Preparation method of high-purity cisatracurium besylate

A high-purity technology of atracurium cis-benzenesulfonate, which is applied in the field of preparation of high-purity atracurium cis-benzenesulfonate, can solve problems such as excitatory effects, and achieve high product purity, small side reactions, and low price Effect

Inactive Publication Date: 2017-08-18
LIANYUNGANG GUIKE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Like atracurium besylate, it belongs to the medium-acting isoquinoline non-depolarizing muscle relaxant, because atracurium has the disadvantages of histamine release and metabolite N-methyltetrahydropapaverine, which may have a central excitatory effect

Method used

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  • Preparation method of high-purity cisatracurium besylate
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  • Preparation method of high-purity cisatracurium besylate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Add 6g of the compound of formula (Ⅲ) and 6ml of 70% benzenesulfonic acid into a 50ml reaction bottle, heat in a water bath, keep the reaction at 50°C for 2h, and cool to room temperature. Add 20ml of acetonitrile and 0.8g of sodium bicarbonate into the reaction flask, react at a temperature below 50°C for 30min, cool and crystallize to obtain the compound of formula (V) as a solid. Add the compound of formula (Ⅴ) into a 100ml reaction flask, add 60ml of dichloromethane, then weigh 1.3g of 1,5-dichloropentane into the reaction flask, start stirring, and heat to reflux for 5h. The feed solution was dropped into 240ml of anhydrous ether with stirring, and the solid was precipitated, filtered, washed with anhydrous ether, and dried in vacuo to obtain 3.96 g of cisatracurium besylate, with a yield of 68.7% and a purity of 99.2%.

Embodiment 2

[0022] Add 6g of the compound of formula (Ⅲ) and 6ml of 70% benzenesulfonic acid into a 50ml reaction bottle, heat in a water bath, keep the reaction at 50°C for 2h, and cool to room temperature. Add 20ml of acetonitrile and 0.4g of sodium hydroxide into the reaction flask, react at a temperature below 50°C for 30min, cool and crystallize to obtain the compound of formula (V) as a solid. Add the compound of formula (Ⅴ) into a 100ml reaction flask, add 60ml of dichloromethane, weigh 1.3g of 1,5-dichloropentane into the reaction flask, start stirring, and heat to reflux for 5h. The feed solution was dripped into 240ml of anhydrous diethyl ether with stirring, and the solid was precipitated, filtered, washed with anhydrous diethyl ether, and dried in vacuo to obtain 3.85 g of cisatracurium besylate with a yield of 66.8% and a purity of 99.0%.

Embodiment 3

[0024] Add 6g of the compound of formula (III) and 6ml of 70% benzenesulfonic acid into a 50ml reaction bottle, heat in a water bath, keep the reaction at 50°C for 2h, and cool to room temperature. Add 20ml of acetonitrile and 0.8g of sodium bicarbonate into the reaction flask, react at a temperature below 30°C for 30min, cool and crystallize to obtain the compound of formula (V) as a solid. Add the compound of formula (Ⅴ) into a 100ml reaction flask, then add 60ml of dichloromethane, weigh 1.3g of 1,5-dichloropentane into the reaction flask, start stirring, and heat to reflux for 5h. The feed solution was dripped into 240ml of anhydrous diethyl ether with stirring, and the solid was precipitated, filtered, washed with anhydrous diethyl ether, and dried in vacuo to obtain 3.79 g of cisatracurium besylate, with a yield of 65.7% and a purity of 98.9%.

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Abstract

The invention relates to the drug synthesis field and particularly relates to a preparation method of high-purity cisatracurium besylate. The preparation method comprises the steps of reacting by virtue of a compound of a formula (III) and benzenesulfonic acid, carrying out substitution reaction on an obtained compound of a formula (IV) so as to generate a compound of a formula (V), and reacting by virtue of the compound of the formula (V) with 1,5-dichloropentane so as to generate cisatracurium besylate. An intermediate and sodium hydroxide or sodium hydrogen carbonate form sodium salt in a preparation process, namely that the intermediate is purified, so that reaction conditions of a laboratory and the production are easily met and controlled, the production efficiency is high, side reaction is little, the product purity is high, and sodium hydroxide or sodium hydrogen carbonate is easily available and relatively low in price.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of high-purity atracurium cis-benzenesulfonate. Background technique [0002] Atracurium besylate is a classic non-depolarizing muscle relaxant with moderate time effect, which is widely used in clinical anesthesia. Cisatracurium besylate is a single isomer of atracurium besylate, which has similar muscle relaxant effect and metabolic mode as atracurium besylate, but its muscle relaxation strength is about It is 3 times that of the drug, does not release histamine, and has a small cardiovascular response. It is an ideal non-depolarizing muscle relaxant with a medium-term effect. [0003] Atracurium besylate is a mixture of ten stereoisomers. Cisatracurium besylate is one of the active ingredients of atracurium besylate, accounting for about 15% of the composition. Like atracurium besylate, it belongs to the medium-acting isoquinoline non-depolarizing muscle r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/20
CPCC07D217/20
Inventor 刘志卓长城王从战刘子畅胡杨
Owner LIANYUNGANG GUIKE PHARMA
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