Preparation method of rivastigmine tartrate

A technology of rivastigmine bitartrate and ethyl acetate, which is applied in the field of medicine and chemical industry, can solve the problems of low purity and low yield of rivastigmine bitartrate, achieve improved yield and purity, simple operation, and is suitable for industrial production Effect

Active Publication Date: 2017-04-19
KUNMING YUANRUI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The purpose of the present invention is to provide a kind of preparation method of rivastigmine bitartrate, by optimizing

Method used

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  • Preparation method of rivastigmine tartrate
  • Preparation method of rivastigmine tartrate
  • Preparation method of rivastigmine tartrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] A. Intermediate 1: Synthesis of (S)-3-(1-(dimethylamino)ethyl)phenol

[0081]

[0082]Add 1L of ethyl acetate and 200.0g of (R,S)-3-(1-(dimethylamino)ethyl)phenol as raw materials into the reaction flask, stir and dissolve at 40°C, and dissolve the prepared S-(+) - Camphorsulfonic acid ethanol (600ml) solution (dissolve 235 grams of S-(+)-camphorsulfonic acid in 600 milliliters of ethanol) into the above-mentioned reaction flask, stir and reflux for 30min, cool to room temperature after the system dissolves, and then cool to 0 ° C, stirred and crystallized for 2h.

[0083] Suction filtration and drying gave 235.9 g of white solid. Add the obtained solid to the reaction flask, then add 500ml of ethanol and 900ml of ethyl acetate, stir and reflux, cool to room temperature naturally after 30min, then cool down to 0°C to crystallize for 2h, and filter with suction to obtain 182.7g of solid.

[0084] The obtained 182.7g solid was dissolved in 600ml of water, stirred and...

Embodiment 2

[0092] A. Intermediate 1: Synthesis of (S)-3-(1-(dimethylamino)ethyl)phenol

[0093]

[0094] Add 0.8L ethyl acetate and 180.0g (R,S)-3-(1-(dimethylamino)ethyl)phenol as raw materials into the reaction flask, stir and dissolve at 30°C, and mix the prepared S-(+ )-camphorsulfonic acid ethanol (480ml) solution (dissolve 170 grams of S-(+)-camphorsulfonic acid in 450 milliliters of ethanol) into the above-mentioned reaction flask, stir and reflux for 25min, cool to room temperature after the system dissolves, and then cool To 0 ℃, stirring crystallization 1.5h.

[0095] Suction filtered and dried to obtain a white solid. Add the obtained solid to the reaction flask, then add 450ml of ethanol and 750ml of ethyl acetate, stir and reflux, cool to room temperature naturally after 25min, cool down to 0°C to crystallize for 1.5h, and filter to obtain the solid.

[0096] The obtained solid was dissolved in 550ml of water, stirred to dissolve, and the insoluble matter was removed by...

Embodiment 3

[0103] A. Intermediate 1: Synthesis of (S)-3-(1-(dimethylamino)ethyl)phenol

[0104]

[0105] Add 2L of ethyl acetate and 300.0g of (R,S)-3-(1-(dimethylamino)ethyl)phenol as raw materials into the reaction flask, stir and dissolve at 50°C, and dissolve the prepared S-(+) - Camphorsulfonic acid ethanol (600ml) solution (dissolve 350 grams of S-(+)-camphorsulfonic acid in 850 milliliters of ethanol) into the above-mentioned reaction flask, stir and reflux for 40min, cool to room temperature after the system dissolves, and then cool to 0 ℃, stirring crystallization 3h.

[0106] Suction filtration, drying to obtain a white solid, the obtained solid was added to a reaction flask, and then 700ml of ethanol and 1100ml of ethyl acetate were added, stirred and refluxed, cooled to room temperature naturally after 40min, and then cooled to 0°C for 3 hours of crystallization, and suction filtered to obtain solid g.

[0107] The obtained solid was dissolved in 800ml of water, stirred ...

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Abstract

The invention discloses a preparation method of rivastigmine tartrate. The preparation method comprises the following steps: using (R, S)-3-(1-(dimethylamino)ethyl)phenol as a raw material, and carrying out resolution on the raw material by the use of S-(+)-camphorsulfonic acid so as to obtain enantiomerically pure (S)-3-(1-(dimethylamino)ethyl)phenol; letting enantiomerically pure (S)-3-(1-(dimethylamino)ethyl)phenol be in butt-joint with N-ethyl-N-methylcarbamyl chloride to obtain rivastigmine free alkali; and finally letting rivastigmine free alkali react with L-(+)-tartaric acid for salifying so as to obtain rivastigmine tartrate. Through process control such as treatment during the synthetic process of raw materials, acid-base alternative impurity removal during refining of an intermediate and acetone pulping for purification during later period, the preparation method of rivastigmine tartrate is obtained. By the method, purity and yield of the product are both raised, the isomer impurity can be more effectively controlled, and cost is greatly reduced and process is simplified. The preparation method is more suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a preparation method of rivastigmine bitartrate. Background technique [0002] Alzheimer's disease (Alzheimerdisease, AD) is a degenerative disease of the central nervous system, with insidious onset and progressive dementia. It is characterized by mental and behavioral abnormalities and obvious social life function decline. Rivastigmine bitartrate can be used to treat mild to moderate symptoms of Alzheimer's disease dementia. The therapeutic mechanism is due to the phenyl carbamate structure in its molecule, which is a carbamate-like brain-selective cholinesterase inhibitor, which can simultaneously inhibit acetylcholinesterase and butyrylcholinesterase, by delaying cholinesterase Alkalinergic neurons degrade the released acetylcholine to promote cholinergic nerve conduction, which can improve cholinergic-mediated cognitive dysfunction, thereby improving the cogniti...

Claims

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Application Information

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IPC IPC(8): C07C269/06C07C269/08C07C271/44C07C51/41C07C59/255
CPCC07C51/41C07C213/10C07C269/00C07C269/06C07C269/08C07C271/44C07C59/255C07C215/50
Inventor 王高华牛树伟朱兴正
Owner KUNMING YUANRUI PHARMA
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