Refinement method of cisatracurium besylate

A technology of cis-atracurium besylate and atracurium besylate, which is applied in the field of pharmaceuticals, can solve the problems of cumbersome post-processing operations, mixing of other miscellaneous acid radicals, and difficult medicinal products, so as to shorten the production cycle and improve the production efficiency. Productivity and the effect of reducing solvent consumption

Active Publication Date: 2015-01-21
大道隆达(北京)医药科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, these improvements cannot get rid of the bottleneck that restricts the large-scale industrial production of this product, which must be eluted by column chromatography.
[0006] In addition, WO 2009057086 reported a method for obtaining atracurium cis-benzenesulfonate without using column chromatography, but because tetrafluoroboric acid was used in the recrystallization resolution stage, not only the post-treatment operation was cumbersome, but also due to its It is easy to mix other mixed acid radicals in the finished product, making it difficult for the product to meet the medicinal needs

Method used

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  • Refinement method of cisatracurium besylate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Embodiment 1 (preparation of cis atracurium besylate crude product)

[0047] Synthesize the crude product of cis-atracurium besylate with reference to the method reported in the published document US 5453510, and the specific operations are as follows:

[0048] Add 1.7Kg of cis-atracurium oxalate to 9Kg of water, 19Kg of dichloromethane, adjust the pH to 13-14 with 20% ammonia water, separate the layers, extract the water layer with dichloromethane, combine the organic layers, and wash with water until medium properties, dried over anhydrous sodium sulfate; evaporated to dryness, dissolved the concentrate in 1.4Kg acetonitrile, added 6.3Kg methyl benzenesulfonate, reacted at room temperature for 20 hours, then dripped it into ether, filtered, and dried under reduced pressure to obtain cisbenzenesulfonate Tracuronium crude product. Detecting by HPLC (normalization method) containing cis-cis, cis-trans, the total content of trans-atracurium besylate is 96.6%, and the con...

Embodiment 2

[0049] Embodiment 2 (comparative research)

[0050] Get cis-atracurium besylate crude product 200g obtained in Example 1 and dissolve in 1Kg dichloromethane, and load the sample in 8Kg silica gel (200~300 order) column, use benzenesulfonic acid: dichloromethane: methyl alcohol The mobile phase of (m / v / v)=0.5:900:100 carries out elution (needs about 200Kg), and liquid phase monitors effluent, and the qualified effluent of merging collection (cis-atracurium ammonium besylate content is not less than 96 %, the sum of other impurities must not exceed 4%, wherein the single quaternary ammonium salt impurities must not exceed 0.5%, and the content of each isomer is all lower than 0.1%) 92Kg, after washing with purified water, concentrate under reduced pressure, add activated carbon for decolorization, filter, The filtrate was dropped into diethyl ether for crystallization, filtered, and vacuum-dried to obtain 53.7 g of cis-atracurium besylate, yield: 26.8%. Detected by HPLC (normal...

Embodiment 3

[0052] Get cis-atracurium besylate crude product 200g obtained in Example 1 and dissolve in 1Kg dichloromethane (pH=4) containing benzenesulfonic acid 2g, then add 1Kg silica gel (200~300 mesh), stir to make it well mixed. Concentrate to dryness under reduced pressure at 40°C, and the obtained residue is further dried at 40°C to obtain cis-atracurium besylate silica gel carrier with uniform content.

[0053] The above-prepared cis-atracurium silica gel carrier was first soaked with 1 Kg of dichloromethane for 15 minutes, and then filtered. The filter cake is soaked back and forth in the mixed solution of 1Kg methylene chloride and methanol with the percentage by weight of methanol being respectively 2%, 5%, 8%, 10%, 12%, 15%, 20% and 35%. The intervals are 15 minutes. The liquid phase monitors the leachate (filtrate), and the qualified leachate collected in combination (the content of cis-atracurium besylate is not less than 96%, and the sum of other impurities must not exce...

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Abstract

The invention relates to an industrial preparation method of cisatracurium besylate. The preparation method simplifies the refinement operation process, and obtains the high-purity cisatracurium besylate in a non-chromatographic column chromatography preparation mode under the condition of not changing the salt base for the first time. The preparation method can greatly shorten the production cycle, enhance the productivity and increase the yield to 45% above. In the product, the content of cisatracurium besylate is not lower than 98%, the content of total impurities does not exceed 2%, the content of mono quaternary ammonium salts does not exceed 0.2%, the content of other maximum individual impurities does not exceed 0.3%, and the content of isomers does not exceed 0.1%.

Description

technical field [0001] The invention relates to the technical field of pharmacy, and describes a method for refining cis-atracurium besylate, which is widely used as a muscle relaxant anesthetic for tracheal intubation, liver and kidney dysfunction, and cardiovascular diseases. surgery etc. Background technique [0002] Cisatracurium besylate (cisatracurium besylate) is the latest generation of muscle relaxants. Compared with the current main clinical muscle relaxant anesthetics, this product has the characteristics of metabolism through non-hepatic and non-renal pathways and cardiovascular stability. The effect of atracurium besylate is 3 times stronger, without cardiovascular side effects. Cisatracurium besylate is mainly suitable for general anesthesia, and can be widely used in endotracheal intubation, liver and kidney dysfunction, cardiovascular surgery and elderly and pediatric patients. Since the drug was first launched in the UK in 1996, it has gradually replaced v...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/20
CPCC07D217/20
Inventor 周华明
Owner 大道隆达(北京)医药科技发展有限公司
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