A preparation method of 4-(tert-butyl)-N-(2,6-difluorobenzoyl)-2-ethoxybenzamide

Abstract

The present invention provides a preparation method of 4-(tert-butyl)-N-(2,6-difluorobenzoyl)-2-ethoxybenzamide shown in M361. The synthetic route of the preparation method is as follows: the preparation method of the present invention has readily available raw materials, a short process route, and a high product yield.

Description

Technical Field

[0001] The invention belongs to the field of pesticide synthesis, and in particular relates to a preparation method of 4-(tert-butyl)-N-(2,6-difluorobenzoyl)-2-ethoxybenzamide. Background Art

[0002] Etoxazole, a diphenyloxazoline acaricide, is used to control a variety of spider mite pests. It primarily inhibits embryogenesis and the molting process from larvae to adults, resulting in excellent contact toxicity against mite eggs, larvae, and pupae. Annual sales currently reach hundreds of millions of US dollars, and its market share in the acaricide market is steadily increasing. According to the current Ministry of Agriculture and Rural Affairs regulations on the marketing of pesticides, pesticides must undergo residue evaluation. The Joint Meeting on Pesticide Residues (JMPR), established in 1963, is one of three expert advisory bodies jointly managed by the Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO) (the other two are the Expert Committee on Food Additives (JECFA) and the Joint Meeting on Microbiological Risk Assessment (JEMRA). To further standardize residue evaluation, the JMPR has compiled a list of metabolites to be tested for major pesticides. Among these, etoxazole has a metabolite called 4-(tert-butyl)-N-(2,6-difluorobenzoyl)-2-ethoxybenzamide, the structure of which is shown in Formula I:

[0003]

[0004] Because this structure is included in the mandatory inspection list and its synthesis is extremely difficult, the current market price of pesticide metabolites can reach 10,000-20,000 RMB per 250mg. The present invention analyzes its structure and finds that it is mainly divided into fragments such as 2,6-difluorobenzoyl and 4-tert-butyl-2-ethoxyphenyl. Therefore, the development of a green, efficient, and universal synthesis method to construct this metabolite is of great research significance.

[0005] After searching Scifinder and other chemical databases, there is no direct literature report on the synthesis of this compound. However, through the search of analog compounds, the following types of literature reports are available:

[0006] (1) [Organic Letters, 8(24), 5669, 2006] reported the direct formation of amide analogs from oxazole rings with the help of cerium ammonium nitrate. This reaction required 2-4 times the amount of CAN reagent and required column purification after the reaction, which also increased the cost of the reaction.

[0007]

[0008] (2) [J. Chem. Soc. 85, 1684, 1904] reported the reaction of aryl acyl chlorides and aryl amides in the presence of a strong base, pyridine, to form amide analogs. This reaction required the synthesis of the corresponding substituted acyl chlorides and substituted amides. In addition, the reaction used pyridine as a strong base, and post-reaction purification with sulfuric acid was required, all of which limited its industrial application.

[0009]

[0010] (3) [Tetrahedron Letters, 14, 879, 1965] reported a reaction in which an amide reacts in the presence of a peracid to produce a mixture of diphenylamide and phenol. However, this reaction has a narrow scope of application, the substrate is difficult to obtain, and the reaction is difficult to scale up. The presence of byproducts makes post-processing cumbersome. Furthermore, the peracid used in the reaction is extremely prone to decomposition, resulting in fire and even explosion, making it extremely dangerous.

[0011]

[0012] (4) In addition, there are literatures such as [J.Org.Chem.44(23),4169,1979], [Synlett,5,675,2008], [Tetrahedron Letters,51(47),6098,2010], [Tetrahedron Letters,55(20),3160,2014] that report that different types of substituted amides can be obtained by photochemical reactions to obtain target products. However, they all have disadvantages such as low reaction yield, complex raw material sources, harsh reaction conditions, narrow substrate applicability, and long reaction time, making them incapable of industrial production.

[0013]

[0014] Therefore, how to obtain the target compound using cheap and readily available raw materials under mild reaction conditions is a very worthy research topic. After conducting a series of extensive chemical experiments, the inventors of this application innovatively discovered an efficient and high-yield preparation route. Summary of the Invention

[0015] The synthesis of the present compound using similar methods in the prior art has problems such as difficult raw materials, harsh reaction conditions, and long routes. The present invention provides a method for preparing 4-(tert-butyl)-N-(2,6-difluorobenzoyl)-2-ethoxybenzamide (M361) with readily available raw materials, mild reaction conditions, and a shorter reaction route. Specifically, the preparation method of the present invention adopts the following technical solution: the readily available commercialized etoxazole raw material reacts with oxygen in the air under the action of an organophosphine catalyst to produce the target product in one step. The synthesis route is as follows:

[0016]

[0017] Furthermore, in some specific embodiments, in the above reaction step, etoxazole reacts with oxygen in the air in the presence of an organic phosphine catalyst to generate the target product M361, and the catalyst is one of diphenyl phosphine, triphenyl phosphine, tricyclohexyl phosphine or bis(diphenylphosphino)ferrocene.

[0018] Preferably, the molar ratio of etoxazole to the catalyst is 1:0.01 to 1:1. Experimental studies have found that when the amount of catalyst used is too small, the raw material conversion is less, and therefore the product yield is low; when the amount of catalyst used is too high, side reactions will occur in the reaction, resulting in a lower product yield.

[0019] Furthermore, in some specific embodiments, the above reaction is carried out in a solvent, and the solvent is one of toluene, dichloroethane, and isopropanol.

[0020] In a preferred embodiment of the above reaction step, the reaction temperature is from room temperature to 130°C, preferably 80-110°C.

[0021] Beneficial effects of the present invention:

[0022] 1. The synthesis of the present invention is simple, requiring only one reaction step and no tedious post-processing, and has the conditions for large-scale industrial production;

[0023] 2. The synthesis process of the present invention has mild conditions and is green and environmentally friendly;

[0024] 3. The raw materials required for the present invention are easily available, and there is no need to prepare intermediates through a large number of reactions before reacting. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the technical solution of the embodiment of the present invention, the following is a brief introduction to the drawings required for use in the embodiment of the present invention.

[0026] Figure 1 Synthesis of 4-(tert-butyl)-N-(2,6-difluorobenzoyl)-2-ethoxybenzamide - H NMR

[0027] Figure 2 Synthesis of 4-(tert-butyl)-N-(2,6-difluorobenzoyl)-2-ethoxybenzamide - mass spectrum DETAILED DESCRIPTION

[0028] The technical scheme of the present invention is further illustrated below by specific embodiments. It should be understood by those skilled in the art that the embodiments are merely for the purpose of helping to understand the present invention and should not be considered as specific limitations of the present invention. The raw materials in the reaction can be purchased from the market or obtained by synthesis.

[0029] The specific implementation methods of the present invention are further described in detail below in conjunction with the examples. 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. Obviously, the described embodiments are part of the embodiments of the present invention, rather than 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. Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "including" will be understood to include the stated components and steps, and does not exclude the presence of other material components or steps.

[0030] Furthermore, in order to better illustrate the present invention, numerous specific details are given in the following detailed description.

[0031] Those skilled in the art will appreciate that the present invention can be practiced without certain specific details. In some embodiments, raw materials, methods, means, etc. well known to those skilled in the art are not described in detail in order to highlight the main purpose of the present invention.

[0032] Hereinafter, embodiments of the present invention are described in detail. However, these embodiments are exemplary and the present invention is not limited thereto, and the present invention is defined by the scope of the claims.

[0033] In the present invention, unless otherwise specified, room temperature refers to approximately "20°C-25°C".

[0034] As used herein, the following terms used in the specification and claims have the following meanings when specific definitions are not otherwise provided.

[0035] The present invention first provides a method for preparing 4-(tert-butyl)-N-(2,6-difluorobenzoyl)-2-ethoxybenzamide (M361), which comprises the following reaction steps: etoxazole reacts in the presence of a catalyst and air to synthesize M361, wherein the catalyst is diphenyl phosphine, triphenylphosphine, tricyclohexylphosphine, and bis(diphenylphosphino)ferrocene. The synthesis route is as follows:

[0036]

[0037] Preferably, in the above preparation method, the molar ratio of etoxazole to the catalyst is 1:0.01 to 1:1. Within this ratio range, a good reaction yield is achieved.

[0038] Preferably, the above reaction can be carried out in a closed reactor or a non-closed reaction system. When the reaction is carried out in a closed reaction system, air is introduced into the reactor; when the reaction is carried out in a non-closed system, the reaction system is kept in contact with air. The reaction of the present invention is to react etoxazole with oxygen in the air to prepare M361.

[0039] Preferably, in the above preparation method, etoxazole and the catalyst are reacted in a solvent, and the solvent is selected from one of toluene, dichloroethane and isopropanol, preferably toluene.

[0040] Preferably, in the above preparation method, the reaction temperature is room temperature to 130°C, preferably 80-110°C.

[0041] The present invention will be further described below with reference to specific examples. The raw materials in the examples can be purchased from the market, and the product purity is detected by HPLC.

[0042] Example 1: Synthesis of 4-(tert-butyl)-N-(2,6-difluorobenzoyl)-2-ethoxybenzamide

[0043] Add diphenyl phosphine (62.2 mg, 0.1 mmol), toluene (3 mL), and etoxazole (359.4 mg, 1 mmol) to a dry three-necked flask and stir at room temperature for 0.1 h. Raise the reaction temperature to 110°C (the reaction does not need to be completely sealed). Continue stirring at 110°C for 3 h. The reaction solution is cooled and filtered. The organic phase is directly concentrated and crystallized to obtain a white solid product (335.9 mg, 93% yield). The product purity can reach over 95%. 1 H NMR (500MHz, Chloroform-d) δ11.07(s,1H),8.07(d,J=8.4Hz,1H),7.40(d,J=6.8Hz,1H),7.10(d,J=8. 4Hz,1H),7.01(s,1H),6.96(t,J=8.0Hz,2H),4.29(q,J=6.9Hz,2H),1.52(t,J=7.0Hz,3H),1.32(s,9H).

[0044] Example 2: Synthesis of 4-(tert-butyl)-N-(2,6-difluorobenzoyl)-2-ethoxybenzamide

[0045] Triphenylphosphine (26.2 mg, 0.1 mmol), toluene (3 mL) and etoxazole (359.4 mg, 1 mmol) were added to a dry three-necked flask and stirred at room temperature for 0.1 h. The reaction temperature was raised to 110 ° C. The reaction did not need to be completely sealed. The reaction was continued at 110 ° C for 3 h. The reaction solution was cooled and filtered. The organic phase was directly concentrated and crystallized to obtain a white solid product (281.6 mg, 78% yield). The product purity can reach more than 95%. 1 H NMR (500MHz, Chloroform-d) δ11.07(s,1H),8.07(d,J=8.4Hz,1H),7.40(d,J=6.8Hz,1H),7.10(d,J=8. 4Hz,1H),7.01(s,1H),6.96(t,J=8.0Hz,2H),4.29(q,J=6.9Hz,2H),1.52(t,J=7.0Hz,3H),1.32(s,9H).

[0046] Example 3: Synthesis of 4-(tert-butyl)-N-(2,6-difluorobenzoyl)-2-ethoxybenzamide

[0047] Tricyclohexylphosphine (28.0 mg, 0.1 mmol), toluene (3 mL) and etoxazole (359.4 mg, 1 mmol) were added to a dry three-necked flask and stirred at room temperature for 0.1 h. The reaction temperature was raised to 110 ° C. The reaction did not need to be completely sealed. The reaction was continued at 110 ° C for 3 h. The reaction solution was cooled and filtered, and the organic phase was directly concentrated to obtain the product (296.0 mg, yield 82%). The product purity can reach more than 95%. 1 H NMR (500MHz, Chloroform-d) δ11.07(s,1H),8.07(d,J=8.4Hz,1H),7.40(d,J=6.8Hz,1H),7.10(d,J=8. 4Hz,1H),7.01(s,1H),6.96(t,J=8.0Hz,2H),4.29(q,J=6.9Hz,2H),1.52(t,J=7.0Hz,3H),1.32(s,9H).

[0048] Example 4: Synthesis of 4-(tert-butyl)-N-(2,6-difluorobenzoyl)-2-ethoxybenzamide

[0049] Add diphenyl phosphine (62.2 mg, 0.1 mmol), dichloroethane (3 mL) and etoxazole (359.4 mg, 1 mmol) to a dry three-necked flask and stir at room temperature for 0.1 h. Raise the reaction temperature to reflux. The reaction does not need to be completely sealed. Continue stirring the reaction for 3 h. The reaction solution is cooled and filtered. The organic phase is directly concentrated and crystallized to obtain a white solid product (216.7 mg, 60% yield). The product purity can reach more than 95%. 1 H NMR (500MHz, Chloroform-d) δ11.07(s,1H),8.07(d,J=8.4Hz,1H),7.40(d,J=6.8Hz,1H),7.10(d,J=8. 4Hz,1H),7.01(s,1H),6.96(t,J=8.0Hz,2H),4.29(q,J=6.9Hz,2H),1.52(t,J=7.0Hz,3H),1.32(s,9H).

[0050] Example 5: Synthesis of 4-(tert-butyl)-N-(2,6-difluorobenzoyl)-2-ethoxybenzamide

[0051] Add diphenyl phosphine (62.2 mg, 0.1 mmol), isopropyl alcohol (3 mL) and etoxazole (359.4 mg, 1 mmol) to a dry three-necked flask and stir at room temperature for 0.1 h. Raise the reaction temperature to reflux; the reaction does not need to be completely sealed. Continue stirring the reaction for 3 h. The reaction solution is cooled and filtered, and the organic phase is directly concentrated and crystallized to give a white solid product (281.8 mg, 78% yield). The product purity can reach more than 95%. 1 H NMR (500MHz, Chloroform-d) δ11.07(s,1H),8.07(d,J=8.4Hz,1H),7.40(d,J=6.8Hz,1H),7.10(d,J=8. 4Hz,1H),7.01(s,1H),6.96(t,J=8.0Hz,2H),4.29(q,J=6.9Hz,2H),1.52(t,J=7.0Hz,3H),1.32(s,9H).

[0052] Example 6: Synthesis of 4-(tert-butyl)-N-(2,6-difluorobenzoyl)-2-ethoxybenzamide

[0053] Add diphenyl phosphine (124.4 mg, 0.2 mmol), toluene (3 mL) and etoxazole (359.4 mg, 1 mmol) to a dry three-necked flask and stir at room temperature for 0.1 h. Raise the reaction temperature to 110 ° C. The reaction does not need to be completely sealed. Continue stirring at 110 ° C for 3 h. The reaction solution is cooled and filtered. The organic phase is directly concentrated and crystallized to obtain a white solid product (289.6 mg, 80% yield). The product purity can reach more than 95%. 1 H NMR (500MHz, Chloroform-d) δ11.07(s,1H),8.07(d,J=8.4Hz,1H),7.40(d,J=6.8Hz,1H),7.10(d,J=8. 4Hz,1H),7.01(s,1H),6.96(t,J=8.0Hz,2H),4.29(q,J=6.9Hz,2H),1.52(t,J=7.0Hz,3H),1.32(s,9H).

[0054] Example 7: Synthesis of 4-(tert-butyl)-N-(2,6-difluorobenzoyl)-2-ethoxybenzamide

[0055] Add diphenyl phosphine (6.22 mg, 0.01 mmol), toluene (3 mL) and etoxazole (359.4 mg, 1 mmol) to a dry three-necked flask and stir at room temperature for 0.1 h. Raise the reaction temperature to 110 ° C. The reaction does not need to be completely sealed. Continue stirring at 110 ° C for 3 h. The reaction solution is cooled and filtered. The organic phase is directly concentrated and crystallized to obtain a white solid product (169.8 mg, 47% yield). The product purity can reach more than 95%. 1 H NMR (500MHz, Chloroform-d) δ11.07(s,1H),8.07(d,J=8.4Hz,1H),7.40(d,J=6.8Hz,1H),7.10(d,J=8. 4Hz,1H),7.01(s,1H),6.96(t,J=8.0Hz,2H),4.29(q,J=6.9Hz,2H),1.52(t,J=7.0Hz,3H),1.32(s,9H).

[0056] Example 8: Synthesis of 4-(tert-butyl)-N-(2,6-difluorobenzoyl)-2-ethoxybenzamide

[0057] In a dry three-necked flask, add diphenyl phosphine (62.2 mg, 0.1 mmol), toluene (3 mL), and etoxazole (359.4 mg, 1 mmol). Stir and react at room temperature for 12 hours. The reaction does not need to be completely sealed. The reaction solution is cooled and filtered. The organic phase is directly concentrated and crystallized to obtain a white solid product (35 mg, 10% yield). The product purity can reach over 90%. 1 H NMR (500MHz, Chloroform-d) δ11.07(s,1H),8.07(d,J=8.4Hz,1H),7.40(d,J=6.8Hz,1H),7.10(d,J=8. 4Hz,1H),7.01(s,1H),6.96(t,J=8.0Hz,2H),4.29(q,J=6.9Hz,2H),1.52(t,J=7.0Hz,3H),1.32(s,9H).

[0058] Example 9: Synthesis of 4-(4-(tert-butyl)-2-(2,6-difluorobenzoyl)-2-ethoxybenzamide

[0059] A dry three-necked flask was charged with CAN (1.59 g, 3 mmol), a mixed solvent of acetonitrile and water (3 mL), and etoxazole (359.4 mg, 1 mmol). The mixture was stirred at room temperature for 3 h. The reaction solution was cooled and filtered, and the organic phase was directly concentrated to detect the formation of no product.

[0060] Example 10: Synthesis of 4-(4-(tert-butyl)-2-(2,6-difluorobenzoyl)-2-ethoxybenzamide

[0061] Add CAN (1.59 g, 3 mmol), toluene (3 mL), and etoxazole (359.4 mg, 1 mmol) to a dry three-necked flask and raise the reaction temperature to 110°C. The reaction does not need to be completely sealed. Continue stirring at 110°C for 3 h. Cool the reaction solution and filter. After cooling, filter the reaction solution and concentrate the organic phase. No product is produced.

[0062] Example 11: Synthesis of 4-(tert-butyl)-N-(2,6-difluorobenzoyl)-2-ethoxybenzamide

[0063] Add bis(diphenylphosphinothiophene)ferrocene (55.4 mg, 0.1 mmol), toluene (3 mL), and etoxazole (359.4 mg, 1 mmol) to a dry three-necked flask and raise the reaction temperature to 110°C. The reaction does not need to be completely sealed. Continue stirring at 110°C for 3 hours. The reaction solution is cooled and filtered. The organic phase is directly concentrated and crystallized to obtain a white solid product (126.4 mg, 35% yield). The product purity can reach over 95%. 1H NMR (500MHz, Chloroform-d) δ11.07(s,1H),8.07(d,J=8.4Hz,1H),7.40(d,J=6.8Hz,1H),7.10(d,J=8. 4Hz,1H),7.01(s,1H),6.96(t,J=8.0Hz,2H),4.29(q,J=6.9Hz,2H),1.52(t,J=7.0Hz,3H),1.32(s,9H).

[0064] Example 12: Synthesis of 4-(tert-butyl)-N-(2,6-difluorobenzoyl)-2-ethoxybenzamide

[0065] Add diphenyl phosphine (62.2 mg, 0.1 mmol) and etoxazole (359.4 mg, 1 mmol) to a dry three-necked flask, evacuate the system three times, and finally fill the system with nitrogen. Then add toluene (3 mL) and increase the reaction temperature to 110 ° C. The reaction system is completely sealed. Continue stirring at 110 ° C for 3 hours. The reaction solution is cooled and filtered. The organic phase is directly concentrated and no product is generated.

[0066] Example 13: Synthesis of 4-(tert-butyl)-N-(2,6-difluorobenzoyl)-2-ethoxybenzamide

[0067] Add etoxazole (359.4 mg, 1 mmol) and toluene (3 mL) to a dry three-necked flask. Stir at room temperature for 0.1 h. Raise the reaction temperature to 110°C (the reaction does not need to be completely sealed). Raise the reaction temperature to 110°C and continue stirring at 110°C for 3 h. Cool the reaction solution, filter it, and concentrate the organic phase directly to detect the presence of product.

[0068] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the scope of protection of the present invention.

Claims

1. A method for preparing 4-(tert-butyl)-N-(2,6-difluorobenzoyl)-2-ethoxybenzamide (M361), characterized in that: The method comprises the following steps: etoxazole is reacted in the presence of a catalyst and air to synthesize M361, wherein the catalyst is one of diphenyl phosphine, triphenyl phosphine, tricyclohexyl phosphine or bis(diphenylphosphino)ferrocene. The synthesis route is as follows: 。 2. The preparation method according to claim 1, characterized in that The molar ratio of etoxazole to the catalyst is 1:0.01 to 1:

1.

3. The preparation method according to claim 1 or 2, characterized in that Ethoxazole and a catalyst react with oxygen in the air in a solvent, and the solvent is selected from one of toluene, dichloroethane and isopropyl alcohol.

4. The preparation method according to claim 3, characterized in that The solvent is selected from toluene.

5. The preparation method according to claim 3, characterized in that The reaction temperature of the reaction is room temperature to 130°C.

6. The preparation method according to claim 5, characterized in that The reaction temperature of the reaction is 80-110°C.

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