The purification method of 1-(4-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline salt

A technology of methoxybenzyl and purification method, which is applied in the field of purification of salt formation of 1-(4-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline , to achieve the effect of convenient and safe process, less waste and high yield

Active Publication Date: 2021-03-23
启东东岳药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the prior art, with respect to the intermediate 1-(4-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline, the arylation impurity 1-(4 -Methoxybenzyl)-5,6,7,8-tetrahydroisoquinoline (see the following formula), and the literature is to do the next step reaction directly, and there is no literature report on its purification method

Method used

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  • The purification method of 1-(4-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline salt

Examples

Experimental program
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Effect test

Embodiment 1

[0014] Add 150 milliliters of xylene, 110 grams of N-(2-(cyclohexenylethyl)-2-(4-methoxyphenyl)acetamide to the three-necked flask. Be warmed up to 85-90 ° C and controlled at this temperature 89.6g of phosphorus oxychloride was added dropwise, kept at 85 to 90°C for 3 hours, and cooled to room temperature. Concentrated under reduced pressure below 70°C, added 80ml of 80% methanol aqueous solution for 30min, then added 320ml of aqueous solution for dilution, and added dichloromethane for extraction. Two times, 200ml each time, the dichloromethane phases were combined, concentrated under reduced pressure to evaporate the dichloromethane, then 300ml of acetone was added, the temperature was raised to dissolve the clear, cooled to 0-10°C for crystallization to obtain 1-(4-methoxybenzyl )-3,4,5,6,7,8-hexahydroisoquinoline hydrochloride 99.8 g, content 99.3%, arylate impurity 1-(4-methoxybenzyl)-5,6, 7,8-tetrahydroisoquinoline content 0.3%.

Embodiment 2

[0016] Add 150 milliliters of xylene, 110 grams of N-(2-(cyclohexenylethyl)-2-(4-methoxyphenyl)acetamide to the three-necked flask. Be warmed up to 85-90 ° C and controlled at this temperature Add 89.6g of phosphorus oxychloride dropwise, keep the temperature at 85-90°C for 3 hours, and cool to room temperature. Concentrate under reduced pressure below 70°C, add 80ml of 80% methanol aqueous solution and keep warm for 30min, add 320ml of aqueous solution for dilution, add chloroform for extraction twice , each time with 200ml, combine the dichloromethane phases, concentrate under reduced pressure to evaporate chloroform, then add 300ml of acetone, heat up the solution, cool to 0-10°C for crystallization to obtain 1-(4-methoxybenzyl)-3, 4,5,6,7,8-Hexahydroisoquinoline hydrochloride 95.8 g, content 98.7%, arylate impurity 1-(4-methoxybenzyl)-5,6,7,8- The content of tetrahydroisoquinoline is 0.8%.

Embodiment 3

[0018] Add 150 milliliters of xylene, 110 grams of N-(2-(cyclohexenylethyl)-2-(4-methoxyphenyl)acetamide to the three-necked flask. Be warmed up to 85-90 ° C and controlled at this temperature 89.6g of phosphorus oxychloride was added dropwise, kept at 85 to 90°C for 3 hours, and cooled to room temperature. Concentrated under reduced pressure below 70°C, added 80ml of 80% methanol aqueous solution for 30min, then added 320ml of aqueous solution for dilution, and added dichloromethane for extraction. Two times, 200ml each time, the dichloromethane phases were combined, concentrated under reduced pressure to evaporate chloroform, then 400ml of ethyl acetate was added, the temperature was warmed to dissolve the clear, cooled to 0-10°C for crystallization to obtain 1-(4-methoxybenzyl )-3,4,5,6,7,8-hexahydroisoquinoline hydrochloride 97.8 g, content 98.9%, arylate impurity 1-(4-methoxybenzyl)-5,6, 7,8-tetrahydroisoquinoline content 0.5%.

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Abstract

The invention discloses a purification method for salifying 1-(4-methoxybenzyl)-3, 4, 5, 6, 7, 8-hexahydroisoquinoline. The method comprises the following steps: allowing N-(2-cyclohexenyl ethyl)-2-(4-methoxyphenyl) acetamide to react with phosphorus oxychloride in xylene to obtain 1-(4-methoxybenzyl)-3, 4, 5, 6, 7, 8-hexahydroisoquinoline, carrying out reduced pressure evaporation to remove xylene and excessive phosphorus oxychloride, and adding a solvent with destroyed phosphorus oxychloride to destroy residual phosphorus oxychloride; and extracting the 1-(4-methoxybenzyl)-3, 4, 5, 6, 7, 8-hexahydroisoquinoline hydrochloride by using halogenated hydrocarbon, carrying out vacuum concentration to remove the solvent, adding a crystallization solvent, and crystallizing to obtain the high-purity 1-(4-methoxybenzyl)-3, 4, 5, 6, 7, 8-hexahydroisoquinoline hydrochloride. The method is convenient and safe in process and high in yield, the content of the arylation compound impurity 1-(4-methoxybenzyl)-5, 6, 7, 8-tetrahydroisoquinoline is low, the amount of three wastes is small, and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to a method for salifying and purifying dextromethorphan intermediate 1-(4-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline. Background technique [0002] Dextromethorphan, with the chemical name (+)-3-methoxy-17-methyl-(9α, 13α, 14α)-morphan hydrobromide monohydrate, is a potent centrally acting antitussive. It exerts an antitussive effect by inhibiting the cough center in the medulla oblongata and blocking the vagus nerve. For the clinical treatment of dry cough and cough during colds, acute or chronic bronchitis, bronchial asthma, pharyngitis, tuberculosis and other upper respiratory tract infections. [0003] Most of the existing technologies for preparing dextromethorphan use a synthetic route using 4-methoxyphenylacetic acid and 2-cyclohexeneethylamine as raw materials, and the amidation reaction of 4-methoxyphenylacetic acid and 2-cyclohexeneethylamine generates N-(2-(Cyclohexenylethyl)-2-(4-methoxyphenyl)acetamide, via c...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D217/18
CPCC07D217/18
Inventor 龙中柱费腾禹艳坤蔡畅蔡水洪
Owner 启东东岳药业有限公司
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