Preparation method of cefixime side chain acid active ester based on high gravity reaction

Abstract

The present invention belongs to the field of medical technology, and in particular relates to a method for preparing a cefixime side chain acid active ester based on a supergravity reaction, comprising the following steps: S1, adding an organic solvent, a cefixime side chain acid, a catalyst, and dibenzothiazole disulfide to the outside of a rotating packed bed of a supergravity reactor through a liquid inlet in sequence, starting the supergravity reactor, and then adding the first batch of triethyl phosphite to the middle of the rotating packed bed of the supergravity reactor through a feed spray pipe to perform a first-stage supergravity reaction; S2, performing a second-stage supergravity reaction; S3, performing a third-stage supergravity reaction; S4, after the third-stage supergravity reaction, obtaining a crude product of the cefixime side chain acid active ester, and obtaining the cefixime side chain acid active ester through separation and drying. The present invention has low power energy consumption, does not require methanol to be used for refining after synthesizing the cefixime side chain acid active ester, reduces losses, and has high product purity, high yield, and short reaction time.

Description

Technical Field

[0001] The invention belongs to the technical field of medicine, and particularly relates to a method for preparing cefixime side chain acid active ester based on supergravity reaction. Background Art

[0002] Hypergravity technology accelerates chemical reactions and reduces side reactions by regulating the flow patterns of multiphase systems under hypergravity, enhancing the relative velocity differences between phases and expanding their contact area. Currently, hypergravity machines can effectively handle reactions in gas-liquid, liquid-liquid, and even gas-liquid-solid three-phase systems. Due to its wide applicability and superiority over traditional equipment, hypergravity technology has been widely researched and applied in various fields, including the preparation of nanomaterials, petroleum refining, and the enhancement of biochemical reactions.

[0003] Currently, the primary method for generating high gravity in a hypergravity machine is to utilize the centrifugal force generated by the machine's rotation. The two phases to be reacted are introduced into the machine through separate pipelines. A slurry is first introduced into the machine's cavity. After the liquid phase is added to the rotating packed bed, the centrifugal force of the packing material disperses it into ever-smaller units and evenly mixes them into the slurry. During this process, the broken droplets form a vast, constantly renewing surface, and the tortuous flow path exacerbates this surface renewal. This creates excellent mass transfer and reaction conditions within the machine.

[0004] Cefixime has excellent antibacterial properties, with a long-lasting effective concentration, stability against β-lactamase, good in vivo dispersibility, and high oral bioavailability. It is significantly effective in treating urinary and biliary tract infections, gonorrhea, scarlet fever, otitis media, and sinusitis. Cefixime is available in a variety of dosage forms, including tablets, capsules, dispersible tablets, dry suspensions, and granules. It is suitable not only for adults but also for children in low-dose formulations, ensuring widespread applicability.

[0005] The preparation of cefixime is primarily based on a semi-synthetic method, with the core focus being the efficient condensation of MICA active esters and subsequent purification. In industrial production, process optimization, such as the "one-pot" method and improved crystallization solvents, can significantly improve yield and product quality while reducing environmental impact.

[0006] Chinese patent CN101362733A discloses a method for preparing a cefixime side chain acid active ester. The method comprises the following steps: mixing 1.0 mol of cefixime side chain acid (MICA Acid) with 1.0-1.4 mol of a rubber accelerator DM (dibenzothiazyl disulfide) in an organic solvent system at -10-50°C, adding 1.0-1.3 mol of an organic amine and 0-0.1 mol of a pyridinium salt derivative catalyst, and dropwise adding 1.1-1.5 mol of triethyl phosphite at -10-50°C over 1-8 hours. The mixture is kept warm for 1-6 hours to obtain the cefixime side chain acid active ester.

[0007] Chinese patent CN112830903A discloses a method for preparing a cefixime side chain acid active ester. The method comprises using cefixime side chain acid and dibenzothiazole disulfide as raw materials, using a mixed solution of dichloroethane and acetonitrile as solvent, adding triethyl phosphite dropwise in the presence of a catalyst, carrying out microwave reaction, and post-processing to obtain the cefixime side chain acid active ester.

[0008] This patent suffers from long reaction time, high energy consumption, and high environmental and cost pressures. Currently, there is a need to improve the synthesis method so that the synthesis of cefixime side chain acid active esters can be rapid and simple, while also taking into account the characteristics of high product purity, high yield, and low cost.

[0009] By enhancing mass transfer and reaction processes, high-gravity technology provides an innovative solution for the synthesis, purification and formulation of cefixime, combining efficiency improvements with environmental advantages.

[0010] Chinese patent CN118788240A discloses a method for synthesizing dimethyl phosphite using a high-gravity reactor. This patent uses a high-gravity reactor for esterification reaction. The high-gravity effect of the high-gravity rotating packed bed promotes the flow and contact of the reaction materials in the porous medium.

[0011] The reactor of this patent needs to maintain a relatively high negative pressure at all times, which results in the obstruction of the normal discharge of exhaust gas, an increase in by-products, and insufficient purity of the obtained product. In addition, long-term high negative pressure also has a great impact on the service life of the equipment. Summary of the Invention

[0012] In view of the above shortcomings in the prior art, the technical problem to be solved by the present invention is to provide a method for preparing a cefixime side chain acid active ester based on a high-gravity reaction, wherein the reaction is carried out under normal pressure, the operation is simpler, the reaction is faster, the power energy consumption is lower, and the yield and purity of the product are effectively improved.

[0013] The technical solution adopted by the present invention to solve its technical problem is:

[0014] The method for preparing the active ester of cefixime side chain acid based on high gravity reaction of the present invention comprises the following steps:

[0015] S1, adding an organic solvent, cefixime side chain acid, a catalyst, and dibenzothiazole disulfide sequentially to the outside of a rotating packed bed of a high-gravity reactor through a top feed liquid port, starting the high-gravity reactor, and then adding a first batch of triethyl phosphite to the middle of the rotating packed bed of the high-gravity reactor through a feed spray pipe to carry out a first-stage high-gravity reaction;

[0016] S2, adding the second batch of triethyl phosphite and activator to the bottom of the outer side of the rotating packed bed of the high gravity reactor through the bottom feed liquid port to carry out the second stage high gravity reaction;

[0017] S3, adding the third batch of triethyl phosphite to the top of the outer side of the rotating packed bed of the high gravity reactor through the top feed liquid port to carry out the third stage high gravity reaction;

[0018] S4. After the third stage high gravity reaction, a crude product of cefixime side chain acid active ester is obtained, which is then separated and dried to obtain cefixime side chain acid active ester.

[0019] in:

[0020] In the step S1, the temperature of the first-stage high-gravity reaction is 5-10° C., the high-gravity reaction time is 20-30 min, and the first batch of triethyl phosphite accounts for 20-30 wt.% of the total amount of triethyl phosphite; in the step S2, the temperature of the second-stage high-gravity reaction is 20-25° C., the high-gravity reaction time is 10-20 min, and the second batch of triethyl phosphite accounts for 50-60 wt.% of the total amount of triethyl phosphite; in the step S3, the temperature of the third-stage high-gravity reaction is 12-18° C., the high-gravity reaction time is 20-30 min, and the third batch of triethyl phosphite is the remainder.

[0021] In the step S1, the organic solvent is a mixed solvent of ethanol, acetonitrile and dichloroethane, the ratio of cefixime side chain acid to the organic solvent is 1:5-6, the cefixime side chain acid is measured in g, the organic solvent is measured in ml, and the volume ratio of ethanol, acetonitrile and dichloroethane is 1:7-8:1.

[0022] In the step S1, the molar ratio of cefixime side chain acid to dibenzothiazyl disulfide is 1:0.8-1.2.

[0023] In the step S1, the catalyst is triethylamine, 2,6-diisopropylaniline or tri-n-propylamine, and the mass ratio of cefixime side chain acid to the catalyst is 1:0.05-0.06.

[0024] The molar ratio of the cefixime side chain acid to the total amount of the first batch, the second batch and the third batch of triethyl phosphite is 1:1-1.2.

[0025] In the step S2, the activator is cetylpyridinium chloride or cetylpyridinium bromide, and the mass ratio of cefixime side chain acid to the activator is 1:0.01-0.03.

[0026] The supergravity reactor in step S1 includes a shell, a rotating packed bed is arranged inside the shell, a feed channel is arranged at the center of the top of the shell, a connecting channel is arranged at the center of the rotating packed bed, a feed spray pipe is arranged in the feed channel, and the bottom of the feed spray pipe passes through the connecting channel and extends to the lower part of the rotating packed bed. A top feed liquid inlet and a leaching port are opened on the shell, a rotating rod is arranged at the bottom of the rotating packed bed, a rotating shaft is arranged between the rotating rod and the bottom of the shell, and the shell is provided with a bottom feed liquid inlet.

[0027] The lower part of the feed spray pipe is provided with a plurality of spray ports, a liquid sealing layer is provided above the rotating shaft, a bearing is provided between the connecting channel and the feed channel, and a liquid sealing layer is provided at the bottom of the bearing.

[0028] In step S4, the separation temperature is -5~5°C, the drying temperature is 35~50°C, and the drying pressure is -0.2~0 MPa.

[0029] The synthetic reaction formula of cefixime side chain acid active ester is as follows:

[0030]

[0031] Traditional synthesis involves mixing reactants evenly through stirring, which results in low mixing efficiency and long reaction time. Ultra-gravity technology, on the other hand, disperses the materials into smaller units through a rotating packed bed. Due to the difference in relative flow rates of the materials and the larger specific surface area of ​​the packing device, the materials are mixed more quickly and evenly, greatly accelerating the reaction rate and effectively avoiding the occurrence of side reactions.

[0032] The reaction state when adding triethyl phosphite three times of the present invention is as follows:

[0033] When triethyl phosphite is first added from the middle of the rotating packed bed, the reaction begins, and the raw materials are gradually converted into the active ester of the cefixime side chain acid. The color of the reaction system gradually changes from milky white to light yellow. This process is mainly reflected in the activation of the carboxyl group in the cefixime side chain acid and the cleavage of the sulfur-sulfur bond in dibenzothiazole disulfide to produce an intermediate transition state.

[0034] After a period of time, triethyl phosphite and an activator are added from the bottom of the rotating packed bed for the second time. During this process, the reaction system changes from light yellow to orange-yellow, and a large amount of heat is released during the reaction. A large amount of cefixime side chain active ester crystals precipitate in the reaction system, and the reaction system becomes viscous. During this stage, the intermediate transition state begins to collide in the mixed solvent, forming cefixime side chain acid active ester crystal nuclei.

[0035] In the present invention, activator is cetylpyridinium chloride or cetylpyridinium bromide, is both activator and acid binding agent, its effect is when reaction system becomes viscous, catalyst activation effect is limited, auxiliary catalyst activates cefixime side chain acid, promotes esterification, because it has long-chain alkyl, and long chain is wound to form network structure, the intermediate formed is protected, also plays viscosity reduction effect simultaneously; And the pyridine group of activator and the amido in catalyst form hydrogen bond composition catalytic activation system, halogen atom participates in hydrogen bond system, is more conducive to catalytic activation of the present invention. In addition, because 2-mercaptobenzothiazole can be continuously produced in the reaction process, the generation of acidic by-product can suppress the carrying out of main reaction, now the halogen atom on the activator attracts 2-mercaptobenzothiazole, pyridine is bound to it, so activator can be used as acid binding agent auxiliary catalyst to bind the 2-mercaptobenzothiazole produced again, promotes main reaction to carry out smoothly, reduces the consumption of catalyst, reduces reaction times.

[0036] After a period of time, triethyl phosphite is added from the top of the rotating packed bed for the third time. This process is in the late stage of the reaction. The reaction is relatively mild and the reaction system changes from viscous to thin. The final stage is mainly the growth of crystal nuclei.

[0037] The present invention innovatively divides triethyl phosphite into three feeding steps, and feeds from the middle, bottom and top of a rotating packed bed respectively. The feeding is performed step by step from different angles according to the reaction progress. The feeding from the bottom and top of the rotating packed bed is used to reversely flush the spray port, thereby preventing the viscous reaction system from adhering to the spray port and the packing surface and affecting further reaction, thereby reducing the reaction time.

[0038] The present invention innovatively adopts a first-stage hypergravity reaction, a second-stage hypergravity reaction and a third-stage hypergravity reaction, and cooperates with a low-temperature-high-temperature-low-temperature reaction mode to reduce the reaction time.

[0039] Adding triethyl phosphite to a rotating packed bed in three separate additions yields the highest product yield and purity. Adding triethyl phosphite all at once causes rapid reaction, large temperature fluctuations, and numerous side reactions, resulting in low product yield and purity. Adding triethyl phosphite in four or more separate additions causes some decomposition of dibenzothiazole disulfide, leading to low product yield and prolonged reaction times, impacting production efficiency.

[0040] In the present invention, triethyl phosphite, a catalyst, and an activator act synergistically on the reaction of cefixime side chain acids. The catalyst activates the formation of an intermediate, enabling the intermediate conversion process to be controlled. Triethyl phosphite can further convert the intermediate into a phosphate intermediate. The intermediate obtained in this reaction is more susceptible to reaction with hydroxyl groups, thereby suppressing the occurrence of side reactions. Furthermore, triethyl phosphite can effectively remove water molecules from the reaction, effectively shifting the esterification equilibrium toward the product.

[0041] The beneficial effects of the present invention are:

[0042] The present invention prepares cefixime side chain active ester in a high-gravity reactor, and improves the way of adding raw materials and the reaction raw material auxiliary agent, thereby increasing the contact area between cefixime side chain acid and dibenzothiazole disulfide, achieving rapid reaction. Due to the large contact area between the two, the reaction can be completed more quickly. Due to the synergistic effect between the catalyst, triethyl phosphite and the activator, the conversion of the intermediate product is increased, the reaction process is controlled, the occurrence of side reactions is reduced, the generation of cefixime side chain active ester is promoted, and the conversion rate of the raw materials is improved. Moreover, the 2-mercaptobenzothiazole generated by the reaction can be well dissolved in a mixed solvent and can be separated from the product in a subsequent centrifugal separation process. The catalyst and the activator selected by the present invention can also be separated together with the generated mother liquor to obtain a purer product. Therefore, the present invention can achieve more efficient conversion, improve reaction efficiency and product yield, and reduce reaction time.

[0043] In summary, the present invention has low power energy consumption, does not require methanol to be used for purification after the synthesis of the active ester of the cefixime side chain acid, thereby reducing losses, and because the present invention changes the reaction aid, the feeding method, and the reaction equipment during the reaction process, fewer side reactions occur during the reaction process, the obtained product has high purity, high yield, and short reaction time. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 Schematic diagram of the structure of the high gravity reactor of the present invention;

[0045] Figure 2 This is the H NMR spectrum of the active ester of the cefixime side chain acid in Example 1 of the present invention;

[0046] Figure 3 yes Figure 2 Enlarged view of point A in the middle;

[0047] Figure 4 1 is a liquid chromatogram of the active ester of cefixime side chain acid in Example 1 of the present invention;

[0048] Figure 5 It is a liquid chromatogram of cefixime side chain acid active ester in Example 2 of the present invention.

[0049] In the figure: 1. Shell; 2. Rotating packed bed; 3. Feed spray pipe; 4. Top liquid inlet; 5. Rinse port; 6. Bottom liquid inlet; 7. Rotating rod; 8. Rotating shaft; 9. Spray port. DETAILED DESCRIPTION

[0050] The embodiments of the present invention will be further described below with reference to the accompanying drawings.

[0051] Example 1

[0052] like Figure 1 As shown, the ultragravity reactor includes a shell 1, a rotating packed bed 2 is arranged inside the shell 1, a feed channel is arranged at the top center of the shell 1, a connecting channel is arranged at the center of the rotating packed bed 2, a feed spray pipe 3 is arranged in the feed channel, and the bottom of the feed spray pipe 3 passes through the connecting channel and extends to the lower part of the rotating packed bed 2. A top feed liquid inlet 4 and a leaching port 5 are provided on the shell 1, a rotating rod 7 is provided at the bottom of the rotating packed bed 2, a rotating shaft 8 is provided between the rotating rod 7 and the bottom of the shell 1, and the shell 1 is provided with a bottom feed liquid inlet 6.

[0053] A plurality of spray ports 9 are provided at the lower portion of the feed spray pipe 3, a liquid sealing layer is provided above the rotating shaft 8, a bearing is provided between the connecting channel and the feed channel, and a liquid sealing layer is provided at the bottom of the bearing.

[0054] The preparation method of cefixime side chain acid active ester based on supergravity reaction comprises the following steps:

[0055] S1, 1000ml ethanol, acetonitrile and ethylene dichloride volume ratio is a mixed solvent of 1:7:1, 200g cefixime side chain acid, 10g triethylamine, 205g dibenzothiazole disulfide are added to high-gravity reactor rotating packed bed 2 outsides through top feed liquid port 4 successively, start high-gravity reactor, add first batch of 25.6g triethyl phosphite to high-gravity reactor rotating packed bed 2 middle part through feed spray pipe 3 again, carry out first stage high-gravity reaction 30min at 5 ℃;

[0056] S2, adding a second batch of 64g of triethyl phosphite and 2g of cetylpyridinium chloride to the outer bottom of the rotating packed bed 2 of the high gravity reactor through the bottom feed liquid port 6, and carrying out the second stage high gravity reaction at 20°C for 20min;

[0057] S3, adding a third batch of 38.4 g of triethyl phosphite to the top of the outer side of the rotating packed bed 2 of the high gravity reactor through the top feed liquid port 4, and carrying out the third stage high gravity reaction at 12° C. for 25 minutes;

[0058] S4. After the third stage of high gravity reaction, the crude product of cefixime side chain acid active ester was obtained, which was centrifuged at 5°C and dried at 40°C and -0.2MPa to obtain cefixime side chain acid active ester with a yield of 99.47% and a purity of 99.6%. The H NMR spectrum was as follows: Figure 2 、 3 As shown in the liquid chromatogram Figure 4 shown.

[0059] Example 2

[0060] The reaction apparatus used in this example is the same as that used in Example 1.

[0061] The preparation method of cefixime side chain acid active ester based on supergravity reaction comprises the following steps:

[0062] S1, 1200ml ethanol, acetonitrile and dichloroethane volume ratio is a mixed solvent of 1:8:1, 200g cefixime side chain acid, 12g 2,6-diisopropylaniline, 256g dibenzothiazole disulfide are added to the outside of the high gravity reactor rotating packed bed 2 through the top liquid port 4 in sequence, the high gravity reactor is started, and then the first batch of 42.3g triethyl phosphite is added to the middle part of the high gravity reactor rotating packed bed 2 through the feed spray pipe 3, and the first stage high gravity reaction is carried out at 10°C for 20min;

[0063] S2, adding a second batch of 77.6g of triethyl phosphite and 4g of cetylpyridinium bromide to the outer bottom of the rotating packed bed 2 of the high-gravity reactor through the bottom feed liquid port 6, and carrying out the second stage high-gravity reaction at 23°C for 15min;

[0064] S3, adding a third batch of 21.2 g of triethyl phosphite to the top of the outer side of the rotating packed bed 2 of the high-gravity reactor through the top feed liquid port 4, and carrying out the third stage high-gravity reaction at 18° C. for 20 minutes;

[0065] S4. After the third stage of high gravity reaction, the crude product of cefixime side chain acid active ester was obtained, which was centrifuged at -5°C and dried at 35°C and 0 MPa to obtain cefixime side chain acid active ester with a yield of 99.45% and a purity of 99.5%. The liquid chromatogram is shown in FIG. Figure 5 shown.

[0066] Example 3

[0067] The reaction apparatus used in this example is the same as that used in Example 1.

[0068] The preparation method of cefixime side chain acid active ester based on supergravity reaction comprises the following steps:

[0069] S1, 1100ml ethanol, acetonitrile and ethylene dichloride volume ratio is a mixed solvent of 1:7:1, 200g cefixime side chain acid, 11g tri-n-propylamine, 307g dibenzothiazole disulfide are added to the outside of the high-gravity reactor rotating packed bed 2 through the top feed liquid port 4 successively, start the high-gravity reactor, then add the first batch of 38.3g triethyl phosphite to the middle part of the high-gravity reactor rotating packed bed 2 through the feed spray pipe 3, carry out the first stage high-gravity reaction 25min at 8 ℃;

[0070] S2, adding a second batch of 91.8 g of triethyl phosphite and 6 g of cetylpyridinium chloride to the outer bottom of the rotating packed bed 2 of the high-gravity reactor through the bottom feed liquid port 6, and carrying out the second stage high-gravity reaction at 25° C. for 10 min;

[0071] S3, adding a third batch of 23 g of triethyl phosphite to the top of the outer side of the rotating packed bed 2 of the high gravity reactor through the top feed liquid port 4, and carrying out the third stage high gravity reaction at 15° C. for 30 min;

[0072] S4. After the third stage high gravity reaction, a crude product of cefixime side chain acid active ester was obtained, which was centrifuged at 0° C. and dried at 50° C. and −0.1 MPa to obtain cefixime side chain acid active ester with a yield of 99.5% and a purity of 99.4%.

[0073] Comparative Example 1

[0074] In step S1, all the triethyl phosphite in Example 1 is added to the rotating packed bed 2 of the high gravity reactor through the feed spray pipe 3 at one time, and the remaining steps are the same as in Example 1 to obtain cefixime side chain acid active ester with a yield of 93.8% and a purity of 94.6%.

[0075] Comparative Example 2

[0076] In step S2, cetylpyridinium chloride was not added as an activating agent, and the remaining steps were the same as in Example 1 to obtain cefixime side chain acid active ester with a yield of 92.4% and a purity of 93.8%.

[0077] Comparative Example 3

[0078] In step S1, triethylamine was not added as a catalyst, and the remaining steps were the same as in Example 1 to obtain cefixime side chain acid active ester with a yield of 91.9% and a purity of 93.2%.

[0079] Comparative Example 4

[0080] In step S1, all the triethyl phosphite in Example 1 was evenly divided into five additions, and the remaining steps were the same as in Example 1. The last two triethyl phosphite additions were added through the feed spray pipe 3 to obtain cefixime side chain acid active ester with a yield of 91.8% and a purity of 94.3%.

[0081] In addition, the present invention has conducted multiple experiments on the feeding method:

[0082] 1. Triethyl phosphite was evenly divided into five feedings, all of which were added through the feed spray pipe 3. The rest was the same as in Example 1;

[0083] 2. The second batch of feed enters through the feed liquid port 4 at the top of the high gravity reactor, and the rest is the same as in Example 1;

[0084] 3. The third batch of feed enters through the liquid inlet 6 at the bottom of the high gravity reactor, and the rest is the same as in Example 1;

[0085] 4. The second batch of feed enters through the feed liquid port 4 at the top of the high gravity reactor, and the third batch of feed enters through the feed liquid port 6 at the bottom of the high gravity reactor. The rest is the same as in Example 1;

[0086] 5. The activator was added to the first batch of feed, and no activator was added to the second and third batches of feed. The rest was the same as in Example 1;

[0087] 6. The activator was added to the third batch of feed, and no activator was added to the first and second batches of feed. The rest was the same as in Example 1.

[0088] The above experiments showed that the results were not ideal. As long as the feeding method of the present invention is not followed, the purpose of the present invention cannot be achieved.

[0089] In summary, by comparing Example 1 and Comparative Example 1, it can be seen that the method of adding triethyl phosphite in three steps has a positive and effective effect on both the yield and purity of the product. At the same time, the high gravity reactor is used to enhance the mass transfer and reaction process, optimize the synthesis and purification of cefixime side chain acid active ester, and have both efficiency improvement and environmental protection advantages. Comparing Example 1, Comparative Example 2 and Comparative Example 3, it can be seen that when triethylamine or cetylpyridinium chloride is added alone to the reaction system, the yield of the obtained cefixime side chain acid active ester is low and the quality is poor. Comparative Example 1 , Comparative Example 2 and Comparative Example 4, it can be seen that increasing the number of additions of triethyl phosphite will lead to the decomposition of dibenzothiazole disulfide, resulting in a low product yield, and using triethylamine alone as a catalyst without adding cetylpyridinium chloride as an activator will cause the reaction system to be too viscous even if the reaction progress is prolonged, and the reaction intermediates cannot be fully converted and protected, resulting in poor product effect and low production efficiency; for the above Examples 1-3 and Comparative Examples 1-4 and multiple experiments, a comparative analysis was conducted, and the method for synthesizing the active ester of the cefixime side chain acid of the present invention was more efficient and had better effects.

Claims

1. A method for preparing a cefixime side chain acid active ester based on a high gravity reaction, characterized in that: The following steps are involved: S1. Add the organic solvent, cefixime side chain acid, catalyst, and dibenzothiazole disulfide to the outside of the rotating packed bed (2) of the high-gravity reactor through the top liquid inlet (4) in sequence, start the high-gravity reactor, and then add the first batch of triethyl phosphite to the middle of the rotating packed bed (2) of the high-gravity reactor through the feed spray pipe (3) to carry out the first stage of high-gravity reaction; the catalyst is triethylamine, 2,6-diisopropylaniline or tri-n-propylamine; S2, adding a second batch of triethyl phosphite and an activator to the outer bottom of the rotating packed bed (2) of the high-gravity reactor through the bottom liquid inlet (6) to carry out the second stage of high-gravity reaction, wherein the activator is cetylpyridinium chloride or cetylpyridinium bromide; S3, adding the third batch of triethyl phosphite to the top of the outer side of the rotating packed bed (2) of the high-gravity reactor through the top feed liquid port (4) to carry out the third stage of high-gravity reaction; S4. After the third stage high gravity reaction, a crude product of cefixime side chain acid active ester is obtained, which is then separated and dried to obtain cefixime side chain acid active ester.

2. The method for preparing cefixime side chain acid active ester based on high gravity reaction according to claim 1, wherein In step S1, the temperature of the first-stage high-gravity reaction is 5-10° C., the high-gravity reaction time is 20-30 min, and the first batch of triethyl phosphite accounts for 20-30 wt.% of the total amount of triethyl phosphite; in step S2, the temperature of the second-stage high-gravity reaction is 20-25° C., the high-gravity reaction time is 10-20 min, and the second batch of triethyl phosphite accounts for 50-60 wt.% of the total amount of triethyl phosphite; in step S3, the temperature of the third-stage high-gravity reaction is 12-18° C., the high-gravity reaction time is 20-30 min, and the third batch of triethyl phosphite is the remainder.

3. The method for preparing cefixime side chain acid active ester based on high gravity reaction according to claim 1, wherein In step S1, the organic solvent is a mixed solvent of ethanol, acetonitrile and dichloroethane, the ratio of cefixime side chain acid to the organic solvent is 1:5-6, cefixime side chain acid is measured in g, the organic solvent is measured in ml, and the volume ratio of ethanol, acetonitrile and dichloroethane is 1:7-8:

1.

4. The method for preparing cefixime side chain acid active ester based on high gravity reaction according to claim 1, wherein In step S1, the molar ratio of cefixime side chain acid to dibenzothiazyl disulfide is 1:0.8-1.

2.

5. The method for preparing cefixime side chain acid active ester based on high gravity reaction according to claim 1, wherein In step S1, the mass ratio of cefixime side chain acid to catalyst is 1:0.05-0.

06.

6. The method for preparing cefixime side chain acid active ester based on high gravity reaction according to claim 1, wherein The molar ratio of cefixime side chain acid to the total amount of triethyl phosphite in the first, second and third batches is 1:1-1.

2.

7. The method for preparing cefixime side chain acid active ester based on high gravity reaction according to claim 1, characterized in that: In step S2, the mass ratio of cefixime side chain acid to activator is 1:0.01-0.

03.

8. The method for preparing cefixime side chain acid active ester based on high gravity reaction according to claim 1, characterized in that: In step S1, the supergravity reactor comprises a shell (1), a rotating packed bed (2) is arranged inside the shell (1), a feed channel is arranged at the center of the top of the shell (1), a connecting channel is arranged at the center of the rotating packed bed (2), a feed spray pipe (3) is arranged in the feed channel, the bottom of the feed spray pipe (3) passes through the connecting channel and extends to the lower part of the rotating packed bed (2), a top feed liquid inlet (4) and a leaching port (5) are opened on the shell (1), a rotating rod (7) is arranged at the bottom of the rotating packed bed (2), a rotating shaft (8) is arranged between the rotating rod (7) and the bottom of the shell (1), and the shell (1) is provided with a bottom feed liquid inlet (6).

9. The method for preparing cefixime side chain acid active ester based on high gravity reaction according to claim 8, characterized in that: A plurality of spray ports (9) are provided at the lower portion of the feed spray pipe (3), a liquid sealing layer is provided above the rotating shaft (8), a bearing is provided between the connecting channel and the feed channel, and a liquid sealing layer is provided at the bottom of the bearing.

10. The method for preparing cefixime side chain acid active ester based on high gravity reaction according to claim 1, characterized in that: In step S4, the separation temperature is -5~5°C, the drying temperature is 35~50°C, and the drying pressure is -0.2~0 MPa.

Images