A process for the carboxamidation of diethyl carbonate to prepare diethyl methyl carbonate

Abstract

The application discloses a method for preparing diethylmethylbenzyl ammonium chloride through carboxylic acid amidation, which uses diethylamine and 3-methylbenzoic acid as raw materials, uses an organic solvent as a reaction solvent, and performs reaction under the conditions of a photocatalyst, an alkaline substance and sulfur hexafluoride and then performs irradiation to obtain the diethylmethylbenzyl ammonium chloride. The method has the characteristics of mild reaction conditions, cheap and easily obtained reaction raw materials, cost saving, environmental friendliness and industrial promotion. The method effectively activates and utilizes SF6, a greenhouse gas, fully utilizes SF6 decomposition products to realize carboxylic acid amidation reaction to obtain the diethylmethylbenzyl ammonium chloride, changes waste into treasure, the required raw materials are simple and easily obtained, the reaction conditions are simple, green and energy-saving, and the method has high application value.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, and specifically to a method for preparing DEET by carboxylic acid amidation. Background Technology

[0002] Amide reactions are among the most commonly used organic synthesis reactions. A study on drug synthesis showed that 65% of drug synthesis processes utilize amidation. Furthermore, amidated products play important roles in the biomedical, pharmaceutical, and food industries, and have wide applications in industrial products. For example, thioamides can modify peptide units and proteins; thioamide modification can significantly improve the stability and activity of peptide drugs. Tyramine-derived hydroxycinnamate in plant-based foods, due to its natural antioxidant properties, can be used as a food preservative. Amide greases, due to their excellent thermal stability, radiation resistance, and mechanical stability, are commonly used in nuclear power and aerospace fields. Currently, methods for synthesizing amide compounds include:

[0003] Method 1: Use 3,4,5-trifluorophenylboronic acid as a catalyst to catalyze the amidation reaction of carboxylic acids and amines.

[0004]

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

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

[0007]

[0008] This method has high yields and can synthesize two drug molecules, acetaminophen and moclobemide, in relatively high yields. However, it introduces metal compounds and requires high-temperature conditions.

[0009] Method 3: Secondary amides were synthesized by using an active ester as an acyl source and zinc powder as a catalyst under microwave heating in DMF solvent or heating in THF solvent.

[0010]

[0011] This reaction is characterized by its simplicity, high efficiency, environmental friendliness, and reusable catalyst. However, it has a narrow substrate applicability and generates alcohols, which poses significant challenges to the separation of subsequent products.

[0012] Based on the above analysis, there is still a need to develop a carboxylic acid amidation method that uses readily available raw materials, is easy to operate, has a high reaction yield, good functional group tolerance, is environmentally friendly, and is easy to promote in industrial production.

[0013] SF6 gas is a colorless, odorless, non-toxic, non-flammable, and non-corrosive gas at normal temperature and pressure. It is an inert gas with high stability, not decomposing even at high temperatures of 500-600℃, and does not react with acids, alkalis, or water. It is also an insulating gas with excellent insulating properties, used to extinguish high-voltage electric arcs, hence its widespread use in the power industry. However, SF6 has a powerful greenhouse effect, with a global warming potential 23,900 times that of CO2. Furthermore, because SF6 is a synthetic gas with remarkably stable chemical properties, it is extremely difficult to decompose, and its natural atmospheric lifespan can reach over three thousand years. As it accumulates in the atmosphere, its greenhouse effect continues to intensify. Therefore, SF6 emissions are strictly limited, and the large quantities of SF6 stored in the power sector face immense pressure in terms of disposal.

[0014] Mosquitoes and other biting pests have long caused serious trouble and even disasters for humans. They not only suck human blood and disturb peace, but also transmit diseases. To eliminate the nuisance caused by biting pests, people have discovered and synthesized a variety of insect repellents. Among the various insect repellents currently known, DEET has the broadest physiological activity and the most significant overall repellent effect. It not only shows highly effective repellent activity against mosquitoes, but also has a repellent effect on other pests such as cockroaches, fleas, midges, sand fleas, and sand mites. Currently, the synthesis process of DEET can be roughly divided into two steps: the first step is to prepare m-methylbenzoyl chloride from m-methylbenzoic acid; the second step is to react the m-methylbenzoyl chloride with diethylamine, and after acid-base treatment, finally obtain the product.

[0015] Chinese patent application CN112724033A discloses a method for synthesizing DEET and its application. Using phosgene as a raw material, the solvent and generated m-methylbenzoyl chloride in the preparation process do not need to be removed by vacuum distillation. They can be directly applied to the second step of the reaction between m-methylbenzoyl chloride and diethylamine, effectively reducing solvent consumption. This avoids the energy consumption problems associated with vacuum distillation, the reduced yield of the final product, the residue from high-temperature distillation of m-methylbenzoyl chloride, and the wastewater problems from cleaning the distillation equipment. It also avoids the impact of high-temperature distillation on product yield. However, the reaction process is complex, involving two steps, and uses the highly toxic gas phosgene as a raw material, limiting its application. Summary of the Invention

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

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

[0018] A method for preparing DEET by amidation of carboxylic acids, wherein diethylamine and 3-methylbenzoic acid are used as raw materials, an organic solvent is used as the reaction solvent, and the reaction is carried out under light irradiation 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 includes the following steps: adding 3-methylbenzoic acid and a photocatalyst into a reaction apparatus, evacuating the apparatus, adding an organic solvent, introducing sulfur hexafluoride gas, then adding diethylamine and an alkaline substance, and placing the reaction system under a light source to react and obtain DEET.

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

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

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

[0023] Preferably, the organic solvent is acetonitrile.

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

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

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

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

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

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

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

[0033] Preferably, 465nm 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, the SF6 gas pressure is 1 atm during the reaction. The product yield is highest when the gas pressure is 1 atm.

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

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

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

[0039] Preferably, during the reaction, the decomposition products of SF6 are used as condensing agents.

[0040] The advantages of this invention are:

[0041] In this invention, readily available diethylamine and 3-methylbenzoic acid are used as reaction substrates, commercially available Ir[dF(CF3)ppy]2(dtbbpy)PF6 is used as a photocatalyst, and inexpensive and readily available N,N-diisopropylethylamine is used as a basic substance. DEET is synthesized simply and efficiently under SF6 gas. This invention features mild reaction conditions, inexpensive and readily available raw materials, cost-effectiveness, environmental friendliness, and industrial applicability. This method effectively activates and utilizes SF6, a greenhouse gas, and fully utilizes the decomposition products of SF6 to achieve the amidation reaction of carboxylic acids to prepare DEET, turning SF6 waste into a valuable resource. The required raw materials are simple and readily available, the reaction conditions are simple, green, and energy-saving, and it has high application value. Attached Figure Description

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

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

[0044] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0045] Unless otherwise specified, all test materials and reagents used in the following examples are commercially available.

[0046] Unless otherwise specified in the embodiments, the techniques or conditions described in the literature in this field or in accordance with the product manual may be followed.

[0047] All raw materials used in the following specific examples are commercially available, and each reagent is purified using methods known in the art when necessary.

[0048] 1 H NMR and 13 All C NMR measurements were performed using a Bruker Avance 400 spectrometer. The test temperature was room temperature, and the solvent was deuterated chloroform. (Reference selection follows.) 1 ¹H NMR: CHCl₃ was 7.260 ppm; 13C NMR: CHCl3 was 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 vial with a PTFE gasket. After evacuation, an SF6 balloon was inserted, followed by the addition of 3.0 mL of anhydrous acetonitrile and bubbling for 3 minutes. Then, diethylamine (517.3 μL) and N,N-diisopropylethylamine (434.6 μL) were added. The reaction system was placed under a 15 W, 465 nm blue LED light source and irradiated at room temperature with stirring for 20 hours, with stirring under SF6 gas at one atmosphere. After the reaction was complete, the organic solvent was removed under vacuum, and N,N-diethyl-3-methylbenzamide, i.e., DEET 64.9 mg, was obtained by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 3:1), with a yield of 68%.

[0052] Product N,N-diethyl-3-methylbenzamide The NMR spectrum is as follows 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 shown in Example 1, this invention uses readily available 3-methylbenzoic acid and diethylamine as reaction substrates, commercially available Ir[dF(CF3)ppy]2(dtbbpy)PF6 as a photocatalyst, and inexpensive and readily available N,N-diisopropylethylamine as a basic substance. Under SF6 gas at one atmosphere, at room temperature, and using 15W 465nm blue light as the light source, DEET was synthesized simply and efficiently. This method is a mild, simple, and easily industrially applicable synthesis method for DEET. Furthermore, this method effectively activates and utilizes SF6, a greenhouse gas, fully utilizing the decomposition products of SF6 to achieve the amidation reaction of carboxylic acids to prepare DEET, turning SF6 waste into a valuable resource.

[0054] Example 2-10

[0055] Examples 2-10 prepared DEET using the preparation method of Example 1, differing only in the types of solvent, photocatalyst, and additives. The specific types of solvent, photocatalyst, and additives used in each example are shown in the table below:

[0056]

[0057]

[0058] The structural formulas of the catalysts used in each embodiment are shown below:

[0059]

[0060] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate 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 DEET is obtained by reacting diethylamine and 3-methylbenzoic acid with an organic solvent as the reaction solvent under light irradiation in the presence of a photocatalyst, an alkaline substance, and sulfur hexafluoride. The photocatalyst is one or a mixture of Ir[dF(CF3)ppy]2(dtbbpy)PF6, Ir(dtbbpy)ppy2PF6, 4DPAIPN, 3CzFIPN, 4CzIPN, 5CzBN, and 3DPA2FBN. During the irradiation process, blue light with a wavelength of 450-480nm is used as the light source.

2. The method for preparing DEET by carboxylic acid amidation according to claim 1, characterized in that: Includes the following steps: 3-Methylbenzoic acid and a photocatalyst were added to a reaction apparatus. After evacuation, an organic solvent was added, sulfur hexafluoride gas was introduced, and then diethylamine and an alkaline substance were added. The reaction system was placed under a light source to obtain the DEET.

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

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

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

1.

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

10.

7. 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℃, and the time is 5~48h.

8. The method for preparing DEET by carboxylic acid amidation according to any one of claims 1-7, characterized in that: The ratio of 3-methylbenzoic acid to organic solvent is 0.5~0.1 mmol: 1 mL.

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