Preparation method of sarafloxacin hydrochloride

Abstract

The invention relates to the technical field of medicine preparation, and discloses a sarafloxacin hydrochloride preparation method, which comprises: preparing a reaction system from salacarboxylic acid, piperazine and a redox medium; applying a pulsed electric field with defined frequency and voltage and ultrasonic irradiation; regulating the surface tension of reaction liquid to form a bubble microreactor; carrying out distributed reaction through a bubble microenvironment carrier; and finally separating and purifying to obtain a high-purity product. According to the method, the purposes of shortening the reaction time and reducing the energy consumption are achieved, the product purity is high, the batch consistency is remarkably improved, and a new way is provided for green and efficient preparation of quinolones.

Description

Technical Field

[0001] The present invention relates to the technical field of drug preparation, and more particularly to a method for preparing sarafloxacin hydrochloride. Background Art

[0002] Sarafloxacin hydrochloride, a broad-spectrum quinolone antibacterial drug, has important clinical applications in the treatment of bacterial infections. The traditional preparation process for sarafloxacin hydrochloride is primarily based on the condensation reaction of sarafloxacin carboxylic acid with piperazine, followed by a salt-forming reaction to obtain the final product.

[0003] However, the existing technology has the following obvious shortcomings: the traditional preparation process requires reaction at high temperature conditions of 120-124°C for more than 1 hour, with high energy consumption and low production efficiency; the conventional method uses catalysts such as aluminum chloride, which is not only difficult to recycle, but also brings serious environmental pollution problems; the product purity in the traditional process fluctuates greatly, and batch consistency control is difficult, which makes it difficult to meet the quality requirements of pharmaceutical production; although electrochemical-assisted synthesis can achieve reaction at room temperature, there is a problem of poor reaction uniformity, resulting in unstable product quality; when ultrasound and electrochemistry are used in conjunction, the cavitation bubbles generated by ultrasound are unevenly distributed, forming different activation areas, further exacerbating the quality fluctuations between product batches; in existing electrochemical synthesis, the reaction is mainly limited to the electrode surface, and a large number of reactants cannot efficiently contact the reaction area, limiting the reaction efficiency.

[0004] Therefore, it is urgent to develop a green, efficient and stable method for preparing sarafloxacin hydrochloride to solve the above technical problems. Summary of the Invention

[0005] In order to solve the above technical problems, the present invention provides a method for preparing sarafloxacin hydrochloride, comprising the following steps:

[0006] Step 1: Prepare a reaction system containing carboxylic acid, piperazine, a redox mediator, and a surfactant, and adjust the surface tension of the reaction liquid to 30-35 mN / m;

[0007] Step 2: Transfer the reaction system to a reaction apparatus and set the reaction temperature to 30±2°C;

[0008] Step 3: Start the ultrasonic device to generate cavitation bubbles in the reaction system. A stable liquid film layer is formed on the surface of the bubbles as a reaction microenvironment carrier.

[0009] Step 4: applying a pulsed electric field, which generates a polarization effect at the bubble-liquid film interface, causing a condensation reaction between salcarboxylic acid and piperazine in the bubble microreactor;

[0010] Step 5: After the reaction is completed, hydrochloric acid is added to the reaction product to perform a salt-forming reaction, and sarafloxacin hydrochloride is obtained through separation and purification.

[0011] Preferably, the redox medium is an electron transfer system composed of potassium ferrocyanide and sodium ferrocyanide.

[0012] Preferably, in step 1, the components of the reaction system are prepared according to the following weight ratio: 1000 parts of salad carboxylic acid, 250 parts of piperazine, 120 parts of potassium ferrocyanide, 80 parts of sodium ferrocyanide, 15-25 parts of surfactant, 3000 parts of water, and 200-300 parts of auxiliary organic solvent.

[0013] Preferably, in step 1, the components of the reaction system are prepared according to the following weight ratio: 1000 parts of salad carboxylic acid, 250 parts of piperazine, 120 parts of potassium ferrocyanide, 80 parts of sodium ferrocyanide, 20 parts of surfactant, 3000 parts of water, and 250 parts of auxiliary organic solvent.

[0014] Preferably, in step 3, the frequency of the ultrasonic wave is 40 kHz, the power density is 0.5 W / cm³, and an intermittent irradiation mode is adopted, with 10 seconds on and 2 seconds off.

[0015] Preferably: in step 4, the waveform of the pulsed electric field is a square wave, the frequency is 50-150 Hz, the pulse width is 1-5 ms, the current density is 50-150 mA / cm², and the on-off ratio is 3:1.

[0016] Preferably, the reaction time in step 4 is 10 minutes.

[0017] Preferably, in step 5, the pH value of the reaction solution is adjusted to 3.5-4.0 by adding 36% hydrochloric acid solution, and the reaction is carried out at 20-25° C. for 20 minutes to perform a salt-forming reaction.

[0018] Preferably: in step 5, the separation and purification process includes:

[0019] Isolate the crude product by centrifugation or filtration;

[0020] Wash the crude product with ice-cold purified water;

[0021] The crude product was recrystallized at a ratio of crude product to water = 1:3;

[0022] The recrystallization solution was cooled to 5°C, allowed to stand for 4 hours and filtered to obtain the product;

[0023] The product was vacuum dried at 50° C. for 12 hours to obtain the finished product sarafloxacin hydrochloride.

[0024] Preferably, 0.3% by weight of activated carbon is added to the crude product during the recrystallization process for decolorization.

[0025] The beneficial effects of the present invention are as follows: the preparation method proposed in the present invention improves the reaction efficiency compared with the traditional process, and compared with the traditional electrochemical-assisted synthesis method, the reaction rate is increased by 3 times, and a higher space-time yield is achieved; the purity of the product prepared by the present invention is stable at above 99.9%, which is higher than the purity level that can be achieved by the traditional method; the impurity content of the product prepared by the present invention is significantly reduced, and the total amount of related impurities does not exceed 0.1%.

[0026] Compared with traditional high-temperature reactions (120-124°C), this method is carried out at around 30°C, reducing energy consumption by more than 60%. The triple synergistic system enables the reaction to proceed efficiently at lower energy input, improving electron utilization efficiency. The bubble microreactor technology makes the energy distribution in the reaction system more uniform, reducing energy waste.

[0027] There is no need to use difficult-to-recycle catalysts such as aluminum trichloride, which avoids catalyst recovery and treatment problems. The reaction conditions are mild, side reactions are reduced, atom economy is improved, the redox medium can be recycled and reused, and waste emissions are reduced.

[0028] The bubble microreactor system reduces the sensitivity of the reaction to fluctuations in external conditions and enhances process robustness. The dispersed reaction area means that the reaction is no longer limited to the electrode surface, avoiding the limitation of the electrode area on the reaction scale and making it easy to scale up. The wide operating parameter window makes control during industrial production easier. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 is the relationship between reaction time and conversion rate of different synthesis methods of the present invention;

[0030] Figure 2 This is a comparison chart of purity fluctuations between batches using different synthesis methods of the present invention;

[0031] Figure 3 It is a comparison diagram of energy consumption composition of different synthesis methods of the present invention;

[0032] Figure 4 This is a comparison chart of energy consumption per unit time and energy efficiency of different synthesis methods of the present invention;

[0033] Figure 5 is a comparison chart of E factors and atom utilization rates of different synthesis methods of the present invention;

[0034] Figure 6 Graph showing the effect of process parameter fluctuations on product purity in the present invention;

[0035] Figure 7 Graph showing the effect of process parameter fluctuations on product yield in the present invention;

[0036] Figure 8This is a trend diagram of product quality and equipment performance changes for 10 consecutive batches of production according to the present invention. DETAILED DESCRIPTION

[0037] The subject matter described herein will now be discussed with reference to example embodiments. It should be understood that these embodiments are discussed solely to enable those skilled in the art to better understand and implement the subject matter described herein, and that the functions and arrangements of the elements discussed may be varied without departing from the scope of this specification. Various examples may omit, substitute, or add various processes or components as needed. Furthermore, features described in some examples may be combined in other examples.

[0038] Example 1

[0039] In this embodiment 1, a method for preparing sarafloxacin hydrochloride is proposed, comprising the following steps:

[0040] Step 1: Prepare a reaction system containing carboxylic acid, piperazine, a redox mediator, and a surfactant, and adjust the surface tension of the reaction liquid to 30 mN / m;

[0041] The redox mediator is an electron transfer system composed of potassium ferrocyanide and sodium ferrocyanide;

[0042] The components of the reaction system are prepared according to the following weight ratio: 1000 parts of salad carboxylic acid, 250 parts of piperazine, 120 parts of potassium ferrocyanide, 80 parts of sodium ferrocyanide, 15 parts of surfactant regulator, 3000 parts of water, and 200 parts of auxiliary organic solvent.

[0043] Step 2: Transfer the reaction system to a reaction apparatus and set the reaction temperature to 28°C.

[0044] Step 3: Start the ultrasonic device to generate cavitation bubbles in the reaction system. A stable liquid film layer is formed on the surface of the bubbles as a reaction microenvironment carrier.

[0045] The frequency of the ultrasound was 40 kHz, the power density was 0.5 W / cm³, and an intermittent irradiation mode was used, with 10 seconds on and 2 seconds off.

[0046] Step 4: applying a pulsed electric field to generate a polarization effect at the bubble-liquid film interface, causing a condensation reaction between salcarboxylic acid and piperazine in the bubble microreactor;

[0047] The waveform of the pulsed electric field is a square wave with a frequency of 50 Hz, a pulse width of 1 ms, a current density of 50 mA / cm², and an on / off ratio of 3:1.

[0048] The reaction time was 10 minutes.

[0049] Step 5: After the reaction is completed, hydrochloric acid is added to the reaction product to perform a salt-forming reaction, and sarafloxacin hydrochloride is obtained through separation and purification;

[0050] The pH value of the reaction solution was adjusted to 3.5 by adding 36% hydrochloric acid solution, and the reaction was carried out at 20° C. for 20 minutes to perform a salt-forming reaction.

[0051] The separation and purification process includes:

[0052] Isolate the crude product by centrifugation or filtration;

[0053] Wash the crude product with ice-cold purified water;

[0054] The crude product was recrystallized at a ratio of crude product to water = 1:3;

[0055] The recrystallization solution was cooled to 5°C, allowed to stand for 4 hours and filtered to obtain the product;

[0056] The product was vacuum dried at 50° C. for 12 hours to obtain the finished product sarafloxacin hydrochloride.

[0057] During the recrystallization process, 0.3% of the weight of the crude product was added with activated carbon for decolorization.

[0058] Example 2

[0059] This embodiment differs from embodiment 1 in that:

[0060] In step 1: preparing a reaction system comprising carboxylic acid, piperazine, a redox mediator, and a surfactant, and adjusting the surface tension of the reaction liquid to 32 mN / m;

[0061] The components of the reaction system are prepared according to the following weight ratio: 1000 parts of salad carboxylic acid, 250 parts of piperazine, 120 parts of potassium ferrocyanide, 80 parts of sodium ferrocyanide, 20 parts of surfactant regulator, 3000 parts of water, and 250 parts of auxiliary organic solvent.

[0062] In step 2: the reaction system was transferred to a reaction apparatus and the reaction temperature was set to 30°C.

[0063] In step 4: the waveform of the pulsed electric field is a square wave, the frequency is 100 Hz, the pulse width is 3 ms, the current density is 100 mA / cm², and the on / off ratio is 3:1.

[0064] In step 5: the pH value of the reaction solution is adjusted to 3.8 by adding 36% hydrochloric acid solution, and the reaction is carried out at 22° C. for 20 minutes to perform a salt-forming reaction.

[0065] Example 3

[0066] This embodiment differs from embodiment 1 in that:

[0067] In step 1: preparing a reaction system comprising carboxylic acid, piperazine, a redox mediator, and a surfactant, and adjusting the surface tension of the reaction liquid to 35 mN / m;

[0068] The components of the reaction system are prepared according to the following weight ratio: 1000 parts of salad carboxylic acid, 250 parts of piperazine, 120 parts of potassium ferrocyanide, 80 parts of sodium ferrocyanide, 25 parts of surfactant regulator, 3000 parts of water, and 300 parts of auxiliary organic solvent.

[0069] In step 2: the reaction system was transferred to a reaction apparatus and the reaction temperature was set to 32°C.

[0070] In step 4: the waveform of the pulsed electric field is a square wave, the frequency is 150 Hz, the pulse width is 5 ms, the current density is 150 mA / cm², and the on / off ratio is 3:1.

[0071] In step 5: the pH value of the reaction solution is adjusted to 4 by adding 36% hydrochloric acid solution, and the reaction is carried out at 25° C. for 20 minutes to perform a salt-forming reaction.

[0072] Example 4

[0073] In this embodiment, a method for preparing sarafloxacin hydrochloride is proposed, comprising the following steps:

[0074] 1. Preparation of reaction raw materials

[0075] This step involves the preparation and pretreatment of the raw materials required for the reaction to create suitable conditions for subsequent reactions:

[0076] Raw material selection:

[0077] Main reaction materials: carboxylic acid, piperazine and hydrochloric acid;

[0078] Redox mediator: Potassium ferrocyanide / sodium ferrocyanide system is used as electron transfer reagent;

[0079] Surfactant regulator: used to regulate the surface tension of the reaction liquid;

[0080] Solvent: a mixture of water and a small amount of organic solvent;

[0081] Raw material purity requirements:

[0082] Salicylic acid: purity ≥98.5%, particle size ≤100 mesh;

[0083] Piperazine: purity ≥99.0%;

[0084] Redox media: analytical grade;

[0085] Surfactant modifier: pharmaceutical grade.

[0086] Raw material pretreatment:

[0087] Salad carboxylic acid: vacuum drying at 45°C for 24 hours to remove residual moisture to prevent moisture from affecting the reaction;

[0088] Piperazine: Store in a dry environment at room temperature;

[0089] Redox medium: Prepare into aqueous solution before use;

[0090] This step is a conventional pretreatment process, which aims to ensure the quality stability of the reaction raw materials and provide a basis for subsequent reaction steps.

[0091] 2. Preparation of reaction system

[0092] This step defines the recipe and preparation method to form a reaction system that is conducive to the generation of bubble microreactors:

[0093] Formula composition (based on 1000g of salad carboxylic acid):

[0094] Salad carboxylic acid: 1000 g;

[0095] Piperazine: 250 g (the molar ratio of salacarboxylic acid to piperazine is 1:1.5);

[0096] Potassium ferrocyanide: 120 g;

[0097] Sodium ferrocyanide: 80 g;

[0098] Surfactant: 20 g (adjust the amount according to the required surface tension);

[0099] It is preferred to use non-ionic surfactants, such as polysorbate series (Tween 20, Tween 80) and polyoxyethylene fatty alcohol ethers (Brij series); amphoteric surfactants, such as lauryl betaine, can also be used in an amount of 15-20 grams; for the more insoluble salad carboxylic acid, a small amount of anionic surfactant sodium dodecyl sulfate (SDS) can be added in an amount of 5-10 grams.

[0100] Water: 3000g;

[0101] Auxiliary organic solvent: 250 g;

[0102] It is preferred to use a low-toxic polar organic solvent, such as ethanol (200-250 g), propylene glycol (220-280 g), or acetone (200-240 g). A single solvent or a mixed solvent can be selected depending on the solubility of the salacarboxylic acid. A typical ratio of the mixed solvent is ethanol:propylene glycol = 2:1 or ethanol:acetone = 3:1.

[0103] Preparation steps:

[0104] First, potassium ferrocyanide and sodium ferrocyanide are dissolved in water to form a redox medium solution;

[0105] Next, add the surfactant and stir evenly;

[0106] Then, the salcarboxylic acid is dissolved in an auxiliary organic solvent to prepare a solution;

[0107] Finally, the salad carboxylic acid solution was mixed with the redox medium solution at 30°C, and piperazine was added and stirred for 10 minutes to form a uniform reaction system.

[0108] Surface tension control:

[0109] By adjusting the type and amount of surfactant, the surface tension of the reaction liquid was controlled within the range of 32 mN / m.

[0110] Experiments have shown that this surface tension range is most conducive to the formation of a stable liquid film layer by bubbles generated by ultrasound;

[0111] The surface tension is measured by the ring method and adjusted in real time to ensure its stability;

[0112] Monitor the surface tension every 2 minutes using an automatic surface tensiometer. If the surface tension deviates from the target range, adjust it by adding a small amount of surfactant (if the surface tension is too high) or pure water (if the surface tension is too low).

[0113] The surface tension control technique used in this step is key to realizing the bubble microreactor. It enables a stable liquid film to form on the surface of the ultrasonically generated bubbles, laying the foundation for the subsequent formation of the bubble microreactor. Compared to traditional electrochemical reaction systems, this step creates a more uniform microenvironment for the reaction by manipulating the physical properties of the liquid.

[0114] 3. Construction and operation of triple synergistic reaction system

[0115] This step involves the construction and operation of a reaction system involving the synergistic effects of pulsed electric field, ultrasound, and redox mediator:

[0116] Reaction device construction:

[0117] Reaction vessel: Teflon-lined stainless steel reactor, volume 5 L;

[0118] Electrode system: platinum-titanium mesh electrode is used as the working electrode, with an area of 500 cm², and nickel-based alloy is used as the counter electrode;

[0119] Working electrode: platinum-titanium mesh electrode, area 500 cm², mesh density 80 mesh / inch, platinum layer thickness 2-5 μm;

[0120] Counter electrode: Ni-Cr-Mo nickel-based alloy (Hastelloy C-276, nickel content 57%, chromium content 15.5%, molybdenum content 16%) plate, thickness 2mm;

[0121] Electrode spacing: The distance between the working electrode and the counter electrode should be kept at 20-30 mm to ensure uniform electric field distribution;

[0122] Electrode arrangement: The working electrode is placed at the center of the bottom of the reactor, and the counter electrode is placed parallel to it above it.

[0123] Ultrasonic generator: frequency adjustable ultrasonic generator (20-60kHz), power density can be controlled at 0.2-1.0W / cm³;

[0124] Temperature control system: water bath circulation temperature control system, temperature control accuracy ±0.5℃;

[0125] Pulsed electric field parameters:

[0126] Pulse electric field waveform: square wave;

[0127] Pulse frequency: 50-150Hz, preferably 80Hz;

[0128] Pulse width: 1-5ms, preferably 2ms;

[0129] Voltage: 3-10V, adjusted according to the reaction scale;

[0130] Current density: 50-150 mA / cm², preferably 100 mA / cm²;

[0131] On / off ratio: 3:1;

[0132] The selection of pulse electric field parameters is based on the following:

[0133] 1) The frequency range of 50-150 Hz can match the molecular relaxation time of the reaction system and promote effective electron transfer; below 50 Hz, the electron transfer efficiency decreases, and above 150 Hz, it is easy to cause excessive polarization of the electrode;

[0134] 2) The pulse width of 1-5ms ensures that a sufficient electric double layer can be formed on the electrode surface within each pulse cycle without causing redox side reactions;

[0135] 3) When the current density is 100mA / cm², the electric field has the most significant polarization effect on the bubble surface. Specifically, the charge density at the gas-liquid interface reaches more than 1.5 times that of the traditional solid-liquid interface.

[0136] Unlike conventional constant electric fields, pulsed electric fields can periodically activate reactants, preventing electrode surface passivation. Furthermore, pulsed electric fields can polarize the bubble interface generated by ultrasound, creating localized high-field regions on the bubble surface, further improving reaction efficiency.

[0137] Ultrasonic parameters:

[0138] Ultrasonic frequency: 40kHz;

[0139] Ultrasonic power density: 0.5W / cm³;

[0140] Ultrasonic irradiation mode: intermittent, 10 seconds on, 2 seconds off;

[0141] The setting of ultrasonic parameters is also a key innovation. By controlling the frequency and power density of the ultrasound, cavitation bubbles of uniform size can be generated. The intermittent irradiation mode enables the bubbles to be generated and collapsed periodically, forming a dynamically balanced bubble microreactor system.

[0142] Bubble microreactor formation and control:

[0143] Bubble formation principle: Ultrasonic waves produce cavitation effect in liquid, forming micron-sized bubbles;

[0144] Bubble stabilization: Due to surface tension regulation, a stable liquid film layer is formed on the bubble surface;

[0145] Enrichment of reactants in the bubble liquid membrane: Salicylic acid and redox mediators are preferentially distributed in the bubble liquid membrane;

[0146] Gas-liquid interface polarization effect: The pulsed electric field generates a local high electric field area at the bubble interface, promoting the activation of reactants;

[0147] Physicochemical mechanism of gas-liquid interface polarization effect:

[0148] 1) Due to the interfacial tension, the bubble surface forms a highly ordered molecular arrangement, and the molecular orientation at the interface is highly consistent;

[0149] 2) When a pulsed electric field acts on the gas-liquid interface, the molecular dipole moments at the interface undergo cooperative orientation.

[0150] 3) According to electrical principles, the bubble interface becomes an electric field enhancement area, and the local electric field strength increases by 3-5 times;

[0151] 4) The enhanced electric field promotes rapid electron transfer from the redox mediator to the reactants;

[0152] 5) This polarization effect has been confirmed by in-situ potential measurements and computational simulations, with the local electric field strength reaching 4.2 times the original electric field;

[0153] 6) Experiments have shown that the electron transfer rate constant at the gas-liquid interface is about 3.6 times higher than that in the bulk region.

[0154] Bubble microreactor technology transforms ultrasonically generated bubbles, a disruptive factor in traditional electrochemical reactions, into a microenvironmental carrier for the reaction. This allows the reaction to proceed simultaneously across the bubble interface, rather than being confined to the electrode surface. This dispersed reaction mode significantly improves reaction uniformity, resolving the problem of uneven reactions in traditional electrochemical synthesis.

[0155] Reaction steps:

[0156] Triple synergistic mechanism:

[0157] 1) Timing coordination relationship:

[0158] The pulsed electric field and the ultrasonic intermittent mode are precisely synchronized, and the ultrasonic wave is turned on and the pulsed electric field is applied at the same time;

[0159] During each ultrasonic cycle (10 seconds on + 2 seconds off), the pulsed electric field always maintains operation

[0160] The redox mediator continuously promotes the electron transfer process throughout the entire process;

[0161] 2) Synergistic enhancement mechanism:

[0162] Ultrasonic waves → pulsed electric field: The bubbles generated by ultrasonic waves increase the gas-liquid interface area and amplify the polarization effect of the pulsed electric field;

[0163] Pulsed electric field → ultrasonic wave: Pulsed electric field promotes uniform distribution of bubbles in the solution and prevents merging;

[0164] Pulsed electric field → redox mediator: The pulsed electric field accelerates the activation and transfer of electrons in the redox mediator;

[0165] Redox mediator → reaction efficiency: Redox mediator transfers electrons from the electrode to the reaction area far away from the electrode, expanding the reaction range;

[0166] Ultrasonic wave → mass transfer efficiency: The microfluidic disturbance generated by ultrasound significantly increases the mass transfer rate of reactants (by about 5 times).

[0167] Reaction steps:

[0168] First, the prepared reaction system is transferred into the reactor;

[0169] Start the temperature control system and control the reaction temperature at 30°C;

[0170] Turn on the ultrasonic device and adjust it to the above parameters to produce evenly distributed bubbles;

[0171] Start the pulsed electric field and adjust it to the above parameters;

[0172] Maintain the reaction for 10 minutes;

[0173] Turn off the pulsed electric field and ultrasonic devices;

[0174] The reaction solution was transferred to the next step of salt formation reaction.

[0175] The construction and operation of the triple synergistic reaction system in this step is the technical core of the present invention. Through the synergistic effect of pulsed electric field, ultrasound and redox mediator, combined with bubble microreactor technology, the efficient and uniform synthesis reaction of sarafloxacin hydrochloride is achieved.

[0176] 4. Salt formation reaction and product separation and purification

[0177] This step is a relatively conventional operation, but has also been appropriately optimized according to the characteristics of the present invention:

[0178] Salt-forming reaction:

[0179] Transferring the reaction solution to a salt-forming reaction vessel;

[0180] Slowly add 36% hydrochloric acid solution to a pH of 3.8, controlling the addition rate to avoid excessive local acidity;

[0181] The reaction temperature is controlled at 20-25°C;

[0182] The reaction was stirred for 20 minutes to ensure that the salt formation reaction was complete;

[0183] Salt formation reaction principle and parameter selection basis:

[0184] 1) The salt formation reaction is a protonation reaction, where the piperazine ring nitrogen atom (pKa approximately 5.7-6.2) on the sarafloxacin molecule combines with the hydrogen ion in hydrochloric acid to form a salt;

[0185] 2) Reasons for controlling pH value within the range of 3.5-4.0:

[0186] When the RI is higher than 4.0, some products are not completely protonated, which reduces the yield;

[0187] When the value is lower than 3.5, excessive acidity leads to product hydrolysis or increased side reactions;

[0188] Experiments show that the product purity and yield are optimal and the impurity content is lowest within the pH range of 3.8±0.2.

[0189] 3) Reasons for controlling the temperature at 20-25℃:

[0190] Too low a temperature (<15°C) will result in a lower reaction rate and require a longer reaction time;

[0191] Too high a temperature (>30°C) may promote side reactions and increase impurity content;

[0192] The solubility of sarafloxacin hydrochloride in this temperature range is low, which is conducive to crystallization separation and purification.

[0193] 4) Stirring speed and reaction time selection basis:

[0194] Stirring speed 200-300 rpm to ensure uniform mixing of the reaction without introducing too many bubbles;

[0195] A reaction time of 20 minutes was determined by kinetic studies to indicate that the protonation reaction is >99.5% complete within this time.

[0196] Product separation:

[0197] Initial separation: Separate the solid crude product by centrifugation (3000-5000 rpm, 10 minutes) or vacuum filtration (pore size 0.45 μm filter membrane);

[0198] Washing: Wash the product twice with ice-cold purified water (5-10°C), using twice the weight of the product each time;

[0199] The first washing: mainly removes residual hydrochloric acid and water-soluble inorganic salts;

[0200] Second washing: mainly removes trace organic impurities and surfactant residues;

[0201] Secondary separation: Centrifuge or filter again to collect the solid product.

[0202] Product purification:

[0203] Recrystallization: Dissolve the crude product in water (crude product: water = 1:3), heat to 60°C, and stir until completely dissolved;

[0204] The reason for choosing water as the recrystallization solvent is that sarafloxacin hydrochloride has high solubility in hot water, low solubility in cold water, and good temperature sensitivity; the temperature of 60°C is selected: below 70°C to avoid thermal degradation of the product, and above 50°C to ensure complete dissolution.

[0205] Add activated carbon (0.3% of the weight of the crude product) and stir for 10 minutes;

[0206] Activated carbon specifications: pharmaceutical grade granular activated carbon, surface area >800m² / g, pore size distribution concentrated in 2-5nm;

[0207] Basis for activated carbon dosage: less than 0.2% will result in poor decolorization effect, while more than 0.5% will lead to increased adsorption loss of the product;

[0208] Use diatomaceous earth (0.2%) as a filter aid and hot filtration to remove the activated carbon; cool the filtrate to 5°C at a rate of 1-2°C / min and let it stand for 4 hours to crystallize; slow cooling can obtain larger and higher-purity crystals; 4 hours is the optimal crystallization time; less than 3 hours will result in insufficient crystal growth, and more than 6 hours will not significantly improve the yield; collect the crystals by filtration and wash with ice-cold purified water (5°C, 0.5 times the weight of the product).

[0209] Drying and packaging:

[0210] The wet product was dried in a vacuum drying oven at 50°C for 12 hours;

[0211] crushing and packaging to obtain the finished product sarafloxacin hydrochloride;

[0212] This step is based on conventional separation and purification technology, and by optimizing operating parameters, the product quality is more stable and the yield is higher.

[0213] Experimental verification

[0214] Experiment 1: Reaction efficiency experiment

[0215] 1.1 Experimental Purpose

[0216] The advantages of the triple synergistic reaction system combined with the bubble microreactor technology in the present invention in terms of reaction efficiency were verified, including shortened reaction time, increased reaction rate and increased conversion rate.

[0217] 1.2 Experimental Methods

[0218] 1.2.1 Control group setting

[0219] Control group A: traditional high-temperature catalytic method (120-124°C, aluminum chloride catalysis);

[0220] Control group B: conventional electrochemical-assisted synthesis method (constant electric field, no ultrasound and specific redox mediator);

[0221] Control group C: electrochemical-ultrasonic synergistic method (bubble-free microreactor technology, without redox mediator);

[0222] Experimental group: the triple synergistic reaction system of the present invention combined with the bubble microreactor technology.

[0223] 1.2.2 Experimental procedures

[0224] The reaction was carried out in the control group and the experimental group according to the same raw material ratio (salacarboxylic acid 1000 g, piperazine at a molar ratio of 1:1.5);

[0225] Control group A was carried out according to the traditional high-temperature catalytic process, with a reaction temperature of 120°C and aluminum chloride as the catalyst;

[0226] Control group B used a constant electric field (6V, 100mA / cm²) and reacted at room temperature;

[0227] Control group C used a constant electric field (6 V, 100 mA / cm²) combined with ultrasound (40 kHz, continuous mode);

[0228] The experimental group used a pulsed electric field (80 Hz, 2 ms pulse width, 100 mA / cm²), intermittent ultrasound (40 kHz, 10 seconds on, 2 seconds off), and a redox mediator (potassium ferricyanide / sodium ferricyanide system) according to the method of the present invention;

[0229] During the reaction, samples were taken at designated intervals and the reaction conversion rate was determined by high performance liquid chromatography (HPLC);

[0230] The reaction time, the time required to reach 90% conversion, the time required to reach 95% conversion, and the final conversion were recorded.

[0231] 1.3 Experimental Results

[0232] 1.3.1 Comparison of reaction time and conversion rate is shown in the following table:

[0233]

[0234] Note: The experimental group completed the reaction within 10 minutes and did not need to react for 1 hour.

[0235] like Figure 1 Shown: The relationship between reaction time and conversion rate of different synthesis methods.

[0236] 1.4 Results Analysis

[0237] Improved reaction rate: The method of the present invention significantly shortens the reaction time. It only takes 5 minutes to reach a 90% conversion rate, while the traditional method takes 42 minutes; it only takes 8 minutes to reach a 95% conversion rate, while the traditional method takes 57 minutes.

[0238] The reaction completion time is shortened: the method of the present invention can complete the reaction and reach the highest conversion rate within 10 minutes, while the traditional method requires more than 1 hour.

[0239] Improved final conversion rate: The final conversion rate of the method of the present invention reaches 97.8%, which is higher than that of the traditional high-temperature catalytic method (97.1%), the conventional electrochemical-assisted synthesis method (96.8%) and the electrochemical-ultrasonic synergistic method (97.2%).

[0240] The acceleration effect in the initial stage of the reaction is significant: from the reaction conversion rate curve, it can be seen that the conversion rate of the method of the present invention is most significantly improved within the first 5 minutes of the reaction, reflecting the significant promoting effect of the triple synergistic system and bubble microreactor technology on reaction activation.

[0241] In summary, this experiment verified the technical effect of the present invention in terms of reaction efficiency, and proved that the triple synergistic reaction system combined with the bubble microreactor technology can significantly shorten the reaction time and improve the reaction rate and conversion rate.

[0242] Experiment 2: Product quality and batch consistency experiment

[0243] 2.1 Experimental Purpose

[0244] The advantages of sarafloxacin hydrochloride synthesized by the method of the present invention in terms of product purity, batch consistency and impurity control were verified.

[0245] 2.2 Experimental methods

[0246] 2.2.1 Experimental Design

[0247] Ten batches of sarafloxacin hydrochloride were produced continuously using a traditional high-temperature catalytic method, a conventional electrochemical-assisted synthesis method, an electrochemical-ultrasonic synergistic method, and the method of the present invention, respectively.

[0248] The sample size of each batch was 0.5 kg of salad carboxylic acid as the starting amount, and the synthesis was carried out according to the corresponding process;

[0249] After each batch of products is processed by standard purification process, the product purity and main impurity content are determined.

[0250] 2.2.2 Analytical methods

[0251] Product purity determination: using high performance liquid chromatography (HPLC);

[0252] Chromatographic column: C18 reverse phase column (250 mm × 4.6 mm, 5 μm);

[0253] Mobile phase: acetonitrile-0.1% phosphoric acid solution (22:78);

[0254] Detection wavelength: 280nm;

[0255] Column temperature: 30°C;

[0256] Flow rate: 1.0 mL / min;

[0257] Injection volume: 10 μL;

[0258] Impurity analysis: The HPLC area normalization method was used to determine the content of each impurity;

[0259] Single impurity limit: ≤0.1%;

[0260] Total impurity limit: ≤0.5%.

[0261] 2.2.3 Batch consistency evaluation

[0262] The consistency between batches was evaluated by calculating the mean, standard deviation and relative standard deviation (RSD) of the purity of each batch of products.

[0263] 2.3 Experimental Results

[0264] 2.3.1 Comparison of purity between batches of products produced by different synthesis methods is shown in the following table:

[0265]

[0266] 2.3.2 Comparison of impurity analysis results is shown in the following table:

[0267]

[0268] like Figure 2 The figure shows a comparison of purity fluctuations between batches using different synthesis methods.

[0269] 2.4 Results Analysis

[0270] Improved product purity: The average purity of sarafloxacin hydrochloride prepared by the method of the present invention reaches 99.92%, which is significantly higher than the traditional high-temperature catalytic method (99.04%), the conventional electrochemical-assisted synthesis method (99.21%), and the electrochemical-ultrasonic synergistic method (99.45%).

[0271] Significantly improved batch consistency: A comparison of relative standard deviations (RSDs) reveals that the method's RSD is only 0.02%, significantly lower than the traditional high-temperature catalytic method (0.26%), conventional electrochemical-assisted synthesis (0.16%), and electrochemical-ultrasonic synergistic methods (0.13%). The maximum inter-batch fluctuation range has been reduced from ±0.39% for traditional methods to ±0.07%, achieving the desired technical results.

[0272] The impurity control effect is significant: the total impurity content of the product prepared by the method of the present invention is only 0.08%, which is much lower than that of other methods. In particular, the content of related impurity A is reduced from 0.35% in the traditional method to 0.02%, a reduction of 94%.

[0273] Batch-to-batch stability: From the inter-batch purity fluctuation graph, it can be seen intuitively that the purity of the product produced by the method of the present invention fluctuates very little between batches, and the curve is basically horizontal, indicating that the robustness and repeatability of the process are significantly improved.

[0274] The experimental results demonstrate that the triple synergistic reaction system of the present invention, combined with bubble microreactor technology, can significantly increase product purity, reduce impurity levels, and significantly improve batch-to-batch consistency, achieving a higher level of product quality. Bubble microreactor technology, by providing a uniform reaction microenvironment, addresses the reaction heterogeneity issues inherent in traditional methods and is a key factor in improving product quality and batch consistency.

[0275] Experiment 3: Energy consumption test experiment

[0276] 3.1 Experimental Purpose

[0277] Verify the advantages of the method of the present invention in terms of energy consumption and quantitatively evaluate the energy-saving effect compared with traditional methods.

[0278] 3.2 Experimental methods

[0279] 3.2.1 Experimental Design

[0280] The energy consumption of the conventional high-temperature catalytic method, conventional electrochemical-assisted synthesis method, electrochemical-ultrasonic synergistic method and the method of the present invention when producing the same amount of sarafloxacin hydrochloride (calculated based on 1 kg of sarafloxacin hydrochloride raw material) was compared.

[0281] Energy consumption measurements include heating energy consumption, electric field energy consumption, ultrasonic energy consumption and stirring energy consumption.

[0282] Each method was tested three times and the average value was taken.

[0283] 3.2.2 Energy consumption measurement method

[0284] Power consumption: Use a precision power meter to measure the power consumption of the entire reaction process, including the total power consumption (kWh) of heating, stirring, electric field, and ultrasonic equipment;

[0285] Heat energy consumption: Calculate the heat transfer by measuring the temperature change and flow rate of the heating medium (such as oil bath or water bath);

[0286] Time factor: record the reaction time required to achieve the same conversion rate and calculate the energy consumption per unit time (kW);

[0287] Total energy consumption index: calculate the energy consumption per unit product (kWh / kg product).

[0288] 3.2.3 Test conditions

[0289] Reaction scale: 1 kg of salcarboxylic acid was used as the starting material;

[0290] Reaction conditions: Each method was performed according to its own optimized conditions;

[0291] End point judgment: the reaction is considered complete when the conversion rate reaches 95% or above;

[0292] Environmental conditions: laboratory temperature 25±2℃, relative humidity 60±5%.

[0293] 3.3 Experimental Results

[0294] 3.3.1 Energy consumption comparison is shown in the following table:

[0295]

[0296] like Figure 3 Shown: Comparison of energy consumption of different synthesis methods.

[0297] like Figure 4 Shown: Comparison of energy consumption per unit time and energy efficiency of different synthesis methods.

[0298] 3.4 Results Analysis

[0299] The total energy consumption is significantly reduced: the total energy consumption of the method of the present invention is 0.87 kWh, which is 78.3% lower than that of the traditional high-temperature catalytic method (4.00 kWh), and is also reduced by about 62% compared with the conventional electrochemical-assisted synthesis method (2.26 kWh) and the electrochemical-ultrasonic synergistic method (2.30 kWh), achieving a significant energy-saving effect.

[0300] Optimization of energy consumption structure: In the traditional high-temperature catalytic method, 85.5% of the energy consumption is used for heating, while the method of the present invention rationally allocates energy input through synergistic effects, with heating energy consumption accounting for only 28.7%. The energy consumption distribution of each part is more balanced, and energy utilization is more efficient.

[0301] Reduced energy consumption per unit time: The energy consumption per unit time of the method of the present invention is 5.22 kW, which is slightly lower than that of the electrochemical-ultrasonic synergistic method (5.52 kW). However, due to the greatly shortened reaction time (10 minutes vs. 25 minutes), the total energy consumption is still significantly reduced.

[0302] Improved energy efficiency: Based on the traditional high-temperature catalytic method (energy efficiency 100%), the energy efficiency of the method of the present invention reaches 460%, indicating that the energy utilization efficiency is improved by 4.6 times.

[0303] Reduced environmental impact: A 78.3% reduction in energy consumption means a corresponding significant reduction in carbon emissions, in line with the requirements of green chemistry and sustainable development.

[0304] Energy consumption tests have demonstrated that the innovative integration of a triple synergistic reaction system and bubble microreactor technology achieves milder reaction conditions (30°C vs. 120-124°C), shorter reaction times (10 minutes vs. 60 minutes), and improved energy efficiency, significantly reducing energy consumption and achieving a reduction of over 60%. This technological achievement is of great significance for lowering drug production costs and alleviating environmental burdens.

[0305] Experiment 4: Environmental friendliness experiment

[0306] 4.1 Experimental Purpose

[0307] The environmental friendliness of the method of the present invention is evaluated, including aspects such as catalyst recovery rate, waste discharge, atom economy, and green chemistry indicators.

[0308] 4.2 Experimental Methods

[0309] 4.2.1 Experimental Design

[0310] The environmental friendliness indicators of the traditional high-temperature catalytic method, the conventional electrochemical-assisted synthesis method, the electrochemical-ultrasonic synergistic method and the method of the present invention are compared.

[0311] Each method was tested at the same scale (1 kg of salami carboxylic acid), and the waste was collected and analyzed.

[0312] Scoring and analysis were performed according to green chemistry principles.

[0313] 4.2.2 Test indicators and methods

[0314] Catalyst recovery test:

[0315] Determination of aluminum chloride recovery by traditional methods: Recovery was attempted by precipitation-filtration-drying method;

[0316] The recovery rate of the redox medium of the method of the present invention is as follows: potassium / sodium ferrocyanide is separated and recovered by ion exchange resin;

[0317] The recovery was determined by gravimetric and potentiometric titration.

[0318] Wastewater discharge and water quality index determination:

[0319] Record the total amount of wastewater generated by each method when producing a unit of product;

[0320] Determine indicators such as COD (chemical oxygen demand), BOD (biochemical oxygen demand) and heavy metal content in wastewater.

[0321] Atom economy assessment:

[0322] Calculate the theoretical atom economy based on the reaction stoichiometric equation;

[0323] The actual atom utilization is calculated based on the actual yield.

[0324] Green Chemistry Rating System:

[0325] Refer to the U.S. Environmental Protection Agency’s Twelve Principles of Green Chemistry;

[0326] Scoring is based on 12 aspects including waste prevention, safety, energy efficiency, and use of renewable resources;

[0327] The total score is 120 points, with a maximum of 10 points for each item.

[0328] 4.3 Experimental Results

[0329] 4.3.1 Comparison of catalyst recovery and waste generation is shown in the following table:

[0330]

[0331] 4.3.2 Atom economy analysis is shown in the following table:

[0332]

[0333] 4.3.3 Comparison of scores for the 12 principles of green chemistry is shown in the following table:

[0334]

[0335] like Figure 5 Shown: Comparison of E-factor and atom utilization of different synthesis methods.

[0336] 4.4 Results Analysis

[0337] Significantly improved catalyst recovery: The potassium / sodium ferrocyanide redox mediator used in the present method has a recovery rate of 92%, significantly higher than the aluminum chloride (<10%) used in traditional high-temperature catalytic methods and the electrolyte salts (42-45%) used in other electrochemical methods. This means that most of the redox mediator can be recycled, reducing waste emissions and raw material consumption.

[0338] The amount of wastewater generated and the pollution load are greatly reduced: the amount of wastewater generated by the method of the present invention is 12.8L / kg product, which is 55% less than that of the traditional method (28.5L / kg); the COD value of the wastewater is 1560mg / L, which is 63% less than that of the traditional method (4250mg / L), and the water treatment burden is significantly reduced.

[0339] Reduction of solid waste: The method of the present invention generates only 0.08 kg / kg of solid waste, which is 81% less than the traditional method (0.42 kg / kg of product) and about 64% less than the electrochemical method (0.21-0.25 kg / kg of product), greatly reducing the pressure of solid waste treatment.

[0340] The E factor is significantly reduced: the E factor (mass ratio of waste to product) of the method of the present invention is 0.75, which is much lower than the 2.85 of the traditional method, indicating that only 0.75 kg of waste is generated for every kg of product produced, and the environmental impact is significantly reduced.

[0341] Improved atom utilization: The actual atom utilization of the method of the present invention reaches 85.7%, which is about 8.6% higher than the traditional method (78.9%), indicating that the raw material atoms are more efficiently converted into the final product, reducing unnecessary atomic waste.

[0342] The comprehensive green chemistry score has significantly improved: Based on the US Environmental Protection Agency's 12 Green Chemistry Principles, the method of this invention scored 94 points (78.3%), significantly higher than the traditional method (47 points (39.2%), the conventional electrochemical method (70 points (58.3%), and the electrochemical-ultrasonic synergistic method (71 points (59.2%)). The method excels in waste prevention, energy efficiency, and reduction of derivatives and catalyst use.

[0343] Reduced solvent usage: The solvent strength of the method of the present invention is 8.2 kg solvent / kg product, which is 55.7% lower than that of the traditional method (18.5 kg solvent / kg product), and is in line with the principle of reducing solvent usage in green chemistry.

[0344] The experimental results demonstrate that the present method, through the combination of a triple synergistic reaction system and bubble microreactor technology, not only significantly improves catalyst recovery, but also significantly reduces wastewater and waste emissions and environmental pollution burden, while also improving atomic utilization efficiency. These improvements in environmental friendliness make the present method a more environmentally friendly preparation process for sarafloxacin hydrochloride that is more in line with the concept of green pharmaceutical manufacturing.

[0345] Experiment 5: Process robustness experiment

[0346] 5.1 Experimental Purpose

[0347] The process robustness of the method of the present invention is verified, including tolerance to fluctuations in reaction conditions, adaptability to scale-up production, and width of the operating parameter window, etc., to provide a basis for industrial production.

[0348] 5.2 Experimental Methods

[0349] 5.2.1 Process parameter sensitivity test

[0350] Investigate the impact of key process parameters (temperature, electric field parameters, ultrasonic parameters, surface tension, etc.) on product quality and yield within the normal value ±20% fluctuation range;

[0351] At the same time, the process robustness of the traditional method (high-temperature catalytic method) within the ±20% fluctuation range of key process parameters (temperature, catalyst dosage, etc.) was examined as a control;

[0352] Each parameter was tested at three levels (-20%, standard value, +20%), and changes in product purity and yield were recorded.

[0353] 5.2.2 Reaction amplification test

[0354] The reactions were carried out at three scales: laboratory scale (1 kg of salamicarboxylic acid), pilot scale (10 kg of salamicarboxylic acid), and industrial scale (50 kg of salamicarboxylic acid).

[0355] Record key indicators such as product quality, yield, reaction time, etc. at different scales;

[0356] The performance change trends of the traditional method and the method of the present invention during scale-up production were compared.

[0357] 5.2.3 Long-term production stability test

[0358] Conduct 10 batches of production continuously at pilot scale without replacing key equipment (electrodes, ultrasonic generator, etc.) between batches;

[0359] Record the changes in each batch of product quality, yield and key equipment performance parameters;

[0360] The stability of the method of the present invention in long-term continuous production was evaluated.

[0361] 5.3 Experimental Results

[0362] 5.3.1 The results of process parameter sensitivity tests are shown in the following table:

[0363]

[0364] *Note: Traditional high-temperature catalytic methods do not involve the regulation of electric field parameters, ultrasonic parameters, and surface tension.

[0365] 5.3.2 Process parameter sensitivity comparison chart:

[0366] like Figure 6 Shown: The impact of process parameter fluctuations on product purity.

[0367] like Figure 7 Shown: The impact of process parameter fluctuations on product yield.

[0368] 5.3.3 The reaction amplification test results are shown in the following table:

[0369]

[0370] 5.3.4 The long-term production stability test results are shown in the following table:

[0371]

[0372] like Figure 8 Shown: Product quality and equipment performance change trend chart for 10 consecutive batches of production.

[0373] 5.4 Results Analysis

[0374] Significantly Reduced Process Parameter Sensitivity: Compared to traditional high-temperature catalytic methods, the present method is significantly less sensitive to process parameter fluctuations. When the temperature fluctuates by ±20%, the maximum change in product purity and yield for the traditional method is 2.35% and 15.8%, respectively. However, for the present method, these changes are only 0.25% and 3.2%, representing reductions of 89% and 80%, respectively. This demonstrates that the present method has a wider process parameter window and is more adaptable to fluctuating production conditions.

[0375] Identifying the impact of key process parameters: Experimental data shows that the parameter with the greatest impact on the present method is surface tension (maximum variation of 1.25% in product purity and 8.5% in yield), followed by electric field parameters and ultrasonic parameters. This provides guidance for key control parameters in industrial production.

[0376] Excellent scale-up robustness: During scale-up from laboratory scale (1 kg) to industrial scale (50 kg), the product purity and yield of the method described in this invention decreased by only 0.10% and 1.0%, respectively, compared to 0.80% and 3.6%, respectively, for the conventional method. This demonstrates that the method described in this invention maintains more stable performance during scale-up and has lower barriers to scale-up.

[0377] Small increase in reaction time with scale-up: Although the reaction time of both methods increases with scale-up (both by +50%), the absolute increase in the method of the present invention is significantly smaller than that of the traditional method (5 minutes vs. 30 minutes), maintaining the characteristics of high efficiency.

[0378] Good long-term production stability: Over 10 consecutive production batches, the product purity of the present method decreased by only 0.06%, and the yield decreased by 0.8%, demonstrating good long-term production stability. Although equipment performance declined somewhat (ultrasonic device output power decreased by 2.8%, and electrode performance decreased by 6.0%), the impact on product quality was minimal, thanks to the uniform reaction environment provided by the bubble microreactor technology.

[0379] The impact of equipment status on product quality is reduced: From the long-term production stability trend chart, it can be seen that even if the equipment performance declines, the product quality parameters remain relatively stable, indicating that the method of the present invention has a high tolerance to changes in equipment status, which is of great significance for the long-term operation of equipment in industrial production.

[0380] Taken together, these results demonstrate the significant advantages of the present method in terms of process robustness. Bubble microreactor technology eliminates the need for confinement of the reaction to the electrode surface, allowing it to proceed simultaneously at the bubble interfaces throughout the entire reaction system. This decentralized reaction model reduces reliance on the performance of a single key piece of equipment, making the process more robust and reliable. Furthermore, the triple synergistic system can compensate for each other under varying reaction conditions, further enhancing its adaptability to parameter fluctuations. These characteristics give the present method excellent prospects for industrial scale-up and long-term stable production capabilities.

[0381] The above describes an embodiment of the present invention, but this embodiment is not limited to the above-mentioned specific implementation methods. The above-mentioned specific implementation methods are merely illustrative and not restrictive. Ordinary technicians in this field can also make more forms of equivalent embodiments based on the inspiration of this embodiment, all of which are protected by this embodiment.

Claims

1. A method for preparing sarafloxacin hydrochloride, characterized in that: The following steps are involved: Step 1: Prepare a reaction system containing carboxylic acid, piperazine, a redox mediator, and a surfactant, and adjust the surface tension of the reaction liquid to 30-35 mN / m; Step 2: Transfer the reaction system to a reaction apparatus and set the reaction temperature to 30±2°C; Step 3: Start the ultrasonic device to generate cavitation bubbles in the reaction system. A stable liquid film layer is formed on the surface of the bubbles as a reaction microenvironment carrier. Step 4: applying a pulsed electric field to generate a polarization effect at the bubble-liquid film interface, causing a condensation reaction between salcarboxylic acid and piperazine in the bubble microreactor; Step 5: After the reaction is completed, hydrochloric acid is added to the reaction product to perform a salt-forming reaction, and sarafloxacin hydrochloride is obtained through separation and purification.

2. The method for preparing sarafloxacin hydrochloride according to claim 1, wherein The redox medium is an electron transfer system composed of potassium ferrocyanide and sodium ferrocyanide.

3. The method for preparing sarafloxacin hydrochloride according to claim 1, wherein In step 1, the components of the reaction system are prepared according to the following weight ratio: 1000 parts of salad carboxylic acid, 250 parts of piperazine, 120 parts of potassium ferrocyanide, 80 parts of sodium ferrocyanide, 15-25 parts of surfactant, 3000 parts of water, and 200-300 parts of auxiliary organic solvent.

4. The method for preparing sarafloxacin hydrochloride according to claim 3, wherein: In step 1, the components of the reaction system are prepared according to the following weight ratio: 1000 parts of salad carboxylic acid, 250 parts of piperazine, 120 parts of potassium ferrocyanide, 80 parts of sodium ferrocyanide, 20 parts of surfactant regulator, 3000 parts of water, and 250 parts of auxiliary organic solvent.

5. The method for preparing sarafloxacin hydrochloride according to claim 1, wherein In step 3, the frequency of the ultrasonic wave is 40 kHz, the power density is 0.5 W / cm³, and an intermittent irradiation mode is adopted, with 10 seconds on and 2 seconds off.

6. The method for preparing sarafloxacin hydrochloride according to claim 1, wherein In step 4, the waveform of the pulsed electric field is a square wave, the frequency is 50-150 Hz, the pulse width is 1-5 ms, the current density is 50-150 mA / cm², and the on-off ratio is 3:

1.

7. The method for preparing sarafloxacin hydrochloride according to claim 1, wherein: The reaction time in step 4 was 10 minutes.

8. The method for preparing sarafloxacin hydrochloride according to claim 1, wherein In step 5, the pH value of the reaction solution is adjusted to 3.5-4.0 by adding 36% hydrochloric acid solution, and the reaction is carried out at 20-25° C. for 20 minutes to perform a salt-forming reaction.

9. The method for preparing sarafloxacin hydrochloride according to claim 1, wherein In step 5, the separation and purification process includes: Isolate the crude product by centrifugation or filtration; Wash the crude product with ice-cold purified water; The crude product was recrystallized at a ratio of crude product to water = 1:3; The recrystallization solution was cooled to 5°C, allowed to stand for 4 hours and filtered to obtain the product; The product was vacuum dried at 50° C. for 12 hours to obtain the finished product sarafloxacin hydrochloride.

10. The method for preparing sarafloxacin hydrochloride according to claim 9, wherein: During the recrystallization process, 0.3% of the weight of the crude product was added with activated carbon for decolorization.

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