A kind of preparation method of 2-bromo-6-fluoroaniline

Abstract

The invention discloses a preparation method of 2-bromo-6-fluoroaniline, and belongs to the technical field of organic synthesis. Specifically, the method comprises the following steps: 1) adding 2-fluoroaniline to sulfuric acid, heating the temperature to 180-200°C to complete the reaction, cooling the temperature to room temperature, adding hydrogen bromide and hydrogen peroxide solution, then heating the temperature to 35-45°C to react, and obtaining 3-amino-5-bromo-4-fluorobenzenesulfonic acid hydrobromide through post-treatment; 2) dissolving 3-amino-5-bromo-4-fluorobenzenesulfonic acid hydrobromide in anisole, then dripping sulfuric acid, heating the temperature to 50-60°C until the reaction is completed, and obtaining 2-fluoro-3-bromoaniline through post-treatment. In the process of preparing 3-amino-5-bromo-4-fluorobenzenesulfonic acid hydrobromide, the present invention adopts a one-pot reaction of 98% sulfuric acid, reduces the post-treatment steps, and reduces the discharge of a large amount of waste water; anisole is used as a solvent in the desulfonation step, and the sulfonic acid removed in the reaction process is transferred to the electron-rich anisole, so that the desulfonation temperature is reduced from 200 DEG C to 50-60 DEG C, which greatly reduces the production energy consumption and is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the field of organic chemical synthesis, and in particular to a method for preparing 2-bromo-6-fluoroaniline. Background Art

[0002] Letermovir (LMV) is a potent anti-cytomegalovirus drug. Its clinical studies have shown that Letermovir has good safety and efficacy. After 28 days of treatment, cytomegalovirus was not detected in the patient's body. Compared with other approved drugs, there is no cross-resistance, and it has good market prospects. 2-Bromo-6-fluoroaniline is an important synthetic intermediate of Letermovir and an excellent drug intermediate with broad market development prospects.

[0003] Patent DE2630060C discloses a method for preparing 2-bromo-6-fluoroaniline, which uses 2-fluoroaniline as the starting material and successively undergoes acetylation, sulfonylation, aminolysis, bromination and desulfonylation to obtain the target product. The reaction process is lengthy and the yield is low. In addition, chlorosulfonic acid is used in the reaction process, which is dangerous to operate and causes great environmental pollution. The reaction equation is as follows:

[0004]

[0005] The document "Synthesis of Pyrrolnitrin and Related Halogenated Phenylpyrroles; Department of Chemistry." discloses another method for preparing 2-fluoro-6-bromoaniline, using 1-bromo-3-fluorobenzene as the starting material. Step 1 requires the use of LDA to extract hydrogen at -78°C to generate a carbon anion, which then reacts with carbon dioxide to generate 2-bromo-6-fluorobenzoic acid. In step 2, sodium azide and m-chloroperbenzoic acid are used, and the target product is obtained after reacting for 42 hours. The reaction equation is as follows:

[0006]

[0007] This route has harsh reaction temperature conditions, and the flammable and explosive chemicals LDA, sodium azide and meta-chloroperbenzoic acid used in the reaction process have a high explosion risk and are not suitable for industrial production.

[0008] Therefore, finding a method for preparing 2-bromo-6-fluoroaniline that is safe and simple to operate, has high product purity, and is low-cost and suitable for industrial production is of great significance for reducing the production cost of related drugs. Summary of the invention

[0009] The purpose of the present invention is to provide a method for preparing 2-bromo-6-fluoroaniline, so as to overcome the shortcomings of the existing process, solve the problems of environmental pollution, explosion and complicated post-treatment that may occur during the reaction process, and obtain high-yield and high-quality 2-bromo-6-fluoroaniline.

[0010] The present invention provides a method for preparing 2-bromo-6-fluoroaniline, which adopts the following technical scheme:

[0011]

[0012] The steps include:

[0013] 1) Add 2-fluoroaniline to sulfuric acid, heat to 180-200°C for complete reaction, cool to room temperature, add hydrogen bromide and hydrogen peroxide solution, then heat to 35-45°C for reaction, and post-treat to obtain 3-amino-5-bromo-4-fluorobenzenesulfonic acid hydrobromide;

[0014] 2) dissolving 3-amino-5-bromo-4-fluorobenzenesulfonic acid hydrobromide in anisole, then adding sulfuric acid dropwise, heating to 50-60° C. until the reaction is complete, and post-treating to obtain 2-fluoro-3-bromoaniline.

[0015] Furthermore, in the above technical scheme, the sulfuric acid in step 1) is 98% sulfuric acid, the hydrogen peroxide is a 25-28% hydrogen peroxide solution, and the hydrogen bromide is 48% hydrobromic acid; the molar ratio of 2-fluoroaniline: sulfuric acid: hydrogen bromide to hydrogen peroxide is 1:1-1.1:4-6:1.1-1.5; the reaction time is 2-7h, and more preferably 5h; the post-treatment step is: after the reaction is completed, the temperature is lowered to 5-10°C and kept warm for 1 hour for crystallization, and then filtered to obtain 3-amino-5-bromo-4-fluorobenzenesulfonic acid hydrobromide.

[0016] Furthermore, in the above technical scheme, the sulfuric acid in step 2) is 60-80% sulfuric acid, and the molar ratio of 3-amino-5-bromo-4-fluorobenzenesulfonic acid hydrobromide: anisole and sulfuric acid is 1:10-15:5.5-7; the reaction time is 2-5h, and more preferably 3h; the post-treatment step is: adding water after cooling to room temperature, adjusting the pH to 8-9 with saturated sodium bicarbonate solution, stirring and stratifying, washing the organic layer with water, drying with sodium sulfate and then evaporating to obtain 2-fluoro-6-bromoaniline.

[0017] Beneficial effects of the present invention:

[0018] 1) In the process of preparing 3-amino-5-bromo-4-fluorobenzenesulfonic acid hydrobromide, the present invention uses 2-fluoroaniline as a starting material and adopts a one-pot preparation method, which reduces the post-treatment steps, reduces the discharge of a large amount of wastewater, and is suitable for industrial production.

[0019] 2) In step 1 of the present invention, 98% sulfuric acid is used instead of chlorosulfonic acid for sulfonation, which has the advantages of low cost, safety and environmental protection, and simpler post-treatment.

[0020] 3) In step 2 of the present invention, anisole is used as a solvent, and the sulfonic acid removed during the reaction is transferred to the electron-rich anisole, thereby reducing the desulfonation temperature from 200° C. to 50-60° C., greatly reducing production energy consumption, and being suitable for industrial production. DETAILED DESCRIPTION

[0021] Example 1

[0022] S1: 2-Fluoroaniline (1.11 g, 10.0 mmol) was added dropwise to 98% sulfuric acid (1.02 g, 10.2 mmol), and the temperature was raised to 200°C, and the mixture was kept warm for 4 hours. The mixture was cooled to room temperature, and 48% hydrobromic acid (8.42 g, 50.0 mmol) and 28% hydrogen peroxide solution (1.58 g, 13.0 mmol) were added, and the mixture was kept warm at 40°C for 5 hours, and the temperature was lowered to 5°C and kept warm for 1 hour, and 2.45 g of white powder was obtained by suction filtration and drying, namely 3-amino-5-bromo-4-fluorobenzenesulfonic acid hydrobromide (yield 70%, HPLC purity 99.2%).

[0023] S2: The above-mentioned 3-amino-5-bromo-4-fluorobenzenesulfonic acid hydrobromide (1.75 g, 5.0 mmol) was added to anisole (6.75 g, 62.4 mmol), and 70% sulfuric acid (4.1 g, 28.9 mmol) was slowly added dropwise while stirring. The temperature was raised to 55°C for reaction for 3 h, then cooled to room temperature, 10 mL of water was added, and the pH was adjusted to 8-9 with saturated sodium bicarbonate aqueous solution. The mixture was stirred and separated into layers. The organic layer was dried over sodium sulfate and then distilled to dryness under reduced pressure to obtain 0.85 g of 2-fluoro-6-bromoaniline. The yield was 89.5%, and the HPLC purity was 99.5%.

[0024] Example 2

[0025] S1: 2-Fluoroaniline (1.11 g, 10.0 mmol) was added dropwise to 98% sulfuric acid (1.1 g, 11.0 mmol), and the temperature was raised to 180°C, and the mixture was kept warm for 4 hours. The mixture was cooled to room temperature, and 48% hydrobromic acid (6.73 g, 40.0 mmol) and 28% hydrogen peroxide solution (1.58 g, 13.0 mmol) were added, and the mixture was kept warm at 40°C for 5 hours, and the temperature was lowered to 5°C and kept warm for 1 hour, and 2.33 g of white powder was obtained by suction filtration and drying, namely 3-amino-5-bromo-4-fluorobenzenesulfonic acid hydrobromide (yield 66.5%, HPLC purity 98.8%).

[0026] S2: The above-mentioned 3-amino-5-bromo-4-fluorobenzenesulfonic acid hydrobromide (1.75 g, 5.0 mmol) was added to anisole (5.94 g, 55.0 mmol), and 70% sulfuric acid (3.85 g, 27.5 mmol) was slowly added dropwise while stirring. The temperature was raised to 60°C for reaction for 2 h, then cooled to room temperature, 10 mL of water was added, and the pH was adjusted to 8-9 with saturated sodium bicarbonate aqueous solution. The mixture was stirred and separated into layers. The organic layer was dried over sodium sulfate and then distilled to dryness under reduced pressure to obtain 0.78 g of 2-fluoro-6-bromoaniline. The yield was 82.1% and the HPLC purity was 98.6%.

[0027] Example 3

[0028] S1: 2-Fluoroaniline (1.11 g, 10.0 mmol) was added dropwise to 98% sulfuric acid (1.02 g, 10.2 mmol), and the temperature was raised to 200°C, and the mixture was kept warm for 4 hours. The mixture was cooled to room temperature, and 48% hydrobromic acid (8.42 g, 50.0 mmol) and 25% hydrogen peroxide solution (1.51 g, 11.1 mmol) were added, and the mixture was kept warm for 6 hours at 40°C, and the temperature was lowered to 5°C and kept warm for 1 hour, and 2.38 g of white powder was obtained by suction filtration and drying, namely 3-amino-5-bromo-4-fluorobenzenesulfonic acid hydrobromide (yield 68.1%, HPLC purity 98.6%).

[0029] S2: The above-mentioned 3-amino-5-bromo-4-fluorobenzenesulfonic acid hydrobromide (1.75 g, 5.0 mmol) was put into anisole (6.75 g, 62.4 mmol), and 70% sulfuric acid (4.20 g, 30.0 mmol) was slowly added dropwise while stirring. The temperature was raised to 50°C for reaction for 4 h, then cooled to room temperature, 10 mL of water was added, and the pH was adjusted to 8-9 with saturated sodium bicarbonate aqueous solution. The mixture was stirred and separated into layers. The organic layer was dried over sodium sulfate and then distilled to dryness under reduced pressure to obtain 0.84 g of 2-fluoro-6-bromoaniline. The yield was 88.4% and the HPLC purity was 99.0%.

[0030] Example 4

[0031] S1: 2-Fluoroaniline (1.11 g, 10.0 mmol) was added dropwise to 98% sulfuric acid (1.05 g, 10.5 mmol), and the temperature was raised to 200°C, and the mixture was kept warm for 4 hours. The mixture was cooled to room temperature, and 48% hydrobromic acid (8.42 g, 50.0 mmol) and 25% hydrogen peroxide solution (1.35 g, 11.1 mmol) were added, and the mixture was kept warm for 3 hours at 45°C, and the temperature was lowered to 5°C and kept warm for 1 hour, and 2.32 g of white powder was obtained by suction filtration and drying, namely 3-amino-5-bromo-4-fluorobenzenesulfonic acid hydrobromide (yield 66.5%, HPLC purity 97.1%).

[0032] S2: The above-mentioned 3-amino-5-bromo-4-fluorobenzenesulfonic acid hydrobromide (1.75 g, 5.0 mmol) was added to anisole (7.57 g, 70.0 mmol), and 60% sulfuric acid (4.58 g, 28.0 mmol) was slowly added dropwise while stirring. The temperature was raised to 60°C for reaction for 4 h, then cooled to room temperature, 10 mL of water was added, and the pH was adjusted to 8-9 with saturated sodium bicarbonate aqueous solution. The mixture was stirred and separated into layers. The organic layer was dried over sodium sulfate and then distilled to dryness under reduced pressure to obtain 0.76 g of 2-fluoro-6-bromoaniline. The yield was 80.0% and the HPLC purity was 98.3%.

[0033] Example 5

[0034] S1: 2-Fluoroaniline (1.11 g, 10.0 mmol) was added dropwise to 98% sulfuric acid (1.05 g, 10.5 mmol), and the temperature was raised to 200°C, and the mixture was kept warm for 4 hours. The mixture was cooled to room temperature, and 48% hydrobromic acid (8.42 g, 50.0 mmol) and 26% hydrogen peroxide solution (1.45 g, 11.1 mmol) were added, and the mixture was kept warm at 35°C for 4 hours, and the temperature was lowered to 5°C and kept warm for 1 hour, and 2.28 g of white powder was obtained by suction filtration and drying, namely 3-amino-5-bromo-4-fluorobenzenesulfonic acid hydrobromide (yield 65.2%, HPLC purity 98.6%).

[0035] S2: The above-mentioned 3-amino-5-bromo-4-fluorobenzenesulfonic acid hydrobromide (1.75 g, 5.0 mmol) was added to anisole (6.75 g, 62.4 mmol), and 70% sulfuric acid (4.87 g, 34.8 mmol) was slowly added dropwise while stirring. The temperature was raised to 50°C for reaction for 5 h, then cooled to room temperature, 10 mL of water was added, and the pH was adjusted to 8-9 with saturated sodium bicarbonate aqueous solution. The mixture was stirred and separated into layers. The organic layer was dried over sodium sulfate and then distilled to dryness under reduced pressure to obtain 0.81 g of 2-fluoro-6-bromoaniline. The yield was 85.3% and the HPLC purity was 98.5%.

[0036] 2-bromo-6-fluoroaniline is synthesized using 2-fluoroaniline as a starting material. The presence of the amino group on the 2-fluoroaniline, on the one hand, leads to an increase in the HOMO energy of the benzene ring, and on the other hand, the para-position coefficient on the HOMO increases more. Therefore, it is difficult to directly bromine 2-fluoroaniline. In addition, the bromination reagent will also preferentially attack the para-position of the amino group. The present invention attempts to use a variety of reagents such as bromine, hydrobromic acid and NBS, all of which have a greater effect of para-bromination than ortho-bromination. The specific reaction effects can be seen in the following comparative examples.

[0037] Comparative Example 1

[0038] 2-Fluoroaniline (1.11 g, 10.0 mmol) was added dropwise to 98% sulfuric acid (1.02 g, 10.2 mmol), and the temperature was raised to 200°C for 4 hours. The temperature was lowered to room temperature, and Br2 (1.6 g, 10.0 mmol) and acetic acid (7.2 g) were added. The temperature was controlled at 35°C for 1 hour. The reaction liquid was tested, and 2,4-dibromo-6-fluoroaniline accounted for 43%, 3-amino-5-bromo-4-fluorobenzenesulfonic acid accounted for 41%, and 3-amino-4-fluorobenzenesulfonic acid accounted for 3%;

[0039] In the following comparative examples, 1.11 g of 2-fluoroaniline was used as the starting material for the reaction, and after sulfonation, different bromination reagents were used for bromination. Unless otherwise specified, other materials and processes were the same.

[0040]

[0041] The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. A method for preparing 2-bromo-6-fluoroaniline, characterized in that: The steps include: 1) Add 2-fluoroaniline to 98% sulfuric acid, heat to 180°C-200°C for complete reaction, cool to room temperature, add 48% hydrobromic acid and hydrogen peroxide solution, then heat to 35-45°C for reaction, and post-treat to obtain 3-bromo-4-amino-5-fluorobenzenesulfonic acid hydrobromide; 2) 3-bromo-4-amino-5-fluorobenzenesulfonic acid hydrobromide is dissolved in anisole, and then 60-80% sulfuric acid is added dropwise, and the temperature is raised to 50-60° C. until the reaction is completed. After cooling to room temperature, water is added, and the pH is adjusted to 8-9 with a saturated sodium bicarbonate solution. The layers are stirred and separated, and the organic layer is washed with water, dried over sodium sulfate, and evaporated to dryness to obtain 2-bromo-6-fluoroaniline.

2. The method for preparing 2-bromo-6-fluoroaniline according to claim 1, characterized in that: The hydrogen peroxide in step 1) is a 25-28% hydrogen peroxide solution.

3. The method for preparing 2-bromo-6-fluoroaniline according to claim 1, characterized in that: Step 1) The molar ratio of 2-fluoroaniline: sulfuric acid: hydrobromic acid to hydrogen peroxide is 1:1-1.1:4-6:1.1-1.

5.

4. The method for preparing 2-bromo-6-fluoroaniline according to claim 1, characterized in that: Step 1) The post-treatment step is: after the reaction is completed, the temperature is lowered to 5-10° C. and kept for 1 hour to crystallize, and then filtered to obtain 3-bromo-4-amino-5-fluorobenzenesulfonic acid hydrobromide.

5. The method for preparing 2-bromo-6-fluoroaniline according to claim 1, characterized in that: Step 2) the molar ratio of 3-bromo-4-amino-5-fluorobenzenesulfonic acid hydrobromide: anisole and sulfuric acid = 1:10-15:5.5-6.

Images