A kind of preparation method of galantamine key intermediate

A technology of galantamine and intermediates, which is applied in the preparation of organic compounds, chemical instruments and methods, preparation of aminohydroxy compounds, etc., can solve the problems of low industrialized production yield of galantamine, etc., and achieves control of production costs, The effect of mild reaction conditions and simple operation

Active Publication Date: 2019-08-02
ZHANG JIA GANG VINSCE BIO PHARM
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Problems solved by technology

[0004] The invention discloses a method for preparing a key intermediate of galantamine—N-methyl-(4-hydroxyphenethyl)-2-bromo-5-hydroxy-4-methoxybenzylamine. It is used for the industrial synthesis of galantamine, which can effectively solve the problem of low yield in industrial production of galantamine

Method used

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  • A kind of preparation method of galantamine key intermediate

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Effect test

Embodiment 1

[0022] (1) Preparation of a dichloromethane solution of N-methyl-(4-benzyloxyphenethyl)-2-bromo-5-benzyloxy-4-methoxybenzylamine cyanoborohydride

[0023] 24g of p-benzyloxyphenethyl alcohol, 35g of 2-bromo-5-benzyloxy-4-methoxybenzaldehyde and 10g of methylamine hydrochloride were dispersed and dissolved in 300ml of 1,4-dioxane, and 30g of cyanoborohydrogenation Dissolve sodium in 10ml acetic acid, drop it into the raw material solution at room temperature, react at room temperature, monitor the reaction by HPLC until the basic reaction of the raw material is complete, add water to quench the reaction, extract with 500ml dichloromethane and 200ml water, obtain the organic phase, and obtain N- A dichloromethane solution of methyl-(4-benzyloxyphenethyl)-2-bromo-5-benzyloxy-4-methoxybenzylamine cyanoborohydride, and N- The purity of methyl-(4-benzyloxyphenethyl)-2-bromo-5-benzyloxy-4-methoxybenzylamine cyanoborohydride was 95.3%.

[0024] (2) Preparation of N-methyl-(4-benzylox...

Embodiment 2

[0029] (1) Preparation of a dichloromethane solution of N-methyl-(4-benzyloxyphenethyl)-2-bromo-5-benzyloxy-4-methoxybenzylamine cyanoborohydride

[0030] 24g p-benzyloxyphenethyl alcohol, 35g 2-bromo-5-benzyloxy-4-methoxybenzaldehyde and 10g methylamine hydrochloride are dispersed and dissolved in 300ml tetrahydrofuran, 30g sodium cyanoborohydride is dissolved in 10ml acetic acid, Drop into the raw material solution at room temperature, react at room temperature, monitor the reaction by HPLC until the basic reaction of the raw material is complete, add water to quench the reaction, extract with 500ml dichloromethane and 200ml water, obtain the organic phase, and obtain N-methyl-(4-benzyl Oxyphenethyl)-2-bromo-5-benzyloxy-4-methoxybenzylamine cyanoborohydride in dichloromethane solution, HPLC measured N-methyl-(4-benzyl The purity of oxyphenethyl)-2-bromo-5-benzyloxy-4-methoxybenzylamine cyanoborohydride was 95.1%.

[0031] (2) Preparation of N-methyl-(4-benzyloxyphenethyl)-2...

Embodiment 3

[0036] (1) Preparation of a dichloromethane solution of N-methyl-(4-benzyloxyphenethyl)-2-bromo-5-benzyloxy-4-methoxybenzylamine cyanoborohydride

[0037] 24g p-benzyloxyphenethyl alcohol, 35g 2-bromo-5-benzyloxy-4-methoxybenzaldehyde and 10g methylamine hydrochloride are dispersed and dissolved in 300ml tetrahydropyran, 30g sodium cyanoborohydride is dissolved in 10ml In acetic acid, drop into the raw material solution at room temperature, react at room temperature, monitor the reaction by HPLC until the basic reaction of the raw material is complete, add water to quench the reaction, extract with 500ml dichloromethane and 200ml water, obtain the organic phase, and obtain N-methyl-( 4-benzyloxyphenethyl)-2-bromo-5-benzyloxy-4-methoxybenzylamine cyanoborohydride dichloromethane solution, HPLC records the solution N-methyl-( The purity of 4-benzyloxyphenethyl)-2-bromo-5-benzyloxy-4-methoxybenzylamine cyanoborohydride was 95.3%.

[0038] (2) Preparation of N-methyl-(4-benzyloxy...

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Abstract

The invention discloses a preparation method of galanthamine key intermediate -N-methyl(4-leptodactyline)-2-bromo-5-hydroxyl-4-methoxybenzylamine. The preparation method comprises the following steps: by taking 2-bromo-5-benzyloxy-4-methoxybenzaldehyde, benzyloxyphenyl ethanol and methylamine hydrochloride as raw materials, condensing, degrading and performing debenylation reaction to prepare N-methyl(4-leptodactyline)-2-bromo-5-hydroxyl-4-methoxybenzylamine. Cheap and easily available raw materials are adopted in the method, so that the production cost can be effectively controlled, the operation is simple, and the reaction conditions are mild. The intermediate is used for industrial synthesis of galanthamine, and the problem that the yield from the industrial production of galanthamine is low can be effectively solved.

Description

technical field [0001] The invention relates to a preparation method of N-methyl-(4-hydroxyphenethyl)-2-bromo-5-hydroxy-4-methoxybenzylamine, a galantamine intermediate, and belongs to the field of medicine and chemical industry. Background technique [0002] Galantamine was first researched and produced by Sopharma Pharmaceutical Company in Bulgaria, and is used for myasthenia gravis, progressive muscular dystrophy, sequelae of poliomyelitis, children with cerebral palsy, sensory or motor disorders caused by nervous system diseases, multiple neuritis etc. It is easy to pass through the blood-brain barrier, so it has a strong central action and can be used for myasthenia gravis. It is currently on the market in many countries around the world under the product name: Nivalin. Galantamine was first isolated and extracted from the bulbs of snowdrops. Because the species to be extracted is rare and the extraction of galantamine is expensive, many companies around the world hav...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C213/08C07C217/64
CPCC07C213/08C07F5/027C07C217/64
Inventor 张梅彭学东赵金召弓旻
Owner ZHANG JIA GANG VINSCE BIO PHARM
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