CN115093432A - Preparation process of ceftiofur sodium - Google Patents
Preparation process of ceftiofur sodium Download PDFInfo
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- CN115093432A CN115093432A CN202210877111.5A CN202210877111A CN115093432A CN 115093432 A CN115093432 A CN 115093432A CN 202210877111 A CN202210877111 A CN 202210877111A CN 115093432 A CN115093432 A CN 115093432A
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- ceftiofur
- sodium
- petroleum ether
- wet product
- acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a new preparation process of ceftiofur sodium, which takes 7-aminocephalosporanic acid and furan-2-methylthiohydroxy acid as raw materials to prepare a triethylamine salt wet product; adding 100g of triethylamine salt wet product of ceftiofur and 200g of petroleum ether into a four-mouth bottle, stirring and dissolving, dropwise adding hydrochloric acid, adding activated carbon, stirring, decoloring and filtering, washing a filter cake with petroleum ether and the like to obtain a thifluzamide wet product; the method takes 7-aminocephalosporanic acid as a raw material, the 7-aminocephalosporanic acid can be directly purchased in the market, the price is low, the reaction conditions of the process are mild and not harsh, the method is simple and easy to operate, the solvent is easy to recover, and the method is environment-friendly and very suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a preparation process of ceftiofur sodium.
Background
With the development of modern animal husbandry, the problems of drug resistance and drug residues generated by a plurality of bacteria due to long-term antibiotic abuse are more and more obvious in the past, and people are more and more concerned. Especially the wide outbreak of avian influenza in recent years has caused the deep thought of the medicine industry.
Chemical name of ceftiofur sodium: [6R- [6 alpha, 7 beta (Z) ] ] -7- [ [ (2-amino-4-thiazolyl) (methoxyimino) acetyl ] amino ] -3- [ [ (2-furancarbonyl) thio ] methyl ] -8 oxo-5-thia-1-amino heterobicyclo [4.2.0] oct-2-ene-2-sodium formate salt, the product is white or yellow powder, the product is a compound preparation with sterilization, inflammation diminishing, heat clearing and pain relieving functions, ceftiofur sodium is a third-generation cephalosporin antibiotic special for veterinary clinical use, has broad-spectrum high-efficiency sterilization function, has strong killing function on G + bacteria and G-bacteria including beta-lactam producing strain bacteria, is quickly absorbed after intramuscular and subcutaneous injection, is mainly used for controlling and killing escherichia coli and salmonella of serious bacterial and viral infection and poultry, high temperature and high fever, cough, asthma, dyspnea, skin redness and purplish color, ear root and purple color, mouth and hoof ulceration, abortion and stillbirth, ring rotation, hind limb paralysis, inappetence, lying on the ground, constipation, diarrhea and the like caused by systemic or local infection of virus and bacteria; infectious pleurisy, actinobacillus, pasteurella multocida, streptococcus mutans, yellow and white scour of piglets, salmonella, haemophilus parasuis, atrophic rhinitis, chlamydia, etc.; high fever before and after the birth of the livestock, endometritis, mastitis, agalactia and hypogalactia syndrome, laminitis, foot rot, pasteurella of cattle and sheep, heat of transportation, pneumonia, nasal atrophy and the like.
At present, the solvent used in the main preparation process of ceftiofur sodium is tetrahydrofuran or a mixed solvent of acetone, dichloromethane, alcohols and the like, tetrahydrofuran is expensive and has high harmfulness, and the product obtained by the mixed solvent of acetone, dichloromethane, alcohols and the like has qualified yield and quality, but has the problems of large solvent recovery loss, environmental pollution, high cost and the like.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a preparation process of ceftiofur sodium, which has the advantages of easily available raw materials, simplicity, easy operation, low cost, easy solvent recovery, environmental friendliness and suitability for industrial production.
In order to achieve the purpose, the invention provides the following technical scheme: a preparation process of ceftiofur sodium comprises the following steps:
1) synthesis of triethylamine salt of ceftiofur: taking 7-aminocephalosporanic acid and furan-2-methylthiohydroxy acid as raw materials to prepare a ceftiofur intermediate through a substitution reaction, and reacting the ceftiofur intermediate with AE-active ester in a triethylamine solution to obtain a triethylamine salt wet product of ceftiofur;
2) adding 100g of ceftiofur triethylamine salt wet product and 200g of petroleum ether into a four-mouth bottle, stirring and dissolving, dropwise adding hydrochloric acid to PH2-3, adding 6g of activated carbon, stirring and decoloring for 15-30 min, filtering, washing a filter cake by 30g of petroleum ether, controlling the temperature to be 30-40 ℃, dropwise adding 33g of saturated sodium salt solution, carrying out crystal growth for 60-90 min after completing dripping, cooling to be 0-5 ℃, carrying out crystal growth for 60-90 min, carrying out suction filtration, washing by 100-300 ml of acetone to obtain a thifluzamide wet product, and drying to obtain 70-75 g of a dry product, wherein the total yield is 80-85%, and the content of ceftiofur sodium is 90-92%.
Further, the sodium salt is sodium carbonate or sodium bicarbonate.
Further, the ratio of the petroleum ether to the sodium salt is 8-10: 1.
Further, the boiling point of the petroleum ether is 60-120 ℃.
Further, the reaction temperature of the step 2) is 0-40 ℃.
Compared with the prior art, the invention has the beneficial effects that: the invention discloses a novel preparation process of ceftiofur sodium, which takes 7-aminocephalosporanic acid as a raw material, the 7-aminocephalosporanic acid can be directly purchased in the market, the price is low, the reaction conditions of the process are mild and not harsh, the operation is simple and easy, the solvent is easy to recover, the environment is friendly, and the industrial production is very suitable.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1:
a novel preparation process of ceftiofur sodium comprises the following steps:
1) and synthesizing triethylamine salt of ceftiofur: taking 7-aminocephalosporanic acid and furan-2-methylthiohydroxy acid as raw materials to prepare a ceftiofur intermediate through substitution reaction, and reacting the ceftiofur intermediate with AE-active ester in triethylamine solution to obtain triethylamine salt wet product of ceftiofur
2) Adding 100g of ceftiofur triethylamine salt wet product and 200g of petroleum ether into a four-mouth bottle, stirring and dissolving, dropwise adding hydrochloric acid to PH2-3, adding 6g of activated carbon, stirring and decoloring for 30min, filtering, washing a filter cake by 30g of petroleum ether, controlling the temperature to be 30-40 ℃, dropwise adding 33g of saturated sodium carbonate solution, completing dripping, growing crystals for 60min, cooling to be 0-5 ℃, growing crystals for 60min, performing suction filtration, and washing with acetone to obtain the thifluzaofuran sodium wet product. Drying to obtain 70g of dry product, the total yield is 80 percent, and the content is 92 percent.
Example 2:
a novel preparation process of ceftiofur sodium comprises the following steps:
1) and synthesizing triethylamine salt of ceftiofur: taking 7-aminocephalosporanic acid and furan-2-methylthiohydroxy acid as raw materials to prepare a ceftiofur intermediate through a substitution reaction, and reacting the ceftiofur intermediate with AE-active ester in triethylamine solution to obtain triethylamine salt wet product of ceftiofur;
2) adding 100g of ceftiofur triethylamine salt wet product and 200g of petroleum ether into a four-mouth bottle, stirring and dissolving, dropwise adding hydrochloric acid to PH3-4, adding 6g of activated carbon, stirring and decoloring for 30min, filtering, washing a filter cake by 30g of petroleum ether, controlling the temperature to be 20-30 ℃, dropwise adding 33g of saturated sodium carbonate solution, completing dripping, growing crystals for 70min, cooling to be 0-5 ℃, growing crystals for 80min, performing suction filtration, and washing with acetone to obtain the thifluzamide wet product. Drying to obtain 72g of dry product, the total yield is 82.3%, and the content is 91.5%.
Example 3:
a novel preparation process of ceftiofur sodium comprises the following steps:
1) and synthesizing triethylamine salt of ceftiofur: taking 7-aminocephalosporanic acid and furan-2-methylthiohydroxy acid as raw materials to prepare a ceftiofur intermediate through a substitution reaction, and reacting the ceftiofur intermediate with AE-active ester in triethylamine solution to obtain triethylamine salt wet product of ceftiofur;
2) adding 100g of ceftiofur triethylamine salt wet product and 200g of petroleum ether into a four-mouth bottle, stirring and dissolving, dropwise adding hydrochloric acid until the pH value is 2.5-3.5, adding 8g of activated carbon, stirring and decoloring for 30min, filtering, washing a filter cake by 30g of petroleum ether, controlling the temperature to be 30-35 ℃, dropwise adding 35g of saturated sodium carbonate solution, completing dripping, growing crystals for 90min, cooling to be 0-5 ℃, growing crystals for 90min, performing suction filtration, and washing with acetone to obtain the thifluzamide wet product. Drying to obtain 74g of dry product, the total yield is 84.6 percent, and the content is 90 percent.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all equivalent flow transformations made by the present specification, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.
Claims (5)
1. A novel preparation process of ceftiofur sodium is characterized by comprising the following steps:
1) synthesis of triethylamine salt of ceftiofur: taking 7-aminocephalosporanic acid and furan-2-methylthiohydroxy acid as raw materials to prepare a ceftiofur intermediate through a substitution reaction, and reacting the ceftiofur intermediate with AE-active ester in triethylamine solution to obtain triethylamine salt wet product of ceftiofur;
2) adding 100g of ceftiofur triethylamine salt wet product and 200g of petroleum ether into a four-mouth bottle, stirring and dissolving, dropwise adding hydrochloric acid to PH2-3, adding 6g of activated carbon, stirring and decoloring for 15-30 min, filtering, washing a filter cake by 30g of petroleum ether, controlling the temperature to be 30-40 ℃, dropwise adding 33g of saturated sodium salt solution, carrying out crystal growth for 60-90 min after completing dripping, cooling to be 0-5 ℃, carrying out crystal growth for 60-90 min, carrying out suction filtration, washing by 100-300 ml of acetone to obtain a thifluzamide wet product, and drying to obtain 70-75 g of a dry product, wherein the total yield is 80-85%, and the content of ceftiofur sodium is 90-92%.
2. The process for preparing ceftiofur sodium according to claim 1, wherein the sodium salt is sodium carbonate or sodium bicarbonate.
3. The preparation process of ceftiofur sodium according to claim 1, wherein the ratio of petroleum ether to sodium salt is 8-10: 1.
4. The process for preparing ceftiofur sodium according to claim 1, wherein the boiling point of petroleum ether is 60-120 ℃.
5. The process for preparing ceftiofur sodium according to claim 1, wherein the reaction temperature in the step 2) is 0-40 ℃.
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN115772179A (en) * | 2022-12-09 | 2023-03-10 | 山东鑫泉医药有限公司 | Recrystallization method of ceftiofur sodium |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN115772179A (en) * | 2022-12-09 | 2023-03-10 | 山东鑫泉医药有限公司 | Recrystallization method of ceftiofur sodium |
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