CN102584856A - Method for preparing cefpirome sulfate - Google Patents
Method for preparing cefpirome sulfate Download PDFInfo
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- CN102584856A CN102584856A CN2012100336530A CN201210033653A CN102584856A CN 102584856 A CN102584856 A CN 102584856A CN 2012100336530 A CN2012100336530 A CN 2012100336530A CN 201210033653 A CN201210033653 A CN 201210033653A CN 102584856 A CN102584856 A CN 102584856A
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Abstract
The invention discloses a novel method for synthesizing cefpirome sulfate serving as a cephalosporin antibiotic, and belongs to the field of medicinal chemistry. The method comprises the following steps of: performing substitution reaction on (6R,7R)-3-(acetoxyl)methyl-7-2-amino-4-thiazolyl-(methoxyimino)acetylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-formic acid serving as an initial raw material and 2,3-cyclopentene pyridine, and performing salt forming reaction on a reaction product and sulfuric acid to obtain the cefpirome sulfate product. By the method, three-step reaction in the step (1) is continuously performed in the same reactor; and an expensive silicon reagent is not used, so that production cost is reduced, and the synthesis process is simple, convenient to operate and favorable for industrial production.
Description
Technical field
The present invention relates to a kind of the 4th generation cephalosporins the preparation method, especially relate to the preparation method of Cefpirome Sulfate, belong to the pharmaceutical chemistry field.
Background technology
Cefpirome belong to the 4th generation cephalosporins; Cefpirome is prepared into vitriol usually; Its chemistry is by name: (6R; 7R)-[(Z)-2-(thiazolamine-4-yl)-2-methoxyimino kharophen]-3-(6,7-dihydro-5H-cyclopentyl [b] pyridine-1-base-methyl)-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-carboxyl monosulfate.Cefpirome Sulfate, went on the market in global twenties countries owing to its ultra spectrographic anti-microbial activity at first in Mexico and Sweden's listing in 1992 now.Have the zwitterionic characteristic of quaternary amine in the cefpirome structure, the superior bacterial outer membrane effect that sees through is arranged, high with penicillin-binding protein avidity, through hindering the synthetic anti-microbial effect that plays of bacteria cell wall.Be specially adapted to neutrophil leucocyte clinically and reduce patient's infection, lower respiratory tract severe infections, septicemia, urethra accompanying infection and skin and soft tissue infection up and down.
The synthetic route of cefpirome mainly contains two kinds at present: 1) 7-amino-cephalosporanic acid (7-ACA) obtains cefotaxime with amino thiophene oxime acid derivative generation acylation reaction, and again with 2,3-cyclopenta pyridine generation substitution reaction obtains cefpirome.2) with 2,3-cyclopenta pyridine generation substitution reaction obtains the pyridine substituent (7-ACP) of 7-ACA to 7-amino-cephalosporanic acid (7-ACA) earlier, obtains cefpirome with amino thiophene oxime acid or its active substance generation acylation reaction again.Wherein route 2 synthetic routes are long, complicated operation, and severe reaction conditions is unfavorable for large-scale industrial production; Cefotaxime and 2 in the route 1; 3-cyclopenta pyridine generation substitution reaction obtains in the process of cefpirome; Need with expensive silica reagent and iodide, severe reaction conditions causes its application prospect to be restricted; Therefore it is lower to develop cost, and the synthetic route of cefpirome easy and simple to handle is significant to large-scale industrial production.
Summary of the invention
The object of the invention provides a kind of improved Cefpirome Sulfate (6R; 7R)-[(Z)-2-(thiazolamine-4-yl)-2-methoxyimino kharophen]-3-(6; 7-dihydro-5H-cyclopentyl [b] pyridine-1-base-methyl)-and the compound method of 8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-carboxyl monosulfate, make it easy to operate, synthetic route is simplified; Cost reduces, and is fit to suitability for industrialized production.
For realizing the object of the invention; The present invention is with (6R; 7R)-3-(acetoxyl group) methyl-7-2-amino-4-thiazolyl-(methoxyimino) acetylaminohydroxyphenylarsonic acid 8-oxo-5-thia-1-azabicyclo 4.2.0 oct-2-ene-2-formic acid (cefotaxime) and 2; The 3-cyclopenta pyridine is a starting raw material, obtains the Cefpirome Sulfate product through substitution reaction and salt-forming reaction, and synthetic route is following:
Concrete through the following steps realization:
(1), cefotaxime is placed the mixed solvent of organic solvent and water, add alkali and catalyzer, stirring and dissolving adds 2 then, the reaction of 3-cyclopenta pyridine, and after reaction was accomplished, decolorizing with activated carbon obtained cefpirome solution.
(2), in step (1) gained cefpirome solution, add sulphuric acid soln and be carried out to reactant salt, crystallization obtains the Cefpirome Sulfate product.
Organic solvent described in the step (1) is generally acetone, acetonitrile or dioxane; The weight ratio of organic solvent and water is 1:5-5:1; Alkali is generally one or more the mixture in sodium hydrogencarbonate, saleratus, the triethylamine; Catalyzer is generally NaI, KI, KSCN, NaSCN etc.; Temperature of reaction is between-10-45 ℃; Reaction times is 1-6 hour.
The volumetric molar concentration of the sulphuric acid soln described in the step (2) is 1 mol-8 mol; In the solution that salt-forming reaction obtains, drip the acetone crystallization, filter, drying obtains Cefpirome Sulfate.
The present invention is with (6R; 7R)-3-(acetoxyl group) methyl-7-2-amino-4-thiazolyl-(methoxyimino) acetylaminohydroxyphenylarsonic acid 8-oxo-5-thia-1-azabicyclo 4.2.0 oct-2-ene-2-formic acid (cefotaxime) is raw material, obtains Cefpirome Sulfate through improved synthesis technique.In the wherein substitution reaction step, realized that three-step reaction carries out continuously in same reactor drum, and do not adopted expensive silica reagent that reduced production cost, synthesis route is simple, and is easy to operate, helps suitability for industrialized production.
Embodiment
For embodiment of the present invention better, lift embodiment at present the present invention is described further, but embodiment not a limitation of the present invention.
Embodiment: (6R; 7R)-[(Z)-2-(thiazolamine-4-yl)-2-methoxyimino kharophen]-preparation of 3-(6,7-dihydro-5H-cyclopentyl [b] pyridine-1-base-methyl)-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-carboxyl monosulfate
In the reaction flask of 500mL, add 45g (6R, 7R)-3-(acetoxyl group) methyl-7-2-amino-4-thiazolyl-(methoxyimino) acetylaminohydroxyphenylarsonic acid 8-oxo-5-thia-1-azabicyclo 4.2.0 oct-2-ene-2-formic acid, 125mL H
2The mixed solvent of O and 275 mL acetone adds 8.4 NaHCO then
3And 16gNaI,, be stirred to dissolving fully, add 12g 2, the 3-cyclopenta pyridine, 40 ℃ of reaction 2h, the HPLC detection reaction reaches terminal point, adds the 5g gac, filters, and obtains cefpirome solution.
In the reaction flask of 5L, add above-mentioned cefpirome solution and the dilution heat of sulfuric acid of 38 mL 6mol/L, behind the stirring 1h, in 2h, drip 2540 mL acetone solvents; Stirring at room 4 hours is cooled to below 10 ℃ filtering for crystallizing; The filter cake that obtains is used the 100mL washing with acetone; 40 ℃ of vacuum-dryings obtain 39.8g Cefpirome Sulfate solid, yield 65%.
Claims (4)
1. the preparation method of a Cefpirome Sulfate is characterized in that, realizes through following steps:
(1), with (6R; 7R)-3-(acetoxyl group) methyl-7-2-amino-4-thiazolyl-(methoxyimino) acetylaminohydroxyphenylarsonic acid 8-oxo-5-thia-1-azabicyclo 4.2.0 oct-2-ene-2-formic acid places the mixed solvent of organic solvent and water; Add alkali and catalyzer, stirring and dissolving; Add 2 then, the reaction of 3-cyclopenta pyridine, decolorizing with activated carbon obtains cefpirome solution; Catalyzer is selected NaI, KI, KSCN or NaSCN for use;
(2), in step (1) gained cefpirome solution, add sulphuric acid soln and be carried out to reactant salt, crystallization is filtered and is obtained the Cefpirome Sulfate product.
2. the preparation method of Cefpirome Sulfate as claimed in claim 1 is characterized in that, organic solvent is selected acetone, acetonitrile or dioxane for use; The weight ratio of organic solvent and water is 1:5-5:1.
3. the preparation method of Cefpirome Sulfate as claimed in claim 1 is characterized in that, alkali is selected one or more the mixture in sodium hydrogencarbonate, saleratus, the triethylamine for use.
4. like the preparation method of claim 1,2 or 3 described Cefpirome Sulfates, it is characterized in that, step (1) temperature of reaction is-10-45 ℃, the reaction times is 1-6 hour.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2012100336530A CN102584856A (en) | 2011-12-27 | 2012-02-15 | Method for preparing cefpirome sulfate |
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| CN201110442698.9 | 2011-12-27 | ||
| CN201110442698 | 2011-12-27 | ||
| CN2012100336530A CN102584856A (en) | 2011-12-27 | 2012-02-15 | Method for preparing cefpirome sulfate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105646542A (en) * | 2016-03-09 | 2016-06-08 | 上海宁瑞生化技术有限公司 | Method using microwave method to synthesize cefpirome sulfate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5071979A (en) * | 1981-05-12 | 1991-12-10 | Hoechst Aktiengesellschaft | Cephalosporin derivatives |
| CN101224195A (en) * | 2008-01-18 | 2008-07-23 | 山东罗欣药业股份有限公司 | Compounding method of cefpirome sulfate raw material and uses thereof |
| CN101284840A (en) * | 2008-05-29 | 2008-10-15 | 管小明 | Synthetic method of cefpirome sulfate |
| CN101323623A (en) * | 2008-07-31 | 2008-12-17 | 中国药科大学 | Novel fourth generation cephalosporin, preparation and use thereof |
| KR20090063817A (en) * | 2007-12-14 | 2009-06-18 | (주) 성운파마코피아 | Direct method for preparing crystalline acid-added salts of cephem derivatives |
-
2012
- 2012-02-15 CN CN2012100336530A patent/CN102584856A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5071979A (en) * | 1981-05-12 | 1991-12-10 | Hoechst Aktiengesellschaft | Cephalosporin derivatives |
| KR20090063817A (en) * | 2007-12-14 | 2009-06-18 | (주) 성운파마코피아 | Direct method for preparing crystalline acid-added salts of cephem derivatives |
| CN101224195A (en) * | 2008-01-18 | 2008-07-23 | 山东罗欣药业股份有限公司 | Compounding method of cefpirome sulfate raw material and uses thereof |
| CN101284840A (en) * | 2008-05-29 | 2008-10-15 | 管小明 | Synthetic method of cefpirome sulfate |
| CN101323623A (en) * | 2008-07-31 | 2008-12-17 | 中国药科大学 | Novel fourth generation cephalosporin, preparation and use thereof |
Non-Patent Citations (4)
| Title |
|---|
| GIORGIO ABBIATI,等: "Sequential Amination/Annulation/Aromatization Reaction of Carbonyl Compounds and Propargylamine: A New One-Pot Approach to Functionalized Pyridines", 《J. ORG. CHEM.》 * |
| ROSANNE BONJOUKLIAN，等: "Reactions of TMSI with cephalosporin esters", 《TETRAHEDRON LETTERS》 * |
| 于文博，等: "头孢匹罗的合成进展", 《化学与生物工程》 * |
| 刘晓，等: "硫酸头孢匹罗的合成工艺改进", 《中国药物化学杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105646542A (en) * | 2016-03-09 | 2016-06-08 | 上海宁瑞生化技术有限公司 | Method using microwave method to synthesize cefpirome sulfate |
| CN105646542B (en) * | 2016-03-09 | 2018-06-01 | 上海宁瑞生化技术有限公司 | The method that microwave method synthesizes Cefpirome Sulfate |
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Application publication date: 20120718 |