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Separation and preparation method and application of cisatracurium besilate impurity H

A technology of cis-atracurium besylate and cis-atracurium besylate, which is applied in the field of separation and preparation of impurity H of cis-atracurium besylate, can solve the problems of difficult separation, no preparation of impurity H, and low content of impurity H and other issues to achieve the effect of improving accuracy

Active Publication Date: 2021-06-11
JIANGSU CHENGXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, none of the above methods involves the preparation of impurity H
[0005] At present, due to the low impurity H content of atracurium besylate, it has similar properties with other isomer materials, making it difficult to separate

Method used

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  • Separation and preparation method and application of cisatracurium besilate impurity H
  • Separation and preparation method and application of cisatracurium besilate impurity H
  • Separation and preparation method and application of cisatracurium besilate impurity H

Examples

Experimental program
Comparison scheme
Effect test

preparation example

[0042] Preparation example The preparation of besylate cisatracurium reaction solution

[0043] Referring to WO9200965A1, the preparation steps are as follows:

[0044] (1) Take R-tetrahydropapaverine-N-acetyl-L-leucine salt (500g, 0.967mol) in toluene (2500mL) and water (2500mL) and adjust the pH to 10 with aqueous sodium hydroxide solution, and separate the liquid , the organic layer was concentrated under reduced pressure at 55°C until no dripping; then added toluene (2500mL) to dissolve, then added pentanediol diacrylate (100.3g, 0.4835mol) and acetic acid (25mL), and reacted at 70°C for 4h; After the reaction is completed, cool to 20°C and filter; the filtrate is concentrated under reduced pressure at 40°C until it does not drip, add acetone (5000mL) to dissolve, add oxalic acid (100.4g, 1.16mol) to form salt and crystallize, and dry the wet product to obtain the intermediate 1 (440g).

[0045] (2) Intermediate 1 (440g, 0.411mol) was dissolved in water (1200mL), adjuste...

Embodiment 1

[0047] This embodiment provides a method for the separation and preparation of cisatracurium besylate impurity H, the specific steps are as follows:

[0048] Get the cisatracurium besylate reaction solution obtained in the preparation example (cisatracurium besylate effective amount 30g), the reaction solution is directly concentrated under reduced pressure at 40°C until no dripping, and carry out column chromatography (300-400 Mesh silica gel, 2kg) purify, use eluent (volume ratio acetone: water=100:1, every liter of eluent contains 0.3g of benzenesulfonic acid) mix thoroughly silica gel wet packing, concentrate adds acetone 200mL to dilute loading , carry out elution with eluent (volume ratio acetone: water=100:1, every liter of eluent contains benzenesulfonic acid 0.3g, flow velocity 1 column volume / hour) and collect cisatracurium besylate, to be finished product After the elution is complete, use an eluent (volume ratio acetone:water=6:1, every liter of eluent contains 0.3...

Embodiment 2

[0050] This embodiment provides a method for the separation and preparation of cisatracurium besylate impurity H, the specific steps are as follows:

[0051] Get the cisatracurium besylate reaction solution obtained in the preparation example (cisatracurium besylate effective amount 30g), the reaction solution is directly concentrated under reduced pressure at 40°C until no dripping, and carry out column chromatography (100-200 Mesh silica gel, 2.1kg) purify, use eluent (volume ratio acetone: water=100:1, every liter of eluent contains 0.03g of benzenesulfonic acid) mix thoroughly silica gel wet packing, add acetone 200mL to dilute the concentrated solution Like, with eluent (volume ratio acetone: water=100:1, every liter of eluent contains benzenesulfonic acid 0.03g, flow velocity 0.3 column volume / hour) carries out elution and collects cisatracurium besylate, treats After the finished product has been eluted, it is eluted with eluent (volume ratio acetone: water=8:1, every l...

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Abstract

The invention provides a separation and preparation method and application of a cisatracurium besilate impurity H. The separation and preparation method comprises the following steps: (1) concentrating a cisatracurium besilate reaction solution under reduced pressure until the reaction solution does not drop, and then carrying out silica gel column chromatography purification and elution; and (2) after the finished cisatracurium besilate product is discharged by the silica gel column chromatography purification elution in the step (1), continuously eluting by changing the proportion of an eluent, and collecting the eluent to obtain the cisatracurium besilate impurity H. The cisatracurium besilate impurity H obtained by the separation and preparation method provided by the invention is high in purity and low in maximum single impurity content, and can improve the detection accuracy when being used for quality control of cisatracurium besilate.

Description

technical field [0001] The invention belongs to the field of analytical chemistry, in particular to a method for separating and preparing impurity H of cis-atracurium besylate and its application, in particular to a method for separating and preparing impurity H of cis-atracurium besylate with high purity and its application. Background technique [0002] Atracurium besylate is a non-depolarizing muscle relaxant, which has the characteristics of quick onset, short duration of action, no effect on heart, liver, kidney function and no accumulation of therapeutic dose, and is widely used clinically to prevent and treat various diseases. A condition that requires muscle relaxation or controlled breathing. Its action strength is about 3 times that of atracurium, through non-hepatic and non-renal metabolism without releasing amines, and has cardiovascular protection. [0003] The current preparation method of atracurium besylate will produce a series of isomers such as cis,trans...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/20C07C303/32C07C309/29G01N30/06
CPCC07D217/20C07C303/32G01N30/06G01N30/04G01N2030/042C07C309/29
Inventor 李斌李二军魏云亮谭从祥张建明何宝亮张晨晨邢飞陈倩
Owner JIANGSU CHENGXIN PHARMA
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