06(s,2H,CH 2 ),5.09(s,2H,CH 2 ),5.12(s,2H,CH 2 ),6.64(dd,J=2.0,8.0Hz,1H,arom...
Embodiment 2
[0148] Embodiment 2, the synthesis of compound DPNB
[0149] Take a 25mL single-necked flask, weigh Danshensu raw material (100mg, 0.505mmol), add about 2mL of DMF to dissolve the compound dropwise, add EDCI (125mg, 0.65mmol) and HOBt (90mg, 0.66mmol) to it, stir at room temperature, The temperature of the reaction system was lowered to 0 °C with an ice bath, and the N 2 Under protection, boc-protected piperazine (112mg, 0.6mmol) was added dropwise to the reaction system, reacted at room temperature for 17 hours, and TLC monitored the reaction. Ester was extracted 3 times (25mL×3), the ethyl acetate layer was washed 3 times with ice brine, and the DMF in the organic phase was washed away, and the organic phase was washed with anhydrous Na 2 SO 4 dry. Silica gel column separation (ethyl acetate:petroleum ether=2:1) gave the target compound (120 mg, yield 65%) as a white loose solid. 1 H NMR (DMSO-d 6 ,500MHz)δ:2.81(dd,J=5.6,13.6Hz,1H,CH 2 ),2.74(dd,J=5.6,13.8Hz,1H,CH 2...
Embodiment 3
[0151] Embodiment 3, the synthesis of compound TMPM
[0152] Take a 25mL single-necked flask, weigh Danshensu (100mg, 0.505mmol), add about 2mL of dry DMF to dissolve the compound dropwise, add NaHCO 3 (50mg, 0.595mmol) was stirred evenly at room temperature, and the temperature of the reaction system was lowered to 0°C with an ice bath, and N 2 Under protection, 2-bromoethyl-3,5,6-trimethylpyrazine (110mg, 0.514mmol) was added to the reaction system, reacted at room temperature for 17 hours, and TLC monitored the reaction. The system was diluted with ice brine and ethyl acetate, extracted three times with ethyl acetate (25mL×3), the ethyl acetate layer was washed three times with ice brine, and the DMF in the organic phase was washed away, and the organic phase was washed with anhydrous Na 2 SO 4 dry. After spin-drying, silica gel column separation (ethyl acetate:petroleum ether=1:2), the target compound (108 mg, yield 65.4%) was obtained as a white solid. 1 H-NMR(DMSO-d6...
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