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Method for synthesizing 2-substituted-3,4-dihydro-1-isoquinoline ketones and use thereof for preparing cardiovascular agents

A technology of isoquinolinone and synthesis method, which is applied in the direction of cardiovascular system diseases, drug combinations, medical preparations containing active ingredients, etc., and can solve the problem that the yield is only 16%.

Inactive Publication Date: 2008-08-27
XI AN JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] The synthetic method of 3,4-dihydro-1-isoquinolinone of bibliographical information has following several: 1) take 4-hydroxyl-1-indanone as raw material, carry out Schmidt with sodium azide under trichloroacetic acid effect. Rearrangement reaction synthesizes 5-hydroxyl-3,4-dihydro-1-isoquinolinone, but the yield is only 16% [Miyake, Yoshinori, et al.Journal of Labeled Compounds & Radiopharmaceuticals, 2000, 43(10): 983~988]

Method used

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  • Method for synthesizing 2-substituted-3,4-dihydro-1-isoquinoline ketones and use thereof for preparing cardiovascular agents
  • Method for synthesizing 2-substituted-3,4-dihydro-1-isoquinoline ketones and use thereof for preparing cardiovascular agents

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Experimental program
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Effect test

Embodiment 1

[0047] Embodiment 1: Preparation of 3-allyloxy-4-methoxybenzoic acid methyl ester

[0048] Take 2.0g (11mmol) methyl isovanillate in a 250ml round bottom flask, add 30ml acetone, 4.6g (33mmol) anhydrous potassium carbonate, stir at room temperature for 30min, add 1.5ml (16.5mmol) allyl bromide, heat to reflux 2h. Cool to room temperature, filter, evaporate the mother liquor to remove acetone under reduced pressure, add 150ml of ethyl acetate for extraction. Sequentially use 2mol·L -1 Wash with hydrochloric acid, saturated sodium bicarbonate solution, water and brine. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol to obtain 2.3 g of white crystals. Yield: 98%, mp: 56.5-58.5°C. 1 HNMR (300MHz, CDCl 3 ),δ H : 7.62(d, 1H, Ar-H), 7.39(s, 1H, Ar-H), 6.82(d, 1H, Ar-H), 6.15(m, 1H, =CH-), 5.33(d, 2H ,=CH 2 ), 4.52 (d, 2H, -OCH 2 -), 3.94(s, 3H, -OCH 3 ), 3.82(s,...

Embodiment 2

[0049] Embodiment 2: Preparation of 2-allyl-3-hydroxyl-4-methoxybenzoic acid methyl ester

[0050] Take 2.0g (9mmol) of methyl 3-allyloxy-4-methoxybenzoate in a 100ml round bottom flask, and add 10ml of freshly steamed N,N-dimethylaniline. Under nitrogen protection, the reaction mixture was heated and stirred at reflux for 4h. Cool to room temperature, add 30ml 3mol·L -1 hydrochloric acid, extracted with ethyl acetate (3 x 40ml), and the organic phases were combined and washed successively with saturated sodium bicarbonate solution, water and brine. The organic phase was dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was separated by flash column chromatography (eluent: petroleum ether: ethyl acetate = 5:1), and ethyl acetate / petroleum ether was crystallized to obtain 1.8g Colorless needle-like crystals. Yield: 90%, mp: 74.0-74.5°C. IR (cm -1 ): 3455, 1701, 1602, 1578. 1 HNMR (300MHz, CDCl 3 ),δ H : 7.52(d, 1H, A...

Embodiment 3

[0051] Embodiment 3: Preparation of 2-oxyethyl-3-hydroxyl-4-methoxybenzoic acid methyl ester

[0052] Get 1.8g (8mmol) compound 2-allyl-3-hydroxyl-4-methoxybenzoic acid methyl ester in 250ml round bottom flask, add 48ml acetone, 16ml water, 16ml tert-butanol and 0.1g (0.4mmol ) osmium tetroxide, stirred at room temperature for 30 min in the dark, added 4.2 g (20 mmol) of sodium periodate, and stirred at room temperature for 4 h in the dark. Diatomaceous earth was filtered, the mother liquor was evaporated under reduced pressure to remove acetone and tert-butanol, and 100ml of ethyl acetate was added for extraction. Wash successively with saturated sodium bisulfite, water and brine. The organic phase was dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was separated by flash column chromatography (eluent: petroleum ether: ethyl acetate = 3:1), and crystallized from ethyl acetate / petroleum ether to obtain 1.47g Colorless n...

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Abstract

The invention discloses a synthesis method of 2-substituted-3, 4-dihyidro-1-isoquinoline ketone compound and a relative application in the drug preparation for cardiovascular disease, wherein the compound is represented as above, R1 is gaseous normal alkyl and aromatic group or various substituted alkyl and aromatic group of C1-C19, R2 is OH, OCH3, CH3, NO2 and halogen or the like and can be one or more substituents. The preparation of 2-substituted-3, 4-dihyidro-1-isoquinoline ketone compound uses isovanillic acid ester as raw material, via six-step reaction as allyl etherified, Claisen rearrangement, oxidation, reaction with primary amine (generating Schiff base), reduction and aminolysis of molecular lactone, to synthesize the product. The isolated arterial ring tension test proves that the compound can relax vessel effectively. The 2-substituted-3, 4-dihyidro-1-isoquinoline ketone compound is a new potential cardiovascular drug, with wide application for preparing the drug of cardiovascular disease.

Description

technical field [0001] The invention discloses a method for synthesizing 2-substituted-3,4-dihydro-1-isoquinolinones with obvious vasodilation effect and its application in preparing pharmaceutical preparations for treating cardiovascular diseases. technical background [0002] With the improvement of people's living standards and the aging of the population, the incidence of cardiovascular diseases, especially hypertension, is increasing day by day. According to statistical data, the incidence rate of hypertension is as high as 27% among people aged 35 to 74 in my country, and the number of patients is close to 130 million, with an increase of more than 3 million every year. Hypertension has become the most common cardiovascular disease in the world, and it is also one of the largest epidemics. It often causes complications in the heart, brain, kidney and other organs, seriously endangering human health. Clinically used vasodilation drugs, such as nitrates, dihydropyridine...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/24A61K31/472A61P9/08
Inventor 张三奇曹永孝祝丽永孙涛李强程彬黄琳红
Owner XI AN JIAOTONG UNIV
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