CN101108855A - Method of preparing ceftiofur - Google Patents
Method of preparing ceftiofur Download PDFInfo
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- CN101108855A CN101108855A CNA200610048426XA CN200610048426A CN101108855A CN 101108855 A CN101108855 A CN 101108855A CN A200610048426X A CNA200610048426X A CN A200610048426XA CN 200610048426 A CN200610048426 A CN 200610048426A CN 101108855 A CN101108855 A CN 101108855A
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Abstract
A preparation method of the ceftiofur is provided. The method is that the sodium hydrosulfide and the furoyl chlorine are adopted as the raw materials and react under the alkali condition to gain the thio furancarboxlic acid. The organic solvents such as ethyl formate, ethyl acetate, acetone, chloroform and methylene chloride are adopted to extract and react in the aqueous solution when the pH value is between 8 to 11 and the temperature between 25 DEG C. to 75 DEG C., and then condensed with 7-aminocephalosporanic acid (7-ACA) and dissolved by the organic solvents such as ethyl formate, ethyl acetate, acetone, chloroform and methylene chloride after reacting with the AE active ester, and is added with the active carbon or diatomite to stir and decolor under normal temperature and is filtered through a titanium bar filter, and is added to the purified water by drops and is stirred, filtered. The filter cake is added with sodium carbonate to dissolve in right amount, and is frozen and dried to gain the ceftiofur.
Description
Technical field:
The present invention relates to technical field of animal remedy preparation, that mainly propose is a kind of preparation method of ceftiofur.
Background technology:
A large amount of human microbiotic do not add the checking of research and science, promptly be used for animal cultivation, so that the pathogenic bacteria resistance strengthens day by day, drug effect is descended rapidly, the drug use lost of life, force people have to once and again the antibiotic working concentration of increasing or abandon once having the microbiotic kind of very good effect; The existence of livestock and poultry cultivation abuse and medication lack of standardization, the livestock product drug residue problem of being brought has directly constituted threat to health of people, causes " food safety " problem that people paid close attention to.In the world selecting for use of animal health product tended to praise highly use wide spectrum, efficient, low residual, hypotoxic animal specific medicine, China's veterinary drug research and development less investment, product structure is unreasonable, the shared medicine of people and animals is still occupied an leading position, be badly in need of to accelerate the paces of adjusting the product mix, the exploitation animal specific is efficient, low toxicity, the new veterinary drug of low residue are used for livestock and poultry cultivation and livestock product production.
Summary of the invention:
In order to make ceftiofur better carry out industrialized production, the purpose of this invention is to provide the preparation method of a kind of ceftiofur (Ceftiofur), solved the variable color and the degradation problem of intermediate and product; Select for use appropriate catalyst to improve reaction yield; Adopt the quality of suitable drying means raising product, the new veterinary drug of high-efficiency low-toxicity better is provided for livestock industry.
In order to realize the foregoing invention purpose, the present invention adopts following technical scheme:
A kind of preparation method of ceftiofur preparation; i.e. [6R-[6 α 7 β (Z)]]-7-[[2-amino-(4-thiazolyl) (methoxyimino) ethanoyl]-3-[[(2-furans carbonyl) sulfo-] methyl]-8-oxo-5-thia-1 azabicyclo [4; 2; 0] during oct-2-ene-2-formic acid; with Sodium sulfhydrate and furoyl chloride is that raw material reacts under alkaline condition and obtains thio-furan formic acid; behind organic solvent extractions such as ethyl formate, ethyl acetate, acetone, chloroform, methylene dichloride; in the aqueous solution; the pH value is reacted between 25-75 ℃ at 8-11.And then with 7-amino-cephalosporanic acid (7-ACA) condensation, after the reaction of AE active ester, use organic solvent dissolutions such as ethyl formate, ethyl acetate, acetone, chloroform, methylene dichloride again, add gac or diatomite and stir the normal temperature decolouring, titanium rod strainer filters, and drops in 2-5 ℃ the purified water, stir, filter, filter cake adds yellow soda ash and dissolves in right amount, and lyophilize promptly.
Its chemical reaction process is as follows:
Reaction (1)
Reaction (2)
Reaction (3)
Reaction (1) is reacted under alkaline condition with Sodium sulfhydrate and furoyl chloride and is obtained thio-furan formic acid, and the raw materials used domestic raw material that is of this step reaction makes product cost reduce greatly.Has market competition advantage.Extraction can be selected organic solvents such as ethyl formate, ethyl acetate, acetone, chloroform, methylene dichloride for use, can improve the purity of final product, is that content is brought up to more than 95% by 60%, and the final product yield reaches more than 60%.Preferred solvent is an ethyl acetate.Be reflected at the pH value between 8-11, preferred pH value is between 9-10, and temperature of reaction is between 25-75 ℃, preferably between 45-55 ℃.
The cephalosporin of reaction (2) thio-furan formic acid and fermentative production gets 7-amino-cephalosporanic acid (7-ACA) condensation through cracking and gets the acid of cephalo furan.
The product that the acid of reaction (3) cephalo furan obtains after reacting with the AE active ester is used organic solvent dissolutions such as ethyl formate, ethyl acetate, acetone, chloroform, methylene dichloride again, add gac or diatomite and stir the normal temperature decolouring, titanium rod strainer filters, drop in 2-5 ℃ the purified water, stir, filter, filter cake adds yellow soda ash and dissolves in right amount, and lyophilize promptly gets highly purified ceftiofur.Organic solvent is preferably acetone or methylene dichloride, the preferred gac of adsorption bleaching, and lyophilize is guaranteeing to have improved quality product under the stable situation of product yield; The ceftiofur total recovery of present method preparation reaches more than 60%, and effective content reaches more than 98%.
Owing to adopted aforesaid technical scheme, the present invention has following positively effect:
This ceftiofur has pharmacology, the pharmacodynamics speciality of several aspects as the semi-synthetic animal specific microbiotic of third generation cephalosporin: 1. broad-spectrum antibacterial property, extremely strong anti-microbial activity; 2. quick-acting double long-acting; 3. be difficult for producing resistance; 4. high security; 5. extremely humble residual quantity.Also there is the ability of its production in China, and on the processing condition, we have had new discovery, better variable color and the degradation problem that solves intermediate and product; Select for use appropriate catalyst to improve reaction yield; Adopt cryodesiccated method to improve the quality of product.
Embodiment one:
Get the 19.2g Sodium sulfhydrate and add and to stir moltenly entirely in the 198g purified water, drip sugared acyl chlorides, drip 40% sodium hydroxide solution, keep pH value 9-10, transfer PH=4-5 with phosphoric acid then.Keep after 1 hour, hydro-oxidation sodium liquid is transferred pH=8-9, uses ethyl acetate extraction twice, and water layer adds the 7-ACA30g reaction, and filter is got rid of in cooling, washing, and washing with acetone, Air drying gets cephalo furan acid 35.2g; 1000ml, the cephalo furan acid 35.2g that adds methylene chloride, AE active ester 40g drips triethylamine 36g, keeps 5-10 ℃ to react 4 hours, with the purified water extraction, combining water layer adds gac 5g, stirs 0.5 hour, get rid of filter, filtrate is transferred pH value 4-5 with 10% hydrochloric acid soln, get rid of filter ceftiofur 35.8g.(total recovery 62.1%, effective content 98.3%).
Embodiment two:
Get the 40g Sodium sulfhydrate and add and to stir moltenly entirely in the 400g purified water, drip sugared acyl chlorides, drip 40% sodium hydroxide solution, keep pH value 9-10, transfer PH=4-5 with phosphoric acid then.Keep after 1 hour, hydro-oxidation sodium liquid is transferred pH=8-9, uses ethyl acetate extraction twice, and water layer adds the 7-ACA62g reaction, and filter is got rid of in cooling, washing, and washing with acetone, Air drying gets cephalo furan acid 71.1g; 1000ml, the cephalo furan acid 71.1g that adds methylene chloride, AE active ester 80g drips triethylamine 72g, keeps 5-10 ℃ to react 3 hours, with the purified water extraction, combining water layer adds gac 8g, stirs 1 hour, get rid of filter, filtrate is transferred pH value 4-5 with 10% hydrochloric acid soln, get rid of filter ceftiofur 73.3g.(total recovery 61.5%, effective content 98.9%).
Embodiment three:
Get the 40g Sodium sulfhydrate and add and to stir moltenly entirely in the 400g purified water, drip sugared acyl chlorides, drip 40% sodium hydroxide solution, keep pH value 9-10, transfer PH=4-5 with phosphoric acid then.Keep after 1 hour, hydro-oxidation sodium liquid is transferred PH=8-9, uses dichloromethane extraction twice, and water layer adds 61g 7-ACA, and filter is got rid of in reaction, washing, and the chloroform washing, Air drying gets cephalo furan acid 72.6g; 500g, the cephalo furan acid 72.6g that adds methylene chloride, AE active ester 80g drips triethylamine 72g, keeps 5-10 ℃ to react 3.5 hours, with the purified water extraction, combining water layer adds gac 10g, stirs 1 hour, get rid of filter, filtrate is transferred pH value 4-5 with 10% hydrochloric acid soln, get rid of filter ceftiofur 75.0g.(total recovery 63.9%, effective content 99.3%).
Claims (4)
1. the preparation method of ceftiofur preparation; i.e. [6R-[6 α 7 β (Z)]]-7-[[2-amino-(4-thiazolyl) (methoxyimino) ethanoyl]-3-[[(2-furans carbonyl) sulfo-] methyl]-8-oxo-5-thia-1 azabicyclo [4; 2; 0] oct-2-ene-2-formic acid; it is characterized in that: with Sodium sulfhydrate and furoyl chloride is raw material; reaction obtains thio-furan formic acid under alkaline condition; behind organic solvent extractions such as ethyl formate, ethyl acetate, acetone, chloroform, methylene dichloride; in the aqueous solution; the pH value is reacted between 25-75 ℃ at 8-11.And then with 7-amino-cephalosporanic acid (7-ACA) condensation, after the reaction of AE active ester, use organic solvent dissolutions such as ethyl formate, ethyl acetate, acetone, chloroform, methylene dichloride again, add gac or diatomite and stir the normal temperature decolouring, titanium rod strainer filters, and drops in 2-5 ℃ the purified water, stir, filter, filter cake adds yellow soda ash and dissolves in right amount, and lyophilize promptly;
Its chemical reaction process is as follows:
Reaction (1)
Reaction (2)
Reaction (3)
Reaction (1) is reacted under alkaline condition with Sodium sulfhydrate and furoyl chloride and is obtained thio-furan formic acid, and the raw materials used domestic raw material that is of this step reaction makes product cost reduce greatly.Has market competition advantage.Extraction can be selected organic solvents such as ethyl formate, ethyl acetate, acetone, chloroform, methylene dichloride for use, can improve the purity of final product, is that content is brought up to more than 95% by 60%, and the final product yield reaches more than 60%; Preferred solvent is an ethyl acetate; Be reflected at the pH value between 8-11, preferred pH value is between 9-10, temperature of reaction is between 25-75 ℃, and preferably between 45-55 ℃, the cephalosporin of reaction (2) thio-furan formic acid and fermentative production gets 7-amino-cephalosporanic acid (7-ACA) condensation through cracking and gets the acid of cephalo furan;
The product that the acid of reaction (3) cephalo furan obtains after reacting with the AE active ester is used organic solvent dissolutions such as ethyl formate, ethyl acetate, acetone, chloroform, methylene dichloride again, add gac or diatomite and stir the normal temperature decolouring, titanium rod strainer filters, drop in 2-5 ℃ the purified water, stir, filter, filter cake adds yellow soda ash and dissolves in right amount, and lyophilize promptly gets highly purified ceftiofur.Organic solvent is preferably acetone or methylene dichloride, the preferred gac of adsorption bleaching, and lyophilize is guaranteeing to have improved quality product under the stable situation of product yield; The ceftiofur total recovery of present method preparation reaches more than 60%, and effective content reaches more than 98%.
2. the preparation method of ceftiofur according to claim 1 preparation is characterized in that: during enforcement, get the 19.2g Sodium sulfhydrate add stir in the 198g purified water molten entirely, drip sugared acyl chlorides, drip 40% sodium hydroxide solution, keep pH value 9-10, transfer PH=4-5 with phosphoric acid then.Keep after 1 hour, hydro-oxidation sodium liquid is transferred pH=8-9, uses ethyl acetate extraction twice, and water layer adds the 7-ACA30g reaction, and filter is got rid of in cooling, washing, and washing with acetone, Air drying gets cephalo furan acid 35.2g; 1000ml, the cephalo furan acid 35.2g that adds methylene chloride, AE active ester 40g drips triethylamine 36g, keep 5-10 ℃ of reaction 4 hours, with the purified water extraction, combining water layer adds gac 5g, stirred 0.5 hour, get rid of filter, filtrate is transferred pH value 4-5 with 10% hydrochloric acid soln, get rid of filter ceftiofur 35.8g, (total recovery 62.1%, effective content 98.3%).
3. the preparation method of ceftiofur according to claim 1 preparation is characterized in that: during enforcement, get the 40g Sodium sulfhydrate add stir in the 400g purified water molten entirely, drip sugared acyl chlorides, drip 40% sodium hydroxide solution, keep pH value 9-10, transfer PH=4-5 with phosphoric acid then.Keep after 1 hour, hydro-oxidation sodium liquid is transferred pH=g-9, uses ethyl acetate extraction twice, and water layer adds the 7-ACA62g reaction, and filter is got rid of in cooling, washing, and washing with acetone, Air drying gets cephalo furan acid 71.1g; 1000ml, the cephalo furan acid 71.1g that adds methylene chloride, AE active ester 80g drips triethylamine 72g, keep 5-10 ℃ of reaction 3 hours, with the purified water extraction, combining water layer adds gac 8g, stirred 1 hour, get rid of filter, filtrate is transferred pH value 4-5 with 10% hydrochloric acid soln, get rid of filter ceftiofur 73.3g, (total recovery 61.5%, effective content 98.9%).
4. the preparation method of ceftiofur according to claim 1 preparation is characterized in that: during enforcement, get the 40g Sodium sulfhydrate add stir in the 400g purified water molten entirely, drip sugared acyl chlorides, drip 40% sodium hydroxide solution, keep pH value 9-10, transfer PH=4-5 with phosphoric acid then; Keep after 1 hour, hydro-oxidation sodium liquid is transferred PH=8-9, uses dichloromethane extraction twice, and water layer adds 61g7-ACA, and filter is got rid of in reaction, washing, and the chloroform washing, Air drying gets cephalo furan acid 72.6g; 500g, the cephalo furan acid 72.6g that adds methylene chloride, AE active ester 80g drips triethylamine 72g, keep 5-10 ℃ of reaction 3.5 hours, with the purified water extraction, combining water layer adds gac 10g, stirred 1 hour, get rid of filter, filtrate is transferred pH value 4-5 with 10% hydrochloric acid soln, get rid of filter ceftiofur 75.0g, (total recovery 63.9%, effective content 99.3%).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200610048426XA CN101108855A (en) | 2006-07-18 | 2006-07-18 | Method of preparing ceftiofur |
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|---|---|---|---|
| CNA200610048426XA CN101108855A (en) | 2006-07-18 | 2006-07-18 | Method of preparing ceftiofur |
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| CN101108855A true CN101108855A (en) | 2008-01-23 |
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| CNA200610048426XA Pending CN101108855A (en) | 2006-07-18 | 2006-07-18 | Method of preparing ceftiofur |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584855A (en) * | 2012-02-16 | 2012-07-18 | 青岛科技大学 | Improved method for preparing ceftiofur |
| CN102993216A (en) * | 2013-01-06 | 2013-03-27 | 瑞普（天津）生物药业有限公司 | Preparation method of ceftiofur hydrochloride |
| CN104530085A (en) * | 2014-12-07 | 2015-04-22 | 河南领先科技药业有限公司 | New preparation method of ceftiofur sodium |
| CN116535421A (en) * | 2023-07-04 | 2023-08-04 | 齐鲁晟华制药有限公司 | Synthesis method of ceftiofur sodium |
-
2006
- 2006-07-18 CN CNA200610048426XA patent/CN101108855A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584855A (en) * | 2012-02-16 | 2012-07-18 | 青岛科技大学 | Improved method for preparing ceftiofur |
| CN102584855B (en) * | 2012-02-16 | 2014-06-25 | 青岛科技大学 | Improved method for preparing ceftiofur |
| CN102993216A (en) * | 2013-01-06 | 2013-03-27 | 瑞普（天津）生物药业有限公司 | Preparation method of ceftiofur hydrochloride |
| CN104530085A (en) * | 2014-12-07 | 2015-04-22 | 河南领先科技药业有限公司 | New preparation method of ceftiofur sodium |
| CN116535421A (en) * | 2023-07-04 | 2023-08-04 | 齐鲁晟华制药有限公司 | Synthesis method of ceftiofur sodium |
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