Synthesis process of N-(5-methoxy-2-phenoxy phenyl) methanesulfonamide

Abstract

The invention discloses a synthesis process of N-(5-methoxy-2-phenoxy phenyl) methanesulfonamide, which takes 1-chloro-4-methoxy-2-nitrobenzene as an initial raw material, and comprises the following steps: (1) nucleophilic aromatic substitution reaction: in the presence of alkali and a solvent, carrying out a reaction for 2-4 hours to obtain 2-(5-methoxy-2-phenoxy phenyl) methanesulfonamide; the preparation method comprises the following steps: reacting 1-chloro-4-methoxy-2-nitrobenzene with phenol to generate 4-methoxy-2-nitro-1-phenoxybenzene; (2) nitro reduction reaction: in the presence of a catalyst and hydrogen, reducing the 4-methoxy-2-nitro-1-phenoxybenzene into 5-methoxy-2-phenoxyaniline; and (3) a methylsulfonylation reaction: in the presence of alkali and a solvent, enabling the 5-methoxy-2-phenoxyaniline to react with methylsulfonyl chloride to generate the N-(5-methoxy-2-phenoxyphenyl) methanesulfonamide. The product provided by the invention has the advantages of high purity and high yield, and can meet the requirements of industrial production on product quality and yield.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a synthesis process of N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide. Background Art

[0002] N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide has potential application value in the fields of medicine, materials, etc. However, traditional processes often use aromatic halides or nitro compounds with special structures as starting materials. These raw materials are difficult to synthesize and the cost is high, resulting in high production costs of the products. At the same time, traditional synthesis methods usually involve multi-step complex reactions, including multi-step substitution, redox and the introduction and removal of protecting groups. The reaction steps are cumbersome, and each step requires separation and purification, which increases the number of operation steps and time costs. In addition, due to the many reaction steps and complex conditions, the yield of traditional synthesis methods is generally low, generally around 30%-50%, and the product purity is not high. It is necessary to perform complex purification operations such as multiple recrystallizations or column chromatography, which further reduces production efficiency. Summary of the Invention

[0003] The purpose of the present invention is to develop an economical, efficient, green and easy-to-produce industrial synthesis process for N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide, so as to solve the problems raised in the above-mentioned background technology.

[0004] To achieve the above object, the present invention provides the following technical solutions:

[0005] The synthesis process of N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide uses 1-chloro-4-methoxy-2-nitrobenzene as a starting material and comprises the following steps:

[0006] (1) Nucleophilic aromatic substitution reaction

[0007] In the presence of a base and a solvent, 1-chloro-4-methoxy-2-nitrobenzene reacts with phenol to generate 4-methoxy-2-nitro-1-phenoxybenzene;

[0008] (2) Nitro reduction reaction

[0009] In the presence of a catalyst and hydrogen, 4-methoxy-2-nitro-1-phenoxybenzene is reduced to 5-methoxy-2-phenoxyaniline;

[0010] (3) Mesylation reaction

[0011] In the presence of a base and a solvent, 5-methoxy-2-phenoxyaniline is reacted with methanesulfonyl chloride to produce N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide.

[0012] Preferably, in step (1), the base is potassium carbonate, the solvent is N,N-dimethylformamide, and the mass volume ratio (g / mL) of 1-chloro-4-methoxy-2-nitrobenzene to the solvent is 1:(5-10).

[0013] Preferably, in step (1), the molar ratio of 1-chloro-4-methoxy-2-nitrobenzene to phenol is 1:(1-1.2), the molar ratio of base to 1-chloro-4-methoxy-2-nitrobenzene is (1-1.5):1, the reaction temperature is 80-120° C., and the reaction time is 4-8 hours.

[0014] Preferably, in step (2), the amount of catalyst used is 3%-8% of the mass of 4-methoxy-2-nitro-1-phenoxybenzene, the hydrogen pressure is 0.3-0.8 MPa, the reaction temperature is 30-60° C., and the reaction time is 3-6 hours.

[0015] Preferably, in step (2), the catalyst is 10% palladium on carbon, the solvent is ethanol, and the mass volume ratio (g / mL) of 4-methoxy-2-nitro-1-phenoxybenzene to the solvent is 1:(4-8).

[0016] Preferably, in step (3), the molar ratio of methanesulfonyl chloride to 5-methoxy-2-phenoxyaniline is (1-1.1):1, and the molar ratio of the base to 5-methoxy-2-phenoxyaniline is (1.1-1.3):1. The reaction is first carried out at 0-5°C for 0.5-2 hours, and then the temperature is raised to room temperature for 2-4 hours.

[0017] Preferably, in step (3), the base is triethylamine, the solvent is dichloromethane, and the mass volume ratio (g / mL) of 5-methoxy-2-phenoxyaniline to the solvent is 1:(15-25).

[0018] In summary, due to the adoption of the above technology, the beneficial effects of the present invention are:

[0019] 1. Innovation in raw material selection: The present invention uses 1-chloro-4-methoxy-2-nitrobenzene as the starting raw material. This raw material is widely available and inexpensive, greatly reducing production costs compared to the special or expensive raw materials used in traditional processes.

[0020] 2. Mild reaction conditions: The reaction conditions in each step are mild, which avoids the high requirements of equipment under extreme conditions such as high temperature and high pressure, reduces equipment investment costs and energy consumption, reduces safety risks, and is also conducive to reducing the occurrence of side reactions.

[0021] 3. The reaction steps are simple and efficient: Through the rational design of the reaction route, the entire synthesis process only requires three steps to obtain the target product. Compared with other multi-step and complex synthesis methods, it shortens the reaction process, reduces the separation and purification steps of intermediate products, improves production efficiency, and reduces losses in the production process.

[0022] 4. High product purity and yield: By optimizing the reaction conditions and post-treatment methods of each step, such as using appropriate extractants, desiccants, and purification methods such as column chromatography and recrystallization, the purity and yield of the product can be effectively improved.

[0023] In summary, the N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide finally obtained by this process has high purity and high yield, and can meet the requirements of industrial production for product quality and output. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide in Example 1 of the present invention. DETAILED DESCRIPTION

[0025] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention. Therefore, the following detailed description of the embodiments of the present invention provided in the drawings is not intended to limit the scope of the invention for which protection is sought, but merely represents selected embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0026] Example 1

[0027] The synthesis process of N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide of the present invention comprises the following steps:

[0028] (1) Synthesis of 4-methoxy-2-nitro-1-phenoxybenzene by nucleophilic aromatic substitution reaction:

[0029] ① In a three-necked flask equipped with a magnetic stirrer, a thermometer and a reflux condenser, add 1-chloro-4-methoxy-2-nitrobenzene (15.95 g, 0.08 mol), phenol (7.61 g, 0.08 mol), potassium carbonate (11.05 g, 0.08 mol) and 100 mL of N,N-dimethylformamide (DMF), heat the reaction system to 100 ° C, and stir at this temperature for 6 hours.

[0030] ② After the reaction, the reaction solution was poured into ice water and extracted with ethyl acetate (3×50 mL). The organic phases were combined, washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain a crude product of 4-methoxy-2-nitro-1-phenoxybenzene. The crude product was further purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 18.2 g of pure product with a yield of 82%.

[0031] The reaction formula for this step is:

[0032]

[0033] (2) Nitro reduction generates 5-methoxy-2-phenoxyaniline:

[0034] ① In a high pressure reactor, add 4-methoxy-2-nitro-1-phenoxybenzene (10 g,

[0035] 0.04 mol), 10% palladium carbon (0.5 g) and 50 mL ethanol. The air in the reactor was replaced with nitrogen three times, and then hydrogen was introduced to a pressure of 0.5 MPa. The reaction temperature was controlled at 40

[0036] ℃, stir and react for 4 hours.

[0037] ②After the reaction is completed, the mixture is cooled to room temperature, the palladium carbon is removed by filtration, and the filtrate is distilled under reduced pressure to remove ethanol to obtain a crude product of 5-methoxy-2-phenoxyaniline. The crude product is recrystallized

[0038] The mixture was purified by adding ethanol (ethanol: water = 3:1) to obtain 7.8 g of pure product with a yield of 85%.

[0039] The reaction formula for this step is:

[0040]

[0041] (3) Mesylation reaction to obtain N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide:

[0042] ① In a three-necked flask equipped with a magnetic stirrer, a thermometer and a dropping funnel, add 5-methoxy-2-phenoxyaniline (5 g, 0.02 mol), dichloromethane (100 mL) and triethylamine (2.42 g, 0.024 mol), cool the reaction system to 0 ° C, and slowly add methanesulfonyl chloride (2.64 g, 0.023 mol) dropwise. After the addition is complete, continue stirring at 0 ° C for 1 hour, then heat to room temperature and react for 3 hours.

[0043] ② After the reaction, the product was washed with 1 mol / L hydrochloric acid solution (50 mL), saturated sodium bicarbonate solution (50 mL) and saturated brine (50 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain a crude product of N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide. The crude product was purified by recrystallization (ethanol: water = 2:1) to obtain 5.8 g of pure product with a yield of 88%.

[0044] The reaction formula for this step is:

[0045]

[0046] Example 2

[0047] The N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide prepared in the example was tested against a commercially available traditional process product, and the results were as follows:

[0048]

[0049]

[0050] 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.

[0051] It should be noted that, in this document, relational terms such as first and second, etc., are used only to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations. Moreover, the terms "comprises," "comprising," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that includes a list of elements includes not only those elements but also other elements not explicitly listed, or elements inherent to such process, method, article, or apparatus.

Claims

1. A process for synthesizing N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide, characterized in that: The method uses 1-chloro-4-methoxy-2-nitrobenzene as a starting material and comprises the following steps: (1) Nucleophilic aromatic substitution reaction In the presence of a base and a solvent, 1-chloro-4-methoxy-2-nitrobenzene reacts with phenol to generate 4-methoxy-2-nitro-1-phenoxybenzene; (2) Nitro reduction reaction In the presence of a catalyst and hydrogen, 4-methoxy-2-nitro-1-phenoxybenzene is reduced to 5-methoxy-2-phenoxyaniline; (3) Mesylation reaction In the presence of a base and a solvent, 5-methoxy-2-phenoxyaniline is reacted with methanesulfonyl chloride to produce N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide.

2. The synthesis process of N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide according to claim 1, characterized in that: In step (1), the base is potassium carbonate, the solvent is N,N-dimethylformamide, and the mass volume ratio (g / mL) of 1-chloro-4-methoxy-2-nitrobenzene to the solvent is 1:(5-10).

3. The synthesis process of N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide according to claim 2, characterized in that: In step (1), the molar ratio of 1-chloro-4-methoxy-2-nitrobenzene to phenol is 1:(1-1.2), the molar ratio of base to 1-chloro-4-methoxy-2-nitrobenzene is (1-1.5):1, the reaction temperature is 80-120° C., and the reaction time is 4-8 hours.

4. The synthesis process of N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide according to claim 1, characterized in that: In step (2), the amount of catalyst used is 3%-8% of the mass of 4-methoxy-2-nitro-1-phenoxybenzene, the hydrogen pressure is 0.3-0.8 MPa, the reaction temperature is 30-60° C., and the reaction time is 3-6 hours.

5. The synthesis process of N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide according to claim 4, characterized in that: In step (2), the catalyst is 10% palladium on carbon, the solvent is ethanol, and the mass volume ratio (g / mL) of 4-methoxy-2-nitro-1-phenoxybenzene to the solvent is 1:(4-8).

6. The synthesis process of N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide according to claim 1, characterized in that: In step (3), the molar ratio of methanesulfonyl chloride to 5-methoxy-2-phenoxyaniline is (1-1.1):1, and the molar ratio of the base to 5-methoxy-2-phenoxyaniline is (1.1-1.3):

1. The reaction is first carried out at 0-5°C for 0.5-2 hours, and then the temperature is raised to room temperature for 2-4 hours.

7. The synthesis process of N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide according to claim 6, characterized in that: In step (3), the base is triethylamine, the solvent is dichloromethane, and the mass volume ratio (g / mL) of 5-methoxy-2-phenoxyaniline to the solvent is 1:(15-25).

8. N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide prepared by the synthesis process according to any one of claims 1 to 7, characterized in that: The N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide is a white to off-white crystalline powder with a melting point of 132-134° C. The purity is ≥99.0% as determined by high performance liquid chromatography (HPLC).

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