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Purification method for cisatracurium besylate

A technology of cisatracurium besylate and besylate, which is applied in the field of pharmaceuticals, can solve the problems of cumbersome post-processing operations, mixing, and difficulty in meeting pharmaceutical needs, shortening the production cycle, reducing pressure, and ensuring reproducibility. present effect

Inactive Publication Date: 2015-09-09
TIANJIN ZHONGRUI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, these improvements can not get rid of the cumbersome predicament of not being able to produce large-scale industrial production after being eluted by column chromatography.
[0006] In addition, WO 2009057086 reports a method for obtaining atracurium cisbenzenesulfonate without using column chromatography, but because tetrafluoroboric acid is used in the recrystallization resolution stage, not only the post-treatment operation is 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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  • Purification method for cisatracurium besylate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment 1 (preparation of besylate cisatracurium crude product)

[0044] Synthesize the crude product of cisatracurium besylate with reference to the method reported in the published document US 5453510, and the specific operations are as follows:

[0045] Add 1.7Kg of besylate cisatracurium 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 with 1.4Kg acetonitrile, added 6.3Kg methyl benzenesulfonate, reacted at room temperature for 20 hours, then dropped it into ether, filtered, and dried under reduced pressure to obtain benzenesulfonate Tracuronium crude product. Detecting by HPLC (normalization method) containing cis-cis, cis-trans, the total content of anti-trans atracurium besylate is 96.6%, a...

Embodiment 2

[0046] Embodiment 2 (comparative research)

[0047] Get the cisatracurium besylate crude product 100g that is obtained in Example 1 and dissolve in 1Kg methylene chloride, and load a sample on a 6Kg silica gel (200~300 mesh) column, use benzenesulfonic acid: methylene chloride: methanol The mobile phase of (m / v / v)=1.0:900:100 carries out elution (needs about 250Kg), and liquid phase monitors effluent, and the qualified effluent of merging collection (besylate cisatracurium content is not less than 97 %, the sum of other impurities must not exceed 5%, wherein the single quaternary ammonium salt impurities must not exceed 1.0%, and the content of each isomer is all lower than 0.1%) 100Kg, wash 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 52 g of cisatracurium besylate, yield: 26.0%. Detected by HPLC (normalization met...

Embodiment 3

[0049] Get cisatracurium besylate crude product 100g that is obtained by embodiment 1 and be dissolved in the 1Kg dichloromethane (pH=3.5) that contains 4g of besylic acid, then add 3Kg silica gel (200~300 orders), stir to make it well mixed. Concentrate to dryness under reduced pressure at 35°C, and the obtained residue is further dried at 30°C to obtain a silica gel mixture of cisatracurium besylate with uniform content.

[0050] The cisatracurium besylate silica gel carrier prepared above was first soaked with 2 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 20 minutes. The liquid phase monitors the leachate (filtrate), and the qualified leachate collected in combination (the content of cisatracurium besylate is not less than 97%, the sum of oth...

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Abstract

The invention discloses an industrial purification and preparation method for cisatracurium besylate. According to the preparation method, the refining operation process is simplified, and firstly, under the circumstance of not changing a base, high-purity cisatracurium besylate is obtained in a non-column chromatography preparation mode. By adopting the preparation method disclosed by the invention, the production cycle is shortened greatly, productivity is improved, the yield reaches 40% or above, the content of cisatracurium besylate in a product is not less than 98%, the total content of impurities is less than or equal to 2%, the content of mono-quaternaries is less than or equal to 0.5%, the content of other single maximum impurity is less than or equal to 0.5%, and the content of all isomers is less than or equal to 0.1%.

Description

technical field [0001] The invention relates to the technical field of pharmacy, in particular to a method for purifying cisatracurium besylate. Background technique [0002] Cisatracurium besylate is the latest generation of muscle relaxants, widely used in tracheal intubation, liver and kidney dysfunction, cardiovascular surgery and other fields. This product has the characteristics of metabolism through non-hepatic and non-renal pathways and cardiovascular protection. It has advantages over similar drugs, and its muscle relaxation effect is 3 times stronger than that of atracurium besylate commonly used in clinical practice. 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 vecuronium bromide and atracurium besylate and has become an indisp...

Claims

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Application Information

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IPC IPC(8): C07D217/20
CPCC07D217/20
Inventor 王洪刚曹志刚马秀玲
Owner TIANJIN ZHONGRUI PHARMA
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