A method for continuously preparing sodium cefotaxime

Abstract

The application relates to the technical field of chemical synthesis, and particularly discloses a method for continuously preparing cefotaxime sodium, which comprises the following steps: mixing 7-aminocephalosporanic acid, an AE active ester, a phase transfer catalyst, water and anhydrous dichloromethane to prepare a suspension, continuously passing the obtained clear liquid through a catalyst column compounded by sodium carbonate and sodium bicarbonate after solid-liquid separation, recycling the effluent and mixing the effluent with the separated solid, and preparing cefotaxime sodium after multiple circulation reactions. The method can maintain a stable weak alkaline environment for the reaction system by cooperation of the composite alkali catalyst column and the circulation reaction mode, reduces the degradation of the cephalosporin nucleus and the generation of by-products, simultaneously realizes synchronous condensation reaction and salt crystallization, and realizes the synchronous precipitation of the product with the generation of the product. The method can improve the reaction conversion rate and the product purity, obtain crystal products with regular morphology and excellent powder performance, simplifies the process steps, and is easy to operate and has good industrial amplification production conditions.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, and in particular to a method for the continuous preparation of cefotaxime sodium. Background Technology

[0002] Cefotaxime sodium belongs to the third-generation semi-synthetic cephalosporin antibiotics. It has advantages such as a broad antibacterial spectrum, strong bactericidal effect, and high stability against β-lactamases, and is a commonly used drug in clinical anti-infective treatment. The current production of cefotaxime sodium generally adopts a stepwise batch preparation process: 7-aminocephalosporanic acid (7-ACA) is used as the starting material, and it undergoes a condensation reaction with AE active ester in a mixed solvent system of dichloromethane and ethanol. After the residual amount of 7-ACA reaches the standard, dichloromethane and water are added to the reaction solution for extraction and phase separation. After multiple water washings and merging of the aqueous phases, the solution is decolorized and filtered to obtain a cefotaxime acid crystallization solution. Hydrochloric acid is added to the crystallization solution to adjust the pH value and allow cefotaxime acid to crystallize out. Cefotaxime acid is then added to an aqueous mixed solvent, and sodium carbonate is added to form a salt, resulting in a cefotaxime sodium crystallization solution. Finally, an organic solvent is added to the cefotaxime sodium crystallization solution to crystallize, yielding the finished cefotaxime sodium product.

[0003] However, this traditional process has several shortcomings in actual production: First, the process route is lengthy, involving multiple extraction steps, two crystallization processes, and multiple drying operations, resulting in complex procedures, a long overall production cycle, and high material loss during multi-step transfer and processing, leading to low product yield and high energy and labor costs. Second, the multi-step separation and purification process increases the risk of impurity introduction, and the final crystalline product has poor powder properties, with uneven particle size distribution and poor flowability, making it unsuitable for subsequent formulation packaging processes and potentially negatively impacting the uniformity of the formulation product quality.

[0004] Therefore, developing a method for preparing cefotaxime sodium with a short process route, high yield, and excellent product powder properties is of great practical value for the efficient industrial production of cefotaxime sodium. Summary of the Invention

[0005] To address the problems of lengthy process routes, complex procedures, low product yield, and poor powder properties in existing technologies, this invention provides a continuous method for preparing cefotaxime sodium. This invention involves continuously passing a suspension of 7-ACA, AE active ester, and tetrabutylammonium bromide through a catalyst column containing a specific ratio of sodium carbonate and sodium bicarbonate. Condensation and salt formation reactions occur simultaneously within the column, resulting in a direct cefotaxime sodium solution after the reaction liquid flows out. Following washing and drying, the final cefotaxime sodium product is obtained. This method significantly shortens the process route, effectively reduces material transfer and processing losses, thereby significantly improving product yield; simultaneously, the flowability of the resulting powder is significantly improved.

[0006] To solve the above-mentioned technical problems, the technical solution provided by the present invention is as follows: A method for continuous preparation of cefotaxime sodium includes the following steps: 7-Aminocephalosporanic acid, AE active ester, phase transfer catalyst, water and dichloromethane were mixed to obtain a suspension; The suspension is subjected to solid-liquid separation. The resulting clear liquid is continuously passed through a catalyst column containing sodium carbonate and sodium bicarbonate. The resulting effluent is recycled back and mixed with the solid obtained from the solid-liquid separation. The solid-liquid separation and passing through the catalyst column are repeated. This cycle is repeated until the reaction is completed to obtain cefotaxime sodium. The mass ratio of sodium carbonate to sodium bicarbonate in the catalyst column is 1:3.0 to 1:3.2.

[0007] Compared to existing technologies, the continuous preparation method of cefotaxime sodium provided by this invention uses dichloromethane and a trace amount of water as reaction solvents. A phase transfer catalyst is used to simultaneously carry out condensation and salt formation reactions in a catalyst column containing sodium carbonate and sodium bicarbonate. During the reaction, the cefotaxime acid generated during condensation rapidly forms a salt in situ upon contact with sodium ions dissolved in the catalyst column. Since cefotaxime sodium has extremely low solubility in dichloromethane, the product is promptly precipitated from the reaction phase in crystalline form. This method of product precipitation upon formation not only disrupts the chemical equilibrium of the condensation reaction, significantly improving the reaction conversion rate and molar yield, but also allows for controlled crystal growth due to the uniform alkaline environment provided by the catalyst column and the low-solubility system. This results in rod-shaped crystals with regular morphology, high bulk density, and good flowability, thereby improving the poor powder properties of products from traditional processes.

[0008] Furthermore, using a catalyst column with a mass ratio of sodium carbonate to sodium bicarbonate of 1:3.0 to 1:3.2 avoids the problems of excessively fast reaction rate and increased impurities in cephalosporin nucleus degradation when using pure sodium carbonate, while also improving the shortcomings of slow reaction rate and low raw material conversion rate in the pure sodium bicarbonate system. This provides a stable and gentle weakly alkaline buffer environment for the salt formation reaction, thereby maintaining the pH of the system within a suitable range. While ensuring the reaction rate, this effectively reduces the generation of by-products and simultaneously improves product purity and reaction conversion rate.

[0009] Furthermore, the mass ratio of 7-aminocephalosporanic acid to AE active ester is 1:1.38 to 1:1.40.

[0010] Furthermore, the phase transfer catalyst is tetrabutylammonium bromide.

[0011] Furthermore, the mass ratio of 7-aminocephalosporanic acid to the phase transfer catalyst is 10:0.9 to 10:1.

[0012] Using tetrabutylammonium bromide as a phase transfer catalyst and controlling its addition within the above range can improve the mass transfer effect at the interface between water and dichloromethane, making the dissolution and reaction of 7-aminocephalosporanic acid more complete, thereby increasing the reaction conversion rate and product yield.

[0013] Furthermore, the mass ratio of 7-aminocephalosporanic acid to water is 100:1.9 to 100:2.1.

[0014] The small amount of water at this ratio provides the necessary medium for the ion dissolution of the compound base in the catalyst column, ensuring the stable functioning of the buffer system and maintaining a stable and controllable reaction pH. At the same time, it can assist the phase transfer catalyst in enhancing the mass transfer efficiency between the two phases and promoting the condensation and salt formation reactions. In addition, this amount of water can moderately adjust the solubility of cefotaxime sodium in the system, ensuring a smooth crystallization process and regular crystal morphology, while avoiding the risk of product dissolution loss and core degradation caused by excessive water.

[0015] Furthermore, the mass-to-volume ratio of 7-aminocephalosporanic acid to dichloromethane is 1g:10mL to 1g:11mL.

[0016] This feed-to-liquid ratio allows 7-aminocephalosporanic acid and reactants to form a uniformly dispersed suspension in anhydrous dichloromethane. This ensures good flowability and mass transfer of the materials, meeting the requirements of continuous circulating column chromatography, while avoiding excessive solvent consumption that would reduce production efficiency and increase solvent recovery costs.

[0017] Furthermore, the dichloromethane is anhydrous dichloromethane.

[0018] Using anhydrous dichloromethane as the reaction solvent helps to accurately control the total water content of the system, build a stable reaction environment, reduce the interference of additional water introduced by the solvent on the crystallization process and the stability of the parent nucleus, and ensure the controllability of product yield and quality.

[0019] Furthermore, the mass ratio of the 7-aminocephalosporanic acid to the total amount of sodium carbonate and sodium bicarbonate packed in the catalyst column is 100:44 to 100:47.

[0020] The above-mentioned amount of alkali can match the requirements of acid neutralization in the condensation reaction and salt formation of cefotaxime acid, maintaining a stable buffering effect over a long operating period.

[0021] Furthermore, the residence time of the clarified liquid in the catalyst column is 15s~25s.

[0022] The residence time of the clear liquid in the catalyst column is set to 15-25 seconds, which allows the liquid phase to fully contact the composite alkali packing material in the column, promoting the condensation and salt formation reactions. If the residence time is too short, the alkali component will not dissolve sufficiently, and the reaction will be incomplete. If the residence time is too long, it will easily cause local alkalinity to be too high, which will increase the risk of cephalosporin nucleus degradation and may cause the product to crystallize and deposit in the column.

[0023] In some specific embodiments of the present invention, the residence time of the clarified liquid in the catalyst column is controlled by adjusting the flow rate of the clarified liquid entering the catalyst column. Specifically, based on the effective packing volume of the catalyst column, a corresponding feed flow rate is set so that the residence time of the clarified liquid flowing through the column is maintained within the range of 15-25 seconds. For example, when the inner diameter of the catalyst column is 20 mm and the effective packing height is 150 mm, adjusting the flow rate of the clarified liquid entering the column to 110-190 mL / min can achieve the above-mentioned residence time. Controlling the residence time by adjusting the flow rate is simple to operate and highly accurate, which is beneficial for maintaining the stability of the alkali dissolution amount in the circulating reaction system and ensuring the consistency of the reaction effect in each batch.

[0024] Furthermore, the temperature of the clarified liquid passing through the catalyst column is 0℃~5℃.

[0025] Furthermore, the continuous cycle time is 2h~3h, and the reaction ends when the residual amount of 7-aminocephalosporanic acid in the reaction system is less than 2mg / mL.

[0026] In some specific embodiments of the present invention, after the reaction is completed, the mixture is filtered, the filter cake is washed with dichloromethane, and dried to obtain cefotaxime sodium.

[0027] It should be noted that the catalyst column mentioned in this invention refers to a column-type reaction device internally filled with a solid composite alkali (a mixture of sodium carbonate and sodium bicarbonate). The liquid-phase reactants flow through the device continuously, where condensation and salt formation reactions occur simultaneously on the surface of the solid alkali and at the liquid-solid interface, accompanied by the controlled dissolution of the alkali components, continuously providing the required alkaline environment for the reaction system. The solid composite alkali packing material of the catalyst column does not enter the main reaction system with the liquid flow during the circulating reaction, constituting a heterogeneous catalytic reaction unit, which differs from the homogeneous salt formation method in traditional processes where the alkali is directly added to the reaction liquid.

[0028] This invention also provides cefotaxime sodium, prepared by the continuous preparation method for cefotaxime sodium described in any of the preceding claims. The obtained cefotaxime sodium powder has a density of ≥0.45 g / mL, an angle of repose of ≤35°, and rod-shaped crystals. Compared with products obtained by traditional batch processes, this product has higher bulk density and better flowability, with a uniform particle size distribution, which better meets the requirements of material uniformity and operability in subsequent formulation dispensing processes, and is beneficial to improving the quality stability of the formulation product.

[0029] In summary, this invention discloses a continuous method for preparing cefotaxime sodium. A suspension is prepared by mixing 7-aminocephalosporanic acid, AE active ester, a phase transfer catalyst, water, and anhydrous dichloromethane. After solid-liquid separation, the resulting clear liquid is continuously passed through a catalyst column composed of sodium carbonate and sodium bicarbonate. The effluent is recycled and mixed with the separated solid. After multiple cycles of reaction, cefotaxime sodium is obtained. This method, through the combination of a composite alkali catalyst column and a cyclic reaction mode, maintains a stable weakly alkaline environment in the reaction system, reducing the degradation of cephalosporin nuclei and the generation of byproducts. Simultaneously, condensation reaction and salt formation crystallization occur concurrently, with the product precipitating as it is formed. This improves reaction conversion rate and product purity, yielding crystalline products with regular morphology and excellent powder properties. Furthermore, the process steps are simplified, material consumption and wastewater discharge are lower, and product quality is more stable between batches. The overall operation is simple, operating costs are controllable, and it possesses good conditions for industrial-scale production and practical application value. Attached Figure Description

[0030] Figure 1 This is a microscope image of the cefotaxime sodium prepared in Example 1 of the present invention; Figure 2 This is a microscope image of cefotaxime sodium prepared in Comparative Example 1 of the present invention. Detailed Implementation

[0031] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0032] To better illustrate the present invention, further examples are provided below.

[0033] Example 1 This embodiment provides a method for the continuous preparation of cefotaxime sodium, including the following steps: Add 100g of 7-aminocephalosporanic acid, 139g of AE active ester and 1050mL of anhydrous dichloromethane to the reactor, then add 9.5g of tetrabutylammonium bromide and 2g of water, and stir at 5℃ for 18min to obtain a suspension. The above suspension was filtered, and the resulting clear liquid was continuously passed through a catalyst column packed with 11.2 g of sodium carbonate and 35 g of sodium bicarbonate at a column temperature of 5 °C. The residence time of the clear liquid in the catalyst column was 20 s. The effluent was recycled back to the reactor, mixed with the solid material retained by filtration, and filtered again. The clear liquid continued to pass through the catalyst column. The reaction ended when the residual amount of 7-aminocephalosporanic acid in the reactor was less than 2 mg / mL. After the reaction was completed, the mixture was filtered, and the reactor and stirring device were rinsed with 100 mL of dichloromethane. The rinsing solution was used to wash the filter cake, and the filter cake was washed several times with 100 mL × 2 dichloromethane. After drying, solid cefotaxime sodium was obtained with a molar yield of 93.5% and an HPLC purity of 99.6%.

[0034] Example 2 This embodiment provides a method for the continuous preparation of cefotaxime sodium, including the following steps: Add 100g of 7-aminocephalosporanic acid, 138g of AE active ester and 1000mL of anhydrous dichloromethane to the reactor, then add 9g of tetrabutylammonium bromide and 1.9g of water, and stir at 10℃ for 15min to obtain a suspension. The suspension was filtered, and the resulting clear liquid was continuously passed through a catalyst column packed with 11g sodium carbonate and 35g sodium bicarbonate at a column temperature of 2°C. The residence time of the clear liquid in the catalyst column was 15s. The effluent was recycled back to the reactor, mixed with the solid material retained by filtration, and filtered again. The clear liquid continued to pass through the catalyst column. The reaction ended when the residual amount of 7-aminocephalosporanic acid in the reactor was less than 2mg / mL. After the reaction was completed, the mixture was filtered, and the reactor and stirring device were rinsed with 100 mL of dichloromethane. The rinsing solution was used to wash the filter cake, and the filter cake was washed several times with 100 mL × 2 dichloromethane. After drying, solid cefotaxime sodium was obtained with a molar yield of 93.1% and an HPLC purity of 99.5%.

[0035] Example 3 This embodiment provides a method for the continuous preparation of cefotaxime sodium, including the following steps: Add 100g of 7-aminocephalosporanic acid, 140g of AE active ester and 1100mL of anhydrous dichloromethane to the reactor, then add 10g of tetrabutylammonium bromide and 2.1g of water, and stir at 0℃ for 20min to obtain a suspension. The above suspension was filtered, and the resulting clear liquid was continuously passed through a catalyst column packed with 11.6 g of sodium carbonate and 35 g of sodium bicarbonate. The column temperature was 0 °C, and the residence time of the clear liquid in the catalyst column was 25 s. The effluent was recycled back to the reactor, mixed with the solid material retained by filtration, and filtered again. The clear liquid continued to pass through the catalyst column. The reaction ended when the residual amount of 7-aminocephalosporanic acid in the reactor was less than 2 mg / mL. After the reaction was completed, the mixture was filtered, and the reactor and stirring device were rinsed with 100 mL of dichloromethane. The rinsing solution was used to wash the filter cake, and the filter cake was washed several times with 100 mL × 2 dichloromethane. After drying, solid cefotaxime sodium was obtained with a molar yield of 93.3% and an HPLC purity of 99.6%.

[0036] Comparative Example 1 This comparative example provides a method for preparing cefotaxime sodium, comprising the following steps: 150g of 7-aminocephalosporanic acid was added to a mixture of 660mL dichloromethane and 90mL 95% ethanol, followed by 210g of AE active ester. The mixture was stirred at 45Hz and 5℃ for 80min, and then 120g of triethylamine was added. After the addition was complete, the stirring frequency was reduced to 25Hz, and the reaction was continued until the 7-ACA residue was ≤2.0%, yielding the cephalosporin acid reaction solution.

[0037] Add 300 mL of dichloromethane and 700 mL of water to the above reaction solution in sequence, stir at 10 °C for 30 min, let stand for 30 min, separate the phases, mix the dichloromethane phase with 100 mL of water and stir, let stand and separate the phases, combine the resulting aqueous phase with the previous primary aqueous phase, decolorize and filter to obtain cefotaxime acid crystallization solution; At 5℃ and 40Hz, a 15% hydrochloric acid solution was added to the solution to be crystallized. The pH was adjusted to 4.2 over 20 minutes. The stirring frequency was reduced to 20Hz, and crystals were grown for 30 minutes. Then, a 15% hydrochloric acid solution was added again, and the pH was adjusted to 2.8 over 90 minutes. Crystals were grown for 30 minutes, filtered, washed, and dried to obtain cefotaxime acid. At -5°C and with stirring at 30 Hz, 30 g of cefotaxime acid was added to a mixed solvent of 3 mL water, 60 mL methanol and 51 mL acetone, 5.5 mL of triethylamine and 4.2 g of sodium carbonate were added, and the mixture was stirred until dissolved to obtain cefotaxime sodium crystallization solution. Add 900 mL of a mixed solvent (methanol:ethyl acetate:acetone = 1:12:4) to the solution to be crystallized for 180 min. Stir at 30 Hz and grow crystals at 0 °C for 30 min. Filter, wash and dry to obtain cefotaxime sodium with a molar yield of 90.8% and an HPLC purity of 99.0%.

[0038] Comparative Example 2 This comparative example provides a method for the continuous preparation of cefotaxime sodium, which differs from Example 1 only in that the catalyst column is replaced with a single sodium carbonate packing, and the rest is exactly the same.

[0039] The molar yield of the obtained cefotaxime sodium was 88.1%, and the HPLC purity was 98.1%.

[0040] Comparative Example 3 This comparative example provides a method for the continuous preparation of cefotaxime sodium, which differs from Example 1 only in that the catalyst column is replaced with a single sodium bicarbonate packing, otherwise it is exactly the same.

[0041] The molar yield of the obtained cefotaxime sodium was 85.5%, and the HPLC purity was 97.7%.

[0042] Powder performance testing The angle of repose of the cefotaxime sodium prepared in Example 1 and the comparative example was determined according to the method provided in the "Guidelines for Determination of Powder Flowability" issued by the National Pharmacopoeia Commission. The results are shown in Table 1.

[0043] Loose density test: Place an appropriate amount of product into a 10mL graduated cylinder, shake it gently horizontally to level the powder on top, and read the volume.

[0044] Tap density: Vibrate the graduated cylinder repeatedly until the volume of powder in the graduated cylinder no longer decreases, and then read the volume.

[0045] Carr index = (tap density - loose density) / tap density. The Carr index reflects the liquidity quality, and the smaller the value, the better the liquidity.

[0046] Table 1 The Karl Fischer index and angle of repose of the cefotaxime sodium prepared in Examples 2 and 3 are comparable to those of Example 1.

[0047] In summary, the cefotaxime sodium preparation process provided by this invention, compared to the traditional two-step method, eliminates the cumbersome intermediate separation, aqueous phase extraction, and multiple dissolution steps. It completes the condensation reaction and salt formation process in a single organic phase system in one step, significantly shortening the process flow and simplifying operation. Furthermore, by using inexpensive and readily available sodium carbonate and sodium bicarbonate as catalysts and salt-forming agents, post-reaction treatment requires only simple filtration and dichloromethane washing, avoiding the generation of large amounts of saline wastewater, reducing environmental protection pressure and production costs, and demonstrating good prospects for industrial application and economic advantages. In addition, the reaction-crystallization coupling technology system constructed in this invention effectively controls the growth rate of cefotaxime sodium crystals by regulating the reaction rate, achieving directional crystal growth, which is beneficial for improving the uniformity of product crystal form and quality stability, and has high application value.

[0048] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for continuous preparation of cefotaxime sodium, characterized in that, Includes the following steps: 7-Aminocephalosporanic acid, AE active ester, phase transfer catalyst, water and dichloromethane were mixed to obtain a suspension; The suspension is subjected to solid-liquid separation. The resulting clear liquid is continuously passed through a catalyst column containing sodium carbonate and sodium bicarbonate. The resulting effluent is recycled back and mixed with the solid obtained from the solid-liquid separation. The solid-liquid separation and passing through the catalyst column are repeated. This cycle is repeated until the reaction is completed to obtain cefotaxime sodium. The mass ratio of sodium carbonate to sodium bicarbonate in the catalyst column is 1:3.0 to 1:3.

2.

2. The method for continuous preparation of cefotaxime sodium as described in claim 1, characterized in that, The mass ratio of 7-aminocephalosporanic acid to AE active ester is 1:1.38 to 1:1.

40.

3. The method for continuous preparation of cefotaxime sodium as described in claim 1, characterized in that, The phase transfer catalyst is tetrabutylammonium bromide.

4. The method for continuous preparation of cefotaxime sodium as described in claim 1 or 3, characterized in that, The mass ratio of 7-aminocephalosporanic acid to phase transfer catalyst is 10:0.9~10:

1.

5. The method for continuous preparation of cefotaxime sodium as described in claim 1, characterized in that, The mass ratio of 7-aminocephalosporanic acid to water is 100:1.9 to 100:2.

1.

6. The method for continuous preparation of cefotaxime sodium as described in claim 1, characterized in that, The mass-to-volume ratio of 7-aminocephalosporanic acid to dichloromethane is 1g:10mL to 1g:11mL; wherein the dichloromethane is anhydrous dichloromethane.

7. The method for continuous preparation of cefotaxime sodium as described in claim 1, characterized in that, The mass ratio of the 7-aminocephalosporanic acid to the total amount of sodium carbonate and sodium bicarbonate packed in the catalyst column is 100:44 to 100:

47.

8. The method for continuous preparation of cefotaxime sodium as described in claim 1, characterized in that, The residence time of the clarified liquid in the catalyst column is 15s~25s; and / or The temperature of the clear liquid passing through the catalyst column is 0℃~5℃.

9. The method for continuous preparation of cefotaxime sodium as described in claim 1, characterized in that, The duration of the continuous cycle is 2 to 3 hours.

10. A cefotaxime sodium, characterized in that, It is prepared by the continuous preparation method of cefotaxime sodium according to any one of claims 1 to 9.

Images