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

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of cefixime side chain acid active ester based on a supergravity reaction, which comprises the following steps: S1, sequentially adding an organic solvent, cefixime side chain acid, a catalyst and dibenzothiazyl disulfide to the outer side of a rotating packed bed of a supergravity reactor through a liquid inlet, starting the supergravity reactor, and reacting for 2-4 hours; adding a first batch of triethyl phosphite into the middle part of a rotating packed bed of the supergravity reactor through a feeding spray pipe, and carrying out a first-stage supergravity reaction; s2, carrying out a second-stage supergravity reaction; s3, carrying out a third-stage supergravity reaction; and S4, after the third-stage supergravity reaction, obtaining a cefixime side chain acid active ester crude product, and separating and drying to obtain the cefixime side chain acid active ester. According to the present invention, the power energy consumption is low, the methanol is not required to refine after the cefixime side chain acid active ester is synthesized, the loss is reduced, and the obtained product has advantages of high purity, high yield and short reaction time.

Description

Technical Field

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

[0002] The high gravity technology is to adjust the flow mode of the multiphase flow system under high gravity conditions, enhance the relative flow velocity difference between different phases and expand the contact area between them, so as to accelerate the chemical reaction process and reduce the occurrence of side reactions. At present, a high gravity machine can effectively handle the reactions of gas-liquid two-phase, liquid-liquid two-phase and even gas-liquid-solid three-phase systems. Because of its wide applicability and superiority compared with traditional equipment, the high gravity technology has been widely studied and used in various fields such as the preparation of nanomaterials, petroleum refining, and strengthening biochemical reactions.

[0003] At present, the main way to obtain high gravity by a high gravity machine is to use the centrifugal force generated by the rotation of the equipment to introduce the two phases to be reacted into the high gravity machine through different pipelines. The slurry is first introduced into the cavity of the high gravity machine, and after the liquid phase is added to the rotating packing bed, it is dispersed into finer units under the action of the centrifugal force of the filler and uniformly mixed into the slurry. During this process, a huge and continuously updated surface is formed by the broken liquid droplets, and the tortuous flow path intensifies the update of this surface. In this way, excellent mass transfer and reaction conditions are formed inside the high gravity machine.

[0004] Cefixime has excellent antibacterial effects, and its effective concentration lasts for a long time. It is stable to β-lactamase, has good dispersion in vivo, and has a high oral bioavailability. It has a significant effect on the treatment of urinary system, biliary system, gonorrhea, scarlet fever, otitis media, and paranasal sinusitis. Cefixime drugs are available in various forms, such as tablets, capsules, dispersible tablets, dry suspensions, and granules. They can be used not only for adult patients but also for children, and small-dose antibiotic drugs have been specially designed and launched, with good wide applicability.

[0005] The preparation of cefixime mainly uses the semi-synthetic method, and the core lies in the efficient condensation of MICA active ester and subsequent purification. In industrial production, through process optimization, such as the "one-pot method" and improvement of the crystallization solvent, the yield and product quality can be significantly improved, and at the same time, the environmental burden can be reduced.

[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 to 1.4 mol of a rubber accelerator DM (dibenzothiazole disulfide) at -10 to 50° C. in an organic solvent system, adding 1.0 to 1.3 mol of an organic amine and 0 to 0.1 mol of a pyridinium salt derivative catalyst, dripping 1.1 to 1.5 mol of triethyl phosphite at -10 to 50° C. within 1 to 8 hours, and keeping the temperature for 1 to 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, which comprises taking cefixime side chain acid and dibenzothiazole disulfide as raw materials, using a mixed solution of ethylene dichloride and acetonitrile as solvent, adding triethyl phosphite dropwise under the catalysis of a catalyst, carrying out microwave reaction, and post-processing to obtain the cefixime side chain acid active ester.

[0008] The patent has the disadvantages of long reaction time, high energy consumption, high environmental protection and cost pressure. At present, it is necessary to improve the synthesis method so that the synthesis of cefixime side chain acid active ester can be fast and simple, and the characteristics of high product purity, high yield and low cost can be taken into account at the same time.

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

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

[0011] The reactor of this patent needs to maintain a relatively high negative pressure all the time, which results in the obstruction of normal exhaust gas discharge, 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 deficiencies 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 supergravity 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: The method for preparing the active ester of cefixime side chain acid based on supergravity reaction of the present invention comprises the following steps: S1. Add organic solvent, cefixime side chain acid, catalyst, and dibenzothiazole disulfide to the outside of the rotating packing bed of the high gravity reactor in sequence through the top liquid inlet. Start the high gravity reactor, and then add the first batch of triethyl phosphite to the middle of the rotating packing bed of the high gravity reactor through the feed spray pipe to carry out the first-stage high gravity reaction; S2. Add the second batch of triethyl phosphite and activator to the bottom outside of the rotating packing bed of the high gravity reactor through the bottom liquid inlet to carry out the second-stage high gravity reaction; S3. Add the third batch of triethyl phosphite to the top outside of the rotating packing bed of the high gravity reactor through the top liquid inlet to carry out the third-stage high gravity reaction; S4. After the third-stage high gravity reaction, obtain the crude product of cefixime side chain acid active ester, and obtain cefixime side chain acid active ester through separation and drying.

[0014] Among them: In the step S1, the temperature of the first-stage high gravity reaction is 5 - 10 °C, the time of the first-stage high gravity reaction 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 time of the second-stage high gravity reaction 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 time of the third-stage high gravity reaction is 20 - 30 min, and the third batch of triethyl phosphite is the remainder.

[0015] In the step S1, the organic solvent is a mixed solvent of ethanol, acetonitrile, and dichloroethane, and the ratio of cefixime side chain acid to the organic solvent is 1:5 - 6, with cefixime side chain acid in g and the organic solvent in ml, and the volume ratio of ethanol, acetonitrile, and dichloroethane is 1:7 - 8:1.

[0016] In the step S1, the molar ratio of cefixime side chain acid to dibenzothiazole disulfide is 1:0.8 - 1.2.

[0017] In the step S1, the catalyst is triethylamine, 2,6 - diisopropyl aniline, or tri - n - propylamine, and the mass ratio of cefixime side chain acid to the catalyst is 1:0.05 - 0.06.

[0018] The molar ratio of cefixime side chain acid to the total amount of the first, second, and third batches of triethyl phosphite is 1:1 - 1.2.

[0019] 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.

[0020] In step S1, the high-gravity reactor includes a housing. Inside the housing, a rotating packed bed is provided. At the center of the top of the housing, a feed channel is provided. At the center of the rotating packed bed, a connection channel is provided. Inside the feed channel, a feed spray pipe is provided. The bottom of the feed spray pipe passes through the connection channel and extends to the lower part of the rotating packed bed. The housing is provided with a top liquid outlet and a washing port. At the bottom of the rotating packed bed, a rotating rod is provided. Between the rotating rod and the bottom of the housing, a rotating shaft is provided. The housing is provided with a bottom liquid outlet.

[0021] A number of spray ports are provided at the lower part of the feed spray pipe. Above the rotating shaft, a liquid seal layer is provided. Between the connection channel and the feed channel, a bearing is provided. At the bottom of the bearing, a liquid seal layer is provided.

[0022] In step S4, the separation temperature is -5 to 5 °C, the drying temperature is 35 to 50 °C, and the drying pressure is -0.2 to 0 MPa.

[0023] The synthesis reaction formula of cefixime side chain acid active ester is as follows:

[0024] In traditional synthesis, the reactants are mixed evenly by stirring, with low mixing efficiency and long reaction time. While in the high-gravity technology, the materials are dispersed into smaller units through the rotating packed bed. And due to the relative flow velocity difference of the materials and the large specific surface area of the packing device, the mixing of the materials is more rapid and uniform, greatly accelerating the reaction rate and effectively avoiding the occurrence of side reactions.

[0025] The reaction states when triethyl phosphite is added three times in the present invention are as follows: For the first time, triethyl phosphite is added from the middle of the rotating packed bed, and the reaction starts. The reaction raw materials gradually transform into cefixime side chain acid active ester, and 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 cefixime side chain acid and the cleavage of the sulfur-sulfur bond in dibenzothiazole disulfide to generate an intermediate transition state. After a period of time, for the second time, triethyl phosphite and an activator are added from the bottom of the rotating packed bed. In this process, the color of the reaction system changes from light yellow to orange, and at this time, the reaction releases a large amount of heat, a large amount of cefixime side chain active ester crystals precipitate out in the reaction system, and the reaction system becomes viscous. In this stage, the intermediate transition state begins to collide in the mixed solvent to generate cefixime side chain acid active ester crystal nuclei. The activator in the present invention is cetylpyridinium chloride or cetylpyridinium bromide, which is both an activator and an acid binding agent. Its effect is that when the reaction system becomes viscous, the catalyst activation effect is limited, and the auxiliary catalyst activates the cefixime side chain acid to promote esterification, because it has a long-chain alkyl group, and the long chain is entangled to form a network structure, the intermediate formed is protected, and viscosity reduction is also played; and the pyridine group of the activator forms a hydrogen bond with the amine group in the catalyst to form a catalytic activation system, and the halogen atom participates in the hydrogen bond system, which is more conducive to the catalytic activation of the present invention. In addition, because 2-mercaptobenzothiazole can be continuously produced in the reaction process, the generation of acidic by-products can suppress the main reaction, and the halogen atom on the activator attracts 2-mercaptobenzothiazole, and pyridine is bound to it, so the activator can be used as an acid binding agent auxiliary catalyst to bind the 2-mercaptobenzothiazole produced, and the main reaction is promoted to proceed smoothly, the amount of catalyst is reduced, and the reaction time is reduced.

[0026] 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.

[0027] The present invention innovatively divides triethyl phosphite into three feedings, and feeds from the middle, bottom and top of a rotating packed bed respectively, feeds in steps from different angles according to the reaction progress, and feeds from the bottom and top of the rotating packed bed to reversely flush the spray port, thereby preventing a viscous reaction system from adhering to the spray port and the surface of the packing to affect further reaction, thereby reducing the reaction time.

[0028] 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.

[0029] The product yield and purity obtained by adding triethyl phosphite to the rotating packed bed three times for reaction are the highest. When triethyl phosphite is added once, the reaction occurs too fast, the temperature fluctuates greatly, more side reactions occur, the product yield is low and the purity is poor. When triethyl phosphite is added 4 times or more, part of dibenzothiazole disulfide begins to decompose, resulting in a low product yield and a long overall reaction time, which affects production efficiency.

[0030] In the present invention, triethyl phosphite, a catalyst, and an activator act synergistically on the reaction of cefixime side chain acid. Since the formation of the activated intermediate by the catalyst enables the control of the intermediate conversion process, and triethyl phosphite can further convert the intermediate into a phosphoric acid ester intermediate state. The intermediate state obtained from this reaction is more likely to react with hydroxyl groups, inhibiting the occurrence of side reactions. Additionally, by virtue of the property of triethyl phosphite to effectively remove water molecules in the reaction, it can also effectively promote the esterification equilibrium to shift towards the product direction.

[0031] The beneficial effects of the present invention are as follows: In the present invention, the preparation of the active ester of cefixime side chain acid is carried out in a high-gravity reactor, and by improving the feeding mode of raw materials and the reaction raw material additives, the contact area between cefixime side chain acid and dibenzothiazole disulfide is increased, and the reaction is rapid. 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 intermediate products is increased, the reaction process is controlled, and the occurrence of side reactions is reduced, promoting the formation of the active ester of cefixime side chain acid and improving the conversion rate of raw materials; moreover, the 2-mercaptobenzothiazole produced by the reaction can be well dissolved in the mixed solvent and can be separated from the product during the subsequent centrifugal separation process; the catalyst and activator selected in the present invention will also be separated together with the generated mother liquor to obtain a purer product. Therefore, the use of the present invention can achieve more efficient conversion, improve the reaction efficiency and product yield, and reduce the reaction time.

[0032] In summary, the present invention has low power consumption and energy consumption. After synthesizing the active ester of cefixime side chain acid, it does not require purification with methanol, reducing losses. Since the reaction auxiliaries, feeding methods, and reaction equipment are changed during the reaction process in the present invention, there are fewer side reactions during the reaction, and the obtained product has high purity, high yield, and short reaction time. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 is a schematic structural diagram of the high-gravity reactor of the present invention; Figure 2 is the 1H NMR spectrum of the active ester of cefixime side chain acid in Example 1 of the present invention; Figure 3 is Figure 2 the enlarged view at A in Figure 4 is the liquid chromatogram of the active ester of cefixime side chain acid in Example 1 of the present invention; Figure 5 is the liquid chromatogram of the active ester of cefixime side chain acid in Example 2 of the present invention.

[0034] In the figure: 1. Shell; 2. Rotating packing bed; 3. Feed spray pipe; 4. Top liquid inlet; 5. Flushing port; 6. Bottom liquid inlet; 7. Rotating rod; 8. Rotating shaft; 9. Spray port. Detailed implementation mode

[0035] The embodiments of the present invention will be further described below in conjunction with the accompanying drawings.

[0036] Embodiment 1 As Figure 1 shown, the high gravity reactor includes a shell 1. Inside the shell 1, a rotating packing bed 2 is provided. At the center of the top of the shell 1, a feed channel is provided. At the center of the rotating packing bed 2, a connecting channel is provided. Inside the feed channel, a feed spray pipe 3 is provided. The bottom of the feed spray pipe 3 passes through the connecting channel and extends to the lower part of the rotating packing bed 2. On the shell 1, a top liquid inlet 4 and a flushing port 5 are provided. At the bottom of the rotating packing bed 2, a rotating rod 7 is provided. Between the rotating rod 7 and the bottom of the shell 1, a rotating shaft 8 is provided. The shell 1 is provided with a bottom liquid inlet 6.

[0037] A number of spray ports 9 are provided at the lower part of the feed spray pipe 3. Above the rotating shaft 8, a liquid seal layer is provided. Between the connecting channel and the feed channel, a bearing is provided. At the bottom of the bearing, a liquid seal layer is provided.

[0038] The preparation method of cefixime side chain acid active ester based on high gravity reaction includes the following steps: S1. Add 1000 ml of a mixed solvent of ethanol, acetonitrile and dichloroethane with a volume ratio of 1:7:1, 200 g of cefixime side chain acid, 10 g of triethylamine, and 205 g of dibenzothiazole disulfide into the outside of the rotating packing 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 25.6 g of triethyl phosphite into the middle of the rotating packing bed 2 of the high gravity reactor through the feed spray pipe 3, and carry out the first stage of high gravity reaction at 5 °C for 30 min; S2. Add the second batch of 64 g of triethyl phosphite and 2 g of cetylpyridinium chloride into the bottom of the outside of the rotating packing bed 2 of the high gravity reactor through the bottom liquid inlet 6, and carry out the second stage of high gravity reaction at 20 °C for 20 min; S3. Add the third batch of 38.4 g of triethyl phosphite into the top of the outside of the rotating packing bed 2 of the high gravity reactor through the top liquid inlet 4, and carry out the third stage of high gravity reaction at 12 °C for 25 min; S4. After the third stage of high gravity reaction, obtain the crude product of cefixime side chain acid active ester, carry out centrifugal separation at 5 °C, and dry at 40 °C and -0.2 MPa to obtain cefixime side chain acid active ester, with a yield of 99.47% and a purity of 99.6%; The nuclear magnetic resonance hydrogen spectrum is as Figure 2 , 3 shown, and the liquid chromatography diagram is as Figure 4 shown.

[0039] Example 2 The reaction device used in this example is the same as that in Example 1.

[0040] A preparation method of cefixime side chain acid active ester based on high gravity reaction includes the following steps: S1. Add 1200 ml of a mixed solvent of ethanol, acetonitrile and dichloroethane with a volume ratio of 1:8:1, 200 g of cefixime side chain acid, 12 g of 2,6 - diisopropylaniline, and 256 g of dibenzothiazole disulfide to the outside of the rotating packing bed 2 of the high gravity reactor through the top feed port 4 in sequence. Start the high gravity reactor, and then add the first batch of 42.3 g of triethyl phosphite to the middle of the rotating packing bed 2 of the high gravity reactor through the feed spray pipe 3, and carry out the first - stage high gravity reaction at 10 °C for 20 min; S2. Add the second batch of 77.6 g of triethyl phosphite and 4 g of cetylpyridinium bromide to the bottom outside of the rotating packing bed 2 of the high gravity reactor through the bottom feed port 6, and carry out the second - stage high gravity reaction at 23 °C for 15 min; S3. Add the third batch of 21.2 g of triethyl phosphite to the top outside of the rotating packing bed 2 of the high gravity reactor through the top feed port 4, and carry out the third - stage high gravity reaction at 18 °C for 20 min; S4. After the third - stage high gravity reaction, obtain the crude product of cefixime side chain acid active ester, carry out centrifugal separation at - 5 °C, and dry 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 as Figure 5 shown.

[0041] Example 3 The reaction device used in this example is the same as that in Example 1.

[0042] A preparation method of cefixime side chain acid active ester based on high gravity reaction includes the following steps: S1. Add 1100 ml of a mixed solvent of ethanol, acetonitrile and dichloroethane with a volume ratio of 1:7:1, 200 g of cefixime side chain acid, 11 g of tri - n - propylamine, and 307 g of dibenzothiazole disulfide to the outside of the rotating packing bed 2 of the high gravity reactor through the top feed port 4 in sequence. Start the high gravity reactor, and then add the first batch of 38.3 g of triethyl phosphite to the middle of the rotating packing bed 2 of the high gravity reactor through the feed spray pipe 3, and carry out the first - stage high gravity reaction at 8 °C for 25 min; S2. Add the second batch of 91.8 g of triethyl phosphite and 6 g of cetylpyridinium chloride to the bottom outside of the rotating packing bed 2 of the high gravity reactor through the bottom feed port 6, and carry out the second - stage high gravity reaction at 25 °C for 10 min; S3. Add 23 g of triethyl phosphite in the third batch through the top liquid inlet 4 to the top outside of the rotating packing bed 2 of the high gravity reactor, and conduct the third-stage high gravity reaction at 15°C for 30 min; S4. After the third-stage high gravity reaction, obtain the crude product of cefixime side chain acid active ester, conduct centrifugal separation at 0°C, and dry it 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%.

[0043] Comparative Example 1 In step S1, add all the triethyl phosphite in Example 1 to the rotating packing bed 2 of the high gravity reactor at one time through the feed spray pipe 3, 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%.

[0044] Comparative Example 2 In step S2, do not add cetylpyridinium chloride as an activator, and the remaining steps are 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%.

[0045] Comparative Example 3 In step S1, do not add triethylamine as a catalyst, and the remaining steps are 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%.

[0046] Comparative Example 4 In step S1, divide all the triethyl phosphite in Example 1 into five equal parts and add them, and the remaining steps are the same as in Example 1. The last two additions of triethyl phosphite are 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%.

[0047] In addition, for the feeding method, the present invention conducted multiple experiments: 1. Divide triethyl phosphite into five equal parts for feeding, and all are added through the feed spray pipe 3, and the rest are in accordance with Example 1; 2. The second batch of feed enters through the top liquid inlet 4 of the high gravity reactor, and the rest are in accordance with Example 1; 3. The third batch of feed enters through the bottom liquid inlet 6 of the high gravity reactor, and the rest are in accordance with Example 1; 4. The second batch of feed enters through the top liquid inlet 4 of the high gravity reactor, and the third batch of feed enters through the bottom liquid inlet 6 of the high gravity reactor, and the rest are in accordance with Example 1; 5. Incorporate the activator into the first batch of feed, and do not add the activator to the second and third batches of feed, and the rest are in accordance with Example 1; 6. Incorporate the activator into the third batch of feed, and do not add the activator to the first and second batches of feed, and the rest are in accordance with Example 1.

[0048] After the above experiments, the effects 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.

[0049] In summary, by comparing Example 1 and Comparative Example 1, it can be seen that the method of adding triethyl phosphite in three portions has a positive and effective effect on both the yield and purity of the product. At the same time, using a rotating packed bed reactor strengthens the mass transfer and reaction processes, optimizes the synthesis and purification of cefixime side chain acid active ester, and has the advantages of improved efficiency and environmental protection; by comparing Example 1, Comparative Example 2 and Comparative Example 3, it can be seen that when triethylamine or cetylpyridinium chloride is added to the reaction system alone, the yield of cefixime side chain acid active ester obtained is low and the quality is poor; by comparing Example 1, Comparative Example 2 and Comparative Example 4, it can be seen that increasing the addition times of triethyl phosphite will cause the decomposition of dibenzothiazole disulfide, resulting in a low product yield. And when using triethylamine alone as a catalyst without adding cetylpyridinium chloride as an activator, even if the reaction progress is extended, the reaction system will become too viscous to fully convert and protect the reaction intermediates, resulting in poor product effects and low production efficiency; through the comparative analysis of the above Examples 1-3 and Comparative Examples 1-4 and multiple experiments, the synthesis method of cefixime side chain acid active ester of the present invention is more efficient and has better effects.

Claims

1. A preparation method of cefixime side chain acid active ester based on high gravity reaction, characterized in that, It includes the following steps: S1. Add organic solvent, cefixime side chain acid, catalyst, and dibenzothiazole disulfide to the outside of the rotating packing bed (2) of the high gravity reactor in sequence through the top liquid inlet (4). Start the high gravity reactor, and then add the first batch of triethyl phosphite to the middle of the rotating packing bed (2) of the high gravity reactor through the feed spray pipe (3) to carry out the first-stage high gravity reaction; S2. Add the second batch of triethyl phosphite and activator to the bottom outside of the rotating packing bed (2) of the high gravity reactor through the bottom liquid inlet (6) to carry out the second-stage high gravity reaction; S3. Add the third batch of triethyl phosphite to the top outside of the rotating packing bed (2) of the high gravity reactor through the top liquid inlet (4) to carry out the third-stage high gravity reaction; S4. After the third-stage high gravity reaction, obtain the crude product of cefixime side chain acid active ester, and obtain cefixime side chain acid active ester through separation and drying.

2. The preparation method of cefixime side chain acid active ester based on a supergravity reaction according to claim 1, characterized in that, In step S1, the temperature of the first-stage high gravity reaction is 5-10°C, the time of the first-stage high gravity reaction 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 time of the second-stage high gravity reaction 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 time of the third-stage high gravity reaction is 20-30 min, and the third batch of triethyl phosphite is the balance.

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

1.

4. The preparation method of cefixime side chain acid active ester based on high gravity reaction according to claim 1, characterized in that In step S1, the molar ratio of cefixime side chain acid to dibenzothiazole disulfide is 1:0.8-1.

2.

5. The preparation method of cefixime side chain acid active ester based on hypergravity reaction according to claim 1, characterized in that, In step S1, the catalyst is triethylamine, 2,6-diisopropyl aniline, or tri-n-propylamine, and the mass ratio of cefixime side chain acid to the catalyst is 1:0.05-0.

06.

6. The preparation method of cefixime side chain acid active ester based on a hypergravity reaction according to claim 1, characterized in that, The molar ratio of cefixime side chain acid to the total amount of the first, second, and third batches of triethyl phosphite is 1:1-1.

2.

7. The preparation method of cefixime side chain acid active ester based on hypergravity reaction according to claim 1, characterized in that, In 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.

8. The preparation method of cefixime side chain acid active ester based on hypergravity reaction according to claim 1, characterized in that In step S1, the high gravity reactor includes a shell (1), a rotating packing 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 packing 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 packing bed (2), a top liquid inlet (4) and a washing port (5) are opened on the shell (1), a rotating rod (7) is arranged at the bottom of the rotating packing bed (2), a rotating shaft (8) is arranged between the rotating rod (7) and the bottom of the shell (1), and a bottom liquid inlet (6) is arranged on the shell (1).

9. The preparation method of cefixime side chain acid active ester based on hypergravity reaction according to claim 8, wherein, A number of spray nozzles (9) are provided at the lower part of the feed spray pipe (3), a liquid seal layer is provided above the rotating shaft (8), a bearing is provided between the connecting channel and the feed channel, and a liquid seal layer is provided at the bottom of the bearing.

10. The preparation method of 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 to 5 °C, the drying temperature is 35 to 50 °C, and the drying pressure is -0.2 to 0 MPa.

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