Method for preparing 2-aminoethyl-3-chloro-5-trifluoromethylpyridine

Abstract

The invention discloses a method for preparing 2-aminoethyl-3-chloro-5-trifluoromethylpyridine, which comprises the following steps: S1, mixing 2-formyl-3-chloro-5-trifluoromethylpyridine, a solvent and a first catalyst, reacting under a heating condition, dropwise adding halogenated nitromethane, and reacting completely to obtain a reaction solution containing a first intermediate; s2, adding a second catalyst into the reaction solution containing the first intermediate obtained in the step S1, reacting under a heating condition until the reaction is complete, dropwise adding a hydrochloric acid solution, stirring, and performing post-treatment to obtain a second intermediate solution; and S3, adding a third catalyst into the second intermediate solution obtained in the step S2, introducing hydrogen, carrying out complete reaction under a heating condition, filtering, and recovering the solvent to obtain the 2-aminoethyl-3-chloro-5-trifluoromethylpyridine. According to the invention, 2-aldehyde-3-chloro-5-trifluoromethylpyridine is adopted as a raw material, and a one-pot method is adopted for preparation, so that the method is efficient and rapid, the reaction yield is high, and the solvent can be recycled and reused.

Description

Technical Field

[0001] This invention belongs to the fields of pesticide and organic synthesis technology, and in particular relates to a method for preparing 2-aminoethyl-3-chloro-5-trifluoromethylpyridine. Background Technology

[0002] Fluopyram is a novel pyridylethylbenzamide fungicide and nematicide developed by Bayer Crop Science. Its chemical name is N-[2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethyl]-2-(trifluoromethyl)benzamide, CAS Registry Number: 658066-35-4, and its English name is fluopyram. Bayer Crop Science has registered 17 products in the United States, covering technical grade, single-agent formulations, and formulations with various active ingredients. Fluopyram is prepared by reacting 2-aminoethyl-3-chloro-5-trifluoromethylpyridine and o-trifluoromethylbenzoyl chloride. While o-trifluoromethylbenzoyl chloride is already in mass production, the main challenge affecting the cost and industrialization of fluopyram is the preparation of 2-aminoethyl-3-chloro-5-trifluoromethylpyridine.

[0003] The preparation methods reported in the literature include: 1. Cyano reduction method: CN118812423, which uses Raney nickel and Raney cobalt to reduce cyano to amino in the presence of hydrazine hydrate catalysis, with a yield of 92.5%.

[0004] 2. Patent CN118851992 discloses a method for preparing fluopyram, which includes the intermediate 2-aminoethyl-3-chloro-5-trifluoromethylpyridine. The patent uses 2,3-dichloro-5-trifluoromethylpyridine as a raw material, reacting it with isoxazolylboronic acid to obtain 2-cyano-3-chloro-5-trifluoromethylpyridine, which is then reduced with borane to obtain the final product, with an overall yield of 65.39%.

[0005] 3. Patent CN118772049 reports a preparation process for 3-chloro-2-aminoethyl-5-trifluoromethylpyridine: 2-aminomethyl-3-chloro-5-trifluoromethylpyridine is reacted with sodium nitrite and a haloalkane to obtain 2-chloromethyl-3-chloro-5-trifluoromethylpyridine, which is then reacted with nitromethane to obtain 3-chloro-2-nitroethyl-5-trifluoromethylpyridine, and finally reduced with Raney nickel to obtain the product, with an overall yield of 78%.

[0006] 4. Patent CN115215793 reports a method for synthesizing fluopyram, and a total of three methods for preparing 2-aminoethyl-3-chloro-5-trifluoromethylpyridine are reported: Method 1: Cyanohydrolysis method, using 2-acetonitrile-3-chloro-5-trifluoromethylpyridine as raw material, the nitrile group is hydrolyzed to carboxylic acid under acidic conditions, then reduced to hydroxyl group by sodium borohydride, then esterified with methanesulfonyl chloride, and finally amination with ammonia methanol to obtain the final product, with an overall yield of 59.76%.

[0007] Method 2: The sulfonate obtained by Method 1 was reacted with sodium azide, and then hydrogenated with palladium on carbon to obtain the final product, with an overall yield of 34.56%.

[0008] Method 3: The 2-hydroxyethyl-3-chloro-5-trifluoromethylpyridine obtained in Method 1 was brominated with NBS to obtain 2-bromoethyl-3-chloro-5-trifluoromethylpyridine, which was then subjected to three amination methods: 1) hydrolysis with N-bromosuccinimide, with an overall yield of 53.28%; 2) amination with ammonia in methanol solution, with an overall yield of 24.48%; 3) reaction with acetamide in pyridine, followed by acidification, with an overall yield of 15.12%. Summary of the Invention

[0009] In view of this, the present invention aims to provide a method for preparing 2-aminoethyl-3-chloro-5-trifluoromethylpyridine to solve at least one technical problem in the prior art.

[0010] To achieve the above objectives, the technical solution of the present invention is implemented as follows: A method for preparing 2-aminoethyl-3-chloro-5-trifluoromethylpyridine includes the following steps: S1: 2-Aldehyde-3-chloro-5-trifluoromethylpyridine, solvent, and first catalyst are mixed and reacted under heating conditions. After the reaction is complete, halonitromethane is added dropwise to obtain a reaction solution containing the first intermediate. S2: Add the second catalyst to the reaction solution containing the first intermediate obtained in step S1 and react under heating conditions until the reaction is complete. Then add hydrochloric acid solution dropwise and stir. After post-treatment, the second intermediate solution is obtained. S3: Add the third catalyst to the second intermediate solution obtained in step S2, introduce hydrogen gas, and react completely under heating conditions. After filtration, recover the solvent to obtain 2-aminoethyl-3-chloro-5-trifluoromethylpyridine.

[0011] The synthesis route is shown in the figure below: ; Further, the solvent in step S1 includes one or more of methanol, acetonitrile, dioxane, tetrahydrofuran, methyltetrahydrofuran, isopropyl ether, ethyl acetate, tert-methyl ether, ethylene glycol dimethyl ether, chloroform, methyl ethyl ketone, dichloromethane, dichloroethane, chloroform, dimethyl sulfoxide, dimethyl acetamide, butyl acetate, and dioxane. And / or, the mass of the solvent in step S1 is 5 to 40 times the mass of 2-aldehyde-3-chloro-5-trifluoromethylpyridine.

[0012] Further, the first catalyst in step S1 includes one or more of the following: potassium fluoride, ammonium chloride, ammonium formate, ammonium acetate, copper iodide, pyridine, sodium iodide, potassium iodide, ammonium iodide, sodium bromide, sodium hydroxide, ammonium carbonate, sodium methoxide, potassium phosphate, potassium carbonate, cesium carbonate, aluminum oxide, sodium carbonate, copper acetate, copper bromide, copper iodide, light copper oxide powder, nano copper oxide powder, ferric nitrate, ferric chloride, and ferric acetate.

[0013] Further, the second catalyst in step S2 includes one or more of the following: potassium fluoride, ammonium chloride, ammonium formate, ammonium acetate, copper iodide, pyridine, sodium iodide, potassium iodide, ammonium iodide, sodium bromide, sodium hydroxide, ammonium carbonate, sodium methoxide, potassium phosphate, potassium carbonate, cesium carbonate, alumina, sodium carbonate, copper acetate, copper bromide, copper iodide, light copper oxide powder, nano copper oxide powder, ferric nitrate, ferric chloride, and ferric acetate.

[0014] Further, in step S1, the mass of the first catalyst is 1%-30% of the mass of 2-aldehyde-3-chloro-5-trifluoromethylpyridine; And / or, in step S2, the mass of the second catalyst is 1%-30% of the mass of 2-aldehyde-3-chloro-5-trifluoromethylpyridine.

[0015] Furthermore, the halogen in the halonitromethane in step S1 includes one of fluorine, chlorine, bromine, and iodine, preferably chlorine or bromine.

[0016] Furthermore, the heating temperature under the heating conditions in step S1 is 30-120℃; And / or, the heating temperature under the heating conditions in step S2 is 30-120℃; And / or, the heating temperature under the heating conditions in step S3 is 30-120℃; And / or, the addition of hydrochloric acid solution and stirring in step S2 includes adding hydrochloric acid solution, adjusting the pH to 3-4, and stirring for 1-3 hours.

[0017] Furthermore, the pressure of the dropwise addition of halonitromethane under heating conditions in step S1 is atmospheric pressure; And / or, the reaction pressure in the hydrochloric acid solution under heating conditions in step S2 is atmospheric pressure; And / or, the reduction reaction in step S3 is carried out at atmospheric pressure.

[0018] Further, the post-processing in step S2 includes adding dichloroethane to the reaction solution, separating the liquid, extracting, washing with alkali and water, combining the organic phases, drying with magnesium sulfate, and filtering to obtain the second intermediate solution.

[0019] Further, the reduction in S3 includes the addition of one or more of the following: palladium on carbon, bis-(1,5-cyclooctadiene) nickel, nickel acetylacetonate, nickel perchlorate, nickel acetate, cobalt chloride, polyethylene glycol succinate, tococelen, methoxy polyethylene glycol succinate N-hydroxysuccinimide, ammonium formate, bromide, cobalt acetate, composite nickel cobalt ferrite, rhenium nickel cobalt, hydrogen, carbonyl iron, iron-nickel powder, nano-carbonyl nickel powder with a particle size of 1.5μm~5μm, electronic grade nickel powder, germanium, cobalt, 5% rhodium on carbon, 5% rhodium alumina, aluminum powder, samarium cobalt powder, etc.

[0020] Compared with existing technologies, the method for preparing 2-aminoethyl-3-chloro-5-trifluoromethylpyridine according to the present invention has the following advantages: 1. This invention proposes a novel method for preparing 2-aminoethyl-3-chloro-5-trifluoromethylpyridine, using 2-aldehyde-3-chloro-5-trifluoromethylpyridine as raw material, and preparing it in a one-pot process. This method is highly efficient, rapid, and yields a high reaction rate, and the solvent can be recycled.

[0021] 2. The entire process route is reasonably designed, avoiding intermediate separation and purification, allowing for solvent recycling, and providing mild reaction conditions with high yields. In particular, the optimization of the catalytic system significantly improves atom economy, providing an efficient, economical, and environmentally friendly synthetic route for the industrial production of pharmaceutical and pesticide intermediates containing trifluoromethylpyridine. Attached Figure Description

[0022] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. In the drawings: Figure 1 The 1H NMR spectrum of the sample indicates that fluopyram is obtained by reacting 2-aminoethyl-3-chloro-5-trifluoromethylpyridine prepared in Example 1 of this invention with o-trifluoromethylbenzoyl chloride. Detailed Implementation

[0023] It should be noted that, unless otherwise specified, the embodiments and features described in the present invention can be combined with each other.

[0024] The present invention will now be described in detail with reference to the accompanying drawings and embodiments.

[0025] Example 1 Add 21g of 2-aldehyde-3-chloro-5-trifluoromethylpyridine, 210g of 2-methyltetrahydrofuran, and 2.1g of ammonium carbonate to a reaction flask and heat to 60℃. Add 18.2g of 2-bromonitromethane dropwise to the reaction solution until the reactants have reacted completely. Then add 2g of copper iodide to the reaction solution and react for 5 hours. After that, lower the temperature of the reaction solution to 40℃ and add 10% hydrochloric acid aqueous solution to adjust the pH to 3-4. Stir for 2 hours and then add 150ml of dichloroethane to the reaction solution. Separate the solution and extract twice with 50ml of dichloroethane. Combine the organic phases and wash with 50ml of 5% sodium carbonate. Wash with water to separate the layers. Dry the organic phase with anhydrous magnesium sulfate and filter to obtain a dichloroethane solution of intermediate 2. Add 0.8 g palladium on carbon and 4.2 g iron carbonyl to this solution, purge with hydrogen gas, react at 0.5 MPa and 40 °C for 3 hours, filter, and recover the solvent from the filtrate under reduced pressure to obtain 21.63 g of a pale yellow solid, 2-aminoethyl-3-chloro-5-trifluoromethylpyridine. Figure 1 As shown. Yield 96.30%, purity 99.73%.

[0026] Example 2 Add 21g of 2-aldehyde-3-chloro-5-trifluoromethylpyridine, 250g of dioxane, and 1.6g of potassium iodide to a reaction flask and heat to 60℃. Add 16.8g of 2-bromonitromethane dropwise to the reaction solution until the reactants have reacted completely. Then add 2g of potassium iodide to the reaction solution and react for 6 hours. Then lower the temperature to 40℃, add 10% hydrochloric acid dropwise to adjust the pH to 3-4, and stir for 2 hours. Add 150ml of dichloroethane to the reaction solution and separate the layers. Extract twice with 50ml of dichloroethane, combine the organic phases, wash with 50ml of 5% sodium carbonate, wash with water to separate the layers, dry the organic phase with anhydrous magnesium sulfate, and filter to obtain a dichloroethane solution of intermediate 2. 1 g of polyethylene glycol succinate and 4 g of 2 μm nano-carbonyl nickel powder were added to this solution. Hydrogen gas was then introduced, and the mixture was reacted at 1.5 MPa and 40 °C for 3 hours. After cooling and filtration, the solvent was recovered from the filtrate under reduced pressure to obtain 20.80 g of a pale yellow solid, 2-aminoethyl-3-chloro-5-trifluoromethylpyridine. The yield was 92.61%, and the purity was 99.12%.

[0027] Example 3 Add 21g of 2-aldehyde-3-chloro-5-trifluoromethylpyridine, 230g of isopropyl ether, and 1.6g of potassium iodide to the reaction flask and heat to 60℃. Add 16.8g of 2-bromonitromethane dropwise to the reaction solution until the reactants have reacted completely. Then add 2g of nano copper oxide powder to the reaction solution and react for 8 hours. Then lower the temperature to 40℃, add 10% hydrochloric acid dropwise to adjust the pH to 3-4, stir for 2 hours, and add 150ml of dichloroethane (recovered) to the reaction solution. Separate the solution and extract twice with 50ml of dichloroethane (recovered). Combine the organic phases, wash with 50ml of 5% sodium carbonate, wash with water to separate the layers, dry the organic phase with anhydrous magnesium sulfate, and filter to obtain a dichloroethane solution of intermediate 2. Add 1.5 g of tocoxexyl and 6 g of electronic-grade nickel powder to this solution, and react at 40 °C under normal pressure for 5 hours after purging with hydrogen. Then cool and filter, and recover the solvent from the filtrate under reduced pressure to obtain 15.82 g of pale yellow solid 2-aminoethyl-3-chloro-5-trifluoromethylpyridine. Yield: 70.44%, purity: 98.50%.

[0028] Example 4 Add 21g of 2-aldehyde-3-chloro-5-trifluoromethylpyridine, 250g of dioxane, and 1.6g of potassium iodide to a reaction flask and heat to 60℃. Add 12.4g of 2-chloronitromethane dropwise to the reaction solution until the reactants have reacted completely. Then add 2g of potassium iodide and 0.5g of aluminum oxide to the reaction solution. After reacting for 6 hours, lower the temperature to 40℃, add 10% hydrochloric acid to adjust the pH to 3-4, and stir for 2 hours. Add 150ml of dichloroethane to the reaction solution and separate the layers. Extract twice with 50ml of dichloroethane, combine the organic phases, wash with 5% sodium carbonate, separate the layers, dry the organic phase with anhydrous magnesium sulfate, and filter to obtain a dichloroethane solution of intermediate 2. Add 1.6 g of 5% rhodium alumina to this solution, and react at 40°C for 7 hours under hydrogen pressure (2.5 MPa). Then cool and filter. Recover the solvent from the filtrate under reduced pressure to obtain 16.03 g of a pale yellow solid, 2-aminoethyl-3-chloro-5-trifluoromethylpyridine. Yield: 71.37%, purity: 98.22%.

[0029] Example 5 Add 21g of 2-aldehyde-3-chloro-5-trifluoromethylpyridine, 260g of ethylene glycol dimethyl ether, 1.6g of potassium iodide, and 0.6g of potassium phosphate to a reaction flask. Heat to 85℃, and add 12.4g of 2-chloronitromethane dropwise to the reaction solution until the reactants have reacted completely. Then, add 2g of potassium iodide to the reaction solution and react for 6 hours. Then, lower the temperature to 40℃, add 10% hydrochloric acid dropwise to adjust the pH to 3-4, and stir for 2 hours. Then, add 150ml of dichloroethane to the reaction solution and separate the layers. Extract twice with 50ml of dichloroethane, combine the organic phases, wash with 5% sodium carbonate, separate the layers, dry the organic phase with anhydrous magnesium sulfate, and filter to obtain a dichloroethane solution of intermediate 2. Add 1.6 g of composite nickel-cobalt ferrite to this solution, and react at 40°C for 5 hours under hydrogen pressure (2 MPa). Then cool and filter. Recover the solvent from the filtrate under reduced pressure to obtain 12.16 g of a pale yellow solid, 2-aminoethyl-3-chloro-5-trifluoromethylpyridine. Yield: 54.14%, purity: 97.76%.

[0030] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing 2-aminoethyl-3-chloro-5-trifluoromethylpyridine, characterized in that: The steps include: S1: 2-Aldehyde-3-chloro-5-trifluoromethylpyridine, solvent, and first catalyst are mixed and reacted under heating conditions. After the reaction is complete, halonitromethane is added dropwise to obtain a reaction solution containing the first intermediate. S2: Add the second catalyst to the reaction solution containing the first intermediate obtained in step S1 and react under heating conditions until the reaction is complete. Then add hydrochloric acid solution dropwise and stir. After post-treatment, the second intermediate solution is obtained. S3: Add the third catalyst to the second intermediate solution obtained in step S2, introduce hydrogen gas, and react completely under heating conditions. After filtration, recover the solvent to obtain 2-aminoethyl-3-chloro-5-trifluoromethylpyridine.

2. The method for preparing 2-aminoethyl-3-chloro-5-trifluoromethylpyridine according to claim 1, characterized in that: The solvent in step S1 includes one or more of methanol, acetonitrile, dioxane, tetrahydrofuran, methyltetrahydrofuran, isopropyl ether, ethyl acetate, tert-methyl ether, ethylene glycol dimethyl ether, chloroform, methyl ethyl ketone, dichloromethane, dichloroethane, chloroform, dimethyl sulfoxide, dimethyl acetamide, butyl acetate, and dioxane. And / or, the mass of the solvent in step S1 is 5 to 40 times the mass of 2-aldehyde-3-chloro-5-trifluoromethylpyridine.

3. The method for preparing 2-aminoethyl-3-chloro-5-trifluoromethylpyridine according to claim 1, characterized in that: The first catalyst in step S1 includes one or more of the following: potassium fluoride, ammonium chloride, ammonium formate, ammonium acetate, copper iodide, pyridine, sodium iodide, potassium iodide, ammonium iodide, sodium bromide, sodium hydroxide, ammonium carbonate, sodium methoxide, potassium phosphate, potassium carbonate, cesium carbonate, aluminum oxide, sodium carbonate, copper acetate, copper bromide, copper iodide, light copper oxide powder, nano copper oxide powder, ferric nitrate, ferric chloride, and ferric acetate.

4. The method for preparing 2-aminoethyl-3-chloro-5-trifluoromethylpyridine according to claim 1, characterized in that: The second catalyst in step S2 includes one or more of the following: potassium fluoride, ammonium chloride, ammonium formate, ammonium acetate, copper iodide, pyridine, sodium iodide, potassium iodide, ammonium iodide, sodium bromide, sodium hydroxide, ammonium carbonate, sodium methoxide, potassium phosphate, potassium carbonate, cesium carbonate, aluminum oxide, sodium carbonate, copper acetate, copper bromide, copper iodide, light copper oxide powder, nano copper oxide powder, ferric nitrate, ferric chloride, and ferric acetate.

5. The method for preparing 2-aminoethyl-3-chloro-5-trifluoromethylpyridine according to claim 4, characterized in that: In step S1, the mass of the first catalyst is 1%-30% of the mass of 2-aldehyde-3-chloro-5-trifluoromethylpyridine; And / or, in step S2, the mass of the second catalyst is 1%-30% of the mass of 2-aldehyde-3-chloro-5-trifluoromethylpyridine.

6. The method for preparing 2-aminoethyl-3-chloro-5-trifluoromethylpyridine according to claim 1, characterized in that: The halogen in the halonitromethane in step S1 includes one of fluorine, chlorine, bromine, and iodine. Preferably, the halogen includes chlorine or bromine.

7. The method for preparing 2-aminoethyl-3-chloro-5-trifluoromethylpyridine according to claim 1, characterized in that: The heating temperature under the heating conditions in step S1 is 30-120℃; And / or, the heating temperature under the heating conditions in step S2 is 30-120℃; And / or, the heating temperature under the heating conditions in step S3 is 30-120℃; And / or, the addition of hydrochloric acid solution and stirring in step S2 includes adding hydrochloric acid solution, adjusting the pH to 3-4, and stirring for 1-3 hours.

8. The method for preparing 2-aminoethyl-3-chloro-5-trifluoromethylpyridine according to claim 1, characterized in that: The pressure of the dropwise addition of halonitromethane under heating conditions in step S1 is atmospheric pressure; And / or, the reaction pressure in the hydrochloric acid solution under heating conditions in step S2 is atmospheric pressure; And / or, the reduction reaction in step S3 is carried out at atmospheric pressure.

9. The method for preparing 2-aminoethyl-3-chloro-5-trifluoromethylpyridine according to claim 1, characterized in that: The post-processing in step S2 includes adding dichloroethane to the reaction solution, separating the liquid, extracting, washing with alkali and water, combining the organic phases, drying with magnesium sulfate, and filtering to obtain the second intermediate solution.

10. The method for preparing 2-aminoethyl-3-chloro-5-trifluoromethylpyridine according to claim 1, characterized in that: The third catalyst in S3 includes one or more of the following: palladium on carbon, bis-(1,5-cyclooctadiene)nickel, nickel acetylacetonate, nickel perchlorate, nickel acetate, cobalt chloride, polyethylene glycol succinate, tococelen, methoxy polyethylene glycol succinate N-hydroxysuccinimide, ammonium formate, bromide, cobalt acetate, composite nickel cobalt ferrite, rhenium nickel cobalt, hydrogen, carbonyl iron, iron-nickel powder, nano-carbonyl nickel powder with a particle size of 1.5μm~5μm, electronic grade nickel powder, germanium, cobalt, 5% rhodium on carbon, 5% rhodium alumina, aluminum powder, samarium cobalt powder, etc.

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