Technical Field [0001] The present invention relates to the technical field of organic synthesis, in particular to a method for preparing a benzamide compound.

Background Art [0002] Benzamide compounds are a class of compounds with a wide range of uses, among them, many compounds have biological activities, such as antibacterial, fungicidal and herbicidal activities; such compounds have very low residual toxicity and are environmentally friendly, therefore they have a very broad application space in the agricultural field.

[0003] The main species of benzamide compound agrochemicals that has been developed at present is Zoxamide, and Zoxamide is a microtubulin aggregation inhibitor that was developed and marketed by Rohm & Haas in the United States in 2001 for the prevention and control of oomycete pathogenic microorganisms, and its structural formula is as shown in formula a:

[0004]

[0005] In the patent CN 1037602 of Rohm and Haas in the United States a method for synthesizing a benzamide compound is disclosed, specifically comprising, in the presence of hydrochloric acid, subjecting aryl-substituted oxazoline to a hydrolysis ring-opening reaction to prepare the target compound, but this method relates to the use of a large amount of hydrochloric acid, which leads to a complex post-treatment, for example, hydrochloric acid needs to be washed with an aqueous sodium bicarbonate solution during the post-treatment, which will produce a large amount of salt-containing wastewater, and the crude product needs to be separated by column chromatography, which cannot meet the requirements of industrialized mass production.

Summary of the Invention

[0006] An object of the present invention is to provide a method for preparing a benzamide compound, the method provided by the present invention relates to the use of p-toluenesulphonic acid or sulphonic acid ion exchange resin as an acidic catalyst to catalyze the hydrolysis ring opening reaction of the aryl-substituted dihydrooxazole to obtain the benzamide compound, only a catalytically metered toluenesulphonic acid or sulphonic acid ion exchange resin is needed, the toluenesulphonic acid or sulphonic acid ion exchange resin is convenient to remove after the reaction is completed, with very little waste, and industrial production is convenient to achieve.

[0007] To achieve the above object of the invention, the present invention provides the following technical solution:

[0008] A method for preparing a benzamide compound, comprising the following steps:

[0009] mixing aryl-substituted dihydrooxazole, an acidic catalyst, water and a reaction solvent, and subjecting same to a hydrolysis ring-opening reaction to obtain the benzamide compound,

[0010] wherein the acidic catalyst is a p- toluenesulphonic acid or sulphonic acid ion exchange resin;

[0011] the aryl-substituted dihydrooxazole has a structure as shown in formula I: formula I;

[0013] In formula I, Ri, R2 and R3 are independently hydrogen, hydrocarbyl or substituted hydrocarbyl, and Xi, X2 and X3 are independently hydrogen or a halogen group.

[0014] Preferably, the numbers of the carbon atoms of the hydrocarbyl and the substituted hydrocarbyl are independently 1 to 5, and the halogen group includes -F, - Cl, -Br or -I. [0015] Preferably, the hydrocarbyl includes methyl or ethyl; the substituted hydrocarbyl includes chloromethyl or bromoethyl.

[0016] Preferably, the reaction solvent includes one or more of ethanol, methanol, methyl tert-butyl ketone and methyl tert-butyl ether.

[0017] Preferably, the molar ratio of the aryl- substituted dihydrooxazole to p-toluenesulphonic acid is 1 : 0.01-0.5, and the mass of the sulphonic acid ion exchange resin is 1 to 5% of the mass of the aryl-substituted dihydrooxazole;

[0018] the molar ratio of the aryl-substituted dihydrooxazole, water and reaction solvent is 1 : 1-1.5 : 1- 20.

[0019] Preferably, the temperature of the hydrolysis ring-opening reaction is 50 to 80°C, and the time is 2 to 10 h.

[0020] The above mentioned method results in obtaining a product material solution comprising a precipitate which comprises the benzamide compound. Preferably, in a first embodiment, when the acidic catalyst is p-toluenesulphonic acid, after the hydrolysis ring opening reaction, the method further comprises:

[0021] subjecting the product material solution obtained after the hydrolysis ring-opening reaction to a first solid-liquid separation, and subjecting the resulting first solid material to a slurrying washing treatment, and then subjecting same to a second solid-liquid separation, and then drying the resulting second solid material to obtain a benzamide compound.

[0022] Preferably, according to this embodiment, the solvent used in the slurrying washing treatment includes one or more of ethanol, methyl tert-butyl ketone and toluene.

[0023] Preferably, in a second embodiment, when the acidic catalyst is a sulphonic acid ion exchange resin, after the hydrolysis ring-opening reaction, the method further comprises:

[0024] subjecting the product material solution obtained after the hydrolysis ring-opening reaction to a first solid-liquid separation, mixing the resulting first solid material with water, heating same until the first solid material of this embodiment is completely dissolved, subjecting same to a second solid-liquid separation while it is hot, and cooling the resulting liquid material to room temperature, with a solid product precipitating, and then subjecting same to a third solid-liquid separation, drying the resulting third solid material to obtain a benzamide compound.

[0025] Preferably, in this embodiment, the temperature of the heating is 70 to 80°C.

[0026] The present invention provides a method for preparing a benzamide compound comprising the following steps: mixing aryl-substituted dihydrooxazole, an acidic catalyst, water and a reaction solvent, and subjecting same to a hydrolysis ring-opening reaction to obtain the benzamide compound, wherein the acidic catalyst is a p- toluenesulphonic acid or sulphonic acid ion exchange resin. According to the present invention, a p-toluenesulphonic acid or sulphonic acid ion exchange resin is used as an acidic catalyst. Under the catalytic action of the p- toluenesulphonic acid or sulphonic acid ion exchange resin, aryl-substituted dihydrooxazole is subjected to a hydrolysis ring-opening reaction to obtain the benzamide compound, only catalytically metered toluenesulphonic acid or sulphonic acid ion exchange resin is needed, the toluenesulphonic acid or sulphonic acid ion exchange resin is convenient to remove after the completion of the reaction, with very little waste, and industrial production is convenient to achieve.

[0027] Further, the method provided by the present invention has mild and controllable reaction conditions, a simple and convenient reaction post-treatment, without needing complicated purification operations, has a high product yield and a high purity, and has the advantages of being green and environmentally friendly. Detailed Description of Embodiments

[0028] The present invention provides a method for preparing a benzamide compound comprising the following steps: [0029] mixing aryl-substituted dihydrooxazole, an acidic catalyst, water and a reaction solvent, and subjecting same to a hydrolysis ring-opening reaction to obtain the benzamide compound,

[0030] wherein the acidic catalyst is a p- toluenesulphonic acid or sulphonic acid ion exchange resin;

[0031] the aryl-substituted dihydrooxazole has a structure as shown in formula I:

[0033] In formula I, Ri, R ₂ and R ₃ are independently hydrogen, hydrocarbyl or substituted hydrocarbyl, and Xi, X ₂ and X ₃ are independently hydrogen or a halogen group.

[0034] In the present invention, the numbers of the carbon atoms of the hydrocarbyl and the substituted hydrocarbyl are independently 1 to 5, more preferably, the hydrocarbyl includes methyl or ethyl; the substituted hydrocarbyl includes chloromethyl or bromoethyl; the halogen group preferably includes -F, -Cl, -Br or -I.

[0035] In the present invention, the benzamide compound has a structure as shown in formula II: [0036] formula II;

[0037] The types of substituents in formula II are the same as those in formula I.

[0038] In the present invention, under the action of an acidic catalyst, the aryl-substituted dihydrooxazole is subjected to a hydrolysis ring-opening reaction to obtain a benzamide compound; the reaction formula is as shown in formula a:

[0039] formula a.

[0040] In the present invention, aryl-substituted dihydrooxazole, an acidic catalyst, water and a reaction solvent are mixed to obtain a reaction solution. In the present invention, the acidic catalyst is a p- toluenesulphonic acid or sulphonic acid ion exchange resin. According to the present invention, a p-toluenesulphonic acid or sulphonic acid ion exchange resin is used as an acidic catalyst. Under the catalytic action of the p- toluenesulphonic acid or sulphonic acid ion exchange resin, aryl-substituted dihydrooxazole is subjected to a hydrolysis ring-opening reaction to obtain the benzamide compound, only catalytically metered toluenesulphonic acid or sulphonic acid ion exchange resin is needed, the toluenesulphonic acid or sulphonic acid ion exchange resin is convenient to remove after the completion of the reaction, with very little waste, and industrial production is convenient to achieve.

[0041] In the present invention, the reaction solvent preferably includes one or more of ethanol, methanol, methyl tert-butyl ketone and methyl tert-butyl ether, more preferably, ethanol and methyl tert-butyl ketone; in the embodiment of the present invention, anhydrous ethanol is specifically used as the reaction solvent.

[0042] In the present invention, the molar ratio of the aryl-substituted dihydrooxazole to p-toluenesulphonic acid is preferably 1 : 0.01-0.5, more preferably 1 : 0.05- 0.1; the mass of the sulphonic acid ion exchange resin is preferably 1 to 5% of the mass of the aryl-substituted dihydrooxazole, more preferably 1 to 3%; the molar ratio of the aryl-substituted dihydrooxazole, water and reaction solvent is preferably 1 : 1-1.5 : 1-20, more preferably 1 : 1-1.2 : 5-10.

[0043] In the present invention, the method of mixing the aryl-substituted dihydrooxazole, acidic catalyst, water and reaction solvent is not particularly limited, as long as they can be uniformly mixed. In the present invention, it is preferable to add the aryl-substituted dihydrooxazole, acidic catalyst, water and reaction solvent to the reactor in sequence, heat and stir the same, such that the components are fully mixed to obtain a reaction solution. In the present invention, the temperature of the heating is preferably 45 to 80°C, more preferably 60 to 65°C, and the stirring time is preferably 5 to 15 min, more preferably 10 min; the present invention has no particular limitation on the stirring, as long as a conventional stirring rate is used.

[0044] In the present invention, after the reaction solution is obtained, a hydrolysis ring opening- reaction is performed to obtain a benzamide compound. In the present invention, the temperature of the hydrolysis ring opening reaction is preferably 50 to 80°C, more preferably 60 to 65°C, and the time is preferably 2 to 10 h. Specifically, the reaction progress is monitored by chromatography. In the present invention, under the action of the acidic catalyst, the aryl-substituted dihydrooxazole undergoes a hydrolysis ring-opening reaction to generate a benzamide compound. During the reaction process, a white solid will gradually precipitate out of the system. When the white solid is completely precipitated, the hydrolysis ring-opening reaction is completed, and the white solid is the benzamide compound.

[0045] In the present invention, it is preferable to select a suitable post-treatment method according to the type of the acidic catalyst.

Specifically, in a first embodiment, when the acidic catalyst is p-toluenesulphonic acid, after the hydrolysis ring opening reaction, the method preferably further comprises:

[0046] subjecting the product material solution obtained after the hydrolysis ring-opening reaction to a first solid-liquid separation, and subjecting the resulting first solid material to a slurrying washing treatment, and then subjecting same to a second solid-liquid separation, and then drying the resulting second solid material to obtain a benzamide compound.

[0047] In this first embodiment of the present invention, the solvent used in the slurrying washing treatment preferably includes one or more of ethanol, methyl tert-butyl ketone and toluene, more preferably ethanol or toluene. In this embodiment of the present invention, anhydrous ethanol is specifically used as the solvent. The present invention has no particular limitation on the amount of solvent and the specific method of the slurrying washing treatment, as long as the amount and method well known to those skilled in the art are used. In the present invention, the impurities in the first solid material are removed through the slurrying washing treatment to realize the purification thereof. The present invention has no particular limitation on the drying, as long as the product can be fully dried.

[0048] In a second embodiment of the present invention, when the acidic catalyst is a sulphonic acid ion exchange resin, after the hydrolysis ring-opening reaction, the method preferably further comprises:

[0049] subjecting the product material solution obtained after the hydrolysis ring-opening reaction to a first solid-liquid separation, mixing the resulting first solid material with water, heating same until the first solid material is completely dissolved, subjecting same to a second solid-liquid separation while it is hot, and cooling the resulting liquid material to room temperature, with a solid product precipitating, and then subjecting same to a third solid-liquid separation, drying the resulting third solid material to obtain a benzamide compound.

[0050] The present invention has no particular limitation on the amount of water used to dissolve the first solid material, as long as it can ensure that the first solid material is fully dissolved under the heating condition and facilitate the precipitation of the solid products by subsequent cooling. In this second embodiment of the present invention, the temperature of the heating is preferably from 70 to 80°C. The present invention has no particular limitation on the drying, as long as the product can be fully dried. The present invention realizes the purification of the benzamide compound through the above-mentioned post treatment, and the solid material obtained by the second solid-liquid separation of this second embodiment is a sulphonic acid ion exchange resin, which can be recycled and reused.

[0051] The present invention has no particular limitation on the methods of the first solid-liquid separation of the first embodiment, the second solid-liquid separation of the first embodiment, the first solid-liquid separation of the second embodiment, the second solid-liquid separation of the second embodiment, and the third solid- liquid separation of the second embodiment, as long as the solid-liquid separation can be realized; in the present invention, the solid-liquid separation is preferably achieved by filtration; the filtration can be performed by using a G-4 sand core funnel or a Buchner funnel, which is not particularly limited in the present invention.

[0052] The technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Apparently, the described embodiments are only some rather than all of the embodiments of the present invention. Based on the embodiments of the present invention, all other examples obtained by those of ordinary skill in the art without involving any inventive effort fall within the scope of protection of the present invention.

[0053] Example 1 [0054] Preparation of Zoxamide, the chemical name is 3, 5-dichloro-N-(l-chloro-3-methyl-2-oxopentan-3-yl)-4- methylbenzamide, the reaction formula is as shown in formula (1): [0055]

(1)

[0056] (1) 31.9 g (0.1 mol) of 5-chlorovinyl-2-

(3,5-dichloro-4-methylphenyl)-4-ethyl-4-methyl-4 ,5- dihydrooxazole, 0.86 g (0.005 mol) of p-toluenesulphonic acid, 1.84 g (0.102 mol) of water and 46 mL of anhydrous ethanol are added to the four-neck reactor in sequence, heated to 60°C, stirred for 10 min to obtain a reaction solution, which is then kept at 60°C and reacted for 1.5 h, a white solid product is precipitated, which is further kept at that temperature for 5 h, and the reaction is monitored by chromatography until it is completed, that is, the white solid product is precipitated completely, and a product material solution was obtained; [0057] (2) The product material solution is filtered by a G-4 sand core funnel, the resulting filter cake is a white powder, and the filtrate is a slightly yellow liquid; the filter cake is mixed with 200 mL of anhydrous ethanol and then subjected to a slurrying washing treatment, and then filtered with a G-4 sand core funnel to obtain a white solid powder, which is dried to obtain 33 g of the product with a yield of 96%; the product is detected by GC, and compared with the standard product, the result shows that the product is indeed Zoxamide with a GC purity of 99.7%. [0058] Example 2

[0059] Preparation of Zoxamide, the chemical name is 3, 5-dichloro-N-(l-chloro-3-methyl-2-oxopentan-3-yl)-4- methylbenzamide, the reaction formula is as shown in formula

(2):

[0060] formula (2)

[0061] (1) 31.9 g (0.1 mol) of 5-chlorovinyl-2-

(3,5-dichloro-4-methylphenyl)-4-ethyl-4-methyl-4, 5- dihydrooxazole, 0.96 g of sulphonic acid ion exchange resin, 1.84 g (0.102 mol) of water and 46 mL of anhydrous ethanol are added to the four-neck reactor in sequence, heated to 60°C, stirred for 10 min to obtain a reaction solution, which is then kept at 60°C and reacted for 1.5 h, a white solid product is precipitated, which is further kept at that temperature for 5 h, and the reaction is monitored by chromatography until it is completed, that is, the white solid product is precipitated completely, and a product material solution is obtained.

[0062] (2) The product material solution is filtered by a G-4 sand core funnel, the resulting filter cake is a white powder, and the filtrate is a slightly yellow liquid; the filter cake is mixed with 100 mL of water and then heated to 75°C until all solids are dissolved, same is filtered by a G-4 sand core funnel while hot to remove the sulphonic acid ion exchange resin, the resulting filtrate is cooled to room temperature, and a white solid product is precipitated, which is then filtered with a G-4 sand core funnel to obtain a white solid powder, dried to obtain 30 g of the product with a yield of 89%; the product is detected by GC, and compared with the standard product, the result shows that the product is indeed Zoxamide with a GC purity of 98.5%.

[0063] Example 3

[0064] Preparation of N-(l-chloro-3-methyl-2- oxopentan-3-yl)-4-methylbenzamide, the reaction formula is as shown in formula (3): formula

[0066] (1) 25 g (0.1 mol) of 5-chlorovinyl-2-il methylphenyl)-4-ethyl-4-methyl-4, 5-dihydrooxazole, 0.86 g (0.005 mol) of p-toluenesulphonic acid, 1.84 g (0.102 mol) of water and 45 mL of anhydrous ethanol are added to the four-neck reactor in sequence, heated to 60°C, stirred for 10 min to obtain a clear and transparent reaction solution, which is then kept at 60°C and reacted for 1.5 h, a white solid product is precipitated, which is further kept at that temperature for 5 h, and the reaction is monitored by chromatography until it is completed, that is, the white solid product is precipitated completely, and a product material solution is obtained.

[0067] (2) The product material solution is filtered by a G-4 sand core funnel, the resulting filter cake is a white powder, and the filtrate is a slightly yellow liquid; the filter cake is mixed with 200 mL of anhydrous ethanol and then subjected to a slurrying washing treatment, and then filtered with a G-4 sand core funnel to obtain a white solid powder, which is dried to obtain 25 g of the product with a yield of 94%; the product is detected by GC, and compared with the standard product, the result shows that the product is indeed N-(l-chloro-3-methyl-2-oxopentan-3- yl)-4-methylbenzamide with a GC purity of 99.5%.

[0068] It can be seen from the above examples that in the method provided by the present invention, only a catalytically metered toluenesulphonic acid or sulphonic acid ion exchange resin is required, the reaction conditions are mild, the reaction process is green and environmentally friendly, without a large amount of hydrochloric acid, the acidic catalyst can be directly removed by slurrying washing after the reaction or using a filtration method without generating a large amount of waste acid, salt-containing wastewater and other wastes, and when a sulphonic acid ion exchange resin is used as the acidic catalyst, it can be recycled; the method provided by the present invention has a simple post-treatment, a high product yield, and can obtain high-purity products without the use of column chromatography for separation and purification, and it is convenient to realize industrialized production.

[0069] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications are also to be regarded as the scope of protection of the present invention.