Process for the preparation of a lufenuron intermediate

Abstract

The present application relates to the field of organic synthesis, in particular to a kind of preparation of flubendiamide intermediate compound I method, the method includes the following steps: compound a occurs reduction in the presence of catalyst and base and obtains compound I.The present application is by adding basic compound in the process of catalytic hydrogenation reaction, effectively 2,5-dichloro-4-(1,1,2,3,3,3-hexafluorophenoxy) nitrobenzene is reduced to only obtain 2,5-dichloro-4-(1,1,2,3,3,3-hexafluorophenoxy) aniline, and the content of dechlorination by-product is low, and the product purity is high.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and in particular to a method for preparing a lufenuron intermediate. Background Technology

[0002] Lufenuron, with the common English name Lufenuron and the chemical name (RS)-1-[2,5-dichloro-4-(1,1,2,3,3,3-hexafluoropropoxy)phenyl]-3-(2,6-difluorobenzoyl)urea, has the following structure: .

[0003] Lufenuron is a highly effective, low-toxicity benzoylurea insect growth regulator. The development of this class of insecticides began in the 1970s. Its mechanism of action differs from traditional neurotoxins (such as organophosphates and pyrethroids). It interferes with the biosynthesis of chitin in the insect's cuticle, preventing normal molting and pupation of larvae, thus causing the insect's death. It has no direct killing effect on adults, but possesses excellent ovicidal and larval-killing activity. The commonly used preparation method for lufenuron is the condensation of 2,6-difluorobenzoyl isocyanate with 2,5-dichloro-4-(1,1,2,3,3,3-hexafluorophenoxy)aniline.

[0004] Patent CN113292458A discloses a preparation process for 2,5-dichloro-4-(1,1,2,3,3,3-hexafluorophenoxy)aniline, in which 2,5-dichloro-4-(1,1,2,3,3,3-hexafluorophenoxy)nitrobenzene is catalytically hydrogenated to obtain 2,5-dichloro-4-(1,1,2,3,3,3-hexafluorophenoxy)aniline. However, this preparation process is prone to dechlorination byproducts. , , This directly affects the purity of the final product, lufenuron. Summary of the Invention

[0005] To address the above problems, the present invention provides a method for preparing lufenuron intermediate compound I, the method comprising the following steps: Compound a is reduced in the presence of a catalyst and a base to give compound I.

[0006] Furthermore, the base is selected from organic bases; preferably from one or more of ethylenediamine, triethylamine, cyclohexylamine, morpholine and DBN; more preferably from DBN.

[0007] Further, the mass ratio of the alkaline compound to compound a is 0.001:1-0.1:1; preferably 0.01:1-0.05:1.

[0008] Furthermore, the reaction is carried out in the presence of a reducing agent.

[0009] Furthermore, the reducing agent is selected from hydrogen.

[0010] Furthermore, the catalyst is selected from one or more of palladium catalysts, platinum catalysts, and nickel catalysts; preferably from one or more of palladium catalysts and nickel catalysts; more preferably from one or more of palladium on carbon and Raney nickel.

[0011] Further, the mass ratio of the catalyst to compound a is 0.001:1-0.2:1; preferably 0.01:1-0.1:1.

[0012] Furthermore, the reaction is carried out in a solvent.

[0013] Further, the solvent is selected from one or more of alcohols, carboxylic acids, carboxylic esters, ethers, nitriles, and water; preferably from one or more of C1-C6 alcohols, carboxylic esters, ethers, nitriles, and water; more preferably from one or more of methanol, ethanol, isopropanol, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, dioxane, acetonitrile, ethylene glycol dimethyl ether, and water; and most preferably from one or more of methanol and ethanol.

[0014] Furthermore, the mass-to-volume ratio of compound a to solvent is 1:5-1:20; preferably 1:10, g / mL.

[0015] Furthermore, the reaction temperature is 30-100℃; preferably 50-80℃.

[0016] Furthermore, the reaction also includes a post-processing step; Preferably, the post-processing step involves filtering after the reaction is complete, and then concentrating the filtrate under reduced pressure to obtain compound I.

[0017] The effects of the invention This invention effectively reduces 2,5-dichloro-4-(1,1,2,3,3,3-hexafluorophenoxy)nitrobenzene to 2,5-dichloro-4-(1,1,2,3,3,3-hexafluorophenoxy)aniline by adding a basic compound during the catalytic hydrogenation reaction, thus removing chlorinated impurities ( , , The content of the pollutants is low, and the product purity is high. The method described in this invention is environmentally friendly, simple to operate, efficient, has mild reaction conditions, is easy to control, safe and reliable, low in cost, and has good economic benefits. Furthermore, the preparation method of this invention has a high reaction yield and is suitable for industrial production. Detailed Implementation

[0018] To make the technical solution and beneficial effects of the present invention more apparent and understandable, a detailed description is provided below by listing specific embodiments. Unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application pertains.

[0019] This invention provides a method for preparing lufenuron intermediate compound I, the method comprising the following steps: Compound a is reduced in the presence of a catalyst and a base to give compound I.

[0020] In some embodiments, the base is selected from organic bases.

[0021] In some embodiments, the base is selected from one or more of ethylenediamine, triethylamine, cyclohexylamine, morpholine, and DBN.

[0022] In some embodiments, the base is selected from DBN.

[0023] In some embodiments, the mass ratio of the basic compound to compound a is 0.001:1 to 0.1:1.

[0024] In some embodiments, the mass ratio of the basic compound to compound a is 0.01:1 to 0.05:1.

[0025] In some embodiments, the mass ratio of the basic compound to compound a is 0.01:1, 0.02:1, 0.03:1, 0.04:1, or 0.05:1.

[0026] In some embodiments, the reaction is carried out in the presence of a reducing agent.

[0027] In some embodiments, the reducing agent is selected from hydrogen.

[0028] In some embodiments, the catalyst is selected from one or more of palladium catalysts, platinum catalysts, and nickel catalysts.

[0029] In some embodiments, the catalyst is selected from palladium catalysts.

[0030] In some embodiments, the catalyst is selected from palladium on carbon.

[0031] In some embodiments, the catalyst is selected from nickel catalysts.

[0032] In some embodiments, the catalyst is selected from Raney nickel.

[0033] In some embodiments, the mass ratio of the catalyst to compound a is 0.001:1 to 0.2:1.

[0034] In some embodiments, the mass ratio of the catalyst to compound a is 0.01:1 to 0.1:1.

[0035] In some embodiments, the mass ratio of the catalyst to compound a is 0.01:1, 0.02:1, 0.03:1, 0.04:1, 0.05:1, 0.06:1, 0.07:1, 0.08:1, 0.09:1, or 0.1:1.

[0036] In some embodiments, the reaction is carried out in a solvent.

[0037] In some embodiments, the solvent is selected from one or more of alcohols, carboxylic acids, carboxylic esters, ethers, nitriles, and water.

[0038] In some embodiments, the solvent is selected from one or more of C1-C6 alcohols, carboxylic acid esters, ethers, nitriles, and water.

[0039] In some embodiments, the solvent is selected from one or more of methanol, ethanol, isopropanol, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, dioxane, acetonitrile, ethylene glycol dimethyl ether, and water.

[0040] In some embodiments, the solvent is selected from one or more of methanol and ethanol.

[0041] In some embodiments, the mass-to-volume ratio of compound a to solvent is 1:5 to 1:20, g / mL.

[0042] In some embodiments, the mass-to-volume ratio of compound a to solvent is 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, or 1:20, g / mL.

[0043] In some embodiments, the reaction temperature is 30-100°C.

[0044] In some embodiments, the reaction temperature is 50-80°C.

[0045] In some embodiments, the reaction temperature is 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, 61°C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C, 68°C, 69°C, 70°C, 71°C, 72°C, 73°C, 74°C, 75°C, 76°C, 77°C, 78°C, 79°C, or 80°C.

[0046] In some embodiments, there are no particular restrictions on the order in which the raw materials, alkali, catalyst, solvent, etc., are added. As long as the reaction proceeds, the order in which they are added can be any.

[0047] In some embodiments, the reaction further includes a post-processing step.

[0048] In some embodiments, the post-processing step involves filtering after the reaction is complete, and then concentrating the filtrate under reduced pressure to obtain compound I.

[0049] In some embodiments, intermediate compound I can be separated and purified from the reaction mixture by methods known to those skilled in the art (e.g., extraction, washing, crystallization including recrystallization, crystal washing and / or other operations), as well as improved methods thereof and any combination thereof.

[0050] DBN refers to 1,5-diazabicyclo[4.3.0]non-5-ene, with the following chemical structure: .

[0051] The term "alcohol" solvent refers to a substance derived from which one or more hydrogen atoms on a C1-C6 alkane are replaced by one or more hydroxyl (OH) groups. The C1-C6 alkane refers to a straight-chain or branched alkane containing 1 to 6 carbon atoms. Specific examples of alcohol solvents include, but are not limited to, methanol, ethanol, isopropanol, or n-propanol.

[0052] The term "carboxylic acid solvent" refers to substances derived from which one or more hydrogen atoms on a C1-C6 alkane are replaced by one or more carboxyl groups (COOH), and the C1-C6 alkane refers to a straight-chain or branched alkane containing 1 to 6 carbon atoms. Specific examples of carboxylic acid solvents include, but are not limited to, acetic acid, propionic acid, butyric acid, trifluoroacetic acid, or pentafluoropropionic acid.

[0053] The term "carboxylic acid ester" solvent refers to a chain compound containing an ester group -COOR and having 3-10 carbon atoms, wherein R is a C1-C6 alkyl group, and the C1-C6 alkyl group refers to a straight-chain or branched alkane containing 1-6 carbon atoms. Specific examples of carboxylic acid ester solvents include, but are not limited to, methyl acetate, ethyl acetate, and propyl acetate.

[0054] The term "ether solvent" refers to chain or cyclic compounds containing an ether bond (-O-) and having 1 to 10 carbon atoms. Specific examples include, but are not limited to, diethyl ether, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, propylene glycol methyl ether, or methyl tert-butyl ether.

[0055] The term "nitrile solvent" refers to a solvent containing nitriles having 2 to 10 carbon atoms. Examples of nitrile solvents include, but are not limited to, acetonitrile, propionitrile, butyronitrile, benzonitrile, phenylacetonitrile, or combinations thereof, preferably acetonitrile, benzonitrile, phenylacetonitrile, or combinations thereof, especially acetonitrile.

[0056] The method of the present invention will be described below through specific embodiments. It should be understood that these embodiments are used to illustrate the basic principles, main features and advantages of the present invention, and the present invention is not limited to the scope of the following embodiments. The implementation conditions used in the embodiments can be further adjusted according to specific requirements, and the implementation conditions not specified are usually the conditions in conventional experiments.

[0057] In the following examples, unless otherwise specified, all temperatures are in Celsius; unless otherwise specified, all starting materials and reagents are commercially available or synthesized according to known methods; commercially available materials and reagents are used directly without further purification; unless otherwise specified, commercially available manufacturers include, but are not limited to, TCI (Shanghai) Chemical Industry Development Co., Ltd., Bailingwei Technology Co., Ltd., Sinopharm Group, Shanghai BIDE Pharmaceutical Technology Co., Ltd., and Shanghai Mairui Chemical Technology Co., Ltd.

[0058] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0059] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0060] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system used for column chromatography to purify the compounds, or the developing solvent system for TLC included: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: n-hexane: ethyl acetate. The volume ratio of the solvent varied depending on the polarity of the compound and could also be adjusted by adding a small amount of acidic or basic reagents, such as acetic acid or triethylamine.

[0061] TLC: Thin-layer chromatography. Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for TLC. The silica gel plates used in TLC have a diameter of 0.2mm-0.3mm, while those used for separating and purifying products are 0.4mm-0.5mm.

[0062] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0063] Example 1 10 g of compound a, 90 mL of ethanol, 0.5 g of palladium on carbon, and 0.3 g of ethylenediamine were added to a reaction flask. The air was replaced three times with hydrogen gas, and then hydrogen gas was introduced again. The mixture was heated to reflux and reacted. After the reaction was complete, the mixture was cooled and filtered under nitrogen pressure. The filter cake was washed with ethanol, and the filtrates were combined and the solvent was removed under reduced pressure to obtain 8.59 g of compound I with a purity of 99.11%. The total content of dechlorinated impurities (impurity compounds 1, 2, and 3) was 0.20%.

[0064] Example 2 10 g of compound a, 100 mL of ethanol, 0.5 g of Raney nickel, and 0.3 g of ethylenediamine were added to a reaction flask. The air was replaced three times with hydrogen gas, and then hydrogen gas was introduced again. The mixture was heated to reflux and reacted. After the reaction was complete, the mixture was cooled and filtered under nitrogen pressure. The filter cake was washed with ethanol, and the filtrates were combined and the solvent was removed under reduced pressure to obtain 8.57 g of compound I with a purity of 99.23%. The total content of dechlorinated impurities (impurity compounds 1, 2, and 3) was 0.17%.

[0065] Example 3 10 g of compound a, 90 mL of ethanol, 0.5 g of palladium on carbon, and 0.3 g of morpholine were added to the reaction flask. The air was replaced three times with hydrogen gas, and then hydrogen gas was introduced again. The mixture was heated to reflux and reacted. After the reaction was complete, the mixture was cooled and filtered under nitrogen pressure. The filter cake was washed with ethanol, and the filtrates were combined and the solvent was removed under reduced pressure to obtain 8.65 g of compound I with a purity of 99.19%. The total content of dechlorinated impurities (impurity compounds 1, 2, and 3) was 0.18%.

[0066] Example 4 10 g of compound a, 100 mL of ethanol, 0.5 g of Raney nickel, and 0.3 g of morpholine were added to a reaction flask. The air was replaced three times with hydrogen gas, and then hydrogen gas was introduced again. The mixture was heated to reflux and reacted. After the reaction was complete, the mixture was cooled and filtered under nitrogen pressure. The filter cake was washed with ethanol, and the filtrates were combined and the solvent was removed under reduced pressure to obtain 8.69 g of compound I with a purity of 99.26%. The total content of dechlorinated impurities (impurity compounds 1, 2, and 3) was 0.15%.

[0067] Example 5 10 g of compound a, 90 mL of ethanol, 0.5 g of palladium on carbon, and 0.3 g of DBN were added to the reaction flask. The air was replaced three times with hydrogen gas, and then hydrogen gas was introduced again. The mixture was heated to reflux and reacted. After the reaction was complete, the mixture was cooled and filtered under nitrogen pressure. The filter cake was washed with ethanol, and the filtrates were combined to remove the solvent under reduced pressure to obtain 8.88 g of compound I with a purity of 99.56%. The total content of dechlorinated impurities (impurity compounds 1, 2, and 3) was 0.10%.

[0068] Example 6 10 g of compound a, 100 mL of ethanol, 0.5 g of Raney nickel, and 0.3 g of DBN were added to the reaction flask. The air was replaced three times with hydrogen gas, and then hydrogen gas was introduced again. The mixture was heated to reflux and reacted. After the reaction was complete, the mixture was cooled and filtered under nitrogen pressure. The filter cake was washed with ethanol, and the filtrates were combined and the solvent was removed under reduced pressure to obtain 8.95 g of compound I with a purity of 99.69%. The total content of dechlorinated impurities (impurity compounds 1, 2, and 3) was 0.05%.

[0069] Example 7 10 g of compound a, 100 mL of methanol, 0.5 g of Raney nickel, and 0.3 g of DBN were added to the reaction flask. The air was replaced three times with hydrogen gas, and then hydrogen gas was introduced again. The mixture was heated to reflux and reacted. After the reaction was complete, the mixture was cooled and filtered under nitrogen pressure. The filter cake was washed with methanol, and the filtrates were combined and the solvent was removed by vacuum evaporation to obtain 8.98 g of compound I with a purity of 99.71%. The total content of dechlorinated impurities (impurity compounds 1, 2, and 3) was 0.04%.

[0070] Comparative Example 1 10 g of compound a, 100 mL of ethanol, and 0.5 g of Raney nickel were added to the reaction flask. The air was replaced three times with hydrogen gas, and then hydrogen gas was introduced again. The mixture was heated and refluxed. After the reaction was complete, the mixture was cooled and filtered under nitrogen pressure. The filter cake was washed with ethanol, and the filtrates were combined and the solvent was removed under reduced pressure to obtain 8.40 g of compound I with a purity of 98.58%. The total content of dechlorinated impurities (impurity compounds 1, 2, and 3) was 0.39%.

[0071] Comparative Example 2 10 g of compound a, 90 mL of ethanol, and 0.5 g of palladium on carbon were added to the reaction flask. The air was replaced three times with hydrogen gas, and then hydrogen gas was introduced again. The mixture was heated to reflux and reacted. After the reaction was complete, the mixture was cooled and filtered under nitrogen pressure. The filter cake was washed with ethanol, and the filtrates were combined and the solvent was removed by vacuum evaporation to obtain 8.32 g of compound I with a purity of 98.63%. The total content of dechlorinated impurities (impurity compounds 1, 2, and 3) was 0.35%.

[0072] It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations included in the claims. Various modifications and changes can be made to the above embodiments without departing from the scope of the invention. Similarly, the various technical features of the above embodiments can be arbitrarily combined to form other embodiments of the invention that may not be explicitly described. Therefore, the above embodiments only illustrate several implementations of the invention and do not limit the scope of protection of this patent.

Claims

1. A method for preparing lufenuron intermediate compound I, characterized in that, The method includes the following steps: Compound a is reduced in the presence of a catalyst and a base to give compound I.

2. The method according to claim 1, characterized in that, The alkali is selected from organic alkalis; Preferably, it is selected from one or more of ethylenediamine, triethylamine, cyclohexylamine, morpholine, and DBN; more preferably, it is selected from DBN.

3. The method according to any one of claims 1-2, characterized in that, The mass ratio of the alkaline compound to compound a is 0.001:1 to 0.1:1; preferably 0.01:1 to 0.05:

1.

4. The method according to claim 1, characterized in that, The reaction is carried out in the presence of a reducing agent; Preferably, the reducing agent is selected from hydrogen.

5. The method according to claim 1, characterized in that, The catalyst is selected from one or more of palladium catalysts, platinum catalysts, and nickel catalysts; preferably from one or more of palladium catalysts and nickel catalysts; more preferably from one or more of palladium on carbon and Raney nickel.

6. The method according to claim 5, characterized in that, The mass ratio of the catalyst to compound a is 0.001:1-0.2:1; preferably 0.01:1-0.1:

1.

7. The method according to any one of claims 1-2, characterized in that, The reaction is carried out in a solvent; Preferably, the solvent is selected from one or more of alcohols, carboxylic acids, carboxylic esters, ethers, nitriles, and water; more preferably from one or more of C1-C6 alcohols, carboxylic esters, ethers, nitriles, and water; more preferably from one or more of methanol, ethanol, isopropanol, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, dioxane, acetonitrile, ethylene glycol dimethyl ether, and water; and most preferably from one or more of methanol and ethanol.

8. The method according to claim 7, characterized in that, The mass-to-volume ratio of compound a to solvent is 1:5-1:20; preferably 1:10, g / mL.

9. The method according to any one of claims 1-2, characterized in that, The reaction temperature is 30-100℃; preferably 50-80℃.

10. The method according to any one of claims 1-2, characterized in that, The reaction also includes a post-processing step; Preferably, the post-processing step involves filtering after the reaction is complete, and then concentrating the filtrate under reduced pressure to obtain compound I.

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