A method for photocatalytic radical coupling continuous flow synthesis of ceftazidime side chain acid ethyl ester

Abstract

The present application belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing cefotetan side chain acid ethyl ester through photocatalytic radical coupling in continuous flow, which comprises the following steps: preparing a reaction solution by mixing nortriptophane oxime acid ethyl ester, 2-bromo-2-methyl propionic acid tert-butyl ester, a photocatalyst and a base in an organic solvent, continuously pumping the reaction solution into a spiral pipe photo reactor through a metering pump, and performing a radical coupling reaction under light irradiation, continuously introducing the reaction effluent into a crystallization kettle for crystallization, centrifugally separating the obtained suspension to obtain cefotetan side chain acid ethyl ester. The present application introduces the photocatalytic radical coupling mechanism into the synthesis of cefotetan side chain for the first time, replaces the traditional ionic nucleophilic substitution reaction, and realizes a mild reaction under room temperature conditions. The total yield is more than 98.0%, the product purity is more than 99.0%, and the solvent, triethylamine and benzophenone used in the reaction process can be reused through simple recovery, which is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for the continuous synthesis of ceftazidime side chain ethyl ester via photocatalytic free radical coupling. Background Technology

[0002] Ethyl ceftazidime ((Z)-2-(2-aminothiazol-4-yl)-2-(1-tert-butoxycarbonyl-1-methyl)ethoxyiminoethyl ester, CAS No.: 86299-46-9) is a key intermediate in the synthesis of the third-generation cephalosporin ceftazidime and the novel side-carrier cephalosporin cefdil. The core of this compound's structure lies in the oxime ether group linked at the 4-position of the 2-aminothiazolium ring; its construction efficiency and selectivity directly affect the overall synthetic quality of the molecule. Its structural formula is as follows:

[0003] .

[0004] In existing technologies, the synthesis of ceftazidime side-chain ethyl ester from ethyl northiamethoxamate generally employs a nucleophilic substitution mode: under alkaline conditions, the oxime hydroxyl group of ethyl northiamethoxamate acts as a nucleophile, attacking the carbon atom of tert-butyl α-bromoisobutyrate, and generating the target product via an SN2 reaction. CN105585539A discloses a one-pot synthesis process that combines the oximeization, cyclization, and condensation of ethyl 4-bromoacetoacetate in three steps, achieving a yield of over 96.5%. CN110790721A further optimizes the process by replacing bromination with chlorination, reducing raw material costs. However, these processes still have the following problems:

[0005] (1) High reaction temperature: The condensation reaction needs to be carried out under heating conditions of 70-85℃. Prolonged high temperature can easily lead to product decomposition.

[0006] (2) Poor selectivity of ionic reactions: Under alkaline conditions, the oxime hydroxyl group is deprotonated to generate an oxygen anion, but other side reactions may also be triggered at the same time;

[0007] (3) Difficult to recover the catalyst: The phase transfer catalyst cannot be recycled, which increases the production cost.

[0008] Photocatalytic radical reactions have become a cutting-edge area in organic synthesis in recent years. Compared with traditional ionic reactions, photocatalytic reactions have advantages such as milder conditions, higher selectivity, and better tolerance to functional groups. However, traditional batch photoreactors still face many engineering bottlenecks: limited light penetration depth, insufficient illumination in the central region of the reaction liquid; uneven light intensity distribution, resulting in a significant "scale-up effect" during scale-up; long reaction time, limiting production efficiency; and difficulty in achieving automated continuous production. In recent years, continuous flow photochemical reactors (such as microchannel reactors and helical photoreactors) have become an important development direction for the industrialization of photocatalytic reactions due to their advantages such as large specific surface area, short light penetration path, high mass and heat transfer efficiency, and precise control of process parameters. However, there are currently no literature or patent reports on combining photocatalytic radical coupling strategies with continuous flow technology for the synthesis of ceftazidime side chain ethyl ester. Summary of the Invention

[0009] The purpose of this invention is to provide a method for the continuous flow synthesis of ceftazidime side chain ethyl ester via photocatalytic free radical coupling. This method uses desaminoglycanthime ethyl ester as a raw material and constructs the oxime ether structure of the target molecule in one step through photocatalytic free radical coupling reaction under light conditions. Combined with continuous flow reaction technology, this method solves the problems of high reaction temperature, poor selectivity, difficulty in catalyst recovery, and difficulty in scale-up of batch photocatalytic reaction in traditional processes, thereby filling the above-mentioned technological gaps.

[0010] The technical solution adopted by this invention to solve its technical problem is: a method for continuous synthesis of ceftazidime side chain ethyl ester via photocatalytic free radical coupling, comprising the following steps:

[0011] Ethyl noraminothiazolate (Formula 2), tert-butyl 2-bromo-2-methylpropionate (Formula 3), photocatalyst, and base were prepared into a reaction solution in an organic solvent and continuously pumped into a spiral tube photoreactor by a metering pump. Free radical coupling reaction was carried out under light irradiation. The reaction effluent was continuously fed into a crystallization vessel for crystallization. The resulting suspension was separated by centrifugation to obtain ethyl ceftazidime (Formula 1).

[0012] .

[0013] Furthermore, the spiral tube photoreactor is made of perfluoroethylene propylene copolymer, the inner diameter of the spiral tube is 1.6-3.0 mm, and the total length of the spiral tube is 20-50 m.

[0014] Furthermore, the flow rate of the metering pump is 0.6-2 mL / min, and the residence time of the reaction solution in the spiral tube photoreactor is 30-90 minutes.

[0015] Furthermore, the photocatalyst is benzophenone, and the amount of photocatalyst used is 5%-15% of the molar amount of ethyl desaminoglycate.

[0016] Furthermore, the illumination wavelength is 350-380nm, preferably 365nm.

[0017] Furthermore, the free radical coupling reaction temperature is 20-30℃.

[0018] Furthermore, the organic solvent is selected from one or more of acetonitrile, dichloromethane, and tetrahydrofuran, preferably acetonitrile.

[0019] Furthermore, the ratio of the organic solvent to ethyl desaminoglycidol is 5-6:1, wherein the organic solvent is expressed in L and the ethyl desaminoglycidol is expressed in mol.

[0020] Furthermore, the base is triethylamine, and the amount of base used is 1-3 times the molar amount of ethyl desaminoglycate.

[0021] Furthermore, the amount of tert-butyl 2-bromo-2-methylpropionate used is 1.0-2.0 times the molar amount of ethyl northiamethoxamate.

[0022] Furthermore, after the reaction is complete, the photocatalyst is recovered by salting out the mother liquor, and the recovered photocatalyst is recycled.

[0023] Furthermore, the recovery of the photocatalyst includes: combining the mother liquor after crystallization and centrifugation, adding sodium chloride to precipitate and separate the organic phase, concentrating and crystallizing it to obtain benzophenone crystals for recycling.

[0024] This invention uses ethyl noraminothiazolate as a starting material. This substrate contains multiple sensitive functional groups, including a 2-aminothiazole ring, an oxime hydroxyl group, and an ethyl ester group. In traditional photocatalytic systems, it readily undergoes side reactions such as amino oxidation, thiazole ring opening or addition, and ester hydrolysis, resulting in poor reaction selectivity and complex products. To overcome this challenge, this invention introduces a bifunctional photocatalytic strategy into the synthesis of cephalosporin side chains for the first time. Through extensive screening and mechanistic studies, a highly synergistic photocatalytic radical coupling system was designed and verified.

[0025] In this system, benzophenone (BP) acts as a single photocatalyst, simultaneously playing a dual role in photoinduced electron transfer (PET) and hydrogen atom transfer (HAT): its excited triplet state can both reduce tert-butyl 2-bromo-2-methylpropionate to generate carbon radicals and abstract hydrogen atoms from oxime hydroxyl groups to generate oxygen radicals, achieving radical-radical coupling. More importantly, the excited state energy of BP (365 nm absorption) falls precisely within the narrow window of "initiating the reduction of bromides without destroying the thiazole ring and amino group," avoiding high-energy side reactions; the use of a single catalyst also eliminates potential cross-reactions that may arise from multi-component systems, significantly improving the selectivity and controllability of the reaction.

[0026] At the same time, triethylamine breaks through the traditional role of bases as merely neutralizing agents, becoming a key electron donor in the catalytic cycle—it reduces BP radical cations (BP... •+ The catalyst regenerates itself and undergoes a controlled conversion to easily removable N,N,N',N'-tetraethylethylenediamine, ensuring high product purity. Acetonitrile, dichloromethane, and tetrahydrofuran, as solvents, avoid solvent participation in side reactions due to their inertness to free radical reactions. The 350-380nm LED light source precisely matches the absorption peak of BP, achieving efficient energy utilization. This multi-factor process is interconnected (the bifunctionality of the catalyst, the electron donor role of the base, the inert solvent, and the precise wavelength). Replacing any single component (such as using other photocatalysts, inorganic bases, or different solvents) will lead to a significant decrease in yield or reaction failure.

[0027] Specifically, under light irradiation, benzophenone (BP) transitions from its ground state to an excited singlet state, and then transforms into a long-lived triplet excited state (BP*) via intersystem crossing (ISC). The excited-state benzophenone acts as a single-electron reducing agent, reducing tert-butyl 2-bromo-2-methylpropionate (Formula 3) to generate a carbon radical (3a) via single-electron transfer, simultaneously generating a benzophenone radical cation (BP). •+ ) and bromide ions.

[0028] Simultaneously, the excited-state benzophenone abstracts a hydrogen atom from the oxime hydroxyl group of ethyl noraminothiazolate (Formula 2), undergoing hydrogen atom transfer (HAT) to generate a halfpinacol radical (BP-H). • ) and oxime oxygen free radicals (2a).

[0029] Nitrogen oxide radicals and carbon radicals undergo radical-radical coupling to generate the target product, ceftazidime ethyl ester.

[0030] In addition, the generated benzophenone radical cation (BP) •+ The triethylamine in the system is reduced to regenerate neutral benzophenone, completing the catalytic cycle. Meanwhile, the half-pinacol radical (BP-H) is reduced... • The catalyst is also oxidized by trace amounts of oxygen in the system and regenerated into benzophenone. Thus, all intermediates in the entire photocatalytic cycle have a clear transformation fate, and the catalyst is completely regenerated.

[0031] .

[0032] In addition, during the reaction, triethylamine is reacted with benzophenone radical cations (BP). •+ Oxidation generates triethylamine radical cations (Et3N). •+Under alkaline conditions (with another molecule, Et3N, as the base), it is deprotonated to generate an α-amino radical (•CH2-CH2-NEt2) and a triethylamine salt. The two α-amino radicals rapidly dimerize to form a stable N,N,N',N'-tetraethylethylenediamine.

[0033] .

[0034] The beneficial effects of this invention are as follows:

[0035] (1) Mechanism innovation: For the first time, a bifunctional photocatalytic cycle is introduced into the synthesis of cephalosporin side chain, and a single benzophenone simultaneously achieves electron transfer and hydrogen atom transfer, fully revealing the six-step catalytic process and filling the technological gap.

[0036] (2) Mild conditions: room temperature reaction avoids high temperature side reactions and reduces energy consumption by 70%; it is tolerant to oxygen and does not require strict anaerobic operation.

[0037] (3) Excellent selectivity: The total yield is over 98.0% with the combined control of polarity matching and steric hindrance, and the product purity is >99.0%. By-products are easy to remove and it is suitable for industrial production.

[0038] (4) Economical catalysts: Benzophenone and triethylamine are inexpensive and can be recycled three times, with costs significantly lower than those of precious metal catalysts.

[0039] (5) Advantages of continuous flow process: By utilizing the high specific surface area and uniform illumination characteristics of the microchannel spiral tube photoreactor, the transmission efficiency of light energy in the reaction system is significantly enhanced, which solves the technical bottleneck of limited light penetration depth and obvious scale-up effect in traditional batch photoreactors. The reaction time is shortened to 30-90 minutes, and it has good process stability and scale-up potential.

[0040] (6) Byproducts are clear and controllable: The conversion pathway of triethylamine radical cations is clear, and the byproduct is N,N,N',N'-tetraethylethylenediamine, which can be easily removed and recovered in post-processing.

[0041] (7) Environmentally friendly: The solvents, triethylamine and benzophenone used in the reaction process can be easily recycled and reused, greatly reducing environmental pollution. Attached Figure Description

[0042] Figure 1 This is a schematic diagram of the synthesis process of ceftazidime side chain ethyl ester of the present invention.

[0043] Figure 2 This is an HPLC chromatogram of ceftazidime ethyl side chain acid prepared in Example 1.

[0044] Figure 3This is the ¹H NMR spectrum of ceftazidime ethyl ester prepared in Example 1.

[0045] Figure 4 This is the ¹³C NMR spectrum of ceftazidime ethyl ester prepared in Example 1.

[0046] In the diagram, 1. Raw material preparation vessel, 2. High-pressure constant flow metering pump, 3. Spiral tube photoreactor, 4. Crystallization vessel, 5. Centrifuge, 6. Vacuum dryer, 7. Salting-out separator, 8. Reduced pressure concentrator, 9. Cooling crystallizer, 10. Filtering device, 11. Alkalization vessel, 12. Distillation column, 13. Filtration and drying unit. Detailed Implementation

[0047] The following are specific embodiments of the present invention, which further describe the technical solution of the present invention. However, the scope of protection of the present invention is not limited to these embodiments. All changes or equivalent substitutions that do not depart from the concept of the present invention are included within the scope of protection of the present invention.

[0048] In this invention, ethyl noraminothiazolate (CAS No.: 64485-82-1) is sourced from Shandong Jincheng Pharmaceutical Group Co., Ltd.; tert-butyl 2-bromo-2-methylpropionate (CAS No.: 23877-12-5) is sourced from Shanghai Hans Chemical Co., Ltd.

[0049] Example 1: Synthesis of ceftazidime side chain ethyl ester

[0050] This embodiment uses a continuous flow reactor to perform a photocatalytic radical coupling reaction, such as... Figure 1 As shown, the continuous flow reactor consists of a raw material preparation vessel 1, a high-pressure constant flow metering pump 2, a spiral tube photoreactor 3, a crystallization vessel 4, a centrifuge 5, and a vacuum dryer 6.

[0051] The spiral tube photoreactor 3 uses a transparent FEP (perfluoroethylene propylene copolymer) tube with an inner diameter of 1.6 mm and a wall thickness of 0.8 mm. The total length is 30 m and the effective volume is about 60 mL. It is wound around a cylindrical light column (365 nm LED, total power 100 W) with an inner diameter of 10 cm to ensure uniform light intensity on the tube wall surface.

[0052] In raw material preparation vessel 1, acetonitrile (5L) was added, followed by ethyl desaminoglycate (215g, 1.0mol, 1.0eq), tert-butyl 2-bromo-2-methylpropionate (245g, 1.1mol, 1.1eq), benzophenone (9.1g, 0.05mol, 5% of the molar amount of ethyl desaminoglycate), and triethylamine (303g, 3.0mol, 3.0eq). The mixture was stirred until completely dissolved to obtain a clear raw material mixture.

[0053] Turn on the 365nm LED light source of the helical photoreactor 3 and preheat for 10 minutes until the light intensity stabilizes. Turn on the high-pressure constant flow metering pump 2 and pump the raw material mixture into the helical photoreactor 3 at a flow rate of 1.0 mL / min. Control the reaction temperature in the helical photoreactor 3 at 25℃ and the residence time of the reaction solution in the helical photoreactor 3 at 60 minutes. After the reaction solution flows out of the helical photoreactor 3, it directly enters the crystallization vessel 4 pre-filled with 5L of pure water, and a white solid precipitates under stirring. After all the reaction solution has been pumped in, continue to pass 0.5L of acetonitrile to clean the pipeline, and the cleaning solution is added to the crystallization vessel 4. The suspension in the crystallization vessel 4 is separated by centrifuge 5, and the filter cake is vacuum dried at 50℃ for 4 hours in a vacuum dryer 6 to obtain 351g of white solid product ceftazidime side chain ethyl ester, with a yield of 98.2% and a purity of 99.16% (HPLC). Its HPLC chromatogram is shown below. Figure 2 As shown, 1 HNMR spectra as follows Figure 3 As shown, 13 CNMR spectrum as follows Figure 4 As shown. After combining the filtrates, benzophenone, acetonitrile, and triethylamine were recovered according to the method in Example 31.

[0054] 1 HNMR (500MHz, CDCl3) δ6.97(s,1H),6.61(s,2H),4.32(q,J=7.1Hz,2H),1.53(s,6H),1.45(s,9H),1.36(t,J=7.1Hz,3H).

[0055] 13 CNMR (125MHz, CDCl3) δ173.90,168.37,162.69,149.75,145.89,108.95,82.46,81.61,61.65,27.85,24.56,14.14.

[0056] Examples 2-5

[0057] The amount of benzophenone used in Example 1 was adjusted to 1%, 6%, 11%, and 15% of the molar amount of ethyl northiamethoxamate, respectively, with the remaining steps being the same as in Example 1. The product yield and purity data for each example are shown in Table 1.

[0058] Table 1. Effect of different catalyst dosages on the reaction in Examples 2-5

[0059] Example Example 2 Example 3 Example 4 Example 5 Benzophenone dosage (percentage of the molar amount of ethyl northiazoxime) 1% 6% 11% 15% Product yield 69.5% 98.18% 98.13% 98.06% Product purity 98.2% 99.13% 99.14% 99.10%

[0060] Examples 6-9

[0061] The amount of triethylamine used in Example 1 was adjusted to 1 eq, 1.5 eq, 2 eq, and 2.5 eq, respectively, while the remaining steps were the same as in Example 1. The product yield and purity data for each example are shown in Table 2.

[0062] Table 2 shows the effect of different alkali dosages on the reaction in Examples 6-9.

[0063] Example Example 6 Example 7 Example 8 Example 9 Triethylamine dosage 1eq 1.5eq 2eq 2.5eq Product yield 98.15% 98.13% 98.18% 98.16% Product purity 99.12% 99.09% 99.10% 99.13%

[0064] Examples 10-13

[0065] In Example 1, the "base" was replaced with N,N-diisopropylethylamine, potassium carbonate, sodium acetate, and pyridine, respectively, with the remaining steps the same as in Example 1. The product yield and purity data for each example are shown in Table 3. As can be seen from Table 3, N,N-diisopropylethylamine exhibits poor catalytic performance, while the inorganic bases potassium carbonate, sodium acetate, and pyridine have almost no catalytic effect.

[0066] Table 3 shows the effect of different types of alkali on the reaction in Examples 10-13.

[0067] Example Example 10 Example 11 Example 12 Example 13 Types of alkalis N,N-Diisopropylethylamine Potassium carbonate Sodium acetate Pyridine Product yield 86.06% <5% <5% <5% Product purity 97.15% <5% — —

[0068] Examples 14-17

[0069] The solvents in Example 1 were replaced with dichloromethane, tetrahydrofuran, N,N-dimethylformamide, and toluene, respectively, with the remaining steps the same as in Example 1. The product yields and purity data for each example are shown in Table 4. Table 4 shows that DMF and toluene performed poorly as solvents.

[0070] Table 4. Effects of different solvents on the reactions in Examples 14-17

[0071] Example Example 14 Example 15 Example 16 Example 17 solvent dichloromethane Tetrahydrofuran DMF Toluene Product yield 98.10% 98.15% 61.9% 52.3% Product purity 99.06% 99.11% 97.1% 96.5%

[0072] Examples 18-21

[0073] The dosage of tert-butyl 2-bromo-2-methylpropionate in Example 1 was adjusted to 1.0 eq, 1.2 eq, 1.8 eq, and 2.0 eq, respectively, with the remaining steps the same as in Example 1. The product yield and purity data for each example are shown in Table 5.

[0074] Table 5. Effect of different amounts of bromide on the reaction in Examples 18-21

[0075] Example Example 18 Example 19 Example 20 Example 21 Brominated product dosage 1.0eq 1.2eq 1.8eq 2.0eq Product yield 98.13% 98.14% 98.15% 98.10% Product purity 99.16% 99.13% 99.11% 99.14%

[0076] Examples 22-25

[0077] The "illumination wavelength" in Example 1 was adjusted to 350nm, 360nm, 370nm, and 380nm, respectively, and the remaining steps were the same as in Example 1. The product yield and purity data for each example are shown in Table 6.

[0078] Table 6. Effects of different light wavelengths on the reaction in Examples 22-25.

[0079] Example Example 22 Example 23 Example 24 Example 25 Light wavelength 350nm 360nm 370nm 380nm Product yield 98.11% 98.14% 98.13% 98.10% Product purity 99.13% 99.15% 99.12% 99.10%

[0080] Examples 26-29

[0081] The reaction temperature in Example 1 was adjusted to 15℃, 20℃, 30℃, and 35℃, respectively, with the remaining steps the same as in Example 1. The product yield and purity data for each example are shown in Table 7. As can be seen from Table 7, in Examples 26-29, the yield was above 98% within the range of 20-30℃; excessively low or high temperatures led to a decrease in yield.

[0082] Table 7 shows the effect of different reaction temperatures on the reactions in Examples 26-29.

[0083] Example Example 26 Example 27 Example 28 Example 29 reaction temperature 15℃ 20℃ 30℃ 35℃ Product yield 80.5% 98.14% 98.12% 82.8% Product purity 98.8% 99.15% 99.16% 98.3%

[0084] Example 30: Parameter Optimization of Continuous Flow Reactor

[0085] Referring to the continuous flow operation of Example 1, the effects of the inner diameter of the helical tube, the length of the helical tube, and the residence time of the reaction liquid in the helical tube photoreactor on the reaction were investigated.

[0086] (1) Effect of the inner diameter of the spiral tube: With a fixed spiral tube length of 30 m and a residence time of 60 minutes (achieved by adjusting the flow rate), FEP tubes with inner diameters of 0.8 mm, 2.0 mm, 2.4 mm, 3.0 mm, and 3.2 mm were used for the reaction. The corresponding product yields and purity data are shown in Table 8. The results show that when the inner diameter is too small (0.8 mm), the back pressure of the system is too high, and it is easy to clog; when the inner diameter is too large (3.2 mm), the light penetration depth is insufficient, the light illumination of the reaction liquid in the central region is uneven, and the yield drops to 88.6%. The best overall effect is achieved when the inner diameter is 1.6 mm (Example 1), with a yield of 98.2% and a purity of 99.16%.

[0087] Table 8. Effect of different spiral tube inner diameters on the reaction in Example 30

[0088] Inner diameter(mm) Length (m) Duration of stay (min) Product yield (%) Product purity (%) 0.8 30 60 Reactor clogging — 2.0 30 60 98.18 99.12 2.4 30 60 98.13 99.08 3.0 30 60 98.15 99.09 3.2 30 60 88.6 98.2

[0089] (2) Effect of spiral tube length: With a fixed inner diameter of 1.6 mm and a residence time of 60 minutes, reactions were carried out using spiral tubes with lengths of 10 m, 20 m, 30 m, 40 m, and 50 m, respectively. The corresponding product yields and purity data are shown in Table 9. The results show that: at a length of 10 m, the reaction was incomplete, with a yield of only 71.8%; at a length of 20 m, the yield increased to 98.10%; at a length of 30 m (Example 1), the yield was the highest (98.20%); at lengths of 40 m and 50 m, the yield did not increase significantly (98.16% and 98.17%, respectively), but the system back pressure increased significantly, and the equipment load increased. The preferred total length is 30 m.

[0090] Table 9 shows the effect of different spiral tube lengths on the reaction in Example 30.

[0091] Length (m) Inner diameter(mm) Duration of stay (min) Product yield (%) Product purity (%) 10 1.6 60 71.8 98.5 20 1.6 60 98.10 99.13 40 1.6 60 98.16 99.08 50 1.6 60 98.17 99.05

[0092] (3) Effect of residence time of the reaction solution in the spiral tube photoreactor: With a fixed inner diameter of 1.6 mm and a length of 30 m, the residence time was adjusted to 15, 30, 80, 90, and 100 minutes by adjusting the flow rate. The corresponding product yield and purity data are shown in Table 10. The results showed that the reaction was incomplete at a residence time of 15 minutes, with a yield of 76.2%; the yield was 98.10% at a residence time of 30 minutes; 98.16% at a residence time of 80 minutes; 98.14% at a residence time of 90 minutes; and 98.01% at a residence time of 100 minutes, but the production capacity decreased. The preferred residence time is 30-90 minutes.

[0093] Table 10 shows the effect of different residence times on the reaction in Example 30.

[0094] Duration of stay (min) Inner diameter(mm) Length (m) Flow rate (mL / min) Product yield (%) Product purity (%) 15 1.6 30 4.0 76.2 98.3 30 1.6 30 2.0 98.10 99.14 80 1.6 30 0.75 98.16 99.14 90 1.6 30 0.67 98.14 99.12 100 1.6 30 0.6 98.01 98.97

[0095] Example 31: Recycling

[0096] In Example 1 of this invention, benzophenone, acetonitrile, and triethylamine can all be recovered. The equipment used for recovery includes: vacuum dryer 6, salting-out separator 7, vacuum concentrator 8, cooling crystallizer 9, filtration device 10, alkalization kettle 11, distillation column 12, and filtration and drying unit 13.

[0097] (1) Benzophenone recovery

[0098] The combined mother liquor from Example 1 and the catalyst cycling experiment (containing approximately 5 L of water, 5.5 L of acetonitrile, and approximately 9.1 g / batch of benzophenone) was collected and processed. Sodium chloride (250 g) was added, and the mixture was vigorously shaken for 2-3 minutes to fully dissolve the sodium chloride. The mixture was then allowed to stand for 10-15 minutes in a salting-out separator 7 to separate the phases. The upper acetonitrile phase was separated and concentrated under reduced pressure in a water bath at 50-55°C using a vacuum concentrator 8. After distilling off approximately 3-3.5 L of acetonitrile, the mixture was allowed to cool naturally to room temperature and then cooled in an ice-water bath using a cooling crystallizer 9 for 30 minutes to ensure complete crystallization. The crystals were collected by vacuum filtration using a suction filter 10. The filter cake was washed once with 5 mL of ice water and then vacuum dried at 40-50°C for 2 hours in a vacuum desiccator 6 to obtain white, flaky crystalline benzophenone. The recovery rate was 81.2%-82.5%, and the recovered benzophenone could be directly used in the next batch of reaction.

[0099] (2) Acetonitrile recovery

[0100] The acetonitrile distilled from vacuum condenser 8, after being dried with anhydrous sodium sulfate, can be directly recycled for the reaction.

[0101] (3) Recovery of triethylamine, N,N,N',N'-tetraethylethylenediamine and sodium chloride

[0102] The lower aqueous phase after separation in salting-out separator 7 (theoretically containing 182.10 g of triethylamine hydrobromide, 101.19 g of triethylamine, 86.16 g of N,N,N',N'-tetraethylethylenediamine, and 250 g of sodium chloride) is added to alkalinization reactor 11. Then, 30% sodium hydroxide solution is added to adjust the pH to above 12. The mixture is heated to 85-90℃ and sent to distillation column 12 for vacuum distillation. The fraction collected at 75-85℃ yields a mixture of triethylamine and water. The distillate is dried with anhydrous potassium carbonate to obtain 172.04 g of anhydrous triethylamine, with a molar recovery of 85%. This can be recycled for further reactions. The fraction collected at 120-130℃ (corresponding to a boiling point of 190-192℃ at atmospheric pressure) yields 81.8 g of colorless to pale yellow liquid N,N,N',N'-tetraethylethylenediamine, with a recovery of 95%. This can be sold as a chemical raw material. After the distillation residue is cooled in the cooling crystallizer 9, sodium bromide and sodium chloride crystals precipitate out. After being filtered and dried in the filtration and drying unit 13, crude salt is obtained, which can be recycled as salt precipitation.

[0103] Example 32: Recycling of the recovered catalyst

[0104] (1) First cycle

[0105] In the raw material preparation vessel, 4.2 L of acetonitrile (including 3.5 L of recovered acetonitrile) was added, followed by the addition of ethyl normethoxythiazolate (179 g, 0.83 mol, 1.0 eq), tert-butyl 2-bromo-2-methylpropionate (204 g, 0.91 mmol, 1.1 eq), recovered benzophenone (7.5 g, 0.041 mol, 0.05 eq), and triethylamine (172.04 g of recovered acetonitrile + 79.96 g of added acetonitrile = 252 g, 3.0 eq). The mixture was stirred until completely dissolved, yielding a clear mixed solution.

[0106] Turn on the 365nm LED light source and preheat for 10 minutes until the light intensity stabilizes. Turn on the high-pressure constant flow metering pump and pump the raw material mixture into the spiral tube photoreactor at a flow rate of 1.0 mL / min. Control the reaction temperature in the spiral tube photoreactor at 25°C and the residence time of the reaction solution in the spiral tube at 60 minutes. After the reaction solution flows out of the spiral tube, it directly enters the crystallization vessel pre-filled with 4.2L of pure water, and a white solid precipitates under stirring. After all the reaction solution has been pumped in, continue to flow 0.42L of acetonitrile to clean the pipeline, and the cleaning solution is added to the crystallization vessel. The suspension in the crystallization vessel is separated by centrifugation, vacuum dried at 50°C for 4 hours, and the post-treatment and recrystallization are the same as in Example 1, yielding 292g of white solid product, with a yield of 98.0% and a purity of 99.16%.

[0107] (2) Used in the 2nd to 3rd cycles

[0108] Following the above method, each time the amount of benzophenone photocatalyst recovered from the previous reaction was used as a baseline, and the material ratio of Example 1 was referenced. Triethylamine and acetonitrile were added back to the required amounts based on the previous recovery amounts for the reaction. The operation was repeated, and the cycle was repeated 3 times. The results are shown in Table 11.

[0109] Table 11. Effect of catalyst recycling in Example 32

[0110] Loop count Product yield Product purity Photocatalyst recovery rate Triethylamine recovery rate Acetonitrile recovery rate 1st time 98.0% 99.16% 82.5% 85% 95% 2nd time 98.2% 99.16% 81.2% 82% 96% 3rd 98.2% 99.16% 81.9% 85% 95%

[0111] Comparative Example 1: Control without photocatalyst

[0112] The "benzophenone" in Example 1 was omitted, and the remaining steps were the same as in Example 1. After 24 hours of reaction, TLC analysis showed no formation of the target product, indicating that the raw materials were essentially recovered.

[0113] Comparative Example 2: No light control

[0114] The FEP (perfluoroethylene propylene copolymer) transparent tube of the spiral photoreactor 3 in Example 1 was wrapped with aluminum foil to block light, and the remaining steps were the same as in Example 1. After 24 hours of reaction, TLC detection showed no formation of the target product, and the raw materials were recovered.

[0115] Comparative Example 3: Alkali-free Control

[0116] The "triethylamine" in Example 1 was omitted, and the remaining steps were the same as in Example 1. After reacting for 24 hours, TLC was used to detect trace amounts of the target product, with a yield of <5%, indicating that most of the starting material remained.

[0117] Comparative Example 4: Traditional Nucleophilic Substitution Method

[0118] DMF (100 mL) was added to a dry 250 mL three-necked flask, followed by ethyl northiamethoxamate (2.15 g, 10 mmol) and potassium carbonate (2.76 g, 20 mmol). The mixture was stirred at room temperature for 1 hour. Tert-butyl α-bromoisobutyrate (2.68 g, 12 mmol) was added dropwise, and the mixture was stirred at 70 °C for 8 hours. After the reaction was complete, the mixture was cooled to room temperature, and water (100 mL) was added. The mixture was extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give 2.54 g of a white solid product, yield 71.2%, purity 98.5%.

[0119] This invention is not limited to the above-described embodiments. Anyone should know that any structural changes made under the guidance of this invention, and any technical solutions that are the same as or similar to this invention, fall within the protection scope of this invention.

[0120] The technologies, shapes, and structures not described in detail in this invention are all known technologies.

Claims

1. A method for the continuous synthesis of ceftazidime side chain ethyl ester via photocatalytic radical coupling, characterized in that, Includes the following steps: Ethyl noraminothiazolate, tert-butyl 2-bromo-2-methylpropionate, photocatalyst, and base were prepared into a reaction solution in an organic solvent and continuously pumped into a spiral tube photoreactor by a metering pump. Free radical coupling reaction was carried out under light irradiation. The reaction effluent was continuously fed into a crystallization vessel for crystallization. The resulting suspension was separated by centrifugation to obtain ethyl ceftazidime side chain acid.

2. The method for photocatalytic radical coupling continuous flow synthesis of ceftazidime side chain ethyl ester according to claim 1, characterized in that, The spiral tube photoreactor is made of perfluoroethylene propylene copolymer, with an inner diameter of 1.6-3.0 mm and a total length of 20-50 m.

3. The method for continuous synthesis of ceftazidime side chain ethyl ester via photocatalytic radical coupling according to claim 1, characterized in that, The metering pump has a flow rate of 0.6-2 mL / min, and the residence time of the reaction solution in the spiral tube photoreactor is 30-90 minutes.

4. The method for continuous synthesis of ceftazidime side chain ethyl ester via photocatalytic radical coupling according to claim 1, characterized in that, The photocatalyst is benzophenone, and the amount of photocatalyst used is 5%-15% of the molar amount of ethyl desaminoglycate.

5. The method for continuous synthesis of ceftazidime side chain ethyl ester via photocatalytic radical coupling according to claim 1, characterized in that, The illumination wavelength is 350-380nm, and the free radical coupling reaction temperature is 20-30℃.

6. The method for continuous synthesis of ceftazidime side chain ethyl ester via photocatalytic radical coupling according to claim 1, characterized in that, The organic solvent is selected from one or more of acetonitrile, dichloromethane, and tetrahydrofuran, and the ratio of organic solvent to ethyl northiazolidinate is 5-6:1, wherein the organic solvent is expressed in L and the ethyl northiazolidinate is expressed in mol.

7. The method for photocatalytic radical coupling continuous flow synthesis of ceftazidime side chain ethyl ester according to claim 1, characterized in that, The alkali is triethylamine, and the amount of alkali used is 1-3 times the molar amount of ethyl desaminoglycidyl ester.

8. The method for continuous synthesis of ceftazidime side chain ethyl ester via photocatalytic radical coupling according to claim 1, characterized in that, The amount of tert-butyl 2-bromo-2-methylpropionate used is 1.0-2.0 times the molar amount of ethyl desaminoglycidyl ester.

9. The method for photocatalytic radical coupling continuous flow synthesis of ceftazidime side chain ethyl ester according to claim 4, characterized in that, After the reaction is complete, the photocatalyst is recovered by salting out the mother liquor, and the recovered photocatalyst is recycled.

10. The method for photocatalytic radical coupling continuous flow synthesis of ceftazidime side chain ethyl ester according to claim 9, characterized in that, The recovery of the photocatalyst includes: combining the mother liquor after crystallization and centrifugation, adding sodium chloride to precipitate and separate the organic phase, concentrating and crystallizing it to obtain benzophenone crystals for recycling.

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