Preparation method of fluralana synthesis intermediate

Abstract

The invention relates to the technical field of pesticide intermediates, in particular to a preparation method of a fluralan synthetic intermediate, which comprises the following synthetic route: taking parachloroaniline as an initial raw material, and carrying out acylation reaction on parachloroaniline and pivaloyl chloride in an alkaline solvent to generate a compound 2; performing chlorination reaction on the compound 2 and a chlorinating agent to generate a compound 3; reacting the compound 3 with magnesium in a nitrogen environment to obtain a Grignard reagent intermediate compound 4; reacting the compound 4 with a trifluoroacetic acid derivative to obtain a compound 5; reacting the compound 5 with concentrated hydrochloric acid to obtain a compound 6; generating a compound 7 from the compound 6 under the action of a chlorinating agent; and finally, synthesizing the compound 7 into a compound 8 under the action of a nitrite reagent. The preparation method has the advantages of safe operation, few by-products, mild conditions, easily available raw materials and simple optimization, and is more suitable for industrial large-scale production.

Description

Technical Field

[0001] This invention relates to the field of pesticide intermediates technology, specifically to a method for preparing a flurana synthetic intermediate. Background Technology

[0002] Fluralaner is an isoxazoline insecticide accidentally developed in 2004 by Nissan Chemical Industries of Japan and DuPont of the United States, initially primarily for the control of agricultural pests. However, in recent years, this drug has received widespread attention from veterinary drug researchers both domestically and internationally, and is widely used for the control of ectoparasites in pets such as dogs and cats. It has gained increasing attention and shows promising development prospects. The key to the synthesis of fluralaner lies in the efficient preparation of the intermediate 1-(3,5-dichloro-4-fluorophenyl)-2,2,2-trifluoroethyl ketone. Previous literature has outlined roughly three methods for its synthesis: (1) The method used in WO2017201134A1 (synthetic process and novel intermediates) is: 5-bromo-1,3-dichloro-2-fluorobenzene is used as the starting material and reacted with methyl trifluoroacetate to obtain 1-(3,5-dichloro-4-fluorophenyl)-2,2,2-trifluoroethyl ketone. Although this method is a one-step reaction, the raw materials are too expensive and are not suitable for large-scale industrial production.

[0003] (2) The method used in CN113461503A (a method for preparing a trifluoroacetophenone derivative) is as follows: 1-(3,5-dichloro-4-fluoroaniline) is obtained by diazotization, coupling, and catalytic reaction. This route has harsh reaction conditions, poor safety, and is prone to producing byproducts, making it unsuitable for large-scale industrial production.

[0004] The method described in CN112110804A (A method for preparing 3,5-dihalotrifluoroacetophenone and its derivatives) involves using 1-(3-chloro-4-nitrophenyl)-2,2,2-trifluoroacetophenone as the starting material. The initial material is reduced to 1-(4-amino-3-chlorophenyl)-2,2,2-trifluoroacetophenone, followed by halogenation to 1-(4-amino-3,5-dichlorophenyl)-2,2,2-trifluoroacetophenone, and finally amino substitution to obtain 1-(3,5-dichloro-4-fluorophenyl)-2,2,2-trifluoroacetophenone. This method suffers from the scarcity of raw materials and an average yield of less than 50%, making it unsuitable for large-scale industrial production.

[0005] Summary of the Invention

[0006] The purpose of this invention is to provide a method for preparing a fluorellana synthesis intermediate, which uses inexpensive and readily available raw materials, is safe to operate, has high selectivity, and uses mild reaction conditions.

[0007] To achieve the above objectives, the present invention provides the following technical solution: A method for preparing a fluorellana synthetic intermediate, the synthetic route of which is as follows: Specifically, the following steps are included: (1) Starting with p-chloroaniline, it undergoes an acylation reaction with pivaloyl chloride in an alkaline solvent to generate compound 2; (2) Compound 2 reacts with the chlorinating agent to form compound 3; (3) Under nitrogen atmosphere, compound 3 reacts with magnesium to give Grignard reagent intermediate compound 4; (4) Compound 4 reacts with a trifluoroacetic acid derivative to give compound 5; (5) Compound 5 reacts with concentrated hydrochloric acid to prepare compound 6; (6) Compound 6 reacts with a chlorinating agent to form compound 7; (7) Compound 7 reacts with nitrous acid to form compound 8.

[0008] In step (1), the alkaline solvent is any one of triethylamine, sodium hydroxide, or potassium hydroxide. The molar ratio of p-chloroaniline to tervaline chloride is 1:1 to 1:1.2, and the reaction temperature is 35 to 42°C.

[0009] In step (2), the chlorinating agent is any one of sodium hypochlorite, potassium hypochlorite, or calcium hypochlorite. The molar ratio of compound 2 to the chlorinating agent is 1:1 to 1:1.4, and the reaction temperature is 0 to 8°C.

[0010] In step (3), the molar ratio of compound 3 to magnesium is 1:1 to 1:1.3, and the reaction temperature is 20 to 25°C.

[0011] In step (4), the trifluoroacetic acid derivative is any one of ethyl trifluoroacetate, methyl trifluoroacetate, or trifluoroacetyldimethylamine. The molar ratio of compound 4 to the trifluoroacetic acid derivative is 1:1 to 1:1.2, and the reaction temperature is 20 to 25°C.

[0012] In step (5), the molar ratio of compound 5 to concentrated hydrochloric acid is 1:35 to 1:37, and the reaction temperature is 100 to 110°C.

[0013] In step (6), the chlorinating agent is any one of thionyl chloride, sodium chloride, or potassium chloride. The molar ratio of compound 6 to the chlorinating agent is 1:2 to 1:2.5, and the reaction temperature is 25 to 30°C.

[0014] In step (7), the nitrite reagent is sodium nitrite or potassium nitrite. The molar ratio of compound 7 to the nitrite reagent is 1:1 to 1:1.1, and the reaction temperature is 110 to 120°C.

[0015] Compared with the prior art, the beneficial effects of the present invention are: The method for preparing the intermediate of freranil in this invention uses steps such as acylation and chlorination reaction for synthesis. Compared with other methods in the prior art, it is safe to operate, produces fewer by-products, has mild conditions, uses readily available raw materials, is simple to optimize, and is more suitable for large-scale industrial production. Detailed Implementation

[0016] 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.

[0017] Example 1: Preparation of N-(4-chlorophenyl)neopentamide Add 5.0 g of p-chloroaniline and 50 mL of anhydrous DCM to a dry round-bottom flask, and start stirring to completely dissolve the p-chloroaniline. Slowly add 4.4 g of triethylamine to the flask through a dropping funnel. Mix 5.2 g of pentanoyl chloride with 10 mL of anhydrous DCM and slowly add the mixture to the reaction flask through a dropping funnel at 0-5 °C. After the addition is complete, remove the ice-water bath and allow the reaction mixture to slowly return to room temperature. Heat the reaction system and maintain the temperature at 40 °C for 2-3 hours. After the reaction is complete, allow the reaction solution to cool to room temperature, transfer the reaction solution to a separatory funnel, wash once with 30 mL of saturated sodium bicarbonate, wash once with 30 mL of dilute hydrochloric acid, and finally wash once with 30 mL of saturated sodium chloride. Separate the organic phase, add an appropriate amount of anhydrous sodium sulfate, filter, and rotary evaporate to obtain 7.1 g of white solid, with a yield of 85.5%.

[0018] Example 2: Preparation of N-(4-chlorophenyl)neopentamide Take a dry reaction flask, place it in an ice-water bath, add 5.0 g of p-chloroaniline and 50 mL of DCM, and start magnetic stirring to dissolve it. Then, add the alkaline solution prepared by dissolving 4.0 g of sodium hydroxide in 20 mL of distilled water to the flask, and keep the system at 0-5℃. Slowly add 5.0 mL of pivaloyl chloride dropwise to the reaction solution through a constant pressure dropping funnel, strictly controlling the temperature not to exceed 10℃. After the addition is complete, remove the ice bath, restore the room temperature, and continue stirring for 1-2 hours. After the reaction is complete, transfer the mixture to a separatory funnel, separate the organic phase, and wash it once each with 20 mL of distilled water, 20 mL of 1M dilute hydrochloric acid, and 20 mL of distilled water. After drying the organic layer with anhydrous magnesium sulfate, filter it, and remove dichloromethane by rotary evaporation to obtain 7.1 g of the target product, with a yield of 85.5%.

[0019] Example 3: Preparation of N-chloro-N-(4-chlorophenyl)neopentamide Under ice-water bath conditions, 7.1 g of N-(4-chlorophenyl)neopentamide and 50 mL of DCM were added to the reaction flask. Stirring was started, and the temperature was controlled at 0-5 °C until fully dissolved. Glacial acetic acid was slowly added dropwise to the reaction flask to adjust the pH to weakly acidic. Under continuous ice-bath cooling, 30 mL of sodium hypochlorite solution was slowly added dropwise to the reaction flask using a dropping funnel, maintaining the temperature below 10 °C throughout. After the addition was complete, the reaction was continued for 1-2 hours. After the reaction was complete, the reaction solution was transferred to a separatory funnel. The organic phase was washed with 30 mL of saturated sodium bicarbonate solution, then washed once with saturated sodium chloride solution. Finally, it was dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain 6.8 g of an oily substance, with a yield of 82.4%.

[0020] Example: Preparation of magnesium tetrachloride (4-(N-chloroneoptiamido)phenyl) Under nitrogen protection, add 0.8g of dry magnesium shavings to a reaction flask. Use a syringe to add 50mL of THF to the flask, submerging the magnesium shavings. Add a small grain of iodine until the brown color of the solution fades and the color lightens, indicating that the magnesium shavings have been activated. In another dry reaction flask, add 50mL of THF and, under nitrogen protection, dissolve 6.8g of N-chloro-N-(4-chlorophenyl)neopentamide to prepare a solution for later use. Place the reaction flask containing 0.8g of activated magnesium and a small amount of THF in an ice-water bath to cool to 0°C. With vigorous stirring, slowly add the prepared amide-THF solution dropwise to the reaction flask using a syringe. Maintain the temperature in the ice bath at 0-10°C. After the addition is complete, remove the ice bath and slowly raise the temperature to room temperature, continuing the reaction for 2-4 hours. After the reaction is complete, proceed directly to the next step.

[0021] Example 5: Preparation of N-chloro-N-(4-(2,2,2-trifluoroacetyl)phenyl)neopentamide Add 20 mL of anhydrous THF to a dry reaction flask. Under nitrogen protection, add 3.67 g of ethyl trifluoroacetate to the THF and mix thoroughly. While continuously cooling in an ice bath, very slowly add the prepared ethyl trifluoroacetate / THF solution to the Grignard reagent solution from the previous step, maintaining the temperature below 5°C. After the addition is complete, stir at 0°C for 30 min, then remove the ice bath and react at room temperature for 1-2 h. Return the reaction flask to an ice-water bath to cool to 0°C. While stirring vigorously, slowly add 50 mL of saturated ammonium chloride aqueous solution to quench the reaction. After the addition is complete, remove the ice bath and slowly raise the temperature to room temperature. Transfer the reaction mixture to a separatory funnel and extract twice with 100 mL of diethyl ether. Combine the organic phases and wash once with 50 mL of saturated sodium chloride. Transfer the organic phase to an Erlenmeyer flask, add an appropriate amount of sodium sulfate for drying, then filter and rotate to obtain 6.0 g of the target compound, with a yield of 83.8%.

[0022] Example 6: Preparation of N-chloro-N-(4-(2,2,2-trifluoroacetyl)phenyl)neopentamide Under nitrogen protection, the reaction continued from the previous step. At 0-5°C, 3.92 g of trifluoroacetyl dimethylamine was slowly added dropwise to the Grignard reagent solution obtained in the previous step, and the mixture was stirred for 30 min after the addition was complete. The reaction was monitored, and after completion, the temperature was controlled below -10°C. 50 mL of water was added to the reaction solution, and the pH was adjusted to 2.5-3.5 with hydrochloric acid. After thorough stirring, the mixture separated into an aqueous layer and an organic layer. The organic layer was washed twice with water, and then the washed organic layer was distilled under reduced pressure to remove the solvent, yielding 5.2 g of an oily substance, with a yield of 71.9%.

[0023] Example 7: Preparation of 1-(4-aminophenyl)-2,2,2-trifluoroethane-1,1-diol Add 6.0 g of N-chloro-N-(4-(2,2,2-trifluoroacetyl)phenyl)neopentamide and 60 mL of concentrated hydrochloric acid to a dry reaction flask. Heat the reaction system to about 100 °C and gently reflux. Stir the reaction at this temperature for 6-8 h.

[0024] After the reaction was complete, the reaction solution was cooled to room temperature. The cooled reaction solution was then slowly poured into 100 mL of ice water. Under ice-water bath cooling, saturated sodium bicarbonate solution was slowly added to the diluted solution to control the pH at 7-8. The neutralized solution was transferred to a separatory funnel and extracted three times with dichloromethane. The organic phases were combined, dried with anhydrous sodium sulfate for 30 min, filtered, and rotary evaporated to obtain 3.5 g of product, with a yield of 82%.

[0025] Example 8: Preparation of 1-(4-amino-3,5-dichlorophenyl)-2,2,2-trifluoroethane-1-one Add 3.5 g of 1-(4-aminophenyl)-2,2,2-trifluoroethane-1,1-diol and 50 mL of anhydrous DCM to a dry reaction flask. Start stirring and, after complete dissolution, place the reaction flask in an ice-water bath to cool to 0 °C. Slowly add 4.4 g of thionyl chloride dropwise using a dropping funnel, controlling the dropping rate and maintaining the reaction temperature below 10 °C. After the addition is complete, remove the ice-water bath and stir the reaction at room temperature for 2-4 hours. After the reaction is complete, pour the reaction solution into 50 mL of ice water. Transfer the reaction solution to a separatory funnel and wash with saturated sodium bicarbonate until neutral or weakly alkaline. Finally, wash once with saturated sodium chloride. Dry the organic layer with anhydrous sodium sulfate, filter to remove the drying agent, and concentrate by rotary evaporation to obtain 3.6 g of product, with a yield of 83.5%.

[0026] Example 9: Preparation of 1-(3,5-dichloro-4-fluorophenyl)-2,2,2-trifluoroethane-1-one Add 3.6 g of 1-(4-amino-3,5-dichlorophenyl)-2,2,2-trifluoroethane-1-one and 15 mL of 48% tetrafluoroboric acid aqueous solution to a dry reaction flask, and stir to dissolve while cooling in an ice bath. Dissolve 1.0 g of sodium nitrite in 5 mL of water in a dry small beaker, and slowly add the sodium nitrite solution dropwise to the cooled prepared solution using a dropper, maintaining the reaction temperature at 0°C. After the addition is complete, keep the mixture warm and stir for 0.5-1 h. After the reaction is complete, a white precipitate will form. Filter the precipitate through a Buchner funnel, recover the filtrate, and keep the white solid for later use. Add 30 mL of anhydrous toluene and the prepared white solid to a dry reaction flask, heat to 110°C in an oil bath, and gently reflux, stirring for 1-2 h. After the reaction was complete, the reaction solution was cooled to room temperature and then transferred to a separatory funnel. It was washed with saturated ammonium bicarbonate solution and then with saturated sodium chloride solution. The organic phase was dried with anhydrous sodium sulfate, filtered to remove the drying agent, and rotary evaporated to obtain 2.8 g of product, with a yield of 81.6%.

[0027] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-disclosed technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A method for preparing a fluorellaranoside synthetic intermediate, the synthetic route of which is as follows: Specifically, the following steps are included: (1) Starting with p-chloroaniline, it undergoes an acylation reaction with pivaloyl chloride in an alkaline solvent to generate compound 2; (2) Compound 2 reacts with the chlorinating agent to form compound 3; (3) Under nitrogen atmosphere, compound 3 reacts with magnesium to give Grignard reagent intermediate compound 4; (4) Compound 4 reacts with a trifluoroacetic acid derivative to give compound 5; (5) Compound 5 reacts with concentrated hydrochloric acid to prepare compound 6; (6) Compound 6 reacts with a chlorinating agent to form compound 7; (7) Compound 7 is converted into compound 8 under the action of nitrite reagent.

2. The method for preparing the intermediate for the synthesis of freranilar according to claim 1, characterized in that: The alkaline solvent mentioned in step (1) is any one of triethylamine, sodium hydroxide, and potassium hydroxide.

3. The method for preparing the intermediate for the synthesis of freranilar according to claim 1, characterized in that: In step (1), the molar ratio of p-chloroaniline to p-pentanoyl chloride is 1:1 to 1:1.2, and the reaction temperature is 35 to 42°C.

4. The method for preparing the intermediate for the synthesis of freranilar according to claim 1, characterized in that: The chlorinating agent mentioned in step (2) is any one of sodium hypochlorite, potassium hypochlorite, and calcium hypochlorite; the molar ratio of compound 2 to the chlorinating agent is 1:1 to 1:1.4, and the reaction temperature is 0 to 8℃.

5. The method for preparing the intermediate for the synthesis of freranilar according to claim 1, characterized in that: In step (3), the molar ratio of compound 3 to magnesium is 1:1 to 1:1.3, and the reaction temperature is 20 to 25°C.

6. The method for preparing the intermediate for the synthesis of freranilar according to claim 1, characterized in that: The trifluoroacetic acid derivative mentioned in step (4) is any one of ethyl trifluoroacetate, methyl trifluoroacetate, and trifluoroacetyl dimethylamine; the molar ratio of compound 4 to the trifluoroacetic acid derivative is 1:1 to 1:1.2, and the reaction temperature is 20 to 25°C.

7. The method for preparing the intermediate for the synthesis of freranilar according to claim 1, characterized in that: In step (5), the molar ratio of compound 5 to concentrated hydrochloric acid is 1:35 to 1:37, and the reaction temperature is 100 to 110°C.

8. The method for preparing the intermediate for the synthesis of freranilar according to claim 1, characterized in that: The chlorinating agent mentioned in step (6) is any one of thionyl chloride, sodium chloride, and potassium chloride.

9. The method for preparing the intermediate for the synthesis of freranilar according to claim 1, characterized in that: In step (6), the molar ratio of compound 6 to chlorinating agent is 1:2 to 1:2.5, and the reaction temperature is 25 to 30°C.

10. The method for preparing the intermediate for the synthesis of freranilar according to claim 1, characterized in that: The nitrite reagent mentioned in step (7) is sodium nitrite or potassium nitrite; the molar ratio of compound 7 to nitrite reagent is 1:1 to 1:1.1, and the reaction temperature is 110 to 120°C.

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