Fipronil-carbamate conjugate, preparation method thereof and application of fipronil-carbamate conjugate in agricultural insecticide

Abstract

The invention discloses a fipronil-carbamate conjugate as well as a preparation method and application thereof. The invention discloses a fipronil-carbamic acid 2-chloroethyl ester conjugate, which is prepared from fipronil-carbamic acid allyl ester, fipronil-carbamic acid propyl ester, fipronil-carbamic acid isopropyl ester, fipronil-carbamic acid butyl ester, fipronil-carbamic acid isobutyl ester, fipronil-carbamic acid 2-ethylhexyl ester, fipronil-carbamic acid benzyl ester, fipronil-carbamic acid butyl ester, fipronil-carbamic acid benzyl ester, fipronil-carbamic acid benzyl ester, fipronil-carbamic acid allyl ester, fipronil-carbamic acid butyl ester, fipronil-carbamic acid benzyl ester, fipronil-carbamic acid benzyl ester, fipronil-carbamic acid benzyl ester, the fipronil-carbamic acid p-nitrobenzyl ester is one of fipronil-carbamic acid p-nitrobenzyl ester and fipronil-carbamic acid p-methoxybenzyl ester, and the preparation method comprises the steps that fipronil is dissolved in anhydrous tetrahydrofuran, sodium hydride is added, stirring reaction is conducted, and a mixed solution is obtained after the reaction is finished; and adding chloroformate into the obtained mixed solution, and purifying after the reaction is finished to obtain the conjugate. Compared with the original insecticidal activity of fipronil, the conjugate prepared by the invention has enhanced insecticidal activity, and meanwhile, the biotoxicity of the conjugate to aquatic organisms is greatly reduced.

Description

Technical Field

[0001] The present invention relates to the technical field of agricultural insecticides, and particularly relates to a fipronil-carbamate conjugate, a preparation method thereof, and an application thereof in agricultural insecticides. Background Art

[0002] The extensive use of insecticides in the agricultural production process has caused great pressure on the environmental ecology. In particular, the continuous increase in pest resistance has made the insecticidal effect of traditional pesticides increasingly low. Fipronil is a broad-spectrum phenylpyrazole insecticide first developed by Rhone-Poulenc. It has the advantages of high insecticidal activity, broad insecticidal spectrum, and no cross-resistance with other traditional insecticides. However, since fipronil has been proven to have a high risk to aquatic organisms, butterflies, and bees during use, and has a slow degradation rate in nature. Therefore, since 2009, the scope of use of fipronil has been restricted. However, due to the excellent insecticidal activity and unique insecticidal mechanism of fipronil itself, domestic and foreign scientific researchers have been conducting research on the synthesis of derivatives based on the basic skeleton of fipronil to develop more effective low-toxic alternatives to replace fipronil. Currently, excellent commercialized fipronil derivatives such as flufiprole (independently developed by Dalian Ruizhe Co., Ltd.), ethiprole, acetoprole, pyriprole, pyrafluprole, and vaniliprole have been developed on the basis of fipronil.

[0003] The insecticides Pyriprole and Pyrafluprole developed by Mitsubishi Chemical Corporation of Japan are obtained by modifying the structure of fipronil through N-alkylation reaction using haloalkanes of pyridine and pyrazine. Dalian Ruizhe Company in China used methallyl chloride to carry out N-alkylation reaction on fipronil to synthesize clothianidin and successfully commercialized it. Invention patents CN201110057113.1, CN200910219776.1, CN200810022982.9, CN2013101427175, CN2014101001641, CN201210074381.9, CN201811232645.2 and CN110256351B disclose different synthesis methods of the pesticide insecticide fipronil; invention patent CN 02128312 provides a class of N-phenylpyrazole derivative insecticides and their preparation methods; invention patent CN 107629005 A describes certain polysubstituted phenylpyrazole derivatives and their preparation methods and uses; and invention patent CN105503829A discloses a fipronil-pyridine compound and its preparation method and application. However, the above patents have problems such as the products prepared having high toxicity, complex preparation processes, high product costs, or low insecticidal activity and easy cross-resistance of pests to the products.

[0004] Therefore, it has become an inevitable trend to develop new type of green insecticides with high efficiency, low toxicity, low residue and no cross-resistance. Summary of the Invention

[0005] In view of the above deficiencies, the present invention provides a fipronil carbamate conjugate and its preparation method. By modifying the structure of the amino group in the fipronil structure, not only the original insecticidal activity of fipronil is maintained or enhanced, but also its biotoxicity to aquatic organisms is greatly reduced, and it can be used as a new agricultural insecticide in agricultural production. The specific technical solutions are as follows:

[0006] A fipronil-carbamate conjugate, the structural formula of the conjugate is as follows:

[0007]

[0008] Wherein, the R group is selected from one of the following substituents 1-10:

[0009]

[0010] The obtained conjugates include one of fipronil-2-chloroethyl carbamate, fipronil allyl carbamate, fipronil propyl carbamate, fipronil isopropyl carbamate, fipronil butyl carbamate, fipronil isobutyl carbamate, fipronil-2-ethylhexyl carbamate, fipronil benzyl carbamate, fipronil p-nitrobenzyl carbamate, and fipronil p-methoxybenzyl carbamate.

[0011] Preferably, the R group is selected from one of substituents 1, 3, 4, 5, 6, 8, 9, and 10.

[0012] The present invention also provides a method for preparing the above fipronil-carbamate conjugate, and the preparation method includes the following steps:

[0013] S1. Dissolve fipronil in anhydrous tetrahydrofuran, cool it to 0 °C in an ice bath, then add sodium hydride, stir and react, and obtain a mixed solution after the reaction ends.

[0014] S2. Add chloroformate to the mixed solution obtained in step S1, react at room temperature, extract, wash, dry, and separate by column chromatography after the reaction ends to obtain the conjugate.

[0015] Preferably, the chloroformate is selected from one of 2-chloroethyl chloroformate, allyl chloroformate, propyl chloroformate, isopropyl chloroformate, butyl chloroformate, isobutyl chloroformate, 2-ethylhexyl chloroformate, benzyl chloroformate, p-nitrobenzyl chloroformate, and p-methoxybenzyl chloroformate.

[0016] Preferably, the molar ratio of sodium hydride to fipronil is 1-3:1.

[0017] Preferably, the molar ratio of chloroformate to fipronil is 1-2:1.

[0018] The present invention also provides an application of the fipronil-carbamate conjugate in the form of a single or a composition as an agricultural insecticide. The insecticide contains the above fipronil-carbamate conjugate and an adjuvant acceptable in a pesticide formulation. The insecticide can be formulated into emulsifiable concentrates, suspension concentrates, wettable powders, powders, granules, emulsifiable oil-in-water concentrates, seed dressings, baits, mother liquors, mother powders, etc. for controlling pests in agricultural production.

[0019] Compared with the prior art, the beneficial effects of the present invention are:

[0020] The present invention provides a fipronil carbamate conjugate and a preparation method thereof. Using fipronil, a pesticide, as a raw material and chloroformate as an attacking reagent, a formate fragment is introduced through an amide bond to the amino group on the fipronil diazole ring, generating a fipronil-carbamate conjugate. By structurally modifying the amino group in the fipronil structure, not only the original insecticidal activity of fipronil is maintained or enhanced, but also its biotoxicity to aquatic organisms is greatly reduced. Detailed implementation manners

[0021] The following describes the detailed implementation manners of the present invention in detail, but it should be understood that the protection scope of the present invention is not limited by the detailed implementation manners. Unless otherwise defined, all professional terms used hereinafter have the same meaning as commonly understood by those skilled in the art. The professional terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the protection scope of the present invention. Unless otherwise specifically stated, various raw materials, reagents, instruments and equipment used in the present invention can be obtained through market purchase or can be prepared by existing methods.

[0022] I. Synthesis method of fipronil-carbamate conjugate

[0023] Example 1

[0024] Synthesis of conjugate 1

[0025] Weigh 436 mg (1 mmol) of fipronil into an eggplant-shaped flask, add 3 mL of dry tetrahydrofuran and stir to dissolve it. Cool it to 0 °C in an ice bath, then add 60 mg (1.5 mmol) of NaH powder pre-cleaned with anhydrous petroleum ether, stir for 15 min under anhydrous conditions, and then add 1.3 mmol of 2-chloroethyl chloroformate. Stop the reaction at room temperature until there is no raw material spot, spin out most of the solvent under reduced pressure, add a small amount of water, extract with ethyl acetate, and combine the organic phases. Wash with water and saturated NaCl solution respectively, then dry with anhydrous Na2SO4, and finally remove the solvent under reduced pressure. The crude product is further separated by column chromatography (developing agent: V PE :V EA = 2:1, eluent: V PE :V EA = 12:1 - 4:1) to obtain the corresponding white solid conjugate 1, namely fipronil-2-chloroethyl carbamate, with a melting point of 71.8 °C and a yield of 57%. Structure characterization: 1 1H NMR (400 MHz, CDCl3) δ: 7.99 (s, 1H, 16-NH-H), 7.81 (d, J = 1.9 Hz, 1H, 8-Ph-H), 7.77 (d, J = 1.9 Hz, 1H, 10-Ph-H), 4.32 (m, 2H, 18-CH2-H), 3.60 (t, J = 5.5 Hz, 2H, 19-CH2-H);13 13C NMR (100 MHz, CDCl3) δ: 151.24, 141.74, 135.80, 135.65, 134.78, 134.75, 126.51, 126.34, 126.10, 123.47, 123.24, 120.52, 109.73, 66.48, 41.13.

[0026] Example 2

[0027] Synthesis of Conjugate 2

[0028] Weigh 436 mg (1 mmol) of fipronil into an eggplant-shaped flask, add 3 mL of dry tetrahydrofuran solvent and stir to dissolve it. Cool it to 0 °C in an ice bath, then add 1.3 mmol of NaH powder pre-cleaned with anhydrous petroleum ether, stir for 20 min under anhydrous conditions, and then add 1.5 mmol of allyl chloroformate. React at room temperature until there is no raw material point, then stop the reaction. Rotate off most of the solvent under reduced pressure, add a small amount of water, extract with ethyl acetate, combine the organic phases, wash with water and saturated NaCl solution respectively, dry with anhydrous Na2SO4, and finally remove the solvent under reduced pressure. The crude product is further separated by column chromatography (developing agent: V PE :V EA = 2:1, eluent: V PE :V EA = 12:1 - 4:1) to obtain the corresponding white solid conjugate 2, namely fipronil-allyl carbamate. Melting point 70.1 °C, yield 73%. Structure characterization: 1 1H NMR (400 MHz, CDCl3) δ: 7.93 (d, J = 3.5 Hz, 1H, 16-NH-H), 7.80 (q, J = 2.0 Hz, 1H, 7-Ph-H), 7.76 (q, J = 1.9 Hz, 1H, 8-Ph-H), 5.77 (m, 1H, 19-CH-H), 5.23 (m, 2H, 18-CH2-H), 4.54 (t, J = 4.5 Hz, 20-CH2-H); 13 13C NMR (100 MHz, CDCl3) δ: 151.24, 142.05, 135.80, 134.79, 130.62, 129.66, 126.52, 126.34, 126.05, 123.26, 121.38, 120.54, 119.60, 109.75, 67.85.

[0029] Example 3

[0030] Synthesis of Conjugate 3

[0031] Weigh 436 mg (1 mmol) of fipronil into a eggplant-shaped flask, add 5 mL of dry tetrahydrofuran solvent and stir to dissolve it. Cool it to 0 °C in an ice bath, then add 1.2 mmol of NaH powder pre-washed with anhydrous petroleum ether, stir for 20 min under anhydrous conditions, and then add 1.4 mmol of propyl chloroformate. Stop the reaction when there is no raw material point at room temperature, distill off most of the solvent under reduced pressure, add a small amount of water, extract with ethyl acetate and combine the organic phases. Wash with water and saturated NaCl solution respectively, dry with anhydrous Na2SO4, and finally remove the solvent under reduced pressure. The crude product is further separated by column chromatography (developing agent: V PE :V EA = 2:1, eluent: V PE :V EA = 12:1 - 4:1) to obtain the corresponding white solid conjugate 3, namely fipronil-propyl carbamate. Melting point: 136.7 °C, yield 63%. Structure characterization: 1 1H NMR (400 MHz, CDCl3) δ: 7.80 (d, J = 1.9 Hz, 1H, 8-Ph-H), 7.78 (s, 1H, 16-NH-H), 7.75 (d, J = 1.8 Hz, 1H, 10-Ph-H), 4.01 (s, 2H, 18-CH2-H), 1.58 (m, 2H, 19-CH2-H), 0.84 (t, J = 7.4 Hz, 3H, 20-CH3-H); 13 13C NMR (101 MHz, CDCl3) δ: 151.57, 142.40, 136.02, 135.79, 134.74, 134.51, 126.83, 126.47, 126.27, 125.99, 123.48, 123.27, 120.55, 109.74, 69.12, 21.84, 9.83.

[0032] Example 4

[0033] Synthesis of conjugate 4

[0034] Weigh 436 mg (1 mmol) of fipronil into a eggplant-shaped flask, add 5 mL of dry tetrahydrofuran solvent and stir to dissolve it. Cool it to 0 °C in an ice bath, then add 1.6 mmol of NaH powder pre-washed with anhydrous petroleum ether, stir for 30 min under anhydrous conditions, and then add 1.6 mmol of isopropyl chloroformate. Stop the reaction when there is no raw material point at room temperature, distill off most of the solvent under reduced pressure, add a small amount of water, extract with ethyl acetate and combine the organic phases. Wash with water and saturated NaCl solution respectively, dry with anhydrous Na2SO4, and finally remove the solvent under reduced pressure. The crude product is further separated by column chromatography (developing agent: V PE :V EA = 2:1, eluent: VPE :V EA = 12:1 - 4:1) to obtain the corresponding white solid conjugate 4, i.e., fipronil - isopropyl carbamate, with a melting point of: 126.9 °C and a yield of 71%. Structure characterization: 1 H NMR (400 MHz, CDCl3) δ: 7.81 (d, J = 1.8 Hz, 1H, 10 - Ph - H), 7.76 (d, J = 1.9 Hz, 1H, 8 - Ph - H), 7.67 (s, 1H, 16 - NH - H), 4.83 (m, 1H, 18 - CH - H), 1.18 (dd, J = 8.6, 6.2 Hz, 6H, 19, 20 - CH3 - H); 13 C NMR (100 MHz, CDCl3) δ: 151.03, 142.29, 135.94, 135.81, 134.67, 126.48, 126.32, 125.99, 123.51, 123.27, 120.55, 109.79, 72.19, 21.46.

[0035] Example 5

[0036] Synthesis of conjugate 5

[0037] Weigh 436 mg (1 mmol) of fipronil into a eggplant - shaped flask, add 6 mL of dry tetrahydrofuran solvent and stir to dissolve it. Cool it to 0 °C in an ice bath, then add 1.5 mmol of NaH powder pre - washed with anhydrous petroleum ether, stir for 25 min under anhydrous conditions, and then add 1.5 mmol of butyl chloroformate. React at room temperature until there is no raw material spot, then stop the reaction. Distill off most of the solvent under reduced pressure, add a small amount of water, extract with ethyl acetate, and combine the organic phases. Wash with water and saturated NaCl solution respectively, then dry with anhydrous Na2SO4, and finally remove the solvent under reduced pressure. The crude product is further separated by column chromatography (developing agent: V PE :V EA = 2:1, eluent: V PE :V EA = 12:1 - 4:1) to obtain the corresponding white solid conjugate 5, i.e., fipronil - butyl carbamate, with a melting point of: 110.8 °C and a yield of 63%. Structure characterization: 11H NMR (400 MHz, CDCl3) δ: 8.05 (d, J = 5.4 Hz, 1H, 16-NH-H), 7.81 (d, J = 1.9 Hz, 1H, 8-Ph-H), 7.77 (d, J = 1.9 Hz, 1H, 10-Ph-H), 4.08 (t, J = 6.7 Hz, 2H, 18-CH2-H), 1.54 (dq, J = 8.6, 6.8 Hz, 2H, 19-CH2-H), 1.27 (m, 2H, 20-CH2-H), 0.86 (t, J = 7.4 Hz, 3H, 21-CH3-H); 13 13C NMR (100 MHz, CDCl3) δ: 151.89, 141.70, 135.88, 135.33, 135.12, 134.98, 134.64, 126.53, 126.36, 126.17, 123.56 (4-Pz-C), 120.53, 109.93, 67.48, 30.43, 18.64, 14.06.

[0038] Example 6

[0039] Synthesis of Conjugate 6

[0040] Weigh 436 mg (1 mmol) of fipronil into a eggplant-shaped flask, add 10 mL of dry tetrahydrofuran solvent and stir to dissolve it. Cool it to 0 °C in an ice bath, then add 1.6 mmol of NaH powder pre-cleaned with anhydrous petroleum ether, stir for 30 min under anhydrous conditions, and then add 1.2 mmol of isobutyl chloroformate. Stop the reaction when there is no raw material spot at room temperature, distill off most of the solvent under reduced pressure, add a small amount of water, extract with ethyl acetate, and combine the organic phases. Wash with water and saturated NaCl solution respectively, and then dry with anhydrous Na2SO4. Finally, remove the solvent under reduced pressure, and further separate the crude product by column chromatography (developing agent: V PE :V EA = 2:1, eluent: V PE :V EA = 12:1 - 4:1) to obtain the corresponding white solid conjugate 6, namely fipronil-isobutyl carbamate, with a melting point of 131.9 °C and a yield of 47%. Structure characterization: 1 1H NMR (400 MHz, CDCl3) δ: 7.90 (s, 1H, 16-NH-H), 7.80 (d, J = 1.9 Hz, 1H, 8-Ph-H), 7.75 (d, J = 1.9 Hz, 1H, 10-Ph-H), 3.85 (m, 2H, 18-CH2-H), 1.85 (dt, J = 13.4, 6.7 Hz, 1H, 19-CH-H), 0.83 (dd, J = 6.8, 1.1 Hz, 6H, 20, 21-CH3-H);13 13C NMR (100 MHz, CDCl3) δ: 151.68, 142.38, 135.97, 135.81, 134.63, 126.84, 126.49, 126.26, 125.98, 123.49, 123.27, 109.77, 73.35, 27.73, 18.54.

[0041] Example 7

[0042] Synthesis of Conjugate 7

[0043] Weigh 436 mg (1 mmol) of fipronil into a round-bottom flask, add 15 mL of dry tetrahydrofuran solvent and stir to dissolve it. Cool it to 0 °C in an ice bath, then add 1.5 mmol of NaH powder pre-washed with anhydrous petroleum ether, stir under anhydrous conditions for 30 min, and then add 1.3 mmol of 2-ethylhexyl chloroformate. Stop the reaction when there is no raw material spot at room temperature. Distill off most of the solvent under reduced pressure, add a small amount of water, extract with ethyl acetate, and combine the organic phases. Wash with water and saturated NaCl solution respectively, and then dry with anhydrous Na2SO4. Finally, remove the solvent under reduced pressure, and further separate the crude product by column chromatography (developing agent: V PE :V EA = 2:1, eluent: V PE :V EA = 12:1 - 4:1) to obtain the corresponding colorless oily liquid conjugate 7, namely fipronil-2-ethylhexyl carbamate, with a yield of 51%. Structure characterization: 1 1H NMR (400 MHz, CDCl3) δ: 7.98 (d, J = 11.0 Hz, 1H, 16-NH-H), 7.81 (d, J = 1.9 Hz, 1H, 8-Ph-H), 7.76 (d, J = 1.8 Hz, 1H, 8-Ph-H), 4.00 (m, 2H, 18-CH2-H), 1.24 (m, 9H, 20, 21, 22, 24-CH2-H, 19-CH-H), 0.83 (m, 6H, 23, 25-CH3-H); 13 13C NMR (100 MHz, CDCl3) δ: 151.94, 141.90, 135.88, 135.54, 134.93, 134.55, 126.54, 126.27, 126.10, 123.55, 123.26, 109.87, 69.97, 38.70, 29.88, 28.70, 23.27, 22.84, 13.91, 10.66.

[0044] Example 8

[0045] Synthesis of Conjugate 8

[0046] Weigh 436 mg (1 mmol) of fipronil into an eggplant-shaped flask, add 16 mL of dry tetrahydrofuran solvent, stir to dissolve it, cool it to 0 °C in an ice bath, then add 1.8 mmol of NaH powder pre-washed with anhydrous petroleum ether, stir for 40 min under anhydrous conditions, and then add 1.8 mmol of benzyl chloroformate. React at room temperature until there is no raw material point, then stop the reaction. Distill off most of the solvent under reduced pressure, add a small amount of water, extract with ethyl acetate, and combine the organic phases. Wash with water and saturated NaCl solution respectively, and then dry with anhydrous Na2SO4. Finally, remove the solvent under reduced pressure, and further separate the crude product by column chromatography (developer: V PE :V EA = 2:1, eluent: V PE :V EA = 12:1 - 4:1) to obtain the corresponding white solid conjugate 8, namely fipronil-benzyl carbamate, with a melting point of 165.6 °C and a yield of 62%. Structure characterization: 1 1H NMR (400 MHz, DMSO-d6) δ: 11.52 (s, 1H, 16-NH-H), 8.32 (m, 2H, 8, 10-Ph-H), 7.36 (s, 5H, 20, 21, 22, 23, 24-Ph-H), 5.19 (m, 2H, 18-CH2-C); 13 13C NMR (101 MHz, DMSO-d6) δ: 153.43, 142.02, 136.08, 135.49, 135.25, 134.99, 134.07, 129.03, 127.94, 127.45, 127.14, 126.17, 124.55, 123.98, 121.26, 111.37, 68.59.

[0047] Example 9

[0048] Synthesis of conjugate 9

[0049] Weigh 436 mg (1 mmol) of fipronil into an eggplant-shaped flask, add 20 mL of dry tetrahydrofuran solvent, stir to dissolve it, cool it to 0 °C in an ice bath, then add 2.0 mmol of NaH powder pre-washed with anhydrous petroleum ether, stir for 50 min under anhydrous conditions, and then add 2.0 mmol of p-nitrobenzyl chloroformate. React at room temperature until there is no raw material point, then stop the reaction. Distill off most of the solvent under reduced pressure, add a small amount of water, extract with ethyl acetate, and combine the organic phases. Wash with water and saturated NaCl solution respectively, and then dry with anhydrous Na2SO4. Finally, remove the solvent under reduced pressure, and further separate the crude product by column chromatography (developer: V PE :V EA = 2:1, eluent: V PE :V EA= 12:1 - 4:1) to obtain the corresponding white solid conjugate 9, i.e., fipronil - p - nitrobenzyl carbamate, with a melting point of 154.8 °C and a yield of 71%. Structure characterization: 1 H NMR (400 MHz, DMSO - d6) δ 11.65 (s, 1H, 16 - NH - H), 8.34 (m, 2H, 21, 23 - Ph - H), 8.25 (m, 2H, 8, 10 - Ph - H), 7.61 (m, 2H, 20, 24 - Ph - H), 5.36 (m, 2H, 18 - CH2 - H); 13 C NMR (100 MHz, DMSO - d6) δ 147.78, 143.33, 136.05, 135.06, 134.03, 129.28, 127.49, 127.19, 126.10, 123.98, 121.25, 111.34, 67.06.

[0050] Example 10

[0051] Synthesis of conjugate 10

[0052] Weigh 436 mg (1 mmol) of fipronil into an eggplant - shaped flask, add 20 mL of dry tetrahydrofuran solvent and stir to dissolve it. Cool it to 0 °C in an ice bath, then add 1.7 mmol of NaH powder pre - washed with anhydrous petroleum ether, stir for 30 min under anhydrous conditions, and then add 1.6 mmol of p - methoxybenzyl chloroformate. React at room temperature until there is no raw material point, then stop the reaction. Distill off most of the solvent under reduced pressure, add a small amount of water, extract with ethyl acetate, and combine the organic phases. Wash with water and saturated NaCl solution respectively, and then dry with anhydrous Na2SO4. Finally, remove the solvent under reduced pressure, and further separate the crude product by column chromatography (developing agent: V PE :V EA = 2:1, eluent: V PE :V EA = 12:1 - 4:1) to obtain the corresponding white solid conjugate 10, i.e., fipronil - p - methoxybenzyl carbamate, with a melting point of 160.8 °C and a yield of 65%. Structure characterization: 1 H NMR (400 MHz, DMSO - d6) δ: 11.56 (s, 1H, 16 - NH - H), 8.35 (m, 2H, 8, 10 - Ph - H), 7.05 (brs, 5H, 20, 21, 22, 23, 24 - Ph - H), 5.24 (m, 2H, 18 - CH2 - C); 1313C NMR (101 MHz, DMSO-d6) δ: 156.32, 141.05, 136.03, 135.57, 135.73, 134.26, 134.05, 129.23, 127.65, 127.37, 127.06, 126.15, 124.83, 123.97, 121.25, 111.36, 68.79.

[0053] II. Preparation of Fipronil-Carbamate Conjugate Formulations

[0054] Example 11

[0055] Preparation of 5% Fipronil-Carbamate Conjugate Liquid Formulation

[0056] Weigh 5.2 kg of fipronil-carbamate conjugate 1 and add it to a 200 L reaction kettle. Add 10 kg of N,N-dimethylacetamide and 20 kg of ethanol, and stir at room temperature until it is completely dissolved. Then add 1.5 kg of Tween-60 and 1.0 kg of sodium lignosulfonate and stir to dissolve. Finally, add ethanol to make up to 100 kg. After stirring evenly, let it stand at room temperature for 1 hour to obtain a 5% fipronil-carbamate conjugate liquid formulation.

[0057] Example 12

[0058] Preparation of 5% Fipronil-Carbamate Conjugate Emulsifiable Concentrate

[0059] Weigh 5.2 kg of fipronil-carbamate conjugate 3 and add it to a 200 L reaction kettle. Add 15 kg of N,N-dimethylacetamide and stir at room temperature until it is completely dissolved. Then add 1.5 kg of fatty alcohol polyoxyethylene ether and 5.0 kg of alkylaryl polyoxypropylene polyoxyethylene ether and stir to dissolve. Finally, add mesitylene to make up to 100 kg. After stirring evenly, let it stand at room temperature for 1 hour to obtain a 5% fipronil-carbamate conjugate emulsifiable concentrate.

[0060] Example 13

[0061] Preparation of 10% Fipronil-Carbamate Conjugate Suspension Concentrate

[0062] Weigh 10.5 kg of fipronil-carbamate conjugate 4, 3 kg of triphenylethylphenol polyoxyethylene ether phosphate ester, 2 kg of polymeric carboxylate, 0.5 kg of magnesium aluminum silicate, 3 kg of ethylene glycol, 50 kg of deionized water, 0.05 kg of defoamer, 0.1 kg of xanthan gum. Grind it through a sand mill to obtain a suspension with a particle size less than 5 microns, and get a 10% fipronil-carbamate conjugate suspension concentrate.

[0063] Example 14

[0064] Preparation of 10% Fipronil-Carbamate Conjugate Wettable Powder

[0065] Weigh 10.5 kg of fipronil-carbamate conjugate 5, add 2 kg of silica white, 2 kg of sodium dodecyl sulfate, 3 kg of polymeric carboxylate dispersant, and supplement with kaolin to 100 kg. Pass through an air-flow pulverizer to obtain 10% fipronil-carbamate conjugate wettable powder.

[0066] Example 15

[0067] Preparation of 1% Fipronil-Carbamate Conjugate Granule

[0068] Weigh 1 kg of fipronil-carbamate conjugate 6, add 2 kg of alkylphenol polyoxyethylene, 1 kg of silica white, 5 kg of 1% rosin ethanol solution, and supplement with soil powder to 100 kg. Then evenly spray tap water and spray while stirring for 15 minutes. Then add the material to a rotary extrusion granulator and dry to obtain 1% fipronil-carbamate conjugate granule.

[0069] Example 16

[0070] Preparation of 5% Fipronil-Carbamate Conjugate Microemulsion

[0071] Weigh 5 kg of fipronil-carbamate conjugate 8, add 10 kg of ethanol, 5 kg of mesitylene, stir and dissolve into a transparent solution, add 5 kg of styrylphenol polyoxyethylene ether, 4 kg of calcium alkylbenzenesulfonate, 3 kg of ethylene glycol, and supplement with deionized water to 100 kg. Stir evenly to obtain 5% fipronil-carbamate conjugate microemulsion.

[0072] Example 17

[0073] Preparation of 20% Fipronil-Carbamate Conjugate Emulsion in Water

[0074] Weigh 21 kg of fipronil-carbamate conjugate 9, add 10 kg of N-methylpyrrolidone, stir and dissolve into a transparent solution, add 2 kg of hydroxyl-terminated polyether, 3 kg of castor oil polyoxyethylene ether, 3 kg of ethylene glycol, and supplement with water to 100 Kg. Shear for 30 min to obtain 20% fipronil-carbamate conjugate emulsion in water.

[0075] Example 18

[0076] Preparation of 20% Fipronil-Carbamate Conjugate Seed Coating Agent

[0077] Weigh 21 kg of the fipronil-carbamate conjugate 10, 3 kg of phenethylphenol polyoxyethyl ether, 2 kg of calcium alkylbenzenesulfonate, 2 kg of 5% aqueous solution of polyvinyl alcohol, 0.5 kg of cyclodextrin, 5 kg of ethylene glycol, 0.1 kg of sodium benzoate, 0.1 kg of acid red, 0.5 kg of magnesium aluminum silicate, 0.1% xanthan gum, and make up to 100 kg with water. Grind it through a sand mill to obtain a suspension with a particle size less than 5 microns, and obtain a 20% fipronil-carbamate conjugate seed coating agent.

[0078] III. Insecticidal activity test of the fipronil-carbamate conjugate

[0079] Dilute the test sample, the fipronil-carbamate conjugate, into different concentration gradients respectively, and conduct parallel experiments 3 times for each concentration. At the same time, set a positive control group (fipronil technical) and a blank control group (CK), and also conduct parallel experiments 3 times.

[0080] The immersion method of water bamboo is adopted in the experiment. Cut the water bamboo into thin slices of equal size (2 - 3 cm), and then soak the cut water bamboo in the test liquid of the corresponding concentration for 30 s, take it out and dry it on an iron rack. Transfer the air-dried water bamboo to a culture box of 11 cm * 7.5 cm * 4 cm, 4 slices / box. Lay clean filter paper at the bottom of the culture box, and then carefully add 25 third-instar resistant rice striped stem borers. Seal it with a plastic cover with small holes, and use fipronil as the positive control. Finally, place the culture box in the greenhouse for feeding, and investigate the death situation of the resistant rice striped stem borers after 48 hours. The effective rate and mortality rate of the insecticidal sample against the striped stem borer are calculated according to the following formula:

[0081]

[0082] Use software for statistical analysis. All data of the experiment are expressed as the mean standard deviation (S.D.), and the median lethal concentration LC of the test sample against the resistant striped stem borer at different concentrations is obtained 50 See Table 1 below:

[0083] Table 1 Insecticidal activities of fipronil-carbamate conjugates against resistant Chilo suppressalis at different concentrations

[0084]

[0085]

[0086] From the results in Table 1, it can be seen that the fipronil-carbamate conjugate 1 - 10 of the present invention has good insecticidal effects against the resistant striped stem borer, and LC 50 Compared with the positive control group of fipronil, it is all reduced, indicating that compared with the original insecticidal activity of fipronil, the insecticidal activity of the conjugate prepared in the present invention is enhanced.

[0087] IV. Biotoxicity test of the fipronil-carbamate conjugate on aquatic organisms

[0088] According to the national standard (test method number: GB / T 31270), zebrafish were selected to conduct bio-safety tests on certain fipronil-carbamate conjugates. The experimental fish were commercial zebrafish with normal body postures, of the same size, 2-3 cm in body length, and with an average weight of 0.3 g. After being purchased, they were raised at room temperature for 7 days, with water changed every 2 days and fed 2 times a day. The water was changed on the day before the experiment and feeding was stopped. All the water used in this experiment was dechlorinated tap water that had been exposed to the sun, and the solution was prepared with the water for raising the fish. Five concentration gradients of 1.6, 2.0, 2.4, 2.8, and 3.2 (mg / L) were set in the experiment. 7 fish were used as test objects in each sample group, and the test duration was 96 hours. The test samples were dissolved in acetone to prepare an acetone solution of 20 g / L, and then a quantitative microliter of the acetone solution at each concentration was mixed into 1 L of water to prepare the required experimental concentration (mg / L).

[0089] The experiment adopted the full-static method. During the experiment, the liquid medicine was not replaced and feeding was not carried out. Dead fish were fished out at any time. By poking the body of the fish with forceps, if it did not move, it was determined to be a dead fish. The experimental period was 96 hours. On the first day, observations were made every 2 hours until 12 hours. After determining that there was no abnormality in the blank control group, the observation interval was changed to once every 12 hours. The poisoning state of zebrafish was judged by comparing the body postures of zebrafish. The fish poisoned by the drug had a bulging belly and a distorted body posture.

[0090] Table 2 Results of biosecurity tests on zebrafish after 96 h of drug exposure to fipronil-carbamate conjugates

[0091]

[0092]

[0093] As can be seen from the results in Table 2, the lethal toxicity of all the conjugates to the tested zebrafish was significantly lower than that of the positive control group, fipronil. Among them, conjugate 2 was 43 times lower than the positive control fipronil, and conjugate 7 was 52 times lower than the positive control fipronil. That is to say, the fipronil-carbamate conjugate of the present invention has lower biotoxicity to aquatic organisms than fipronil.

[0094] In summary, a fipronil-carbamate conjugate and a preparation method thereof provided by an embodiment of the present invention use fipronil, a pesticide, as a raw material and chloroformate as an attacking reagent. A formate fragment is introduced through an amide bond at the amino group on the fipronil diazole ring to generate a fipronil-carbamate conjugate. Compared with the original insecticidal activity of fipronil, through the structural modification of the amino group in the fipronil structure, the conjugate prepared by the present invention has enhanced insecticidal activity and greatly reduced its biotoxicity to aquatic organisms.

[0095] The foregoing description of the specific exemplary embodiments of the present invention is for purposes of illustration and exemplification. These descriptions are not intended to limit the invention to the precise forms disclosed, and it is apparent that many modifications and variations are possible in light of the above teachings. The purpose of selecting and describing the exemplary embodiments is to explain the specific principles of the present invention and its practical applications, so that those skilled in the art can implement and utilize the various different exemplary embodiments of the present invention, as well as various different selections and modifications. The scope of the present invention is intended to be defined by the claims and their equivalents.

Claims

1. A fipronil-carbamate conjugate, characterized in that, The structural formula of the conjugate is as follows: The R is selected from any one of the following substituents 1-10:

2. A method for preparing a fipronil-carbamate conjugate as described in claim 1, characterized in that, The preparation method comprises the following steps: S1. Dissolve fipronil in anhydrous tetrahydrofuran, cool it to 0 °C in an ice bath, then add sodium hydride, stir and react, and obtain a mixed solution after the reaction ends; S2. Add chloroformate to the mixed solution obtained in step S1, react at room temperature, extract, wash, dry, and separate by column chromatography after the reaction ends to obtain the conjugate.

3. The preparation method of a fipronil-carbamate conjugate according to claim 2, characterized in that, The chloroformate is selected from one of 2-chloroethyl chloroformate, allyl chloroformate, propyl chloroformate, isopropyl chloroformate, butyl chloroformate, isobutyl chloroformate, 2-ethylhexyl chloroformate, benzyl chloroformate, p-nitrobenzyl chloroformate, and p-methoxybenzyl chloroformate.

4. The preparation method of a fipronil-carbamate conjugate according to claim 2, characterized in that, The molar ratio of the sodium hydride to fipronil is 1-3:

1.

5. The preparation method of a fipronil-carbamate conjugate according to claim 2, characterized in that, The molar ratio of the chloroformate to fipronil is 1-2:

1.

6. Use of the fipronil-carbamate conjugate according to claim 1 in the preparation of agricultural insecticides.

7. Use of the fipronil-carbamate conjugate according to claim 6 in the preparation of an agricultural insecticide, characterized in that, The R group is selected from any one of substituents 1, 3, 4, 5, 6, 8, 9, and 10.

8. Use of the fipronil-carbamate conjugate according to claim 7 in the preparation of an agricultural insecticide, characterized in that, The dosage form of the agricultural insecticide is emulsifiable concentrate, suspension concentrate, wettable powder, powder, granule, emulsion in water, or seed coating agent.

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