CN101891755B - Cefsulodin sodium compound and novel preparation method thereof - Google Patents
Cefsulodin sodium compound and novel preparation method thereof Download PDFInfo
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- CN101891755B CN101891755B CN2010102374877A CN201010237487A CN101891755B CN 101891755 B CN101891755 B CN 101891755B CN 2010102374877 A CN2010102374877 A CN 2010102374877A CN 201010237487 A CN201010237487 A CN 201010237487A CN 101891755 B CN101891755 B CN 101891755B
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- cefsulodin
- sulcephalosporin
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- solution
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Abstract
The invention provides a method for refining a cefsulodin sodium compound. The method has the advantages of fulfilling the aims of refining and purification through an acid-alkali reaction, active carbon adsorption and preparative chromatography separation and purification, finally obtaining a high-purity cefsulodin sodium compound, greatly enhancing the purity and content of cefsulodin sodium, optimizing the product quality of a preparation and ensuring the safety of clinical application, along with simple process, low cost, high yield and suitability for industrial production.
Description
Technical field
The present invention relates to a kind of process for purification of cefsulodin sodium compound, can obtain highly purified Sulcephalosporin product, belong to medical technical field through method of the present invention.
Background technology
Sulcephalosporin, its chemical name are [6R-[6R, 7 β (R*)]]-4 (formamyl)-1-[3-[2-carboxyl-8-oxidation-7-[(phenylbenzimidazole sulfonic acid yl acetamide)]-5-thia-1-azabicyclic [4,2,0] oct-2-ene] methyl] pyridinium inner salt sodium salts, and molecular formula is C
22H
19N
4NaO
8S
2, molecular weight is: 554.52, and structural formula is:
Sulcephalosporin belongs to third generation cephalosporin analog antibiotic; English name Cefsulodine; Having another name called cefsulodin sodium, Takesulin, Cefsulodine Sodium etc., is first anti Bacillus pyocyaneu Flugge injection cephalosporin analog antibiotic of being developed by Japan's military field drug company.Be mainly used in the secondary infection of various septicemia, pneumonia, bronchitis, bronchiectasis complication, pyelonephritis, urocystitis, peritonitis, wound or the burns that cause by Pseudomonas aeruginosa clinically, determined curative effect.
Sulcephalosporin is a kind of semisynthetic cephalosporin analog antibiotic, is parent nucleus with 7-ACA.7 side chains of Sulcephalosporin have then improved its stability to the cynnematin enzymic hydrolysis of P.aeruginosa generation significantly.Mostly this medicine is to carry out acylation reaction with 7-ACA, alpha-sulfo phenyllacetyl chloride, and then makes with Isonicotinamide is quaternary ammoniated.Because the difficult preparation of alpha-sulfo phenyllacetyl chloride, purifying, so seldom relevant for the report of its preparation aspect.
Summary of the invention
The object of the present invention is to provide a kind of process for purification of cefsulodin sodium compound; Reach the purpose of refining purifying through acidification reaction, charcoal absorption and preparative hplc column separating purification; Finally obtain highly purified cefsulodin sodium compound, remedied the low defective of material purity of present production.
The process for purification of cefsulodin sodium compound provided by the invention comprises the steps:
(1) the Sulcephalosporin bullion is soluble in water, slowly add acid then, the pH of stirring reaction to solution is 1.5-2.5, produces the cefsulodin deposition, and suction filtration obtains cefsulodin, and wherein, described acid is selected from a kind of in hydrochloric acid, phosphoric acid, oxalic acid, the acetate;
(2) will go up the cefsulodin that obtains of step is dissolved in the solvent of 3-8 times of weight; The gac that adds overall solution volume 0.1-0.5% (g/ml); Be incubated 50 ℃ and stir 10-30min; Filter decarburization, collect filtrating, wherein said solvent is selected from a kind of in acetonitrile, normal butane, Virahol and the methylene dichloride;
(3) will go up the filtrating that obtains of step utilizes the preparative hplc post to carry out separation and purification to obtain the Sulcephalosporin highly finished product; Wherein the moving phase used of chromatographic column is that 1: 3 acetone and pH is the mixing solutions of the alkaline solution of 8-10 as volume ratio; Described alkali is selected from a kind of in sodium hydroxide, sodium hydrogencarbonate and the yellow soda ash, and preferred sodium hydroxide; Fixed phase stuffing is selected from silica gel or aluminum oxide, and flow velocity is 3.8-5.6ml/min, column temperature 30-35 ℃; Collect filtrating, drying under reduced pressure obtains the purified Sulcephalosporin.
As the present invention's one preferred embodiment, wherein the pH value of stirring reaction to solution is 1.8-2.2 in the step (1).
As the present invention's one preferred embodiment, wherein step (2) adds the gac of overall solution volume 0.2-0.4% (g/ml), whip attachment 20-30min.
As the present invention's one preferred embodiment, wherein the pH of alkaline solution is 8.5-9.5 in the step (3).
The process for purification of cefsulodin sodium compound provided by the invention through acid-base reaction, charcoal absorption and preparative hplc separation and purification, has improved the purity and the content of Sulcephalosporin greatly; Optimized the quality product of preparation; Ensured safety of clinical administration, present method technology is simple, and cost is low; Yield is high, is suitable for suitability for industrialized production.
Embodiment
Below further explain or explanation content of the present invention, but embodiment should not be understood that the restriction to protection domain of the present invention through embodiment.
Making with extra care of embodiment 1 Sulcephalosporin
(1) 100g Sulcephalosporin bullion is dissolved in the 1000ml water, slowly adds the hydrochloric acid of 0.1mol/L then, the pH of stirring reaction to solution is 1.5, produces the cefsulodin deposition, and suction filtration obtains cefsulodin 90.3g;
(2) will go up the 90.3g cefsulodin that obtains of step and be dissolved in the 271g acetonitrile, add the gac of 0.35g, and be incubated 50 ℃ and stir 10min, filter decarburization, and collect and filtrate;
(3) will go up the filtrating that obtains of step and utilize the preparative hplc post to carry out separation and purification to obtain the Sulcephalosporin highly finished product, wherein the moving phase used of chromatographic column is that 1: 3 acetone and pH is the mixing solutions of 10 sodium hydroxide solution as volume ratio; Fixed phase stuffing is selected from silica gel or aluminum oxide, and flow velocity is 3.8ml/min, 35 ℃ of column temperatures; Collect filtrating, drying under reduced pressure obtains purified Sulcephalosporin 91.8g, yield 91.8%.
Making with extra care of embodiment 2 Sulcephalosporins
(1) 100g Sulcephalosporin bullion is dissolved in the 1200ml water, slowly adds 10% phosphoric acid solution then, the pH of stirring reaction to solution is 2.5, produces the cefsulodin deposition, and suction filtration obtains cefsulodin 89.8g;
(2) will go up the 89.8g cefsulodin that obtains of step and be dissolved in the 718g normal butane, add the gac of 4g, and be incubated 50 ℃ and stir 30min, filter decarburization, and collect and filtrate;
(3) will go up the filtrating that obtains of step and utilize the preparative hplc post to carry out separation and purification to obtain the Sulcephalosporin highly finished product, wherein the moving phase used of chromatographic column is that 1: 3 acetone and pH is the mixing solutions of 8 sodium hydrogen carbonate solution as volume ratio; Fixed phase stuffing is selected from silica gel or aluminum oxide, and flow velocity is 5.6ml/min, 30 ℃ of column temperatures; Collect filtrating, drying under reduced pressure obtains purified Sulcephalosporin 90.1g, yield 90.1%.
Making with extra care of embodiment 3 Sulcephalosporins
(1) 100g Sulcephalosporin bullion is dissolved in the 1000ml water, slowly adds the oxalic acid solution of 1mol/L then, the pH of stirring reaction to solution is 1.8, produces the cefsulodin deposition, and suction filtration obtains cefsulodin 90.7g;
(2) will go up the 90.7g cefsulodin that obtains of step and be dissolved in the 450g Virahol, add the gac of 1.1g, and be incubated 50 ℃ and stir 20min, filter decarburization, and collect and filtrate;
(3) will go up the filtrating that obtains of step and utilize the preparative hplc post to carry out separation and purification to obtain the Sulcephalosporin highly finished product, wherein the moving phase used of chromatographic column is that 1: 3 acetone and pH is the mixing solutions of 9 sodium hydrogen carbonate solution as volume ratio; Fixed phase stuffing is selected from silica gel or aluminum oxide, and flow velocity is 4.3ml/min, 33 ℃ of column temperatures; Collect filtrating, drying under reduced pressure obtains purified Sulcephalosporin 90.5g, yield 90.5%.
Making with extra care of embodiment 4 Sulcephalosporins
(1) 100g Sulcephalosporin bullion is dissolved in the 1000ml water, slowly adds 5% acetic acid soln then, the pH of stirring reaction to solution is 2.2, produces the cefsulodin deposition, and suction filtration obtains cefsulodin 91.0g;
(2) will go up the 91.0g cefsulodin that obtains of step and be dissolved in the 520ml methylene dichloride, add the 2.4g gac, and be incubated 50 ℃ and stir 25min, filter decarburization, and collect and filtrate;
(3) will go up the filtrating that obtains of step and utilize the preparative hplc post to carry out separation and purification to obtain the Sulcephalosporin highly finished product, wherein the moving phase used of chromatographic column is that 1: 3 acetone and pH is the mixing solutions of 9.5 sodium hydroxide solution as volume ratio; Fixed phase stuffing is selected from silica gel or aluminum oxide, and flow velocity is 4.5ml/min, 30 ℃ of column temperatures; Collect filtrating, drying under reduced pressure obtains purified Sulcephalosporin 89.6g, yield 89.6%.
Embodiment 5 structural identifications
The cefsulodin sodium compound of embodiment 1-5 preparation is carried out mass spectroscopy, further carry out structural confirmation.
1HNMR(D
2O)：δ3.10(1H，d，J＝18Hz)，3.63(1H，d，J＝18Hz)，5.08(1H，s)，5.20(1H，d，J＝5Hz)，5.37(1H，d，J＝15Hz)，5.66(1H，d，J＝15Hz)，5.74(1H，d，J＝5Hz)，7.45-7.64(5H，m)，8.26(2H，d，J＝6.5Hz)，9.04(2H，d，J＝6.5Hz)。
IR(KBr)cm
-1：3330(CH，NH)，3200(OH，broad)，1760(C＝O，β-lactam)，1684(-CONH-)，1616(-COO-)，1555(-NH
2，deformation)，1454，1396(C＝C，SO
2)，1200(SO
2，broad)，1120，1040(-SO
3-)。
Claims (4)
1. the process for purification of the cefsulodin sodium compound of structure shown in the formula (I) comprises the steps:
(1) the Sulcephalosporin bullion is soluble in water, slowly add acid then, the pH of stirring reaction to solution is 1.5-2.5, produces the cefsulodin deposition, and suction filtration obtains cefsulodin, and wherein, described acid is selected from a kind of in hydrochloric acid, phosphoric acid, oxalic acid, the acetate;
(2) will go up the cefsulodin that obtains of step is dissolved in the solvent of 3-8 times of weight; The gac that adds overall solution volume 0.1-0.5%g/ml is incubated 50 ℃ and stirs 10-30min, filters decarburization; Collect filtrating, wherein said solvent is selected from a kind of in acetonitrile, normal butane, Virahol and the methylene dichloride;
(3) will go up the filtrating that obtains of step utilizes the preparative hplc post to carry out separation and purification to obtain the Sulcephalosporin highly finished product; Wherein the moving phase used of chromatographic column is that 1: 3 acetone and pH is the mixing solutions of the alkaline solution of 8-10 as volume ratio, and described alkali is selected from a kind of in sodium hydroxide, sodium hydrogencarbonate and the yellow soda ash; Fixed phase stuffing is selected from silica gel or aluminum oxide, and flow velocity is 3.8-5.6ml/min, column temperature 30-35 ℃; Collect filtrating, drying under reduced pressure obtains the purified Sulcephalosporin.
2. process for purification according to claim 1 is characterized in that the pH value of stirring reaction to solution in the step (1) is 1.8-2.2.
3. process for purification according to claim 1 is characterized in that step (2) adds the gac of overall solution volume 0.2-0.4%g/ml, whip attachment 20-30min.
4. process for purification according to claim 1 is characterized in that the pH of alkaline solution in the step (3) is 8.5-9.5.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2010102374877A CN101891755B (en) | 2010-07-27 | 2010-07-27 | Cefsulodin sodium compound and novel preparation method thereof |
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| CN2010102374877A CN101891755B (en) | 2010-07-27 | 2010-07-27 | Cefsulodin sodium compound and novel preparation method thereof |
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| CN101891755B true CN101891755B (en) | 2012-01-11 |
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| CN103755726A (en) * | 2013-12-12 | 2014-04-30 | 福建省福抗药业股份有限公司 | Cefalonium refinement purification method |
| CN106317075B (en) * | 2016-08-23 | 2019-02-12 | 中国医药集团总公司四川抗菌素工业研究所 | A kind of preparation method of cephalo sulphur benzyl pyridine acid |
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| CN101279979B (en) * | 2008-06-03 | 2010-07-28 | 海南本创医药科技有限公司 | Separation and purification method of cefamandole nafate and preparation of cefathiamidine freeze-dried injectable powder |
| CN101550145B (en) * | 2009-05-07 | 2011-04-27 | 王明 | Cefradine compound preparation method |
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