A preparation method of cefotaxime acid

Abstract

The present invention provides a preparation method of cefotaxime acid. The method uses 1-ethyl-2,3-dimethylimidazolium bromide or 1-butyl-2,3-dimethylimidazolium bromide as a catalyst, uses dichloromethane and isopropanol as solvents, reacts 7-ACA and AE-active ester in the presence of an appropriate amount of aqueous sodium bisulfite solution and triethylamine, after the reaction is completed, extracts with purified water, decolorizes the aqueous phase with activated carbon, filters, adds acetone, adjusts the pH for crystallization, and controls the crystallization temperature to obtain the target product cefotaxime acid. The preparation method of the present invention not only shortens the reaction time, but also reduces the impurity content, especially reduces the contents of impurity M and impurity N, and improves the product purity and yield. And this method has a simple process, has low requirements for equipment, has a simple post-treatment method, low cost, is convenient for industrial production, and has good application prospects.

Description

Technical Field

[0001] The present invention belongs to the field of organic chemical synthesis, and particularly relates to a method for preparing cefotaxime acid. Background Art

[0002] Cefotaxime acid, whose chemical name is (6R,7R)-3-[(acetyloxy)methyl]-7-[(2-amino-4-thiazolyl)-(methoxyimino)acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, is the main raw material for synthesizing cefotaxime sodium for injection, the third-generation antibacterial drug. Cefotaxime sodium is a third-generation cephalosporin, which was first marketed in Germany in 1980. It was developed by Hoechst Company in Germany and Roussel Company in France. It acylates the amino group at the 7th position of the cephalosporin skeleton with aminothiazolyl-cis-methoxyiminoacetyl group, and has good antibacterial activity against G(-) bacilli and drug-resistant bacteria. Clinically, it is mainly used for pneumonia and other lower respiratory tract infections, urinary tract infections, meningitis, septicemia, abdominal infections, pelvic infections, skin and soft tissue infections, genital tract infections, bone and joint infections, etc. caused by sensitive bacteria.

[0003] The product quality of cefotaxime sodium is related to the allergic reactions that occur clinically, and the impurity level in cefotaxime acid is directly related to the quality of cefotaxime sodium. At present, the synthetic methods of cefotaxime acid include the active ester method, the acid anhydride method, and the acyl chloride method. The method mainly used in industrial production is the active ester method. Commonly used active esters include AE-active ester, phosphorus-containing active ester, thiadiazole active ester, triazinone active ester, and benzotriazole active ester, among which the AE-active ester method is the most commonly used. Patent CN101560217A discloses a method using chloroform as a reaction solvent, reacting AE-active ester with 7-ACA, and directly adjusting the pH to obtain cefotaxime acid without extraction. The cefotaxime acid obtained by this method has a high impurity level. Therefore, after being prepared into cefotaxime sodium, the impurities are difficult to be effectively controlled. Patent CN101613360 discloses a method using dichloromethane as a reaction solvent, adding AE-active ester, 7-ACA, and triethylamine in sequence under stirring for reaction. After the reaction is completed, purified water is used for extraction, and the aqueous phase is decolorized, filtered, and the pH is adjusted for crystallization to obtain cefotaxime acid. However, the unknown impurities of the cefotaxime acid obtained by this method are relatively high. Therefore, after being prepared into cefotaxime sodium, the impurities are also difficult to be effectively controlled. Patent US20070004916A1 discloses a method for obtaining cefotaxime acid by reacting 7-ACA with 2-(2-chloroacetamidothiazol-4-yl)-2-Z-methoxyiminoacetyl chloride. This method has high requirements for moisture, and the reaction conditions are relatively harsh. In addition, the cost of 2-(2-chloroacetamidothiazol-4-yl)-2-Z-methoxyiminoacetyl chloride used is relatively high, and there are few manufacturers.

[0004] In summary, the existing methods have problems such as high impurity levels in the product, resulting in low product purity, or high raw material prices, being economically unfeasible, or having many synthesis steps and low product yield, or relatively harsh reaction conditions, not being suitable for industrial production, etc. Therefore, developing a preparation method for cefotaxime acid with high product yield, low impurity content, and high purity has become a current research hotspot. Summary of the Invention

[0005] In view of the deficiencies of the existing technology, the technical problem to be solved by the present invention is to provide a preparation method for cefotaxime acid with high yield, low impurity content, high purity, easy purification, simple post-treatment method, low cost, and convenient for industrial production.

[0006] To achieve the object of the present invention, the following technical solutions are adopted:

[0007] The present invention provides a preparation method for cefotaxime acid, and the method comprises the following steps:

[0008] Step 1:

[0009] Add a mixed solvent composed of dichloromethane and isopropanol to the reaction tank, cool down to 10°C - 15°C, then add an appropriate amount of aqueous sodium bisulfite solution, and then add 7-ACA and a catalyst. Control the temperature at 10°C - 15°C, and then dropwise add triethylamine. When the solution temperature drops to -5°C - 5°C, add AE-active ester, and control the reaction temperature at 8°C - 15°C for reaction. The reaction time is 40 - 60 min to obtain a reaction solution; the catalyst is one of 1-ethyl-2,3-dimethylimidazolium bromide or 1-butyl-2,3-dimethylimidazolium bromide; the mass ratio of 7-ACA to AE-active ester is 1:1.3 - 1.5; the volume ratio of dichloromethane to isopropanol is 7 - 8:1; the mass-volume ratio (g / mL) of 7-ACA to the mixed solvent is 1:8 - 8.5; the mass-volume ratio of 7-ACA to triethylamine is (g / mL) 1:0.5 - 0.7; the addition amount of the catalyst is 0.2 - 2% of the mass of 7-ACA; the reaction equation is as follows:

[0010]

[0011] Step 2:

[0012] Add purified water to the reaction solution obtained in Step 1 for extraction twice, combine the aqueous phases, add activated carbon for decolorization, then perform plate-and-frame filtration, wash with purified water, and collect the filtrate;

[0013] Step 3:

[0014] Add acetone to the filtrate obtained in Step 2, control the temperature at 15°C - 25°C, slowly dropwise add hydrochloric acid, stop adding when the pH value reaches 4.0 - 5.0, stir until crystallization occurs, stop stirring after crystallization for 25 - 35 min, continue to dropwise add hydrochloric acid until the pH value of the solution is 2.5 - 3.5, then cool down to 10°C and stir for 30 - 40 min, filter the well-crystallized solution, control the temperature at 10°C, wash twice with acetone, and finally dry under vacuum to obtain the target product cefotaxime acid; the cefotaxime acid contains impurity M, and the mass content of impurity M is within 0.02%; the cefotaxime acid contains impurity N, and the mass content of impurity N is within 3.0 ppm;

[0015]

[0016] Preferably, in Step 1:

[0017] The mass ratio of the 7-ACA to the AE-active ester is 1:1.4.

[0018] The volume ratio of the dichloromethane to the isopropanol is 7.3:1.

[0019] The mass-volume ratio (g / mL) of the 7-ACA to the triethylamine is 1:0.6.

[0020] The addition amount of the catalyst is 0.8% of the mass of the 7-ACA.

[0021] Preferably, in Step 2:

[0022] Cool down the reaction solution obtained in Step 1 to 5°C, then add ice-cold purified water, and perform extraction twice at 10°C - 15°C.

[0023] Preferably, in Step 3:

[0024] The temperature of the vacuum drying is 30°C - 40°C, and the time of the vacuum drying is 40 - 60 min.

[0025] The present invention has the following beneficial effects compared with the prior art:

[0026] The present invention provides a method for preparing cefotaxime acid. This method uses 1-ethyl-2,3-dimethylimidazolium bromide or 1-butyl-2,3-dimethylimidazolium bromide as a catalyst, which not only shortens the reaction time but also can well reduce the generation amount of impurities, especially the generation amounts of impurity M and impurity N, and improves the purity and yield of the product. At the same time, by limiting the mass ratio of 7-ACA to AE-active ester, the volume ratio of dichloromethane to isopropanol, adding an appropriate amount of aqueous sodium bisulfite solution, and controlling the pH and crystallization temperature of crystallization, the content of impurities is further reduced, especially the contents of impurity M and impurity N, and the product purity and yield are significantly improved. Moreover, this method has a simple process, low requirements for equipment, a simple post-treatment method, low cost, is convenient for industrial production, and has good application prospects. Detailed implementation manners

[0027] The following details the embodiments of the present invention. The examples are given to better illustrate the content of the present invention and are only used to explain the present invention, and should not be construed as a limitation to the present invention.

[0028] For those not specifying specific techniques or conditions in the examples, they shall be in accordance with the techniques or conditions described in the literature in this field or in accordance with the product specifications. For reagents or instruments not indicating the manufacturer, they are all conventional products that can be obtained through regular channels.

[0029] Example 1

[0030] Add a mixed solvent composed of 73 mL of dichloromethane and 10 mL of isopropanol to the reaction kettle, cool down to 12 °C, then add 5 mL of aqueous sodium bisulfite solution, stir evenly, and then add 10.0 g of 7-ACA and 0.08 g of catalyst 1-ethyl-2,3-dimethylimidazolium bromide, stir, control the temperature at 12 °C, then dropwise add 6 mL of triethylamine, and when the solution temperature is cooled to -3 °C after stirring, add 14.0 g of AE-active ester, stir evenly and then control the reaction temperature at 12 °C for reaction, the reaction time is 50 min, and a reaction solution is obtained. Then cool the obtained reaction solution to 5 °C, add ice-cold purified water, extract twice at 12 °C, add activated carbon to the combined aqueous phase for decolorization, stir for 30 min and then filter through a plate and frame, wash with purified water, and collect the filtrate. Then add 35 mL of acetone to the obtained filtrate, control the temperature at 20 °C, slowly dropwise add hydrochloric acid, stop dropping when the pH value = 4.5, stir until crystallization, stop stirring after crystallization for 30 min, continue to dropwise add hydrochloric acid until the solution pH value = 3.0, then cool down to 10 °C and stir for 35 min, filter the crystallized solution, control the temperature at 10 °C, wash twice with acetone, and finally dry in vacuo at 35 °C for 50 min to obtain 16.54 g of the target product cefotaxime acid, the product yield is 98.9%, the purity detected by HPLC is 99.5%, the mass content of impurity M is 0.01%, and the mass content of impurity N is 2.0 ppm, as shown in Table 1.

[0031] Example 2

[0032] Add a mixed solvent composed of 73 mL of dichloromethane and 10 mL of isopropanol to the reaction kettle, cool down to 12 °C, then add 5 mL of aqueous sodium bisulfite solution, stir evenly, and then add 10.0 g of 7-ACA and 0.08 g of catalyst 1-butyl-2,3-dimethylimidazolium bromide, stir, control the temperature at 12 °C, then dropwise add 6 mL of triethylamine, and when the solution temperature drops to -3 °C after stirring, add 14.0 g of AE-active ester, stir evenly and then control the reaction temperature at 12 °C for reaction, the reaction time is 50 min to obtain a reaction solution. Then cool the obtained reaction solution to 5 °C, add ice-cold purified water, extract twice at 12 °C, add activated carbon to the combined aqueous phase for decolorization, stir for 30 min and then filter through a plate and frame, wash with purified water, and collect the filtrate. Then add 35 mL of acetone to the obtained filtrate, control the temperature at 20 °C, slowly dropwise add hydrochloric acid, stop dropping when the pH value = 4.5, stir until crystallization, stop stirring after crystallization for 30 min, continue to dropwise add hydrochloric acid until the solution pH value = 3.0, then cool down to 10 °C and stir for 35 min, filter the crystallized solution, control the temperature at 10 °C, wash twice with acetone, and finally dry in vacuo at 35 °C for 50 min to obtain 16.41 g of the target product cefotaxime acid, the product yield is 98.1%, the HPLC detection purity is 99.4%, the mass content of impurity M is 0.01%, and the mass content of impurity N is 2.5 ppm, as shown in Table 1.

[0033] Comparative Example 1

[0034] Add a mixed solvent composed of 73 mL of dichloromethane and 10 mL of isopropanol to the reaction kettle, cool down to 12 °C, then add 5 mL of aqueous sodium bisulfite solution, stir evenly, and then add 10.0 g of 7-ACA, stir. Control the temperature at 12 °C, then dropwise add 6 mL of triethylamine. After stirring, when the solution temperature drops to -3 °C, add 14.0 g of AE-activator ester, stir evenly, and then control the reaction temperature at 12 °C for reaction. The reaction time is 50 min to obtain the reaction solution. Then cool down the obtained reaction solution to 5 °C, add ice-cold purified water, and perform extraction twice at 12 °C. Combine the aqueous phases, add activated carbon for decolorization after combination, stir for 30 min, then filter through a plate and frame, wash with purified water, and collect the filtrate. Then add 35 mL of acetone to the obtained filtrate, control the temperature at 20 °C, slowly dropwise add hydrochloric acid, stop adding when the pH value = 4.5, stir until crystallization occurs, stop stirring after crystallization for 30 min, continue to dropwise add hydrochloric acid until the solution pH value = 3.0, then cool down to 10 °C and stir for 35 min. Filter the crystallized solution, control the temperature at 10 °C, wash twice with acetone, and finally dry in vacuum at 35 °C for 50 min to obtain 14.91 g of the target product cefotaxime acid. The product yield is 89.1%, the purity detected by HPLC is 94.9%, the mass content of impurity M is 0.65%, and the mass content of impurity N is 402.8 ppm, as shown in Table 1.

[0035] Table 1: Influence of the catalyst on the preparation of cefotaxime acid

[0036]

[0037] As can be seen from Table 1, for the preparation method of cefotaxime acid provided by the present invention, since 1-ethyl-2,3-dimethylimidazolium bromide or 1-butyl-2,3-dimethylimidazolium bromide is used as the catalyst, not only the reaction time is shortened, but also the generation amount of impurities can be well reduced, especially the generation amounts of impurity M and impurity N are reduced, and the purity and yield of the product are significantly improved.

[0038] Obviously, the above embodiments are only examples for clearly illustrating the present invention, and are not limitations on the implementation manners of the present invention. Those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalent technologies, the present invention also intends to include these modifications and variations.

Claims

1. A method for preparing cefotaxime acid, characterized in that: The method comprises the following steps: Step 1: A mixed solvent consisting of dichloromethane and isopropanol is added to the reaction tank, the temperature is lowered to 10°C-15°C, an appropriate amount of sodium bisulfite aqueous solution is added, and then 7-ACA and a catalyst are added, the temperature is controlled to be 10°C-15°C, and triethylamine is added dropwise. When the solution temperature is lowered to -5°C-5°C, AE-active ester is added, the reaction temperature is controlled to be 8°C-15°C for reaction, and the reaction time is 40-60min to obtain a reaction solution; the catalyst is 1-ethyl-2,3-dimethylimidazolium bromide or 1- One of butyl-2,3-dimethylimidazolium bromide; the mass ratio of 7-ACA to AE-active ester is 1:1.3-1.5; the volume ratio of dichloromethane to isopropanol is 7-8:1; the mass volume ratio (g / mL) of 7-ACA to mixed solvent is 1:8-8.5; the mass volume ratio of 7-ACA to triethylamine is (g / mL) 1:0.5-0.7; the amount of the catalyst added is 0.8% of the mass of 7-ACA; the reaction equation is as follows: Step 2: The reaction solution obtained in step 1 was cooled to 5°C, and then ice purified water was added, and extraction was performed twice at 10°C-15°C. After the aqueous phases were combined, activated carbon was added for decolorization, and then plate and frame filtration was performed, and purified water was washed to collect the filtrate; Step 3: Add acetone to the filtrate obtained in step 2, control the temperature to 15°C-25°C, slowly drop hydrochloric acid, stop dropping when the pH value reaches 4.0-5.0, stir until crystallization, stop stirring after 25-35 minutes of crystallization, continue to drop hydrochloric acid until the pH value of the solution reaches 2.5-3.5, then cool to 10°C and stir for 30-40 minutes, filter the crystallized solution, control the temperature at 10°C, wash twice with acetone, and finally vacuum dry to obtain the target product cefotaxime acid; the cefotaxime acid contains impurity M, and the mass content of impurity M is within 0.02%; the cefotaxime acid contains impurity N, and the mass content of impurity N is within 3.0ppm; 2. The preparation method according to claim 1, characterized in that: The mass ratio of 7-ACA to AE-active ester in step 1 is 1:1.

4.

3. The preparation method according to claim 1, characterized in that: The volume ratio of dichloromethane to isopropanol in step 1 is 7.3:

1.

4. The preparation method according to claim 1, characterized in that: The mass volume ratio (g / mL) of 7-ACA and triethylamine described in step 1 is 1:0.

6.

5. The preparation method according to claim 1, characterized in that: The vacuum drying temperature in step 3 is 30° C.-40° C., and the vacuum drying time is 40-60 min.

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