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Warfarin-4-o-acetyl-gprp, its synthesis, activity and application

A kind of technology of warfarin and acetyl, applied in the field of biomedicine

Active Publication Date: 2021-03-30
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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  • Warfarin-4-o-acetyl-gprp, its synthesis, activity and application
  • Warfarin-4-o-acetyl-gprp, its synthesis, activity and application
  • Warfarin-4-o-acetyl-gprp, its synthesis, activity and application

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Experimental program
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Effect test

Embodiment 1

[0020] Embodiment 1 prepares warfarin-4-O-acetic acid benzyl ester

[0021] Put 6.62g (20.00mmol) of warfarin in a 250mL eggplant bottle, add about 70mL of acetone, but it cannot be completely dissolved, heat and stir in an oil bath at 45°C until warfarin dissolves, add 3.50mL (22.00mmol) of bromoacetic acid Benzyl ester, continue to react under 45°C oil bath. After reacting for 72 hours, thin layer chromatography (TLC, petroleum ether / ethyl acetate=2:1) ​​monitored the reaction process, and warfarin had basically disappeared, and the colorless solid produced in the reaction was removed by filtration, and the filtrate was evaporated under reduced pressure to remove acetone. A pale yellow oil was obtained, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=8:1) to obtain 5.4 g (59%) of the title compound as a colorless solid. ESI-MS(m / e):457[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 )δ / ppm=7.89(dd,J 1 =3.0Hz,J 2 =9.0Hz,1H),7.63(dt,J 1 =3.0Hz,J...

Embodiment 2

[0022] Embodiment 2 prepares warfarin-4-O-acetic acid

[0023] Dissolve 4.01g (8.79mmol) of warfarin-4-O-benzyl acetate in 50mL of methanol, add 405mg of Pd / C, evacuate the air in the water pump while stirring, and inject hydrogen, repeat this operation 4 times, Introduce hydrogen and stir at room temperature for 30 h. The completion of the reaction was monitored by TLC, palladium on carbon (Pd / C) was removed by filtration, and the solvent was evaporated from the filtrate under reduced pressure to obtain 2.74 g (85.2%) of the title compound as a colorless solid. ESI-MS(m / e):367[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ):δ / ppm=12.86(s,1H),7.90(d,J=6.0Hz,1H),7.63(t,J=6.0Hz,1H),7.43~7.34(m,4H),7.27(t, J=9.0Hz, 2H), 7.17(t, J=9.0Hz, 1H), 4.99(t, J=9.0Hz, 1H), 4.75(q, J 1 =15.0Hz,J 2 =30.0Hz, 2H), 3.54~3.47(m, 2H), 2.14(s, 3H).

Embodiment 3

[0024] Embodiment 3 prepares Boc-R (NO 2 )-P-OBzl

[0025] 3.509g (11.00mmol) Boc-R (NO 2 )-OH was added to a 250mL eggplant bottle, dissolved in 80mL dry tetrahydrofuran, and 1.485g (11.00mmol) HOBt was added in an ice bath (0°C). After stirring for 10 minutes, 2.632g (12.19mmol) of DCC was added to activate 30min. A colorless solid precipitated out of the reaction solution. Add 2.516g (10.41mmol) HCl Pro-OBzl to the reaction solution under ice-cooling, adjust the pH value to 9 with N-methylmorpholine, stir and react at room temperature for 12h, then TLC (dichloromethane / methanol=20 : 1) monitor the reaction process, the raw material point disappears, filter out the colorless solid in the reaction solution, the filtrate is evaporated under reduced pressure to remove the solvent, the residue is dissolved with 100mL ethyl acetate, and the insolubles are filtered out, and the filtrate is washed with saturated NaHCO 3 solution (30mL×3), saturated NaCl solution (30mL×3), 5% KH...

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Abstract

The invention discloses warfarin-4-O-acetyl-GPRP, discloses a preparation method thereof, discloses phlebothrombosis resisting activity thereof, discloses ferric trichloride induced mouse artery thrombosis resisting activity thereof, discloses in-vivo blood coagulation factor IX content reducing activity thereof and discloses the advantage thereof no warfarin sample bleeding risk. Therefore, the invention discloses application thereof in preparing phlebothrombosis resisting medicine, application thereof in preparing artery thrombosis resisting medicine and application thereof in preparing blood coagulation factor IX antagonists.

Description

technical field [0001] The present invention relates to warfarin-4-O-acetyl-GPRP, to its preparation method, to its anti-venous thrombosis activity, to its anti-arterial thrombosis activity, and to its function of reducing the content of coagulation factor IX in vivo. Therefore, the present invention relates to its application in the preparation of anti-venous thrombosis medicine, its application in the preparation of anti-arterial thrombosis medicine and its application in the preparation of blood coagulation factor IX antagonist. The invention belongs to the field of biomedicine. Background technique [0002] Both arterial thrombosis and venous thrombosis have become diseases with high morbidity and mortality. Among them, venous thrombosis mainly includes deep vein thrombosis and pulmonary embolism. Deep vein thrombosis and pulmonary embolism account for more patients than myocardial infarction and stroke combined, and more deaths than breast cancer and AIDS combined. S...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/103C07K1/02A61K38/07A61P7/02
CPCA61K38/00C07K5/0806
Inventor 彭师奇赵明吴建辉王玉记侯梦雨
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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