Method for preparing N-(3-chloro-4-fluorophenyl)-4-fluoro-3, 5-dimethylbenzenesulfonamide by one-pot method

Abstract

The invention discloses a method for preparing N-(3-chloro-4-fluorophenyl)-4-fluoro-3, 5-dimethyl benzenesulfonamide by a one-pot method. The method comprises the following steps: adding a catalyst into a reaction kettle; comprising the following steps: reacting 2, 6-dimethyl fluorobenzene with chlorosulfonic acid to generate 4-fluoro-3, 5-dimethyl benzene sulfonyl chloride, then adding 3-chloro-4-fluoroaniline, and carrying out an amidation reaction to generate N-(3-chloro-4-fluorophenyl)-4-fluoro-3, 5-dimethyl benzene sulfonamide. And refining the crude product by using an n-hexane / ethyl acetate mixed solution to obtain a target compound. The N-(3-chloro-4-fluorophenyl)-4-fluoro-3, 5-dimethyl benzene sulfonamide prepared by the process has high purity, and the HPLC (High Performance Liquid Chromatography) purity is gt; the content is 99.0%. The method has the advantages of easily available raw materials, mild operation conditions and low production cost, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis and relates to a method for synthesizing N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide. Background Art

[0002] Chinese name: N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide.

[0003] The structural formula is as follows:

[0004]

[0005] N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide is an important chemical intermediate, which has important applications in medicine, pesticides, special materials, etc. In particular, studies have shown that this compound exhibits high drug activity in intestinal diseases, and has attracted widespread attention from chemical researchers in recent years.

[0006] As an important chemical intermediate, the research and development of its synthesis route is still blank, and there is no relevant literature or patent publicly reporting its synthesis route.

[0007] Therefore, it is necessary to develop an efficient, mild, and commercially feasible synthesis process for N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide. Summary of the invention

[0008] The technical problem to be solved by the present invention is to develop a highly efficient, mild reaction condition and commercially easy synthesis process of N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide. The present invention has the following advantages: a short synthesis route, mild reaction conditions, high product purity, a liquid phase purity of more than 99%, a molar yield of more than 80%, and the synthesis route of the present invention is suitable for commercial large-scale production.

[0009] The present invention solves the above technical problems through the following technical solutions:

[0010] A one-pot method for preparing N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide comprises the following steps:

[0011] (1) dissolving 2,6-dimethylfluorobenzene in a reaction solvent, slowly dropping chlorosulfonic acid therein after cooling, and heating to react after the dropping is completed to obtain a reaction solution containing 4-fluoro-3,5-dimethylbenzenesulfonyl chloride;

[0012] (2) adding an organic base to the reaction solution containing 4-fluoro-3,5-dimethylbenzenesulfonyl chloride in the above step to adjust the pH to 8, then adding 3-chloro-4-fluoroaniline, concentrating the reaction solution to dryness after the temperature reaction is completed, adding a mixed solvent system of n-hexane / ethyl acetate to recrystallize to obtain the product; the reaction equation is as follows:

[0013]

[0014] Furthermore, in the step (1), the molar ratio of 2,6-dimethylfluorobenzene to chlorosulfonic acid is 1.0:3.0-5.0; preferably 1.0:3.5-4.5.

[0015] Furthermore, in the step (1), the dropping temperature is 5°C to 10°C, the dropping time is 30 to 45 minutes, the heating reaction temperature is 25°C to 30°C, and the reaction time is 5 to 6 hours.

[0016] Furthermore, in step (1), the reaction solvent is one of dichloromethane and chloroform, preferably dichloromethane.

[0017] Furthermore, the molar ratio of the 2,6-dimethylfluorobenzene to the 3-chloro-4-fluoroaniline is 1.0:0.9 to 1.3, preferably 1.0:0.9 to 1.0.

[0018] Furthermore, in the step (2), the temperature of the reaction is 50°C to 60°C, and the reaction time is 2 to 3 hours.

[0019] Furthermore, in step (2), the organic base is one of pyridine and triethylamine, preferably pyridine.

[0020] Furthermore, in the step (2), in the n-hexane / ethyl acetate mixed solvent system, the volume ratio of n-hexane to ethyl acetate is 2 to 3:1, preferably 2:1.

[0021] Furthermore, the dosage of the n-hexane / ethyl acetate mixed solvent system is 1 to 10 L / 1 mol 2,6-dimethylfluorobenzene, preferably 3 to 5 L / 1 mol 2,6-dimethylfluorobenzene.

[0022] The above invention has the following advantages:

[0023] (1) The present invention provides a one-pot method for preparing N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide, which uses 2,6-dimethylfluorobenzene, chlorosulfonic acid, 3-chloro-4-fluoroaniline and the like as raw materials for one-pot preparation, and successfully prepares N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide with high reaction yield and purity. For the first time, an efficient and mild reaction condition synthesis route for N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide is developed, filling the gap in related research, and the raw materials used are cheap and readily available, and commercial production is easy to achieve;

[0024] (2) The present invention provides a one-pot method for preparing N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide, which uses a one-pot method to achieve a two-step reaction in the synthesis path, avoiding the separation and purification process of the intermediates, and has a short process route and is easy for commercial large-scale production;

[0025] (3) The present invention provides a one-pot method for preparing N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide. The prepared product has high reaction yield and purity. The liquid phase purity of the final product is above 99% and the total molar yield is above 80%. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is the HPLC spectrum of N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide prepared in Example 1 of the present invention.

[0027] Figure 2 N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide prepared in Example 1 of the present invention 1 HNMR data spectrum. DETAILED DESCRIPTION

[0028] The technical solutions in the embodiments of the present invention will be described clearly and completely below, but the implementation manner of the present invention is not limited thereto.

[0029] In the following examples, the experimental methods without specific conditions are all operated according to conventional methods and conditions. Unless otherwise specified, the raw materials are obtained through commercial channels;

[0030] Example 1: Preparation of N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide

[0031] Add 2,6-dimethylfluorobenzene (50g, 0.4mol) and 400ml of dichloromethane to a 2L reaction bottle, cool to 5℃, slowly add chlorosulfonic acid (185.6g, 1.6mol) and add it over 45min. Then heat to 30℃ and keep warm for 6 hours. Slowly add pyridine to the reaction solution to adjust the pH to 8, then add 3-chloro-4-fluoroaniline (52.2g, 0.36mol) at room temperature, heat to 55℃ and keep warm for 2 hours. Concentrate the reaction solution to dryness under reduced pressure, add 1600ml of a mixed solvent of n-hexane: ethyl acetate = 2:1 for recrystallization, filter and vacuum dry to obtain N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide, with a liquid chromatography purity of 99.5% and a molar yield of 85.3%.

[0032] Example 2: Preparation of N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide

[0033] Add 2,6-dimethylfluorobenzene (50g, 0.4mol) and 400ml of chloroform to a 2L reaction bottle, cool to 10℃, slowly add chlorosulfonic acid (185.6g, 1.6mol) and add it over 45min. Then heat to 30℃ and keep warm for 6 hours. Slowly add pyridine to the reaction solution to adjust the pH to 8, then add 3-chloro-4-fluoroaniline (52.2g, 0.36mol) at room temperature, heat to 50℃ and keep warm for 2 hours. Concentrate the reaction solution to dryness under reduced pressure, add 1600ml of a mixed solvent of n-hexane: ethyl acetate = 2:1 for recrystallization, filter and vacuum dry to obtain N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide, with a liquid chromatography purity of 97.5% and a molar yield of 82.3%.

[0034] Example 3: Preparation of N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide

[0035] Add 2,6-dimethylfluorobenzene (50g, 0.4mol) and 400ml of dichloromethane to a 2L reaction bottle, cool to 5℃, slowly add chlorosulfonic acid (139.2g, 1.2mol), and add it in 45min. Then heat to 30℃ and keep warm for 6 hours. Slowly add triethylamine to the reaction solution to adjust the pH to 8, then add 3-chloro-4-fluoroaniline (52.2g, 0.36mol) at room temperature, heat to 55℃ and keep warm for 2 hours. Concentrate the reaction solution to dryness under reduced pressure, add 1600ml of a mixed solvent of n-hexane: ethyl acetate = 3:1 for recrystallization, filter and vacuum dry to obtain N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide, with a liquid chromatography purity of 94.5% and a molar yield of 75.3%.

[0036] Example 4: Preparation of N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide

[0037] Add 2,6-dimethylfluorobenzene (50g, 0.4mol) and 400ml of dichloromethane to a 2L reaction bottle, cool to 15℃, slowly add chlorosulfonic acid (185.6g, 1.6mol), and add it in 45min. Then heat to 30℃ and keep warm for 6 hours. Slowly add triethylamine to the reaction solution to adjust the pH to 8, then add 3-chloro-4-fluoroaniline (52.2g, 0.36mol) at room temperature, heat to 60℃ and keep warm for 2 hours. Concentrate the reaction solution to dryness under reduced pressure, add 1600ml of a mixed solvent of n-hexane: ethyl acetate = 2:1 for recrystallization, filter and vacuum dry to obtain N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide, with a liquid chromatography purity of 93% and a molar yield of 76%.

[0038] Example 5: Preparation of N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide

[0039] Add 2,6-dimethylfluorobenzene (50g, 0.4mol) and 400ml of dichloromethane to a 2L reaction bottle, cool to 10℃, slowly add chlorosulfonic acid (232g, 2mol) and add it over 45min. Then heat to 30℃ and keep warm for 6 hours. Slowly add pyridine to the reaction solution to adjust the pH to 8, then add 3-chloro-4-fluoroaniline (75.4g, 0.52mol) at room temperature, heat to 60℃ and keep warm for 2 hours. Concentrate the reaction solution to dryness under reduced pressure, add 1600ml of a mixed solvent of n-hexane: ethyl acetate = 2:1 for recrystallization, filter and vacuum dry to obtain N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide, with a liquid chromatography purity of 98.5% and a molar yield of 84.0%

[0040] Example 6: Preparation of N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide

[0041] Add 2,6-dimethylfluorobenzene (50g, 0.4mol) and 400ml of dichloromethane to a 2L reaction bottle, slowly add chlorosulfonic acid (185.6g, 1.6mol) at 25℃, and add it in 45min. Then heat it to 30℃ and keep it warm for 6 hours. Slowly add triethylamine to the reaction solution to adjust the pH to 8, then add 3-chloro-4-fluoroaniline (52.2g, 0.36mol) at room temperature, heat it to 55℃ and keep it warm for 2 hours. Concentrate the reaction solution to dryness under reduced pressure, add 1600ml of a mixed solvent of n-hexane: ethyl acetate = 2:1 for recrystallization, filter and vacuum dry to obtain N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide, with a liquid chromatography purity of 89.7% and a molar yield of 70.5%

[0042] Example 7: Preparation of N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide

[0043] Add 2,6-dimethylfluorobenzene (50g, 0.4mol) and 400ml of dichloroform to a 2L reaction bottle, cool to 5°C, slowly add chlorosulfonic acid (185.6g, 1.6mol), and add it over 45 minutes. Then heat to 30°C and keep warm for 5 hours. Slowly add pyridine to the reaction solution to adjust the pH to 8, then add 3-chloro-4-fluoroaniline (58g, 0.4mol) at room temperature, heat to 55°C and keep warm for 3 hours. Concentrate the reaction solution to dryness under reduced pressure, add 2000ml of a mixed solvent of n-hexane: ethyl acetate = 2:1 for recrystallization, filter and vacuum dry to obtain N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide, with a liquid chromatography purity of 98.0% and a molar yield of 84.7%.

[0044] Example 8: Preparation of N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide

[0045] Add 2,6-dimethylfluorobenzene (50g, 0.4mol) and 400ml of chloroform to a 2L reaction bottle, cool to 5℃, slowly add chlorosulfonic acid (232g, 2mol) and add it over 30min. Then heat to 30℃ and keep warm for 5 hours. Slowly add triethylamine to the reaction solution to adjust the pH to 8, then add 3-chloro-4-fluoroaniline (52.2g, 0.36mol) at room temperature, heat to 55℃ and keep warm for 2 hours. Concentrate the reaction solution to dryness under reduced pressure, add 1600ml of a mixed solvent of n-hexane: ethyl acetate = 2:1 for recrystallization, filter and vacuum dry to obtain N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide, with a liquid chromatography purity of 95.5% and a molar yield of 83.3%.

Claims

1. A one-pot method for preparing N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide, characterized in that: The following steps are involved: (1) dissolving 2,6-dimethylfluorobenzene in a reaction solvent, slowly dropping chlorosulfonic acid therein after cooling, and heating to react after the dropping is completed to obtain a reaction solution containing 4-fluoro-3,5-dimethylbenzenesulfonyl chloride; (2) adding an organic base to the reaction solution containing 4-fluoro-3,5-dimethylbenzenesulfonyl chloride in the above step to adjust the pH to 8, then adding 3-chloro-4-fluoroaniline, concentrating the reaction solution to dryness after the temperature reaction is completed, adding a mixed solvent system of n-hexane / ethyl acetate to recrystallize to obtain the product; the reaction equation is as follows:

2. The method for preparing N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide by a one-pot process according to claim 1, characterized in that: In the step (1), the molar ratio of 2,6-dimethylfluorobenzene to chlorosulfonic acid is 1.0:3.0-5.

0.

3. The method for preparing N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide by a one-pot process according to claim 1 or 2, characterized in that: In the step (1), the dropping temperature is 5°C to 10°C, the dropping time is 30 to 45 minutes, the heating reaction temperature is 25°C to 30°C, and the reaction time is 5 to 6 hours.

4. The one-pot method for preparing N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide according to claim 1, characterized in that: In the step (1), the reaction solvent is any one of dichloromethane and chloroform.

5. The method for preparing N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide by one-pot method according to claim 1, characterized in that: The molar ratio of the 2,6-dimethylfluorobenzene to 3-chloro-4-fluoroaniline is 1.0:0.9-1.

3.

6. The method for preparing N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide by a one-pot process according to claim 1 or 5, characterized in that: In the step (2), the temperature of the reaction is 50°C to 60°C, and the reaction time is 2 to 3 hours.

7. The one-pot method for preparing N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide according to claim 1, characterized in that: In the step (2), the organic base is any one of pyridine and triethylamine.

8. The method for preparing N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide by a one-pot process according to claim 1 or 5, characterized in that: In the n-hexane / ethyl acetate mixed solvent system, the volume ratio of n-hexane to ethyl acetate is 2-3:

1.

9. The one-pot method for preparing N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide according to claim 8, characterized in that: The dosage of the n-hexane / ethyl acetate mixed solvent system is 1-10 L / 1 mol 2,6-dimethylfluorobenzene.

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