A process for the synthesis of afurenane

Abstract

The application discloses a synthesis method of afugan, which comprises the following steps: 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroacetone and 4-acetylnaphthalene carboxylic acid are added into a solvent, a base is added, DMAP is added after complete reaction at 50-80 DEG C, acetic anhydride is added dropwise, tetrabutylammonium bromide is added after complete reaction, and an aqueous solution of sodium hydroxide and hydroxylamine hydrochloride is added, and reaction is carried out at 0-5 DEG C, so that an intermediate is obtained; the intermediate is reacted with acyl chloride under the action of DMF and dichloromethane, so that 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)-1-naphthalene carboxylic chloride is prepared; 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride and a dichloromethane solution of a base are added dropwise, and reaction is carried out at 0-5 DEG C, so that afugan is obtained. The method has a short route, high yield and suitability for large-scale industrial production.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, and in particular to a method for synthesizing afolanar. Background Technology

[0002] Afoxolaner is an isoxazoline insecticide and acaricide, originally developed and produced by Boehringer Ingelheim. It works by inhibiting GABA chloride channels, causing hyperexcitability and death in arthropods, making it a revolutionary and potent insecticide. Approved for marketing in China in August 2017, it is the first oral deworming medication for dogs in the country that kills both ticks and fleas. It is safe for mammals, has high insecticidal activity, and also shows excellent insecticidal activity against pests such as fall armyworm, cotton bollworm, broad bean leafhopper, and western flower thrips. Its scientific name is 4[5[3-chloro-5-(trifluoromethyl)phenyl]4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]nitro[2-oxygen-2-[(2,2,2-trifluoroethyl)amino]ethyl]1-naphthylcarbamate, with the following structural formula:

[0003]

[0004] In the existing technology, the synthesis of afolanar focuses on the generation of the isoxazole ring and the introduction of side chains. The synthetic route of patent WO2009126668 introduces a side chain before the synthesis of the isoxazole ring. This method reduces molecular polarity and introduces multiple new reaction sites, resulting in more impurities generated in subsequent reactions and making purification difficult, thus increasing the purification cost of the finished product. Chinese patent CN112457267 reports a synthetic route for preparing afolanar by performing a [3+2] cyclization reaction. Although this route is shorter, it uses nitromethane reagents that are prone to explosion and expensive palladium catalysts, which is not conducive to the scale-up of the reaction. The afolanar preparation route disclosed in patent WO2009002809A2 is longer, with a lower yield in the isoxazole ring formation step, making purification more difficult, and generating more waste in the post-processing, increasing production costs. Although the afolanar preparation route disclosed in patent WO2021038501A1 is shorter and uses inexpensive and readily available excipients, each reaction requires post-processing to obtain the intermediate before proceeding to the next step, and even requires column chromatography purification, which greatly increases the number of post-processing steps and waste costs.

[0005] Based on current methods for preparing afollana, we found that the reported methods are difficult to compete with in terms of both cost and product quality under intense market competition. Therefore, improving the preparation method of afollana is crucial for its industrialization, reducing industrialization costs, and enhancing the product's market competitiveness. Summary of the Invention

[0006] To address the shortcomings of the aforementioned methods for preparing afollana, this invention provides a method for preparing afollana that features a short route, high yield, simple operation, simple purification, low waste generation, and suitability for large-scale industrial production.

[0007] This invention provides a method for synthesizing afolanar, comprising the following steps:

[0008] Step 1: Add 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethyl ketone and 4-acetylnaphthoic acid to a solvent, add a base, and react completely at 50-80℃. Then add DMAP, add acetic anhydride dropwise, and react completely at 50-80℃. Then add tetrabutylammonium bromide, and then add an aqueous solution of sodium hydroxide and hydroxylamine hydrochloride. React at 0-5℃ to obtain the intermediate 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid;

[0009] Step 2: The intermediate reacts with acyl chloride in the presence of DMF and dichloromethane to prepare 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo-3-yl)-1-naphthoyl chloride; then 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride and a base in dichloromethane solution are added dropwise, and the reaction is carried out at 0-5℃. After the reaction is completed, afolanar is obtained.

[0010] The reaction formula is as follows:

[0011]

[0012] In some embodiments, the solvent in step 1 is at least one or a combination of tetrahydrofuran, benzene, toluene, xylene, and acetonitrile, preferably toluene or xylene.

[0013] In some embodiments, the base in step 1 is triethylamine, pyridine, or N-methylmorpholine, preferably triethylamine.

[0014] In some embodiments, the molar ratio of 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethyl ketone, 4-acetylnaphthoic acid, base, DMAP, acetic anhydride, tetrabutylammonium bromide, sodium hydroxide and hydroxylamine hydrochloride in step 1 is 1:1:(2-5):(0.6-1.6):(1.2-3):(0.5-1):(4-8):(2-3).

[0015] In some embodiments, the amount of solvent used in step 1 is 5 to 12 times the mass of 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethyl ketone; and the amount of water used in step 1 is 2 to 5 times the mass of 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethyl ketone.

[0016] In some implementations, step 1 further includes adjusting the pH, separating the contents, washing with water, drying, and concentrating after the reaction is complete;

[0017] Among them: use hydrochloric acid to adjust the pH to 6-7.

[0018] In some implementations, the hydrochloric acid used in step 1 is hydrochloric acid with a mass percentage concentration of 10%.

[0019] In some implementations, step 1 specifically includes:

[0020] 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethyl ketone and 4-acetylnaphthoic acid were added to a solvent. The mixture was heated to 50–80°C, and a base was added with stirring. Nitrogen was used for purging. The reaction was maintained at 50–80°C until a solid precipitated. DMAP was then added, and nitrogen was used for purging. The reaction was stirred, and acetic anhydride was slowly added dropwise. After the addition was complete, the reaction was maintained at 50–80°C for a period of time. Tetrabutylammonium bromide was then added, and the temperature was lowered to 0–5°C for later use. Sodium hydroxide was dissolved in water, and hydroxylamine hydrochloride was added. The temperature was lowered to 0–5°C, and the solution was slowly added dropwise to the above reaction mixture. After the addition was complete, the reaction was maintained at 0–5°C for a period of time. The pH was adjusted to 6–7 with hydrochloric acid, and the mixture was heated to room temperature. After separation, washing with water, drying, and concentration, 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid was obtained for later use.

[0021] In some implementations, step 2 specifically includes:

[0022] Add 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid and DMF to dichloromethane, add acyl chloride dropwise at 0-5℃, stir for 1 hour after the addition is complete, concentrate to dryness, and dissolve in a small amount of dichloromethane for later use; add 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride to dichloromethane, cool to 0-5℃, add alkali and stir for 10 minutes, then add the above dissolved dichloromethane solution dropwise, stir for 2 hours after the addition is complete to obtain afolanar.

[0023] In some embodiments, the acyl chloride in step 2 is acetyl chloride, benzoyl chloride, oxalyl chloride, sulfonyl chloride, methanesulfonyl chloride, or p-toluenesulfonyl chloride, preferably acetyl chloride or oxalyl chloride; the base in step 2 is triethylamine, pyridine, or N-methylmorpholine, preferably triethylamine.

[0024] In some embodiments, the molar ratio of 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid, 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride, acyl chloride, and base in step 2 is 1:1:1.5 to 3:2 to 5; the amount of dichloromethane used in both the acylation and condensation reactions in step 2 is 3 to 8 times the mass of 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid; and the amount of DMF used in step 2 is 0.001 times the mass of 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid.

[0025] In some embodiments, the volume ratio of petroleum ether to ethyl acetate required for crystallization in step 2 is 2:1.

[0026] In some embodiments, the amount of the petroleum ether and ethyl acetate mixture required for crystallization in step 2 is 5 to 8 times the amount of crude afranal.

[0027] In some implementations, step 2 further includes a post-processing step, specifically:

[0028] After the reaction was completed, crude afolanar was obtained by extraction, drying and concentration, and then purified afolanar was obtained by crystallization with a mixed solution of petroleum ether and ethyl acetate.

[0029] Beneficial effects: The route of this invention adopts a method of first synthesizing the isoxazole ring and then introducing the side chain, which reduces the generation of impurities and thus improves the reaction yield, with an overall yield of up to 75%, reducing raw material costs and purification costs; This invention obtains the intermediate 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisooxazol-3-yl)-1-naphthoic acid by continuous feeding, reducing post-processing operations, simplifying the route, and greatly improving production efficiency; The solvents and excipients required by this invention are relatively simple and inexpensive and readily available, greatly reducing production costs; The reaction conditions required by this invention are mild, and the scale-up effect is not obvious; In summary, this invention is more suitable for large-scale industrial production. Detailed Implementation

[0030] The present invention will be further described in detail below with reference to specific embodiments, so that those skilled in the art can better understand the present invention. However, this is not intended to limit the present invention. Any equivalent substitutions made in the art based on the disclosure of the present invention shall fall within the protection scope of the present invention.

[0031] Example 1

[0032] Step 1: Preparation of 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid:

[0033]

[0034] Take a 5000ml three-necked flask and add 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethyl ketone (400g, 1.44mol), xylene (2000ml), and 4-acetylnaphthoic acid (310g, 1.44mol) sequentially. Add triethylamine (365.5g, 3.62mol) to a constant-pressure dropping funnel and assemble for later use. Stir at room temperature and purge with nitrogen three times. After purging, raise the temperature to 50℃ and stir the reaction. After 10 minutes, triethylamine was rapidly added dropwise. After the addition was complete, the mixture was stirred at 50°C for 6 hours. Then, DMAP (176 g, 1.44 mol) was added. Acetic anhydride (293.8 g, 2.88 mol) was added to another constant-pressure dropping funnel for later use. Nitrogen purging was performed, and the mixture was stirred for 10 minutes. Then, acetic anhydride was slowly added dropwise. After the addition was complete, the mixture was kept at 50°C for 2 hours. Then, tetrabutylammonium bromide (232.1 g, 0.72 mol) was added, and the reaction mixture was... Cool to 0-5℃ and set aside. Take a 2000ml single-necked flask, add 800ml of water, and cool to 0-5℃. Add sodium hydroxide (230.4g, 5.76mol) in three batches, stirring until dissolved. Maintain the temperature at 0-5℃, then add hydroxylamine hydrochloride (200.2g, 2.88mol), stirring until dissolved. Transfer the solution to another constant-pressure dropping funnel and add it dropwise to a 5000ml three-necked flask, maintaining the temperature at 0-5℃. After the addition is complete, maintain the reaction temperature at 0℃ for 3 hours. Use 10... Adjust the pH of the reaction solution to 6-7 with % hydrochloric acid and heat to 20-25℃. Separate the solution, wash once with 1000ml of water and once with 1000ml of saturated saline solution, dry with anhydrous sodium sulfate, filter, and concentrate at 50℃ to obtain crude 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid (576g, yield: 82.1%, purity: 94.2%), which does not require purification and can be used for later use.

[0035] Step 2: Preparation of afolanar:

[0036]

[0037] (1) Take a 5000ml three-necked flask and add 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid (1000g, 2.05mol), dichloromethane (3800ml), and DMF (1ml) in sequence. Add oxaloyl chloride (521g, 4.1mol) to a constant pressure dropping funnel for assembly. Cool the reaction to 0-5℃, stir, and purge with nitrogen three times. After the displacement is completed, slowly add oxaloyl chloride. After the addition is completed, stir at 0-5℃ for 1 hour and then transfer the reaction solution to a 5000ml single-necked flask under a dry environment. Concentrate to dryness at 40℃, then add 500ml dichloromethane twice to dryness. Finally, add 500ml dichloromethane to dissolve the substrate and transfer it to a constant pressure dropping funnel for later use. (2) Take another 5000ml three-necked flask and add 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (395g, 2 0.05 mol), dichloromethane (3800 ml), triethylamine (415 g, 4.1 mol) was added to a constant pressure dropping funnel and assembled for later use. The reaction was cooled to 0-5℃, stirred and purged with nitrogen three times. After the purging was completed, triethylamine was added dropwise. After the addition was completed, the temperature was controlled at 0-5℃ and stirred for 10 min. Then, the dichloromethane solution in (1) was added dropwise. After the addition was completed, the mixture was stirred for 2 h. The reaction was brought back to room temperature, and water was added for extraction (1000 ml × 2) and saturated saline solution was added for washing (1000 ml × 2). (1×2) Drying with anhydrous sodium sulfate and concentrating at 40℃ to obtain crude afolanar. The crude afolanar was transferred to a 3000ml single-necked flask and a mixed solution of petroleum ether:ethyl acetate = 2:1 (7500ml) was added. The reaction was heated to reflux, stirred until dissolved, and then naturally cooled to room temperature. After cooling to 0℃, the mixture was stirred and crystallized for 2 hours. The mixture was filtered, washed with a small amount of petroleum ether, and dried to obtain purified afolanar (1170g, yield: 91.2%, purity: 99.62%).

[0038] Example 2

[0039] Step 1: Preparation of 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid:

[0040] Take a 2000ml three-necked flask and add 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethyl ketone (100g, 0.36mol), toluene (700ml), and 4-acetylnaphthoic acid (77.5g, 0.36mol) sequentially. Add triethylamine (109g, 1.08mol) to a constant-pressure dropping funnel and assemble for later use. Stir at room temperature and purge with nitrogen three times. After purging, raise the temperature to 80℃ and stir the reaction. After 10 minutes, triethylamine was rapidly added dropwise. After the addition was complete, the mixture was stirred at 80°C for 7 hours. Then, DMAP (26.4 g, 0.22 mol) was added. Acetic anhydride (44 g, 0.43 mol) was added to another constant-pressure dropping funnel for assembly and later use. Nitrogen purging was performed, and the mixture was stirred for 10 minutes. Then, acetic anhydride was slowly added dropwise. After the addition was complete, the mixture was kept at 80°C for 2 hours. Then, tetrabutylammonium bromide (58 g, 0.18 mol) was added, and the reaction was cooled. Set aside at 0-5℃; take a 500ml single-necked flask, add water (300ml), and cool to 0-5℃. Add sodium hydroxide (86.4g, 2.16mol) in three batches, stirring until dissolved. Maintain the temperature at 0-5℃, add hydroxylamine hydrochloride (50g, 0.72mol), stirring until dissolved, and transfer to another constant-pressure dropping funnel. Maintain the temperature at 0-5℃ and add dropwise to a 2000ml three-necked flask. After the addition is complete, maintain the reaction at 0℃ for 3 hours, then use 10% hydrochloric acid. Adjust the pH of the reaction solution to 6-7 and heat to 20-25℃. Separate the solution, wash once with 300ml of water and once with 300ml of saturated saline solution, dry with anhydrous sodium sulfate, filter, and concentrate at 50℃ to obtain crude 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid (134.6g, yield: 76.8%, purity: 91.8%), which does not require purification and can be used for later use.

[0041] Step 2: Preparation of afolanar:

[0042] (1) Take a 1000ml three-necked flask and add 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid (100g, 0.2mol), dichloromethane (500ml), and DMF (0.1ml) in sequence. Add acetyl chloride (23.6g, 0.3mol) to a constant pressure dropping funnel and assemble for later use. Cool the reaction to 0-5℃, stir, and purge with nitrogen. After the displacement was completed, acetyl chloride was slowly added dropwise. After the addition was completed, the temperature was controlled at 0-5℃ and stirred for 1 hour. The reaction solution was then transferred to a 1000ml single-necked flask under a dry environment and concentrated to dryness at 40℃. Then, 100ml of dichloromethane was added twice to carry it to dryness. Finally, 100ml of dichloromethane was added to dissolve the substrate and transferred to a constant pressure dropping funnel for later use. (2) Take another 1000ml three-necked flask and add 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (38.5g) in sequence. 0.2 mol g of dichloromethane (500 ml) was added to a constant pressure dropping funnel. Pyridine (47.5 g, 0.6 mol) was added and assembled for later use. The reaction was cooled to 0-5℃, stirred, and nitrogen was purged three times. After the purging was completed, pyridine was added dropwise. After the addition was completed, the temperature was controlled at 0-5℃ and stirred for 10 min. Then, the dichloromethane solution in (1) was added dropwise. After the addition was completed, the mixture was stirred for 2 h. The reaction was brought back to room temperature. Water was added for extraction (200 ml × 2), and saturated saline was added for washing (200 ml). ×2) Drying with anhydrous sodium sulfate and concentrating at 40℃ to obtain crude afolanar. The crude afolanar was transferred to a 1000ml single-necked flask and a mixed solution of petroleum ether and ethyl acetate (2:1) (800ml) was added. The reaction was heated to reflux, stirred until dissolved, and then allowed to cool naturally to room temperature. The mixture was then cooled to 0℃ and stirred to crystallize for 2 hours. After filtration, the mixture was washed with a small amount of petroleum ether and dried to obtain purified afolanar (116.8g, yield: 93.3%, purity: 99.54%).

[0043] Example 3

[0044] Step 1: Preparation of 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid:

[0045] In a 100L glass reactor, add 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethyl ketone (10kg, 36mol), toluene (40L), and 4-acetylnaphthoic acid (7.75kg, 36mol). In a dropping vessel, add triethylamine (7.3kg, 72.3mol) for later use. Stir at room temperature and purge with nitrogen three times. After purging, heat to 60℃ and stir for 10 min. Then, rapidly add triethylamine dropwise. After the addition is complete, stir at 60℃ for 12 h. Add DMAP (2.64kg, 21.6mol). In a dropping vessel, add acetic anhydride (5.5kg, 54mol) for later use. Purge with nitrogen and stir for 10 min. Then, slowly add acetic anhydride dropwise. After the addition is complete, maintain the temperature at 60℃ for 3 h. Finally, add tetrabutylammonium bromide (7kg, 21.6mol). 1. Add water (20L) to another 50L reactor and cool it to 0-5℃. Add sodium hydroxide (5.76kg, 144mol) in three batches and stir until dissolved. Control the temperature at 0-5℃ and add hydroxylamine hydrochloride (5kg, 72mol), stir until dissolved, and slowly pump it into a 100L glass reactor. Maintain the reaction temperature at 0℃ for 5 hours. Adjust the pH of the reaction solution to 6-7 with 10% hydrochloric acid and raise the temperature to 20-25℃. Separate the solution, wash with water and saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate at 50℃ to obtain crude 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid (14.7kg, yield: 83.7%, purity: 93.33%), which does not require purification and is ready for use.

[0046] Step 2: Preparation of afolanar:

[0047] (1) In a 100L glass reactor, add 10kg (20.5mol) of 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid, 40L of dichloromethane, and 10ml of DMF. In a dropping vessel, add 7.8kg (61.5mol) of oxaloyl chloride for later use. Cool the reaction mixture to 0-5℃, stir, and purge with nitrogen three times. After purging, slowly add oxaloyl chloride dropwise. After the addition is complete, maintain the temperature at 0-5℃ and stir for 3 hours. Then concentrate at 40℃. Add 10L of dichloromethane twice to remove excess liquid. Finally, add 10L of dichloromethane to dissolve the substrate and transfer it to a dropping vessel. (2) In a 100L glass reactor, add 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (3.95kg, 20.5mol) and dichloromethane (40L). In another dropper, add triethylamine (5.2kg, 51.3mol) for later use. Cool the reaction to 0-5℃, stir and replace with nitrogen three times. After replacement, add triethylamine. After addition, control the temperature at 0-5℃ and stir for 10min. Then add the dichloromethane solution from (1). After addition, stir for 3h. The reaction is brought back to room temperature. Add water to quench the reaction. Wash with water, wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate at 40℃ to obtain crude afranal. Add a mixed solution of petroleum ether and ethyl acetate in a ratio of 2:1 (60 L), heat the reaction mixture to reflux, stir until dissolved, allow it to cool naturally to room temperature, then cool to 0 °C and stir to crystallize for 5 h. Filter, rinse with a small amount of petroleum ether, and dry to obtain purified afolanar (11.8 kg, yield: 91.8%, purity: 99.68%).

[0048] In summary: This invention employs a method of first synthesizing the isoxazole ring and then introducing the side chain, reducing impurity formation and thus improving the reaction yield, with an overall yield of up to 75%, while reducing raw material and purification costs. This invention uses a continuous feeding method to obtain the intermediate 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisooxazol-3-yl)-1-naphthoic acid, reducing post-processing operations, simplifying the route, and significantly improving production efficiency. The solvents and excipients required by this invention are relatively simple and readily available, greatly reducing production costs. The reaction conditions required by this invention are mild, with minimal scale-up effects. Therefore, this invention is more suitable for large-scale industrial production.

[0049] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the inventive concept of the present invention, and these should also be considered within the scope of protection of the invention.

Claims

1. A method for synthesizing afolanar, characterized in that, Includes the following steps: Step 1: Add 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethyl ketone and 4-acetylnaphthoic acid to a solvent, add a base, and react completely at 50-80℃. Then add DMAP, add acetic anhydride dropwise, and react completely at 50-80℃. Then add tetrabutylammonium bromide, and then add an aqueous solution of sodium hydroxide and hydroxylamine hydrochloride. React at 0-5℃ to obtain the intermediate 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid; Step 2: The intermediate reacts with acyl chloride in the presence of DMF and dichloromethane to prepare 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo-3-yl)-1-naphthoyl chloride; then 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride and a base in dichloromethane solution are added dropwise, and the reaction is carried out at 0-5℃. After the reaction is completed, afolanar is obtained. The reaction formula is as follows: Wherein: the solvent in step 1 is toluene or xylene; the base in step 1 is triethylamine; In step 1, the molar ratio of 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethyl ketone, 4-acetylnaphthoic acid, base, DMAP, acetic anhydride, tetrabutylammonium bromide, sodium hydroxide, and hydroxylamine hydrochloride is 1:1:(2-5):(0.6-1.6):(1.2-3):(0.5-1):(4-8):(2-3).

2. The method for synthesizing afolanar according to claim 1, characterized in that, In step 1, the amount of solvent used is 5 to 12 times the mass of 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethyl ketone; in step 1, the amount of water used is 2 to 5 times the mass of 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethyl ketone.

3. The method for synthesizing afolanar according to claim 1, characterized in that, Step 1 also includes adjusting pH, separating the liquids, washing with water, drying, and concentrating after the reaction is complete; Among them: use hydrochloric acid to adjust the pH to 6-7.

4. The method for synthesizing afolanar according to claim 1, characterized in that, Step 2 is as follows: Add 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid and DMF to dichloromethane, add acyl chloride dropwise at 0-5℃, stir for 1 hour after the addition is complete, concentrate to dryness, and dissolve in a small amount of dichloromethane for later use; add 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride to dichloromethane, cool to 0-5℃, add alkali and stir for 10 minutes, then add the above dissolved dichloromethane solution dropwise, stir for 2 hours after the addition is complete to obtain afolanar.

5. The method for synthesizing afolanar according to claim 4, characterized in that, The acyl chloride mentioned in step 2 is acetyl chloride, benzoyl chloride, oxalyl chloride, sulfonyl chloride, methanesulfonyl chloride, or p-toluenesulfonyl chloride; the base mentioned in step 2 is triethylamine, pyridine, or N-methylmorpholine.

6. The method for synthesizing afolanar according to claim 4, characterized in that, The acyl chloride mentioned in step 2 is acetyl chloride or oxalyl chloride; the base mentioned in step 2 is triethylamine.

7. The method for synthesizing afolanar according to claim 4, characterized in that, In step 2, the molar ratio of 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid, 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride, acyl chloride, and base is 1:1:1.5 to 3:2 to 5; the amount of dichloromethane used in both the acylation and condensation reactions in step 2 is 3 to 8 times the mass of 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid; and the amount of DMF used in step 2 is 0.001 times the mass of 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid.

8. The method for synthesizing afolanar according to claim 4, characterized in that, Step 2 also includes a post-processing step, specifically: After the reaction was completed, crude afolanar was obtained by extraction, drying and concentration, and then purified afolanar was obtained by crystallization with a mixed solution of petroleum ether and ethyl acetate.

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