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: (1) dissolving 2-amino-5-bromobenzoic acid in an organic solvent A, adding dimethyl hydroxylamine hydrochloride, a condensing agent and organic alkali, and carrying out condensation reaction to obtain 2-amino-5-bromo-N-methoxy-N-methyl benzamide; and (2) in an organic solvent B, enabling 2-bromopyridine to react with the 2-amino-5-bromo-N-methoxy-N-methyl benzamide in the step (1) under the action of an organic strong base, so as to obtain the 2-(2-amino-5-bromo-benzoyl) pyridine. The preparation method provided by the invention has the advantages of easily available synthesis raw materials, low cost, simple synthesis route, safe and controllable synthesis process and simple post-treatment method, has no amplification effect, and is suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention relates to the technical field of organic compound synthesis, and in particular to a method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine. Background Art

[0002] Remimazolam is a water-soluble, ultra-short-acting intravenous anesthetic drug with the advantages of rapid onset of action, short half-life, and rapid elimination even after long-term infusion. These characteristics make it a potentially ideal drug for perioperative and ICU sedation.

[0003] 2-(2-amino-5-bromo-benzoyl)pyridine is a key intermediate for the preparation of remimazolam, and the design of its efficient synthesis route plays an important role in the preparation of remimazolam drugs. WO0069836A1 discloses a short-acting benzodiazepine drug, and the synthesis method of the intermediate 2-(2-amino-5-bromo-benzoyl)pyridine disclosed therein comprises: mixing a hexane solution of n-butyl lithium and an ether solution, adding 2-bromopyridine at -40°C, and then dripping a tetrahydrofuran solution of 5-bromo-o-aminobenzoic acid to react and prepare the drug. However, the synthesis method not only uses extremely flammable and explosive dangerous substances such as n-butyl lithium and ether, but also needs to react at a low temperature of -40°C, which makes it very demanding on process equipment, brings great danger and inconvenience to production, and is not conducive to industrial production.

[0004] Therefore, it is of great significance to design a method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine with high purity and high yield that can meet the needs of industrial production. Summary of the invention

[0005] In view of the deficiencies in the prior art, the object of the present invention is to provide a method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine, which has low production cost, simple production process, high product purity, high yield, high safety, and is easy to realize industrial production.

[0006] To achieve this object, the present invention adopts the following technical solutions:

[0007] In a first aspect, the present invention provides a method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine, the preparation method comprising the following steps:

[0008] (1) dissolving 2-amino-5-bromobenzoic acid in an organic solvent A, adding dimethylhydroxylamine hydrochloride, a condensing agent and an organic base to carry out a condensation reaction to obtain 2-amino-5-bromo-N-methoxy-N-methylbenzamide (a compound represented by Formula II);

[0009] (2) In an organic solvent B, 2-bromopyridine reacts with the 2-amino-5-bromo-N-methoxy-N-methylbenzamide of step (1) under the action of a strong organic base to obtain 2-(2-amino-5-bromo-benzoyl)pyridine.

[0010] The synthetic route of the preparation method provided by the present invention is as follows:

[0011]

[0012] The invention uses 2-amino-5-bromobenzoic acid and dimethylhydroxylamine hydrochloride as starting materials, designs a two-step synthesis method for 2-(2-amino-5-bromo-benzoyl)pyridine, improves the yield of intermediates by optimizing the starting materials in the traditional 2-(2-amino-5-bromo-benzoyl)pyridine preparation process, and further improves the yield and purity of the target product 2-(2-amino-5-bromo-benzoyl)pyridine. The preparation method provided by the invention has the advantages of simple and easy-to-obtain raw materials, simple synthesis route, and high product yield and purity.

[0013] Preferably, the organic solvent A in step (1) comprises any one of tetrahydrofuran (THF), dichloromethane (DCM), methyl tert-butyl ether (MTBE) or ethanol, or a combination of at least two thereof, more preferably dichloromethane.

[0014] Preferably, the condensing agent in step (1) includes any one of dicyclohexylcarbodiimide (DCC), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBT), propyl phosphoric anhydride (T3P), N,N'-carbonyldiimidazole (CDI), N,N-diisopropylcarbodiimide (DIC) or isobutyl chloroformate, or a combination of at least two thereof, and more preferably a combination of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole.

[0015] In the first step condensation reaction of the present invention, the condensing agent is preferably a combination of EDCI and HOBT. Through the synergistic effect of the two, not only can the generation of cross-linked products and the generation of by-products be reduced during the reaction, but also it is easy to remove during the post-treatment process after the experiment is completed, which is beneficial to improve the reaction efficiency and synthesis purity of the intermediate 2-amino-5-bromo-N-methoxy-N-methylbenzamide, making the reaction economical, environmentally friendly and efficient.

[0016] Preferably, the organic base in step (1) includes any one or a combination of at least two of triethylamine (TEA), triethylenediamine (DABCO), 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), 1,5-diazabicyclo[4,3,0]non-5-ene (DBN), pyridine or N,N-diisopropylethylamine (DIPEA), and triethylamine is more preferably used.

[0017] Preferably, the molar ratio of 2-amino-5-bromobenzoic acid to dimethylhydroxylamine hydrochloride in step (1) is 1:(1-2), for example, it can be 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6 or 1:1.8, and more preferably 1:(1-1.3).

[0018] In the present invention, when the molar ratio of 2-amino-5-bromobenzoic acid to dimethylhydroxylamine hydrochloride is 1:(1-2), the yield of the intermediate 2-amino-5-bromo-N-methoxy-N-methylbenzamide is increased to more than 91%, and can even reach 94%.

[0019] Preferably, the molar ratio of the 2-amino-5-bromobenzoic acid to the condensing agent in step (1) is 1:(2-3), for example, it can be 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8 or 1:2.9, etc.

[0020] Preferably, the molar ratio of the 2-amino-5-bromobenzoic acid to the organic base in step (1) is 1:(2-3), for example, it can be 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8 or 1:2.9, etc.

[0021] Preferably, the molar concentration of the 2-amino-5-bromobenzoic acid in the organic solvent A in step (1) is 0.8 to 1.2 mol / L, for example, 0.82 mol / L, 0.85 mol / L, 0.87 mol / L, 0.9 mol / L, 0.95 mol / L, 1.0 mol / L, 1.05 mol / L, 1.1 mol / L or 1.15 mol / L, etc.

[0022] Preferably, the organic base in step (1) is added dropwise.

[0023] Preferably, the dropping temperature is -5°C to 0°C, for example, -5°C, -4°C, -3°C, -2°C, -1°C or 0°C.

[0024] Preferably, the condensation reaction in step (1) is carried out at room temperature (20°C-30°C, for example, 20°C, 22°C, 25°C, 28°C or 30°C).

[0025] Preferably, the condensation reaction time in step (1) is 12 to 16 hours, for example, it can be 12.5 hours, 13 hours, 13.5 hours, 14 hours, 14.5 hours, 15 hours or 15.5 hours.

[0026] Preferably, the condensation reaction in step (1) is carried out under a protective gas atmosphere.

[0027] Preferably, the protective gas includes any one of nitrogen, argon or helium, or a combination of at least two of them.

[0028] Preferably, after the condensation reaction in step (1) is completed, a post-treatment step A is also included.

[0029] Preferably, the post-processing step A comprises extraction A and concentration.

[0030] Preferably, the extraction A comprises a first extraction and a second extraction.

[0031] Preferably, the extractant for the first extraction is 2N dilute hydrochloric acid.

[0032] Preferably, the extractant for the second extraction is ethyl acetate (EA).

[0033] Preferably, the concentration method is rotary evaporation concentration.

[0034] Preferably, the organic solvent B in step (2) comprises any one of tetrahydrofuran, methyl tert-butyl ether or n-hexane, or a combination of at least two thereof, and more preferably tetrahydrofuran and / or n-hexane.

[0035] Preferably, the organic strong base in step (2) comprises any one of an amide lithium compound, an alkyl lithium compound or a Grignard reagent.

[0036] Preferably, the lithium amide compound includes lithium diisopropylamide or lithium hexamethyldisilazide.

[0037] Preferably, the alkyl metal lithium compound includes any one of butyl lithium, phenyl lithium or diisopropylamine lithium.

[0038] Preferably, the Grignard reagent includes any one of isopropylmagnesium chloride, isopropylmagnesium bromide, methylmagnesium chloride or methylmagnesium bromide, and isopropylmagnesium chloride is more preferred.

[0039] In the present invention, the organic strong base is preferably a Grignard reagent. Compared with n-butyl lithium, the Grignard reagent is easier to prepare, and it is relatively stable, has strong reactivity, and its reaction is milder, and the reaction conditions are easy to control, which increases the safety of the preparation process. At the same time, the use of the Grignard reagent is also beneficial to the post-processing process after the reaction is completed, thereby increasing the convenience of production.

[0040] Preferably, the molar ratio of 2-amino-5-bromo-N-methoxy-N-methylbenzamide to 2-bromopyridine in step (2) is 1:(1-1.6), for example, it can be 1:1, 1:1.05, 1:1.1, 1:1.15, 1:1.2, 1:1.3, 1:1.4, 1:1.5 or 1:1.6, and more preferably 1:(1-1.3).

[0041] Preferably, the molar ratio of the 2-bromopyridine to the organic strong base in step (2) is 1:(1-1.3), for example, it can be 1:1, 1:1.05, 1:1.1, 1:1.15, 1:1.2, 1:1.25 or 1:1.3, etc.

[0042] Preferably, the molar concentration of the 2-amino-5-bromo-N-methoxy-N-methylbenzamide in the organic solvent B in step (2) is 0.8 to 1.2 mol / L, for example, it can be 0.82 mol / L, 0.85 mol / L, 0.87 mol / L, 0.9 mol / L, 0.95 mol / L, 1.0 mol / L, 1.05 mol / L, 1.1 mol / L or 1.15 mol / L, etc.

[0043] Preferably, the reaction in step (2) specifically comprises the following steps:

[0044] S1: dissolving 2-bromopyridine in an organic solvent B, stirring and cooling, and adding an organic strong base to react;

[0045] S2: Dissolve 2-amino-5-bromo-N-methoxy-N-methylbenzamide in organic solvent B, stir evenly, and then add it into step S1 to react to obtain 2-(2-amino-5-bromo-benzoyl)pyridine.

[0046] Preferably, the cooling in step S1 is to -23°C to -13°C, for example, -22°C, -21°C, -20°C, -19°C, -18°C, -17°C, -16°C, -15°C or -14°C.

[0047] Preferably, the organic strong base in step S1 is added dropwise.

[0048] Preferably, the reaction time in step S1 is 1 to 2 h, for example, 1 h, 1.1 h, 1.2 h, 1.3 h, 1.4 h, 1.5 h, 1.6 h, 1.7 h, 1.8 h or 1.9 h.

[0049] Preferably, the reaction in step S1 is carried out under a protective gas atmosphere, and the protective gas includes any one of nitrogen, argon or helium, or a combination of at least two of them.

[0050] Preferably, after the reaction in step S1 is completed, cooling is further included, and the cooling is to -23°C to -13°C, for example, -22°C, -21°C, -20°C, -19°C, -18°C, -17°C, -16°C, -15°C or -14°C.

[0051] Preferably, the adding method in step S2 is dropwise addition.

[0052] Preferably, during the dropping process, the temperature of the system is controlled to be -15°C to -5°C, for example, -14°C, -13°C, -14°C, -11°C, -10°C, -9°C, -8°C, -7°C or -6°C.

[0053] Preferably, the reaction time in step S2 is 1 to 2 h, for example, the temperature may be -22°C, -21°C, -20°C, -19°C, -18°C, -17°C, -16°C, -15°C or -14°C.

[0054] Preferably, after the reaction in step S2 is completed, a post-treatment step B is also included.

[0055] Preferably, the post-treatment step B comprises quenching, extraction B, washing, concentration and crystallization.

[0056] Preferably, the quenching agent for quenching is ammonium chloride solution.

[0057] Preferably, the ammonium chloride solution is an aqueous ammonium chloride solution with a mass percentage concentration of 5% to 10% (for example, 5%, 6%, 7%, 8%, 9% or 10%, etc.).

[0058] Preferably, the extractant of the extraction B is ethyl acetate (EA).

[0059] Preferably, the washing detergent is a 5% sodium bicarbonate aqueous solution.

[0060] Preferably, the concentration method is rotary evaporation concentration.

[0061] Preferably, the crystallization system of the crystallization is ethyl acetate (EA) / petroleum ether (PE) system.

[0062] Preferably, the preparation method of 2-(2-amino-5-bromo-benzoyl)pyridine specifically comprises the following steps:

[0063] (1) Dissolve 2-amino-5-bromobenzoic acid in an organic solvent A, add dimethylhydroxylamine hydrochloride and a condensing agent, and dropwise add an organic base at -5°C to 0°C in a protective gas atmosphere. After the dropwise addition is completed, the temperature is raised to room temperature and the condensation reaction is carried out for 12 to 16 hours. After the reaction is completed, the reaction solution is extracted with 2N dilute hydrochloric acid and ethyl acetate, and concentrated by rotary evaporation to obtain 2-amino-5-bromo-N-methoxy-N-methylbenzamide;

[0064] (2) dissolving 2-bromopyridine in an organic solvent B, stirring and cooling to -23°C to -13°C, adding a strong organic base dropwise under a protective gas atmosphere, reacting for 1 to 2 hours after the addition is complete, and cooling the reaction solution to -23°C to -13°C after the reaction is complete;

[0065] (3) 2-amino-5-bromo-N-methoxy-N-methylbenzamide is dissolved in an organic solvent B, stirred evenly, and then added dropwise to the reaction solution in step S1. During the addition, the temperature of the system is controlled to be -15°C to -5°C. After the addition is completed, the reaction is carried out for 1 to 2 hours. After the reaction is completed, a 5% to 10% aqueous solution of ammonium chloride is added to quench the reaction. The mixture is then extracted with ethyl acetate, washed with a 5% aqueous solution of sodium bicarbonate, concentrated by rotary evaporation, and finally crystallized from an ethyl acetate / petroleum ether system to obtain 2-(2-amino-5-bromo-benzoyl)pyridine.

[0066] In the present invention, 2-(2-amino-5-bromo-benzoyl)pyridine is synthesized through a specific two-step reaction, wherein the first step condensation reaction is step (1), and an intermediate 2-amino-5-bromo-N-methoxy-N-methylbenzamide with a yield of 91.8-94% is synthesized, and the second step reaction is steps (2) and (3). By optimizing the synthesis conditions, the synthesis of the target product 2-(2-amino-5-bromo-benzoyl)pyridine with a high yield is achieved.

[0067] Compared with the prior art, the present invention has at least the following beneficial effects:

[0068] (1) The present invention uses 2-amino-5-bromobenzoic acid and dimethylhydroxylamine hydrochloride as starting materials, designs a two-step synthesis method for 2-(2-amino-5-bromo-benzoyl)pyridine, and improves the yield of the intermediate by optimizing the starting materials in the traditional preparation process of 2-(2-amino-5-bromo-benzoyl)pyridine, thereby improving the yield and purity of the target product 2-(2-amino-5-bromo-benzoyl)pyridine;

[0069] (2) The 2-(2-amino-5-bromo-benzoyl)pyridine prepared by the present invention through a two-step synthesis reaction has a yield higher than 75.8% and a purity higher than 97%;

[0070] (3) The preparation method provided by the present invention has the advantages of simple and easy-to-obtain raw materials, simple synthesis route, safe and easy-to-control synthesis process, high product yield and purity, and is suitable for industrial large-scale production. DETAILED DESCRIPTION

[0071] For the convenience of understanding the present invention, the present invention lists the following embodiments. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0072] Example 1

[0073] This embodiment provides a method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine, the preparation method comprising the following steps:

[0074] (1) 2-amino-5-bromobenzoic acid (21.6 g, 0.10 mol) was dissolved in dichloromethane (100 mL), stirred and mixed, and then dimethylhydroxylamine hydrochloride (10.64 g, 0.12 mol), EDCI (21.09 g, 0.11 mol), and 1-hydroxybenzotriazole (14.86 g, 0.11 mol) were added in sequence. In a nitrogen atmosphere, triethylamine (22.26 g, 0.22 mol) was slowly added dropwise while maintaining the temperature at -5°C to 0°C. After the addition was completed, the temperature was slowly raised to 25°C and the reaction was continued for 14 h. After the reaction was terminated by HPLC, the reaction solution was added dropwise to 2N dilute hydrochloric acid (100 mL) for extraction and stratification. EA (2×100 mL) was added to the aqueous phase for secondary extraction. The organic phases were combined and concentrated by rotary evaporation to obtain 2-amino-5-bromo-N-methoxy-N-methylbenzamide (24.37 g) as an oil.

[0075] The NMR characterization data of the intermediate 2-amino-5-bromo-N-methoxy-N-methylbenzamide are as follows:

[0076] 1 H NMR (300MHz, DMSO-d6): δ8.10 (s, 1H), 7.53~7.51 (d, 1H, J=6.0Hz), 6.81~6.78 (d, 1H, J=9.0Hz), 5.62 (s, 2H), 3.68 (s, 3H), 2.64 (s, 3H).

[0077] (2) Dissolve 2-bromopyridine (15.7 g, 0.1 mol) in THF (60 mL), stir and mix, cool to -18 °C under nitrogen atmosphere, slowly add 2M isopropylmagnesium chloride solution (55 mL, 0.11 mol), control the temperature below -10 °C, and react for 1.5 hours after the addition is complete. After the reaction is completed by HPLC detection, the reaction solution is cooled to -18 °C;

[0078] (3) Dissolve the 2-amino-5-bromo-N-methoxy-N-methylbenzamide (24.37 g, 0.09 mol) obtained in step (1) in THF (40 mL), stir and mix, and then slowly drip into the reaction solution in step (2), control the temperature of the system to be lower than -10°C, and react for 1.5 hours after the dripping is completed. After the reaction is completed by HPLC detection, 8% ammonium chloride aqueous solution is added to quench the reaction, and then extracted with EA (2×100 mL), the organic phases are combined, washed with 5% sodium bicarbonate aqueous solution, and concentrated by rotary evaporation to obtain an oily substance, which is crystallized in an ethyl acetate / petroleum ether system to obtain an off-white solid 2-(2-amino-5-bromo-benzoyl)pyridine (24.45 g).

[0079] The NMR characterization data of the compound 2-(2-amino-5-bromo-benzoyl)pyridine are as follows:

[0080] 1 H NMR (300MHz, CDCl3): δ8.76~8.72(d,1H,J=6Hz), 8.20(s,1H), δ7.98~7.94(t,1H,J=4Hz), 7.94~7.92(d,1 H, J=6Hz), 7.85~7.80 (t, 1H, J=15Hz), 7.48~7.44 (d, 1H, J=12Hz), 6.81~6.78 (d, 1H, J=9Hz), 6.27 (s, 2H).

[0081] Example 2

[0082] This embodiment provides a method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine, the preparation method comprising the following steps:

[0083] (1) 2-amino-5-bromobenzoic acid (1.08 kg, 5.0 mol) was dissolved in dichloromethane (5 L), stirred and mixed, and then dimethylhydroxylamine hydrochloride (0.54 kg, 5.5 mol), EDCI (1.05 kg, 5.5 mol), and 1-hydroxybenzotriazole (0.75 kg, 5.5 mol) were added in sequence. In a nitrogen atmosphere, triethylamine (1.11 kg, 11 mol) was slowly added dropwise while maintaining the temperature at -5°C to 0°C. After the addition was completed, the temperature was slowly raised to 25°C and the reaction was continued for 14 h. After the reaction was terminated by HPLC, the reaction solution was added dropwise to 2N dilute hydrochloric acid (5 L) for extraction and stratification. EA (2×5 L) was added to the aqueous phase for secondary extraction. The organic phases were combined and concentrated by rotary evaporation to obtain an oily substance, 2-amino-5-bromo-N-methoxy-N-methylbenzamide (1.21 kg).

[0084] (2) 2-bromopyridine (0.81 kg, 5.16 mol) was dissolved in THF (3 L), stirred and mixed, and then cooled to -18 °C under a nitrogen atmosphere. 2 M isopropyl magnesium chloride solution (2.75 L) was slowly added dropwise, and the temperature was controlled below -10 °C during the process. After the addition was completed, the reaction was allowed to proceed for 1.5 h. After the reaction was completed by HPLC detection, the reaction solution was cooled to -18 °C;

[0085] (3) Dissolve the 2-amino-5-bromo-N-methoxy-N-methylbenzamide (1.21 kg, 4.69 mol) obtained in step (1) in THF (2 L), stir and mix, and then slowly drip into the reaction solution in step (2), control the temperature of the system to be lower than -10°C, and react for 1.5 hours after the dripping is completed. After the reaction is completed by HPLC detection, 8% ammonium chloride aqueous solution is added to quench the reaction, and then extracted with EA (2×5 L), the organic phases are combined, washed with 5% sodium bicarbonate aqueous solution, and concentrated by rotary evaporation to obtain an oily substance, which is crystallized in an ethyl acetate / petroleum ether system to obtain an off-white solid 2-(2-amino-5-bromo-benzoyl)pyridine (1.21 kg).

[0086] Example 3

[0087] This embodiment provides a method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine, the preparation method comprising the following steps:

[0088] (1) 2-amino-5-bromobenzoic acid (21.6 g, 0.10 mol) was dissolved in dichloromethane (100 mL). After stirring and mixing, dimethylhydroxylamine hydrochloride (11.7 g, 0.12 mol), EDCI (23.0 g, 0.12 mol), and 1-hydroxybenzotriazole (16.2 g, 0.12 mol) were added in sequence. In a nitrogen atmosphere, triethylamine (24.3 g, 0.24 mol) was slowly added dropwise while maintaining the temperature at -5°C to 0°C. After the addition was completed, the temperature was slowly raised to room temperature and the reaction was continued for 14 h. After the reaction was terminated by HPLC, the reaction solution was added dropwise to 2N dilute hydrochloric acid (100 mL) for extraction and stratification. EA (2×100 mL) was added to the aqueous phase for secondary extraction. The organic phases were combined and concentrated by rotary evaporation to obtain 2-amino-5-bromo-N-methoxy-N-methylbenzamide (23.86 g) as an oil.

[0089] (2) 2-bromopyridine (17.4 g, 0.11 mol) was dissolved in THF (60 mL), stirred and mixed, and then cooled to -18 °C under a nitrogen atmosphere. 2 M isopropyl magnesium chloride solution (60.5 mL) was slowly added dropwise, and the temperature was controlled below -10 °C. After the addition was completed, the reaction was allowed to react for 1.5 h. After the reaction was completed by HPLC detection, the reaction solution was cooled to -18 °C;

[0090] (3) Dissolve the 2-amino-5-bromo-N-methoxy-N-methylbenzamide (23.86 g, 0.09 mol) obtained in step (1) in THF (40 mL), stir and mix, and then slowly drip into the reaction solution in step (2), control the temperature of the system to be lower than -10°C, and react for 1.5 hours after the dripping is completed. After the reaction is completed by HPLC, 8% aqueous ammonium chloride solution is dripped to quench the reaction, and then extracted with EA (2×100 mL), the organic phases are combined, washed with 5% aqueous sodium bicarbonate solution, and concentrated by rotary evaporation to obtain an oily substance, which is crystallized in an ethyl acetate / petroleum ether system to obtain an off-white solid 2-(2-amino-5-bromo-benzoyl)pyridine (23.5 g).

[0091] Example 4

[0092] This embodiment provides a method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine, the preparation method comprising the following steps:

[0093] (1) 2-amino-5-bromobenzoic acid (21.6 g, 0.10 mol) was dissolved in THF (80 mL), stirred and mixed, and then dimethylhydroxylamine hydrochloride (14.55 g, 0.15 mol), EDCI (19.17 g, 0.1 mol), and 1-hydroxybenzotriazole (13.51 g, 0.1 mol) were added in sequence. In a nitrogen atmosphere, triethylamine (20.24 g, 0.2 mol) was slowly added dropwise while maintaining the temperature at -5°C to 0°C. After the addition was completed, the temperature was slowly raised to 20°C and the reaction was continued for 12 h. After the reaction was terminated by HPLC, the reaction solution was added dropwise to 2N dilute hydrochloric acid (80 mL) for extraction and stratification. EA (2×80 mL) was added to the aqueous phase for secondary extraction. The organic phases were combined and concentrated by rotary evaporation to obtain 2-amino-5-bromo-N-methoxy-N-methylbenzamide (23.81 g) as an oil.

[0094] (2) 2-bromopyridine (20.25 g, 0.13 mol) was dissolved in n-hexane (67.5 mL), stirred and mixed, and then cooled to -23°C under a nitrogen atmosphere. 2M isopropylmagnesium chloride solution (64.5 mL) was slowly added dropwise, and the temperature was controlled below -10°C. After the addition was completed, the reaction was allowed to react for 1 hour. After the reaction was completed by HPLC detection, the reaction solution was cooled to -23°C;

[0095] (3) Dissolve the 2-amino-5-bromo-N-methoxy-N-methylbenzamide (23.81 g, 0.09 mol) obtained in step (1) in n-hexane (45 mL), stir and mix, and then slowly drip into the reaction solution in step (2), control the temperature of the system to be lower than -15°C, and react for 1 hour after the dripping is completed. After the reaction is completed by HPLC detection, 5% ammonium chloride aqueous solution is added to quench the reaction, and then extracted with EA (2×112 mL), the organic phases are combined, washed with 5% sodium bicarbonate aqueous solution, and concentrated by rotary evaporation to obtain an oily substance, which is crystallized in an ethyl acetate / petroleum ether system to obtain an off-white solid 2-(2-amino-5-bromo-benzoyl)pyridine (23.33 g).

[0096] Example 5

[0097] This embodiment provides a method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine, the preparation method comprising the following steps:

[0098] (1) 2-amino-5-bromobenzoic acid (21.6 g, 0.10 mol) was dissolved in ethanol (110 mL), stirred and mixed, and then dimethylhydroxylamine hydrochloride (17.47 g, 0.18 mol), EDCI (24.92 g, 0.13 mol), and 1-hydroxybenzotriazole (17.57 g, 0.13 mol) were added in sequence. In a nitrogen atmosphere, triethylamine (26.3 g, 0.26 mol) was slowly added dropwise while maintaining the temperature at -5°C to 0°C. After the addition was completed, the temperature was slowly raised to 23°C and the reaction was continued for 15 h. After the reaction was terminated by HPLC, the reaction solution was added dropwise to 2N dilute hydrochloric acid (110 mL) for extraction and stratification. EA (2×110 mL) was added to the aqueous phase for secondary extraction. The organic phases were combined and concentrated by rotary evaporation to obtain an oily substance, 2-amino-5-bromo-N-methoxy-N-methylbenzamide (23.76 g).

[0099] (2) 2-bromopyridine (21.66 g, 0.14 mol) was dissolved in methyl tert-butyl ether (49 mL), stirred and mixed, and then cooled to -20°C under a nitrogen atmosphere. 2M isopropyl magnesium chloride solution (83 mL) was slowly added dropwise, and the temperature was controlled below -10°C. After the addition was completed, the reaction was allowed to react for 1.6 hours. After the reaction was completed by HPLC detection, the reaction solution was cooled to -20°C;

[0100] (3) Dissolve the 2-amino-5-bromo-N-methoxy-N-methylbenzamide (23.76 g, 0.09 mol) obtained in step (1) in methyl tert-butyl ether (33 mL), stir and mix, and then slowly drip into the reaction solution in step (2), control the temperature of the system to be lower than -10°C, and react for 1.6 hours after the dripping is completed. After the reaction is completed by HPLC detection, 8% ammonium chloride aqueous solution is added to quench the reaction, and then extracted with EA (2×82 mL), the organic phases are combined, washed with 5% sodium bicarbonate aqueous solution, and concentrated by rotary evaporation to obtain an oily substance, which is crystallized in an ethyl acetate / petroleum ether system to obtain an off-white solid 2-(2-amino-5-bromo-benzoyl)pyridine (23.23 g).

[0101] Example 6

[0102] This embodiment provides a method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine, the preparation method comprising the following steps:

[0103] (1) 2-amino-5-bromobenzoic acid (21.6 g, 0.10 mol) was dissolved in methyl tert-butyl ether (120 mL), and after stirring and mixing, dimethylhydroxylamine hydrochloride (19.4 g, 0.2 mol), EDCI (28.76 g, 0.15 mol), and 1-hydroxybenzotriazole (20.27 g, 0.15 mol) were added in sequence. In a nitrogen atmosphere, triethylamine (30.36 g, 0.3 mol) was slowly added dropwise while maintaining the temperature at -5°C to 0°C. After the addition was completed, the temperature was slowly raised to 30°C and the reaction was continued for 16 hours. After the reaction was terminated by HPLC, the reaction solution was added dropwise to 2N dilute hydrochloric acid (120 mL) for extraction and stratification. EA (2×120 mL) was added to the aqueous phase for secondary extraction. The organic phases were combined and concentrated by rotary evaporation to obtain 2-amino-5-bromo-N-methoxy-N-methylbenzamide (23.68 g) as an oil.

[0104] (2) 2-bromopyridine (23.05 g, 0.15 mol) was dissolved in THF (45 mL), stirred and mixed, and then cooled to -13 °C under a nitrogen atmosphere. 2 M isopropyl magnesium chloride solution (95.5 mL) was slowly added dropwise, and the temperature was controlled below -10 °C. After the addition was completed, the reaction was allowed to proceed for 2 h. After the reaction was completed by HPLC detection, the reaction solution was cooled to -13 °C.

[0105] (3) Dissolve the 2-amino-5-bromo-N-methoxy-N-methylbenzamide (23.68 g, 0.09 mol) obtained in step (1) in THF (30 mL), stir and mix, and then slowly drip into the reaction solution in step (2), control the temperature of the system to be lower than -5°C, and react for 2 hours after the dripping is completed. After the reaction is completed by HPLC, drip 10% ammonium chloride aqueous solution to quench the reaction, and then extract with EA (2×75 mL), combine the organic phases, wash with 5% sodium bicarbonate aqueous solution, and concentrate by rotary evaporation to obtain an oily substance, which is crystallized in an ethyl acetate / petroleum ether system to obtain an off-white solid 2-(2-amino-5-bromo-benzoyl)pyridine (23.08 g).

[0106] Example 7

[0107] This embodiment provides a method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine, the preparation method comprising the following steps:

[0108] The difference between step (1) and step (1) in Example 1 is that dimethylhydroxylamine hydrochloride (8.73 g, 0.09 mol) is added, and the other raw materials, contents and synthesis methods are the same as those in step (1) in Example 1 to obtain an oily substance 2-amino-5-bromo-N-methoxy-N-methylbenzamide (21.62 g).

[0109] (2) 2-bromopyridine (11.84 g, 0.08 mol) was dissolved in THF (52 mL), stirred and mixed, and then cooled to -18°C under a nitrogen atmosphere. 2M isopropylmagnesium chloride solution (38 mL, 0.0792) was slowly added dropwise, and the temperature was controlled below -10°C. After the addition was completed, the reaction was allowed to react for 1.5 hours. After the reaction was completed by HPLC detection, the reaction solution was cooled to -18°C;

[0110] (3) Dissolve the 2-amino-5-bromo-N-methoxy-N-methylbenzamide (21.62 g, 0.08 mol) obtained in step (1) in THF (35 mL), stir and mix, and then slowly drip into the reaction solution in step (2), control the system temperature below -10°C, and react for 1.5 h after the addition is complete.

[0111] The post-treatment method of this example is the same as that of Example 1 to obtain an off-white solid 2-(2-amino-5-bromo-benzoyl)pyridine (19.03 g).

[0112] Example 8

[0113] This embodiment provides a method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine, the preparation method comprising the following steps:

[0114] The difference between step (1) and step (1) in Example 1 is that dimethylhydroxylamine hydrochloride (9.7 g, 0.1 mol) is added, and the other raw materials, contents and synthesis methods are the same as those in step (1) in Example 1 to obtain an oily substance 2-amino-5-bromo-N-methoxy-N-methylbenzamide (24.12 g).

[0115] (2) 2-bromopyridine (14.67 g, 0.09 mol) was dissolved in THF (60 mL), stirred and mixed, and then cooled to -18°C under a nitrogen atmosphere. 2M isopropylmagnesium chloride solution (51.5 mL) was slowly added dropwise, and the temperature was controlled below -10°C. After the addition was completed, the reaction was allowed to react for 1.5 hours. After the reaction was completed by HPLC detection, the reaction solution was cooled to -18°C;

[0116] (3) Dissolve the 2-amino-5-bromo-N-methoxy-N-methylbenzamide (24.12 g, 0.09 mol) obtained in step (1) in THF (40 mL), stir and mix, and then slowly drip into the reaction solution in step (2), control the system temperature below -10°C, and react for 1.5 h after the dripping is completed.

[0117] The post-treatment method of this example is the same as that of Example 1 to obtain an off-white solid 2-(2-amino-5-bromo-benzoyl)pyridine (23.66 g).

[0118] Example 9

[0119] This embodiment provides a method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine, the preparation method comprising the following steps:

[0120] The difference between step (1) and step (1) in Example 1 is that dimethylhydroxylamine hydrochloride (12.61 g, 0.13 mol) is added, and the other raw materials, contents and synthesis method are the same as those in step (1) in Example 1 to obtain an oily substance 2-amino-5-bromo-N-methoxy-N-methylbenzamide (24.15 g).

[0121] (2) 2-bromopyridine (19.1 g, 0.12 mol) was dissolved in THF (60 mL), stirred and mixed, and then cooled to -18°C under a nitrogen atmosphere. 2M isopropylmagnesium chloride solution (67 mL) was slowly added dropwise, and the temperature was controlled below -10°C. After the addition was completed, the reaction was allowed to proceed for 1.5 h. After the reaction was completed by HPLC detection, the reaction solution was cooled to -18°C.

[0122] (3) Dissolve the 2-amino-5-bromo-N-methoxy-N-methylbenzamide (24.15 g, 0.09 mol) obtained in step (1) in THF (40 mL), stir and mix, and then slowly drip into the reaction solution in step (2), control the temperature of the system to be below -10°C, and react for 1.5 hours after the addition is completed.

[0123] The post-treatment method of this example is the same as that of Example 1 to obtain an off-white solid 2-(2-amino-5-bromo-benzoyl)pyridine (23.72 g).

[0124] Example 10

[0125] This embodiment provides a method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine, the preparation method comprising the following steps:

[0126] The difference between step (1) and step (1) in Example 1 is that dimethylhydroxylamine hydrochloride (13.58 g, 0.14 mol) is added, and the other raw materials, contents and synthesis methods are the same as those in step (1) in Example 1 to obtain an oily substance 2-amino-5-bromo-N-methoxy-N-methylbenzamide (24.05 g).

[0127] (2) 2-bromopyridine (20.48 g, 0.13 mol) was dissolved in THF (60 mL), stirred and mixed, and then cooled to -18°C under a nitrogen atmosphere. 2M isopropylmagnesium chloride solution (72 mL) was slowly added dropwise, and the temperature was controlled below -10°C. After the addition was completed, the reaction was allowed to react for 1.5 h. After the reaction was completed by HPLC detection, the reaction solution was cooled to -18°C;

[0128] (3) Dissolve the 2-amino-5-bromo-N-methoxy-N-methylbenzamide (24.05 g, 0.09 mol) obtained in step (1) in THF (40 mL), stir and mix, and then slowly drip into the reaction solution in step (2), control the temperature of the system to be below -10°C, and react for 1.5 hours after the addition is completed.

[0129] The post-treatment method of this example is the same as that of Example 1 to obtain an off-white solid 2-(2-amino-5-bromo-benzoyl)pyridine (23.54 g).

[0130] Embodiment 11

[0131] This embodiment provides a method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine, the preparation method comprising the following steps:

[0132] The only difference between step (1) and step (1) in Example 1 is that dichloromethane is replaced by THF, EDCI (21.1 g, 0.11 mol) and 1-hydroxybenzotriazole (14.9 g, 0.11 mol) are replaced by CDI (35.67 g, 0.22 mol), and other raw materials, contents and synthesis methods are the same as those in step (1) in Example 1, to obtain 2-amino-5-bromo-N-methoxy-N-methylbenzamide (24.07 g) as an oil.

[0133] (2) 2-bromopyridine (16.1 g, 0.1 mol) was dissolved in THF (60 mL), stirred and mixed, and then cooled to -18°C under a nitrogen atmosphere. 2M isopropylmagnesium chloride solution (56 mL) was slowly added dropwise, and the temperature was controlled below -10°C. After the addition was completed, the reaction was allowed to proceed for 1.5 h. After the reaction was completed by HPLC detection, the reaction solution was cooled to -18°C.

[0134] (3) Dissolve the 2-amino-5-bromo-N-methoxy-N-methylbenzamide (24.07 g, 0.09 mol) obtained in step (1) in THF (40 mL), stir and mix, and then slowly drip into the reaction solution in step (2). Control the temperature of the system below -10°C. After the dripping is completed, react for 1.5 hours.

[0135] The post-treatment method of this example is the same as that of Example 1 to obtain an off-white solid 2-(2-amino-5-bromo-benzoyl)pyridine (24.1 g).

[0136] Example 12

[0137] This embodiment provides a method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine, the preparation method comprising the following steps:

[0138] The difference between step (1) and step (1) in Example 1 is that EDCI (21.1 g, 0.11 mol) and 1-hydroxybenzotriazole (14.9 g, 0.11 mol) are replaced by DCC (45.39 g, 0.22 mol), and triethylamine (22.3 g, 0.22 mol) is replaced by pyridine (17.4 g, 0.22 mol). Other raw materials, contents and synthesis methods are the same as those in step (1) in Example 1, and 2-amino-5-bromo-N-methoxy-N-methylbenzamide (23.94 g) is obtained as an oil.

[0139] (2) Dissolve 2-bromopyridine (16 g, 0.1 mol) in THF (60 mL), stir and mix, cool to -78 °C under nitrogen atmosphere, slowly add 2.5 M n-butyllithium hexane solution (44.8 mL) dropwise, and stir at -78 °C for 30 min after the addition is complete;

[0140] (3) Dissolve the 2-amino-5-bromo-N-methoxy-N-methylbenzamide (23.94 g, 0.09 mol) obtained in step (1) in THF (40 mL), stir and mix, and then slowly drip into the reaction solution in step (2). After the dripping is completed, the system temperature is raised to 0° C. and the reaction is carried out for 1.5 h.

[0141] After the reaction, 10% aqueous ammonium chloride solution was added dropwise to the reaction solution to quench the reaction, and EA (2×100 mL) was added for extraction. The organic phases were combined and washed with 5% aqueous sodium bicarbonate solution. The organic phase was concentrated under reduced pressure to give an off-white solid 2-(2-amino-5-bromo-benzoyl)pyridine (20.92 g).

[0142] Embodiment 13

[0143] This embodiment provides a method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine, the preparation method comprising the following steps:

[0144] The difference between step (1) and step (1) in Example 1 is that EDCI (21.1 g, 0.11 mol) and 1-hydroxybenzotriazole (14.9 g, 0.11 mol) are replaced by PyBOP (114.48 g, 0.22 mol), and triethylamine (22.3 g, 0.22 mol) is replaced by DMAP (26.88 g, 0.22 mol). Other raw materials, contents and synthesis methods are the same as those in step (1) in Example 1, and 2-amino-5-bromo-N-methoxy-N-methylbenzamide (23.97 g) is obtained as an oil.

[0145] (2) Dissolve 2-bromopyridine (16 g, 0.1 mol) in THF (60 mL), stir and mix, cool to -18 °C under nitrogen atmosphere, slowly add 2 M LDA solution (56 mL), and stir at -5 °C for 1 h after the addition is complete;

[0146] (3) Dissolve the 2-amino-5-bromo-N-methoxy-N-methylbenzamide (23.97 g, 0.09 mol) obtained in step (1) in THF (40 mL), stir to mix, and then slowly dropwise add to the reaction solution in step (2). After the addition is complete, react at -15°C for 1 h.

[0147] After the reaction, the system temperature was controlled at 5°C, 10% aqueous ammonium chloride solution was added dropwise to the reaction solution to quench the reaction, EA (2×100 mL) was added for extraction, the organic phases were combined, washed with 5% aqueous sodium bicarbonate solution, and the organic phase was concentrated under reduced pressure to give an off-white solid 2-(2-amino-5-bromo-benzoyl)pyridine (22.31 g).

[0148] Embodiment 14

[0149] This embodiment provides a method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine, the preparation method comprising the following steps:

[0150] The difference between step (1) and step (1) in Example 1 is that EDCI (21.1 g, 0.11 mol) and 1-hydroxybenzotriazole (14.9 g, 0.11 mol) are replaced by EDCI (17.25 g, 0.09 mol) and 1-hydroxybenzotriazole (12.16 g, 0.09 mol), and the other raw materials, contents and synthesis methods are the same as those in step (1) in Example 1 to obtain 2-amino-5-bromo-N-methoxy-N-methylbenzamide (24.07 g) as an oil.

[0151] (2) 2-bromopyridine (16.1 g, 0.1 mol) was dissolved in THF (60 mL), stirred and mixed, and then cooled to -18°C under a nitrogen atmosphere. 2M isopropylmagnesium chloride solution (46 mL) was slowly added dropwise, and the temperature was controlled below -10°C. After the addition was completed, the reaction was allowed to proceed for 1.5 h. After the reaction was completed by HPLC detection, the reaction solution was cooled to -18°C.

[0152] (3) Dissolve the 2-amino-5-bromo-N-methoxy-N-methylbenzamide (24.07 g, 0.09 mol) obtained in step (1) in THF (40 mL), stir and mix, and then slowly drip into the reaction solution in step (2). Control the temperature of the system below -10°C. After the dripping is completed, react for 1.5 hours.

[0153] The post-treatment method of this example is the same as that of Example 1 to obtain an off-white solid 2-(2-amino-5-bromo-benzoyl)pyridine (23.4 g).

[0154] Embodiment 15

[0155] This embodiment provides a method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine, the preparation method comprising the following steps:

[0156] The difference between step (1) and step (1) in Example 1 is that EDCI (21.1 g, 0.11 mol) and 1-hydroxybenzotriazole (14.9 g, 0.11 mol) are replaced by EDCI (30.67 g, 0.16 mol) and 1-hydroxybenzotriazole (21.62 g, 0.16 mol), and the other raw materials, contents and synthesis methods are the same as those in step (1) in Example 1 to obtain 2-amino-5-bromo-N-methoxy-N-methylbenzamide (24.09 g) as an oil.

[0157] (2) 2-bromopyridine (16.1 g, 0.1 mol) was dissolved in THF (60 mL), stirred and mixed, and then cooled to -18°C under a nitrogen atmosphere. 2M isopropylmagnesium chloride solution (51.5 mL) was slowly added dropwise, and the temperature was controlled below -10°C. After the addition was completed, the reaction was allowed to react for 1.5 hours. After the reaction was completed by HPLC detection, the reaction solution was cooled to -18°C;

[0158] (3) Dissolve the 2-amino-5-bromo-N-methoxy-N-methylbenzamide (24.09 g, 0.09 mol) obtained in step (1) in THF (40 mL), stir and mix, and then slowly drip into the reaction solution in step (2). Control the temperature of the system below -10°C. After the dripping is completed, react for 1.5 hours.

[0159] The post-treatment method of this example is the same as that of Example 1 to obtain an off-white solid 2-(2-amino-5-bromo-benzoyl)pyridine (23.71 g).

[0160] Example 16

[0161] This embodiment provides a method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine, the preparation method comprising the following steps:

[0162] The difference between step (1) and step (1) in Example 1 is that triethylamine (22.3 g, 0.22 mol) is replaced by triethylamine (22.26 g, 0.18 mol), and the other raw materials, contents and synthesis method are the same as those in step (1) in Example 1, to obtain 2-amino-5-bromo-N-methoxy-N-methylbenzamide (24.09 g) as an oil.

[0163] (2) 2-bromopyridine (16.1 g, 0.1 mol) was dissolved in THF (60 mL), stirred and mixed, and then cooled to -18°C under a nitrogen atmosphere. 2M isopropylmagnesium chloride solution (66.8 mL) was slowly added dropwise, and the temperature was controlled below -10°C. After the addition was completed, the reaction was allowed to proceed for 1.5 h. After the reaction was completed by HPLC detection, the reaction solution was cooled to -18°C.

[0164] (3) Dissolve the 2-amino-5-bromo-N-methoxy-N-methylbenzamide (24.09 g, 0.09 mol) obtained in step (1) in THF (40 mL), stir and mix, and then slowly drip into the reaction solution in step (2). Control the temperature of the system below -10°C. After the dripping is completed, react for 1.5 hours.

[0165] The post-treatment method of this example is the same as that of Example 1 to obtain an off-white solid 2-(2-amino-5-bromo-benzoyl)pyridine (23.76 g).

[0166] Embodiment 17

[0167] This embodiment provides a method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine, the preparation method comprising the following steps:

[0168] The difference between step (1) and step (1) in Example 1 is that triethylamine (22.3 g, 0.22 mol) is replaced by triethylamine (32.38 g, 0.32 mol), and the other raw materials, contents and synthesis method are the same as those in step (1) in Example 1, to obtain 2-amino-5-bromo-N-methoxy-N-methylbenzamide (24.12 g) as an oil.

[0169] (2) 2-bromopyridine (16.2 g, 0.1 mol) was dissolved in THF (60 mL), stirred and mixed, and then cooled to -18°C under a nitrogen atmosphere. 2M isopropylmagnesium chloride solution (72 mL) was slowly added dropwise, and the temperature was controlled below -10°C. After the addition was completed, the reaction was allowed to proceed for 1.5 h. After the reaction was completed by HPLC detection, the reaction solution was cooled to -18°C.

[0170] (3) Dissolve the 2-amino-5-bromo-N-methoxy-N-methylbenzamide (24.12 g, 0.09 mol) obtained in step (1) in THF (40 mL), stir and mix, and then slowly drip into the reaction solution in step (2), control the system temperature below -10°C, and react for 1.5 h after the dripping is completed.

[0171] The post-treatment method of this example is the same as that of Example 1 to obtain an off-white solid 2-(2-amino-5-bromo-benzoyl)pyridine (23.66 g).

[0172] Comparative Example 1

[0173] This comparative example provides a method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine, and its synthetic route is as follows:

[0174]

[0175] The preparation method comprises:

[0176] (1) A 2.5 M hexane solution of n-butyl lithium (160 mL, 0.4 mol) and diethyl ether (1 L) were stirred and mixed under a nitrogen atmosphere, cooled to -40°C, and 2-bromopyridine (69.06 g, 0.44 mol) was slowly added dropwise. After the addition was complete, the mixture was stirred at -40°C for 1 h;

[0177] (2) 2-amino-5-bromobenzoic acid (21.6 g, 0.10 mol) was dissolved in THF (400 mL), stirred and mixed, and then slowly dripped into the reaction solution in step (2). After the dripping was completed, the system temperature was raised to 0° C. and stirred for 2 h. After the reaction was completed, it was quenched with trimethylsilyl chloride (253 mL, 2 mol) and stirred at room temperature for 30 min, then cooled to 0° C., 3N dilute hydrochloric acid (2×253 mL) was added for extraction, and the combined aqueous layer was neutralized with solid sodium hydroxide particles, cooled in an ice bath, and then extracted with ether (3×400 mL). The combined ether layers were concentrated to a black oil, which was purified by flash chromatography (1 L silica gel, ethyl acetate / n-hexane 20-30%) to obtain a brown solid 2-(2-amino-5-bromo-benzoyl)pyridine (13.8 g, yield 50%, purity 99.2%).

[0178] Comparative Example 2

[0179] This comparative example provides a method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine, and its synthetic route is as follows:

[0180]

[0181] The preparation method comprises:

[0182] (1) Methanol (60 g), 2-amino-5-bromobenzoic acid (21.6 g, 0.10 mol), and DMAP (1.22 g, 0.01 mol) were mixed and stirred at room temperature for 30 min, and BOC anhydride (24 g, 0.11 mol) was slowly added dropwise, and the temperature was maintained at 20°C to 30°C during the addition process. After the reaction was completed by HPLC detection, the reaction solution was concentrated to dryness by rotary evaporation, EA (60 g) was added to dissolve, and then washed with 5% citric acid solution, 5% sodium bicarbonate solution, and deionized water in sequence. 5-bromo-2-Boc aminobenzoic acid was obtained by rotary evaporation, and then THF (20 mL) was added to dissolve;

[0183] (2) THF (15 g) was added with 2-bromopyridine (15.8 g, 0.1 mol), the mixture was stirred for 30 min, 2 M isopropylmagnesium chloride solution (55 mL) was added dropwise, and the mixture was stirred at 25 °C for 5 h. After the reaction was completed, a mixed solution was obtained by HPLC.

[0184] (3) The THF solution containing 5-bromo-2-Boc aminobenzoic acid (26.2 g, 0.08 mol) in step (1) was added dropwise to the mixed solution in step (2), and the mixture was stirred at 40° C. for 4 h. After the reaction was completed by HPLC, EA (20 mL) was added to the mixture for dissolution after rotary evaporation, and the mixture was washed with 10% ammonium chloride aqueous solution and deionized water, and then concentrated to obtain 2-(2-Boc amino-5-bromo-benzoyl) pyridine, and dichloromethane (80 g) was added to dissolve the mixture;

[0185] (4) The dichloromethane solution containing 2-(2-Bocamino-5-bromo-benzoyl)pyridine in step (3) was cooled to 5°C, trifluoroacetic acid (34 g, 0.3 mol) was added dropwise at 5°C to 10°C, and the temperature was slowly raised to 25°C after the addition was completed. The temperature was kept for 3 hours. After the reaction was completed by HPLC, the organic solvent was removed by rotation, and EA (50 g) was added to dissolve. The mixture was washed with 5% sodium bicarbonate solution and deionized water in turn, and then anhydrous sodium sulfate was added for filtration and then hexane was added for crystallization to obtain 2-(2-amino-5-bromo-benzoyl)pyridine (11.7 g);

[0186] The total yield of the above four-step reaction was 42.2% and the purity was 95.3%.

[0187] The yield and purity of the product 2-(2-amino-5-bromo-benzoyl)pyridine obtained in the above Examples 1-17 and Comparative Examples 1 and 2 are shown in Table 1.

[0188] Table 1

[0189]

[0190]

[0191] The test results show that:

[0192] (1) It can be seen from Examples 1-6 that the yield of 2-(2-amino-5-bromo-benzoyl)pyridine prepared by the specific preparation method of the present invention is higher than 75.8% and the purity is higher than 97%.

[0193] (2) By comparing Example 1 with Example 2, it can be seen that the preparation method of 2-(2-amino-5-bromo-benzoyl)pyridine provided by the present invention has no amplification effect in the synthesis process of a large amount of 2-(2-amino-5-bromo-benzoyl)pyridine, and is suitable for large-scale production in factories.

[0194] (3) By comparing Example 1 with Examples 7-10, it can be seen that the present invention uses 2-amino-5-bromobenzoic acid and dimethylhydroxylamine hydrochloride as starting materials to synthesize a high-yield intermediate 2-amino-5-bromo-N-methoxy-N-methylbenzamide. By optimizing the molar ratio of the two, the yield of the intermediate can be further improved. When the molar ratio of the two is 1:(1-1.3), the yield of the intermediate is not less than 93.5%. In addition, by optimizing the molar ratio of the intermediate 2-amino-5-bromo-N-methoxy-N-methylbenzamide to 2-bromopyridine, it can be seen that when the molar ratio of the two is 1:(1-1.3), the yield of the target product 2-(2-amino-5-bromo-benzoyl)pyridine can be improved.

[0195] (4) By comparing Example 1 with Examples 12 and 13, it can be seen that the specific combination of the specific condensing agent and the organic base in the present invention can further improve the yield of the intermediate 2-amino-5-bromo-N-methoxy-N-methylbenzamide; in addition, the selection of a specific organic strong base can also further improve the yield of the target product.

[0196] (5) By comparing Example 1 with Examples 14-17, it can be seen that the selection of the content of the specific condensing agent and the specific organic base in the present invention can improve the yield of the intermediate; in addition, the selection of the specific molar ratio of 2-bromopyridine to the organic strong base can further improve the yield of the target product.

[0197] (6) By comparing Example 1 with Comparative Examples 1 and 2, it can be seen that the preparation method of 2-(2-amino-5-bromo-benzoyl)pyridine provided by the present invention has the advantages of short synthesis route, high yield and high purity, and high safety.

[0198] In summary, the preparation method provided by the present invention has the advantages of easy availability of synthetic raw materials and low cost, simple synthetic route, safe and controllable synthetic process and simple post-treatment method, no amplification effect, high yield and purity, and is suitable for industrial large-scale production.

[0199] Compared with the one-step reaction in the prior art, the present invention does not use extremely flammable and explosive substances such as n-butyl lithium and ether with high risk factors in the preparation process, which not only further improves the safety and controllability of the reaction, but also simplifies the post-processing steps; and reduces the reaction condition requirements, and does not need to reach an extremely low temperature reaction condition of -40°C to achieve the preparation of the target product, thereby increasing the convenience of production and facilitating industrial production. In addition, the specific two-step reaction of the present invention can also improve the yield and purity of the target product 2-(2-amino-5-bromo-benzoyl)pyridine.

[0200] The applicant declares that the above is only a specific implementation mode of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily thought of by those skilled in the art within the technical scope disclosed by the present invention shall fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine, characterized in that: The preparation method comprises the following steps: (1) dissolving 2-amino-5-bromobenzoic acid in an organic solvent A, adding dimethylhydroxylamine hydrochloride, a condensing agent and an organic base to carry out a condensation reaction to obtain 2-amino-5-bromo-N-methoxy-N-methylbenzamide; (2) In an organic solvent B, 2-bromopyridine reacts with the 2-amino-5-bromo-N-methoxy-N-methylbenzamide of step (1) under the action of a strong organic base to obtain 2-(2-amino-5-bromo-benzoyl)pyridine.

2. The preparation method according to claim 1, characterized in that: The organic solvent A in step (1) comprises any one of tetrahydrofuran, dichloromethane, methyl tert-butyl ether or ethanol, or a combination of at least two thereof, and dichloromethane is more preferred; Preferably, the condensing agent in step (1) includes any one or a combination of at least two of dicyclohexylcarbodiimide, 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazole-tetramethyluronium hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, propylphosphoric anhydride, N,N'-carbonyldiimidazole, N,N-diisopropylcarbodiimide or isobutyl chloroformate, and more preferably a combination of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole; Preferably, the organic base in step (1) comprises any one of triethylamine, triethylenediamine, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,5-diazabicyclo[4,3,0]non-5-ene, pyridine or N,N-diisopropylethylamine, or a combination of at least two thereof, and triethylamine is further preferred.

3. The preparation method according to claim 1 or 2, characterized in that: The molar ratio of 2-amino-5-bromobenzoic acid to dimethylhydroxylamine hydrochloride in step (1) is 1:(1-2), more preferably 1:(1-1.3); Preferably, the molar ratio of 2-amino-5-bromobenzoic acid to the condensing agent in step (1) is 1:(2-3); Preferably, the molar ratio of 2-amino-5-bromobenzoic acid to the organic base in step (1) is 1:(2-3).

4. The preparation method according to any one of claims 1 to 3, characterized in that: The organic base in step (1) is added dropwise; Preferably, the temperature of the dropping is -5°C to 0°C; Preferably, the condensation reaction in step (1) is carried out at room temperature; Preferably, the condensation reaction time in step (1) is 12 to 16 hours; Preferably, the condensation reaction in step (1) is carried out under a protective gas atmosphere; Preferably, the protective gas comprises any one of nitrogen, argon or helium, or a combination of at least two thereof; Preferably, after the condensation reaction in step (1) is completed, a post-treatment step A is also included; Preferably, the post-processing step A comprises extraction A and concentration.

5. The preparation method according to claim 4, characterized in that: The extraction A includes a first extraction and a second extraction; Preferably, the extractant for the first extraction is 2N dilute hydrochloric acid; Preferably, the extractant for the second extraction is ethyl acetate; Preferably, the concentration method is rotary evaporation concentration.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The organic solvent B in step (2) comprises any one of tetrahydrofuran, methyl tert-butyl ether or n-hexane, or a combination of at least two thereof, and is more preferably tetrahydrofuran and / or n-hexane; Preferably, the organic strong base in step (2) comprises any one of an amide lithium compound, an alkyl lithium compound or a Grignard reagent; Preferably, the lithium amide compound includes lithium diisopropylamide or lithium hexamethyldisilazide; Preferably, the alkyl metal lithium compound includes any one of butyl lithium, phenyl lithium or diisopropylamine lithium; Preferably, the Grignard reagent includes any one of isopropylmagnesium chloride, isopropylmagnesium bromide, methylmagnesium chloride or methylmagnesium bromide, and isopropylmagnesium chloride is more preferred.

7. The preparation method according to any one of claims 1 to 6, characterized in that: The molar ratio of 2-amino-5-bromo-N-methoxy-N-methylbenzamide to 2-bromopyridine in step (2) is 1:(1-1.6), more preferably 1:(1-1.3); Preferably, the molar ratio of 2-bromopyridine to the organic strong base in step (2) is 1:(1-1.3); Preferably, the molar concentration of the 2-amino-5-bromo-N-methoxy-N-methylbenzamide in the organic solvent B in step (2) is 0.8 to 1.2 mol / L.

8. The preparation method according to any one of claims 1 to 7, characterized in that: The reaction in step (2) specifically comprises the following steps: S1: dissolving 2-bromopyridine in an organic solvent B, stirring and cooling, and adding an organic strong base to react; S2: dissolving 2-amino-5-bromo-N-methoxy-N-methylbenzamide in an organic solvent B, stirring evenly, and adding the organic solvent B into step S1 for reaction to obtain 2-(2-amino-5-bromo-benzoyl)pyridine; Preferably, the cooling in step S1 is cooling to -23°C to -13°C; Preferably, the organic strong base in step S1 is added dropwise; Preferably, the reaction time in step S1 is 1 to 2 hours; Preferably, the reaction in step S1 is carried out under a protective gas atmosphere, wherein the protective gas comprises any one of nitrogen, argon or helium, or a combination of at least two thereof; Preferably, after the reaction in step S1 is completed, cooling is further performed, and the cooling is performed to a temperature of -23°C to -13°C; Preferably, the adding method in step S2 is dropwise addition; Preferably, the temperature of the system is controlled to be -15°C to -5°C during the dropwise addition process; Preferably, the reaction time in step S2 is 1 to 2 hours; Preferably, after the reaction in step S2 is completed, a post-treatment step B is also included; Preferably, the post-treatment step B comprises quenching, extraction B, washing, concentration and crystallization.

9. The preparation method according to claim 8, characterized in that: The quenching agent used in the quenching is an ammonium chloride solution; Preferably, the ammonium chloride solution is an ammonium chloride aqueous solution with a mass percentage concentration of 5% to 10%; Preferably, the extractant of the extraction B is ethyl acetate; Preferably, the washing detergent is a 5% sodium bicarbonate aqueous solution; Preferably, the concentration method is rotary evaporation concentration; Preferably, the crystallization system of the crystallization is an ethyl acetate / petroleum ether system.

10. The preparation method according to any one of claims 1 to 9, characterized in that: The preparation method specifically comprises the following steps: (1) Dissolve 2-amino-5-bromobenzoic acid in an organic solvent A, add dimethylhydroxylamine hydrochloride and a condensing agent, and dropwise add an organic base at -5°C to 0°C in a protective gas atmosphere. After the dropwise addition is completed, the temperature is raised to room temperature and the condensation reaction is carried out for 12 to 16 hours. After the reaction is completed, the reaction solution is extracted with 2N dilute hydrochloric acid and ethyl acetate, and concentrated by rotary evaporation to obtain 2-amino-5-bromo-N-methoxy-N-methylbenzamide; (2) dissolving 2-bromopyridine in an organic solvent B, stirring and cooling to -23°C to -13°C, adding a strong organic base dropwise under a protective gas atmosphere, reacting for 1 to 2 hours after the addition is complete, and cooling the reaction solution to -23°C to -13°C after the reaction is complete; (3) 2-amino-5-bromo-N-methoxy-N-methylbenzamide is dissolved in organic solvent B, stirred evenly, and then added dropwise to the reaction solution in step (2). During the addition, the temperature of the system is controlled to be -15°C to -5°C. After the addition is completed, the reaction is carried out for 1 to 2 hours. After the reaction is completed, a 5% to 10% aqueous solution of ammonium chloride is added to quench the reaction. The mixture is then extracted with ethyl acetate, washed with a 5% aqueous solution of sodium bicarbonate, concentrated by rotary evaporation, and finally crystallized from an ethyl acetate / petroleum ether system to obtain 2-(2-amino-5-bromo-benzoyl)pyridine.

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