Method for preparing deet through carboxylic acid amidation

Abstract

The invention discloses a method for preparing deet through carboxylic acid amidation, which comprises the following steps: by taking diethylamine and 3-methyl benzoic acid as raw materials and an organic solvent as a reaction solvent, carrying out illumination reaction in the presence of a photocatalyst, an alkaline substance and sulfur hexafluoride to obtain the deet. The reaction conditions are mild, the used reaction raw materials are cheap and easy to obtain, and the method has the characteristics of cost saving, environment friendliness and industrial popularization. According to the method, the greenhouse gas SF6 is effectively activated and utilized, the amidation reaction of carboxylic acid is realized by fully utilizing the decomposition product SF6 to obtain the deet, the SF6 is turned into wealth, the required raw materials are simple and easy to obtain, the reaction conditions are simple and convenient, the method is green and energy-saving, and the method has relatively high application value.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, and in particular to a method for preparing DEET by carboxylic acid amidation. Background Art

[0002] Amidation reaction is the most commonly used organic synthesis reaction. A study on drug synthesis shows that 65% of drug synthesis processes use amidation reactions. In addition, amidation products play an important role in the biomedical, pharmaceutical and food industries, and are also widely used in industrial products. For example, sulfamide can modify peptide units and proteins, and sulfamide modification can significantly improve the stability and activity of peptide drugs; tyramine-derived hydroxycinnamamide in plant-based foods can be used as a food preservative due to its natural antioxidant effect; amide greases are often used in nuclear power and aerospace fields due to their excellent properties such as strong thermal stability, radiation resistance and mechanical stability. At present, the methods for synthesizing amide compounds are:

[0003] Method 1: Use 3,4,5-trifluorophenylboronic acid to catalyze the amidation reaction between carboxylic acid and amine.

[0004]

[0005] This method is not only applicable to the reaction of primary and tertiary amines with carboxylic acids, but is also applicable to some special substrates with large steric hindrance and olefin groups. However, it requires high temperature (>100°C) and anhydrous conditions, and has the problem of low atom economy.

[0006] Method 2: Using two zirconium catalysts (ZrCp2Cl2 / ZrCl4) in toluene solvent and heating reflux at 110°C, the amidation reaction of carboxylic acid and amine can be efficiently catalyzed.

[0007]

[0008] This method has a high yield and can achieve the synthesis of two drug molecules, acetaminophen and moclobemide, with a high yield, but this method introduces metal compounds and requires high temperature conditions.

[0009] Method 3: Using active ester as acyl source and zinc powder as catalyst, the synthesis of secondary amide was achieved under the conditions of microwave heating in DMF solvent or heating in THF solvent.

[0010]

[0011] The reaction has the following characteristics: simple, efficient, environmentally friendly and the catalyst can be reused. However, the substrate has a narrow scope of application and alcohol is also generated, which makes it very difficult to separate the subsequent products.

[0012] According to the above analysis, there is still a need to develop a carboxylic acid amidation method that has simple and readily available raw materials, simple operation, high reaction yield, good functional group tolerance, environmental friendliness, and is easy to promote in industrial production.

[0013] SF6 gas is a colorless, odorless, non-toxic, non-combustible, non-corrosive gas at room temperature and pressure. It is an inert gas with high stability. It does not decompose at high temperatures of 500-600°C and does not react with acids, alkalis, water, etc. It is also an insulating gas with excellent insulation properties and can be used to extinguish high-voltage arcs. Therefore, SF6 is widely used in the power sector. However, SF6 has a strong greenhouse effect, and its climate warming power is 23,900 times that of CO2. Secondly, because SF6 is an artificially synthesized gas with quite stable chemical properties, SF6 is extremely difficult to decompose and its natural lifespan in the atmosphere can be as long as more than 3,000 years. As it continues to accumulate in the atmosphere, the greenhouse effect it brings is also continuously increasing. Therefore, the emission of SF6 is strictly restricted, and the large amount of SF6 stored in the power sector faces tremendous pressure in treatment.

[0014] Biting insects such as mosquitoes have always brought serious troubles and even disasters to humans. They not only suck human blood and disturb people's peace, but also spread diseases. In order to eliminate the troubles caused by biting insects to humans, people have discovered and synthesized a variety of insect repellents. Among the various insect repellents currently known, DEET is the one with the broadest spectrum of physiological activity and the most significant comprehensive repellent effect. It not only shows high repellent activity against mosquitoes, but also has repellent effects on other pests, such as cockroaches, fleas, midges, sand fleas, sand mites, etc. At present, the synthesis process of DEET can be roughly divided into two steps. The first step is to prepare m-toluic acid into m-toluyl chloride; the second step is to react the m-toluyl chloride with diethylamine, and finally obtain the product after acid-base treatment.

[0015] The Chinese patent application document with publication number CN112724033A discloses a synthesis method of DEET and its application. It uses phosgene as raw material, so that the solvent in the process of preparing m-toluoyl chloride and the generated m-toluoyl chloride do not need to be removed by vacuum distillation, and can be directly applied to the reaction process of m-toluoyl chloride and diethylamine in the second step, thereby effectively reducing solvent consumption, and avoiding the energy consumption problem caused by vacuum distillation solvent, the yield reduction problem of the final product, the kettle residue caused by high-temperature distillation of m-toluoyl chloride, and the wastewater problem caused by cleaning the distillation equipment, and also avoiding the influence of high-temperature distillation on the product yield. However, its reaction process is carried out in two steps, the process is complicated, and the highly toxic gas phosgene is used as a raw material, which limits its application. Summary of the invention

[0016] The technical problem to be solved by the present invention is how to prepare DEET in a simple, safe and green manner.

[0017] The present invention solves the above technical problems through the following technical means:

[0018] A method for preparing DEET by carboxylic acid amidation, which uses diethylamine and 3-methylbenzoic acid as raw materials, an organic solvent as a reaction solvent, and performs light irradiation reaction in the presence of a photocatalyst, an alkaline substance, and sulfur hexafluoride to obtain the DEET.

[0019] Preferably, the method for preparing DEET by carboxylic acid amidation comprises the following steps: adding 3-methylbenzoic acid and a photocatalyst into a reaction device, adding an organic solvent after evacuation, introducing sulfur hexafluoride gas, and then adding diethylamine and an alkaline substance, placing the reaction system under a light source to react and obtain the DEET.

[0020] Preferably, the photocatalyst is a mixture of one or more organic photocatalysts or transition metal photocatalysts.

[0021] Preferably, the photocatalyst is Ir[dF(CF3)ppy]2(dtbbpy)PF6, Ir(dtbbpy)ppy2PF6, 4DPAIPN, 3CzFIPN, 4CzIPN, 5CzBN, 3DPA2FBN, Mes-Acr + ClO4 — A mixture of one or more of.

[0022] Preferably, the organic solvent is a mixture of one or more of tetrahydrofuran, acetonitrile and dichloromethane.

[0023] Preferably, the organic solvent is acetonitrile.

[0024] The present invention is carried out in a system with a single organic solvent; if necessary, other organic solvents may also be present in the system, but from the perspective of reaction yield and simplicity of operation, it is preferred not to add other organic solvents, that is, to use a single organic solvent as the reaction solvent.

[0025] Preferably, the alkaline substance is a mixture of one or more of N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and K2CO3.

[0026] Preferably, the alkaline substance is N,N-diisopropylethylamine. When the alkaline substance is N,N-diisopropylethylamine, the product yield is the highest.

[0027] Preferably, the molar ratio of diethylamine to 3-methylbenzoic acid is 1:1 to 20:1.

[0028] Preferably, the molar ratio of diethylamine to 3-methylbenzoic acid is 10:1.

[0029] Preferably, the molar ratio of the 3-methylbenzoic acid to the photocatalyst is 100:0.2-1; the molar ratio of the 3-methylbenzoic acid to the alkaline substance is 1:1-1:10.

[0030] Preferably, the molar ratio of the 3-methylbenzoic acid to the alkaline substance is 1:5.

[0031] Preferably, the molar ratio of the 3-methylbenzoic acid to the photocatalyst is 100:0.5.

[0032] Preferably, during the illumination process, blue light with a wavelength of 450-480 nm is used as the light source.

[0033] Preferably, 465 nm blue light is used as the light source.

[0034] Preferably, during the reaction process, the SF6 gas pressure is 1 atm, the reaction temperature is 0-50°C, and the reaction time is 5-48 hours.

[0035] Preferably, during the reaction, the SF6 gas pressure is 1 atm. When the pressure is 1 atm, the yield of the product is the highest.

[0036] Preferably, the reaction temperature is room temperature and the reaction time is 20 hours.

[0037] Preferably, the usage ratio of the 3-methylbenzoic acid and the organic solvent is 0.5-0.1 mmol:1 mL.

[0038] Preferably, the dosage ratio of the 3-methylbenzoic acid and the organic solvent is 0.5 mmol:3 mL; when the dosage ratio is 0.5 mmol:3 mL, the yield is the highest.

[0039] Preferably, during the reaction, the decomposition products of SF6 serve as condensation agents.

[0040] The advantages of the present invention are:

[0041] In the present invention, easily available diethylamine and 3-methylbenzoic acid are used as reaction substrates, commercially available Ir[dF(CF3)ppy]2(dtbbpy)PF6 and the like are used as photocatalysts, and cheap and easily available N,N-diisopropylethylamine and the like are used as alkaline substances, and DEET is simply and efficiently synthesized under SF6 gas. The reaction conditions of the present invention are mild, the reaction raw materials used are cheap and easily available, and it has the characteristics of cost saving, environmental friendliness, and industrial promotion. The method effectively activates and utilizes SF6, a greenhouse gas, and fully utilizes the decomposition product of SF6 to realize the amidation reaction of carboxylic acid to prepare DEET, turning SF6 into treasure, the required raw materials are simple and easy to obtain, the reaction conditions are simple, green and energy-saving, and it has high application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 This is the H NMR spectrum of N,N-diethyl-3-methylbenzamide described in Example 1 of the present invention;

[0043] Figure 2 This is the NMR carbon spectrum of N, N-diethyl-3-methylbenzamide described in Example 1 of the present invention. DETAILED DESCRIPTION

[0044] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described in combination with 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 creative work are within the scope of protection of the present invention.

[0045] Unless otherwise specified, the test materials and reagents used in the following examples can be obtained from commercial sources.

[0046] If no specific techniques or conditions are specified in the examples, they can be carried out according to the techniques or conditions described in the literature in the art or according to the product instructions.

[0047] The raw materials used in the following specific examples are all commercially available, and each reagent is purified by means known in the art before use when necessary.

[0048] 1 H NMR and 13 C NMR was measured using a Bruker Avance 400 spectrometer. The test temperature was room temperature, the solvent was deuterated chloroform, and the references were: 1 H NMR: CHCl3 7.260 ppm; 13C NMR: CHCl3: 77.000 ppm.

[0049] Example 1

[0050] Synthesis of N, N-Diethyl-3-methylbenzamide (DEET)

[0051] 3-Methylbenzoic acid (68.0 mg) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace glass vial with a PTFE gasket, and then evacuated and an SF6 balloon was inserted, and then 3.0 mL of anhydrous acetonitrile was added and bubbled for 3 minutes. Subsequently, diethylamine (517.3 μL) and N,N-diisopropylethylamine (434.6 μL) were added, and the reaction system was placed under a 15W, 465 nm blue LED light source, irradiated and stirred at room temperature for 20 hours, wherein the reaction was stirred under an atmospheric pressure of SF6 gas, and the organic solvent was removed under vacuum after the reaction was completed, and N,N-diethyl-3-methylbenzamide, i.e., DEET 64.9 mg, was obtained by silica gel column chromatography separation (petroleum ether: ethyl acetate volume ratio = 3:1), with a yield of 68%.

[0052] Product N, N-diethyl-3-methylbenzamide The NMR spectrum of Figure 1 and 2 As shown, the NMR data are as follows: 1 H NMR (400MHz, CDCl3) δ7.15–7.11(m,1H),7.06–7.01(m,3H),3.40–3.12(m,4H),2.23(s,3H),1.12–0.97(m,4H)ppm. 13 C NMR (101MHz, CDCl3) δ170.9,137.7,136.8,129.3,127.7,126.4,122.6,42.8,38.6,20.9,13.7,12.4ppm.

[0053] As can be seen from Example 1, the present invention uses easily available 3-methylbenzoic acid and diethylamine as reaction substrates, commercially available Ir[dF(CF3)ppy]2(dtbbpy)PF6 as a photocatalyst, and cheap and easily available N,N-diisopropylethylamine as an alkaline substance. Under an atmospheric pressure of SF6 gas, at room temperature, 15W of 465nm blue light is used as a light source to simply and efficiently synthesize DEET. This method is a method for synthesizing DEET with mild conditions, simple operation, and easy industrial promotion. In addition, this method effectively activates and utilizes SF6, a greenhouse gas, and fully utilizes the decomposition products of SF6 to realize the amidation reaction of carboxylic acid to prepare DEET, turning SF6 into treasure.

[0054] Embodiment 2-10

[0055] Examples 2-10 use the preparation method of Example 1 to prepare DEET, and the only difference from Example 1 is that the types of solvents, photocatalysts, and additives are changed. The specific types of solvents, photocatalysts, and additives used in each example are shown in the following table:

[0056]

[0057]

[0058] The structural formula of the catalyst used in each embodiment is as follows:

[0059]

[0060] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing DEET by carboxylic acid amidation, characterized in that: The method uses diethylamine and 3-methylbenzoic acid as raw materials, an organic solvent as a reaction solvent, and performs light irradiation reaction in the presence of a photocatalyst, an alkaline substance and sulfur hexafluoride to obtain the DEET.

2. The method for preparing DEET by carboxylic acid amidation according to claim 1, characterized in that: The following steps are involved: 3-Methylbenzoic acid and a photocatalyst are added into a reaction device, and an organic solvent is added after vacuuming, sulfur hexafluoride gas is introduced, and then diethylamine and an alkaline substance are added, and the reaction system is placed under a light source to react and obtain the DEET.

3. The method for preparing DEET by carboxylic acid amidation according to claim 1, characterized in that: The photocatalyst is Ir[dF(CF3)ppy]2(dtbbpy)PF6, Ir(dtbbpy)ppy2PF6, 4DPAIPN, 3CzFIPN, 4CzIPN, 5CzBN, 3DPA2FBN, Mes-Acr + ClO4 — A mixture of one or more of.

4. The method for preparing DEET by carboxylic acid amidation according to claim 1, characterized in that: The organic solvent is a mixture of one or more of tetrahydrofuran, acetonitrile and dichloromethane.

5. The method for preparing DEET by carboxylic acid amidation according to claim 1, characterized in that: The alkaline substance is a mixture of one or more of N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and K2CO3.

6. The method for preparing DEET by carboxylic acid amidation according to claim 1, characterized in that: The molar ratio of the diethylamine to 3-methylbenzoic acid is 1:1 to 20:

1.

7. The method for preparing DEET by carboxylic acid amidation according to claim 1, characterized in that: The molar ratio of the 3-methylbenzoic acid to the photocatalyst is 100:0.2-1; the molar ratio of the 3-methylbenzoic acid to the alkaline substance is 1:1-1:

10.

8. The method for preparing DEET by carboxylic acid amidation according to claim 1, characterized in that: During the illumination process, blue light with a wavelength of 450-480nm was used as the light source.

9. The method for preparing DEET by carboxylic acid amidation according to claim 1, characterized in that: During the reaction, the SF6 gas pressure is 1 atm, the reaction temperature is 0-50°C, and the reaction time is 5-48 hours.

10. The method for preparing DEET by carboxylic acid amidation according to any one of claims 1 to 9, characterized in that: The usage ratio of the 3-methylbenzoic acid and the organic solvent is 0.5-0.1 mmol:1 mL.

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