A process for the preparation of eprinomectin

Abstract

This invention discloses a method for preparing ivermectin. Using avermectin oxide as the starting material, ivermectin is obtained through amination, reduction, deprotection, acylation, and purification reactions. This invention employs a novel amination reagent, carrying out the amination reaction under the dehydration effect of a desiccant. The amination, reduction, and deprotection reactions are performed in a one-pot process, which is simple to operate, has a high yield, is environmentally friendly, and is easy to industrialize. 1a The purity can reach over 99.5%, with impurity A less than 0.05%, impurities C+D less than 0.1%, impurity E less than 0.05%, and 8a-oxo-B... 1a Oxidation impurities are less than 0.1%.

Description

Technical Field

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

[0002] Epramycin, also known as acetaminophen, is a macrolide antibiotic developed by Merck in the United States in 1996. It possesses high biological activity and low toxicity (in mammals and aquatic organisms), making it a highly effective, broad-spectrum, and low-residue veterinary antiparasitic drug of the latest generation. It is primarily used to control internal and external parasites in livestock (especially lactating animals), and is particularly effective against most nematodes and arthropods. The mechanism of action of eprammycin involves binding to specific receptors at the synapses of the parasite's neurons or neuromuscular synapses, stimulating the nerve endings to release the neurotransmitter inhibitor gamma-aminobutyric acid (GABA) and opening glutamate-controlled chloride ion channels, ultimately causing paralysis, anorexia, and death in the parasite.

[0003] Due to its extremely high activity against various internal and external parasites in livestock and its extremely low partition coefficient (0.17) in dairy products, ephemeralin has become the first insecticide that can be used for any growth stage of livestock, making it a preferred agent for the prevention and control of various internal and external parasites in livestock. In addition, with the international and domestic livestock markets recognizing the high efficiency and environmentally friendly biological characteristics of ephemeralin, the market demand for ephemeralin is showing a trend of rapid expansion year by year, and it has a good market prospect.

[0004] There are three main routes for the synthesis of ephemeralin:

[0005] One route is glycosylation. First, the second sugar ring of AVMB1 is cleaved in sulfuric acid / methanol. Then, methylation yields methyl oleanrosol and AVMB1 monosaccharide. The methyl oleanrosol is then oxidized by potassium dichromate pyridinium salt, carbonyl amination, and sodium borohydride reduction of the imine to an amino group. The amino nitrogen of the oleanrosol is then protected with an allyloxyformyl group. It is then reacted with propiothiophenol to generate phenylthio-4"-ep-(N-allyloxyformyl)-amino-4"-deoxyoleanrosol. This is then condensed with the C5-OH allyloxyformyl protectant of the AVMB1 monosaccharide and deprotected to obtain aminoavermectin. Finally, it is acetylated.

[0006] The second route (J. Org. Chem., 1994, 59, 7704-7708) reports the following steps: protection of the 5-hydroxyl group in avermectin, oxidation of the 4-hydroxyl group, deprotection of the 5-hydroxyl group, amination of the 4-carbonyl group, reduction of the 4-imino group, and acetylation of the 4-amino group. Zhao Yonghua reported that hexamethyldisilazane (HMDS) was used as the amination agent and zinc chloride as the catalyst for the 4-amino amination, reacting at 50-60°C for 5 hours, achieving an amination yield of 85.3%. Wensey reported that using zinc trifluoroacetate instead of zinc chloride increased the yield to 89.5%, but the content was only 16.7%.

[0007] The third route (WO 2016 / 063058 A1) reports the protection reaction of the 5-hydroxyl group, the oxidation reaction of the 4-hydroxyl group, the amination reaction of the 4-carbonyl group, the reduction reaction of the 4-imino group, the deprotection reaction of the 5-hydroxyl group, and the acetylation reaction of the 4-amino group. The 4-amino group is amination using hexamethyldisilazane or heptamethyldisilazane. The liquid phase content of the amination product obtained by this route is only 73.51%.

[0008] Currently, industrial-scale production mainly adopts the second route. Hexamethyldisilazane protects the sterically hindered tertiary hydroxyl group of avermectin, thus deprotection requires two steps: first, reducing the allyloxyformyl group to a hydroxyl group under sodium borohydride / anhydrous ethanol / catalyst conditions; second, removing the tertiary hydroxyl protecting compound under hydrochloric acid conditions. Using hexamethyldisilazane (HMDS) as an amination agent is problematic due to its high cost, complex reaction, the added tertiary hydroxyl protection and deprotection steps, and the difficulty in handling the resulting hexamethyldisilazane and zinc hydroxide waste.

[0009] Current industrial-scale refining processes often use acetonitrile for recrystallization. However, the residual acetonitrile solvent makes it difficult to meet the quality requirements for injectable pharmaceutical raw materials. CN201510513336 reports a process where the crude product is pretreated with a mixed solvent of ethyl acetate / n-hexane, then dissolved in a mixed solvent of ethanol / acetone / water, seed crystals are added, followed by cooling and crystallization, solid-liquid separation, and finally slurrying with diethyl ether. This refining process is quite cumbersome, the use of mixed solvents is difficult, and diethyl ether has a low boiling and flash point, posing safety hazards during production. Diethyl ether is a medical anesthetic, and long-term exposure can be harmful to humans.

[0010] Given the aforementioned shortcomings in existing methods for preparing ephemeralin, there is an urgent need to develop a green, environmentally friendly method with high yield and ease of industrial production. Summary of the Invention

[0011] The technical problem to be solved by the present invention is to overcome the shortcomings of the prior art and provide a one-pot method for preparing ephemeralin that is simple to operate, has a high yield, is environmentally friendly, and is easy to industrialize.

[0012] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0013] A method for preparing ephemeralin, characterized by preparation via the following chemical reaction equation:

[0014]

[0015] in,

[0016] The specific preparation according to the above reaction equation includes the following steps:

[0017] 1) Amination, reduction, and deprotection

[0018] In an alcohol solvent, an amination agent, a dehydrating agent, and avermectin oxide are added. Under nitrogen protection, the reaction is maintained at a certain temperature for a period of time. Reducing agent A is added to the reaction solution, and the reaction is maintained at a certain temperature for a period of time. Reducing agent B is added to the reaction solution, and the reaction is maintained at a certain temperature for a period of time. Catalyst and reducing agent C are added, and the reaction is maintained at a certain temperature for a period of time. Acid is added dropwise to decompose the excess reducing agent. The mixture is filtered, and isopropyl acetate and water are added to the filtrate. After stirring, the mixture is allowed to stand and separate into layers. The lower water layer is removed to obtain an aminoavermectin isopropyl acetate solution for later use.

[0019] (2) Acylation

[0020] Add an acid-binding agent to an isopropyl acetate solution of aminoavermectin, add acetic anhydride dropwise, keep the reaction at a certain temperature for a period of time after the addition is complete, add water, separate the lower aqueous layer, distill the solvent isopropyl acetate under reduced pressure, add acetonitrile, cool down to crystallize, filter, and wash the filter cake with acetonitrile to obtain crude ivermectin.

[0021] (3) Refined

[0022] In an alcohol solvent, crude ephemeralin, activated carbon, and an antioxidant are added. The mixture is heated and kept warm for a period of time to decolorize. After filtration, purified water is added dropwise to the filtrate. The mixture is then cooled, kept warm, filtered again, and dried under vacuum to obtain refined ephemeralin.

[0023] In reaction step (1), the alcohol solvent is at least one of methanol, ethanol, n-propanol, and isopropanol, and the amount of alcohol solvent used is 2 to 8 times the mass of abamectin oxide; the amination agent is at least one of ammonium carbonate, ammonium chloride, ammonium formate, ammonium acetate, and ammonium propionate, and the molar ratio of the amination agent to abamectin oxide is 10 to 18:1; the dehydrating agent is at least one of montmorillonite desiccant, silica gel desiccant, 3A molecular sieve, 4A molecular sieve, 5A molecular sieve, and attapulgite desiccant, and the amount of dehydrating agent used is 0.2 to 2 times the weight of abamectin oxide; the temperature for the reaction is -5 to 20°C, and the temperature for the reaction is 2 to 6 hours.

[0024] In reaction step (1), the reducing agent A is at least one of sodium borohydride, potassium borohydride, lithium borohydride, and zinc borohydride, and the molar ratio of the reducing agent to abamectin oxide is 0.3 to 0.8:1; the temperature for the reaction is -5 to 20°C and the temperature for the reaction is 0.5 to 2 hours.

[0025] In reaction step (1), reducing agent B is at least one of sodium borohydride, potassium borohydride, lithium borohydride, and zinc borohydride, and the molar ratio of reducing agent B to abamectin oxide is 0.6 to 1.5:1; the reaction temperature is -5 to 20°C, and the holding time is 1 to 3 hours.

[0026] In reaction step (1), the catalyst is at least one of bis(tri-tert-butylphenylphosphine)palladium, bis(tricyclohexylphosphine)palladium chloride, [1,3-bis(diphenylphosphine)propane]palladium dichloride, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, bis(dibenzylacetone)palladium, and tri(dibenzylacetone)palladium, and the amount of catalyst used is 0.1-0.8% of the weight of abamectin oxide; the reducing agent C is at least one of sodium borohydride, potassium borohydride, lithium borohydride, and zinc borohydride, and the molar ratio of reducing agent C to abamectin oxide is 0.6-1.5:1; the reaction temperature is -5-20℃, and the holding time is 0.5-3 hours.

[0027] In reaction step (1), the acid is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid; the acid is added over a period of 1 to 3 hours; the molar ratio of acid to avermectin oxide is 1.2 to 4.5:1; the amount of isopropyl acetate is 6 to 10 times the weight of avermectin oxide; and the amount of water is 3 to 7 times the weight of avermectin oxide.

[0028] In reaction step (2), the acid-binding agent is at least one of triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, 4-dimethylaminopyridine, N,N-diisopropylethylamine, tetramethylethylenediamine, pyridine, N,N-dimethylformamide, N,N-dimethylacetamide, tripropylamine, triethylenediamine, tetrabutylammonium hydroxide, γ-chloropropylmethyldimethoxysilane, and N-methylmorpholine; the molar ratio of the acid-binding agent to abamectin oxide is 0.6–1.2:1; the molar ratio of acetic anhydride to abamectin oxide is 0.95–1.3:1; the acetic anhydride is added dropwise over a period of 0.5–4 hours; the reaction temperature is maintained at 10–40°C for a period of 0.5–3 hours.

[0029] In reaction step (2), the amount of water used is 1 to 3 times the weight of abamectin oxide; the amount of acetonitrile used is 1 to 5 times the weight of abamectin oxide; the cooling temperature is 0 to 30°C; and the crystallization time is 0.5 to 2 hours.

[0030] In reaction step (3), the alcohol solvent is at least one of methanol, ethanol, n-propanol, and isopropanol, and the amount of alcohol solvent used is 1.5 to 5 times the weight of crude ephemeralin; the amount of activated carbon used is 1 to 5% of the weight of crude ephemeralin; the antioxidant is vitamin E acetate, and the amount of antioxidant used is 0.2 to 1.0% of the weight of crude ephemeralin; the heat preservation temperature is 50 to 75°C, and the heat preservation time is 1 to 3 hours.

[0031] In reaction step (3), the amount of purified water added is 1.8 to 5 times the weight of crude ephemeralin; the cooling temperature is 10 to 30°C, the crystallization time is 0.5 to 3 hours; the drying temperature is 55 to 95°C, the vacuum degree is less than -0.06 MPa, and the time is 12 to 24 hours.

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

[0033] 1) This invention employs a novel amination agent, which carries out the amination reaction under the dehydration effect of a desiccant. The amination, reduction, and deprotection reactions are carried out in a one-pot process, which is simple to operate, reduces the generation of side reactions, has a high yield, is environmentally friendly, and is easy to industrialize. In addition, it does not generate large amounts of hexamethyldisiloxane and zinc hydroxide waste, and the desiccant can be reused after high-temperature activation.

[0034] 2) Because the crude ephemeralin prepared by the process of this invention has high purity, the complicated three-step refining process can be reduced to one step, which improves production efficiency, greatly reduces the generation of waste solvent, and lowers production costs.

[0035] 3) Eplagin, B, prepared by the process of this invention. 1a The purity can reach over 99.5%, with impurity A less than 0.05%, impurities C+D less than 0.1%, impurity E less than 0.05%, and 8a-oxo-B... 1a Oxidation impurities are less than 0.1%. Attached Figure Description

[0036] Figure 1 The hydrogen NMR spectrum of ephemeralin

[0037] Figure 2 Carbon NMR spectrum of ephemeralin

[0038] Figure 3 A mass spectrogram of Iprodione

[0039] Figure 4 X-ray diffraction pattern of ephemeralin Detailed Implementation

[0040] 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.

[0041] Example 1

[0042] (1) Amination, reduction, and deprotection

[0043] Add 750g isopropanol, 94.5g (1.5mol) ammonium formate, 50g montmorillonite desiccant, and 95.5g (0.1mol) aminoavermectin oxide to a 2L reaction flask. Under nitrogen protection, adjust the temperature to 10℃ and maintain the reaction for 2 hours. Control the temperature at 5-10℃, add 2.7g (0.05mol) potassium borohydride, and maintain the reaction at 5-10℃ for 2 hours. Add 0.3g of bis(dibenzylacetone)palladium and 4.3g (0.08mol) potassium borohydride, and stir at 5-10℃ for 1 hour. Add 14.7g (0.15mol) sulfuric acid dropwise over 1 hour. Filter the solution and transfer the filtrate to another 3L reaction flask. Add 570g isopropyl acetate and 450g water, stir for 5 minutes, and let stand for 20 minutes. Separate the layers, remove the lower aqueous layer, and obtain the aminoavermectin isopropyl acetate solution for later use. HPLC analysis showed that the purity of avermectin was 89.2%.

[0044] (2) Acylation

[0045] Add 7.2 g (0.06 mol) of 4-dimethylaminopyridine to the aminoavermectin solution from step (1), then add 10.2 g (0.1 mol) of acetic anhydride dropwise over 1 hour. After the addition is complete, maintain the reaction temperature at 10-15℃ for 2 hours. Add 150 g of water, separate the lower aqueous layer, distill off isopropyl acetate under reduced pressure, add 280 g of acetonitrile, cool to crystallize, filter, and wash the filter cake with 30 g of acetonitrile to obtain 68.5 g of crude ephemeralin, with a dry weight loss of 21.5%, yielding 53.8 g of crude ephemeralin. The combined yield of amination, reduction, deprotection, and acylation was 58.9%. HPLC analysis showed the purity of crude ephemeralin to be 97.2%.

[0046] (3) Refined

[0047] 300g of isopropanol, 53.8g of crude ephemeralin (dry weight), 1g of activated charcoal, and 0.4g of vitamin E acetate were added to a 2L reaction flask. The mixture was heated to 60℃ and maintained at this temperature for 1 hour for decolorization. After filtration, 350g of purified water was added dropwise to the filtrate. The mixture was then cooled to 15℃ and maintained at this temperature for 2 hours. After filtration, the filtrate was dried under vacuum (-0.09MPa) at 80℃ for 20 hours to obtain 51.4g of purified ephemeralin, with a yield of 95.5%. The HPLC results of ephemeralin analysis are as follows:

[0048] Table 1. Chemical structures of epromycin and its impurities

[0049]

[0050]

[0051]

[0052] [M-2] = 623.75 (see details) Figure 3 )

[0053] 1 HNMR (DMSO-d6) analysis (see details) Figure 1 ):

[0054]

[0055] Table 2. Eprimectin 1 H-NMR spectroscopy results

[0056]

[0057]

[0058] 13 CNMR (DMSO-d6) analysis (see details) Figure 2 ):

[0059] Table 3. Results of 13C-NMR spectroscopy for ephemeralin

[0060]

[0061]

[0062] Example 2

[0063] (1) Amination, reduction, and deprotection

[0064] Add 500g ethanol, 65g ammonium formate (1.03mol), 40g 5A molecular sieve, and 95.5g aminoavermectin oxide (0.1mol) to a 2L reaction flask. Under nitrogen protection, freeze-dry to 5℃ and react for 3 hours. Controlling the temperature at 5-10℃, add 3g sodium borohydride (0.08mol) and react at 5-10℃ for 2 hours. Add 0.3g bis(tri-tert-butylphenylphosphine)palladium and 4.3g (0.11mol) sodium borohydride, and stir at 5-10℃ for 0.5 hours. Add 15g (0.15mol) 36% hydrochloric acid dropwise over 2 hours. Filter and transfer the filtrate to another 3L reaction flask. Add 765g isopropyl acetate and 450g water, stir for 5 minutes, and let stand for 20 minutes. Separate the layers, remove the lower aqueous layer, and obtain the aminoavermectin isopropyl acetate solution for later use. HPLC analysis showed that the purity of avermectin was 88.9%.

[0065] (2) Acylation

[0066] Add 10.2 g (0.08 mol) of N,N-diisopropylethylamine to the aminoavermectin solution from step (1), and then add 11.7 g (0.115 mol) of acetic anhydride dropwise over 2 hours. After the addition is complete, maintain the reaction temperature at 20-25℃ for 1 hour. Add 200 g of water, separate the lower aqueous layer, distill the solvent isopropyl acetate under reduced pressure, add 280 g of acetonitrile, cool to crystallize, filter, and wash the filter cake with 30 g of acetonitrile to obtain 66.9 g of crude ephemeralin, with a dry weight loss of 20.3%, yielding 53.3 g of crude ephemeralin. The combined yield of amination, reduction, deprotection, and acylation was 58.3%. HPLC analysis showed that the purity of the crude ephemeralin was 97.5%.

[0067] (3) Refined

[0068] 210 g of methanol, 53.3 g of crude ephemeralin (dry weight), 3 g of activated carbon, and 0.3 g of vitamin E acetate were added to a 1 L reaction flask. The mixture was heated to 45 °C and maintained at this temperature for 1 hour for decolorization. The mixture was then filtered, and 210 g of purified water was added dropwise to the filtrate. The mixture was cooled to 10 °C and maintained at this temperature for 2 hours. The mixture was then filtered again and dried under vacuum (-0.09 MPa) at 70 °C for 24 hours to obtain 51.1 g of purified ephemeralin, with a yield of 95.8%. HPLC analysis of ephemeralin results is as follows:

[0069] Table 4. Chemical Structures of Iprofen and Impurities

[0070]

[0071]

[0072] Example 3

[0073] (1) Amination, reduction, and deprotection

[0074] Add 500g ethanol, 105.7g (1.1mol) ammonium carbonate, 30g silica gel desiccant, and 95.5g (0.1mol) aminoavermectin oxide to a 2L reaction flask. Under nitrogen protection, freeze-dry to 5℃ and react for 3 hours. Controlling the temperature at 5-10℃, add 3g (0.08mol) sodium borohydride and react at 5-10℃ for 2 hours. Add 0.1g of bis(triphenylphosphine)palladium dichloride and 4.3g (0.11mol) sodium borohydride, and stir at 5-10℃ for 0.5 hours. Add 15g (0.12mol) 30% hydrochloric acid dropwise over 3 hours. Filter the solution and transfer the filtrate to another 3L reaction flask. Add 765g isopropyl acetate and 450g water, stir for 5 minutes, and let stand for 20 minutes. Separate the layers, remove the lower aqueous layer, and obtain the aminoavermectin isopropyl acetate solution for later use. HPLC analysis showed that the purity of avermectin was 89.4%.

[0075] (2) Acylation

[0076] Add 13.8 g (0.12 mol) of tetramethylethylenediamine to the aminoavermectin solution in step (1), then add 10.7 g (0.105 mol) of acetic anhydride dropwise over 0.5 hours. After the addition is complete, maintain the reaction temperature at 25-30℃ for 1 hour, add 250 g of water, separate the lower aqueous layer, distill the solvent isopropyl acetate under reduced pressure, add 230 g of acetonitrile, cool to crystallize, filter, and wash the filter cake with 30 g of acetonitrile to obtain 67.1 g of crude ephemeralin, with a dry weight loss of 18.6%, yielding 54.6 g of crude ephemeralin. The combined yield of amination, reduction, deprotection, and acylation was 59.7%. HPLC analysis showed that the purity of crude ephemeralin was 97.8%.

[0077] (3) Refined

[0078] 210 g of ethanol, 54.6 g of crude ephemeralin (dry weight), 2.5 g of activated charcoal, and 0.5 g of vitamin E acetate were added to a 1 L reaction flask. The mixture was heated to 55 °C and maintained at this temperature for 1 hour for decolorization. The mixture was then filtered, and 210 g of purified water was added dropwise to the filtrate. The mixture was cooled to 10 °C and maintained at this temperature for 2 hours. The mixture was then filtered again and dried under vacuum (-0.09 MPa) at 70 °C for 24 hours to obtain 52.5 g of purified ephemeralin, with a yield of 96.2%. HPLC analysis of ephemeralin results is as follows:

[0079] Table 5. Chemical structures of epromycin and its impurities

[0080]

[0081]

[0082]

[0083] Example 4

[0084] The 5A molecular sieve recovered in Example 2 was placed in a muffle furnace and dried at 180-250°C for 10 hours. After cooling, it was sealed and packaged for use in 5A molecular sieve reuse tests.

[0085] (1) Amination, reduction, and deprotection

[0086] Add 500g ethanol, 75.7g ammonium formate (1.2mol), 30g of recovered 5A molecular sieve, and 95.5g aminoavermectin oxide (0.1mol) to a 2L reaction flask. Under nitrogen protection, freeze-dry to 5℃ and react for 3 hours. Controlling the temperature at 5-10℃, add 3.3g lithium borohydride (0.15mol) and react at 5-10℃ for 2 hours. Add 0.2g tetra(triphenylphosphine)palladium and 2.4g (0.11mol) lithium borohydride, and stir at 5-10℃ for 0.5 hours. Add 14.7g (0.15mol) phosphoric acid dropwise over 1.5 hours. Filter and transfer the filtrate to another 3L reaction flask. Add 600g isopropyl acetate and 400g water, stir for 5 minutes, and let stand for 20 minutes. Separate the layers, remove the lower aqueous layer, and obtain the aminoavermectin isopropyl acetate solution for later use. HPLC analysis showed that the purity of avermectin was 88.3%.

[0087] (2) Acylation

[0088] Add 10.2 g (0.1 mol) of triethylamine to the aminoavermectin solution from step (1), then add 12.3 g (0.12 mol) of acetic anhydride dropwise over 3 hours. After the addition is complete, maintain the reaction temperature at 20-25℃ for 1 hour. Add 180 g of water, separate the lower aqueous layer, distill off the isopropyl acetate solvent under reduced pressure, add 280 g of acetonitrile, cool to crystallize, filter, and wash the filter cake with 30 g of acetonitrile to obtain 67.4 g of crude ephemeralin, with a dry weight loss of 19.6%, yielding 54.2 g of crude ephemeralin. The combined yield of amination, reduction, deprotection, and acylation was 59.3%. HPLC analysis showed the purity of crude ephemeralin to be 97.7%.

[0089] (3) Refined

[0090] 280g of methanol, 54.2g of crude ephemeralin (dry weight), 2g of activated carbon, and 0.4g of vitamin E acetate were added to a 1L reaction flask. The mixture was heated to 50℃ and maintained at this temperature for 1 hour for decolorization. The mixture was then filtered, and 280g of purified water was added dropwise to the filtrate. The mixture was cooled to 10℃ and maintained at this temperature for 2 hours. After filtration, the filtrate was dried under vacuum (-0.09MPa) at 85℃ for 18 hours to obtain 52.4g of purified ephemeralin, with a yield of 96.8%. HPLC analysis of ephemeralin results is as follows:

[0091] Table 6. Chemical structures of epromycin and its impurities

[0092]

[0093]

[0094] 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 ephemeralin, characterized in that, Prepared via the following chemical reaction equation: in, The specific preparation according to the above reaction equation includes the following steps: (1) Amination, reduction, and deprotection In an alcohol solvent, an amination agent, a dehydrating agent, and avermectin oxide are added. Under nitrogen protection, the reaction is maintained at a certain temperature for a period of time. Reducing agent A is added to the reaction solution, and the reaction is maintained at a certain temperature for a period of time. Reducing agent B is added to the reaction solution, and the reaction is maintained at a certain temperature for a period of time. Catalyst and reducing agent C are added, and the reaction is maintained at a certain temperature for a period of time. Acid is added dropwise to decompose the excess reducing agent. The mixture is filtered, and isopropyl acetate and water are added to the filtrate. After stirring, the mixture is allowed to stand and separate into layers. The lower water layer is removed to obtain an aminoavermectin isopropyl acetate solution for later use. (2) Acylation Add an acid-binding agent to an isopropyl acetate solution of aminoavermectin, add acetic anhydride dropwise, keep the reaction at a certain temperature for a period of time after the addition is complete, add water, separate the lower aqueous layer, distill the solvent isopropyl acetate under reduced pressure, add acetonitrile, cool down to crystallize, filter, and wash the filter cake with acetonitrile to obtain crude ivermectin. (3) Refined In an alcohol solvent, crude ephemeralin, activated carbon, and antioxidants are added. The mixture is heated and kept warm for a period of time to decolorize. The mixture is then filtered, purified water is added dropwise to the filtrate, the mixture is cooled, kept warm, filtered again, and dried under vacuum to obtain refined ephemeralin. In reaction step (1): The alcohol solvent is at least one selected from methanol, ethanol, n-propanol, and isopropanol. The amination agent is at least one of ammonium carbonate, ammonium chloride, ammonium formate, ammonium acetate, and ammonium propionate; the dehydrating agent is at least one of montmorillonite desiccant, silica gel desiccant, 3A molecular sieve, 4A molecular sieve, 5A molecular sieve, and attapulgite desiccant. The reducing agent A is at least one of sodium borohydride, potassium borohydride, lithium borohydride, and zinc borohydride; The reducing agent B is at least one of sodium borohydride, potassium borohydride, lithium borohydride, and zinc borohydride; The reducing agent C is at least one of sodium borohydride, potassium borohydride, lithium borohydride, and zinc borohydride; The catalyst is at least one of bis(tri-tert-butylphenylphosphine)palladium, bis(tricyclohexylphosphine)palladium chloride, [1,3-bis(diphenylphosphine)propane]palladium dichloride, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, bis(dibenzylacetone)palladium, and tri(dibenzylacetone)palladium. The acid mentioned is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid; In reaction step (2): The acid-binding agent is at least one of the following: triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, 4-dimethylaminopyridine, N,N-diisopropylethylamine, tetramethylethylenediamine, pyridine, N,N-dimethylformamide, N,N-dimethylacetamide, tripropylamine, triethylenediamine, tetrabutylammonium hydroxide, γ-chloropropylmethyldimethoxysilane, and N-methylmorpholine. In reaction step (3): The alcohol solvent is at least one selected from methanol, ethanol, n-propanol, and isopropanol; The antioxidant mentioned is vitamin E acetate.

2. The method for preparing ephemeralin according to claim 1, characterized in that: In reaction step (1), the amount of alcohol solvent used is 2 to 8 times the mass of abamectin oxide; the molar ratio of the amination agent to abamectin oxide is 10 to 18:1; the amount of dehydrating agent used is 0.2 to 2 times the weight of abamectin oxide; the heat preservation reaction is at -5 to 20°C and the heat preservation time is 2 to 6 hours.

3. The method for preparing ephemeralin according to claim 1, characterized in that: In reaction step (1), the molar ratio of reducing agent A to abamectin oxide is 0.3 to 0.8:1; the heat preservation reaction is at -5 to 20°C and the heat preservation time is 0.5 to 2 hours.

4. The method for preparing ephemeralin according to claim 1, characterized in that: In reaction step (1), the molar ratio of reducing agent B to abamectin oxide is 0.6 to 1.5:1; the heat preservation reaction temperature is -5 to 20°C, and the heat preservation time is 1 to 3 hours.

5. The method for preparing ephemeralin according to claim 1, characterized in that: In reaction step (1), the amount of catalyst used is 0.1 to 0.8% of the weight of abamectin oxide; the molar ratio of reducing agent C to abamectin oxide is 0.6 to 1.5:1; the heat preservation reaction temperature is -5 to 20°C, and the heat preservation time is 0.5 to 3 hours.

6. The method for preparing ephemeralin according to claim 1, characterized in that: In reaction step (1), the acid is added over a period of 1 to 3 hours; the molar ratio of acid to avermectin oxide is 1.2 to 4.5:1; the amount of isopropyl acetate used is 6 to 10 times the weight of avermectin oxide; and the amount of water used is 3 to 7 times the weight of avermectin oxide.

7. The method for preparing ephemeralin according to claim 1, characterized in that: In reaction step (2), the molar ratio of the acid-binding agent to abamectin oxide is 0.6 to 1.2:1; the molar ratio of the acetic anhydride to abamectin oxide is 0.95 to 1.3:1; the acetic anhydride is added over a period of 0.5 to 4 hours; the reaction temperature is 10 to 40°C and the holding time is 0.5 to 3 hours.

8. The method for preparing ephemeralin according to claim 1, characterized in that: In reaction step (2), the amount of water used is 1 to 3 times the weight of abamectin oxide; the amount of acetonitrile used is 1 to 5 times the weight of abamectin oxide; the cooling temperature is 0 to 30°C; and the crystallization time is 0.5 to 2 hours.

9. The method for preparing ephemeralin according to claim 1, characterized in that: In reaction step (3), the amount of alcohol solvent used is 1.5 to 5 times the weight of crude ephemeralin; the amount of activated carbon used is 1 to 5% of the weight of crude ephemeralin; the amount of antioxidant used is 0.2 to 1.0% of the weight of crude ephemeralin; the heat preservation temperature is 50 to 75°C, and the heat preservation time is 1 to 3 hours.

10. The method for preparing ephemeralin according to claim 1, characterized in that: In reaction step (3), the amount of purified water added is 1.8 to 5 times the weight of crude ephemeralin; the cooling temperature is 10 to 30°C, and the crystallization time is 0.5 to 3 hours; the drying temperature is 55 to 95°C, the vacuum degree is less than -0.06 MPa, and the time is 12 to 24 hours.

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