CN101812076B - Cefuroxime sodium and preparation method thereof - Google Patents
Cefuroxime sodium and preparation method thereof Download PDFInfo
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- CN101812076B CN101812076B CN 200910118718 CN200910118718A CN101812076B CN 101812076 B CN101812076 B CN 101812076B CN 200910118718 CN200910118718 CN 200910118718 CN 200910118718 A CN200910118718 A CN 200910118718A CN 101812076 B CN101812076 B CN 101812076B
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Abstract
The invention provides cefuroxime sodium and a preparation method thereof. The preparation method comprises the following steps that: (1) 7-aminocephalosporanic acid reacts with 2-(furan-2-base)-2-(methoxyimino) acetyl chloride to produce 3-deacety-7-aminocephalosporanic acid; (2) crystallization is conducted after the 3-deacety-7-aminocephalosporanic acid reacts with chlorosulfonyl isocyanate to produce cefuroxime acid; and (3) the cefuroxime acid is salified to obtain the cefuroxime sodium, wherein solvent for crystallization is selected from one or more of petroleum ether, normal hexane, cyclohexane, solvent oil and tetrahydrofuran. Since the preparation method adopts solvents such as petroleum ether for crystallization in the process of the preparation of the cefuroxime acid, the invention has the advantages that the yield of the product is effectively improved, the product purity is further improved, the impurity content is reduced, the product quality is compliant with Chinese Pharmacopoeia of version 2005, the operation of the method is simple, the raw materials can be easily obtained, the cost is relatively low and the industrial production can be realized easily.
Description
Technical field
The invention belongs to technical field of medicine synthesis, relate to a kind of cephalosporins and preparation method thereof, be specifically related to Cefuroxime sodium and preparation method thereof.
Background technology
Cefuroxime sodium is the sodium salt of cephalofruxin, belongs to second generation cephalosporin class antibiotic medicine.Its has a broad antifungal spectrum; Effective to most of Gram-negative bacterias, comprise the positive sex change bacillus of hemophilus influenzae, gonococcus, meningococcus, intestinal bacteria, klebsiella spp, Proteus mirabilis, enterobacteria, citrobacter, Salmonella, Shigella and some indoles etc.Antimicrobial spectrum to gram-positive microorganism is similar to Cephalexin Monohydrate Micro/Compacted, mainly comprises staphylococcus and suis.These article are comparatively stable to β-Nei Xiananmei; Its stability is not second to third generation cephalosporin; Stable to nearly all standard enzyme and the β-Nei Xiananmei that from clinical isolating negative bacillus, extracts, the bacterium of many product β-Nei Xiananmeis comprises that Gram-positive and negative bacterium are all to its sensitivity.These article are stable to the negative bacillus enzyme; Anti-negative bacillus effect is suitable with third generation cephalosporin; And stable to golden Portugal bacterium enzyme, the bacterium effect of anti-golden Portugal is better than third generation cephalosporin, and these advantages make it become the first-selected medication of treatment Gram-negative bacteria or the polyinfection of gram-negative positive bacteria.Characteristics such as in addition, these article also have good pharmacokinetic properties, and distribution is wide in low like protein binding rate, free blood concentration height, the body, tissue permeability is good, the intramuscular injection bioavailability high, renal toxicity is lower.
Chinese invention patent application CN101054386A discloses a kind of compound method of Cefuroxime sodium; This method may further comprise the steps: will be 3-deacetylation-7-amino-cephalosporanic acid and cis-2-(furans-2-yl)-2-(methoxyimino) excess acetyl chloride that raw material makes with 7-amino-cephalosporanic acid (7-ACA); Generate the 3-formyl radical cefuroxime acid that deaminizes; The 3-formyl radical cefuroxime acid that deaminizes obtains cefuroxime acid with chlorosulfonic acid isocyanate reaction again, behind the direct salify of cefuroxime acid through the refining Cefuroxime sodium finished product that obtains.In this compound method, the unprocessed direct salify of the intermediate product cefuroxime acid of generation causes product yield on the low side, is merely 85%.
Summary of the invention
Therefore, the purpose of this invention is to provide a kind of preparation method who improves the Cefuroxime sodium of product yield and purity.
Be used to realize that the technical scheme of above-mentioned purpose of the present invention is following:
A kind of preparation method of Cefuroxime sodium, it may further comprise the steps:
(1) 7-amino-cephalosporanic acid and 2-(furans-2-yl)-2-(methoxyimino) excess acetyl chloride generates 3-deacetylation-7-amino-cephalosporanic acid;
(2) carry out crystallization operation after the reaction of 3-deacetylation-7-amino-cephalosporanic acid and chlorosulfonic acid isocyanate generates cefuroxime acid;
(3) the cefuroxime acid salify obtains Cefuroxime sodium,
Wherein the solvent of crystallization employing is selected from one or more in sherwood oil, normal hexane, hexanaphthene, solvent oil and the THF.
In above-mentioned preparation method, solvent is preferably sherwood oil.
Above-mentioned preparation method can also comprise the step of the concentrating under reduced pressure reaction product before the crystallization and/or the drying step after the crystallization.
Specifically, above-mentioned preparation method may further comprise the steps:
(1) 7-amino-cephalosporanic acid being dissolved in pH is in 8.0～10.0 the alkaline aqueous solution, carries out condensation reaction with methoxy imino furans ammonium acetate and phosphorus pentachloride and makes 3-deacetylation-7-amino-cephalosporanic acid;
(2) in 3-deacetylation-7-amino-cephalosporanic acid solution, drip chlorosulfonic acid isocyanate; React under the low temperature, add sour adjust pH to 1.0～3.0, reaction generates cefuroxime acid; Underpressure distillation concentrates the back and adds the sherwood oil crystallization, and suction filtration, drying obtain cefuroxime acid;
(3) with cefuroxime acid with proper amount of acetone and water stirring and dissolving after, add charcoal absorption decolouring, filter the back and add the mixed sodium salts solution and generate Cefuroxime sodium, drip the acetone crystallization, suction filtration, drying makes the Cefuroxime sodium finished product.
In a specific embodiments of the present invention, above-mentioned preparation method can may further comprise the steps:
(1) 7-amino-cephalosporanic acid is added in the entry; Regulate pH to 8.0～10.0 with 15% (weight/volume) NaOH solution; It is dissolved fully; Carry out condensation reaction with methoxy imino furans ammonium acetate and phosphorus pentachloride, the dripping hydrochloric acid crystallization, suction filtration, drying make 3-deacetylation-7-amino-cephalosporanic acid;
(2) 3-deacetylation-7-amino-cephalosporanic acid is dissolved in the THF, stirs cooling, drip chlorosulfonic acid isocyanate; Kept low-temp reaction 0.5～1.5 hour; Dripping hydrochloric acid adjust pH to 1.0～3.0, reaction generates cefuroxime acid, and underpressure distillation concentrates; Add the sherwood oil crystallization, suction filtration, drying obtain cefuroxime acid;
(3) with cefuroxime acid with proper amount of acetone and water stirring and dissolving after, add charcoal absorption decolouring, filter; Add the mixed sodium salts solution that comprises Sodium isooctanoate, sodium-acetate and Sodium.alpha.-hydroxypropionate in the filtrating and generate Cefuroxime sodium, drip the acetone crystallization, suction filtration; Drying makes the Cefuroxime sodium finished product.
Above-mentioned preparing method's concrete synthetic route is following:
2-(furans-2-yl)-2-(methoxyimino) Acetyl Chloride 98Min. 3-deacetylation-7-amino-cephalosporanic acid
The chlorosulfonic acid isocyanate cefuroxime acid
Cefuroxime sodium
With respect to the preparation method of existing Cefuroxime sodium, preparation method of the present invention has adopted the sherwood oil equal solvent to carry out crystallization in the process of preparation cefuroxime acid, has improved the yield of product effectively; Product purity further improves, and foreign matter content reduces, and quality product meets 2005 editions " regulations of Chinese pharmacopoeia; And this method is simple to operate; Raw material is easy to get, and cost is relatively low, easy realization of industrial production.
Embodiment
The preparation of embodiment 1:3-deacetylation-7-amino-cephalosporanic acid
In four-hole bottle, add 230ml purified water and 50g 7-ACA (7-amino-cephalosporanic acid), temperature control drips 15% (weight/volume) NaOH solution for 0～5 ℃, transfers pH to 8.0～10.0, dissolves it for use fully; Add phosphorus pentachloride 51.3g in another four-hole bottle, methylene dichloride 350ml, temperature control-12 ℃ adding N,N-DIMETHYLACETAMIDE (DMA) 75ml; Furfuran amine salt (being methoxy imino furans ammonium acetate) 41g, insulation reaction 1 hour adds purified water 175ml; Standing demix behind the stirring 10min is integrated with organic phase in the 7-ACA solution, 0～10 ℃ of reaction of temperature control 3 hours; And drip 15% (weight/volume) NaOH solution keep pH value of reaction system in 6～8 scopes to reacting completely standing demix.Water adds the 250ml methylene dichloride, stirs fast, and 10min drips 15% (weight/volume) HCl solution and transfers pH to 2.0 crystallization.Suction filtration, vacuum-drying 15 hours obtains 3-deacetylation-7-amino-cephalosporanic acid.It is 98.5% that HPLC detects purity, and maximum contaminant content is 0.5%.
Embodiment 2: the preparation of cefuroxime acid
The 3-deacetylation that makes-7-amino-cephalosporanic acid is dropped in the 1000ml four-hole bottle; Add THF 240ml; Temperature control is to-40～-50 ℃ of adding chlorosulfonic acid isocyanate 15.8ml; Behind the insulation reaction 40min, adding 54ml purified water is complete with excessive chlorosulfonic acid isocyanate hydrolysis, adds 53gNaHCO
3, stirring 10min, standing demix is abandoned water; Organic phase drips 30% (weight/volume) HCl solution 16ml and transfers pH to 2.0, adds the 5g gac and stirs the 10min filtration, has been evaporated to crystal and has separated out in a small amount, adds the sherwood oil crystallization; Suction filtration, vacuum-drying 4 hours obtains cefuroxime acid.Purity is 99.0%, maximum contaminant content 0.2%.
Embodiment 3: the preparation of cefuroxime acid sodium
In the 500ml there-necked flask, add acetone 200ml, purified water 30ml, drop into cefuroxime acid 40g, temperature control is stirred to complete dissolving for 25 ℃, adds the 4g gac; Suction filtration, temperature control 25～-30 ℃ add in filtrating and dissolve Sodium isooctanoate, sodium-acetate and Sodium.alpha.-hydroxypropionate mixing solutions completely, add and stir 15min; Drip acetone 600ml crystallization, stir the 30min growing the grain at a slow speed, suction filtration, washing with acetone; 40 ℃ of dryings 2 hours obtain Cefuroxime sodium finished product 39.9g, and yield reaches 99.75%; Purity is 99.8%, and maximum contaminant content is 0.2%, and quality meets 2005 editions " regulations of Chinese pharmacopoeia.
Claims (2)
1. the preparation method of a Cefuroxime sodium is characterized in that, said preparation method may further comprise the steps:
(1) 7-amino-cephalosporanic acid being dissolved in pH is in 8.0～10.0 the alkaline aqueous solution, carries out condensation reaction [(Z)-furans-2-base-2-methoxyimino acetamido]-3-methylol cephalo-3-alkene-4-carboxylic acid that makes 7 with methoxy imino furans ammonium acetate and phosphorus pentachloride;
(2) drip chlorosulfonic acid isocyanate in [(Z)-furans-2-base-2-methoxyimino acetic amide base]-3-methylol cephalo-3-alkene-4-carboxylic acid solution to 7; React under the low temperature; Add sour adjust pH to 1.0～3.0; Reaction generates cefuroxime acid, and underpressure distillation concentrates the back and adds the sherwood oil crystallization, and suction filtration, drying obtain cefuroxime acid;
(3) with cefuroxime acid with proper amount of acetone and water stirring and dissolving after, add charcoal absorption decolouring, filter the back and add the mixed sodium salts solution and generate Cefuroxime sodium, drip the acetone crystallization, suction filtration, drying makes the Cefuroxime sodium finished product.
2. preparation method according to claim 1 is characterized in that, said preparation method may further comprise the steps:
(1) 7-amino-cephalosporanic acid is added in the entry; NaOH solution with 15% weight/volume is regulated pH to 8.0～10.0; After it is dissolved fully; Carry out condensation reaction with methoxy imino furans ammonium acetate and phosphorus pentachloride, dripping hydrochloric acid crystallization, suction filtration, drying make 7 [(Z)-furans-2-base-2-methoxyimino acetamido]-3-methylol cephalo-3-alkene-4-carboxylic acid;
(2) [(Z)-furans-2-base-2-methoxyimino acetamido]-3-methylol cephalo-3-alkene-4-carboxylic acid is dissolved in the THF with 7, stirs cooling, drips chlorosulfonic acid isocyanate; Kept low-temp reaction 0.5～1.5 hour; Dripping hydrochloric acid adjust pH to 1.0～3.0, reaction generates cefuroxime acid, and underpressure distillation concentrates; Add the sherwood oil crystallization, suction filtration, drying obtain cefuroxime acid;
(3) with cefuroxime acid with proper amount of acetone and water stirring and dissolving after, add charcoal absorption decolouring, filter; Add the mixed sodium salts solution that comprises Sodium isooctanoate, sodium-acetate and Sodium.alpha.-hydroxypropionate in the filtrating and generate Cefuroxime sodium, drip the acetone crystallization, suction filtration; Drying makes the Cefuroxime sodium finished product.
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Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102617604A (en) * | 2012-02-24 | 2012-08-01 | 天津大学 | Method utilizing coupling reaction crystallization to prepare cefuroxime sodium |
| CN102702231B (en) * | 2012-06-18 | 2014-10-29 | 山东大学 | Method for preparing 3-descarbamoyl-cefuroxime acid |
| CN103102357B (en) * | 2013-02-21 | 2016-01-13 | 广东立国制药有限公司 | A kind of synthetic method of Cefuroxime sodium |
| CN104774211A (en) * | 2015-04-27 | 2015-07-15 | 四川制药制剂有限公司 | Preparation technique of cefuroxime sodium for injection |
| CN105669700A (en) * | 2016-02-18 | 2016-06-15 | 海南灵康制药有限公司 | Cefuroxime sodium new crystal type compound and preparation adopting particle process crystal product molecular assembly and form optimizing technology |
| CN106565748B (en) * | 2016-09-30 | 2019-03-22 | 华北制药河北华民药业有限责任公司 | The preparation method of Cefuroxime Sodium and its preparation |
| CN107652306B (en) * | 2017-10-24 | 2021-02-09 | 北京红太阳药业有限公司 | Cefuroxime sodium crystal compound |
| CN110483553A (en) * | 2019-08-12 | 2019-11-22 | 上海龙翔生物医药开发有限公司 | A kind of stable Cefuroxime Sodium and preparation method thereof |
| CN110950892A (en) * | 2019-12-16 | 2020-04-03 | 山东金城柯瑞化学有限公司 | Method for optimizing and removing impurities from cefuroxime intermediate (3-decarbamoyl-cefuroxime acid) |
| CN115353524A (en) * | 2022-08-25 | 2022-11-18 | 浙江东盈药业有限公司 | Synthesis method of cefuroxime sodium |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040092735A1 (en) * | 2002-11-08 | 2004-05-13 | Orchid Chemicals & Pharmaceuticals Limited | Process for the preparation of cefuroxime sodium |
| CN101054386A (en) * | 2006-11-12 | 2007-10-17 | 西南合成制药股份有限公司 | Method of synthesizing cefuroxime |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040092735A1 (en) * | 2002-11-08 | 2004-05-13 | Orchid Chemicals & Pharmaceuticals Limited | Process for the preparation of cefuroxime sodium |
| CN101054386A (en) * | 2006-11-12 | 2007-10-17 | 西南合成制药股份有限公司 | Method of synthesizing cefuroxime |
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