Preparation method of amorphous arfamarin

Abstract

The invention discloses a preparation method of amorphous arfamarin. The method comprises the following steps: by taking 4-[3-(3-chloro-5-trifluoromethyl-phenyl)-4, 4, 4-trifluoro-1-oxo-2-butene-1-yl]-naphthalene-1-methyl formate and hydroxylamine hydrochloride as initial raw materials, carrying out cyclization reaction under the catalysis of a phase transfer catalyst and an acid-binding agent, then carrying out alkaline hydrolysis reaction, and finally, carrying out reaction with 2-amino-N-(2, 2, 2-triazole-1-yl)-1-methyl-2-oxo-2-butene-1-yl)-1-methyl-2-oxo-2-butene-1-yl)-2-amino-N-(2, 2, 2-triazole-1-yl)-1-methyl-2- 2, 2, 2-trifluoroethyl) acetamide is subjected to a condensation reaction to obtain a crude product of arfola, and the amorphous arfola is obtained through dissolution, decoloration and spray drying. The method is short in synthetic route, mild in reaction condition, simple and convenient to operate, high in conversion rate and suitable for industrial production, the purity can reach 99.5% or above, the single impurity content is smaller than 0.1%, and the finished product crystal form is amorphous.

Description

Technical Field

[0001] This invention belongs to the field of chemistry or medicinal chemistry, and specifically relates to a method for preparing amorphous afolanar. Background Technology

[0002] Afoxolaner is a member of the isoxazoline family. As an isoxazoline insecticide and acaricide, it works by acting on ligand-gated chloride channels, particularly inhibiting channels gated by the neurotransmitter gamma-aminobutyric acid (GABA), blocking the transmission of chloride ions from the presynaptic to the postsynaptic membrane, leading to increased neuronal activity and death in insects. This drug is approved by the US FDA for use in combination with milbemime. As the first oral product for dogs to treat both internal and external parasites, it conveniently meets the needs of pet owners for comprehensive care. Dogs only need to take it once a month to treat and prevent six major categories of common internal and external parasites, including heartworms, roundworms, hookworms, whipworms, fleas, and ticks. The imported drug, Afoxolaner milbemime chewable tablets, is used to treat flea and tick infections in dogs, while also preventing heartworm infections and / or treating gastrointestinal nematode infections. In addition, afolanar can also be marketed as a standalone medication (NexGard, afolanar chewable tablets), and is the first oral deworming medication for dogs in China that kills both ticks and fleas. Its chemical structure is as follows:

[0003]

[0004] The following six synthetic routes for afranal have been reported so far:

[0005] (1) Patent WO2009002809A2 discloses a method for preparing afolanar. The preparation route disclosed in this patent is relatively long. In the final docking step, a carbonyl insertion reaction is used in the presence of a catalyst. The yield is low and it is difficult to purify. Furthermore, fragments 1, 2, and 3 are not produced in large quantities in the industrial production and all need to be customized or synthesized by ourselves.

[0006]

[0007] (2) Patent CN113651765A uses 1-(3-chloro-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroethyl-1-one and 4-acetyl-1-naphthonitrile as starting materials. In the last step, the nitrile group of the intermediate directly undergoes a condensation reaction with 2-amino-N-(2,2,2-trifluoroethyl)acetamide under the action of Zn(OTf)2 / hydroxylamine hydrochloride to achieve the preparation of afolanar.

[0008]

[0009] (3) The synthetic route of patent WO2009126668 begins with the condensation reaction of 4-acetyl-1-naphthoic acid and 2-amino-N-(2,2,2-trifluoroethyl)acetamide to prepare 4-acetyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-1-naphthoic acid; then 4-acetyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-1-naphthoic acid and 1-(3-chloro-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroethyl-1-one are reacted in an alkaline environment. A condensation reaction under certain conditions yielded (Z)-4-(3-(3-chloro-5-(trifluoromethyl)phenyl)-4,4,4-trifluorobut-2-enoyl)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-1-naphthocarboxamide; finally, (Z)-4-(3-(3-chloro-5-(trifluoromethyl)phenyl)-4,4,4-trifluorobut-2-enoyl)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-1-naphthocarboxamide was reacted with hydroxylamine sulfate to prepare afolanar. This route first uses the more expensive 2-amino-N-(2,2,2-trifluoroethyl)acetamide, and then adds the cheaper hydroxylamine sulfate, resulting in low atom economy. The synthetic route is shown below:

[0010]

[0011] Patent CN 116143652 B is similar to WO2009126668, except that 2-amino-N-(2,2,2-trifluoroethyl)acetamide is attached separately. It reports the reaction of compound a with a glycine ester derivative to obtain intermediate (1), the reaction of intermediate (1) with trifluoroethylamine hydrochloride to obtain intermediate d, the reaction with 1-(3-chloro-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroethane-1-one to obtain intermediate e, and finally the reaction with a hydroxylamine derivative to obtain afolanar. The synthetic route is shown below:

[0012]

[0013] (4) Patent CN109879826 B reports the reaction of an ester compound with hydroxylamine hydrochloride to prepare 4-((hydroxyimino)methyl)-1-naphthoate; then, 4-((hydroxyimino)methyl)-1-naphthoate is subjected to NCS and alkaline conditions to produce an N-oxygen compound intermediate, which is further reacted with 1-chloro-3-(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene in a 1,3-dipolar cycloaddition reaction to prepare 4-(5- -(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazolyl-3-yl)-1-naphthyl carboxylate; finally, 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazolyl-3-yl)-1-naphthyl carboxylate and 2-amino-N-(2,2,2-trifluoroethyl)acetamide undergo a condensation reaction to obtain afolanar. The starting material 1-chloro-3-(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene used in this route is expensive and not suitable for industrial production. The synthetic route is shown below:

[0014]

[0015] (5) Patent CN112457267 reports a dipolar cycloaddition reaction between a nitromethane intermediate and a 1-chloro-3-(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene compound. The starting material, a nitromethane compound, is prepared by coupling a bromobenzene derivative with nitromethane in the presence of a palladium catalyst and ligands. Although this route is relatively short, it has the following drawbacks: it involves the use of industrially explosive nitromethane as a reactant; it involves the use of relatively expensive palladium catalysts and ligands; and the yields of each step are low. The synthetic route is shown below:

[0016]

[0017] (6) Patent CN 115433140 B reports the synthesis of afolanar via oxidation-condensation of key intermediate III with 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride and tert-butanol hydrogen peroxide at 30°C. This route is lengthy, has low yield, and uses tert-butanol hydrogen peroxide, which has a pungent odor and is a strong oxidizing and flammable agent. Heating or contact with reducing agents may trigger combustion or explosion, posing a safety risk. The synthetic route is shown below:

[0018]

[0019] In summary, all of the above routes have certain limitations and are not suitable for large-scale production. Therefore, there is a need to develop a method for preparing high-purity afolanar that has a short synthetic route, mild reaction conditions, simple operation, high yield, and is suitable for industrial production. Summary of the Invention

[0020] The purpose of this invention is to provide a method for preparing high-purity afolanar with a short synthetic route, mild reaction conditions, simple operation, high yield, and suitability for industrial production. The specific technical solution is as follows:

[0021] A method for preparing amorphous afolanar, characterized by preparation via the following chemical reaction equation:

[0022]

[0023] The specific preparation steps for the above reaction equation are as follows:

[0024] (1) Cyclic reaction and hydrolysis: In a nonpolar solvent and water, methyl 4-[3-(3-chloro-5-trifluoromethyl-phenyl)-4,4,4-trifluoro-1-oxo-2-buten-1-yl]-naphthalene-1-carboxylate and hydroxylamine hydrochloride, a phase transfer catalyst, and an acid-binding agent are added in a certain proportion. The reaction is carried out under heat, and after the heat is maintained, the mixture is allowed to stand and separate into layers. The organic layer is concentrated under reduced pressure to obtain the cyclized compound.

[0025] (2) Add a certain amount of polar solvent and base to the cyclized compound, heat up, keep the reaction at the temperature, cool down, adjust the acid, filter, and dry to obtain the hydrolysate;

[0026] (3) Condensation: In a solvent, hydrolysate, condensing agent, and 2-amino-N-(2,2,2-trifluoroethyl)acetamide are added in a certain proportion. The temperature is raised and the reaction is kept at the temperature. After the temperature is kept at the temperature, water is added to separate the layers. The organic layer is concentrated under reduced pressure. A crystallization solvent is added to cool down and crystallize. The mixture is filtered and dried to obtain crude afranal.

[0027] (4) Refining: Crude afolanar is dissolved in a refining solvent, activated carbon is added in a certain proportion for decolorization, and the filtrate is dried by a spray dryer to obtain amorphous afolanar.

[0028] In step (1), the nonpolar solvent is at least one of ethyl acetate, isopropyl acetate, butyl acetate, amyl acetate, isoamyl acetate, hexyl acetate, methyl tert-butyl ether, diethyl ether, and toluene, preferably at least one of butyl acetate, amyl acetate, isoamyl acetate, hexyl acetate, and methyl tert-butyl ether, and the amount used is 2-10 times the weight of methyl 4-[3-(3-chloro-5-trifluoromethyl-phenyl)-4,4,4-trifluoro-1-oxo-2-buten-1-yl]-naphthalene-1-carboxylate, preferably 3-6 times; the amount of water used is nonpolar... The amount of polar solvent is 5%-30%; the molar ratio of hydroxylamine hydrochloride to methyl 4-[3-(3-chloro-5-trifluoromethyl-phenyl)-4,4,4-trifluoro-1-oxo-2-buten-1-yl]-naphthalene-1-carboxylate is 1.1-3.5:1, preferably 1.5-2.5:1; the phase transfer catalyst is at least one selected from benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, and tetradecyltrimethylammonium chloride, preferably benzyltriethylammonium chloride. At least one of ethylammonium chloride, tetrabutylammonium bisulfate, and tetrabutylammonium chloride is used in a molar ratio to methyl 4-[3-(3-chloro-5-trifluoromethyl-phenyl)-4,4,4-trifluoro-1-oxo-2-buten-1-yl]-naphthalene-1-carboxylate of 0.01-0.5:1, preferably 0.05-0.3:1; the acid-binding agent is at least one of ammonia, triethylamine, pyridine, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide, preferably at least one of potassium hydroxide and lithium hydroxide. The molar ratio of the amount of methyl 4-[3-(3-chloro-5-trifluoromethyl-phenyl)-4,4,4-trifluoro-1-oxo-2-buten-1-yl]-naphthalene-1-carboxylate used to the total ...

[0029] The polar solvent mentioned in step (2) is at least one of methanol, isopropanol, and acetone, and the amount used is 2-10 times the weight of the cyclized compound; the alkali mentioned is at least one of ammonia, triethylamine, potassium carbonate, sodium carbonate, potassium hydroxide, and lithium hydroxide, and the molar ratio of the amount used to the cyclized compound is 1.5-3:1; the heat preservation reaction temperature is 40-80℃; the heat preservation reaction time is 2-6 hours; the cooling endpoint temperature is 10-30℃; the pH adjustment endpoint is 1-3, and the acid used is at least one of phosphoric acid, sulfuric acid, hydrochloric acid, nitric acid, oxalic acid (oxalic acid), sulfurous acid, phosphoric acid, pyruvic acid, nitrous acid, carbonic acid, citric acid, hydrofluoric acid, malic acid, formic acid, acrylic acid, acetic acid, propionic acid, hydrosulfuric acid, hypochlorous acid, and boric acid; the drying temperature is 50-90℃, and the drying time is 10-16 hours.

[0030] The solvent mentioned in step (3) is at least one of ethyl acetate, isopropyl acetate, butyl acetate, amyl acetate, isoamyl acetate, hexyl acetate, and toluene, preferably at least one of ethyl acetate and isopropyl acetate; the amount used is 2-15 times the weight of the hydrolysate, preferably 6-15 times the weight of the hydrolysate; the condensing agent is dicyclohexylcarbodiimide, bis(2-oxo-3-oxazolyl)phosphine chloride, 1H-benzotriazol-1-yloxotripyrrolidinyl hexafluorophosphate, N,N-carbonyldiimide At least one of the following: azole, diisopropylcarbodiimide, 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(1H-benzotriazolyl-L-1-yl)-1,1,3,3-tetramethylurea tetrafluoroborate, preferably dicyclohexylcarbodiimide, N,N-carbonyldiimidazole, or diisopropyl... The mixture contains at least one of carbodiimide and 1-hydroxybenzotriazole; the molar ratio of the 2-amino-N-(2,2,2-trifluoroethyl)acetamide to the hydrolysate is 0.3-1.5:1, preferably 0.8-1.3:1; the molar ratio of the 2-amino-N-(2,2,2-trifluoroethyl)acetamide to the hydrolysate is 1.05-2:1, preferably 1.05-1.3:1; the reaction temperature is 25-40℃, preferably 30-35℃; the reaction time is 3-7 hours; and the amount of water added is the solvent amount. The concentration temperature under reduced pressure is 30-80℃, and the vacuum degree is -0.06 to -0.1 MPa. The crystallization solvent is at least one of acetonitrile, cyclohexane, n-hexane, n-heptane, toluene, ethanol, isopropanol, water, acetone, and petroleum ether, preferably at least one of ethanol, isopropanol, acetonitrile, and toluene, and the amount used is 6-15 times the weight of the hydrolysate, preferably 10-15 times the weight of the hydrolysate. The drying temperature is 50-90℃, and the drying time is 8-16 hours.

[0031] The refining solvent mentioned in step (4) is at least one of ethyl acetate, isopropyl acetate, methanol, ethanol, isopropanol, and acetone, and the amount used is 3-10 times the weight of crude afranal; the amount of activated carbon used is 1%-10% of the weight of crude afranal; the spray drying conditions are: nitrogen pressure 0.1-0.3MPa, needle setting 280-350, fan frequency 45-60 Hz, air inlet temperature 75-90℃, condensation temperature 15-35℃, and peristalsis speed 35-50 rpm.

[0032] The beneficial effects of this invention are as follows:

[0033] 1) The preparation method of afolanar provided by this invention has a short synthetic route, mild reaction conditions, simple operation, and high yield, with an overall yield of 82%-88%.

[0034] 2) According to the preparation method provided by the present invention, the purity of the prepared product can reach more than 99.5%, and the single impurity is less than 0.1%.

[0035] 3) This invention provides the structure of impurities in intermediate hydrolysates and finished products, enabling better control of afolanar product quality and ensuring medication safety.

[0036] 4) This invention provides a preparation process for amorphous afolanar, which can effectively avoid the protection of the crystal form of afolanar by the original drug, and facilitate earlier formulation development and market launch. Attached Figure Description

[0037] Figure 1 Spectroscopy of Afrana hydrolysate

[0038] Figure 2 The 1H NMR spectrum of Afrana hydrolysate

[0039] Figure 3 Carbon NMR spectrum of Afrana hydrolysate

[0040] Figure 4 Afrana mass spectra

[0041] Figure 5 Afrana's 1H NMR spectrum

[0042] Figure 6 Carbon NMR spectrum of Avrana

[0043] Figure 7 Afrana X-ray diffraction pattern Detailed Implementation

[0044] The present invention will be described in detail below through specific embodiments. These embodiments are used to explain the present invention, but not to limit it.

[0045] Example 1

[0046] (1) Cyclohydration: 48.6 g (0.1 mol) of methyl 4-[3-(3-chloro-5-trifluoromethyl-phenyl)-4,4,4-trifluoro-1-oxo-2-buten-1-yl]-naphthalene-1-carboxylate, 13.9 g (0.2 mol) of hydroxylamine hydrochloride, 350 g of isoamyl acetate, and 10.2 g (0.03 mol) of tetrabutylammonium hydrogen sulfate were added in portions with stirring. After the addition was complete, the mixture was kept at 25-30℃ for 5 hours. The reaction was then allowed to stand and separate into layers. The upper organic layer was concentrated under reduced pressure at 60℃ and a vacuum of -0.09 MPa to obtain 50.2 g of the condensate. The purity was 98.1% as determined by HPLC.

[0047] (2) Hydrolysis: The above condensate (0.1 mol), 320 g of methanol, and 20.2 g (0.25 mol) of ammonia were added to a 500 ml reaction flask. The mixture was heated to 60-65℃ and maintained at this temperature for 6 hours, then cooled by 10-15℃. The pH was adjusted to 2-3 with phosphoric acid. The mixture was filtered and washed with water until neutral. It was dried at 50℃ for 16 hours to obtain 47.4 g of hydrolysate. The combined yield of the cyclization and hydrolysis steps was 94.5%. The HPLC results are as follows:

[0048]

[0049] [MH] - =486.03 (see details) Figure 1 )

[0050] (3) Condensation: 43.9 g (0.09 mol) of hydrolysate and 300 g of isoamyl acetate were added to a 1 L reaction flask. 20.3 g (0.13 mol) of 2-amino-N-(2,2,2-trifluoroethyl)acetamide and 21.1 g (0.13 mol) of N,N-carbazide diimidazole were added under stirring. The mixture was kept at 30 °C for 7 hours. After the reaction was complete, 100 g of water was added and stirred for 20 minutes. The mixture was allowed to stand and separate into layers. The upper organic layer was concentrated under reduced pressure at 60 °C and a vacuum of -0.09 MPa. 180 g of toluene was added, and the mixture was cooled to allow crystals to precipitate. The crystals were filtered, and the filter cake was dried at 50 °C for 16 hours to obtain 52.3 g of crude afolanar, with a yield of 92.9%.

[0051] (4) Refined

[0052] 52.3 g of crude afolanar, 210 g of methanol, and 1.5 g of activated carbon were added to a 1 L reaction flask. The mixture was stirred and dissolved at room temperature, then filtered. The filtrate was pumped into a spray dryer using a peristaltic pump. The spray drying conditions were: nitrogen pressure 0.2 MPa, needle setting 280°C, fan frequency 45 Hz, inlet air temperature 90°C, condensation temperature 15°C, and peristaltic speed 35 rpm. 50.73 g of purified afolanar was obtained. HPLC results are as follows:

[0053]

[0054]

[0055] MS(m / z): [MH] - =624.07 (see details) Figure 4 ) 1 ¹H NMR (CDCl₃) δ: 8.75–8.77 (t, ¹H), 8.16–8.18 (d, ¹H), 7.86 (t, ¹H), 7.81 (d, ¹H), 7.72 (d, ¹H), 7.56–7.60 (m, 2H), 7.52–7.54 (d, ¹H), 7.42–7.45 (m, 2H), 7.35–7.36 (s, ¹H), 4.22–4.27 (m, 3H), 3.98–4.02 (m, ¹H), 3.85–3.90 (m, 3H). (See details) Figure 5 )

[0056] 13 CNMR(CDCl3):25.24,40.32-41.01,43.63,46.70,64.41,76.78-77.20,85.93

[0057] -86.54, 120.15, 120.94, 121.15, 121.90 -121.92, 122.83, 123.00, 124.00, 124.71, 124.84, 125.59, 126.62 -126.67, 126.88 -126.93, 127.06, 127.85, 128.40, 130.41 -130.58, 132.61, 132.83, 133.06, 133.28, 135.82, 136.08, 138.62, 156.19, 169.41 -169.70. (See details) Figure 6 )

[0058] Example 2

[0059] (1) Cyclolysis: 48.6 g (0.1 mol) of methyl 4-[3-(3-chloro-5-trifluoromethyl-phenyl)-4,4,4-trifluoro-1-oxo-2-buten-1-yl]-naphthalene-1-carboxylate, 7.6 g (0.11 mol) of hydroxylamine hydrochloride, 250 g of butyl acetate, and 1.14 g (0.005 mol) of benzyltriethylammonium chloride were added in portions under stirring. After the addition was complete, the mixture was kept at 25-30℃ for 2 hours. After the reaction was complete, the mixture was allowed to stand and separate into layers. The upper organic layer was concentrated under reduced pressure at 60℃ and a vacuum of -0.095 MPa to obtain 46.8 g of the condensate. The purity was 98.0% as determined by HPLC.

[0060] (2) Hydrolysis: The above condensate and 320g of isopropanol, 10.1g (0.18mol) of potassium hydroxide / 25g of water were added to a 500ml reaction flask. The mixture was heated to 40-45℃ and kept at that temperature for 4 hours, then cooled by 10-15℃. The pH was adjusted to 1-2 with 30% hydrochloric acid. The mixture was filtered and rinsed with water until neutral. It was dried at 60℃ for 15 hours to obtain 46.3g of hydrolysate. The combined yield of the cyclization and hydrolysis steps was 94.9%. The HPLC results are as follows:

[0061]

[0062] (3) Condensation: 43.9 g (0.09 mol) of hydrolysate and 600 g of butyl acetate were added to a 1 L reaction flask. 17.2 g (0.11 mol) of 2-amino-N-(2,2,2-trifluoroethyl)acetamide and 30.9 g (0.15 mol) of dicyclohexylcarbodiimide (DCC) were added under stirring. The mixture was kept at 40 °C for 3 hours. After the reaction was complete, 150 g of water was added and stirred for 20 minutes. The mixture was allowed to stand and separate into layers. The upper organic layer was concentrated under reduced pressure at 60 °C and a vacuum of -0.1 MPa. 220 g of isopropanol was added, and the mixture was cooled to allow crystals to precipitate. The crystals were filtered, and the filter cake was dried at 60 °C under forced air for 15 hours to obtain 51.5 g of afolanar, with a yield of 91.5%.

[0063] (4) Refined

[0064] 51.5 g of crude afolanar, 210 g of ethyl acetate, and 2.5 g of activated carbon were added to a 1 L reaction flask. The mixture was stirred and dissolved at room temperature, then filtered. The filtrate was pumped into a spray dryer using a peristaltic pump. The spray drying conditions were: nitrogen pressure 0.2 MPa, needle setting 350°C, fan frequency 60 Hz, inlet air temperature 90°C, condensation temperature 35°C, and peristaltic speed 35 rpm. 49.6 g of purified afolanar was obtained. HPLC results are as follows:

[0065]

[0066] Example 3

[0067] (1) Cyclolysis: 48.6 g (0.1 mol) of methyl 4-[3-(3-chloro-5-trifluoromethyl-phenyl)-4,4,4-trifluoro-1-oxo-2-buten-1-yl]-naphthalene-1-carboxylate, 11.1 g (0.16 mol) of hydroxylamine hydrochloride, 280 g of methyl tert-butyl ether, and 4.04 g (0.01 mol) of trioctylmethylammonium chloride were added in portions with stirring. After the addition was complete, the mixture was kept at 25-30℃ for 2 hours. After the reaction was complete, the mixture was allowed to stand and separate into layers. The upper organic layer was concentrated under reduced pressure at 40℃ and a vacuum of -0.08 MPa to obtain 50.3 g of the condensate. The purity was 98.2% as determined by HPLC.

[0068] (2) Hydrolysis: The above condensate and 460g of methanol, 26.5g (0.25mol) of sodium carbonate, and 100g of water were added to a 500ml reaction flask. The mixture was heated to 75-80℃ and kept at that temperature for 4 hours, then cooled by 10-15℃. The pH was adjusted to 1-2 with formic acid. The mixture was filtered and washed with water until neutral. It was dried at 90℃ for 10 hours to obtain 45.9g of hydrolysate. The combined yield of the cyclization and hydrolysis steps was 94.0%. The HPLC results are as follows:

[0069]

[0070] (3) Condensation: 43.9 g (0.09 mol) of hydrolysate and 550 g of isopropyl acetate were added to a 1 L reaction flask. 25.0 g (0.16 mol) of 2-amino-N-(2,2,2-trifluoroethyl)acetamide and 37.9 g (0.1 mol) of benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate were added under stirring. The mixture was kept at 35 °C for 4 hours. After the reaction was complete, 80 g of water was added and stirred for 20 minutes. The mixture was allowed to stand and separate into layers. The upper organic layer was concentrated under reduced pressure at 40 °C and a vacuum of -0.08 MPa. 260 g of cyclohexane was added, and the mixture was cooled to allow crystals to precipitate. The crystals were filtered, and the filter cake was dried at 90 °C for 10 hours to obtain 52.7 g of afolanar, with a yield of 93.5%.

[0071] (4) Refined

[0072] 52.7 g of crude afolanar, 210 g of ethanol, and 2 g of activated carbon were added to a 1 L reaction flask. The mixture was stirred and dissolved at room temperature, then filtered. The filtrate was pumped into a spray dryer using a peristaltic pump. The spray drying conditions were: nitrogen pressure 0.2 MPa, needle setting 290°, fan frequency 55 Hz, inlet air temperature 85°C, condensation temperature 25°C, and peristaltic speed 35 rpm. 50.9 g of purified afolanar was obtained. HPLC results are as follows:

[0073]

[0074] Example 4

[0075] (1) Cyclolysis: 48.6 g (0.1 mol) of methyl 4-[3-(3-chloro-5-trifluoromethyl-phenyl)-4,4,4-trifluoro-1-oxo-2-buten-1-yl]-naphthalene-1-carboxylate, 20.8 g (0.3 mol) of hydroxylamine hydrochloride, 300 g of hexyl acetate, and 5.56 g (0.02 mol) of tetrabutylammonium chloride were added in portions with stirring. After the addition was complete, the mixture was kept at 40 °C for 1 hour. After the reaction was completed, the mixture was allowed to stand and separate into layers. The upper organic layer was concentrated under reduced pressure at 60 °C and a vacuum of -0.1 MPa to obtain 52.0 g of the condensate. The purity was 98.5% as determined by HPLC.

[0076] (2) Hydrolysis: Add the above condensate and 250g of acetone, 8.4g (0.15mol) of potassium hydroxide / 25g of water to a 500ml reaction flask. Heat to 50-55℃ and maintain the temperature for 3 hours, then cool down by 10-15℃. Adjust the pH to 2-3 with acetic acid. Filter and wash with water until neutral. Dry at 80℃ for 12 hours to obtain 46.0g of hydrolysate.

[0077] The combined yield of cyclization and hydrolysis steps was 94.3%. HPLC results are as follows:

[0078]

[0079] (3) Condensation: 43.9 g (0.09 mol) of hydrolysate and 400 g of hexyl acetate were added to a 1 L reaction flask. While stirring, 31.2 g (0.2 mol) of 2-amino-N-(2,2,2-trifluoroethyl)acetamide, 18.9 g (0.15 mol) of diisopropylcarbodiimide, and 6.8 g (0.05 mol) of 1-hydroxybenzotriazole were added. The mixture was kept at 25 °C for 6 hours. After the reaction was complete, 50 g of water was added and stirred for 20 minutes. The mixture was allowed to stand and separate into layers. The upper organic layer was concentrated under reduced pressure at 60 °C and a vacuum of -0.095 MPa. 300 g of acetonitrile was added, and the mixture was cooled to allow crystals to precipitate. The crystals were filtered, and the filter cake was dried at 80 °C for 12 hours to obtain 52.4 g of afolanar, with a yield of 93.1%.

[0080] (4) Refined

[0081] 52.4 g of crude afolanar, 300 g of isopropanol, and 3.5 g of activated carbon were added to a 1 L reaction flask. The mixture was stirred and dissolved at room temperature, then filtered. The filtrate was pumped into a spray dryer using a peristaltic pump. The spray drying conditions were: nitrogen pressure 0.3 MPa, needle setting 300, fan frequency 50 Hz, inlet air temperature 80℃, condensation temperature 25℃, and peristaltic speed 40 rpm. 50.8 g of purified afolanar was obtained. HPLC results are as follows:

[0082]

[0083] This invention is not limited to the above embodiments. Any simple or equivalent changes or modifications made to the above embodiments based on the technical essence of this invention shall fall within the scope of this invention.

Claims

1. A method for preparing amorphous afolanar, characterized in that, Prepared via the following chemical reaction equation: The specific preparation steps for the above reaction equation are as follows: (1) Cyclic reaction and hydrolysis: In a nonpolar solvent and water, methyl 4-[3-(3-chloro-5-trifluoromethyl-phenyl)-4,4,4-trifluoro-1-oxo-2-buten-1-yl]-naphthalene-1-carboxylate and hydroxylamine hydrochloride, a phase transfer catalyst, and an acid-binding agent are added in a certain proportion. The reaction is carried out under heat, and after the heat is maintained, the mixture is allowed to stand and separate into layers. The organic layer is concentrated under reduced pressure to obtain the cyclized compound. (2) Add a certain amount of polar solvent and base to the cyclized compound, heat up, keep the reaction at the temperature, cool down, adjust the acid, filter, and dry to obtain the hydrolysate; (3) Condensation: In a solvent, hydrolysate, condensing agent, and 2-amino-N-(2,2,2-trifluoroethyl)acetamide are added in a certain proportion. The temperature is raised and the reaction is kept at the temperature. After the temperature is kept at the temperature, water is added to separate the layers. The organic layer is concentrated under reduced pressure. A crystallization solvent is added to cool down and crystallize. The mixture is filtered and the filter cake is dried to obtain crude afrana. (4) Refining: Crude afolanar is dissolved in a refining solvent, activated carbon is added in a certain proportion for decolorization, and the filtrate is dried by a spray dryer to obtain amorphous afolanar.

2. The method for preparing amorphous afolanar according to claim 1, characterized in that: In reaction step (1), the nonpolar solvent is at least one selected from ethyl acetate, isopropyl acetate, butyl acetate, amyl acetate, isoamyl acetate, hexyl acetate, methyl tert-butyl ether, diethyl ether, and toluene, and the amount used is 2-10 times the weight of methyl 4-[3-(3-chloro-5-trifluoromethyl-phenyl)-4,4,4-trifluoro-1-oxo-2-buten-1-yl]-naphthalene-1-carboxylate; the amount of water used is the same as the amount of nonpolar solvent used. 5%-30%; the molar ratio of hydroxylamine hydrochloride to methyl 4-[3-(3-chloro-5-trifluoromethyl-phenyl)-4,4,4-trifluoro-1-oxo-2-buten-1-yl]-naphthalene-1-carboxylate is 1.1-3.5:1; the phase transfer catalyst is benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, tetradecyl... At least one of trimethylammonium chloride, wherein the molar ratio of its content to methyl 4-[3-(3-chloro-5-trifluoromethyl-phenyl)-4,4,4-trifluoro-1-oxo-2-buten-1-yl]-naphthalene-1-carboxylate is 0.01-0.5:1; the acid-binding agent is at least one of ammonia, triethylamine, pyridine, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide, wherein the molar ratio of its content to methyl 4-[ The molar ratio of methyl 3-(3-chloro-5-trifluoromethyl-phenyl)-4,4,4-trifluoro-1-oxo-2-buten-1-yl]-naphthalene-1-carboxylate is 1.5-4:1; the holding temperature of the reaction is 10-50℃; the holding time of the reaction is 0.5-6 hours; the vacuum concentration temperature is 30-80℃, the vacuum degree is -0.06 to -0.1 MPa, and the endpoint of vacuum distillation is no continuous distillate outflow.

3. The method for preparing amorphous afolanar according to claim 2, characterized in that: The nonpolar solvent is preferably at least one of butyl acetate, amyl acetate, isoamyl acetate, hexyl acetate, and methyl tert-butyl ether, and the amount used is preferably 3-6 times the weight of methyl 4-[3-(3-chloro-5-trifluoromethyl-phenyl)-4,4,4-trifluoro-1-oxo-2-buten-1-yl]-naphthalene-1-carboxylate; the molar ratio of hydroxylamine hydrochloride to methyl 4-[3-(3-chloro-5-trifluoromethyl-phenyl)-4,4,4-trifluoro-1-oxo-2-buten-1-yl]-naphthalene-1-carboxylate is preferably 1.5-2.5:1; the phase transfer catalyst is preferably benzyltriethylammonium chloride, tetrabutylammonium hydrogen sulfate, or tetrabutylammonium chloride. The preferred molar ratio of at least one of ammonium chloride to methyl 4-[3-(3-chloro-5-trifluoromethyl-phenyl)-4,4,4-trifluoro-1-oxo-2-buten-1-yl]-naphthalene-1-carboxylate is 0.05-0.3:1; the preferred acid-binding agent is at least one of potassium hydroxide and lithium hydroxide, and the preferred molar ratio of its content to methyl 4-[3-(3-chloro-5-trifluoromethyl-phenyl)-4,4,4-trifluoro-1-oxo-2-buten-1-yl]-naphthalene-1-carboxylate is 1.8-2.5:1; the preferred heat preservation reaction temperature is 10-30℃; and the preferred heat preservation reaction time is 1-4 hours.

4. The method for preparing amorphous afolanar according to claim 1, characterized in that: In reaction step (2), the polar solvent is at least one of methanol, isopropanol, and acetone, and the amount used is 2-10 times the weight of the cyclized compound; the base is at least one of ammonia, triethylamine, potassium carbonate, sodium carbonate, potassium hydroxide, and lithium hydroxide, and the molar ratio of the amount used to the cyclized compound is 1.5-3:1; the heat preservation reaction temperature is 40-80℃; the heat preservation reaction time is 2-6 hours; the cooling endpoint temperature is 10-30℃; the pH adjustment endpoint is 1-3, and the acid used is at least one of phosphoric acid, sulfuric acid, hydrochloric acid, nitric acid, oxalic acid (oxalic acid), sulfurous acid, phosphoric acid, pyruvic acid, nitrous acid, carbonic acid, citric acid, hydrofluoric acid, malic acid, formic acid, acrylic acid, acetic acid, propionic acid, hydrosulfuric acid, hypochlorous acid, and boric acid; the drying temperature is 50-90℃, and the drying time is 10-16 hours.

5. The method for preparing amorphous afolanar according to claim 1, characterized in that: In reaction step (3), the solvent is at least one of ethyl acetate, isopropyl acetate, butyl acetate, amyl acetate, isoamyl acetate, and hexyl acetate, and the amount used is 2-15 times the weight of the hydrolysate; the condensing agent is dicyclohexylcarbodiimide, bis(2-oxo-3-oxazolyl)phosphine chloride, 1H-benzotriazol-1-yloxotripyrrolidinyl hexafluorophosphate, N,N-carbodiimidazole, diisopropylcarbodiimide, 1-hydroxybenzotriazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 2-(7-azabenzotriazol)-N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazol-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(1H-benzotriazol-L-1-yl)-1,1,3,3 At least one of tetramethylurea tetrafluoroborate, the molar ratio of its dosage to the hydrolysate is 0.3-1.5:1; the molar ratio of 2-amino-N-(2,2,2-trifluoroethyl)acetamide to the hydrolysate is 1.05-2:1; the heat preservation reaction temperature is 25-40℃; the heat preservation reaction time is 3-7 hours; the amount of water added is 0.5-2 times the amount of solvent; the vacuum concentration temperature is 30-80℃, and the vacuum degree is -0.06 to -0.1 MPa; the crystallization solvent is at least one of acetonitrile, cyclohexane, n-hexane, n-heptane, toluene, ethanol, isopropanol, water, acetone, and petroleum ether, and the amount used is 6-15 times the weight of the hydrolysate; the drying temperature is 50-90℃, and the drying time is 8-16 hours.

6. The method for preparing amorphous afolanar according to claim 5, characterized in that: The solvent is preferably at least one of ethyl acetate and isopropyl acetate, and the amount used is preferably 6-15 times the weight of the hydrolysate; the condensing agent is preferably at least one of dicyclohexylcarbodiimide, N,N-carbodiimidazole, diisopropylcarbodiimide, and 1-hydroxybenzotriazole, and the molar ratio of the amount used to the amount of the hydrolysate is preferably 0.8-1.3:1; the molar ratio of the amount of 2-amino-N-(2,2,2-trifluoroethyl)acetamide used to the amount of the hydrolysate is preferably 1.05-1.3:1; the heat preservation reaction temperature is preferably 30-35℃; the crystallization solvent is preferably at least one of ethanol, isopropanol, acetonitrile, and toluene, and the amount used is preferably 10-15 times the weight of the hydrolysate.

7. The method for preparing amorphous afolanar according to claim 1, characterized in that: In reaction step (4), the refining solvent is at least one of ethyl acetate, isopropyl acetate, methanol, ethanol, isopropanol, and acetone, and the amount used is 3-10 times the weight of crude afolanar; the amount of activated carbon used is 1%-10% of the weight of crude afolanar; the spray drying conditions are: nitrogen pressure 0.1-0.3 MPa, needle setting 280-350, fan frequency 45-60 Hz, air inlet temperature 75-90℃, condensation temperature 15-35℃, and peristalsis speed 35-50 rpm.

Images