Method for preparing 3-methylquinoline

A technology of methylquinoline and palladium carbon, which is applied in the field of preparation of 3-methylquinoline, can solve the problems of high price, affecting the quality and yield of finished products, and affecting the cost of raw materials, so as to reduce the cost of raw materials and increase the number of applications , the effect of good economic benefits

Active Publication Date: 2012-07-11
天津药物研究院药业有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The catalyst used in this reaction - 5% palladium carbon, generally can only be applied mechanically once, if it is applied repeatedly, it will seriously affect the quality and yield of the finished product
Moreover, the price of 5% palladium carbon is relatively high, so the number of application times will seriously affect its raw material cost.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] The technical scheme of the present invention is as follows, and the reference synthesis route is the reference document EP823430A1.

[0018] Add 25kg of absolute ethanol and 2kg of pure water into a 100L reaction kettle, put in 2kg of anhydrous sodium acetate, heat up to 60°C, stir to dissolve it, add 4kg of 2-chloro-3-methylquinoline, and stir at 60°C for half Hour, after dissolving clear, stop stirring, drop into 500 grams of 5% palladium carbon (industrial), after nitrogen ventilation 3 times, hydrogen ventilation three times, open stirring, heating, at 50~55 ℃, react until substantially not absorbing hydrogen, Stop the reaction, ventilate (air), after the palladium carbon is filtered out from the reaction solution, distill ethanol under reduced pressure to dryness, add chloroform to the residue, wash with 10% sodium bicarbonate solution, until the water layer is neutral, then wash twice with water, no dried over magnesium sulfate. The solvent was distilled under r...

Embodiment 2

[0020] Add 25kg of absolute ethanol and 2kg of pure water into a 100L reaction kettle, put in 2kg of anhydrous sodium acetate, heat up to 60°C, stir to dissolve it, add 4kg of 2-chloro-3-methylquinoline, and stir at 60°C for half hour, after dissolving, stop stirring, drop into 550 grams of 5% palladium carbon (applied mechanically for the 10th time); Absorb hydrogen, stop the reaction, and ventilate. After the palladium carbon is filtered out from the reaction solution, distill ethanol under reduced pressure to dryness. dried over magnesium sulfate. The solvent was distilled under reduced pressure, the residue paste was distilled under vacuum, and the 120-135°C / 5mmHg fraction was collected to obtain 3-methylquinoline. Content 95.1%, yield 74.5%.

Embodiment 3

[0022] Add 30kg of absolute ethanol and 2kg of pure water into a 100L reaction kettle, put in 2kg of anhydrous sodium acetate, heat up to 60°C, stir to dissolve it, add 4kg of 2-chloro-3-methylquinoline, and stir at 60°C for half hour, after dissolving, stop stirring, drop into 550 grams of 5% palladium carbon (applied mechanically for the 30th time); Absorb hydrogen, stop the reaction, and ventilate. After the palladium carbon is filtered out from the reaction solution, distill ethanol under reduced pressure to dryness. dried over magnesium sulfate. The solvent was distilled under reduced pressure, the residue paste was distilled under vacuum, and fractions at 120-135°C / 0.665kPa were collected to obtain 3-methylquinoline. Content 93.1%, yield 75.1%.

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PUM

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Abstract

The invention relates to a method for preparing 3-methylquinoline, in particular to a method for preparing 3-methylquinoline serving as an argatroban intermediate. The method comprises the following steps of: adding 2-chloro-3-methylquinoline into an ethanol aqueous solution of sodium acetate, stirring, and adding 5 percent palladium carbon; and introducing nitrogen for ventilation, introducing hydrogen for ventilation, stirring, reacting at the temperature of between 50 and 55 DEG C until the hydrogen is not absorbed, ventilating, filtering out the palladium carbon, evaporating ethanol, adding chloroform into residues, washing by using a 10 percent sodium bicarbonate solution until a water layer is neutral, washing, distilling residue paste in vacuum, and collecting fractions at the temperature of between 120 and 135 DEG C under the pressure of 5mmHg. The originally used glacial acetic acid serving as a solvent is changed into ethanol-water, and the use times of the palladium carbon during production is greatly increased from 1 to 20-30, so that raw material cost is reduced; and yield and quality are not reduced, and good economic benefits are achieved.

Description

technical field [0001] The invention relates to a preparation method of 3-methylquinoline, more specifically a preparation method of argatroban intermediate 3-methylquinoline. technical background [0002] Argatroban is a low-molecular-weight thrombin inhibitor derived from L-arginine, and it is the only synthetic drug approved for the treatment of acute ischemic stroke in the world so far. In 1978, Japan’s Mitsubishi Chemical Company first reported the antithrombin activity of argatroban monohydrate, which was used for the clinical treatment of peripheral arterial occlusive disease, and then for the treatment of arterial thrombosis. The United States approved argatroban in 2000. Troban is used to treat HIT patients. In 2002, FDA approved argatroban for anticoagulant treatment of HIT patients requiring interventional therapy. In recent years, with the introduction of the concept of acute coronary syndrome (acllte coronary syndrome, ACs), antiplatelet, anticoagulant, and fib...

Claims

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Application Information

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IPC IPC(8): C07D215/06
Inventor 张士欣王凯杨雪刘伍山
Owner 天津药物研究院药业有限责任公司
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