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Preparation method and use of quercetin amide derivative

A quercetin amide and derivative technology, applied in the field of medicinal chemistry, can solve the problems of low bioavailability, limitation of quercetin activity research and clinical application, poor solubility of quercetin and the like

Inactive Publication Date: 2013-07-24
ZHENGZHOU UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, because quercetin is a planar molecule, the molecular packing is relatively tight, the intermolecular attraction is large, and it is not easy to be dispersed by solvents, so the solubility of quercetin is poor and the bioavailability is low (the peak plasma concentration is only 0.13~ 7.6 μM / L), which greatly limits the activity research and clinical application of quercetin (Sun Tiemin, Sun Changshan, Dai Guangyuan, etc. Chinese Journal of Medicinal Chemistry, 2003,13(6):345~348; Bakhtiyor F. Rasulev, Nasrulla D. Abdullaev, Vladimir N. Syrov, et al. QSAR Comb. Sci.24, 2005, 9:1056~1065.)

Method used

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  • Preparation method and use of quercetin amide derivative
  • Preparation method and use of quercetin amide derivative
  • Preparation method and use of quercetin amide derivative

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preparation example Construction

[0040] 2 Preparation of compounds

[0041] 2.1 Synthesis of 3′,4′,7-O-tribenzylquercetin (1)

[0042] Place rutin in a vacuum oven at 80°C for 10 hours to remove crystal water, dissolve 4.88g (8 mmol) of rutin in 40mL N,N-dimethylformamide (DMF), and then add 3.86g (28 mmol) anhydrous K 2 CO 3, stirred at room temperature for 15 min, slowly added benzyl bromide 3.4 mL (28 mmol) dropwise under ice bath, and reacted at room temperature for 16 h. Adjust the pH to 6~7 with glacial acetic acid, add 200 mL of distilled water, and stir for 3 h until the solid precipitates and the water becomes clear. Discard the water layer, add 80 mL of ethanol to dissolve, add 18 mL of concentrated hydrochloric acid, reflux in water bath for 2 h, precipitate a large amount of yellow precipitate, filter, wash with water to obtain the crude product, and recrystallize with chloroform / methanol to obtain 3.72 g of pure product 1, yield 81.2% .

[0043] 1 H NMR (400 MHz, DMSO) δ 12.42 (s, 1H,5-...

Embodiment 1

[0049] Example 1: Preparation of quercetin-3-O-acetyl-isopropylamine (3-1)

[0050] Add 1.26g (2mmol) of compound 2 into a round bottom flask, add 40mL of anhydrous dichloromethane and stir to dissolve, add 454mg (2.2mmol) of DCC and 297mg (2.2mmol) of HOBt, and stir for 1h in an ice-salt bath. Dilute 130mg (2.2mmol) of isopropylamine with 20mL of anhydrous DCM, and slowly add it dropwise into the reaction flask with a constant pressure dropping funnel. After 20 minutes, gradually turn to room temperature and stir for 8-24 hours. After the reaction, put it in the refrigerator for half an hour. Most of the by-product DCU was removed by filtration, the filtrate was extracted, HOBt was easily soluble in water and removed, and the organic layer was dried overnight with anhydrous sodium sulfate. Filter, concentrate by rotary evaporation, add a small amount of acetone, a small amount of white granular solid precipitates, filter, and spin dry the filtrate. Recrystallization from ...

Embodiment 2

[0053] Embodiment 2: the synthesis of quercetin-3-O-acetyl-tert-butylamine (3-2)

[0054] The synthesis method is the same as 3-1. Compound 3-2 is a light yellow solid with a yield of 44.3%.

[0055] M.p: 274.8~276.6 ℃; 1 H NMR (400 MHz, DMSO) δ 12.49 (s, 1H,5-OH), 10.93 (s, 1H,7-OH), 9.84 (s, 1H, 4′-OH), 9.41 (s, 1H, 3 ′-OH), 7.77 (s, 1H,NH), 7.46 (dt, J = 8.3, 2.2 Hz, 2H, 2′-H, 6′-H), 6.92 (d, J = 8.3 Hz, 1H, 5 ′-H), 6.44 (d, J = 2.0 Hz, 1H, 8-H), 6.23 (d, J = 2.0 Hz, 1H, 6-H), 4.25 (s, 2H,COCH2), 1.29 (s, 9H.3×CH 3 ).

[0056] 13 C NMR (101 MHz, DMSO) δ 178.16, 167.47, 164.84, 161.61, 156.88, 156.54, 149.41, 145.86, 137.49, 121.46, 120.91, 116.28, 115.95, 104.43, 99.20, 94.22, 72.38, 50.68, 28.86.

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Abstract

The invention discloses a preparation method of a quercetin amide derivative and application of the quercetin amide derivative in preparing an antitumor drug. The preparation method of the quercetin amide derivative comprises the following steps of: carrying out benzyl selective protection, a Williamson ether forming reaction, a DCC (Dicyclohexylcarbodiimide) condensation reaction, catalytic hydrogenation and the line by using cheap rutin as the material. The preparation method of the quercetin amide derivative can be used for realizing the orientation and efficient modification of the quercetin, and is gentle in reaction conditions, simple to operate, simple in post-treatment and convenient for industrial production. The obtained quercetin amide derivative obviously has a stronger inbibitional effect to proliferation of a human esophageal squamous carcinoma cell EC (Ethyl Cellulose)109, a human esophageal squamous carcinoma cell EC9706, a human gastric carcinoma cell SGC (Soluble Guanylyl Cyclase) 7901 and a mouse melanoma cell B16-f10 relative to the quercetin, and therefore, the quercetin amide derivative is an anti-tumor candidate compound with great potential.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a synthesis method of quercetin derivatives and research on their antitumor activity. Background technique [0002] Flavonoids are a class of natural polyphenolic compounds that widely exist in the plant kingdom, and quercetin (3,3′,4′,5,7-pentahydroxyflavone) is a typical representative of them, widely present in In daily edible vegetables, fruits, Chinese herbal medicines and beverages, such as onions, apples, grapes, strawberries, ginkgo, green tea and red wine, the average content is about 10 mg / Kg, and the high content can even reach 300 mg / Kg (Pietta P G. J Nat Prod, 2000, 63(7): 1035~1042; Manach C, Wiliamsoni G, Morand C, et al. Am J Clin Nutrit, 2005, 81: 230~242.). Studies have shown that quercetin has various pharmacological and biological activities, such as anti-oxidation, anti-tumor, anti-bacterial, anti-infection, anti-mutation and protection of card...

Claims

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Application Information

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IPC IPC(8): C07D311/30A61K31/352A61P35/00
Inventor 翟广玉渠文涛颜子童马海英王俊巍
Owner ZHENGZHOU UNIV
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