Synthetic method of arfampanaga

Abstract

The method comprises the following steps: adding 1-[3-chloro-5-(trifluoromethyl) phenyl]-2, 2, 2-trifluoroethanone and 4-acetyl naphthoic acid into a solvent, adding alkali, completely reacting at 50-80 DEG C, then adding DMAP, dropwise adding acetic anhydride, completely reacting, then adding tetrabutylammonium bromide, and reacting at 50-80 DEG C for 2-3 hours to obtain the arfamarana. Adding an aqueous solution of sodium hydroxide and hydroxylamine hydrochloride, and reacting at 0-5 DEG C to obtain an intermediate; reacting the intermediate with acyl chloride under the action of DMF (Dimethyl Formamide) and dichloromethane to obtain 4-(5-(3-chloro-5-(trifluoromethyl) phenyl)-5-(trifluoromethyl)-4, 5-dihydroisoxazole-3-yl)-1-naphthoyl chloride; the preparation method comprises the following steps of: adding a catalyst into an organic solvent, dropwise adding into a dichloromethane solution of 2-amino-N-(2, 2, 2-trifluoroethyl) acetamide hydrochloride and alkali, and reacting at the temperature of between 0 and 5 DEG C, so as to obtain the arfola sodium. The method is short in route, high in yield and suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, in particular to a method for synthesizing afoxol. Background Art

[0002] Afoxolaner is an isoxazoline insecticide and acaricide, first developed and produced by Boehringer Ingelheim. It inhibits GABA chloride channels, causing arthropod nerves to become highly excited and cause death. It is a revolutionary and powerful insecticide. The drug was approved for marketing in China in August 2017. It is the first oral anthelmintic for dogs in China that kills both ticks and fleas. It is safe for mammals and has high insecticidal activity. In addition, it shows excellent insecticidal activity against pests such as fall armyworm, cotton bollworm, broad bean leafhopper and western flower thrips. The cultural name is 4[5[3-chloro-5(trifluoromethyl)phenyl]4,5-dihydro-5(trifluoromethyl)3-isoxazolyl]nitrogen[2-oxygen-2[(2,2,2-trifluoroethyl)amino]ethyl]1-naphthamide, and the structural formula is as follows:

[0003]

[0004] In the prior art, the synthesis of afoxol is mainly focused on the formation of the isoxazole ring and the introduction of the side chain. The synthesis route of patent WO2009126668 adopts a method of introducing a side chain before the synthesis of the isoxazole ring. This method reduces the molecular polarity and introduces multiple new reaction sites, resulting in more impurities generated in subsequent reactions and difficult to purify, thereby increasing the refining cost of the finished product; Chinese patent CN112457267 reports a synthesis route for preparing afollana by performing a [3+2] cyclization reaction. Although the synthesis route is shorter, the use of explosive nitromethane reaction reagents and expensive metal palladium catalysts is not conducive to reaction scale-up production; the preparation route of afollana disclosed in patent WO2009002809A2 is longer, the yield of the isoxazole ring generation step is low, it is difficult to purify, and the post-treatment produces more three wastes, which increases the production cost; the preparation route of afollana disclosed in patent WO2021038501A1 is short, and the auxiliary materials used are cheap and easy to obtain, but each step of the reaction requires post-treatment to obtain the intermediate separately before the next step of the reaction, and even requires column chromatography purification, which greatly increases the post-treatment operation steps and the cost of three wastes.

[0005] Based on the current preparation methods of Afollana, we found that the reported methods are difficult to have advantages in terms of cost and product quality under fierce market competition. Therefore, improving the preparation method of Afollana is very important for the industrialization of Afollana, reducing the industrialization cost, and improving the market competitiveness of the product. Summary of the invention

[0006] In view of the shortcomings of the above-mentioned preparation method of afoxolane, the present invention provides a preparation method of afoxolane, which has the characteristics of short route, high yield, simple operation, simple refining, less generation of three wastes, and is suitable for large-scale industrial production.

[0007] The present invention provides a method for synthesizing afoxol, comprising the following steps:

[0008] Step 1: Add 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethanone and 4-acetylnaphthoic acid to a solvent, add a base, add DMAP after the reaction is complete at 50-80°C, add acetic anhydride dropwise, add tetrabutylammonium bromide after the reaction is complete at 50-80°C, then add an aqueous solution of sodium hydroxide and hydroxylamine hydrochloride, and react at 0-5°C 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 is reacted with an acyl chloride in the presence of DMF and dichloromethane to obtain 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoyl chloride; and then added dropwise to a dichloromethane solution of 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride and a base, and reacted at 0-5°C. After the reaction is completed, afolanine is obtained;

[0010] The reaction formula is as follows:

[0011]

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

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

[0014] In certain embodiments, the molar ratio of 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethanone, 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 certain 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-trifluoroethanone; 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-trifluoroethanone.

[0016] In certain embodiments, step 1 further comprises adjusting pH, separating liquids, washing, drying and concentrating after the reaction is completed;

[0017] Wherein: Use hydrochloric acid to adjust the pH to 6-7.

[0018] In certain embodiments, the hydrochloric acid used in step 1 is hydrochloric acid with a mass percent concentration of 10%.

[0019] In certain embodiments, step 1 is specifically:

[0020] 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethanone and 4-acetylnaphthoic acid are added to a solvent, the temperature is raised to 50-80°C, a base is added under stirring, nitrogen replacement is carried out, the temperature is kept at 50-80°C for reaction and solid is precipitated, DMAP is added, nitrogen replacement is carried out, the temperature is stirred for reaction, acetic anhydride is slowly added dropwise, the addition is completed, the temperature is kept at 50-80°C for reaction for a period of time, tetrabutylammonium bromide is added, the temperature is lowered to 0-5°C for use; sodium hydroxide is dissolved in water, hydroxylamine hydrochloride is added, the temperature is lowered to 0-5°C, the reaction solution is slowly added dropwise, the addition is completed, the temperature is kept at 0-5°C for reaction for a period of time, hydrochloric acid is used to adjust the pH to 6-7, the temperature is raised to room temperature, the liquid is separated, washed with water, dried and concentrated to obtain 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid for use.

[0021] In certain embodiments, step 2 is specifically:

[0022] 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid and DMF are added to dichloromethane, and the acid chloride is added dropwise at 0-5°C. After the addition is completed, the mixture is stirred for 1 hour and then concentrated to dryness. A small amount of dichloromethane is added to dissolve the mixture for later use. 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride is added to dichloromethane, the temperature is lowered by 0-5°C, a base is added and stirred for 10 minutes, and then the above-dissolved dichloromethane solution is added dropwise. After the addition is completed, the mixture is stirred for 2 hours to obtain afoxolamide.

[0023] In certain 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 certain embodiments, 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 1:1:1.5~3:2~5; in step 2, the amount of dichloromethane used in the acylation reaction and the condensation reaction 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; in step 2, the amount of DMF used 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 certain embodiments, the volume ratio of petroleum ether to ethyl acetate required for crystallization in step 2 is 2:1.

[0026] In certain embodiments, the amount of the mixed solution of petroleum ether and ethyl acetate required for crystallization in step 2 is 5 to 8 times the amount of the crude afoxolan.

[0027] In certain embodiments, step 2 further comprises a post-processing step, specifically:

[0028] After the reaction is completed, the crude afoxolan is obtained through extraction, drying and concentration, and then the refined afoxolan is obtained through crystallization with a mixed solution of petroleum ether and ethyl acetate.

[0029] Beneficial effects: The route of the present invention adopts a method of first synthesizing the isoxazole ring and then introducing the side chain, which reduces the generation of impurities, thereby improving the reaction yield, and the total yield can reach 75%, reducing the raw material cost and the refining cost; the present invention obtains the intermediate 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid in a continuous manner, reduces the post-processing operation, has a short route, and greatly improves the production efficiency; the types of solvents and auxiliary materials required by the present invention are relatively single, and they are all cheap and easy to obtain, which greatly reduces the production cost; the conditions required for the reaction of the present invention are mild, and the amplification effect is not obvious; in summary, the present invention is more in line with industrial large-scale production. DETAILED DESCRIPTION

[0030] The present invention is further described in detail below in conjunction with specific implementation methods so that those skilled in the art can better understand the present invention, but this is not a limitation of the present invention. Any equivalent replacements in the art made in accordance with the contents disclosed in the present invention shall fall within the scope of protection 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, add 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethanone (400g, 1.44mol), xylene (2000ml), 4-acetylnaphthoic acid (310g, 1.44mol) in sequence, add triethylamine (365.5g, 3.62mol) to the constant pressure dropping funnel, assemble for standby use, stir at room temperature and replace with nitrogen three times, heat to 50℃ and stir to react after replacement After 10 minutes, triethylamine was added dropwise quickly. After the addition was completed, DMAP (176 g, 1.44 mol) was added after stirring at 50°C for 6 hours. Acetic anhydride (293.8 g, 2.88 mol) was added to another constant pressure dropping funnel for standby use. Nitrogen was replaced. After stirring for 10 minutes, acetic anhydride was slowly added dropwise. After the addition was completed, tetrabutylammonium bromide (232.1 g, 0.72 mol) was added after the reaction was kept at 50°C for 2 hours. Cool to 0-5℃ for use; take a 2000ml single-necked bottle, add water (800ml) and cool to 0-5℃, add sodium hydroxide (230.4g, 5.76mol) in 3 batches, stir to dissolve, control the temperature at 0-5℃, add hydroxylamine hydrochloride (200.2g, 2.88mol), stir to dissolve and transfer to another constant pressure dropping funnel, control the temperature at 0-5℃ and dropwise add to a 5000ml three-necked flask, after the addition is complete, keep 0℃ for 3h, and use 10 % hydrochloric acid to adjust the pH of the reaction solution to 6-7 and heat to 20-25°C, separate the liquids, wash once with 1000 ml of water, wash once with 1000 ml of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate at 50°C to obtain a crude product of 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid (576 g, yield: 82.1%, purity: 94.2%), which can be used without purification.

[0035] Step 2: Preparation of Afollana:

[0036]

[0037] (1) Take a 5000ml three-necked flask, 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 oxalyl chloride (521g, 4.1mol) into a constant pressure dropping funnel, assemble and set aside, cool the reaction to 0-5°C, stir and replace with nitrogen three times After the replacement is completed, slowly add oxalyl chloride dropwise. After the addition is completed, stir at 0-5°C for 1h, transfer the reaction solution to a 5000ml single-necked bottle under dry conditions and concentrate at 40°C. Then add 500ml of dichloromethane to dryness twice, and finally add 500ml of dichloromethane to dissolve the substrate and transfer to a constant pressure dropping funnel for use; (2) Take another 5000ml three-necked bottle and add 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (395g, 2 .05mol), dichloromethane (3800ml), triethylamine (415g, 4.1mol) was added to the constant pressure dropping funnel and assembled for use. The reaction temperature was lowered to 0-5°C, stirred and nitrogen replaced three times. After the replacement was completed, triethylamine was added dropwise. After the addition was completed, the temperature was controlled at 0-5°C and stirred for 10min. After that, the dichloromethane solution in (1) was added dropwise. After the addition was completed, the mixture was stirred for 2h. The reaction was returned to room temperature, extracted with water (1000ml×2), and washed with saturated brine (1000m l×2), dried over anhydrous sodium sulfate, and concentrated at 40°C to obtain a crude afoxolane, which was transferred to a 3000ml single-mouth bottle, and a mixed solution (7500ml) of petroleum ether:ethyl acetate = 2:1 was added, the reaction was heated to reflux, stirred to dissolve, and then naturally cooled to room temperature, then cooled to 0°C and stirred for crystallization for 2h, filtered, washed with a small amount of petroleum ether, and dried to obtain refined afoxolane (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, add 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethanone (100g, 0.36mol), toluene (700ml), 4-acetylnaphthoic acid (77.5g, 0.36mol) in sequence, add triethylamine (109g, 1.08mol) to the constant pressure dropping funnel, assemble for standby use, stir at room temperature and replace with nitrogen three times, heat to 80℃ and stir to react after replacement After 10 minutes, triethylamine was added dropwise quickly. After the addition was completed, DMAP (26.4 g, 0.22 mol) was added after stirring at 80°C for 7 hours. Acetic anhydride (44 g, 0.43 mol) was added to another constant pressure dropping funnel for standby use. Nitrogen was replaced. After stirring for 10 minutes, acetic anhydride was slowly added dropwise. After the addition was completed, tetrabutylammonium bromide (58 g, 0.18 mol) was added after the reaction was kept at 80°C for 2 hours and the reaction was cooled. Take a 500ml single-necked bottle, add water (300ml), cool to 0-5℃, add sodium hydroxide (86.4g, 2.16mol) in 3 batches, stir to dissolve, control the temperature at 0-5℃, add hydroxylamine hydrochloride (50g, 0.72mol), stir to dissolve and transfer to another constant pressure dropping funnel, control the temperature at 0-5℃, dropwise add to a 2000ml three-necked bottle, after the addition is complete, keep 0℃ for 3h, and use 10% hydrochloric acid The reaction solution was adjusted to a pH of 6-7 and heated to 20-25°C, separated, washed once with 300 ml of water, washed once with 300 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated at 50°C to obtain a crude product of 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid (134.6 g, yield: 76.8%, purity: 91.8%), which was used for later use without purification.

[0041] Step 2: Preparation of Afollana:

[0042] (1) Take a 1000 ml three-necked flask, add 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid (100 g, 0.2 mol), dichloromethane (500 ml), and DMF (0.1 ml) in sequence, add acetyl chloride (23.6 g, 0.3 mol) into a constant pressure dropping funnel, assemble and set aside, cool the reaction mixture to 0-5°C, stir and replace with nitrogen for three times. After the replacement is completed, slowly add acetyl chloride dropwise. After the addition is completed, control the temperature at 0-5°C and stir for 1 hour. Then transfer the reaction solution to a 1000ml single-necked bottle and concentrate it at 40°C under a dry environment. Then add 100ml of dichloromethane to dry it twice. Finally, add 100ml of dichloromethane to dissolve the substrate and transfer it to a constant pressure dropping funnel for use. (2) Take another 1000ml three-necked bottle and add 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (38.5 g, 0.2mol), dichloromethane (500ml), pyridine (47.5g, 0.6mol) was added to the constant pressure dropping funnel for assembly and standby use, the reaction temperature was lowered to 0-5℃, stirred and nitrogen purged three times, pyridine was added dropwise after the replacement was completed, the temperature was controlled at 0-5℃ and stirred for 10min, then the dichloromethane solution in (1) was added dropwise, after the addition was completed, stirred for 2h, the reaction returned to room temperature, water was added for extraction (200ml×2), and saturated brine was washed (200ml ×2), dried over anhydrous sodium sulfate, concentrated at 40°C to obtain a crude afoxolane, the crude afoxolane was transferred to a 1000ml single-mouth bottle, and a mixed solution (800ml) of petroleum ether:ethyl acetate = 2:1 was added, the reaction was heated to reflux, stirred to dissolve and then naturally cooled to room temperature, then cooled to 0°C and stirred for crystallization for 2h, filtered, rinsed with a small amount of petroleum ether, and dried to obtain refined afoxolane (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 kettle, 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethanone (10kg, 36mol), toluene (40L), and 4-acetylnaphthoic acid (7.75kg, 36mol) were added. Triethylamine (7.3kg, 72.3mol) was added to the dropping tank for standby use. The mixture was stirred at room temperature and nitrogen was replaced three times. After the replacement was completed, the mixture was heated to 60°C and stirred for reaction for 10min. Triethylamine was added dropwise quickly. After the addition was completed, DMAP (2.64kg, 21.6mol) was added after the addition was completed. Acetic anhydride (5.5kg, 54mol) was added to the dropping tank for standby use. The mixture was nitrogen replaced. After the reaction was stirred for 10min, acetic anhydride was slowly added dropwise. After the addition was completed, tetrabutylammonium bromide (7kg, 21.6mol) was added after the reaction was completed at 60°C for reaction for 3h. mol) and the reaction was cooled to 0-5°C for standby use; water (20L) was added to another 50L kettle and cooled to 0-5°C, sodium hydroxide (5.76kg, 144mol) was added in 3 batches and stirred to dissolve, the temperature was controlled at 0-5°C, hydroxylamine hydrochloride (5kg, 72mol) was added and stirred to dissolve, and the temperature was controlled at 0-5°C and slowly pumped into a 100L glass kettle, and the reaction was maintained at 0°C for 5h, and the reaction solution was adjusted to PH 6-7 with 10% hydrochloric acid and heated to 20-25°C, separated, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated at 50°C to obtain a crude product of 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 was set aside without purification.

[0046] Step 2: Preparation of Afollana:

[0047] (1) A 100 L glass kettle was added with 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid (10 kg, 20.5 mol), dichloromethane (40 L), and DMF (10 ml). Oxalyl chloride (7.8 kg, 61.5 mol) was added to the dropping tank for later use. The reaction temperature was lowered to 0-5°C, stirred, and nitrogen purged three times. After the purging was completed, oxalyl chloride was slowly added dropwise. After the addition was completed, the temperature was controlled at 0-5°C and stirred for 3 h. After the mixture was concentrated at 40°C, 10 L of dichloromethane was added to dryness twice. Finally, 10 L of dichloromethane was added to dissolve the substrate and the mixture was transferred to the dropping tank. (2) Add 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (3.95kg, 20.5mol) and dichloromethane (40L) into a 100L glass kettle. Add triethylamine (5.2kg, 51.3mol) into another dropping tank for later use. Cool the reaction mixture to 0-5°C, stir and replace with nitrogen three times. After replacement, add triethylamine dropwise. After addition, control the temperature to 0-5°C and stir for 10min. Then, add the dichloromethane solution in (1) dropwise. After addition, stir for 3h. Return the reaction mixture 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°C to obtain a crude product of afoxolamide. A mixed solution of petroleum ether and ethyl acetate = 2:1 (60 L) was added, the reaction temperature was raised to reflux, and the mixture was stirred until dissolved and then naturally cooled to room temperature, and then cooled to 0°C and stirred for crystallization for 5 h, filtered, rinsed with a small amount of petroleum ether, and dried to obtain refined afoxolane (11.8 kg, yield: 91.8%, purity: 99.68%).

[0048] In summary, the route of the present invention adopts a method of first synthesizing an isoxazole ring and then introducing a side chain, thereby reducing the generation of impurities, thereby improving the reaction yield, and the total yield can reach 75%, thereby reducing the raw material cost and the refining cost; the present invention obtains the intermediate 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid in a continuous addition manner, thereby reducing post-processing operations, shortening the route, and greatly improving the production efficiency; the types of solvents and auxiliary materials required by the present invention are relatively single, and are all cheap and easy to obtain, thereby greatly reducing the production cost; the conditions required for the reaction of the present invention are mild, and the amplification effect is not obvious; in summary, the present invention is more in line with industrial large-scale production.

[0049] The above description is only a preferred embodiment of the present invention. It should be pointed out that, for ordinary technicians in this field, several modifications and improvements can be made without departing from the creative concept of the present invention, and these should also be regarded as within the scope of protection of the invention.

Claims

1. A method for synthesizing afoxol, characterized in that: The following steps are involved: Step 1: Add 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethanone and 4-acetylnaphthoic acid to a solvent, add a base, add DMAP after the reaction is complete at 50-80°C, add acetic anhydride dropwise, add tetrabutylammonium bromide after the reaction is complete at 50-80°C, then add an aqueous solution of sodium hydroxide and hydroxylamine hydrochloride, and react at 0-5°C 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 is reacted with an acyl chloride in the presence of DMF and dichloromethane to obtain 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoyl chloride; and then added dropwise to a dichloromethane solution of 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride and a base, and reacted at 0-5°C. After the reaction is completed, afolanine is obtained; The reaction formula is as follows:

2. The method for synthesizing afoxolamide according to claim 1, characterized in that: The solvent in step 1 is at least one of tetrahydrofuran, benzene, toluene, xylene, acetonitrile or a combination thereof, preferably toluene or xylene.

3. The method for synthesizing afoxolamide according to claim 1, characterized in that: The base in step 1 is triethylamine, pyridine or N-methylmorpholine, preferably triethylamine.

4. The method for synthesizing afoxolamide according to claim 1, characterized in that: In step 1, the molar ratio of 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethanone, 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).

5. The method for synthesizing afoxolamide according to claim 1, characterized in that: 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-trifluoroethanone; 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-trifluoroethanone.

6. The method for synthesizing afoxolamide according to claim 1, characterized in that: Step 1 also includes adjusting pH, separating liquids, washing, drying and concentrating after the reaction is completed; Wherein: Use hydrochloric acid to adjust the pH to 6-7.

7. The method for synthesizing afoxlan according to claim 1, characterized in that: Step 2 is as follows: 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid and DMF are added to dichloromethane, and the acid chloride is added dropwise at 0-5°C. After the addition is completed, the mixture is stirred for 1 hour and then concentrated to dryness. A small amount of dichloromethane is added to dissolve the mixture for later use. 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride is added to dichloromethane, the temperature is lowered by 0-5°C, a base is added and stirred for 10 minutes, and then the above-dissolved dichloromethane solution is added dropwise. After the addition is completed, the mixture is stirred for 2 hours to obtain afoxolamide.

8. The method for synthesizing afoxolamide according to claim 7, characterized in that: 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.

9. The method for synthesizing afoxolamide according to claim 7, 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 1:1:1.5-3:2-5; in step 2, the amount of dichloromethane used in the acylation reaction and the condensation reaction is 3-8 times the mass of 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid; in step 2, the amount of DMF used is 0.001 times the mass of 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid.

10. The method for synthesizing afoxolamide according to claim 7, characterized in that: Step 2 also includes post-processing steps, specifically: After the reaction is completed, the crude afoxolan is obtained through extraction, drying and concentration, and then the refined afoxolan is obtained through crystallization with a mixed solution of petroleum ether and ethyl acetate.

Images