CN113024580A - Preparation method of cefotaxime sodium - Google Patents
Preparation method of cefotaxime sodium Download PDFInfo
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- CN113024580A CN113024580A CN202110257891.9A CN202110257891A CN113024580A CN 113024580 A CN113024580 A CN 113024580A CN 202110257891 A CN202110257891 A CN 202110257891A CN 113024580 A CN113024580 A CN 113024580A
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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
- C07D501/06—Acylation of 7-aminocephalosporanic 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
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
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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
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
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- Cephalosporin Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of cefotaxime sodium, which comprises the steps of taking pure water as a solvent, adding reaction raw materials of 7-ACA and AE active ester at the temperature of 15-20 ℃, stirring for reaction for 15-25 min, adding sodium hydrosulfide, and then continuously and slowly adding triethylamine under the stirring condition; then cooling to 0-3 ℃, slowly adding a sodium hydroxide solution under the stirring condition, and after the completion, keeping the temperature at 0-3 ℃ to continue stirring and reacting until the 7-ACA reaction is completed; heating to 15-20 ℃, adding active carbon, stirring for decoloring, and filtering; maintaining the temperature at 15-20 ℃, adding acetone and seed crystals, and stirring for growing crystals for 30-40 min; maintaining the temperature at 15-20 ℃, continuously and slowly adding acetone, and continuing growing the crystals for 40-50min after the addition is finished; filtering and drying to obtain the cefotaxime sodium. The method adopts a one-step method to synthesize cefotaxime sodium, and compared with a two-step synthesis method, the yield and the purity of the obtained product are greatly improved.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a synthetic method of cefotaxime sodium.
Background
Anti-infective therapy is one of the most clinically important treatments. Cefotaxime sodium is the third generation semi-synthetic cephalosporin developed by hoechst, russell, germany, and pharmacy in japan. The antibacterial spectrum of the compound has wider range than cefuroxime, has stronger effect on gram-negative bacteria, and comprises haemophilus influenzae, escherichia coli, salmonella klebsiella, proteus mirabilis, neisseria, staphylococcus, pneumococcus, streptococcus and the like.
Cefotaxime sodium was first marketed by hoechst in germany under the trade name "claunn" in 1980, while the product of russell was marketed in italy, and cefotaxime sodium was approved by the us FDA in 1981. In recent years, cefotaxime sodium has excellent performance in the global market, and the global sales amount is 5.5 billion dollars in 2000. The traditional Chinese medicine composition is mainly used for treating various sensitive bacteria infections in clinic, such as respiratory tract infection, five sense organs infection, abdominal cavity infection, biliary tract infection, meningitis infection, gonorrhea infection, urinary system infection, septicemia infection and the like. At present, cefotaxime sodium is still one of the middle and strong forces of cephalosporin medicines in China, and at present, manufacturers holding cefotaxime sodium powder injection production lots in China are nearly hundreds of families, so that the development and supply of raw material medicines with low cost and high quality can generate great economic benefits for enterprises, improve the competitiveness of the enterprises and generate good social benefits.
The existing cefotaxime sodium is mostly synthesized by a two-step method, namely 7-ACA is taken as a raw material to react with AE active ester to synthesize cefotaxime acid, and then the cefotaxime acid reacts with sodium acetate to prepare the cefotaxime sodium. The product prepared by the two-step synthesis method has low yield and purity, and is not beneficial to the industrial production of cefotaxime sodium. And when the cefotaxime acid is prepared, an organic phase is usually adopted as a solvent, so that the cost is high, and the environmental pollution is easily caused.
Disclosure of Invention
The invention aims to solve the defects in the prior art and provide a synthetic process of cefotaxime sodium, which has low reaction cost and can effectively provide purity and yield.
In order to achieve the purpose, the invention provides a preparation method of cefotaxime sodium, which takes pure water as a solvent, adds reaction raw materials of 7-ACA and AE active ester at the temperature of 15-20 ℃, stirs for reaction for 15-25 min, adds sodium hydrosulfide, then continuously and slowly adds triethylamine under the stirring condition, and controls the adding time of the triethylamine for 20-30 min; then cooling to 0-3 ℃, preserving heat, slowly adding a sodium hydroxide solution under the stirring condition, controlling the adding time of the sodium hydroxide solution to be 30-50min, and after the completion, keeping the temperature at 0-3 ℃ to continue stirring and reacting until the 7-ACA reaction is completed; heating to 15-20 ℃, adding active carbon, stirring for decoloring, and filtering; maintaining the temperature at 15-20 ℃, adding acetone and seed crystals, and stirring for growing crystals for 30-40 min; maintaining the temperature at 15-20 ℃, continuously and slowly adding acetone, controlling the adding time to be 50-60min, and continuously growing the crystals for 40-50min after the adding is finished; filtering and drying to obtain the cefotaxime sodium.
In some embodiments, it is preferable that the addition amount of each reaction component is: 100L of pure water, 7-ACA10kg, 14kg of AE active ester, 1.8kg of sodium hydrosulfide, 7L of triethylamine and 20L of sodium hydroxide solution; the concentration of the sodium hydroxide solution was 10%.
In some embodiments, it is preferable that the amount of acetone added is 170L after the activated carbon decolorization is completed and the activated carbon is filtered.
In some embodiments, it is preferable that the subsequent continuous slow addition of acetone is in an amount of 100L.
In some embodiments, the amount of activated carbon added is preferably 1 kg.
Compared with the prior art, the invention has the following advantages:
1. the method adopts a one-step method to synthesize cefotaxime sodium, and compared with a two-step synthesis method, the yield and the purity of the obtained product are greatly improved.
2. The invention takes water as the reaction solvent, greatly reduces the cost of raw materials, greatly reduces the usage amount of the organic solvent and reduces the influence of the organic solvent on the production environment. Meanwhile, after the reaction is finished, the decoloration is applied to the water phase, the decoloration effect is superior to that of the organic phase, and the product quality is effectively ensured.
3. Meanwhile, the antioxidant is added in the early stage of the reaction, so that the oxidation of the product in the reaction process is avoided, the side reaction of the product is greatly reduced, and the yield of the product is obviously improved.
4. The method effectively controls the reaction by controlling the adding speed of each raw material in the reaction process, improves the conversion rate of the 7-ACA, reduces the generation of byproducts, and further improves the yield and the purity of the cefotaxime sodium.
Drawings
FIG. 1 shows the reaction equation for the synthesis of cefotaxime sodium of the present invention.
Detailed Description
The present invention will be described in detail with reference to specific examples.
Example 1
The preparation process of cefotaxime sodium comprises the following steps:
adding reaction raw materials 7-ACA10kg and AE active ester 14kg at 20 ℃ by taking pure water 100L as a solvent, stirring for reacting for 15min, adding sodium hydrosulfide 1.8kg, then continuously and slowly adding triethylamine 7L under the stirring condition, and controlling the adding time of the triethylamine for 20 min; then cooling to 0-3 ℃, preserving heat, slowly adding 20L of 10% sodium hydroxide solution under stirring, controlling the adding time of the sodium hydroxide solution to be 30-50min, and after the completion, keeping stirring and reacting for 1h at 0-3 ℃; heating to about 20 ℃, adding 1kg of active carbon, stirring for decoloring, and filtering; maintaining the temperature, adding 170L of acetone and seed crystals, and stirring for crystal growth for 30 min; continuously maintaining the temperature, continuously and slowly adding 100L of acetone, controlling the adding time for 50min, and continuously growing the crystal for 40min after the adding is finished; filtering and drying to obtain 17.1kg of cefotaxime sodium with the purity of 97.5 percent.
Example 2
The preparation process of cefotaxime sodium comprises the following steps:
adding reaction raw materials 7-ACA10kg and AE active ester 14kg at 15 ℃ by taking pure water 100L as a solvent, stirring for reaction for 25min, adding sodium hydrosulfide 1.8kg, then continuously and slowly adding triethylamine 7L under the stirring condition, and controlling the adding time of the triethylamine for 30 min; then cooling to 0-3 ℃, preserving heat, slowly adding 20L of 10% sodium hydroxide solution under stirring, controlling the adding time of the sodium hydroxide solution to be 50min, and after the completion, keeping stirring and reacting for 1h at 0-3 ℃; heating to 15 ℃, adding 1kg of active carbon, stirring for decoloring, and filtering; maintaining the temperature, adding 170L of acetone and seed crystals, and stirring for growing crystals for 40 min; maintaining the temperature at 15 deg.C, continuously and slowly adding acetone 100L, controlling the addition time for 60min, and continuing to grow crystal for 50min after the addition is finished; filtering and drying to obtain 17.3kg of cefotaxime sodium with the purity of 97.8 percent.
Example 3
The preparation process of cefotaxime sodium comprises the following steps:
taking 100L of pure water as a solvent, adding 7-ACA10kg of reaction raw materials and 14kg of AE active ester at the temperature of about 20 ℃, stirring for reacting for 20min, adding 1.8kg of sodium hydrosulfide, then continuously and slowly adding 7L of triethylamine under the stirring condition, and controlling the adding time of the triethylamine for 25 min; then cooling to 0-3 ℃, preserving heat, slowly adding 20L of 10% sodium hydroxide solution under stirring, controlling the adding time of the sodium hydroxide solution to be 45min, and after the completion, keeping stirring and reacting for 1h at 0-3 ℃; heating to 15-20 ℃, adding 1kg of active carbon, stirring for decoloring, and filtering; maintaining the temperature at 20 deg.C, adding 170L acetone and seed crystal, stirring, and growing crystal for 35 min; maintaining the temperature at 20 deg.C, continuously and slowly adding acetone 100L, controlling the addition time for 55min, and continuing to grow crystal for 45min after the addition is finished; filtering and drying to obtain 17.3kg of cefotaxime sodium with the purity of 97.5 percent.
Comparative example 1
The preparation process of cefotaxime sodium comprises the following steps:
taking 100L of pure water as a solvent, adding 7-ACA10kg of reaction raw materials and 14kg of AE active ester at the temperature of about 20 ℃, stirring for reaction for 15min, adding 1.8kg of sodium hydrosulfide, then continuously and slowly adding 7L of triethylamine under the stirring condition, and controlling the adding time of the triethylamine for 15 min; then cooling to 0-3 ℃, preserving heat, slowly adding 20L of 10% sodium hydroxide solution under stirring, controlling the adding time of the sodium hydroxide solution to be 250min, and after the adding is finished, keeping stirring and reacting for 1h at 0-3 ℃; heating to 20 ℃, adding 1kg of active carbon, stirring for decoloring, and filtering; maintaining the temperature at 20 deg.C, adding 170L acetone and seed crystal, stirring, and growing crystal for 25 min; maintaining the temperature at 20 deg.C, continuously and slowly adding acetone 100L, controlling the addition time for 45min, and continuing growing crystal for 35min after the addition is finished; filtering and drying to obtain 16.96kg of cefotaxime sodium with the purity of 96.9 percent.
As can be seen from examples 1, 2, 3 and comparative example 1, when the rate of addition of the reaction raw materials was increased, the yield and purity of the obtained product were reduced due to insufficient progress of the reaction.
Comparative example 2
The preparation process of cefotaxime sodium comprises the following steps:
adding reaction raw materials 7-ACA10kg and AE active ester 14kg at the temperature of about 20 ℃ by taking pure water 100L as a solvent, stirring for reaction for 30min, adding sodium hydrosulfide 1.8kg, then continuously and slowly adding triethylamine 7L under the stirring condition, and controlling the adding time of the triethylamine for 35 min; then cooling to 0-3 ℃, preserving heat, slowly adding 20L of 10% sodium hydroxide solution under stirring, controlling the adding time of the sodium hydroxide solution to be 55min, and after completion, keeping stirring and reacting for 1h at 0-3 ℃; heating to 20 ℃, adding 1kg of active carbon, stirring for decoloring, and filtering; maintaining the temperature at 20 deg.C, adding 170L acetone and seed crystal, stirring, and growing crystal for 45 min; maintaining the temperature at 20 deg.C, continuously and slowly adding acetone 100L, controlling the addition time 65min, and continuing growing crystal for 55min after the addition is finished; filtering and drying to obtain 17.33kg of cefotaxime sodium with the purity of 97.7 percent.
As can be seen from examples 1, 2, 3 and comparative example 2, when the reaction raw materials were slowly added, the reaction was promoted to be sufficiently performed, and the yield and purity of the obtained product were all 97% or more. From the viewpoint of cost and production efficiency, the reaction raw material addition time is not easy to be controlled too long.
Claims (5)
1. The preparation method of cefotaxime sodium is characterized by taking pure water as a solvent, adding reaction raw materials of 7-ACA and AE active ester at the temperature of 15-20 ℃, stirring for reaction for 15-25 min, adding sodium hydrosulfide, then continuously and slowly adding triethylamine under the stirring condition, and controlling the adding time of the triethylamine for 20-30 min; then cooling to 0-3 ℃, preserving heat, slowly adding a sodium hydroxide solution under the stirring condition, controlling the adding time of the sodium hydroxide solution to be 30-50min, and after the completion, keeping the temperature at 0-3 ℃ to continue stirring and reacting until the 7-ACA reaction is completed; heating to 15-20 ℃, adding active carbon, stirring for decoloring, and filtering; maintaining the temperature at 15-20 ℃, adding acetone and seed crystals, and stirring for growing crystals for 30-40 min; maintaining the temperature at 15-20 ℃, continuously and slowly adding acetone, controlling the adding time to be 50-60min, and continuously growing the crystals for 40-50min after the adding is finished; filtering and drying to obtain the cefotaxime sodium.
2. The preparation method according to claim 1, wherein the addition amount of each reaction component in the preparation method is respectively as follows: 100L of pure water, 10kg of 7-ACA, 14kg of AE active ester, 1.8kg of sodium hydrosulfide, 7L of triethylamine and 20L of sodium hydroxide solution; the concentration of the sodium hydroxide solution was 10%.
3. The method according to claim 2, wherein the amount of acetone added is 170L after the decolorization of the activated carbon is completed and the activated carbon is filtered.
4. The method according to claim 3, wherein the continuous slow addition of acetone is carried out in an amount of 100L.
5. The method according to claim 4, wherein the activated carbon is added in an amount of 1 kg.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113666947A (en) * | 2021-07-23 | 2021-11-19 | 无锡海伦生物科技有限公司 | Preparation method of cefotaxime sodium |
| WO2023202567A1 (en) * | 2022-04-21 | 2023-10-26 | 华北制药河北华民药业有限责任公司 | Method for refining cefotaxime sodium |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004063203A1 (en) * | 2003-01-10 | 2004-07-29 | Orchid Chemicals & Pharmaceuticals Ltd | Process for the preparation of cefotaxime sodium |
| CN1765901A (en) * | 2004-10-27 | 2006-05-03 | 山东瑞阳制药有限公司 | One-step preparation process of aseptic cefotaxime sodium for injection |
| CN105646535A (en) * | 2016-01-24 | 2016-06-08 | 哈尔滨合佳制药有限公司 | Synthesis method of cefotaxime sodium |
| WO2017140072A1 (en) * | 2016-02-18 | 2017-08-24 | 海南灵康制药有限公司 | Novel polymorphic cefuroxime sodium compound and preparation employing particle process crystal product molecular assembly and morphological optimization technique |
| CN110283187A (en) * | 2019-07-10 | 2019-09-27 | 辽宁美亚制药有限公司 | A kind of preparation method promoting Cefotaxime Sodium product quality |
| CN111875621A (en) * | 2020-08-26 | 2020-11-03 | 山东鲁抗医药股份有限公司 | Preparation method of cephalosporin salt for injection |
-
2021
- 2021-03-10 CN CN202110257891.9A patent/CN113024580B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004063203A1 (en) * | 2003-01-10 | 2004-07-29 | Orchid Chemicals & Pharmaceuticals Ltd | Process for the preparation of cefotaxime sodium |
| CN1765901A (en) * | 2004-10-27 | 2006-05-03 | 山东瑞阳制药有限公司 | One-step preparation process of aseptic cefotaxime sodium for injection |
| CN105646535A (en) * | 2016-01-24 | 2016-06-08 | 哈尔滨合佳制药有限公司 | Synthesis method of cefotaxime sodium |
| WO2017140072A1 (en) * | 2016-02-18 | 2017-08-24 | 海南灵康制药有限公司 | Novel polymorphic cefuroxime sodium compound and preparation employing particle process crystal product molecular assembly and morphological optimization technique |
| CN110283187A (en) * | 2019-07-10 | 2019-09-27 | 辽宁美亚制药有限公司 | A kind of preparation method promoting Cefotaxime Sodium product quality |
| CN111875621A (en) * | 2020-08-26 | 2020-11-03 | 山东鲁抗医药股份有限公司 | Preparation method of cephalosporin salt for injection |
Non-Patent Citations (2)
| Title |
|---|
| 孙津鸽: "头孢噻肟钠制备工艺的改进", 《山东化工》 * |
| 孙津鸽等: "头孢噻肟酸合成工艺的研究", 《广东化工》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113666947A (en) * | 2021-07-23 | 2021-11-19 | 无锡海伦生物科技有限公司 | Preparation method of cefotaxime sodium |
| WO2023202567A1 (en) * | 2022-04-21 | 2023-10-26 | 华北制药河北华民药业有限责任公司 | Method for refining cefotaxime sodium |
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