Continuous preparation method of sulfamonomethoxine

Abstract

The invention provides a continuous preparation method of sulfamonomethoxine, which comprises the following steps: mixing and dissolving sulfamonomethoxine, alkali, methanol and purified water to prepare a mixed solution; wherein the mass ratio of the mixed solution to the purified water is (5-20): 1, injecting the mixed solution into a micro-channel reactor, and reacting at 100-160 DEG C to obtain a reaction solution; and distilling the reaction liquid, adding water for dissolving, adjusting the pH value to 5-6 by using an acid, and filtering to obtain sulfamonomethoxine. Based on the micro-channel reactor, physical dosages of methanol, purified water and the like are controlled at the same time, and the reaction temperature and retention time are controlled, so that the continuous reaction efficiency of sulfamonomethoxine is effectively improved, the reaction time is shortened, the yield is high, the safety risk is low, and the problem of pipeline blockage caused by solid salt generation is solved; impurities can be controlled in a controllable range; the reaction temperature range is wide, and industrial production is facilitated.

Description

TECHNICAL FIELD

[0001] The present application relates to a preparation method of a compound, in particular to a continuous preparation method of sulfisoxazole. BACKGROUND

[0002] Sulfisoxazole, 4-p-aminobenzene sulfonamide-6-methoxypyrimidine, alias sulfabenzamide, DS-36, chemical formula is C 11 H 12 N4O5S, white to white crystalline powder, odorless, almost tasteless, color gradually dark in light, melting point 204-206℃, insoluble in water, easily soluble in dilute hydrochloric acid or sodium hydroxide solution. Sulfisoxazole is an important sulfonamide antibacterial drug, mainly used for prevention and treatment of hemolytic streptococcus, pneumococcus and meningococcus caused by infection. Can treat coccidiosis, urinary tract and respiratory tract infection and other diseases, also used as feed additive to prepare antibacterial agent.

[0003] At present, the production route of sulfisoxazole only has an old process of Harbin Pharmaceutical Factory, wherein the methoxylation process is that sulfisoxazole, sodium hydroxide and methanol are put into a high-pressure reaction kettle, heated to 120-130℃, 0.6-0.8 MPa / cm 2 , and reacted for 2 h, and then treated to obtain the product. The traditional high-pressure reaction for methoxylation has long reaction time, the reaction temperature is not easy to control, and has potential danger.

[0004] Therefore, a continuous preparation method of sulfisoxazole is studied, which has small production safety risk, short reaction period and easy operation. SUMMARY

[0005] The continuous flow microchannel reaction technology has the characteristics of small liquid holdup, intrinsically safe high-temperature and high-pressure reaction process, short reaction time, small back mixing effect and high production efficiency, and is suitable for industrial production. Based on this, the present application provides a continuous preparation method of sulfisoxazole, which can reduce the production safety risk, improve the production efficiency, and avoid the blockage of the reaction pipeline.

[0006] Specifically, the technical scheme of the present application is as follows: A continuous preparation method of sulfisoxazole, comprising the steps of: Mixing: sulfisoxazole, alkaline reagent, methanol and purified water are mixed and dissolved to prepare a mixed solution; wherein the mass ratio of the mixed solution to purified water is 5-20:1; Microchannel reaction: the mixed solution is injected into a microchannel reactor, and a reaction liquid is obtained by reacting at 100-160℃; Purification: the reaction solution is subjected to distillation, water dissolution, and acid pH adjustment to 5-6, filtration, to obtain sulfanilamide metformin.

[0007] In the present application, "sulfanilamide chlorpyrifos" refers to "sulfanilamide-6-chloropyrimidine".

[0008] To improve the conversion rate of sulfanilamide chlorpyrifos, the molar ratio of the basic reagent to sulfanilamide chlorpyrifos is 1.0-3.0:1, preferably 1.5-2.5:1.

[0009] To effectively provide methoxy for methanol, the basic reagent is one or more of potassium hydroxide, sodium hydroxide, or sodium methoxide, preferably sodium hydroxide.

[0010] To effectively promote the methoxylation reaction and avoid subsequent channel blockage of the microchannel reactor, the mass ratio of methanol to sulfanilamide chlorpyrifos is 12-20:1, preferably 16-18:1.

[0011] To further ensure that the microchannel reactor is not blocked and effectively control the content of impurity sulfanilamide hydroxypyrimidine in the final product, the mass ratio of the mixed solution to purified water is preferably 10-12:1.

[0012] To further ensure the yield of the product, the reaction temperature of the mixed solution in the microchannel reactor is preferably 120-140°C.

[0013] To ensure a high yield of the product while not blocking the microchannel reactor, the residence time of the mixed solution in the microchannel reactor is 15-60 min, preferably 20-30 min.

[0014] Compared with the prior art, the above-mentioned continuous preparation method of sulfanilamide metformin provided by the present application has the following advantages: (1) The present application uses a microchannel reactor to prepare sulfanilamide metformin. Compared with traditional kettle-type high-pressure reactions, the microchannel reaction has a small liquid holdup, and the high-temperature high-pressure reaction process is intrinsically safe, avoiding the dangers brought by traditional kettle-type high-pressure operations and reducing equipment requirements. (2) Compared with traditional kettle-type high-pressure reactions, the preparation method of the present application can be continuously produced, shortening the reaction time (residence time), improving the production efficiency, and reducing the production cost; (3) The present application adds purified water during production, avoiding the occurrence of pipeline blockage due to the generation of solid salt, and by controlling the addition of water, the content of impurity sulfanilamide hydroxypyrimidine can be effectively controlled, so that the content of impurity sulfanilamide hydroxypyrimidine is controlled within 0.6%; (4); compared with the reaction temperature control at 120-130 DEG C of the traditional kettle type high pressure reaction, the reaction temperature of the present application is 100-160 DEG C, the reaction temperature control range is wide, and the reaction time is 15-60 min, easy to operate, and beneficial to industrial application. BRIEF DESCRIPTION OF DRAWINGS

[0015] Figure 1 Liquid chromatogram of sulfonamide sulfadimethoxine synthesized by the method provided for the embodiment 2 of the present application. DETAILED DESCRIPTION

[0016] Unless specifically indicated otherwise, the terms used in the present application are all the terms commonly used in the art, and the technical means used in the embodiments, such as preparation process, test method and the like, are all the conventional means known to those skilled in the art, and the reagents and products used are all commercially available.

[0017] As a chemical process intensification technology, the continuous flow microchannel reaction technology has the characteristics of small liquid holdup, high temperature and high pressure reaction process intrinsic safety, short reaction time, small back mixing effect, high production efficiency, and is suitable for industrial production. The traditional high pressure reaction process for preparing sulfonamide sulfadimethoxine is combined with the continuous flow microchannel reaction technology, and there is a problem of easy blockage of the channel of the microchannel reactor in the process of preparing sulfonamide sulfadimethoxine. In order to solve this problem, the following scheme is adopted in the specific embodiment of the present application: Specifically, the technical scheme protected by the present application is as follows: A continuous preparation method of sulfonamide sulfadimethoxine, comprising the steps of: Mixing: sulfonamide chlorpyrifos, alkaline reagent, methanol and purified water are mixed and dissolved to prepare a mixed solution; wherein the mass ratio of the mixed solution to purified water is 5-20:1; Microchannel reaction: the mixed solution is injected into a microchannel reactor, and a reaction liquid is obtained by reacting at 100-160 DEG C; Purification: the reaction liquid is distilled, dissolved in water, and the pH value is adjusted to 5-6 with acid, filtered, and sulfonamide sulfadimethoxine is prepared.

[0018] In the present application, "sulfonamide chlorpyrifos" refers to "sulfonamide-6-chloropyrimidine".

[0019] In order to improve the conversion rate of sulfonamide chlorpyrifos, the molar ratio of the alkaline reagent to sulfonamide chlorpyrifos is 1.0-3.0:1, such as 1.0:1, 1.5:1, 2:1, 2.5:1, 3:1 and the like, and preferably 1.5-2.5:1. The alkaline reagent is one or more of potassium hydroxide, sodium hydroxide or sodium methoxide, and preferably sodium hydroxide.

[0020] Methanol is used as a methoxy donor and a solvent for sulfanilamide in the preparation of the target compound sulfisomidine. If the amount of methanol is small, the subsequent reaction solution is turbid and is difficult to dissolve in the micro-channel reactor; if the amount of methanol is large, the post-processing cost is increased. Therefore, the mass ratio of methanol to sulfachloropyridazine is 12-20:1, such as 12:1, 14:1, 16:1, 17:1, 18:1, 20:1, and preferably 16-18:1.

[0021] The main purpose of adding purified water in the mixing process is to avoid the blockage of the micro-channel reactor. The hydroxyl group in the purified water can react with sulfachloropyridazine to form sulfanilamide hydroxypyrimidine. If the amount of purified water is large, the content of impurities sulfanilamide hydroxypyrimidine in the final product is high; if the amount of purified water is small, the problem of blockage of the micro-channel reactor cannot be effectively solved; therefore, the mass ratio of the mixed solution to purified water is limited to 5-20:1, such as 5:1, 6:1, 8:1, 10:1, 11:1, 12:1, 15:1, 18:1, 20:1, and preferably 10-12:1.

[0022] In the step of micro-channel reaction, if the reaction temperature is lower than 100℃, the product yield is reduced; if the reaction temperature is higher than 160℃, the side reaction is generated, thereby increasing the content of impurities in the product; therefore, the reaction temperature of the mixed solution in the micro-channel reactor is limited to 100-160℃, such as 100℃, 110℃, 120℃, 130℃, 140℃, 150℃, 160℃, and preferably 120-140℃.

[0023] If the residence time of the mixed solution in the micro-channel reactor is too short, the reaction of sulfachloropyridazine and other raw materials is incomplete and the conversion rate is low; if the residence time is too long, the risk of blockage of the micro-channel reactor is increased; therefore, the residence time of the mixed solution in the micro-channel reactor is 15-60 min, such as 15 min, 20 min, 25 min, 30 min, 35 min, 40 min, 50 min, 60 min, and preferably 20-30 min.

[0024] In the micro-channel reaction, one or more than two micro-channel reactors can be used in series. The micro-channel reactor is a prior art, and the existing industrial micro-channel reactor is suitable for the present application. Preferably, the reaction pipeline of a single micro-channel reactor of the reactor is 0.5-2 mm, and the total volume of the reaction zone is 17.5-300 mL, and the reaction efficiency is higher.

[0025] Therefore, the application provides the above-mentioned continuous preparation method of sulfonamide metformin, which comprises the following steps: firstly, sulfonamide chlorpyrifos, an alkaline reagent, methanol and purified water are mixed and dissolved, and then the mixed solution is injected into a micro-channel reactor through a feeding pump for reaction; and finally, the reaction solution is collected, post-treated, and sulfonamide metformin is obtained.

[0026] The application will be further described below in combination with examples, and it should be noted that the following description is only for the purpose of explaining the application and does not limit the content thereof.

[0027] The micro-channel reactor used in the following examples and comparative examples of the application is a continuous flow reactor produced by Shandong Nuwei Company, which is used for the preparation of sulfonamide metformin. The inner diameter of the reaction pipeline of the reactor is 2 mm, and the total volume of the reaction area is 300 mL.

[0028] Example 1 The application provides a continuous preparation method of sulfonamide metformin, which comprises the following steps: firstly, sulfonamide chlorpyrifos, potassium hydroxide, methanol and purified water are mixed and dissolved to prepare a mixed solution; wherein the molar ratio of potassium hydroxide to sulfonamide chlorpyrifos is 2.5:1.0, the mass ratio of methanol to sulfonamide chlorpyrifos is 18:1, and the mass ratio of the mixed solution to purified water is 20:1; then the mixed solution is injected into a micro-channel reactor through a feeding pump, the feeding speed of the pump is controlled to be 15 ml / min, the reaction temperature is 130 DEG C, the reaction residence time is 27.6 min, the reaction liquid is transferred into a vacuum distillation kettle through the outlet, methanol is recovered by vacuum distillation, then water is added for dissolution, the pH value of the system is adjusted to 5-6 by using an acid, and filtration is performed, so as to obtain sulfonamide metformin, the yield is 98.3%, and the impurity content is 0.12%.

[0029] Example 2 The application provides a continuous preparation method of sulfonamide metformin, which comprises the following steps: firstly, sulfonamide chlorpyrifos, potassium hydroxide, methanol and purified water are mixed and dissolved to prepare a mixed solution; wherein the molar ratio of potassium hydroxide to sulfonamide chlorpyrifos is 2.5:1.0, the mass ratio of methanol to sulfonamide chlorpyrifos is 18:1, and the mass ratio of the mixed solution to purified water is 20:1; then the mixed solution is injected into a micro-channel reactor through a feeding pump, the feeding speed of the pump is controlled to be 15 ml / min, the reaction temperature is 130 DEG C, the reaction residence time is 27.6 min, the reaction liquid is transferred into a vacuum distillation kettle through the outlet, methanol is recovered by vacuum distillation, then water is added for dissolution, the pH value of the system is adjusted to 5-6 by using an acid, and filtration is performed, so as to obtain sulfonamide metformin, the yield is 98.3%, and the impurity content is 0.12%. Figure 1

[0030] Example 3 ​The embodiment provides a continuous preparation method of sulfisomidine, which is basically same as the preparation method provided in the embodiment 2, and the main difference is that the reaction temperature of the mixed solution in the micro-channel reactor is 100 DEG C, and other process steps and parameters are same, finally the yield of the sulfisomidine is 96.1%, and the impurity content is 0.45%.

[0031] Embodiment 4 The embodiment provides a continuous preparation method of sulfisomidine, which is basically same as the preparation method provided in the embodiment 2, and the main difference is that the reaction temperature of the mixed solution in the micro-channel reactor is 160 DEG C, and other process steps and parameters are same, finally the yield of the sulfisomidine is 99.5%, and the impurity content is 0.31%.

[0032] Embodiment 5 The embodiment provides a continuous preparation method of sulfisomidine, which comprises the following steps: dissolving sulfisomidine, sodium methoxide, methanol and purified water to prepare a mixed solution; wherein the molar ratio of the sodium methoxide and the sulfisomidine is 1.5:1.0, the mass ratio of the methanol and the sulfisomidine is 12:1, and the mass ratio of the mixed solution and the purified water is 10:1. The mixed solution is introduced into a micro-channel reactor by a feeding pump, the feeding speed of the pump is controlled to be 20ml / min, the reaction temperature is 140 DEG C, the reaction residence time is 20.7min, the reaction liquid is introduced into a vacuum distillation kettle through a discharge port, methanol is recovered by vacuum distillation, then water is added for dissolution, the pH value of the system is adjusted to be 5-6 by using an acid, and then sulfisomidine is obtained by filtration, the yield is 97.2%, and the impurity content is 0.3%.

[0033] Embodiment 6 The embodiment provides a continuous preparation method of sulfisomidine, which comprises the following steps: dissolving sulfisomidine, sodium methoxide, methanol and purified water to prepare a mixed solution; wherein the molar ratio of the sodium methoxide and the sulfisomidine is 1.5:1.0, the mass ratio of the methanol and the sulfisomidine is 12:1, and the mass ratio of the mixed solution and the purified water is 10:1. The mixed solution is introduced into a micro-channel reactor by a feeding pump, the feeding speed of the pump is controlled to be 20ml / min, the reaction temperature is 140 DEG C, the reaction residence time is 20.7min, the reaction liquid is introduced into a vacuum distillation kettle through a discharge port, methanol is recovered by vacuum distillation, then water is added for dissolution, the pH value of the system is adjusted to be 5-6 by using an acid, and then sulfisomidine is obtained by filtration, the yield is 97.2%, and the impurity content is 0.3%.

[0034] Embodiment 7 The embodiment provides a continuous preparation method of sulfanilamide metoxymidazoles, which is basically same as the preparation method provided in the embodiment 6, and the main difference is that the mass ratio of methanol and sulfanilamide chlormidazole is 20:1, and the other process steps and parameters are same, finally the yield of sulfanilamide metoxymidazoles is 99.3%, and the impurity content is 0.46%.

[0035] Embodiment 8 The embodiment provides a continuous preparation method of sulfanilamide metoxymidazoles, which is basically same as the preparation method provided in the embodiment 6, and the main difference is that the mass ratio of mixed solution and purified water is 5:1, and the other process steps and parameters are same, finally the yield of sulfanilamide metoxymidazoles is 97.2%, and the impurity content is 0.60%.

[0036] Embodiment 9 The embodiment provides a continuous preparation method of sulfanilamide metoxymidazoles, which is basically same as the preparation method provided in the embodiment 2, and the main difference is that the reaction residence time of the mixed solution in the micro-channel reactor is 55 min, and the other process steps and parameters are same, finally the yield of sulfanilamide metoxymidazoles is 99.3%, and the impurity content is 0.26%.

[0037] Comparative example 1 The molar ratio of sodium hydroxide and sulfanilamide chlormidazole is 2.0:1.0, and the mass ratio of methanol and sulfanilamide chlormidazole is 14:1, which is mixed and then added into a high-pressure reaction kettle, the reaction temperature is 120 DEG C, the reaction pressure is 0.7-0.8 MPa, the reaction time is 3h, after the reaction is finished, the methanol is recovered by reducing pressure distillation in a distillation kettle, then water is added for dissolution, the system pH is adjusted to 5-6 by using acid, and then sulfanilamide metoxymidazoles is obtained by filtration, the yield is 94.3%, and the impurity content is 0.13%.

[0038] Comparative example 2 The comparative example provides a continuous preparation method of sulfanilamide metoxymidazoles, which is basically same as the preparation method provided in the embodiment 6, and the main difference is that the purified water is not added in the mixed solution, and the other process steps and parameters are same, finally the yield of sulfanilamide metoxymidazoles is 21.7%, the impurity content is 0.08%, and obvious blockage is found in the channel of the micro-channel reactor.

[0039] Comparative example 3-high purified water dosage The comparative example provides a continuous preparation method of sulfanilamide metoxymidazoles, which is basically same as the preparation method provided in the embodiment 6, and the main difference is that the mass ratio of mixed solution and purified water is 4:1, and the other process steps and parameters are same, finally the yield of sulfanilamide metoxymidazoles is 96.5%, and the impurity content is 1.32%.

[0040] Comparative example 4-low purified water dosage The comparative example provides a continuous preparation method of sulfisomidine, which is basically the same as the preparation method provided in Example 2, and the main difference is that the mass ratio of the mixed solution to purified water is 22:1, and the other process steps and parameters are the same. Finally, the yield of sulfisomidine is 35.4%, and the impurity content is 0.09%.

[0041] Comparative Example 5 - Low methanol dosage The comparative example provides a continuous preparation method of sulfisomidine, which is basically the same as the preparation method provided in Example 6, and the main difference is that the mass ratio of methanol to sulfachloropyridazine is 10:1, and the other process steps and parameters are the same. Finally, the yield of sulfisomidine is 95.3%, and the impurity content is 1.47%.

[0042] Comparative Example 6 - High methanol dosage The comparative example provides a continuous preparation method of sulfisomidine, which is basically the same as the preparation method provided in Example 2, and the main difference is that the mass ratio of methanol to sulfachloropyridazine is 22:1, and the other process steps and parameters are the same. Finally, the yield of sulfisomidine is 99.3%, and the impurity content is 0.23%.

[0043] Comparative Example 7 - Low reaction temperature The comparative example provides a continuous preparation method of sulfisomidine, which is basically the same as the preparation method provided in Example 2, and the main difference is that the reaction temperature of the mixed solution in the micro-channel reactor is 90°C, and the other process steps and parameters are the same. Finally, the yield of sulfisomidine is 92.1%, and the impurity content is 2.64%.

[0044] Comparative Example 8 - High reaction temperature The comparative example provides a continuous preparation method of sulfisomidine, which is basically the same as the preparation method provided in Example 2, and the main difference is that the reaction temperature of the mixed solution in the micro-channel reactor is 170°C, and the other process steps and parameters are the same. Finally, the yield of sulfisomidine is 99.2%, and the impurity content is 0.23%.

[0045] Comparative Example 9 - Short residence time The comparative example provides a continuous preparation method of sulfisomidine, which is basically the same as the preparation method provided in Example 2, and the main difference is that the reaction residence time of the mixed solution in the micro-channel reactor is 10 min, and the other process steps and parameters are the same. Finally, the yield of sulfisomidine is 95.2%, and the impurity content is 15.7%.

[0046] Comparative Example 10 - Long residence time The comparative example provides a continuous preparation method of sulfonamide metformin, which is basically the same as the preparation method provided in example 2, and the main difference is that the reaction residence time of the mixed solution in the micro-channel reactor is 75 min, and other process steps and parameters are the same, and finally the yield of sulfonamide metformin is 98.9%, and the impurity content is 0.78%.

[0047] From the above examples and comparative examples, it can be seen that: From examples 6, 8 and comparative examples 2-4, it can be seen that too little or too much purified water will lead to a decrease in product yield and an increase in impurity content, and even block the pipeline, affect the normal reaction, and cause equipment failure.

[0048] From examples 6-7 and comparative examples 5-6, it can be seen that within a certain range, the yield increases with the increase of the amount of methanol, but when it exceeds the range, too little methanol will lead to incomplete product dissolution, thereby affecting the reaction yield and causing pipeline blockage, and when the amount of methanol is too large, the yield remains basically unchanged, and the cost of post-treatment is also increased.

[0049] From examples 2-4 and comparative examples 7-8, it can be seen that too low a temperature will lead to incomplete reaction, reduced yield and increased impurity content of the product; and too high a temperature will lead to the occurrence of side reactions, thereby increasing the impurity content and ultimately affecting the product quality.

[0050] From examples 2-4 and comparative examples 9-10, it can be seen that too short a residence time will lead to incomplete reaction of the raw materials and unreacted raw materials in the product; and too long a reaction time will also lead to the occurrence of side reactions, thereby increasing the impurity content and ultimately affecting the product quality. Therefore, the above-mentioned continuous preparation method of sulfonamide metformin provided in the examples of the application controls the amount of methanol, purified water and other physical quantities, and controls the reaction temperature and residence time based on the micro-channel reactor, effectively improving the continuous reaction efficiency of sulfonamide metformin, shortening the reaction time, having high yield, low safety risk, solving the problem of pipeline blockage caused by the generation of solid salt, and being able to control the impurities within a controllable range; the wide reaction temperature range is conducive to industrial production.

[0051] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the application and not to limit them; although the application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the specific embodiments of the application can be modified or some technical features can be replaced by equivalents; without departing from the spirit of the technical solutions of the application, they should be covered in the technical solution range of the application claimed by the application.

Claims

1.A method for continuously preparing sulfisoxazole, comprising the steps of: mixing sulfanilamide, sulfachloropyridazine, and a basic reagent to obtain a mixed solution; and purifying the mixed solution; wherein a mass ratio of the mixed solution to purified water is 5-20:1; wherein a molar ratio of the basic reagent to sulfachloropyridazine is 1.0-3.0:1; wherein the basic reagent is one or more of potassium hydroxide, sodium hydroxide, or sodium methoxide; wherein a mass ratio of methanol to sulfachloropyridazine is 12-20:1; wherein a mass ratio of the mixed solution to purified water is 10-12:1; wherein a molar ratio of the basic reagent to sulfachloropyridazine is 1.5-2.5:1; wherein a mass ratio of methanol to sulfachloropyridazine is 16-18:1; wherein a reaction temperature of the mixed solution in a micro-channel reactor is 120-140℃; wherein a residence time of the mixed solution in the micro-channel reactor is 15-60 min; wherein a residence time of the mixed solution in the micro-channel reactor is 20-30 min; and wherein the sulfisoxazole is obtained by distilling the mixed solution, dissolving the mixed solution in water, adjusting a pH value of the mixed solution to 5-6, and filtering the mixed solution. Mixing: sulfadimidine, alkaline reagent, methanol and purified water are mixed and dissolved to form a mixed solution; wherein, 1.A method for continuously preparing sulfisoxazole, comprising the steps of: mixing sulfanilamide, sulfachloropyridazine, and a basic reagent to obtain a mixed solution; and purifying the mixed solution; wherein a mass ratio of the mixed solution to purified water is 5-20:1; wherein a molar ratio of the basic reagent to sulfachloropyridazine is 1.0-3.0:1; wherein the basic reagent is one or more of potassium hydroxide, sodium hydroxide, or sodium methoxide; wherein a mass ratio of methanol to sulfachloropyridazine is 12-20:1; wherein a mass ratio of the mixed solution to purified water is 10-12:1; wherein a molar ratio of the basic reagent to sulfachloropyridazine is 1.5-2.5:1; wherein a mass ratio of methanol to sulfachloropyridazine is 16-18:1; wherein a reaction temperature of the mixed solution in a micro-channel reactor is 120-140℃; wherein a residence time of the mixed solution in the micro-channel reactor is 15-60 min; wherein a residence time of the mixed solution in the micro-channel reactor is 20-30 min; and wherein the sulfisoxazole is obtained by distilling the mixed solution, dissolving the mixed solution in water, adjusting a pH value of the mixed solution to 5-6, and filtering the mixed solution. ​ ​ 2. The production method according to claim 1, characterized by, ​ 3. The production method according to claim 1 or 2, characterized by, ​ 4. The production method according to claim 3, characterized by, ​ 5. The production method according to claim 1 or 2, characterized by, ​ 6. The production method according to claim 1 or 2, characterized by, ​ 7. The production method according to claim 6, characterized by, ​ 8. The production method according to claim 1 or 2 or 7, characterized by, ​ 9. The production method according to claim 1 or 2, characterized by; ​ 10. The method of claim 9, wherein, ​

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