A method for preparing a pyridine amide compound

Abstract

The present application relates to the technical field of organic synthesis, and particularly relates to a preparation method of a pyridine amide compound, which comprises the following steps: dissolving an aromatic aldehyde in a first solvent to obtain a first solution; dissolving a substituted silane, a catalyst and an acidic reagent in a second solvent respectively to obtain a second solution; uniformly mixing the first solution and the second solution to obtain a third solution; adding a nitro compound into the third solution under the action of sunlight, so that the aromatic aldehyde and the nitro compound undergo a reductive coupling reaction to obtain the pyridine amide compound. The preparation method is novel, the yield of the product is high, the selectivity is good, the impurities are few, the solvent can be recycled and used, the environment is friendly, and the method is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing pyridine amide compounds. Background Technology

[0002] Pyridine amides are a class of novel agricultural fungicides with broad-spectrum antifungal activity, effectively controlling a variety of fungal diseases in crops. They exhibit excellent control effects against powdery mildew, anthracnose, scab, leaf blight, sclerotinia rot, gray mold, and early blight, combining a unique mechanism of action with good safety profiles. Pyridine amides such as pyridine amide, fenpicoxamid, fluopyram, boscalid, and fluopyram have been widely used in over thirty cultivated crops, including cereals, grapes, fruit trees, nut trees, vegetables, rapeseed, and sugar beets. They can also be used for disease control in lawns and golf courses.

[0003] Currently, the main method for preparing pyridine amides involves using substituted acyl chlorides and amino compounds as raw materials, followed by a condensation reaction to obtain the target product. However, the substituted acyl chlorides and amino compounds used in this synthetic route are highly reactive and prone to deterioration during storage. This not only reduces the quality of the raw materials but also adversely affects subsequent reaction processes, thus hindering the industrial production and practical application of pyridine amides.

[0004] Therefore, finding a new method for preparing pyridine amide compounds has become a research hotspot. Summary of the Invention

[0005] To solve at least one of the above-mentioned technical problems, the present invention provides a method for preparing pyridine amide compounds, wherein the preparation method yields products with high yield and selectivity.

[0006] In one aspect, the present invention provides a method for preparing pyridine amide compounds, comprising: dissolving an aromatic aldehyde in a first solvent to obtain a first solution; dissolving a substituted silane, a catalyst, and an acidic reagent in a second solvent to obtain a second solution; mixing the first solution and the second solution uniformly to obtain a third solution; and adding a nitro compound to the third solution under sunlight, wherein the aromatic aldehyde and the nitro compound undergo a reductive coupling reaction to obtain a pyridine amide compound; wherein the aromatic aldehyde includes at least one of o-trifluoromethylbenzaldehyde and 2,6-dichlorobenzaldehyde; and the nitro compound includes at least one of 2-nitroethyl-3-chloro-5-trifluoromethylpyridine and 2-nitromethyl-3-chloro-5-trifluoromethylpyridine.

[0007] Further, the substituted silanes include at least one of methyltrimethoxysilane, 2-cyanoethyltriazine, dodecafluoroheptylpropyltrimethoxysilane, isopropoxytrimethylsilane, 2-allyltrimethylsilane, tris(trimethylsilyl)silanol, octadecylmethylchlorosilane, diisopropyldihydrosilane, vinylphenyldiethoxysilane, perfluorohexyltrichlorosilane, trimethylchlorosilane, tert-butylpropylaminotrimethoxysilane, 1,2-dibromotetramethyldisilane, chloromethyltriisopropoxysilane, tris(trimethylsiloxy)silane, ethyltriethoxysilane, tris(silylmethyl)silane, and hexadecyltrimethoxysilane.

[0008] Furthermore, the catalyst includes at least one of the following: molybdenum dialkyldithiophosphate, molybdenum dialkyldithiocarbamate, ammonium molybdate, ammonium phosphomolybdate, ammonium phosphomolybdate trihydrate, ammonium tetrathiomolybdate, ammonium octamolybdate, molybdic acid, bismuth molybdenum oxide, cerium molybdate oxide, molybdenum 2-ethylhexanoate, molybdenum hexacarbonyl, molybdenum glycinate, molybdenum acetate, molybdenum dibutyldithiocarbamate, molybdenum dithiocarbamate, and sulfonated di-2-ethylhexyldithiophosphate.

[0009] Furthermore, the acidic reagent includes at least one of trichloroacetic acid, formic acid, acetic acid, trifluoroacetic acid, pentafluoropropionic acid, heptafluorobutyric acid, perfluorohexanoic acid, methanesulfonic acid, and cyanoacetic acid.

[0010] Furthermore, the first solvent and the second solvent are each independently selected from at least one of methanol, ethanol, isopropanol, petroleum ether, n-butanol, acetonitrile, ethyl acetate, ethyl formate, acetone, pentanone, dimethyl sulfoxide, dimethylformamide, dioxane, and tetrahydrofuran.

[0011] Furthermore, in the reductive coupling reaction, the molar ratio of the reactants nitrate, aromatic aldehyde, substituted silane, catalyst and acidic reagent is 1:(1~1.1):(1~2):(0.1~1):(0.1~1).

[0012] Furthermore, in the reductive coupling reaction, the mass ratio of nitro compound to solvent is 1:(3~15); wherein the solvent includes a first solvent and a second solvent.

[0013] Furthermore, the reaction temperature for the reductive coupling reaction is 20~100℃.

[0014] The technical solution provided by this invention has the following advantages: In the preparation method of pyridine amide compounds of the present invention, the raw materials for the preparation method are bulk commodities, the operation steps are simple and safe, the product selectivity is higher, the yield is high and the quality is good, and it is suitable for industrial production. Detailed Implementation

[0015] To better understand the above-mentioned objectives, features, and advantages of the present invention, the solutions of the present invention will be further described below. It should be noted that, unless otherwise specified, the embodiments of the present invention and the features thereof can be combined with each other.

[0016] Many specific details are set forth in the following description in order to provide a full understanding of the invention, but the invention may also be practiced in other ways different from those described herein; obviously, the embodiments in the specification are only some embodiments of the invention, and not all embodiments.

[0017] According to embodiments of the present invention, a method for preparing pyridine amide compounds is provided, comprising the following steps: (1) Under sunlight, add aromatic aldehyde and first solvent to an open bottle, heat and stir for a period of time to obtain the first solution; (2) The substituted silane, catalyst, and acidic reagent are added to the second solvent in sequence to obtain the second solution; (3) Mix the first solution obtained in step (1) and the second solution obtained in step (2) evenly to obtain the third solution; (4) Under sunlight, the nitro compound was added to the third solution obtained in step (3) to carry out a reducing coupling reaction. After the reaction was completed, the reaction solution was cooled to room temperature and then filtered. The filter cake was washed with ethyl acetate, the filtrate was evaporated under reduced pressure, water was added and stirred, then filtered, and vacuum dried to obtain the product pyridine amide compound.

[0018] In some embodiments of the present invention, in step (1), the aromatic aldehyde includes at least one of o-trifluoromethylbenzaldehyde, 2,6-dichlorobenzaldehyde, and other aldehyde-containing aromatic hydrocarbons.

[0019] In some embodiments of the present invention, in step (1), the first solvent includes at least one of methanol, ethanol, isopropanol, petroleum ether, n-butanol, acetonitrile, ethyl acetate, ethyl formate, acetone, pentanone, dimethyl sulfoxide, dimethylformamide, dioxane, and tetrahydrofuran.

[0020] In some embodiments of the present invention, in step (1), the temperature of heating and stirring is 25~40°C.

[0021] In some embodiments of the present invention, in step (2), the substituted silane includes at least one of methyltrimethoxysilane, 2-cyanoethyltriazine, dodecafluoroheptylpropyltrimethoxysilane, isopropoxytrimethylsilane, 2-allyltrimethylsilane, tris(trimethylsilyl)silanol, octadecylmethylchlorosilane, diisopropyldihydrosilane, vinylphenyldiethoxysilane, perfluorohexyltrichlorosilane, trimethylchlorosilane, tert-butylpropylaminotrimethoxysilane, 1,2-dibromotetramethyldisilane, chloromethyltriisopropoxysilane, tris(trimethylsiloxy)silane, ethyltriethoxysilane, tris(silylmethyl)silane, and hexadecyltrimethoxysilane.

[0022] In some embodiments of the present invention, in step (2), the catalyst includes at least one of the following: molybdenum dialkyl dithiophosphate, molybdenum dialkyl dithiocarbamate, ammonium molybdate, ammonium phosphomolybdate, ammonium phosphomolybdate trihydrate, ammonium tetrathiomolybdate, ammonium octamolybdate, molybdenum silimolybdate, bismuth molybdenum oxide, cerium molybdate oxide, molybdenum 2-ethylhexanoate, molybdenum hexacarbonyl, molybdenum glycinate, molybdenum acetate, molybdenum dibutyl dithiocarbamate, molybdenum dithiocarbamate, and sulfonated di-2-ethylhexyl dithiophosphate.

[0023] In some embodiments of the present invention, in step (2), the acidic reagent includes at least one of trichloroacetic acid, formic acid, acetic acid, pentafluoropropionic acid, heptafluorobutyric acid, perfluorohexanoic acid, methanesulfonic acid, and cyanoacetic acid.

[0024] In some embodiments of the present invention, in step (2), the second solvent includes at least one of methanol, ethanol, isopropanol, petroleum ether, n-butanol, acetonitrile, ethyl acetate, ethyl formate, acetone, pentanone, dimethyl sulfoxide, dimethylformamide, dioxane, and tetrahydrofuran.

[0025] In some embodiments of the present invention, in step (4), the nitro compound includes at least one of 2-nitroethyl-3-chloro-5-trifluoromethylpyridine, 2-nitromethyl-3-chloro-5-trifluoromethylpyridine, and nitro compounds containing other substituents.

[0026] In some embodiments of the present invention, in step (4), during the reductive coupling reaction, the mass of the solvent is 3 to 15 times the mass of the nitrated substance. The mass of the solvent is the sum of the masses of the first solvent and the second solvent.

[0027] In some embodiments of the present invention, in step (4), during the reductive coupling reaction, the molar ratio of the nitrate, aromatic aldehyde, substituted silane, catalyst and acidic reagent is 1:(1~1.1):(1~2):(0.1~1):(0.1~1).

[0028] In some embodiments of the present invention, in step (4), the reaction temperature in the reduction coupling reaction is 20~100℃, preferably 60~90℃.

[0029] The following detailed description and explanation are provided through specific examples.

[0030] Example 1 Under sunlight, 17.59 g of o-trifluoromethylbenzaldehyde and 76 mL of ethyl acetate were added to an open flask. The mixture was heated to 30°C and stirred for 1 hour. Then, 24.68 g of tris(silylmethyl)silane, 76 mL of ethanol, 4.25 g of cyanoacetic acid, and 5.2 g of ammonium tetrathiomolybdate were added. After mechanical stirring for 10 minutes, 25.4 g of 2-nitroethyl-3-chloro-5-trifluoromethylpyridine was added. The mixture was heated to 75°C and reacted. After the reactants had reacted completely, the reaction solution was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate, and the filtrate was evaporated to dryness under reduced pressure. 300 mL of water was added, and the mixture was stirred, filtered, and dried under vacuum to obtain 35.7 g of N-[(3-chloro-5-trifluoromethyl-2-pyridyl)ethyl]2-trifluoromethylbenzamide, an off-white solid with a yield of 96.29% and a liquid phase purity of 99.76%.

[0031] Example 2 Under sunlight, 17.76 g of o-trifluoromethylbenzaldehyde and 76 mL of ethyl acetate were added to an open flask. The mixture was heated to 30 °C and stirred for 1 hour. Then, 23.16 g of methyltrimethoxysilane, 120 mL of methanol, 5.1 g of cyanoacetic acid, and 6 g of ammonium octamolate were added. After mechanical stirring for 20 minutes, 25.4 g of 2-nitroethyl-3-chloro-5-trifluoromethylpyridine was added. The mixture was heated to 80 °C and reacted. After the reactants had reacted completely, the reaction solution was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate, and the filtrate was evaporated to dryness under reduced pressure. 250 mL of water was added, and the mixture was stirred, filtered, and dried under vacuum to give 35.7 g of N-[(3-chloro-5-trifluoromethyl-2-pyridyl)ethyl]-2-trifluoromethylbenzamide, an off-white solid with a yield of 80.16% and a liquid phase purity of 99.32%.

[0032] Example 3 Under sunlight, 17.76 g of o-trifluoromethylbenzaldehyde and 76 mL of ethyl acetate were added to an open flask. The mixture was heated to 30 °C and stirred for 1 hour. Then, 19.84 g of isopropoxytrimethylsilane, 120 mL of methanol, 5.1 g of cyanoacetic acid, and 7.3 g of glycine molybdenum were added. After mechanical stirring for 30 minutes, 25.4 g of 2-nitroethyl-3-chloro-5-trifluoromethylpyridine was added. The mixture was heated to 80 °C and reacted. After the reactants had reacted completely, the reaction solution was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate, and the filtrate was evaporated to dryness under reduced pressure. 250 mL of water was added, and the mixture was stirred, filtered, and dried under vacuum to give 26.3 g of N-[(3-chloro-5-trifluoromethyl-2-pyridyl)ethyl]-2-trifluoromethylbenzamide, an off-white solid with a yield of 66.3% and a liquid phase purity of 98.87%.

[0033] Example 4 Under sunlight, 17.68 g of 2,6-dichlorobenzaldehyde and 70 mL of ethyl acetate were added to an open flask. The mixture was heated to 30 °C and stirred for 1 hour. Then, 24.68 g of methyltrimethoxysilane, 70 mL of methanol, 5.1 g of cyanoacetic acid, and 4.3 g of ammonium tetrathiomolybdate were added. After mechanical stirring for 30 minutes, 24 g of 2-nitromethyl-3-chloro-5-trifluoromethylpyridine was added. The mixture was heated to 80 °C and reacted. After the reactants had reacted completely, the reaction solution was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate, and the filtrate was evaporated to dryness under reduced pressure. 250 mL of water was added, and the mixture was stirred, filtered, and dried under vacuum to give 37.7 g of N-[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl]-2-trifluoromethylbenzamide, an off-white solid with a yield of 98.28% and a liquid phase purity of 99.86%.

[0034] Example 5 Under sunlight, 17.59 g of 2,6-dichlorobenzaldehyde and 80 mL of ethyl acetate were added to an open flask. The mixture was heated to 30 °C and stirred for 1 hour. Then, 21.4 g of methyltrimethoxysilane, 80 mL of methanol, 11.5 g of pentafluoropropionic acid, and 12 g of ammonium octamolate were added. After mechanical stirring for 40 minutes, 24 g of 2-nitromethyl-3-chloro-5-trifluoromethylpyridine was added. The mixture was heated to 70 °C and reacted. After the reactants had reacted completely, the reaction solution was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate, and the filtrate was evaporated to dryness under reduced pressure. 250 mL of water was added, and the mixture was stirred, filtered, and dried under vacuum to give 32.6 g of N-[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl]-2-trifluoromethylbenzamide, an off-white solid with a yield of 84.99% and a liquid phase purity of 99.15%.

[0035] Example 6 Under sunlight, 17.68 g of 2,6-dichlorobenzaldehyde and 75 mL of ethyl acetate were added to an open flask. The mixture was heated to 30 °C and stirred for 1 hour. Then, 17.2 g of isopropoxytrimethylsilane, 75 mL of methanol, 5.1 g of cyanoacetic acid, and 4.3 g of ammonium tetrathiomolybdate were added. After mechanical stirring for 30 minutes, 24 g of 2-nitromethyl-3-chloro-5-trifluoromethylpyridine was added. The mixture was heated to 80 °C and reacted. After the reactants had reacted completely, the reaction solution was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate, and the filtrate was evaporated to dryness under reduced pressure. 250 mL of water was added, and the mixture was stirred, filtered, and dried under vacuum to give 30.4 g of N-[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl]-2-trifluoromethylbenzamide, an off-white solid with a yield of 79.28% and a liquid phase purity of 98.03%.

[0036] In summary, the method for preparing pyridine amide compounds of the present invention involves the reaction of aromatic aldehydes and nitro compounds under sunlight, in the presence of an acidic reagent, a catalyst, and a substituted silane, via heating to prepare substituted amide compounds. The method for preparing pyridine amide compounds of the present invention features a novel process route, simple and safe operation steps, higher reaction selectivity, high product yield, excellent quality, recyclable solvent, and does not involve hazardous reactions, making it suitable for industrial production.

[0037] It should be noted that, in this document, relational terms such as "first" and "second" are used merely to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitations, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0038] The above description is merely a specific embodiment of the present invention, enabling those skilled in the art to understand or implement the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the present invention is not to be limited to the embodiments described herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for preparing a pyridine amide compound, characterized in that, include: Aromatic aldehydes are dissolved in a first solvent to obtain a first solution; The substituted silane, catalyst, and acidic reagent are dissolved in a second solvent to obtain a second solution; The first solution and the second solution are mixed evenly to obtain a third solution; Under sunlight, the nitro compound is added to the third solution, and the aromatic aldehyde and the nitro compound undergo a reductive coupling reaction to obtain pyridine amide compounds; The aromatic aldehydes include at least one of o-trifluoromethylbenzaldehyde and 2,6-dichlorobenzaldehyde; The nitro compound includes at least one of 2-nitroethyl-3-chloro-5-trifluoromethylpyridine and 2-nitromethyl-3-chloro-5-trifluoromethylpyridine.

2. The preparation method according to claim 1, characterized in that, The substituted silanes include at least one of methyltrimethoxysilane, 2-cyanoethyltriazine, dodecafluoroheptylpropyltrimethoxysilane, isopropoxytrimethylsilane, 2-allyltrimethylsilane, tris(trimethylsilyl)silanol, octadecylmethylchlorosilane, diisopropyldihydrosilane, vinylphenyldiethoxysilane, perfluorohexyltrichlorosilane, trimethylchlorosilane, tert-butylpropylaminotrimethoxysilane, 1,2-dibromotetramethyldisilane, chloromethyltriisopropoxysilane, tris(trimethylsiloxy)silane, ethyltriethoxysilane, tris(silylmethyl)silane, and hexadecyltrimethoxysilane.

3. The preparation method according to claim 1 or 2, characterized in that, The catalyst comprises at least one of the following: molybdenum dialkyl dithiophosphate, molybdenum dialkyl dithiocarbamate, ammonium molybdate, ammonium phosphomolybdate, ammonium phosphomolybdate trihydrate, ammonium tetrathiomolybdate, ammonium octamolybdate, molybdenum silicon, bismuth molybdenum oxide, cerium molybdate oxide, molybdenum 2-ethylhexanoate, molybdenum hexacarbonyl, molybdenum glycinate, molybdenum acetate, molybdenum dibutyl dithiocarbamate, molybdenum dithiocarbamate, and sulfonated di-2-ethylhexyl dithiophosphate.

4. The preparation method according to any one of claims 1 to 3, characterized in that, The acidic reagent includes at least one of trichloroacetic acid, formic acid, acetic acid, trifluoroacetic acid, pentafluoropropionic acid, heptafluorobutyric acid, perfluorohexanoic acid, methanesulfonic acid, and cyanoacetic acid.

5. The preparation method according to any one of claims 1 to 4, characterized in that, The first solvent and the second solvent are each independently selected from at least one of methanol, ethanol, isopropanol, petroleum ether, n-butanol, acetonitrile, ethyl acetate, ethyl formate, acetone, pentanone, dimethyl sulfoxide, dimethylformamide, dioxane, and tetrahydrofuran.

6. The preparation method according to any one of claims 1 to 5, characterized in that, In the reductive coupling reaction, the molar ratio of the reactants nitrate, aromatic aldehyde, substituted silane, catalyst and acidic reagent is 1:(1~1.1):(1~2):(0.1~1):(0.1~1).

7. The preparation method according to any one of claims 1 to 6, characterized in that, In the reductive coupling reaction, the mass ratio of nitro compound to solvent is 1:(3~15); The solvent includes a first solvent and a second solvent.

8. The preparation method according to any one of claims 1 to 7, characterized in that, The reaction temperature for the reduction coupling reaction is 20~100℃.