Application of isoxazolidine compound in preparation of mosquito repellent

Abstract

The invention provides an application of an isoxazolidine compound as shown in a formula I and / or an isoxazolidine compound as shown in a formula II in preparation of a mosquito repellent. In a # imgabs0 # formula, R1, R2, R3 and R5 are H, methyl or phenyl, and R4 is methyl, ethyl, n-propyl, isopropyl, cyclohexyl or benzyl. The repelling rate of the isoxazolidine compounds is 100%, the mosquito repelling effect is good, A-level mosquito repelling is achieved, and part of the isoxazolidine compounds also have the cooling effect. The isoxazolidine compound provided by the invention has good safety, and is safe and non-toxic to human body and environment.

Description

Technical Field

[0001] The invention belongs to the technical field of mosquito repellent small molecules, and specifically relates to the application of isoxazolidine compounds in the preparation of mosquito repellents. Background Art

[0002] Currently, effective mosquito repellent ingredients on the market are mainly divided into four categories: DEET, chlorpyrifos, picaridin and citral essential oils. DEET, chlorpyrifos and picaridin are all pesticides with certain toxicity. Long-term use may pollute the environment and cause toxic side effects to the human body, such as neurological symptoms and skin damage. Citral essential oils repel mosquitoes by aroma, and the repellent effect is shorter than 2 hours, requiring repeated application or spraying; aldehydes are easily oxidized and deteriorated, and lose their mosquito repellent effect after deterioration; and citral essential oils are unresponsive to environmental humidity, pH and other factors that affect mosquitoes. Summary of the invention

[0003] In order to solve the problems in the prior art, the present invention provides the use of isoxazolidine compounds in the preparation of mosquito repellents.

[0004] The specific technical solutions of the present invention are as follows:

[0005] The use of the isoxazolidine compound represented by formula I and / or the isoxazolidine compound represented by formula II provided by the present invention in the preparation of mosquito repellents:

[0006] In the formula, R 1 , R 2 , R 3 , R 5 is H, methyl or phenyl, R 4 It is methyl, ethyl, n-propyl, isopropyl, cyclohexyl or benzyl.

[0007] The above-mentioned application provided by the present invention also has such a technical feature, wherein the mosquito repellent is selected from mosquito repellent liquid, mosquito repellent aromatherapy, mosquito repellent spray, mosquito repellent gel, mosquito repellent bracelet, mosquito repellent patch or electric mosquito coil.

[0008] Functions and Effects of the Invention

[0009] The present invention uses isoxazolidine compounds as effective mosquito repellent ingredients for the first time, and provides the use of isoxazolidine compounds in the preparation of mosquito repellents. The repellency rate of the compounds is 100%, the mosquito repellent effect is good, and the mosquito repellent reaches Class A mosquito repellent. Some isoxazolidine compounds also have a cooling effect. The isoxazolidine compounds of the present invention have good safety and are safe and non-toxic to the human body and the environment. DETAILED DESCRIPTION

[0010] The terms used in the present invention, unless otherwise specified, generally have the meanings that are commonly understood by those of ordinary skill in the art.

[0011] In the following examples, various processes and methods not described in detail are conventional methods well known in the art.

[0012] The reagents used in the following examples were purchased from common commercial sources, and the experimental operations and experimental conditions not specified were referred to the conventional operations and conventional conditions in the art.

[0013] The specific implementation of the present invention is described below with reference to embodiments.

[0014] <Example>

[0015] In this example, isoxazolidine compounds as shown in Formula I and Formula II were prepared.

[0016]

[0017] In the formula, R 1 , R 2 , R 3 , R 5 is H, methyl or phenyl, R 4 It is methyl, ethyl, n-propyl, isopropyl, cyclohexyl or benzyl.

[0018] The preparation methods of isoxazolidine compounds include a one-step method, a three-step method and a four-step method.

[0019] 1. Citronellal is used as a raw material to synthesize isoxazolidine compounds in one step. The synthesis route is as follows:

[0020]

[0021] The specific preparation process is: using self-purchased citronellal as a raw material to react with differently substituted hydroxylamines.

[0022] 1-1, (1,3,3,6-Tetramethyloctahydrobenzo[c]isoxazole)

[0023] Under nitrogen protection, NaOH (4.8 g, 0.12 mol, 1.2 eq) was dissolved in 60 mL of water, cooled to room temperature, and N-methylhydroxylamine hydrochloride (9.96 g, 0.12 mol, 1.2 eq) was added, and stirring continued to room temperature, followed by citronellal (15.42 g, 0.1 mol, 1.0 eq) and toluene (50 mL). Stirring continued at room temperature for 1 hour, and then the temperature was raised to reflux for 12 hours, and the reaction was monitored by GC and TLC. After cooling to room temperature, the reaction mixture was diluted with MTBE (methyl ether tert-butyl ether), washed with water and brine, and MgSO 4Drying, filtration, and evaporation under reduced pressure gave a crude product, which was purified by distillation under reduced pressure to give the product 1,3,3,6-tetramethyloctahydrobenzo[c]isoxazole (9.16 g, 50% yield) as a colorless oil.

[0024] The analysis results of the product are as follows: 1 H NMR (400 MHz, CDCl 3 )δ2.58(s,3H),2.14(td,J=10.9,3.5Hz,1H),1.81-1.55(m,4H),1.49-1.28(m,1H),1.27-1.10(m,4H),1.05(d,J=9.8Hz,3H),0.99-0.81(m,5H)

[0025] GC / MS(EI):m / z(%):183(71)[M] + ,168(54),137(94),126(9),109(15),100(100),95(43),81(44)

[0026] 1-2, (1-Isopropyl-3,3,6-trimethyloctahydrobenzo[c]isoxazole)

[0027] Method 1: Under nitrogen protection, NaOH (12.98 g, 0.324 mol, 1.0 eq) was dissolved in 60 mL of water, cooled to room temperature, and N-isopropylhydroxylamine hydrochloride (36.05 g, 0.324 mmol, 1.0 eq) was added, and stirring continued to room temperature, followed by citronellal (50.05 g, 0.324 mol, 1.0 eq) and toluene (190 mL), and stirring continued at room temperature for 1 hour, then the temperature was raised to reflux for 12 hours, and the reaction was monitored by GC and TLC. After cooling to room temperature, the reaction mixture was diluted with MTBE (methyl ether tert-butyl ether), washed with water and brine, and MgSO 4 Drying, filtration, and evaporation under reduced pressure gave a crude product, which was purified by distillation to give the product 1-isopropyl-3,3,6-trimethyloctahydrobenzo[c]isoxazole (27.50 g, 40% yield) as a colorless oil.

[0028] Method 2: Under nitrogen protection, 95% pure citronellal (32.47 g, 0.200 mol, 1.0 eq) was added to 15% N-isopropylhydroxylamine aqueous solution (100.15 g, 0.200 mmol, 1.0 eq), and the mixture was stirred at room temperature for 1 hour, then heated and refluxed for 24 hours, and the reaction was monitored by GC and TLC. After cooling to room temperature, the upper liquid was taken out to obtain a crude product, which was purified by distillation to obtain a colorless oil product 1-isopropyl-3,3,6-trimethyloctahydrobenzo[c]isoxazole (38.06 g, yield 82%).

[0029] The analysis results of the product are as follows: 1 H NMR (400 MHz, CDCl 3 )δ2.62 (s, 3H), 2.11 (td, J=10.9, 3.1Hz, 1H), 1.78 (dd, J=15.9, 7.2Hz, 3H) , 1.66 (d, J=12.3Hz, 1H), 1.38-1.13 (m, 9H), 1.05 (s, 3H), 0.95-0.73 (m, 5H)

[0030] GC / MS(EI):m / z(%):211(23)[M] + ,210(100),196(33),165(48),153(85),126(61),109(33),96(41),82(66),67(34),55(26)

[0031] The mosquito repellent effect was rated as A by the third-party Qingxi Research Institute. It has a strong mint aroma and a cooling effect on the skin.

[0032] 1-3. (1-cyclohexyl-3,3,6-trimethyloctahydrobenzo[c]isoxazole)

[0033] Under nitrogen protection, NaOH (4.80 g, 0.12 mol, 1.2 eq) was dissolved in 60 mL of water, cooled to room temperature, and N-cyclohexylhydroxylamine hydrochloride (18.12 g, 0.12 mol, 1.2 eq) was added, and stirring continued to room temperature, followed by citronellal (15.42 g, 0.1 mol, 1.0 eq) and toluene (50 mL), and stirring continued at room temperature for 1 hour, then the temperature was raised to reflux for 12 hours, and the reaction was monitored by GC and TLC. After cooling to room temperature, the reaction mixture was diluted with MTBE (methyl ether tert-butyl ether), washed with water and brine, and MgSO 4Drying, filtration, and evaporation under reduced pressure gave a crude product, which was purified by distillation under reduced pressure to give the product 1-cyclohexyl-3,3,6-trimethyloctahydrobenzo[c]isoxazole (8.269 g, 33% yield) as a colorless oil.

[0034] The analysis results of the product are as follows: 1 H NMR (400 MHz, CDCl 3 )δ2.78–2.55(m,2H),2.14–2.04(m,1H),1.96–1.89(m,1H),1.88–1.83(m,1H),1.82–1.72(m,4H), 1.71–1.55(m,3H),1.54–1.40(m,1H),1.36–1.15(m,9H),1.08(d,J=6.2Hz,3H),0.99–0.92(m,4H)

[0035] GC / MS(EI):m / z(%):251(36)[M] + ,236(10),208(100),168(15),137(30),81(28),55(29),41(27)

[0036] 1-4, (3,3,6-Trimethyl-1-benzyloctahydrobenzo[c]isoxazole)

[0037] Under nitrogen protection, NaOH (4.80 g, 0.12 mol, 1.2 eq) was dissolved in 60 mL of water, cooled to room temperature, and N-benzylhydroxylamine hydrochloride (19.08 g, 0.12 mol, 1.2 eq) was added, and stirring continued to room temperature, followed by citronellal (15.42 g, 0.01 mol, 1.0 eq) and toluene (50 mL), and stirring continued at room temperature for 1 hour, then the temperature was raised to reflux for 12 hours, and the reaction was monitored by GC and TLC. After cooling to room temperature, the reaction mixture was diluted with MTBE (methyl ether tert-butyl ether), washed with water and brine, and MgSO 4 Drying, filtration, and evaporation under reduced pressure gave a crude product, which was purified by distillation under reduced pressure to give the product 3,3,6-trimethyl-1-benzyloctahydrobenzo[c]isoxazole (8.021 g, 31% yield) as a colorless oil.

[0038] The analysis results of the product are as follows: 1 H NMR (400 MHz, CDCl 3)δ7.38(d,J=7.4Hz,2H),7.29(t,J=7.4Hz,2H),7.26–7.20(m,1H),4.10–3.85(m,2H),2.73–2.27(m,1H),1.91– 1.72(m,2H),1.71–1.59(m,2H),1.48–1.34(m,1H),1.27(d,J=13.9Hz,3H),1.24–1.14(m,1H),1.11–0.81(m,8H)

[0039] GC / MS(EI):m / z(%):259(56)[M] + ,244(31),201(20),176(32),137(45),106(38),91(100),81(26),41(17)

[0040] 2. Use melonaldehyde as raw material to synthesize isoxazolidine compounds in one step. The synthesis route is as follows:

[0041]

[0042] The specific preparation process is: using melonaldehyde with a purity of 85% purchased from home as a raw material to react with hydroxylamines with different substitutions.

[0043] 2-1, (1,3,3,6-Tetramethyl-hexahydro-cyclopenta[c]isoxazole)

[0044] Under nitrogen protection, melonaldehyde (14.02 g, 0.1 mol), N-methylhydroxylamine hydrochloride (8.35 g, 0.1 mol), NaOH (4.0 g, 0.1 mol) were refluxed in toluene (60 mL) for 12 hours, and the reaction was monitored by GC and TLC. After cooling to room temperature, the reaction mixture was diluted with MTBE (methyl ether tert-butyl ether), washed with water and brine, and MgSO 4 Drying, filtration, and evaporation under reduced pressure gave a crude product, which was purified by distillation to give the product 1,3,3,6-tetramethyl-hexahydro-cyclopenta[c]isoxazole (6.02 g, 35% yield) as a colorless oil.

[0045] The analysis results of the product are as follows: 1 H NMR (400 MHz, CDCl 3 )δ2.77–2.65(m,2H),2.61(s,3H),2.05–1.88(m,2H),1.72–1.56(m,2H),1.39–1.29(m,1H),1.26(s,6H),0.92(d,J=7.1Hz,3H)

[0046] GC / MS(EI):169(75)[M] + ,154(95),123(100),112(30),96(62),87(70),68(55),42(62)

[0047] 2-2, (1-Isopropyl-3,3,6-trimethyl-hexahydro-cyclopenta[c]isoxazole)

[0048] Method 1: Under nitrogen protection, melonaldehyde (14.02 g, 0.1 mol), N-isopropylhydroxylamine hydrochloride (11.10 g, 0.1 mol), NaOH (4.0 g, 0.1 mol) were refluxed in toluene (80 mL) and water (10 mL) for 12 hours, and the reaction was monitored by GC and TLC. After cooling to room temperature, the reaction mixture was diluted with MTBE (methyl ether tert-butyl ether), washed with water and brine, and MgSO 4 Drying, filtration, and evaporation under reduced pressure gave a crude product, which was purified by distillation to give the product 1-isopropyl-3,3,6-trimethyl-hexahydro-cyclopenta[c]isoxazole (5.31 g, 27% yield) as a colorless oil.

[0049] Method 2: Under nitrogen protection, 85% pure melonaldehyde (8.24g, 0.05mol, 1.0eq) was added to 15% N-isopropylhydroxylamine aqueous solution (25.02g, 0.05mol, 1.0eq), and stirred at room temperature for 1 hour, then heated and refluxed for 12 hours, and the reaction was monitored by GC and TLC. After cooling to room temperature, the upper liquid was taken out to obtain a crude product, which was purified by distillation to obtain a colorless oil product 1-isopropyl-3,3,6-trimethyl-hexahydro-cyclopenta[c]isoxazole (10.12g, yield 88%).

[0050] The analysis results of the product are as follows: 1 H NMR (400 MHz, CDCl 3 )δ3.11–3.01(m,1H),2.96–2.80(m,1H),2.73–2.59(m,1H),2.13–1.91(m,2H),1.75–1.57(m,2H),1.28–1.24(m,3H), 1.24–1.18(m,4H),1.14(d,J=6.2Hz,3H),1.02(d,J=6.2Hz,3H),0.94(d,J=7.0Hz,3H)GC / MS(EI):m / z(%):197(25)[M] +,182(100),140(37),123(35),81(30),55(13),43(31),41(26)

[0051] 2-3. (1-cyclohexyl-3,3,6-trimethyl-hexahydro-cyclopenta[c]isoxazole)

[0052] Under nitrogen protection, melonaldehyde (5.60 g, 0.04 mol), N-cyclohexylhydroxylamine hydrochloride (7.27 g, 0.048 mol), NaOH (1.92 g, 0.048 mol) were refluxed in toluene (60 mL) for 12 hours, and the reaction was monitored by GC and TLC. After cooling to room temperature, the reaction mixture was diluted with MTBE (methyl ether tert-butyl ether), washed with water and brine, and MgSO 4 Drying, filtration, and evaporation under reduced pressure gave a crude product, which was purified by distillation to give the product 1-cyclohexyl-3,3,6-trimethyl-hexahydro-cyclopenta[c]isoxazole (6.66 g, 63% yield) as a colorless oil.

[0053] The analysis results of the product are as follows: 1 H NMR (400 MHz, CDCl 3 )δ3.16–2.99(m,1H),2.72–2.49(m,2H),2.24–2.09(m,1H),2.07–1.90(m,2H), 1.84–1.51(m,7H),1.31–1.23(m,5H),1.23–1.17(m,6H),0.92(d,J=6.9Hz,3H)

[0054] GC / MS(EI):m / z(%):237(40)[M] + ,222(37),194(100),140(55),123(42),55(39),41(25)

[0055] 2-4, (3,3,6-Trimethyl-1-benzyl-hexahydro-cyclopenta[c]isoxazole)

[0056] Under nitrogen protection, melonaldehyde (5.61 g, 0.04 mol), N-benzylhydroxylamine hydrochloride (7.66 g, 0.048 mol), NaOH (1.92 g, 0.048 mol) were refluxed in toluene (60 mL) for 12 hours, and the reaction was monitored by GC and TLC. After cooling to room temperature, the reaction mixture was diluted with MTBE (methyl ether tert-butyl ether), washed with water and brine, and MgSO 4Drying, filtration, and evaporation under reduced pressure gave a crude product, which was purified by distillation to give the product 3,3,6-trimethyl-1-benzyl-hexahydro-cyclopenta[c]isoxazole (2.71 g, 28% yield) as a colorless oil.

[0057] The analysis results of the product are as follows: 1 H NMR (400 MHz, CDCl 3 )δ7.44–7.35(m,2H),7.34–7.27(m,2H),7.26–7.18(m,1H),4.15–3.77(m,2H),2.99(dd,J=8.3,2.4Hz,1H),2.78 –2.64(m,1H),2.09–1.94(m,1H),1.92–1.81(m,1H),1.76–1.60(m,2H),1.33–1.26(m,7H),0.79(d,J=7.1Hz,3H)

[0058] GC / MS(EI):m / z(%):245(40)[M] + ,230(37),186(14),163(16),123(30),91(100),81(20),65(15),41(13)

[0059] 3. The three-step method for synthesizing isoxazolidine compounds is as follows:

[0060]

[0061] The specific preparation process is:

[0062] 3-1, (1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole)

[0063] In the first step, under nitrogen protection, (E)-2-methylpent-2-enal (34.78 g, 354 mmol), 3-methylbut-2-en-1-ol (30.52 g, 354 mmol) and 2.05 g Et 3 NHCl was mixed in xylene and refluxed for 20 hours. During this period, water was collected and removed using a Dean-Stark apparatus, and the reaction was monitored by GC and TLC. After cooling to room temperature, the reaction mixture was diluted with MTBE (methyl tert-butyl ether), washed with water and brine, and MgSO 4 Drying, filtration, and evaporation under reduced pressure gave a crude product, which was purified by distillation to give (E)-2,4,7-trimethylocta-2,6-dienal (38.22 g, 65% yield).

[0064] In the second step, the Lindela catalyst (Pd / CaCO 3 A mixture of (E)-2,4,7-trimethylocta-2,6-dienal and ethyl acetate (40 mL) was stirred at room temperature overnight under a hydrogen atmosphere, and the reaction was monitored by GC and GC-MS. The mixture was passed through a small MgSO 4 The mixture was filtered through a pad of Celite® and the filtrate was washed with MTBE. The combined filtrates were concentrated in vacuo to give the crude product 2,4,7-trimethyloct-6-enal as a colorless oil (3.08 g, 12.9 mmol, 76% yield), which was used directly in the next step without further purification.

[0065] In the third step, under nitrogen protection, 2,4,7-trimethyloct-6-enal (16.82 g, purity 60%, 0.06 mol), N-methylhydroxylamine hydrochloride and NaOH aqueous solution were refluxed in toluene (50 mL) for 12 hours to obtain a light yellow oily product 1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole (6.02 g, yield 50%).

[0066] The analysis results of the product are as follows: 1 H NMR (400 MHz, CDCl 3 )δ2.91-2.50 (m, 3H), 2.01 (ddd, J=21.1, 15.3, 5.2Hz, 3H), 1.55 (ddd, J=18.9, 17. 9, 9.5Hz, 3H), 1.40 (dd, J=10.7, 7.0Hz, 1H), 1.30-1.05 (m, 5H), 1.04-0.64 (m, 8H)

[0067] GC / MS(EI): m / z(%):: 197(32)[M+], 182(100), 151(17), 126(22), 109(18), 100(47), 60(19)

[0068] It has a skin cooling effect and a strong minty aroma, and was rated A in mosquito repellent testing by a third-party Qingxi Research Institute.

[0069] 3-2, (1-Isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole)

[0070] In the first step, under nitrogen protection, (E)-2-methylpent-2-enal (34.78 g, 354 mmol), 3-methylbut-2-en-1-ol (30.52 g, 354 mmol) and 2.05 g Et 3NHCl was mixed in xylene and refluxed for 20 hours. During this period, water was collected and removed using a Dean-Stark apparatus, and the reaction was monitored by GC and TLC. After cooling to room temperature, the reaction mixture was diluted with MTBE (methyl tert-butyl ether), washed with water and brine, and MgSO 4 Drying, filtration, and evaporation under reduced pressure gave a crude product, which was purified by distillation to give (E)-2,4,7-trimethylocta-2,6-dienal (38.22 g, 65% yield).

[0071] In the second step, the Lindela catalyst (Pd / CaCO 3 A mixture of (E)-2,4,7-trimethylocta-2,6-dienal and ethyl acetate (40 mL) was stirred at room temperature overnight under a hydrogen atmosphere, and the reaction was monitored by GC and GC-MS. The mixture was passed through a small MgSO 4 The mixture was filtered through a pad of Celite® and the filtrate was washed with MTBE. The combined filtrates were concentrated in vacuo to give the crude product 2,4,7-trimethyloct-6-enal as a colorless oil (3.08 g, 12.9 mmol, 76% yield), which was used directly in the next step without further purification.

[0072] In the third step, under nitrogen protection, 2,4,7-trimethyloct-6-enal (14.02 g, 60% purity, 0.05 mol) and N-isopropylhydroxylamine (15% aqueous solution or prepared in situ from N-isopropylhydroxylamine hydrochloride and NaOH aqueous solution) were reacted in toluene (50 mL) to obtain a light yellow oily product 1-isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole (3.64 g, yield was 33%).

[0073] The analysis results of the product are as follows: 1 H NMR (400 MHz, CDCl 3 )δ3.05 (dd, J=13.0, 6.5Hz, 1H), 2.22 (t, J=9.9Hz, 1H), 1.94-1.76 (m, 1H), 1.61-1.35 (m, 4H), 1. 16-1.07(m,6H),0.98-0.90(m,6H),0.83(dt,J=14.1,7.0Hz,6H),0.69(dd,J=24.9,12.7Hz,2H)

[0074] GC / MS(EI): m / z(%): 225(18)[M+], 210(100), 168(19), 151(7), 128(9), 109(10),95(19)

[0075] It has a skin cooling effect and a strong minty aroma, and was rated A in mosquito repellent testing by a third-party Qingxi Research Institute.

[0076] 4. The four-step method for synthesizing isoxazolidine compounds is as follows:

[0077]

[0078] The specific preparation process is:

[0079] 4-1、 (Rac-(3aR,5R,7S,7aR)-5-phenyl-1,3,3,5,7-pentamethyl-octahydrobenzo[c]isoxazole)

[0080] In the first step, under nitrogen protection, propionaldehyde (80.5 g, 1.386 mol) was slowly added dropwise to a mixture of 2-methylphenylacetaldehyde (100 g, 0.745 mol), 60 mL of methanol and 25 mL of a 10% aqueous NaOH solution, the temperature was kept below 40°C, and the reaction was allowed to proceed for 16 hours. During this period, the reaction was monitored by TLC and GC. After cooling to room temperature, the reaction mixture was diluted with MTBE (methyl ether tert-butyl ether), washed with water and brine, and MgSO 4 Drying, filtration, and evaporation under reduced pressure gave a crude product, which was purified by distillation to give (E)-4-phenyl-2-methylpent-2-enal (23.82 g, 9.8% yield).

[0081] In the second step, under nitrogen protection, (E)-4-phenyl-2-methylpent-2-enal (52 g, 0.298 mol), 3-methylbut-2-en-1-ol (100 g, 1.16 mol) and 1.5 g Et 3 NHCl was mixed in xylene and refluxed for 20 hours. During this period, water was collected and removed using a Dean-Stark apparatus and the reaction was monitored by GC. After cooling to room temperature, the reaction mixture was diluted with MTBE (methyl tert-butyl ether) and washed with water and brine, and MgSO 4 Drying, filtration, and evaporation under reduced pressure gave a crude product, which was purified by column chromatography to give (E)-4-phenyl-2,4,7-trimethylocta-2,6-dienal (38.96 g, 54% yield).

[0082] In the third step, Lindela catalyst (Pd / CaCO 3 A mixture of (E)-4-phenyl-2,4,7-trimethylocta-2,6-dienal (23 g, 0.094 mol) and ethyl acetate (40 mL) was stirred at room temperature overnight under a hydrogen atmosphere, and the reaction was monitored by GC and GC-MS. The mixture was passed through a small MgSO 4The combined filtrates were concentrated in vacuo to give the crude product 4-phenyl-2,4,7-trimethyloct-6-enal as a colorless oil (22.41 g, 0.091 mol, 97.5% yield), which was used directly in the next step without further purification.

[0083] In the fourth step, 4-phenyl-2,4,7-trimethyloct-6-enal (8.4 g, 0.03 mol), N-methylhydroxylamine hydrochloride (2.87 g, 0.03 mol), and NaOH (1.2 g, 0.03 mmol) were reacted in toluene (50 mL) under nitrogen protection for 12 hours and the reaction was monitored by GC and GC-MS. The reaction mixture was diluted with MTBE (methyl ether tert-butyl ether), washed with water and brine, and MgSO 4 Drying, filtration, and evaporation under reduced pressure gave a crude product, which was purified by column chromatography to give the product Rac-(3aR,5R,7S,7aR)-5-phenyl-1,3,3,5,7-pentamethyl-octahydrobenzo[c]isoxazole (2.71 g, 33% yield) as a colorless oil.

[0084] The analysis results of the product are as follows: 1 H NMR (400 MHz, CDCl 3 )δ7.45-7.38(m,2H),7.37-7.29(m,2H),7.24-7.16(m,1H),2.90-2.66(m,3H),2.43-2.25(m,1H),2.13-2.02(m,1H),2.01-1.90(m,1H),

[0085] 1.87-1.75(m,2H),1.65-1.52(m,1H),1.50-1.42(m,1H),1.36(s,3H),1.27(s,3H),1.19-0.99(m,6H)

[0086] GC / MS(EI):m / z(%):273(52)[M] + ,258(5),227(3),171(12),180(11),157(17),126(100),100(40),87(44)

[0087] 4-2, (Rac-(3aR,5R,7S,7aR)-5-phenyl-1-isopropyl-3,3,5,7-tetramethyl-octahydrobenzo[c]isoxazole)

[0088] In the first step, under nitrogen protection, propionaldehyde (80.5 g, 1.386 mol) was slowly added dropwise to a mixture of 2-methylphenylacetaldehyde (100 g, 0.745 mol), 60 mL of methanol and 25 mL of a 10% aqueous NaOH solution, the temperature was kept below 40°C, and the reaction was allowed to proceed for 16 hours. During this period, the reaction was monitored by TLC and GC. After cooling to room temperature, the reaction mixture was diluted with MTBE (methyl ether tert-butyl ether), washed with water and brine, and MgSO 4 Drying, filtration, and evaporation under reduced pressure gave a crude product, which was purified by distillation to give (E)-4-phenyl-2-methylpent-2-enal (23.82 g, 9.8% yield).

[0089] In the second step, under nitrogen protection, (E)-4-phenyl-2-methylpent-2-enal (52 g, 0.298 mol), 3-methylbut-2-en-1-ol (100 g, 1.16 mol) and 1.5 g Et 3 NHCl was mixed in xylene and refluxed for 20 hours. During this period, water was collected and removed using a Dean-Stark apparatus and the reaction was monitored by GC. After cooling to room temperature, the reaction mixture was diluted with MTBE (methyl tert-butyl ether) and washed with water and brine, and MgSO 4 Drying, filtration, and evaporation under reduced pressure gave a crude product, which was purified by column chromatography to give (E)-4-phenyl-2,4,7-trimethylocta-2,6-dienal (38.96 g, 54% yield).

[0090] In the third step, Lindela catalyst (Pd / CaCO 3 A mixture of (E)-4-phenyl-2,4,7-trimethylocta-2,6-dienal (23 g, 0.094 mol) and ethyl acetate (40 mL) was stirred at room temperature overnight under a hydrogen atmosphere, and the reaction was monitored by GC and GC-MS. The mixture was passed through a small MgSO 4 The combined filtrates were concentrated in vacuo to give the crude product 4-phenyl-2,4,7-trimethyloct-6-enal as a colorless oil (22.41 g, 0.091 mol, 97.5% yield), which was used directly in the next step without further purification.

[0091] In the fourth step, 4-phenyl-2,4,7-trimethyloct-6-enal (8.4 g, GC purity 70%, 24 mmol) and N-isopropylhydroxylamine (15% aqueous solution or prepared in situ from N-isopropylhydroxylamine hydrochloride and NaOH aqueous solution) were reacted in toluene (50 mL) for 12 hours under nitrogen protection and the reaction was monitored by GC and GC-MS. The reaction mixture was diluted with MTBE (methyl ether tert-butyl ether), washed with water and brine, and MgSO 4 Drying, filtration and evaporation under reduced pressure gave a crude product, which was purified by column chromatography to give the product Rac-(3aR,5R,7S,7aR)-5-phenyl-1-isopropyl-3,3,5,7-tetramethyl-octahydrobenzo[c]isoxazole (4.39 g, 48% yield) as a colorless oil.

[0092] The analysis results of the product are as follows: 1 H NMR (400 MHz, CDCl 3 )δ7.45-7.37(m,2H),7.33(t,J=7.7Hz,2H),7.24-7.16(m,1H),3.32-3.08(m,1H),2.48-2.26(m,2H),2.05-1.90(m,1H),1.87-1. 72(m,2H),1.62-1.41(m,2H),1.36(s,3H),1.31(s,3H),1.26(d,J=6.7Hz,3H),1.13-0.97(m,9H)GC / MS(EI):m / z(%):301(35)[M] + ,286(100),171(11),154(70),126(25),115(24),105(20),91(23)

[0093] <Test example>

[0094] 1. This test example tests the mosquito repellent effect of the isoxazolidine compounds prepared in the above examples.

[0095] The density is 0.153g / cm 3The trimethylsilyl modified aerogel blocks were used as carriers to saturate adsorb 1-isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole, 1-isopropyl-3,3,6-trimethyloctahydrobenzo[c]isoxazole, 1,3,3,6-tetramethyloctahydrobenzo[c]isoxazole, 1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole, 1,3,3,6-tetramethyl-hexahydro-cyclopenta[c]isoxazole, and 1-isopropyl-3,3,6-trimethyl-hexahydro-cyclopenta[c]isoxazole prepared in the above embodiments, and the mosquito repellent effect was tested after being placed in a non-sealed environment for 24 hours (tested by Beijing Qingxi Technology Research Institute).

[0096] The preparation steps of trimethylsilyl modified aerogel block are as follows:

[0097] Step S1, mixing tetraethyl orthosilicate, ethanol, water, and ethylene glycol, wherein the mass ratio of tetraethyl orthosilicate, ethanol, water, and ethylene glycol is 1:5:0.2:0.5, and performing a hydrolysis reaction at 60° C. and pH 2.0 for 8 hours to obtain a hydrolysis solution.

[0098] Step S2, adjusting the pH of the hydrolysis solution to 7.6, injecting the solution into a mold to make it gel, and then placing the solution in a 70° C. oven for curing for 12 hours to obtain a gel block after heat curing;

[0099] Step S3, uniformly mix solvent 2 (a mixture of acetone and ethanol, with a mixing mass ratio of 2:1) and modifier hexamethyldisilazane at a mass ratio of 10:1 to obtain a modified solution, immerse the heat-cured gel block obtained in step S2 in the modified solution, place it in an oven at 70°C for curing for 12 hours, and obtain a gel block after heat curing again.

[0100] Step S4, taking out the gel block after heat drying and curing again, and placing it in supercritical CO 2 The extraction reactor was set at 55°C for the extraction stage, 10 MPa for the extraction stage, 45°C for the separation stage, and 5.5 MPa for the separation stage. The extraction was carried out for 6 h, and the density was 0.153 g / cm 3 Trimethylsilyl-modified aerogel blocks.

[0101] The mosquito repellent effect test method is as follows: the test is conducted in accordance with GB / T 30126-2013. Each test consists of two male and two female volunteers. 0.1 g of aerogel blocks adsorbed with the isoxazolidine sample after being placed for 24 hours are spread out and placed on the arms of the volunteers (5 cm × 5 cm). 300 active Aedes albopictus (female adults 4-7 days after emergence) are used in each test. The volume of the mosquito cage is 40 cm × 40 cm × 40 cm. The temperature is 26 ± 1 ° C and the relative humidity is 65 ± 10%.

[0102] The test results are: the avoidance rate is 100%, and the mosquito repellent effect is very good.

[0103] 2. This test example also uses a carrier (self-made with a density of 0.153 g / cm 3 The trimethylsilyl modified aerogel block was placed in a non-sealed environment for 24 hours and then tested for mosquito repellent effect (tested by Beijing Qingxi Technology Research Institute). The test method was the same as above. The test result was: no mosquito repellent effect.

[0104] Comparing the above two test results, it can be seen that the isoxazolidine compounds prepared in the above examples do have excellent mosquito repellent effects.

[0105] The above is a detailed description of the embodiments, which is convenient for those skilled in the art to correctly understand and use the present invention. Any improvements or modifications to the technical solutions obtained by those skilled in the art based on the present invention on the basis of the prior art, without innovative work, only through analysis, analogy or limited enumeration, etc., should be within the scope of protection determined by the claims.

Claims

1. Use of the isoxazolidine compound represented by formula I and / or the isoxazolidine compound represented by formula II in the preparation of mosquito repellents: In the formula, R 1 , R 2 , R 3 , R 5 is H, methyl or phenyl, R 4 It is methyl, ethyl, n-propyl, isopropyl, cyclohexyl or benzyl.

2. The use according to claim 1, characterized in that: The mosquito repellent is selected from mosquito repellent liquid, mosquito repellent incense, mosquito repellent spray, mosquito repellent gel, mosquito repellent bracelet, mosquito repellent patch or electric mosquito coil.

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