A method for synthesizing 6-bromopenicillanic acid based on continuous flow microreaction

Abstract

This invention relates to the field of drug synthesis and microchemical technology, and discloses a method for synthesizing 6-bromopenicillinic acid based on continuous flow microreactors. The method includes dissolving 6-aminopenicillinic acid in ethanol and stirring until clear to obtain liquid A; preparing an aqueous solution of sodium nitrite and hydrobromic acid to obtain liquid B; mixing liquid A and liquid B in a first micromixer and then passing them into a microreactor pipeline for diazotization and bromination reactions, with inert gas purging the pipeline online to obtain a reaction effluent; extracting the reaction effluent with dichloromethane online in a second micromixer, then separating the organic phase using a membrane phase separator, and concentrating to obtain 6-bromopenicillinic acid. This invention utilizes the advantages of efficient mixing and precise temperature control in a continuous flow microreactor, combined with inert gas purging, to achieve continuous and stable preparation. It features safe operation, good batch stability, high production efficiency, and environmental friendliness, making it suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis and microchemical technology, specifically relating to a method for synthesizing 6-bromopenicillinic acid based on continuous flow microreaction. Background Technology

[0002] Sulbactam is a β-lactamase inhibitor widely used in antibiotic combination preparations. 6-Bromopenicillanic acid is a key intermediate in the synthesis of sulbactam. Traditional batch processing uses 6-APA as a raw material, synthesizing 6-bromopenicillanic acid through diazotization and bromination reactions. This traditional method has the following prominent problems: Highly exothermic reaction: Diazotization is a violently exothermic reaction with rapid temperature rise, easily leading to the decomposition of diazonium salts and product degradation. As a highly exothermic and fast-reacting reaction, uneven mixing of materials in the batch reactor can easily result in localized excessively high reactant concentrations and sudden temperature rises, potentially triggering side reactions such as over-bromination and intermolecular polymerization. This leads to lower yields and higher impurity content of the target product, increasing the process load and cost of subsequent separation and purification, and potentially affecting the synthesis quality of downstream drugs such as sulbactam. Furthermore, the wide residence time distribution of materials in batch reaction systems makes it difficult to precisely control process parameters such as reaction temperature and feed ratios, resulting in significant fluctuations in product yield and purity between different batches, poor production stability, and difficulty meeting the standardized requirements of large-scale industrial production.

[0003] Long reaction time: Feeding, reaction and post-processing take several hours, resulting in low efficiency and poor batch stability.

[0004] The products are unstable: the diazonium salt and the brominated products are easily decomposed in acidic aqueous systems, with yields of only 40% to 65%.

[0005] High safety risks: The reaction process releases a large amount of nitrogen oxide gas (reddish-brown NO2), and the large liquid hold-up in the reactor makes it prone to splashing or explosion.

[0006] Air pollution: Nitrogen oxides are difficult to treat, putting great pressure on environmental protection. Summary of the Invention

[0007] This invention provides a method for synthesizing 6-bromopenicillinic acid based on continuous flow microreaction, in order to solve the problems of low purity and yield of 6-bromopenicillinic acid in the prior art.

[0008] This invention provides the following technical solution: a method for synthesizing 6-bromopenicillinic acid based on continuous flow microreaction, comprising the following steps: S1. Dissolve 6-aminopenicillanic acid in ethanol and stir until clear to obtain liquid A; S2. Prepare an aqueous solution by reacting sodium nitrite with hydrobromic acid to obtain liquid B; S3. After mixing liquid A and liquid B in the first micro mixer, the mixture is introduced into the micro-reaction pipeline for diazotization and bromination reactions. During the reaction, inert gas is introduced into the pipeline for online purging to obtain the reaction mixture outflow. S4. The reaction mixture effluent is mixed with dichloromethane in a second micro mixer. The dichloromethane is used to extract the reaction mixture effluent online to obtain a mixture. The mixture enters a membrane phase separator to continuously separate the organic phase and the aqueous phase. The organic phase is collected and concentrated to obtain 6-bromopenicillinic acid.

[0009] Furthermore, the concentration of the 6-aminopenicillanic acid in ethanol is 0.3-0.55 mol / L; The ethanol is 95% ethanol.

[0010] Furthermore, the molar ratio of sodium nitrite to hydrobromic acid is 1:1.24~1.25.

[0011] Furthermore, the flow rate of liquid A in S3 is 5-7 mL / min; The flow rate of liquid B in S3 is 4-8 mL / min.

[0012] Furthermore, the first micro mixer is either a micro-sieve mixer or a Y-type microchannel mixer; The second micro mixer is any one of a T-type three-way mixer, a built-in low-shear static mixer, or a cross-shaped microchannel mixer.

[0013] Furthermore, the inert gas is nitrogen, and the nitrogen purging rate is 10-30 mL / min; The online extraction rate of dichloromethane is 12-22 mL / min.

[0014] Furthermore, the reaction pressure of the back pressure valve is 0.3-0.4 MPa.

[0015] Furthermore, the membrane phase separator is any one of polytetrafluoroethylene hollow fiber membrane and ceramic hollow fiber membrane.

[0016] Compared with the prior art, the present invention has the following technical effects: The diazotization and bromination reactions are carried out in a segmented, temperature-controlled series within a microchannel. The low-temperature zone stably generates the diazonium salt, while the high-temperature zone rapidly completes the bromination, inhibiting the decomposition of the diazonium salt and reducing byproducts.

[0017] By utilizing the gas-liquid-solid micro-dispersion characteristics within microchannels, a small amount of nitrogen gas is introduced to form microbubbles, which rapidly carry the generated NO2 gas out of the reaction system, preventing it from undergoing side reactions with diazonium salts, while simultaneously enhancing mixing.

[0018] It achieves continuous integration of reaction-extraction-separation, and the product is immediately extracted into the organic phase after generation, avoiding degradation caused by prolonged retention in the acidic aqueous phase. Attached Figure Description

[0019] Figure 1 This is a flowchart of the technology of the present invention.

[0020] Figure 2 This is a schematic diagram of the synthesis steps of 6-bromopenicillinic acid.

[0021] Figure 3 The liquid chromatogram of 6-bromopenicillinic acid prepared in Example 6 is shown. Detailed Implementation

[0022] The present invention will be further illustrated below with reference to embodiments. These embodiments are for illustrative purposes only and are not intended to limit the invention in any way. It should be understood that the described embodiments are merely some, not all, of the embodiments described in this application. All other embodiments obtained by those skilled in the art based on the embodiments in this application without inventive effort are within the scope of protection of this application.

[0023] like Figure 1 As shown, Figure 1 This is a flowchart of the technology of the present invention. Figure 2 This is a schematic diagram of the synthesis steps of 6-bromopenicillinic acid. This embodiment provides a method for synthesizing 6-bromopenicillinic acid based on continuous flow microreactions, including the following steps: Equipment parameters: The first micro-mixer is a micro-sieve mixer (20 sieves, 0.1mm sieve diameter), and the micro-reaction pipeline is a 15m long 316L stainless steel coil with an inner diameter of 1.5mm, divided into two sections: the first section (0~5℃) is 6m long, and the second section (25℃) is 9m long. The second micro-mixer is a T-type three-way mixer, and the membrane phase separator is a polytetrafluoroethylene hollow fiber membrane with a back pressure valve set at 0.3MPa.

[0024] Preparation of raw material solution: Solution A: Dissolve 6-aminopenicillanic acid (6-APA) in 95% ethanol to prepare a 0.3 mol / L solution, and stir at room temperature until clear; Solution B: Prepare an aqueous solution by mixing 0.36 mol / L NaNO2 and 0.45 mol / L HBr. Diazotization-bromination reaction Liquid A was fed into the first micromixer at a rate of 5 mL / min and liquid B at a rate of 4 mL / min, respectively, using high-pressure metering pumps. After mixing, the mixture entered the microreactor, which was a 15 m long, 1.5 mm inner diameter 316L stainless steel coil with segmented temperature control. First temperature zone (0~5℃): Diazotization reaction, residence time 3.2min; Second temperature zone (35℃): bromination reaction (nucleophilic substitution), residence time 4.8 min.

[0025] The reaction pressure is controlled at 0.3 MPa by a back pressure valve. At the same time, nitrogen gas is introduced into the reaction mixture at a flow rate of 20 mL / min through nitrogen purging to carry away the generated nitrogen oxide gas in time, thus obtaining a reaction mixture. Online extraction The reaction mixture flowing out of the stainless steel coil is introduced into the second micro-mixer along with dichloromethane for online mixing and extraction. The extraction flow rate of dichloromethane is set to 12 mL / min. The extracted and mixed fluid is then fed into a polytetrafluoroethylene hollow fiber membrane (hollow fiber membrane pore size 0.1–0.4 μm, effective area 0.2–0.25 m²) for continuous phase separation, separating the organic phase containing the product and the waste acid aqueous phase.

[0026] After 6 hours of continuous operation, the product yield was 88.5% and the purity was 96.8% (HPLC area normalization method). The product was confirmed as 6-bromopenicillinic acid by ¹H NMR and MS.

[0027] Example 2 Equipment parameters: The micro-reaction channel has an inner diameter of 2mm and a length of 20m. The first section (0~5℃) is 5m long, and the second section (30℃) is 15m long. The rest is the same as in Example 1.

[0028] Raw material ratio: Solution A: Dissolve 6-APA in 95% ethanol to prepare a solution with a concentration of 0.5 mol / L, and stir at room temperature until clear; Solution B: Prepare an aqueous solution by mixing 0.6 mol / L NaNO2 and 0.75 mol / L HBr. Diazotization-bromination reaction Liquid A was fed into the first micro mixer at a rate of 6 mL / min and liquid B at a rate of 6 mL / min respectively through a high-pressure metering pump. After mixing, the mixture entered the micro-reaction pipeline. After being mixed in the first micro mixer, liquid A and liquid B were fed into the micro-reaction pipeline with an inner diameter of 2 mm and a total length of 20 m for segmented temperature-controlled reaction. The total residence time in the micro-reaction pipeline was 6.5 min. The reaction pressure is controlled at 0.3 MPa by a back pressure valve. At the same time, nitrogen gas is introduced into the reaction mixture at a flow rate of 30 mL / min through nitrogen purging to carry away the generated nitrogen oxide gas in time, thus obtaining a reaction mixture. Online extraction The reaction mixture flowing out of the micro-reaction pipeline is introduced into the second micro-mixer along with dichloromethane for online mixing and extraction. The extraction flow rate of dichloromethane is set to 15 mL / min. The extracted and mixed fluid is then fed into a polytetrafluoroethylene hollow fiber membrane (hollow fiber membrane pore size 0.1–0.4 μm, effective area 0.2–0.25 m²) for continuous phase separation, separating the organic phase containing the product and the waste acid aqueous phase.

[0029] After 6 hours of continuous operation, the product yield was 91.2% and the purity was 97.5%.

[0030] Example 3 Equipment parameters: The first micro-mixer is a micro-sieve mixer (20 sieves, sieve diameter of 0.1 mm). The micro-reaction pipeline is equipped with a low-shear static mixer. The total length is 12 m and it is divided into three temperature zones: Zone 1 (0~5℃) 4 m, Zone 2 (20℃) 4 m, and Zone 3 (30℃) 4 m. The second micro-mixer is a T-type three-way mixer (hydraulic diameter of 1.5 mm). Each temperature zone is equipped with a nitrogen purging port and an ethanol replenishment port. The back pressure valve is set to 0.3 MPa.

[0031] Raw material ratio: Same as Example 1.

[0032] Diazotization-bromination reaction Liquid A was fed into the first micromixer at a rate of 5 mL / min and liquid B at a rate of 4 mL / min using high-pressure metering pumps. After mixing, the mixture entered the microreaction pipeline. The microreaction pipeline contained a low-shear static mixer with a total length of 12 m. Temperature control was implemented in segments within the microreaction pipeline: Zone 1 (0~5℃) 4 m, Zone 2 (20℃) 4 m, and Zone 3 (30℃) 4 m. 95% ethanol was added at the inlet of Zone 2 at a rate of 2 mL / min, and nitrogen was purged at the inlet of Zone 3 at a rate of 15 mL / min. The total residence time within the microreaction pipeline was 6.5 min. The reaction pressure was controlled at 3 MPa by a back pressure valve to promptly remove the generated nitrogen oxide gas, resulting in the reaction mixture. Online extraction The reaction mixture flowing out of the micro-reaction pipeline is introduced into the second micro-mixer along with dichloromethane for online mixing and extraction. The extraction flow rate of dichloromethane is set to 18 mL / min. The extracted and mixed fluid is then fed into a polytetrafluoroethylene hollow fiber membrane (hollow fiber membrane pore size 0.1–0.4 μm, effective area 0.2–0.25 m²) for continuous phase separation, separating the organic phase containing the product and the waste acid aqueous phase.

[0033] After 6 hours of continuous operation, the yield was 90.3% and the purity was 97.1%. Multi-point dilution further suppressed polymerization side reactions and resulted in a more concentrated molecular weight distribution.

[0034] Example 4 Equipment parameters: The first micromixer is a micro-sieve mixer (0.2mm sieve diameter, 10 sieves), and the second micromixer is a built-in low-shear static mixer (static mixing unit length 3cm, inner diameter 1.5mm). The total length of the microreactor pipeline is 12m, divided into three temperature zones: the first zone (0~2℃) is 4m, the second zone (20℃) is 4m, and the third zone (35℃) is 4m. The back pressure valve is set to 0.4MPa. The membrane phase separator uses a ceramic hollow fiber membrane. Nitrogen purging is done in two streams: 10mL / min each at the inlet of the second and third temperature zones, with the back pressure valve set to 0.4MPa.

[0035] Raw material ratio: Solution A: Dissolve 6-APA in 95% ethanol to prepare a 0.4 mol / L solution, and stir at room temperature until clear; Solution B: Prepare an aqueous solution by mixing 0.48 mol / L NaNO2 and 0.6 mol / L HBr; Diazotization-bromination reaction Liquid A and liquid B were separately fed into the first micromixer at a rate of 8 mL / min and 8 mL / min respectively using high-pressure metering pumps. After mixing, the mixture entered the microreaction pipeline. The microreaction pipeline was 12 m long and divided into three temperature zones: the first zone (0~2℃) was 4 m long, the second zone (20℃) was 4 m long, and the third zone (35℃) was 4 m long. The total residence time in the microreaction pipeline was 5.4 min (1.8 min + 1.8 min + 1.8 min). The reaction pressure was controlled at 0.4 MPa by a back pressure valve. Nitrogen purging was carried out in two ways: at the inlet of the second temperature zone and at the inlet of the third temperature zone, at a rate of 10 mL / min each, to promptly remove the generated nitrogen oxide gas and obtain the reaction mixture.

[0036] Online extraction The reaction mixture flowing out of the micro-reaction pipeline is introduced into the second micro-mixer along with dichloromethane for online mixing and extraction. The extraction flow rate of dichloromethane is set to 20 mL / min. The extracted and mixed fluid is then fed into a ceramic hollow fiber membrane (hollow fiber membrane pore size 0.1–0.4 μm, effective area 0.2–0.25 m²) for continuous phase separation, separating the organic phase containing the product and the waste acid aqueous phase.

[0037] After 8 hours of continuous operation, the yield was 92.0% and the purity was 97.8% (HPLC). Nitrogen oxide emissions were minimal, and the reactor pressure differential remained stable at 0.25 MPa. Compared to Example 1, the higher temperature and shorter residence time further suppressed diazonium salt decomposition, resulting in an improved yield.

[0038] Example 5 Equipment parameters: The first micromixer is a Y-type microchannel mixer (hydraulic diameter 0.8 mm), and the second micromixer is a cross-type microchannel mixer. The microreactor piping uses 316L stainless steel coils with an inner diameter of 1.2 mm and a total length of 18 m. The first temperature zone (0~5℃) is 6 m long, and the second temperature zone (30℃) is 12 m long. A replenishment port is added in the middle of the second temperature zone (6 m from the inlet) for adding 95% ethanol (flow rate 1.5 mL / min) to reduce the system viscosity and prevent high-concentration product precipitation and pipe blockage. The back pressure valve is 0.35 MPa.

[0039] Raw material ratio: Solution A: Dissolve 6-APA in 95% ethanol to prepare a solution with a concentration of 0.55 mol / L, and stir at room temperature until clear; Solution B: Prepare an aqueous solution by mixing 0.66 mol / L NaNO2 and 0.82 mol / L HBr; Diazotization-bromination reaction Liquid A and liquid B are fed into the first micro-mixer at a rate of 7 mL / min and 7 mL / min respectively using high-pressure metering pumps. After mixing, they enter the micro-reaction pipeline. The micro-reaction pipeline is a 316L stainless steel coil with an inner diameter of 1.2 mm and a total length of 18 m, divided into two temperature zones: the first temperature zone (0~5℃) is 6 m long, and the second temperature zone (30℃) is 12 m long. A replenishment port is added in the middle section of the second temperature zone (6m from the inlet of the second temperature zone) to replenish 95% ethanol (flow rate 1.5mL / min) to reduce the viscosity of the system and prevent high-concentration products from precipitating and clogging the pipeline. The reaction is carried out in the first section for 3.0min, in the second section (excluding the dilution section) for 3.0min, and continues to react for 3.0min after the dilution section. The total residence time in the micro-reaction pipeline is 9min. The reaction pressure is controlled at 0.35MPa by the back pressure valve. The total nitrogen purging rate is 25mL / min (divided into two streams: 10mL / min at the outlet of the first temperature zone and 15mL / min at the inlet of the second temperature zone) to carry out the generated nitrogen oxide gas in time, thus obtaining the reaction mixture. Online extraction The reaction mixture flowing out of the micro-reaction pipeline is introduced into the second micro-mixer along with dichloromethane for online mixing and extraction. The extraction flow rate of dichloromethane is set to 22 mL / min. The fluid after extraction and mixing is sent into a ceramic hollow fiber membrane for continuous phase separation, separating the organic phase containing the product and the waste acid aqueous phase.

[0040] After 10 hours of continuous operation, no blockages occurred, with a yield of 90.5% and a purity of 97.1%.

[0041] Example 6 Equipment parameters: An online thin-film evaporation unit (heating temperature 45℃, vacuum degree -0.08MPa) is added after the membrane phase separator (PTFE hollow fiber membrane) for continuous concentration of the organic phase to directly obtain a solid crude product. Other equipment parameters are the same as in Example 1. The concentrated dichloromethane vapor is condensed and recovered for recycling. The system back pressure valve is located after the thin-film evaporator and set at 0.3MPa.

[0042] Raw material ratio: Same as Example 1 Diazotization-bromination reaction Liquid A was fed into the first micromixer at a rate of 5 mL / min and liquid B at a rate of 4 mL / min, respectively, using high-pressure metering pumps. After mixing, the mixture entered the microreactor, which was a 15 m long, 1.5 mm inner diameter 316L stainless steel coil with segmented temperature control. First temperature zone (0~5℃): diazotization reaction; second temperature zone (35℃): bromination reaction (nucleophilic substitution); the total residence time in the microreactor is 7 min; the reaction pressure is controlled at 0.3 MPa by the back pressure valve; at the same time, nitrogen gas is purged into the reaction mixture at a flow rate of 20 mL / min to carry out the generated nitrogen oxide gas in time, and the reaction mixture is obtained. Online extraction The reaction mixture flowing out of the stainless steel coil is introduced into the second micro-mixer along with dichloromethane for online mixing and extraction. The extraction flow rate of dichloromethane is set to 12 mL / min. The extracted and mixed fluid is then fed into a polytetrafluoroethylene hollow fiber membrane (hollow fiber membrane pore size 0.1–0.4 μm, effective area 0.2–0.25 m²) for continuous phase separation, separating the organic phase containing the product and the waste acid aqueous phase. The organic phase enters the thin film evaporation unit, and the concentrate flows out continuously in a semi-solid form. After collection, it is dried in a vacuum drying oven (40℃, 2 h) to obtain the final product.

[0043] After 12 hours of continuous operation, the yield was 89.2% and the purity was 96.5%. Dichloromethane recovery was 92% (condensation recovery), significantly reducing solvent consumption. The product requires no additional rotary evaporation, simplifying post-processing and making it suitable for continuous industrial production. Compared to traditional batch processing, organic solvent consumption is reduced by 60%.

[0044] The final product (after vacuum drying) was analyzed by high-performance liquid chromatography (HPLC). The chromatographic conditions were as follows: C18 column (4.6 mm × 250 mm, 5 μm); mobile phase: acetonitrile-0.1% phosphoric acid aqueous solution (30:70 v / v); flow rate: 1.0 mL / min; detection wavelength: 210 nm; column temperature: 30 °C. The resulting HPLC chromatogram is shown below. Figure 3 As shown.

[0045] Depend on Figure 3It can be seen that the retention time of the main peak of the product is 5.035 min, and the peak area accounts for 96.8% (area normalization method), while the peak area of ​​the impurity peak (retention time 5.341 min) accounts for only 3.2%. This result is basically consistent with the purity of 96.5% (HPLC area normalization method) recorded in Example 6, proving that the continuous flow microreaction-online extraction-thin film evaporation integrated process of the present invention can stably obtain high-purity 6-bromopenicillinic acid product, which meets the quality requirements as a key intermediate in the synthesis of sulbactam.

[0046] Comparative example (traditional autoclave process) 10g 6-APA, 50mL hydrobromic acid, 30mL 95% ethanol, cooled to -5~0℃, sodium nitrite aqueous solution (1.5g dissolved in 10mL water) was slowly added dropwise over 1 hour, and the reaction was maintained at this temperature for 2 hours. The mixture was allowed to stand for phase separation, extracted with dichloromethane (50mL × 2), and concentrated. Yield 52%, purity 83%, with a large amount of reddish-brown fumes.

[0047] Of course, the above description is not intended to limit the present invention, and the present invention is not limited to the examples given above. Any changes, modifications, additions or substitutions made by those skilled in the art within the scope of the present invention should also fall within the protection scope of the present invention.

Claims

1. A method for synthesizing 6-bromopenicillinic acid based on continuous flow microreaction, characterized in that, Includes the following steps: S1. Dissolve 6-aminopenicillanic acid in ethanol and stir until clear to obtain liquid A; S2. Prepare an aqueous solution by reacting sodium nitrite with hydrobromic acid to obtain liquid B; S3. After mixing liquid A and liquid B in the first micro mixer, the mixture is introduced into the micro-reaction pipeline for diazotization and bromination reactions. During the reaction, inert gas is introduced into the pipeline for online purging to obtain the reaction mixture outflow. S4. The reaction mixture effluent is mixed with dichloromethane in a second micro mixer. The dichloromethane is used to extract the reaction mixture effluent online to obtain a mixture. The mixture enters a membrane phase separator to continuously separate the organic phase and the aqueous phase. The organic phase is collected and concentrated to obtain 6-bromopenicillinic acid.

2. The method for synthesizing 6-bromopenicillinic acid based on continuous flow microreaction according to claim 1, characterized in that, The concentration of 6-aminopenicillanic acid in ethanol is 0.3-0.55 mol / L; The ethanol is 95% ethanol.

3. The method for synthesizing 6-bromopenicillinic acid based on continuous flow microreaction according to claim 1, characterized in that, The molar ratio of sodium nitrite to hydrobromic acid is 1:1.24~1.

25.

4. The method for synthesizing 6-bromopenicillinic acid based on continuous flow microreaction according to claim 1, characterized in that, The flow rate of liquid A in S3 is 5-7 mL / min; The flow rate of liquid B in S3 is 4-8 mL / min.

5. The method for synthesizing 6-bromopenicillinic acid based on continuous flow microreaction according to claim 1, characterized in that, The first micro mixer is either a micro-sieve mixer or a Y-type microchannel mixer; The second micro mixer is any one of a T-type three-way mixer, a built-in low-shear static mixer, or a cross-shaped microchannel mixer.

6. The method for synthesizing 6-bromopenicillinic acid based on continuous flow microreaction according to claim 1, characterized in that, The inert gas is nitrogen, and the nitrogen purging rate is 10-30 mL / min; The online extraction rate of dichloromethane is 12-22 mL / min.

7. The method for synthesizing 6-bromopenicillinic acid based on continuous flow microreaction according to claim 1, characterized in that, The back pressure valve has a reaction pressure of 0.3-0.4 MPa.

8. The method for synthesizing 6-bromopenicillinic acid based on continuous flow microreaction according to claim 1, characterized in that, The membrane phase separator is either a polytetrafluoroethylene hollow fiber membrane or a ceramic hollow fiber membrane.

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