A kind of refining method of atracurium besylate
A technology of cis-atracurium sulfonate and benzene sulfonic acid, which is applied in the field of refining cis-atracurium benzene sulfonate, can solve the problems of difficult medicinal use of the product, cumbersome post-processing operations, and mixing of other miscellaneous acid radicals, etc., to achieve Improve production efficiency, shorten production cycle, and reduce solvent consumption
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Embodiment 1
[0047] Embodiment 1 (preparation of cis atracurium besylate crude product)
[0048] Synthesize the crude product of atracurium cisbesylate with reference to the method reported in the published document US5453510, and the specific operations are as follows:
[0049] 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 conte...
Embodiment 2
[0050] Embodiment 2 (comparative research)
[0051] 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
[0053] 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.
[0054] 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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