Synthesis method of ceftazidime side chain acid ethyl ester

Abstract

The present invention belongs to the technical field of heterocyclic compounds, and in particular to a method for synthesizing ceftazidime side chain acid ethyl ester. N,N-dimethylformamide solution of isobutyric acid and chlorine are added to a chlorination microchannel reactor for mixing, added to a pipeline reactor for reaction, and N,N-dimethylformamide solution of chloroisobutyric acid is obtained; N,N-dimethylformamide solution of chloroisobutyric acid and isobutylene are added to a loop reactor for reaction, and N,N-dimethylformamide solution of tert-butyl chloroisobutyrate is obtained; N,N-dimethylformamide solution of ethyl demethylaminothioxamyl, N,N-dimethylformamide solution of tert-butyl chloroisobutyrate and a composite condensation catalyst solution are added to a primary microchannel reactor for primary reaction; a primary reaction liquid and water are added to a secondary microchannel reactor for secondary reaction, and ceftazidime side chain acid ethyl ester is obtained. The present invention has the advantages of high reaction efficiency and high reaction yield.

Description

Technical Field

[0001] The invention belongs to the technical field of heterocyclic compounds, and particularly relates to a method for synthesizing ceftazidime side chain acid ethyl ester. Background Art

[0002] Ceftazidime side chain acid ethyl ester is one of the important intermediates for the synthesis of ceftazidime drugs. The preparation process of ceftazidime side chain acid ethyl ester is to use ethyl acetoacetate to obtain nor-methylaminothioxime acid ethyl ester through oximation, chlorination and cyclization, and use isobutyric acid to obtain tert-butyl bromide isobutyrate through bromination and acylation, and then the two are condensed to obtain ceftazidime side chain acid ethyl ester. In the condensation process, tert-butyl bromide isobutyrate and nor-methylaminothioxime acid ethyl ester are used for condensation; and the synthesis of tert-butyl bromide isobutyrate requires the use of isobutyric acid and bromine to react to prepare bromoisobutyric acid, and then react with isobutylene to prepare tert-butyl bromide isobutyrate. In actual production, due to the high price of bromine, the reaction cost is high, so the process of using low-cost chlorine to replace bromine has been studied. However, due to the high bond energy of chlorine-carbon bond, the reaction activity is low when used in the condensation process, the reaction efficiency is poor, and the reaction yield is low. Although increasing the reaction temperature and changing the condensation catalyst can speed up the reaction, the reaction yield decreases rapidly. This is mainly because the product decomposes under the action of high temperature for a long time. The structural form and reaction characteristics of the conventional reactor determine that this solution is difficult to implement in actual production. Summary of the invention

[0003] The invention aims to provide a method for synthesizing ceftazidime side chain acid ethyl ester, which has the advantages of high reaction efficiency and high reaction yield and is suitable for the synthesis of pharmaceutical intermediates.

[0004] The method for synthesizing the ceftazidime side chain acid ethyl ester of the present invention comprises the following steps:

[0005] (1) adding an N,N-dimethylformamide solution of isobutyric acid and chlorine gas into a chlorination microchannel reactor and mixing to obtain a mixed material, and adding the mixed material into a pipeline reactor for reaction to obtain an N,N-dimethylformamide solution of chloroisobutyric acid;

[0006] (2) adding the N,N-dimethylformamide solution of chloroisobutyric acid obtained in step (1) and isobutylene into a loop reactor for reaction to obtain an N,N-dimethylformamide solution of tert-butyl chloroisobutyrate;

[0007] (3) Ethyl demethylaminothioxime and N,N-dimethylformamide are mixed to obtain an N,N-dimethylformamide solution of ethyl demethylaminothioxime; the N,N-dimethylformamide solution of ethyl demethylaminothioxime, the N,N-dimethylformamide solution of tert-butyl chloroisobutyrate obtained in step (2) and the composite condensation catalyst solution are added to a primary microchannel reactor for primary reaction to obtain a primary reaction liquid; the primary reaction liquid and water are added to a secondary microchannel reactor for secondary reaction to obtain a secondary reaction liquid; the secondary reaction liquid is added to a time-delay reactor for retention to obtain a feed liquid; the feed liquid is separated, cooled, centrifuged and dried to obtain ceftazidime side chain acid ethyl ester.

[0008] In step (1), the mass concentration of the N,N-dimethylformamide solution of isobutyric acid is 20-50%, the mass ratio of the N,N-dimethylformamide solution of isobutyric acid to chlorine is 21-100:8.5-16.3, and the N,N-dimethylformamide solution of isobutyric acid is prepared by mixing isobutyric acid and N,N-dimethylformamide.

[0009] In step (1), the mixing temperature is -25 to -20°C and the mixing time is 6 to 30 seconds.

[0010] In step (1), the reaction temperature is 30-50°C and the reaction time is 1-5 min.

[0011] The back pressure of the pipeline reactor in step (1) is 0.5-0.7 MPa.

[0012] In step (2), the mass ratio of the N,N-dimethylformamide solution of chloroisobutyric acid to isobutylene is 29-117:6-13; the reaction temperature is 10-30° C., and the reaction time is 5-30 min.

[0013] The mass concentration of the N,N-dimethylformamide solution of ethyl demethylaminothioxamate in step (3) is 22-34%.

[0014] In step (3), the composite condensation catalyst solution is prepared by mixing sodium hydroxide, sodium hypochlorite, iodine, copper sulfate and N,N-dimethylformamide, and the mass ratio of sodium hydroxide, sodium hypochlorite, iodine, copper sulfate and N,N-dimethylformamide is 0.3-0.8:1:0.01-0.05:0.2-0.5:3-8.

[0015] The mass ratio of the N,N-dimethylformamide solution of ethyl demethylaminothioxime in step (3), the N,N-dimethylformamide solution of tert-butyl chloroisobutyrate obtained in step (2) and the composite condensation catalyst solution is 1:0.4-0.6:0.1-0.2; the reaction temperature of the primary reaction is 70-85°C, and the reaction time of the primary reaction is 12-34s.

[0016] In step (3), the mass ratio of water to the N,N-dimethylformamide solution of ethyl demethylaminothioxime is 0.5-0.6:1; the reaction temperature of the secondary reaction is 30-50° C., the reaction time of the secondary reaction is 10-30 s; and the residence time is 1-10 min.

[0017] The device used in the synthesis method of ceftazidime side chain acid ethyl ester comprises a first preparation kettle, wherein the first preparation kettle, a chlorination microchannel reactor, a pipeline reactor, a loop reactor, a circulation pump, a primary microchannel reactor, a secondary microchannel reactor and a time delay reactor are connected in sequence, the chlorination microchannel reactor is connected to a chlorine buffer tank, the loop reactor is connected to an isobutylene buffer tank, the circulation pump, a heat exchanger and the loop reactor are connected in sequence, the primary microchannel reactor is respectively connected to a second preparation kettle and a third preparation kettle, and the secondary microchannel reactor is connected to a water storage tank.

[0018] A first delivery pump is arranged between the first preparation kettle and the chlorination microchannel reactor, a first gas mass flowmeter is arranged between the chlorination microchannel reactor and the chlorine buffer tank, a second gas mass flowmeter is arranged between the loop reactor and the isobutylene buffer tank, a second delivery pump is arranged between the first-level microchannel reactor and the second preparation kettle, and a third delivery pump is arranged between the first-level microchannel reactor and the third preparation kettle.

[0019] The chlorination microchannel reactor, the primary microchannel reactor and the secondary microchannel reactor are all conventional microchannel reactors.

[0020] In order to make the condensation reaction efficient, the present invention uses a composite condensation catalyst composed of sodium hydroxide, iodine, copper sulfate and sodium hypochlorite, and the iodine element undergoes a halogen atom exchange reaction with tert-butyl chloroisobutyrate to obtain tert-butyl iodoisobutyrate, thereby improving the electrophilicity of the halogen-substituted product; the outer empty orbit of the copper ion is coordinated with ethyl demethylaminothioxime to form a six-membered ring transition state, i.e., the active transition state of ethyl demethylaminothioxime, thereby improving the nucleophilicity of the oxime hydroxyl group; under the synergistic effect of the composite condensation catalyst, the active transition state of ethyl demethylaminothioxime undergoes a substitution reaction with tert-butyl iodoisobutyrate to obtain ceftazidime side chain acid ethyl ester, thereby generating hydrogen iodide. Hydrogen iodide reacts with sodium hydroxide to form sodium iodide. Sodium iodide reacts with sodium hypochlorite to generate iodine, which continues to react with tert-butyl chloroisobutyrate.

[0021] The reaction mechanism is as follows:

[0022]

[0023] The reaction equation is as follows:

[0024]

[0025] The composite condensation catalyst of the present invention has the following advantages over traditional quaternary ammonium salt catalysts:

[0026] (1) Although conventional quaternary ammonium salt catalysts can improve the mass transfer efficiency between reaction substrates, they cannot fundamentally solve the problem that chlorine atoms in chlorides are difficult to remove. The composite condensation catalyst of the present invention uses iodine atoms that are easy to leave to replace the chlorine atoms in chlorides, thereby greatly improving the reaction progress.

[0027] (2) The metal copper ions in the composite condensation catalyst of the present invention form a six-membered ring transition state with ethyl demethylaminothioxamate, thereby increasing the nucleophilicity of the oxime hydroxyl group, accelerating the substitution reaction, and improving the reaction efficiency.

[0028] The beneficial effects of the present invention are as follows:

[0029] The invention provides a method for continuously synthesizing ceftazidime side chain acid ethyl ester by using tert-butyl chloroisobutyrate, wherein the method continuously prepares chloroisobutyric acid by using a pipeline reactor, continuously prepares tert-butyl chloroisobutyrate by using a loop reactor, and continuously prepares ceftazidime side chain acid ethyl ester by using a microchannel reactor, thereby overcoming the problems of high cost, low reaction activity, poor reaction efficiency, and low reaction yield of using tert-butyl bromoisobutyrate in the traditional method. The invention has the advantages of high reaction efficiency and high reaction yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 It is a schematic structural diagram of the device used in the method for synthesizing ceftazidime side chain acid ethyl ester in the present invention;

[0031] In the figure: 1, first preparation kettle; 2, chlorine buffer tank; 3, chlorination microchannel reactor; 4, isobutylene buffer tank; 5, pipeline reactor; 6, loop reactor; 7, heat exchanger; 8, second preparation kettle; 9, third preparation kettle; 10, primary microchannel reactor; 11, water storage tank; 12, secondary microchannel reactor; 13, time-delay reactor; 14, first gas mass flowmeter; 15, first delivery pump; 16, second gas mass flowmeter; 17, circulation pump; 18, second delivery pump; 19, third delivery pump. DETAILED DESCRIPTION

[0032] The present invention is further described below with reference to the embodiments.

[0033] Example 1

[0034] like Figure 1As shown, the device used in the synthesis method of ceftazidime side chain acid ethyl ester includes a first preparation kettle 1, the first preparation kettle 1, a chlorination microchannel reactor 3, a pipeline reactor 5, a loop reactor 6, a circulation pump 17, a primary microchannel reactor 10, a secondary microchannel reactor 12 and a delay reactor 13 are connected in sequence, the chlorination microchannel reactor 3 is connected to the chlorine buffer tank 2, the loop reactor 6 is connected to the isobutylene buffer tank 4, the circulation pump 17, the heat exchanger 7 and the loop reactor 6 are connected in sequence, the primary microchannel reactor 10 is respectively connected to the second preparation kettle 8 and the third preparation kettle 9, and the secondary microchannel reactor 12 is connected to the water storage tank 11.

[0035] A first delivery pump 15 is arranged between the first preparation kettle 1 and the chlorination microchannel reactor 3, a first gas mass flowmeter 14 is arranged between the chlorination microchannel reactor 3 and the chlorine buffer tank 2, a second gas mass flowmeter 16 is arranged between the loop reactor 6 and the isobutylene buffer tank 4, a second delivery pump 18 is arranged between the first-level microchannel reactor 10 and the second preparation kettle 8, and a third delivery pump 19 is arranged between the first-level microchannel reactor 10 and the third preparation kettle 9.

[0036] The synthesis method of ceftazidime side chain acid ethyl ester comprises the following steps:

[0037] (1) in a first preparation kettle 1, isobutyric acid and N,N-dimethylformamide are mixed to obtain an N,N-dimethylformamide solution of isobutyric acid with a mass concentration of 20%, the N,N-dimethylformamide solution of isobutyric acid with a mass concentration of 20% and the chlorine in the chlorine buffer tank 2 are added to a chlorination microchannel reactor 3 and mixed at -20°C for 6.12s to obtain a mixed material, the feed flow rate of the N,N-dimethylformamide solution of isobutyric acid is 100g / min, the feed flow rate of the chlorine is 16.3g / min, the mixed material is added to a pipeline reactor 5 and reacted at 50°C for 1.02min, the back pressure of the pipeline reactor 5 is 0.55MPa, and the N,N-dimethylformamide solution of chloroisobutyric acid is obtained;

[0038] (2) The N,N-dimethylformamide solution of chloroisobutyric acid obtained in step (1) and isobutylene in the isobutylene buffer tank 4 are added to the loop reactor 6 for reaction at 25° C. for 15 min. The feed flow rate of the N,N-dimethylformamide solution of chloroisobutyric acid is 116.3 g / min, and the feed flow rate of isobutylene is 12.7 g / min to obtain the N,N-dimethylformamide solution of tert-butyl chloroisobutyrate. The circulation flow rate is controlled by the circulation pump 17 to be 2.1 m 3 / h;

[0039] (3) In a second preparation kettle 8, ethyl demethylaminothioxime and N,N-dimethylformamide are mixed to obtain an N,N-dimethylformamide solution of ethyl demethylaminothioxime with a mass concentration of 22.5%. In a third preparation kettle 9, sodium hydroxide, sodium hypochlorite, iodine, copper sulfate and N,N-dimethylformamide are mixed to obtain a composite condensation catalyst solution, wherein the mass ratio of sodium hydroxide, sodium hypochlorite, iodine, copper sulfate and N,N-dimethylformamide is 0.3:1:0.01:0.2:8. The N,N-dimethylformamide solution of ethyl demethylaminothioxime, the N,N-dimethylformamide solution of tert-butyl chloroisobutyrate obtained in step (2) and the composite condensation catalyst solution are added to a primary microchannel reactor 10 for a primary reaction at 85° C. for 12 seconds to obtain a primary reaction solution. The feed flow rate of the N,N-dimethylformamide solution of ethyl chloroisobutyrate is 217.4 g / min, the feed flow rate of the N,N-dimethylformamide solution of tert-butyl chloroisobutyrate is 120.7 g / min, and the feed flow rate of the composite condensation catalyst solution is 22.69 g / min; the primary reaction liquid and the water in the water storage tank 11 are added to the secondary microchannel reactor 12 for a secondary reaction at 35° C. for 20 seconds to obtain a secondary reaction liquid, and the feed flow rate of water is 109 g / min; the secondary reaction liquid is added to the delayed reactor 13 and retained for 10 minutes to obtain a feed liquid, and the feed liquid is separated, cooled, centrifuged, and dried to obtain ceftazidime side chain acid ethyl ester, and the product generation rate is 69.37 g / min (calculated as ceftazidime side chain acid ethyl ester), and the molar yield is 85.5% (calculated as isobutyric acid).

[0040] Example 2

[0041] The apparatus used in the synthesis method of ceftazidime side chain acid ethyl ester is the same as that in Example 1.

[0042] The synthesis method of ceftazidime side chain acid ethyl ester comprises the following steps:

[0043] (1) in a first preparation kettle 1, isobutyric acid and N,N-dimethylformamide are mixed to obtain an N,N-dimethylformamide solution of isobutyric acid with a mass concentration of 50%, the N,N-dimethylformamide solution of isobutyric acid with a mass concentration of 50% and the chlorine in the chlorine buffer tank 2 are added to a chlorination microchannel reactor 3 and mixed at -25°C for 29.3s to obtain a mixed material, the feed flow rate of the N,N-dimethylformamide solution of isobutyric acid is 21g / min, the feed flow rate of the chlorine is 8.53g / min, the mixed material is added to a pipeline reactor 5 and reacted at 40°C for 4.89min, the back pressure of the pipeline reactor 5 is 0.6MPa, and an N,N-dimethylformamide solution of chloroisobutyric acid is obtained;

[0044] (2) The N,N-dimethylformamide solution of chloroisobutyric acid obtained in step (1) and isobutylene in the isobutylene buffer tank 4 are added to the loop reactor 6 for reaction at 10° C. for 30 min. The feed flow rate of the N,N-dimethylformamide solution of chloroisobutyric acid is 29.53 g / min, and the feed flow rate of isobutylene is 6.68 g / min to obtain the N,N-dimethylformamide solution of tert-butyl chloroisobutyrate. The circulation flow rate is controlled by the circulation pump 17 to be 2.2 m 3 / h;

[0045] (3) In a second preparation kettle 8, ethyl demethylaminothioxime and N,N-dimethylformamide are mixed to obtain an N,N-dimethylformamide solution of ethyl demethylaminothioxime with a mass concentration of 33.3%. In a third preparation kettle 9, sodium hydroxide, sodium hypochlorite, iodine, copper sulfate and N,N-dimethylformamide are mixed to obtain a composite condensation catalyst solution, wherein the mass ratio of sodium hydroxide, sodium hypochlorite, iodine, copper sulfate and N,N-dimethylformamide is 0.8:1:0.05:0.5:3. The N,N-dimethylformamide solution of ethyl demethylaminothioxime, the N,N-dimethylformamide solution of tert-butyl chloroisobutyrate obtained in step (2) and the composite condensation catalyst solution are added to a primary microchannel reactor 10 for a primary reaction at 70° C. for 34 seconds to obtain a primary reaction solution. The feed flow rate of the N,N-dimethylformamide solution of ethyl thioxamate is 77 g / min, the feed flow rate of the N,N-dimethylformamide solution of tert-butyl chloroisobutyrate is 31.8 g / min, and the feed flow rate of the composite condensation catalyst solution is 11.92 g / min; the primary reaction liquid and the water in the water storage tank 11 are added to the secondary microchannel reactor 12 for a secondary reaction at 30°C for 30 seconds to obtain a secondary reaction liquid, and the feed flow rate of water is 38.5 g / min; the secondary reaction liquid is added to the delayed reactor 13 and retained for 1 minute to obtain a feed liquid, and the feed liquid is separated, cooled, centrifuged, and dried to obtain ceftazidime side chain acid ethyl ester, and the product generation rate is 35.3 g / min (calculated as ceftazidime side chain acid ethyl ester), and the molar yield is 82.9% (calculated as isobutyric acid).

[0046] Example 3

[0047] The apparatus used in the synthesis method of ceftazidime side chain acid ethyl ester is the same as that in Example 1.

[0048] The synthesis method of ceftazidime side chain acid ethyl ester comprises the following steps:

[0049] (1) in a first preparation kettle 1, isobutyric acid and N,N-dimethylformamide are mixed to obtain an N,N-dimethylformamide solution of isobutyric acid with a mass concentration of 30%, the N,N-dimethylformamide solution of isobutyric acid with a mass concentration of 30% and the chlorine in the chlorine buffer tank 2 are added to a chlorination microchannel reactor 3 and mixed at -23°C for 11.7s to obtain a mixed material, the feed flow rate of the N,N-dimethylformamide solution of isobutyric acid is 50g / min, the feed flow rate of the chlorine is 12.19g / min, the mixed material is added to a pipeline reactor 5 and reacted at 30°C for 1.96min, the back pressure of the pipeline reactor 5 is 0.7MPa, and an N,N-dimethylformamide solution of chloroisobutyric acid is obtained;

[0050] (2) The N,N-dimethylformamide solution of chloroisobutyric acid obtained in step (1) and isobutylene in the isobutylene buffer tank 4 are added to the loop reactor 6 for reaction at 30° C. for 5 min. The feed flow rate of the N,N-dimethylformamide solution of chloroisobutyric acid is 62.19 g / min, and the feed flow rate of isobutylene is 9.55 g / min to obtain the N,N-dimethylformamide solution of tert-butyl chloroisobutyrate. The circulation flow rate is controlled by the circulation pump 17 to be 2.2 m 3 / h;

[0051] (3) In a second preparation kettle 8, ethyl demethylaminothioxime and N,N-dimethylformamide are mixed to obtain an N,N-dimethylformamide solution of ethyl demethylaminothioxime with a mass concentration of 25%. In a third preparation kettle 9, sodium hydroxide, sodium hypochlorite, iodine, copper sulfate and N,N-dimethylformamide are mixed to obtain a composite condensation catalyst solution, wherein the mass ratio of sodium hydroxide, sodium hypochlorite, iodine, copper sulfate and N,N-dimethylformamide is 0.5:1:0.03:0.3:5. The N,N-dimethylformamide solution of ethyl demethylaminothioxime, the N,N-dimethylformamide solution of tert-butyl chloroisobutyrate obtained in step (2) and the composite condensation catalyst solution are added to a primary microchannel reactor 10 for a primary reaction at 80° C. for 17.47 s to obtain a primary reaction solution. The feed flow rate of the N,N-dimethylformamide solution of methylaminothioxamic acid ethyl ester is 146 g / min, the feed flow rate of the N,N-dimethylformamide solution of tert-butyl chloroisobutyrate is 65.5 g / min, and the feed flow rate of the composite condensation catalyst solution is 17 g / min; the primary reaction liquid and the water in the water storage tank 11 are added to the secondary microchannel reactor 12 for a secondary reaction at 50° C. for 10 seconds to obtain a secondary reaction liquid, and the feed flow rate of water is 73.3 g / min; the secondary reaction liquid is added to the delayed reactor 13 and retained for 8 minutes to obtain a feed liquid, and the feed liquid is separated, cooled, centrifuged, and dried to obtain ceftazidime side chain acid ethyl ester, and the product generation rate is 50.4 g / min (calculated as ceftazidime side chain acid ethyl ester), and the molar yield is 82.8% (calculated as isobutyric acid).

[0052] Comparative Example 1

[0053] No sodium hydroxide was added, and the other steps were the same as in Example 1. The product generation rate was 58.31 g / min (calculated as ceftazidime side chain acid ethyl ester), and the molar yield was 71.7% (calculated as isobutyric acid).

[0054] Comparative Example 2

[0055] Without adding iodine, the other steps were the same as in Example 1, and the product generation rate was 62.66 g / min (calculated as ceftazidime side chain acid ethyl ester), and the molar yield was 77.1% (calculated as isobutyric acid).

[0056] Comparative Example 3

[0057] Without adding copper sulfate, the other steps were the same as in Example 1, and the product generation rate was 65.45 g / min (calculated as ceftazidime side chain acid ethyl ester), and the molar yield was 80.5% (calculated as isobutyric acid).

[0058] Comparative Example 4

[0059] Without adding sodium hypochlorite, the other steps were the same as in Example 1, and the product generation rate was 56.32 g / min (calculated as ceftazidime side chain acid ethyl ester), and the molar yield was 69.3% (calculated as isobutyric acid).

[0060] Comparative Example 5

[0061] The composite condensation catalyst solution was changed to potassium carbonate solution, and the other steps were the same as in Example 1. The product generation rate was 50.84 g / min (calculated as ceftazidime side chain acid ethyl ester), and the molar yield was 62.5% (calculated as isobutyric acid).

Claims

1. A method for synthesizing ceftazidime side chain acid ethyl ester, characterized in that The steps include: (1) adding an N,N-dimethylformamide solution of isobutyric acid and chlorine gas to a chlorination microchannel reactor (3) and mixing to obtain a mixed material, and adding the mixed material to a pipeline reactor (5) for reaction to obtain an N,N-dimethylformamide solution of chloroisobutyric acid; (2) the N,N-dimethylformamide solution of chloroisobutyric acid obtained in step (1) and isobutylene are added to a loop reactor (6) for reaction to obtain an N,N-dimethylformamide solution of tert-butyl chloroisobutyrate; (3) mixing ethyl demethylaminothioxime and N,N-dimethylformamide to obtain an N,N-dimethylformamide solution of ethyl demethylaminothioxime; adding the N,N-dimethylformamide solution of ethyl demethylaminothioxime, the N,N-dimethylformamide solution of tert-butyl chloroisobutyrate obtained in step (2) and the composite condensation catalyst solution to a primary microchannel reactor (10) for primary reaction to obtain a primary reaction liquid; adding the primary reaction liquid and water to a secondary microchannel reactor (12) for secondary reaction to obtain a secondary reaction liquid; adding the secondary reaction liquid to a time delay reactor (13) for retention to obtain a feed liquid; and subjecting the feed liquid to separation, cooling, centrifugation and drying to obtain ceftazidime side chain acid ethyl ester; In step (3), the composite condensation catalyst solution is prepared by mixing sodium hydroxide, sodium hypochlorite, iodine, copper sulfate and N,N-dimethylformamide, and the mass ratio of sodium hydroxide, sodium hypochlorite, iodine, copper sulfate and N,N-dimethylformamide is 0.3-0.8:1:0.01-0.05:0.2-0.5:3-8.

2. The method for synthesizing ceftazidime side chain acid ethyl ester according to claim 1, characterized in that In step (1), the mass concentration of the N,N-dimethylformamide solution of isobutyric acid is 20-50%, the mass ratio of the N,N-dimethylformamide solution of isobutyric acid to chlorine is 21-100:8.5-16.3, and the N,N-dimethylformamide solution of isobutyric acid is prepared by mixing isobutyric acid and N,N-dimethylformamide.

3. The method for synthesizing ceftazidime side chain acid ethyl ester according to claim 1, characterized in that In step (1), the mixing temperature is -25 to -20°C and the mixing time is 6 to 30 seconds.

4. The method for synthesizing ceftazidime side chain acid ethyl ester according to claim 1, characterized in that In step (1), the reaction temperature is 30-50°C and the reaction time is 1-5 min.

5. The method for synthesizing ceftazidime side chain acid ethyl ester according to claim 1, characterized in that In step (2), the mass ratio of the N,N-dimethylformamide solution of chloroisobutyric acid to isobutylene is 29-117:6-13; the reaction temperature is 10-30° C., and the reaction time is 5-30 min.

6. The method for synthesizing ceftazidime side chain acid ethyl ester according to claim 1, characterized in that The mass concentration of the N,N-dimethylformamide solution of ethyl demethylaminothioxamate in step (3) is 22-34%.

7. The method for synthesizing ceftazidime side chain acid ethyl ester according to claim 1, characterized in that The mass ratio of the N,N-dimethylformamide solution of ethyl demethylaminothioxime in step (3), the N,N-dimethylformamide solution of tert-butyl chloroisobutyrate obtained in step (2) and the composite condensation catalyst solution is 1:0.4-0.6:0.1-0.2; the reaction temperature of the primary reaction is 70-85°C, and the reaction time of the primary reaction is 12-34s.

8. The method for synthesizing ceftazidime side chain acid ethyl ester according to claim 1, characterized in that In step (3), the mass ratio of water to the N,N-dimethylformamide solution of ethyl demethylaminothioxime is 0.5-0.6:1; the reaction temperature of the secondary reaction is 30-50° C., the reaction time of the secondary reaction is 10-30 s; and the residence time is 1-10 min.

9. The method for synthesizing ceftazidime side chain acid ethyl ester according to claim 1, characterized in that The device used in the method for synthesizing ceftazidime side chain acid ethyl ester comprises a first preparation kettle (1), wherein the first preparation kettle (1), a chlorination microchannel reactor (3), a pipeline reactor (5), a loop reactor (6), a circulation pump (17), a primary microchannel reactor (10), a secondary microchannel reactor (12) and a delay reactor (13) are connected in sequence, the chlorination microchannel reactor (3) is connected to a chlorine buffer tank (2), the loop reactor (6) is connected to an isobutylene buffer tank (4), the circulation pump (17), a heat exchanger (7) and the loop reactor (6) are connected in sequence, the primary microchannel reactor (10) is connected to a second preparation kettle (8) and a third preparation kettle (9) respectively, and the secondary microchannel reactor (12) is connected to a water storage tank (11).

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