A method for synthesizing 2-(2-amino-5-bromo-benzoyl)pyridine

Abstract

This invention provides a method for synthesizing 2-(2-amino-5-bromo-benzoyl)pyridine, belonging to the field of pharmaceutical synthesis technology. The method employs a one-pot reaction, using 2-cyanopyridine and 4-bromoaniline as raw materials, BCl3 as a catalyst, and dichloromethane as a solvent. The reaction is carried out at -10℃ to 40℃ for 5 to 25 hours. Extraction with ethyl acetate, drying with anhydrous sodium sulfate, and recrystallization from dichloromethane and petroleum ether yields the product 2-(2-amino-5-bromo-benzoyl)pyridine. The method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine provided by this invention eliminates the need for the use of highly hazardous butyllithium, and features simple reaction steps, stable yield, easy processing, and high production rate.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, and more particularly to a method for synthesizing 2-(2-amino-5-bromo-benzoyl)pyridine. Background Technology

[0002] Remimazolam is a short-acting GABAa receptor agonist used for general anesthesia during surgery. It is characterized by rapid onset of action, short half-life, and high safety profile. Remimazolam combines the safety of midazolam with the effectiveness of propofol, and is more effective than propofol for intravenous anesthesia.

[0003] 2-(2-Amino-5-bromo-benzoyl)pyridine is a key component in constructing the benzimidazolone skeleton, the core structure of remimazolam. It is a crucial intermediate in the synthesis of the intravenous anesthetic remimazolam. In the synthetic route, this intermediate typically undergoes a cyclization reaction with a carboxylic acid derivative (such as an ester or acyl chloride) to form the final remimazolam molecule. Besides remimazolam, this intermediate possesses a wider range of potential applications in pharmaceutical synthesis due to its structure incorporating advantageous pharmacophores such as aniline, aromatic bromine, and arylpyridone. The multifunctional reaction sites and advantageous structure of 2-(2-amino-5-bromo-benzoyl)pyridine make it a promising candidate for research and application in the development of novel benzodiazepine drugs and protease inhibitors (especially kinase inhibitors).

[0004] Currently, there are many existing technologies for the synthesis of 2-(2-amino-5-bromo-benzoyl)pyridine. For example, the invention patent application No. 202411301851.X discloses a method for synthesizing 2-(2-amino-5-bromo-benzoyl)pyridine using 2-amino-5-bromobenzoic acid as a starting material. The target product is constructed through a two-step reaction of "amidation condensation-nucleophilic addition," yielding an oily crude product. This crude product is then purified by column chromatography with ethyl acetate / petroleum ether to obtain 2-(2-amino-5-bromo-benzoyl)pyridine. This method uses isopropyl magnesium chloride and reacts at -18°C. The production process requires strict temperature control, precise order of reactant addition, and strict solvent ratio requirements for column chromatography. The operation is cumbersome, the yield is low, and impurities are difficult to remove.

[0005] The invention patent disclosed in application number 202411771787.1 discloses a method for synthesizing 2-(2-amino-5-bromo-benzoyl)pyridine, which uses 1,2-diphenyl-1H-benzimidazole as the starting material and constructs the target product through a three-step reaction of "oxidative ring-opening-acidic hydrolysis-selective bromination". Although the reaction conditions are mild throughout and no high-risk reagents or extreme low-temperature equipment are required, this method has strict requirements on the dropping rate of the reactants, requires the addition of highly corrosive concentrated sulfuric acid, requires a large amount of solvent in the purification process, and has low yield, strict operation, and high production cost.

[0006] The invention patent application No. 202211046698.1 discloses a method for synthesizing 2-(2-amino-5-bromo-benzoyl)pyridine, which uses 2-amino-5-bromobenzonitrile and 2-bromopyridine as starting materials and constructs the target product through a one-pot method of "nucleophilic addition-hydrolysis cyclization". However, this method requires the addition of flammable and explosive n-butyllithium, the production process requires a reaction condition of -40°C, and the crystallization cooling rate needs to be strictly controlled, making the operation cumbersome.

[0007] Therefore, a method for synthesizing 2-(2-amino-5-bromo-benzoyl)pyridine that does not use highly hazardous butyllithium, has stable product yield, is easy to handle, has high yield, and has simple reaction steps is a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0008] In view of this, the present invention provides a method for synthesizing 2-(2-amino-5-bromo-benzoyl)pyridine, comprising the following steps:

[0009] (1) Dissolve 4-bromoaniline and 2-cyanopyridine in organic solvent A, add a catalyst to carry out the reaction, and after the reaction is completed, quench the reaction with organic solvent B to obtain the crude product of 2-(2-amino-5-bromo-benzoyl)pyridine;

[0010] (2) The crude product of 2-(2-amino-5-bromo-benzoyl)pyridine was reacted in an acidic solution. After the reaction was completed, the product was concentrated to obtain a concentrated crude product. The crude product was then extracted in an organic solvent C. The pH of the system was adjusted and the liquid was separated to obtain an aqueous phase a and an organic phase a. The aqueous phase a was extracted in an organic solvent D and the liquid was separated to obtain an aqueous phase b and an organic phase b. The organic phase a and organic phase b were combined, washed with water, dried and concentrated to obtain an oily substance.

[0011] (3) Add organic solvent E to the oily substance, heat to dissolve, cool to obtain 2-(2-amino-5-bromo-benzoyl)pyridine.

[0012] Furthermore, the molar ratio of 4-bromoaniline and 2-cyanopyridine in step (1) is 1:1-3.

[0013] Furthermore, the organic solvent A in step (1) is selected from at least one of dichloromethane, trichloromethane, tetrahydrofuran, ethanol, diethyl ether, N,N-dimethylacetamide, 1,2-dichloroethane, and 2-methyltetrahydrofuran.

[0014] Furthermore, the catalyst in step (1) is selected from at least one of aluminum trichloride, zinc chloride, ferric chloride, titanium tetrachloride, tri(pentafluorophenyl)borane, and boron trichloride.

[0015] Furthermore, the reaction temperature in step (1) is -10℃ to 40℃, and the reaction time is 5h to 25h.

[0016] Furthermore, the organic solvent B in step (1) is selected from at least one of ethanol, methanol, diethyl ether, isopropanol, ethyl acetate, petroleum ether, and tetrahydrofuran.

[0017] Furthermore, the acidic solution in step (2) is selected from any one of hydrochloric acid, sulfuric acid, and nitric acid.

[0018] Furthermore, the reaction temperature in step (2) is 0℃~70℃, and the pH of the system in step (2) is adjusted to 8-9.

[0019] Furthermore, the organic solvent C in step (2) is selected from at least one of methanol, ethanol, diethyl ether, tetrahydrofuran, and ethyl acetate, and the organic solvent D in step (2) is selected from at least one of methanol, diethyl ether, acetone, ethyl acetate, benzene, and carbon tetrachloride.

[0020] Furthermore, the organic solvent E in step (3) is selected from at least one of dichloromethane, trichloromethane, tetrahydrofuran, and petroleum ether, and the cooling in step (3) is to -10°C to 10°C.

[0021] Compared with the prior art, the present invention has the following advantages: The preparation method of 2-(2-amino-5-bromo-benzoyl)pyridine provided by the present invention does not require the use of highly dangerous butyllithium, and the reaction steps are simple, the yield is stable, easy to handle, and the yield is high. Attached Figure Description

[0022] Figure 1 This is a high-performance liquid chromatogram of 2-(2-amino-5-bromo-benzoyl)pyridine synthesized in Example 1 of this invention.

[0023] Figure 2 This is the 1H NMR spectrum of 2-(2-amino-5-bromo-benzoyl)pyridine synthesized in Example 1 of this invention.

[0024] Figure 3This is the carbon NMR spectrum of 2-(2-amino-5-bromo-benzoyl)pyridine synthesized in Example 1 of this invention. Detailed Implementation

[0025] A method for synthesizing 2-(2-amino-5-bromo-benzoyl)pyridine includes the following steps:

[0026]

[0027] (1) Dissolve 4-bromoaniline and 2-cyanopyridine in organic solvent A, add a catalyst to carry out the reaction, and after the reaction is completed, quench the reaction with organic solvent B to obtain the crude product of 2-(2-amino-5-bromo-benzoyl)pyridine;

[0028] (2) The crude product of 2-(2-amino-5-bromo-benzoyl)pyridine was reacted in an acidic solution. After the reaction was completed, the product was concentrated to obtain a concentrated crude product. The crude product was then extracted in an organic solvent C. The pH of the system was adjusted and the liquid was separated to obtain an aqueous phase a and an organic phase a. The aqueous phase a was extracted in an organic solvent D and the liquid was separated to obtain an aqueous phase b and an organic phase b. The organic phase a and organic phase b were combined, washed with water, dried and concentrated to obtain an oily substance.

[0029] (3) Add organic solvent E to the oily substance, heat to dissolve, cool to obtain 2-(2-amino-5-bromo-benzoyl)pyridine.

[0030] In this invention, the molar ratio of 4-bromoaniline to 2-cyanopyridine in step (1) is 1:1-3. This molar ratio range can meet the purity requirements of laboratory small-scale tests and can be directly scaled up to pilot-scale and mass production without the risk of scale-up effects. Preferably, the molar ratio of 4-bromoaniline to 2-cyanopyridine is 1:1, 1:1.5, 1:2, 1:2.5, and 1:3, respectively. More preferably, the molar ratio of 4-bromoaniline to 2-cyanopyridine is 1:1.5.

[0031] In this invention, the organic solvent A in step (1) is selected from at least one of dichloromethane, trichloromethane, tetrahydrofuran, ethanol, diethyl ether, N,N-dimethylacetamide, 1,2-dichloroethane, and 2-methyltetrahydrofuran. Preferably, the organic solvent A is dichloromethane.

[0032] The core function of organic solvent A selected in this invention is to dissolve reactants / catalysts, provide a stable reaction environment, and regulate reaction rate and selectivity. Its functions are compatible with most organic reaction mechanisms. Among them, dichloromethane has a wide solubility, regulates reactions, facilitates separation, and is compatible with mechanisms, making it an excellent organic solvent.

[0033] In this invention, the catalyst in step (1) is selected from at least one of aluminum trichloride, zinc chloride, ferric chloride, titanium tetrachloride, tris(pentafluorophenyl)borane, and boron trichloride, preferably boron trichloride.

[0034] This invention selects boron trichloride as a catalyst, which activates the polar groups of the substrate through the Lewis acid active center, promotes the efficient conduction of electrophilic reactions, and controls the selectivity.

[0035] A significant synergistic effect exists between the catalyst BCl3 and the organic solvent ACH2Cl2 in the reaction system. This is because CH2Cl2 maximizes the Lewis acid catalytic activity of BCl3 through dissolution, stabilization, and polarity regulation, while ensuring reaction selectivity and mass transfer efficiency. In organic synthesis reactions, the reaction yield (typically ≥85%) and selectivity of the BCl3 / CH2Cl2 system are significantly higher than those of combinations of BCl3 with nonpolar solvents (such as n-hexane, yield ≤60%) or strongly polar solvents (such as methanol, which easily leads to the hydrolysis and deactivation of BCl3), directly demonstrating the synergistic effect between the two.

[0036] In this invention, the catalyst in step (1) is added by dripping.

[0037] In this invention, the reaction temperature in step (1) is -10℃ to 40℃. Preferably, the reaction temperatures are -10℃, 0℃, room temperature, 30℃, and 40℃, respectively. More preferably, the reaction temperature is 0-10℃.

[0038] In this invention, the reaction time in step (1) is 5h to 25h, preferably 5h, 10h, 14h, 19h and 24h respectively, and more preferably 10-14h.

[0039] By limiting the reaction temperature and time to a specific range, this invention can better balance the reaction rate, product purity and safety, avoid side reactions and waste of raw materials, and is more suitable for industrial-scale production.

[0040] In this invention, the organic solvent B in step (1) is selected from at least one of ethanol, methanol, diethyl ether, isopropanol, ethyl acetate, petroleum ether, and tetrahydrofuran. Preferably, the organic solvent B is methanol.

[0041] This invention selects organic solvent B to quench the reaction, primarily because it possesses moderate polarity and reactivity. This allows it to rapidly react with excess reagents (such as organometallic compounds or Lewis acids) to terminate the main reaction, while its mild nature avoids violent exothermic reactions or the formation of complex byproducts. Methanol is readily soluble in most organic solvents and water, facilitating subsequent liquid-liquid separation or distillation. Its low boiling point (64.7°C) also makes it easy to remove from the product. Balancing quenching efficiency and ease of post-processing, this invention preferentially uses methanol as organic solvent B.

[0042] The organic solvent B, methanol, exhibits a weak nucleophilicity to the catalyst BCl3, and can rapidly react with the residual BCl3 in the system (to generate methoxyboranes), thus gently terminating the catalytic reaction and avoiding product decomposition caused by high temperatures or strong nucleophiles.

[0043] Organic solvent B, methanol, is partially miscible with organic solvent A, dichloromethane, and can be uniformly dispersed in the reaction system, avoiding local quenching and violent exothermic reactions. At the same time, its polarity can promote the conversion of BCl3 hydrolysis products (boric acid, hydrochloric acid) into water-soluble species, paving the way for subsequent separation.

[0044] In this invention, the acidic solution in step (2) is selected from any one of hydrochloric acid, nitric acid, and sulfuric acid, preferably hydrochloric acid.

[0045] In this invention, the reaction temperature in step (2) is 0°C to 70°C. Preferably, the reaction temperatures are room temperature, 30°C, 50°C, 70°C and 0°C, respectively. More preferably, the reaction temperature is 50°C.

[0046] In this invention, step (2) involves adjusting the pH of the system to 8-9. The core purpose of adjusting the pH to 8-9 is to specifically separate the hydrolysis products HCl and boric acid impurities of the acidic solution HCl and BCl3 added in the reaction, thereby protecting the target product.

[0047] In this invention, a sodium carbonate solution with a mass concentration of 10% is used to adjust the pH of the system.

[0048] In this invention, the organic solvent C in step (2) is selected from at least one of methanol, ethanol, diethyl ether, tetrahydrofuran, and ethyl acetate. Preferably, the organic solvent C is ethyl acetate.

[0049] This invention disperses crude organic products by adding organic solvent C, achieving preliminary separation of products and impurities and creating conditions for subsequent purification. Ethyl acetate is preferred as organic solvent C because it has better solubility for neutral / weakly polar products, readily separates with water, has a moderate boiling point, is inexpensive, and facilitates product enrichment and post-processing.

[0050] In this invention, the organic solvent D in step (2) is selected from at least one of methanol, diethyl ether, acetone, ethyl acetate, benzene, and carbon tetrachloride. Preferably, the organic solvent D is ethyl acetate.

[0051] This invention utilizes the addition of organic solvent D to efficiently recover residual target products in the aqueous phase, reducing losses and thus increasing the overall yield of the target products. Ethyl acetate is preferred as organic solvent D in this invention because it has stronger solubility for residual neutral / weakly polar products in the aqueous phase, is immiscible with water and easily separates into layers, and is convenient for post-processing, making it suitable for efficient extraction and enrichment of products.

[0052] Organic solvent D, ethyl acetate, is miscible with organic solvent A, dichloromethane (without affecting product solubility), but it forms clear layers with the aqueous phase (containing methanol, borate water, and hydrochloride), and can quickly separate the organic phase (product + dichloromethane + ethyl acetate) from the aqueous phase impurities.

[0053] Organic solvent A, dichloromethane, ensures the catalytic activity of catalyst BCl3. Organic solvent B, methanol, precisely quenches the catalytic reaction and converts impurities into water-soluble forms. Organic solvents C and D, ethyl acetate, efficiently extract the product and achieve phase separation. The four solvents each perform their respective functions and are well-matched with each other. This avoids the defects of using a single reagent (such as the tendency of BCl3 to aggregate when used alone, and the product dissolution and loss due to excessive methanol), and forms a synergistic effect of "highly efficient catalysis, mild quenching, and convenient separation", which significantly improves the reaction yield and product purity.

[0054] This invention does not impose any special limitations on the drying method. Preferably, the drying in step (2) of this invention uses anhydrous sodium sulfate.

[0055] In this invention, the organic solvent E in step (3) is selected from at least one of dichloromethane, trichloromethane, tetrahydrofuran, and petroleum ether. Preferably, the organic solvent E is a combination of dichloromethane and petroleum ether. Dichloromethane has strong dissolving power and can dissolve clear oily substances, while petroleum ether reduces solubility. The combination of the two, through temperature control, achieves efficient precipitation and purification of the product.

[0056] In this invention, the volume ratio of dichloromethane to petroleum ether is 1-5:1. Preferably, the volume ratio of dichloromethane to petroleum ether is 1:1, 1:2, 2:1, 3:1, 4:1, or 5:1. More preferably, the volume ratio of dichloromethane to petroleum ether is 4:1.

[0057] This invention achieves a better balance between solubility and precipitation efficiency by limiting the volume ratio of dichloromethane and petroleum ether within a specific range. Dichloromethane ensures complete dissolution of the oily substance, while petroleum ether moderately reduces polarity. Both work together to promote the precise precipitation of the product during cooling.

[0058] In this invention, step (3) involves cooling to -10°C to 10°C. Preferably, the temperature is cooled to 10°C, 0°C, and -10°C respectively. More preferably, the temperature is cooled to 0°C to 10°C.

[0059] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0060] Unless otherwise specified, the test methods or experimental methods described in the following examples are all conventional methods; unless otherwise specified, the raw materials and additives are obtained from conventional commercial sources or prepared by conventional methods.

[0061] Example 1

[0062] A method for synthesizing 2-(2-amino-5-bromo-benzoyl)pyridine, the specific steps of which are as follows:

[0063] (1) Weigh 5g of 4-bromoaniline and 4.54g of 2-cyanopyridine and dissolve them in 25mL of dichloromethane. Lower the temperature of the system to 10℃ and add BCl3 dropwise to carry out the reaction. The reaction temperature is 10℃ and the reaction is kept at the temperature for 14h. Take a sample for detection (HPLC monitoring reaction: SM≤1%, main peak≥90%). Stop the reaction. After the reaction is completed, add 30mL of methanol to the system to quench the reaction. After quenching, evaporate to dryness to obtain the crude product of 2-(2-amino-5-bromo-benzoyl)pyridine.

[0064] (2) Add 50 mL of 6M hydrochloric acid to the crude product of 2-(2-amino-5-bromo-benzoyl)pyridine, start stirring, and after the system temperature is 20℃ for 2 hours, send it to TLC for monitoring. A small amount of target product is generated. The system temperature is raised to 50℃ and reacted overnight. The reaction is controlled by HPLC (HPLC monitoring reaction: SM≤1%, main peak≥90%). The raw material spots / peaks completely disappear or their content is lower than the set threshold (usually ≤5%), and the target product spots / peaks are stable and no longer change. No new major impurities are generated. Stop the reaction. After the reaction is completed, concentrate the obtained product to obtain the concentrated crude product. Then disperse the crude product with ethyl acetate, adjust the pH to 8~9 with 10% sodium carbonate solution, extract, separate the liquid to obtain aqueous phase a and organic phase a. Place the aqueous phase a in ethyl acetate for extraction, separate the liquid to obtain aqueous phase b and organic phase b. Combine organic phase a and organic phase b, wash with water, dry with anhydrous sodium sulfate, concentrate, and obtain 8.2 g of oil.

[0065] (3) Add 20 mL of dichloromethane and 5 mL of petroleum ether to the oily substance, heat to dissolve, cool to 10 °C, the product precipitates, filter, and obtain 7.1 g of 2-(2-amino-5-bromo-benzoyl)pyridine (HPLC=98.77%), with a yield of about 90%.

[0066] Example 2

[0067] (1) Weigh 5g of 4-bromoaniline and 3.02g of 2-cyanopyridine and dissolve them in 25mL of dichloromethane. Lower the temperature of the system to 10℃ and add BCl3 dropwise to carry out the reaction. The reaction temperature is 10℃ and the reaction is kept at this temperature for 14h. Take a sample for testing and stop the reaction. After the reaction is completed, add 30mL of methanol to the system to quench the reaction. After quenching, evaporate to dryness to obtain the crude product of 2-(2-amino-5-bromo-benzoyl)pyridine.

[0068] (2) Add 50 mL of 6M hydrochloric acid to the crude product of 2-(2-amino-5-bromo-benzoyl)pyridine, start stirring, and after the system temperature is 20℃ for 2 hours, send it to TLC for monitoring. A small amount of target product is generated. The system temperature is raised to 50℃ and reacted overnight. The reaction is controlled by HPLC (HPLC monitoring reaction: SM≤1%, main peak≥90%). The raw material spots / peaks completely disappear or their content is lower than the set threshold (usually ≤5%), and the target product spots / peaks are stable and no longer change. No new major impurities are generated. Stop the reaction. After the reaction is completed, concentrate the obtained product to obtain the concentrated crude product. Then disperse the crude product with ethyl acetate, adjust the pH to 8~9 with 10% sodium carbonate solution, extract, separate the liquid to obtain aqueous phase a and organic phase a. Place the aqueous phase a in ethyl acetate for extraction, separate the liquid to obtain aqueous phase b and organic phase b. Combine organic phase a and organic phase b, wash with water, dry with anhydrous sodium sulfate, concentrate, and obtain 6.2 g of oil.

[0069] (3) Add 20 mL of dichloromethane and 5 mL of petroleum ether to the oily substance, heat to dissolve, cool to 10 °C, the product precipitates, filter, and obtain 4.01 g of 2-(2-amino-5-bromo-benzoyl)pyridine, with a yield of about 50%.

[0070] Example 3

[0071] (1) Weigh 5g of 4-bromoaniline and 9.06g of 2-cyanopyridine and dissolve them in 25mL of dichloromethane. Lower the temperature of the system to 10℃ and add BCl3 dropwise to carry out the reaction. The reaction temperature is 10℃ and the reaction is kept at the temperature for 14h. Take a sample for detection and stop the reaction. After the reaction is completed, add 30mL of methanol to the system to quench the reaction. After quenching, evaporate to dryness to obtain the crude product of 2-(2-amino-5-bromo-benzoyl)pyridine.

[0072] (2) Add 50 mL of 6M hydrochloric acid to the crude product of 2-(2-amino-5-bromo-benzoyl)pyridine, start stirring, and react at 20°C for 2 hours. After TLC monitoring, a small amount of target product is generated. The system is heated to 50°C and reacted overnight. The reaction is controlled by HPLC. After the reaction is completed, the product is concentrated to obtain the concentrated crude product. Then, the crude product is dispersed with ethyl acetate, and the pH is adjusted to 8-9 with 10% sodium carbonate solution. Extraction is performed, and the liquid is separated to obtain aqueous phase a and organic phase a. The aqueous phase a is placed in ethyl acetate for extraction, and the liquid is separated to obtain aqueous phase b and organic phase b. Organic phase a and organic phase b are combined, washed with water, dried with anhydrous sodium sulfate, and concentrated to obtain 8.6 g of oil.

[0073] (3) Add 20 mL of dichloromethane and 5 mL of petroleum ether to the oily substance, heat to dissolve, cool to 10 °C, the product precipitates, filter, and obtain 7.0 g of 2-(2-amino-5-bromo-benzoyl)pyridine, with a yield of about 90%.

[0074] Example 4

[0075] (1) Weigh 5g of 4-bromoaniline and 4.54g of 2-cyanopyridine and dissolve them in 25mL of chloroform. Lower the temperature of the system to 10℃ and add BCl3 dropwise to carry out the reaction. The reaction temperature is 10℃ and the reaction is kept at the temperature for 14h. Take a sample for detection (HPLC monitoring reaction: SM≤1%, main peak≥90%). Stop the reaction. After the reaction is completed, add 30mL of methanol to the system to quench the reaction. After quenching, evaporate to dryness to obtain the crude product of 2-(2-amino-5-bromo-benzoyl)pyridine.

[0076] (2) Add 50 mL of 6M hydrochloric acid to the crude product of 2-(2-amino-5-bromo-benzoyl)pyridine, start stirring, and react at 20℃ for 2 hours. After TLC monitoring, a small amount of target product is generated. The system is heated to 50℃ and reacted overnight. The reaction is controlled by HPLC (HPLC monitoring reaction: SM≤1%, main peak≥90%). The raw material spots / peaks completely disappear or their content is lower than the set threshold (usually ≤5%), and the target product spots / peaks are stable and no longer change. No new major impurities are generated. Stop the reaction. After the reaction, concentrate the obtained product to obtain the concentrated crude product. Then disperse the crude product with ethyl acetate, adjust the pH to 8~9 with 10% sodium carbonate solution, extract, and separate to obtain aqueous phase a and organic phase a. Place the aqueous phase a in ethyl acetate for extraction, separate to obtain aqueous phase b and organic phase b. Combine organic phase a and organic phase b, wash with water, dry with anhydrous sodium sulfate, concentrate, and obtain 5.6 g of oil.

[0077] (3) Add 20 mL of dichloromethane and 5 mL of petroleum ether to the oily substance, heat to dissolve, cool to 10 °C, the product precipitates, filter, and obtain 4.8 g of 2-(2-amino-5-bromo-benzoyl)pyridine, with a yield of about 60%.

[0078] Example 5

[0079] (1) Weigh 5g of 4-bromoaniline and 4.54g of 2-cyanopyridine and dissolve them in 25mL of dichloromethane. Lower the temperature of the system to -10℃ and add BCl3 dropwise to carry out the reaction. The reaction temperature is -10℃ and the reaction is kept at this temperature for 5h. Take a sample for testing and stop the reaction. After the reaction is completed, add 30mL of methanol to the system to quench the reaction. After quenching, evaporate to dryness to obtain the crude product of 2-(2-amino-5-bromo-benzoyl)pyridine.

[0080] (2) Add 50 mL of 6M hydrochloric acid to the crude product of 2-(2-amino-5-bromo-benzoyl)pyridine, start stirring, and react overnight at 0°C. Control the reaction in HPLC. Stop the reaction. After the reaction is completed, concentrate the product to obtain the concentrated crude product. Then disperse the crude product with ethyl acetate, adjust the pH to 8-9 with 10% sodium carbonate solution, extract, and separate to obtain aqueous phase a and organic phase a. Extract the aqueous phase a with ethyl acetate, separate to obtain aqueous phase b and organic phase b. Combine organic phase a and organic phase b, wash with water, dry with anhydrous sodium sulfate, and concentrate to obtain 7.2 g of oil.

[0081] (3) Add 20 mL of dichloromethane and 5 mL of petroleum ether to the oily substance, heat to dissolve, cool to 10 °C, the product precipitates, filter, and obtain 6.0 g of 2-(2-amino-5-bromo-benzoyl)pyridine, with a yield of about 75%.

[0082] Example 6

[0083] (1) Weigh 5g of 4-bromoaniline and 4.54g of 2-cyanopyridine and dissolve them in 25mL of dichloromethane. Lower the temperature of the system to 10℃ and add BCl3 dropwise to carry out the reaction. Raise the temperature to 40℃ and keep the reaction at this temperature for 25h. Take a sample for testing and stop the reaction. After the reaction is completed, add 30mL of methanol to the system to quench the reaction. After quenching, evaporate to dryness to obtain the crude product of 2-(2-amino-5-bromo-benzoyl)pyridine.

[0084] (2) Add 50 mL of 6M hydrochloric acid to the crude product of 2-(2-amino-5-bromo-benzoyl)pyridine, start stirring, raise the system temperature to 70°C and react overnight, control the reaction in HPLC, stop the reaction, concentrate the obtained product after the reaction to obtain the concentrated crude product, then disperse the crude product with ethyl acetate, adjust the pH to 8~9 with 10% sodium carbonate solution, extract, separate the liquid to obtain aqueous phase a and organic phase a, extract the aqueous phase a in ethyl acetate, separate the liquid to obtain aqueous phase b and organic phase b, combine organic phase a and organic phase b, wash with water, dry with anhydrous sodium sulfate, concentrate to obtain 5.8 g of oil;

[0085] (3) Add 20 mL of dichloromethane and 5 mL of petroleum ether to the oily substance, heat to dissolve, cool to 10 °C, the product precipitates, filter, and obtain 4.1 g of 2-(2-amino-5-bromo-benzoyl)pyridine, with a yield of about 51.2%.

[0086] Comparative Example 1

[0087] (1) Weigh 5g of 4-bromoaniline and 3.02g of 2-cyanopyridine and dissolve them in 25mL of dichloromethane. Lower the temperature of the system to 10℃ and keep it at the temperature for 14h. Take a sample for detection (HPLC monitoring reaction: SM≤1%, main peak≥90%). Stop the reaction. After the reaction is completed, add 30mL of methanol to the system to quench the reaction. After quenching, evaporate to dryness to obtain the crude product of 2-(2-amino-5-bromo-benzoyl)pyridine.

[0088] (2) Add 50 mL of 6M hydrochloric acid to the crude product of 2-(2-amino-5-bromo-benzoyl)pyridine, start stirring, and react at 20℃ for 2 hours. After TLC monitoring, a small amount of target product is generated. The system is heated to 50℃ and reacted overnight. The reaction is controlled by HPLC (HPLC monitoring reaction: SM≤1%, main peak≥90%). The raw material spots / peaks completely disappear or their content is lower than the set threshold (usually ≤5%), and the target product spots / peaks are stable and no longer change. No new major impurities are generated. Stop the reaction. After the reaction is completed, concentrate the obtained product to obtain the concentrated crude product. Then disperse the crude product with ethyl acetate, adjust the pH to 8~9 with 10% sodium carbonate solution, extract, and separate to obtain aqueous phase a and organic phase a. Place the aqueous phase a in ethyl acetate for extraction, separate to obtain aqueous phase b and organic phase b. Combine organic phase a and organic phase b, wash with water, dry with anhydrous sodium sulfate, concentrate, and obtain 1.1 g of oil.

[0089] (3) Add 20 mL of dichloromethane and 5 mL of petroleum ether to the oily substance, heat to dissolve, cool to 10 °C, the product precipitates, filter, and 0.2 g of 2-(2-amino-5-bromo-benzoyl)pyridine is obtained, with a yield of about 2.5%.

[0090] Comparative Example 2

[0091] (1) Weigh 5g of 4-bromoaniline and 3.02g of 2-cyanopyridine and dissolve them in 25mL of dichloromethane. Lower the temperature of the system to 10℃ and add BCl3 dropwise to carry out the reaction. Raise the reaction temperature to 60℃ and keep the reaction at this temperature for 10h. Take a sample for detection (HPLC monitoring reaction: SM≤1%, main peak≥90%). Stop the reaction. After the reaction is completed, add 30mL of methanol to the system to quench the reaction. After quenching, evaporate to dryness to obtain the crude product of 2-(2-amino-5-bromo-benzoyl)pyridine.

[0092] (2) Add 50 mL of 6M hydrochloric acid to the crude product of 2-(2-amino-5-bromo-benzoyl)pyridine, start stirring, and react at 20℃ for 2 hours. After TLC monitoring, a small amount of target product is generated. The system is heated to 50℃ and reacted overnight. The reaction is controlled by HPLC (HPLC monitoring reaction: SM≤1%, main peak≥90%). The raw material spots / peaks completely disappear or their content is lower than the set threshold (usually ≤5%), and the target product spots / peaks are stable and no longer change. No new major impurities are generated. Stop the reaction. After the reaction is completed, concentrate the obtained product to obtain the concentrated crude product. Then disperse the crude product with ethyl acetate, adjust the pH to 8~9 with 10% sodium carbonate solution, extract, and separate to obtain aqueous phase a and organic phase a. Place the aqueous phase a in ethyl acetate for extraction, separate to obtain aqueous phase b and organic phase b. Combine organic phase a and organic phase b, wash with water, dry with anhydrous sodium sulfate, concentrate, and obtain 2.2 g of oil.

[0093] (3) Add 20 mL of dichloromethane and 5 mL of petroleum ether to the oily substance, heat to dissolve, cool to 10 °C, the product precipitates, filter, and 0.81 g of 2-(2-amino-5-bromo-benzoyl)pyridine is obtained, with a yield of about 10%.

[0094] Comparative Example 3

[0095] (1) Weigh 5g of 4-bromoaniline and 3.02g of 2-cyanopyridine and dissolve them in 25mL of dichloromethane. Lower the temperature of the system to 10℃ and add BCl3 dropwise to carry out the reaction. The reaction temperature is 10℃ and the reaction is kept at this temperature for 14h. Take a sample for testing and stop the reaction. After the reaction is completed, add 30mL of methanol to the system to quench the reaction. After quenching, evaporate to dryness to obtain the crude product of 2-(2-amino-5-bromo-benzoyl)pyridine.

[0096] (2) Add 50 mL of 6M hydrochloric acid to the crude product of 2-(2-amino-5-bromo-benzoyl)pyridine, start stirring, and react at 20℃ for 2 h. After TLC monitoring, a small amount of target product was generated. The system was heated to 50℃ and reacted overnight. The reaction was controlled by HPLC. Stop the reaction. After the reaction was completed, concentrate the obtained product to obtain the concentrated crude product. Then disperse the crude product with ethyl acetate, adjust the pH to 8-9 with 10% sodium carbonate solution, extract, and separate to obtain aqueous phase a and organic phase a. Extract the aqueous phase a with ethyl acetate, separate to obtain aqueous phase b and organic phase b. Combine organic phase a and organic phase b, wash with water, dry with anhydrous sodium sulfate, concentrate, and obtain 6.2 g of oil.

[0097] (3) Add 20 mL of toluene to the oily substance, heat to dissolve, cool to 10 °C, the product precipitates, filter, and obtain 1.02 g of 2-(2-amino-5-bromo-benzoyl)pyridine, with a yield of about 12.5%.

[0098] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for synthesizing 2-(2-amino-5-bromo-benzoyl)pyridine, characterized in that, Includes the following steps: (1) Dissolve 4-bromoaniline and 2-cyanopyridine in organic solvent A, add a catalyst to carry out the reaction, and after the reaction is completed, quench the reaction with organic solvent B to obtain the crude product of 2-(2-amino-5-bromo-benzoyl)pyridine; (2) The crude product of 2-(2-amino-5-bromo-benzoyl)pyridine was reacted in an acidic solution. After the reaction was completed, the product was concentrated to obtain a concentrated crude product. The crude product was then extracted in an organic solvent C. The pH of the system was adjusted and the liquid was separated to obtain an aqueous phase a and an organic phase a. The aqueous phase a was extracted in an organic solvent D and the liquid was separated to obtain an aqueous phase b and an organic phase b. The organic phase a and organic phase b were combined, washed with water, dried and concentrated to obtain an oily substance. (3) Add organic solvent E to the oily substance, heat to dissolve, cool to obtain 2-(2-amino-5-bromo-benzoyl)pyridine; The catalyst in step (1) is boron trichloride; In step (1), the organic solvent A is selected from at least one of dichloromethane and trichloromethane; The organic solvent B in step (1) is selected from at least one of ethanol, methanol, and isopropanol; The organic solvent C in step (2) is selected from at least one of diethyl ether and ethyl acetate, and the organic solvent D in step (2) is selected from at least one of diethyl ether, ethyl acetate, benzene, and carbon tetrachloride; The organic solvent E mentioned in step (3) is a mixed solvent of dichloromethane and petroleum ether.

2. The method for synthesizing 2-(2-amino-5-bromo-benzoyl)pyridine according to claim 1, characterized in that, The molar ratio of 4-bromoaniline and 2-cyanopyridine in step (1) is 1:1-3.

3. The method for synthesizing 2-(2-amino-5-bromo-benzoyl)pyridine according to claim 1, characterized in that, The reaction temperature in step (1) is -10℃ to 40℃, and the reaction time is 5h to 25h.

4. The method for synthesizing 2-(2-amino-5-bromo-benzoyl)pyridine according to claim 1, characterized in that, The acidic solution in step (2) is selected from any one of hydrochloric acid, sulfuric acid, and nitric acid.

5. The method for synthesizing 2-(2-amino-5-bromo-benzoyl)pyridine according to claim 1, characterized in that, The reaction temperature in step (2) is 0℃~70℃, and the pH of the system in step (2) is adjusted to 8-9.

6. The method for synthesizing 2-(2-amino-5-bromo-benzoyl)pyridine according to claim 1, characterized in that, Step (3) involves cooling to -10℃ to 10℃.

Images