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Method for synthetizing (R)-(plus)-pinocembrin and (S)-(minus)-pinocembrin

A technology of pinoxerine and compounds, which is applied in the field of chemical drugs for the treatment of cardiovascular and cerebrovascular diseases, and can solve problems that have not been reported in the literature

Inactive Publication Date: 2012-11-28
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] At present, the total synthesis of R-(+)-pinocerin and (S)-(-)-pinocerin has not been reported in the literature

Method used

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  • Method for synthetizing (R)-(plus)-pinocembrin and (S)-(minus)-pinocembrin
  • Method for synthetizing (R)-(plus)-pinocembrin and (S)-(minus)-pinocembrin
  • Method for synthetizing (R)-(plus)-pinocembrin and (S)-(minus)-pinocembrin

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Experimental program
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Effect test

Embodiment 1

[0029] The preparation of embodiment 1 (S)-3-hydroxyl-N-methoxy-N-methyl-3-phenylpropanamide (3)

[0030] Dissolve 66.9 g (0.672 mol) of N, O-dimethylhydroxylamine hydrochloride in 1200 mL of anhydrous THF, and add 840 mL of n-BuLi (1.6 mol·L -1 , 0.134mol), after dropping, stir at room temperature for 15min, then lower the temperature to -78°C, add dropwise a solution of 43.4g (0.224mol) of compound (2) in THF (300mL), dropwise, continue to react for 2h, with saturated ammonium chloride The reaction was quenched by the solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, evaporated to dryness, and obtained a colorless oily substance (S)-3-(tert-butyldimethylsilyloxy)-N-methyl Oxy-N-methyl-3-phenylpropanamide (3) 43.0 g, yield 93%.

[0031] 1 H NMR (CDCl 3 )δ (ppm): 2.81 (m, 2H), 3.20 (s, 3H), 3.62 (s, 3H), 4.26 (s, 1H), 5.15 (d, 1H, J=2.5and 9.2Hz,), 7.26 -7.42 (m, 5H).

Embodiment 2

[0032] The preparation of embodiment 2 (S)-3-(tert-butyldimethylsilyloxy)-N-methoxy-N-methyl-3-phenylpropanamide (4)

[0033] Dissolve compound (3) (20.9g, 100mmol) in 500mL of dichloromethane, add 13.6g (200mmol) of imidazole, 16.5g (110mmol) of tert-butyldimethylchlorosilane, stir overnight at room temperature, pour into saturated ammonium chloride solution, extracted with dichloromethane, combined extracts, dried over anhydrous sodium sulfate, evaporated to dryness, and obtained colorless oily substance (S)-3-(tert-butyldimethylsilyloxy)- N-methoxy-N-methyl-3-phenylpropanamide (4) 28.7 g, yield 89%.

[0034] 1 H NMR (CDCl 3 )δ(ppm): -0.13(s, 3H), 0.10(s, 3H), 0.84(s, 9H), 2.47(dd, 1H, J=3.5, 14.5Hz), 3.02-3.07(brs, 1H) , 3.18(s, 3H), 3.64(s, 3H), 5.26(dd, 1H, J=3.5, 9.0Hz), 7.24-7.39(m, 5H).

[0035] FAB-MS 341.2 (M+NH 4 + , 100%);

Embodiment 33

[0036] Embodiment 33, the preparation of 5-dimethoxyphenol (6)

[0037] Dissolve 126.0 g (1 mol) of phloroglucinol in 1000 mL of anhydrous methanol, slowly add 126.0 g of concentrated sulfuric acid dropwise under vigorous stirring, after the drop is completed, heat and reflux for 24 hours, cool to room temperature, evaporate the remaining methanol to dryness, and wash with a large amount of water to neutrality, extracted with ethyl acetate, dried over anhydrous sodium sulfate, evaporated to dryness, and obtained 101.0 g of a colorless oily substance 3,5-dimethoxyphenol (6) through silica gel column chromatography, with a yield of 65.6%.

[0038] 1 H NMR (CDCl 3) δ (ppm): 3.74 (s, 6H), 5.53 (brs, 1H), 6.03 (d, 2H, J=2.0Hz), 6.08 (t, 1H, J=2.0Hz).

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Abstract

The invention relates to a method for synthetizing (R)-(plus)-pinocembrin and (S)-(minus)-pinocembrin, phloroglucinol and (S)-3-hydroxyl-3 ethyl phenylpropiolate are taken as raw materials, the hydroxyl of the phloroglucinol is protected by methyl or methoxy methyl and Weinreb amine ((S)-3-(tert-butyl dimethyl silyl)-N-methoxy-N-methyl-3-phenyl acrylic amide) which is protected by silyl carry out Weinreb reaction under the organic alkali condition, so (S)-1-[2, 4-dimethoxy-6-(methoxy-methyl)-phenyl]-3-phenyl-3-(tert-butyl dimethyl silyl)-propyl-1-ketone is obtained, the methoxy-methyl is removed under the acid condition, intramolecular Mitsunobu cyclization is carried out, and finally, the (R)-(plus)-pinocembrin is obtained after removing the methyl. According to the same method, (R)-3-hydroxyl-3 ethyl phenylpropiolate is taken as the raw material, so the (S)-(minus)-pinocembrin can be obtained.

Description

technical field [0001] The invention relates to the field of chemical medicines for treating cardiovascular and cerebrovascular diseases, in particular to a combination of (R)-(+)-pinoxerin and (S)-(-)-pinoxetine which have the effect of treating cardiovascular and cerebrovascular diseases Lin's method of synthesis. Background technique [0002] The chemical name of pinocembrin is 2,3-dihydro-5,7-dihydroxy-2-phenyl-4H-1-benzopyran-4-one (2,3-Dihydro-5, 7-dihydroxy-2-phenyl-4H-1-benzopyran-4-one). Pinoccelin is a flavanone compound isolated from propolis. Its chemical structure contains a chiral center. The natural pinoccelin three-dimensional structure is S configuration, and its specific rotation [α]D 15 It is -45.3 (c, 0.9, acetone is the solvent). In addition, the compound is also isolated from Swiss five-needle pine (Pinus cembra), eucalyptus (Eucalyptus sieberi), red poplar (Alnussieboldiana) and other plants, but the content is very low. The currently developed pro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/32
Inventor 吴松魏金钊童元峰戚燕杨庆云王冬梅
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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