CN114409677A - Preparation method of high-purity cefotaxime acid - Google Patents
Preparation method of high-purity cefotaxime acid Download PDFInfo
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- CN114409677A CN114409677A CN202111676312.0A CN202111676312A CN114409677A CN 114409677 A CN114409677 A CN 114409677A CN 202111676312 A CN202111676312 A CN 202111676312A CN 114409677 A CN114409677 A CN 114409677A
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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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- 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
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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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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a preparation method of high-purity cefotaxime acid, belonging to the technical field of antibacterial drug preparation, comprising the following steps: preparing a condensation solution, carrying out salt forming reaction, removing genotoxic impurities and preparing a finished product; the method comprises the following steps of converting cefotaxime acid into cefotaxime sodium by using a sodium salt forming agent, extracting by using a water-insoluble organic solvent II, transferring 2-mercaptobenzothiazole into the organic solvent II, adjusting the pH of cefotaxime sodium in a water phase to convert the cefotaxime sodium into cefotaxime acid, adjusting the pH of the water-soluble cefotaxime sodium to 6.5-7.0 by using acetic acid before the cefotaxime sodium is completely acidified into the cefotaxime acid, wherein the cefotaxime acid is in a weak acid state, and the method has the beneficial effects that: the phenomenon of high impurity level and the like caused by direct crystallization of the product is avoided, the pH value is adjusted to 6.5-7.0 by using acetic acid and is in a weak acid state, so that the 2-mercaptobenzothiazole is effectively transferred to an organic phase, and the cefotaxime sodium is retained in a water phase, so that the separation is realized, and the problems that the 2-mercaptobenzothiazole and the cefotaxime acid are difficult to distinguish and remove are solved.
Description
The technical field is as follows:
the invention belongs to the technical field of antibacterial drug preparation, and particularly relates to a preparation method of high-purity cefotaxime acid.
Background art:
the high-purity Cefotaxime acid is a key intermediate for synthesizing a third-generation antibacterial Cefotaxime sodium, the Cefotaxime sodium (Cefotaxime sodium) is a 3 rd-generation oral cephalosporin, is firstly marketed in Germany in 1980, is developed by Germany Hoechst company and French Roussel company, is acylated with aminothiazolyl-cis-methoxyiminoacetyl at the 7-position of a cephalosporin skeleton, and has good antibacterial activity on G (-) bacillus and drug-resistant bacteria.
The product quality of the cephalosporin antibacterial drugs has relevance to clinically occurring anaphylactic reactions, the polymer in the cephalosporin antibiotics is a main impurity causing the anaphylactic reactions of patients, and the content of the polymer has positive relevance to the risks of the patients of the anaphylactic reactions. According to the standard of Chinese pharmacopoeia, the limit of the polymer in cefotaxime sodium is less than 0.5%. Calculation mode of genotoxic impurity 2-mercaptobenzothiazole (impurity M): 344 μ g d-1/12g·d-1＝28.7ppm。
The genotoxic impurity M and the polymer level in cefotaxime acid are directly related to the quality of cefotaxime sodium. At present, there are many reports that most of genotoxic impurities M and polymers are converted from 7-aminocephalosporanic acid (7-ACA) and AE active ester, such as:
WO9620198 adopts di (2-benzothiazole) disulfide to react with aminothiazoly loximate to obtain AE-active ester, and then reacts with 7-ACA to obtain cefotaxime acid, although this method uses acetone as a solvent, which saves operations such as extraction, the cefotaxime acid obtained by the method is difficult to be filtered by suction, and the genotoxic impurity 2-mercaptobenzothiazole (impurity M) has high level, so that after cefotaxime sodium is prepared, the impurity M is difficult to be effectively controlled.
CN101560217A adopts chloroform as a reaction solvent, AE-active ester reacts with 7-ACA, extraction is not needed, pH is directly adjusted to obtain cefotaxime acid, the level of genotoxic impurity M in cefotaxime acid obtained by the method is high, and therefore, after cefotaxime sodium is prepared, impurity M is difficult to be effectively controlled. In addition, the method also uses chloroform with high toxicity, and is not suitable for industrial production.
US20070004916A1 and WO2005076694A2 report that 7-ACA and 2- (2-chloroacetamidothiazole-4-yl) -2-Z-methoxyimino acetyl chloride are adopted to react to obtain cefotaxime acid, but the price of the 2- (2-chloroacetamidothiazole-4-yl) -2-Z-methoxyimino acetyl chloride is higher, the number of manufacturers is less, in addition, the method has higher requirement on moisture and severer reaction conditions.
CN101613360 adopts dichloromethane as a reaction solvent, AE-active ester, 7-ACA and triethylamine are added in sequence to react under stirring, purified water is used for extraction after the reaction is finished, and the cefotaxime acid is obtained by decoloring, leaching and adjusting pH crystallization of a water phase. However, the cefotaxime acid obtained by the method has high unknown impurity, and the limit of the unknown impurity in the cefotaxime acid is not more than 0.2 percent in the specification of USP pharmacopoeia, so that higher requirements on the quality of the cefotaxime acid are provided.
In summary, the following steps: the above methods all have more or less problems: some synthesis steps are multiple, and the product yield is low; some raw materials are expensive and are not economically feasible; some products have high impurity level, so that the purity of the products is low; some reaction conditions are harsh and not suitable for industrial production. Therefore, the development of an economically feasible and high-purity synthetic method of cefotaxime acid becomes a hotspot of the current research.
The invention content is as follows:
in order to solve the problems and overcome the defects of the prior art, the invention provides a method for purifying cefotaxime acid, which can effectively solve the problems of poor purity and high genotoxicity impurities.
The specific technical scheme for solving the technical problems comprises the following steps: a preparation method of high-purity cefotaxime acid is characterized by comprising the following steps:
(1) preparation of the condensation solution
Adding an organic solvent I into a reactant 7-ACA, adding MEAM to react under the action of a catalyst to obtain an organic phase containing cefotaxime acid, wherein the catalyst is diisopropylamine or N, N-diisopropylethylamine, the molar ratio of the 7-ACA to the catalyst is 1 (1.4-2.0), and the molar ratio of the 7-ACA to the MEAM is 1 (1.05-1.2);
the organic solvent I is a mixture of isopropanol and an organic auxiliary agent, and the organic auxiliary agent is one of dichloromethane, ethyl acetate and toluene;
the mass volume ratio of the 7-ACA to the organic solvent 1 is 1g (6-12) ml;
(2) salt-forming reaction
Adding water and sodium salt forming agent into an organic phase containing cefotaxime acid, separating liquid to obtain salifying reaction solution containing cefotaxime sodium,
(3) genotoxic impurity removal
Adding an organic solvent II into a salifying reaction solution for extraction, and adding activated carbon into a water phase for decolorization;
the organic solvent II is one of dichloromethane, ethyl acetate and toluene;
(4) preparation of finished product
And (3) after decoloring and suction filtration, adjusting the pH value to 2.2-2.8 by using dilute hydrochloric acid for crystallization, cooling, growing crystals, suction filtration, washing with water and ethyl acetate, and drying to obtain a dry cefotaxime acid product.
Further, the sodium salt forming agent is sodium carbonate or sodium bicarbonate or sodium thiocyanate or sodium acetate;
further, in the step (3), the organic solvent II is added into the salt-forming reaction solution for extraction, acetic acid is used for adjusting the pH value to 6.5-7.0 for impurity removal, the water phase is separated after standing, and then activated carbon is added into the water phase for decoloration.
The invention has the beneficial effects that: according to the invention, cefotaxime acid is converted into cefotaxime sodium by adopting a sodium salt forming agent, then, a water-insoluble organic solvent II is used for extraction, 2-mercaptobenzothiazole is transferred to the organic solvent II, and cefotaxime sodium in a water phase is converted into cefotaxime acid after the pH value is adjusted, so that the phenomena of high impurity level and the like caused by direct crystallization of a product are avoided, and meanwhile, the operation is convenient. The molar yield of the process can reach 98% or more, the product purity is 98.5% or more, and the maximum single unknown impurity is controlled below 0.3%;
according to the method, before water-soluble cefotaxime sodium is completely acidified into cefotaxime acid, acetic acid is used for adjusting the pH value to be 6.5-7.0 and the cefotaxime sodium is in a weak acid state, so that the 2-mercaptobenzothiazole is effectively transferred to an organic phase, the cefotaxime sodium is retained in a water phase, separation is realized, and the problems that the 2-mercaptobenzothiazole and the cefotaxime acid are difficult to distinguish and remove are solved.
The specific implementation mode is as follows:
in the description of the invention, specific details are given only to enable a full understanding of the embodiments of the invention, but it should be understood by those skilled in the art that the invention is not limited to these details for the implementation. In other instances, well-known structures and functions have not been described or shown in detail to avoid obscuring the points of the embodiments of the invention. The specific meanings of the above terms in the present invention can be understood in specific cases to those skilled in the art.
The specific implementation mode of the invention is as follows:
(1) preparation of the condensation solution
Adding an organic solvent I into a reactant 7-ACA, adding MEAM to react under the action of a catalyst to obtain an organic phase containing cefotaxime acid, wherein the catalyst is diisopropylamine or N, N-diisopropylethylamine, the molar ratio of the 7-ACA to the catalyst is 1 (1.4-2.0), and the molar ratio of the 7-ACA to the MEAM is 1 (1.05-1.2);
the organic solvent I is a mixture of isopropanol and an organic auxiliary agent, and the organic auxiliary agent is one of dichloromethane, ethyl acetate and toluene;
the mass volume ratio of the 7-ACA to the organic solvent 1 is 1g (6-12) ml;
(2) salt-forming reaction
Adding water and a sodium salt forming agent into an organic phase containing cefotaxime acid, and separating liquid to obtain a salifying reaction solution containing cefotaxime sodium, wherein the sodium salt forming agent is sodium carbonate, sodium bicarbonate, sodium thiocyanate or sodium acetate;
(3) genotoxic impurity removal
Adding an organic solvent II into a salifying reaction solution for extraction, and adding activated carbon into a water phase for decolorization;
the organic solvent II is one of dichloromethane, ethyl acetate and toluene;
(4) preparation of finished product
And (3) after decoloring and suction filtration, adjusting the pH value to 2.2-2.8 by using dilute hydrochloric acid for crystallization, cooling, growing crystals, suction filtration, washing with water and ethyl acetate, and drying to obtain a dry cefotaxime acid product.
The specific implementation mode is as follows:
example 1:
taking 10.0g (36.7mmol) of 7-ACA in a three-neck flask, taking 78ml of dichloromethane as an organic solvent I and 5ml of isopropanol as an organic auxiliary agent, uniformly stirring, cooling to-10-10 ℃, adding 5.95g (58.8mmol) of diisopropylamine while stirring, controlling the temperature to be-10-10 ℃, adding 14.2g (38.54mmol) of MEAM, and reacting for 1-2 hours while timing.
After the reaction is finished, 100ml of water and 6.23g (58.8mmol) of sodium carbonate serving as a sodium salt forming agent are added into the reaction liquid, then the temperature is raised to 20-25 ℃, extraction is carried out for 15min, standing phase separation is carried out, an organic phase is discarded, an aqueous phase is extracted for 15min by using 50ml of ethyl acetate serving as an organic solvent II, standing phase separation is carried out, the organic phase is discarded, activated carbon is added into the aqueous phase for decoloration and suction filtration after half an hour, the pH of the aqueous phase is adjusted to 2.2-2.7 by using 1mol/L hydrochloric acid solution, then crystal growth is carried out for 0.5h at 20-25 ℃, then the temperature is lowered to 0-5 ℃ for crystal growth for 2h, and the target product cefotaxime acid is obtained by suction filtration, wherein the molar yield of the product is 95.0%, and the purity is 98.6%. 7-ACA residue less than 0.05%; genotoxic impurity M is 4.1 ppm; the polymer content was 0.08%.
Example 2:
taking 10.0g (36.7mmol) of 7-ACA in a three-neck flask, taking 86ml ethyl acetate as an organic solvent I and 5ml isopropanol as an organic auxiliary agent as a reaction solvent, uniformly stirring, cooling to-10-10 ℃, adding 5.95g (58.8mmol) of diisopropylamine while stirring, controlling the temperature to be-10-10 ℃, adding 14.2g (38.54mmol) of MEAM, and reacting for 1-2 hours while timing.
After the reaction is finished, adding 100ml of water and 6.23g (58.8mmol) of sodium carbonate into the reaction solution, heating to 20-25 ℃, extracting for 15min, standing for phase separation, discarding the organic phase, extracting the water phase for 15min by using 50ml of ethyl acetate, standing for phase separation, discarding the organic phase, adding activated carbon into the water phase, decoloring for half an hour, then performing suction filtration, adjusting the pH of the water phase to 2.2-2.7 by using 1mol/L hydrochloric acid solution, performing crystal growth for 0.5h at 20-25 ℃, cooling to 0-5 ℃ for crystal growth for 2h, and performing suction filtration to obtain 164.0g of target product cefotaxime acid, wherein the molar yield of the product is 95.0%, and the purity is 98.8%. 7-ACA residue less than 0.05%; genotoxic impurity M is less than 3.8 ppm; the polymer content was 0.06%.
Example 3:
taking 10.0g (36.7mmol) of 7-ACA in a three-neck flask, taking 94ml of toluene and 5ml of isopropanol as reaction solvents, uniformly stirring, cooling to-10-10 ℃, adding 5.95g (58.8mmol) of diisopropylamine while stirring, controlling the temperature to-10-10 ℃, adding 14.2g (38.54mmol) of MEAM, and reacting for 1-2h while timing.
After the reaction is finished, adding 100ml of water and 6.23g (58.8mmol) of sodium carbonate into the reaction solution, heating to 20-25 ℃, extracting for 15min, standing for phase separation, discarding the organic phase, extracting the water phase for 15min by using 50ml of ethyl acetate, standing for phase separation, discarding the organic phase, adding activated carbon into the water phase, decoloring for half an hour, then performing suction filtration, adjusting the pH of the water phase to 2.2-2.7 by using 1mol/L hydrochloric acid solution, performing crystal growth for 0.5h at 20-25 ℃, cooling to 0-5 ℃ for crystal growth for 2h, and performing suction filtration to obtain 164.0g of target product cefotaxime acid, wherein the molar yield of the product is 95.0%, and the purity is 98.9%. 7-ACA residue less than 0.05%; genotoxic impurity M is less than 4.6 ppm; the polymer content was 0.09%.
Example 4:
taking 10.0g (36.7mmol) of 7-ACA in a three-neck flask, taking 78ml of dichloromethane and 5ml of isopropanol as reaction solvents, uniformly stirring, cooling to-10-10 ℃, adding 5.95g (58.8mmol) of diisopropylamine while stirring, controlling the temperature to-10-10 ℃, adding 14.2g (38.54mmol) of MEAM, and reacting for 1-2h while timing.
After the reaction is finished, adding 100ml of water and 5.06g (58.8mmol) of sodium bicarbonate into the reaction solution, heating to 20-25 ℃, extracting for 15min, standing for phase separation, discarding the organic phase, extracting for 15min by using 50ml of ethyl acetate for the aqueous phase, standing for phase separation, discarding the organic phase, adding activated carbon into the aqueous phase, decoloring for half an hour, then performing suction filtration, adjusting the pH of the aqueous phase to 2.2-2.7 by using 1mol/L hydrochloric acid solution, performing crystal growth for 0.5h at 20-25 ℃, cooling to 0-5 ℃ for crystal growth for 2h, and performing suction filtration to obtain 164.0g of target product cefotaxime acid, wherein the molar yield of the product is 95.0%, and the purity is 98.6%. 7-ACA residue less than 0.05%; genotoxic impurity M is 3.6 ppm; the polymer content was 0.08%.
Example 5:
taking 10.0g (36.7mmol) of 7-ACA in a three-neck flask, taking 86ml of ethyl acetate and 5ml of isopropanol as reaction solvents, uniformly stirring, cooling to-10-10 ℃, adding 5.95g (58.8mmol) of diisopropylamine while stirring, controlling the temperature to-10-10 ℃, adding 14.2g (38.54mmol) of MEAM, and reacting for 1-2h while timing.
After the reaction is finished, adding 100ml of water and 5.06gg (58.8mmol) of sodium bicarbonate into the reaction solution, heating to 20-25 ℃, extracting for 15min, standing for phase separation, discarding the organic phase, extracting for 15min by using 65ml of toluene for the aqueous phase, standing for phase separation, discarding the organic phase, adding activated carbon into the aqueous phase, decoloring for half an hour, then performing suction filtration, adjusting the pH of the aqueous phase to 2.2-2.7 by using 1mol/L hydrochloric acid solution, performing crystal growth for 0.5h at 20-25 ℃, cooling to 0-5 ℃ for crystal growth for 2h, and performing suction filtration to obtain 164.0g of target product cefotaxime acid, wherein the molar yield of the product is 95.0% and the purity is 99.1%. 7-ACA residue less than 0.05%; genotoxic impurity M is less than 4.1 ppm; the polymer content was 0.07%.
Example 6:
taking 10.0g (36.7mmol) of 7-ACA in a three-neck flask, taking 94ml of toluene and 5ml of isopropanol as reaction solvents, uniformly stirring, cooling to-10-10 ℃, adding 5.95g (58.8mmol) of diisopropylamine while stirring, controlling the temperature to-10-10 ℃, adding 14.2g (38.54mmol) of MEAM, and reacting for 1-2h while timing.
After the reaction is finished, adding 100ml of water and 4.77g (58.8mmol) of sodium thiocyanate into the reaction solution, heating to 20-25 ℃, extracting for 15min, standing for phase separation, discarding the organic phase, extracting the water phase for 15min by using 50ml of ethyl acetate, standing for phase separation, discarding the organic phase, adding activated carbon into the water phase, decoloring for half an hour, performing suction filtration, adjusting the pH of the water phase to 2.2-2.7 by using 1mol/L hydrochloric acid solution, performing crystal growth for 0.5h at 20-25 ℃, cooling to 0-5 ℃ for crystal growth for 2h, and performing suction filtration to obtain a target product
164.0g of cefotaxime acid, 95.0 percent of product molar yield and 98.9 percent of purity. 7-ACA residue less than 0.05%; genotoxic impurity M is less than 5.2 ppm; the polymer content was 0.06%.
Example 7:
taking 10.0g (36.7mmol) of 7-ACA in a three-neck flask, taking 94ml of toluene and 5ml of isopropanol as reaction solvents, uniformly stirring, cooling to-10-10 ℃, adding 5.95g (58.8mmol) of diisopropylamine while stirring, controlling the temperature to-10-10 ℃, adding 14.2g (38.54mmol) of MEAM, and reacting for 1-2h while timing.
After the reaction is finished, adding 100ml of water and 4.82g (58.8mmol) of sodium acetate into the reaction solution, heating to 20-25 ℃, extracting for 15min, standing for phase separation, discarding the organic phase, extracting for 15min by using 70ml of dichloromethane for the aqueous phase, standing for phase separation, discarding the organic phase, adding activated carbon into the aqueous phase, decoloring for half an hour, then performing suction filtration, adjusting the pH of the aqueous phase to 2.2-2.7 by using 1mol/L hydrochloric acid solution, performing crystal growth for 0.5h at 20-25 ℃, cooling to 0-5 ℃ for crystal growth for 2h, and performing suction filtration to obtain 164.0g of target product cefotaxime acid, wherein the molar yield of the product is 95.0%, and the purity is 99.2%. 7-ACA residue less than 0.05%; genotoxic impurity M is less than 3.2 ppm; the polymer content was 0.08%.
In order to more intuitively show the advantages of the reaction process, the method for detecting the 2-mercaptobenzothiazole adopts a sodium salt forming agent method and an equivalent replacement method for the same process for comparison, wherein the detection method of the 2-mercaptobenzothiazole adopts an external standard method and utilizes high performance liquid chromatography for detection, and the detection conditions are as follows:
a chromatographic column: octadecylsilane chemically bonded silica is used as a filler; flow rate: 1.0ml/min detection wavelength: column temperature at 320 nm: sample volume at 30 ℃: 20 mu l of the mixture; mobile phase: ammonium acetate solution (1.9g to 2000ml water) acetic acid adjusted ph 5.5: acetonitrile 40: 60; and (3) dissolving phase: 60% acetonitrile solution; impurity stock solution: precisely weighing 24mg of 2-mercaptobenzothiazole, placing the 2-mercaptobenzothiazole in a 100ml volumetric flask, adding a proper amount of a dissolving phase to dissolve and dilute the 2-mercaptobenzothiazole to a scale, shaking up, transferring 1ml of the dissolving phase, placing the dissolving phase in a 50ml volumetric flask, diluting the dissolving phase to the scale, and shaking up; control solution: transferring 1ml of impurity stock solution, placing the impurity stock solution in a 10ml volumetric flask, adding a dissolved phase to dilute the impurity stock solution to a scale, and shaking up the impurity stock solution; test solution: precisely weighing 400mg of the sample, placing the sample in a 10ml volumetric flask, adding the dissolved phase to dissolve and dilute the sample to a scale, and shaking up.
Comparative example 1:
the preparation method is the same as the embodiment except that: in the preparation process of the comparative example, no organic auxiliary agent isopropanol is added in the example;
table 1: effect of different reagents on product quality
Table 2: effect of different organic solvents on product quality in various examples
From the data analysis in table 1, it can be seen that:
compared with the comparative example 1, the difference is that no organic auxiliary agent isopropanol is added, and a single solvent is adopted as a reaction reagent, so that the product purity is lower;
according to the data analysis of the table 2, the following results are obtained:
the comparison between example 1 and example 2 shows that: when the organic solvent I is the same as the organic solvent II, the content of the impurity 2-mercaptobenzothiazole is increased, and the purity of the product is reduced; the mixed solvent has positive significance for improving the purity of the product.
Meanwhile, compared with the examples, the differences exist, wherein the organic solvent I and the organic solvent II are the best combination of the toluene and ethyl acetate, and the content of the impurity 2-mercaptobenzothiazole is lower and the purity of the product is higher.
In order to more intuitively show the advantages of the salt-forming reaction process, the invention compares the method of adopting the sodium salt-forming agent with the method of adopting equivalent replacement in the same process,
comparative example 2:
the preparation method is the same as the embodiment except that: in the preparation process of the comparative example, the sodium salt forming agent in the example was replaced with sodium hydroxide;
comparative example 3:
the preparation method introduces the national invention patent 201510508234.1 'one-pot synthesis method of cefotaxime acid' by way of reference;
table 3: effect of different reagents on product quality
From the data analysis in table 3, it can be seen that:
in the comparative example 2, under the strong alkali condition, the cephalosporin beta-lactam ring is easy to generate ring-opening reaction, so that the product yield is low, and meanwhile, a plurality of byproducts are added, thereby affecting the product quality.
In comparative example 3, organic base is added into an organic phase containing cefotaxime acid, the reaction is continued to be carried out under heat preservation, water is added after the reaction is finished, a water phase is taken out in a layered mode, crystal growing, filtering, washing and drying are carried out, and cefotaxime acid is obtained.
According to the embodiment of the invention, cefotaxime acid is converted into cefotaxime sodium by adopting a sodium salt forming agent, then the water-insoluble organic solvent II is used for extraction, 2-mercaptobenzothiazole is transferred into the organic solvent II, and the cefotaxime sodium in the water phase is converted into the cefotaxime acid after the pH value is adjusted, so that the phenomena of high impurity level and the like caused by direct crystallization of a product are avoided, and the operation is convenient. The molar yield of the process can reach 98% or more, the product purity is 98.5% or more, and the maximum single unknown impurity is controlled below 0.3%;
as another embodiment of the present invention, it is,
(1) preparation of the condensation solution
Adding an organic solvent I into a reactant 7-ACA, adding MEAM to react under the action of a catalyst to obtain an organic phase containing cefotaxime acid, wherein the catalyst is diisopropylamine or N, N-diisopropylethylamine, the molar ratio of the 7-ACA to the catalyst is 1 (1.4-2.0), and the molar ratio of the 7-ACA to the MEAM is 1 (1.05-1.2);
the organic solvent I is a mixture of isopropanol and an organic auxiliary agent, and the organic auxiliary agent is one of dichloromethane, ethyl acetate and toluene;
the mass volume ratio of the 7-ACA to the organic solvent 1 is 1g (6-12) ml;
(2) salt-forming reaction
Adding water and a sodium salt forming agent into an organic phase containing cefotaxime acid, and separating liquid to obtain a salifying reaction solution containing cefotaxime sodium, wherein the sodium salt forming agent is sodium carbonate or sodium bicarbonate or sodium thiocyanate or sodium acetate;
(3) genotoxic impurity removal
Adding an organic solvent II into a salifying reaction solution for extraction, adjusting the pH to 6.5-7.0 by using acetic acid, standing, separating a water phase, and adding activated carbon into the water phase for decolorization;
the organic solvent II is one of dichloromethane, ethyl acetate and toluene;
(4) preparation of finished product
And (3) after decoloring and suction filtration, adjusting the pH value to 2.2-2.8 by using dilute hydrochloric acid for crystallization, cooling, growing crystals, suction filtration, washing with water and ethyl acetate, and drying to obtain a dry cefotaxime acid product.
In order to better understand the present invention, the specific embodiments are specifically illustrated, and it is emphasized that the effects of the embodiments are not substantially different from the various embodiments within the scope of the present invention, and the effects described in the present invention and the above problems can be achieved; the method comprises the following specific steps:
example 8:
the preparation method is the same as the embodiment except that: in the preparation process of the comparative example, the organic solvent II in the step (3) in the embodiment is added into a salt forming reaction solution for extraction, acetic acid is also used for adjusting the pH value to 6.5-7.0, the water phase is separated after standing, and then activated carbon is added into the water phase for decoloration;
comparative example 4:
preparation method the national invention patent 201511010952.2 "a preparation method of cefotaxime acid" is introduced by reference:
table 4: influence of different acid regulating processes on gene impurity removal
Examples 1-7 compared to comparative example 3:
comparative example 3 is that the aqueous solution containing cefotaxime sodium and 2-mercaptobenzothiazole impurities is added with acetone and directly acidified to grow the crystals of cefotaxime acid, 2-mercaptobenzothiazole and cefotaxime acid exist in an organic form, and the acetone and water are mutually soluble, so that the 2-mercaptobenzothiazole and the cefotaxime acid are mixed together in the organic form and are difficult to distinguish and remove;
in the examples 1-7, one of dichloromethane, ethyl acetate and toluene is added into the aqueous solution containing cefotaxime sodium and 2-mercaptobenzothiazole impurities, most of 2-mercaptobenzothiazole is dissolved in an organic solvent II and separated from the water phase of the product, and the separated water phase is acidified, so that the impurity content is low;
examples 1-7 compare example 8: adjusting the pH value to weak acidity before extraction, namely adjusting the pH value to 6.5-7.0 by using acetic acid, wherein the cefotaxime acid exists in an aqueous phase in the form of cefotaxime salt, the 2-mercaptobenzothiazole is completely dissolved in an organic phase in the pH range, and then the aqueous phase is separated after standing, and the 2-mercaptobenzothiazole dissolved in the organic phase is further removed;
in summary, the following steps: the method adopts a sodium salt forming agent to convert cefotaxime acid into cefotaxime sodium, then utilizes a water-insoluble organic solvent II for extraction, transfers 2-mercaptobenzothiazole to the organic solvent II, and converts the cefotaxime sodium in a water phase into cefotaxime acid after adjusting the pH value, thereby avoiding the phenomena of high impurity level and the like caused by direct crystallization of products and having convenient operation. The molar yield of the process can reach 98% or more, the product purity is 98.5% or more, and the maximum single unknown impurity is controlled below 0.3%;
according to the method, before water-soluble cefotaxime sodium is completely acidified into cefotaxime acid, acetic acid is used for adjusting the pH value to 6.5-7.0 to be in a weak acid state, and an organic solvent is added for extraction, so that the 2-mercaptobenzothiazole is further transferred to an organic phase effectively, the cefotaxime sodium is retained in a water phase, separation is realized, and the problem that the 2-mercaptobenzothiazole and the cefotaxime acid are difficult to separate and remove is solved.
Claims (8)
1. A preparation method of high-purity cefotaxime acid is characterized by comprising the following steps:
(1) adding the reactant 7-ACA into an organic solvent I and an organic auxiliary agent, adding MEAM to react under the action of a catalyst to obtain an organic phase containing cefotaxime acid,
(2) adding water and sodium salt forming agent into an organic phase containing cefotaxime acid, separating liquid to obtain salifying reaction solution containing cefotaxime sodium,
(3) adding an organic solvent II into a salifying reaction solution for extraction, and adding activated carbon into a water phase for decolorization;
(4) and (3) after decoloring and suction filtration, adjusting the pH value to 2.2-2.8 by using dilute hydrochloric acid for crystallization, cooling, growing crystals, suction filtration, washing with water and ethyl acetate, and drying to obtain a dry cefotaxime acid product.
2. The process for preparing cefotaxime acid in high purity according to claim 1, wherein the catalyst is diisopropylamine or N, N-diisopropylethylamine, and the molar ratio of 7-ACA to the catalyst is 1 (1.4-2.0).
3. The process for preparing cefotaxime acid in high purity according to claim 1, wherein the molar ratio of 7-ACA to MEAM is 1 (1.05-1.2).
4. The method for preparing cefotaxime acid with high purity according to claim 1, wherein the organic auxiliary is isopropanol, and the organic solvent I is one of dichloromethane, ethyl acetate and toluene.
5. The method for preparing cefotaxime acid with high purity according to claim 1, wherein the organic solvent II is one of dichloromethane, ethyl acetate and toluene.
6. The process for preparing cefotaxime acid in high purity according to claim 1, wherein the mass/volume ratio of 7-ACA to organic solvent 1 is 1g (6-12) ml.
7. The method for preparing cefotaxime acid in high purity according to claims 1-6, wherein the sodium salt forming agent is sodium carbonate or sodium bicarbonate or sodium thiocyanate or sodium acetate.
8. The method for preparing cefotaxime acid with high purity according to claim 7, wherein the organic solvent II is added into the salt-forming reaction solution for extraction in the step (3), acetic acid is used for adjusting the pH value to 6.5-7.0 for impurity removal, the aqueous phase is separated after standing, and then activated carbon is added into the aqueous phase for decoloration.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105503904A (en) * | 2015-12-30 | 2016-04-20 | 河南康达制药有限公司 | Preparation method for cefotaxime acid |
| CN108586490A (en) * | 2018-04-04 | 2018-09-28 | 淄博鑫泉医药技术服务有限公司 | The preparation method of cefotaxime acid |
| CN110117291A (en) * | 2019-06-24 | 2019-08-13 | 华北制药股份有限公司 | A kind of synthetic method of cefotaxime acid |
-
2021
- 2021-12-31 CN CN202111676312.0A patent/CN114409677B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105503904A (en) * | 2015-12-30 | 2016-04-20 | 河南康达制药有限公司 | Preparation method for cefotaxime acid |
| CN108586490A (en) * | 2018-04-04 | 2018-09-28 | 淄博鑫泉医药技术服务有限公司 | The preparation method of cefotaxime acid |
| CN110117291A (en) * | 2019-06-24 | 2019-08-13 | 华北制药股份有限公司 | A kind of synthetic method of cefotaxime acid |
Non-Patent Citations (8)
| Title |
|---|
| 唐双强，等: "头孢噻肟酸的合成工艺研究", 《河北化工》 * |
| 孙津鸽，等: "头孢噻肟酸合成工艺的研究", 《广东化工》 * |
| 张军立，等: "头孢噻肟酸合成方法研究", 《河北化工》 * |
| 方时亮，等: "头孢噻肟酸合成新方法研究", 《化学世界》 * |
| 洪玲娟，等: "头孢噻肟酸的环境友好合成工艺", 《浙江化工》 * |
| 胡文滨，等: "头孢噻肟酸的合成", 《河北化工》 * |
| 胡文滨，等: "新方法合成头孢噻肟酸", 《河北省科学院学报》 * |
| 赵德明，等: "头孢噻肟酸的合成研究", 《浙江工业大学学报》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116655559A (en) * | 2023-04-19 | 2023-08-29 | 济宁市食品药品检验检测研究院(济宁市药品不良反应监测中心) | Process and device for recovering 2-mercaptobenzothiazole from cefotaxime acid mother liquor |
| CN116655559B (en) * | 2023-04-19 | 2024-04-09 | 济宁市食品药品检验检测研究院(济宁市药品不良反应监测中心) | Process and device for recovering 2-mercaptobenzothiazole from cefotaxime acid mother liquor |
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