CN1394863A - Method for synthesizing cefotaxime sodium - Google Patents
Method for synthesizing cefotaxime sodium Download PDFInfo
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- CN1394863A CN1394863A CN 02112393 CN02112393A CN1394863A CN 1394863 A CN1394863 A CN 1394863A CN 02112393 CN02112393 CN 02112393 CN 02112393 A CN02112393 A CN 02112393A CN 1394863 A CN1394863 A CN 1394863A
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- cefotaxime
- acid
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- meam
- cefotaxime sodium
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Abstract
The present invention discloses a method for synthesizing cefotaxime sodium, and said method includes the following steps: placing 7-amino cephaloalkyl acid (7-ACA) and benzothiazol active ester (MEAM) in organic solvent, using triethylamine as condensation agent, under the catalysis of phase transfer catalyst making them produce condensation reaction to obtain cefotaxime acid, and making the cefotaxime acid react with trihydrated sodium acetate to obtain the invented cefotaxime sodium.
Description
Technical field:
The invention belongs to technical field of medicine synthesis.Be specifically related to a kind of synthetic method of cefotaxime sodium.
Background technology:
The structural formula of cefotaxime sodium is:
It is widely used clinically third generation cephalosporin analog antibiotic, its chemical name is (6R, 7R)-and the 3-[(acetoxyl group) methyl]-7-[(2-amino-4-thiazolyl)-(methoxyimino) acetamido]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid sodium salt, this medicine is developed jointly by German Hoechst and French Roussel company, succeeded in developing in 1977, in listing in 1980, the commodity of its powder injection are called Claforan, have wide spectrum, efficient, anti-enzyme, characteristics that toxic side effect is little, existing synthetic route is as follows:
Cefotaxime acid (IV) synthetic be with 7-amino-cephalosporanic acid (7-ACA, II) and MEAM (MEAM is a raw material III), generates in inert organic solvents, and used organic solvent mainly contains methylene dichloride, 1,2-ethylene dichloride etc.Add triethylamine and phase-transfer catalyst in the reaction process, operational here phase-transfer catalyst has N,N-dimethylacetamide (DMA), N-methylmorpholine, pyridine etc., promptly obtains through the salt acid crystal of 3N.The second step cefotaxime acid (IV) changes cefotaxime sodium (I) salt forming agent and mainly contains sodium acetate trihydrate, sodium bicarbonate, sodium formiate etc., and recrystallisation solvent mainly contains ethanol, acetone, Virahol.
With MEAM (MEAM, III) the synthetic cefotaxime sodium of method existing report in European patent (EP-0037380) and world patent (WO96/20198), wherein WO96/20198 improves to some extent to the method for EP-0037380, save the process of the estersilization in the cefotaxime acid building-up reactions, and in reaction process, used same solvent---acetone.According to the example that WO96/20198 provided, experiment can be carried out according to following processes: (1) is made into suspension liquid with 7-ACA (II) with acetone-water, stirring back adding triethylamine and MEAM reacts, drip the acidity of acid-conditioning solution after reacting completely, separate out cefotaxime acid, add an amount of crystal seed in case of necessity.(2) cefotaxime acid (IV) reacts in acetone-water solution with sodium acetate trihydrate and generates cefotaxime sodium, and acetone adds crystal seed and separates out cefotaxime sodium (I) as recrystallisation solvent in crystallisation process.
This experimentation reaction conditions is relatively gentleer, operate also easier, but the synthesis yield of this process cefotaxime acid lower (the highest by 89.4%), the salify crystallization of second step easily forms colloid, and in crystallisation process, need to add crystal seed, be not suitable for suitability for industrialized production.
Summary of the invention:
Technical problem to be solved by this invention is to overcome above-mentioned weak point, designs a kind of new synthetic method, reaches easy and simple to handle, the purpose that yield is high.
The invention provides a kind of synthetic method of cefotaxime sodium, method of the present invention comprises the following steps: that (1) mix with MEAM (III) 7-amino-cephalosporanic acid (II) in reaction solvent, add triethylamine and catalyzer, stirring reaction 2h, organic phase extracts with an amount of water, regulate pH with 3N hydrochloric acid, separate out white crystal, promptly obtain cefotaxime acid (IV); (2) sodium acetate trihydrate and cefotaxime acid (IV) are dissolved in 60% aqueous isopropanol, add decolorizing with activated carbon, filter, filtrate slowly is added drop-wise in the aqueous isopropanol and constantly and stirs, and can form cefotaxime sodium (I).
The used catalyzer of the first step is pyridine or N-methylmorpholine in the method for the present invention; 7-amino-cephalosporanic acid (II) is 1 with the mole ratio of MEAM (III): 1-1.2; Cefotaxime acid (IV) is 1 with the mole ratio of sodium acetate trihydrate: 1-1.3, reaction solvent are methylene dichloride, 1, and 2-ethylene dichloride, recrystallisation solvent are ethanol or Virahol, wherein the best is a Virahol.
Method of the present invention has following characteristics: add phase-transfer catalyst in the reaction of (1) the first step, make the yield in this step surpass 97%.(2) use the recrystallisation solvent of Virahol instead, overcome easy formation colloidal weakness as cefotaxime sodium.(3) saved and added this operation of crystal seed, made operating process more easy.
Embodiment:
The preparation of embodiment 1, cefotaxime acid
10.00g7-ACA and 14.18gMEAM are mixed in 150ml 1, in the 2-ethylene dichloride, add 1.0ml pyridine and triethylamine 7.0ml, add the 73.5ml water stratification behind the stirring at room 2h, organic phase is used equal-volume 1 again with the extraction of 36ml water, the washing of 2-ethylene dichloride, 3N hydrochloric acid is regulated pH=2.5-3.0, there are a large amount of crystal to separate out, growing the grain 1.5h, suction filtration, filter cake is used 20ml Virahol and 20ml washing with acetone respectively, and vacuum-drying gets cefotaxime acid 16.30g.Yield 97.44%, content 95.44%, moisture 1.27%.
IR(KBr，cm
-1)：1780(C＝O)
1H-NMR(DMSO-d
6，δ，ppm)：2.1(s，3H)，3.6(bs，2H)，3.9(s，3H)，4.9(m，2H)，5.2(d，1H，J＝5Hz)，5.8(dd，1H，J＝5.8Hz)，6.8(s，1H)，9.6(d，1H，J＝8Hz)
The preparation of embodiment 2, cefotaxime acid
Press the program of embodiment 1, use the 1.0ml N-methylmorpholine instead, get cefotaxime acid 16.4g as phase-transfer catalyst.Yield 98.04%, content 95.20%, moisture 1.24%.
The preparation of embodiment 3, cefotaxime acid
Press the program of embodiment 2, use the 150ml methylene dichloride instead, get cefotaxime acid 16.50g as solvent.Yield 98.64%, content 95.80%, moisture 1.28%.
IR and
1The H-NMR spectrum data is with embodiment 1.
The preparation of embodiment 4, cefotaxime acid
Press the program of embodiment 3, use the 1.0ml pyridine instead, get cefotaxime acid 16.4g as phase-transfer catalyst.Yield 98.04%, content 95.22%, moisture 1.69%.
The preparation of embodiment 5, cefotaxime sodium
3.5g sodium acetate trihydrate is dissolved in the 20ml60% ethanolic soln, adds 10.00g cefotaxime acid and constantly stirring, dissolving back fully adds 1.7g activated carbon stirring 30min.Filter, with 10ml80% ethanolic soln washing leaching cake, filtrate slowly is added drop-wise in the 200ml ethanolic soln, has a large amount of crystal to separate out, growing the grain 1h, and suction filtration, 25ml washing with acetone 2 times, vacuum-drying gets cefotaxime sodium 8.0g.Yield 76.24%, content 92.3%, [standards of pharmacopoeia content＞86%] moisture 2.4%.[standards of pharmacopoeia content＜6%]
The program of embodiment 5 is pressed in the preparation of embodiment 6, cefotaxime sodium, replaces ethanol with Virahol, gets cefotaxime sodium 9.6g.Yield 91.49%, content 92.83%, moisture 3.96%.
Claims (3)
1, a kind of synthetic method of cefotaxime sodium, it is characterized in that this method comprises the following steps: that (1) mix with MEAM (III) 7-amino-cephalosporanic acid (II) in reaction solvent, add triethylamine and catalyzer, stirring reaction 2h, organic phase extracts with an amount of water, regulate pH with 3N hydrochloric acid, separate out white crystal, promptly obtain cefotaxime acid (IV); (2) sodium acetate trihydrate and cefotaxime acid (IV) are dissolved in 60% aqueous isopropanol, add decolorizing with activated carbon, filter, filtrate slowly is added drop-wise in the aqueous isopropanol and constantly and stirs, and can form cefotaxime sodium (I).
2, the synthetic method of a kind of cefotaxime sodium according to claim 1 is characterized in that catalyzer used in the wherein said the first step is pyridine or N-methylmorpholine.
3, the synthetic method of a kind of cefotaxime sodium according to claim 1 is characterized in that the wherein said 7-amino-cephalosporanic acid (II) and the mole ratio of MEAM (III) are 1: 1-1.2; Cefotaxime acid (IV) is 1 with the mole ratio of sodium acetate trihydrate: 1-1.3, recrystallisation solvent are Virahol.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021123934A CN1164593C (en) | 2002-07-05 | 2002-07-05 | Method for synthesizing cefotaxime sodium |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021123934A CN1164593C (en) | 2002-07-05 | 2002-07-05 | Method for synthesizing cefotaxime sodium |
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| CN1394863A true CN1394863A (en) | 2003-02-05 |
| CN1164593C CN1164593C (en) | 2004-09-01 |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1305877C (en) * | 2004-07-07 | 2007-03-21 | 广州白云山医药科技发展有限公司 | Process for preparing cefpiramide sodium |
| CN100361995C (en) * | 2004-10-27 | 2008-01-16 | 山东瑞阳制药有限公司 | One-step preparation process of aseptic cefotaxime sodium for injection |
| CN1958591B (en) * | 2006-09-06 | 2010-08-11 | 珠海联邦制药股份有限公司 | Method for preparing intermediate in cephalosporins, and method for preparing ceftizoxime alapivoxil |
| WO2011042775A1 (en) * | 2009-10-09 | 2011-04-14 | Nectar Lifesciences Ltd. | Process for preparation of cefotaxime acid |
| CN102584854A (en) * | 2012-02-02 | 2012-07-18 | 瑞阳制药有限公司 | Preparation technology of anhydrous crystal of cefotaxime sodium |
| CN102702230A (en) * | 2012-05-30 | 2012-10-03 | 华北制药河北华民药业有限责任公司 | Method for preparing cefotaxime acid |
| CN103183687A (en) * | 2011-12-30 | 2013-07-03 | 山东天绿制药有限公司 | Phase transfer catalysis method for preparing cefdinir |
| CN103275101A (en) * | 2013-05-17 | 2013-09-04 | 天津大学 | Preparation method of cefotaxime sodium crystal |
| CN103319504A (en) * | 2013-06-28 | 2013-09-25 | 华北制药河北华民药业有限责任公司 | Crystallization method for cefotaxime sodium |
| CN104840423A (en) * | 2015-04-27 | 2015-08-19 | 四川制药制剂有限公司 | Preparation process of cefotaxime sodium for injection |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101613360B (en) * | 2009-08-07 | 2011-04-27 | 哈药集团制药总厂 | Method for preparing cefotaxime |
-
2002
- 2002-07-05 CN CNB021123934A patent/CN1164593C/en not_active Expired - Fee Related
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1305877C (en) * | 2004-07-07 | 2007-03-21 | 广州白云山医药科技发展有限公司 | Process for preparing cefpiramide sodium |
| CN100361995C (en) * | 2004-10-27 | 2008-01-16 | 山东瑞阳制药有限公司 | One-step preparation process of aseptic cefotaxime sodium for injection |
| CN1958591B (en) * | 2006-09-06 | 2010-08-11 | 珠海联邦制药股份有限公司 | Method for preparing intermediate in cephalosporins, and method for preparing ceftizoxime alapivoxil |
| WO2011042775A1 (en) * | 2009-10-09 | 2011-04-14 | Nectar Lifesciences Ltd. | Process for preparation of cefotaxime acid |
| CN103183687A (en) * | 2011-12-30 | 2013-07-03 | 山东天绿制药有限公司 | Phase transfer catalysis method for preparing cefdinir |
| CN102584854A (en) * | 2012-02-02 | 2012-07-18 | 瑞阳制药有限公司 | Preparation technology of anhydrous crystal of cefotaxime sodium |
| CN102702230A (en) * | 2012-05-30 | 2012-10-03 | 华北制药河北华民药业有限责任公司 | Method for preparing cefotaxime acid |
| CN102702230B (en) * | 2012-05-30 | 2014-09-10 | 华北制药河北华民药业有限责任公司 | Method for preparing cefotaxime acid |
| CN103275101A (en) * | 2013-05-17 | 2013-09-04 | 天津大学 | Preparation method of cefotaxime sodium crystal |
| CN103275101B (en) * | 2013-05-17 | 2015-08-05 | 天津大学 | Prepare the method for cefotaxime sodium crystal |
| CN103319504A (en) * | 2013-06-28 | 2013-09-25 | 华北制药河北华民药业有限责任公司 | Crystallization method for cefotaxime sodium |
| CN104840423A (en) * | 2015-04-27 | 2015-08-19 | 四川制药制剂有限公司 | Preparation process of cefotaxime sodium for injection |
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| Publication number | Publication date |
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| CN1164593C (en) | 2004-09-01 |
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