1-Chloro-6,8-difluoro-7-isopropylbenzofuro[2,3-c]pyridine and its synthesis method and application

Abstract

The present invention relates to the technical field of organic synthesis, and in particular to a 1-chloro-6,8-difluoro-7-isopropylbenzofuro[2,3-c]pyridine, its synthesis method and application. The present invention uses 1-chloro-6,8-difluoro-7-isopropylbenzofuro[2,3-c]pyridine to cooperate with nano-gold to cover the surface of a glassy carbon electrode (GCE), and develops a novel electrochemically modified electrode AuNPs / 1 / GCE. The modified glassy carbon electrode shows good selectivity, high stability, sensitivity and a wide detection range for the detection of the agricultural residue pymetrozine.

Description

Technical Field

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

[0002] Pesticide residues have always been a very serious environmental problem. Since most pesticides have significant biological toxicity, once excessive pesticide residues accumulate and pollute the soil and water bodies, 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 triazinone insecticides, and this product shows excellent control effects on piercing-sucking mouthpart pests of various crops. However, due to the fact that the pesticide residue content in actual samples is often very small 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, etc. 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, and there may be cross-interference problems for compounds with similar structures. Complex sample matrices may cause signal suppression or enhancement in LC-MS / MS, affecting the quantitative accuracy, and elaborate optimization of the pretreatment steps is required 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. The fluorescence detector can only detect substances with specific fluorescence properties, while pymetrozine itself does not have strong fluorescence characteristics, so a fluorescence label needs to be introduced through a chemical reaction, and this step increases the possibility of errors.

[0004] In the prior art, electrochemical sensors enhanced with nanomaterials, such as electrochemical sensors based on gold nanoparticles or other noble metal nanoparticles, are used to modify the electrode surface to improve the detection sensitivity and stability. However, their long-term stability and service life still need to be further optimized. Especially under complex environmental conditions (such as temperature changes, humidity, pH value fluctuations, etc.), the nanomaterials may aggregate or degrade, affecting the performance of the sensor. Moreover, the preparation process of nanomaterials is relatively complex, which may lead to differences between batches, thus affecting the reproducibility and consistency of the sensor. By synthesizing an imprinted polymer layer for specific target molecules on the electrode surface, the selectivity and sensitivity of the sensor can be improved. However, due to the presence of structural analogs 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 polymerization conditions, and a slight deviation may lead to a decrease in performance.

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

[0006] The first aspect of the present invention provides a method for synthesizing 1-chloro-6,8-difluoro-7-isopropylbenzofuro[2,3-c]pyridine, comprising the following steps:

[0007] (1) Synthesizing 1-bromo-3,5-difluoro-4-iodo-2-methoxybenzene from 1-bromo-3,5-difluoro-2-methoxybenzene and iodine;

[0008] (2) Synthesizing 1-bromo-3,5-difluoro-2-methoxy-4-(prop-1-en-2-yl)benzene from 1-bromo-3,5-difluoro-4-iodo-2-methoxybenzene, 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane, and 1,1-bis(diphenylphosphino)ferrocene dichloropalladium;

[0009] (3) Synthesizing 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-carbon;

[0010] (4) Synthesizing 2-chloro-4-(3,5-difluoro-4-isopropyl-2-methoxyphenyl)-3-fluoropyridine from 1-bromo-3,5-difluoro-2-methoxy-4-isopropylbenzene, (2-chloro-3-fluoropyridin-4-yl)boronic acid, and 1,1-bis(diphenylphosphino)ferrocene dichloropalladium;

[0011] (5) Synthesizing 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;

[0012] (6) 1-chloro-6,8-difluoro-7-isopropylbenzofuro[2,3-c]pyridine is synthesized from 2-chloro-4-(3,5-difluoro-4-isopropyl-2-hydroxyphenyl)-3-fluoropyridine and N,N-dimethylformamide.

[0013] The reaction formula is as follows:

[0014]

[0015] As a preferred embodiment, the molar ratio of 1-bromo-3,5-difluoro-2-methoxybenzene to iodine is 1:(1 - 1.2).

[0016] 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).

[0017] 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.

[0018] As a preferred embodiment, the molar ratio of 1-bromo-3,5-difluoro-2-methoxy-4-isopropylbenzene to (2-chloro-3-fluoropyridin-4-yl)boronic acid is 1:(1 - 1.3).

[0019] 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).

[0020] The second aspect of the present invention provides a 1-chloro-6,8-difluoro-7-isopropylbenzofuro[2,3-c]pyridine obtained by the above synthesis method.

[0021] The third aspect of the present invention provides an application of 1-chloro-6,8-difluoro-7-isopropylbenzofuro[2,3-c]pyridine for detecting the content of the pesticide residue pymetrozine.

[0022] As a preferred embodiment, 1-chloro-6,8-difluoro-7-isopropylbenzofuro[2,3-c]pyridine and gold nanoparticles are coated on the surface of a glassy carbon electrode to obtain an electrochemically modified electrode AuNPs / 1 / GCE for detecting the content of the pesticide residue pymetrozine.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] 1. The present invention synthesizes an organic compound, 1-chloro-6,8-difluoro-7-isopropylbenzofuro[2,3-c]pyridine, which is a very promising organic intermediate and material intermediate and has important significance in the fields of material chemistry and the like.

[0025] 2. The present invention uses 1-chloro-6,8-difluoro-7-isopropylbenzofuro[2,3-c]pyridine to cooperate with nano-gold to cover the surface of a glassy carbon electrode (GCE), and develops a new type of electrochemical modified electrode AuNPs / 1 / GCE. The modified glassy carbon electrode shows good selectivity, high stability and sensitivity, and a wide detection range for the detection of the pesticide pymetrozine. Description of the Drawings

[0026] Figure 1 It is a graph of the experimental results for measuring the conductivity of each electrode by cyclic voltammetry.

[0027] Figure 2 It is a standard curve for the detection of pymetrozine by the modified electrode AuNPs / 1 / GCE.

[0028] Figure 3 It is a graph of the experimental results for the detection of pymetrozine by the modified electrode AuNPs / 1 / GCE.

[0029] Figure 4 It is a graph of the experimental results for the detection of other pesticides by the modified electrode AuNPs / 1 / GCE.

[0030] Figure 5 It is a graph of the experimental results for the detection of pymetrozine containing interfering substances by the modified electrode AuNPs / 1 / GCE.

[0031] Figure 6 It is a graph of the experimental results for the influence of time factors on the detection of pymetrozine by the modified electrode AuNPs / 1 / GCE. Detailed Embodiments

[0032] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0033] Example 1

[0034] This example provides a synthesis method of 1-chloro-6,8-difluoro-7-isopropylbenzofuro[2,3-c]pyridine, including the following steps:

[0035] (1) Synthesis of 1-bromo-3,5-difluoro-4-iodo-2-methoxybenzene

[0036] ;

[0037] To a 100 mL reaction flask, diisopropylamine (3.5 g, 34.5 mmol) and 10 mL of tetrahydrofuran were added successively. The flask was purged with nitrogen three times and then cooled to -10 °C under nitrogen protection. While maintaining the temperature at -10 °C, 14 mL of n-butyllithium (2.5 M, 34.5 mmol) was added dropwise. After the addition was complete, the mixture was kept at 0 °C for standby (LDA solution). Separately, to a 250 mL reaction flask, 1-bromo-3,5-difluoro-2-methoxybenzene (7 g, 31.4 mmol) and 35 mL of tetrahydrofuran were added. Under nitrogen protection, the previously prepared LDA solution was added dropwise at -60 °C. After the addition was complete, the reaction mixture was kept warm for 1 hour. A mixed solution of iodine (8.8 g, 34.5 mmol) and 20 mL of tetrahydrofuran was added dropwise at -60 °C, and then the reaction was carried out at room temperature for 16 hours. After the reaction was completed, 150 mL of water was added to the reaction solution, and the product was extracted with dichloromethane. The organic phase was washed with water and then dried and concentrated. The resulting oil was purified by silica gel column chromatography using PE as the eluent to obtain 8.6 g of the target product, yellow solid 1-bromo-3,5-difluoro-4-iodo-2-methoxybenzene, with a yield of 79%.

[0038] Synthesis of 1-bromo-3,5-difluoro-2-methoxy-4-(prop-1-en-2-yl)benzene

[0039] ;

[0040] To a 1 L reaction flask, 1-bromo-3,5-difluoro-4-iodo-2-methoxybenzene (100 g, 287 mmol), sodium carbonate (99 g, 718 mmol), 0.5 L of 1,4-dioxane, 0.1 L of water, 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (48.3 g, 287 mmol), and 1,1-bis(diphenylphosphino)ferrocene dichloropalladium(II) (10.5 g, 14.4 mmol) were added. After purging with nitrogen, the reaction was carried out at 80 °C for 16 hours under nitrogen protection. The reaction solution was cooled to 40 °C, 3 L of water was added, and then the mixture was extracted with dichloromethane. After drying, the mixture was concentrated and purified by silica gel column chromatography using pure petroleum ether as the eluent to obtain 70 g of the target product, yellow liquid 1-bromo-3,5-difluoro-2-methoxy-4-(prop-1-en-2-yl)benzene, with a yield of 93%.

[0041] 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).

[0042] (3) Synthesis of 1-bromo-3,5-difluoro-2-methoxy-4-isopropylbenzene

[0043] ;

[0044] Add 1-bromo-3,5-difluoro-2-methoxy-4-(prop-1-en-2-yl)benzene (90 g, 0.342 mol) and 0.45 L of methanol to a 1 L reaction flask. Under nitrogen protection, add platinum-carbon (15 g, 10% platinum), and then replace the reaction system with hydrogen. Keep the temperature at 25 °C overnight. Filter the reaction solution, concentrate and dry the filtrate to obtain 72 g of the target product, 1-bromo-3,5-difluoro-2-methoxy-4-isopropylbenzene, as a yellow liquid, with a yield of 79%.

[0045] (4) Synthesis of 2-chloro-4-(3,5-difluoro-4-isopropyl-2-methoxyphenyl)-3-fluoropyridine

[0046] ;

[0047] Add 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 of 1,4-dioxane, 6 mL of water, (2-chloro-3-fluoropyridin-4-yl)boronic acid (5.03 g, 28.5 mmol), and 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (0.86 g, 1.19 mmol) to a 100 mL reaction flask. After replacing with nitrogen, react at 80 °C for 16 hours under nitrogen protection. Cool the reaction solution to 40 °C, add 50 mL of water, then extract with dichloromethane, dry and concentrate. Purify by silica gel column chromatography using 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%.

[0048] (5) Synthesis of 2-chloro-4-(3,5-difluoro-4-isopropyl-2-hydroxyphenyl)-3-fluoropyridine

[0049] ;

[0050] To a 100 mL reaction flask, 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 successively. The mixture was purged with nitrogen three times and then cooled to -10 °C under nitrogen protection. While maintaining the temperature at -10 °C, a mixed solution of boron tribromide (3.02 g, 120.6 mmol) and 20 mL of dichloromethane was added dropwise. Subsequently, the reaction was carried out at room temperature for 4 hours. After the reaction was completed, 50 mL of water was added dropwise to the reaction solution at 0 °C. The product was extracted with dichloromethane. The organic phase was washed with water and then dried and concentrated to obtain an oily substance. The oily substance was purified by silica gel column chromatography using 100% petroleum ether to obtain 1.8 g of the target product, 2-chloro-4-(3,5-difluoro-4-isopropyl-2-hydroxyphenyl)-3-fluoropyridine, with a yield of 98%.

[0051] (6) Synthesis of 1-chloro-6,8-difluoro-7-isopropylbenzofuro[2,3- c pyridine

[0052] ;

[0053] To a 50 mL reaction flask, 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 successively. The reaction system was purged with nitrogen and stirred at a temperature within 45 °C for 16 hours. Then the temperature was cooled to room temperature, and 150 mL of water was added to quench the reaction. The product was extracted with dichloromethane. The organic phase was dried and concentrated, and purified by silica gel column chromatography with PE / EA = 10 / 1 to obtain 0.8 g of the target product, 1-chloro-6,8-difluoro-7-isopropylbenzofuro[2,3- c pyridine, with a yield of 47.3%.

[0054] 1 H NMR (400 MHz, CDCl3) δ 8.42 (d, J J = 5.1 Hz, 1H), 7.79 (d, J J = 5.1Hz, 1H), 7.48 (dd, J J = 9.1, 1.1 Hz, 1H), 3.61 (dt, J J = 14.2, 7.1 Hz, 1H),1.48 (d, J J = 7.1 Hz, 6H).

[0055] Performance Test

[0056] Experiment 1: Electrochemical detection of pymetrozine in agricultural residues using 1-chloro-6,8-difluoro-7-isopropylbenzofuro[2,3-c]pyridine prepared in Example 1. The specific method is as follows:

[0057] (1) 1-Chloro-6,8-difluoro-7-isopropylbenzofuro[2,3-c]pyridine was combined with gold nanoparticles and coated on the surface of a glassy carbon electrode (GCE) to obtain an electrochemically modified electrode AuNPs / 1 / GCE. The bare GCE electrode and the 1 / GCE electrode were used as control experiments. Cyclic voltammetry (CVS) (scan rate: 100 mV•s -1 ) was used 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, sensitivity, and a wide detection range for the detection of pymetrozine in agricultural residues.

[0058] (2) The number of gold deposition segments was 4, and the electrolyte was potassium chloride solution; the electrolyte concentration was 0.05 M potassium chloride, and the rest time was 80 seconds. The modified electrode AuNPs / 1 / GCE showed a good linear relationship for the concentration of pymetrozine in the range of 1×10 -9 mol / l - 5×10 -6 mol / l (the standard curve is shown in Figure 2 , R 2 = 0.97). The detection results are shown in Figure 3 . This is much 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 shows a wide linear range and a low detection limit for pymetrozine, which has a great advantage compared with the mercury electrode detection method.

[0059] Experiment 2: Electrochemical detection of other agricultural residues using 1-chloro-6,8-difluoro-7-isopropylbenzofuro[2,3-c]pyridine prepared in Example 1. The specific method is as follows:

[0060] As can be seen from Figure 4 , the electrochemically modified electrode AuNPs / 1 / GCE showed weak electrochemical signal intensity for the detection of other pesticides such as [glyphosate (GLY), chlorpyrifos (CHL), glufosinate (GLA), acetamiprid (ACE), atrazine (ATR), matrine (MAT), difenoconazole (DIF), pyraclostrobin (PYR)]. This indicates that the modified electrode AuNPs / 1 / GCE has good selectivity for pymetrozine.

[0061] As can be seen from Figure 5It can be seen that before and after adding interfering substances, the detection of pymetrozine by AuNPs / 1 / GCE has little effect, indicating that the influence of the co-existing pesticides on the detection of pymetrozine by the modified electrode AuNPs / 1 / GCE can be ignored.

[0062] The present invention explores the detection experiment of pymetrozine by the AuNPs / 1 / GCE sensor every other day. Figure 6 It can be seen that the results show that the decrease in the peak intensity is very small, which indicates that the modified electrode AuNPs / 1 / GCE has high repeatability in the detection of pymetrozine. Therefore, the modified electrode AuNPs / 1 / GCE sensor has high selectivity, good anti-interference ability, high sensitivity and wide detection limit for the detection of pymetrozine.

[0063] The above is the preferred embodiment of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A method for synthesizing 1-chloro-6,8-difluoro-7-isopropylbenzofuro[2,3-c]pyridine, characterized in that, It includes the following steps: (1) Synthesize 1-bromo-3,5-difluoro-4-iodo-2-methoxybenzene from 1-bromo-3,5-difluoro-2-methoxybenzene and iodine. (2) Synthesize 1-bromo-3,5-difluoro-2-methoxy-4-(prop-1-en-2-yl)benzene from 1-bromo-3,5-difluoro-4-iodo-2-methoxybenzene, 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane and 1,1-bis(diphenylphosphino)ferrocene dichloropalladium. (3) Synthesize 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 carbon. (4) Synthesize 2-chloro-4-(3,5-difluoro-4-isopropyl-2-methoxyphenyl)-3-fluoropyridine from 1-bromo-3,5-difluoro-2-methoxy-4-isopropylbenzene, (2-chloro-3-fluoropyridin-4-yl)boronic acid and 1,1-bis(diphenylphosphino)ferrocene dichloropalladium. (5) Synthesize 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) Synthesize 1-chloro-6,8-difluoro-7-isopropylbenzofuro[2,3-c]pyridine by reacting 2-chloro-4-(3,5-difluoro-4-isopropyl-2-hydroxyphenyl)-3-fluoropyridine in N,N-dimethylformamide.

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

3. The synthesis method according to claim 2, wherein The molar ratio of the 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, wherein 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)boronic 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-isopropylbenzofuro[2,3-c]pyridine, characterized in that, Obtained by the synthesis method according to any one of claims 1 - 6.

8. Use of 1-chloro-6,8-difluoro-7-isopropylbenzofuro[2,3-c]pyridine, characterized in that, For detecting the content of the pesticide residue pymetrozine.

9. The application according to claim 8, characterized in that, Cover 1-chloro-6,8-difluoro-7-isopropylbenzofuro[2,3-c]pyridine and gold nanoparticles on the surface of a glassy carbon electrode to obtain an electrochemical modified electrode AuNPs / 1 / GCE, which is used for detecting the content of the pesticide residue pymetrozine.

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