A process for the preparation of N-(3-bromo-5-fluoro-4-methylphenyl)acetamide

Abstract

The application belongs to the technical field of biological medicine, and particularly relates to a preparation method of N-(3-bromo-5-fluoro-4-methylphenyl)acetamide. The application takes 3,4-difluoro-5-bromonitrobenzene as an initial raw material, first carries out a coupling reaction with malonic acid diethyl ester, then carries out a decarboxylation reaction in the presence of a chlorinated salt, then carries out a nitro reduction reaction in the presence of a reducing agent and a catalyst, and finally carries out amino protection by using acetic anhydride. The preparation method provided by the application obtains the target product N-(3-bromo-5-fluoro-4-methylphenyl)acetamide through four-step reactions, has high total yield of the target product, is simple to operate, has good repeatability, has few side reactions, is simple to purify, has low production cost, and is suitable for industrialized scale production. As shown in the test results of examples, the total yield of N-(3-bromo-5-fluoro-4-methylphenyl)acetamide prepared by the preparation method provided by the application is 78.4%.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to a method for preparing N-(3-bromo-5-fluoro-4-methylphenyl)acetamide. Background Technology

[0002] Icitecan is a water-soluble topoisomerase I inhibitor, a camptothecin derivative, with broad-spectrum in vitro antitumor activity. The compound N-(3-bromo-5-fluoro-4-methylphenyl)acetamide is an important intermediate in the preparation of icitecan, and its structural formula is as follows:

[0003]

[0004] Patents WO2023004266A1, US11318212A1, and JPWO2019044946A1 disclose methods for synthesizing N-(3-bromo-5-fluoro-4-methylphenyl)acetamide. All methods use 2-fluoro-4-nitrotoluene as a starting material and prepare N-(3-bromo-5-fluoro-4-methylphenyl)acetamide through a three-step reaction involving bromination, reduction, and amino protection. The synthetic routes are as follows:

[0005]

[0006] However, the overall yield of N-(3-bromo-5-fluoro-4-methylphenyl)acetamide obtained by the above synthesis method is only 20-40%, which is low. Summary of the Invention

[0007] In view of this, the object of the present invention is to provide a method for preparing N-(3-bromo-5-fluoro-4-methylphenyl)acetamide. The preparation method provided by the present invention has a high overall yield of the target product.

[0008] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0009] This invention provides a method for preparing N-(3-bromo-5-fluoro-4-methylphenyl)acetamide, comprising the following steps:

[0010] 3,4-Difluoro-5-bromonitrobenzene, diethyl malonate, a basic reagent, and a first organic solvent were mixed and coupled under a protective atmosphere to give compound IM1.

[0011] The compound IM1, its chloride salt, and a solvent are mixed and subjected to a decarboxylation reaction to obtain compound IM2; the solvent includes a second organic solvent and / or water.

[0012] The compound IM2, a reducing agent, a catalyst, and a solvent are mixed and a reduction reaction is carried out to obtain compound IM3; the solvent includes a third organic solvent and / or water.

[0013] The compound IM3, acetic anhydride, and a fourth organic solvent were mixed and subjected to an amino protection reaction under a protective atmosphere to obtain N-(3-bromo-5-fluoro-4-methylphenyl)acetamide;

[0014]

[0015] Preferably, the first organic solvent includes one or more of furan solvents, ether solvents, amide solvents, and aromatic hydrocarbon solvents;

[0016] The second organic solvent includes one or more of amide solvents, ketone solvents, sulfoxide solvents, and nitrile solvents;

[0017] The third organic solvent includes one or more of lower alcohols, oxygen-containing cycloalkane solvents, and nitrile solvents;

[0018] The fourth organic solvent includes one or more of furan solvents, halogenated hydrocarbon solvents, ester solvents, and lower alcohols.

[0019] Preferably, the molar ratio of 3,4-difluoro-5-bromonitrobenzene to diethyl malonate is 1:1 to 4;

[0020] The alkaline reagent includes one or more of the following: n-butyllithium, diisopropylaminolithium, potassium carbonate, cesium carbonate, sodium hydroxide, potassium phosphate, and sodium hydride.

[0021] The molar ratio of the 3,4-difluoro-5-bromonitrobenzene to the alkaline reagent is 1:1.5 to 3.5.

[0022] Preferably, the coupling reaction is carried out at a temperature of 15–35°C for 15–20 hours.

[0023] Preferably, the chloride salt includes one or more of zinc chloride, magnesium chloride, sodium chloride, lithium chloride, calcium chloride, and ferric chloride;

[0024] The molar ratio of compound IM1 to chloride salt is 1:1 to 10.

[0025] Preferably, the decarboxylation reaction is carried out at a temperature of 80–170°C for a time of 20–72 h.

[0026] Preferably, the reducing agent includes one or more of iron, zinc, sodium dithionite, stannous chloride, palladium on carbon, and platinum on carbon;

[0027] The molar ratio of the compound IM2 to the reducing agent is 1:2 to 10;

[0028] The catalyst includes one or more of hydrochloric acid, sulfuric acid, acetic acid, ammonium chloride, trifluoroacetic acid, ammonium acetate, and p-toluenesulfonic acid.

[0029] Preferably, the reduction reaction is carried out at a temperature of 45–85°C for 1–20 hours.

[0030] Preferably, the molar ratio of compound IM3 to acetic anhydride is 1:1 to 8;

[0031] The amino protection reaction is carried out at a temperature of 15–35°C for 15–20 hours.

[0032] Preferably, the amino protection reaction further includes a post-treatment, which includes concentrating the obtained amino protection reaction solution and recrystallizing it.

[0033] This invention uses 3,4-difluoro-5-bromonitrobenzene as the initial raw material, first undergoing a coupling reaction with diethyl malonate, followed by a decarboxylation reaction in the presence of a chloride salt, then a nitro reduction reaction under reducing agent and catalyst conditions, and finally amino protection using acetic anhydride. The preparation method provided by this invention yields the target product N-(3-bromo-5-fluoro-4-methylphenyl)acetamide through four steps, with few side reactions in each step, high overall yield of the target product, simple operation, good reproducibility, simple subsequent purification, and low production cost, making it suitable for industrial-scale production. As shown in the test results of the examples, the overall yield of N-(3-bromo-5-fluoro-4-methylphenyl)acetamide provided by this invention is 78.4%. Detailed Implementation

[0034] This invention provides a method for preparing N-(3-bromo-5-fluoro-4-methylphenyl)acetamide, comprising the following steps:

[0035] 3,4-Difluoro-5-bromonitrobenzene, diethyl malonate, a basic reagent, and a first organic solvent were mixed and coupled under a protective atmosphere to give compound IM1.

[0036] The compound IM1, its chloride salt, and a solvent are mixed and subjected to a decarboxylation reaction to obtain compound IM2; the solvent includes a second organic solvent and / or water.

[0037] The compound IM2, a reducing agent, a catalyst, and a solvent are mixed and a reduction reaction is carried out to obtain compound IM3; the solvent includes a third organic solvent and / or water.

[0038] The compound IM3, acetic anhydride, and a fourth organic solvent were mixed and subjected to an amino protection reaction under a protective atmosphere to obtain N-(3-bromo-5-fluoro-4-methylphenyl)acetamide;

[0039]

[0040] Unless otherwise specified, all materials and equipment used in this invention are commercially available products in the field.

[0041] In this invention, 3,4-difluoro-5-bromonitrobenzene, diethyl malonate, a basic reagent, and a first organic solvent are mixed and coupled under a protective atmosphere to obtain compound IM1.

[0042] In this invention, the molar ratio of 3,4-difluoro-5-bromonitrobenzene to diethyl malonate is preferably 1:1 to 4, more preferably 1:1.5 to 3, and even more preferably 1:1.5 to 2.

[0043] In this invention, the alkaline reagent preferably includes one or more of n-butyllithium, diisopropylaminolithium (LDA), potassium carbonate, cesium carbonate, sodium hydroxide, potassium phosphate, and sodium hydride (NaH), more preferably NaH; the NaH is preferably used in the form of a NaH-silicone oil mixture or a NaH-mineral oil mixture, and the NaH content in the NaH-silicone oil mixture and the NaH-mineral oil mixture is preferably 40-60 wt%, more preferably 50-60 wt%; the alkaline reagent is preferably added in 5-10 (more preferably 6-9, further preferably 7-8) batches. In this invention, the molar ratio of 3,4-difluoro-5-bromonitrobenzene to the alkaline reagent is preferably 1:1.5-3.5, more preferably 1:2-3.5, and further preferably 1:3-3.5.

[0044] In this invention, the first organic solvent preferably includes one or more of furan solvents, ether solvents, amide solvents, and aromatic hydrocarbon solvents, more preferably one or more of tetrahydrofuran, methyltetrahydrofuran, diethyl ether, N,N-dimethylformamide, and toluene. In this invention, the solid-liquid ratio of 3,4-difluoro-5-bromonitrobenzene to the first organic solvent is preferably 1 kg: 4–15 L, more preferably 1: 5–8 L.

[0045] In this invention, the protective atmosphere preferably includes nitrogen, argon or helium.

[0046] In this invention, the mixing is preferably performed by mixing a first organic solvent, diethyl malonate, and 3,4-difluoro-5-bromonitrobenzene, cooling the mixture to -5 to 5°C (more preferably 0°C) under a protective atmosphere, and then adding the second alkaline reagent solution in 5 to 10 batches.

[0047] In this invention, the temperature of the coupling reaction is preferably 15-35°C, more preferably room temperature; the time of the coupling reaction is preferably 15-20h, more preferably 15-17h.

[0048] Following the coupling reaction, the present invention preferably includes a post-treatment, which preferably includes: quenching the reaction with hydrochloric acid solution in the obtained coupling reaction solution, extracting with an organic extractant, washing the obtained organic phase with saturated brine, and concentrating until no distillate is obtained to obtain compound IM1. In the present invention, the concentration of the hydrochloric acid solution is preferably 1–12 mol / L, more preferably 1 mol / L; the molar ratio of 3,4-difluoro-5-bromonitrobenzene to the volume of the hydrochloric acid solution is preferably 1 mol: 1–2 L, more preferably 1 mol: 1.5–2 L. In the present invention, the organic extractant preferably includes one or more of methyl tert-butyl ether, isopropyl ether, ethyl acetate, and isopropyl acetate; the number of extractions is preferably 3–5 times, more preferably 4 times. In the present invention, the number of saturated brine washes is preferably 2–4 times, more preferably 3 times. The present invention does not have a special limitation on the concentration; concentration can be carried out using a concentration method well known to those skilled in the art until no distillate is effluent. In the present invention, compound IM1 is used directly in the next reaction without purification.

[0049] After obtaining compound IM1, the present invention mixes compound IM1, chloride salt and solvent to carry out decarboxylation reaction to obtain compound IM2; the solvent includes a second organic solvent and / or water.

[0050] In this invention, the chloride salt preferably includes one or more of zinc chloride, magnesium chloride, sodium chloride, lithium chloride, calcium chloride, and ferric chloride, more preferably lithium chloride; the chloride salt is preferably anhydrous chloride; the chloride salt is preferably added in 5 to 7 (more preferably 6) batches. In this invention, the molar ratio of compound IM1 to chloride salt is preferably 1:1 to 10, more preferably 1:5 to 10, and even more preferably 1:8 to 10.

[0051] In this invention, the second organic solvent preferably includes one or more of amide solvents, ketone solvents, sulfoxide solvents, and nitrile solvents, and more preferably includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolinone, and acetonitrile. In this invention, the solid-liquid ratio of the compound IM1 to the solvent (the second organic solvent and / or water) is preferably 1 kg: 4–15 L, more preferably 1: 5–8 L.

[0052] In this invention, the mixing is preferably performed by dissolving compound IM1 in a solvent and adding the chloride salt in 5 to 7 batches.

[0053] In this invention, the temperature of the decarboxylation reaction is preferably 80-170°C, more preferably 90-150°C, and even more preferably 100-120°C; the time of the decarboxylation reaction is preferably 20-72 h, more preferably 30-60 h, and even more preferably 40-50 h.

[0054] Following the decarboxylation reaction, the present invention preferably includes a post-treatment process, which preferably includes: cooling the obtained decarboxylation reaction solution to -5 to 5°C (more preferably 0°C), quenching the reaction with water dropwise, adding an organic extractant for extraction, sequentially washing the obtained organic phase with water, washing with saturated brine, concentrating, recrystallizing, and separating the solid and liquid phases, and drying the obtained solid product to obtain compound IM2. The present invention does not have a specific limitation on the cooling process; any cooling method well known to those skilled in the art can be used, such as natural cooling. In the present invention, the organic extractant preferably includes one or more of methyl tert-butyl ether, isopropyl ether, ethyl acetate, and isopropyl acetate; the number of extractions is preferably 1 to 3 times, more preferably 2 times. In the present invention, the number of saturated brine washes is preferably 1 to 2 times, more preferably 1 time. The present invention does not have a specific limitation on the concentration process; any concentration method well known to those skilled in the art can be used to concentrate until no fractions flow out. In this invention, the crystallization solvent for recrystallization is preferably a mixed solvent of a lower alcohol and water, wherein the lower alcohol preferably includes one or more of methanol, ethanol, isopropanol, and tert-butanol; the volume ratio of the lower alcohol to water in the crystallization solvent is preferably 0.5–5:1, more preferably 1–3:1, and even more preferably 2:1. This invention does not impose any special limitations on the solid-liquid separation; any solid-liquid separation method well known to those skilled in the art can be used, such as natural filtration, vacuum filtration, or centrifugation. In this invention, the drying temperature is preferably 45–55°C, more preferably 50°C; this invention does not impose any special limitations on the drying time, drying to constant weight is sufficient.

[0055] After obtaining compound IM2, the present invention mixes the compound IM2, a reducing agent, a catalyst and a solvent to carry out a reduction reaction to obtain compound IM3; the solvent includes a third organic solvent and / or water.

[0056] In this invention, the reducing agent preferably includes one or more of iron powder, zinc powder, sodium dithionite (sodium hydrosulfite), stannous chloride, palladium on carbon, and platinum on carbon, and more preferably iron powder. In this invention, the molar ratio of the compound IM2 to the reducing agent is preferably 1:2 to 10, more preferably 1:3 to 8, and even more preferably 1:4 to 5.

[0057] In this invention, the catalyst preferably comprises one or more of hydrochloric acid, sulfuric acid, acetic acid, ammonium chloride, trifluoroacetic acid, ammonium acetate, and p-toluenesulfonic acid, more preferably hydrochloric acid. In this invention, the molar ratio of the compound IM2 to the catalyst is preferably 1:4 to 10, more preferably 1:4 to 6, and even more preferably 1:4 to 5.

[0058] In this invention, the third organic solvent preferably includes one or more of lower alcohols, oxycycloalkanes, and nitrile solvents, and more preferably includes one or more of methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, and acetonitrile. In this invention, the solid-liquid ratio of the compound IM2 to the solvent (the third organic solvent and / or water) is preferably 1 kg: 4–15 L, and more preferably 1 kg: 10–12 L.

[0059] In this invention, the mixing is preferably performed by mixing the compound IM2, the catalyst, and the solvent, and then adding a reducing agent under stirring conditions.

[0060] In this invention, the temperature of the reduction reaction is preferably 45-85°C, more preferably 60-80°C; in a specific embodiment of this invention, the reduction reaction is preferably carried out under reflux conditions; the time of the reduction reaction is preferably 1-20 h, more preferably 10-15 h.

[0061] Following the reduction reaction, the present invention preferably further includes post-treatment, which preferably includes: cooling the obtained reduction reaction solution to below 30°C and then performing solid-liquid separation; concentrating the obtained liquid component until no distillate is obtained to obtain compound IM3. The present invention does not have specific limitations on the cooling process; any cooling method well-known to those skilled in the art can be used, such as natural cooling. The present invention also does not have specific limitations on the solid-liquid separation process; any solid-liquid separation method well-known to those skilled in the art can be used, such as natural filtration, vacuum filtration, or centrifugation. The present invention does not have specific limitations on the concentration process; any concentration method well-known to those skilled in the art can be used to concentrate until no distillate is effluent. In the present invention, compound IM3 is used directly in the next reaction without purification.

[0062] After obtaining compound IM3, the present invention mixes the compound IM3, acetic anhydride and a fourth organic solvent, and carries out an amino protection reaction under a protective atmosphere to obtain N-(3-bromo-5-fluoro-4-methylphenyl)acetamide.

[0063] In this invention, the molar ratio of the compound IM3 to acetic anhydride is preferably 1:1 to 8, more preferably 1:1.5 to 5, and even more preferably 1:2 to 3.

[0064] In this invention, the fourth organic solvent preferably includes one or more of furan solvents, halogenated hydrocarbon solvents, ester solvents, and lower alcohols, more preferably one or more of tetrahydrofuran, methyltetrahydrofuran, dichloromethane, ethyl acetate, methanol, and ethanol. In this invention, the solid-liquid ratio of the compound IM3 to the fourth organic solvent is preferably 1 kg: 2–20 L, more preferably 1 kg: 15–20 L.

[0065] In this invention, the protective atmosphere preferably includes nitrogen, argon or helium.

[0066] In this invention, the mixing is preferably performed by dissolving compound IM3 in a fourth organic solvent and then adding acetic anhydride for mixing.

[0067] In this invention, the temperature of the amino protection reaction is preferably 15-35°C, more preferably room temperature; the time of the amino protection reaction is preferably 10-20 h, more preferably 15 h.

[0068] Following the amino protection reaction, the present invention preferably further includes a post-treatment, which preferably includes: concentrating the obtained amino protection reaction solution and recrystallizing it. Specifically, the obtained amino protection reaction solution is concentrated to constant weight, then recrystallized and separated into solid and liquid components. The resulting solid product is dried to obtain N-(3-bromo-5-fluoro-4-methylphenyl)acetamide. The present invention does not have a specific limitation on the concentration; concentration methods well known to those skilled in the art can be used until no fraction effluent flows out. In the present invention, the crystallization solvent preferably includes one or more of ethyl acetate, methyl tert-butyl ether, isopropyl ether, toluene, isopropyl acetate, dichloromethane, petroleum ether, methanol, ethanol, isopropanol, tert-butanol, and water, more preferably an ethyl acetate-petroleum ether mixed solvent. The volume ratio of ethyl acetate to petroleum ether in the ethyl acetate-petroleum ether mixed solvent is preferably 1:1 to 3, more preferably 1:2. The present invention does not have a specific limitation on the solid-liquid separation; solid-liquid separation methods well known to those skilled in the art can be used, such as natural filtration, vacuum filtration, or centrifugation. In this invention, the drying temperature is preferably 45-55°C, more preferably 50°C. This invention does not have a special limitation on the drying time; drying to a constant weight is sufficient.

[0069] To further illustrate the present invention, the preparation method of N-(3-bromo-5-fluoro-4-methylphenyl)acetamide is described in detail below with reference to the accompanying drawings and embodiments, but these should not be construed as limiting the scope of protection of the present invention.

[0070] Example 1

[0071]

[0072] Step 1: Add 400 mL of N,N-dimethylformamide, 52 g of diethyl malonate, and 51 g of 3,4-difluoro-5-bromonitrobenzene. Cool to 0°C under nitrogen protection. Add 60 wt% NaH-silicone oil mixture (17 g NaH) in 5 batches. After addition, react at room temperature with stirring for 15 h. Quench the reaction with 400 mL of 1 mol / L hydrochloric acid solution. Extract four times with methyl tert-butyl ether (400 mL per extraction). Combine the organic phases and wash three times with saturated brine (400 mL per extraction). Concentrate the organic phase until no more distillate is obtained to give crude compound IM1 (107 g, brown liquid, used directly in the next reaction without purification).

[0073] Step 2: The crude compound IM1 was dissolved in 650 mL of dimethyl sulfoxide. 90 g of anhydrous lithium chloride was added in five portions. After the addition was complete, the mixture was heated to 110 °C and reacted for 48 h. The temperature was lowered to 0 °C, and 650 mL of water was added dropwise to quench the reaction. The mixture was extracted twice with methyl tert-butyl ether (650 mL per extraction). The organic phases were combined and washed twice with water (650 mL per extraction) and once with 650 mL of saturated brine. The organic phase was concentrated until no more distillate was observed. Recrystallization was performed using a 2:1 ethanol / water mixture. The mixture was filtered, and the resulting solid product was dried to constant weight at 50 °C to obtain compound IM2 (50 g, orange-yellow solid; the overall yield of Step 1 and Step 2 was 98%, and the purity was 99.0%). Compound IM2: 1 H-NMR (400MHz, CDCl3): δ=8.19 (1H, t, J=1.6Hz), δ=7.81 (1H, dd, J=2.0, 8.8Hz), δ=2.36 (3H, d, J=1.6Hz).

[0074] Step 3: Add 500 mL of ethanol, 100 mL of tetrahydrofuran, 15 g of 12 mol / L hydrochloric acid, and 50 g of compound IM2. Add 50 g of iron powder while stirring. After the addition is complete, reflux for 15 h. Cool to <30℃, filter, and concentrate the filtrate until no distillation occurs to obtain crude compound IM3 (44.0 g, which can be used directly in the next step without purification).

[0075] Step 4: Dissolve the crude compound IM3 in 800 mL of tetrahydrofuran, add 50 g of acetic anhydride, and react for 15 h under nitrogen protection, room temperature, and stirring. Concentrate the reaction solution to dryness, recrystallize with a 1:2 mixture of ethyl acetate and petroleum ether, filter, and dry the resulting solid product to constant weight at 50 °C to obtain N-(3-bromo-5-fluoro-4-methylphenyl)acetamide (42 g, pale yellow solid; the overall yield of Steps 3 and 4 was 80%, and the purity was 99.9%). N-(3-bromo-5-fluoro-4-methylphenyl)acetamide: 1 H-NMR (400MHz, CDCl3): δ=7.32(3H,m), δ=2.20(3H,d,J=2.0Hz), δ=2.10(3H,s).

[0076] Example 2

[0077] Step 1: Add 50 mL of tetrahydrofuran, 5 g of diethyl malonate, and 5 g of 3,4-difluoro-5-bromonitrobenzene. Under nitrogen protection, lower the temperature to 0 °C. Add 60 wt% NaH-silicone oil mixture (1.7 g NaH) in portions. After the addition is complete, react at room temperature with stirring for 15 h. Quench the reaction with 40 mL of 1 mol / L hydrochloric acid solution, and then extract four times with 40 mL of methyl tert-butyl ether. Combine the organic phases, wash three times with 40 mL of saturated brine, and concentrate the organic phase until no distillate is obtained to give crude compound IM1 (9.6 g, brown liquid, used directly in the next reaction without purification).

[0078] Step 2: Dissolve the crude compound IM1 in 65 mL of N,N-dimethylacetamide, and add 8 g of anhydrous magnesium chloride in 5 portions. After the addition is complete, heat to 130 °C and react for 24 h. Cool to 0 °C, quench the reaction with 65 mL of water dropwise, and extract twice with methyl tert-butyl ether (65 mL per extraction). Combine the organic phases, wash twice with water (65 mL per extraction) and once with 65 mL of saturated brine. Concentrate the organic phase until no distillate is obtained, recrystallize with a 2:1 ethanol / water mixture, filter, and dry the resulting solid product at 50 °C to constant weight to obtain compound IM2 (4 g, orange-yellow solid, overall yield of Step 1 and Step 2 is 65%, purity is 99.0%). Compound IM2: 1 H-NMR (400MHz, CDCl3): δ=8.19 (1H, t, J=1.6Hz), δ=7.81 (1H, dd, J=2.0, 8.8Hz), δ=2.36 (3H, d, J=1.6Hz).

[0079] Step 3: Add 180 mL of ethanol, 15 mL of water, 4.7 g of 12 mol / L hydrochloric acid, and 18 g of compound IM2. Add 18 g of iron powder while stirring. After the addition is complete, react at 65–70 °C for 2 hours. Cool to <30 °C, filter, and concentrate the filtrate until no more distillate is obtained to obtain crude compound IM3, which can be used directly in the next step without purification.

[0080] Step 4: Dissolve the crude compound IM3 in 180 mL of ethyl acetate, then add 18 g of acetic anhydride. React under nitrogen protection at 15–35 °C with stirring for 15 h. Concentrate the reaction solution to dryness, recrystallize with a 1:2 mixture of ethyl acetate and petroleum ether, filter, and dry the resulting solid product to constant weight at 50 °C to obtain N-(3-bromo-5-fluoro-4-methylphenyl)acetamide (14.5 g, pale yellow solid, purity 99%, total yield of Steps 3 and 4 77%). N-(3-bromo-5-fluoro-4-methylphenyl)acetamide: 1 H-NMR (400MHz, CDCl3): δ=7.32(3H,m), δ=2.20(3H,d,J=2.0Hz), δ=2.10(3H,s).

[0081] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, not all embodiments. People can obtain other embodiments based on the present invention without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for preparing N-(3-bromo-5-fluoro-4-methylphenyl)acetamide, characterized in that, Includes the following steps: Step 1: Add 400 mL of N,N-dimethylformamide, 52 g of diethyl malonate, and 51 g of 3,4-difluoro-5-bromonitrobenzene. Under nitrogen protection, cool to 0 °C. Add 60 wt% NaH-silicone oil mixture in 5 batches. After addition, react at room temperature with stirring for 15 h. Quench the reaction with 400 mL of 1 mol / L hydrochloric acid solution. Extract four times with methyl tert-butyl ether. Combine the organic phases, wash three times with saturated brine, and concentrate the organic phase until no more distillate is obtained to obtain crude compound IM1. The mass of NaH in the NaH-silicone oil mixture is 17 g. The single-use volume of methyl tert-butyl ether is 400 mL. The single-use volume of saturated brine is 400 mL. Step 2: Dissolve the crude compound IM1 in 650 mL of dimethyl sulfoxide, add 90 g of anhydrous lithium chloride in 5 batches, and after the addition is complete, heat to 110 °C and react for 48 h. Cool to 0 °C, quench the reaction by adding 650 mL of water dropwise, extract twice with methyl tert-butyl ether, combine the organic phases, wash twice with water and once with 650 mL of saturated brine, concentrate the organic phase until no distillate is obtained, recrystallize with a 2:1 ethanol / water mixture, filter, and dry the obtained solid product to constant weight at 50 °C to obtain compound IM2; the single volume of methyl tert-butyl ether used is 650 mL; the single volume of washing water used is 650 mL. Step 3: Add 500 mL of ethanol, 100 mL of tetrahydrofuran, 15 g of 12 mol / L hydrochloric acid and 50 g of compound IM2. Add 50 g of iron powder under stirring. After the addition is complete, reflux for 15 h, cool to <30℃, filter, and concentrate the filtrate until no distillation occurs to obtain crude compound IM3. Step 4: Dissolve the crude compound IM3 in 800 mL of tetrahydrofuran, add 50 g of acetic anhydride, and react for 15 h under nitrogen protection, room temperature and stirring. Concentrate the reaction solution to dryness, recrystallize with a mixed solvent of ethyl acetate / petroleum ether (volume ratio = 1:2), filter, and dry the obtained solid product to constant weight at 50 °C to obtain N-(3-bromo-5-fluoro-4-methylphenyl)acetamide. 。

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