Preparation method of 4-fluoro-3, 5-dimethylphenylhydrazine hydrochloride

Abstract

The invention provides a preparation method of 4-fluoro-3, 5-dimethylphenylhydrazine hydrochloride, which comprises the following steps: salifying 4-fluoro-3, 5-dimethylaniline serving as a substrate with concentrated hydrochloric acid, reacting with sodium nitrite to prepare a diazo solution, reducing the diazo solution into corresponding phenylhydrazine by using alkaline sodium sulfite as a reducing agent system, and reacting the 4-fluoro-3, 5-dimethylphenylhydrazine hydrochloride with the diazo solution to prepare the 4-fluoro-3, 5-dimethylphenylhydrazine hydrochloride. And acidizing the 2, 5-dimethyl phenylhydrazine to obtain corresponding phenylhydrazine hydrochloride. According to the preparation method, sodium sulfite which is low in cost and easy to obtain is used as a reducing agent, the defects that metal residues are high, the environment is prone to being polluted and the raw material cost is high due to the fact that a metal reducing agent is adopted when phenylhydrazine hydrochloride is prepared in the prior art are overcome, the reaction is completed in a water phase, no organic solvent is adopted, and the concept of green chemistry is met; and the problems of complicated post-treatment and easy pollution caused by the adoption of an organic solvent can be effectively avoided.

Description

Technical Field

[0001] The present application relates to the technical field of organic synthesis, and in particular to a method for preparing 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride. Background Art

[0002] GLP-1 receptor agonists (GLP-1RAs) are a class of drugs used to treat type 2 diabetes. They lower blood sugar levels by mimicking the effects of the incretin hormone GLP-1. GLP-1 is a hormone released by intestinal cells after eating that stimulates insulin secretion, inhibits glucagon release, slows gastric emptying, and increases satiety.

[0003] 4-Fluoro-3,5-dimethylphenylhydrazine hydrochloride is a key intermediate for GLP-1 receptor agonists. As the GLP-1 market continues to expand, demand for 4-Fluoro-3,5-dimethylphenylhydrazine hydrochloride is expected to increase. Developing a method suitable for commercial scale-up is essential.

[0004] Currently disclosed 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride synthesis technologies include: In patent US2019225604A1, 4-fluoro-3,5-dimethylaniline is used as a substrate, salified with concentrated hydrochloric acid, and then reacted with sodium nitrite to form a diazonium salt, which is then reduced and acidified with stannous chloride to prepare 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride.

[0005] In the patent with international publication number WO2024 / 137426A1, 5-bromo-2-fluoro-1,3-dimethylbenzene and (diphenylmethyl)hydrazine are used as substrates. After nitrogen displacement with NaOH, Pd(OAc)2 and Xantphos are added to react to obtain 1-(diphenylmethylene)-2-(4-fluoro-3,5-dimethylphenyl)hydrazine.

[0006] Then, 1-(diphenylmethylene)-2-(4-fluoro-3,5-dimethylphenyl) was added to dioxane saturated with HCl gas, hydrazine was added, and the mixture was heated. After cooling, 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride was obtained with a total yield of 78.3%.

[0007] Regarding the process in patent US2019225604A1, firstly, the cost is high. Stannous chloride itself is relatively expensive. In order to ensure that the reduction reaction is fully carried out during the reaction, excessive stannous chloride needs to be used, which further increases the cost of raw materials. Secondly, the product yield is low. When stannous chloride is used to reduce diazo liquid to prepare hydrazine products, the yield is generally not high. This method is often used when synthesizing a small amount of samples in the laboratory. Thirdly, the product purification is difficult. Stannous chloride will be oxidized into tin ions during the reaction and mixed into the reaction system, which is very likely to cause residual tin metal ions in the product. In fields such as pharmaceutical production that have extremely strict requirements on metal ion content, this not only seriously affects product quality, but also requires complex post-processing methods such as ion exchange resins and precipitation filtration to remove tin ions, which greatly increases the difficulty of product purification and production costs. Fourthly, the treatment of tin salt wastewater is difficult and does not meet the requirements of green chemistry.

[0008] International Publication No. WO2024 / 137426A1, first, Pd (OAc) 2 is expensive and used in large quantities, resulting in high production costs. In addition, the palladium catalyst is easily deactivated and the yield fluctuates greatly. Second, hydrogen chloride is used in the process, which is not only volatile, corrosive, but also seriously excessive. Third, while the second step reaction obtains the product, an equimolar by-product, benzophenone, is also generated simultaneously. Benzophenone is not only large in quantity, but also easily soluble in dioxane. During post-processing filtration, it is bound to be entrained into the product, which also affects product quality. Summary of the Invention

[0009] The present application provides a method for preparing 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride, which is used to overcome the disadvantages of high metal residue, easy environmental pollution and high raw material cost in the above-mentioned existing synthesis of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride.

[0010] The present application provides a method for preparing 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride, comprising the following steps: Adding bottom water and 4-fluoro-3,5-dimethylaniline into a reaction apparatus to obtain a premixed solution; The first concentrated hydrochloric acid is added dropwise to the premixed solution under stirring, and the system temperature is controlled not to exceed 30°C. The mixture is stirred and kept warm for 0.5 to 1 hour, and then cooled to obtain an acidified mixed solution. Prepare a sodium nitrite aqueous solution and cool it to 5-15°C. Add the cooled sodium nitrite aqueous solution dropwise to the acidified mixed solution under inert gas protection. Keep the solution warm for 2-3 hours to obtain a diazo solution. Prepare an alkaline reducing solution of sodium sulfite, add the diazonium solution dropwise into the alkaline reducing solution of sodium sulfite, control the temperature at 65-75°C, and react for 2-3 hours to obtain a reaction solution; Add the second concentrated hydrochloric acid to the reaction solution, raise the temperature to 85-100°C and reflux for 3-4 hours to obtain an acidified reaction solution; The acidified reaction liquid is subjected to post-processing operation to obtain a finished product.

[0011] Optionally, the amount of bottom water added is 2 to 2.5 times the weight of 4-fluoro-3,5-dimethylaniline.

[0012] Optionally, the amount of the first concentrated hydrochloric acid added to the premixed solution is 3 to 3.2 times the weight of 4-fluoro-3,5-dimethylaniline, and the addition rate is 3 to 6 L / min.

[0013] Optionally, the temperature of the acidified mixed solution is 5-15°C.

[0014] Optionally, the concentration of the sodium nitrite aqueous solution is 25-30 wt %, and the amount of sodium nitrite used is 1.02-1.07 of the molar amount of 4-fluoro-3,5-dimethylaniline; The addition rate of the sodium nitrite aqueous solution is 6~8L / min.

[0015] Optionally, the inert gas is nitrogen or argon.

[0016] Optionally, the alkaline reducing solution of sodium sulfite is prepared according to the following steps: Adding a water-soluble weak base and sodium sulfite into water to prepare an alkaline reduction solution of sodium sulfite; The concentration of sodium sulfite in the alkaline reduction solution of sodium sulfite is 12~15wt%; The amount of water-soluble weak base added is 0.52 to 0.55 of the molar amount of 4-fluoro-3,5-dimethylaniline; The amount of sodium sulfite added is 1.05 to 1.1 of the molar amount of 4-fluoro-3,5-dimethylaniline; The addition rate of diazo solution is 3~6L / min; The water-soluble weak base is sodium carbonate or potassium carbonate.

[0017] Optionally, the concentrations of the first hydrochloric acid and the second hydrochloric acid are both 32-37 wt %; The pH of the acidified reaction solution is ≤1.

[0018] Optionally, the post-processing operation includes cooling and crystallization, impurity removal and drying processes; The cooling and crystallization process includes: cooling the acidified reaction solution to 20-30° C., and filtering to obtain a crude product of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride after the product is completely precipitated; The impurity removal process includes: adding toluene to the crude product obtained in the cooling and crystallization process, stirring at room temperature for 2 to 2.5 hours, and filtering to obtain a refined wet product; The drying process includes: drying the refined wet product under reduced pressure to obtain the finished product.

[0019] Optionally, the negative pressure during the drying process is -0.06~-0.09MPa, the drying temperature is 65~75°C, and the drying is performed to a constant weight.

[0020] The preparation method of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride provided in this application has the following beneficial effects: 1) The use of sodium sulfite as a reducing agent in the reaction of the present application can effectively avoid the disadvantage of high metal residues caused by the use of metallic reducing agents such as stannous chloride. In addition, sodium sulfite is cheap and readily available, which can effectively reduce production costs.

[0021] 2) The reaction of the present application is completed in an aqueous phase without using an organic solvent, which is in line with the concept of green chemistry and can effectively avoid the problems of complex post-processing and easy pollution caused by the use of organic solvents. DETAILED DESCRIPTION

[0022] To make the purpose, technical solutions, and advantages of the embodiments of this application more clear, the technical solutions in the embodiments of this application are clearly and completely described below. Obviously, the described embodiments are part of the embodiments of this application, not all of them. Based on the embodiments in this application, all other embodiments obtained by ordinary technicians in this field without making creative efforts also fall within the scope of protection of this application.

[0023] The present application provides a method for preparing 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride, comprising the following steps: Adding bottom water and 4-fluoro-3,5-dimethylaniline into a reaction apparatus to obtain a premixed solution; The first concentrated hydrochloric acid is added dropwise to the premixed solution under stirring, and the system temperature is controlled not to exceed 30°C. The mixture is stirred and kept warm for 0.5 to 1 hour, and then cooled to obtain an acidified mixed solution. In the present application, concentrated hydrochloric acid is added to the reaction system formed by bottom water and 4-fluoro-3,5-dimethylaniline. Since the neutralization reaction between amine and strong acid releases a large amount of heat, and the dilution process of concentrated hydrochloric acid also releases heat, in order to avoid an abnormal increase in the reaction temperature, the temperature of the reaction system is controlled below 30°C, which can effectively avoid the occurrence of safety accidents.

[0024] Prepare a sodium nitrite aqueous solution and cool it to 5-15°C. Add the cooled sodium nitrite aqueous solution dropwise to the acidified mixed solution under inert gas protection. Keep the solution warm for 2-3 hours to obtain a diazo solution. Prepare an alkaline reducing solution of sodium sulfite, add the diazonium solution dropwise into the alkaline reducing solution of sodium sulfite, control the temperature at 65-75°C, and react for 2-3 hours to obtain a reaction solution; In the present application, the volume of the alkaline reducing solution of sodium sulfite is larger than the volume of the diazo liquid during production (approximately 3 to 3.5 times the volume of the diazo liquid). In this way, the diazo liquid is added to the alkaline reducing solution of sodium sulfite. The alkaline reducing solution can buffer the heat of the reaction, thereby preventing the diazo liquid from releasing heat during the reduction process, which may cause an abnormal increase in the system temperature and thus a safety accident.

[0025] Add the second concentrated hydrochloric acid to the reaction solution, raise the temperature to 85-100°C and reflux for 3-4 hours to obtain an acidified reaction solution; In the present application, the addition of the second concentrated hydrochloric acid can convert 4-fluoro-3,5-dimethylphenylhydrazine in the reaction solution into the corresponding phenylhydrazine hydrochloride.

[0026] The acidified reaction liquid is subjected to post-processing operation to obtain a finished product.

[0027] The preparation method of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride provided in this application has the following beneficial effects: 1) The use of sodium sulfite as a reducing agent in the reaction of the present application can effectively avoid the disadvantage of high metal residues caused by the use of metallic reducing agents such as stannous chloride. In addition, sodium sulfite is cheap and readily available, which can effectively reduce production costs.

[0028] 2) The reaction of the present application is completed in an aqueous phase without using an organic solvent, which is in line with the concept of green chemistry and can effectively avoid the problems of complex post-processing and easy pollution caused by the use of organic solvents.

[0029] Optionally, the amount of bottom water added is 2 to 2.5 times the weight of 4-fluoro-3,5-dimethylaniline.

[0030] In the present application, the addition of bottom water can play a buffering role, and can absorb heat and dilute the 4-fluoro-3,5-dimethylaniline when the first concentrated hydrochloric acid is subsequently used to acidify the 4-fluoro-3,5-dimethylaniline into a salt.

[0031] Optionally, the amount of the first concentrated hydrochloric acid added to the premixed solution is 3 to 3.2 times the weight of 4-fluoro-3,5-dimethylaniline, and the addition rate is 3 to 6 L / min.

[0032] In this application, because concentrated hydrochloric acid is added to the reaction system, the reaction and dissolution heat will cause the temperature of the reaction system to rise. In order to avoid the temperature rise caused by the addition of concentrated hydrochloric acid too quickly, which may cause a safety accident, the addition rate of concentrated hydrochloric acid is controlled at 3 to 6 L / min. It should be noted that the addition rate of each substance in this application is based on the reaction of large-scale industrial production. If it is a small laboratory test, the addition rate should be appropriately reduced.

[0033] Optionally, the temperature of the acidified mixed solution is 5-15°C.

[0034] In the present application, since a large amount of heat is released during the diazotization reaction and the diazonium salt is explosive, the reaction temperature should be controlled at a low level to avoid safety accidents.

[0035] Optionally, the concentration of the sodium nitrite aqueous solution is 25-30 wt %, and the amount of sodium nitrite used is 1.02-1.07 of the molar amount of 4-fluoro-3,5-dimethylaniline; In the present application, the amount of sodium nitrite added is appropriately excessive, which helps to fully react the reaction substrate 4-fluoro-3,5-dimethylaniline.

[0036] The addition rate of the sodium nitrite aqueous solution is 6~8L / min.

[0037] Optionally, the inert gas is nitrogen or argon.

[0038] In this application, nitrogen or argon is used as the protective gas, which is cheap and readily available.

[0039] Optionally, the alkaline reducing solution of sodium sulfite is prepared according to the following steps: Adding a water-soluble weak base and sodium sulfite into water to prepare an alkaline reduction solution of sodium sulfite; The concentration of sodium sulfite in the alkaline reduction solution of sodium sulfite is 12~15wt%; The amount of water-soluble weak base added is 0.52 to 0.55 of the molar amount of 4-fluoro-3,5-dimethylaniline; The amount of sodium sulfite added is 1.05 to 1.1 of the molar amount of 4-fluoro-3,5-dimethylaniline; The addition rate of diazo solution is 3~6L / min; The water-soluble weak base is sodium carbonate or potassium carbonate.

[0040] In the present application, the pH of the alkaline reducing solution of sodium sulfite is 9-10, and the pH of the entire reaction system should be maintained at 9-10 after the addition of the diazo solution, so that the reaction can proceed under weak alkaline conditions.

[0041] In the present application, the water-soluble weak base is sodium carbonate or potassium carbonate. This binary carbonate first generates the corresponding bicarbonate when reacting with the acid, and then undergoes the second step reaction. Therefore, it has a certain buffering capacity and can effectively avoid the disadvantage of large fluctuations in the reaction pH caused by the lack of buffering capacity when the strong base reacts with hydrochloric acid.

[0042] Optionally, the concentrations of the first hydrochloric acid and the second hydrochloric acid are both 32-37 wt %; The pH of the acidified reaction solution is ≤1.

[0043] In the present application, the reaction system is in a strongly acidic condition when 32-37 wt% is used, which is conducive to the reaction. In the present application, the pH of the acidified reaction solution is ≤ 1 to ensure that the phenylhydrazine in the reaction system is fully converted into the corresponding phenylhydrazine hydrochloride.

[0044] Optionally, the post-processing operation includes cooling and crystallization, impurity removal and drying processes; The cooling and crystallization process includes: cooling the acidified reaction solution to 20-30° C., and filtering after the product is completely precipitated to obtain a crude product of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride; The impurity removal process includes: adding toluene to the crude product obtained in the cooling and crystallization process, stirring at room temperature for 2 to 2.5 hours, and filtering to obtain a refined wet product; The drying process includes: drying the refined wet product under reduced pressure to obtain the finished product.

[0045] In the present application, the impurity removal process uses toluene as a solvent for pulping and purification. Since the product is insoluble in toluene, purification by pulping can reduce product loss.

[0046] Optionally, the negative pressure during the drying process is -0.06~-0.09MPa, the drying temperature is 65~75°C, and the drying is performed to a constant weight.

[0047] In the present application, the use of reduced pressure drying can improve processing efficiency and shorten drying time. Specific embodiment: Example 1 A method for preparing 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride is achieved by the following steps: S101. Add bottom water and 4-fluoro-3,5-dimethylaniline to a reaction device to obtain a premixed solution; the amount of bottom water added is twice the weight of 4-fluoro-3,5-dimethylaniline.

[0049] S102, adding a first concentrated hydrochloric acid having an amount three times the weight of 4-fluoro-3,5-dimethylaniline dropwise to the premixed solution at a rate of 3 L / min under stirring, controlling the system temperature not to exceed 30° C., stirring and keeping the temperature to react for 0.5 h, and then cooling the temperature to 5-15° C. to obtain an acidified mixed solution; S103. Prepare a sodium nitrite aqueous solution with a concentration of 25-30 wt %, cool it to 5° C., and drip the cooled sodium nitrite aqueous solution into the acidified mixed solution at a rate of 6 L / min under inert gas protection. After the dripping is completed, keep the mixture warm for 2 h to obtain a diazo solution; the amount of sodium nitrite added is 1.02 of the molar amount of 4-fluoro-3,5-dimethylaniline.

[0050] S104. Prepare an alkaline reducing solution of sodium sulfite, add the diazo solution dropwise into the alkaline reducing solution of sodium sulfite at a rate of 3 L / min, control the temperature to 65°C and react for 3 hours to obtain a reaction solution; the concentration of sodium sulfite in the alkaline reducing solution of sodium sulfite is 12 wt%; the amount of sodium carbonate added is 0.52 of the molar amount of 4-fluoro-3,5-dimethylaniline; and the amount of sodium sulfite added is 1.05 of the molar amount of 4-fluoro-3,5-dimethylaniline.

[0051] S105. Add a second concentrated hydrochloric acid to the reaction solution to adjust the pH of the reaction solution to ≤1. After the addition is complete, heat the reaction solution to 85° C. and reflux for 4 h to obtain an acidified reaction solution.

[0052] S106, cooling the acidified reaction solution to 20° C., and after the product is completely precipitated, filtering to obtain crude 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride; The crude product obtained during the cooling and crystallization process was added with toluene twice the mass of the crude product, stirred at room temperature for 2.5 h, and filtered to obtain a refined wet product; The refined wet product was dried at a negative pressure of -0.06 MPa and a drying temperature of 75° C. to a constant weight to obtain a finished product.

[0053] Example 2 A method for preparing 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride is achieved by the following steps: S201. Add bottom water and 4-fluoro-3,5-dimethylaniline to a reaction device to obtain a premixed solution; the amount of bottom water added is 2.5 times the weight of 4-fluoro-3,5-dimethylaniline.

[0054] S202, adding a first concentrated hydrochloric acid having an amount 3.2 times the weight of 4-fluoro-3,5-dimethylaniline to the premixed solution at a rate of 6 L / min under stirring, controlling the system temperature not to exceed 30° C., stirring and keeping the temperature to react for 1 hour, and then cooling to 15° C. to obtain an acidified mixed solution; S203. Prepare a 30 wt % sodium nitrite aqueous solution, cool it to 15° C., and drip the cooled sodium nitrite aqueous solution into the acidified mixed solution at a rate of 8 L / min under inert gas protection. After the dripping, keep the mixture warm for 3 h to obtain a diazo solution; the amount of sodium nitrite added is 1.07 of the molar amount of 4-fluoro-3,5-dimethylaniline.

[0055] S204. Prepare an alkaline reducing solution of sodium sulfite, add the diazo solution dropwise into the alkaline reducing solution of sodium sulfite at a rate of 6 L / min, control the temperature to 75°C and react for 2 hours to obtain a reaction solution; the concentration of sodium sulfite in the alkaline reducing solution of sodium sulfite is 15 wt%; the amount of the water-soluble weak base added is 0.55 of the molar amount of 4-fluoro-3,5-dimethylaniline; and the amount of the sodium sulfite added is 1.1 of the molar amount of 4-fluoro-3,5-dimethylaniline.

[0056] S205. Add a second concentrated hydrochloric acid to the reaction solution to adjust the pH of the reaction solution to ≤1. After the addition is complete, heat the reaction solution to 100° C. and reflux for 3 h to obtain an acidified reaction solution.

[0057] S206, cooling the acidified reaction solution to 30° C., and after the product is completely precipitated, filtering to obtain crude 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride; Add 2-3 times the mass of toluene to the crude product obtained during the cooling and crystallization process, stir at room temperature for 2-2.5 hours, and filter to obtain a refined wet product; The refined wet product was dried at a negative pressure of -0.09 MPa and a drying temperature of 65° C. to a constant weight to obtain a finished product.

[0058] Example 3 A method for preparing 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride is achieved by the following steps: S301. Add bottom water and 4-fluoro-3,5-dimethylaniline to a reaction device to obtain a premixed solution; the amount of bottom water added is 2.3 times the weight of 4-fluoro-3,5-dimethylaniline.

[0059] S302, adding a first concentrated hydrochloric acid of 3.1 times the weight of 4-fluoro-3,5-dimethylaniline to the premixed solution at a rate of 3-6 L / min under stirring, controlling the system temperature not to exceed 30° C., stirring and keeping the temperature to react for 0.8 h, and then cooling to 10° C. to obtain an acidified mixed solution; S303. Prepare a 28 wt% sodium nitrite aqueous solution, cool it to 10°C, and drip the cooled sodium nitrite aqueous solution into the acidified mixed solution at a rate of 7 L / min under inert gas protection. After the dripping is completed, keep the temperature and react for 2.5 hours to obtain a diazo solution; the amount of sodium nitrite added is 1.05 of the molar amount of 4-fluoro-3,5-dimethylaniline.

[0060] S304. Prepare an alkaline reducing solution of sodium sulfite, add the diazo solution dropwise into the alkaline reducing solution of sodium sulfite at a rate of 4 L / min, control the temperature to 70°C and react for 2.5 hours to obtain a reaction solution; the concentration of sodium sulfite in the alkaline reducing solution of sodium sulfite is 14 wt%; the amount of the water-soluble weak base added is 0.54 of the molar amount of 4-fluoro-3,5-dimethylaniline; and the amount of the sodium sulfite added is 1.08 of the molar amount of 4-fluoro-3,5-dimethylaniline.

[0061] S305. Add a second concentrated hydrochloric acid to the reaction solution to adjust the pH of the reaction solution to ≤ 1. After the addition is complete, heat the reaction solution to 90° C. and reflux for 3 to 4 hours to obtain an acidified reaction solution.

[0062] S306, cooling the acidified reaction solution to 25°C, and after the product is completely precipitated, filtering to obtain crude 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride; The crude product obtained during the cooling and crystallization process was added with toluene 2.5 times the mass of the crude product, stirred at room temperature for 2.3 h, and filtered to obtain a refined wet product; The refined wet product was dried at a negative pressure of -0.07 MPa and a drying temperature of 70° C. to a constant weight to obtain a finished product.

[0063] Example 4 A method for preparing 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride is achieved by the following steps: S401: Same operation as S301.

[0064] S402: The rest of the operations are the same as S302, except that the acidified mixed liquid is cooled to 5°C.

[0065] S403: The rest of the operation is the same as S303, except that the sodium nitrite aqueous solution is cooled to 15°C.

[0066] S404: Same operation as S304.

[0067] S405: Same operation as S305.

[0068] S406: Same operation as S306.

[0069] Comparative Example 1 A method for preparing 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride is achieved by the following steps: D101: Same operation as S301.

[0070] D102: Same operation as S302.

[0071] D103: Same operation as S303.

[0072] D104: The rest of the operations are the same as those in S304, except that after the diazo solution is added, the pH of the reaction system is adjusted to 7 and maintained until the end of the reaction.

[0073] D105: Same operation as S305.

[0074] D106: Same operation as S306.

[0075] The yield and purity of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloric acid prepared by the methods of Examples 1 to 3 above were calculated, and the results were statistically summarized in Table 1. The results are as follows: Table 1 Yield % purity% Example 1 84.32 99.5 Example 2 84.71 99.3 Example 3 85.24 99.5 Example 4 84.81 99.4 Comparative Example 1 74.16 99.2 Comparative Example 2 47.13 87.6 It can be seen from the data in Table 1 that the method of the present application can obtain a product with a yield of 84%, while the data of Comparative Example 1 show that when the diazo solution is reduced, neutral conditions are not conducive to the formation of the product, indicating that weak alkaline conditions (pH>9) are conducive to the reduction reaction.

[0076] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present application, rather than to limit them. Although the present application has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or make equivalent replacements for some or all of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A method for preparing 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride, characterized in that: The steps include: Adding bottom water and 4-fluoro-3,5-dimethylaniline into a reaction apparatus to obtain a premixed solution; The first concentrated hydrochloric acid is added dropwise to the premixed solution under stirring, and the system temperature is controlled not to exceed 30°C. The mixture is stirred and kept warm for 0.5 to 1 hour, and then cooled to obtain an acidified mixed solution. Prepare a sodium nitrite aqueous solution and cool it to 5-15°C. Add the cooled sodium nitrite aqueous solution dropwise to the acidified mixed solution under inert gas protection. Keep the solution warm for 2-3 hours to obtain a diazo solution. Prepare an alkaline reducing solution of sodium sulfite, add the diazonium solution dropwise into the alkaline reducing solution of sodium sulfite, control the temperature at 65-75°C, and react for 2-3 hours to obtain a reaction solution; Add the second concentrated hydrochloric acid to the reaction solution, raise the temperature to 85-100°C and reflux for 3-4 hours to obtain an acidified reaction solution; The acidified reaction liquid is subjected to post-processing operation to obtain a finished product.

2. The preparation method of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride according to claim 1, characterized in that The amount of the bottom water added is 2 to 2.5 times the weight of 4-fluoro-3,5-dimethylaniline.

3. The preparation method of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride according to claim 1, characterized in that, The amount of the first concentrated hydrochloric acid added to the premixed solution is 3 to 3.2 times the weight of 4-fluoro-3,5-dimethylaniline, and the addition rate is 3 to 6 L / min.

4. The method for preparing 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride according to claim 1, wherein The temperature of the acidified mixed solution is 5-15°C.

5. The method for preparing 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride according to claim 1, wherein The concentration of the sodium nitrite aqueous solution is 25-30 wt %, and the amount of sodium nitrite used is 1.02-1.07 of the molar amount of 4-fluoro-3,5-dimethylaniline; The addition rate of the sodium nitrite aqueous solution is 6-8 L / min.

6. The method for preparing 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride according to claim 1, wherein The inert gas is nitrogen or argon.

7. The method for preparing 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride according to claim 1, wherein The alkaline reducing solution of sodium sulfite is prepared according to the following steps: Adding a water-soluble weak base and sodium sulfite into water to prepare an alkaline reduction solution of sodium sulfite; The concentration of sodium sulfite in the alkaline reducing solution of sodium sulfite is 12-15wt%; The amount of the water-soluble weak base added is 0.52 to 0.55 of the molar amount of 4-fluoro-3,5-dimethylaniline; The amount of sodium sulfite added is 1.05 to 1.1 of the molar amount of 4-fluoro-3,5-dimethylaniline; The addition rate of the diazo solution is 3-6 L / min; The water-soluble weak base is sodium carbonate or potassium carbonate.

8. The method for preparing 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride according to claim 1, wherein The concentrations of the first hydrochloric acid and the second hydrochloric acid are both 32-37 wt %; The pH of the acidified reaction solution is ≤1.

9. The method for preparing 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride according to claim 1, wherein The post-processing operation includes cooling and crystallization, impurity removal and drying processes; The cooling and crystallization process comprises: cooling the acidified reaction solution to 20-30° C., and filtering to obtain a crude product of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride after the product is completely precipitated; The impurity removal process comprises: adding toluene to the crude product obtained in the cooling and crystallization process, stirring at room temperature for 2 to 2.5 hours, and filtering to obtain a refined wet product; The drying process includes: drying the refined wet product under reduced pressure to obtain a finished product.

10. The method for preparing 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride according to claim 9, characterized in that: The negative pressure of the drying process is -0.06~-0.09MPa, the drying temperature is 65~75°C, and the drying is performed to a constant weight.