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Method for purifying cisatracuriumbesylate

A technology of cistracurium besylate and a purification method, which is applied in the purification field of cistracurium besylate, can solve the problems of high cost, low production capacity, complicated technological process, etc. The effect of production costs

Active Publication Date: 2016-10-12
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] CN101475530A discloses a method for separating and purifying citracurium benzenesulfonate by preparative liquid chromatography, after atracurium benzenesulfonate is used as an eluent solvent, it is loaded on a preparative liquid chromatography silica gel column, and after washing Carry out normal phase or reverse phase chromatographic separation under the elution of stripping agent, reclaim citracurium benzenesulfonate, this method can obtain the citracurium benzenesulfonate of better purity, but is not suitable for industrial production, its production Lower productivity and better cost
[0012] CN104892508A discloses a method for obtaining citracurium benzenesulfonate by using a silica gel loading extraction method, the sum of impurities is not higher than 2%, wherein the impurity content of single quaternary ammonium salt is less than 0.5%, and the content of other impurities is less than 0.5%, each isomer The content is less than 0.1%, the whole technological process is relatively complicated, not suitable for production, and its production capacity is low
[0013] At present, in industrial production, silica gel column chromatography is mostly used to purify citracurium benzenesulfonate. During industrial production, it is easy to cause the increase of degraded related substances, and it is difficult to further remove them by conventional purification methods.

Method used

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  • Method for purifying cisatracuriumbesylate
  • Method for purifying cisatracuriumbesylate
  • Method for purifying cisatracuriumbesylate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Embodiment 1: the preparation of citracurium besylate crude product (with reference to WO92 / 00965)

[0039] a) Preparation of Condensate Oxalate (3)

[0040]

[0041] (R)‐1,2,3,4‐tetrahydropapaverine N‐acetylleucine salt (2,180g, 98.6%, 0.348mol) was dissolved in 2700ml of water and treated with ammonia water to adjust the pH value to 9‐10. After the precipitate was filtered with suction, toluene (900ml×3) was added, the combined toluene layer was washed with deionized water (900ml×3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain oil 3 (123.6g). (R)‐1,2,3,4‐tetrahydropapaverine was reacted with 1,5‐pentamethylene diacrylate (33g, 0.156mol) and toluene (180ml) at 80°C for 48 hours. The reaction solution was concentrated to obtain 3 as a yellow oil. The product was dissolved in ethanol (360ml) and treated with oxalic acid (37.5g, 0.417mol) in ethanol (360ml) to give a white precipitate as the condensate oxalate...

Embodiment 2

[0044] Embodiment 2: DiaionHP20ss resin purifies citracurium besylate

[0045] Use DiaionHP20ss type macroporous adsorption resin 150g to pack chromatography column (effective column height 50cm, inner diameter 6cm), wash a moment with eluent, the composition of this eluent is deionized water: benzenesulfonic acid (500ml: 1g), column Cool with ice water and keep the column temperature below 5°C. Dissolve 10g of cistracurium benzenesulfonate crude product with pre-cooled eluent and put it on the column, and carry out gradient elution after half an hour of elution, and gradually add 1‐6% isopropanol for gradient elution during the elution process, until When the product component appears, continue to elute with eluent (deionized water: isopropanol: benzenesulfonic acid (100m: 6ml: 1g), and start to collect the component solution containing citracurium benzenesulfonate at the same time, and combine the components containing After all the components of cistracurium benzenesulfona...

Embodiment 3

[0046] Embodiment 3: DiaionHP20 resin purifies citracurium benzenesulfonate

[0047] Use HP20 type macroporous resin 150g to pack chromatography column (effective column height 50cm, internal diameter 6cm), wash a moment with eluent, the composition of eluent is deionized water: benzenesulfonic acid (500ml: 1g), the column passes through Cool with ice water and keep the column temperature below 5°C. Dissolve 10g of cistracurium benzenesulfonate crude product with pre-cooled eluent and put it on the column, and carry out gradient elution after half an hour of elution, and gradually add 1‐6% isopropanol for gradient elution during the elution process, until When product component occurs, continue eluting with eluent (deionized water: isopropanol: benzenesulfonic acid (100ml: 6ml), begin to collect the component solution that contains citracurium benzenesulfonate simultaneously, add two after merging Extract with methyl chloride, wash with water to remove excess benzenesulfonic ...

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Abstract

The invention relates to a method for purifying cisatracuriumbesylate. Specifically, the purification method is by using macroporous resin as a filler, eluting impurities by an eluent, then eluting a sample, and collecting an eluate. The samples elution employs a gradient elution method, can effectively separate cis-csi isomers and cis-trans isomer in the sample; at the same time, the method is conducive to the removal of residual methyl benzenesulfonate in the sample, and can effectively obtain the cisatracuriumbesylate product, significantly reduce the residual amount of toxic solvent in the cisatracuriumbesylate product, and significantly improve the medication safety and also reduce the cost of production.

Description

technical field [0001] The invention relates to a new purification process of citracurium benzenesulfonate, specifically, the separation and purification of citracurium benzenesulfonate by using an aqueous phase elution method using a macroporous adsorption resin as a filler. Background technique [0002] Atracurium besylate was developed by the British Glaxo welcome company, and it was listed in the UK in 1996. It is a non-depolarizing muscle relaxant. It has the same effect as tubocurarine, but its potency is 2.5 times that of tubocurarine. It has the characteristics of quick onset, short duration of action, no effect on heart, liver, kidney function and no accumulation of therapeutic dose, etc. It is widely used clinically to prevent and treat various situations that require muscle relaxation or control of breathing. [0003] Cisatracurium besylate is a single isomer of atracurium besylate, which has a similar muscle relaxant effect and metabolic mode as atracurium besyla...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/20
CPCC07D217/20
Inventor 侯宪山仲新光徐燕陈永江
Owner JIANGSU HENGRUI MEDICINE CO LTD
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