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Synthetic method of polyhydroxy isoflavone

A technology of polyhydroxy isoflavones and hydroxy isoflavones, which is applied in the direction of drug combinations, pharmaceutical formulations, organic active ingredients, etc., can solve problems such as unseen synthetic methods, and achieve the effects of easy industrial production, good selectivity, and high yield

Active Publication Date: 2020-08-21
中国人民解放军联勤保障部队第九四〇医院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, 3′, 4′, 6,7,8-pentahydroxyisoflavone does not exist in natural products, and there is no relevant synthetic method for the two compounds

Method used

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  • Synthetic method of polyhydroxy isoflavone
  • Synthetic method of polyhydroxy isoflavone
  • Synthetic method of polyhydroxy isoflavone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Preparation of 4′,7,8-trihydroxyisoflavone

[0051]

[0052] (1) Preparation of 8-bromo-7-hydroxy-4′-methoxyisoflavone

[0053] Formononetin (2.68 g, 10 mmol) was dissolved in anhydrous DMF (20 mL), cooled to 0° C., NBS (1.94 g, 11 mmol) was added under stirring, and the reaction was carried out for 4 h. The reaction was stopped, 100 mL of 2M hydrochloric acid was added to quench the reaction, 200 mL of water was added, and the mixture was allowed to stand overnight in the refrigerator. After filtration, the filter cake was dried to obtain 3.31 g of 8-bromo-7-hydroxy-4′-methoxyisoflavone, a white powder, The rate is 95%. m.p.268.5~270.3℃. IR (KBr, v): 3094, 2939, 1607, 1588, 1511, 1424, 1293, 1246, 1179, 825 cm-1. 1 H-NMR (400MHz, d 6 -DMSO)δ: 11.64(s, 1H, C7'-OH), 8.49(s, 1H, C2-H), 7.80(d, J=8.8Hz, 1H, C5-H), 7.54(d, J= 8.4Hz, 2H, C2'-H, C6'-H), 7.14(d, J=8.8Hz, 1H, C6-H), 7.01(d, J=8.8Hz, 2H, C3'-H, C5' -H), 3.80(s, 3H, CH 3 O). 13 C-NMR(101MHz, d 6 -DMSO)δ: 174.85(C4...

Embodiment 2

[0059] Preparation of 4′,6,7,8-tetrahydroxyisoflavone

[0060]

[0061] (1) Synthesis of 6,8-dibromo-4′-methoxyisoflavone

[0062] Formononetin (2.68g, 10mmol) was dissolved in DMF (40mL), and NBS (4.4g, 25mmol) was added under stirring at room temperature. After 1.5 hours of reaction, the reaction was monitored by TLC and the reaction was complete. 100mL of 2M hydrochloric acid was added to quench the reaction , Add 200 mL of water, put it in the refrigerator overnight, filter, wash and dry the filter cake to obtain 4.10 g of white powder, which is 6,8-dibromo-4'-methoxyisoflavone, and the yield is 95%. m.p.278.0~278.8℃. IR (KBr, v): 3078, 2840, 1631, 1609, 1582, 1540, 1512, 1442, 1249, 1184, 1139, 832cm -1 . 1 H-NMR(400MHz, DMSO-d 6 )δ: 8.54(s, 1H, C2-H), 8.20(s, 1H, C5-H), 7.54(d, J=8.4Hz, 2H, C2'-H, C6'-H), 7.01(d , J=8.4Hz, 2H, C3'-H, C5'-H), 3.79(s, 3H, CH 3 O). 13 C-NMR(101MHz, DMSO-d 6 )δ: 173.94(C4), 159.66(C4'), 156.29(C7), 154.30(C9), 153.46(C2), 130.54(C5), 128.51(C2'...

Embodiment 3

[0068] Preparation of 3',4',6,7,8-pentahydroxyisoflavone

[0069]

[0070] (1) Synthesis of 3',6,8-tribromo-7-hydroxy-4'-methoxy isoflavone

[0071] Formononetin (1.34 g, 5 mmol) was dissolved in DMF (30 mL), NBS (3.52 g, 20 mmol) was added, and the reaction was refluxed at 80° C. for 1 hour. TLC monitoring showed that the reaction was complete. After cooling to room temperature, add 50mL of 2M hydrochloric acid to quench the reaction, add 150mL of water, stand in the refrigerator overnight, filter, wash and dry the filter cake to obtain 2.37g of white solid, which is 3′,6,8-tribromo-7-hydroxy-4′ -Methoxyisoflavones with a yield of 94%. m.p.261.3~261.9℃. m.p.261.3~261.9℃. IR (KBr, v): 3094, 1633, 1605, 1544, 1498, 1431, 1262, 1232, 1147, 813cm -1 . 1 H-NMR(400MHz, DMSO-d 6 )δ: 8.62 (s, 1H, C2-H), 8.19 (s, 1H, C5-H), 7.84 (d, J=2.0, 1H, C2'-H), 7.60 (dd, J=8.8, 2.0 Hz, 1H, C6'-H), 7.20(d, J=8.4Hz, 1H, C5'-H), 3.89(s, 3H, CH 3 O). 13 C-NMR(101MHz, DMSO-d 6 )δ: 173.72(C4), 156.42(...

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Abstract

The invention discloses a synthetic method of polyhydroxy isoflavone. The method comprises the following steps: (1) enabling formononetin to react with N-bromosuccinimide serving as a bromination reagent, and replacing one or more hydrogen atoms on a formononetin carbon ring with bromine atoms by controlling a molar ratio of formononetin to N-bromosuccinimide and controlling a reaction temperatureso as to obtain corresponding bromide; (2) enabling the bromide in the step (1) to react with sodium methoxide under the action of cuprous salt so as to allow bromine atoms on a carbon ring of the bromide to be substituted by a methoxy group, thereby obtaining a methoxylation product; and (3) subjecting the methoxylation product obtained in the step (2) to a demethylation reaction under the action of aluminum trichloride and dimethyl sulfide so as to obtain the polyhydroxy isoflavone. Compared with the prior art, the method of the invention has the advantages of rich sources of initial raw materials, mild reaction conditions, short steps, high yield and easiness in industrial production. The purity of the produced polyhydroxy isoflavone is greater than 99.0%, and the polyhydroxy isoflavone can be used for pharmacological activity research.

Description

Technical field [0001] The invention belongs to the field of drug synthesis, and specifically relates to a method for synthesizing polyhydroxy isoflavones. Background technique [0002] The structural formulas of 4′,7,8-trihydroxyisoflavone, 4′,6,7,8-tetrahydroxyisoflavone and 3′,4′,6,7,8-pentahydroxyisoflavone are as follows: [0003] [0004] The three polyhydroxyisoflavone flavonoids should have excellent antioxidant activity in terms of their molecular structure, but they cannot be obtained in large quantities from natural products because they are less distributed in natural products and their content is very low. [0005] 4',7,8-Trihydroxyisoflavone is one of the main metabolites of daidzein in the body (Clin Chim Acta, 2003, 334(1-2): 77-85), which can be isolated from Korean fermented soybeans (J Soc.Cosmet.Sci.Korea, 2010, 36(3):221-226), with significant free radical scavenging (Xenobiotica, 2013, 33(9):913-925, Biosci Biotechnol Biochem, 2004, 68( 6): 1372-1374) and anti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/36A61P39/06A61K31/352
CPCC07D311/36A61P39/06
Inventor 景临林马慧萍张冬梅邵瑾赵彤
Owner 中国人民解放军联勤保障部队第九四〇医院