CN112851657B - 3-hydroxyisothiazole derivative and preparation method and application thereof - Google Patents

3-hydroxyisothiazole derivative and preparation method and application thereof Download PDF

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CN112851657B
CN112851657B CN202011624117.9A CN202011624117A CN112851657B CN 112851657 B CN112851657 B CN 112851657B CN 202011624117 A CN202011624117 A CN 202011624117A CN 112851657 B CN112851657 B CN 112851657B
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hydroxyisothiazole
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刘根炎
黄成�
吴贇
罗晓刚
吴风收
巨修练
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Abstract

The invention provides a 3-hydroxyisothiazole derivative, a preparation method and application thereof, and relates to a 3-hydroxyisothiazole derivative or pharmaceutically acceptable salt, stereoisomer, isotope label, solvate, polymorph or prodrug thereof, the 3-hydroxyisothiazole derivative compound is a novel GABA receptor antagonist, has obvious insecticidal activity, can be used for further developing into an insecticide, has wide application prospect, and has a chemical structure general formula I, wherein R is shown in the specification 1 Is aryl or substituted aryl; r 2 Is benzyloxy or hydroxy:

Description

3-hydroxyisothiazole derivative and preparation method and application thereof
Technical Field
The invention relates to the technical field of heterocyclic compounds, in particular to a 3-hydroxyisothiazole derivative and a preparation method and application thereof.
Background
Pesticides are currently developing towards high efficiency, low toxicity and environmental protection, and particularly in nitrogen-containing heterocyclic compounds in recent years. The existing pesticides acting on GABA receptors, such as fipronil, lindane and the like, have the characteristics of environmental pollution, high toxicity to aquatic organisms and the like. Some isothiazole and its derivatives have high-efficiency broad-spectrum insecticidal, acaricidal, antibacterial and herbicidal activities, and have high agricultural value, such as Thio-4-PIOL and its derivatives can act on GABA receptors of insects, but the synthetic route is long and the process is complex. The research on the 3-hydroxyl isothiazole derivative further develops a novel isothiazole structure which is environment-friendly, short in synthetic route, acts on an insect GABA receptor and has agricultural value.
Disclosure of Invention
The invention aims to provide a 3-hydroxyisothiazole derivative, a preparation method and application thereof aiming at the existing problems, and the derivative can be used as a novel environment-friendly pesticide targeting GABA receptor with a short synthetic route.
The invention realizes the purpose through the following technical scheme:
according to one aspect of the present invention, there is provided a 3-hydroxyisothiazole derivative which is a compound represented by formula i, a pharmaceutically acceptable salt, a stereoisomer, an isotopic label, a solvate, a polymorph or a prodrug thereof:
Figure BDA0002877010550000011
wherein R is 1 Is aryl or substituted aryl, R 2 Is benzyloxy or hydroxy.
Preferably, said R is 1 Selected from 2-naphthyl, 1-naphthyl, 3-biphenyl, 4-biphenyl, 3-furyl, 3-thienyl, 4-pyridyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl and 4-hydroxyphenyl.
Further preferably, the 3-hydroxyisothiazole derivative is selected from the following compounds (BnO represents benzyloxy):
Figure BDA0002877010550000021
the pharmaceutically acceptable salt refers to the 3-hydroxyisothiazole derivative which can form an acid addition salt with a pharmaceutically acceptable acid, wherein the acid comprises hydrogen chloride, hydrogen bromide and the like.
According to a second aspect of the present invention, there is provided a process for preparing the above 3-hydroxyisothiazole derivative, the synthetic route of which is shown in the following formula II:
Figure BDA0002877010550000031
wherein R is 1 Is aryl or substituted aryl;
the method comprises the following specific steps:
1) Performing halogenation reaction on the compound 1, lithium Diisopropylamide (LDA) and iodine simple substance to obtain a compound 2;
2) Carrying out Suzuki coupling reaction on the compound 2, 4-pyridine boric acid, potassium carbonate and tetrakis (triphenylphosphine) palladium to obtain a compound 3;
3) Deprotecting compound 3 in hydrobromic acid in acetic acid solution as required to obtain compound 4;
4) Compound 4 is further prepared as a pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polymorph or prodrug as desired.
Preferably, said R is 1 Selected from 2-naphthyl, 1-naphthyl, 3-biphenyl, 4-biphenyl, 3-furyl, 3-thienyl, 4-pyridyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl and 4-hydroxyphenyl.
According to the scheme, the solvent used in the halogenation reaction in the step 1) is a mixed solvent of 1, 4-dioxane, tetrahydrofuran, DMF (dimethylformamide) or 1, 4-dioxane and water.
According to the scheme, the molar ratio of the compound 1, lithium diisopropylamide and iodine in the step 1) is 1: (1-2): (1-1.5), the temperature of halogenation is-55 to-95 ℃, and the reaction time is 10-60 minutes.
According to the scheme, the solvent used in the Suzuki coupling reaction in the step 2) is a mixed solvent of 1, 4-dioxane, tetrahydrofuran, DMF or 1, 4-dioxane and water.
According to the scheme, the molar ratio of the compound 2 in the step 2) to 4-pyridine boric acid, potassium carbonate and tetrakis (triphenylphosphine) palladium is 1: (1-1.5): (1-1.5): 0.1, the reaction temperature is 60-110 ℃, and the reaction time is 6-10 hours. Tetrakis (triphenylphosphine) palladium is used as a reaction catalyst, and potassium carbonate provides an alkaline environment to activate a boric acid substrate.
According to the scheme, the mass-to-volume ratio of the compound 3 in the step 3) to the hydrobromic acid in acetic acid (HBr mass concentration is 33%) is 1g: (5-25) mL. Stirring for 10-12 hours at normal temperature during deprotection.
According to a third aspect of the present invention, there is provided the use of the above 3-hydroxyisothiazole derivative for the preparation of a GABA (gamma-aminobutyric acid) receptor antagonist.
According to a fourth aspect of the present invention, there is provided a GABA receptor antagonist comprising the above 3-hydroxyisothiazole derivative.
According to a fifth aspect of the present invention, there is provided the use of the above-mentioned 3-hydroxyisothiazole derivative as an insecticide.
According to a sixth aspect of the present invention, there is provided an insecticide drug comprising the above-mentioned 3-hydroxyisothiazole derivative.
The invention has the beneficial effects that: compared with the prior art, the 3-hydroxyisothiazole derivative provided by the invention has a novel structure, has a good antagonistic effect on insect GABA receptors and good insecticidal activity, can be further developed into a novel insecticide, and has a wide application prospect.
Detailed Description
The present invention will be described in further detail with reference to examples. It is to be understood that these examples are for the purpose of illustrating the invention and are not to be construed as limiting the invention.
Example 1
Preparation of 3-hydroxy-4- (2-naphthyl) -5- (4-pyridyl) -isothiazole (I-1)
The preparation of I-1 comprises the following three steps:
the method comprises the following steps: preparation of 3-benzyloxy-4- (2-naphthyl) -5-iodo-isothiazole
After adding 0.66g (2.06 mmol) of 3-benzyloxy-4- (2-naphthyl) -isothiazole into a 50mL two-neck flask, under the protection of argon, 1.55mL (3.10 mmol) of LDA was added dropwise at-78 deg.C, and after stirring for 15 minutes, 0.63g (2.48 mmol) of iodine was dissolved in 20mL of tetrahydrofuran, and slowly added dropwise to the flask, and stirring was continued for 30 minutes. After the reaction was completed, 10mL of water was added to quench, a small amount of sodium thiosulfate solid was added and stirred for 2 hours, followed by extraction with ethyl acetate (30 mL. Times.3),dried over anhydrous sodium sulfate, filtered and concentrated. Purifying by column chromatography to obtain white solid with yield of 90.11%; hydrogen spectrum test result of product 1 H NMR(400MHz，CDCl 3 )：δ7.97-7.94(m，1H，ArH)，7.92-7.85(m，3H，ArH)，7.57(dd，J＝8.5，1.8Hz，1H，ArH)，7.54-7.49(m，2H，ArH)，7.41-7.25(m，5H，ArH)，5.46(s，2H，CH 2 )；MS(ESI)：m/z 444.05(M+H) + 。
Step two: preparation of 3-benzyloxy-4- (2-naphthyl) -5- (4-pyridyl) -isothiazole
In a 50mL two-necked flask were sequentially added 0.50g (1.13 mmol) of 3-benzyloxy-4- (2-naphthyl) -5-iodo-isothiazole, 0.21g (1.69 mmol) of 4-pyridineboronic acid, 0.23g (1.69 mmol) of potassium carbonate, and 0.065g (0.056 mmol) of tetrakis (triphenylphosphine) palladium, and then 20mL of 1, 4-dioxane and 5mL of water were added thereto, and the mixture was refluxed at 90 ℃ under the protection of argon gas for 10 hours, and after completion of the reaction, it was extracted with ethyl acetate (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered and concentrated. Obtaining white solid after column chromatography and drying, the yield is 78.57%; mp (melting point) 134-136 ℃; 1 HNMR(400MHz，CDCl 3 )：δ8.54(d，J＝5.6Hz，2H，ArH)，7.44-7.19(m，11H，ArH)，7.12(d，J＝5.6Hz，2H，ArH)，5.49(d，J＝2.4Hz，2H，CH 2 )；MS(ESI)：m/z 394.90(M+H) + 。
step three: preparation of 3-hydroxy-4- (2-naphthyl) -5- (4-pyridyl) -isothiazole (I-1) in a 25mL single-necked flask was added 0.30g (0.760 mmol) of 3-benzyloxy-4- (2-naphthyl) -5- (4-pyridyl) -isothiazole, 33wt% HBr in acetic acid (10 mL), stirred at room temperature for 12h, after completion of the reaction, filtered, the filter cake was put in a 50mL flask, 30mL of ethyl acetate was added, stirred at room temperature for 30min, filtered, and dried to obtain a white solid in a yield of 69.33%; mp (melting point) 209-211 ℃; 1 HNMR(400MHz，DMSO-d 6 )：δ10.84(s，1H，OH)，8.93-8.87(m，2H，ArH)，8.00-7.88(m，4H，ArH)，7.88-7.82(m，2H，ArH)，7.57(qd，J＝6.4，5.6，3.6Hz，2H，ArH)，7.40(dd，J＝8.8，1.6Hz，1H，ArH)； 13 C NMR(100MHz，DMSO-d 6 )：δ168.29，156.52，146.37，144.02，133.85，131.76，129.68，129.31，129.28，129.06，127.41，126.89，126.29，125.27，125.10；HRMS(ESI)：m/z[M-Br] + )calcd for C 18 H 12 N 2 OS 305.0749，found 305.0736。
example 2
Preparation of 3-hydroxy-4- (1-naphthyl) -5- (4-pyridyl) -isothiazole (I-2)
The preparation of I-2 comprises the following three steps:
the method comprises the following steps: preparation of 3-benzyloxy-4- (1-naphthyl) -5-iodo-isothiazole
Adding 0.66g (2.06 mmol) of 3-benzyloxy-4- (1-naphthyl) -isothiazole into a 50mL two-neck flask, then using argon for protection, dropwise adding 1.55mL (3.10 mmol) of LDA at-78 ℃, stirring for 15 minutes, dissolving 0.63g (2.48 mmol) of iodine into 20mL of tetrahydrofuran, slowly dropwise adding into the flask, continuing to stir for 30 minutes, after the reaction is finished, adding 10mL of water for quenching, adding a little sodium thiosulfate solid, stirring for 2 hours, extracting with ethyl acetate (30 mL multiplied by 3), drying with anhydrous sodium sulfate, filtering and concentrating, and purifying by column chromatography to obtain a white solid with the yield of 88.65%; mp (melting point) 127-129 ℃; 1 HNMR(400MHz，CDCl 3 )：δ7.98-7.88(m，2H，ArH)，7.61-7.35(m，5H，ArH)，7.30-7.12(m，5H，ArH)，5.37(s，2H，CH 2 )；MS(ESI)：m/z 443.95(M+H) + 。
step two: preparation of 3-benzyloxy-4- (1-naphthyl) -5- (4-pyridyl) -isothiazole
Sequentially adding 0.50g (1.13 mmol) of 3-benzyloxy-4- (1-naphthyl) -5-iodine-isothiazole, 0.21g (1.69 mmol) of 4-pyridineboronic acid, 0.23g (1.69 mmol) of potassium carbonate and 0.065g (0.056 mmol) of tetrakis (triphenylphosphine) palladium into a 50mL two-neck flask, then adding 20mL of 1, 4-dioxane and 5mL of water, heating to 90 ℃ under the protection of argon, carrying out reflux reaction for 10h, after the reaction is finished, extracting with ethyl acetate (30 mL multiplied by 3), drying with anhydrous sodium sulfate, filtering, concentrating, carrying out column chromatography, drying to obtain a white solid, and obtaining the yield of 71.33%; 1 H NMR(400MHz，CDCl 3 )：δ8.59(s，2H，ArH)，7.65-7.51(m，2H，ArH)，7.51-7.28(m，10H，ArH)，7.29-7.18(m，3H，ArH)，5.53(d，2H，CH 2 )；MS(ESI)：m/z 395.05(M+H) + 。
step three: preparation of 3-hydroxy-4- (1-naphthyl) -5- (4-pyridyl) -isothiazole (I-2) A25 mL single-neck flask was charged with 0.30g (0.760 mmol) of 3-benzyloxy-4- (1-naphthyl) -5- (4-pyridyl) -isothiazole and a solution of 33% HBr in acetic acid (10 mL), stirred at room temperature for 12h, after completion of the reaction, filtered, the filter cake was placed in a 50mL flask, 30mL of ethyl acetate was added, stirred at room temperature for 30min, filtered, and dried to give a white solid with a yield of 56.22%; mp 242-244 ℃. 1 HNMR(400MHz，CDCl 3 )δ8.74-8.64(m，2H)，7.88-7.66(m，6H)，7.56-7.41(m，2H)，7.31-7.21(m，1H)，4.14(s，1H，OH)； 13 C NMR(100MHz，DMSO-d 6 )：δ167.60，155.53，146.94，144.09，141.05，140.01，132.08，129.90，129.48，129.43，128.57，128.20，127.22，127.17，125.96，125.73；HRMS(ESI)：m/z([M-Br] + )calcd for C 18 H 12 N 2 OS 305.0749，found 305.0737。
Example 3
Preparation of 3-hydroxy-4- (3-biphenyl) -5- (4-pyridyl) -isothiazole (I-3)
The preparation of I-3 comprises the following three steps:
the method comprises the following steps: preparation of 3-benzyloxy-4- (3-biphenyl) -5-iodo-isothiazole
Adding 0.71g (2.06 mmol) of 3-benzyloxy-4- (3-biphenyl) -isothiazole into a 50mL two-neck flask, then using argon for protection, dropwise adding 1.55mL (3.10 mmol) of LDA at-78 ℃, stirring for 15 minutes, dissolving 0.63g (2.48 mmol) of iodine into 20mL of tetrahydrofuran, slowly dropwise adding into the flask, continuing to stir for 30 minutes, after the reaction is finished, adding 10mL of water for quenching, adding a little of sodium thiosulfate solid, stirring for 2 hours, extracting with ethyl acetate (30 mL multiplied by 3), drying with anhydrous sodium sulfate, filtering and concentrating, purifying by column chromatography to obtain a white solid with the yield of 87.34%; mp 105-107 ℃; 1 H NMR(400MHz，CDCl 3 )δ7.99-7.84(m，5H)，7.59(d，J＝1.6Hz，1H)，7.57(d，J＝1.6Hz，1H)，7.55-7.46(m，2H)，7.43-7.27(m，5H)，5.48(s，2H)。
step two: preparation of 3-benzyloxy-4- (3-biphenyl) -5- (4-pyridyl) -isothiazole
In 50mLTo a two-necked flask were added 0.53g (1.13 mmol) of 3-benzyloxy-4- (3-biphenyl) -5-iodo-isothiazole, 0.21g (1.69 mmol) of 4-pyridineboronic acid, 0.23g (1.69 mmol) of potassium carbonate, and 0.065g (0.056 mmol) of tetrakis (triphenylphosphine) palladium in this order, followed by addition of 20mL of 1, 4-dioxane and 5mL of water, reflux reaction at 90 ℃ under argon atmosphere for 10 hours, extraction with ethyl acetate (30 mL. Times.3) after completion of the reaction, drying over anhydrous sodium sulfate, filtration and concentration. Obtaining white solid after column chromatography and drying, the yield is 79.22%; mp 39-41 deg.C; 1 H NMR(400MHz，CDCl 3 )δ8.62-8.56(m，2H)，7.59-7.52(m，2H)，7.48-7.43(m，2H)，7.42-7.37(m，5H)，7.37-7.32(m，4H)，7.25-7.18(m，3H)，5.53(s，2H).MS(ESI)：m/z421.15(M+H) + 。
step three: preparation of 3-hydroxy-4- (3-biphenyl) -5- (4-pyridyl) -isothiazole (I-3)
Adding 0.32g (0.760 mmol) of 3-benzyloxy-4- (3-biphenyl) -5- (4-pyridyl) -isothiazole (0.32 g) in 33% HBr acetic acid (10 mL) into a 25mL single-neck flask, stirring at room temperature for 12h, after the reaction, filtering, putting the filter cake into a 50mL flask, adding 30mL of ethyl acetate, stirring at room temperature for 30min, filtering, drying to obtain a white solid with a yield of 59.31%; mp 221-223 ℃; 1 H NMR(400MHz，DMSO-d 6 )：δ10.21(s，1H，OH)，8.94(d，J＝5.9Hz，2H，ArH)，7.91-7.85(m，2H，ArH)，7.74-7.57(m，4H，ArH)，7.55-7.42(m，3H，ArH)，7.42-7.33(m，1H，ArH)，7.27(d，J＝7.8Hz，1H，ArH)； 13 C NMR(100MHz，DMSO-d 6 )：δ167.70，155.28，147.28，143.63，133.33，132.89，129.65，128.80，128.76，128.57，128.09，127.84，127.30，127.01，126.07；HRMS(ESI)：m/z([M-Br] + )calcd for C 20 H 14 N 2 OS 331.0900，found 331.0890。
example 4
Preparation of 3-hydroxy-4- (4-biphenyl) -5- (4-pyridyl) -isothiazole (I-4)
The preparation of I-4 comprises the following three steps:
the method comprises the following steps: preparation of 3-benzyloxy-4- (4-biphenyl) -5-iodo-isothiazole
After adding 0.71g (2.06 mmol) of 3-benzyloxy-4- (4-biphenyl) -isothiazole in a 50mL two-neck flask under the protection of argon, 1.55mL (3.10 mmol) of LDA was added dropwise at-78 deg.C, and stirred for 15 minutes, 0.63g (2.48 mmol) of iodine was dissolved in 20mL of tetrahydrofuran and slowly added to the flask. Stirring was continued for 30min. After the reaction is finished, adding 10mL of water for quenching, adding a little sodium thiosulfate solid, stirring for 2h, extracting with ethyl acetate (30 mL multiplied by 3), drying with anhydrous sodium sulfate, filtering, concentrating, and purifying by column chromatography to obtain a white solid with the yield of 84.31%; mp 117-119 ℃. 1 H NMR(400MHz，CDCl 3 )δ7.75-7.61(m，4H)，7.61-7.55(m，2H)，7.47(t，J＝7.6Hz，2H)，7.43-7.28(m，6H)，5.47(s，2H)；MS(ESI)：m/z 470.05(M+H) + 。
Step two: preparation of 3-benzyloxy-4- (4-biphenyl) -5- (4-pyridyl) -isothiazole
In a 50mL two-necked flask were sequentially added 0.53g (1.13 mmol) of 3-benzyloxy-4- (4-biphenyl) -5-iodo-isothiazole, 0.21g (1.69 mmol) of 4-pyridineboronic acid, 0.23g (1.69 mmol) of potassium carbonate, and 0.065g (0.056 mmol) of tetrakis (triphenylphosphine) palladium, and then 20mL of 1, 4-dioxane and 5mL of water were added thereto, and the mixture was refluxed at 90 ℃ under the protection of argon gas for 10 hours, and after completion of the reaction, it was extracted with ethyl acetate (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered and concentrated. After column chromatography and drying, white solid is obtained with the yield of 69.85 percent; mp 124-126 ℃. 1 H NMR(400MHz，CDCl 3 )：δ8.59-8.57(s，2H，ArH)，7.60(s，2H，ArH)，7.59–7.56(m，2H，ArH)，7.44(m，4H，ArH)，7.36(m，6H，ArH)，7.19(m，J＝4.8Hz，2H，ArH)，5.52(s，2H，CH 2 )；MS(ESI)：m/z 421.15(M+H) + 。
Step three: preparation of 3-hydroxy-4- (4-biphenyl) -5- (4-pyridyl) -isothiazole (I-4)
Adding 0.32g (0.760 mmol) of 3-benzyloxy-4- (4-biphenyl) -5- (4-pyridyl) -isothiazole, which was 33% HBr in acetic acid (10 mL) to a 25mL single-neck flask, stirring at room temperature for 12 hours, after the reaction was completed, filtering, putting the filter cake into a 50mL flask, adding 30mL of ethyl acetate, stirring at room temperature for 30min, filtering, and drying to obtain a white solid with a yield of 69.81%; mp 254-256 deg.C; 1 H NMR(400MHz，DMSO-d 6 )：δ11.24(s，1H，OH)，8.96(d，J＝6.0Hz，2H，ArH)，7.90(d，J＝6.0Hz，2H，ArH)，7.79-7.67(m，4H，ArH)，7.50(t，J＝7.5Hz，2H，ArH)，7.46-7.07(m，4H，ArH)； 13 C NMR(100MHz，DMSO-d 6 )：δ167.53，155.34，146.76，144.25，140.29，139.69，130.92，130.43，129.49，128.26，127.35，127.07，125.69，125.50；HRMS(ESI)：m/z([M-Br] + )calcd for C 20 H 14 N 2 OS 331.0900，found 331.0892。
example 5
Preparation of 3-hydroxy-4- (3-furyl) -5- (4-pyridyl) -isothiazole (I-5)
The preparation of I-5 comprises the following three steps:
the method comprises the following steps: preparation of 3-benzyloxy-4- (3-furyl) -5-iodoisothiazole
After adding 0.53g (2.06 mmol) of 3-benzyloxy-4- (3-furyl) -isothiazole in a 50mL two-necked flask under protection of argon, 1.55mL (3.10 mmol) of LDA was added dropwise at-78 deg.C, and after stirring for 15 minutes, 0.63g (2.48 mmol) of iodine was dissolved in 20mL of tetrahydrofuran and slowly added dropwise. Stirring was continued for 30min. After the reaction was complete, quench with 10mL of water, add a small amount of sodium thiosulfate solid, stir for 2h, extract with ethyl acetate (30 mL. Times.3), dry over anhydrous sodium sulfate, filter and concentrate. Purifying by column chromatography to obtain white solid with yield of 78.36%; mp 38-40 ℃; 1 H NMR(400MHz，CDCl 3 )δ8.05-7.96(m，1H)，7.53-7.30(m，6H)，7.06(t，J＝2.8Hz，1H)，5.47(d，J＝2.8Hz，2H)；MS(ESI)：m/z 384.0(M+H) + 。
step two: preparation of 3-benzyloxy-4- (3-furyl) -5- (4-pyridyl) -isothiazole
0.43g (1.13 mmol) of 3-benzyloxy-4- (3-furyl) -5-iodoisothiazole, 0.21g (1.69 mmol) of 4-pyridineboronic acid, 0.23g (1.69 mmol) of potassium carbonate and 0.065g (0.056 mmol) of tetrakis (triphenylphosphine) palladium were sequentially added to a 50mL two-neck flask, 20mL of 1, 4-dioxane and 5mL of water were added, the mixture was refluxed to 90 ℃ under the protection of argon for 10 hours, and after the reaction was completed, the mixture was extracted with ethyl acetate (30 mL. Times.3) and dried over anhydrous sodium sulfate,filtering, concentrating, performing column chromatography, and drying to obtain white solid with yield of 66.2%; mp 81-83 ℃. 1 H NMR(400MHz，CDCl 3 )δ8.73-8.67(m，2H)，7.71(dd，J＝1.6，0.9Hz，1H)，7.53-7.47(m，2H)，7.47-7.33(m，6H)，6.22(dd，J＝2.0，0.8Hz，1H)，5.54(s，2H)。MS(ESI)：m/z 335.1(M+H) + 。
Step three: preparation of 3-hydroxy-4- (3-furyl) -5- (4-pyridyl) -isothiazole (I-5)
Adding 0.26g (0.760 mmol) of 3-benzyloxy-4- (3-furyl) -5- (4-pyridyl) -isothiazole, a solution of 33% HBr in acetic acid (10 mL) into a 25mL single-neck flask, stirring at room temperature for 12 hours, after the reaction, filtering, putting the filter cake into a 50mL flask, adding 30mL of ethyl acetate, stirring at room temperature for 30 minutes, filtering, drying to obtain a white solid with a yield of 94.12%; mp 218-220 ℃; 1 H NMR(400MHz，DMSO-d 6 )：δ11.42(s，1H，OH)，9.05(d，J＝6.0Hz，2H，ArH)，8.11(dd，J＝16.8，6.5Hz，2H，ArH)，7.95(s，1H，ArH)，7.82-7.72(m，1H，ArH).6.47-6.34(m，1H，ArH)；HRMS(ESI)：m/z([M-Br] + )calcd for C 12 H 8 N 2 O 2 S 245.0379，found 245.0374。
compounds I-6 to I-10 were prepared in a similar manner to examples 1-5, and the structural formulae and test data for the compounds are given in Table 1 below:
TABLE 1 structural formula of 3-hydroxyisothiazole derivatives and melting point, nuclear magnetic and mass spectral data
Figure BDA0002877010550000091
Figure BDA0002877010550000101
Figure BDA0002877010550000111
Figure BDA0002877010550000121
Experimental example 6
(I) test of inhibitory activity of 3-hydroxyisothiazole derivative on prodenia litura and housefly GABA (gamma-aminobutyric acid) receptors
The experimental method comprises the following steps:
the invention uses housefly and prodenia litura GABA receptor RDL bd Subunit cDNA as template, T7 polymerase (mMESSAGE mMACHINE) TM T7 Ultra Kit; ambion, austin, TX, USA) as a promoter, performing in vitro transcription, purifying to obtain cRNA of two insect GABA receptor subunits, injecting the cRNA into Xenopus laevis oocytes through a nanoliter microinjection system, injecting 5ng of each cell, culturing for 48h, and testing the inhibition rate of the target compound on the GABA receptors of houseflies and prodenia litura by adopting a double-electrode voltage clamp method after confirming the receptor expression.
The inhibition rate of the 3-hydroxyisothiazole derivative on GABA receptors of houseflies and spodoptera litura at the concentration of 100 mu M is determined as shown in the table 2.
TABLE 2 inhibitory Activity of 3-Hydroxyisothiazole derivatives (100. Mu.M) on GABA-induced currents of Prodenia litura and Musca receptors (repetition number n = 3-4)
Figure BDA0002877010550000131
Note: values represent mean ± SEM (n = 3-4).
As shown in the results of Table 2, the tested 3-hydroxyisothiazole derivatives show certain inhibition effect on prodenia litura and housefly GABA receptors at 100 mu M, wherein the inhibition rate on the prodenia litura GABA receptors is 5.8-97.6%, and the inhibition rate on the housefly GABA receptors is 11.4-97.5%.
(II) compounds I-1, I-3, I-4, I-5, I-6 and I-8 with high inhibition rate are tested to have inhibitory activity IC on GABA receptor of housefly and prodenia litura 50 See table 3.
TABLE 3 IC of some compounds on GABA receptors of spodoptera litura and houseflies 50 Value of
Figure BDA0002877010550000132
Note: values represent mean ± SEM (n = 3-4), ND means not determined.
Except for the undetermined items, all 6 compounds in Table 3 showed better inhibitory activity against the GABA receptor of Spodoptera litura or Musca domestica, among which compound I-4,IC having the best inhibitory activity against the GABA receptor of Spodoptera litura 50 Compound I-1, IC with best inhibitory activity on GABA receptors of Musca domestica at a value of 7.1. Mu.M 50 The value was 7.9. Mu.M.
Pesticidal activity test of (tri) 3-hydroxyisothiazole derivative
The experimental method comprises the following steps:
the invention uses an artificial feed mixing method (NY/T1154.10-2008, pesticide indoor bioassay test rule) to measure the toxicity of 10 compounds to prodenia litura larvae at the concentration of 100mg/Kg and 500mg/Kg indoors.
Preparing 100mg/Kg of toxic feed: test compounds were formulated in DMSO (dimethyl sulfoxide) at a concentration of 1X 10 5 Taking 10 mu L of mother liquor from the mother liquor, adding 90 mu L of LDMSO, uniformly mixing to prepare 100 mu L of liquid medicine with the concentration of 10000mg/L, adding 500 mu L of LDMSO, uniformly mixing with 10g of newly prepared feed to prepare toxic feed with the concentration of 100mg/Kg (600 mu L of LDMSO is directly added to a blank control group and is uniformly mixed with 10g of feed), pouring the fresh toxic feed into a disposable culture dish, placing the culture dish in a ventilated cabinet to ventilate so as to fully volatilize the organic solvent DMSO.
Preparing 500mg/Kg of toxic feed: test compounds were formulated in DMSO at a concentration of 1X 10 5 Taking 50 mu L of mother liquor from the mother liquor, adding 50 mu L of DMSO, uniformly mixing to prepare 100 mu L of liquid medicine with the concentration of 10000mg/L, adding 500 mu L of DMSO, uniformly mixing with 10g of newly prepared feed to prepare toxic feed with the concentration of 500mg/Kg (600 mu L of DMSO is directly added to a blank control group, and the mixture is uniformly mixed with 10g of feed), pouring fresh toxic feed into a disposable culture dish, placing the culture dish in a ventilation cabinet for ventilation, and fully volatilizing the organic solvent DMSO.
Respectively putting two batches of toxic feeds with different concentrations into two six-hole plates, putting 0.5g of each hole, inoculating 10 healthy 3-instar spodoptera litura larvae with the same size into each hole, and replacing the fresh toxic feeds every 24 hours; after 48h, larval mortality was observed (the test insects which touched their bodies and did not respond to any reaction were all considered dead). The above procedure was repeated three times for each compound, and the number of deaths was counted and the mortality was calculated and corrected. Corrected mortality calculation formula:
Figure BDA0002877010550000141
P 1 indicating corrected mortality, P 0 Indicating mortality in the control group, P t Indicating the mortality of the experimental group.
The insecticidal effects of the compounds obtained by statistical analysis are shown in tables 4 and 5.
TABLE 4 insecticidal Activity of the target Compounds on Spodoptera litura at 100mg/Kg concentration
Figure BDA0002877010550000151
Note: mortality and corrected mortality were mean ± SEM (n = 3)
TABLE 5 insecticidal Activity of the target Compounds on Spodoptera litura at a concentration of 500mg/Kg
Figure BDA0002877010550000152
Note: mortality and corrected mortality were mean ± SEM (n = 3)
According to the insecticidal results of 10 compounds on 3-instar spodoptera litura larvae at two different concentrations of 100mg/Kg and 500mg/Kg, I-1, I-4, I-5, I-6 and I-8 in the 3-hydroxyisothiazole derivative provided by the invention have certain insecticidal activity. Wherein, I-1, I-4, I-6 and I-8 have better insecticidal activity under different concentrations, and the insecticidal effects of I-1, I-4 and I-8 are improved to a certain extent along with the increase of the concentrations.
The activity experiments show that the 3-hydroxyisothiazole derivative has inhibitory activity on insect GABA receptors, has obvious insecticidal action and has application prospect in developing novel GABA receptor insecticides.

Claims (8)

1. A 3-hydroxyisothiazole derivative which is a compound represented by the formula i:
Figure FDA0003719703240000011
the R is 1 Selected from 2-naphthyl, 1-naphthyl, 3-biphenyl, 4-biphenyl, 3-furyl, 3-thienyl, 4-pyridyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-hydroxyphenyl; r 2 Is a hydroxyl group.
2. A process for preparing 3-hydroxyisothiazole derivative according to claim 1, wherein the synthetic route is represented by the following formula ii:
Figure FDA0003719703240000012
wherein R is 1 Selected from 2-naphthyl, 1-naphthyl, 3-biphenyl, 4-biphenyl, 3-furyl, 3-thienyl, 4-pyridyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-hydroxyphenyl;
the method comprises the following specific steps:
1) Performing halogenation reaction on the compound 1, lithium diisopropylamide and iodine simple substance to obtain a compound 2;
2) Carrying out Suzuki coupling reaction on the compound 2, 4-pyridine boric acid, potassium carbonate and tetrakis (triphenylphosphine) palladium to obtain a compound 3;
3) Deprotecting compound 3 in hydrobromic acid in acetic acid as required to give compound 4;
4) Compound 4 was further prepared as a pharmaceutically acceptable salt as needed.
3. The process for producing 3-hydroxyisothiazole derivative according to claim 2, wherein the solvent used in the halogenation reaction in the step 1) is 1, 4-dioxane, tetrahydrofuran, DMF or a mixed solvent of 1, 4-dioxane and water;
the molar ratio of the compound 1, lithium diisopropylamide and iodine in the step 1) is 1: (1-2): (1-1.5), the temperature of the halogenation reaction is-55 to-95 ℃, and the reaction time is 10-60 minutes.
4. The method for preparing 3-hydroxyisothiazole derivative according to claim 2, wherein the solvent used in the step 2) Suzuki coupling reaction is 1, 4-dioxane, tetrahydrofuran, DMF or a mixed solvent of 1, 4-dioxane and water;
the molar ratio of the compound 2 in the step 2) to 4-pyridine boric acid, potassium carbonate and tetrakis (triphenylphosphine) palladium is 1: (1-1.5): (1-1.5): 0.1, the reaction temperature is 60-110 ℃, and the reaction time is 6-10 hours.
5. The process for producing a 3-hydroxyisothiazole derivative according to claim 2, wherein the mass-to-volume ratio of the compound 3 in the step 3) to the solution of hydrobromic acid in acetic acid is 1g: (5-25) mL.
6. Use of a 3-hydroxyisothiazole derivative according to claim 1 for the preparation of a GABA receptor antagonist.
7. A GABA receptor antagonist, characterized in that it comprises the 3-hydroxyisothiazole derivative according to claim 1.
8. Use of the 3-hydroxyisothiazole derivative according to claim 1 for the preparation of a pesticide.
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