4-chloro-1-methyl-6H-heterochromene [3, 4-c] pyridine as well as synthesis method and application thereof

Abstract

The invention relates to the technical field of organic synthesis, in particular to 4-chloro-1-methyl-6H-heterochromene [3, 4-c] pyridine as well as a synthesis method and application of the 4-chloro-1-methyl-6H-heterochromene [3, 4-c] pyridine. The synthesis method comprises the following steps: (1) synthesizing 2-chloro-3-fluoro-4-iodine-5-methylpyridine from 2-chloro-3-fluoro-5-methylpyridine and an iodine elementary substance to obtain 2-chloro-3-fluoro-4-iodine-5-methylpyridine; (2) synthesizing 2-(2-chloro-3-fluoro-5-methylpyridine-4-yl) benzaldehyde from the 2-chloro-3-fluoro-4-iodo-5-methylpyridine, the 1, 1-bis (diphenylphosphine) ferrocene palladium dichloride, the tripotassium phosphate and the (2-formyl phenyl) boric acid, and further synthesizing the 2-(2-chloro-3-fluoro-5-methylpyridine-4-yl) benzaldehyde from the 2-chloro-3-fluoro-4-iodo-5-methylpyridine and the 1, 1-bis (diphenylphosphine) ferrocene palladium dichloride. And (3) synthesizing the 4-chloro-1-methyl-6H-heterochromene [3, 4-c] pyridine by using the 2-(2-chloro-3-fluoro-5-methylpyridine-4-yl) benzaldehyde and sodium tert-butoxide. The 4-chloro-1-methyl-6H-heterochromene [3, 4-c] pyridine compound constructed by the invention can be used for detecting the content of pesticide residue glyphosate.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to 4-chloro-1-methyl-6H-isocyaneno[3,4-c]pyridine, its synthesis method and application. Background Technology

[0002] Glyphosate is a broad-spectrum, highly effective organophosphorus systemic herbicide that has become the most widely used herbicide in global agriculture since its introduction. It works by inhibiting 5-enolpyruvylshikimate-3-phosphate synthase in the shikimic acid pathway, thereby interrupting the synthesis of aromatic amino acids and leading to plant death. The widespread use of glyphosate has played a crucial role in ensuring global food production and simplifying farmland management, and its use is closely intertwined with the promotion of genetically modified glyphosate-resistant crops (such as soybeans, corn, and cotton).

[0003] Glyphosate can enter the human body through contact with skin, mouth and esophagus, respiratory tract, and eyes. It can also easily enter rivers, lakes, and even groundwater through surface runoff and soil leaching, and pollute the surrounding environment and crops through dust drift. Although it degrades relatively quickly in soil, its metabolite, aminomethylphosphonic acid, is more persistent in the environment, causing complex residue problems. This can lead to accumulation in certain human organs, causing poisoning and endangering human health.

[0004] Early detection of glyphosate residues primarily relied on chromatographic techniques (such as HPLC and GC). However, due to glyphosate's small molecular weight, lack of chromophores and fluorescence properties, strong polarity, and tendency to complex with metal ions, pretreatment was complex, derivatization steps were cumbersome, instrumental analysis sensitivity was insufficient, and the process was time-consuming and labor-intensive. Although modern technologies such as enzyme-linked immunosorbent assay (ELISA) and liquid chromatography-tandem mass spectrometry (LC-MS / MS) have improved detection efficiency and sensitivity, challenges remain in achieving rapid, low-cost, and high-precision screening of large-scale samples, including high technical barriers and high costs.

[0005] Therefore, developing rapid, highly sensitive, and highly selective methods for detecting pesticide residues is not only an urgent need to ensure food safety and meet increasingly stringent trade barriers, but also an inevitable measure to respond to public concerns. Summary of the Invention

[0006] The first aspect of the present invention provides a method for synthesizing 4-chloro-1-methyl-6H-isocyaneno[3,4-c]pyridine, comprising the following steps:

[0007] (1) 2-Chloro-3-fluoro-4-iodo-5-methylpyridine was synthesized from 2-chloro-3-fluoro-5-methylpyridine and elemental iodine;

[0008] (2) 2-(2-chloro-3-fluoro-5-iodo-5-methylpyridine was synthesized from 2-chloro-3-fluoro-4-iodo-5-methylpyridine, 1,1-bis(diphenylphosphine)ferrocene palladium dichloride, tripotassium phosphate, and (2-formylphenyl)boronic acid;

[0009] (3) 4-chloro-1-methyl-6H-isocyaneno[3,4-c]pyridine is synthesized from 2-(2-chloro-3-fluoro-5-methylpyridin-4-yl)benzaldehyde and sodium tert-butoxide; the 4-chloro-1-methyl-6H-isocyaneno[3,4-c]pyridine has the following structural formula;

[0010] .

[0011] In some preferred embodiments, the mass ratio of 2-chloro-3-fluoro-5-methylpyridine to elemental iodine is (3-5):(7-8).

[0012] In some preferred embodiments, the molar ratio of 2-chloro-3-fluoro-4-iodo-5-methylpyridine to 1,1-bis(diphenylphosphine)ferrocene palladium dichloride, tripotassium phosphate, and (2-formylphenyl)boronic acid is (3-4):(150-160):(6-7):(3-4).

[0013] In some preferred embodiments, the molar ratio of 2-(2-chloro-3-fluoro-5-methylpyridin-4-yl)benzaldehyde to sodium tert-butoxide is (3.8-4.2):10.

[0014] In some preferred embodiments, the specific operation of step (1) is as follows: diisopropylamine and tetrahydrofuran are added to the reaction vessel, and after cooling, n-butyllithium is added dropwise to maintain the low temperature reaction. 2-chloro-3-fluoro-5-methylpyridine is added to maintain the low temperature reaction. Iodine is added, and the temperature is raised to room temperature to react. After quenching the reaction, extraction is performed, the organic phase is dried, and 2-chloro-3-fluoro-4-iodo-5-methylpyridine is obtained by column chromatography.

[0015] In some preferred embodiments, the temperature of the low-temperature reaction is -60 to -90°C.

[0016] In some preferred embodiments, step (2) is specifically performed as follows: 2-chloro-3-fluoro-4-iodo-5-methylpyridine, 1,1-bis(diphenylphosphine)ferrocene palladium dichloride, tripotassium phosphate, and (2-formylphenyl)boronic acid and solvent are added to the reaction vessel. The reaction is carried out under an inert gas atmosphere, and after cooling, the mixture is extracted, the organic phase is dried, and 2-(2-chloro-3-fluoro-5-methylpyridin-4-yl)benzaldehyde is obtained by column chromatography.

[0017] In some preferred embodiments, the specific operation of step (3) is as follows: 2-(2-chloro-3-fluoro-5-methylpyridin-4-yl)benzaldehyde and solvent are added to the reaction flask, sodium tert-butoxide is added, the temperature is raised and the reaction is carried out overnight, the mixture is cooled and extracted, the organic phase is dried, and 4-chloro-1-methyl-6H-isocyaneno[3,4-c]pyridine is obtained by column chromatography.

[0018] A second aspect of the invention provides 4-chloro-1-methyl-6H-isocyaneno[3,4-c]pyridine, obtained by the above-described synthetic method.

[0019] A third aspect of the invention provides the application of 4-chloro-1-methyl-6H-isocyaneno[3,4-c]pyridine for the detection of glyphosate residues.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] (1) This invention synthesizes an organic compound for the first time: 4-chloro-1-methyl-6H-isocyaneno[3,4-c]pyridine. This compound is a very promising organic intermediate and material intermediate. Directly constructing 4-chloro-1-methyl-6H-isocyaneno[3,4-c]pyridine compounds can be used to detect the content of glyphosate pesticide residues.

[0022] (2) 4-Chloro-1-methyl-6H-isocyaneno[3,4-c]pyridine compounds have fluorescent properties and contain multiple active sites that can rapidly interact with pollutants in the environment.

[0023] (3) Multiple experiments have shown that 4-chloro-1-methyl-6H-isocyaneno[3,4-c]pyridine compounds can detect pesticide molecules in the fluorescent probe environment with high sensitivity and selectivity, especially glyphosate. Attached Figure Description

[0024] Figure 1 This is a fluorescence sensing result diagram of compound 1 for various pesticide molecules.

[0025] Figure 2 The figure shows the results of the fluorescence quenching and refinement experiment of glyphosate.

[0026] Figure 3 The graph shows the linear relationship of glyphosate concentrations within the range of 90 ppm.

[0027] Figure 4 The figure shows the results of the anti-interference test for glyphosate. Detailed Implementation

[0028] 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.

[0029] Example 1

[0030] This embodiment provides a method for synthesizing 4-chloro-1-methyl-6H-isocyaneno[3,4-c]pyridine, including the following steps:

[0031] (1) Synthesis of 2-chloro-3-fluoro-4-iodo-5-methylpyridine

[0032]

[0033] Diisopropylamine (392 g, 3.87 mol) and tetrahydrofuran (4 L) were added sequentially to a 5 L reactor. The mixture was cooled to -78 °C, and n-butyllithium (1.4 L, 3.5 mol) was added dropwise. After the addition was complete, the reaction was maintained at -78 °C for 1 hour. 2-Chloro-3-fluoro-5-methylpyridine (400 g) was added, and the reaction was maintained at -78 °C for 1 hour. Elemental iodine (765 g, 3.01 mol) was added, and the mixture was warmed to room temperature and reacted for 16 hours. The reaction was quenched with saturated ammonium chloride, and the mixture was extracted with ethyl acetate. After drying the organic phase, column chromatography was performed to obtain 600 g of the target product, a pale yellow solid 2-chloro-3-fluoro-4-iodo-5-methylpyridine, with a yield of 80.4%.

[0034] (2) Synthesis of 2-(2-chloro-3-fluoro-5-methylpyridin-4-yl)benzaldehyde

[0035]

[0036] 2-Chloro-3-fluoro-4-iodo-5-methylpyridine (858 g, 3.16 mol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (115 g, 157.5 mmol), tripotassium phosphate (1341 g, 6.32 mol), (2-formylphenyl)boronic acid (569 g, 3.78 mol), 5.2 L of 1,4-dioxane, and 1.3 L of water were added to a 10 L reactor. The mixture was purged with nitrogen three times, and the system was heated to 80 °C under nitrogen protection and reacted overnight. After cooling to room temperature, water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, and the product was obtained by silica gel column chromatography (PE / EA = 10 / 1-8 / 1) as a yellow solid, yielding 476 g of 2-(2-chloro-3-fluoro-5-methylpyridin-4-yl)benzaldehyde (60.3%).

[0037] 1 H NMR (400 MHz, CDCl3) δ 9.87 (s, 1H), 8.21 (s, 1H), 8.09 (dd, J =8.0, 1.6 Hz, 1H), 7.78 (td, J = 7.6, 1.6 Hz, 1H), 7.73-7.69 (m, 1H), 7.30 (d,J = 7.6 Hz, 1H), 2.08 (s, 3H).

[0038] (3) Synthesis of 4-chloro-1-methyl-6H-isocyaneno[3,4-c]pyridine

[0039]

[0040] 2-(2-chloro-3-fluoro-5-methylpyridin-4-yl)benzaldehyde (10 g, 40.1 mmol) and 100 mL of tetrahydrofuran were added to a 250 mL reaction flask, followed by the addition of sodium tert-butoxide (9.6 g, 100 mmol) in portions. The mixture was heated to reflux and reacted overnight. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (PE / EA = 100 / 1-50 / 1) to obtain 4.3 g of the target product, a white solid 4-chloro-1-methyl-6H-isocyaneno[3,4-c]pyridine, in 46.3% yield.

[0041] 1 HNMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.83-7.81 (m, 1H), 7.47-7.41(m, 2H), 7.29 -7.27 (m, 1H), 5.12 (s, 2H), 2.64 (s, 3H).

[0042] Performance testing

[0043] Experiment 1: The 4-chloro-1-methyl-6H-isocyaneno[3,4-c]pyridine (hereinafter referred to as compound 1) prepared in Example 1 was used for the fluorescence detection of pesticide molecules.

[0044] 4 mg of compound 1 was ground and dispersed in 3.0 mL of the following pesticide solutions at 0.1 mol / L: acetamiprid (ACE), difenoconazole (DIF), matrine (MAT), atrazine (ATR), pyraclostrobin (PYR), chlorpyrifos (CHL), glufosinate (GLA), and glyphosate (GLY).

[0045] The fluorescence intensity of the above-mentioned pesticide molecule containing compound 1 was measured using a fluorescence spectrometer (RF-5301PC). Figure 1 As shown, compound 1 exhibits excellent fluorescence quenching activity against glyphosate (GLY). This result demonstrates that compound 1 can achieve highly selective and sensitive fluorescence sensing of the pesticide glyphosate.

[0046] Experiment 2: In order to further refine the fluorescence process of glyphosate, this invention continues to explore the fluorescence quenching refinement experiment of glyphosate.

[0047] Four mg of compound 1 was added to glyphosate solutions of different concentrations, and the changes in fluorescence intensity of the glyphosate solutions with different concentrations were measured using a fluorescence spectrometer (RF-5301PC). Figure 2 As shown, when the fluorescence intensity is quenched by 90%, the glyphosate concentration is 90 ppm. Compound 1 exhibits a good linear relationship with the glyphosate concentration within the concentration range of 90 ppm (R0). 2 = 0.97097, Figure 3 ),

[0048] Experiment 3: This invention further investigated the effect of compound 1 on glyphosate detection in the presence of coexisting pesticides.

[0049] 4 mg of compound 1 was dispersed in each of the following coexisting pesticides: GLY (1.5 mL 0.1 mol / L) + ACE (1.5 mL 0.1 mol / L), GLY (1.5 mL 0.1 mol / L) + DIF (1.5 mL 0.1 mol / L), GLY (1.5 mL 0.1 mol / L) + MAT (1.5 mL 0.1 mol / L), GLY (1.5 mL 0.1 mol / L) + ATR (1.5 mL 0.1 mol / L), GLY (1.5 mL 0.1 mol / L) + PYR (1.5 mL 0.1 mol / L), GLY (1.5 mL 0.1 mol / L) + CHL (1.5 mL 0.1 mol / L), and GLY (1.5 mL 0.1 mol / L) + GLA (1.5 mL 0.1 mol / L). mol / L), GLY (1.5mL 0.1 mol / L).

[0050] The fluorescence intensity of the aforementioned coexisting pesticides containing compound 1 was measured using a fluorescence spectrometer (RF-5301PC). Figure 4 As shown, the addition of the interfering agent had almost no effect on the detection of glyphosate. Therefore, compound 1 exhibits high selectivity, high anti-interference ability, and high sensitivity in the detection of glyphosate.

[0051] 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 1,4-chloro-1-methyl-6H-isochromeno[3,4-c]pyridine, characterized in that, Includes the following steps: (1) 2-Chloro-3-fluoro-4-iodo-5-methylpyridine was synthesized from 2-chloro-3-fluoro-5-methylpyridine and elemental iodine; (2) 2-(2-chloro-3-fluoro-5-iodo-5-methylpyridine was synthesized from 2-chloro-3-fluoro-4-iodo-5-methylpyridine, 1,1-bis(diphenylphosphine)ferrocene palladium dichloride, tripotassium phosphate, and (2-formylphenyl)boronic acid; (3) 4-chloro-1-methyl-6H-isocyaneno[3,4-c]pyridine is synthesized from 2-(2-chloro-3-fluoro-5-methylpyridin-4-yl)benzaldehyde and sodium tert-butoxide; the 4-chloro-1-methyl-6H-isocyaneno[3,4-c]pyridine has the following structural formula; 。 2. The synthesis method according to claim 1, characterized in that, The mass ratio of 2-chloro-3-fluoro-5-methylpyridine to iodine is (3-5):(7-8).

3. The synthesis method according to claim 2, characterized in that, The molar ratio of 2-chloro-3-fluoro-4-iodo-5-methylpyridine to 1,1-bis(diphenylphosphine)ferrocene palladium dichloride, tripotassium phosphate, and (2-formylphenyl)boronic acid is (3-4):(150-160):(6-7):(3-4).

4. The synthesis method according to claim 3, characterized in that, The molar ratio of 2-(2-chloro-3-fluoro-5-methylpyridin-4-yl)benzaldehyde to sodium tert-butoxide is (3.8-4.2):

10.

5. The synthesis method according to claim 4, characterized in that, The specific operation of step (1) is as follows: Diisopropylamine and tetrahydrofuran are added to the reaction vessel, and after cooling, n-butyllithium is added dropwise to maintain the low temperature reaction. 2-chloro-3-fluoro-5-methylpyridine is added and the low temperature reaction is maintained. Iodine is added and the temperature is raised to room temperature to react. After quenching the reaction, it is extracted, the organic phase is dried, and 2-chloro-3-fluoro-4-iodo-5-methylpyridine is obtained by column chromatography.

6. The synthesis method according to claim 5, characterized in that, The temperature of the low-temperature reaction is -60 to -90°C.

7. The synthesis method according to claim 6, characterized in that, The specific operation of step (2) is as follows: 2-chloro-3-fluoro-4-iodo-5-methylpyridine, 1,1-bis(diphenylphosphine)ferrocene palladium dichloride, tripotassium phosphate, and (2-formylphenyl)boronic acid and solvent are added to the reaction vessel. The reaction is carried out under an inert gas atmosphere, and after cooling, the mixture is extracted, the organic phase is dried, and 2-(2-chloro-3-fluoro-5-methylpyridin-4-yl)benzaldehyde is obtained by column chromatography.

8. The synthesis method according to claim 7, characterized in that, The specific operation of step (3) is as follows: 2-(2-chloro-3-fluoro-5-methylpyridin-4-yl)benzaldehyde and solvent are added to the reaction flask, sodium tert-butoxide is added, the temperature is raised and the reaction is carried out overnight, and after cooling, the mixture is extracted, the organic phase is dried, and 4-chloro-1-methyl-6H-isocyaneno[3,4-c]pyridine is obtained by column chromatography.

9. A 4-chloro-1-methyl-6H-isochromeno[3,4-c]pyridine obtained by the synthetic method according to any one of claims 1-8, characterized in that, The 4-chloro-1-methyl-6H-isocyaneno[3,4-c]pyridine has the following structural formula: 。 10. The application of the 4-chloro-1-methyl-6H-isocyaneno[3,4-c]pyridine according to claim 9, characterized in that, The 4-chloro-1-methyl-6H-isocyaneno[3,4-c]pyridine used for detecting the content of glyphosate pesticide residue has the following structural formula; 。

Images