4-chloro-1-methyl-6h-isochromeno[3,4-c]pyridine and synthesis method and application thereof

Abstract

The present application relates to the technical field of organic synthesis, and particularly relates to 4-chloro-1-methyl-6H-isochromeno[3,4-c]pyridine and a synthesis method and application thereof. The synthesis method comprises the following steps: (1) synthesizing 2-chloro-3-fluoro-4-iodo-5-methylpyridine from 2-chloro-3-fluoro-5-methylpyridine and iodine; (2) synthesizing 2-(2-chloro-3-fluoro-5-methylpyridin-4-yl)benzaldehyde from 2-chloro-3-fluoro-4-iodo-5-methylpyridine, 1,1-bis(diphenylphosphino)ferrocene palladium dichloride, potassium phosphate and (2-formylphenyl)boronic acid; and (3) synthesizing 4-chloro-1-methyl-6H-isochromeno[3,4-c]pyridine from 2-(2-chloro-3-fluoro-5-methylpyridin-4-yl)benzaldehyde and sodium tert-butoxide. The 4-chloro-1-methyl-6H-isochromeno[3,4-c]pyridine compound constructed by the present application can be used for detecting the content of the pesticide glyphosate.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to 4-chloro-1-methyl-6H-isochromeno[3,4-c]pyridine and a synthesis method and application thereof. BACKGROUND

[0002] Glyphosate is an organic phosphorus type of systemic herbicide with broad-spectrum and high efficiency. Since its advent, it has become the most widely used herbicide in global agricultural production. It can inhibit the synthesis of aromatic amino acids by inhibiting 5-enolpyruvylshikimate-3-phosphate synthase in the shikimic acid pathway of plants, thereby causing plant death. The wide use of glyphosate plays a crucial role in ensuring global food production and simplifying farmland management, especially in the promotion of genetically modified glyphosate-resistant crops such as soybeans, corn, and cotton.

[0003] Glyphosate can enter the human body through the skin, oral cavity and esophagus, respiratory tract, and eyes, and can also easily enter rivers, lakes, and even underground water through surface runoff and soil leaching, and can contaminate the surrounding environment and crops through dust drift. Although its degradation rate in soil is relatively fast, its metabolite aminomethyl phosphonic acid has stronger persistence in the environment, causing complex residue problems, and then accumulating in some organs of the human body, causing poisoning and harming human health.

[0004] Early detection of glyphosate residues mainly relies on chromatographic techniques (such as HPLC and GC). However, due to the small molecular weight of glyphosate, the lack of chromophore and fluorescence characteristics, the strong polarity and the easy complexation with metal ions, the pretreatment is complex, the derivatization step is tedious, the instrument analysis sensitivity is insufficient, and it is time-consuming and labor-intensive. Although modern technologies such as enzyme-linked immunosorbent assay and liquid chromatography-tandem mass spectrometry have improved detection efficiency and sensitivity, there are still challenges such as high technical threshold and high cost for realizing rapid, low-cost, and high-precision screening of large-scale samples.

[0005] Therefore, developing a rapid, high-sensitivity, and high-selectivity pesticide residue detection method is not only an urgent need to ensure food safety and meet the increasingly strict trade barriers, but also an inevitable measure to respond to public concerns. SUMMARY

[0006] The first aspect of the present application provides a synthesis method of 4-chloro-1-methyl-6H-isochromeno[3,4-c]pyridine, comprising the following steps:

[0007] (1) synthesizing 2-chloro-3-fluoro-4-iodo-5-methylpyridine from 2-chloro-3-fluoro-5-methylpyridine and iodine;

[0008] (2) 2-(2-chloro-3-fluoro-5-methylpyridin-4-yl)benzaldehyde is synthesized from 2-chloro-3-fluoro-4-iodo-5-methylpyridine, 1,1-bis(diphenylphosphino) ferrocene palladium dichloride, potassium phosphate tribasic, (2-formylphenyl)boronic acid;

[0009] (3) 4-chloro-1-methyl-6H-isochromeno[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-isochromeno[3,4-c]pyridine has the following structural formula:

[0010] .

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

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

[0013] In some preferred embodiments, the molar ratio of the 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 a reaction kettle, after cooling, n-butyllithium is added dropwise, low-temperature reaction is maintained, 2-chloro-3-fluoro-5-methylpyridine is added, low-temperature reaction is maintained, elemental iodine is added, the temperature is raised to room temperature for reaction, after quenching the reaction, extraction is performed, the organic phase is dried, and column chromatography is performed to obtain 2-chloro-3-fluoro-4-iodo-5-methylpyridine.

[0015] In some preferred embodiments, the temperature of the low-temperature reaction is -60~-90℃.

[0016] In some preferred embodiments, the specific operation of step (2) is as follows: 2-chloro-3-fluoro-4-iodo-5-methylpyridine, 1,1-bis(diphenylphosphino) ferrocene palladium dichloride, potassium phosphate tribasic, (2-formylphenyl)boronic acid and a solvent are added to a reaction kettle, under an inert gas atmosphere, the temperature is raised for reaction, after cooling, extraction is performed, the organic phase is dried, and column chromatography is performed to obtain 2-(2-chloro-3-fluoro-5-methylpyridin-4-yl)benzaldehyde.

[0017] In some preferred embodiments, the specific operation of step (3) is: adding 2-(2-chloro-3-fluoro-5-methylpyridin-4-yl)benzaldehyde and a solvent into a reaction bottle, adding sodium tert-butoxide, warming and reacting overnight, extracting after cooling, drying the organic phase, and column chromatography to obtain 4-chloro-1-methyl-6H-isochromeno[3,4-c]pyridine.

[0018] The second aspect of the present application provides 4-chloro-1-methyl-6H-isochromeno[3,4-c]pyridine obtained by the above synthesis method.

[0019] The third aspect of the present application provides an application of 4-chloro-1-methyl-6H-isochromeno[3,4-c]pyridine for detecting the content of pesticide glyphosate.

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

[0021] (1) The present application first synthesizes an organic compound: 4-chloro-1-methyl-6H-isochromeno[3,4-c]pyridine, which is a very promising organic intermediate and material intermediate. Direct construction of 4-chloro-1-methyl-6H-isochromeno[3,4-c]pyridine compound can be used for detecting the content of pesticide glyphosate.

[0022] (2) The 4-chloro-1-methyl-6H-isochromeno[3,4-c]pyridine compound has fluorescent properties, and contains multiple active sites in the compound. These active sites can quickly react with pollutants in the environment.

[0023] (3) According to a plurality of experiments, the 4-chloro-1-methyl-6H-isochromeno[3,4-c]pyridine compound can be a high-sensitivity and high-selectivity fluorescent probe for pesticide molecules in the environment, especially for glyphosate. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1 The figure is a fluorescence sensing result graph of compound 1 for various pesticide molecules.

[0025] Figure 2 The figure is a fluorescence quenching detailed experiment result graph of glyphosate.

[0026] Figure 3 The figure is a linear relationship result graph of glyphosate concentration in the range of 90 ppm.

[0027] Figure 4 The figure is a glyphosate detection anti-interference experiment result graph. DETAILED DESCRIPTION

[0028] The technical solutions in the embodiments of the present application will be clearly and completely described below. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative work fall within the protection scope of the present application.

[0029] Embodiment 1

[0030] The embodiment provides a synthesis method of 4-chloro-1-methyl-6H-isochromeno[3,4-c]pyridine, comprising the following steps:

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

[0032]

[0033] Into a 5-liter reaction kettle, diisopropylamine (392 g, 3.87 mol) and 4 liters of tetrahydrofuran were sequentially added, and the temperature was lowered to-78°C. Then, n-butyl lithium (1.4 L, 3.5 mol) was added dropwise. After the dropwise addition was completed, the reaction was maintained at-78°C for 1 hour. Then, 2-chloro-3-fluoro-5-methylpyridine (400 g) was added, and the reaction was maintained at-78°C for 1 hour. Then, iodine (765 g, 3.01 mol) was added, and the reaction was maintained at room temperature for 16 hours. After the reaction was quenched by adding saturated ammonium chloride, the reaction mixture was extracted with ethyl acetate. After the organic phase was dried, the target product 2-chloro-3-fluoro-4-iodo-5-methylpyridine was obtained in the form of light yellow solid by column chromatography, and the yield was 80.4%.

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

[0035]

[0036] Into a 10-liter reaction kettle, 2-chloro-3-fluoro-4-iodo-5-methylpyridine (858 g, 3.16 mol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (115 g, 157.5 mmol), potassium phosphate tribasic (1341 g, 6.32 mol), (2-formylphenyl)boronic acid (569 g, 3.78 mol), 5.2 liters of 1,4-dioxane and 1.3 liters of water were added, and the system was replaced with nitrogen for three times. Then, the temperature was raised to 80°C under the protection of nitrogen, and the reaction was maintained overnight. After the reaction was cooled to room temperature, water was added, and the reaction mixture was extracted with dichloromethane. After the organic phase was dried with anhydrous sodium sulfate, the target product 2-(2-chloro-3-fluoro-5-methylpyridin-4-yl)benzaldehyde was obtained in the form of yellow solid by column chromatography with PE / EA=10 / 1-8 / 1 silica gel, and the yield was 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-l-methyl-6H-isochromeno[3,4-c]pyridine

[0039]

[0040] Into a 250 mL reaction flask was added 2-(2-chloro-3-fluoro-5-methylpyridin-4- yl)benzaldehyde (10 g, 40.1 mmol) and 100 mL of tetrahydrofuran, then added sodium tert-butoxide (9.6 g, 100 mmol) in portions, warmed to reflux, and reacted overnight. Cooled to room temperature, added water, extracted with ethyl acetate, dried the organic phase with anhydrous sodium sulfate, and column chromatographed with PE / EA = 100 / 1-50 / 1 silica gel to obtain the target product 4-chloro-l-methyl-6H-isochromeno[3,4-c]pyridine as a white solid 4.3 grams, yield 46.3%.

[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 test

[0043] Experiment one: 4-chloro-l-methyl-6H-isochromeno[3,4-c]pyridine (hereinafter referred to as compound 1) prepared in example 1 was used for fluorescent detection of pesticide molecules.

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

[0045] The fluorescence intensity of the above pesticide molecules containing compound 1 was determined by a fluorescence spectrometer (RF-5301PC). As shown inFigure 1 As shown in the figure, compound 1 has a good fluorescence quenching effect on glyphosate (GLY). This result proves that compound 1 can selectively and sensitively sense the pesticide glyphosate by fluorescence.

[0046] Experiment two: In order to further refine the fluorescence process of glyphosate, the present application continues to explore the fluorescence quenching refinement experiment of glyphosate.

[0047] 4 mg of compound 1 was added to glyphosate solutions with different contents, respectively, and the fluorescence intensity changes of the glyphosate solutions with different contents were measured by a fluorescence spectrometer (RF-5301PC). As shown in the figure, Figure 2 When the fluorescence intensity is quenched by 90%, the glyphosate concentration at this time is 90 ppm. Compound 1 shows a good linear relationship with the concentration of glyphosate in the concentration range of 90 ppm (R 2 = 0.97097, Figure 3 ),

[0048] Experiment three: The present application continues to study the influence of compound 1 on the detection of glyphosate in the presence of coexisting pesticides.

[0049] 4 mg of compound 1 was dispersed into the following coexisting pesticides, respectively: 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), GLY (1.5 mL 0.1 mol / L) + GLA (1.5 mL 0.1 mol / L), GLY (1.5 mL 0.1 mol / L).

[0050] The fluorescence intensity of the above coexisting pesticides containing compound 1 was measured by a fluorescence spectrometer (RF-5301PC). As shown in the figure, Figure 4 Before and after adding the interference, the detection of glyphosate by compound 1 has little influence, so the detection of glyphosate by compound 1 has high selectivity, high anti-interference and high sensitivity.

[0051] The above is the preferred embodiment of the present application, it should be noted that for those skilled in the art, without departing from the principles described in the present application, can also make several improvements and refinements, these improvements and refinements should also be considered as the scope of protection of the present application.

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 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 was synthesized from 2-(2-chloro-3-fluoro-5-methylpyridin-4-yl)benzaldehyde under sodium tert-butoxide catalysis; 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-isochromeno[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; 。

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