Cefotaxime acid and a continuous process for its preparation

Abstract

The application belongs to the technical field of biological medicine, and specifically provides a cefotaxime acid and a continuous preparation method thereof. The method comprises the following steps: firstly, mixing 7-ACA suspension liquid with triethylamine solution; then, condensing the mixture with AE-active ester solution; then, extracting and separating the condensate liquid twice through an extraction separation device and methylene chloride back extraction to obtain an aqueous phase; reacting the aqueous phase with hydrochloric acid to obtain cefotaxime acid crystallization liquid; finally, taking part of the cefotaxime acid crystallization liquid to prepare seed crystal mixture liquid, adding the remaining cefotaxime acid crystallization liquid and crystallization solvent into the seed crystal mixture liquid at a specific speed to obtain cefotaxime acid. The method realizes continuous preparation of cefotaxime acid, significantly shortens the preparation period, improves the production efficiency, reduces the side reaction and product degradation, lays a foundation for preparing high-quality cefotaxime acid, and is beneficial to industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biological medicine, and specifically relates to a cefotaxime acid and a continuous preparation method thereof. BACKGROUND

[0002] Cefotaxime acid, with the chemical name of (6R, 7R)-3-[(acetyloxy) methyl]-7-[(2-amino-4-thiazolyl)-(methoxyimino) acetylamino]-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-2-ene-2-carboxylic acid, is an important intermediate of cephalosporin antibiotics and has broad-spectrum antibacterial activity. The corresponding antibiotic drugs made of cefotaxime acid are widely used in the clinical treatment of various bacterial infectious diseases, such as respiratory tract infections, urinary system infections, septicemia, etc. The antibiotic drugs have strong antibacterial effect and good inhibitory effect on gram-negative bacteria and part of gram-positive bacteria.

[0003] The structure and properties of cefotaxime acid make it play a key role in drug research and production and play an important role in protecting human health. Continuously optimizing and innovating the preparation method of cefotaxime acid is of great significance to improve the quality of drugs, reduce costs, and meet the needs of medical treatment.

[0004] At present, the production of cefotaxime acid mainly adopts a tank-type intermittent production process. In the process, 7-ACA, AE-activated ester and other materials are added to dichloromethane, and then triethylamine is added for reaction. After the reaction is completed, hydrolysis, extraction, phase separation, filtration, crystallization, washing and drying are carried out to obtain cefotaxime acid. In the process, the tank-type intermittent production process has a long production cycle, and the uniformity of the mixed materials is poor, and the local pH is high, which leads to side reactions, product degradation and other problems, and the impurity content of the finished product is high. In addition, the traditional intermittent production process often involves complex operation steps and more intermediate links, resulting in high production cost, low efficiency, and difficult to guarantee 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 cost, enhancing product quality stability, and reducing impurities. Therefore, it is necessary to develop an innovative continuous preparation method to overcome the shortcomings of the prior art and promote the development of cefotaxime acid production technology to better meet the growing needs of the pharmaceutical industry. SUMMARY

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

[0007] In order to achieve the above-mentioned purpose, the following technical solutions are adopted in the present application:

[0008] A cefotaxime acid, product particle size D90: ≥92 μm, angle of repose: ≤43°, bulk density: ≥0.46 g / ml, total impurities: ≤0.93%, solution color: ≤1 # .

[0009] The continuous preparation method of the cefotaxime acid comprises the following steps:

[0010] (1) Control the temperature below 0°C, and pass the 7-ACA suspension and the triethylamine solution through the first rapid pipe mixer at the same time, pass the obtained mixed solution and the AE-active ester solution through the solid alkali catalyst column at the same time, and obtain a condensation liquid;

[0011] (2) Control the temperature at 0-2°C, pass the condensation liquid and dichloromethane and water through the second rapid pipe mixer at the same time, and continuously separate the obtained mixed liquid through the first extraction phase separation device to obtain water phase 1 and dichloromethane phase;

[0012] (3) Control the temperature at 0-2°C, pass the dichloromethane phase obtained in step (2) and water through the third rapid pipe mixer at the same time, continuously separate the obtained mixed liquid through the second extraction phase separation device, and reserve water phase 2; combine the water phase 1 and the water phase 2, and then perform dichloromethane back extraction twice to obtain water phase 3;

[0013] (4) Control the temperature at 0-2°C, add hydrochloric acid with a mass fraction of 10%-15% to the water phase 3, and adjust the pH to 5.8-6.2; under stirring, add activated carbon and sodium pyrosulfite, vacuum decolorize and filter to obtain a cefotaxime acid to be crystallized liquid;

[0014] (5) Mix a part of the cefotaxime acid to be crystallized liquid with water and 95% ethanol to prepare a seed crystal mixed liquid; add the remaining cefotaxime acid to be crystallized liquid and hydrochloric acid ethanol solution to the seed crystal mixed liquid, control the pH to be 2.5-3.0, incubate the crystals for 30-60 min, and then filter, wash and dry to obtain the cefotaxime acid.

[0015] Further, the pH of the solid alkali catalyst column in step (1) is constant, and is 7.5-10.

[0016] Further, the preparation method of the 7-ACA suspension in step (1) is as follows: control the temperature below 0°C, mix 7-ACA, dichloromethane, anhydrous methanol and DMF, and stir uniformly; wherein, the amount ratio of 7-ACA, dichloromethane, anhydrous methanol and DMF is 150 Kg: 200-210 L: 80-85 L: 50-60 L.

[0017] Further, the preparation method of the triethylamine solution in step (1) is as follows: under the condition of temperature control below 0 DEG C and stirring, triethylamine is added into dichloromethane; wherein the dosage ratio of triethylamine to dichloromethane is 100-105 Kg: 200 L.

[0018] Further, the preparation method of the AE-active ester solution in step (1) is as follows: under the condition of temperature control below 0 DEG C, AE-active ester and dichloromethane are simultaneously added into DMF and stirred until completely dissolved; wherein the dosage ratio of AE-active ester, dichloromethane and DMF is 115-120 Kg: 250-270 L: 200-220 L.

[0019] Further, in step (1), the 7-ACA suspension and the triethylamine solution are simultaneously mixed through the first fast pipe mixer at a volume ratio of 350: 290-310, and then the obtained mixed solution and the AE-active ester solution are simultaneously passed through the solid alkali catalyst column at a volume ratio of 650: 450-460; in step (2), the condensation liquid, dichloromethane and water are simultaneously passed through the second fast pipe mixer at a volume ratio of 1120: (500-550): (400-450); in step (3), the dichloromethane phase and water are simultaneously passed through the third fast pipe mixer at a volume ratio of 500: (400-410).

[0020] Further, in step (3), the volume ratio of the dosage of dichloromethane to the water phase is 1:3.

[0021] Further, in step (4), the mass of the activated carbon is 3%-5% of the mass of 7-ACA, and the mass of sodium pyrosulfite is 3%-5% of the mass of 7-ACA.

[0022] Further, in step (4), the vacuum decolorization is carried out at-0.95 MPa for 30-60 minutes.

[0023] Further, in step (5), the volume ratio of the cefotaxime acid to be crystallized liquid to water and 95% ethanol in the crystal seed mixed solution is 1: (4-7): (10-20); and the volume of the crystal seed mixed solution is controlled according to the reachability of the stirring device.

[0024] Further, in step (5), the volume ratio of the remaining cefotaxime acid to be crystallized liquid 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 at a volume ratio of 28: (100-110).

[0025] The beneficial effects of the present application are as follows:

[0026] (1) The 7-ACA suspension and triethylamine solution are mixed, and the mixture is passed through the solid base catalyst column at the same time as the AE-active ester solution. 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-alkaline during the reaction, but also significantly shortens the reaction period of 7-ACA and AE-active ester, and reduces the occurrence of side reactions and product degradation under long-term alkaline conditions;

[0027] (2) After obtaining the cefotaxime acid crystallization solution, a part of the cefotaxime acid crystallization solution is taken to prepare a seed crystal mixture, and then the crystallization solution and the hydrochloric acid-ethanol solution are added to the seed crystal mixture at a specific speed and manner. On the one hand, the mixed solution of hydrochloric acid and ethanol is used as the crystallization solvent, which avoids the problem of local over-acid caused by the delay of mixing of the hydrochloric acid solution and the ethanol solution; on the other hand, this crystallization method can better control the quality and quantity of the cefotaxime acid crystal nucleus, and then precisely control the crystal growth.

[0028] The method realizes the continuous production of cefotaxime acid, greatly shortens the preparation period of cefotaxime acid, reduces the occurrence of side reactions and product degradation, and the obtained cefotaxime acid product has high and stable quality, the molar yield is more than 98.5%, and the purity is more than 99%. BRIEF DESCRIPTION OF DRAWINGS

[0029] Figure 1 It is a flowchart of the continuous preparation method of cefotaxime acid of the present application. DETAILED DESCRIPTION

[0030] Figure 1 It is a flowchart of the continuous preparation method of cefotaxime acid of the present application. The technical solutions of the present application will be further described below in combination with the drawings and specific embodiments.

[0031] In the following examples, various processes and methods that are not described in detail are conventional methods known in the art, and the reagents used are commercially available and are of analytical purity or chromatographic purity.

[0032] Example 1

[0033] (1) Temperature control-2~0℃, first, 7-ACA suspension and triethylamine solution are mixed at a volume ratio of 350:300, and then mixed solution 1 is obtained by flowing out after 0.5s; then, mixed solution 1 and AE-active ester solution are mixed at a volume ratio of 650:450, and then condensation solution is obtained by flowing out after 15min;

[0034] The preparation method of the 7-ACA suspension is: temperature control -2~0℃, 150Kg 7-ACA, 200L dichloromethane, 80L anhydrous methanol, 50L DMF are mixed, and stirred uniformly;

[0035] The preparation method of the triethylamine solution is: temperature control -2~0℃, 50HZ stirring conditions, 100kg of triethylamine is added into 200L dichloromethane;

[0036] The preparation method of the AE-active ester solution is: temperature control -2~0℃, 118Kg AE-active ester, 250L dichloromethane are simultaneously added into 200L DMF, and stirred until completely dissolved;

[0037] (2) Temperature control 0-2℃, the condensation liquid, dichloromethane and water are simultaneously added into the second fast pipe mixer at a volume ratio of 1120:500:400, and flow out after 0.5s, to obtain mixed liquid 2; the mixed liquid 2 is continuously separated by the first extraction phase separation device, to obtain water phase 1 and dichloromethane phase;

[0038] (3) Temperature control 0-2℃, the dichloromethane phase obtained in step (2) and water are simultaneously added into the third fast pipe mixer at a volume ratio of 500:400, and flow out after 0.5s, to obtain mixed liquid 3; the mixed liquid 3 is continuously separated by the second extraction phase separation device, to reserve water phase 2;

[0039] (4) The water phase 1 obtained in step (2) and the water phase 2 obtained in step (3) are combined, and then subjected to twice dichloromethane back extraction, to obtain water phase 3; the amount of dichloromethane is 150L each time;

[0040] (5) Temperature control 0-2℃, 10% hydrochloric acid by mass fraction is added into the water phase 3, to adjust the pH to 5.8; under the stirring condition of 30HZ, 5kg of activated carbon and 3kg of sodium pyrosulfite are added, and the decolorization is carried out under vacuum-0.95MPa for 30-60 minutes, to obtain the cefotaxime acid crystallization liquid after filtration;

[0041] (6) 10L of the cefotaxime acid crystallization liquid is taken out and mixed with 40L of water, 100L of 95% ethanol is added under the condition of fast stirring, and stirred for 30min, to obtain the crystal seed mixed liquid;

[0042] (7) The remaining cefotaxime acid crystallization liquid and the hydrochloric acid ethanol solution are added into the crystal seed mixed liquid at a volume ratio of 1:7, and the time is 120min, the pH is controlled to be 2.5-3.0, after the addition is completed, the crystal is maintained for 30-60min, and then filtration, washing and drying are carried out, to obtain cefotaxime acid;

[0043] The hydrochloric acid ethanol solution is obtained by mixing 280L of 30% hydrochloric acid solution and 1000L of 95% ethanol.

[0044] Example 2

[0045] (1) Temperature control -4~-2℃, firstly, 7-ACA suspension and triethylamine solution enter the first rapid pipeline mixer at a volume ratio of 350:290 at the same time, and flow out after 3s to obtain mixed solution 1; then, mixed solution 1 and AE-active ester solution enter the solid alkali catalyst column at a volume ratio of 650:460 at the same time, and flow out after 15min to obtain the condensation liquid;

[0046] The preparation method of the 7-ACA suspension is: temperature control -4~-2℃, 150Kg 7-ACA, 210L dichloromethane, 85L anhydrous methanol, 60L DMF are mixed and stirred uniformly;

[0047] The preparation method of the triethylamine solution is: temperature control -4~-2℃, 105kg of triethylamine is added to 200L of dichloromethane under the condition of 50HZ stirring;

[0048] The preparation method of the AE-active ester solution is: temperature control -4~-2℃, 115Kg of AE-active ester and 260L of dichloromethane are added to 210L of DMF at the same time, and stirred until completely dissolved;

[0049] (2) Temperature control 0-2℃, the condensation liquid, dichloromethane and water enter the second rapid pipeline mixer at a volume ratio of 1120:550:450 at the same time, and flow out after 3s to obtain mixed solution 2; mixed solution 2 is continuously separated by the first extraction separation device to obtain water phase 1 and dichloromethane phase;

[0050] (3) Temperature control 0-2℃, the dichloromethane phase obtained in step (2) and water enter the third rapid pipeline mixer at a volume ratio of 500:410 at the same time, and flow out after 3s to obtain mixed solution 3; mixed solution 3 is continuously separated by the second extraction separation device to retain water phase 2;

[0051] (4) The water phase 1 obtained in step (2) and the water phase 2 obtained in step (3) are combined, and then subjected to twice dichloromethane back extraction to obtain water phase 3; the amount of dichloromethane is 150L each time;

[0052] (5) Temperature control 0-2℃, 15% mass fraction of hydrochloric acid is added to the water phase 3 to adjust the pH to 6.2; under the condition of 30HZ stirring, 5kg of activated carbon and 3kg of sodium pyrosulfite are added, and the solution is decolorized under vacuum-0.95MPa for 30-60min, and then filtered to obtain the cefotaxime acid crystallization solution;

[0053] (6) 10L of the cefotaxime acid crystallization solution is taken out and mixed with 70L of water, 200L of 95% ethanol is added under the condition of rapid stirring, and stirred for 30min to obtain the crystal seed mixed solution;

[0054] (7) the remaining cefotaxime acid crystallization solution and hydrochloric acid ethanol solution are added into the seed crystal mixed solution at a volume ratio of 1:5, and the pH is controlled at 2.5-3.0 for 120 min, and then the crystal is maintained for 30-60 min, and then filtered, washed and dried to obtain cefotaxime acid;

[0055] The hydrochloric acid ethanol solution is obtained by mixing 280 L of 30% hydrochloric acid solution and 1000 L of 95% ethanol.

[0056] Example 3

[0057] (1) temperature control at -5~-4℃, first, the 7-ACA suspension solution and the triethylamine solution are simultaneously added into the first rapid pipe mixer at a volume ratio of 350:310, and the mixture 1 is obtained after 1.5 s, then the mixture 1 and the AE-active ester solution are simultaneously added into the solid alkali catalyst column at a volume ratio of 650:455, and the condensation solution is obtained after 15 min;

[0058] The preparation method of the 7-ACA suspension solution is as follows: temperature control at -5~-4℃, 150Kg 7-ACA, 205L dichloromethane, 82L anhydrous methanol and 55L DMF are mixed and stirred uniformly;

[0059] The preparation method of the triethylamine solution is as follows: temperature control at -5~-4℃, 50HZ stirring, 103kg of triethylamine is added into 200L dichloromethane;

[0060] The preparation method of the AE-active ester solution is as follows: temperature control at -5~-4℃, 120Kg AE-active ester and 270L dichloromethane are simultaneously added into 220L DMF, and stirred until completely dissolved;

[0061] (2) temperature control at 0-2℃, the condensation solution, dichloromethane and water are simultaneously added into the second rapid pipe mixer at a volume ratio of 1120:525:425, and the mixture 2 is obtained after 1.5 s, and then the mixture 2 is continuously separated by the first extraction separation device to obtain the water phase 1 and the dichloromethane phase;

[0062] (3) temperature control at 0-2℃, the dichloromethane phase obtained in step (2) and water are simultaneously added into the third rapid pipe mixer at a volume ratio of 500:405, and the mixture 3 is obtained after 1.5 s, and then the mixture 3 is continuously separated by the second extraction separation device to obtain the water phase 2;

[0063] (4) the water phase 1 obtained in step (2) and the water phase 2 obtained in step (3) are combined, and then subjected to twice dichloromethane back extraction to obtain the water phase 3; the amount of dichloromethane is 150L each time;

[0064] (5) Control temperature 0-2℃, add 13% hydrochloric acid to water phase 3 to adjust pH to 6.0; under 30HZ stirring condition, add 5kg activated carbon and 3kg sodium pyrosulfite, decolorize under vacuum-0.95MPa for 30-60 minutes, filter to obtain cefotaxime acid to be crystallized;

[0065] (6) Mix 10L of cefotaxime acid to be crystallized with 55L water, under fast stirring condition, add 150L 95% ethanol, stir for 30 minutes to obtain seed crystal mixture;

[0066] (7) Add the remaining cefotaxime acid to be crystallized and hydrochloric acid ethanol solution to the seed crystal mixture at a volume ratio of 1:6, control pH at 2.5-3.0, and incubate for 30-60 minutes after addition. After filtration, washing and drying, cefotaxime acid is obtained.

[0067] The hydrochloric acid ethanol solution is obtained by mixing 280L 30% hydrochloric acid solution with 1100L 95% ethanol.

[0068] Comparative Example 1

[0069] (1) Under nitrogen protection, control temperature ≤2℃, disperse 150g 7-ACA in 700L dichloromethane, stir and cool to 0-2℃, add 110kg triethylamine dropwise, stir for 30 minutes, add 210kg AE-activated ester to the reaction system, and continue to react until the reaction endpoint is reached.

[0070] (2) After the reaction is completed, add 600L dichloromethane and 600L water to tank 1, stir for 30 minutes, and stand for 30 minutes. The lower dichloromethane phase is separated into tank 2, and tank 1 retains water phase 1.

[0071] (3) Add 400L water to tank 2, stir for 30 minutes, stand for 30 minutes, and separate to obtain water phase 2.

[0072] (4) Combine water phase 1 and water phase 2 to obtain water phase 3.

[0073] (5) Control temperature ≤2℃, add 10-30% hydrochloric acid to water phase 3 to adjust pH to 6.0; then add 5kg activated carbon, control temperature at 5℃, stir for 30 minutes, filter to obtain cefotaxime acid to be crystallized.

[0074] (6) Add 450L ethanol to the to-be-crystallized liquid, stir uniformly, adjust pH to 3.5-4.0 with 10-30% dilute hydrochloric acid, and incubate for 30 minutes. Then adjust pH to 2.5-3.0 with 10-30% hydrochloric acid, incubate for 30 minutes, control temperature at 5℃, filter, wash and dry to obtain cefotaxime acid.

[0075] Comparative Example 2

[0076] (1) Temperature control below 0 ℃, 700 L of dichloromethane was added into tank 1, 150 kg of 7-ACA, 210 kg of AE-active ester, 3 kg of sodium pyrosulfite and 50 L of methanol were put in;

[0077] (2) Temperature control ≤2 ℃, 110 kg of triethylamine was added into tank 1 at a uniform speed within 60 minutes; continue to react until the reaction endpoint is reached, and a condensation liquid is obtained;

[0078] The preparation method of the 7-ACA suspension is as follows: temperature control -2~0 ℃, 150 Kg of 7-ACA, 200 L of dichloromethane, 80 L of anhydrous methanol and 50 L of DMF are mixed and stirred uniformly;

[0079] The preparation method of the triethylamine solution is as follows: temperature control -2~0 ℃, 100 kg of triethylamine is added into 200 L of dichloromethane under the condition of 50 HZ stirring;

[0080] The preparation method of the AE-active ester solution is as follows: temperature control -2~0 ℃, 118 Kg of AE-active ester and 250 L of dichloromethane are simultaneously added into 200 L of DMF, and stirring is performed until complete dissolution;

[0081] (3) Temperature control 0-2 ℃, the condensation liquid, dichloromethane and water are simultaneously introduced into a rapid pipeline mixer 2 at a volume ratio of 1120:500:400, and the mixture 2 is obtained after 0.5 s, the mixture 2 is continuously separated by an extraction separation device 1, and water phase 1 and dichloromethane phase are obtained;

[0082] (4) Temperature control 0-2 ℃, the dichloromethane phase obtained in step (2) and 1500 L of water are simultaneously introduced into a third rapid pipeline mixer, and the mixture 3 is obtained after 0.5 s, the mixture 3 is continuously separated by an extraction separation device 2, and water phase 2 is reserved;

[0083] (5) The water phase 1 obtained in step (2) and the water phase 2 obtained in step (3) are combined, and then subjected to twice dichloromethane back extraction, and water phase 3 is obtained; the amount of dichloromethane is 150 L each time;

[0084] (6) Temperature control 0-2 ℃, 10% of hydrochloric acid by mass fraction is added into the water phase 3, and the pH is adjusted to 5.8; under the condition of 30 HZ stirring, 5 kg of activated carbon and 3 kg of sodium pyrosulfite are added, and decolorization is performed under vacuum-0.95 MPa for 30-60 minutes, and filtration is performed to obtain a cefotaxime acid crystallization liquid;

[0085] (7) 10 L of the cefotaxime acid crystallization liquid is taken out and mixed with 40 L of water, 100 L of 95% ethanol is added under the condition of rapid stirring, and stirring is performed for 30 min to obtain a crystal seed mixture;

[0086] (8) The remaining cefotaxime acid crystallization solution and hydrochloric acid ethanol solution are added to the seed crystal mixture at a volume ratio of 1:7, and the pH is controlled at 2.5-3.0 for 120 min. After the addition is completed, the crystals are aged for 30-60 min, and then filtered, washed, and dried to obtain cefotaxime acid;

[0087] The hydrochloric acid ethanol solution is obtained by mixing 280 L of 30% hydrochloric acid solution and 1000 L of 95% ethanol.

[0088] Comparative Example 3

[0089] (1) Temperature control -2~0℃, first, 7-ACA suspension and triethylamine solution are simultaneously added to the first rapid pipe mixer at a volume ratio of 350:300, and the mixture 1 is obtained after 0.5s; then, the mixture 1 and AE-active ester solution are added to the solid base catalyst column at a volume ratio of 650:450, and the condensation solution is obtained after 15 min;

[0090] The preparation method of the 7-ACA suspension is as follows: temperature control -2~0℃, 150Kg 7-ACA, 200L dichloromethane, 80L anhydrous methanol, 50L DMF are mixed and stirred uniformly;

[0091] The preparation method of the triethylamine solution is as follows: temperature control -2~0℃, 100kg of triethylamine is added to 200L of dichloromethane under the condition of 50HZ stirring;

[0092] The preparation method of the AE-active ester solution is as follows: temperature control -2~0℃, 118Kg AE-active ester, 250L dichloromethane are simultaneously added to 200L DMF, and stirred until completely dissolved;

[0093] (2) Temperature control 0-2℃, the condensation solution, dichloromethane and water are simultaneously added to the second rapid pipe mixer at a volume ratio of 1120:500:400, and the mixture 2 is obtained after 0.5s; the mixture 2 is continuously separated by the first extraction separation device to obtain water phase 1 and dichloromethane phase;

[0094] (3) Temperature control 0-2℃, the dichloromethane phase obtained in step (2) and 1500L water are simultaneously added to the third rapid pipe mixer, and the mixture 3 is obtained after 0.5s; the mixture 3 is continuously separated by the second extraction separation device to obtain water phase 2;

[0095] (4) The water phase 1 obtained in step (2) and the water phase 2 obtained in step (3) are combined, and then subjected to twice dichloromethane back extraction to obtain water phase 3; the amount of dichloromethane is 150L each time;

[0096] (5) Controlling temperature at 0-2°C, adding 5 kg of activated carbon into water phase 3, decolorizing for 30-60 minutes under vacuum-0.95 MPa, and filtering to obtain cefotaxime acid to be crystallized;

[0097] (6) Adding hydrochloric acid ethanol solution into cefotaxime acid to be crystallized at a volume ratio of 1:7 to perform crystallization, adjusting pH to 3.5-4.0 by using 10-30% dilute hydrochloric acid, and aging for 30 minutes; then adjusting pH to 2.5-3.0 by using 10-30% hydrochloric acid, and aging for 30 minutes, controlling temperature at 5°C, and filtering, washing, and drying to obtain cefotaxime acid.

[0098] The hydrochloric acid ethanol solution is obtained by mixing 280 L of 30% hydrochloric acid solution with 1000 L of 95% ethanol.

[0099] Comparative Example 4

[0100] (1) Controlling temperature at -2-0°C, first, 7-ACA suspension and triethylamine solution enter a first rapid pipe mixer at a volume ratio of 350:300 to mix, and flow out after 0.5 s to obtain mixed solution 1; then, mixed solution 1 and AE-active ester solution enter a solid alkali catalyst column at a volume ratio of 650:450 to flow out after 15 min to obtain condensation liquid;

[0101] The preparation method of the 7-ACA suspension is as follows: controlling temperature at -2-0°C, mixing 150 kg of 7-ACA, 200 L of dichloromethane, 80 L of anhydrous methanol, and 50 L of DMF, and stirring uniformly;

[0102] The preparation method of the triethylamine solution is as follows: controlling temperature at -2-0°C, and adding 100 kg of triethylamine into 200 L of dichloromethane under the condition of 50 HZ stirring;

[0103] The preparation method of the AE-active ester solution is as follows: controlling temperature at -2-0°C, and adding 118 kg of AE-active ester and 250 L of dichloromethane into 200 L of DMF at the same time, and stirring until completely dissolved;

[0104] (2) Controlling temperature at 0-2°C, condensation liquid and dichloromethane and water enter a second rapid pipe mixer at a volume ratio of 1120:500:400 to flow out after 0.5 s to obtain mixed solution 2; mixed solution 2 is continuously separated by a first extraction separation device to obtain water phase 1 and dichloromethane phase;

[0105] (3) Controlling temperature at 0-2°C, the dichloromethane phase obtained in step (2) and 1500 L of water enter a third rapid pipe mixer at the same time, and mixed solution 3 is obtained after staying in the third rapid pipe mixer for 0.5 s; mixed solution 3 is continuously separated by a second extraction separation device to retain water phase 2;

[0106] (4) Combine the water phase 1 obtained in step (2) with the water phase 2 obtained in step (3), and then perform twice dichloromethane back extraction, to obtain water phase 3; the amount of dichloromethane is 150 L each time;

[0107] (5) Under the condition of temperature control at 0-2°C, add 10% hydrochloric acid to the water phase 3, and adjust the pH to 5.8; under the condition of 30 HZ stirring, add 5 kg of activated carbon and 3 kg of sodium pyrosulfite, and perform decolorization under vacuum-0.95 MPa for 30-60 minutes, to obtain the cefotaxime acid crystallization solution;

[0108] (6) Mix 10 L of the cefotaxime acid crystallization solution with 40 L of water, and then add 100 L of 95% ethanol under the condition of rapid stirring, and stir for 30 min, to obtain the crystal seed mixture;

[0109] (7) Adjust the pH of the remaining cefotaxime acid crystallization solution to 3.5-4.0 by using hydrochloric acid ethanol solution, add the crystal seed mixture, and incubate for 30 min, then adjust the pH to 2.5-3.0 by using hydrochloric acid ethanol solution, and incubate for 30-60 min, and then perform filtration, washing, and drying, to obtain cefotaxime acid;

[0110] The hydrochloric acid ethanol solution is obtained by mixing 280 L of 30% hydrochloric acid solution with 1000 L of 95% ethanol.

[0111] The test results of the cefotaxime acid products prepared in Examples 1-3 and Comparative Examples 1-4 are shown in Table 1:

[0112] Table 1

[0113]

Claims

1. A continuous process for the preparation of Cefotaxime acid, characterized in that, The product particle size D90 of the cefotaxime acid: > 92 pm, the resting angle: < 43°, the bulk density: > 0.46 g / ml, the total impurities: < 0.93%, the solution color: < 1 # comprising the steps of: (1) Controlling temperature below 0℃, mixing 7-ACA suspension solution and triethylamine solution through the first fast pipe mixer at the same time, mixing the obtained mixture solution and AE-active ester solution through the solid base catalyst column at the same time to obtain a condensation solution; (2) Controlling temperature 0-2℃, mixing the condensation solution, dichloromethane and water through the second fast pipe mixer at the same time, continuously separating the obtained mixture solution through the first extraction separation device to obtain water phase 1 and dichloromethane phase; (3) Controlling temperature 0-2℃, mixing the dichloromethane phase obtained in step (2) and water through the third fast pipe mixer at the same time, continuously separating the obtained mixture solution through the second extraction separation device to obtain water phase 2; combining water phase 1 and water phase 2, and then performing twice dichloromethane back extraction to obtain water phase 3; (4) Controlling temperature 0-2℃, adding hydrochloric acid with a mass fraction of 10%-15% into water phase 3 to adjust pH to 5.8-6.2; under stirring condition, adding activated carbon and sodium pyrosulfite, vacuum decolorizing and filtering to obtain cefotaxime acid to be crystallized solution; (5) Mixing a part of cefotaxime acid to be crystallized solution with water and 95% ethanol to prepare seed mixture solution; adding the remaining cefotaxime acid to be crystallized solution and hydrochloric acid ethanol solution into the seed mixture solution, controlling pH to be 2.5-3.0, and aging crystal for 30-60 min, then filtering, washing and drying to obtain cefotaxime acid.

2. The continuous process for the preparation of Cefinax according to claim 1, characterized in that, The pH of the solid base catalyst column in step (1) is constant, being 7.5-10.

3. The continuous process for the preparation of Cefinax according to claim 1, characterized in that, The preparation method of the 7-ACA suspension solution in step (1) is as follows: controlling temperature below 0℃, mixing 7-ACA, dichloromethane, anhydrous methanol and DMF, and stirring uniformly; wherein the amount ratio of 7-ACA, dichloromethane, anhydrous methanol and DMF is 150Kg: 200-210L: 80-85L: 50-60L.

4. The continuous process for the preparation of Cefinax according to claim 1, characterized in that, The preparation method of the triethylamine solution in step (1) is as follows: controlling temperature below 0℃, and adding triethylamine into dichloromethane under stirring condition; wherein the amount ratio of triethylamine and dichloromethane is 100-105Kg: 200L.

5. The continuous process for the preparation of Cefinax according to claim 1, characterized in that, The preparation method of the AE-active ester solution in step (1) is as follows: controlling temperature below 0℃, and adding AE-active ester and dichloromethane into DMF at the same time, and stirring until completely dissolved; wherein the amount ratio of AE-active ester, dichloromethane and DMF is 115-120Kg: 250-270L: 200-220L. In step (1), the volume ratio of 7-ACA suspension solution and triethylamine solution is 350: 290-310, and the volume ratio of the obtained mixture solution and AE-active ester solution is 650: 450-460, which pass through the solid base catalyst column at the same time; in step (2), the volume ratio of condensation solution, dichloromethane and water is 1120: (500-550): (400-450), which pass through the second fast pipe mixer at the same time; in step (3), the volume ratio of dichloromethane phase and water is 500: (400-410), which pass through the third fast pipe mixer at the same time.

6. The continuous process for the preparation of Cefinax according to claim 1, characterized in that, The mass of activated carbon in step (4) is 3%-5% of the mass of 7-ACA, and the mass of sodium pyrosulfite is 3%-5% of the mass of 7-ACA.

7. The continuous process for the preparation of Cefinax according to claim 1, characterized in that, ​ 8. The continuous process for the preparation of Cefinax according to claim 1, characterized in that, The volume ratio of the cefotaxime acid to be crystallized solution, water and 95% ethanol in the seed crystal mixture is 1:(4-7):(10-20); the volume of the seed crystal mixture is measured when the stirring device can reach.

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

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