Method for synthesis of rivastigmine

A synthetic method, ethyl technology, applied in the field of anti-senile dementia drug rivastigmine, which can solve the problems of long synthetic route, high cost, and low yield, and achieve less reaction by-products, low cost, and good recovery yield Effect

Inactive Publication Date: 2009-02-04
JINAN UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This synthetic method solves the problems of long synthetic route, low yield and high cost in the existing process

Method used

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  • Method for synthesis of rivastigmine
  • Method for synthesis of rivastigmine

Examples

Experimental program
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Embodiment 1

[0024] (1) Under ice-bath conditions, slowly add 33% dimethylamine aqueous solution (54.5g, 0.4mol) to a 250ml there-necked flask containing 88% formic acid (20.9g, 0.4mol), after adding, heat and distill , and about 46ml of water was evaporated to obtain the new ecological N,N-dimethylformamide (DMF). When the temperature drops below 100°C, add m-hydroxyacetophenone (13.6g, 0.1mol), formic acid (concentration 88%) (4.6g, 0.1mol), MgCl 2 ·6H 2 O (3 g, 0.015 mol). Directly raise the temperature to 170°C, heat the reaction for 5 hours, after the reaction is completed, pour the reaction solution into 80ml of water, wash the reaction bottle with about 5ml of water and combine them together, adjust the pH value to about 1-2 with concentrated hydrochloric acid, filter, and extract with ether , the ether phase was dried with anhydrous magnesium sulfate, and evaporated to dryness by rotary evaporation to obtain 6.47 g of m-hydroxyacetophenone as a solid raw material for recycling. ...

Embodiment 2

[0027] (1) In a 100ml three-necked flask, add m-hydroxyacetophenone (4g, 0.029mol), 88% formic acid (4ml, 0.093mol), N,N-dimethylformamide (DMF) (20ml, 0.26mol) . Heat to 155°C and reflux for 24 hours, adjust the pH value to about 1-2 with concentrated hydrochloric acid, filter, extract with ether, dry the ether phase with anhydrous magnesium sulfate, first remove the ether by ordinary distillation, and then remove excess DMF by distillation under reduced pressure to obtain a solid raw material m-Hydroxyacetophenone 2.55g. The aqueous phase was adjusted to pH 8.5 with sodium bicarbonate, extracted with ethyl acetate, anhydrous MgSO 4 Drying, rotary evaporation and concentration, the remaining raffinate was cooled, and the solid was precipitated, filtered, and vacuum-dried to obtain the product 3-(1-(dimethylamino)ethyl)phenol (0.65g, yield: 13.4%; recovery yield : 36.9%).

[0028] (2) With embodiment 1.

Embodiment 3

[0030] (1) Same as Example 1, in the 2000ml there-necked flask filled with 88% formic acid (418g, 8mol), slowly add 33% dimethylamine aqueous solution (1090g, 8mol), after adding, heat and distill, evaporate water, The new ecological N,N-dimethylformamide (DMF) was obtained. After being cooled to about 100°C, add m-hydroxyacetophenone (1.36g, 0.01mol), formic acid (88% concentration) (4.6g, 0.1mol), MgCl 2 ·6H 2 O (2 g, 0.01 mol). The temperature was directly raised to 170° C., and the reaction was heated for 5 hours. After the reaction was completed, excess DMF was distilled off under reduced pressure, and the residue was poured into 10 ml of water. Other operations are the same as in Example 1. 3-(1-(Dimethylamino)ethyl)phenol (0.7 g, yield: 42.4%; recovered yield: 79.0%) was obtained.

[0031] (2) With embodiment 1.

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Abstract

The invention discloses a synthesizing method of (S)-N-ethyl-3-[(1-dimethylamino) acetyl]-N-methyl amido phenyl formate, which is characterized by the following: adopting m-hydroxy acetophenone as raw material; synthesizing intermediate 3-(1-(dimethylamino) ethyl) phenol; condensing 3-(1-(dimethylamino) ethyl) phenol and formyl chloride to produce the product with high receiving rate.

Description

technical field [0001] The present invention relates to anti-senile dementia drug rivastigmine, in particular to a kind of rivastigmine ((S)-N-ethyl-3-[(1-dimethylamino)acetyl]-N-methylcarbamate phenyl ester) synthetic method. Background technique [0002] Rivastigmine (Rivastigmine) is an acetylcholinesterase inhibitor (AchEI) for the treatment of moderate to mild Alzheimer's disease. There are two types of existing rivastigmine synthesis techniques, 1) conventional synthesis and chiral resolution; 2) asymmetric synthesis. Asymmetric synthesis methods all require the use of relatively expensive catalysts. Conventional synthesis methods use common reagents, and are generally synthesized through the important intermediate 3-(1-(dimethylamino)ethyl)phenol to obtain the racemic compound. The rivastigmine of rotation mainly contains two kinds of methods for the synthesis of intermediate 3-(1-(dimethylamino) ethyl) phenol at present: a, take m-methoxy acetophenone as raw materi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C269/00C07C271/44
Inventor 陈卫民冯金孙平华
Owner JINAN UNIVERSITY
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