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1,2,3,4-Tetrahydroisoquinoline derivatives and their synthesis method and use

A technology of tetrahydroisoquinoline and its derivatives, applied in 1 field, can solve the problems of high toxicity and little curative effect

Inactive Publication Date: 2011-12-28
CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Research on this treatment strategy at home and abroad has also made some progress. Some compounds have entered clinical research, but due to shortcomings such as little curative effect and high toxicity, they have not been listed on the market ( D. Curr. Med. Chem., 2008, 15: 2433)

Method used

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  • 1,2,3,4-Tetrahydroisoquinoline derivatives and their synthesis method and use
  • 1,2,3,4-Tetrahydroisoquinoline derivatives and their synthesis method and use
  • 1,2,3,4-Tetrahydroisoquinoline derivatives and their synthesis method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] 2-(3',4'-dimethoxyphenylacetyl)-4,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinoline (VI 1 ) preparation

[0042] (1) Preparation of 3,4-dimethoxy-β-nitrostyrene (II)

[0043] Dissolve 16.60 g of 3,4-dimethoxybenzaldehyde in 20 mL of methanol, add 6.10 g of nitromethane, and slowly add 10 mL of cooled NaOH solution (10.5 mmol / mL) dropwise in an ice bath, and a large amount of white solids appear. Pour into 60mL of ice water to dissolve, and put it in an ice bath to cool down. At 5°C, pour it into 60mL of hydrochloric acid (1:1) under vigorous stirring, and a large amount of yellow precipitate precipitates out. Suction filtration, drying, recrystallization from absolute ethanol, and vacuum drying gave yellow crystals with a yield of 88.6% and a melting point of 141.2-142.0°C.

[0044] (2) 1,2-dimethoxy-4-(2-nitro-1-methoxyethyl)benzene (III 1 ) preparation

[0045] Dissolve 8.42g of 3,4-dimethoxy-β-nitrostyrene (II) in 80ml of dry diethyl ether and mix, cool in an ice bat...

Embodiment 2

[0055] 2-(3',4'-dimethoxyphenylacetyl)-4-benzyloxy-7,8-trimethoxy-1,2,3,4-tetrahydroisoquinoline (VI 2 ) preparation

[0056] (1) 1,2-dimethoxy-4-(2-nitro-1-benzyloxyethyl)benzene (III 2 ) preparation

[0057] Mix 80 mL of ether solution of 8.25 g of 3,4-dimethoxy-β-nitrostyrene (II) with ether suspension (40 mL) of newly prepared sodium benzyl alcohol (160 mmol), and press III 1 During the preparation process, yellow crystals were obtained, yield: 75.8%, melting point: 77.2-78.6°C.

[0058] (2) 2-(3,4-dimethoxyphenyl)-2-benzyloxyethylamine (VI 2 ) preparation

[0059] 6.34g of 1,2-dimethoxy-4-(2-nitro-1-benzyloxyethyl)benzene (III 2 ) in anhydrous tetrahydrofuran solution 40mL was added dropwise to 3.92g lithium aluminum hydride in anhydrous tetrahydrofuran solution (80mL), according to IV 1 After treatment in the preparation process, an orange-yellow oil was obtained, the yield: 70.5%, and the product was directly put into the next step without purification.

[0060] ...

Embodiment 3

[0067] 2-(3',4'-dimethoxyphenylacetyl)-4-cyclohexyloxy-7,8-trimethoxy-1,2,3,4-tetrahydroisoquinoline (VI 3 ) preparation

[0068] (1) 1,2-dimethoxy-4-(2-nitro-1-cyclohexyloxyethyl)benzene (III 3 ) preparation

[0069] Put 8.09g of 3,4-dimethoxy-β-nitrostyrene (II), newly prepared sodium cyclohexylate (160mmol) and 100mL of dioxane 100mL into a 250mL three-necked bottle, and force Stir the reaction, trace with thin-layer chromatography (TLC), after the reaction is complete, add 10.5mL of glacial acetic acid dropwise to produce a light yellow viscous liquid, spin the solvent, add 30mL of water, extract the aqueous phase with 30mL×3 methylene chloride, anhydrous sulfuric acid Dried over magnesium, spin-dried the solvent, and distilled under reduced pressure to obtain a brownish-yellow oil, yield: 45.8%.

[0070] (2) 2-(3,4-dimethoxyphenyl)-2-cyclohexyloxyethylamine (IV 3 ) preparation

[0071] 6.20g of 1,2-dimethoxy-4-(2-nitro-1-cyclohexyloxyethyl)benzene (III 3 ) of 40mL o...

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Abstract

1,2,3,4-Tetrahydroisoquinoline derivatives and their synthesis method and application, the invention belongs to the technical field of drug synthesis, and relates to the general formula (I): X=(CH2)n, n=1-15 Or X=CO(CH2)n-1, n=1-15; R1, R2, R3, R4, R5, R6 are 1,2,3,4-tetrahydroisoquinoline compounds and their salts with different substituents , its preparation method and application in medicine. The invention discloses the chemical structure, synthesis method and in vitro acetylcholinesterase inhibitory activity of these compounds, which can be further developed as novel drugs for treating Alzheimer's disease.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and relates to a class of 1,2,3,4-tetrahydroisoquinoline derivatives with novel structures, in particular to a 1,2,4,6,7-position substituted with various groups , 2,3,4-tetrahydroisoquinoline derivatives, their synthesis method and application in medicine. Background technique [0002] Alzheimer's Disease (AD) is a neurodegenerative disease that seriously endangers the health of the elderly. With the aging of the population, Alzheimer's disease, mainly AD, has become the third major disease that threatens the lives of the elderly after cardiovascular and cerebrovascular diseases and malignant tumors. AD not only seriously endangers the health of the elderly, but also brings a heavy mental burden to the family members of patients, brings a huge health crisis to the society, and has a huge impact on the economy (Mount C, Downton C.Nat.Med., 2006, 12:780). Therefore, it is of great medica...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D217/24C07D217/22C07D401/14C07D491/048A61K31/472A61K31/4725A61K31/4741A61P43/00A61P25/28
Inventor 蒋玉仁许慧马贯军周晓红
Owner CENT SOUTH UNIV
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