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Method for synthesis of rivastigmine

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

Inactive Publication Date: 2007-05-16
JINAN UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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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Effect test

Embodiment 1

[0024] (1) Under ice bath conditions, slowly add 33% dimethylamine aqueous solution (54.5g, 0.4mol) to a 250ml three-necked flask containing 88% formic acid (20.9g, 0.4mol). After the addition is complete, heat for distillation , Distill about 46ml of water to prepare new ecological N,N-dimethylformamide (DMF). When the temperature drops below 100°C, add m-hydroxyacetophenone (13.6g, 0.1mol), formic acid (88% concentration) (4.6g, 0.1mol), MgCl to the reaction flask 2 ·6H 2 O (3g, 0.015mol). Raise the temperature to 170℃ directly, heat the reaction for 5h, after the reaction is completed, pour the reaction solution into 80ml water, wash the reaction flask with about 5ml 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 is dried with anhydrous magnesium sulfate, rotary evaporated to dryness, the solid raw material m-hydroxyacetophenone 6.47g is recovered and reused. Adjust the pH va...

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 24h, adjust the pH to about 1-2 with concentrated hydrochloric acid, filter, extract with ether, dry the ether phase with anhydrous magnesium sulfate, first distill off the ether by ordinary distillation, and then distill under reduced pressure to remove excess DMF to obtain a solid raw material 2.55g of m-hydroxyacetophenone. Adjust the pH value of the aqueous phase to 8.5 with sodium bicarbonate, extract with ethyl acetate, anhydrous MgSO 4 Drying, rotary evaporation and concentration, the remaining residual liquid is cooled, the solid is separated out, filtered, and vacuum dried to obtain the product 3-(1-(dimethylamino)ethyl)phenol (0.65g, yield: 13.4%; recovery yield) : 36.9%).

[0028] (2) Same as Example 1.

Embodiment 3

[0030] (1) Same as in Example 1, to a 2000ml three-necked flask containing 88% formic acid (418g, 8mol), slowly add 33% dimethylamine aqueous solution (1090g, 8mol), after the addition is complete, heat and distill to remove water. The new ecological N,N-dimethylformamide (DMF) is prepared. After cooling to about 100°C, add m-hydroxyacetophenone (1.36g, 0.01mol), formic acid (88% concentration) (4.6g, 0.1mol), MgCl to the reaction flask 2 ·6H 2 O (2g, 0.01mol). The temperature was directly raised to 170°C, and the reaction was heated for 5 hours. After the reaction was completed, the 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. The 3-(1-(dimethylamino)ethyl)phenol (0.7 g, yield: 42.4%; recovery yield: 79.0%) was obtained.

[0031] (2) Same as Example 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 invention relates to an anti-senile dementia drug rivastigmine, in particular to a rivastigmine ((S)-N-ethyl-3-[(1-dimethylamino)acetyl]-N-methylcarbamic acid phenyl ester) Synthetic method. Background technique [0002] Rivastigmine (Rivastigmine) is an acetylcholinesterase inhibitor (AchEI) used to treat moderate to mild Alzheimer's disease. There are two types of existing rivastigmine synthesis processes, 1) conventional synthesis and chiral resolution; 2) asymmetric synthesis. Asymmetric synthesis methods all require the use of more expensive catalysts. Conventional synthesis methods use common reagents, and they generally need to be synthesized through the important intermediate 3-(1-(dimethylamino)ethyl)phenol to obtain exogenous products. Rotary rivastigmine, currently there are two main methods for the synthesis of intermediate 3-(1-(dimethylamino)ethyl)phenol: a. Using m-methoxyacetophenone as a raw material, first synthesize 1 -(3-Methoxypheny...

Claims

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Application Information

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IPC IPC(8): C07C271/44C07C269/00
Inventor 陈卫民冯金孙平华
Owner JINAN UNIVERSITY
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