Preparation method of 2-fluoro-4-methylaniline

Abstract

The invention discloses a preparation method of 2-fluoro-4-methylaniline, which has the following synthetic route: # imgabs0 #, wherein R1 is selected from one of-CN,-CX3 (wherein X is halogen) and-COOR (wherein R is H or C1-C6 alkyl). The synthesis method disclosed by the invention is simple, has the advantages of high yield, simple post-treatment, low cost and the like, meanwhile, the raw materials are easy to obtain, the reaction danger coefficient is low, the problems of high synthesis cost, low yield, high reaction danger coefficient and the like in the prior art are solved, and the method has a good industrial application prospect.

Description

Technical Field

[0001] The invention belongs to the field of pesticide chemical synthesis, and specifically relates to a preparation method of 2-fluoro-4-methylaniline. Background Art

[0002] In recent years, the synthesis and application research of fluorine-containing compounds has attracted more and more attention. Their special properties make them have very important application value in the fields of biochemistry, pesticides, functional materials, etc.

[0003] 2-Fluoro-4-methylaniline is an important fluorine-containing intermediate compound. It is mainly used as a key intermediate of a new type of highly efficient acaricide trifluoroethyl sulfide (sulfoxide) substituted benzene compound (see the acaricide structure below). Patents CN110028431A, CN11197822A, and CN111978226A disclose trifluoroethyl sulfide (sulfoxide) substituted benzene compounds, which can be used to control various harmful mites. This type of compound has a novel structure and good acaricidal activity; therefore, this type of compound has a broad market prospect.

[0004] Acaricide

[0005] There are currently three main methods for preparing 2-fluoro-4-methylaniline:

[0006] Method 1: Patent CN109704987 reports a method for synthesizing 2-fluoro-4-methylaniline: p-toluidine is used as a raw material, and an azobenzene compound is obtained through a coupling reaction; the azobenzene compound is then reacted with a palladium catalyst, a fluorination agent, an additive, an organic solvent, etc. in a closed container to obtain a fluorinated azobenzene compound; the fluorinated azobenzene compound is reduced to obtain 2-fluoro-4-methylaniline; this method has harsh reaction conditions, and the fluorination agent and catalyst used are relatively expensive, the reaction risk factor is high, and the yield is low. The specific route is as follows:

[0007]

[0008] Method 2: (Journal of Organic Chemistry, 1961, vol. 26, p. 3351-3356; Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8448-8454) m-fluorotoluene is used as a raw material, and 2-fluoro-4-methylaniline is obtained by nitration and reduction; the nitration product accounts for about 20%, and the product can be obtained by hydrogenation reduction;

[0009]

[0010] Method 3: (J.Org.Chem.2012,77,7471-7478) 4-bromo-3-fluoromethylbenzene and liquid ammonia are used as raw materials and reacted with cuprous iodide and ascorbic acid as catalysts to obtain the product with a yield of 92%;

[0011]

[0012] The above methods have many disadvantages, including expensive reagents, harsh reaction conditions, high risk factors, and low yields. Therefore, it is of great significance to develop a new method for preparing 2-fluoro-4-methylaniline. Summary of the invention

[0013] Aiming at various defects existing in the preparation of 2-fluoro-4-methylaniline in the prior art, the present invention provides a preparation method of 2-fluoro-4-methylaniline, which has the advantages of simple synthesis, high reaction yield, simple post-treatment, low cost and the like, and at the same time, the raw materials are easily available and the reaction risk factor is low, thus overcoming the problems of high synthesis cost, low yield and high reaction risk factor existing in the prior art, and having good industrial application prospect.

[0014] To achieve the above object, the present invention proposes the following technical solutions:

[0015] A method for preparing 2-fluoro-4-methylaniline comprises the following steps:

[0016] Step (1),

[0017] Compound III is mixed with an organic acid and acylated by Lewis acid. The acylated product is aminated with an aminating agent to prepare compound II.

[0018] or compound II prepared by hydrolysis of compound III in the presence of a base,

[0019] or compound III is mixed with an organic solvent and a catalyst, acylated with an acylating agent, and then aminated with an aminating agent to obtain compound II;

[0020] Step (2),

[0021] Compound II is degraded by Hofmann to obtain compound I.

[0022] Its synthetic route is as follows:

[0023]

[0024] Wherein, R1 is independently selected from one of -CN, -CX3 (wherein X is halogen), and -COOR (wherein R=H or C1~C6 alkyl).

[0025] Preferably, in the above method, compound III is prepared by the following route:

[0026]

[0027] Wherein R1 is independently selected from one of -CN, -CX3 (wherein X is halogen), and -COOR (wherein R is H or C1-C6 alkyl).

[0028] Furthermore, the present invention also discloses a method for synthesizing the compound of formula IV, and the synthetic route thereof is as follows:

[0029]

[0030] Wherein, R1 is independently selected from one of -CN, -CX3 (wherein X is halogen), -COOR (wherein R is H or C1~C6 alkyl); R4 is halogen; R2 and R3 are independently selected from one of -H, -CN, -COOR' (wherein R' is H or C1~C6), provided that R2 and R3 are not H at the same time.

[0031] The beneficial effects of the present invention are:

[0032] 1. The synthetic route of 2-fluoro-4-methylaniline of the present invention is simple and easy to prepare;

[0033] 2. The reaction conditions of the present invention are mild, the reaction raw materials are easily available, the reaction operation is simple, and it is easy to industrialize;

[0034] 3. The synthetic route of the present invention has a high yield and low comprehensive cost. DETAILED DESCRIPTION

[0035] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "including" will be understood to include the stated components or steps, without excluding other material components or steps.

[0036] In addition, in order to better illustrate the present invention, numerous specific details are given in the following detailed description.

[0037] Those skilled in the art will appreciate that the present invention can be implemented without certain specific details. In some embodiments, raw materials, methods, means, etc. that are well known to those skilled in the art are not described in detail in order to highlight the main purpose of the present invention.

[0038] In the present invention, C n -C m The subscripts n and m in each case indicate the number of carbon atoms in the group. For example, C1-C6 means containing 1 to 6 carbon atoms. The alkyl group appearing in the definition of the substituent may be straight-chain or branched, preferably C1-C4 alkyl, such as methyl, ethyl, n-propyl, n-butyl.

[0039] In the present invention, halogen means fluorine, chlorine, bromine and iodine.

[0040] The present invention first discloses a method for preparing 2-fluoro-4-methylaniline, comprising the following steps:

[0041] Step (1)

[0042] Compound III is mixed with an organic acid and acylated by Lewis acid, and the acylated product is aminated with an aminating agent to prepare compound II;

[0043] or compound II prepared by hydrolyzing compound III in the presence of a base;

[0044] or compound III is mixed with an organic solvent and a catalyst, acylated with an acylating agent, and then aminated with an aminating agent to obtain compound II;

[0045] Step (2), Hofmann degradation of compound II to obtain compound I,

[0046] Its synthetic route is as follows:

[0047]

[0048] Wherein, R1 is selected from one of -CN, -CX3 (wherein X is halogen), and -COOR (wherein R is H or C1~C6 alkyl).

[0049] Preferably, in step (1), R1 is selected from -CX3 (wherein X is a halogen), compound III is first mixed with an organic acid and then catalyzed by a Lewis acid to obtain an acylated product; the acylated product is then aminated with an aminating agent to obtain compound II, wherein the Lewis acid is one of copper chloride, copper bromide, copper iodide, ferric chloride, zinc dichloride, tin dichloride, tin tetrachloride, aluminum chloride, and boron trifluoride, preferably ferric chloride; the organic acid is one of formic acid, acetic acid, oxalic acid, propionic acid, and malonic acid, preferably acetic acid; the aminating agent is ammonia gas or ammonia water, and the mass percentage concentration of the ammonia water is 10-28%, preferably 20-25%;

[0050] Preferably, in step (1), R1 is selected from -CN, and compound III is hydrolyzed in the presence of a base to obtain compound II, wherein the base is one of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate, cesium carbonate, and potassium hydroxide, preferably sodium carbonate; the mass percentage concentration of the base in the alkaline solution is 2-20%, preferably 14-18%; the weight ratio of the alkaline solution to compound III is 0.5-6:1, preferably 1-3:1; the hydrolysis reaction temperature is 0-80°C, preferably 50-60°C; the hydrolysis reaction time is 0.5-6h, preferably 3-5h;

[0051] Preferably, in step (1), R1 is selected from -COOR (wherein, when R is a C1-C6 alkyl group, it is first hydrolyzed into an acid), compound III is mixed with an organic solvent and a catalyst, acylated with an acylating agent, and then aminated with an aminating agent to obtain compound II, wherein the acylating agent is one of thionyl chloride, oxalyl chloride, phosgene, and phosphorus trichloride, preferably thionyl chloride; the molar ratio of the acylating agent to compound III is 1.001-1.5:1, preferably 1.01-1.1:1; the organic The solvent is one of dichloroethane, toluene, dichloromethane, xylene, cyclohexane and n-hexane, preferably dichloroethane; the catalyst is N,N-dimethylformamide (DMF), and the weight ratio of the catalyst to compound III is 0.001-0.1:1, preferably 0.01-0.03:1; the reaction temperature is 20-150°C, preferably 80-85°C; the aminating agent is ammonia gas or ammonia water, and the mass percentage concentration of the ammonia water is 10-28%, preferably 20-25%.

[0052] Preferably, in the above preparation method, the Hofmann degradation reaction in step (2) is carried out in the presence of a halogenating agent and a base, wherein the halogenating agent is one of chlorine, bromine, iodine, chlorosuccinimide, bromosuccinimide, iodosuccinimide, trichloroisocyanuric acid (TCCA), tribromoisocyanuric acid, sodium hypochlorite, sodium hypobromite, and sodium hypoiodite, preferably bromine, chlorine, sodium hypochlorite, and sodium hypobromite; the base is one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate, cesium carbonate, sodium hydroxide, and potassium hydroxide, preferably sodium hydroxide; the reaction in step (2) is carried out in a solvent, and the solvent is one of water, ethanol, methanol, dichloroethane, tetrahydrofuran, dioxane, and ethyl acetate, preferably water.

[0053] The present invention also provides a method for preparing compound III, and its synthetic route is as follows:

[0054]

[0055] Wherein R1 is selected from one of -CN, -CX3 (wherein X is halogen), and -COOR (wherein R is H or C1-C6 alkyl).

[0056] In the preparation method of the above III compound, the IV compound is contacted with a catalyst to obtain the III compound, wherein the catalyst is one of silver halide, silver carbonate, silver acetate, nickel chloride, nickel acetate, manganese acetate, palladium acetate, palladium chloride, copper chloride, and ferric chloride, preferably silver acetate. Preferably, the V compound is contacted with the catalyst in a solvent, wherein the solvent is one of tetrahydrofuran, dioxane, dichloroethane, ethyl acetate, toluene, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), and sulfolane, preferably dioxane. Preferably, the weight ratio of the solvent to the IV compound is 0.5 to 4:1, preferably 1.5 to 2.5:1; the molar ratio of the catalyst to the IV compound is 0.001 to 0.1:1, preferably 0.004 to 0.006:1; the reaction temperature is 20 to 150°C, preferably 55 to 60°C; and the reaction time is 0.5 to 8h, preferably 4 to 6h.

[0057] The present invention also discloses a method for preparing compound IV, and the synthetic route thereof is as follows:

[0058]

[0059] Wherein, R1 is selected from one of -CN, -CX3 (wherein X is halogen), -COOR (wherein R is H or C1~C6 alkyl); R4 is halogen, and R2 and R3 are independently selected from one of -H, -CN, -COOR' (R' is H or C1~C6 alkyl), provided that R2 and R3 are not H at the same time.

[0060] In the preparation method of the above IV compound, the VI compound is subjected to a substitution reaction with a substitution reagent in the presence of a base and a catalyst to obtain the V compound; the base is one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, sodium hydroxide, and potassium hydroxide, preferably potassium carbonate; the catalyst is one of cuprous chloride, cuprous bromide, cuprous iodide, and manganese chloride, or a combination of two or more, preferably cuprous iodide; the substitution reagent is one of dimethyl malonate, diethyl malonate, dipropyl malonate, dibutyl malonate, diisopropyl malonate, diisobutyl malonate, di-tert-butyl malonate, methyl cyanoacetate, ethyl cyanoacetate, propyl cyanoacetate, butyl cyanoacetate, isopropyl cyanoacetate, tert-butyl cyanoacetate, isobutyl cyanoacetate, and isoamyl cyanoacetate, preferably diethyl malonate. Preferably, the substitution reaction is carried out in an organic solvent, wherein the organic solvent is one of n-butanol, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), and sulfolane, preferably N,N-dimethylformamide.

[0061] Preferably, the molar ratio of the substitution reagent to the VI compound is 1.01 to 1.5:1, preferably 1.05 to 1.2:1; the weight of the organic solvent is 0.5 to 5 times that of the VI compound, preferably 1 to 3 times; the molar ratio of the base to the VI compound is 1.01 to 1.5:1, preferably 1.05 to 1.3:1; the molar ratio of the catalyst to the compound VI is 0.01 to 0.2:1, preferably 0.03 to 0.15:1; the reaction temperature is 80 to 160°C, preferably 100 to 120°C; the reaction time is 1 to 12 hours, preferably 4 to 10 hours.

[0062] In the preparation method of the above IV compound, the V compound is dissolved in a solvent, and the IV compound is prepared under the action of an inorganic acid; preferably, the V compound and the inorganic acid are contacted and reacted in a solvent, and the solvent is one of water, formic acid, acetic acid, dioxane, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), toluene, and xylene, preferably acetic acid; the inorganic acid is one of hydrochloric acid, sulfuric acid, and phosphoric acid, more preferably sulfuric acid. The weight of the solvent is 0.5 to 5 times that of the V compound, preferably 1 to 4 times; the mass percentage concentration of the acid is 30 to 90wt%, preferably 80wt%, and further, the molar ratio of the acid to the V compound is 1.0 to 4.0:1, preferably 1.5 to 3:1; the reaction temperature is 50 to 110°C, preferably 95 to 100°C; the reaction time is 1 to 15h, preferably 6 to 12h.

[0063] The present invention is further described with the following examples, but the protection scope of the present invention is not limited to the examples. The amounts of reactants and products were measured by liquid chromatography (Agilent HPLC 1260).

[0064] The conversion and selectivity of the reaction were calculated by the following formula:

[0065] Conversion rate = (molar amount of raw material input - molar amount of raw material remaining in the product) / molar amount of raw material input × 100%.

[0066] Selectivity = actual molar amount of target product / theoretical molar amount of target product × 100%

[0067] Yield = actual mass of target product / theoretical mass of target product × 100%

[0068] Unless otherwise specified, all raw materials used were commercially available products.

[0069] Example 1 Preparation of 2-fluoro-4-methylaniline

[0070] In a four-necked reaction bottle equipped with a mechanical stirrer, a thermometer, a condenser, and a dropping funnel, add the compound 2-fluoro-4-iodotrichlorotoluene (1 mol, 349.9 g), potassium carbonate (160.5 g), cuprous iodide (9.72 g) and DMF (875 g) in sequence, heat to 105-110°C, dropwise add diethyl malonate (178 g) to the system, keep the temperature for 8 hours, recover DMF by vacuum distillation, cool the kettle residue to 0°C, filter, rinse the filter cake with ethyl acetate, adjust the pH of the filtrate to neutral with hydrochloric acid, extract and separate, and concentrate the organic phase to obtain 379.4 g of diethyl 2-(3-fluoro-4-(trichloromethyl)phenyl)malonate with a yield of 97.2%, which is directly used in the next step;

[0071] In a four-necked reaction flask equipped with a mechanical stirrer, a thermometer, and a condenser, 379.4 g of the compound obtained in the previous step, acetic acid (948.5 g), and 80% sulfuric acid (285.77 g) were added in sequence, and the temperature was raised to 95-100°C, and the reaction was kept warm for 9 hours. After the reaction was completed, the acetic acid was recovered by vacuum distillation, and the residue was extracted with ethyl acetate. The organic phase was desolventized to obtain 268.1 g of 2-(3-fluoro-4-(trichloromethyl)phenyl)acetic acid with a yield of 96.4%, which was directly used in the next step;

[0072] In a four-necked reaction flask equipped with a mechanical stirrer, a thermometer, and a condenser, 268.1 g of the compound obtained in the previous step, silver acetate (0.80 g) and dioxane (536 g) were added in sequence, and the temperature was raised to 55-60°C, and the reaction was kept warm for 4 hours. After the reaction was completed, the dioxane solvent was recovered under reduced pressure, and the residue was extracted with ethyl acetate to obtain 222.5 g of 2-fluoro-4-methyl-1-(trichloromethyl)benzene, with a yield of 98.2%; it was directly used in the next step;

[0073] In a four-mouth reaction bottle equipped with a mechanical stirrer, a thermometer, and a condenser, 222.5 g of the compound obtained in the previous step, ferric chloride (2.23 g), and acetic acid (61.3 g) were added in sequence, and the temperature was raised to 100°C, and the reaction was kept warm for 5 hours. In another four-mouth reaction bottle, ammonia water (25%, 262 g) was added, and the temperature was lowered to 0°C, and the above reaction liquid was added dropwise to the ammonia water, and the temperature was maintained at 2-5°C, and the reaction was maintained for 2 hours, and the temperature was returned to room temperature and stirred for 1 hour, and the filter cake was filtered with suction, and the filter cake was rinsed with cold water and dried to obtain 140.55 g of 2-fluoro-4-methylbenzamide, with a yield of 94.67%;

[0074] Add 140.55g of the compound obtained in the previous step and water (600g) to a four-necked reaction bottle equipped with a mechanical stirrer, a thermometer, and a condenser, cool to 0°C, slowly introduce chlorine (67.9g) into the system, then maintain the temperature at 3-7°C and react for 5h. Slowly add 30% sodium hydroxide lye (278.67g) to the reaction system, control the temperature at 25-30°C, and react at room temperature for 4h after the addition is completed. Extract with ethyl acetate and separate the layers. Desolventize the organic phase to obtain 110.5g of 2-fluoro-4-methylaniline with a yield of 94.83%.

[0075] Example 2 Preparation of diethyl 2-(3-fluoro-4-(trichloromethyl)phenyl)malonate

[0076] The preparation method of Example 1 was followed, except that 2,4-difluorobenzotrichloride (236.2 g) was used instead of 2-fluoro-4-iodobenzotrichloride for the reaction, and other ratios remained unchanged, to obtain 399.1 g of crude diethyl 2-(3-fluoro-4-(trichloromethyl)phenyl)malonate with a yield of 67.5%.

[0077] Example 3 Preparation of methyl 2-cyano-2-(3-fluoro-4-(trifluoromethyl)phenyl)acetate

[0078] In a four-necked reaction flask equipped with a mechanical stirrer, a thermometer, a condenser and a dropping funnel, the compound 2-fluoro-4-iodobenzotrifluoride (299 g), potassium carbonate (160.5 g), cuprous iodide (9.72 g) and DMF (492 mL) were added in sequence. After the temperature was raised to 105-110° C., methyl cyanoacetate (110.1 g) was added dropwise to the system. The reaction was kept warm for 8 h. DMF was recovered by distillation under reduced pressure. The kettle residue was cooled to 0° C. and filtered. The filter cake was rinsed with ethyl acetate. The pH of the filtrate was adjusted to neutral using hydrochloric acid. The extraction was performed and the layers were separated. The organic phase was concentrated to obtain 263.8 g of methyl 2-cyano-2-(3-fluoro-4-(trifluoromethyl)phenyl)acetate with a yield of 96.05%.

[0079] Example 4 Preparation of 2-(3-fluoro-4-(trichloromethyl)phenyl)acetic acid

[0080] In a four-necked reaction flask equipped with a mechanical stirrer, a thermometer, and a condenser, diethyl 2-(3-fluoro-4-(trichloromethyl)phenyl)malonate (1.0 mol, 391.2 g), formic acid (978 g), and 80% sulfuric acid (294 g) were added in sequence, and the temperature was raised to 95-100° C., and the reaction was kept warm for 9 hours. After the reaction was completed, acetic acid was recovered by vacuum distillation, the kettle residue was extracted with ethyl acetate, and the organic phase was desolventized to obtain 288.3 g of 2-(3-fluoro-4-(trichloromethyl)phenyl)acetic acid, with a yield of 75.4%.

[0081] Example 5 Preparation of 2-fluoro-4-methylbenzoic acid

[0082] In a four-necked reaction flask equipped with a mechanical stirrer, a thermometer, and a condenser, 4-(carboxymethyl)-2-fluorobenzoic acid (203.3 g), dioxane (407 g), and silver acetate (0.85 g) were added in sequence, and the temperature was raised to 55-60° C., and the reaction was kept warm for 4 hours. After the reaction was completed, the dioxane solvent was recovered under reduced pressure, and the residue was extracted with ethyl acetate for desolventization to obtain 157.5 g of 2-fluoro-4-methylbenzoic acid, with a yield of 97.1%.

[0083] Example 6 Preparation of 2-(4-cyano-3-fluorophenyl)acetic acid

[0084] In a four-necked reaction flask equipped with a mechanical stirrer, a thermometer, a condenser, and a dropping funnel, compound 2-fluoro-4-iodobenzonitrile (1 mol, 254.7 g), potassium carbonate (160.5 g), cuprous iodide (9.72 g) and DMF (636.5 g) were added in sequence, and the temperature was raised to 100-105°C, and dimethyl malonate (146.8 g) was added dropwise to the system, and the reaction was kept warm for 8 hours. DMF was recovered by vacuum distillation, and the kettle residue was cooled to 0°C, filtered, and the filter cake was rinsed with ethyl acetate. The filtrate was adjusted to a neutral pH with hydrochloric acid, and the extraction was separated into layers. The organic phase was concentrated to obtain 228 g of dimethyl 2-(4-cyano-3-fluorophenyl)malonate with a yield of 82.6%, which was directly used in the next step;

[0085] In a four-necked reaction flask equipped with a mechanical stirrer, a thermometer, and a condenser, 228 g of the compound obtained in the previous step, acetic acid (570 g), and 80% sulfuric acid (242.8 g) were added in sequence, and the temperature was raised to 95-100°C, and the reaction was kept warm for 9 hours. After the reaction was completed, the acetic acid was recovered by vacuum distillation, the kettle residue was extracted with ethyl acetate, and the organic phase was desolventized to obtain 170.5 g of 2-(4-cyano-3-fluorophenyl)acetic acid, with a yield of 59.9%.

[0086] Example 7 Preparation of Compound 2-Fluoro-4-Methylaniline

[0087] In a four-necked reaction flask equipped with a mechanical stirrer, a thermometer, and a condenser, add the compound 2-fluoro-4-methylbenzonitrile (137.9) g and a 15% sodium carbonate solution (365.4 g) in sequence, raise the temperature to 55-60°C, and keep the temperature for 5 hours. Cool down to room temperature and filter, rinse the filter cake with cold water, and dry to obtain 155.4 g of 2-fluoro-4-methylbenzamide, with a yield of 97.4%. The crude product is directly used for the next step;

[0088] Add 155.4 g of the compound obtained in the previous step and water (663 g) to a four-necked reaction bottle equipped with a mechanical stirrer, a thermometer, and a condenser, cool to 0°C, and slowly introduce chlorine (76.8 g) into the system, then maintain the temperature at 3-7°C and react for 5 hours. Slowly add the prepared 30% sodium hydroxide lye (311.7 g) dropwise to the reaction system, control the temperature at 25-30°C, and react at room temperature for 4 hours after the addition is completed. Extract and separate the layers with ethyl acetate, and desolventize the organic phase to obtain 121.67 g of 2-fluoro-4-methylaniline with a yield of 93.5%.

[0089] Example 8 Preparation of Compound 2-Fluoro-4-Methylaniline

[0090] In a four-mouth reaction bottle equipped with a mechanical stirrer, a thermometer, and a condenser, compound III (2-fluoro-4-methylbenzoic acid) (157.3) g, dichloroethane (473 g), and N,N-dimethylformamide (1.6 g) were added in sequence, and the temperature was raised to 85°C, and thionyl chloride (127.5 g) was added dropwise to keep the temperature for 4 hours. In another four-mouth reaction bottle, ammonia water (25%, 262 g) was added, and the temperature was lowered to 0°C, and the above reaction liquid was added dropwise to the ammonia water, and the temperature was maintained at 2-5°C. The reaction was maintained for 2 hours, and the mixture was returned to room temperature and stirred for 1 hour, and then filtered. The filter cake was rinsed with cold water and dried to obtain 154.7 g of 2-fluoro-4-methylbenzamide, with a yield of 98%. The crude product was directly used for the next step;

[0091] In a four-necked reaction flask equipped with a mechanical stirrer, a thermometer, and a condenser, 154.7 g of the compound obtained in the previous step and water (309.4 g) were added, the temperature was lowered to 0°C, and the prepared 30% sodium hydroxide alkali solution (313.6 g) was added dropwise, the temperature was controlled to be stable at 0-10°C, and then 7.5% sodium hypochlorite solution (1167.2 g) was slowly added dropwise to the system, and then the temperature was maintained at 5-10°C, stirred for 1 hour, and then the temperature was slowly raised to 50-55°C over 2 hours, and the reaction was kept warm for 2 hours. The ethyl acetate extraction was carried out, and the organic phase was desolvated to obtain 103.3 g of 2-fluoro-4-methylaniline, with a yield of 80.4%.

[0092] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A method for preparing 2-fluoro-4-methylaniline, characterized in that: The steps include: Step (1) Compound III is mixed with an organic acid and acylated by Lewis acid, and the acylated product is aminated with an aminating agent to prepare compound II; or compound II prepared by hydrolyzing compound III in the presence of a base; or compound III is mixed with an organic solvent and a catalyst, acylated with an acylating agent, and then aminated with an aminating agent to obtain compound II; Step (2), Hofmann degradation of compound II to obtain compound I, Its synthetic route is as follows: Wherein R1 is selected from one of -CN, -CX3 (wherein X is halogen), and -COOR (wherein R is H or C1-C6 alkyl).

2. The preparation method according to claim 1, characterized in that: In step (1), R1 is selected from -CX3 (wherein X is a halogen), compound III is first mixed with an organic acid and then acylated by Lewis acid to obtain an acylated product; the acylated product is then aminated with an ammonia reagent to obtain compound II, wherein the Lewis acid is one of copper dichloride, copper bromide, copper iodide, ferric chloride, zinc dichloride, tin dichloride, tin tetrachloride, aluminum chloride, and boron trifluoride, preferably ferric chloride; the organic acid is one of formic acid, acetic acid, oxalic acid, propionic acid, and malonic acid, preferably acetic acid; the ammonia reagent is ammonia gas or ammonia water, and the mass percentage concentration of the ammonia water is 10-28%, preferably 20-25%.

3. The preparation method according to claim 1, characterized in that: In step (1), R1 is selected from -CN, and compound III is hydrolyzed in the presence of a base to obtain compound II, wherein the base is one of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate, cesium carbonate, and potassium hydroxide, preferably sodium carbonate. Preferably, the mass percentage concentration of the base in the alkaline solution is 2 to 20%, preferably 14 to 18%; the weight ratio of the alkaline solution to compound III is 0.5 to 6:1, preferably 1 to 3:1; the hydrolysis reaction temperature is 0 to 80°C, preferably 50 to 60°C; the hydrolysis reaction time is 0.5 to 6h, preferably 3 to 5h.

4. The preparation method according to claim 1, characterized in that: In step (1), R1 is selected from -COOR, When R is H, compound III is mixed with an organic solvent and a catalyst, acylated with an acylating agent, and then aminated with an aminating agent to obtain compound II; When R is a C1-C6 alkyl group, compound III is first hydrolyzed into an acid, and then compound III is mixed with an organic solvent and a catalyst, acylated with an acylating agent, and then aminated with an ammonating agent to obtain compound II; Wherein, the acylating agent is one of thionyl chloride, oxalyl chloride, phosgene, phosphorus trichloride, preferably thionyl chloride; the molar ratio of the acylating agent to compound III is 1.001-1.5:1, preferably 1.01-1.1:1; the organic solvent is one of dichloroethane, toluene, dichloromethane, xylene, cyclohexane, and n-hexane, preferably dichloroethane; the aminating agent is ammonia gas or ammonia water, and the mass percentage concentration of the ammonia water is 10-28%, preferably 20-25%; the catalyst is N,N-dimethylformamide (DMF). Preferably, the ratio of the catalyst to compound III is 0.001-0.1:1, more preferably 0.01-0.03:1; the reaction temperature is 20-150°C, more preferably 80-85°C.

5. The preparation method according to claim 1, characterized in that: The Hofmann degradation reaction in step (2) is carried out in the presence of a halogenating agent and a base, wherein the halogenating agent is one of chlorine, bromine, iodine, chlorosuccinimide, bromosuccinimide, iodosuccinimide, trichloroisocyanuric acid, tribromoisocyanuric acid, sodium hypochlorite, sodium hypobromite, and sodium hypoiodite, preferably bromine, chlorine, sodium hypochlorite, and sodium hypobromite; the base is one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate, cesium carbonate, sodium hydroxide, and potassium hydroxide, preferably sodium hydroxide; the reaction in step (2) is carried out in a solvent, and the solvent is one of water, ethanol, methanol, dichloroethane, tetrahydrofuran, dioxane, and ethyl acetate, preferably water.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The compound of formula III is prepared by the following route: Wherein R1 is selected from one of -CN, -CX3 (wherein X is halogen), and -COOR (wherein R is H or C1-C6 alkyl).

7. The preparation method according to claim 6, characterized in that: The compound of formula III is prepared by contacting the compound of formula IV with a catalyst, wherein the catalyst is one of silver halide, silver carbonate, silver acetate, nickel chloride, nickel acetate, manganese acetate, palladium acetate, palladium chloride, copper chloride, and ferric chloride, preferably silver acetate; preferably, the compound of formula IV is contacted with the catalyst in a solvent, wherein the solvent is one of tetrahydrofuran, dioxane, dichloroethane, ethyl acetate, toluene, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), and sulfolane, preferably dioxane. Preferably, the weight ratio of the solvent to the compound of formula IV is 0.5 to 4:1, more preferably 1.5 to 2.5:1; the molar ratio of the catalyst to the compound of formula IV is 0.001 to 0.1:1, more preferably 0.004 to 0.006:1; the reaction temperature is 20 to 150°C, more preferably 55 to 60°C; the reaction time is 0.5 to 8h, more preferably 4 to 6h.

8. The preparation method according to any one of claims 6 to 7, characterized in that: The compound of formula IV is prepared by the following route: Wherein R1 is selected from one of -CN, -CX3 (wherein X is halogen), -COOR (wherein R is H or C1~C6 alkyl); wherein R4 is halogen, R2 and R3 are selected from one of -H, -CN, COOR' (R' is H or C1~C6 alkyl), provided that R2 and R3 are not H at the same time.

9. The preparation method according to claim 8, characterized in that: The compound of formula VI is subjected to a substitution reaction with a substitution reagent in the presence of a base and a catalyst to obtain a compound of formula V; the base is one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, sodium hydroxide, and potassium hydroxide, preferably potassium carbonate; the catalyst is one or a combination of two or more of cuprous chloride, cuprous bromide, cuprous iodide, and manganese chloride, preferably cuprous iodide; the substitution reagent is dimethyl malonate, diethyl malonate, dipropyl malonate, dibutyl malonate, diisopropyl malonate, diisobutyl malonate, di-tert-butyl malonate The substitution reaction is preferably carried out in an organic solvent, wherein the organic solvent is one of n-butanol, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), and sulfolane, preferably N,N-dimethylformamide. Preferably, the molar ratio of the substitution reagent to the compound of formula VI is 1.01-1.5:1, preferably 1.05-1.2:1; preferably, the weight of the organic solvent is 0.5-5 times, preferably 1-3 times, of the compound of formula VI; the molar ratio of the base to the compound of formula VI is 1.01-1.5:1, preferably 1.05-1.3:1; the molar ratio of the catalyst to compound VI is 0.01-0.2:1, preferably 0.03-0.15:1; the reaction temperature is 80-160°C, preferably 100-120°C; the reaction time is 1-12h, preferably 4-10h.

10. The preparation method according to claim 9, characterized in that: The compound of formula V is dissolved in a solvent, and a compound of formula IV is prepared under the action of an inorganic acid; preferably, the compound of formula V and the inorganic acid are contacted and reacted in a solvent, and the solvent is one of water, formic acid, acetic acid, dioxane, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), toluene, and xylene, preferably acetic acid; the inorganic acid is one of hydrochloric acid, sulfuric acid, and phosphoric acid, preferably sulfuric acid. The weight of the solvent is 0.5 to 5 times that of the compound of formula V, preferably 1 to 4 times; the mass percentage concentration of the inorganic acid is 30 to 90 wt%, preferably 80 wt%, and further, the molar ratio of the inorganic acid to the compound of formula V is 1.0 to 4.0:1, preferably 1.5 to 3:1; the reaction temperature is 50 to 110°C, preferably 95 to 100°C; the reaction time is 1 to 15 hours, preferably 6 to 12 hours.

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