A scaled-up preparation method for 2-(2-amino-5-bromo-benzoyl)pyridine

Abstract

The present invention provides an amplified preparation method of 2-(2-amino-5-bromo-benzoyl)pyridine. The core point of the present invention is to react 2-picolinic acid with a chlorinating agent in an organic solvent to generate 2-pyridinecarbonyl chloride hydrochloride. 2-pyridinecarbonyl chloride hydrochloride and 1-bis(trimethylsilyl)amino-4-bromobenzene react in an organic solvent under the action of a metal catalyst and a Lewis acid to generate 2-(2-bis(trimethylsilyl)amino-5-bromo-benzoyl)pyridine, and finally deprotect to generate 2-(2-amino-5-bromo-benzoyl)pyridine. This method greatly shortens the reaction steps, avoids the use of hazardous reagents, reduces raw material costs, has a simple and reliable process, is easy to industrialize, and provides a new reaction path for the synthesis of 2-(2-amino-5-bromo-benzoyl)pyridine.

Description

Technical Field

[0001] The present invention relates to a preparation method of 2-(2-amino-5-bromo-benzoyl)pyridine, a key intermediate of remimazolam, and particularly relates to an amplified preparation method of 2-(2-amino-5-bromo-benzoyl)pyridine, belonging to the field of pharmaceutical synthetic chemistry. Background Art

[0002] Remimazolam is a short-acting GABAa receptor agonist developed by Paion, a German company, for general anesthesia during surgery. Combining the safety of midazolam with the effectiveness of propofol, it is used for intravenous anesthesia, offering superior results compared to propofol. Its indications have been expanded to include analgesia during microscopy, preoperative anesthesia, and ICU sedation. 2-(2-amino-5-bromobenzoyl)pyridine is a key intermediate in the synthesis of remimazolam.

[0003] The currently reported synthesis method, first disclosed in patent EP1183243, involves adding 2-bromopyridine to a -40°C solution of n-butyl lithium in hexane and diethyl ether over approximately 30 minutes. A solution of 5-bromoanthranilic acid in tetrahydrofuran is then added dropwise. After the reaction, the mixture is concentrated to a black oil, which is then purified by flash chromatography to yield the desired compound, 2-(2-amino-5-bromobenzoyl)pyridine, as a brown solid.

[0004]

[0005] The above method requires the use of extremely flammable and explosive hazardous substances such as n-butyl lithium and ether, and requires a temperature of -40°C, which places high demands on equipment and brings great risks and inconveniences to production.

[0006] CN110746345 discloses that starting from 2-bromomethyl-4-bromophenol, the product 2-(2-amino-5-bromo-benzoyl)pyridine is obtained after six steps of reaction, including protection, borylation, coupling, oxidation, deprotection and amination.

[0007]

[0008] This method has lengthy steps, resulting in a long overall yield, complicated operation, and requires the use of expensive palladium reagents, making it unsuitable for industrial scale-up production.

[0009] In summary, the synthesis of 2-(2-amino-5-bromobenzoyl)pyridine in the prior art is complex, involves large amounts of three wastes, and has high overall costs. Therefore, it is particularly important to develop a synthetic route that is concise, simple, reliable, low-cost, and suitable for industrial production. Summary of the Invention

[0010] In order to overcome the above-mentioned technical defects, the present invention provides an amplified preparation method of 2-(2-amino-5-bromo-benzoyl)pyridine, a key intermediate of remimazolam. The core point of the present invention is to react 2-pyridinecarboxylic acid with a chlorinating agent in an organic solvent to generate 2-pyridinecarboxylic acid chloride hydrochloride. 2-pyridinecarboxylic acid chloride hydrochloride and 1-bis(trimethylsilyl)amino-4-bromobenzene react in an organic solvent under the joint action of a metal catalyst and a Lewis acid to generate 2-(2-bis(trimethylsilyl)amino-5-bromo-benzoyl)pyridine, and finally deprotect to generate 2-(2-amino-5-bromo-benzoyl)pyridine. This method greatly shortens the reaction steps, avoids the use of hazardous reagents, reduces the cost of raw materials, has a simple and reliable process, is easy to industrialize, and provides a new reaction path for the synthesis of 2-(2-amino-5-bromo-benzoyl)pyridine.

[0011] The amplified preparation method of 2-(2-amino-5-bromo-benzoyl)pyridine of the present invention is represented by the following reaction equation:

[0012]

[0013] The steps include:

[0014] Step 1: 2-pyridinecarboxylic acid reacts with a chlorination reagent in an organic solvent to generate 2-pyridinecarboxylic acid chloride hydrochloride.

[0015] Furthermore, in the above technical solution, the chlorination agent is selected from phosphorus trichloride, phosphorus oxychloride or thionyl chloride.

[0016] Furthermore, in the above technical solution, the molar ratio of 2-pyridinecarboxylic acid to the chlorination reagent is 1:2-4; and the reaction temperature is 20°C to 40°C.

[0017] Furthermore, in the above technical solution, the organic solvent is selected from dichloromethane, 1,2-dichloroethane, tetrahydrofuran, and 2-methyltetrahydrofuran.

[0018] Step 2: 2-pyridinecarbonyl chloride hydrochloride reacts with protected amino-4-bromobenzene in an organic solvent under the action of a metal catalyst and a Lewis acid to generate 2-(2-protected amino-5-bromo-benzoyl)pyridine.

[0019] Furthermore, in the above technical solution, the protecting group in the protected amino group is diphenylmethylene (Ph2C=N), bistrimethylsilyl, acetyl, benzoyl, etc., preferably bistrimethylsilyl protection.

[0020] Furthermore, in the above technical solution, the organic solvent is selected from dichloromethane, dichloroethane, nitromethane and nitrobenzene.

[0021] Furthermore, in the above technical solution, the molar ratio of protected amino-4-bromobenzene to 2-pyridinecarbonyl chloride hydrochloride is 1.1-1.5:1; and the reaction temperature is -10°C to 20°C.

[0022] Furthermore, in the above technical solution, the metal catalyst is selected from aluminum trichloride, zinc chloride, ferric trichloride or titanium tetrachloride, the Lewis acid is selected from tris(pentafluorophenyl)borane complex, and the molar ratio of 4-bromoaniline, metal catalyst and Lewis acid is 1:1-1.5:0.02-0.1.

[0023] Step 3: After deprotection of 2-(2-protected amino-5-bromo-benzoyl)pyridine, 2-(2-amino-5-bromo-benzoyl)pyridine is generated.

[0024] The process of the present invention avoids the disadvantages of a long synthetic route and complicated reaction steps. It does not require the use of hazardous reagents such as n-butyl lithium, making it more practical and cost-effective. The process is short, significantly reduces the amount of three wastes, and makes the entire preparation process more environmentally friendly. The overall production cost is significantly lower than that of production processes described in existing literature or patents, making the product more competitive in the market. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The HNMR spectrum of the product 2-(2-amino-5-bromo-benzoyl)pyridine in Example 1 is shown. DETAILED DESCRIPTION

[0026]

[0027] The present invention will be further described below in conjunction with specific examples. These examples should be understood to be merely illustrative of the present invention and not intended to limit the scope of protection of the present invention. After reading the contents described herein, those skilled in the art may make various changes or modifications to the present invention, and these equivalent variations and modifications also fall within the scope defined by the claims of the present invention.

[0028] Example 1

[0029] 2-Picolidinecarboxylic acid (0.12 g, 1 mmol) was added to a solution of thionyl chloride (0.24 g, 2 mmol) in 1,2-dichloroethane (10 ml) under temperature control of 0-10°C. The mixture was stirred at 50°C for 2 hours. After sampling and quenching, HPLC detection showed that the starting material disappeared and the product was 76%. The reaction was completed and the crude product of 2-pyridinecarbonyl chloride hydrochloride was obtained by spin drying.

[0030] Example 2

[0031] 2-Picolidinecarboxylic acid (8.0 g, 65 mmol) was added to a solution of thionyl chloride (15.5 g, 130 mmol) in dichloromethane (80 ml) under temperature control of 0-5 ° C. The mixture was stirred at 20-25 ° C for 40 hours. After sampling and quenching, HPLC detection showed that the raw material disappeared and the product peak was 92%. The mixture was poured into n-pentane (30 mL) and stirred for 30 minutes. The solid was then filtered and dried under reduced pressure to obtain 10.35 g (yield 90%) of 2-pyridinecarbonyl chloride hydrochloride.

[0032] Example 3

[0033] 2-Picolidinecarboxylic acid (8.0 g, 65 mmol) was added to a solution of phosphorus oxychloride (29.90 g, 195 mmol) in dichloromethane (80 ml) under temperature control at 5-10 ° C. The mixture was stirred at 20-25 ° C for 35 hours. After sampling and quenching, HPLC detection showed that the raw material disappeared and the product peak was 95%. The mixture was poured into n-pentane (30 mL) and stirred for 30 minutes. The solid was then filtered and dried under reduced pressure to obtain 10.58 g (yield 92%) of 2-pyridinecarbonyl chloride hydrochloride.

[0034] Example 4

[0035] 2-Pyridinecarboxylic acid (8.0 kg, 65 mol) was added to a solution of phosphorus oxychloride (34.88 kg, 227.5 mol) in 1,2-dichloroethane (70 L) under temperature control of 0-10 ° C. The mixture was stirred at 20-25 ° C for 35 hours. After sampling and quenching, HPLC detection showed that the raw material disappeared and the product peak was 94%. The mixture was poured into n-pentane (30 L) and stirred for 30 minutes. The solid was then filtered and dried under reduced pressure to obtain 10.70 kg (yield 93%) of 2-pyridinecarbonyl chloride hydrochloride.

[0036] Example 5

[0037] Under 0°C temperature control, aluminum chloride (10 kg, 75 mol) and pentafluorophenylborane (0.51 kg, 1 mol), 2-pyridinecarbonyl chloride hydrochloride (8.8 kg, 50 mol) and dichloromethane (44 L) were added sequentially into the reactor and stirred evenly. Subsequently, N-acetyl-4-bromoaniline (10.65 kg, 50 mol) / dichloromethane (30 L) solution was added dropwise. The reaction was slowly warmed to room temperature and stirred for 12 hours. The mixture was poured into ice water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, slurried with petroleum ether, filtered, and dried to give 9.70 kg (yield 61%) of 2-(2-acetylamino-5-bromo-benzoyl)pyridine.

[0038] Example 6

[0039] Potassium carbonate (8.26 kg, 59.74 mol) was added to a solution of 2-(2-acetylamino-5-bromo-benzoyl)pyridine (9.5 kg, 29.87 mol) / methanol (50 L), stirred at room temperature overnight, filtered and dried. Ethyl acetate (20 L) was added and stirred until dissolved, filtered and dried to obtain 6.92 kg of yellow powder (yield 84%). The NMR spectrum of the yellow powder was tested. Figure 1 , it can be determined that the final product is 2-(2-amino-5-bromo-benzoyl)pyridine.

[0040] 1 H NMR (CDCl3, 400MHz) δ8.70-8.69(m,1H),7.87-7.76(m,3H),7.45-7.44(m,1H),7.42-7.32(m,1H),6.62-6.60(m,1H),6.32(s,2H).

[0041] Example 7

[0042] Under 0°C temperature control, aluminum chloride (8kg, 60mol), pentafluorophenylborane (2.56kg, 5mol), 2-pyridinecarbonyl chloride hydrochloride (8.8kg, 50mol) and dichloromethane (40L) were added sequentially into the reactor. After stirring, 1-bis(trimethylsilyl)amino-4-bromobenzene (18.90kg, 60mol) / dichloromethane (75L) solution was added dropwise. The reaction was slowly warmed to room temperature and stirred for 12 hours. The mixture was poured into ice water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, slurried with petroleum ether, filtered, and dried to give 17.43kg (yield 83%) of 2-(2-bis(trimethylsilyl)amino-5-bromo-benzoyl)pyridine.

[0043] Example 8

[0044] A 4N hydrochloric acid solution in dioxane (51 kg) was added to a solution of 2-(2-bistrimethylsilylamino-5-bromobenzoyl)pyridine (17 kg, 40.47 mol) in dioxane (85 L). The mixture was heated to 45° C. and reacted for 4 hours. The reaction was monitored for completion by HPLC. The solution was then spin-dried to dryness, ethyl acetate (40 L) was added, and the mixture was beaten for 4 hours. The mixture was filtered and spin-dried to obtain 9.61 kg of a yellow powder (86% yield). The yellow powder was confirmed to be 2-(2-amino-5-bromobenzoyl)pyridine hydrochloride by nuclear magnetic resonance (NMR) analysis.

[0045] Example 9

[0046] Under temperature control of 0°C, zinc chloride (8.86kg, 65mol) and pentafluorophenylborane (1.54kg, 3mol) were added to a solution of 2-pyridinecarbonyl chloride hydrochloride (8.8kg, 50mol) in dichloromethane (45L), and a solution of 1-benzophenone amino-4-bromobenzene (16.75kg, 50mol) in dichloromethane (50L) was slowly added to the reaction solution. The reaction was slowly warmed to room temperature and stirred for 12 hours, poured into ice water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, slurried with petroleum ether, filtered, and dried to give 15.84kg (yield 72%) of 2-(2-benzophenone amino-5-bromo-benzoyl)pyridine.

[0047] Example 10

[0048] A dioxane hydrochloride solution (4N, 50 L) was added to a dioxane solution of 2-(2-benzophenone amino-5-bromo-benzoyl)pyridine (15 kg, 34.09 mol) (45 L), and the temperature was raised to 45 ° C. for 4 hours. The reaction was completed by HPLC monitoring. After the solution was dried, ethyl acetate (30 L) was added, and the mixture was beaten for 4 hours. It was filtered and dried to obtain 8.09 kg of yellow powder (yield 86%).

[0049] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any technician familiar with the technical field, within the technical scope disclosed by the present invention, who makes equivalent replacements or changes based on the technical solution and inventive concept of the present invention, should be covered by the scope of protection of the present invention.

Claims

1. A method for the enlarged preparation of 2-(2-amino-5-bromo-benzoyl)pyridine, characterized in that: The steps include: Step 1: 2-picolinic acid reacts with a chlorination reagent in an organic solvent to generate 2-picolinoyl chloride hydrochloride; the molar ratio of 2-picolinic acid to the chlorination reagent is 1:2-4; the reaction temperature is 20°C to 40°C; Step 2: 2-pyridinecarbonyl chloride hydrochloride and N,N-bistrimethylsilylamino-4-bromobenzene react in an organic solvent under the action of a metal catalyst and a Lewis acid to produce 2-(2-N,N-bistrimethylsilylamino-5-bromo-benzoyl)pyridine; the metal catalyst is selected from aluminum chloride, and the Lewis acid is selected from tris(pentafluorophenyl)borane; Step 3: After deprotection of 2-(2-N,N-bistrimethylsilylamino-5-bromo-benzoyl)pyridine, 2-(2-amino-5-bromo-benzoyl)pyridine is generated.

2. The method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine according to claim 1, wherein: In the first step, the chlorinating agent is selected from phosphorus trichloride, phosphorus oxychloride or thionyl chloride.

3. The method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine according to claim 1, wherein: In the first step, the organic solvent is selected from dichloromethane, 1,2-dichloroethane, tetrahydrofuran or 2-methyltetrahydrofuran.

4. The method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine according to claim 1, wherein: In the second step, the organic solvent is selected from dichloromethane, dichloroethane, nitromethane or nitrobenzene.

5. The method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine according to claim 1, wherein: In the second step, the molar ratio of N,N-bistrimethylsilylamino-4-bromobenzene to 2-pyridinecarbonyl chloride hydrochloride is 1.1-1.5:1; and the reaction temperature is -10°C to 20°C.

6. The method for preparing 2-(2-amino-5-bromo-benzoyl)pyridine according to claim 1, wherein: In the second step, the molar ratio of N,N-bistrimethylsilylamino-4-bromobenzene, metal catalyst and Lewis acid is 1:1-1.5:0.02-0.1.