Green synthesis method of m-aminobenzoic acid ethyl ester methyl sulfonate

Abstract

The invention relates to a green synthesis method of ethyl m-aminobenzoate mesylate, which comprises the following steps: carrying out catalytic hydrogenation or continuous hydrogenation reduction on m-nitrobenzoic acid in an ethanol solvent to obtain an ethanol solution of m-aminobenzoic acid, and adding methanesulfonic acid to react to obtain the ethyl m-aminobenzoate mesylate in one step. The method has the advantages of high atom economy, simple synthesis method, simple post-treatment, greenness, no pollution and the like, and a simple, convenient and efficient thought and method are provided for large-scale industrial preparation of the ethyl m-aminobenzoate mesylate.

Description

TECHNICAL FIELD

[0001] The present application relates to a synthetic method, in particular to a green synthetic method of ethyl m-aminobenzoate methanesulfonate. BACKGROUND

[0002] Fish anesthetic (tricaine) is also known as ethyl m-aminobenzoate methanesulfonate, and its trade name is MS-222. It is used as a narcotic sedative for fish during transportation, sales and spawning. It is an FDA-approved narcotic for live fish transportation, and has a sedative effect. It is used for long-distance transportation of salmon in the United States, which can improve the survival rate of fish during transportation and the freshness of the product on the market. Ethyl m-aminobenzoate methanesulfonate has a short onset time and fast drug metabolism, resulting in small drug residues and being relatively safe for fish and humans, and thus can be widely used in the transportation of various fish.

[0003] The existing synthetic routes of ethyl m-aminobenzoate methanesulfonate mainly include the following three routes: Route 1: Salicylic acid is used as a starting material to obtain ethyl salicylate by esterification. Then, triethylamine is used as an acid-binding agent to react with methanesulfonyl chloride to obtain 2-[(methylsulfonyl)oxy]benzoic acid ethyl ester. Nitration obtains a mixture of 2-[(methylsulfonyl)oxy]-3-nitrobenzoic acid ethyl ester and 2-[(methylsulfonyl)oxy]-5-nitrobenzoic acid ethyl ester. Catalytic hydrogenation reduces the nitro group, and at the same time, the methylsulfonate (Oms) group is removed and salted with the by-product methanesulfonic acid to obtain ethyl m-aminobenzoate methanesulfonate. The route flow is as follows: Route 2: m-Nitrobenzoic acid is used as a raw material, and palladium / carbon catalytic hydrogenation is used to obtain an intermediate, m-aminobenzoic acid. The intermediate is esterified with ethanol to obtain m-aminobenzoic acid ethyl ester hydrochloride. After being freed, it is salted with methanesulfonic acid to obtain ethyl m-aminobenzoate methanesulfonate. The route flow is as follows: Route 3: m-Nitrobenzoic acid is used as a starting material, and is esterified by sulfuric acid catalysis or sulfoxide to obtain an intermediate, m-nitrobenzoic acid ester. Catalytic hydrogenation is used to obtain m-aminobenzoic acid ethyl ester, which is salted with methanesulfonic acid to obtain ethyl m-aminobenzoate methanesulfonate. The route flow is as follows: The above three routes each have their own advantages and disadvantages. Among them, Route 1 has many steps and is long, and will produce a large amount of acidic wastewater and triethylamine hydrochloride solid waste. The total yield is 56%, which is lower than Route 2 and Route 3. It is economical and not suitable for industrial production. Route 2 is of moderate length, but a large amount of thionyl chloride is used in esterification, which will produce hydrogen chloride and sulfur dioxide by-products, which is not environmentally friendly. If sulfuric acid is used as a catalyst, it is necessary to first free the sulfuric acid and then use methanesulfonic acid to form a salt. The operation is cumbersome and a large amount of inorganic salt wastewater is produced. Route 3 is of moderate length. The difference from Route 2 is that the order of the reduction and esterification steps is different. Route 3 first esterifies and then reduces. The sulfuric acid or sulfur dioxide used in the esterification process may cause poisoning of the metal catalyst in the next step, reduce the reduction effect, and affect the recovery and recycling of the catalyst. The above three methods are all not conducive to industrial production. Summary of the Invention

[0004] To overcome the shortcomings of the prior art, the present invention provides a green synthesis method for ethyl m-aminobenzoate methanesulfonate. The present invention redesigns the industrial process for ethyl m-aminobenzoate methanesulfonate, achieving a one-pot preparation of ethyl m-aminobenzoate methanesulfonate, simplifying the process while improving atom economy and enhancing commercial value.

[0005] In order to achieve the above-mentioned object of the invention, the technical solution adopted by the present invention is: The invention discloses a green synthesis method for ethyl m-aminobenzoate methanesulfonate. The method comprises the following steps: catalytically hydrogenating or continuously hydrogenating m-nitrobenzoic acid in an ethanol solvent to obtain an ethanol solution of m-aminobenzoic acid, and then adding methanesulfonic acid to react in one step to obtain ethyl m-aminobenzoate methanesulfonate.

[0006] Preferably, the green synthesis method of ethyl m-aminobenzoate methanesulfonate comprises the following steps: S1: m-nitrobenzoic acid and anhydrous ethanol are mixed, and palladium / carbon catalytic hydrogenation reduction or continuous hydrogenation reduction is performed under heating conditions to obtain a m-aminobenzoic acid ethanol solution; S2: Methanesulfonic acid is added to the m-aminobenzoic acid ethanol solution obtained in the previous step, and the mixture is refluxed and dehydrated until the reaction is complete. The reaction solution is post-treated to obtain ethyl m-aminobenzoate methanesulfonate.

[0007] Preferably, in step S1, the volume ratio of m-nitrobenzoic acid to anhydrous ethanol is 1:2-20; and in the hydrogenation reduction reaction, the reaction temperature is 50-110°C.

[0008] Preferably, step S1 specifically comprises: mixing m-nitrobenzoic acid, palladium carbon and anhydrous ethanol, replacing with nitrogen, hydrogenating and reducing until the reaction is completed to obtain m-aminobenzoic acid, cooling and filtering, recovering the palladium carbon and reusing it, and the filtrate is directly used in the next reaction without treatment.

[0009] Preferably, step S1 specifically comprises: m-nitrobenzoic acid and ethanol are mixed into a solution, the solution is passed through a palladium-carbon catalyst bed after nitrogen displacement, and continuously hydrogenated and reduced to obtain a reaction solution, which is directly subjected to the next reaction.

[0010] Preferably, in step S2, the molar ratio of m-nitrobenzoic acid to methanesulfonic acid is 1:1.0-5.0, and the reaction temperature is 60-100°C.

[0011] Preferably, in step S2, the post-processing includes cooling, filtering and drying.

[0012] Preferably, in step S1, the volume ratio of m-nitrobenzoic acid to anhydrous ethanol is 1:4-9; and in the hydrogenation reduction reaction, the reaction temperature is 70-100°C.

[0013] Preferably, in step S2, the molar ratio of m-nitrobenzoic acid to methanesulfonic acid is 1:1.4-1.8, and the reaction temperature is 75-85°C.

[0014] The invention discloses a method for reducing m-nitrobenzoic acid in ethanol by palladium-carbon catalytic hydrogenation to obtain a m-aminobenzoic acid ethanol solution, or a m-aminobenzoic acid ethanol solution prepared by continuous flow hydrogenation, adding methanesulfonic acid, and subjecting the solution to reflux, cooling, filtering and drying to obtain ethyl m-aminobenzoate methanesulfonate in one step.

[0015] The beneficial effects of the present invention are: 1. The present invention adopts a one-pot synthesis method, and the intermediates do not need to be separated. The production operation is simple and efficient, the product yield is high, the purity is good, and it has excellent industrial value; 2. The present invention has the advantages of strong atom economy, cheap and readily available raw materials, simple synthesis method, simple post-treatment, mild conditions and green and pollution-free, which conforms to the development concept of green chemistry and provides a simple and efficient idea and method for the large-scale industrial preparation of ethyl m-aminobenzoate methanesulfonate. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 The present invention provides a hydrogen nuclear magnetic spectrum of ethyl m-aminobenzoate methylsulfonate prepared by the present invention. DETAILED DESCRIPTION

[0017] The technical solutions of the present invention are further specifically described below through examples. These examples are for explanation of the present invention and are not intended to limit the present invention. All other examples obtained by persons of ordinary skill in the art based on the examples in this application without creative work are intended to fall within the scope of protection of this application.

[0018] The experimental methods described in the examples are conventional methods unless otherwise specified; the reagents and materials described are commercially available unless otherwise specified.

[0019] Example 1 S1: Add 100 g of m-nitrobenzoic acid, 600 ml of anhydrous ethanol and 15 g of Pd / C catalyst into a reactor. Replace with nitrogen, maintain hydrogenation pressure at 4 MPa, heat to 95°C, react to the end point, monitor the reaction progress by liquid phase; filter while hot, recover the filter cake, and use the filtrate; S2: Add 86 g of methanesulfonic acid to the filtrate from the previous step and add to the reactor, replace with nitrogen, heat to reflux and react to the end point, monitor the reaction progress by liquid phase; cool the reaction liquid to 20-30°C, filter, wash, and dry to obtain white m-amino benzoic acid ethyl ester methanesulfonic acid salt 132.5 g, yield 86%, HPLC purity 99.6%. The nuclear magnetic resonance hydrogen spectrum of the prepared m-amino benzoic acid ethyl ester methanesulfonic acid salt is shown in Figure 1

[0020] Example 2 S1: Add 100 g of m-nitrobenzoic acid, 600 ml of anhydrous ethanol and 15 g of Pd / C catalyst into a reactor. Replace with nitrogen, maintain hydrogenation pressure at 4 MPa, heat to 95°C, react to the end point, monitor the reaction progress by liquid phase; filter while hot, recover the filter cake, and use the filtrate; S2: Add 86 g of methanesulfonic acid to the filtrate from the previous step and add to the reactor, replace with nitrogen, heat to reflux and react to the end point, monitor the reaction progress by liquid phase; cool the reaction liquid to 20-30°C, filter, wash, and dry to obtain white m-amino benzoic acid ethyl ester methanesulfonic acid salt 132.5 g, yield 86%, HPLC purity 99.6%. The nuclear magnetic resonance hydrogen spectrum of the prepared m-amino benzoic acid ethyl ester methanesulfonic acid salt is shown in

[0021] Example 3 S1: Mix and dissolve 100 g of m-nitrobenzoic acid and 800 ml of anhydrous ethanol, replace with nitrogen, continuously hydrogenate and reduce the solution through a fixed bed loaded with palladium / carbon catalyst, maintain hydrogen pressure at 3 MPa, control the flow rate of the m-nitrobenzoic acid solution at 0.5 ml / min, continuously hydrogenate and reduce to obtain m-amino benzoic acid ethyl alcohol solution.

[0022] S2: Add 103 g of methanesulfonic acid to the m-amino benzoic acid ethyl alcohol solution obtained in the previous step and add to the reactor, replace with nitrogen, heat to reflux and react to the end point, monitor the reaction progress by liquid phase. Cool the reaction liquid to 20-30°C, filter, wash, and dry to obtain white m-amino benzoic acid ethyl ester methanesulfonic acid salt 132.8 g, yield 85%, HPLC purity 99.5%.

[0023] Example 4 ​S1: Add 100g of m-nitrobenzoic acid, 300ml of anhydrous ethanol, and 10g of Pd / C catalyst to a reactor; replace with nitrogen, maintain hydrogenation pressure at 3MPa, raise the temperature to 110°C, and react until the end point. Monitor the reaction progress using the liquid phase. Filter while hot, and set aside the filtrate. S2: The filtrate from the previous step and 72 g of methanesulfonic acid were added to a reactor, the atmosphere was replaced with nitrogen, and the reaction was heated to reflux until the reaction reached endpoint. The reaction progress was monitored by liquid chromatography. The reaction solution was cooled to 20-30°C, filtered, washed, and dried to obtain 109.4 g of off-white ethyl m-aminobenzoate methanesulfonate in a 70% yield with an HPLC purity of 98.1%.

[0024] Example 5 S1: 100 g of m-nitrobenzoic acid and 300 ml of anhydrous ethanol were mixed and dissolved, and the atmosphere was replaced with nitrogen. The solution was continuously hydrogenated and reduced over a fixed bed of a palladium / carbon catalyst. The hydrogen pressure was maintained at 4.5 MPa, and the flow rate of the m-nitrobenzoic acid solution was controlled at 1.0 ml / min. Continuous hydrogenation and reduction were performed to obtain an ethanolic solution of m-aminobenzoic acid.

[0025] S2: The m-aminobenzoic acid ethanol solution obtained in the previous step and 60 g of methanesulfonic acid were added to a reactor, the atmosphere was replaced with nitrogen, and the reaction was heated to reflux until the reaction reached the endpoint. The reaction progress was monitored by liquid chromatography. The reaction solution was cooled to 20-30°C, filtered, washed, and dried to obtain 112.6 g of off-white ethyl m-aminobenzoate methanesulfonate, with a yield of 72% and an HPLC purity of 98.7%.

[0026] The invention has the advantages of strong atom economy, simple synthesis method, concise post-processing, green and pollution-free, etc., and provides a simple and efficient idea and method for large-scale industrial preparation of ethyl m-aminobenzoate methanesulfonate.

[0027] Finally, it should be noted that the above examples are merely specific embodiments of the present invention. Obviously, the present invention is not limited to the above examples and is subject to numerous variations. All variations that can be directly derived or conceived by a person of ordinary skill in the art from the disclosure of the present invention are considered to be within the scope of protection of the present invention.

Claims

1. A green synthesis method for ethyl m-aminobenzoate methanesulfonate, characterized in that: m-Nitrobenzoic acid is subjected to catalytic hydrogenation or continuous hydrogenation reduction in an ethanol solvent to obtain an ethanol solution of m-aminobenzoic acid, and methanesulfonic acid is added to react in one step to obtain ethyl m-aminobenzoate methanesulfonate.

2. The green synthesis method of ethyl m-aminobenzoate methylsulfonate according to claim 1, wherein The steps include: S1: m-nitrobenzoic acid and anhydrous ethanol are mixed, and palladium / carbon catalytic hydrogenation reduction or continuous hydrogenation reduction is performed under heating conditions to obtain a m-aminobenzoic acid ethanol solution; S2: Methanesulfonic acid is added to the m-aminobenzoic acid ethanol solution obtained in the previous step, and the mixture is refluxed and dehydrated until the reaction is complete. The reaction solution is post-treated to obtain ethyl m-aminobenzoate methanesulfonate.

3. The green synthesis method of ethyl m-aminobenzoate methylsulfonate according to claim 2, wherein: In step S1, the mass ratio of m-nitrobenzoic acid to anhydrous ethanol is 1:2-20; in the hydrogenation reduction reaction, the reaction temperature is 50-110°C.

4. The green synthesis method of ethyl m-aminobenzoate methylsulfonate according to claim 2, wherein: Step S1 specifically comprises: mixing m-nitrobenzoic acid, palladium carbon and anhydrous ethanol, replacing with nitrogen, hydrogenating and reducing until the reaction is complete to obtain m-aminobenzoic acid, cooling and filtering, recovering the palladium carbon and reusing it, and directly using the filtrate in the next reaction without treatment.

5. The green synthesis method of ethyl m-aminobenzoate methylsulfonate according to claim 2, wherein: Step S1 specifically comprises: m-nitrobenzoic acid and ethanol are mixed into a solution, the solution is passed through a palladium-carbon catalyst bed after nitrogen displacement, and continuously hydrogenated and reduced to obtain a reaction solution, which is directly subjected to the next reaction.

6. The green synthesis method of ethyl m-aminobenzoate methylsulfonate according to claim 2, characterized in that: In step S2, the molar ratio of m-nitrobenzoic acid to methanesulfonic acid is 1:1.0-5.0, and the reaction temperature is 60-100°C.

7. The green synthesis method of ethyl m-aminobenzoate methylsulfonate according to claim 2, characterized in that: In step S2, the post-processing includes cooling, filtering, and drying.

8. The green synthesis method of ethyl m-aminobenzoate methylsulfonate according to claim 3, characterized in that: In step S1, the mass ratio of m-nitrobenzoic acid to anhydrous ethanol is 1:4-9; in the hydrogenation reduction reaction, the reaction temperature is 70-100°C.

9. The green synthesis method of ethyl m-aminobenzoate methylsulfonate according to claim 6, characterized in that: In step S2, the molar ratio of m-nitrobenzoic acid to methanesulfonic acid is 1:1.4-1.8, and the reaction temperature is 75-85°C.

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