A sterile cefepime hydrochloride and a direct preparation method thereof

Abstract

The application belongs to the technical field of biological medicine, and particularly relates to a sterile cefepime hydrochloride and a direct preparation method thereof. The method comprises the following steps: firstly, 7-MPCA solution and AE active ester solution are simultaneously subjected to condensation reaction through a solid alkali catalyst column; then, the condensation liquid is subjected to extraction and phase separation, twice pH adjustment and crystallization, active carbon decolorization and sodium sulfite reduction to obtain cefepime hydrochloride to be crystallized; then, a part of the cefepime hydrochloride to be crystallized is prepared into a seed crystal mixed solution, the remaining cefepime hydrochloride to be crystallized and a crystallization solvent are added into the seed crystal mixed solution at a specific speed to obtain sterile cefepime hydrochloride. The method realizes continuous production of sterile cefepime hydrochloride, greatly shortens the preparation period of sterile cefepime hydrochloride, reduces side reactions and product degradation, and the obtained cefepime hydrochloride product is high in quality and yield and stable, and is beneficial to industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine, and particularly relates to sterile cefepime hydrochloride and a direct preparation method thereof. Background Art

[0002] Sterile cefepime hydrochloride is an important fourth-generation cephalosporin antibiotic with broad-spectrum antimicrobial activity against a wide range of Gram-positive and Gram-negative bacteria. It is widely used clinically to treat various serious infections, such as respiratory tract infections, urinary tract infections, and skin and soft tissue infections, with significant efficacy and safety.

[0003] The current industrial production process for sterile cefepime hydrochloride involves mixing 7-MPCA ((6R,7R)-7-amino-3-[(1-methyl-1-pyrrolidino)methyl]ceph-3-ene-4-carboxylic acid inner salt) and AE active ester ((Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminothioacetic acid-2'-benzothiazole active ester) in a specific proportion, dissolving them in dichloromethane, and then adding triethylamine to react to produce cefepime hydrochloride. Research has found that this process, primarily a batch-type, tank-type production process, results in a long cycle time, leading to increased side reactions and product degradation. This results in a high level of impurities in the finished product, necessitating the production of crude cefepime hydrochloride followed by recrystallization to obtain high-purity sterile cefepime hydrochloride (as described in Chinese Patent CN105859747A). Furthermore, this intermittent tank production process has several other drawbacks: relatively low production efficiency, making it difficult to ensure consistent quality between batches; a complex process involving multiple steps and operations, prone to errors and deviations; long reaction times, which extend the overall production cycle and increase costs and resource consumption; and inconsistent material residence time during intermittent operation, further impacting product purity and consistency. These drawbacks limit the scale-up and quality improvement of sterile cefepime hydrochloride production, hindering its wider and more efficient medical application.

[0004] Therefore, in order to overcome the shortcomings of the existing intermittent preparation method, it is urgent to develop a new sterile cefepime hydrochloride production method to improve production efficiency, ensure the stability of product quality, reduce costs and achieve more efficient industrial production. Summary of the Invention

[0005] The present invention aims to provide a sterile cefepime hydrochloride and a direct preparation method thereof. The method significantly shortens the preparation cycle of sterile cefepime hydrochloride, greatly reduces side reactions and product degradation, improves production efficiency and product quality, and lays a foundation for directly crystallizing sterile cefepime hydrochloride.

[0006] In order to achieve the above object, the present invention adopts the following technical solutions:

[0007] The present invention first provides a sterile cefepime hydrochloride, the product particle size D90: 100-110 μm, angle of repose: 45-65°, bulk density: 0.35-0.50 g / ml, tap density: 0.67-0.78 g / ml, total impurities: ≤0.17%, solution color: ≤1 # .

[0008] The present invention also provides a direct method for preparing the above-mentioned sterile cefepime hydrochloride, comprising the following steps:

[0009] (1) The 7-MPCA solution and the AE active ester solution are simultaneously passed through a solid base catalyst column for condensation reaction to obtain a condensation solution;

[0010] (2) Controlling the temperature at 0-2°C, the condensation liquid, dichloromethane and water are simultaneously passed through a rapid pipeline mixer, and the resulting mixed liquid is continuously separated through an extraction phase separation column to obtain an aqueous phase;

[0011] (3) Add concentrated hydrochloric acid to the aqueous phase under vacuum and rapid stirring conditions to adjust the pH to 3.5-4.5 to obtain cefepime solution 1; add activated carbon and sodium sulfite to cefepime solution 1, stir and filter to obtain cefepime solution 2; pass cefepime solution 2 and concentrated hydrochloric acid through a microchannel reactor at the same time, adsorb on granular activated carbon, and precisely filter to obtain cefepime hydrochloride crystallization solution; wherein the pH of the mixed solution at the outlet of the microchannel reactor is 0.8-1.0;

[0012] (4) A portion of the cefepime hydrochloride crystallization solution is taken out and mixed with water and acetone to prepare a seed crystal mixture; the remaining cefepime hydrochloride crystallization solution and acetone are added to the seed crystal mixture, and the crystals are grown for 30-60 minutes, and then filtered, washed, and dried to obtain sterile cefepime hydrochloride.

[0013] Furthermore, the volume ratio of the 7-MPCA solution to the AE active ester solution in step (1) is (100-110):(60-65); and the volume ratio of the condensation solution to dichloromethane and water in step (2) is 120:(60-70):(30-40).

[0014] Furthermore, the pH of the solid base catalyst column in step (1) is constant and is between 7.5 and 10.

[0015] Furthermore, the time for the 7-MPCA solution and the AE active ester solution in step (1) to pass through the solid base catalyst column is 15 to 20 minutes.

[0016] Furthermore, the preparation method of the 7-MPCA solution in step (1) is as follows: 7-MPCA, dichloromethane, methanol, and DMF are mixed, the temperature is controlled at -5~0°C, triethylamine is added under rapid stirring, and stirring is continued until it is completely dissolved; wherein the dosage ratio of 7-MPCA, dichloromethane, methanol, DMF, and triethylamine is 100Kg:300-350L:250-270L:400-430L:30-35Kg.

[0017] Furthermore, the preparation method of the AE active ester solution in step (1) is: mixing the AE active ester with dichloromethane and DMF at -5~0°C and stirring until dissolved; wherein the usage ratio of AE active ester to dichloromethane and DMF is 110Kg:250-300L:300-350L.

[0018] Furthermore, in step (3), the mass of the activated carbon is 3%-5% of the mass of 7-MPCA, and the mass of the sodium sulfite is 1%-2% of the mass of 7-MPCA.

[0019] Furthermore, the mass fraction of the concentrated hydrochloric acid in step (3) is 25% to 30%.

[0020] Furthermore, the volume ratio of the remaining cefepime hydrochloride crystallization solution in step (4) to acetone is 8:(40-45).

[0021] Furthermore, in the seed crystal mixture of step (4), the volume ratio of the cefepime hydrochloride solution to be crystallized to water and acetone is 1: (4-5): (20-25), and the volume of the seed crystal mixture is based on the volume that can be touched by the stirring device.

[0022] The present invention (1) first passes 7-MPCA and AE active ester in the form of a solution through a solid base catalyst column, so that they can undergo a condensation reaction 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-MPCA and AE active ester, and reduces the occurrence of side reactions and product degradation under long-term over-alkalinity conditions; (2) then extracts the condensed liquid for phase separation and adjusts the pH twice for crystallization, combined with activated carbon decolorization and sodium sulfite reduction, further improving the quality and color of the cefepime hydrochloride crystallization solution and avoiding recrystallization; (3) after obtaining the cefepime hydrochloride crystallization solution, first take a portion of the cefepime hydrochloride crystallization solution to be prepared into a seed crystal mixture, and then add the remaining cefepime hydrochloride crystallization solution and the crystallization solvent to the seed crystal mixture at a specific speed and method, which can better control the quality and quantity of sterile cefepime hydrochloride crystal nuclei, and then accurately control the crystal growth.

[0023] The method of the present invention realizes the continuous production of sterile cefepime hydrochloride, greatly shortens the preparation cycle of sterile cefepime hydrochloride, reduces the occurrence of side reactions and product degradation, and the obtained cefepime hydrochloride product is high in quality and stable, with a molar yield of more than 91.5% and a purity of more than 99.9%. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The present invention is a schematic flow diagram of a straight-through method for preparing sterile cefepime hydrochloride. DETAILED DESCRIPTION

[0025] like Figure 1 The figure shows a schematic flow diagram of the direct-through method for preparing sterile cefepime hydrochloride of the present invention. The technical solution of the present invention will be further described below in conjunction with the accompanying drawings and specific examples.

[0026] In the following examples, various processes and methods not described in detail are conventional methods known in the art, and all reagents used without indicating their sources and specifications are commercially available of analytical grade or chromatographic grade.

[0027] Example 1

[0028] (1) Mix 100 kg 7-MPCA, 300 L dichloromethane, 250 L methanol and 400 L DMF, control the temperature at -5~0°C, and add 30 kg triethylamine to the mixed solution at a rate greater than 0.5 kg / min under rapid stirring conditions. Continue stirring until the solution is completely dissolved to obtain a 7-MPCA solution.

[0029] (2) Add 110 kg of AE active ester and 250 L of dichloromethane into 300 L of DMF at the same time, stir at -5 to 0 °C until dissolved, and obtain an AE active ester solution;

[0030] (3) 7-MPCA solution and AE active ester solution were introduced into the solid base catalyst column at a volume ratio of 100:60 for condensation reaction. After 15 minutes, the condensation liquid was discharged.

[0031] (4) The condensation liquid is mixed with dichloromethane and water in a volume ratio of 120:64:30 at 0-2°C and passed through a rapid pipeline mixer to obtain a mixed liquid; the mixed liquid enters an extraction phase separation column for continuous phase separation, and the aqueous phase is retained;

[0032] (5) Control the temperature at 0-2°C, add 30% hydrochloric acid by mass to the aqueous phase under vacuum and rapid stirring conditions, and control the pH to 3.5-4.5 to obtain cefepime solution 1; add 3 kg of activated carbon and 1 kg of sodium sulfite to cefepime solution 1, stir for 30 minutes and filter to obtain cefepime solution 2;

[0033] (6) The cefepime solution 2 and 30% hydrochloric acid with a mass fraction of 7:9 were passed through a microchannel reactor, and then adsorbed on activated carbon and finely filtered to obtain a cefepime hydrochloride solution to be crystallized; the pH of the mixed solution flowing out of the outlet of the microchannel reactor was 0.8-1.0;

[0034] (7) Take 20 L of cefepime hydrochloride crystallization solution and mix it with 80 L of water. After stirring evenly, add 400 L of acetone under rapid stirring conditions and stir until the mixture is evenly mixed to obtain a seed crystal mixture;

[0035] (8) The remaining cefepime hydrochloride crystals and acetone were added to the seed crystal mixture at a volume ratio of 800:4000. After the addition, the crystals were grown for 60 minutes, filtered, washed, and dried to obtain sterile cefepime hydrochloride.

[0036] Example 2

[0037] (1) Mix 100 kg 7-MPCA, 350 L dichloromethane, 270 L methanol and 430 L DMF, control the temperature at -5~0°C, add 35 kg triethylamine to the mixed solution at a rate greater than 0.5 kg / min under rapid stirring conditions, and continue stirring until it is completely dissolved to obtain a 7-MPCA solution;

[0038] (2) Add 110 kg of AE active ester and 300 L of dichloromethane into 350 L of DMF at the same time, stir at -5 to 0 °C until dissolved, and obtain an AE active ester solution;

[0039] (3) The 7-MPCA solution and the AE active ester solution were introduced into the solid base catalyst column at a volume ratio of 110:65 for condensation reaction. After 15 minutes, the condensation liquid was discharged.

[0040] (4) The condensation liquid is mixed with dichloromethane and water in a volume ratio of 120:70:40 at 0-2°C and passed through a rapid pipeline mixer to obtain a mixed liquid; the mixed liquid enters an extraction phase separation column for continuous phase separation, and the aqueous phase is retained;

[0041] (5) Control the temperature at 0-2°C, add 30% hydrochloric acid to the aqueous phase under vacuum and rapid stirring conditions, and control the pH to 3.5-4.5 to obtain cefepime solution 1; add 5 kg of activated carbon and 2 kg of sodium sulfite to cefepime solution 1, stir for 30 minutes, and filter to obtain cefepime solution 2;

[0042] (6) The cefepime solution 2 and 30% hydrochloric acid with a mass fraction of 7:12 were passed through a microchannel reactor, and then adsorbed on activated carbon and finely filtered to obtain a cefepime hydrochloride solution to be crystallized; the pH of the mixed solution flowing out of the outlet of the microchannel reactor was 0.8-1.0;

[0043] (7) Take 20L of cefepime hydrochloride to be crystallized and mix it with 100L of water. After stirring evenly, add 500L of acetone under rapid stirring conditions and stir until the mixture is evenly mixed to obtain a seed crystal mixture;

[0044] (8) The remaining cefepime hydrochloride crystals and acetone were added to the seed crystal mixture at a volume ratio of 800:4500. After the addition, the crystals were grown for 60 minutes, filtered, washed, and dried to obtain sterile cefepime hydrochloride.

[0045] Example 3

[0046] (1) Mix 100 kg of 7-MPCA, 320 L of dichloromethane, 270 L of methanol, and 410 L of DMF. Control the temperature at -5 to 0 °C. Add 31 kg of triethylamine to the mixed solution at a rate greater than 0.5 kg / min under rapid stirring. Continue stirring until the solution is completely dissolved to obtain a 7-MPCA solution.

[0047] (2) Add 110 kg of AE active ester and 265 L of dichloromethane into 320 L of DMF at the same time, stir at -5 to 0 °C until dissolved, and obtain an AE active ester solution;

[0048] (3) The 7-MPCA solution and the AE active ester solution were introduced into the solid base catalyst column at a volume ratio of 105:62 for condensation reaction. After 15 minutes, the condensation liquid was discharged.

[0049] (4) The condensation liquid is mixed with dichloromethane and water in a volume ratio of 120:65:35 at 0-2°C and passed through a rapid pipeline mixer to obtain a mixed liquid; the mixed liquid enters an extraction phase separation column for continuous phase separation, and the aqueous phase is retained;

[0050] (5) Control the temperature at 0-2°C, add 30% hydrochloric acid to the aqueous phase under vacuum and rapid stirring conditions, and control the pH to 3.5-4.5 to obtain cefepime solution 1; add 4 kg of activated carbon and 1.5 kg of sodium sulfite to cefepime solution 1, stir for 30 minutes and filter to obtain cefepime solution 2;

[0051] (6) The cefepime solution 2 and 30% hydrochloric acid with a mass fraction of 7:10 were passed through a microchannel reactor, and then adsorbed on activated carbon and finely filtered to obtain a cefepime hydrochloride solution to be crystallized; the pH of the mixed solution flowing out of the outlet of the microchannel reactor was 0.8-1.0;

[0052] (7) Take 20 L of cefepime hydrochloride to be crystallized and mix it with 85 L of water. After stirring evenly, add 500 L of acetone under rapid stirring conditions and stir until the mixture is evenly mixed to obtain a seed crystal mixture;

[0053] (8) The remaining cefepime hydrochloride crystals and acetone were added to the seed mixture at a volume ratio of 800:4300. After the addition, the crystals were grown for 60 minutes, filtered, washed, and dried to obtain sterile cefepime hydrochloride.

[0054] Comparative Example 1

[0055] (1) 100 kg 7-MPCA, 110 kg AE active ester, 550 L dichloromethane, 250 L methanol and 700 L DMF were mixed and stirred, the temperature was controlled at -5~0°C, and triethylamine was slowly added for about 60-120 min; the reaction was then continued until the 7-MPCA reaction was complete to obtain a condensation solution;

[0056] (2) The condensation liquid is mixed with dichloromethane and water in a volume ratio of 120:64:30 at 0-2°C and passed through a rapid pipeline mixer to obtain a mixed liquid; the mixed liquid enters an extraction phase separation column for continuous phase separation, and the aqueous phase is retained;

[0057] (3) Control the temperature at 0-2°C, add 30% hydrochloric acid by mass to the aqueous phase under vacuum and rapid stirring conditions, and control the pH to 3.5-4.5 to obtain cefepime solution 1; add 3 kg of activated carbon and 1 kg of sodium sulfite to cefepime solution 1, stir for 30 minutes and filter to obtain cefepime solution 2;

[0058] (4) After the cefepime solution 2 and 30% hydrochloric acid with a mass fraction of 7:9 are passed through a microchannel reactor, the mixture is adsorbed on activated carbon and finely filtered to obtain a cefepime hydrochloride solution to be crystallized; the pH of the mixed solution flowing out of the outlet of the microchannel reactor is 0.8-1.0;

[0059] (5) Take 20L of cefepime hydrochloride to be crystallized and mix it with 80L of water. After stirring evenly, add 400L of acetone under rapid stirring conditions and stir until the mixture is evenly mixed to obtain a seed crystal mixture;

[0060] (6) The remaining cefepime hydrochloride crystals and acetone were added to the seed crystal mixture at a volume ratio of 800:4000. After the addition, the crystals were grown for 60 minutes, filtered, washed, and dried to obtain sterile cefepime hydrochloride.

[0061] Comparative Example 2

[0062] (1) Mix 100 kg 7-MPCA, 300 L dichloromethane, 250 L methanol and 400 L DMF, control the temperature at -5~0°C, and add 30 kg triethylamine to the mixed solution at a rate greater than 0.5 kg / min under rapid stirring conditions. Continue stirring until the solution is completely dissolved to obtain a 7-MPCA solution.

[0063] (2) Add 110 kg of AE active ester and 250 L of dichloromethane into 300 L of DMF at the same time, stir at -5 to 0 °C until dissolved, and obtain an AE active ester solution;

[0064] (3) The 7-MPCA solution and the AE active ester solution were introduced into the solid base catalyst column at a flow rate of 100:60 for condensation reaction, and the condensation liquid was obtained after 15 minutes.

[0065] (4) The condensation liquid is mixed with dichloromethane and water in a volume ratio of 120:64:30 at 0-2°C and passed through a rapid pipeline mixer to obtain a mixed liquid; the mixed liquid enters an extraction phase separation column for continuous phase separation, and the aqueous phase is retained;

[0066] (5) Control the temperature at 0-2°C, add 30% hydrochloric acid by mass to the aqueous phase under vacuum and rapid stirring conditions, and control the pH to 3.5-4.5 to obtain cefepime solution 1; add 3 kg of activated carbon and 1 kg of sodium sulfite to cefepime solution 1, stir for 30 minutes and filter to obtain cefepime solution 2;

[0067] (6) The cefepime solution 2 and 30% hydrochloric acid with a mass fraction of 7:9 were passed through a microchannel reactor, and then adsorbed on activated carbon and finely filtered to obtain a cefepime hydrochloride solution to be crystallized; the pH of the mixed solution flowing out of the outlet of the microchannel reactor was 0.8-1.0;

[0068] (7) Acetone was added to the cefepime hydrochloride crystallization solution at a volume ratio of 5:1, and then the crystals were grown for 60 minutes. The mixture was then filtered, washed, and dried to obtain sterile cefepime hydrochloride.

[0069] Comparative Example 3

[0070] (1) Mix 100 kg 7-MPCA, 300 L dichloromethane, 250 L methanol and 400 L DMF, control the temperature at -5~0°C, and add 30 kg triethylamine to the mixed solution at a rate greater than 0.5 kg / min under rapid stirring conditions. Continue stirring until the solution is completely dissolved to obtain a 7-MPCA solution.

[0071] (2) Add 110 kg of AE active ester and 250 L of dichloromethane into 300 L of DMF at the same time, stir at -5 to 0 °C until dissolved, and obtain an AE active ester solution;

[0072] (3) 7-MPCA solution and AE active ester solution were introduced into the solid base catalyst column at a volume ratio of 100:60 for condensation reaction. After 15 minutes, the condensation liquid was discharged.

[0073] (4) The condensation liquid, dichloromethane and water are mixed at a flow rate of 120:64:30 at 0-2°C through a rapid pipeline mixer to obtain a mixed liquid; the mixed liquid enters the extraction phase separation column for continuous phase separation, and the aqueous phase is retained;

[0074] (5) Control the temperature at 0-2°C, add 30% hydrochloric acid to the aqueous phase under vacuum and rapid stirring conditions, and control the pH to 3.5-4.5 to obtain cefepime solution 1; add 3 kg of activated carbon and 1 kg of sodium sulfite to cefepime solution 1, stir for 30 minutes and filter to obtain cefepime solution 2;

[0075] (6) The cefepime solution 2 and 30% hydrochloric acid with a mass fraction of 7:9 were passed through a microchannel reactor, and then adsorbed on activated carbon and finely filtered to obtain a cefepime hydrochloride solution to be crystallized; the pH of the mixed solution flowing out of the outlet of the microchannel reactor was 0.8-1.0;

[0076] (7) Take 20 L of cefepime hydrochloride crystallization solution and mix it with 80 L of water. After stirring evenly, add 400 L of acetone under rapid stirring conditions and stir until the mixture is evenly mixed to obtain a seed crystal mixture;

[0077] (8) Add 1-2 times the amount of acetone to the remaining cefepime hydrochloride solution to be crystallized, stir evenly, and then add the same volume of acetone and seed crystal mixture as in Example 1. After the addition is complete, grow the crystals for 30 minutes, add 3-4 times the amount of acetone as the remaining crystallization solution again, grow the crystals for 30 minutes, and then filter, wash, and dry to obtain sterile cefepime hydrochloride.

[0078] Comparative Example 4

[0079] (1) Mix 100 kg 7-MPCA, 300 L dichloromethane, 250 L methanol and 400 L DMF, control the temperature at -5~0°C, and add 30 kg triethylamine to the mixed solution at a rate greater than 0.5 kg / min under rapid stirring conditions. Continue stirring until the solution is completely dissolved to obtain a 7-MPCA solution.

[0080] (2) Add 110 kg of AE active ester and 250 L of dichloromethane into 300 L of DMF at the same time, stir at -5 to 0 °C until dissolved, and obtain an AE active ester solution;

[0081] (3) 7-MPCA solution and AE active ester solution were introduced into the solid base catalyst column at a volume ratio of 100:60 for condensation reaction. After 15 minutes, the condensation liquid was discharged.

[0082] (4) The condensation liquid is mixed with dichloromethane and water in a volume ratio of 120:64:30 at 0-2°C and passed through a rapid pipeline mixer to obtain a mixed liquid; the mixed liquid enters an extraction phase separation column for continuous phase separation, and the aqueous phase is retained;

[0083] (5) Control the temperature at 0-2°C, add 30% hydrochloric acid by mass to the aqueous phase under vacuum and rapid stirring conditions, and control the pH to 0.8-1.0 to obtain a cefepime hydrochloride crystallization solution; add 3 kg of activated carbon and 1 kg of sodium sulfite to the cefepime hydrochloride crystallization solution, stir for 30 minutes, and filter;

[0084] (6) Take 20 L of the cefepime hydrochloride solution to be crystallized obtained in step (5) and mix it with 80 L of water. After stirring evenly, add 400 L of acetone under rapid stirring conditions and stir until the mixture is evenly mixed to obtain a seed crystal mixture;

[0085] (7) The remaining cefepime hydrochloride crystallization solution and acetone are added to the seed crystal mixture at a volume ratio of 800:4000. After the addition, the crystals are grown for 60 minutes, and then filtered, washed, and dried to obtain sterile cefepime hydrochloride.

[0086] The test results of the sterile cefepime hydrochloride products prepared in Examples 1-3 and Comparative Examples 1-4 are shown in Table 1:

[0087] Table 1

[0088] .

Claims

1. A direct preparation method for sterile cefepime hydrochloride, characterized in that: The sterile cefepime hydrochloride product has a particle size D90 of 100-110 μm, an angle of repose of 45-65°, a bulk density of 0.35-0.50 g / ml, a tap density of 0.67-0.78 g / ml, total impurities of ≤0.17%, and a solution color of ≤1. # , its preparation comprises the following steps: (1) The 7-MPCA solution and the AE active ester solution are simultaneously passed through a solid base catalyst column for condensation reaction to obtain a condensation solution; (2) Controlling the temperature at 0-2°C, the condensation liquid, dichloromethane and water are simultaneously passed through a rapid pipeline mixer, and the resulting mixed liquid is continuously separated through an extraction phase separation column to obtain an aqueous phase; (3) Add concentrated hydrochloric acid to the aqueous phase under vacuum and rapid stirring to adjust the pH to 3.5-4.5 to obtain cefepime solution 1; add activated carbon and sodium sulfite to cefepime solution 1, stir and filter to obtain cefepime solution 2; The cefepime solution 2 and concentrated hydrochloric acid are simultaneously passed through a microchannel reactor, and then adsorbed on granular activated carbon and finely filtered to obtain a cefepime hydrochloride solution to be crystallized; wherein the pH of the mixed solution at the outlet of the microchannel reactor is 0.8-1.0; (4) A portion of the cefepime hydrochloride crystallization solution is taken out and mixed with water and acetone to prepare a seed crystal mixture; the remaining cefepime hydrochloride crystallization solution and acetone are added to the seed crystal mixture, and the crystals are grown for 30-60 minutes, and then filtered, washed, and dried to obtain sterile cefepime hydrochloride.

2. The direct preparation method of sterile cefepime hydrochloride according to claim 1, characterized in that: The volume ratio of the 7-MPCA solution to the AE active ester solution in step (1) is (100-110):(60-65); the volume ratio of the condensation solution to dichloromethane and water in step (2) is 120:(60-70):(30-40).

3. The direct preparation method of sterile cefepime hydrochloride according to claim 1, characterized in that: The time for the 7-MPCA solution and the AE active ester solution in step (1) to pass through the solid base catalyst column is 15 to 20 minutes.

4. The direct preparation method of sterile cefepime hydrochloride according to claim 1, characterized in that: The preparation method of the 7-MPCA solution in step (1) is as follows: 7-MPCA, dichloromethane, methanol, and DMF are mixed, the temperature is controlled at -5~0°C, triethylamine is added under rapid stirring, and stirring is continued until it is completely dissolved; wherein the dosage ratio of 7-MPCA, dichloromethane, methanol, DMF, and triethylamine is 100 kg: 300-350 L: 250-270 L: 400-430 L: 30-35 kg.

5. The direct preparation method of sterile cefepime hydrochloride according to claim 1, characterized in that: The preparation method of the AE active ester solution in step (1) is as follows: mixing the AE active ester with dichloromethane and DMF at -5~0°C and stirring until dissolved; wherein the dosage ratio of the AE active ester to dichloromethane and DMF is 110Kg:250-300L:300-350L.

6. The direct preparation method of sterile cefepime hydrochloride according to claim 1, characterized in that: The mass of the activated carbon in step (3) is 3%-5% of the mass of 7-MPCA, and the mass of the sodium sulfite is 1%-2% of the mass of 7-MPCA.

7. The direct preparation method of sterile cefepime hydrochloride according to claim 1, characterized in that: The mass fraction of the concentrated hydrochloric acid in step (3) is 25% to 30%.

8. The direct-through preparation method of sterile cefepime hydrochloride according to claim 1, characterized in that: The volume ratio of the remaining cefepime hydrochloride to be crystallized in step (4) to acetone is 8:(40-45).

9. The direct preparation method of sterile cefepime hydrochloride according to claim 1, characterized in that: In the seed crystal mixture of step (4), the volume ratio of the cefepime hydrochloride solution to be crystallized to water and acetone is 1: (4-5): (20-25), and the volume of the seed crystal mixture is based on the volume that can be touched by the stirring device.

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