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Nitrogen monoxide donor type dihydromyricetin derivative as well as preparation and application thereof

A technology of dihydromyricetin and nitric oxide, which is applied in the field of medicine and can solve the problems of high price, low water solubility, and limited number of enzymes

Active Publication Date: 2017-12-01
SHIJIAZHUANG UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Dihydromyricetin has low water solubility, but poor fat solubility
However, due to the limited quantity and high price of the enzyme, its application in the glycoside reaction is restricted.

Method used

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  • Nitrogen monoxide donor type dihydromyricetin derivative as well as preparation and application thereof
  • Nitrogen monoxide donor type dihydromyricetin derivative as well as preparation and application thereof
  • Nitrogen monoxide donor type dihydromyricetin derivative as well as preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Preparation of intermediate (I):

[0020] Weigh 1.6g (5mmol) of dihydromyricetin (98%) into a 50mL Erlenmeyer flask, then add 15ml of acetic anhydride and 1.2g of boric acid in sequence, mix well, place in the dark for 3 days, pour into ice water and grind, A yellow boric acid complex precipitates, filter, add the resulting yellow solid to 40mL of 10% HCl solution, react at 60°C for 30 minutes, remove boric acid, a yellow-white solid is formed, filter, rinse with water until neutral, and collect the solid , the crude product was obtained after drying. Recrystallization with EtOH gave white crystals, namely dihydromyricetin tetraacetylation product (intermediate I), with a yield of 89%. m.p.205-206°C.

Embodiment 2

[0022] Preparation of intermediates (IIa-f):

[0023] 3,4-Diphenylsulfonyl-1,2,5-oxadiazole-2-oxide was prepared according to the literature (Chemical Journal of Chinese Universities, 2010, 31(8):1541-1547).

[0024] Add 2.4mL (40mmol) ethylene glycol, 1.46g (4mmol) intermediate (I) and 20mLTHF into the reactor, stir, add 0.72mL (12mmol) 50% NaOH solution dropwise, a yellow solid is formed, and the dropwise addition is completed , reacted for 1h, filtered, concentrated to dryness, added 50mL of water to the residue, extracted with ethyl acetate (3×20mL), washed with saturated sodium chloride solution, dried, concentrated, purified by silica gel column chromatography (eluent: V 乙酸乙酯 :V 石油醚 = 1:1.5), to obtain intermediate (IIa) white solid 0.8g, yield 70%, m.p.111-113°C.

[0025] Substitute 2.4mL (40mmol) of ethylene glycol with 2.9mL (40mmol) of 1,3-propanediol and perform the same operation as above to obtain intermediate (IIb) as a white solid with a yield of 80% and m.p....

Embodiment 3

[0031] Preparation of compound (1):

[0032] In the reactor, add 6mL of anhydrous DMF, 0.39g (1.5mmol) PPh 3 , 0.488g (1.0mmol) of intermediate (I) and 0.287g (1.0mmol) of intermediate (IIa), stirring, dropwise adding a solution of 0.404g (1.5mmol) of diisopropyl azodicarboxylate and 4mL of DMF, at room temperature Reaction for 1h, TLC detection (developing agent: V 乙酸乙酯 :V 氯仿 :V 甲酸 = 10:6:2), the reaction was completed, and purified by polyamide column chromatography to obtain a light yellow solid with a yield of 61%. ESI-MS (m / z): 756[M] + , 757[M+1] + ; [α] D 20 = +30.4˚; 1 H-NMR (400MHz, DMSO-d6)δ (ppm): 2.28 (s, 6H), 2.31 (s, 3H), 2.34 (s, 3H), 3.62 (t, 4H), 4.40 (d, J = 11Hz, 1H), 4.89 (d, J = 11Hz, 1H), 5.85 (s,1H), 5.90(s, 1H), 6.40 (s, 2H), 7.57-7.87 (m, 5H), 11.88 (s, 1H).

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PUM

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Abstract

The invention discloses a nitrogen monoxide donor type dihydromyricetin derivative or a pharmaceutically acceptable hydrate. The nitrogen monoxide donor type dihydromyricetin derivative has the efficiencies of regulating blood sugar and blood fat, promoting angiogenesis and improving vascular endothelial functions and can be applied to drugs for preventing diabetes mellitus, diabetic cardiovascular complications and metabolic syndromes. The invention further discloses a preparation method of the nitrogen monoxide donor type dihydromyricetin derivative.

Description

technical field [0001] The invention relates to a derivative of nitric oxide donor type dihydromyricetin and its application in pharmacy, belonging to the technical field of medicine. Background technique [0002] Dihydromyricetin (DMY) is an active ingredient in Vitis vinifera tea, which has pharmacological activities such as regulating blood sugar and blood lipid, antibacterial, antioxidation, antithrombotic, liver protection and anticancer. Dihydromyricetin has low water solubility, but poor fat solubility. Domestic scholars reacted dihydromyricetin with lauryl chloride, lauroyl chloride, and stearyl chloride to form corresponding esters, which increased its lipophilicity and satisfied its application in the food industry. Ning Zhengxiang and others used glycosidase to catalyze the synthesis of a flavonoid glucoside compound, dihydromyricetin-7-a-D-glucoside, which can basically return the blood sugar metabolism of diabetic patients to normal levels. However, due to the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/12C07D413/14A61P3/10A61P3/06A61P9/00A61P9/14
CPCC07D413/12C07D413/14
Inventor 史兰香张冀男张宝华刘斯婕郭瑞霞
Owner SHIJIAZHUANG UNIVERSITY