A class of fluorinated benzoyl diethylamine compounds with mosquito-repellent properties, their methods, and their application in mosquito repellents.

Abstract

This invention belongs to the field of compound technology and discloses a class of fluorinated benzoyl diethylamine compounds with mosquito-repellent effects. The general structural formula of the fluorinated benzoyl diethylamine compounds is as follows: In Formula I, R1-R5 are individually or collectively selected from any one of hydrogen, fluorine, methyl, and trifluoromethyl, and at least one of R1-R5 groups contains fluorine. The fluorinated benzoyl diethylamine compounds of this invention have a significant repellent effect on mosquitoes at a mass concentration of 1% and an application dose of 0.04 mg / cm³. 2 Under the given conditions, the most active compound provided effective protection against mosquitoes for 162 minutes, which is twice as long as DEET.

Description

Technical Field

[0001] This invention belongs to the field of compound technology, and in particular to a class of fluorinated benzoyl diethylamine compounds with mosquito-repellent properties, methods, and applications in mosquito repellents. Background Technology

[0002] Mosquitoes are vectors for several dangerous diseases, including malaria, dengue fever, and Zika virus. These diseases cause millions of infections and deaths worldwide. Reducing the frequency of contact between mosquito vectors and their human hosts is the most effective way to control the spread of these vector-borne diseases.

[0003] Mosquito repellents serve this purpose by significantly reducing the chances of mosquitoes coming into contact with human skin, thus decreasing the likelihood of being bitten. Mosquito repellents are broadly classified into two categories based on their origin: synthetic repellents and natural repellents. Both natural and synthetic repellents work by creating a vapor layer on the skin. This vapor has an unpleasant odor for insects, causing them to change their path and avoid contact with their host. Many effective mosquito repellents contain synthetic chemicals, such as N,N-diethyl-m-toluamide (DEET), also known as DEET, which is the most widely used and highly effective broad-spectrum mosquito repellent ingredient. It provides a strong and long-lasting repellency against a variety of mosquitoes. Although DEET has relatively high toxicity, it is a reference repellent used by the World Health Organization because it provides effective and long-lasting repellency. A recommended concentration of 7-10% DEET provides a short-term repellent effect (up to 2 hours), while 20-30% DEET provides a longer-lasting effect (up to 6 hours). Besides DEET, other commonly used repellents on the market include Icaridin and IR3535. Icaridin, developed by Bayer AG in Germany, is an effective repellent against mosquitoes, flies, bees, ticks, and fleas, with particularly good repellency against Aedes mosquitoes. Repellent concentrations start at 5%. The recommended dosage for short-term protection (3 to 5 hours) is 5% to 10%, and for long-term protection (10 hours) it is 20%. IR3535 is an oily organic liquid that is volatile at normal pressure and room temperature, slightly soluble in water but soluble in organic solvents. It is odorless and transparent. Repellent effects are observed at concentrations exceeding 10% in formulations, and use is permitted at concentrations between 10% and 30%. It is chemically stable under operating conditions and exhibits high thermal stability. Its repellency is lower than that of DEET, but it has better biocompatibility and can be used to develop topical repellent formulations for children over 6 months of age and pregnant women.

[0004] However, despite their effectiveness, these repellents have some drawbacks. Most commonly used mosquito repellent ingredients have high concentrations, with high concentrations of DEET easily absorbed through the skin and penetrating the skin barrier to reach deeper blood vessels. Therefore, pregnant women should avoid prolonged exposure to high concentrations of DEET. Excessive DEET in the blood can also cause adverse reactions such as central nervous system toxicity, encephalopathy, seizures, and rashes, including contact urticaria, skin rashes, or toxic encephalopathy in children aged 10-12. IR3535 is also not recommended for pure application to the skin due to its poor feel and high skin penetration. Furthermore, picaridin has been reported to cause eye and skin irritation in sensitive individuals and discoloration of materials and animal leather clothing. For a long time, people have used chemical mosquito repellents to reduce the risk of mosquito bites and disease transmission. However, prolonged use of the same repellent has led to mosquitoes developing resistance to these chemicals. This has led to previously effective mosquito repellents becoming less efficient. Therefore, continuous research is needed to develop new mosquito repellents to reduce the effective concentration of repellent compounds, extend the duration of protection, address drug resistance issues, and mitigate the potential negative environmental and human health impacts of some traditional chemical mosquito repellents. Currently, most mosquito repellents in China are formulations of existing active ingredients. Therefore, focusing on the research and development of new compounds, while improving the physicochemical properties of formulations (such as improving sustained-release properties and controlling skin absorption and evaporation), and finding more environmentally friendly alternatives to mosquito repellents, is an effective way to ensure that people can still effectively prevent mosquito bites.

[0005] Mosquito bites are not only a health issue but also affect people's comfort and quality of life. Therefore, developing effective mosquito repellents has been a focus of public attention. These factors have collectively driven progress in mosquito repellent research, aiming to provide people with safer and more effective methods of mosquito control. Thus, this work is crucial for public health and helps create a safer and healthier living environment. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of the prior art and provide a class of fluorinated benzoyl diethylamine compounds with mosquito-repellent effect, a method thereof, and its application in mosquito repellents.

[0007] The technical solution adopted by this invention to solve its technical problem is:

[0008] A class of fluorinated benzoyl diethylamine compounds with mosquito-repellent properties, the general structural formula of which is as follows:

[0009]

[0010] In Formula I, R1-R5 are individually or collectively selected from any one of hydrogen, fluorine, methyl, and trifluoromethyl, and at least one of R1-R5 contains fluorine.

[0011] Further, the fluorinated benzoyl diethylamine compounds are N,N-diethyl-3-fluoro-5-methylbenzamide, N,N-diethyl-3-fluoro-5-(trifluoromethyl)benzamide, N,N-diethyl-4-fluoro-2-trifluoromethylbenzamide, N,N-diethyl-3,5-bis(trifluoromethyl)benzamide, N,N-diethyl-3,5-difluorobenzamide, N,N-diethyl-3-(trifluoromethyl)benzamide, N,N-diethyl- 3,4,5-Trifluorobenzamide, N,N-Diethyl-2-(trifluoromethyl)benzamide, N,N-Diethyl-3-fluorobenzamide, N,N-Diethyl-4-(trifluoromethyl)benzamide, N,N-Diethyl-5-fluoro-2-methylbenzamide, N,N-Diethyl-3-fluoro-4-methylbenzamide, N,N-Diethyl-2,3,4,5,6-pentafluorobenzamide, N,N-Diethyl-2,6-difluoro-3-methylbenzamide;

[0012] The structural formula of N,N-diethyl-3-fluoro-5-methylbenzamide (F-1001) is as follows:

[0013] The structural formula of N,N-diethyl-3-fluoro-5-(trifluoromethyl)benzamide (F-1002) is:

[0014] The structural formula of N,N-diethyl-4-fluoro-2-trifluoromethylbenzamide (F-1003) is:

[0015] The structural formula of N,N-diethyl-3,5-bis(trifluoromethyl)benzamide (F-1004) is:

[0016] The structural formula of N,N-diethyl-3,5-difluorobenzamide (F-1005) is: The structural formula of N,N-diethyl-3-(trifluoromethyl)benzamide (F-1006) is: The structural formula of N,N-diethyl-3,4,5-trifluorobenzamide (F-1007) is: The structural formula of N,N-diethyl-2-(trifluoromethyl)benzamide (F-1008) is: The structural formula of N,N-diethyl-3-fluorobenzamide (F-1009) is: The structural formula of N,N-diethyl-4-(trifluoromethyl)benzamide (F-1010) is: The structural formula of N,N-diethyl-5-fluoro-2-methylbenzamide (F-1011) is: The structural formula of N,N-diethyl-3-fluoro-4-methylbenzamide (F-1012) is: The structural formula of N,N-diethyl-2,3,4,5,6-pentafluorobenzamide (F-1014) is: The structural formula of N,N-diethyl-2,6-difluoro-3-methylbenzamide (F-1015) is: The use of fluorinated benzoyl diethylamine compounds as described above in the preparation of mosquito repellents.

[0017] The synthetic route for the fluorinated benzoyl diethylamine compounds described above is as follows:

[0018]

[0019] Furthermore, the specific steps are as follows:

[0020] Weigh out benzoic acid raw material and place it in a dry, pressure-resistant bottle. Add thionyl chloride and N,N-dimethylformamide. Stir the mixture in an oil bath at 80°C for 3 hours. The solid powder gradually dissolves and the system becomes clear. After stirring, transfer the system to a dry round-bottom flask, evaporate the solvent, and leave a pale yellow-green liquid in the flask, which is reaction solution 1. The ratio of benzoic acid raw material: thionyl chloride: N,N-dimethylformamide is 1:2:20 (g:mL:μL).

[0021] Diethylamine and dichloromethane were added to a dry round-bottom flask and the mixture was thoroughly frozen in an ice bath. Reaction solution 1 was slowly added dropwise. During the addition, a solid was formed, white fumes were emitted, and a slight sound was heard. Stirring was stopped 5 minutes after the addition was completed. The reaction system was transferred to a separatory funnel, the reaction solution was washed once with water, and the layers were allowed to stand. The organic phase was collected, and the aqueous phase was back-extracted with ethyl acetate. The layers were allowed to stand, and the organic phases obtained from the two extractions were combined. The mixture was dried over anhydrous Na2SO4, and the solvent was evaporated to obtain the crude product. The crude product was obtained by silica gel column chromatography. Fluorobenzoyl diethylamine compounds were obtained.

[0022] The ratio of diethylamine: dichloromethane: reaction solution 1 (g:mL:g) is 0.52-0.92:4:1.

[0023] The advantages and positive effects of this invention are as follows:

[0024] 1. The fluorinated benzoyl diethylamine compounds of this invention have a significant repellent effect on mosquitoes, as shown in Table 1. At a mass concentration of 1% and an application dose of 0.04 mg / cm³, the repellent effect is significant. 2Under these conditions, compound F-1001 exhibits 100% protection for up to 162 minutes, providing twice the effective protection time compared to DEET, the gold standard for mosquito repellents.

[0025] 2. The protection time of the 14 compounds is shown in [reference needed]. Figure 15 Among them, compound F-1015 has an effective protection time of 138.5 minutes, which is 1.62 times that of DEET, the gold standard for mosquito repellents. Compounds F-10071 and F-1011 have effective protection times of 89.5 minutes and 90.5 minutes, respectively, which are comparable to the protection time of DEET.

[0026] 3. This invention provides a drug design approach, demonstrating that introducing fluorine-containing groups to alter the electron cloud distribution on the benzene ring is feasible and effective. Introducing fluorine atoms often enhances the bioactivity of target compounds, making it an effective structural modification method. This invention further reveals the increasingly important role of fluorine-containing compounds in medicinal chemistry.

[0027] 4. The design of the novel mosquito repellent compound in this invention helps to overcome the problem of drug resistance in existing mosquito repellent compounds, providing new ideas for developing more efficient mosquito repellents and showing good application prospects.

[0028] 5. The compounds discovered in this invention can be used as mosquito repellents in mosquito repellent products, such as mosquito repellent patches, electric mosquito coils, mosquito repellent bracelets, and mosquito repellent liquids. Attached Figure Description

[0029] Figure 1 The present invention refers to N,N-diethyl-3-fluoro-5-methylbenzamide (F-1001). 1 H nuclear magnetic resonance spectrum ( 1 HNMR(400MHz,Chloroform-d)δ6.84(s,1H),6.75(t,J=9.3Hz,2H),3.39(s,2H),3.13(s,2H),2.23(s,3H),1.11(s,3H),0.98(s,3H).);

[0030] Figure 2 The present invention refers to N,N-diethyl-3-fluoro-5-(trifluoromethyl)benzamide (F-1002). 1 H nuclear magnetic resonance spectrum ( 1 HNMR (400MHz, Chloroform-d) δ7.37 (s, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.21 (d, J = 9. 5Hz,1H),3.48(d,J=8.0Hz,2H),3.16(d,J=7.9Hz,2H),1.13(d,J=44.9Hz,6H).);

[0031] Figure 3 The present invention refers to N,N-diethyl-4-fluoro-2-trifluoromethylbenzamide (F-1003). 1 H nuclear magnetic resonance spectrum ( 1 HNMR(400MHz,Chloroform-d)δ7.36–7.14(m,3H),3.74(dd,J=14.2,7.2Hz,1H),3.19(q ,J=7.3Hz,1H),3.00(t,J=7.7Hz,2H),1.14(q,J=4.5,4.0Hz,3H),1.02–0.92(m,3H).);

[0032] Figure 4 The present invention refers to N,N-diethyl-3,5-bis(trifluoromethyl)benzamide (F-1004). 1 H nuclear magnetic resonance spectrum ( 1 HNMR(400MHz,Chloroform-d)δ7.81(s,1H),7.75(s,2H),3.45(s,2H),3.14(s,2H),1.15(s,3H),1.03(s,3H).);

[0033] Figure 5 The present invention refers to N,N-diethyl-3,5-difluorobenzamide (F-1005). 1 H nuclear magnetic resonance spectrum ( 1 H NMR (400MHz, Chloroform-d) δ6.94–6.66(m,3H),3.41(s,2H),3.15(s,2H),1.13(s,3H),1.02(s,3H).);

[0034] Figure 6 The present invention refers to N,N-diethyl-3-(trifluoromethyl)benzamide (F-1006). 1 H nuclear magnetic resonance spectrum ( 1 HNMR(400MHz,Chloroform-d)δ7.57(d,J=5.8Hz,2H),7.51–7.40(m,2H),3.48(s,2H),3.13(s,2H),1.17(s,3H),1.03(s,3H).);

[0035] Figure 7 The present invention refers to N,N-diethyl-3,4,5-trifluorobenzamide (F-1007). 1 H nuclear magnetic resonance spectrum ( 1HNMR(400MHz,Chloroform-d)δ6.95(t,J=6.8Hz,2H),3.41(s,2H),3.19(s,2H),1.09(s,6H).);

[0036] Figure 8 The present invention refers to N,N-diethyl-2-(trifluoromethyl)benzamide (F-1008). 1 H nuclear magnetic resonance spectrum ( 1 HNMR(400MHz,Chloroform-d)δ7.60(d,J=7.9Hz,1H),7.50(t,J=7.5Hz,1H),7.41(t,J=7.7Hz,1H),7.25(d,J=7.5Hz,1H),3.77(d q,J=14.2,7.2Hz,1H),3.19(dq,J=14.0,7.1Hz,1H),3.00(qd,J=7.2,4.8Hz,2H),1.15(t,J=7.2Hz,3H),0.96(t,J=7.1Hz,3H).);

[0037] Figure 9 The present invention refers to N,N-diethyl-3-fluorobenzamide (F-1009). 1 H nuclear magnetic resonance spectrum ( 1 H NMR (400MHz, Chloroform-d) δ7.17(q,J=7.4Hz,1H),6.94(d,J=7.6Hz,1H),6.88(d,J=8.8Hz,2H),3.32(s,2H),3.02(s,2H),1.02(s,3H),0.90(s,3H).);

[0038] Figure 10 The present invention refers to N,N-diethyl-4-(trifluoromethyl)benzamide (F-1010). 1 H nuclear magnetic resonance spectrum ( 1 HNMR(400MHz,Chloroform-d)δ7.51(d,J=8.0Hz,2H),7.36(d,J=8.0Hz,2H),3.40(d,J=7.5Hz,2H),3.06(d,J=7.4Hz,2H),1.09(s,3H),0.93(s,3H).);

[0039] Figure 11 The present invention refers to N,N-diethyl-5-fluoro-2-methylbenzamide (F-1011). 1 H nuclear magnetic resonance spectrum ( 1HNMR(400MHz,Chloroform-d)δ7.05(dd,J=8.5,5.4Hz,1H),6.83(td,J=8.5,2.8Hz,1H),6.76(dd,J=8.5,2.8Hz, 1H),3.44(d,J=100.2Hz,2H),3.01(q,J=7.1Hz,2H),2.12(s,3H),1.13(t,J=7.2Hz,3H),0.92(t,J=7.1Hz,3H).);

[0040] Figure 12 The present invention refers to N,N-diethyl-3-fluoro-4-methylbenzamide (F-1012). 1 H nuclear magnetic resonance spectrum ( 1 HNMR(400MHz,Chloroform-d)δ7.00–6.52(m,3H),2.73(d,J=81.5Hz,4H),1.77(s,2H),0.72(s,6H).);

[0041] Figure 13 The present invention refers to N,N-diethyl-2,3,4,5,6-pentafluorobenzamide (F-1014). 1 H nuclear magnetic resonance spectrum ( 1 HNMR (400MHz, Chloroform-d) δ3.49(q,J=7.1Hz,2H),3.16(q,J=7.2Hz,2H),1.16(t,J=7.2Hz,3H),1.04(t,J=7.2Hz,3H).);

[0042] Figure 14 The present invention refers to N,N-diethyl-2,6-difluoro-3-methylbenzamide (F-1015). 1 H nuclear magnetic resonance spectrum ( 1 HNMR (400MHz, Chloroform-d) δ3.51–3.39(m,2H),3.09(q,J=7.1Hz,2H),2.09(s,3H),1.11(t,J=7.1Hz,3H),0.95(t,J=7.2Hz,3H).);

[0043] Figure 15 The diagram shows the space repellency effect of 14 compounds in this invention (with effective protection time as the activity evaluation index);

[0044] Figure 16 The present invention refers to N,N-diethyl-3-fluoro-5-methylbenzamide (F-1001). 13 C NMR spectrum ( 13C NMR(101MHz,Chloroform-d)δ169.63,163.45,161.00,138.94,138.86,122.50, 122.48,116.46,116.25,110.33,110.10,43.08,39.10,20.98,13.94,12.61.);

[0045] Figure 17 The present invention refers to N,N-diethyl-3-fluoro-5-(trifluoromethyl)benzamide (F-1002). 13 C NMR spectrum ( 13 CNMR(101MHz,Chloroform-d)δ163.45,160.95,140.37,140.30,133.07,132.99,132.74,132.66,126.94,124.23,121.52,121 .49,119.15,119.11,119.08,119.04,117.25,117.03,113.60,113.39,113.35,113.32,113.28,43.31,39.54,14.00,12.64.);

[0046] Figure 18 The present invention refers to N,N-diethyl-4-fluoro-2-trifluoromethylbenzamide (F-1003). 13 C NMR spectrum ( 13 CNMR(101MHz,Chloroform-d)δ167.17,163.22,160.73,131.94,129.35,128.91,128.83,128.51, 124.19,124.16,121.47,121.44,119.28,119.07,114.33,114.08,42.85,38.78,13.40,11.98.);

[0047] Figure 19 The present invention refers to N,N-diethyl-3,5-bis(trifluoromethyl)benzamide (F-1004). 13 C NMR spectrum ( 13CNMR(101MHz,Chloroform-d)δ167.85,139.21,132.30,131.97,131.63,131.30,126.92,126.66,126 .59,124.21,122.79,122.75,122.71,122.67,122.64,121.50,118.79,43.29,39.56,13.71,12.37.);

[0048] Figure 20 The present invention refers to N,N-diethyl-3,5-difluorobenzamide (F-1005). 13 C NMR spectrum ( 13 CNMR(101MHz,Chloroform-d)δ168.22,164.04,163.91,161.54,161.42,140 .34,109.60,109.34,104.62,104.37,104.12,43.12,39.32,13.94,12.56.);

[0049] Figure 21 The present invention refers to N,N-diethyl-3-(trifluoromethyl)benzamide (F-1006). 13 C NMR spectrum ( 13 CNMR(101MHz,Chloroform-d)δ169.23,137.96,130.96,130.64,130.31,129.99,129.42,128.85,127.66,125.54, 125.50,125.47,125.43,124.96,123.10,123.06,123.02,122.98,122.25,119.54,43.05,39.18,13.64,12.35.);

[0050] Figure 22 The present invention refers to N,N-diethyl-3,4,5-trifluorobenzamide (F-1007). 13 C NMR spectrum ( 13 CNMR (125MHz, Common NMR Solvents) δ169.53,151.24,151.18,149.22,149.16,145.82,143.81,132.74,112.67,41.39,13.41.);

[0051] Figure 23 The present invention refers to N,N-diethyl-2-(trifluoromethyl)benzamide (F-1008). 13C NMR spectrum ( 13 CNMR(101MHz,Chloroform-d)δ167.93,135.59,135.57,131.97,128.73,127.79,126 .43,126.29,126.08,125.76,125.07,122.34,119.62,42.68,38.48,13.18,11.86.);

[0052] Figure 24 The present invention refers to N,N-diethyl-3-fluorobenzamide (F-1009). 13 C NMR spectrum ( 13 C NMR (101MHz, Chloroform-d) δ169.39,163.51,161.05,139.18,130.16,121.82,115.74,113.49,43.09,39.17,13.92,12.60.);

[0053] Figure 25 The present invention refers to N,N-diethyl-4-(trifluoromethyl)benzamide (F-1010). 13 C NMR spectrum ( 13 CNMR(101MHz,Chloroform-d)δ169.81,140.76,131.23,130.91,130.58,125.55,125.51,125.47,125.14,122.44,43.25,39.37,14.10,12.77.);

[0054] Figure 26 The present invention refers to N,N-diethyl-5-fluoro-2-methylbenzamide (F-1011). 13 C NMR spectrum ( 13 C NMR (101MHz, Chloroform-d) δ169.12,161.85,159.41,138.42,131.74,129.35,115.03,112.09,42.46,38.65,17.75,13.75.);

[0055] Figure 27 The present invention refers to N,N-diethyl-3-fluoro-4-methylbenzamide (F-1012). 13 C NMR spectrum ( 13C NMR(101MHz,Chloroform-d)δ169.11,161.62,159.18,136.36,131.12,131.06, 125.32,125.25,121.55,121.50,112.89,112.74,42.91,39.02,13.67,12.41.);

[0056] Figure 28 The present invention refers to N,N-diethyl-2,3,4,5,6-pentafluorobenzamide (F-1014). 13 C NMR spectrum ( 13 CNMR(101MHz,Chloroform-d)δ157.45,143.67,142.71,141.40,141.32,141.24,141.20,140.17,138.78, 138.72,138.65,138.59,136.42,136.36,136.29,136.23,136.08,111.76,43.12,39.60,13.51,12.19.);

[0057] Figure 29 The present invention refers to N,N-diethyl-2,6-difluoro-3-methylbenzamide (F-1015). 13 C NMR spectrum ( 13 CNMR(101MHz,Chloroform-d)δ161.09,157.72,157.55,155.36,155.28,155.10,131.51, 120.78,120.74,114.38,114.13,113.89,110.77,110.73,42.89,39.08,13.56,12.48.); Detailed Implementation

[0058] The present invention will be further described below with reference to the embodiments. The following embodiments are descriptive and not limiting, and should not be used to limit the scope of protection of the present invention.

[0059] The various experimental operations involved in the specific embodiments are all conventional techniques in the field. For parts not specifically annotated in this document, those skilled in the art can refer to various commonly used reference books, scientific and technological documents or related instructions and manuals prior to the filing date of this invention to carry out the operations.

[0060] A class of fluorinated benzoyl diethylamine compounds with mosquito-repellent properties, the general structural formula of which is as follows:

[0061]

[0062] In Formula I, R1-R5 are individually or collectively selected from any one of hydrogen, fluorine, methyl, and trifluoromethyl, and at least one of R1-R5 contains fluorine.

[0063] Preferably, the fluorinated benzoyl diethylamine compound is N,N-diethyl-3-fluoro-5-methylbenzamide, N,N-diethyl-3-fluoro-5-(trifluoromethyl)benzamide, N,N-diethyl-4-fluoro-2-trifluoromethylbenzamide, N,N-diethyl-3,5-bis(trifluoromethyl)benzamide, N,N-diethyl-3,5-difluorobenzamide, N,N-diethyl-3-(trifluoromethyl)benzamide, N,N-diethyl-3,4,5-trifluorobenzamide, N,N-diethyl... The following are listed: N,N-diethyl-2-(trifluoromethyl)benzamide, N,N-diethyl-3-fluorobenzamide, N,N-diethyl-4-(trifluoromethyl)benzamide, N,N-diethyl-5-fluoro-2-methylbenzamide, N,N-diethyl-3-fluoro-4-methylbenzamide, N,N-diethyl-2,3,4,5,6-pentafluorobenzamide, and N,N-diethyl-2,6-difluoro-3-methylbenzamide; among which, the structural formula of N,N-diethyl-3-fluoro-5-methylbenzamide (F-1001) is: The structural formula of N,N-diethyl-3-fluoro-5-(trifluoromethyl)benzamide (F-1002) is: The structural formula of N,N-diethyl-4-fluoro-2-trifluoromethylbenzamide (F-1003) is: The structural formula of N,N-diethyl-3,5-bis(trifluoromethyl)benzamide (F-1004) is: The structural formula of N,N-diethyl-3,5-difluorobenzamide (F-1005) is: The structural formula of N,N-diethyl-3-(trifluoromethyl)benzamide (F-1006) is: The structural formula of N,N-diethyl-3,4,5-trifluorobenzamide (F-1007) is: The structural formula of N,N-diethyl-2-(trifluoromethyl)benzamide (F-1008) is: The structural formula of N,N-diethyl-3-fluorobenzamide (F-1009) is: The structural formula of N,N-diethyl-4-(trifluoromethyl)benzamide (F-1010) is:

[0064] The structural formula of N,N-diethyl-5-fluoro-2-methylbenzamide (F-1011) is:

[0065] The structural formula of N,N-diethyl-3-fluoro-4-methylbenzamide (F-1012) is:

[0066] The structural formula of N,N-diethyl-2,3,4,5,6-pentafluorobenzamide (F-1014) is:

[0067] The structural formula of N,N-diethyl-2,6-difluoro-3-methylbenzamide (F-1015) is:

[0068] The use of fluorinated benzoyl diethylamine compounds as described above in the preparation of mosquito repellents.

[0069] The synthetic route for the fluorinated benzoyl diethylamine compounds described above is as follows:

[0070]

[0071] Preferably, the specific steps are as follows:

[0072] Weigh out benzoic acid raw material and place it in a dry, pressure-resistant bottle. Add thionyl chloride and N,N-dimethylformamide. Stir the mixture in an oil bath at 80°C for 3 hours. The solid powder gradually dissolves and the system becomes clear. After stirring, transfer the system to a dry round-bottom flask, evaporate the solvent, and leave a pale yellow-green liquid in the flask, which is reaction solution 1. The ratio of benzoic acid raw material: thionyl chloride: N,N-dimethylformamide is 1:2:20 (g:mL:μL).

[0073] Diethylamine and dichloromethane were added to a dry round-bottom flask and the mixture was thoroughly frozen in an ice bath. Reaction solution 1 was slowly added dropwise. During the addition, a solid was formed, white fumes were emitted, and a slight sound was heard. Stirring was stopped 5 minutes after the addition was completed. The reaction system was transferred to a separatory funnel, the reaction solution was washed once with water, and the layers were allowed to stand. The organic phase was collected, and the aqueous phase was back-extracted with ethyl acetate. The layers were allowed to stand, and the organic phases obtained from the two extractions were combined. The mixture was dried over anhydrous Na2SO4, and the solvent was evaporated to obtain the crude product. The crude product was obtained by silica gel column chromatography. Fluorobenzoyl diethylamine compounds were obtained.

[0074] The ratio of diethylamine: dichloromethane: reaction solution 1 (g:mL:g) is 0.52-0.92:4:1.

[0075] Specifically, the relevant preparation and testing methods are as follows:

[0076] Example 1. Preparation of N,N-diethyl-3-fluoro-5-methylbenzamide (F-1001)

[0077] 1.1 Synthetic Route

[0078]

[0079] 1.2 Synthesis Method

[0080] Weigh 1.00 g (6.48 mol) of 3-fluoro-5-methylbenzoic acid into a dry 100 mL pressure-resistant bottle, and add 2 mL of thionyl chloride and 20 μL of N,N-dimethylformamide. Stir the mixture in an oil bath at 80 °C for 3 h. The solid powder gradually dissolves, and the system becomes clear. After stirring, transfer the system to a dry 50 mL round-bottom flask, evaporate the solvent, and leave a pale yellow-green liquid, which is reaction solution 1. Add 0.84 g (11.58 mol) of diethylamine and 4 mL of dichloromethane to a dry 50 mL round-bottom flask. After freezing thoroughly in an ice bath, slowly add reaction solution 1 (1.00 g, 5.79 mol). During the addition, a solid is formed, white fumes are emitted, and a slight hissing sound is heard. Stop stirring 5 minutes after the addition is complete. The reaction solution was washed with water, allowed to stand and separate into layers, and the organic phase was collected. The aqueous phase was back-extracted with ethyl acetate, allowed to stand and separate into layers, and the organic phases were combined and dried over anhydrous Na₂SO₄ to remove the solvent. Silica gel column chromatography was performed with petroleum ether:ethyl acetate in a 3:1 ratio. The product was a clear liquid, 450 mg, yield 58%.

[0081] 1.3 Experimental Results

[0082] The products were analyzed using a Bruker AV400 nuclear magnetic resonance spectrometer with CDCl3 as the solvent. 1 HNMR analysis, spectrum shown in [reference] Figure 1 ,in: 1 HNMR(400MHz,Chloroform-d)δ6.84(s,1H),6.75(t,J=9.3Hz,2H),3.39(s,2H),3.13(s,2H),2.23(s,3H),1.11(s,3H),0.98(s,3H).

[0083] Example 2. Preparation of N,N-diethyl-3-fluoro-5-(trifluoromethyl)benzamide (F-1002)

[0084] 2.1 Synthetic Route

[0085]

[0086] 2.2 Synthesis Method

[0087] Weigh 1.00 g (4.80 mol) of 3-fluoro-5-(trifluoromethyl)benzoic acid into a dry 100 mL pressure-resistant bottle, and add 2 mL of thionyl chloride and 20 μL of N,N-dimethylformamide. Stir the mixture in an oil bath at 80 °C for 3 h. The solid powder gradually dissolves, and the system becomes clear. After stirring, transfer the system to a dry 50 mL round-bottom flask, evaporate the solvent, and leave a pale yellow-green liquid, which is reaction solution 1. Add 0.65 g (8.82 mol) of diethylamine and 4 mL of dichloromethane to a dry 50 mL round-bottom flask. After freezing thoroughly in an ice bath, slowly add reaction solution 1 (1.00 g, 4.41 mol). During the addition, a solid is formed, white fumes are emitted, and a slight hissing sound is heard. Stop stirring 5 minutes after the addition is complete. The reaction solution was washed with water, allowed to stand and separate into layers, and the organic phase was collected. The aqueous phase was back-extracted with ethyl acetate, allowed to stand and separate into layers, and the organic phases were combined and dried over anhydrous Na₂SO₄ to remove the solvent. Silica gel column chromatography was performed with petroleum ether:ethyl acetate in a 3:1 ratio. The product was a pale yellow liquid, 372 mg, in yield (48%).

[0088] 2.3 Experimental Results

[0089] The products were analyzed using a Bruker AV400 nuclear magnetic resonance spectrometer with CDCl3 as the solvent. 1 HNMR analysis, spectrum shown in [reference] Figure 2 ,in: 1 HNMR(400MHz,Chloroform-d)δ7.37(s,1H),7.30(d,J=8.3Hz,1H),7.21(d,J=9 .5Hz,1H),3.48(d,J=8.0Hz,2H),3.16(d,J=7.9Hz,2H),1.13(d,J=44.9Hz,6H).

[0090] Example 3. Preparation of N,N-diethyl-4-fluoro-2-trifluoromethylbenzamide (F-1003)

[0091] 3.1 Synthetic Route

[0092]

[0093] Weigh 1.00 g (4.80 mol) of 4-fluoro-2-trifluoromethylbenzoic acid into a dry 100 mL pressure-resistant bottle, and add 2 mL of thionyl chloride and 20 μL of N,N-dimethylformamide. Stir the mixture in an oil bath at 80 °C for 3 h. The solid powder gradually dissolves, and the system becomes clear. After stirring, transfer the system to a dry 50 mL round-bottom flask, evaporate the solvent, and leave a pale yellow-green liquid, which is reaction solution 1. Add 0.65 g (8.82 mol) of diethylamine and 4 mL of dichloromethane to a dry 50 mL round-bottom flask. After freezing thoroughly in an ice bath, slowly add reaction solution 1 (1.00 g, 4.41 mol). During the addition, a solid is formed, white fumes are emitted, and a slight hissing sound is heard. Stop stirring 5 minutes after the addition is complete. The reaction solution was washed with water, allowed to stand and separate into layers, and the organic phase was collected. The aqueous phase was back-extracted with ethyl acetate, allowed to stand and separate into layers, and the organic phases were combined and dried over anhydrous Na₂SO₄ to remove the solvent. Silica gel column chromatography was performed with petroleum ether:ethyl acetate in a 3:1 ratio. The product was a pale yellow liquid, 372 mg, in yield of 36%.

[0094] 3.3 Experimental Results

[0095] The products were analyzed using a Bruker AV400 nuclear magnetic resonance spectrometer with CDCl3 as the solvent. 1 HNMR analysis, spectrum shown in [reference] Figure 3 ,in: 1 H NMR(400MHz,Chloroform-d)δ7.36–7.14(m,3H),3.74(dd,J=14.2,7.2Hz,1H),3.19( q,J=7.3Hz,1H),3.00(t,J=7.7Hz,2H),1.14(q,J=4.5,4.0Hz,3H),1.02–0.92(m,3H).

[0096] Example 4. Preparation of N,N-diethyl-3,5-bis(trifluoromethyl)benzamide (F-1004)

[0097] 4.1 Synthetic Route

[0098]

[0099] 4.2 Synthesis Method

[0100] Weigh 1.00 g (3.87 mol) of 3,5-bis(trifluoromethyl)benzoic acid into a dry 100 mL pressure-resistant bottle, and add 2 mL of thionyl chloride and 20 μL of N,N-dimethylformamide. Stir the mixture in an oil bath at 80 °C for 3 h. The solid powder gradually dissolves, and the system becomes clear. After stirring, transfer the system to a dry 50 mL round-bottom flask, evaporate the solvent, and leave a pale yellow-green liquid, which is reaction solution 1. Add 0.52 g (7.20 mol) of diethylamine and 4 mL of dichloromethane to a dry 50 mL round-bottom flask. After freezing thoroughly in an ice bath, slowly add reaction solution 1 (1.00 g, 3.60 mol). During the addition, a solid is formed, white fumes are emitted, and a slight hissing sound is heard. Stop stirring 5 minutes after the addition is complete. The reaction solution was washed with water, allowed to stand and separate into layers, and the organic phase was collected. The aqueous phase was back-extracted with ethyl acetate, allowed to stand and separate into layers, and the organic phases were combined, dried over anhydrous Na₂SO₄, and the solvent was evaporated. Silica gel column chromatography was performed with petroleum ether:ethyl acetate in a 4:1 ratio. The product was a pale yellow liquid, 271 mg, in yield of 35%.

[0101] 4.3 Experimental Results

[0102] The products were analyzed using a Bruker AV400 nuclear magnetic resonance spectrometer with CDCl3 as the solvent. 1 HNMR analysis, spectrum shown in [reference] Figure 4 ,in: 1 HNMR(400MHz,Chloroform-d)δ7.81(s,1H),7.75(s,2H),3.45(s,2H),3.14(s,2H),1.15(s,3H),1.03(s,3H).

[0103] Example 5. Preparation of N,N-diethyl-3,5-difluorobenzamide (F-1005)

[0104] 5.1 Synthetic Route

[0105]

[0106] Weigh 1.00 g (6.30 mol) of 3,5-difluorobenzoic acid into a dry 100 mL pressure-resistant bottle, and add 2 mL of thionyl chloride and 20 μL of N,N-dimethylformamide. Stir the mixture in an oil bath at 80 °C for 3 h. The solid powder gradually dissolves, and the system becomes clear. After stirring, transfer the system to a dry 50 mL round-bottom flask, evaporate the solvent, leaving a pale yellow-green liquid, which is reaction solution 1. Add 0.83 g (11.30 mol) of diethylamine and 4 mL of dichloromethane to a dry 50 mL round-bottom flask. After freezing thoroughly in an ice bath, slowly add reaction solution 1 (1.00 g, 5.66 mol). During the addition, a solid is formed, white fumes are emitted, and a slight hissing sound is heard. Stop stirring 5 minutes after the addition is complete. The reaction solution was washed with water, allowed to stand and separate into layers, and the organic phase was collected. The aqueous phase was back-extracted with ethyl acetate, allowed to stand and separate into layers, and the organic phases were combined, dried over anhydrous Na₂SO₄, and the solvent was evaporated. Silica gel column chromatography was performed with petroleum ether:ethyl acetate in a 6:1 ratio. The product was a pale yellow liquid, 456 mg, in yield (60%).

[0107] 5.3 Experimental Results

[0108] The products were analyzed using a Bruker AV400 nuclear magnetic resonance spectrometer with CDCl3 as the solvent. 1 HNMR analysis, spectrum shown in [reference] Figure 5 ,in: 1 H NMR (400MHz, Chloroform-d) δ6.94–6.66(m,3H),3.41(s,2H),3.15(s,2H),1.13(s,3H),1.02(s,3H).

[0109] Example 6. Preparation of N,N-diethyl-3-(trifluoromethyl)benzamide (F-1006)

[0110] 6.1 Synthetic Route

[0111]

[0112] 6.2 Synthesis Method

[0113] Weigh 1.00 g (5.26 mol) of 3-(trifluoromethyl)benzoic acid into a dry 100 mL pressure-resistant bottle, and add 2 mL of thionyl chloride and 20 μL of N,N-dimethylformamide. Stir the mixture in an oil bath at 80 °C for 3 h. The solid powder gradually dissolves, and the system becomes clear. After stirring, transfer the system to a dry 50 mL round-bottom flask, evaporate the solvent, leaving a pale yellow-green liquid, which is reaction solution 1. Add 0.74 g (7.82 mol) of diethylamine and 4 mL of dichloromethane to a dry 50 mL round-bottom flask. After freezing thoroughly in an ice bath, slowly add reaction solution 1 (1.00 g, 4.79 mol). During the addition, a solid is formed, white fumes are emitted, and a slight hissing sound is heard. Stop stirring 5 minutes after the addition is complete. The reaction solution was washed with water, allowed to stand and separate into layers, and the organic phase was collected. The aqueous phase was back-extracted with ethyl acetate, allowed to stand and separate into layers, and the organic phases were combined and dried over anhydrous Na₂SO₄ to remove the solvent. Silica gel column chromatography was performed with petroleum ether:ethyl acetate in a 5:1 ratio. The product was a pale yellow liquid, 433 mg, in yield (57%).

[0114] 6.3 Experimental Results

[0115] The products were analyzed using a Bruker AV400 nuclear magnetic resonance spectrometer with CDCl3 as the solvent. 1 HNMR analysis, spectrum shown in [reference] Figure 6 ,in: 1 H NMR (400MHz, Chloroform-d) δ7.57(d,J=5.8Hz,2H),7.51–7.40(m,2H),3.48(s,2H),3.13(s,2H),1.17(s,3H),1.03(s,3H).

[0116] Example 7. Preparation of N,N-diethyl-3,4,5-trifluorobenzamide (F-1007)

[0117] 7.1 Synthetic Route

[0118]

[0119] 7.2 Synthesis Method

[0120] Weigh 1.00 g (5.70 mol) of 3,4,5-trifluorobenzoic acid into a dry 100 mL pressure-resistant bottle, and add 2 mL of thionyl chloride and 20 μL of N,N-dimethylformamide. Stir the mixture in an oil bath at 80 °C for 3 h. The solid powder gradually dissolves, and the system becomes clear. After stirring, transfer the system to a dry 50 mL round-bottom flask, evaporate the solvent, leaving a pale yellow-green liquid, which is reaction solution 1. Add 0.75 g (10.20 mol) of diethylamine and 4 mL of dichloromethane to a dry 50 mL round-bottom flask. After freezing thoroughly in an ice bath, slowly add reaction solution 1 (1.00 g, 5.10 mol). During the addition, a solid is formed, white fumes are emitted, and a slight hissing sound is heard. Stop stirring 5 minutes after the addition is complete. The reaction solution was washed with water, allowed to stand and separate into layers, and the organic phase was collected. The aqueous phase was back-extracted with ethyl acetate, allowed to stand and separate into layers, and the organic phases were combined, dried over anhydrous Na₂SO₄, and the solvent was evaporated. Silica gel column chromatography was performed with petroleum ether:ethyl acetate in a 4:1 ratio. The product was a pale yellow liquid, 418 mg, yield 55%.

[0121] 7.3 Experimental Results

[0122] The products were analyzed using a Bruker AV400 nuclear magnetic resonance spectrometer with CDCl3 as the solvent. 1 HNMR analysis, spectrum shown in [reference] Figure 7 ,in: 1 H NMR (400MHz, Chloroform-d) δ6.95 (t, J = 6.8Hz, 2H), 3.41 (s, 2H), 3.19 (s, 2H), 1.09 (s, 6H).

[0123] Example 8. Preparation of N,N-diethyl-2-(trifluoromethyl)benzamide (F-1008)

[0124] 8.1 Synthetic Route

[0125]

[0126] 8.2 Synthesis Method

[0127] Weigh 1.00 g (5.26 mol) of 2-(trifluoromethyl)benzoic acid into a dry 100 mL pressure-resistant bottle, and add 2 mL of thionyl chloride and 20 μL of N,N-dimethylformamide. Stir the mixture in an oil bath at 80 °C for 3 h. The solid powder gradually dissolves, and the system becomes clear. After stirring, transfer the system to a dry 50 mL round-bottom flask, evaporate the solvent, leaving a pale yellow-green liquid, which is reaction solution 1. Add 0.70 g (9.59 mol) of diethylamine and 4 mL of dichloromethane to the dry 50 mL round-bottom flask. After freezing thoroughly in an ice bath, slowly add reaction solution 1 (1.00 g, 4.79 mol). During the addition, a solid is formed, white fumes are emitted, and a slight hissing sound is heard. Stop stirring 5 minutes after the addition is complete. The reaction solution was washed with water, allowed to stand and separate into layers, and the organic phase was collected. The aqueous phase was back-extracted with ethyl acetate, allowed to stand and separate into layers, and the organic phases were combined and dried over anhydrous Na₂SO₄ to remove the solvent. Silica gel column chromatography was performed with petroleum ether:ethyl acetate in a 4:1 ratio. The product was a very clear liquid, 425 mg, yield 56%.

[0128] 8.3 Experimental Results

[0129] The products were analyzed using a Bruker AV400 nuclear magnetic resonance spectrometer with CDCl3 as the solvent. 1 HNMR analysis, spectrum shown in [reference] Figure 8 ,in: 1 H NMR(400MHz,Chloroform-d)δ7.60(d,J=7.9Hz,1H),7.50(t,J=7.5Hz,1H),7.41(t,J=7.7Hz,1H),7.25(d,J=7.5Hz,1H),3.77( dq,J=14.2,7.2Hz,1H),3.19(dq,J=14.0,7.1Hz,1H),3.00(qd,J=7.2,4.8Hz,2H),1.15(t,J=7.2Hz,3H),0.96(t,J=7.1Hz,3H).

[0130] Example 9. Preparation of N,N-diethyl-3-fluorobenzamide (F-1009)

[0131] 9.1 Synthetic Route

[0132]

[0133] 9.2 Synthesis Method

[0134] Weigh 1.00 g (7.10 mol) of 3-fluorobenzoic acid into a dry 100 mL pressure-resistant bottle, and add 2 mL of thionyl chloride and 20 μL of N,N-dimethylformamide. Stir the mixture in an oil bath at 80 °C for 3 h. The solid powder gradually dissolves, and the system becomes clear. After stirring, transfer the system to a dry 50 mL round-bottom flask, evaporate the solvent, leaving a pale yellow-green liquid, which is reaction solution 1. Add 0.92 g (12.60 mol) of diethylamine and 4 mL of dichloromethane to a dry 50 mL round-bottom flask. After freezing thoroughly in an ice bath, slowly add reaction solution 1 (1.00 g, 6.31 mol). During the addition, a solid is formed, white fumes are emitted, accompanied by a slight hissing sound. Stop stirring 5 minutes after the addition is complete. The reaction solution was washed with water, allowed to stand and separate into layers, and the organic phase was collected. The aqueous phase was back-extracted with ethyl acetate, allowed to stand and separate into layers, and the organic phases were combined and dried over anhydrous Na₂SO₄ to remove the solvent. Silica gel column chromatography was performed with petroleum ether:ethyl acetate in a 6:1 ratio. The product was a pale yellow liquid, 344 mg, in yield (44%).

[0135] 9.3 Experimental Results

[0136] The products were analyzed using a Bruker AV400 nuclear magnetic resonance spectrometer with CDCl3 as the solvent. 1 HNMR analysis, spectrum shown in [reference] Figure 9 ,in: 1 H NMR (400MHz, Chloroform-d) δ7.17(q,J=7.4Hz,1H),6.94(d,J=7.6Hz,1H),6.88(d,J=8.8Hz,2H),3.32(s,2H),3.02(s,2H),1.02(s,3H),0.90(s,3H).

[0137] Example 10. Preparation of N,N-diethyl-4-(trifluoromethyl)benzamide (F-1010)

[0138] 10.1 Synthesis Route

[0139]

[0140] 10.2 Synthesis Method

[0141] Weigh 1.00 g (5.26 mol) of 4-(trifluoromethyl)benzoic acid into a dry 100 mL pressure-resistant bottle, and add 2 mL of thionyl chloride and 20 μL of N,N-dimethylformamide. Stir the mixture in an oil bath at 80 °C for 3 h. The solid powder gradually dissolves, and the system becomes clear. After stirring, transfer the system to a dry 50 mL round-bottom flask, evaporate the solvent, leaving a pale yellow-green liquid, which is reaction solution 1. Add 0.70 g (9.59 mol) of diethylamine and 4 mL of dichloromethane to a dry 50 mL round-bottom flask. After freezing thoroughly in an ice bath, slowly add reaction solution 1 (1.00 g, 4.79 mol). During the addition, a solid is formed, white fumes are emitted, and a slight hissing sound is heard. Stop stirring 5 minutes after the addition is complete. The reaction solution was washed with water, allowed to stand and separate into layers, and the organic phase was collected. The aqueous phase was back-extracted with ethyl acetate, allowed to stand and separate into layers, and the organic phases were combined, dried over anhydrous Na₂SO₄, and the solvent was evaporated. Silica gel column chromatography was performed with petroleum ether:ethyl acetate in a 6:1 ratio. The product was a pale yellow liquid, 516 mg, in yield (68%).

[0142] 10.3 Experimental Results

[0143] The products were analyzed using a Bruker AV400 nuclear magnetic resonance spectrometer with CDCl3 as the solvent. 1 HNMR analysis, spectrum shown in [reference] Figure 10 ,in: 1 H NMR (400MHz, Chloroform-d) δ7.51(d,J=8.0Hz,2H),7.36(d,J=8.0Hz,2H),3.40(d,J=7.5Hz,2H),3.06(d,J=7.4Hz,2H),1.09(s,3H),0.93(s,3H).

[0144] Example 11. Preparation of N,N-diethyl-5-fluoro-2-methylbenzamide (F-1011)

[0145] 11.1 Synthetic Route

[0146]

[0147] 11.2 Synthesis Method

[0148] Weigh 1.00 g (6.49 mol) of 5-fluoro-2-methylbenzoic acid into a dry 100 mL pressure-resistant bottle, and add 2 mL of thionyl chloride and 20 μL of N,N-dimethylformamide. Stir the mixture in an oil bath at 80 °C for 3 h. The solid powder gradually dissolves, and the system becomes clear. After stirring, transfer the system to a dry 50 mL round-bottom flask, evaporate the solvent, and leave a pale yellow-green liquid, which is reaction solution 1. Add 0.85 g (11.59 mol) of diethylamine and 4 mL of dichloromethane to a dry 50 mL round-bottom flask. After freezing thoroughly in an ice bath, slowly add reaction solution 1 (1.00 g, 5.79 mol). During the addition, a solid is formed, white fumes are emitted, and a slight hissing sound is heard. Stop stirring 5 minutes after the addition is complete. The reaction solution was washed with water, allowed to stand and separate into layers, and the organic phase was collected. The aqueous phase was back-extracted with ethyl acetate, allowed to stand and separate into layers, and the organic phases were combined and dried over anhydrous Na₂SO₄ to remove the solvent. Silica gel column chromatography was performed with petroleum ether:ethyl acetate in a 5:1 ratio. The product was a pale yellow liquid, 440 mg, in yield (58%).

[0149] 11.3 Experimental Results

[0150] The products were analyzed using a Bruker AV400 nuclear magnetic resonance spectrometer with CDCl3 as the solvent. 1 HNMR analysis, spectrum shown in [reference] Figure 11 ,in: 1 H NMR (400MHz, Chloroform-d) δ7.05 (dd, J=8.5, 5.4Hz, 1H), 6.83 (td, J=8.5, 2.8Hz, 1H), 6.76 (dd, J=8.5, 2.8Hz, 1H), 3.44 (d, J = 100.2Hz, 2H), 3.01 (q, J = 7.1Hz, 2H), 2.12 (s, 3H), 1.13 (t, J = 7.2Hz, 3H), 0.92 (t, J = 7.1Hz, 3H).

[0151] Example 12. Preparation of N,N-diethyl-3-fluoro-4-methylbenzamide (F-1012)

[0152] 12.1 Synthetic Route

[0153]

[0154] 12.2 Synthesis Method

[0155] Weigh 1.00 g (6.49 mol) of 3-fluoro-4-methylbenzoic acid into a dry 100 mL pressure-resistant bottle, and add 2 mL of thionyl chloride and 20 μL of N,N-dimethylformamide. Stir the mixture in an oil bath at 80 °C for 3 h. The solid powder gradually dissolves, and the system becomes clear. After stirring, transfer the system to a dry 50 mL round-bottom flask, evaporate the solvent, leaving a pale yellow-green liquid, which is reaction solution 1. Add 0.85 g (11.59 mol) of diethylamine and 4 mL of dichloromethane to a dry 50 mL round-bottom flask. After freezing thoroughly in an ice bath, slowly add reaction solution 1 (1.00 g, 5.79 mol). During the addition, a solid is formed, white fumes are emitted, and a slight hissing sound is heard. Stop stirring 5 minutes after the addition is complete. The reaction solution was washed with water, allowed to stand and separate into layers, and the organic phase was collected. The aqueous phase was back-extracted with ethyl acetate, allowed to stand and separate into layers, and the organic phases were combined and dried over anhydrous Na₂SO₄ to remove the solvent. Silica gel column chromatography was performed with petroleum ether:ethyl acetate in a 6:1 ratio. The product was a pale yellow liquid, 372 mg, in yield (48%).

[0156] 12.3 Experimental Results

[0157] The products were analyzed using a Bruker AV400 nuclear magnetic resonance spectrometer with CDCl3 as the solvent. 1 HNMR analysis, spectrum shown in [reference] Figure 12 ,in: 1 HNMR (400MHz, Chloroform-d) δ7.00–6.52 (m, 3H), 2.73 (d, J = 81.5Hz, 4H), 1.77 (s, 2H), 0.72 (s, 6H).

[0158] Example 13. Preparation of N,N-diethyl-2,3,4,5,6-pentafluorobenzamide (F-1014)

[0159] 13.1 Synthetic Route

[0160]

[0161] 13.2 Synthesis Method

[0162] Weigh 1.00 g (4.70 mol) of 2,3,4,5,6-pentafluorobenzoic acid into a dry 100 mL pressure-resistant bottle, and add 2 mL of thionyl chloride and 20 μL of N,N-dimethylformamide. Stir the mixture in an oil bath at 80 °C for 3 h. The solid powder gradually dissolves, and the system becomes clear. After stirring, transfer the system to a dry 50 mL round-bottom flask, evaporate the solvent, leaving a pale yellow-green liquid, which is reaction solution 1. Add 0.63 g (8.60 mol) of diethylamine and 4 mL of dichloromethane to a dry 50 mL round-bottom flask. After freezing thoroughly in an ice bath, slowly add reaction solution 1 (1.00 g, 4.41 mol). During the addition, a solid is formed, white fumes are emitted, accompanied by a slight hissing sound. Stop stirring 5 minutes after the addition is complete. The reaction solution was washed with water, allowed to stand and separate into layers, and the organic phase was collected. The aqueous phase was back-extracted with ethyl acetate, allowed to stand and separate into layers, and the organic phases were combined and dried over anhydrous Na₂SO₄ to remove the solvent. Silica gel column chromatography was performed with petroleum ether:ethyl acetate in a 3:1 ratio. The product was a pale yellow liquid, 372 mg, in yield (48%).

[0163] 13.3 Experimental Results

[0164] The products were analyzed using a Bruker AV400 nuclear magnetic resonance spectrometer with CDCl3 as the solvent. 1 HNMR analysis, spectrum shown in [reference] Figure 13 ,in: 1 H NMR (400MHz, Chloroform-d) δ3.49(q,J=7.1Hz,2H),3.16(q,J=7.2Hz,2H),1.16(t,J=7.2Hz,3H),1.04(t,J=7.2Hz,3H).

[0165] Example 14. Preparation of N,N-diethyl-2,6-difluoro-3-methylbenzamide (F-1015)

[0166] 14.1 Synthetic Route

[0167]

[0168] 14.2 Synthesis Method

[0169] Weigh 1.00 g (5.80 mol) of 2,6-difluoro-3-methylbenzoic acid into a dry 100 mL pressure-resistant bottle, and add 2 mL of thionyl chloride and 20 μL of N,N-dimethylformamide. Stir the mixture in an oil bath at 80 °C for 3 h. The solid powder gradually dissolves, and the system becomes clear. After stirring, transfer the system to a dry 50 mL round-bottom flask, evaporate the solvent, and leave a pale yellow-green liquid, which is reaction solution 1. Add 0.77 g (10.50 mol) of diethylamine and 4 mL of dichloromethane to a dry 50 mL round-bottom flask. After freezing thoroughly in an ice bath, slowly add reaction solution 1 (1.00 g (5.25 mol) dropwise. During the dropwise addition, a solid is formed, white fumes are emitted, and a slight hissing sound is heard. Stop stirring 5 minutes after the dropwise addition is complete. The reaction solution was washed with water, allowed to stand and separate into layers, and the organic phase was collected. The aqueous phase was back-extracted with ethyl acetate, allowed to stand and separate into layers, and the organic phases were combined, dried over anhydrous Na₂SO₄, and the solvent was evaporated. Silica gel column chromatography was performed with petroleum ether:ethyl acetate in a 6:1 ratio. The product was a pale yellow liquid, 425 mg, yield 56%.

[0170] 14.3 Experimental Results

[0171] The products were analyzed using a Bruker AV400 nuclear magnetic resonance spectrometer with CDCl3 as the solvent. 1 HNMR analysis, spectrum shown in [reference] Figure 14 ,in: 1 HNMR (400MHz, Chloroform-d) δ3.51–3.39(m,2H),3.09(q,J=7.1Hz,2H),2.09(s,3H),1.11(t,J=7.1Hz,3H),0.95(t,J=7.2Hz,3H).

[0172] Example 15. Mosquito repellent activity test

[0173] 15.1 Test mosquitoes used in the experiment

[0174] In this experiment, commercially available Aedes aegypti mosquito larvae were cultured in several cylindrical plastic containers (8 cm in diameter and 10 cm in height) at 25 ± 2°C, under a 16h:8h (daylight:night) light condition. The larvae were fed a mixture of fish feed and yeast (1:1 by weight) until pupation. The pupae were then transferred to containers filled with distilled water and placed in 40×30×40 cm mesh mosquito cages. Adult mosquitoes emerged from the water surface within 2-3 days. Soft cotton balls soaked in a 10% glucose solution were placed in the mosquito cages as a food source for the adult mosquitoes. Three to five days after emergence, mice were fixed in wire mesh and provided for female mosquitoes to feed on. Two to three days after blood feeding, the female mosquitoes laid eggs on the clean surface of distilled water, awaiting hatching. This procedure was continued for several generations to obtain a sufficient number of mosquitoes for bioassay.

[0175] 15.2 Biological assay of mosquito repellent activity

[0176] To test the mosquito-repellent effect of the sample solution, the subjects wore a device with an exposure area of ​​5×5cm. 2 A 100 μL solution of the test sample in ethanol (1% by mass) was evenly applied to the exposed skin using a glass rod on a 40×40×30cm experimental latex glove. After 2 minutes of complete solvent evaporation, the treated hand was placed into a biological test chamber containing approximately 300 Aedes albopictus mosquitoes (male to female ratio of 1:1) made of mesh. The number of mosquitoes that landed on the exposed area and attempted to bite within 3 minutes was recorded. If no mosquitoes landed during the initial 3-minute exposure, the exposure was repeated for 3 minutes every 30 minutes until two mosquitoes landed and attempted to bite. The time required for the application of the drug and the cumulative number of mosquito bites was recorded as the effective protection time (PT). The biological test chamber was made of white mesh on all four sides to allow air circulation, and the front and back were made of transparent plastic. The front had a 15cm×5cm opening connected to a long mesh sleeve, allowing the tester to insert their hand into the chamber for repellency testing.

[0177] Before each experiment, a hand treated with only 100 μL of ethanol (control group) was placed into the mosquito cage for 3 minutes to assess the mosquito's attack power. If the mosquito bite frequency in the control group was 8-10 bites / min, the attack power was considered acceptable, and the mosquito cage could be used for subsequent experiments. The above test was repeated for two volunteers (one male and one female), and the repellency experiment was conducted between 09:00 and 18:00.

[0178] 15.3 Results of mosquito-repellent activity tests for each compound

[0179] The repellent activity of each compound against Aedes albopictus was tested using a 1% ethanol solution prepared with the fluorinated benzoyldiethylamine compounds, following the method described above. DEET was purchased from Bidex Pharmaceuticals (Shanghai, China) and prepared as a 1% ethanol solution as a positive control. The test results are as follows: Figure 15 As shown.

[0180] Figure 15 The effective protective time for each compound at a 1% (w / w) concentration is expressed as the time of protection until the arm is cumulatively bitten by two mosquitoes. In this case, the dose after applying 100 μL of a 1% (w / w) concentration sample solution is equivalent to 0.04 mg / cm². 2 .

[0181] Table 1

[0182]

[0183] Table 1 shows the protective efficacy measured every 30 minutes after applying a 1% (w / v) concentration test solution to the back of the hand. In this case, the dose after applying 100 μL of the 1% concentration sample solution is equivalent to 0.04 mg / cm². 2 .

[0184] The protection efficiency is calculated using Equation 1 below.

[0185]

[0186] Based on the above Figure 15 And the results in Table 1, at 0.04 mg / cm 2 At appropriate application doses, these fluorinated benzoyl diethylamine compounds all exhibited certain mosquito-repellent activity. In particular, N,N-diethyl-3-fluoro-5-methylbenzamide (F-1001) demonstrated 100% protection for up to 162 minutes. The results showed that at a 1% mass concentration, compound F-1001 provided twice the effective protection time compared to the gold standard mosquito repellent DEET.

[0187] Although embodiments of the invention have been disclosed for illustrative purposes, those skilled in the art will understand that various substitutions, variations, and modifications are possible without departing from the spirit and scope of the invention and the appended claims. Therefore, the scope of the invention is not limited to the contents disclosed in the embodiments.

Claims

1. The use of fluorinated benzoyl diethylamine compounds as and / or in the preparation of mosquito repellents, wherein the general structural formula of the fluorinated benzoyl diethylamine compound is as follows: Equation (I); Fluorinated benzoyl diethylamine compounds are N,N-diethyl-3-fluoro-5-methylbenzamide (F-1001) or N,N-diethyl-2,6-difluoro-3-methylbenzamide (F-1015). The general structural formula of N,N-diethyl-3-fluoro-5-methylbenzamide (F-1001) is: ; The structural formula of N,N-diethyl-2,6-difluoro-3-methylbenzamide (F-1015) is: .

2. The method for synthesizing fluorinated benzoyl diethylamine compounds as described in claim 1, characterized in that: The synthesis route is as follows: ； The specific steps are as follows: Weigh out benzoic acid raw material and place it in a dry, pressure-resistant bottle. Add thionyl chloride and N,N-dimethylformamide. Stir the mixture in an oil bath at 80 ℃ for 3 hours. The solid powder gradually dissolves and the system becomes clear. After stirring, transfer the system to a dry round-bottom flask, evaporate the solvent, and leave a pale yellow-green liquid in the flask, which is reaction solution 1. The ratio of benzoic acid raw material: thionyl chloride: N,N-dimethylformamide is 1:2:20 (g: mL: μL). Diethylamine and dichloromethane were added to a dry round-bottom flask and the mixture was thoroughly frozen in an ice bath. Reaction solution 1 was slowly added dropwise. During the addition, a solid was formed, white fumes were emitted, and a slight sound was heard. Stirring was stopped 5 minutes after the addition was completed. The reaction system was transferred to a separatory funnel, the reaction solution was washed once with water, and the layers were allowed to stand. The organic phase was collected, and the aqueous phase was back-extracted with ethyl acetate. The layers were allowed to stand, and the organic phases obtained from the two extractions were combined. The mixture was dried over anhydrous Na2SO4, and the solvent was evaporated to obtain the crude product. The crude product was obtained by silica gel column chromatography. Fluorobenzoyl diethylamine compounds were obtained. The ratio of diethylamine: dichloromethane: reaction solution 1 (g: mL: g) is 0.52-0.92:4:1.

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