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Production process of rivastigmine

A synthesis process and a dimethylamino technology are applied in the field of synthesis technology of rivastigmine, can solve the problems of low yield, long reaction steps, complicated reaction operations, etc., and achieve the advantages of simplifying production process, improving practicability and reducing cost. Effect

Inactive Publication Date: 2014-03-26
CHENGDU YILUKANG MEDICAL TECH & SERVICE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The main purpose of the present invention is to provide a new rivastigmine synthesis process for the problems that the reaction steps in the prior art are too long, and the complex operation of each step causes the yield to be low.

Method used

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  • Production process of rivastigmine
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  • Production process of rivastigmine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 13

[0018] The synthesis of embodiment 13-(1-(dimethylamino) ethyl) phenol

[0019] Under the condition of ice-water bath, slowly add 54.5g (0.4mol) of 33% dimethylamine aqueous solution into a 250ml three-necked flask containing 20.9g (0.4mol) of 88w% formic acid. 46ml to obtain dimethylammonium formate. When the temperature drops below 100°C, add m-hydroxyacetophenone 13.6g (0.1mol), formic acid (concentration 88w%) 4.6g (0.1mol), MgCl 2 ·6H 2 O3g (0.015mol). Raise the temperature to 170°C, heat and react 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 1-2 with concentrated hydrochloric acid, filter, extract with ether, and use ether for phase use Drying over anhydrous magnesium sulfate and rotary evaporating to dryness yielded 6.47 g of m-hydroxyacetophenone as a solid raw material for recycling. The aqueous phase was adjusted to pH...

Embodiment 2

[0020] The synthesis of embodiment 2 rivastigmine

[0021] Add 1.65g (0.01mol) of 3-(1-(dimethylamino)ethyl)phenol, 0.42g (0.0105mol) of 60% NaH, and 15ml of tetrahydrofuran into a 50ml flask. After mixing thoroughly, add methylethylcarbamoyl chloride 1.28g. Stir at room temperature for 2 hours, recover THF, add diethyl ether for extraction, wash with 0.1mol / L NaOH solution, wash with water, evaporate diethyl ether, and dry under reduced pressure at 40°C to constant weight to obtain a yellow liquid rivastigmine free base (2.34g, 93.6%).

[0022]

Embodiment 3

[0023] The resolution of the rivastigmine of embodiment 3 racemic

[0024] Add 40ml of methanol / water (2:1) and 4g of racemic rivastigmine and 6.2g of D-(+)-p-methyldibenzoyl tartaric acid into a 100ml flask, heat to reflux to dissolve, and cool White crystals precipitated out. Repeat crystallization three times to obtain 3.3 g of DTTA salt of rivastigmine

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Abstract

The invention discloses a production process of rivastigmine. The production process comprises the steps as follows: 1), m-hydroxyacetophenone and dimethylamine are taken as raw materials, and 3-(1-(dimethylamino) ethyl) phenol is synthesized through one-step Leucart reaction; and 2), 3-(1-(dimethylamino) ethyl) phenol and ethylmethyl-carbamic chloride result in condensation reaction to produce rivastigmine. With the adoption of the production process, the production yield and the purity of rivastigmine can be improved remarkably, the process steps are reduced, and the production cost is reduced.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a synthesis process of rivastigmine. Background technique [0002] Rivastigmine Tartrate (Rivastigmine Tartrate), chemical name (S)-N-ethyl-N-methyl-3-(1-(dimethylamino)ethyl)penyl carbamatehydrogen-(2R,3R)-tartrate. It is a drug for senile dementia exclusively researched and developed by Swiss Novartis company. [0003] [0004] Belonging to the third generation of drugs for improving choline system function, it is a carbamate acetylcholinesterase (AchE) inhibitor and butyrylcholinesterase (BuchE) inhibitor that selectively acts on the brain. It was first launched in Switzerland in 1997 , and later listed in the United States, Canada, China and many other countries. Now it has become one of the main drugs for the treatment of Alzheimer's disease. [0005] The yield of rivastigmine in the existing synthesis technology is not high, resulting in high cost of raw materials, wh...

Claims

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Application Information

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IPC IPC(8): C07C271/44C07C269/00C07C215/50C07C213/02
Inventor 彭超陶长戈
Owner CHENGDU YILUKANG MEDICAL TECH & SERVICE
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