Rivastigmine precursor [1-(3-methoxyphenyl)ethyl]dimethylamine preparation method

A technology of methoxyphenyl and m-methoxyacetophenone, which is applied in the field of preparation of [1-ethyl]dimethylamine, can solve the problems of high cost, long synthetic route, environmental pollution, etc., and achieve low cost , reflecting the effect of less by-products and environmental friendliness

Inactive Publication Date: 2014-07-02
JIANGSU KANGBEIDE PHARMA
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  • Abstract
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  • Application Information

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Problems solved by technology

[0005] In order to overcome the above-mentioned shortcoming of the prior art, the object of the present invention is to provide a kind of synthetic method of [1-(3-methoxyphenyl) ethyl] dimethylamine, and this method solves the relatively long synthetic route of existing technology , high cost, environmental pollution

Method used

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  • Rivastigmine precursor [1-(3-methoxyphenyl)ethyl]dimethylamine preparation method

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Embodiment 1

[0018] Add 400ml of absolute ethanol to a 1000ml four-neck round bottom flask, stir mechanically, slowly add metallic sodium (15.0g, 652mmol) at 50°C, and reflux. After all the sodium has reacted, cool to room temperature, and then use ice salt The bath was cooled to 0°C, blown with nitrogen, slowly added dimethylamine hydrochloride (50.6g, 621mmol), controlled the temperature below 5°C, reacted for 3 hours, slowly added dropwise tetraisopropyl titanate (62.5ml, 211mmol ) and m-methoxyacetophenone (18.6g, 124mmol), the reaction temperature was controlled to be lower than 30°C, and the reaction was carried out for 12 hours. Then, add 0.1gPd / C catalyst, feed H 2 , reacted at 60°C for 48 hours. 100ml of ammonia water was added dropwise, and the reaction was continued for 40 minutes. Filter, wash the filter cake with anhydrous methanol, collect the filtrate, then evaporate the solvent to dryness with a rotary evaporator, add 100ml of water, then use ethyl acetate to extract 3 ti...

Embodiment 2

[0020] Add 400ml of absolute ethanol to a 1000ml four-neck round bottom flask, stir mechanically, slowly add metallic sodium (12.0g, 522mmol) at 50°C, and reflux. After all the sodium has reacted, cool to room temperature, and then use ice salt The bath was cooled to 0°C, blown with nitrogen, slowly added dimethylamine hydrochloride (40.5g, 497mmol), controlled the temperature below 5°C, reacted for 3 hours, slowly added dropwise tetraisopropyl titanate (62.5ml, 211mmol ) and m-methoxyacetophenone (18.6g, 124mmol), the reaction temperature was controlled to be lower than 30°C, and the reaction was carried out for 12 hours. Then, add 0.1gPd / C catalyst, feed H 2 , reacted at 60°C for 48 hours. 100ml of ammonia water was added dropwise, and the reaction was continued for 40 minutes. Filter, wash the filter cake with anhydrous methanol, collect the filtrate, then evaporate the solvent to dryness with a rotary evaporator, add 100ml of water, then use ethyl acetate to extract 3 ti...

Embodiment 3

[0022] Add 400ml of absolute ethanol to a 1000ml four-neck round bottom flask, stir mechanically, slowly add metallic sodium (12.0g, 522mmol) at 50°C, and reflux. After all the sodium has reacted, cool to room temperature, and then use ice salt The bath was cooled to 0°C, blown with nitrogen, slowly added dimethylamine hydrochloride (40.5g, 497mmol), controlled the temperature below 5°C, reacted for 3 hours, slowly added dropwise tetraisopropyl titanate (62.5ml, 211mmol ) and m-methoxyacetophenone (18.6g, 124mmol), the reaction temperature was controlled to be lower than 30°C, and the reaction was carried out for 12 hours. Then, add 0.9gPd / C catalyst, feed H 2 , reacted at 60°C for 36 hours. 100ml of ammonia water was added dropwise, and the reaction was continued for 40 minutes. Filter, wash the filter cake with anhydrous methanol, collect the filtrate, then evaporate the solvent to dryness with a rotary evaporator, add 100ml of water, then use ethyl acetate to extract 3 ti...

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Abstract

The invention relates to a rivastigmine precursor [1-(3-methoxyphenyl)ethyl]dimethylamine preparation method, which is characterized by comprising that: a dimethylamine hydrochloride reacts with an alkali to produce dimethylamine, the dimethylamine reacts with m-methoxyacetophenone for 5-24 h at a reaction temperature of 0-50 DEG C in the presence of titanium tetraisopropanolate, hydrogen gas is introduced in the presence of a catalyst, a reaction is performed for 12-72 h at a reaction temperature of 20-100 DEG C to prepare the [1-(3-methoxyphenyl)ethyl]dimethylamine. According to the present invention, the preparation method is the normal pressure reaction, and has characteristics of mild reaction conditions, low equipment investment, easy and safe operation, environmental pollution, less pollution and the like, and is easily subjected to large-scale industrial production.

Description

technical field [0001] The present invention relates to the preparation method of rivastigmine precursor [1-(3-methoxyphenyl) ethyl] dimethylamine, especially [1-(3-methoxyphenyl) ethyl] dimethylamine Background technique [0002] Rivastigmine is an acetylcholinesterase inhibitor (AchEl), mainly used in the treatment of moderate to mild Alzheimer's disease. The synthesis of rivastigmine is mainly obtained by reacting methyl ethyl carbamoyl chloride with intermediate 3-[1-(dimethylamino)ethyl]phenol. 3-[1-(dimethylamino) ethyl] phenol is as the important intermediate of reaction, and its synthetic method mainly contains two kinds: the first method is to be starting raw material with m-hydroxyacetophenone, by reacting with hydroxylamine hydrochloride Oxime, then reduced by Al-Ni alloy to obtain primary amine, and then obtained by Eschweiler-Clarke (Eschweiler-Clarke) reaction methylation (Jiang Yongwen et al., Synthesis of rivastigmine tartrate [J]. East China Normal Univers...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C217/58C07C213/00
Inventor 王树明薛慧勇王丽高中远刘喜全宋莉孙莺郑志红谢昀石晓燕其他发明人请求不公开姓名
Owner JIANGSU KANGBEIDE PHARMA
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