1-chloro-6, 8-difluoro-7-isopropyl benzofuro [2, 3-c] pyridine as well as synthesis method and application of 1-chloro-6, 8-difluoro-7-isopropyl benzofuro [2, 3-c] pyridine

Abstract

The invention relates to the technical field of organic synthesis, in particular to 1-chloro-6, 8-difluoro-7-isopropylbenzofuro [2, 3-c] pyridine as well as a synthesis method and an application of the 1-chloro-6, 8-difluoro-7-isopropylbenzofuro [2, 3-c] pyridine. According to the invention, 1-chloro-6, 8-difluoro-7-isopropyl benzofuro [2, 3-c] pyridine is utilized to cooperate with nanogold to cover the surface of a glassy carbon electrode (GCE), and a novel electrochemical modified electrode AuNPs / 1 / GCE is developed. The modified glassy carbon electrode shows good selectivity, high stability and sensitivity and wide detection range on detection of pesticide residue pymetrozine.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to 1-chloro-6,8-difluoro-7-isopropylbenzofurano[2,3-c]pyridine and a synthesis method and application thereof. Background Art

[0002] Pesticide residues have always been a very serious environmental problem. Since most pesticides have significant and biological toxicity, once excessive pesticides accumulate and remain in the soil and water and cause pollution, they can enter the human body through the atmosphere, water, food, etc., accumulate in certain organs of the human body, cause poisoning, and endanger human health.

[0003] Pymetrozine (PYM) belongs to the triazone insecticide class. This product has excellent control effects on piercing-sucking mouthparts pests of various crops. However, the pesticide residue content in actual samples is often very low and the coexisting substances are complex. A variety of methods for detecting pymetrozine residues have been developed, including but not limited to high performance liquid chromatography (HPLC), tandem mass spectrometry (LC-MS / MS), gas chromatography (GC) and fluorescence spectrophotometer. These methods have their own characteristics and are suitable for the detection of pymetrozine residues in different matrices, but they also have their own limitations. HPLC mainly relies on the interaction between the sample and the stationary phase to separate compounds. There may be cross-interference problems for compounds with similar structures. Complex sample matrices may cause LC-MS / MS signal suppression or enhancement, affecting quantitative accuracy. The pretreatment steps need to be carefully optimized to reduce this effect. Due to the polarity and thermal instability of pymetrozine, direct GC analysis is difficult and usually requires derivatization, which increases the time and complexity of sample preparation. Fluorescence detectors can only detect substances with specific fluorescent properties, and pymetrozine itself does not have strong fluorescent properties, so fluorescent labels need to be introduced through chemical reactions. This step increases the possibility of errors.

[0004] In the prior art, electrochemical sensors enhanced by nanomaterials, such as electrochemical sensors based on nanogold or other precious metal nanoparticles, are used to modify the electrode surface to improve the sensitivity and stability of detection, but their long-term stability and service life still need to be further optimized, especially under complex environmental conditions (such as temperature changes, humidity, pH fluctuations, etc.), nanomaterials may aggregate or degrade, affecting the performance of the sensor, and the preparation process of nanomaterials is relatively complicated, which may lead to batch differences, thereby affecting the reproducibility and consistency of the sensor. By synthesizing an imprinted polymer layer for a specific target molecule on the electrode surface, the selectivity and sensitivity of the sensor can be improved, but due to the presence of structural similarities of the target molecule or other competing substances, the imprinting efficiency and selectivity may be affected. In addition, the imprinting effect also depends on the precise control of the polymerization conditions, and a slight deviation may lead to performance degradation.

[0005] Therefore, it is of great practical significance to establish a rapid, highly sensitive and highly selective method for detecting pesticide residues. Summary of the invention

[0006] The first aspect of the present invention provides a method for synthesizing 1-chloro-6,8-difluoro-7-isopropylbenzofurano[2,3-c]pyridine, comprising the following steps: (1) Synthesis of 1-bromo-3,5-difluoro-4-iodo-2-methoxybenzene from 1-bromo-3,5-difluoro-2-methoxybenzene and iodine; (2) 1-Bromo-3,5-difluoro-2-methoxy-4-(prop-1-en-2-yl)benzene was synthesized from 1-bromo-3,5-difluoro-4-iodo-2-methoxybenzene, 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborane and 1,1-bis(diphenylphosphine)diferropalladium dichloride; (3) Synthesis of 1-bromo-3,5-difluoro-2-methoxy-4-isopropylbenzene from 1-bromo-3,5-difluoro-2-methoxy-4-(prop-1-en-2-yl)benzene and platinum on carbon; (4) 2-Chloro-4-(3,5-difluoro-4-isopropyl-2-methoxyphenyl)-3-fluoropyridine was synthesized from 1-bromo-3,5-difluoro-2-methoxy-4-isopropylbenzene, (2-chloro-3-fluoropyridin-4-yl)boric acid and 1,1-bis(diphenylphosphine)diferropalladium dichloride; (5) Synthesis of 2-chloro-4-(3,5-difluoro-4-isopropyl-2-hydroxyphenyl)-3-fluoropyridine from 2-chloro-4-(3,5-difluoro-4-isopropyl-2-methoxyphenyl)-3-fluoropyridine and boron tribromide; (6) 1-Chloro-6,8-difluoro-7-isopropylbenzofurano[2,3-c]pyridine was synthesized from 2-chloro-4-(3,5-difluoro-4-isopropyl-2-hydroxyphenyl)-3-fluoropyridine and N,N-dimethylformamide.

[0007] The reaction formula is as follows:

[0008] As a preferred embodiment, the molar ratio of 1-bromo-3,5-difluoro-2-methoxybenzene to elemental iodine is 1:(1-1.2).

[0009] As a preferred embodiment, the molar ratio of 1-bromo-3,5-difluoro-4-iodo-2-methoxybenzene to 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane is (1-2):(1-2).

[0010] As a preferred embodiment, the mass ratio of 1-bromo-3,5-difluoro-2-methoxy-4-(prop-1-en-2-yl)benzene to platinum carbon is (5-7):1.

[0011] As a preferred embodiment, the molar ratio of 1-bromo-3,5-difluoro-2-methoxy-4-isopropylbenzene to (2-chloro-3-fluoropyridin-4-yl)boric acid is 1:(1-1.3).

[0012] As a preferred embodiment, the molar ratio of 2-chloro-4-(3,5-difluoro-4-isopropyl-2-methoxyphenyl)-3-fluoropyridine to boron tribromide is 1:(1.5-3).

[0013] The second aspect of the present invention provides 1-chloro-6,8-difluoro-7-isopropylbenzofurano[2,3-c]pyridine, which is obtained by the above-mentioned synthesis method.

[0014] The third aspect of the present invention provides an application of 1-chloro-6,8-difluoro-7-isopropylbenzofurano[2,3-c]pyridine for detecting the content of the pesticide residue pymetrozine.

[0015] As a preferred embodiment, 1-chloro-6,8-difluoro-7-isopropylbenzofurano[2,3-c]pyridine and nano-gold are coated on the surface of a glassy carbon electrode to obtain an electrochemically modified electrode AuNPs / 1 / GCE, which is used to detect the content of the pesticide residue pymetrozine.

[0016] Compared with the prior art, the present invention has the following beneficial effects: 1. The present invention synthesizes an organic compound 1-chloro-6,8-difluoro-7-isopropylbenzofurano[2,3-c]pyridine, which is an organic intermediate and material intermediate with great application prospects and has important significance in the fields of material chemistry and the like.

[0017] 2. The present invention uses 1-chloro-6,8-difluoro-7-isopropylbenzofurano[2,3-c]pyridine to cover the surface of glassy carbon electrode (GCE) with gold nanoparticles to develop a new electrochemical modified electrode AuNPs / 1 / GCE. The modified glassy carbon electrode shows good selectivity, high stability and sensitivity as well as a wide detection range for the detection of the pesticide residue pymetrozine. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 This is the experimental result diagram of the conductivity of each electrode determined by cyclic voltammetry.

[0019] Figure 2 This is the standard curve of the modified electrode AuNPs / 1 / GCE for the detection of pymetrozine.

[0020] Figure 3 This is the experimental result of the detection of pymetrozine by the modified electrode AuNPs / 1 / GCE.

[0021] Figure 4 This is the experimental results of the modified electrode AuNPs / 1 / GCE for detecting other pesticides.

[0022] Figure 5 This is the experimental result of the detection of pyriproxyfen containing interfering substances by the modified electrode AuNPs / 1 / GCE.

[0023] Figure 6 This is the experimental result of the effect of time factor on the detection of pymetrozine at the modified electrode AuNPs / 1 / GCE. DETAILED DESCRIPTION

[0024] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0025] Example 1 This embodiment provides a method for synthesizing 1-chloro-6,8-difluoro-7-isopropylbenzofurano[2,3-c]pyridine, comprising the following steps: (1) Synthesis of 1-bromo-3,5-difluoro-4-iodo-2-methoxybenzene ; Add diisopropylamine (3.5 g, 34.5 mmol) and 10 mL of tetrahydrofuran to a 100 mL reaction bottle. Replace with nitrogen three times, then cool to -10°C under nitrogen protection, add 14 mL of n-butyl lithium (2.5 M, 34.5 mmol) dropwise at -10°C, keep warm at 0°C for later use (LDA solution), take another 250 mL reaction bottle, add 1-bromo-3,5-difluoro-2-methoxybenzene (7 g, 31.4 mmol) and 35 mL of tetrahydrofuran, add the previously prepared LDA solution dropwise at -60°C under nitrogen protection, keep warm for 1 hour after the addition is complete, add a mixed solution of iodine (8.8 g, 34.5 mmol) and 20 mL of tetrahydrofuran dropwise at -60°C, and then react at room temperature for 16 hours. After the reaction, 150 mL of water was added to the reaction solution, and the product was extracted with dichloromethane. The organic phase was washed with water, dried and concentrated to obtain an oily substance, which was purified by PE silica gel column chromatography to obtain 8.6 g of the target product, 1-bromo-3,5-difluoro-4-iodo-2-methoxybenzene, as a yellow solid, with a yield of 79%.

[0026] (2) Synthesis of 1-bromo-3,5-difluoro-2-methoxy-4-(prop-1-en-2-yl)benzene ; To a 1L reaction bottle, 1-bromo-3,5-difluoro-4-iodo-2-methoxybenzene (100 g, 287 mmol), sodium carbonate (99 g, 718 mmol), 0.5L 1, 4-dioxane, 0.1L water, 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborane (48.3 g, 287 mmol), 1,1-bis(diphenylphosphino)diborane iron dichloride palladium (10.5 g, 14.4 mmol) were added. After nitrogen replacement, the reaction was carried out at 80°C under nitrogen protection for 16 hours. The reaction solution was cooled to 40°C, 3 L of water was added, and then extracted with dichloromethane. After drying, it was concentrated and purified by pure petroleum ether silica gel column chromatography to obtain 70 g of the target product, a yellow liquid 1-bromo-3,5-difluoro-2-methoxy-4-(prop-1-en-2-yl)benzene, with a yield of 93%.

[0027] 1 H NMR (400 MHz, DMSO-d6) δ 7.52 (dd, J = 9.2, 2.2 Hz, 1H), 5.56 -5.45 (m, 1H), 5.14 (s, 1H), 3.85 (s, 3H), 2.04 (s, 3H).

[0028] (3) Synthesis of 1-bromo-3,5-difluoro-2-methoxy-4-isopropylbenzene ; 1-Bromo-3,5-difluoro-2-methoxy-4-(prop-1-en-2-yl)benzene (90g, 0.342mol) and 0.45L methanol were added to a 1L reaction bottle, and platinum carbon (15g, 10% platinum) was added under nitrogen protection. Then the reaction system was replaced with hydrogen and kept warm at 25 degrees overnight. The reaction solution was filtered, and the filtrate was concentrated and dried to obtain the target product, yellow liquid 1-bromo-3,5-difluoro-2-methoxy-4-isopropylbenzene 72g, with a yield of 79%.

[0029] (4) Synthesis of 2-chloro-4-(3,5-difluoro-4-isopropyl-2-methoxyphenyl)-3-fluoropyridine ; To a 100 mL reaction bottle, 1-bromo-3,5-difluoro-2-methoxy-4-isopropylbenzene (6.5 g, 23.8 mmol), potassium carbonate (9.85 g, 71.4 mmol), 30 mL 1,4-dioxane, 6 mL water, (2-chloro-3-fluoropyridin-4-yl)boric acid (5.03 g, 28.5 mmol), 1,1-bis(diphenylphosphino)diferroni palladium dichloride (0.86 g, 1.19 mmol) were added. After nitrogen replacement, the reaction was carried out at 80 °C for 16 hours under nitrogen protection. The reaction solution was cooled to 40°C, 50 mL of water was added, and then extracted with dichloromethane. After drying, it was concentrated and purified by silica gel column chromatography with 100% petroleum ether to obtain 1.9 g of the target product, 2-chloro-4-(3,5-difluoro-4-isopropyl-2-methoxyphenyl)-3-fluoropyridine, as a yellow liquid, with a yield of 25.3%.

[0030] (5) Synthesis of 2-chloro-4-(3,5-difluoro-4-isopropyl-2-hydroxyphenyl)-3-fluoropyridine ; 2-Chloro-4-(3,5-difluoro-4-isopropyl-2-methoxyphenyl)-3-fluoropyridine (1.9 g, 60.3 mmol) and 20 mL of dichloromethane were added to a 100 mL reaction bottle in sequence. The mixture was replaced with nitrogen three times, then cooled to -10 °C under nitrogen protection, and a mixed solution of boron tribromide (3.02 g, 120.6 mmol) and 20 mL of dichloromethane was added dropwise at -10 °C, and then reacted at room temperature for 4 hours. After the reaction, 50 mL of water was added dropwise to the reaction solution at 0 °C, and the product was extracted with dichloromethane. The organic phase was washed with water, dried and concentrated to obtain an oily substance, which was purified by silica gel column chromatography with 100% petroleum ether to obtain 1.8 g of the target product 2-chloro-4-(3,5-difluoro-4-isopropyl-2-hydroxyphenyl)-3-fluoropyridine as a yellow oily substance with a yield of 98%.

[0031] (6) 1-Chloro-6,8-difluoro-7-isopropylbenzofuran[2,3- c Synthesis of pyridine ; 2-Chloro-4-(3,5-difluoro-4-isopropyl-2-hydroxyphenyl)-3-fluoropyridine (1.8 g, 6 mmol), 20 mL of N,N-dimethylformamide, potassium carbonate (3.3 g, 24 mmol) were added to a 50 mL reaction bottle in sequence, and the atmosphere was replaced with nitrogen. The reaction system was stirred at 45 °C for 16 hours. Then the temperature was cooled to room temperature, 150 mL of water was added to quench the reaction, and the dichloromethane was extracted. The organic phase was dried and concentrated, and purified by PE / EA=10 / 1 silica gel column to obtain the target product as an off-white solid 1-chloro-6,8-difluoro-7-isopropylbenzofuran[2,3- c ]Pyridine 0.8g, yield: 47.3%.

[0032] 1 H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 5.1 Hz, 1H), 7.79 (d, J = 5.1Hz, 1H), 7.48 (dd, J = 9.1, 1.1 Hz, 1H), 3.61 (dt, J = 14.2, 7.1 Hz, 1H),1.48 (d, J = 7.1 Hz, 6H).

[0033] Performance Testing Experiment 1: The 1-chloro-6,8-difluoro-7-isopropylbenzofurano[2,3-c]pyridine prepared in Example 1 was subjected to an electrochemical detection experiment of the pesticide residue pymetrozine. The specific method is as follows: (1) 1-Chloro-6,8-difluoro-7-isopropylbenzofuran[2,3-c]pyridine was synergistically coated with gold nanoparticles on the surface of glassy carbon electrode (GCE) to obtain an electrochemically modified electrode AuNPs / 1 / GCE. The bare GCE electrode and 1 / GCE electrode were used as comparative experiments. Cyclic voltammetry (CVS) (scan rate of 100 mV•s -1 ) to probe the conductivity of each electrode, the experimental results are shown in Figure 1 As can be seen from the figure, the AuNPs / 1 / GCE electrode has good conductivity and shows good selectivity, high stability and sensitivity as well as a wide detection range for the detection of the pesticide residue pymetrozine.

[0034] (2) The number of gold deposition segments is 4, the electrolyte is potassium chloride solution; the electrolyte concentration is 0.05 M potassium chloride, and the static time is 80 seconds. The modified electrode AuNPs / 1 / GCE has a good stability to pymetrozine concentration of 1×10 -9 mol / l - 5×10 -6 mol / l concentration range shows a good linear relationship (standard curve see Figure 2 , R 2 = 0.97), the test results are shown in Figure 3 , which is far lower than the limit concentration set by the US Environmental Protection Agency and the World Health Organization. In particular, the modified electrode AuNPs / 1 / GCE exhibits a wide linear range and low detection limit for pymetrozine, which is a great advantage compared to the mercury electrode detection method.

[0035] Experiment 2: The 1-chloro-6,8-difluoro-7-isopropylbenzofurano[2,3-c]pyridine prepared in Example 1 was subjected to an electrochemical detection experiment for other pesticide residues. The specific method is as follows: Depend on Figure 4 It can be seen that the electrochemical signal intensity of the modified electrode AuNPs / 1 / GCE for the detection of other pesticides such as [glyphosate (GLY), chlorpyrifos (CHL), glufosinate (GLA), acetamiprid (ACE), atrazine (ATR), matrine (MAT), difenoconazole (DIF), pyraclostrobin (PYR)] is weak, which shows that the modified electrode AuNPs / 1 / GCE has good selectivity for pymetrozine.

[0036] Depend on Figure 5 It can be seen that AuNPs / 1 / GCE has almost no effect on the detection of pymetrozine before and after the addition of interfering substances, indicating that the effect of the modified electrode AuNPs / 1 / GCE on the detection of pymetrozine in the presence of coexisting pesticides can be ignored.

[0037] The present invention explores the AuNPs / 1 / GCE sensor to detect pymetrozine every other day. Figure 6 It can be seen that the peak intensity decreases slightly, which indicates that the modified electrode AuNPs / 1 / GCE has a high repeatability in the detection of pymetrozine. Therefore, the modified electrode AuNPs / 1 / GCE sensor has high selectivity, good anti-interference, high sensitivity and wide detection limit for the detection of pymetrozine.

[0038] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for synthesizing 1-chloro-6,8-difluoro-7-isopropylbenzofurano[2,3-c]pyridine, characterized in that: The steps include: (1) Synthesis of 1-bromo-3,5-difluoro-4-iodo-2-methoxybenzene from 1-bromo-3,5-difluoro-2-methoxybenzene and iodine; (2) 1-Bromo-3,5-difluoro-2-methoxy-4-(prop-1-en-2-yl)benzene was synthesized from 1-bromo-3,5-difluoro-4-iodo-2-methoxybenzene, 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborane and 1,1-bis(diphenylphosphine)diferropalladium dichloride; (3) Synthesis of 1-bromo-3,5-difluoro-2-methoxy-4-isopropylbenzene from 1-bromo-3,5-difluoro-2-methoxy-4-(prop-1-en-2-yl)benzene and platinum on carbon; (4) 2-Chloro-4-(3,5-difluoro-4-isopropyl-2-methoxyphenyl)-3-fluoropyridine was synthesized from 1-bromo-3,5-difluoro-2-methoxy-4-isopropylbenzene, (2-chloro-3-fluoropyridin-4-yl)boric acid and 1,1-bis(diphenylphosphine)diferropalladium dichloride; (5) Synthesis of 2-chloro-4-(3,5-difluoro-4-isopropyl-2-hydroxyphenyl)-3-fluoropyridine from 2-chloro-4-(3,5-difluoro-4-isopropyl-2-methoxyphenyl)-3-fluoropyridine and boron tribromide; (6) 1-Chloro-6,8-difluoro-7-isopropylbenzofurano[2,3-c]pyridine was synthesized from 2-chloro-4-(3,5-difluoro-4-isopropyl-2-hydroxyphenyl)-3-fluoropyridine and N,N-dimethylformamide.

2. The synthesis method according to claim 1, characterized in that The molar ratio of the 1-bromo-3,5-difluoro-2-methoxybenzene to the iodine element is 1:(1-1.2).

3. The synthesis method according to claim 2, characterized in that The molar ratio of 1-bromo-3,5-difluoro-4-iodo-2-methoxybenzene to 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane is (1-2):(1-2).

4. The synthesis method according to claim 3, characterized in that The mass ratio of the 1-bromo-3,5-difluoro-2-methoxy-4-(prop-1-en-2-yl)benzene to platinum carbon is (5-7):

1.

5. The synthesis method according to claim 4, characterized in that The molar ratio of the 1-bromo-3,5-difluoro-2-methoxy-4-isopropylbenzene to (2-chloro-3-fluoropyridin-4-yl)boric acid is 1:(1-1.3).

6. The synthesis method according to claim 5, characterized in that The molar ratio of the 2-chloro-4-(3,5-difluoro-4-isopropyl-2-methoxyphenyl)-3-fluoropyridine to boron tribromide is 1:(1.5-3).

7. A 1-chloro-6,8-difluoro-7-isopropylbenzofurano[2,3-c]pyridine, characterized in that: Obtained by the synthesis method according to any one of claims 1 to 6.

8. An application of 1-chloro-6,8-difluoro-7-isopropylbenzofurano[2,3-c]pyridine, characterized in that: Used to detect the content of the pesticide residue pymetrozine.

9. The use according to claim 8, characterized in that: 1-Chloro-6,8-difluoro-7-isopropylbenzofuran[2,3-c]pyridine and gold nanoparticles were coated on the surface of glassy carbon electrode to obtain the electrochemically modified electrode AuNPs / 1 / GCE, which was used to detect the content of the pesticide residue pymetrozine.

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