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Method for preparing cisatracurium besylate

A technology of atracurium cis-benzenesulfonate and benzenesulfonic acid, which is applied in the field of preparation of atracurium cis-benzenesulfonate, can solve the problems of post-processing scheme mixing and no method for removal, etc., so as to reduce product cost, The effect of quality improvement

Active Publication Date: 2011-11-23
ZHEJIANG XIANJU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The post-treatment scheme used will incorporate other acid groups with no proposed method of removal

Method used

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  • Method for preparing cisatracurium besylate
  • Method for preparing cisatracurium besylate
  • Method for preparing cisatracurium besylate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment 1, the preparation of compound (IV)

[0044] Put 700 g of R-tetrahydropapaverine-N-acetyl-L-leucine salt (II) into the reactor (the S type is less than 0.5%). Add 1.8L of water to dissolve. Adjust the pH to 7-8 with ammonia water. Extracted with 3.6L of dichloromethane, concentrated to dryness under high vacuum to obtain compound (III), added 143ml of compound 1,5-pentanediol diacrylate and 38ml of glacial acetic acid at an external temperature of 70°C for 14 hours. Reaction solution (1R, 1'R)-2,2'-(3,11-dioxo-4,10-dioxa-1,13-tridecylene)-bis[1,2,3, 4-tetrahydro-6,7-dimethoxy-1-(3,4-dimethoxy)benzyl]isoquinoline (IV) HPLC purity 92.4%. Preheated in a salt-forming reactor at 45°C 6L absolute ethanol. Dilute the reaction liquid with 400ml of dichloromethane, wash it out and add it to the salt-forming reaction tank, and then add 180g of oxalic acid. Insulate and react for 2 hours, turn off the heating, and stir at room temperature for 20 hours. Filter to g...

Embodiment 2

[0045] The refining of embodiment 2, compound (IV) oxalate:

[0046] Dissolve the crude oxalate wet product in 4L of water, extract with 4L of dichloromethane, concentrate to a small volume, add ethanol to continue concentration under reduced pressure, then add 6L of absolute ethanol, turn on cooling, stir for 20 hours, filter to obtain (1R, 1'R)-2,2'-(3,11-dioxo-4,10-dioxa-1,13-tridecylene)-bis[1,2,3,4-tetrahydro- 6,7-Dimethoxy-1-(3,4-dimethoxy)benzyl]isoquinoline oxalate wet product. Wet weight 1.5kg, HPLC99.5%.

Embodiment 3

[0047] Embodiment 3, the preparation of compound (V)

[0048] Dissolve 1.5kg of wet product in 5L of water, and adjust the pH to 7-8 with ammonia water. Extract with 4 L of dichloromethane. The organic layer was dehydrated and concentrated below 60°C to an oil. Cool down to below 30°C, throw in 450ml of methyl benzenesulfonate, 700ml of acetonitrile, and 1.55g of anhydrous sodium carbonate. Reaction at an external temperature of 28-30°C for 20 hours. Diluted with 2L of dichloromethane and added dropwise to 20L of anhydrous ether. Filtration and vacuum drying for 24 hours gave 1R, 1'R-atracurium besylate 632g. HPLC purity of 3 chiral isomers and 97.6%.

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Abstract

The invention discloses a preparation method of cisatracurium besylate. The method comprises the following steps: carrying out weal base dissociation on a R-tetrahydropapaverine-N-acetyl-L-leucine salt having a chiral purity of above 99.5% as a starting material so as to obtain R-tetrahydropapaverine; then carrying out a reaction on R-tetrahydropapaverine and 1,5-pentyl glycol diacrylate so as toobtain (1R,1'R)-2,2'-(3,11-dioxo-4,10-dioxa-1,13-subtridecyl) di[1,2,3,4-tetralin-6,7-dimethoxy-1-(3,4-dimethoxyl)benzyl]isoquinoline; after carrying out oxalate refinement and weal base dissociation, carrying out a reaction on (1R,1'R)-2,2'-(3,11-dioxo-4,10-dioxa-1,13-subtridecyl) di[1,2,3,4-tetralin-6,7-dimethoxy-1-(3,4-dimethoxyl)benzyl]isoquinoline and methyl benzenesulfonate so as to prepare1R,1'R-atracurium besilate; and finally, carrying out column chromatography separation on 1R,1'R-atracurium besilate so as to obtain cisatracurium besylate. By using the preparation method, the yieldof cisatracurium besylate can reach 30%, the purity of the product reaches above 98.6%, and single impurity content is below 0.3; and the process is brief, the yield is stable, and the product quality is good, thus the preparation method disclosed by the invention has an industrial application prospect.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a method for preparing atracurium cis-benzenesulfonate. Background technique [0002] Atracurium besylate is widely used in clinical anesthesia as a classic medium-time non-polarizing muscle relaxant. The structure of atracurium besylate is complex, containing 4 chiral centers, including 2 chiral carbons and 2 chiral nitrogens. Theoretically, 16 isomers can be produced, but due to the symmetrical structure, there are actually only 10 isomers. Atracurium cis-besylate is one of the single (1R, 1'R, 2R, 2'R) isomers, which has a similar muscle relaxation effect and metabolic mode as atracurium besylate. The strength of muscle relaxation is about 3 times that of atracurium, and does not release histamine, and the side effects of the cardiovascular system are small. [0003] The chemical name of atracurium cis-benzenesulfonate is: (1R, 1'R, 2R, 2'R)-2,2'-(3,11-dioxo-4,10-dioxotrid...

Claims

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Application Information

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IPC IPC(8): C07D217/20
Inventor 林庆恩徐顺广
Owner ZHEJIANG XIANJU PHARMA
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