Preparation method of fluralana

Abstract

The preparation method comprises the following steps: S100, dissolving a first compound in a first solvent, and carrying out an amidation reaction on the first compound and a second compound to prepare a third compound; s200, dissolving the third compound in a second solvent, carrying out aldol condensation reaction on the third compound and a fourth compound under the action of a catalyst, and then adding a dehydration reagent to prepare a fifth compound; and S300, dissolving the fifth compound in a third solvent, adding a hydroxylamine hydrochloride solution, reacting to obtain a mixture containing fluralana, and purifying to obtain the fluralana, the three-step reaction route is reasonable in design, the steps are simple and short, the reaction conditions of all the steps are relatively mild, no special strict requirement on equipment exists, aftertreatment is simple and convenient, large-scale amplification and continuous production are easy to achieve, and the method has a good industrial application prospect.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic chemical synthesis, in particular to a preparation method of fluralaner. BACKGROUND

[0002] Fluralaner is a new isoxazoline broad-spectrum insecticide and acaricide, which can antagonize the GABA receptor and glutamate receptor gate-keeping chloride ion channel of insects and mites, interfere with nerve signal transmission, and cause parasitic worms to rapidly paralyze and die. The drug has the characteristics of high efficiency, long-acting and safety, and is especially suitable for the prevention and treatment of external parasites such as fleas and ticks in pets such as dogs and cats. A single dose can provide protection for up to 12 weeks, which is significantly better than traditional insect repellents.

[0003] With the rapid development of pet economy in China, the pet owner group mainly composed of post-80s and post-90s is expanding. Under the promotion of changes in population structure and consumption habits, the demand for pet medical treatment and medication market continues to grow. However, domestic veterinary drug enterprises have long been dominated by livestock and poultry drugs, and the research and development and production capacity of pet-specific drugs are relatively weak. Therefore, the development of pet-specific drugs with independent intellectual property rights, high efficiency and safety is of great significance to improve the competitiveness of China's animal health industry.

[0004] As one of the mainstream products in the pet insect repellent market, the synthesis process of fluralaner and the preparation technology of its intermediates have become the key link restricting domestic production. At present, the synthesis route of fluralaner still mainly relies on the methods reported in foreign company patents, which generally have problems such as complex reaction steps, low yield, use of highly toxic or high-risk reagents (such as cyanide, phosgene or its derivatives), large environmental pollution and poor process safety. For example, some existing methods need to be carried out under high temperature, high pressure or strong corrosive conditions when constructing the key isoxazoline ring or modifying the fluorine aryl structure, which requires high equipment, has many side reactions, is difficult to handle, and is not conducive to industrialization and production cost control.

[0005] In addition, some intermediates involved in the existing synthesis route have poor stability and are difficult to purify, which also affects the quality and yield of the final product. Therefore, it has become a technical problem to be solved in the field to develop a synthesis process for a key intermediate of fluralaner which is mild in reaction conditions, simple in operation, green and safe, and suitable for large-scale production.

[0006] In summary, a new synthesis method for an important intermediate of fluralaner which is safer, more economical and more suitable for industrial production is provided, which not only has important scientific value, but also has significant market application prospect. SUMMARY

[0007] Therefore, it is necessary to provide a preparation method of fluralaner to solve the problems in the prior art.

[0008] To achieve the above object, the present application provides a technical solution: The preparation method of fluralaner comprises the following steps: S100. The first compound is dissolved in a first solvent and subjected to an amide reaction with a second compound to obtain a third compound; S200. The third compound is dissolved in a second solvent and subjected to an aldol condensation reaction with a fourth compound under the action of a catalyst, and then a dehydrating agent is added to obtain a fifth compound; S300. The fifth compound is dissolved in a third solvent, hydroxylamine hydrochloride solution is added, and a mixture containing fluralaner is obtained by reaction, and the fluralaner is obtained after purification; The preparation flow chart of fluralaner is as follows: → → → ; The first compound is The third compound is The fluralaner is The structural formula of the second compound is The structural formula of the fourth compound is The structural formula of the fifth compound is .

[0009] Preferably, in step S100, an acylating agent or a condensing agent is added to accelerate the reaction rate of the amide reaction, and the acylating agent includes at least one of thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus trichloride and oxalyl chloride; The condensing agent includes at least one of EDCI / DMAP, HOBT / EDCI, DCC, BOP and PyBOP.

[0010] Preferably, in step S100, the molar ratio of the first compound to the second compound is 1: (1.0-1.3), and the reaction temperature of the amide reaction is -10℃-50℃.

[0011] Preferably, in step S200, the catalyst includes a basic substance or an acidic substance.

[0012] Preferably, the basic substance includes pyridine, imidazole, triethylamine, diisopropyl ethylamine or DBU; The acidic substance includes sulfuric acid, dilute hydrochloric acid, phosphoric acid, benzoic acid or acetic acid.

[0013] Preferably, the dehydrating reagent comprises concentrated sulfuric acid, acetic anhydride, propionic anhydride, DCC or TsCl.

[0014] Preferably, the molar ratio of the third compound, the fourth compound and the dehydrating agent is 1: (1.0-1.5): (1.0-5.0).

[0015] Preferably, in step S200, the reaction temperature of the aldol condensation reaction is 20-120°C.

[0016] Preferably, in step S300, the molar ratio of the fifth reactant to the hydroxylamine hydrochloride solution is 1.0:5.0.

[0017] Preferably, the first solvent comprises at least one of dichloromethane, toluene, ethyl acetate, methyl tert-butyl ether, 1,2-dichloroethane, tetrahydrofuran, ethyl acetate and dioxane solvent; the second solvent comprises at least one of dichloromethane, ethyl acetate, methyl tert-butyl ether, 1,2-dichloroethane, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide and dioxane solvent; the third solvent comprises at least one of dichloromethane, ethyl acetate, methyl tert-butyl ether, 1,2-dichloroethane, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide and dioxane solvent.

[0018] Advantages of the present application: 1. Safety is significantly improved: the present application successfully avoids the high-risk reaction steps, the use of highly toxic or highly corrosive reagents (such as phosgene, cyanide, etc.) that may be involved in the prior art, greatly reduces the safety risks and environmental hazards in the production process, and effectively controls the protection pressure of the operating personnel and the production safety hidden danger.

[0019] 2. The route is simple and suitable for industrial production: the three-step reaction route of the present application is reasonable, the steps are short, the reaction conditions of each step are relatively mild, there is no special harsh requirement for the equipment, the post-treatment is simple, and it is easy to realize scale-up and continuous production, which has good industrial application prospect.

[0020] 3. Product quality and yield are improved: the process route has good selectivity, less side reactions, high stability of intermediates and easy purification, thereby ensuring high purity and high yield of the final product, meeting the quality standards of the raw material drug.

[0021] 4. Cost-effectiveness optimization: due to the avoidance of expensive or difficult to handle hazardous reagents, the simplification of the purification process and the improvement of the total yield, the present process effectively reduces the raw material cost and waste treatment cost, and has superior overall economy and strong competitiveness. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 LCMS chart of the third compound; Figure 2 H-NMR chart of the third compound; Figure 3 LCMS chart of the fifth compound; Figure 4 H-NMR chart of the fifth compound; Figure 5 C-NMR chart of the fifth compound; Figure 6 H-NMR chart of fluralaner; Figure 7 C-NMR chart of fluralaner; Figure 8 F-NMR chart of fluralaner; Figure 9 ESI (+) MS chart of fluralaner. DETAILED DESCRIPTION

[0023] For the purpose of better illustrating the object, technical scheme and advantages of the present application, the present application will be further described in conjunction with specific examples.

[0024] In the examples, the test methods used are conventional methods unless otherwise specified, and the materials, reagents, etc. used are commercially available unless otherwise specified.

[0025] A preparation method of fluralaner, comprising the steps of: S100. dissolving a first compound in a first solvent, and performing an amide reaction with a second compound to obtain a third compound; S200. dissolving the third compound in a second solvent, and performing an aldol condensation reaction with a fourth compound under the action of a catalyst, and then adding a dehydrating agent to obtain a fifth compound; S300. dissolving the fifth compound in a third solvent, adding a hydroxylamine hydrochloride solution, and reacting to obtain a mixture containing fluralaner, and after purification, the fluralaner is obtained; Wherein, the preparation flow chart of fluralaner is as follows: → → → ; the first compound is the third compound is fluralaner; the structural formula of the second compound is , and the structural formula of the fourth compound is , the structural formula of the fifth compound is .

[0026] In some embodiments, in step S100, the reaction rate of the amide reaction is accelerated by adding an acylating agent or a condensing agent, the acylating agent including at least one of dichlorosulfoxide, phosphorus pentachloride, phosphorus oxychloride, phosphorus trichloride and oxalyl chloride; The condensing agent includes at least one of EDCI / DMAP, HOBT / EDCI, DCC, BOP and PyBOP.

[0027] In some embodiments, in step S100, the molar ratio of the first compound and the second compound is 1: (1.0-1.3), and the reaction temperature of the amide reaction is -10°C-50°C.

[0028] In some embodiments, in step S200, the catalyst includes a basic substance or an acidic substance. In some embodiments, petroleum ether is added in step S200, the solubility of petroleum ether is not good, it belongs to a poor solvent, and is used to force out materials in a good solvent.

[0029] In some embodiments, the basic substance includes pyridine, imidazole, triethylamine, diisopropylethylamine or DBU; The acidic substance includes sulfuric acid, dilute hydrochloric acid, phosphoric acid, benzoic acid or acetic acid.

[0030] In some embodiments, the dehydrating agent includes concentrated sulfuric acid, acetic anhydride, propionic anhydride, DCC or TsCl.

[0031] In some embodiments, the molar ratio of the third compound, the fourth compound and the dehydrating agent is 1: (1.0-1.5): (1.0-5.0).

[0032] In some embodiments, in step S200, the reaction temperature of the aldol condensation reaction is 20°C-120°C.

[0033] In some embodiments, in step S300, the molar ratio of the fifth reactant and the hydroxylamine hydrochloride solution is 1.0:5.0.

[0034] In some embodiments, the first solvent includes at least one of dichloromethane, toluene, ethyl acetate, methyl tert-butyl ether, 1,2-dichloroethane, tetrahydrofuran, ethyl acetate and dioxane solvent; The second solvent includes at least one of dichloromethane, ethyl acetate, methyl tert-butyl ether, 1,2-dichloroethane, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide and dioxane solvent; The third solvent includes at least one of dichloromethane, ethyl acetate, methyl tert-butyl ether, 1,2-dichloroethane, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, and dioxane.

[0035] In some embodiments, sodium hydroxide is added in step S300 to neutralize hydrogen chloride molecules in hydroxylamine hydrochloride, release hydroxylamine and double bond reaction.

[0036] In some embodiments, tetrabutylammonium fluoride with catalytic effect is added in step S300 to increase the nucleophilicity of the reaction.

[0037] Specific embodiments I. Preparation of the fifth compound Example 1 S100. Dissolve the first compound in a first solvent to react with the second compound to prepare the third compound, and the specific steps are as follows: Put the first compound (50g of 4-acetyl-2-methyl-benzoic acid) into a single-neck flask with a capacity of 1L; Add the first solvent (300g of toluene + 2 drops of DMF) to the single-neck flask; At room temperature, add the acylation reagent (50g of thionyl chloride) dropwise to the single-neck flask, and after the dropwise addition is completed, heat to 80°C for 6h. After the reaction is completed, evaporate the solvent in the single-neck flask, add 300g of dichloromethane solvent, and then add the second compound (i.e., 48g of 2-amino-N-(2,2,2-trifluoroethyl)acetamide). After the plate reaction is completed, add 200ml of water to quench the reaction, and then adjust the pH value to 7~8 with a saturated Na2CO3 solution. Separate the layers, and then wash the organic layer with 200ml of water once. Dry the organic phase, and then evaporate to a paste. Then, add methyl tert-butyl ether solvent to treat the paste, filter and dry the solid to obtain 75.2g of the third compound (4-acetyl-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethylbenzamide), with a purity of 98.3% and a yield of 85%.

[0038] S200. Dissolve the third compound in a second solvent, and then perform aldol condensation reaction with the fourth compound under the action of a catalyst, and then add a dehydration reagent to prepare the fifth compound, and the specific steps are as follows: Weigh 100g of the third compound (4-acetyl-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethylbenzamide) prepared in step S100 into a reaction flask with a capacity of 1L; Add the second solvent (500g of methyl tert-butyl ether) to the above reaction flask, then add the fourth compound (92g of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethane-1-one), then add the alkaline substance (50g of pyridine), heat to 55℃ and reflux for 16h, cool to 10℃, and then add the dehydrating agent (31g of concentrated sulfuric acid) at a controlled temperature of 10-30℃. After the addition is complete, keep the reaction at 20-30℃ for 6h. After confirming the reaction was complete by TLC, sodium carbonate aqueous solution was added dropwise at a temperature below 40°C to adjust the pH to 7. The mixture was separated, and the organic layer was collected. The organic layer was then washed with 300g of water, removed, dried, and concentrated into a paste. 400g of petroleum ether was added dropwise with stirring to precipitate the solid from the good solvent. After the addition was complete, the mixture was stirred at room temperature for 2 hours, filtered, and dried. The resulting solid was added to a 1L single-necked flask, and 3 times the amount of water and acetone were added. The mixture was heated to 70°C and stirred under reflux for 1 hour, then cooled to 20°C and stirred for 2 hours. After filtration, the mixture was placed in a 50°C oven and dried for 24 hours to obtain 152g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobutyl-2-buten-1-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide solid, which is the fifth compound, with a yield of 88% and a purity of 95%.

[0039] Example 2 S100. Weigh 50g of 4-acetyl-2-methyl-benzoic acid and 48g of 2-amino-N-(2,2,2-trifluoroethyl)acetamide into a 1L reaction flask, add 300g of ethyl acetate, and add condensation reagents (DMAP / EDCI 5g and 65g respectively). Heat to 50℃ and react for 8h. After the reaction is complete, add 300ml of water, separate the layers, take the organic layer, concentrate to dryness, add methyl tert-butyl ether to slurry, filter, and place the filter cake in a forced-air drying oven to dry for 24h to obtain 80g of solid with a purity of 97.6% and a yield of 90%.

[0040] S200. Weigh 100g of 4-acetyl-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethylbenzamide from step S100 and add it to a 1L reaction flask. Add 400g of DMF, 400g of methyl tert-butyl ether, 62g of triethylamine, and 92g of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethane-1-one. Heat to 60℃ and react for 2 hours. Cool to 0℃ and add 64g of acetic anhydride dropwise while maintaining the temperature at 0-20℃. After the addition is complete, maintain the temperature at 10-15℃ and react for 4 hours. After confirming the reaction is complete by TLC, add 600g of methyl tert-butyl ether and 200g of water. Adjust the pH with a 2mol / L hydrochloric acid aqueous solution. 2. Separate the liquid and take the upper organic layer. Then, wash the organic layer once with 200g of water. Concentrate the organic layer to a paste, add 400g of petroleum ether dropwise, filter, dry, and add the obtained solid to a 1L single-necked flask. Add 3 times the amount of water and ethanol, heat to 80℃ and stir under reflux for 1h, then cool to 20℃ and stir for 2h. Filter and dry in a 50℃ forced-air drying oven for 24h to obtain 130g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobutyl-2-buten-1-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide solid, which is the fifth compound, with a yield of 76% and a purity of 97%.

[0041] Example 3 S100. Weigh 50g of 4-acetyl-2-methyl-benzoic acid into a 1L single-necked flask, add 500g of dichloromethane, 45g of HOBT / EDCI and 65g of EDCI, then add 48g of 2-amino-N-(2,2,2-trifluoroethyl)acetamide, and dropwise add 28g of triethylamine. React for 4 hours. After the reaction is complete by TLC, add 200ml of water to quench the reaction, extract by separation, wash the organic layer once with 200ml of water, dry the organic phase, and evaporate by rotary evaporation to a paste. Then add methyl tert-butyl ether to slurry, filter, and dry in a forced-air drying oven for 24 hours. 82.4g of 4-acetyl-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethylbenzamide solid was obtained with a purity of 98.2% and a yield of 92.5%.

[0042] S200. Weigh 100g of 4-acetyl-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethylbenzamide obtained in Step 1 (Example 3) and add it to a 1L reaction flask. Add 500g of dichloromethane, 120g of DBU, and 92g of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethane-1-one. React at room temperature for 3 hours, then cool to 0℃ and add 67g of DCC dropwise while maintaining the temperature at 0-20℃. After the addition is complete, maintain the temperature at 10-15℃ and react for 4 hours. After confirming the completeness of the reaction by TLC, add 200g of water and adjust the pH to 2 with a 2mol / L hydrochloric acid aqueous solution. Separately extract the solution. Take the sample, then wash the organic layer once with 200g of water, concentrate the organic layer to a paste, add 400g of petroleum ether dropwise, filter, dry, and add the obtained solid to a 1L single-necked flask, add 4 times the amount of water and ethanol, heat to reflux and stir for 1h, then cool to 20℃, stir for 2h, filter, and place in a 50℃ forced-air drying oven to dry for 24h, to obtain 140g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobutyl-2-buten-1-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide solid, which is the fifth compound, with a yield of 82% and a purity of 96%.

[0043] Example 4 S100. Weigh 50g of 4-acetyl-2-methyl-benzoic acid and add it to a 500ml reaction flask. Add 200g of DMF and 160g of PyBOP. Cool to 10℃ and add 48g of 2-amino-N-(2,2,2-trifluoroethyl)acetamide. After the addition is complete, keep the temperature at 10-20℃ and stir for 2 hours. After confirming the reaction is complete by TLC, pour the reaction solution into 800ml of ice water to quench the reaction. Stir at room temperature for 3 hours. Filter the precipitated solid and dry it in a forced-air drying oven for 24 hours to obtain 85.5g of 4-acetyl-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethylbenzamide solid with a purity of 99.1% and a yield of 96.2%.

[0044] S200. Weigh 100g of 4-acetyl-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethylbenzamide obtained from S100 and add it to a 1L reaction flask. Add 500g of DMF and 2g of concentrated sulfuric acid, then add 92g of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethane-1-one. Heat to 80℃ and react for 3h. Then cool to 0℃ and add 70g of triethylamine. Control the temperature at 0-20℃ and add 60g of TsCl. Control the temperature at 10-15℃ and react for 4h. After confirming the reaction is complete by TLC, add 200g of water and adjust the pH to 2 with 2mol / L hydrochloric acid solution. Extract by separation, then wash the organic layer once with 200g of water. Concentrate the organic layer to a paste and then add petroleum ether dropwise. 400g of ether was filtered, dried, and the resulting solid was added to a 1L single-necked flask. Water and isopropanol were added, and the mixture was heated to reflux and stirred for 1 hour. Then, the temperature was lowered to 20°C, stirred for 2 hours, filtered, and dried in a forced-air drying oven for 24 hours to obtain 135g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobutyl-2-buten-1-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide solid, which is the fifth compound, with a yield of 79% and a purity of 98%.

[0045] II. Preparation of the aforementioned Freranar S300. The fifth compound is dissolved in a third solvent, and hydroxylamine hydrochloride solution is added. The mixture containing fluorellana is prepared by reaction. After purification, fluorellana is obtained. The specific steps are as follows: Example 5 Weigh 40.4 g of water and add it to a 500 ml three-necked flask. Add 7.5 g of sodium hydroxide, stir to dissolve, and then cool to -5 °C. While maintaining the temperature at -5 °C, add 7.5 g of hydroxylamine hydrochloride dropwise with stirring. Add 0.1 g of tetrabutylammonium fluoride. Dissolve 20.2 g of the fifth compound obtained in Example 1 in 40.4 g of the third solvent (tetrahydrofuran). Then, slowly add the solution dropwise while maintaining the temperature below 0 °C. After the addition is complete, maintain the temperature at 0 °C and react for 2 hours. Then, add 60 g of 2 mol of sodium hydroxide dropwise. The pH of the aqueous layer was adjusted to 6-7 using a 1 / L hydrochloric acid solution. The layers were separated, and the upper tetrahydrofuran layer was collected. The aqueous layer was extracted once with 20g of ethyl acetate. The tetrahydrofuran and ethyl acetate layers were combined, and 30g of solvent was distilled off under reduced pressure at 45°C. Then, 100g of water was added dropwise with stirring, and distillation continued under reduced pressure at 40°C until the flow stopped. The temperature was lowered to 20°C, and the mixture was stirred for 2 hours. After filtration, the solution was dried at 50°C for 12 hours to obtain 20.2g of flurranar, with a yield of 92% and a purity of 99.2%. The characterization spectral data are shown below. Figures 1-9 As shown.

[0046] Example 6 Weigh 40.4 g of water and add it to a 500 ml three-necked flask. Add 7.5 g of sodium hydroxide, stir to dissolve, and then cool to -5 °C. While maintaining the temperature at -5 °C, add 10.5 g of hydroxylamine hydrochloride dropwise with stirring. Add 0.1 g of tetrabutylammonium fluoride. Dissolve 20.2 g of the fifth compound obtained in Example 1 in 40.4 g of the third solvent (dichloromethane). Then, slowly add the solution dropwise while maintaining the temperature below 0 °C. After the addition is complete, react at 0 °C for 2 hours. Finally, add 60 g of 2 mol of [a specific solvent / solvent]. The solution was diluted with 1 / L hydrochloric acid to adjust the pH to 6-7. The mixture was then separated, and the lower dichloromethane layer was collected. The aqueous layer was extracted once more with 20g of ethyl acetate. The dichloromethane and ethyl acetate layers were combined, and 30g of solvent was distilled off under reduced pressure at 30°C. Then, 100g of water was added dropwise with stirring, and distillation continued under reduced pressure at 40°C until the flow stopped. The solution was then cooled to 20°C, stirred for 2 hours, filtered, and dried at 50°C for 12 hours to obtain 19.7g of flurranar, with a yield of 90% and a purity of 99.1%. Example 7 Weigh 40.4g of water and add it to a 500ml three-necked flask. Add 7.5g of sodium hydroxide, stir to dissolve, and then cool to -5℃. While maintaining the temperature at -5℃, add 12g of hydroxylamine hydrochloride dropwise with stirring. Dissolve 20.2g of the fifth compound obtained in Example 1 in 120g of ethyl acetate. Then, slowly add the solution dropwise while maintaining the temperature below 0℃. After the addition is complete, react at 0℃ for 2 hours. Take the upper ethyl acetate layer. Extract the aqueous layer once more with 20g of ethyl acetate. After removing the ethyl acetate layer, 30 g of solvent was distilled off under reduced pressure at 40 °C. Then, 100 g of water was added dropwise with stirring, and distillation continued under reduced pressure at 40 °C until the flow stopped. The temperature was lowered to 20 °C, and the mixture was stirred for 2 hours. The mixture was then filtered and dried at 50 °C for 12 hours to obtain 18.6 g of fluorellaranosine methyl 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)glycine methyl ester, with a yield of 85% and a purity of 99.6%. III. Screening Criteria: 1. Solvent screening experiment in step S100.

[0047] The other steps are the same as in Example 1, except for the first solvent in step S100. The yield and purity of the obtained third compound are shown in Table 1.

[0048] Table 1. Solvent screening results in step S100 As shown in Table 1, dichloromethane, toluene, ethyl acetate, methyl tert-butyl ether, 1,2-dichloroethane, tetrahydrofuran, ethyl acetate, and dioxane can all undergo this reaction.

[0049] When DMSO is used as the solvent, both the purity and yield of the product decrease. 2. Solvent selection in step S200.

[0050] 2. Screening of the second solvent in step S200 The other steps are the same as in Example 1, except for the second solvent in step S200. The yield and purity of the fifth compound obtained in S200 are shown in Table 2.

[0051] Table 2. Solvent screening results in step S200. As shown in Table 2, dichloromethane, ethyl acetate, methyl tert-butyl ether, 1,2-dichloroethane, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, and dioxane solvents can all carry out this reaction.

[0052] 3. Solvent selection in step S300 The other steps are the same as in Example 5, except for the third solvent in step S300. The yield and purity of the obtained freranil are shown in Table 1.

[0053] Table 3. Solvent screening results in step S300 As shown in Table 3, dichloromethane, ethyl acetate, methyl tert-butyl ether, 1,2-dichloroethane, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, and dioxane can all carry out this reaction.

[0054] 4. Screening of acylation reagents in the S100 reaction: The other steps are the same as in Example 1, except for the acylation reagent in step S100. The yield and purity of the third compound obtained in S100 are shown in Table 4.

[0055] Table 4. Screening results of acylation reagents in step S100 As shown in Table 4, thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus trichloride, and oxalyl chloride can all carry out this reaction well.

[0056] 5. Screening of condensation reagents in S100: The other steps are the same as in Example 1, except for the condensation reagent in step S100. The yield and purity of the third compound obtained in S100 are shown in Table 5.

[0057] Table 5. Screening results of condensation reagents in step S100. As shown in Table 5, at least one of EDCI / DMAP, HOBT / EDCI, DCC, BOP and PyBOP can carry out this reaction well.

[0058] 6. Screening of alkaline catalysts in S200: The other steps are the same as in Example 1, except for the alkaline catalyst in step S200. The yield and purity of the fifth compound obtained in S200 are shown in Table 6.

[0059] Table 6 Screening Results of Alkali Catalysts in Step S200 As shown in Table 6, pyridine, imidazole, triethylamine, diisopropylethylamine, or DBU can all carry out this reaction well.

[0060] 7. Screening of acid catalysts in S200: The other steps are the same as in Example 1, except for the acidic catalyst in step S200. The yield and purity of the fifth compound obtained in S200 are shown in Table 7.

[0061] Table 7. Screening Results of Acidic Catalysts in Step S200 As shown in Table 7, sulfuric acid, dilute hydrochloric acid, phosphoric acid, benzoic acid, or acetic acid can be used as acidic catalysts in S200 to carry out the reaction well.

[0062] 8. Selection of dehydrating agent in S200: The other steps are the same as in Example 1, except for the dehydrating agent in step S200. The yield and purity of the fifth compound obtained in S200 are shown in Table 8.

[0063] Table 8. Screening results of dehydrating agents in step S200 As shown in Table 8, concentrated sulfuric acid, acetic anhydride, propionic anhydride, DCC, or TsCl can be used as dehydrating agents in S200 to facilitate the reaction.

[0064] 9. Screening of the reaction ratio of the first and second compounds in S100: The other steps are the same as in Example 1, except that the reaction ratio of the first compound and the second compound in step S100, and the yield and purity of the third compound obtained in S100 are shown in Table 8.

[0065] Table 9 Screening table of reaction ratios of the first and second compounds in step S100 As shown in Table 9, the reaction can be carried out well when the molar ratio of the first compound to the second compound is 1:(1.0-1.3).

[0066] 10. The molar ratio of the third compound, the fourth compound, and the dehydrating agent is used for screening: The other steps are the same as in Example 1, except for the molar ratio of the third compound, the fourth compound and the dehydrating agent in step S200. The yield and purity of the third compound obtained in S100 are shown in Table 10.

[0067] Table 10 Screening table of molar ratios of the third and fourth compounds and the dehydrating agent in step S200. As shown in Table 10, in the S200 reaction, the molar ratio of the third compound, the fourth compound, and the dehydrating agent is 1:(1.0-1.5):(1.0-5.0), which allows the reaction to proceed well.

[0068] 11. Screening of the molar ratio of the fifth reactant and hydroxylamine hydrochloride in S300: The other steps are the same as in Example 6, except for the molar ratio of the fifth reactant and hydroxylamine hydrochloride in step S300. The yield and purity of the fluranar product obtained in S300 are shown in Table 11.

[0069] Table 11 Screening of the molar ratio of the fifth reactant and hydroxylamine hydrochloride in step S300 As shown in Table 11, the molar ratio of the fifth reactant to hydroxylamine hydrochloride in step S300 is 1.0:(1.0-5.0), which allows the reaction to proceed well.

[0070] It should be noted that the specific parameters or reagents in the above embodiments are specific or preferred embodiments under the concept of the present invention, and not limitations thereof; those skilled in the art can make adaptive adjustments within the concept and protection scope of the present invention.

Claims

1. A method for preparing fluorellanar, characterized in that, Including the following steps: S100. Dissolve the first compound in a first solvent and react it with the second compound via an amide reaction to obtain the third compound; S200. The third compound is dissolved in a second solvent and, under the action of a catalyst, undergoes an aldol condensation reaction with the fourth compound. Then, a dehydrating agent is added to obtain the fifth compound. S300. The fifth compound is dissolved in a third solvent, and hydroxylamine hydrochloride solution is added. The mixture containing fluorellana is prepared by reaction, and after purification, fluorellana is obtained. The preparation process of freranil is shown in the following flowchart: → → → ； As the first compound, It is the third compound. It is the fifth compound. For Freranal; The structural formula of the second compound is: The structural formula of the fourth compound is .

2. The method for preparing freranal according to claim 1, characterized in that, In step S100, the reaction rate of the amide reaction is accelerated by adding an acylation reagent or a condensation reagent, wherein the acylation reagent includes at least one of thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus trichloride, and oxalyl chloride; The condensation reagent includes at least one of EDCI / DMAP, HOBT / EDCI, DCC, BOP, and PyBOP.

3. The method for preparing freranal according to claim 1, characterized in that, In step S100, the molar ratio of the first compound to the second compound is 1:(1.0-1.3), and the reaction temperature for the amide reaction is -10℃ to 50℃.

4. The method for preparing freranal according to claim 1, characterized in that, In step S200, the catalyst comprises an alkaline substance or an acidic substance.

5. The method for preparing freranel according to claim 4, characterized in that, The alkaline substances include pyridine, imidazole, triethylamine, diisopropylethylamine, or DBU; The acidic substances include sulfuric acid, dilute hydrochloric acid, phosphoric acid, benzoic acid, or acetic acid.

6. The method for preparing freranal according to claim 1, characterized in that, The dehydrating agents include concentrated sulfuric acid, acetic anhydride, propionic anhydride, DCC, or TsCl.

7. The method for preparing freranal according to claim 1, characterized in that, The molar ratio of the third compound, the fourth compound, and the dehydrating agent is 1:(1.0-1.5):(1.0-5.0).

8. The method for preparing freranal according to claim 1, characterized in that, In step S200, the reaction temperature of the aldol condensation reaction is 20℃-120℃.

9. The method for preparing freranal according to claim 1, characterized in that, In step S300, the molar ratio of the fifth reactant to the hydroxylamine hydrochloride solution is 1.0:(4.0-7.0).

10. The method for preparing freranal according to claim 1, characterized in that, The first solvent includes at least one of 1,2-dichloroethane, toluene, ethyl acetate, dichloromethane, methyl tert-butyl ether, tetrahydrofuran, and dioxane solvent; The second solvent includes at least one of dichloromethane, ethyl acetate, methyl tert-butyl ether, 1,2-dichloroethane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, and dioxane solvent; The third solvent includes at least one of dichloromethane, ethyl acetate, methyl tert-butyl ether, 1,2-dichloroethane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, and dioxane.

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