3-bromo-6-chloro-4-methylbenzofuro[3,2-c]pyridine and synthesis method and application thereof

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to 3-bromo-6-chloro-4-methylbenzofuro[3,2-c]pyridine and a synthesis method and application thereof. The synthesis method comprises the following steps: (1) synthesizing 2-bromo-5-(3-chloro-2-methoxyphenyl)pyridine-4-amine; (2) synthesizing 3-bromo-6-chlorobenzofuro[3,2-c]pyridine; and (3) synthesizing 3-bromo-6-chloro-4-methylbenzofuro[3,2-c]pyridine. The 3-bromo-6-chloro-4-methylbenzofuro[3,2-c]pyridine is cooperated with nano gold to cover the surface of a glassy carbon electrode, and the modified glassy carbon electrode shows good selectivity, high stability and sensitivity and a wide detection range for the detection of the antibiotic nitroimidazole.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to 3-bromo-6-chloro-4-methylbenzofurano[3,2-c]pyridine, its synthesis method, and its application. Background Technology

[0002] In recent years, the overuse of antibiotics has become increasingly serious, leading to a large amount of residue entering the soil and water environment, posing a significant threat to ecosystems and human health. Excessive accumulation of antibiotics not only pollutes soil and water bodies but also induces antibiotic resistance in bacteria, increasing the difficulty of clinical treatment and medical costs. Therefore, antibiotics have been considered a new type of environmental pollutant, with ronidazole (RDZ) being a typical example. Ronidazole is commonly used to prevent and treat protozoan infections in livestock and poultry, but if its residues in edible animal tissues exceed the limit, it will produce significant toxic effects, damaging the liver and kidneys in humans and posing a potential carcinogenic risk. Various countries have strict regulations on the maximum residue limits for ronidazole; however, the actual ronidazole content in samples is usually extremely low, and the coexisting matrix is ​​complex. Therefore, establishing a rapid, highly sensitive, and highly selective method for the detection of ronidazole is of significant practical importance.

[0003] Currently, the main methods for detecting ronidazole include high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC-MS), capillary electrophoresis, and electrochemical analysis. While chromatography and mass spectrometry offer high sensitivity and accuracy, they involve cumbersome sample pretreatment, long detection times, and expensive instruments, making them unsuitable for rapid on-site detection. Electrochemical analysis offers high sensitivity, but the stability and selectivity of electrode modification materials still need improvement. In recent years, fluorescence sensing technology has attracted widespread attention in the field of trace pollutant detection due to its advantages of rapid response, ease of operation, and high sensitivity. However, existing fluorescent probes often suffer from poor selectivity, weak anti-interference ability, and complex synthesis, limiting their application in practical samples.

[0004] Benzofuranopyridine compounds are a class of fluorescent skeletons with fused heterocyclic structures. Due to their excellent photophysical properties and structural tunability, they show broad application prospects in fluorescence sensing, bioimaging, and other fields. By introducing different substituents (such as halogen atoms, alkyl groups, etc.) onto the benzofuranopyridine parent compound, its electron cloud density, conjugation degree, and intramolecular charge transfer behavior can be tuned, thereby achieving selective recognition and response to specific analytes. Currently, there are no reports on the use of 3-bromo-6-chloro-4-methylbenzofurano[3,2-c]pyridine for the detection of ronidazole.

[0005] Therefore, developing a simple and novel 3-bromo-6-chloro-4-methylbenzofurano[3,2-c]pyridine compound and exploring its application in the highly sensitive and selective detection of ronidazole is of great significance for overcoming the shortcomings of existing detection methods and ensuring food safety and environmental monitoring. Summary of the Invention

[0006] The first aspect of this invention provides a method for synthesizing 3-bromo-6-chloro-4-methylbenzofurano[3,2-c]pyridine, comprising the following steps:

[0007] (1) Synthesis of 2-bromo-5-(3-chloro-2-methoxyphenyl)pyridine-4-amine

[0008] 2-Bromo-5-(3-chloro-2-methoxyphenyl)pyridine-4-amine was synthesized from 2-bromo-5-iodo-4-aminopyridine, 1,1-bis(diphenylphosphine)ferrocene palladium dichloride and (3-chloro-2-methoxyphenyl)boronic acid under catalyst 1.

[0009] (2) Synthesis of 3-bromo-6-chlorobenzofurano[3,2-c]pyridine

[0010] 3-Bromo-6-chlorobenzofurano[3,2-c]pyridine was synthesized from 2-bromo-5-(3-chloro-2-methoxyphenyl)pyridine-4-amine and tert-butyl nitrite.

[0011] (3) Synthesis of 3-bromo-6-chloro-4-methylbenzofurano[3,2-c]pyridine

[0012] 3-Bromo-6-chloro-4-methylbenzofuran[3,2-c]pyridine was synthesized from diisopropylamine, n-butyllithium, and 3-bromo-6-chlorobenzofuran[3,2-c]pyridine under catalyst 2.

[0013] The reaction formula of this invention is as follows:

[0014]

[0015] In a preferred embodiment, the molar ratio of 2-bromo-5-iodo-4-aminopyridine, 1,1-bis(diphenylphosphine)ferrocene palladium dichloride and (3-chloro-2-methoxyphenyl)boronic acid is (50-55):(2-3):(50-55).

[0016] In a preferred embodiment, the molar ratio of 2-bromo-5-(3-chloro-2-methoxyphenyl)pyridine-4-amine to tert-butyl nitrite is (50-55):1000.

[0017] In a preferred embodiment, the molar ratio of diisopropylamine, n-butyllithium, and 3-bromo-6-chlorobenzofurano[3,2-c]pyridine is (30-35):(30-35):(20-25).

[0018] In a preferred embodiment, the catalyst 1 is potassium carbonate.

[0019] In a preferred embodiment, the catalyst 2 is iodomethane.

[0020] A second aspect of the present invention provides a 3-bromo-6-chloro-4-methylbenzofurano[3,2-c]pyridine, obtained by the aforementioned synthetic method, and its structural formula is as follows:

[0021] .

[0022] A third aspect of the present invention provides an application of 3-bromo-6-chloro-4-methylbenzofurano[3,2-c]pyridine, wherein the 3-bromo-6-chloro-4-methylbenzofurano[3,2-c]pyridine is coated with gold nanoparticles 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 antibiotic ronidazole.

[0023] The fourth aspect of the present invention provides an electrochemically modified electrode AuNPs / 1 / GCE for detecting the content of the antibiotic ronidazole, the electrode comprising 3-bromo-6-chloro-4-methylbenzofurano[3,2-c]pyridine and gold nanoparticles coated on the surface of a glassy carbon electrode.

[0024] Compared with the prior art, the advantages and beneficial effects of the present invention are as follows:

[0025] 1. This invention synthesizes an organic compound, 3-bromo-6-chloro-4-methylbenzofurano[3,2-c]pyridine. This compound is a promising organic intermediate and material intermediate. Currently, there is no existing method for synthesizing 3-bromo-6-chloro-4-methylbenzofurano[3,2-c]pyridine, thus limiting its large-scale application in industry and pharmaceuticals. Therefore, this invention is of great significance for the synthesis of 3-bromo-6-chloro-4-methylbenzofurano[3,2-c]pyridine.

[0026] 2. This invention discovers that 3-bromo-6-chloro-4-methylbenzofurano[3,2-c]pyridine possesses active sites. Experimentally, 3-bromo-6-chloro-4-methylbenzofurano[3,2-c]pyridine, in conjunction with gold nanoparticles, was coated onto the surface of a glassy carbon electrode (GCE) to develop a novel electrochemically modified electrode, AuNPs / 1 / GCE. The modified glassy carbon electrode exhibits excellent selectivity, high stability, sensitivity, and a wide detection range for the antibiotic ronidazole. Attached Figure Description

[0027] Figure 1 The CVs curves are for the modified electrode in Example 2.

[0028] Figure 2 The figure shows the electrolyte test results in Example 3.

[0029] Figure 3 The graph shows the electrolyte concentration test results in Example 3.

[0030] Figure 4 The graph shows the enrichment time test results in Example 3.

[0031] Figure 5-6 Under the optimal conditions described in Example 3, the modified electrode AuNPs / 1 / GCE showed a concentration of 1×10⁻⁶ for the antibiotic ronidazole. -9 mol / L ~ 1×10 -6 It exhibits a good linear relationship within the concentration range of mol / L.

[0032] Figure 7 This is a graph showing the selectivity test results of the modified electrode for various other antibiotics in Example 4.

[0033] Figure 8 The graph shows the test results of the effect of the modified electrode on the detection of ronidazole in the presence of coexisting substances in Example 5.

[0034] Figure 9 The graph shows the repeatability test results of the modified electrode for ronidazole detection in Example 5. Detailed Implementation

[0035] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0036] Example 1

[0037] This embodiment provides a 3-bromo-6-chloro-4-methylbenzofurano[3,2-c]pyridine, the synthesis method of which includes the following steps:

[0038] (1) Synthesis of 2-bromo-5-(3-chloro-2-methoxyphenyl)pyridine-4-amine

[0039]

[0040] To a 250 mL reaction flask, add 15.8 g (52.9 mmol) of 2-bromo-5-iodo-4-aminopyridine, 1.84 g (2.5 mmol) of 1,1-bis(diphenylphosphine)ferrocene palladium dichloride, 13.9 g (101 mmol) of potassium carbonate, 9.39 g (50.4 mmol) of (3-chloro-2-methoxyphenyl)boronic acid, 120 mL of 1,4-dioxane, and 30 mL of water. Purge with nitrogen and, under nitrogen protection, heat to 75 °C and react overnight. Cool to room temperature, add water, and extract with ethyl acetate. Dry the organic phase with anhydrous sodium sulfate. Analyze by silica gel column chromatography (PE / EA = 10 / 1-8 / 1) to obtain 10.3 g of the target product, a colored oily substance 2-bromo-5-(3-chloro-2-methoxyphenyl)pyridine-4-amine, in a yield of 62.1%.

[0041] (2) Synthesis of 3-bromo-6-chlorobenzofurano[3,2-c]pyridine

[0042]

[0043] Add 200 mL of acetic acid and 16 mL of concentrated sulfuric acid to a 500 mL reaction flask, then add 16.5 g (52.5 mmol) of 2-bromo-5-(3-chloro-2-methoxyphenyl)pyridine-4-amine. After stirring at room temperature for 10 minutes, carefully add 103 g (1000 mmol) of tert-butyl nitrite dropwise, keeping the reaction temperature below 35°C during the addition. Keep the mixture at room temperature and stir for about 6 hours. Filter the mixture, and thoroughly stir the filter cake with petroleum ether. Filter again, and dry the filter cake to give 7.4 g of a pale yellow solid, 3-bromo-6-chlorobenzofurano[3,2-c]pyridine, in 49.9% yield.

[0044] (3) Synthesis of 3-bromo-6-chloro-4-methylbenzofurano[3,2-c]pyridine

[0045]

[0046] Diisopropylamine (3.3 g, 32.7 mmol) and 100 mL of tetrahydrofuran were added to a 250 mL reaction flask. Under nitrogen protection, the mixture was cooled to -50 °C, and n-butyllithium (12.8 mL, 31.8 mmol, 2.5 N) was added dropwise. The reaction was maintained at -50 °C for half an hour, followed by the addition of 20 mL of a tetrahydrofuran solution of 3-bromo-6-chlorobenzofurano[3,2-c]pyridine (6 g, 21.2 mmol). After the addition was complete, the mixture was stirred at -50 °C for 4 hours, followed by the addition of iodomethane (9.07 g, 31.8 mmol). After the addition was complete, the mixture was slowly heated to room temperature and stirred overnight. The solution was quenched with water, extracted with ethyl acetate, dried and concentrated in the organic phase, pulped with petroleum ether, filtered, and the filter cake was dried to obtain 4 g of the target product, a white solid 3-bromo-6-chloro-4-methylbenzofurano[3,2-c]pyridine, with a yield of 42.4%.

[0047] 1 H NMR (400 MHz, DMSO-d6) 9.14 (s, 1H), 8.25 (dd, J = 8.0, 1.2 Hz, 1H), 7.78 (dd, J = 8.0, 1.2 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 2.60 (s, 3H).

[0048] Example 2

[0049] In this embodiment, the product prepared in Example 1 (denoted as Compound 1) was electrochemically detected as the antibiotic ronidazole, and the method is as follows:

[0050] A novel electrochemically modified electrode, AuNPs / 1 / GCE, was developed by coating the surface of a glassy carbon electrode (GCE) with gold nanoparticles in conjunction with compound 1.

[0051] The modified glassy carbon electrode exhibits excellent selectivity, high stability and sensitivity, and a wide detection range for the detection of the antibiotic ronidazole.

[0052] Cyclic voltammetry (CVS) is used to probe the conductivity of each electrode. Figure 1 CVs curves for the modified electrode (scan rate 100 mV•s) -1 Experimental results show that the AuNPs / 1 / GCE electrode has good conductivity.

[0053] Example 3

[0054] To better utilize the modified electrode AuNPs / 1 / GCE for the detection of rotenidazole, this embodiment optimizes the effects of the number of gold deposition segments, electrolyte, electrolyte concentration, and enrichment time on the detection results. The specific steps are as follows:

[0055] Selection of the number of gold deposition segments: The calomel electrode and platinum wire electrode were cleaned, and then immersed in chloroauric acid solution to half the solution level. Cyclic voltammetry was used to determine the number of gold deposition segments. After one cycle, the three electrodes were cleaned and then immersed in 0.1 M HCl solution to stack the gold deposition segments. The same electrode was then immersed in chloroauric acid solution for another cycle, cleaned, and then stacked in concentrated sulfuric acid. This process was repeated to continuously stack the gold deposition segments. In this experiment, six gold deposition segments were obtained.

[0056] Electrolyte selection: The electrolytes to be considered in the experiment are potassium chloride, potassium nitrate, potassium sulfate, potassium carbonate, potassium acetate, and PBS (phosphate buffer solution). Add 5 mL of electrolyte solution to the reagent bottle, then add the same amount of 1×10⁻⁶ electrolyte solution. -5 M ronidazole, keeping conditions consistent, and comparing to select the optimal electrolyte solution. The optimal electrolyte selected for this experiment was potassium chloride solution, such as... Figure 2 .

[0057] Determination of electrolyte concentration: Select potassium chloride solutions with electrolyte concentrations of 0.02 M, 0.04 M, 0.06 M, 0.08 M, 0.1 M, 0.12 M, and 0.14 M, and add the same amount of 1×10⁻⁶ potassium chloride solution. -5 M. rotenidazole. (e.g.) Figure 3 As shown, the experimental results indicate that the optimal electrolyte concentration is a 0.1 M potassium chloride solution (SWASV parameters: frequency 40 Hz, amplitude 20 mV, voltage increment 4 mV).

[0058] Determination of enrichment time: Chemically modified AuNPs / 1 / GCE were detected at rest times of 10 s, 20 s, 30 s, 40 s, 50 s, 60 s, 70 s, and 80 s, respectively, with a concentration of 1.0 × 10⁻⁶. -5 M is an antibiotic called ronidazole. For example... Figure 4 As shown, the experimental results indicate that the optimal enrichment time is 60 s (SWASV parameters: frequency 40 Hz, amplitude 20 mV, voltage increment 4 mV).

[0059] The optimal conditions are as follows: 6 gold deposition segments, potassium chloride solution as electrolyte, 0.1 M potassium chloride as electrolyte concentration, and 60 s enrichment time.

[0060] Under optimal conditions, the modified electrode AuNPs / 1 / GCE effectively controlled the concentration of the antibiotic ronidazole at 1 × 10⁻⁶. -9 mol / L ~ 1×10 -6 It exhibits a good linear relationship (R0) within the concentration range of mol / L. 2= 0.995), see Figure 5 and Figure 6 As shown, the modified electrode AuNPs / 1 / GCE exhibits a wide linear range and low detection limit for ronidazole, which is a significant advantage compared to mercury electrodes and their detection methods.

[0061] Example 4

[0062] High specificity is the most significant advantage of chemically modified electrodes. This example tests the selectivity of the modified electrode AuNPs / 1 / GCE for other antibiotics, using the same experimental method as in Example 2.

[0063] The modified electrode exhibits weaker electrochemical signals for the detection of various other antibiotics [metronidazole (MDZ), dimetronidazole (DTZ), ornidazole (ODZ), nitrofurazone (NZF), nitrofurantoin (NFT), furazolidone (FZD), sulfadiazine (SDZ), sulfadimidine (SMZ), norfloxacin (NOR), chloramphenicol (CAP), florfenicol (FFC), penicillin (PCL)], such as... Figure 7 This demonstrates that the modified electrode AuNPs / 1 / GCE exhibits excellent selectivity for the antibiotic ronidazole.

[0064] Example 5

[0065] Excellent electrochemical sensors are not interfered with by other coexisting substances during detection. Therefore, this example investigates the effect of the modified electrode AuNPs / 1 / GCE on the detection of ronidazole in the presence of coexisting antibiotics.

[0066] The addition of interfering substances had almost no effect on the detection of ronidazole, such as... Figure 8 As shown.

[0067] Furthermore, this embodiment investigated the probe experiment of the modified electrode AuNPs / 1 / GCE for ronidazole every 3 days. The results showed that the peak intensity decreased only slightly, indicating that the modified electrode AuNPs / 1 / GCE has high repeatability for the detection of ronidazole. Figure 9 As shown. Therefore, the modified electrode AuNPs / 1 / GCE sensor exhibits high selectivity, good anti-interference ability, high sensitivity, and wide detection limit for the detection of ronidazole.

[0068] The above description represents the preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

A method for synthesizing 1,3-bromo-6-chloro-4-methylbenzofurano[3,2-c]pyridine, characterized in that, Includes the following steps: (1) Synthesis of 2-bromo-5-(3-chloro-2-methoxyphenyl)pyridine-4-amine 2-Bromo-5-(3-chloro-2-methoxyphenyl)pyridine-4-amine was synthesized from 2-bromo-5-iodo-4-aminopyridine, 1,1-bis(diphenylphosphine)ferrocene palladium dichloride, and (3-chloro-2-methoxyphenyl)boronic acid in the presence of catalyst 1; catalyst 1 was potassium carbonate. (2) Synthesis of 3-bromo-6-chlorobenzofurano[3,2-c]pyridine 3-Bromo-6-chlorobenzofurano[3,2-c]pyridine was synthesized from 2-bromo-5-(3-chloro-2-methoxyphenyl)pyridine-4-amine and tert-butyl nitrite in a mixed environment of acetic acid and concentrated sulfuric acid. (3) Synthesis of 3-bromo-6-chloro-4-methylbenzofurano[3,2-c]pyridine 3-Bromo-6-chloro-4-methylbenzofuran[3,2-c]pyridine was synthesized from diisopropylamine, n-butyllithium, and 3-bromo-6-chlorobenzofuran[3,2-c]pyridine with iodomethane.

2. The synthesis method according to claim 1, characterized in that, The molar ratio of 2-bromo-5-iodo-4-aminopyridine, 1,1-bis(diphenylphosphine)ferrocene palladium dichloride and (3-chloro-2-methoxyphenyl)boronic acid is (50-55):(2-3):(50-55).

3. The synthesis method according to claim 1, characterized in that, The molar ratio of 2-bromo-5-(3-chloro-2-methoxyphenyl)pyridine-4-amine to tert-butyl nitrite is (50-55):1000.

4. The synthesis method according to claim 1, characterized in that, The molar ratio of diisopropylamine, n-butyllithium, and 3-bromo-6-chlorobenzofurano[3,2-c]pyridine is (30-35):(30-35):(20-25). 5.3-Bromo-6-chloro-4-methylbenzofurano[3,2-c]pyridine, characterized in that, The structure obtained by the synthesis method according to any one of claims 1-4 is as follows: 。 The application of 6,3-bromo-6-chloro-4-methylbenzofurano[3,2-c]pyridine, characterized in that, The 3-bromo-6-chloro-4-methylbenzofurano[3,2-c]pyridine described in claim 5 was coated with gold nanoparticles onto the surface of a glassy carbon electrode to obtain an electrochemically modified electrode AuNPs / 1 / GCE, which was used to detect the content of the antibiotic ronidazole.

7. An electrochemically modified electrode AuNPs / 1 / GCE for detecting the content of the antibiotic ronidazole, characterized in that, The electrode comprises 3-bromo-6-chloro-4-methylbenzofurano[3,2-c]pyridine as described in claim 5, with gold nanoparticles coated on the surface of the glassy carbon electrode.

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