Synthesis process of 4-fluoro-3, 5-dimethylphenylhydrazine hydrochloride

Abstract

The invention relates to the technical field of chemistry, in particular to a synthesis process of 4-fluoro-3, 5-dimethylphenylhydrazine hydrochloride, which comprises the following steps: by taking 4-fluoro-3, 5-dimethylbromobenzene as a raw material and hydrazine hydrate as a hydrazine source, matching with alkali such as potassium hydroxide, sodium hydroxide or potassium phosphate and the like, reacting at the temperature of 60-80 DEG C to obtain the 4-fluoro-3, 5-dimethylphenylhydrazine hydrochloride. The preparation method comprises the following steps: by taking copper or nickel source catalysts such as cuprous bromide, cuprous iodide, nickel salicylate and the like, N, N-bis (2, 6-dimethylphenyl) oxamide as a ligand, hexadecyl trimethyl ammonium bromide as a stabilizer and a dioxane-water mixed system as a solvent, reacting at 80-110 DEG C under the protection of nitrogen, separating a reaction mixed solution after the reaction is finished, and separating the reaction liquid to obtain the target product. And purifying to obtain a finished product of the 4-fluoro-3, 5-dimethyl phenylhydrazine hydrochloride. Therefore, the problems that the synthesis of the 4-fluoro-3, 5-dimethylphenylhydrazine hydrochloride is poor in safety, low in production efficiency, poor in environmental friendliness, small in substrate application range and the like are solved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of chemistry, and particularly relates to a synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride. BACKGROUND

[0002] Aromatic hydrazine is an important organic synthesis intermediate, and is also an intermediate in the manufacturing process of agricultural chemicals, medicines and other chemical materials, and is widely used in pesticide and medicine science, so how to more conveniently and quickly prepare aromatic hydrazine compounds has attracted widespread attention. Hydrazine is a cheap nitrogen source, and aromatic hydrazine compounds can be directly synthesized by using aromatic halides and hydrazine. In recent years, a large number of literatures or patents have reported research results of palladium or copper-catalyzed aromatic carbon-nitrogen coupling reactions. However, in the C-N coupling reaction process of aromatic halides and hydrazine, the aromatic primary amine generated in the reaction competes with hydrazine, which may lead to the generation of a large amount of by-products, and hydrazine has strong reducing property, which has a fatal effect on the activity of the catalyst, thereby reducing the yield of aromatic hydrazine. Therefore, there is still a great challenge for the method of preparing aromatic primary amine by the reaction of aromatic halides and hydrazine.

[0003] At present, more and more literatures report the synthesis of aromatic hydrazine, but these reactions usually have high raw material prices, long steps, low yield and large pollution. With the increasing environmental awareness of human beings and the proposal of the concept of green chemistry, how to reduce or even eliminate harmful substances discharged in the chemical industry has become a problem that human beings are increasingly concerned about and need to solve. SUMMARY

[0004] The present application provides a synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride, thereby solving the problems of poor safety, low production efficiency, poor environmental friendliness and small substrate application range in the synthesis of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride.

[0005] The first aspect of the present application provides a synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride, wherein the 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride is prepared by using aromatic halides and hydrazine as raw materials, water and dioxane as solvents, alkali metal or alkaline earth metal carbonates, fluorides, phosphates and hydroxides or compounds that can be converted into corresponding bases in water as bases, oxalyl amide substitutes and their salt compounds as ligands, and using copper or nickel source catalysts to catalyze the synthesis of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride from aromatic halides and hydrazine.

[0006] The second aspect embodiment of the application provides a synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride, which comprises the following steps: adding aromatic halide, solvent, stabilizer, hydrazine, base, ligand, copper or nickel source catalyst into a reactor, stirring and reacting under nitrogen protection at 80-110 DEG C, after the reaction is completed, separating the reaction mixture, and purifying to obtain 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride finished product.

[0007] It can be understood that, in the embodiment of the application, the aromatic halide is difficult to be directly nucleophilically substituted due to the stable structure of the aromatic ring, the copper or nickel as the catalyst can form an aromatic-metal intermediate with the aromatic halide through oxidative addition, activate the aromatic halide bond, the hydrazine as the nucleophile, under the action of the base, neutralize the generated hydrogen halide, activate the hydrazine to enhance its nucleophilicity, exchange the ligand with the aromatic-metal intermediate, reduce and eliminate to generate the aromatic hydrazine product, the catalyst is regenerated to enter the next cycle, the ligand coordinates with the transition metal to form a stable complex, which can improve the activity and selectivity of the catalyst, the nitrogen protection is used to avoid the oxidation of the catalyst or the hydrazine by oxygen, prevent the deactivation thereof, and the heating at 80-110 DEG C provides the activation energy required by the reaction, promotes the efficient performance of the catalytic cycle, and finally the 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride finished product is obtained through separation and purification.

[0008] The solvent is dioxane and water, and the molar ratio of dioxane, water and aromatic halide is 4.5-5:4.5-5:1.

[0009] The aromatic halide is 4-fluoro-3,5-dimethylbromobenzene, the ligand is N,N'-di(2,6-dimethylphenyl)oxamide, and the stabilizer is hexadecyltrimethylammonium bromide.

[0010] The copper or nickel source catalyst is any one of copper powder, copper oxide, cuprous oxide, copper sulfate, copper bromide, cuprous bromide, copper chloride, cuprous chloride, copper iodide, cuprous iodide, copper acetate, nickel chloride, nickel bromide, nickel salicylate, nickel dibromobispyridine, and nickel acetate.

[0011] The stirring reaction time is 5-14 h.

[0012] The molar ratio of the ligand, the stabilizer and the copper or nickel source catalyst is 0.5:0.2:1-0.2:0.1, 1.

[0013] The molar ratio of the aromatic halide and the hydrazine is 1:0.8-1.5.

[0014] The base is any one of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, and potassium phosphate, and the molar ratio of the aromatic halide and the base is 1:0.8-1.5.

[0015] The molar ratio of the aromatic halide to the copper or nickel source catalyst is 100:1-30:1.

[0016] Therefore, the present application has at least the following beneficial effects: 1. The present application realizes the dual advantages of high selectivity and catalytic stability by constructing a synergistic catalytic system of cuprous halide and oxamide derivative ligand, and forming a stable Cu(I) active center with nitrogen protection. When cuprous halide is used as a catalyst, its +1 valence state is easy to form a chelate structure with the oxamide derivative ligand through N and O atoms, which stabilizes the electronic configuration of copper ions and regulates the reaction path through the steric hindrance effect of the ligand. Under the condition of nitrogen protection, Cu(I) is effectively prevented from being oxidized to Cu(II), maintaining the stability of the catalytically active center. The chelate structure can form a spatial barrier to prevent the excessive reduction of copper ions by hydrazine. At the same time, the steric hindrance effect of the ligand can selectively guide the direction of nucleophilic attack of hydrazine, reducing the excessive coupling between aromatic hydrazine molecules and the reduction to aromatic amines, thereby improving the purity of the product. The ratio of catalyst to aromatic halide in the system is extremely low, and there is no need to rely on noble metals, which greatly reduces the cost of raw materials. The strong binding force between the ligand and the copper ion reduces the loss of the catalyst, prolonging its service life, thereby enabling industrial production and reducing production costs. 2. The present application uses a dioxane-water mixed solvent system to improve reaction efficiency through the synergistic effect of the two solvents. Dioxane is a high-boiling polar aprotic solvent that significantly enhances the solubility of hydrophobic aromatic halides, avoiding the formation of local high-concentration areas in the reaction system and the initiation of side reactions such as aromatic radical self-coupling. The introduction of water promotes the dispersion and ionization of hydrazine hydrate, enhances its nucleophilic activity, and reduces the overall viscosity of the system, accelerating the diffusion and collision of reactant molecules and improving mass transfer efficiency. The mixed system formed by the two solvents maintains a stable homogeneous environment at the reaction temperature, and is efficiently recovered by reduced pressure distillation, reducing the emission of volatile organic compounds. Compared with a single organic solvent system, the present application reduces the reaction activation energy, improves the reaction yield, and reduces the amount of organic solvent used, thereby reducing the risk of fire and toxic pollution and conforming to the development concept of green chemistry. 3. The present application adopts direct reaction at 80-110°C without stage control of temperature, saves complex temperature switching and holding parameter setting, reduces process control points, reduces operation complexity, shortens production preparation time, and also reduces human error and equipment fluctuation, improves production stability, and at the same time, 80-110°C provides sufficient energy for the complex of catalyst and ligand to form high-activity catalytic species. The continuous high temperature in this interval can directly activate the cleavage of C-Br bond in aromatic halide, promote the formation of aromatic copper intermediate and nucleophilic substitution reaction, both of which are carried out in cooperation, avoiding the time loss of step-by-step operation, significantly shortening the overall reaction time, improving the product output efficiency per unit time, and the process only needs to maintain a single temperature interval of 80-110°C, the heating system does not need to frequently switch power, energy consumption is reduced, and the requirement for temperature control accuracy of the equipment is relaxed, allowing small fluctuations, reducing the dependence on high-end temperature control equipment, reducing the initial investment and long-term maintenance cost of the production line. At the same time, the wide temperature interval of 80-110°C has strong inclusiveness. For aromatic halides with high C-Br bond activity, 80-90°C can meet the reaction requirements, and for substrates with low activity, the temperature can be appropriately increased to 100-110°C to accelerate the reaction, without the need to redesign complex parameters, thereby adapting to more types of raw materials, expanding the application range of the process, and the upper limit of the temperature of 80-110°C is not much different from the original high temperature stage, and hydrazine and aromatic halide can quickly mix and participate in the reaction at the appropriate temperature in the initial stage of the reaction, reducing the probability of decomposition of hydrazine due to long residence time. The continuous reaction shortens the total residence time of the product in the high temperature environment, effectively inhibits the overreaction of the product, and the content of by-products can be maintained at a low level, thereby simplifying the production process, improving production efficiency, and reducing production energy consumption; 4. The present application has strong compatibility and flexibility in raw material selection. In the selection of alkali, the process can flexibly adapt to various alkali agents according to the reaction requirements. Strong alkali is suitable for scenarios that require rapid dehalogenation, which can significantly accelerate the cleavage of C-Br bond and the formation of intermediate, shorten the reaction period, and weak alkali can realize the reaction under mild conditions, effectively protecting sensitive groups such as ester and amide, avoiding side reactions, and improving product purity. Therefore, production enterprises can dynamically adjust the formula according to raw material supply, cost fluctuations, and product quality requirements, while ensuring efficiency and reducing supply chain risk. The post-processing link can be completed by conventional filtration, extraction, washing, etc. without the need for complex purification equipment such as chromatographic separation and supercritical extraction, reducing equipment investment cost. Product drying only requires medium-temperature air blowing conditions, which reduces energy consumption compared to traditional vacuum drying processes, shortens drying time, and significantly improves post-processing efficiency. The low-threshold and highly adaptable process design provides convenience for industrialization, without the need for large-scale equipment replacement, and only by adjusting the temperature control module of the reaction kettle and optimizing the stirring parameters, different scale enterprises can quickly realize mass production, thereby significantly reducing the difficulty and cost of industrialization. 5. The present application optimizes the raw material ratio of aromatic halide and hydrazine, and the molar ratio of aromatic halide and hydrazine is controlled at 1:0.8-1.5, which ensures sufficient supply of hydrazine as a nucleophile, promotes the full conversion of aromatic halide, avoids excessive accumulation of hydrazine, reduces the waste of hydrazine, and the ratio of aromatic halide and base is also set at 1:0.8-1.5. The base is used to neutralize the hydrogen halide generated in the reaction, avoiding its inhibition of catalyst activity, and the slight excess of base can maintain the alkaline environment of the system, promote the formation and stability of aromatic copper intermediates, and the precise ratio design reduces the invalid consumption of raw materials, improves the atom utilization rate, and at the same time, the by-product is only halide when each mole of aromatic halide is converted into product, which can be recycled through simple treatment. The optimized ratio makes the residual amount of unreacted raw materials in the reaction system very low, reducing the pollutant load in wastewater treatment, and at the same time, the improvement of raw material utilization rate reduces the production cost, realizing the double optimization of environmental protection and benefit. BRIEF DESCRIPTION OF DRAWINGS

[0017] The above and / or additional aspects and advantages of the present application will become apparent and more readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings, in which: Figure 1 A reaction equation diagram of a synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride according to the embodiment of the present application is provided; Figure 2 An N,N'-di(2,6-dimethylphenyl)oxamide structure diagram of a synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride according to the embodiment of the present application is provided; Figure 3 A 4-fluoro-3,5-dimethylbromobenzene structure diagram of a synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride according to the embodiment of the present application is provided; Figure 4 A dioxane structure diagram of a synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride according to the embodiment of the present application is provided; Figure 5 A cetyltrimethylammonium bromide structure diagram of a synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride according to the embodiment of the present application is provided; Figure 6 A 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride finished product purity diagram of a synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride according to the embodiment of the present application is provided. DETAILED DESCRIPTION

[0018] The technical solutions of the present application are illustrated below through specific examples. It should be understood that the one or more method steps mentioned in the present application do not exclude the existence of other method steps before and after the mentioned combination steps or the insertion of other method steps between these explicitly mentioned steps; it should also be understood that these examples are only used to illustrate the present application and not to limit the scope of the present application. Moreover, unless otherwise specified, the numbering of each method step is only a convenient tool to identify each method step, and is not a limitation on the arrangement order of each method step or a limitation on the scope of the present application that can be implemented, and the change or adjustment of the relative relationship without substantial change of the technical content is also regarded as the scope of the present application that can be implemented.

[0019] In order to better understand the above technical solutions, the exemplary embodiments of the present application are described in more detail below. Although exemplary embodiments of the present application are shown, it should be understood that the present application can be implemented in various forms and should not be limited by the embodiments set forth herein. On the contrary, these embodiments are provided so that the present application can be more thoroughly understood and the scope of the present application can be completely conveyed to those skilled in the art.

[0020] The dioxane used in the embodiments of the present application is from Shanghai Aladdin Bio-Chem Technology Co., Ltd.; the water used is from Guangzhou He Wei Pharmaceutical Technology Co., Ltd.; the 2,6-dimethylbenzene used is from Shanghai Macklin Biochemical Technology Co., Ltd.; the 4-fluoro-3,5-dimethylbromobenzene used is from Shanghai Fuduo Chemical Co., Ltd.; the copper powder used is from Tianjin Guangfu Science and Technology Development Co., Ltd.; the copper oxide used is from Shanghai Aladdin Bio-Chem Technology Co., Ltd.; the cuprous oxide used is from Shanghai Macklin Biochemical Technology Co., Ltd.; the copper sulfate used is from Tianjin Xinsiyuan Biochemical Technology Co., Ltd.; the copper bromide used is from Shanghai Aladdin Bio-Chem Technology Co., Ltd.; the cuprous bromide used is from Shanghai Aladdin Bio-Chem Technology Co., Ltd.; the copper chloride used in the embodiments of the present application is from Suzhou Senfine Chemical Co., Ltd.; the cuprous chloride used is from Shanghai Macklin Biochemical Technology Co., Ltd.; the copper iodide used is from Shanghai Yenn Chemical Technology Co., Ltd.; the cuprous iodide used is from Shanghai Aladdin Bio-Chem Technology Co., Ltd.; the copper acetate used is from Tianjin Guangfu Science and Technology Development Co., Ltd.; the nickel chloride used is from Shanghai Bangcheng Chemical Co., Ltd.; the nickel bromide used is from Shanghai Macklin Biochemical Technology Co., Ltd.; the nickel salicylate used is from Shanghai Aladdin Bio-Chem Technology Co., Ltd.; the nickel dibromobispyridine used is from Shanghai Aladdin Bio-Chem Technology Co., Ltd.; the nickel acetate used is from Shanghai Macklin Biochemical Technology Co., Ltd.; the potassium hydroxide used is from Shanghai Hongrui Chemical Co., Ltd.; the sodium hydroxide used is from Shanghai Macklin Biochemical Technology Co., Ltd.; the potassium carbonate used is from Shanghai Aladdin Bio-Chem Technology Co., Ltd.; the sodium carbonate used is from Beijing Comfywell Technology Co., Ltd.; the cesium carbonate used is from Shanghai Macklin Biochemical Technology Co., Ltd.; the sodium bicarbonate used is from Shanghai Aladdin Bio-Chem Technology Co., Ltd.; the potassium phosphate used is from Tianjin Xinsiyuan Biochemical Technology Co., Ltd.

[0021] A synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride is described below with reference to the accompanying drawings. In view of the poor safety, low production efficiency, poor environmental friendliness, and small substrate application range of the synthesis of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride mentioned in the background art, the present application provides a synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride, which uses 4-fluoro-3,5-dimethylbromobenzene as a raw material, hydrazine hydrate as a hydrazine source, and potassium hydroxide, sodium hydroxide, or potassium phosphate as an alkali, uses cuprous bromide, cuprous iodide, or the like as a halogenated cuprous catalyst, uses N,N,-bis(2,6-dimethylphenyl)oxamide as a ligand, uses cetyltrimethylammonium bromide as a stabilizer, uses a dioxane-water mixed system as a solvent, and realizes efficient synthesis through a temperature rising reaction under nitrogen protection. The halogenated cuprous catalyst and the oxamide ligand form a stable chelate structure, the N and O atoms coordinate to stabilize the Cu(I) active center, the reduction of hydrazine is inhibited to prevent catalyst deactivation, the ligand steric hindrance effect effectively reduces excessive coupling of aromatic hydrazine, the purity of the product is improved, dioxane enhances the solubility of organic raw materials, water promotes the dispersion of hydrazine, and the mass transfer efficiency is improved, thereby reducing side reactions caused by excessive local concentration, nitrogen protection avoids decomposition of hydrazine and oxidation of the catalyst, the C-Br bond is accurately activated at a reaction temperature of 80-110°C, the reaction time is shortened, the catalyst is removed by filtering through diatomite after treatment, dichloromethane is used for extraction, the pH is adjusted to 2.5-3.0 by hydrochloric acid to make the product salt precipitate, and the purity is further improved through a washing and drying step, thereby obtaining high-purity 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride. Thus, the problems of poor safety, low production efficiency, poor environmental friendliness, and small substrate application range in the synthesis of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride are solved.

[0022] A synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride is described below with reference to the accompanying drawings.

[0023] Specifically, Figure 1 A reaction equation diagram of the synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride provided in the embodiments of the present application is shown.

[0024] As Figure 1 shown, the synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride includes the following steps: aromatic halide, solvent, stabilizer, hydrazine, base, ligand, copper or nickel source catalyst are added to the reactor, nitrogen protection is performed at 80-110°C, and stirring reaction is performed. After the reaction is completed, the reaction mixture is separated, and 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride is obtained by purification.

[0025] The solvent is dioxane and water, the molar ratio of dioxane, water and aromatic halide is 4.5-5:4.5-5:1, the aromatic halide is 4-fluoro-3,5-dimethylbromobenzene, the ligand is N,N'-di(2,6-dimethylphenyl)oxamide, the stabilizer is hexadecyl trimethyl ammonium bromide, the copper or nickel source catalyst is any one of copper powder, copper oxide, cuprous oxide, copper sulfate, copper bromide, cuprous bromide, copper chloride, cuprous chloride, copper iodide, cuprous iodide, copper acetate, nickel chloride, nickel bromide, nickel salicylate, nickel dibromobispyridine, nickel acetate, the stirring reaction time is 5-14h, the molar ratio of ligand, stabilizer and copper or nickel source catalyst is 0.5:0.2:1-0.2:0.1, the molar ratio of aromatic halide and hydrazine is 1:0.8-1.5, the base is any one of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium phosphate, the molar ratio of aromatic halide and base is 1:0.8-1.5, and the molar ratio of aromatic halide and copper or nickel source catalyst is 100:1-30:1.

[0026] It can be understood that, in the embodiments of the present application, the aromatic halide is difficult to be directly subjected to nucleophilic substitution due to the stable structure of the aromatic ring, the copper or nickel as a catalyst can form an aromatic-metal intermediate with the aromatic halide through oxidative addition, activate the aromatic halide bond, the hydrazine as a nucleophile can be neutralized with the base to generate hydrogen halide, activate the hydrazine to enhance its nucleophilicity, exchange ligands with the aromatic-metal intermediate, and reduce and eliminate to generate an aromatic hydrazine product, the catalyst is regenerated to enter the next cycle, the ligand is coordinated with the transition metal to form a stable complex, the activity and selectivity of the catalyst can be improved, the nitrogen protection is used to avoid the oxidation of the catalyst or the hydrazine by oxygen and prevent the deactivation thereof, and heating at 80-110 DEG C provides the activation energy required by the reaction and promotes the efficient performance of the catalytic cycle, and finally, the 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride product is obtained through separation and purification.

[0027] Specifically, the aromatic halide is added to a reactor, then the solvent is added, followed by the addition of the hydrazine, the stirring is started, then the stabilizer, the base and the ligand are added, the nitrogen protection is performed, the system is warmed, then the copper or nickel source catalyst is added under the condition of controlling the temperature, after the addition is completed, the reaction temperature is controlled and the stirring is performed for a period of time, during which the reaction is detected by sampling to determine whether the reaction is completed, after the reaction is completed, the system is cooled, the system is filtered under the nitrogen protection through diatomite, the filtrate is collected, the filtrate is subjected to desolventization under reduced pressure until almost no liquid flows out, while the filter cake is eluted with the solvent and water respectively, the elution liquid is collected, the residual liquid after the desolventization is added to the solvent and water, mixed with the previously collected filtrate and elution liquid, stirred and extracted at a certain temperature, and separated, the organic phase is washed with saturated sodium chloride aqueous solution, after the treatment of the aqueous phase, concentrated hydrochloric acid is added to the organic phase to adjust the pH to a certain range, stirred at a certain temperature, then suction filtered, the filter cake is washed with the solvent and then filtered dry, dried at a certain temperature until the constant weight, and the 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride product is obtained.

[0028] The application provides a synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride, which uses 4-fluoro-3,5-dimethylbromobenzene as raw material, hydrazine hydrate as hydrazine source, and potassium hydroxide, sodium hydroxide or potassium phosphate as base, uses cuprous bromide, cuprous iodide and other cuprous halides as catalyst, N,N,-di(2,6-dimethylphenyl)oxamide as ligand, cetyltrimethylammonium bromide as stabilizer, uses dioxane-water mixed system as solvent, and realizes efficient synthesis through temperature rising reaction under nitrogen protection, cuprous halide and oxamide ligand form a stable chelate structure, the N and O atom coordination stabilizes the Cu(I) active center, inhibits the deactivation of the catalyst caused by the reducing property of hydrazine, the ligand steric effect effectively reduces the excessive coupling of aromatic hydrazine, the product purity is improved, dioxane enhances the solubility of organic raw materials, water promotes the dispersion of hydrazine, and the mass transfer efficiency is improved, the decomposition of hydrazine and the oxidation of the catalyst are avoided through nitrogen protection, the C-Br bond is accurately activated at a reaction temperature of 80-110 DEG C, the reaction time is shortened, the catalyst is removed through diatomite filtration, dichloromethane extraction, and pH adjustment to 2.5-3.0 through hydrochloric acid to make the product salt precipitate, and the purity is further improved through the washing and drying steps, so that high-purity 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride is obtained. Thus, the problems of poor safety, low production efficiency, poor environmental friendliness and small substrate application range in the synthesis of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride are solved.

[0029] The synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride will be described below through specific examples, including:

[0030] Example 1 The application provides a synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride, which uses aromatic halide and hydrazine as raw material, dioxane and water as solvent, alkali metal or alkaline earth metal carbonate, fluoride, phosphate and hydroxide or compounds that can be converted into corresponding alkali in water as base, oxamide substitutes and their salt compounds as ligand, and uses copper or nickel source catalyst to catalyze the synthesis of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride from aromatic halide and hydrazine.

[0031] The application also provides a synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride, which includes the following steps: 4-fluoro-3,5-dimethylbromobenzene 348 kg was added into a reaction kettle, 2.5 tons of 1,4-dioxane was added, 201 kg of 85% hydrazine hydrate was added, stirring was started, 180 kg of potassium hydroxide was weighed and added into the above system, 9 kg of cetyltrimethylammonium bromide was weighed and added into the above reaction liquid system, under the condition of nitrogen protection, the above reaction liquid was heated to above 80°C, 8.9 kg of copper bromide and 16.7 kg of N,N'-di(2,6-dimethylphenyl)oxamide were weighed and mixed as shown in Figure 2 , under the condition of nitrogen protection, the temperature in the reaction kettle was controlled below 100°C, the mixture of copper bromide and the ligand was added into the above system, after the addition was completed, the temperature in the reaction kettle was controlled at 80-90°C, stirring was carried out for 5-6 h, sampling was carried out, HPLC detection was carried out, after the reaction was completed, the above system was cooled to 30-50°C, nitrogen protection was carried out, diatomite was filtered, the filtrate was collected, under the condition of 50-55°C, the filtrate was vacuum desolventized until no liquid dropped into the condenser, the next operation was entered, the filter cake was eluted with 850 kg of dichloromethane and 650 kg of water, the filtrate was collected separately, after the desolventization was completed, the residual liquid was added into 3.4 tons of dichloromethane and 1.3 tons of water, the filtrate of dichloromethane and water was mixed, stirring extraction separation was carried out under the condition of 10-30°C, the dichloromethane phase was washed once with 650 kg of saturated sodium chloride aqueous solution, the organic phase was obtained, the organic phase was adjusted to a pH of 2.5-3.0 with 12 mol / L concentrated hydrochloric acid, after the adjustment was completed, stirring was carried out at 20-30°C for 1 h, suction filtration was carried out, the filter cake was washed once with 420 kg of dichloromethane, after the filtration was completed, drying was carried out at 50-55°C until the constant weight, 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride was obtained.

[0032] Example 2 The present application provides a synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride, which takes aromatic halide and hydrazine as raw materials, takes dioxane and water as solvents, takes carbonates, fluorides, phosphates and hydroxides of alkali metals or alkaline earth metals or compounds that can be converted into corresponding bases in water as bases, takes oxamide substitutes and their salt compounds as ligands, adopts copper or nickel source catalyst to catalyze the synthesis of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride from aromatic halide and hydrazine.

[0033] The present application also provides a synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride, which comprises the following steps: 4-fluoro-3,5-dimethylbromobenzene 337 kg was added into a reaction kettle as shown in Figure 3 , 1.6 tons of 1,4-dioxane was added as shown in Figure 4As shown, 203 kg of 85% hydrazine hydrate is added, stirring is started, 100 kg of potassium hydroxide is weighed and added to the above system, 58 kg of cetyltrimethylammonium bromide is weighed and added to the above system, and Figure 5 As shown, the above reaction liquid system is added, and the reaction liquid is heated to above 80°C under nitrogen protection. 6.9 kg of cuprous bromide and 17.7 kg of N,N'-di(2,6-dimethylphenyl)oxamide are mixed, and the mixture is added to the above system under nitrogen protection, and the temperature in the reaction kettle is controlled below 100°C. After the addition is completed, the temperature in the reaction kettle is controlled at 90-100°C, and stirring is carried out for 1-2 h. After the reaction is completed, the above system is cooled to 30-50°C, and the system is filtered through diatomite under nitrogen protection. The filtrate is collected, and the filtrate is concentrated under reduced pressure at 50-55°C until no liquid drops fall into the condenser. The next operation is carried out. The filter cake is eluted with 850 kg of dichloromethane and 650 kg of water. The filtrate is collected separately. After complete desolventization, the residual liquid is added to 3.4 tons of dichloromethane and 1.3 tons of water. The dichloromethane and water filtrate are mixed and stirred at 10-30°C for extraction and separation. The dichloromethane phase is washed once with 650 kg of saturated sodium chloride aqueous solution to obtain an organic phase. The organic phase is adjusted to a pH of 2.5-3.0 with 12 mol / L concentrated hydrochloric acid. After the adjustment is completed, the system is stirred at 20-30°C for 1 h, and then filtered. The filter cake is washed once with 420 kg of dichloromethane, and then dried at 50-55°C until the weight is constant to obtain 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride.

[0034] Example 3 The present application provides a synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride. The synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride uses aromatic halide and hydrazine as raw materials, dioxane and water as solvents, alkali metal or alkaline earth metal carbonate, fluoride, phosphate and hydroxide or a compound that can be converted into a corresponding base in water as a base, oxamide substituent and its salt compound as a ligand, and a copper or nickel source catalyst to catalyze the synthesis of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride from aromatic halide and hydrazine.

[0035] The present application also provides a synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride. The synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride includes the following steps: In a reaction kettle, 332 kg of 4-fluoro-3,5-dimethylbromobenzene was added, 1.6 tons of 1,4-dioxane was added, 150 kg of 85% hydrazine hydrate was added, stirring was started, 100 kg of sodium hydroxide was weighed, 23.7 kg of N,N'-di(2,6-dimethylphenyl)oxamide was added to the above system, 30 kg of cetyltrimethylammonium bromide was added to the above reaction liquid system, the above reaction liquid was heated to above 80°C under nitrogen protection, 15.3 kg of copper iodide was weighed, the temperature in the reaction kettle was controlled below 100°C under nitrogen protection, the above system was added, after the addition was completed, the temperature in the reaction kettle was controlled at 90-100°C, stirring was carried out for 1-2 h, sampling was carried out, HPLC detection was carried out, after the reaction was completed, the above system was cooled to 30-50°C, nitrogen protection was carried out, diatomite was filtered, the filtrate was collected, under the condition of 50-55°C, the filtrate was vacuum desolventized until no liquid dropped into the condenser, the next operation was carried out, the filter cake was eluted with 850 kg of dichloromethane, 650 kg of water was eluted, the filtrate was collected separately, after the desolventization was completed, the residual liquid was added to 3.4 tons of dichloromethane and 1.3 tons of water, the dichloromethane and water filtrate was mixed, stirring extraction separation was carried out under the condition of 10-30°C, the dichloromethane phase was washed once with 650 kg of saturated sodium chloride aqueous solution, the organic phase was obtained, the organic phase was adjusted to a pH of 2.5-3.0 with 12 mol / L concentrated hydrochloric acid, after the adjustment was completed, stirring was carried out at 20-30°C for 1 h, filtration was carried out, the filter cake was washed once with 420 kg of dichloromethane, after the filtration was completed, drying was carried out at 50-55°C until the constant weight, 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride was obtained.

[0036] Example 4 The present application provides a synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride, which uses aromatic halide and hydrazine as raw materials, dioxane and water as solvents, alkali metal or alkaline earth metal carbonate, fluoride, phosphate and hydroxide or a compound that can be converted into a corresponding base in water as a base, oxamide substitute and its salt compound as a ligand, and uses a copper or nickel source catalyst to catalyze the synthesis of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride from aromatic halide and hydrazine.

[0037] The present application also provides a synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride, which comprises the following steps: The 4-fluoro-3,5-dimethylbenzene hydrazine hydrochloride product is obtained by adding 4-fluoro-3,5-dimethylbromobenzene 328 kg into a reaction kettle, adding 1.6 tons of water, adding 150 kg of 85% hydrazine hydrate, starting stirring, weighing 407 kg of potassium phosphate, weighing 23.7 kg of N,N'-di(2,6-dimethylphenyl)oxamide into the above system, weighing 30 kg of cetyltrimethylammonium bromide into the above reaction liquid system, heating the above reaction liquid to 80°C under nitrogen protection, weighing 9.3 kg of cuprous iodide, controlling the temperature in the reaction kettle to be below 80°C under nitrogen protection, adding the above system, controlling the temperature in the reaction kettle to be 80°C, stirring for 1-2 h, sampling and detecting by HPLC, cooling the above system to 30-50°C after the reaction is completed, filtering under nitrogen protection and with diatomite, collecting the filtrate, reducing and dissolving under reduced pressure at 50-55°C until no liquid drops fall into the condenser, entering the next operation, using 850 kg of dichloromethane to elute the filter cake, using 650 kg of water to elute, separately collecting the filtrate, adding the residual liquid into 3.4 tons of dichloromethane and 1.3 tons of water after complete dissolution, mixing the dichloromethane and water filtrate, stirring and extracting at 10-30°C, washing the dichloromethane phase once with 650 kg of saturated sodium chloride aqueous solution to obtain an organic phase, adjusting the pH of the organic phase to 2.5-3.0 with 12 mol / L concentrated hydrochloric acid, stirring at 20-30°C for 1 h after the adjustment is completed, filtering, soaking the filter cake with 420 kg of dichloromethane once, drying after filtering to constant weight at 50-55°C to obtain 4-fluoro-3,5-dimethylbenzene hydrazine hydrochloride.

[0038] Example 5 The present application provides a synthesis process of 4-fluoro-3,5-dimethylbenzene hydrazine hydrochloride, which uses aromatic halide and hydrazine as raw materials, dioxane and water as solvents, alkali metal or alkaline earth metal carbonate, fluoride, phosphate and hydroxide or a compound that can be converted into a corresponding base in water as a base, oxamide substitute and its salt compound as a ligand, and a copper or nickel source catalyst to catalyze the synthesis of 4-fluoro-3,5-dimethylbenzene hydrazine hydrochloride from aromatic halide and hydrazine.

[0039] The present application also provides a synthesis process of 4-fluoro-3,5-dimethylbenzene hydrazine hydrochloride, which comprises the following steps: Put 4-fluoro-3, 5-dimethylbromobenzene 321 kg into the reaction kettle, add 1.6 tons of water, add 150 kg of 85% hydrazine hydrate, start stirring, weigh 407 kg of potassium phosphate, 23.7 kg of N, N'-di(2, 6-dimethylphenyl) oxalate is added to the above system, weigh 30 kg of cetyltrimethylammonium bromide and add it to the above reaction liquid system, under the condition of nitrogen protection, the above reaction liquid is heated to 80℃, weigh 8.5 kg of nickel acetate, under the condition of nitrogen protection, control the temperature in the reaction kettle below 80℃, add the above system, control the temperature in the reaction kettle below 80℃, stir for 1-2h, sample HPLC detection, after the reaction is completed, the above system is cooled to 30-50℃, nitrogen protection pad diatomite filtration, collect the filtrate, under the condition of 50-55℃, reduce pressure desolventization to the condenser without liquid drop, enter the next operation, the filter cake is eluted with dichloromethane 850 kg, water 650 kg, the filtrate is collected separately, after complete desolventization, the residual liquid is added to dichloromethane 3.4 tons of water 1.3 tons, mixed with dichloromethane and water filtrate, stirred extraction separation under the condition of 10-30℃, the dichloromethane phase is washed once with saturated sodium chloride aqueous solution 650 kg, to obtain the organic phase, the organic phase is adjusted to PH 2.5-3.0 with 12 mol / L concentrated hydrochloric acid, after adjustment, stir at 20-30℃ for 1h, filter, the filter cake is washed once with 420 kg of dichloromethane, after drying, the product 4-fluoro-3, 5-dimethylphenylhydrazine hydrochloride is obtained under the condition of 50-55℃.

[0040] Comparative example 1, compared with example 1, the solvent 1, 4-dioxane is replaced with water, and copper bromide is replaced with nickel salicylate.

[0041] The present application provides a synthesis process of 4-fluoro-3, 5-dimethylphenylhydrazine hydrochloride, which uses aromatic halide and hydrazine as raw materials, dioxane and water as solvent, alkali metal or alkaline earth metal carbonate, fluoride, phosphate and hydroxide or compounds that can be converted into corresponding bases in water as base, oxamide substitutes and their salt compounds as ligand, and uses copper or nickel source catalyst to catalyze the synthesis of 4-fluoro-3, 5-dimethylphenylhydrazine hydrochloride from aromatic halide and hydrazine.

[0042] The present application also provides a synthesis process of 4-fluoro-3, 5-dimethylphenylhydrazine hydrochloride, which comprises the following steps: 4-fluoro-3,5-dimethylbromobenzene 348 kg was added into a reaction kettle, 2.5 tons of water was added, 201 kg of 85% hydrazine hydrate was added, stirring was started, 180 kg of potassium hydroxide was weighed and added into the above system, 9 kg of cetyltrimethylammonium bromide was weighed and added into the above reaction liquid system, under the condition of nitrogen protection, the above reaction liquid was heated to above 80°C, 8.9 kg of nickel salicylate and 16.7 kg of N,N'-di(2,6-dimethylphenyl)oxamide were mixed, under the condition of nitrogen protection, the temperature in the reaction kettle was controlled to be below 100°C, the mixture of copper bromide and the ligand was added into the above system, after the addition was completed, the temperature in the reaction kettle was controlled to be 80-90°C, stirring was carried out for 5-6 h, sampling was carried out, HPLC detection was carried out, after the reaction was completed, the temperature of the above system was lowered to 30-50°C, nitrogen protection was carried out, diatomite was used for filtration, the filtrate was collected, under the condition of 50-55°C, the filtrate was subjected to vacuum desolventization until no liquid dropped into the condenser, the next operation was entered, the filter cake was eluted with 850 kg of dichloromethane and 650 kg of water, the filtrate was collected separately, after the desolventization was completed, the residual liquid was added into 3.4 tons of dichloromethane and 1.3 tons of water, the filtrate of dichloromethane and water was mixed, stirring extraction separation was carried out under the condition of 10-30°C, the dichloromethane phase was washed once with 650 kg of saturated sodium chloride aqueous solution, the organic phase was obtained, the organic phase was adjusted to PH 2.5-3.0 with 12 mol / L concentrated hydrochloric acid, after the adjustment was completed, stirring was carried out at 20-30°C for 1 h, filtration was carried out, the filter cake was washed once with 420 kg of dichloromethane, after the filtration was completed, drying was carried out at 50-55°C until the constant weight, 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride was obtained.

[0043] In Comparative Example 2, the addition concentration of hydrazine hydrate and the reaction temperature were increased compared with Example 1.

[0044] The application provides a synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride, which uses aromatic halide and hydrazine as raw materials, dioxane and water as solvents, a carbonate, a fluoride, a phosphate and a hydroxide of an alkali metal or an alkaline earth metal or a compound capable of being converted into a corresponding base in water as a base, an oxamide substitute and a salt compound thereof as a ligand, and a copper or nickel source catalyst, and catalyzes the synthesis of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride from aromatic halide and hydrazine.

[0045] The application further provides a synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride, and the synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride comprises the following steps. Put 4-fluoro-3, 5-dimethyl bromobenzene 348 kg into the reaction kettle, add 2 tons of 1, 4-dioxane, add 201 kg of 90% hydrazine hydrate, start stirring, weigh 180 kg of potassium hydroxide and add it to the above system, weigh 9 kg of cetyl trimethyl ammonium bromide and add it to the above reaction liquid system, under the condition of nitrogen protection, heat the above reaction liquid to above 80℃, weigh 8.9 kg of copper bromide and 16.7 kg of N, N'-di (2, 6-dimethyl phenyl) oxamide mixture, under the condition of nitrogen protection, control the temperature in the reaction kettle below 100℃, add the mixture of copper bromide and ligand to the above system, after adding, control the temperature in the reaction kettle at 90-95℃, stir for 5-6h, take sample for HPLC detection, after the reaction is completed, cool the above system to 30-50℃, filter with nitrogen protection pad diatomite, collect the filtrate, under the condition of 50-55℃, reduce pressure to remove the solvent to the condenser without liquid drop, enter the next operation, use dichloromethane 850 kg to elute the filter cake, wash with water 650 kg, collect the filtrate separately, after complete removal of the solvent, add the residual liquid to dichloromethane 3.4 tons, water 1.3 tons, mix with the dichloromethane and water filtrate, stir to extract and separate liquid under the condition of 10-30℃, wash the dichloromethane phase with saturated sodium chloride aqueous solution 650 kg once, obtain the organic phase, use 12 mol / L concentrated hydrochloric acid to adjust the PH to 2.5-3.0, after adjustment, stir at 20-30℃ for 1h, filter, use 420 kg of dichloromethane to soak the filter cake once, after drying, dry at 50-55℃ to constant weight to obtain 4-fluoro-3, 5-dimethyl phenylhydrazine hydrochloride product.

[0046] Comparative example 3, compared with example 1, replace potassium hydroxide with cesium carbonate, and replace copper bromide with nickel dibromobispyridine.

[0047] The present application provides a synthesis process of 4-fluoro-3, 5-dimethyl phenylhydrazine hydrochloride, which uses aromatic halide and hydrazine as raw materials, dioxane and water as solvent, alkali metal or alkaline earth metal carbonate, fluoride, phosphate and hydroxide or compounds that can be converted into corresponding alkali in water as base, oxamide substitute and its salt compounds as ligand, and uses copper or nickel source catalyst to catalyze the synthesis of 4-fluoro-3, 5-dimethyl phenylhydrazine hydrochloride from aromatic halide and hydrazine.

[0048] The present application also provides a synthesis process of 4-fluoro-3, 5-dimethyl phenylhydrazine hydrochloride, which comprises the following steps: Into a reaction vessel was added 4-fluoro-3,5-dimethylbromobenzene 348 kg, 2.5 tons of 1,4-dioxane, 201 kg of 85% hydrazine hydrate, and stirring was started. 180 kg of cesium carbonate was weighed into the system, and 9 kg of cetyltrimethylammonium bromide was weighed into the reaction liquid system. The reaction liquid was heated to above 80°C under nitrogen protection, and 8.9 kg of nickel dibromobipyridine and 16.7 kg of N,N'-di(2,6-dimethylphenyl)oxamide were mixed. The mixture of copper bromide and the ligand was added to the system under nitrogen protection, and the temperature in the reaction vessel was controlled to be below 100°C. The bromide copper and the ligand mixture were added to the system, and the temperature in the reaction vessel was controlled to be 80-90°C. After stirring for 5-6 h, the sample was detected by HPLC. After the reaction was completed, the system was cooled to 30-50°C, and the filter cake was filtered with nitrogen protection and diatomite. The filtrate was collected, and the residual liquid was added to 3.4 tons of dichloromethane and 1.3 tons of water. The filtrate was mixed with dichloromethane and water, and stirring extraction was performed at 10-30°C. The dichloromethane phase was washed once with 650 kg of saturated sodium chloride aqueous solution to obtain an organic phase. The organic phase was adjusted to a pH of 2.5-3.0 with 12 mol / L concentrated hydrochloric acid. After adjustment, the system was stirred at 20-30°C for 1 h, and then filtered. The filter cake was washed once with 420 kg of dichloromethane, and then dried at 50-55°C to constant weight to obtain 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride.

[0049] The purity of the 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride product of Examples 1-5 and Comparative Examples 1-3 was obtained as shown in Table 1, and the yield data are shown in Table 1. Figure 6

[0050] ​Compared with Example 2, the yield range of Example 1 is consistent, the purity is consistent, the catalyst type, the amount of base, the amount of phase transfer catalyst and the reaction parameters are different, the difference of catalyst, the copper bromide is used in Example 1, the cuprous bromide is used in Example 2, the oxidation state of copper ions will affect the coordination mode of the ligand, the coordination of divalent copper with the ligand is more stable but the activity is slightly lower, the monovalent copper forms a more active catalytic intermediate, but both can combine with the oxamide ligand to form an effective catalytic center, the balance of base and phase transfer catalyst, the amount of potassium hydroxide is higher in Example 1, but the amount of phase transfer catalyst is lower, and the amount of phase transfer catalyst is higher in Example 2, the phase transfer catalyst can promote the mass transfer of the organic phase aromatic bromide, dioxane and hydrazine hydrate, and the base, the increase of the amount of phase transfer catalyst can compensate for the influence of the decrease of the amount of base, and ensure the deprotonation efficiency of hydrazine, the hydrazine needs to be deprotonated to act as a nucleophile to attack the aromatic bromide, the matching of reaction temperature and time, the reaction temperature of Example 1 is slightly lower, but the time is longer, the temperature of Example 2 is slightly higher, but the time is shorter, the increase of temperature can accelerate the reaction rate, and the similar conversion rate can be achieved after the time is shortened, so the yield range is consistent.

[0051] Compared with Example 2, the type of base, the type of copper salt and the amount of ligand are different, in terms of the type of base, potassium hydroxide is used in Example 2, and sodium hydroxide is used in Example 3, both of which are strong bases, only the cations are different, one is potassium ion, and the other is sodium ion, and the role of base is to promote the deprotonation of hydrazine to generate a nucleophile, the difference of ionic radius of potassium ion and sodium ion has little effect on the process, so the type of base does not significantly change the yield, in terms of the type of copper salt, cuprous bromide is used in Example 2, and copper iodide is used in Example 3, in the monovalent copper salt, the leaving ability of bromide ion and iodide ion is different, iodide ion is more easily left, but both can coordinate with the oxamide ligand to form an active species, and the amount of ligand is increased in Example 3, which can more fully combine with CuI, offsetting the influence of anion difference, ensuring the catalytic activity, and in terms of the amount of phase transfer catalyst, the amount of phase transfer catalyst in Example 3 is between Example 1 and Example 2, which still meets the mass transfer requirement, so it does not cause the yield to decrease.

[0052] Compared with Example 4, the types of solvent, base and reaction temperature are different in Example 3. In terms of solvent system, 1,4-dioxane is used as organic solvent in Example 3, and water is used as solvent in Example 4. The aromatic bromide 4-fluoro-3,5-dimethylbromobenzene is a hydrophobic organic substance, and its solubility in dioxane is much higher than that in water. Even with a phase transfer catalyst, the contact efficiency of the reactants in the aqueous system is still significantly reduced, resulting in a decrease in reaction rate and conversion. In terms of the type of base, strong base sodium hydroxide is used in Example 3, and weak base potassium phosphate is used in Example 4. The deprotonation of hydrazine requires a strong basic environment, and the basicity of potassium phosphate is weaker than that of sodium hydroxide, which cannot efficiently promote the activation of hydrazine, resulting in a decrease in nucleophilic substitution activity. In terms of reaction temperature, the reaction temperature of Example 4 is lower than that of Example 3, which further reduces the reaction rate. The combined effects of solvent and base result in a decrease in yield.

[0053] Compared with Example 4, the types of catalyst are different in Example 5. Cuprous iodide is used as a copper source catalyst in Example 4, and nickel acetate is used as a nickel source catalyst in Example 5. The ligand designed in this system is an oxamide substitute, which has a stronger coordination ability with copper ions, especially monovalent copper. The amide bond of oxamide can form a stable chelate with copper ions through N and O atoms, which can efficiently form a catalytically active center. The coordination stability of nickel ions with oxamide ligand is poor, and the efficiency of forming a catalytically active center is low, resulting in a lower conversion rate than the copper salt system. Therefore, the catalytic activity of nickel salt is weaker than that of copper salt, so the highest yield of Example 4 is slightly higher than that of Example 5.

[0054] Compared with Example 5, the types of solvent, base, catalyst and reaction temperature are different in Example 3. In terms of solvent, 1,4-dioxane is used in Example 3, which has a higher solubility for the hydrophobic raw material 4-fluoro-3,5-dimethylbromobenzene, which can improve the contact efficiency of the reactants. Water is used as the solvent in Example 5, and the solubility of the raw material is low, even with a phase transfer catalyst, the mass transfer efficiency is still significantly reduced. In terms of the type of base, strong base sodium hydroxide is used in Example 3, which can efficiently promote the deprotonation of hydrazine hydrate to form an active nucleophilic species, enhancing the reaction activity. Weak base potassium phosphate is used in Example 5, which has weak deprotonation ability, resulting in insufficient activation of hydrazine. In terms of the type of catalyst, the coordination ability of copper source cuprous iodide with oxamide ligand in Example 3 is strong, which can form a stable and efficient catalytically active center. The coordination stability of nickel source nickel acetate with oxamide ligand in Example 5 is poor, and the efficiency of forming a catalytically active center is low. In addition, the reaction temperature of Example 3 is higher than that of Example 5, which further accelerates the reaction rate, and a higher conversion rate is achieved in the same time. Therefore, the yield of Example 3 is higher than that of Example 5.

[0055] Compared with Example 1, the solvent is replaced by water instead of 1,4-dioxane as a polar aprotic solvent, 1,4-dioxane is good for dissolving organic substrate 4-fluoro-3,5-dimethylbromobenzene and ligand N,N'-di(2,6-dimethylphenyl)oxamide, can maintain a homogeneous reaction environment, promote the stable formation of catalyst-ligand complex, potassium hydroxide slowly releases hydroxide in the organic solvent in the form of suspension, which can avoid the hydrolysis of halogenated aromatic hydrocarbons caused by the excessive local strong alkali concentration, while water is a strong polar protic solvent, which can reduce the solubility of organic substrate and ligand, resulting in the reaction system from homogeneous to heterogeneous, the contact efficiency of substrate and catalyst is reduced, potassium hydroxide is completely dissolved in water, which makes the system alkaline increase suddenly, which can easily cause the hydrolysis of fluorine atom and the decomposition of hydrazine, at the same time, cetyltrimethylammonium bromide may lose surface activity in high concentration of alkali water, which cannot effectively improve the heterogeneous dispersion effect, the catalyst is replaced by nickel salicylate instead of copper bromide, copper bromide and oxamide ligand can form a stable square planar complex in organic phase, which can effectively activate the nucleophilicity of hydrazine as an oxidation-reduction catalyst, and the compatibility of bromide ion with solvent and ligand is good, the salicylate ligand of nickel salicylate has strong coordination ability with nickel ion, which can easily combine with water molecules / hydroxide in aqueous phase, and it is difficult to compete with oxamide ligand to form active catalyst species, at the same time, nickel salt may generate nickel hydroxide precipitate in alkaline aqueous solution, which further reduces the catalytic activity, and the activity of nickel catalytic system for hydrazinolysis of halogenated aromatic hydrocarbons is lower than that of copper catalytic system, so the yield of Comparative Example 1 is lower than that of Example 1.

[0056] Compared with Example 1, the concentration of hydrazine hydrate is increased to 90% and the reaction temperature is increased to 90-95℃, the increase of hydrazine hydrate concentration increases the effective concentration of nucleophilic reagent, the increase of free hydrazine content in the system enhances the nucleophilic attack ability of hydrazine hydrate to halogenated aromatic hydrocarbon 4-fluoro-3,5-dimethylbromobenzene, accelerates the reaction rate, and reduces the competition of side reactions, at the same time, the increase of hydrazine hydrate concentration can inhibit the hydrolysis of copper bromide catalyst by water, avoid the generation of copper hydroxide precipitate from Cu2+, and reduce the solvation effect of hydrazine hydrate, which makes it easier to combine with catalyst-ligand complex to form active intermediate, the increase of reaction temperature provides higher activation energy for the reaction, promotes the cleavage of halogenated aromatic hydrocarbon C-Br bond, and the leaving ability of bromine is stronger than that of fluorine, which preferentially occurs in bromohydrazinolysis, which improves the limited contact between substrate and catalyst in heterogeneous system, at the same time, the increase of temperature increases the molecular motion rate, the coordination exchange rate of catalyst copper bromide-oxamide ligand is accelerated, the circulation efficiency of active species is improved, the reaction time is shortened, and the accumulation of by-products caused by long time heating is reduced, so the yield is higher than that of Example 1.

[0057] Comparative Example 3, compared with Example 1, potassium hydroxide is replaced by cesium carbonate, which is a stronger inorganic base, and cesium ion has weak coordination, which can more effectively activate the nucleophilicity of hydrazine hydrate, promote the deprotonation of NH2NH2to generate NH2NH - , while reducing the coordination interference of transition metal catalysts, compared with K + , Cs + The salt effect on halogenated aromatic hydrocarbons is more significant, which can accelerate the C-Br bond rupture. In 1,4-dioxane, the solubility of cesium carbonate is higher than that of potassium hydroxide, which can form a more uniform suspension system, avoid the hydrolysis side reaction of fluorine atom caused by excessive local alkalinity, and the catalyst is replaced by nickel dibromide bispyridine instead of copper bromide. Nickel ion in nickel dibromide bispyridine has more flexible redox properties, and the carbon-halogen bond activation ability of halogenated aromatic hydrocarbons is stronger than that of copper catalyst. The electron-withdrawing effect of fluorine can enhance the reactivity of C-Br bond and the synergistic effect with nickel catalyst. The pyridine ligand and N,N'-di(2,6-dimethylphenyl)oxamide may form a bidentate coordination environment, stabilize the nickel active intermediate, reduce catalyst agglomeration, compared with the coordination of copper bromide and oxamide, the steric hindrance of nickel-pyridine-oxamide ternary system is more matched, which can reduce the probability of side reaction. The strong alkalinity and high solubility of cesium carbonate can improve the activity of nucleophilic reagent. The high catalytic activity and substrate adaptability of nickel dibromide bispyridine can accelerate the reaction rate and improve the selectivity. The synergistic effect of the two can improve the yield compared with Example 1.

[0058] The application provides a synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride, taking 4-fluoro-3,5-dimethylbromobenzene as a raw material, hydrazine hydrate as a hydrazine source, and potassium hydroxide, sodium hydroxide or potassium phosphate as an alkali, adopting cuprous bromide, cuprous iodide and other cuprous halides as a catalyst, N, N, -di(2,6-dimethylphenyl) oxamide as a ligand, cetyltrimethylammonium bromide as a stabilizer, and a dioxane-water mixed system as a solvent, to realize efficient synthesis through slow warming reaction under nitrogen protection, the cuprous halide and the oxamide ligand form a stable chelate structure, the N and O atoms are used for coordination to stabilize the Cu(I) active center, the reducing property of hydrazine is inhibited to cause catalyst deactivation, the ligand steric effect effectively reduces excessive coupling of aromatic hydrazine, the product purity is improved, dioxane enhances the solubility of organic raw materials, water promotes the dispersion of hydrazine, and the mass transfer efficiency is improved, the slow warming and nitrogen protection avoid decomposition of hydrazine and oxidation of the catalyst, the C-Br bond is accurately activated at a reaction temperature of 80-100 DEG C, the reaction time is shortened, the catalyst is removed through diatomite filtration, dichloromethane extraction, and adjustment of the pH to 2.5-3.0 through hydrochloric acid to make the product salt precipitate, and the purity is further improved through the washing and drying steps, so that high-purity 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride is obtained. Therefore, the problems of poor safety, low production efficiency, poor environmental friendliness, small substrate application range and the like in the synthesis of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride are solved.

[0059] Although the embodiments of the present application have been shown and described above, it should be understood that the above embodiments are exemplary and should not be construed as limiting the present application, and the present application is protected by the patent law as long as it is within the scope of claims of the present application.

Claims

1. A process for synthesizing 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride, characterized in that, The 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride is synthesized from aromatic halides and hydrazine using dioxane and water as solvents, alkali metal or alkaline earth metal carbonates, fluorides, phosphates and hydroxides or compounds that can be converted into corresponding bases in water as bases, oxamide substitutes and their salts as ligands, and using copper or nickel source catalysts to catalyze the synthesis of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride from aromatic halides and hydrazine.

2. The synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride according to claim 1, characterized in that... The synthesis process of the 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride includes the following steps: adding aromatic halogenated compound, solvent, stabilizer, hydrazine, base, ligand, and copper or nickel source catalyst into a reactor, stirring the reaction under nitrogen protection at 80-110℃, and after the reaction is completed, separating the reaction mixture and purifying it to obtain the 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride product.

3. The synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride according to claim 2, characterized in that, The solvent is dioxane and water, and the molar ratio of dioxane and water to the aromatic halogen is 4.5-5:4.5-5:

1.

4. The synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride according to claim 2, characterized in that, The aromatic halogen is 4-fluoro-3,5-dimethylbromobenzene, the ligand is N,N'-bis(2,6-dimethylphenyl)oxalamide, and the stabilizer is hexadecyltrimethylammonium bromide.

5. The synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride according to claim 2, characterized in that, The copper or nickel source catalyst is any one of copper powder, copper oxide, cuprous oxide, copper sulfate, copper bromide, cuprous bromide, copper chloride, cuprous chloride, copper iodide, cuprous iodide, copper acetate, nickel chloride, nickel bromide, nickel salicylate, nickel dibromobispyridine, and nickel acetate.

6. The synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride according to claim 2, characterized in that, The stirring reaction time is 5-14 hours.

7. The synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride according to claim 2, characterized in that, The molar ratio of the ligand, stabilizer, to copper or nickel source catalyst is 0.5:0.2:1 to 0.2:0.

1.

8. The synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride according to claim 2, characterized in that, The molar ratio of the aromatic halide to hydrazine is 1:0.8-1.

5.

9. The synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride according to claim 2, characterized in that, The alkali is any one of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, and potassium phosphate, and the molar ratio of the aromatic halide to the alkali is 1:0.8-1.

5.

10. The synthesis process of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride according to claim 2, characterized in that, The molar ratio of the aromatic halide to the copper or nickel source catalyst is 100:1 to 30:1.

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