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Chrysotoxine bibenzyl derivative and preparation method and application thereof

A technology of Dendrobium Dendrobium and Dendrobium bibenzyl, which is applied in the field of Dendrobium Dendrobium bibenzyl derivatives and preparation thereof, can solve the problems of expensive raw material source, low bioavailability, weak protective effect and the like, and achieves the Easily reproducible, mild reaction conditions

Inactive Publication Date: 2015-12-23
CHINA PHARM UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Dendrobium (Chrysotoxine, CTX, 4-(3,4-dimethoxyphenethyl)-2,6-dimethoxyphenol) is a kind of orchidaceae (Orchidaceae) Dendrobium The natural bibenzyl compound of Dendrobium medicinal material, CTX has neuroprotective effect according to previous studies, but the bioavailability is low, and the protective effect is not strong, and CTX is extracted from the famous and precious traditional Chinese medicine Dendrobium, and the source of raw materials is expensive

Method used

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  • Chrysotoxine bibenzyl derivative and preparation method and application thereof
  • Chrysotoxine bibenzyl derivative and preparation method and application thereof
  • Chrysotoxine bibenzyl derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Preparation of Example 14-(3,4-dimethoxyphenethyl)-2,6-dimethoxyphenyl acetate (CTX-0) and Dendrobium tympanodin (CTX)

[0036] a. 4-formyl 2,6-dimethoxyphenyl acetate

[0037]

[0038] Add 8.33 g (0.046 mol) of syringaldehyde powder, 10 mL of dichloromethane, and catalytically metered DMAP (4-dimethylaminopyridine) into a 100 mL single-necked bottle, and stir to fully dissolve. Slowly add 4.75 mL (0.051 mol) of acetic anhydride dropwise, and react at room temperature for 1 h. Add water to wash away DMAP and acetic anhydride, wash 3 times in total, each time with 10 mL of water. Anhydrous Na 2 SO 4 The organic layer was dried and concentrated to recover dichloromethane to obtain 10.19 g of white crystals with a yield of 99.8%. Identified as 4-formyl 2,6-dimethoxyphenyl acetate.

[0039] ESI-MSm / z:225[M+H] + , The relative molecular mass is 224.

[0040] 1 H-NMR (300MHz, CDCl 3 )δ: 9.93 (1H, s, -CHO), 7.17 (2H, s, H-2, H-6), 3.92 (6H, s, 2×-OCH 3 ),2.38(3H,s...

Embodiment 2

[0076] Preparation of Example 24-(3,4-dimethoxyphenethyl)-2,6-dimethoxyphenylpropionate (CTX-1)

[0077]

[0078] Add 30 mg (0.094 mmol) of Dendrobium tympanodin, 27 mg (0.141 mmol) of EDC·HCl, 11 μL (0.141 mmol) of propionic acid, a catalyst amount of DMAP, and 3 mL of dichloromethane into a 50 mL single-necked bottle. Stir well and react at room temperature for 48h. Cool, extract with water to remove water-soluble impurities, and use anhydrous Na for the organic layer 2 SO 4 Dry and concentrate under reduced pressure to obtain the mixture, which is purified by silica gel column chromatography (PE-EA20:1-8:1) to obtain 22.1 mg of white solid with a yield of 63.4%. It was identified as 4-(3,4-dimethoxyphenethyl)-2,6-dimethoxyphenylpropionate.

[0079] ESI-MSm / z:392.3[M+NH 4 ] + ,375.2[M+H] + , The relative molecular mass is 374.

[0080] 1 H-NMR (300MHz, CDCl 3 )δ: 6.82 (1H, d, J = 8.1Hz, H-5'), 6.74 (1H, dd, J = 1.8, 8.1Hz, H-6'), 6.67 (1H, d, J = 1.8Hz, H-2'),6....

Embodiment 3

[0081] Preparation of Example 34-(3,4-dimethoxyphenethyl)-2,6-dimethoxyphenylbutyrate (CTX-2)

[0082]

[0083] Referring to the synthesis method of CTX-1, 30 mg (0.094 mmol) of Dendrobium tympani was added, 27 mg (0.141 mmol) of EDC·HCl, 14 μL (0.150 mmol) of butyric acid, DMAP as catalyst, and 3 mL of dichloromethane were added. Stir well and react at room temperature for 48h. Cool, extract with water to remove water-soluble impurities, and use anhydrous Na for the organic layer 2 SO 4 Dry and concentrate under reduced pressure to obtain the mixture, which is purified by silica gel column chromatography (PE-EA 20:1-8:1) to obtain 14 mg of light yellow oil with a yield of 38.3%. It was identified as 4-(3,4-dimethoxyphenethyl)-2,6-dimethoxyphenylbutyrate.

[0084] ESI-MSm / z:406.3[M+NH 4 ] + ,389.2[M+H] + , The relative molecular mass is 388.

[0085] 1 H-NMR (300MHz, CDCl 3 )δ: 6.82 (1H, d, J = 8.1Hz, H-5'), 6.74 (1H, dd, J = 1.8, 8.1Hz, H-6'), 6.67 (1H, d, J = 1.8...

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Abstract

The present invention discloses a chrysotoxine bibenzyl derivative shown as a formula I. R1 represents C=O, CH2, NH, S=O or a covalent bond; R2 represents alkyl, phenyl, substituted phenyl, benzene ring substituted C1-3 alkyl, C5-C6 cycloalkyl, and a pentabasic or hexahydric unsaturated heterocyclic group containing one or more O, S and N. The invention also discloses a simple and efficient preparation method of the chrysotoxine bibenzyl derivative, and application of the derivative to the preparation of neuroprotective drugs and drugs for treating Alzheimer disease. The chrysotoxine 4-O-substituted bibenzyl derivative has significant protective effect on A beta-induced neuronal apoptosis, and is a potential novel chemical entity for the treatment of AD.

Description

technical field [0001] The present invention relates to a kind of bibenzyl derivative of Dendrobium pachyrhiza and its preparation method and application, in particular to a 4-O-substituted bibenzyl derivative and its preparation method, and in the preparation of neuroprotective drugs and Use in medicines for the treatment of Alzheimer's disease. Background technique [0002] Alzheimer's disease (Alzheimer's Disease, AD) is a common neurodegenerative disease in the elderly. Its main clinical manifestations are progressive memory loss, cognitive dysfunction, abnormal behavior and social impairment. The etiology and pathogenesis of Alzheimer's disease are not yet fully understood. There are currently many theories. The hypothesis of Aβ toxicity suggests that the abnormal deposition of Aβ leads to the formation of senile plaques, which may be the common pathway of all factors leading to AD. The degeneration and deposition of Aβ can lead to neuron damage, and then lead to the ...

Claims

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Application Information

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IPC IPC(8): C07C69/24C07C69/78C07C69/612C07C67/08C07D213/79C07D213/803C07C43/205C07C43/235C07C41/01A61P25/00A61P25/28
CPCC07C69/24C07C67/08C07C69/145C07C67/29C07C67/287C07C67/293C07C67/283C07C41/26C07C43/23
Inventor 冯锋曲玮关丽柳文媛李凌超郝艳峰陈垒
Owner CHINA PHARM UNIV
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