Preparation method of 2-(2-amino-5-bromo-benzoyl) pyridine

Abstract

The invention relates to a preparation method of 2-(2-amino-5-bromo-benzoyl) pyridine, which comprises the following steps: by taking 1, 2-diphenyl-1H-benzimidazole (I) as a starting material, oxidizing under the action of chromium trioxide and acetic acid to obtain N-[2-(2-pyridinecarbonyl) phenyl] benzamide (II), hydrolyzing the N-[2-(2-pyridinecarbonyl) phenyl] benzamide (II) under the action of sulfuric acid to obtain 2-(2-aminobenzoyl) pyridine (III), and reacting the 2-(2-amino-5-bromo-benzoyl) pyridine (III) with the 2-(2-amino-5-bromo-benzoyl) pyridine (III) to obtain the 2-(2-amino-5-bromo-benzoyl) pyridine. And (III) performing substitution reaction with NBS in DCM to obtain the target product 2-(2-amino-5-bromo-benzoyl) pyridine. The method has the advantages of mild reaction conditions, higher product purity, high yield, simplicity and convenience in operation, low cost and easiness in industrialization.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical drug synthesis, and specifically relates to a method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine. Background Art

[0002] 2-(2-amino-5-bromobenzoyl)pyridine, chemical formula: ; 2-(2-amino-5-bromo-benzoyl)pyridine is an important chemical intermediate, which is widely used in the field of drug synthesis and has broad application prospects. It can be used as an electrophilic reagent to participate in a variety of coupling reactions, substitution reactions, etc., providing rich synthetic strategies and paths for organic synthetic chemistry. Therefore, the study and optimization of the preparation process of 2-(2-amino-5-bromo-benzoyl)pyridine is of great significance for improving the production efficiency and reducing the cost of 2-(2-amino-5-bromo-benzoyl)pyridine. At the same time, 2-(2-amino-5-bromo-benzoyl)pyridine is a key intermediate of the intravenous anesthetic drug remimazolam. Remimazolam was designed by GlaxoSmithKline (GSK) in the UK and later developed by PAION in Germany. It is an ultra-fast sedative and anesthetic drug.

[0003] The method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine disclosed in the literature is as follows: Method 1: The route publicly reported in WO0069836, this method points out that 2-bromopyridine is added to a hexane and ether solution of n-butyl lithium at -40°C, and then a tetrahydrofuran solution of 5-bromo-o-aminobenzoic acid is added dropwise, and the reaction is concentrated to obtain a black oily substance, which is then passed through column chromatography to obtain the desired compound as a brown solid. This method uses inflammable and explosive dangerous reagents such as n-butyl lithium and ether, and the production process requires a production condition of -40°C, which has high requirements for equipment. At the same time, column chromatography uses a large amount of solvent, the operation is cumbersome, the yield is low, and it is difficult to industrialize production. The synthetic route is as follows:

[0004] Method 2: The route publicly reported in CN110746345, this method uses 4-bromo-2-bromomethylphenol as the starting material, reacts with methoxyethoxymethyl chloride to protect the hydroxyl group, and then reacts with trimethyl borate to generate boric acid, and the boric acid compound is then condensed with 2-bromopyridine, and then oxidized and deprotected to obtain 2-(2-hydroxy-5-bromo-benzoyl)pyridine, and then condensed with 2-bromoisobutyramide and rearranged to obtain 2-(2-amino-5-bromo-benzoyl)pyridine. This method has a long route, a low total yield, and a high industrialization cost. The synthetic route is as follows:

[0005] Method 3: The route publicly reported in patent CN105541825, this method uses 2-(2-aminobenzoyl)pyridine to prepare 2-(2-amino-5-bromo-benzoyl)pyridine through bromination reaction with N-bromosuccinimide (NBS). The raw material 2-(2-aminobenzoyl)pyridine in this method is relatively expensive, and the product in the bromination reaction will have multiple brominated impurities generated and difficult to separate, affecting the product quality of 2-(2-amino-5-bromo-benzoyl)pyridine, and the industrial production cost is relatively high. The synthetic route is as follows:

[0006] Method 4: The route publicly reported in patent CN115322144, this preparation method is to react 2-amino-5-bromobenzonitrile and 2-bromopyridine in the presence of an organic strong base, and then continue the reaction under the condition of an inorganic acid to obtain 2-(2-amino-5-bromo-benzoyl)pyridine, which optimizes the preparation method, but this preparation method uses n-butyl lithium, which is extremely dangerous, and the production process needs to be carried out at a low temperature environment below -45°C, and the production conditions are strict. The synthetic route is as follows:

[0007] Method 5: The route publicly reported in patent CN116041254, the raw material 2-amino-5-bromobenzoic acid is dissolved in methanol, catalytic DMAP is added, Boc anhydride is added dropwise for reaction, 5-bromo-2-Boc aminobenzoic acid is post-treated, and 2-bromopyridine and isopropylmagnesium chloride are reacted at room temperature for 5 hours to generate 2-pyridylmagnesium bromide to obtain 2-(2-Bocamino-5-bromo-benzoyl)pyridine, and then reacted with trifluoroacetic acid to obtain the product 2-(2-amino-5-bromo-benzoyl)pyridine. This method has a long route, uses a more dangerous Grignard reagent in the synthesis, and has a high production cost, and is not suitable for industrial production. The synthetic route is as follows:

[0008] Method 6: The route publicly reported in patent CN116751157, 2-pyridine carboxylic acid is reacted with a chlorination reagent in an organic solvent to generate 2-pyridine carboxylic acid hydrochloride, which is then reacted with 1-bis(trimethylsilyl)amino 4-bromobenzene, and 2-(2-bistrimethylsilylamino-5-bromo-benzoyl)pyridine is generated under the action of a metal catalyst and a Lewis acid, and finally deprotected to generate 2-(2-amino 5-bromo-benzoyl)pyridine. This method has a long reaction time, and metal catalysts and Lewis acids are used in the production process. The reaction process is difficult to control and the yield is low. The synthetic route is as follows: Summary of the invention In order to solve the above problems, the present invention aims to provide a method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine.

[0009] The technical solution of the present invention is as follows: A method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine, characterized in that it comprises the following steps: ; (1) 1,2-diphenyl-1H-benzimidazole (I) was dissolved in acetic acid, and a chromium trioxide solution in water was added at 20-30°C with stirring. After the addition was complete, the mixture was reacted at 25-35°C for 4-5 hours. After the reaction was completed, the mixture was quenched with isopropanol, extracted with DCM, washed with water, sodium bicarbonate solution, and sodium chloride solution, dried, filtered, concentrated, and anhydrous ethanol was added for recrystallization. The mixture was filtered and dried to obtain N-[2-(2-pyridinyl)phenyl]benzamide (II).

[0010] (2) Add N-[2-(2-pyridinyl)phenyl]benzamide (II) to a 4-7M sulfuric acid solution and react at 95-105°C for 3-4 hours. After the reaction, adjust the pH of the system to 7-8 with potassium carbonate, extract with EA (ethyl acetate), wash, dry and concentrate, add n-hexane to the concentrate, stir and disperse, filter and dry to obtain the product 2-(2-aminobenzoyl)pyridine (III).

[0011] (3) 2-(2-Aminobenzoyl)pyridine (III) was dissolved in DCM, and NBS (N-bromosuccinimide) was added at 20-30°C. After the addition, the mixture was reacted at 30-40°C for 2-3 hours. After the reaction, the mixture was washed with sodium bicarbonate solution, sodium chloride solution and water. The organic phase was concentrated, dissolved in dichloromethane, and then crystallized by adding n-hexane. The filter cake was dissolved in ethanol, and then washed with water to obtain the crystals. The product 2-(2-amino-5-bromobenzoyl)pyridine was obtained by filtering and drying.

[0012] Preferably, the reaction solvent in step (3) is DCM (dichloromethane); wherein the molar ratio of 2-(2-aminobenzoyl)pyridine to NBS is 1:(0.8-1.5).

[0013] Preferably, in step (3), the product is purified using a system of dichloromethane / n-hexane in a volume ratio of 1:(3-5) and anhydrous ethanol / water in a volume ratio of 1:(1-3).

[0014] Compared with the prior art, the present invention has the following beneficial effects: In the present invention, step (i) uses an efficient chromium catalyst. In an acidic reaction environment, the reaction conditions are mild, the conversion efficiency of the raw materials is high, and the chromium catalyst is easy to remove. The post-treatment is simple and controllable, which helps to obtain high-yield and high-purity intermediate products. Step (ii) uses an acidic hydrolysis process, which has high conversion efficiency, is not easy to cause side reactions, can effectively control the purity of the product, and is easy to handle sulfuric acid waste liquid, has little harm to the environment, and is easy to achieve industrial production. Step (iii) uses NBS as the reaction raw material, which has low material cost, mild reaction conditions, high reaction efficiency, and the raw material is easy to remove in this solvent system, which can reduce the risk of the impurity remaining in the product; the product refining adopts dichloromethane / n-hexane and anhydrous ethanol / water systems, the loss of the two refined products is low, the impurity removal efficiency is high, the content of dibromo-mono impurities can be controlled, and high-purity 2-(2-amino-5-bromo-benzoyl)pyridine can be obtained. The present invention adopts common process principles, and the raw materials are all common chemical reagents. The raw materials are easy to remove and will not cause excessive raw material residues in the product.

[0015] The synthetic route has the characteristics of short steps, mild and simple reaction conditions, easy treatment of generated waste liquid, little harm to the environment and few process impurities, and at the same time, low production cost and easy to realize industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 is the infrared spectrum of 2-(2-amino-5-bromo-benzoyl)pyridine; Figure 2 H NMR spectrum of intermediate product 1; Figure 3 NMR carbon spectrum of intermediate product 1; Figure 4 H NMR spectrum of intermediate product 2; Figure 5 NMR carbon spectrum of intermediate product 2; Figure 6 It is the H NMR spectrum of 2-(2-amino-5-bromo-benzoyl)pyridine; Figure 7 This is the carbon NMR spectrum of 2-(2-amino-5-bromo-benzoyl)pyridine. DETAILED DESCRIPTION

[0017] The following will be combined with the specific embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. The embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work belong to the protection scope of the present invention.

[0018] In the context of this specification, except for the contents explicitly described, any matters or items not mentioned directly use the technology known in the art. Moreover, any embodiment described in this patent can be freely combined with one or more other embodiments described in this patent, and the technical solutions or technical ideas formed thereby are regarded as part of the original disclosure or original record of the present invention, and should not be regarded as new content not disclosed in this patent, unless a person skilled in the art considers that the combination is obviously unreasonable.

[0019] The data points disclosed in the present invention include not only the specifically disclosed numerical points, but also the endpoints of each numerical range. Any combination of these data points should be regarded as the disclosed or recorded range of the present invention, regardless of whether these numerical points are disclosed one by one in this article.

[0020] Example 1 (1) Add 1,2-diphenyl-1H-benzimidazole (100.0 g, 369.90 mmol) and 1.2 L acetic acid to a 3 L three-necked flask, start stirring, and slowly drip chromium trioxide (74 g, 740.07 mmol) dissolved in 130 mL of water into the three-necked flask, maintaining the reaction temperature at 25 °C. After the addition is completed, keep the temperature at 30 °C and stir for 6 hours. Control the temperature of the reaction solution at 25 °C, slowly add 180 ml of isopropanol to quench, and continue stirring for 0.5 h. Add 1.5 L DCM and 2.3 L water to the reaction solution, let it stand for stratification, and separate the lower organic phase. Wash with sodium bicarbonate solution and sodium chloride solution respectively. Add anhydrous sodium sulfate to dry, filter, and distill under reduced pressure to obtain a yellow oxidation product (120.0 g). Add 480 ml of anhydrous ethanol to the above crude product in a round-bottom flask, heat to 70~80 °C, and cool to -5~5 °C for crystallization. The mixture was filtered, and the filter cake was washed with ethanol and dried to obtain a yellow oxidation product (79.3 g, 262.30 mmol, yield: 70.91%, purity: 97.2%).

[0021] (2) Add 1,2-diphenyl-1H-benzimidazole (100.0 g, 369.90 mmol) and 1.2 L acetic acid to a 3 L three-necked flask, start stirring, and slowly drip chromium trioxide (74 g, 740.07 mmol) dissolved in 130 mL of water into the three-necked flask, maintaining the reaction temperature at 25 °C. After the addition is completed, keep the temperature at 30 °C and stir for 4 hours. Control the temperature of the reaction solution at 25 °C, slowly add 180 ml of isopropanol to quench, and continue stirring for 0.5 h. Add 1.5 L DCM and 2.3 L water to the reaction solution, let it stand for stratification, and separate the lower organic phase. Wash with sodium bicarbonate solution and sodium chloride solution respectively. Add anhydrous sodium sulfate to dry, filter, and distill under reduced pressure to obtain a yellow oxidation product (148.5 g). Add 480 ml of anhydrous ethanol of the above crude product to a round-bottom flask, heat to 75 °C, and cool to 0 °C for crystallization. The mixture was filtered, and the filter cake was washed with ethanol and dried to obtain a yellow oxidation product (94.0 g, 310.92 mmol, yield: 84.05%, purity: 99.0%).

[0022] (3) Add 1,2-diphenyl-1H-benzimidazole (100.0 g, 369.92 mmol) and 1.2 L acetic acid to a 3 L three-necked flask, start stirring, and slowly drip potassium permanganate (120.0 g, 759.33 mmol) dissolved in 130 mL of water into the three-necked flask, maintaining the reaction temperature at 25 °C. After the addition is completed, keep the temperature at 30 °C and stir for 4 hours. Control the temperature of the reaction solution at 25 °C, slowly add 180 ml of isopropanol to quench, and continue stirring for 0.5 h. Add 1.5 L DCM and 2.3 L water to the reaction solution, let it stand for stratification, and separate the lower organic phase. Wash with sodium bicarbonate solution and sodium chloride solution respectively. Add anhydrous sodium sulfate to dry, filter, and distill under reduced pressure to obtain a yellow oxidation product (138.3 g). Add 480 ml of anhydrous ethanol of the above crude product to a round-bottom flask, heat to 75 °C, and cool to 0 °C for crystallization. The mixture was filtered, and the filter cake was washed with ethanol and dried to obtain a yellow oxidation product (87.9 g, 290.74 mmol, yield: 78.60%, purity: 84.0%).

[0023] In Example 1, the intermediate products obtained by changing the oxidation reaction time and prolonging the reaction time are of poor quality and low yield. This is because excessive reaction will cause the product to be converted into other impurities. In experiment (3), the type of oxidant is changed. The purity of the intermediate obtained by using potassium permanganate oxidant is significantly lower. The chromium catalyst has obvious advantages and can effectively control the occurrence of side reactions.

[0024] Example 2 (1) Weigh 400.0g of concentrated H2SO4 and slowly add it to 670.0g of water to prepare a sulfuric acid solution of about 4M. Add intermediate 1 (80.0g, 264.61mmol) and sulfuric acid solution to a 3L three-necked flask and start stirring. Maintain the reaction temperature at 100℃ and stir for 3 hours. After the reaction is complete, reduce the temperature of the reaction solution to 25℃. Transfer the reaction solution to a 5L beaker, add 1.8L of water to the reaction solution, and slowly add K2CO3 solid particles in batches to adjust the pH to 7-8. Add 1.8L of ethyl acetate, stir for more than 5min, let stand for more than 15min, and separate the lower aqueous phase. Continue to add 1.0L of ethyl acetate, stir for more than 5min, let stand for more than 15min, and separate the aqueous phase. Add 1.0L of ethyl acetate again, stir for more than 5min, let stand for more than 15min, and combine the organic phases. Add 1.5L of drinking water to the organic phase, stir for more than 5min, let stand for more than 15min, separate the upper organic phase, and discard the aqueous phase. Continue to add 1.5L of drinking water to the organic phase, stir for more than 5min, let stand for more than 15min. Separate the organic phase, add 140.0g of anhydrous sodium sulfate and dry for more than 2h. Filter by suction, wash the filter cake with ethyl acetate, and distill under reduced pressure; after evaporation, add 100ml of n-hexane to a rotary evaporator to disperse, filter, and obtain the product (38.6g, 194.72mmol, yield: 73.59%, purity: 93.5%).

[0025] (2) Weigh 600.0g of concentrated H2SO4 and slowly add it to 670.0g of water to prepare a sulfuric acid solution of about 6M. Add intermediate 1 (80.0g, 264.61mmol) and sulfuric acid solution to a 3L three-necked flask and start stirring. Maintain the reaction temperature at 100℃ and stir for 3 hours. After the reaction is complete, reduce the temperature of the reaction solution to 25℃. Transfer the reaction solution to a 5L beaker, add 1.8L of water to the reaction solution, and slowly add K2CO3 solid particles in batches to adjust the pH to 7-8. Add 1.8L of ethyl acetate, stir for more than 5min, let stand for more than 15min, and separate the lower aqueous phase. Continue to add 1.0L of ethyl acetate, stir for more than 5min, let stand for more than 15min, and separate the aqueous phase. Add 1.0L of ethyl acetate again, stir for more than 5min, let stand for more than 15min, and combine the organic phases. Add 1.5L of drinking water to the organic phase, stir for more than 5min, let stand for more than 15min, separate the upper organic phase, and discard the aqueous phase. Continue to add 1.5L of drinking water to the organic phase, stir for more than 5min, let stand for more than 15min. Separate the organic phase, add 140.0g of anhydrous sodium sulfate and dry for more than 2h. Filter by suction, wash the filter cake with ethyl acetate, and distill under reduced pressure; after evaporation, add 100ml of n-hexane to a rotary evaporator to disperse, filter, and obtain the product (48.9g, 246.68mmol, yield: 93.22%, purity: 99.4%).

[0026] In Example 2, the concentration of the sulfuric acid solution was changed in experiments (1) and (2). The concentration of the sulfuric acid solution was too low, resulting in incomplete hydrolysis, affecting the reaction conversion rate and thus the product yield. A 6M sulfuric acid solution was relatively suitable and could obtain a high-yield, high-purity intermediate product.

[0027] Example 3 (1) 510.0 g of DCM and intermediate 2 (40.0 g, 201.79 mmol) were added to a 3 L three-necked flask, and 37.0 g of NBS was added at 25 °C. After the addition was complete, the mixture was reacted at 35 °C for 3 hours. The organic phase was washed twice with sodium bicarbonate aqueous solution and then twice with water. After washing, the organic phase was concentrated to dryness, 127.0 g of DCM was added at room temperature to dissolve, 250.0 g of n-hexane was added to crystallize for 1 hour, and the mixture was filtered. The filter cake was added to 90 g of anhydrous ethanol, the mixture was heated to 80 °C to dissolve, and the mixture was cooled to 5 °C to crystallize for 1 hour. During the cooling process, 230.0 g of water was added, the mixture was filtered, and the product 2-(2-amino-5-bromo-benzoyl)pyridine (29.4 g, 106.09 mmol, yield: 52.57%, purity: 96.1%) was obtained.

[0028] (2) 510.0 g of DCM and intermediate 2 (40.0 g, 201.79 mmol) were added to a 3 L three-necked flask, and 48.8 g of NBS was added at 25 °C. After the addition was complete, the mixture was reacted at 35 °C for 3 hours. The organic phase was washed twice with sodium bicarbonate aqueous solution and then twice with water. After washing, the organic phase was concentrated to dryness, 127.0 g of DCM was added at room temperature to dissolve, 250.0 g of n-hexane was added to crystallize for 1 hour, and the mixture was filtered. The filter cake was added to 90 g of anhydrous ethanol, heated to 80 °C to dissolve, cooled to 5 °C to crystallize for 1 hour, and 230.0 g of water was added during the cooling process. The mixture was filtered and dried to obtain the product 2-(2-amino-5-bromo-benzoyl)pyridine (44.9 g, 162.02 mmol, yield: 80.29%, purity: 97.7%).

[0029] (3) 510.0 g of DCM and intermediate 2 (40.0 g, 201.79 mmol) were added to a 3 L three-necked flask, and 48.8 g of NBS was added at 25 °C. After the addition was complete, the mixture was reacted at 35 °C for 2 hours. The organic phase was washed twice with an aqueous sodium bicarbonate solution and then twice with water. After washing, the organic phase was concentrated to dryness, 127.0 g of DCM was added at room temperature to dissolve, 250.0 g of n-hexane was added to crystallize for 1 hour, and the mixture was filtered. The filter cake was added to 90 g of anhydrous ethanol, heated to 80 °C to dissolve, cooled to 5 °C to crystallize for 1 hour, and 230.0 g of water was added during the cooling process. The mixture was filtered and dried to obtain the product 2-(2-amino-5-bromo-benzoyl)pyridine (45.5 g, 164.19 mmol, yield: 81.37%, purity: 99.6%).

[0030] (4) 510.0 g of DCM and intermediate 2 (40.0 g, 201.79 mmol) were added to a 3 L three-necked flask, and 48.8 g of NBS was added at 25 °C. After the addition, the mixture was reacted at 35 °C for 2 hours. The organic phase was washed twice with sodium bicarbonate aqueous solution and then twice with water. After washing, the organic phase was concentrated to dryness, 127.0 g of DCM was added at room temperature to dissolve, 250.0 g of petroleum ether was added to crystallize for 1 hour, and the mixture was filtered. The filter cake was added to 90 g of anhydrous ethanol, the mixture was heated to 80 °C to dissolve, and the mixture was cooled to 5 °C to crystallize for 1 hour. During the cooling process, 230.0 g of water was added, the mixture was filtered, and the product 2-(2-amino-5-bromo-benzoyl)pyridine (38.7 g, 139.65 mmol, yield: 69.21%, purity: 99.2%) was obtained.

[0031] In Example 3, the NBS feed amount was changed in experiments (1) and (2). The NBS feed amount was 1 eq, which would result in incomplete reaction and affect the product yield. By comparison, when the NBS feed amount was 1.3 eq, the raw material was almost completely reacted. In experiment (3), by reducing the substitution reaction time, it can be seen that extending the reaction time may lead to overreaction, resulting in low product purity. This is because the substitution reaction rate is relatively fast and the product has poor stability in the reaction solution. In experiment (4), the refining crystallization solvent was changed from n-hexane to petroleum ether. It can be seen that the use of petroleum ether solvent for crystallization will result in insufficient product precipitation and significantly low yield. The dichloromethane / n-hexane refining system is a better combination after industrial screening and can effectively remove dibromo impurities.

[0032] Example 4 (1) Add 27.0 kg of 1,2-diphenyl-1H-benzimidazole and 324.0 L of acetic acid to the reactor, start stirring, maintain the reaction temperature at 25°C, and drop chromium trioxide aqueous solution (20.0 kg of chromium trioxide dissolved in 35.1 L of water). After the dropwise addition is completed, keep the temperature at 30°C and stir for 4 hours. Control the temperature of the reaction solution at 25°C, slowly add 48.6 kg of isopropanol to quench, and continue stirring for 0.5 hours. Add 405.0 L of DCM and 621.0 L of water to the reaction solution, let it stand for stratification, separate the lower organic phase, and wash it with sodium bicarbonate solution and sodium chloride solution respectively. Add anhydrous sodium sulfate to dry, filter, and concentrate under reduced pressure to obtain 24.0 kg of yellow oxidation product. Add the above crude product and 129.6 L of anhydrous ethanol to the reactor, heat to 75°C, and cool to 0°C for crystallization. Filter, wash the filter cake with ethanol, and dry to obtain a yellow oxidation product - intermediate product 1 (25.6 kg, yield: 84.78%, purity: 99.2%). 19 H 14 N2O2, Gray solid, 1H NMR (400 MHz, CDCl3) δ 12.21 (s, 1H), 8.97 (d, J = 8.4Hz, 1H), 8.73 (d, J = 4.6 Hz, 1H), 8.09 (d, J = 7.2 Hz, 2H), 7.86 (d, J = 20.4 Hz,3H), 7.65 (t, J = 7.9 Hz, 1H), 7.58 – 7.44 (m, 4H), 7.13 (t, J = 7.6 Hz, 1H). 13 CNMR (101 MHz, CDCl3) δ 197.63, 165.75, 155.90, 148.72, 142.03, 136.98,135.24, 134.98, 134.60, 131.93, 128.72 (2C), 127.35 (2C), 125.86, 124.50,122.03, 121.40, 120.92).

[0033] (2) Add 215.2 kg of water and 193.8 kg of concentrated H2SO4 to the reactor to prepare a 6 M sulfuric acid solution, add 25.6 kg of the above product, control the reaction temperature to 100 °C and stir for 3 h. Lower the temperature of the reaction solution to 25 °C, add 575.3 L of water to the reaction solution, and slowly add K2CO3 solid particles to adjust the pH to 7-8. Add 274.2 L of ethyl acetate, stir for more than 5 min, let stand for more than 15 min, and separate the lower aqueous phase. Continue to add 287.7 L of ethyl acetate, stir for more than 5 min, let stand for more than 15 min, and separate the aqueous phase. Add 287.7 L of ethyl acetate again, stir for more than 5 min, let stand for more than 15 min, and combine the organic phases. Add 431.4 L of water to the organic phase, stir for more than 5 min, let stand for more than 15 min, separate the upper organic phase, and discard the aqueous phase. Continue to add 431.4L of water to the organic phase, stir for more than 5min, let stand for more than 30min, separate the organic phase, add 44.6kg of anhydrous sodium sulfate and dry for more than 2h. Filter, wash the filter cake with ethyl acetate, distill under reduced pressure, disperse the concentrate with 32.0L of n-hexane, filter, and obtain the product - intermediate product 2 (15.7kg yield: 93.53%, purity: 99.4%. C 12 H 10 N2O, Yellowsolid, 1H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 4.7 Hz, 1H), 7.84 (td, J = 7.7, 1.7Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.63 (dd, J = 8.1, 1.5 Hz, 1H), 7.40 (ddd, J =7.6, 4.8, 1.3 Hz, 1H), 7.32 – 7.23 (m, 1H), 6.70 (d, J = 8.1 Hz, 1H), 6.64 –6.55 (m, 1H), 6.32 (s, 2H). 13 C NMR (101MHz, CDCl3) δ 195.90, 157.39, 151.71,148.32, 136.75, 134.89, 134.66, 124.81, 123.73, 116.90, 116.65, 115.42).

[0034] (3) Add 206.8 kg of DCM and 15.6 kg of the above product to the reactor, add 13.3 kg of NBS at 25 °C, and react at 35 °C for 2 hours. Wash the organic phase twice with sodium bicarbonate aqueous solution, and then wash the organic phase twice with water. After washing, concentrate the organic phase to dryness, add 51.6 kg of DCM at room temperature to dissolve, add 102.8 kg of n-hexane to crystallize for 1 hour, filter, add the filter cake to 37.0 kg of anhydrous ethanol, heat to 80 °C to dissolve, cool to 5 °C to crystallize for 1 hour, add 93.6 kg of water during the cooling process, filter, and dry to obtain the product 2-(2-amino-5-bromo-benzoyl)pyridine (17.8 kg, yield: 81.62%, purity: 99.4%). 12 H9BrN2O, Yellow solid, 1 H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 4.7 Hz, 1H), 7.92– 7.82 (m, 2H), 7.78 (d, J = 7.8 Hz, 1H), 7.45 (ddd, J = 7.8, 4.0, 2.5 Hz, 1H),7.34 (dq, J = 8.9, 2.3 Hz, 1H), 6.62 (dd, J= 8.9, 3.6 Hz, 1H), 6.33 (s, 2H). 13 CNMR (101 MHz, CDCl3) δ 194.64, 156.60, 150.56, 148.41, 137.27, 137.05,136.77, 125.32, 124.00, 118.74, 117.86, 106.56).

[0035] Through Examples 1-3, a better production process was screened out for scaled-up production, and the scaled-up production was completely consistent with the test results, and was able to stably produce high-yield, high-purity products, meeting the needs of industrial production.

[0036] The technical solution of the present invention is explained through the above embodiments, but the present invention is not limited to the above embodiments, that is, it does not mean that the present invention must rely on the above specific embodiments to be implemented. Any improvements made by technicians in the relevant field based on the present invention, or equivalent replacement of the materials selected by the present invention, etc., fall within the scope of protection of the patent.

Claims

1. A method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine, characterized in that: The method comprises the following steps: ； (1) 1,2-diphenyl-1H-benzimidazole (Ⅰ) was slowly added dropwise with chromium trioxide dissolved in water to react with the acetic acid. After the reaction was completed, the reaction was quenched with isopropanol, extracted with DCM, concentrated, and crystallized to obtain N-[2-(2-pyridinyl)phenyl]benzamide (Ⅱ); (2) N-[2-(2-pyridinyl)phenyl]benzamide (II) reacts in a sulfuric acid solution, and then quenches, extracts, concentrates, and crystallizes to obtain 2-(2-aminobenzoyl)pyridine (III); (3) 2-(2-Aminobenzoyl)pyridine (III) was dissolved in DCM, and NBS (N-bromosuccinimide) was added for reaction. The product 2-(2-amino-5-bromobenzoyl)pyridine was obtained by purification with a dichloromethane / n-hexane mixed solution and an ethanol / water mixed solution.

2. The method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine according to claim 1, characterized in that: The starting material synthesized in step (1) is bromine-free 1,2-diphenyl-1H-benzimidazole.

3. The method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine according to claim 1, characterized in that: In the step (1), the starting material 1,2-diphenyl-1H-benzimidazole is used as the reaction solvent and the oxidant is chromic acid; preferably, the molar ratio of 1,2-diphenyl-1H-benzimidazole to chromic acid is 1:(1-3).

4. The method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine according to claim 1, characterized in that: The reaction conditions of step (1) are 25-35° C. and the reaction time is 4-5 hours.

5. The method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine according to claim 1, characterized in that: In the step (2), the reaction solvent of N-[2-(2-pyridinyl)phenyl]benzamide (II) is a 4-7M sulfuric acid solution.

6. The method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine according to claim 1, characterized in that: The reaction conditions of step (2) are 95-105° C. and the reaction time is 3-4 hours.

7. The method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine according to claim 1, characterized in that: In the step (2), the concentrate is dispersed and slurried using n-hexane solvent.

8. The method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine according to claim 1, characterized in that: The reaction solvent in step (3) is DCM; wherein the molar ratio of 2-(2-aminobenzoyl)pyridine to NBS is 1:(0.8-1.5).

9. The method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine according to claim 1, characterized in that: The reaction conditions of step (3) are 30-40° C. and the reaction time is 2-3 hours.

10. The method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine according to claim 1, characterized in that: In the step (3), the product is purified using a dichloromethane / n-hexane system with a volume ratio of 1:(3-5) and anhydrous ethanol / water system with a volume ratio of 1:(1-3).

Images