Process for the preparation of a quinolone intermediate by a polymerization-inhibiting condensation

Abstract

This invention relates to the field of synthesis of fluoroquinolone pharmaceutical intermediates, and discloses a method for preparing quinolone intermediates through inhibitory condensation. The method involves mixing an organic solvent, ethyl 3-(dimethylamino)acrylate, a trialkylamine acid-binding agent, and a free radical polymerization inhibitor to form a reaction premix. Under the pre-prepared condition of the polymerization inhibitor, all of the 2,4-dichloro-5-fluorobenzoyl chloride is continuously added, causing the reaction system to heat to 80–95°C via exothermic condensation and maintain this temperature for 0.5–2 hours. After the reaction is complete, water and hydrochloric acid are added to adjust the pH of the aqueous phase to 1–2. The mixture is then stirred at 60–70°C, allowed to stand for separation, and the resulting organic phase is subjected to low-temperature crystallization, filtration, washing, and vacuum drying to obtain the target product. This method can reduce colored byproducts during the condensation process, shorten the reaction time, and improve the separation yield and purity of the target product.

Description

Technical Field

[0001] This invention relates to the field of synthesis of fluoroquinolone pharmaceutical intermediates, and specifically to a method for preparing quinolone intermediates by polymerization inhibition condensation. Background Technology

[0002] Ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(dimethylamino)acrylate is an important intermediate in the preparation of fluoroquinolone compounds such as ciprofloxacin, enrofloxacin, and gatifloxacin. Its purity, color, and separation yield directly affect the reaction stability and final product quality of subsequent processes such as amine exchange and cyclization. Current preparation processes typically use 2,4-dichloro-5-fluorobenzoyl chloride and ethyl 3-(dimethylamino)acrylate as raw materials, carrying out a condensation reaction in the presence of organic solvents such as toluene and trialkylamine acid-binding agents, followed by acidification, layering, crystallization, and drying to obtain the target intermediate.

[0003] In the aforementioned condensation process, ethyl 3-(dimethylamino)acrylate contains unsaturated double bonds. When the acyl chloride is added in concentrated quantities and the reaction system is rapidly heated, the reaction solution is prone to darkening in color and an increase in high-boiling byproducts, leading to raw material loss, increased product color, and a decrease in crystallization yield. To mitigate these problems, existing processes typically employ lower temperatures and extended acyl chloride dropping times to reduce instantaneous exothermic reactions and local reactant concentrations. However, this approach prolongs the condensation reaction cycle, makes temperature control and feeding operations more cumbersome, and limits the processing capacity of the reaction equipment per unit time.

[0004] Existing technological improvements primarily focus on the selection of organic solvents, replacement of trialkylamine acid-binding agents, adjustment of feed ratios, and the recovery and reuse of amines and solvents after the reaction. However, they lack targeted control over the formation of colored, high-boiling byproducts during the initiation stage of the condensation reaction. Without effective suppression measures, directly increasing the reaction temperature or shortening the acyl chloride feeding time can easily further exacerbate product coloring; while simply relying on low-temperature, long-duration dropwise addition makes it difficult to balance reaction efficiency and equipment capacity. Therefore, it is necessary to provide a method for preparing quinolone intermediates that can suppress side reactions before the condensation reaction begins and can be combined with continuous full-volume feeding of acyl chlorides and high-temperature, short-time reactions. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a method for preparing quinolone intermediates through polymerization inhibition condensation, thereby solving the technical problems existing in the prior art.

[0006] The above-mentioned technical objective of the present invention is achieved through the following technical solution: A method for preparing a quinolone intermediate by polymerization inhibition condensation includes the following steps: S1: Add organic solvent, ethyl 3-(dimethylamino)acrylate, trialkylamine acid-binding agent and free radical polymerization inhibitor to a closed reaction vessel, and stir to form a reaction premix; The organic solvent is at least one of toluene and xylene; the free radical polymerization inhibitor is added before the addition of 2,4-dichloro-5-fluorobenzoyl chloride; and the amount of the free radical polymerization inhibitor added is 0.01% to 2.0% of the molar amount of ethyl 3-(dimethylamino)acrylate. S2: Under the condition of maintaining stirring and introducing cooling medium into the cooling structure of the closed reaction vessel, all of the 2,4-dichloro-5-fluorobenzoyl chloride is added to the reaction premix in one feeding stage, wherein the molar ratio of the 2,4-dichloro-5-fluorobenzoyl chloride to the ethyl 3-(dimethylamino)acrylate is 1:1.0 to 1.5; The reaction system was heated under the exothermic effect of the condensation reaction, and the maximum temperature of the reaction system was controlled at 80-95℃. The reaction was kept at 80-95℃ for 0.5-2 hours to obtain an organic crude liquid containing ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(dimethylamino)acrylate. S3: Add water to the crude organic liquid, add hydrochloric acid while stirring until the pH of the aqueous phase is 1-2, stir at 60-70°C and let stand to separate the layers, separate the aqueous phase and collect the organic phase containing ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(dimethylamino)acrylate.

[0007] Preferably, the amount of the free radical polymerization inhibitor added is 0.02% to 1.0% of the amount of ethyl 3-(dimethylamino)acrylate.

[0008] Preferably, the free radical polymerization inhibitor is one of hydroquinone, p-methoxyphenol, 2,6-di-tert-butyl-p-cresol, p-benzoquinone, tetrachlorobenzoquinone, and tert-butylhydroquinone, or a mixture of two or more of these.

[0009] Preferably, the free radical polymerization inhibitor is p-methoxyphenol, and the amount of p-methoxyphenol added is 0.05% to 0.5% of the amount of ethyl 3-(dimethylamino)acrylate.

[0010] Preferably, the trialkylamine acid-binding agent is at least one of tri-n-propylamine, triethylamine, and tri-n-butylamine, and the molar ratio of the trialkylamine acid-binding agent to the 2,4-dichloro-5-fluorobenzoyl chloride is 1.0 to 2.0:1.

[0011] Preferably, the trialkylamine acid-binding agent is tri-n-propylamine, and the molar ratio of tri-n-propylamine to 2,4-dichloro-5-fluorobenzoyl chloride is 1.1 to 1.5:1; the organic solvent is toluene, and the mass ratio of toluene to 2,4-dichloro-5-fluorobenzoyl chloride is 1.5 to 2.5:1.

[0012] Preferably, after adding the 2,4-dichloro-5-fluorobenzoyl chloride to the reaction premix, the reaction system is heated under the exothermic effect of the condensation reaction, and the maximum temperature of the reaction system is controlled at 85-93°C. After reaching 85-93°C, the reaction is maintained at this temperature for 0.5-1.5 hours.

[0013] Preferably, the mass of water added to the organic crude liquid is 1 to 3 times the mass of tri-n-propylamine; after adding hydrochloric acid until the pH of the aqueous phase is 1 to 2, the mixture is stirred at 60 to 70°C for 20 to 40 minutes, and then allowed to stand to separate into layers.

[0014] Preferably, the separated organic phase is cooled to -10 to 10°C and stirred at -10 to 10°C for 0.5 to 1.5 hours to precipitate ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(dimethylamino)acrylate. The resulting crystals and organic mother liquor are separated by filtration. The filter cake is washed with toluene at 0 to 5°C to remove the organic mother liquor entrained in the filter cake. The mass of the toluene is 0.3 to 0.8 times the mass of the obtained wet product. The washed wet product is vacuum dried at a temperature not exceeding 70°C and a vacuum gauge pressure not exceeding -0.09 MPa in the vacuum drying equipment for 3 to 5 hours to obtain solid ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(dimethylamino)acrylate.

[0015] In summary, the present invention has the following main beneficial effects: By pre-adding a free radical polymerization inhibitor to a reaction system containing ethyl 3-(dimethylamino)acrylate and a trialkylamine acid-binding agent before feeding 2,4-dichloro-5-fluorobenzoyl chloride, the free radical polymerization inhibitor is uniformly distributed in the reaction solution when the condensation reaction starts. This inhibits the free radical chain side reactions that may occur during the heated condensation process, reduces the formation of colored high-boiling byproducts, and achieves the effects of reducing the color of the crude reaction solution and the obtained intermediates, reducing the loss of target raw materials, and improving the separation yield and purity of the target product.

[0016] By combining the pre-addition of free radical polymerization inhibitors with continuous full-volume feeding of 2,4-dichloro-5-fluorobenzoyl chloride and short-term high-temperature holding at 80-95℃, the reaction system can quickly reach the reaction temperature by utilizing the exothermic reaction of condensation, eliminating the need for continuous low-temperature drop-addition for several hours. This achieves the effects of shortening the condensation reaction cycle, simplifying the feeding and temperature control of acyl chloride, and improving the processing capacity of the reaction equipment per unit time. At the same time, it avoids the product coloring and yield reduction caused by simply increasing the reaction temperature.

[0017] By acidifying the crude organic liquor obtained from condensation with water, the trialkylamine acid-binding agent is transferred to the aqueous phase in the form of hydrochloride. The separated organic phase is then subjected to low-temperature crystallization, cold toluene washing, and vacuum drying, which reduces colored impurities and residual acid-binding agent entrainment and simplifies the purification process of the target product. Attached Figure Description

[0018] Figure 1 This is a flowchart of the method of the present invention.

[0019] Figure 2 This is the HPLC chromatogram of ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(dimethylamino)acrylate from Example 1 of the present invention.

[0020] Figure 3 This is the HPLC chromatogram of ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(dimethylamino)acrylate from Example 2 of the present invention.

[0021] Figure 4 This is the HPLC chromatogram of ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(dimethylamino)acrylate from Example 3 of the present invention.

[0022] Figure 5 This is the HPLC detection chromatogram of the target product in Example 4 of the present invention.

[0023] Figure 6 This is the color contrast diagram of the present invention. Detailed Implementation

[0024] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0025] refer to Figure 1 A method for preparing a quinolone intermediate by inhibited polymerization condensation includes the following steps: S1: Add organic solvent, ethyl 3-(dimethylamino)acrylate, trialkylamine acid-binding agent and free radical polymerization inhibitor to a closed reaction vessel, and stir to form a reaction premix; The organic solvent is at least one of toluene and xylene; the free radical polymerization inhibitor is added before the addition of 2,4-dichloro-5-fluorobenzoyl chloride; and the amount of the free radical polymerization inhibitor added is 0.01% to 2.0% of the molar amount of ethyl 3-(dimethylamino)acrylate. S2: Under the condition of maintaining stirring and introducing cooling medium into the cooling structure of the closed reaction vessel, all of the 2,4-dichloro-5-fluorobenzoyl chloride is added to the reaction premix in one feeding stage, wherein the molar ratio of the 2,4-dichloro-5-fluorobenzoyl chloride to the ethyl 3-(dimethylamino)acrylate is 1:1.0 to 1.5; The reaction system was heated under the exothermic effect of the condensation reaction, and the maximum temperature of the reaction system was controlled at 80-95℃. The reaction was kept at 80-95℃ for 0.5-2 hours to obtain an organic crude liquid containing ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(dimethylamino)acrylate. S3: Add water to the crude organic liquid, add hydrochloric acid while stirring until the pH of the aqueous phase is 1-2, stir at 60-70°C and let stand to separate the layers, separate the aqueous phase and collect the organic phase containing ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(dimethylamino)acrylate.

[0026] The target product referred to in this application is ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(dimethylamino)acrylate, and the olefinic ester used as the condensation raw material is ethyl 3-(dimethylamino)acrylate. The amounts of raw materials, reaction temperatures, holding times, separation yields, HPLC purity, and product color in the examples are all based on the data recorded in the technical disclosure.

[0027] In this invention, before the initial feeding of 2,4-dichloro-5-fluorobenzoyl chloride, a free radical polymerization inhibitor is pre-added to a reaction system containing ethyl 3-(dimethylamino)acrylate, a trialkylamine acid-binding agent, and an organic solvent, ensuring that the free radical polymerization inhibitor is dispersed in the reaction premix before the condensation reaction begins. Based on this, all of the 2,4-dichloro-5-fluorobenzoyl chloride is added in a continuous feeding stage, utilizing the exothermic reaction to raise the temperature of the reaction system, and then maintaining this temperature for a short period at 80–95°C.

[0028] The above process does not involve adding the polymerization inhibitor after the target product is obtained, nor does it involve using the polymerization inhibitor for the distillation or storage of ethyl 3-(dimethylamino)acrylate. Instead, the polymerization inhibitor is directly applied to the condensation reaction stage of the target intermediate. The pre-addition of the polymerization inhibitor, the continuous full-volume feeding of the acyl chloride, and the high-temperature short-time heat preservation together constitute the polymerization inhibition condensation process.

[0029] This invention does not assume that all colored byproducts formed during the reaction are single-radical polymers. Under conditions of one-time acyl chloride feeding and heated condensation, ethyl 3-(dimethylamino)acrylate and the unsaturated intermediates formed in the reaction may undergo side reactions that increase the color of the reaction solution, increase its viscosity, or decrease the separation yield. Radical inhibitors are used to suppress free radical chain side reactions; the actual inhibition effect is judged comprehensively by the target product separation yield, HPLC purity, and product color.

[0030] The organic solvent used is toluene, xylene, or a mixture of both, with toluene being preferred. The organic solvent should be clear before use, free of visible water and solid impurities. After cleaning, the reaction vessel should be drained of free water to prevent significant hydrolysis of 2,4-dichloro-5-fluorobenzoyl chloride during the feeding process.

[0031] The trialkylamine acid-binding agent is tri-n-propylamine, triethylamine, or tri-n-butylamine, with tri-n-propylamine being preferred. During the condensation reaction, the trialkylamine acid-binding agent accepts the hydrogen chloride produced. After condensation, it is converted into a water-soluble amine salt by adding water and hydrochloric acid and then enters the aqueous phase.

[0032] The free radical polymerization inhibitor is at least one selected from hydroquinone, p-methoxyphenol, 2,6-di-tert-butyl-p-cresol, p-benzoquinone, tetrachlorobenzoquinone, or tert-butylhydroquinone. P-methoxyphenol is preferred. The amount of free radical polymerization inhibitor added is determined based on the molar amount of ethyl 3-(dimethylamino)acrylate.

[0033] The reaction equipment should be equipped with a mechanical stirring structure, a material temperature detection structure, a jacketed or coiled cooling structure, a condensation reflux structure, and a pressure balancing structure. The working volume of the reaction equipment should be able to accommodate all the materials in the condensation stage, and a safe space should be reserved for stirring and exothermic reactions.

[0034] After the condensation reaction is complete, if the original reaction equipment cannot safely hold the acidification water, the crude organic liquid can be transferred to another acidification container with sufficient working volume for the addition of water and hydrochloric acid, followed by settling and separation. Condensation, acidification, and crystallization do not necessarily have to be completed in the same container.

[0035] The ambient temperature referred to in this instruction manual is the temperature of the material when the reactants are not actively heated, typically 15–30°C.

[0036] The statement in this manual that all 2,4-dichloro-5-fluorobenzoyl chloride is added in a continuous feeding stage means that all the acyl chloride in this batch is added continuously while the stirring and cooling structures are in operation, without any intermediate heat preservation steps or low-temperature dripping for several hours during the feeding process.

[0037] Continuous full-volume feeding is not the same as instantaneous dumping. The actual feeding rate is determined based on the reaction scale, the heat exchange area of ​​the reaction vessel, the temperature of the cooling medium, and the temperature rise of the reaction system. During the continuous addition of acyl chloride, the reaction temperature is controlled by adjusting the flow rate of the cooling medium to prevent the maximum temperature of the reaction system from exceeding 95°C.

[0038] The reaction system temperature referred to in this manual is the material temperature measured after the temperature sensing end is inserted into the main liquid phase region of the reaction liquid, and is not replaced by the cooling jacket temperature or the outer wall temperature of the reaction vessel.

[0039] The term "heat preservation reaction start point" as used in this specification refers to the moment when the reaction system, under the exothermic condensation effect, heats up and first reaches the lower limit of the adopted heat preservation temperature range. During the heat preservation period, the reaction system is maintained within the selected temperature range by adjusting the flow rate of the cooling medium.

[0040] The free radical polymerization inhibitor is added before the 2,4-dichloro-5-fluorobenzoyl chloride is started. After adding the inhibitor, stirring continues until there are no visible undispersed inhibitor particles in the reaction premix before adding the acyl chloride.

[0041] Based on the amount of ethyl 3-(dimethylamino)acrylate, the amount of free radical polymerization inhibitor added is 0.01 mol% to 2.0 mol%, preferably 0.02 mol% to 1.0 mol.

[0042] The amount of polymerization inhibitor added should be selected based on the type of inhibitor, its solubility or dispersion in the organic solvent, the reaction temperature, the product color, and the crystallization separation. If the amount of inhibitor added is too low, it will not adequately suppress the colored byproducts formed under high-temperature concentrated feeding conditions; if the amount added is too high, it may increase inhibitor residue or affect crystallization separation. Therefore, in actual production, an amount that balances separation yield, purity, and color should be selected within the above range.

[0043] The polymerization inhibitor additions directly verified in the examples include: 0.2 mol% hydroquinone, 0.5 mol% p-methoxyphenol, and 1.0 mol% tert-butylhydroquinone.

[0044] Add organic solvent, ethyl 3-(dimethylamino)acrylate and trialkylamine acid binder to the reaction vessel and start stirring.

[0045] Add the free radical polymerization inhibitor and continue stirring until the free radical polymerization inhibitor is evenly dispersed in the reaction premix. The free radical polymerization inhibitor must be added before the 2,4-dichloro-5-fluorobenzoyl chloride is started to be fed, and cannot be replaced by adding the polymerization inhibitor after the acyl chloride is fed.

[0046] After confirming that the temperature detection and cooling structures are operating normally, add all of the 2,4-dichloro-5-fluorobenzoyl chloride in this batch during a continuous feeding phase. The molar ratio of acyl chloride to ethyl 3-(dimethylamino)acrylate is 1:1.0 to 1.5.

[0047] During the addition of acyl chloride, continuous stirring is carried out, and the reaction system heats up under the exothermic condensation effect. By adjusting the flow rate of the cooling medium, the maximum temperature of the reaction system is controlled at 80–95°C, preferably at 85–93°C.

[0048] After the reaction system reaches the selected holding temperature, continue the reaction at this temperature for 0.5–2 hours. The reaction time is determined based on the reaction temperature and the residual acyl chloride. The holding time can be extended at lower temperatures and shortened accordingly at higher temperatures, but the endpoint should be determined by the completion of the reaction of 2,4-dichloro-5-fluorobenzoyl chloride.

[0049] After the incubation period, the reaction solution samples were obtained and analyzed using an HPLC method confirmed by 2,4-dichloro-5-fluorobenzoyl chloride and the target product reference standard. The same chromatographic conditions and integration rules were used in all examples and comparative examples.

[0050] When the chromatographic peak corresponding to 2,4-dichloro-5-fluorobenzoyl chloride in the reaction solution is lower than the quantitation limit validated by the detection method, the acyl chloride reaction is determined to be complete, the condensation reaction is terminated, and an organic crude solution containing ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(dimethylamino)acrylate is obtained.

[0051] If the chromatographic peak corresponding to the acyl chloride is still higher than the limit of quantitation within the specified incubation time, the incubation should continue within the specified incubation time and temperature range and the test should be repeated. Simply reaching a fixed time should not replace the detection of the reaction endpoint.

[0052] Add water to the crude organic liquid. When using tri-n-propylamine as an acid-binding agent, the mass of water added is 1 to 3 times the mass of tri-n-propylamine, preferably 1.5 to 2 times.

[0053] The amount of water added is determined based on the entry of the amine salt into the aqueous phase and the separation of the two phases. The amount of water should be sufficient to dissolve the trialkylamine hydrochloride formed by acidification and form a separable, continuous aqueous phase. If the amount of water is insufficient and amine salt precipitation or unclear phase interface occurs, water should be added within the scope defined in the claims; once the amount of water reaches a level sufficient to form a stable aqueous phase, it is unnecessary to increase the amount of water further, in order to reduce the loss of the target product into the aqueous phase and the subsequent wastewater volume.

[0054] While stirring, slowly add hydrochloric acid. During the addition of hydrochloric acid, obtain aqueous phase samples in several batches, cool the aqueous phase samples to 20-25°C, and measure them using a pH meter calibrated with standard buffer solution.

[0055] Stop adding hydrochloric acid when the pH of the aqueous phase reaches 1-2. The pH value mentioned is the pH of the aqueous sample, not a value obtained by directly measuring a two-phase mixture of toluene and water.

[0056] The system was kept at 60–70°C and stirred for 20–40 minutes to allow the trialkylamine hydrochloride to fully enter the aqueous phase. After stirring was stopped, the mixture was allowed to stand until a continuous and clear phase interface was formed between the aqueous and organic phases, and there was no continuous emulsion layer at the interface that would hinder liquid separation.

[0057] When toluene or xylene is used as the organic solvent, the upper organic phase is usually collected and the lower aqueous phase is discharged. In practice, the discharge direction should be determined based on the density of the two phases and the interface position, and separation should not be based solely on the fixed designation of the upper or lower layer.

[0058] When a solid target product is required, the separated organic phase is transferred to a low-temperature crystallization device.

[0059] The organic phase is cooled to -10 to 10°C, preferably to -5 to 0°C. After reaching the crystallization temperature, the mixture is stirred for 0.5 to 1.5 hours to form a filterable slurry from the target product.

[0060] The crystallization temperature and time are determined based on the crystal precipitation state, the residual target product in the mother liquor, and filtration performance. If the temperature is too high and precipitation is insufficient, the temperature can be lowered further within the range defined in the claims. If crystals continue to precipitate after the set temperature is reached, the holding time can be extended, but the total crystallization time shall not exceed 1.5 hours.

[0061] The resulting slurry is filtered, and the wet filter cake is collected. The wet filter cake is washed with toluene at 0–5°C to reduce colored impurities and residual trialkylamines in the mother liquor. When controlling the amount of detergent according to the quality of the wet product, the actual mass of the wet product should be weighed after filtration, and the amount of toluene added should be 0.3–0.8 times the mass of the wet product.

[0062] The washed wet product was placed in a vacuum drying device and dried for 3 to 5 hours at a temperature not exceeding 70°C and a vacuum gauge pressure not exceeding -0.09 MPa to obtain solid ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(dimethylamino)acrylate.

[0063] The drying time is determined based on the thickness of the wet product loading and the mass transfer status of the equipment. After drying, the moisture content or loss on drying is tested according to the product quality standard; if the specified limit is not reached, vacuum drying continues under conditions not exceeding the product's stable temperature. The specific moisture content or loss on drying limit is determined according to the product quality standard implemented by the applicant.

[0064] The purity of the target product was evaluated using the HPLC area normalization method. The retention times of the target product and main raw materials were determined using corresponding reference standards. All examples and comparative examples used the same sample preparation methods, chromatographic columns, mobile phases, detection wavelengths, injection volumes, and integration rules.

[0065] The color of the product was tested using a standardized sample preparation method. 5.0 g of the dried target product was weighed, dissolved in toluene, and diluted to 100 mL. The product was then visually compared with platinum-cobalt series standard solutions under the same light source and colorimetric container conditions of 20–25 °C.

[0066] The target product separation yield is calculated based on the actual mass of the target product obtained after drying and the theoretical product mass corresponding to the limiting feedstock.

[0067] Example 1 Add 500 mL of toluene, 143.18 g (1.0 mol) of ethyl 3-(dimethylamino)acrylate, and 157.6 g (1.1 mol) of tri-n-propylamine to a reaction vessel equipped with a stirring structure, a temperature detection structure, a condensation reflux structure, and a cooling structure, and capable of meeting the safe working liquid level requirements.

[0068] Start stirring and add 0.62 g of p-methoxyphenol, which is 0.005 mol. The amount of p-methoxyphenol added is 0.5 mol% of the molar amount of ethyl 3-(dimethylamino)acrylate. Continue stirring to ensure that p-methoxyphenol is evenly dispersed in the reaction premix.

[0069] The cooling structure is activated, and under stirring conditions, 227.45 g (1.0 mol) of 2,4-dichloro-5-fluorobenzoyl chloride is added in a continuous feeding stage. The molar ratio of acyl chloride to ethyl 3-(dimethylamino)acrylate is 1:1.

[0070] During the feeding process, the flow rate of the cooling medium is adjusted according to the reaction temperature rise, so that the reaction system can be heated under the action of condensation exothermic effect, and the maximum temperature is controlled at 92-93℃.

[0071] After the reaction system reached 92℃, it was kept at 92-93℃ and stirred for 1 hour. After the incubation period, a sample of the reaction solution was obtained and analyzed by HPLC. It was confirmed that the chromatographic peak corresponding to 2,4-dichloro-5-fluorobenzoyl chloride was below the limit of quantitation of the detection method, and a crude organic solution containing the target product was obtained.

[0072] Add 314g of industrial water (approximately twice the mass of tri-n-propylamine) to the crude organic liquid. Slowly add 30% hydrochloric acid while stirring. Obtain aqueous samples in portions, cool the samples to 20–25°C, and then measure the pH. Stop adding hydrochloric acid when the pH of the aqueous phase reaches 1–2.

[0073] The system was kept at 60-70℃ and stirred for 30 minutes. After stirring was stopped, the mixture was allowed to stand until the interface between the two phases was clear. The aqueous phase was separated and the organic phase was collected.

[0074] The organic phase was cooled to -5°C and stirred at -5°C for 1 hour to induce crystallization. After filtration, the filter cake was washed with 100g of toluene at 0°C. The washed wet product was placed in a vacuum drying apparatus and dried for 4 hours at a temperature not exceeding 70°C and a vacuum gauge pressure not exceeding -0.09MPa, yielding 330.8g of an off-white solid.

[0075] The target product was separated and yielded at 99.0%, with an HPLC purity of 99.7%. 5.0 g of the product was weighed and diluted to 100 mL with toluene for platinum-cobalt color comparison. The color of the test solution was lighter than that of the platinum-cobalt standard solution numbered 3.

[0076] Example 2 The amounts of toluene, ethyl 3-(dimethylamino)acrylate, tri-n-propylamine, and 2,4-dichloro-5-fluorobenzoyl chloride used in this embodiment, as well as the method of adding acyl chloride, reaction temperature, holding time, acidification and stratification, crystallization, washing, and drying processes, are the same as in Example 1. The difference is that hydroquinone is used as the free radical polymerization inhibitor.

[0077] Before the addition of 2,4-dichloro-5-fluorobenzoyl chloride, 0.22 g (0.002 mol) of hydroquinone was added to the reaction premix. The amount of hydroquinone added was 0.2 mol% of the molar amount of ethyl 3-(dimethylamino)acrylate.

[0078] After completing the inhibition condensation, acidification and layering, low-temperature crystallization, filtration, washing and vacuum drying, 327.4 g of the off-white target product was obtained.

[0079] The target product was separated with a yield of 98.0% and an HPLC purity of 99.0%. Platinum-cobalt colorimetry was compared according to the sample preparation method in Example 1; the test solution was lighter in color than the platinum-cobalt standard solution numbered 4.

[0080] Example 3 The raw material ratio, solvent, acid-binding agent, acyl chloride feeding method, reaction temperature, heat preservation time and post-treatment process in this embodiment are the same as those in Example 1. The difference is that the free radical polymerization inhibitor is tert-butylhydroquinone.

[0081] Before the addition of 2,4-dichloro-5-fluorobenzoyl chloride, 1.66 g (0.01 mol) of tert-butylhydroquinone was added to the reaction premix. The amount of tert-butylhydroquinone added was 1.0 mol% of the molar amount of ethyl 3-(dimethylamino)acrylate.

[0082] After completing the polymerization inhibition condensation, acidification and layering, low-temperature crystallization, filtration, washing and vacuum drying, 324.1g of the target product was obtained.

[0083] The target product was separated and yielded at 97.0%, with an HPLC purity of 99.2%. Platinum-cobalt colorimetric comparison was performed according to the sample preparation method in Example 1; the test solution was lighter in color than the platinum-cobalt standard solution numbered 3.

[0084] Examples 1 to 3 demonstrate that p-methoxyphenol, hydroquinone, and tert-butylhydroquinone can all be added before the acyl chloride feed, and are combined with continuous full-volume feeding of the acyl chloride and high-temperature short-time condensation. Different types and amounts of polymerization inhibitors affect the separation yield and purity of the target product. Among them, Example 1 achieved better overall results when using 0.5 mol% p-methoxyphenol.

[0085] Example 4 Industrial reaction equipment with mechanical stirring, temperature detection, cooling, condensation reflux, and pressure balancing structures is used. The allowable working liquid level of the equipment can accommodate all the raw materials in the condensation stage; when the materials in the acidification stage cannot be safely contained by the original reaction equipment, the crude organic liquid is transferred to the acidification equipment with sufficient working volume.

[0086] Add 50 L of toluene, 14.3 kg (100.0 mol) of ethyl 3-(dimethylamino)acrylate, and 15.76 kg (110.0 mol) of tri-n-propylamine to the reaction apparatus. Start the mechanical stirrer at a speed of 180 r / min.

[0087] Add 62g of p-methoxyphenol, which is 0.5mol. The amount of p-methoxyphenol added is 0.5mol% of the molar amount of ethyl 3-(dimethylamino)acrylate. Stir at room temperature for 30 minutes to ensure that the p-methoxyphenol is evenly distributed in the reaction premix.

[0088] The cooling system was activated, and 22.75 kg (100.0 mol) of 2,4-dichloro-5-fluorobenzoyl chloride was added in a continuous feeding phase while maintaining stirring. The reaction system heated up under the exothermic condensation effect, and the reaction temperature was controlled at 90–91 °C by adjusting the flow rate of the cooling medium.

[0089] After the reaction system reached 90℃, it was kept at 90-91℃ and stirred for 1 hour. After the incubation period, the sample was obtained and analyzed by HPLC. It was confirmed that the chromatographic peak corresponding to 2,4-dichloro-5-fluorobenzoyl chloride was below the limit of quantitation of the detection method.

[0090] Add 31.4 kg of industrial water (approximately twice the mass of tri-n-propylamine) to the crude organic liquid. Slowly add 30% hydrochloric acid (by mass) while stirring until the pH of the aqueous phase reaches 1–2.

[0091] The system was kept at 60-70℃ and stirred for 30 minutes. After stirring was stopped, the mixture was allowed to stand and separate into layers. The aqueous phase was separated and the organic phase was collected.

[0092] The organic phase was transferred to a low-temperature crystallization apparatus, cooled to -3 to -5°C, and stirred for 1 hour to induce crystallization. The resulting slurry was filtered, and the filter cake was washed twice with 10 kg of toluene at 0°C. The wet product was then placed in a vacuum drying apparatus and dried for 5 hours at 65°C with a vacuum gauge pressure not exceeding -0.09 MPa.

[0093] The final product yielded 33.0 kg of off-white solid, with a separation yield of 98.8% and an HPLC purity of 99.6%. 5.0 g of the product was weighed and diluted to 100 mL with toluene for platinum-cobalt color comparison. The color of the test solution was lighter than that of the platinum-cobalt standard solution numbered 3.

[0094] This embodiment demonstrates that, at a feed scale of 100 mol, the process relationship of pre-addition of the polymerization inhibitor, continuous full-volume feeding of the acyl chloride, and short-term heat preservation at 90–91 °C can still be implemented.

[0095] Comparative Example 1 The same amounts of toluene, ethyl 3-(dimethylamino)acrylate, tri-n-propylamine, and 2,4-dichloro-5-fluorobenzoyl chloride were used as in Example 1, along with the same method of adding acyl chloride, reaction temperature, holding time, and post-treatment process. The difference was that no free radical polymerization inhibitor was added before adding the acyl chloride.

[0096] All of the 2,4-dichloro-5-fluorobenzoyl chloride was added in a continuous feeding stage, and the reaction system was heated to 92-93°C and held at that temperature for 1 hour. Subsequently, acidification, low-temperature crystallization, filtration, cold toluene washing, and vacuum drying were carried out according to Example 1.

[0097] A final yield of 311.4 g of yellow solid was obtained, with a target product separation yield of 93.2% and an HPLC purity of 98.7%. 5.0 g of the product was weighed and diluted to 100 mL with toluene for platinum-cobalt color comparison. The color of the test solution was deeper than that of the platinum-cobalt standard solution numbered 10.

[0098] The main difference between Comparative Example 1 and Example 1 is whether a free radical polymerization inhibitor is added before the acyl chloride is fed. Under the same continuous full-volume feeding of acyl chloride and high-temperature short-time condensation conditions, without the addition of a free radical polymerization inhibitor, the color of the target product is significantly darker and the separation yield is reduced.

[0099] Comparative Example 2 The same amounts of toluene, ethyl 3-(dimethylamino)acrylate, tri-n-propylamine, and 2,4-dichloro-5-fluorobenzoyl chloride were used as in Example 1, but without the addition of a free radical polymerization inhibitor.

[0100] The reaction system was controlled at 40–60°C, and 2,4-dichloro-5-fluorobenzoyl chloride was slowly added over a period of 4 hours. After the addition was complete, the temperature was maintained for another 2 hours, for a total condensation stage time of 6 hours.

[0101] After condensation, acidification, low-temperature crystallization, filtration, cold toluene washing, and vacuum drying were carried out in accordance with Example 1.

[0102] The final product was a light yellow color of 320.8 g, with a separation yield of 96.0% and an HPLC purity of 99.1%. 5.0 g of the product was weighed and diluted to 100 mL with toluene for platinum-cobalt color comparison. The color of the test solution was deeper than that of the platinum-cobalt standard solution numbered 5.

[0103] Comparative Example 2 used a low-temperature, long-time feeding method, which reduced the product coloring compared to Comparative Example 1, but the condensation stage was extended to 6 hours, and the separation yield and color of the resulting product were still lower than those of Example 1.

[0104] Example 1, Comparative Example 1, and Comparative Example 2 used the same main raw material system and the same post-processing procedure. The differences lay mainly in the addition of the free radical polymerization inhibitor and the feeding and condensation temperature regime of the acyl chloride. In Example 1, by pre-adding p-methoxyphenol before feeding the acyl chloride, all the acyl chloride could be added in the same continuous feeding stage, and the temperature was maintained at 92-93°C for 1 hour. The separation yield, purity, and color of its target product were all superior to the high-temperature concentrated feeding process without the addition of the polymerization inhibitor and the low-temperature long-time dropping process without the addition of the polymerization inhibitor.

[0105] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for preparing a quinolone intermediate by inhibited polymerization condensation, characterized in that, Includes the following steps: S1: Add organic solvent, ethyl 3-(dimethylamino)acrylate, trialkylamine acid-binding agent and free radical polymerization inhibitor to a closed reaction vessel, and stir to form a reaction premix; The organic solvent is at least one of toluene and xylene, and the free radical polymerization inhibitor is one of hydroquinone, p-methoxyphenol, and tert-butylhydroquinone. The free radical polymerization inhibitor is added before the addition of 2,4-dichloro-5-fluorobenzoyl chloride, and the amount of the free radical polymerization inhibitor added is 0.01% to 2.0% of the molar amount of ethyl 3-(dimethylamino)acrylate. S2: Under the condition of maintaining stirring and introducing cooling medium into the cooling structure of the closed reaction vessel, all of the 2,4-dichloro-5-fluorobenzoyl chloride is added to the reaction premix in one feeding stage, wherein the molar ratio of the 2,4-dichloro-5-fluorobenzoyl chloride to the ethyl 3-(dimethylamino)acrylate is 1:1.0 to 1.5; The reaction system was heated under the exothermic effect of the condensation reaction, and the maximum temperature of the reaction system was controlled at 80-95℃. The reaction was kept at 80-95℃ for 0.5-2 hours to obtain an organic crude liquid containing ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(dimethylamino)acrylate. S3: Add water to the crude organic liquid, add hydrochloric acid while stirring until the pH of the aqueous phase is 1-2, stir at 60-70°C and let stand to separate the layers, separate the aqueous phase and collect the organic phase containing ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(dimethylamino)acrylate.

2. The method for preparing a quinolone intermediate by inhibited polymerization condensation according to claim 1, characterized in that, The amount of the free radical polymerization inhibitor added is 0.02% to 1.0% of the amount of ethyl 3-(dimethylamino)acrylate.

3. The method for preparing a quinolone intermediate by inhibited polymerization condensation according to claim 2, characterized in that, The free radical polymerization inhibitor is p-methoxyphenol.

4. The method for preparing a quinolone intermediate by inhibited polymerization condensation according to claim 3, characterized in that, The amount of p-methoxyphenol added is 0.05% to 0.5% of the amount of ethyl 3-(dimethylamino)acrylate.

5. The method for preparing a quinolone intermediate by inhibited polymerization condensation according to claim 1, characterized in that, The trialkylamine acid-binding agent is at least one of tri-n-propylamine, triethylamine, and tri-n-butylamine, and the molar ratio of the trialkylamine acid-binding agent to the 2,4-dichloro-5-fluorobenzoyl chloride is 1.0 to 2.0:

1.

6. The method for preparing a quinolone intermediate by inhibited polymerization condensation according to claim 5, characterized in that, The trialkylamine acid-binding agent is tri-n-propylamine, and the molar ratio of tri-n-propylamine to 2,4-dichloro-5-fluorobenzoyl chloride is 1.1 to 1.5:1; the organic solvent is toluene, and the mass ratio of toluene to 2,4-dichloro-5-fluorobenzoyl chloride is 1.5 to 2.5:

1.

7. The method for preparing a quinolone intermediate by inhibited polymerization condensation according to claim 6, characterized in that, After adding the 2,4-dichloro-5-fluorobenzoyl chloride to the reaction premix, the reaction system is heated under the exothermic effect of the condensation reaction, and the maximum temperature of the reaction system is controlled at 85-93℃. After reaching 85-93℃, the reaction is maintained at this temperature for 0.5-1.5 hours.

8. The method for preparing a quinolone intermediate by inhibited polymerization condensation according to claim 7, characterized in that, The mass of water added to the organic crude liquid is 1 to 3 times the mass of the tri-n-propylamine; hydrochloric acid is added until the pH of the aqueous phase is 1 to 2, and then the mixture is stirred at 60 to 70°C for 20 to 40 minutes, and then allowed to stand to separate into layers.

9. The method for preparing a quinolone intermediate by inhibited polymerization condensation according to claim 1, characterized in that, The separated organic phase is cooled to -10 to 10°C and stirred at -10 to 10°C for 0.5 to 1.5 hours to precipitate ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(dimethylamino)acrylate. The resulting crystals and organic mother liquor are separated by filtration. The filter cake is washed with toluene at 0 to 5°C to remove the organic mother liquor entrained in the filter cake. The mass of the toluene is 0.3 to 0.8 times the mass of the obtained wet product. The washed wet product is vacuum dried at a temperature not exceeding 70°C and a vacuum gauge pressure not exceeding -0.09 MPa for 3 to 5 hours to obtain solid ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(dimethylamino)acrylate.

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