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Method for synthesizing rivastigmine hydrogen tartrate

A technology of rivastigmine bitartrate and heavy tartaric acid, which is applied in the field of preparation of high-purity rivastigmine bitartrate, can solve the problems of high synthesis cost and high market price of rivastigmine bitartrate, and is beneficial to large-scale industrial production, The effect of reducing the burden of three wastes treatment and easy operation

Inactive Publication Date: 2016-03-30
HARBIN PHARM GROUP SANJING PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the high synthetic cost of rivastigmine hydrotartrate leads to high market price, so it is necessary to continuously study the improvement of its synthetic route to reduce the cost

Method used

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  • Method for synthesizing rivastigmine hydrogen tartrate
  • Method for synthesizing rivastigmine hydrogen tartrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] (1) Add 3-(1-(dimethylamino)ethyl)phenol (19.8g, 0.12mol) and 250ml pyridine in a three-necked flask, add methylethylcarbamoyl chloride (15.9g, 0.13mol), and reflux under reduced pressure 3h, vacuum control 0.06MPa-0.08MPa, temperature 60°C-75°C, after recovering pyridine, add 100ml of isopropyl ether for extraction, wash with 0.1mol / L NaOH solution, wash with water, dry over anhydrous magnesium sulfate, evaporate under reduced pressure to remove isopropyl ether Combined with ether and dried in vacuo, 29.2 g of rivastigmine free base was obtained as a yellow liquid with a yield of 97.5%.

[0016] (2) Dissolve the product obtained in 1 in 180ml of 1.2-propylene glycol, add L-(+) tartaric acid (18g, 0.12mol), heat and stir at 90°C, and after the reaction solution is clear, naturally cool down to room temperature under stirring, and the product precipitates , suction filtration, and dried to obtain 42.5 g of rivastigmine bitartrate finished product, with a yield of 91%.

Embodiment 2

[0018] (1) Add 3-(1-(dimethylamino)ethyl)phenol (19.8g, 0.12mol) and 130ml of acetone into a three-necked flask, add 4.5g of anhydrous sodium carbonate to activate for a certain period of time, add methylethylcarbamoyl chloride (15.9g, 0.13mol), react for 8 hours, after recovering acetone, add 110ml of dichloromethane and 150ml of water, adjust the pH to 3 with hydrochloric acid, extract, discard the organic phase, add 150ml of dichloromethane to the water layer, and add concentrated ammonia Adjust the pH to 10, separate the water layer, wash the organic phase with 100 mi of water, separate the dichloromethane layer and evaporate the solvent under reduced pressure to obtain 29.3 g of rivastigmine free base as a yellow liquid with a yield of 97.6%.

[0019] (2) Dissolve the product obtained in 1 in 200ml of isopropanol, add L-(+) tartaric acid (18g, 0.12mol), and heat to reflux. After the reaction solution is clear, it is naturally cooled to room temperature while stirring, and ...

Embodiment 3

[0021] (1) Add 3-(1-(dimethylamino)ethyl)potassium phenate (19.8g, 0.12mol) and 130ml of tetrahydrofuran in a three-necked flask, add methylethylcarbamoyl bromide (15.9g, 0.13mol), 50 React at ℃ for 1 hour, after recovering the solvent, add 110ml of ethyl acetate and 150ml of water, adjust the pH to 3 with hydrochloric acid, extract, discard the organic phase, add 150ml of ethyl acetate to the aqueous layer, add concentrated ammonia water to adjust the pH to 10, and separate the water layer, washed the organic phase with 100 ml of water, separated the ethyl acetate layer and evaporated the solvent to dryness under reduced pressure to obtain 28.9 g of rivastigmine free base as a yellow liquid with a yield of 96.3%.

[0022] (2) Dissolve the product obtained in 1 in 200ml of isopropanol, add L-(+) tartaric acid (18g, 0.12mol), and heat to reflux. After the reaction solution is clear, it is naturally cooled to room temperature while stirring, and after separation and drying, hydro...

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Abstract

The invention provides a method for synthesizing rivastigmine hydrogen tartrate. The method includes the following steps that firstly, a compound II and a compound III are condensed into a compound I in a proper solvent without a catalyst or with a catalyst, and the compound I and L-(+)tartaric acid are salified to obtain rivastigmine tartrate in a proper solvent. The molecular formula of rivastigmine tartrate is shown in the specification, wherein R1 is H, K or Na, and R is Cl, Br, I, CN or SCN. The method has the advantages that a process route is short, reaction is moderate, reagents which are used are easy to recycle and the yield is high, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a method for preparing rivastigmine bitartrate as an anti-senile dementia drug, in particular to a method for preparing high-purity rivastigmine bitartrate. Background technique [0002] Rivastigmine bitartrate is a second-generation selective central, reversible, long-acting non-competitive acetylcholinesterase (AchEI) and butyrylcholinesterase (BchE) inhibitor developed by Novartis, which can not only be used for the treatment of Moderate and mild senile dementia, and has a more significant effect on late-stage severe AD patients. It is currently internationally recognized and the highest-rated drug for improving symptoms of Alzheimer's dementia. However, the high synthetic cost of rivastigmine hydrotartrate leads to high market price, so it is necessary to continuously study the improvement of its synthetic route to reduce the cost. Invention content: [0003] The present invention improves and optimizes an industrialized...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/44C07C269/00C07C269/06
CPCC07C269/00C07C269/06
Inventor 芦传有赵冬艳范宁周辉金连玉张晓霞俄丽丹
Owner HARBIN PHARM GROUP SANJING PHARMACEUTICAL CO LTD
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