Cefotaxime acid and continuous preparation method thereof

Abstract

The invention belongs to the technical field of biological medicine, and particularly provides cefotaxime acid and a continuous preparation method thereof. The method comprises the following steps: firstly, mixing a 7-ACA suspension with a triethylamine solution; carrying out condensation on the mixed solution and an AE-active ester solution; carrying out two times of extraction and dichloromethane back extraction on the condensation liquid through an extraction phase-splitting device to obtain a water phase; reacting the water phase with hydrochloric acid to obtain a cefotaxime acid solution to be crystallized; and finally, taking out a part of the cefotaxime acid to-be-crystallized solution to prepare a seed crystal mixed solution, and adding the rest of the cefotaxime acid to-be-crystallized solution and the crystallization solvent into the seed crystal mixed solution at a specific speed to obtain the cefotaxime acid. According to the method, continuous preparation of the cefotaxime acid is achieved, the preparation period is remarkably shortened, the production efficiency is improved, side reactions and product degradation are reduced, a foundation is laid for preparing the high-quality cefotaxime acid, and industrial production is facilitated.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine, and specifically relates to ceftriaxone acid and a continuous preparation method thereof. Background Art

[0002] Cefotaxime acid, chemical name is (6R,7R)-3-[(acetoxy)methyl]-7-[(2-amino-4-thiazolyl)-(methoxyimino)acetylamino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. It is an important intermediate of cephalosporin antibiotics and has broad-spectrum antibacterial activity. The corresponding antibiotic drugs made from cefotaxime acid are widely used in the clinic to treat a variety of bacterial infectious diseases, such as respiratory tract infections, urinary tract infections, sepsis, etc. It has a strong antibacterial effect and has a good inhibitory effect on Gram-negative bacteria and some Gram-positive bacteria.

[0003] The structure and properties of cefotaxime acid make it a key player in drug development and production, and play an important role in protecting human health. Continuously optimizing and innovating its preparation methods are of great significance for improving drug quality, reducing costs, and meeting medical needs.

[0004] At present, the intermittent production process of cefotaxime acid is mainly based on a tank-type process, in which materials such as 7-ACA and AE-active ester are added to dichloromethane, and then triethylamine is added to react. After the reaction is completed, the hydrolysis extraction phase is separated, and cefotaxime acid is obtained after filtration, crystallization, washing, and drying. In this process, due to the long production cycle of the tank-type intermittent production process, the poor uniformity of material mixing, and the high local pH, side reactions, product degradation, etc., lead to a high content of impurities in the finished product. In addition, the traditional intermittent production process often involves complex operating steps and more intermediate links, resulting in high production costs, low efficiency, and it is difficult to ensure the quality stability between batches.

[0005] With the continuous development and progress of the pharmaceutical industry, higher requirements are put forward for the production of cefotaxime acid, including improving production efficiency, reducing costs, enhancing product quality stability, and reducing impurities. Therefore, it is necessary to develop an innovative continuous preparation method to overcome the shortcomings of the existing technology and promote the development of cefotaxime acid production technology to better meet the growing needs of the pharmaceutical industry. Summary of the invention

[0006] The purpose of the present invention is to provide a cefotaxime acid and a continuous preparation method thereof, so as to solve the problems of long preparation cycle, low production efficiency, high side reactions and product degradation of cefotaxime acid in the existing preparation method, and lay a foundation for preparing high-quality cefotaxime acid.

[0007] In order to achieve the above object, the present invention adopts the following technical solutions: A cefotaxime acid, the product particle size D90: ≥92μm, angle of repose: ≤43°, bulk density: ≥0.46g / ml, total impurities: ≤0.93%, solution color: ≤1 # .

[0008] The continuous preparation method of cefotaxime acid comprises the following steps: (1) Controlling the temperature below 0°C, passing the 7-ACA suspension and the triethylamine solution through a first rapid pipeline mixer at the same time, and passing the resulting mixed solution and the AE-active ester solution through a solid base catalyst column at the same time to obtain a condensation solution; (2) Controlling the temperature at 0-2°C, passing the condensation liquid, dichloromethane and water simultaneously through a second rapid pipeline mixer, and continuously separating the obtained mixed liquid through a first extraction phase separation device to obtain an aqueous phase 1 and a dichloromethane phase; (3) Controlling the temperature at 0-2°C, passing the dichloromethane phase obtained in step (2) and water simultaneously through a third rapid pipeline mixer, and continuously separating the resulting mixed solution through a second extraction phase separation device, retaining aqueous phase 2; combining aqueous phase 1 and aqueous phase 2, and then extracting twice with dichloromethane to obtain aqueous phase 3; (4) Controlling the temperature at 0-2°C, adding 10%-15% hydrochloric acid by mass to the aqueous phase 3 to adjust the pH to 5.8-6.2; adding activated carbon and sodium pyrosulfite under stirring, vacuum decolorizing and filtering to obtain cefotaxime acid to be crystallized; (5) A portion of the cefotaxime acid crystallization solution is taken out and mixed with water and 95% ethanol to prepare a seed crystal mixture; the remaining cefotaxime acid crystallization solution and the hydrochloric acid ethanol solution are added to the seed crystal mixture, the pH is controlled to be 2.5-3.0, and the crystals are grown for 30-60 minutes, and then filtered, washed, and dried to obtain cefotaxime acid.

[0009] Furthermore, the pH of the solid base catalyst column in step (1) is constant and is between 7.5 and 10.

[0010] Furthermore, the preparation method of the 7-ACA suspension in step (1) is as follows: controlling the temperature below 0°C, mixing 7-ACA, dichloromethane, anhydrous methanol and DMF, and stirring evenly; wherein the dosage ratio of 7-ACA, dichloromethane, anhydrous methanol and DMF is 150Kg: 200-210L: 80-85L: 50-60L.

[0011] Furthermore, the preparation method of the triethylamine solution in step (1) is: controlling the temperature below 0°C and adding triethylamine to dichloromethane under stirring; wherein the dosage ratio of triethylamine to dichloromethane is 100-105Kg:200L.

[0012] Furthermore, the preparation method of the AE-active ester solution in step (1) is: controlling the temperature below 0°C, adding AE-active ester and dichloromethane into DMF at the same time, and stirring until completely dissolved; wherein the dosage ratio of AE-active ester, dichloromethane, and DMF is 115-120Kg: 250-270L: 200-220L.

[0013] Furthermore, in step (1), the 7-ACA suspension and the triethylamine solution are simultaneously passed through a first rapid pipeline mixer at a volume ratio of 350:290-310, and then the resulting mixed solution and the AE-active ester solution are simultaneously passed through a solid base catalyst column at a volume ratio of 650:450-460; in step (2), the condensation liquid, dichloromethane and water are simultaneously passed through a second rapid pipeline mixer at a volume ratio of 1120:(500-550):(400-450); in step (3), the dichloromethane phase and water are simultaneously passed through a third rapid pipeline mixer at a volume ratio of 500:(400-410).

[0014] Furthermore, during the dichloromethane stripping in step (3), the volume ratio of the amount of dichloromethane used each time to the aqueous phase is 1:3.

[0015] Furthermore, in step (4), the mass of the activated carbon is 3%-5% of the mass of 7-ACA, and the mass of the sodium metabisulfite is 3%-5% of the mass of 7-ACA.

[0016] Furthermore, the vacuum decolorization in step (4) is carried out at -0.95 MPa for 30-60 minutes.

[0017] Furthermore, in the seed crystal mixture of step (5), the volume ratio of cefotaxime acid to be crystallized to water and 95% ethanol is 1:(4-7):(10-20); the volume of the seed crystal mixture is based on the volume that can be touched by the stirring device.

[0018] Furthermore, the volume ratio of the remaining cefotaxime acid to be crystallized in step (5) to the hydrochloric acid ethanol solution is 1: (5-7); wherein the hydrochloric acid ethanol solution is obtained by mixing 30% hydrochloric acid solution and 95% ethanol in a volume ratio of 28: (100-110).

[0019] The beneficial effects of the present invention are: (1) The present invention mixes a 7-ACA suspension and a triethylamine solution, and then passes the mixed solution and the AE-active ester solution through a solid base catalyst column simultaneously. This specific mixing order and the use of the solid base catalyst column enable the condensation reaction to be carried out under constant alkaline conditions, which not only solves the problem of local over-alkalinity during the reaction process, but also significantly shortens the reaction cycle of 7-ACA and AE active ester, and reduces the occurrence of side reactions and product degradation under long-term alkaline conditions; (2) After obtaining the cefotaxime acid to-be-crystallized solution, the present invention first takes a portion of the cefotaxime acid to-be-crystallized solution to prepare a seed crystal mixture, and then adds the to-be-crystallized solution and a hydrochloric acid ethanol solution crystallization solvent into the seed crystal mixture at a specific speed and in a specific manner. On the one hand, the use of a mixed solution of hydrochloric acid and ethanol as the crystallization solvent avoids the problem of untimely mixing of the hydrochloric acid solution and local over-acidification, which causes degradation reaction when the hydrochloric acid solution and the ethanol solution are added separately. On the other hand, this crystallization method can better control the quality and quantity of the cefotaxime acid crystal nuclei, thereby accurately controlling the crystal growth.

[0020] The method of the present invention realizes the continuous production of cefotaxime acid, greatly shortens the preparation cycle of cefotaxime acid, reduces the occurrence of side reactions and product degradation, and the obtained cefotaxime acid product has high and stable quality, and its molar yield can reach more than 98.5% and the purity is more than 99%. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 The present invention is a schematic diagram of the process of the continuous preparation method of cefotaxime acid. DETAILED DESCRIPTION

[0023] Figure 1 The schematic diagram of the process of the continuous preparation method of cefotaxime acid of the present invention is shown in the figure below, and the technical scheme of the present invention is further described in conjunction with the accompanying drawings and specific embodiments.

[0024] In the following examples, various processes and methods not described in detail are conventional methods known in the art, and reagents used without indicating the source and specifications are commercially available in analytical grade or chromatographic grade.

[0025] Example 1 (1) Temperature control at -2 to 0°C. First, 7-ACA suspension and triethylamine solution are simultaneously introduced into the first rapid pipeline mixer at a volume ratio of 350:300, and flow out after 0.5 seconds to obtain a mixed solution 1. Then, the mixed solution 1 and AE-active ester solution are introduced into the solid base catalyst column at a volume ratio of 650:450, and flow out after 15 minutes to obtain a condensation solution. The preparation method of the 7-ACA suspension is as follows: controlling the temperature at -2 to 0°C, mixing 150 kg 7-ACA, 200 L dichloromethane, 80 L anhydrous methanol, and 50 L DMF, and stirring evenly; The preparation method of the triethylamine solution is as follows: under the condition of controlling the temperature at -2 to 0°C and stirring at 50HZ, 100kg of triethylamine is added into 200L of dichloromethane; The preparation method of the AE-active ester solution is as follows: controlling the temperature at -2 to 0°C, adding 118 kg AE-active ester and 250 L dichloromethane into 200 L DMF at the same time, and stirring until completely dissolved; (2) The temperature is controlled at 0-2°C, and the condensation liquid, dichloromethane and water are simultaneously introduced into the second rapid pipeline mixer at a volume ratio of 1120:500:400, and flow out after 0.5 seconds to obtain a mixed solution 2; the mixed solution 2 is continuously phase-separated by the first extraction phase separation device to obtain an aqueous phase 1 and a dichloromethane phase; (3) Controlling the temperature at 0-2°C, the dichloromethane phase obtained in step (2) and water at a volume ratio of 500:400 are simultaneously introduced into a third rapid pipeline mixer, and flow out after 0.5s to obtain a mixed solution 3; the mixed solution 3 is continuously phase-separated by a second extraction phase separation device, and the aqueous phase 2 is retained; (4) The aqueous phase 1 obtained in step (2) is combined with the aqueous phase 2 obtained in step (3), and then back-extracted with dichloromethane twice to obtain an aqueous phase 3; the amount of dichloromethane each time is 150 L; (5) Control the temperature at 0-2°C, add 10% hydrochloric acid by mass to the aqueous phase 3, and adjust the pH to 5.8; under stirring at 30 Hz, add 5 kg of activated carbon and 3 kg of sodium pyrosulfite, and decolorize for 30-60 minutes under vacuum at -0.95 MPa, and filter to obtain the cefotaxime acid to be crystallized solution; (6) Take out 10 L of the cefotaxime acid crystal solution and mix it with 40 L of water. Add 100 L of 95% ethanol under rapid stirring and stir for 30 min to obtain a seed crystal mixture. (7) adding the remaining cefotaxime acid crystallization liquid and the hydrochloric acid ethanol solution to the seed crystal mixture in a volume ratio of 1:7 for 120 minutes, controlling the pH value to be 2.5-3.0, and growing the crystals for 30-60 minutes after the addition, and then filtering, washing, and drying to obtain cefotaxime acid; The hydrochloric acid ethanol solution is obtained by mixing 280L of 30% hydrochloric acid solution and 1000L of 95% ethanol.

[0026] Example 2 (1) Controlling the temperature at -4 to -2°C, first, 7-ACA suspension and triethylamine solution are simultaneously introduced into the first rapid pipeline mixer at a volume ratio of 350:290, and flow out after 3 seconds to obtain a mixed solution 1; then, the mixed solution 1 and AE-active ester solution are simultaneously introduced into the solid base catalyst column at a volume ratio of 650:460, and flow out after 15 minutes to obtain a condensation solution; The preparation method of the 7-ACA suspension is as follows: controlling the temperature at -4 to -2°C, mixing 150 kg 7-ACA, 210 L dichloromethane, 85 L anhydrous methanol, and 60 L DMF, and stirring evenly; The preparation method of the triethylamine solution is as follows: 105 kg of triethylamine is added to 200 L of dichloromethane under the condition of temperature control of -4 to -2°C and stirring at 50 Hz; The preparation method of the AE-active ester solution is as follows: controlling the temperature at -4 to -2°C, adding 115 kg AE-active ester and 260 L dichloromethane into 210 L DMF at the same time, and stirring until completely dissolved; (2) The temperature is controlled at 0-2°C, and the condensation liquid, dichloromethane and water are simultaneously introduced into the second rapid pipeline mixer at a volume ratio of 1120:550:450, and flow out after 3 seconds to obtain a mixed solution 2; the mixed solution 2 is continuously phase-separated by the first extraction phase separation device to obtain an aqueous phase 1 and a dichloromethane phase; (3) Controlling the temperature at 0-2°C, the dichloromethane phase obtained in step (2) and water are simultaneously introduced into a third rapid pipeline mixer at a volume ratio of 500:410, and flow out after 3 seconds to obtain a mixed solution 3; the mixed solution 3 is continuously phase-separated by a second extraction phase separation device, and the aqueous phase 2 is retained; (4) The aqueous phase 1 obtained in step (2) is combined with the aqueous phase 2 obtained in step (3), and then back-extracted with dichloromethane twice to obtain an aqueous phase 3; the amount of dichloromethane each time is 150 L; (5) Control the temperature at 0-2°C, add 15% hydrochloric acid by mass to the aqueous phase 3, and adjust the pH to 6.2; under stirring at 30 Hz, add 5 kg of activated carbon and 3 kg of sodium pyrosulfite, and decolorize for 30-60 minutes under vacuum at -0.95 MPa, and filter to obtain the cefotaxime acid to be crystallized solution; (6) 10 L of the cefotaxime acid crystal solution was taken out and mixed with 70 L of water. Under rapid stirring conditions, 200 L of 95% ethanol was added and stirred for 30 min to obtain a seed crystal mixture. (7) adding the remaining cefotaxime acid crystallization liquid and the hydrochloric acid ethanol solution to the seed crystal mixture in a volume ratio of 1:5 for 120 minutes, controlling the pH value to be 2.5-3.0, and growing the crystals for 30-60 minutes after the addition, and then filtering, washing, and drying to obtain cefotaxime acid; The hydrochloric acid ethanol solution is obtained by mixing 280L of 30% hydrochloric acid solution and 1000L of 95% ethanol.

[0027] Example 3 (1) The temperature was controlled at -5 to -4 °C. First, the 7-ACA suspension and the triethylamine solution were simultaneously introduced into the first rapid pipeline mixer at a volume ratio of 350:310, and flowed out after 1.5 seconds to obtain a mixed solution 1. Then, the mixed solution 1 and the AE-active ester solution were simultaneously introduced into the solid base catalyst column at a volume ratio of 650:455, and flowed out after 15 minutes to obtain a condensation solution. The preparation method of the 7-ACA suspension is as follows: controlling the temperature at -5 to -4°C, mixing 150 kg 7-ACA, 205 L dichloromethane, 82 L anhydrous methanol, and 55 L DMF, and stirring evenly; The preparation method of the triethylamine solution is as follows: 103 kg of triethylamine is added to 200 L of dichloromethane under the condition of controlling the temperature at -5 to -4°C and stirring at 50 Hz; The preparation method of the AE-active ester solution is as follows: controlling the temperature at -5 to -4°C, adding 120 kg AE-active ester and 270 L dichloromethane into 220 L DMF at the same time, and stirring until completely dissolved; (2) The temperature is controlled at 0-2°C, and the condensation liquid, dichloromethane and water at a volume ratio of 1120:525:425 simultaneously enter the second rapid pipeline mixer and flow out after 1.5 seconds to obtain a mixed solution 2; the mixed solution 2 is continuously phase-separated by the first extraction phase separation device to obtain a water phase 1 and a dichloromethane phase; (3) Controlling the temperature at 0-2°C, the dichloromethane phase obtained in step (2) and water at a volume ratio of 500:405 are simultaneously introduced into a third rapid pipeline mixer, and flow out after 1.5 seconds to obtain a mixed solution 3; the mixed solution 3 is continuously phase-separated by a second extraction phase separation device, and the aqueous phase 2 is retained; (4) The aqueous phase 1 obtained in step (2) is combined with the aqueous phase 2 obtained in step (3), and then back-extracted with dichloromethane twice to obtain an aqueous phase 3; the amount of dichloromethane each time is 150 L; (5) Control the temperature at 0-2°C, add 13% hydrochloric acid by mass to the aqueous phase 3, and adjust the pH to 6.0; under stirring at 30 Hz, add 5 kg of activated carbon and 3 kg of sodium pyrosulfite, decolorize for 30-60 minutes under vacuum at -0.95 MPa, and filter to obtain the cefotaxime acid to be crystallized solution; (6) Take out 10 L of the cefotaxime acid crystal solution and mix it with 55 L of water. Add 150 L of 95% ethanol under rapid stirring and stir for 30 min to obtain a seed crystal mixture. (7) adding the remaining cefotaxime acid crystallization liquid and the hydrochloric acid ethanol solution to the seed crystal mixture in a volume ratio of 1:6 for 120 minutes, controlling the pH value to be 2.5-3.0, and growing the crystals for 30-60 minutes after the addition, and then filtering, washing, and drying to obtain cefotaxime acid; The hydrochloric acid ethanol solution is obtained by mixing 280L of 30% hydrochloric acid solution and 1100L of 95% ethanol.

[0028] Comparative Example 1 (1) Under nitrogen protection, control the temperature at ≤2°C, disperse 150g 7-ACA in 700L dichloromethane, stir and cool to 0-2°C, stir for 30min, add 110kg triethylamine dropwise, stir for 30min, add 210kg AE-active ester to the reaction system, and continue the reaction until the reaction end point; (2) After the reaction is completed, add 600L of dichloromethane and 600L of water to tank 1, stir for 30 minutes, let stand for 30 minutes, separate the lower dichloromethane phase into tank 2, and retain the water phase 1 in tank 1; (3) Add 400 L of water to tank 2, stir for 30 minutes, let stand for 30 minutes, and separate the phases to obtain aqueous phase 2; (4) combining aqueous phase 1 and aqueous phase 2 to obtain aqueous phase 3; (5) Control the temperature to ≤ 2°C, add 10-30% hydrochloric acid to the aqueous phase 3 to adjust the pH to 6.0; then add 5 kg of activated carbon, control the temperature to 5°C, stir for 30 minutes, filter, and obtain a cefotaxime acid crystallization solution; (6) Add 450 L of ethanol to the crystallization solution, stir evenly, adjust the pH to 3.5-4.0 with 10-30% dilute hydrochloric acid, and grow the crystal for 30 minutes; then adjust the pH to 2.5-3.0 with 10-30% hydrochloric acid, grow the crystal for 30 minutes, control the temperature at 5°C, filter, wash, and dry to obtain thioxamic acid.

[0029] Comparative Example 2 (1) Control the temperature below 0°C, add 700L of dichloromethane into tank 1, add 150kg of 7-ACA, 210kg of AE-active ester, 3kg of sodium metabisulfite, and 50L of methanol; (2) Control the temperature to ≤2°C, and add 110 kg of triethylamine to tank 1 at a uniform rate within 60 minutes; continue the reaction until the reaction endpoint is reached to obtain a condensation solution; The preparation method of the 7-ACA suspension is as follows: controlling the temperature at -2 to 0°C, mixing 150 kg 7-ACA, 200 L dichloromethane, 80 L anhydrous methanol, and 50 L DMF, and stirring evenly; The preparation method of the triethylamine solution is as follows: under the condition of controlling the temperature at -2 to 0°C and stirring at 50HZ, 100kg of triethylamine is added into 200L of dichloromethane; The preparation method of the AE-active ester solution is as follows: controlling the temperature at -2 to 0°C, adding 118 kg AE-active ester and 250 L dichloromethane into 200 L DMF at the same time, and stirring until completely dissolved; (3) Controlling the temperature at 0-2°C, the condensation liquid, dichloromethane and water are simultaneously introduced into the fast pipeline mixer 2 at a volume ratio of 1120:500:400, and flow out after 0.5 seconds to obtain a mixed liquid 2; the mixed liquid 2 is continuously separated into phases by the extraction phase separation device 1 to obtain an aqueous phase 1 and a dichloromethane phase; (4) Controlling the temperature at 0-2°C, the dichloromethane phase obtained in step (2) and 1500L of water simultaneously enter the third rapid pipeline mixer and flow out after 0.5s to obtain a mixed solution 3; the mixed solution 3 is continuously separated by the extraction phase separation device 2, and the aqueous phase 2 is retained; (5) The aqueous phase 1 obtained in step (2) is combined with the aqueous phase 2 obtained in step (3), and then back-extracted with dichloromethane twice to obtain an aqueous phase 3; the amount of dichloromethane each time is 150 L; (6) Control the temperature at 0-2°C, add 10% hydrochloric acid by mass to the aqueous phase 3, and adjust the pH to 5.8; under stirring at 30 Hz, add 5 kg of activated carbon and 3 kg of sodium pyrosulfite, and decolorize for 30-60 minutes under vacuum at -0.95 MPa, and filter to obtain the cefotaxime acid to be crystallized solution; (7) Take out 10 L of the cefotaxime acid crystal solution and mix it with 40 L of water. Add 100 L of 95% ethanol under rapid stirring and stir for 30 min to obtain a seed crystal mixture. (8) adding the remaining cefotaxime acid crystallization liquid and the hydrochloric acid ethanol solution to the seed crystal mixture in a volume ratio of 1:7 for 120 minutes, controlling the pH value to be 2.5-3.0, and growing the crystals for 30-60 minutes after the addition, and then filtering, washing, and drying to obtain cefotaxime acid; The hydrochloric acid ethanol solution is obtained by mixing 280L of 30% hydrochloric acid solution and 1000L of 95% ethanol.

[0030] Comparative Example 3 (1) Temperature control at -2 to 0°C. First, 7-ACA suspension and triethylamine solution are simultaneously introduced into the first rapid pipeline mixer at a volume ratio of 350:300, and flow out after 0.5 seconds to obtain a mixed solution 1. Then, the mixed solution 1 and AE-active ester solution are introduced into the solid base catalyst column at a volume ratio of 650:450, and flow out after 15 minutes to obtain a condensation solution. The preparation method of the 7-ACA suspension is as follows: controlling the temperature at -2 to 0°C, mixing 150 kg 7-ACA, 200 L dichloromethane, 80 L anhydrous methanol, and 50 L DMF, and stirring evenly; The preparation method of the triethylamine solution is as follows: under the condition of controlling the temperature at -2 to 0°C and stirring at 50HZ, 100kg of triethylamine is added into 200L of dichloromethane; The preparation method of the AE-active ester solution is as follows: controlling the temperature at -2 to 0°C, adding 118 kg AE-active ester and 250 L dichloromethane into 200 L DMF at the same time, and stirring until completely dissolved; (2) The temperature is controlled at 0-2°C, and the condensation liquid, dichloromethane and water are simultaneously introduced into the second rapid pipeline mixer at a volume ratio of 1120:500:400, and flow out after 0.5 seconds to obtain a mixed solution 2; the mixed solution 2 is continuously phase-separated by the first extraction phase separation device to obtain an aqueous phase 1 and a dichloromethane phase; (3) Controlling the temperature at 0-2°C, the dichloromethane phase obtained in step (2) and 1500L of water simultaneously enter the third rapid pipeline mixer and flow out after 0.5s to obtain a mixed solution 3; the mixed solution 3 is continuously phase-separated by the second extraction phase separation device, and the aqueous phase 2 is retained; (4) The aqueous phase 1 obtained in step (2) is combined with the aqueous phase 2 obtained in step (3), and then back-extracted with dichloromethane twice to obtain an aqueous phase 3; the amount of dichloromethane each time is 150 L; (5) Control the temperature at 0-2°C, add 5 kg of activated carbon to the aqueous phase 3, decolorize under vacuum at -0.95 MPa for 30-60 minutes, and filter to obtain the cefotaxime acid crystallization solution; (6) Add hydrochloric acid ethanol solution to the cefotaxime acid crystallization solution at a volume ratio of 1:7 for crystallization, adjust the pH to 3.5-4.0 with 10-30% dilute hydrochloric acid, and grow the crystal for 30 minutes; then adjust the pH to 2.5-3.0 with 10-30% hydrochloric acid, grow the crystal for 30 minutes, control the temperature at 5°C, filter, wash, and dry to obtain cefotaxime acid.

[0031] The hydrochloric acid ethanol solution is obtained by mixing 280L of 30% hydrochloric acid solution and 1000L of 95% ethanol.

[0032] Comparative Example 4 (1) Temperature control at -2 to 0°C. First, 7-ACA suspension and triethylamine solution are simultaneously introduced into the first rapid pipeline mixer at a volume ratio of 350:300, and flow out after 0.5 seconds to obtain a mixed solution 1. Then, the mixed solution 1 and AE-active ester solution are introduced into the solid base catalyst column at a volume ratio of 650:450, and flow out after 15 minutes to obtain a condensation solution. The preparation method of the 7-ACA suspension is as follows: controlling the temperature at -2 to 0°C, mixing 150 kg 7-ACA, 200 L dichloromethane, 80 L anhydrous methanol, and 50 L DMF, and stirring evenly; The preparation method of the triethylamine solution is as follows: under the condition of controlling the temperature at -2 to 0°C and stirring at 50HZ, 100kg of triethylamine is added into 200L of dichloromethane; The preparation method of the AE-active ester solution is as follows: controlling the temperature at -2 to 0°C, adding 118 kg AE-active ester and 250 L dichloromethane into 200 L DMF at the same time, and stirring until completely dissolved; (2) The temperature is controlled at 0-2°C, and the condensation liquid, dichloromethane and water are simultaneously introduced into the second rapid pipeline mixer at a volume ratio of 1120:500:400, and flow out after 0.5 seconds to obtain a mixed solution 2; the mixed solution 2 is continuously phase-separated by the first extraction phase separation device to obtain an aqueous phase 1 and a dichloromethane phase; (3) Controlling the temperature at 0-2°C, the dichloromethane phase obtained in step (2) and 1500L of water simultaneously enter the third rapid pipeline mixer, and then flow out after staying in the third rapid pipeline mixer for 0.5s to obtain a mixed solution 3; the mixed solution 3 is continuously separated by a second extraction phase separation device, and the aqueous phase 2 is retained; (4) The aqueous phase 1 obtained in step (2) is combined with the aqueous phase 2 obtained in step (3), and then back-extracted with dichloromethane twice to obtain an aqueous phase 3; the amount of dichloromethane each time is 150 L; (5) Control the temperature at 0-2°C, add 10% hydrochloric acid by mass to the aqueous phase 3, and adjust the pH to 5.8; under stirring at 30 Hz, add 5 kg of activated carbon and 3 kg of sodium pyrosulfite, and decolorize for 30-60 minutes under vacuum at -0.95 MPa, and filter to obtain the cefotaxime acid to be crystallized solution; (6) Take out 10 L of the cefotaxime acid crystal solution and mix it with 40 L of water. Add 100 L of 95% ethanol under rapid stirring and stir for 30 min to obtain a seed crystal mixture. (7) The remaining cefotaxime acid solution to be crystallized is adjusted to a pH value of 3.5-4.0 with a hydrochloric acid ethanol solution, the seed crystal mixture is added, and the crystals are grown for 30 minutes, and then the pH is adjusted to 2.5-3.0 with a hydrochloric acid ethanol solution, and the crystals are grown for 30-60 minutes, and then filtered, washed, and dried to obtain cefotaxime acid; The hydrochloric acid ethanol solution is obtained by mixing 280L of 30% hydrochloric acid solution and 1000L of 95% ethanol.

[0033] The test results of the cefotaxime acid products prepared in Examples 1-3 and Comparative Examples 1-4 are shown in Table 1: Table 1

Claims

1. A ceftriaxone acid, characterized in that: Product particle size D90: ≥92μm, repose angle: ≤43°, bulk density: ≥0.46g / ml, total impurities: ≤0.93%, solution color: ≤1 # .

2. The continuous preparation method of ceftriaxone acid according to claim 1, characterized in that: The steps include: (1) Controlling the temperature below 0°C, passing the 7-ACA suspension and the triethylamine solution through a first rapid pipeline mixer at the same time, and passing the resulting mixed solution and the AE-active ester solution through a solid base catalyst column at the same time to obtain a condensation solution; (2) Controlling the temperature at 0-2°C, passing the condensation liquid, dichloromethane and water simultaneously through a second rapid pipeline mixer, and continuously separating the obtained mixed liquid through a first extraction phase separation device to obtain an aqueous phase 1 and a dichloromethane phase; (3) Controlling the temperature at 0-2°C, passing the dichloromethane phase obtained in step (2) and water simultaneously through a third rapid pipeline mixer, and continuously separating the resulting mixed solution through a second extraction phase separation device, retaining aqueous phase 2; combining aqueous phase 1 and aqueous phase 2, and then extracting twice with dichloromethane to obtain aqueous phase 3; (4) Controlling the temperature at 0-2°C, adding 10%-15% hydrochloric acid by mass to the aqueous phase 3 to adjust the pH to 5.8-6.2; adding activated carbon and sodium pyrosulfite under stirring, vacuum decolorizing and filtering to obtain cefotaxime acid to be crystallized; (5) A portion of the cefotaxime acid crystallization solution is taken out and mixed with water and 95% ethanol to prepare a seed crystal mixture; the remaining cefotaxime acid crystallization solution and the hydrochloric acid ethanol solution are added to the seed crystal mixture, the pH is controlled to be 2.5-3.0, and the crystals are grown for 30-60 minutes, and then filtered, washed, and dried to obtain cefotaxime acid.

3. The continuous preparation method of ceftriaxone acid according to claim 2, characterized in that: The pH of the solid base catalyst column in step (1) is constant and is between 7.5 and 10.

4. The continuous preparation method of ceftriaxone acid according to claim 2, characterized in that: The preparation method of the 7-ACA suspension in step (1) is as follows: controlling the temperature below 0°C, mixing 7-ACA, dichloromethane, anhydrous methanol and DMF, and stirring evenly; wherein the dosage ratio of 7-ACA, dichloromethane, anhydrous methanol and DMF is 150Kg: 200-210L: 80-85L: 50-60L.

5. The continuous preparation method of ceftriaxone acid according to claim 2, characterized in that: The preparation method of the triethylamine solution in step (1) is as follows: controlling the temperature below 0°C and adding triethylamine to dichloromethane under stirring; wherein the dosage ratio of triethylamine to dichloromethane is 100-105Kg:200L.

6. The continuous preparation method of ceftriaxone acid according to claim 2, characterized in that: Step (1) The preparation method of the AE-active ester solution is: controlling the temperature below 0° C., adding AE-active ester and dichloromethane into DMF simultaneously, and stirring until completely dissolved; wherein the usage ratio of AE-active ester, dichloromethane, and DMF is 115-120 Kg: 250-270 L: 200-220 L.

7. The continuous preparation method of ceftriaxone acid according to claim 2, characterized in that: In step (1), the 7-ACA suspension and the triethylamine solution are simultaneously passed through a first rapid pipeline mixer at a volume ratio of 350:290-310, and then the resulting mixed solution and the AE-active ester solution are simultaneously passed through a solid base catalyst column at a volume ratio of 650:450-460; in step (2), the condensed liquid, dichloromethane and water are simultaneously passed through a second rapid pipeline mixer at a volume ratio of 1120:(500-550):(400-450); in step (3), the dichloromethane phase and water are simultaneously passed through a third rapid pipeline mixer at a volume ratio of 500:(400-410).

8. The continuous preparation method of ceftriaxone acid according to claim 2, characterized in that: The mass of the activated carbon in step (4) is 3%-5% of the mass of 7-ACA, and the mass of the sodium metabisulfite is 3%-5% of the mass of 7-ACA.

9. The continuous preparation method of ceftriaxone acid according to claim 2, characterized in that: In the seed crystal mixture of step (5), the volume ratio of cefotaxime acid to be crystallized to water and 95% ethanol is 1:(4-7):(10-20); the volume of the seed crystal mixture is based on the volume that can be touched by the stirring device.

10. The continuous preparation method of ceftriaxone acid according to claim 2, characterized in that: The volume ratio of the remaining cefotaxime acid to be crystallized in step (5) to the hydrochloric acid ethanol solution is 1: (5-7); wherein the hydrochloric acid ethanol solution is obtained by mixing 30% hydrochloric acid solution and 95% ethanol in a volume ratio of 28: (100-110).

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