A kind of synthetic method of emamectin benzoate

Abstract

The present application relates to the technical field of pharmaceutical intermediate synthesis, and specifically discloses a method for synthesizing emamectin benzoate. A method for synthesizing emamectin benzoate comprises the following steps: 1) protection reaction: performing a protection reaction on avermectin and a hydroxyl protective agent to obtain a protected product solution; 2) oxidation reaction: adding an oxidizing agent to the protected product solution to perform an oxidation reaction to obtain an oxidized product solution; 3) amination reaction: adding glacial acetic acid and methylamine methanol to the oxidized product solution to react to obtain an amination product solution; 4) reduction reaction: adding methanol to the amination product solution, adding sodium borohydride to react to obtain a reduction product solution; 5) deprotection reaction: adding methanol and a catalyst to the reduction product solution to perform a deprotection reaction to obtain a deprotected product solution; 6) salt formation: adding benzoic acid to the deprotected product solution to obtain emamectin benzoate. The method for synthesizing emamectin benzoate of the present application has the advantages of low cost, high efficiency and high product purity.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical intermediate synthesis, and more specifically, to a method for synthesizing emamectin benzoate. Background Art

[0002] Emamectin benzoate (abbreviated as emamectin benzoate) is a derivative synthesized from avermectin through a series of reactions. It has relevant biological characteristics such as high efficiency, low toxicity and pollution-free. Compared with avermectin, its insecticidal activity is increased by 3 orders of magnitude. It has both stomach poison and contact killing effects, and does not harm beneficial insects and humans and animals in the process of pest control. Therefore, it is widely used in the agricultural field as an excellent antibiotic insecticide.

[0003] In the synthesis route of emamectin benzoate, avermectin is used as the starting material. Among the three hydroxyl groups in its molecular structure, the C5 hydroxyl group belongs to the pharmacophore. In order to modify avermectin, it needs to be protected. Then the C4" hydroxyl group is oxidized, aminated and reduced, followed by deprotection and salt formation of the C5 hydroxyl group, and finally the emamectin benzoate product is obtained.

[0004] Therefore, in the whole synthesis process, the oxidation reaction of the C4" hydroxyl group and the deprotection reaction of the C5 position are key. On the one hand, the oxidation reaction of the C4" hydroxyl group has a long reaction time and low efficiency. On the other hand, the C5 position deprotection reaction requires the use of a homogeneous catalyst tetrakis(triphenylphosphine)palladium as a catalyst and sodium borohydride as an allyl scavenger. The loss of the catalyst during the deprotection process and the residue of heavy metals all lead to high production costs, many by-products, and low synthesis efficiency.

[0005] For example, a Chinese patent application with application publication number CN117263997A discloses a one-pot method for synthesizing emamectin benzoate, using avermectin B2a as the initial raw material, adding tetrakis(triphenylphosphine)palladium as a catalyst, and adding dilute hydrochloric acid and sodium borohydride to react to obtain emamectin benzoate B2. Another example is a Chinese patent application with application publication number CN115109103A, which discloses a method for synthesizing emamectin benzoate, by using triethylenediamine instead of tetramethylethylenediamine in the 5-hydroxyl protection step and the 4"-hydroxyl oxidation step, and using a new geminal dichloro activator 3,3-dichloro-1,2-di(1-methylcyclopropyl)cyclopropene in the 4"-hydroxyl oxidation step, so that the production conditions of emamectin benzoate are milder.

[0006] However, the reaction temperature of the above method must be controlled under a relatively low temperature condition, and a noble metal catalyst is used, so the reaction efficiency, product purity and production cost are still relatively high. Therefore, how to control the synthesis cost and synthesis efficiency of emamectin benzoate is a problem that the technicians need to solve urgently. Summary of the invention

[0007] In order to further improve the production efficiency and product purity of emamectin benzoate and reduce production costs, the present application provides a method for synthesizing emamectin benzoate.

[0008] The present application provides a method for synthesizing emamectin benzoate, which adopts the following technical scheme:

[0009] A method for synthesizing emamectin benzoate comprises the following steps:

[0010] 1) Protection reaction: A protection reaction is carried out between avermectin and a hydroxyl protective agent to obtain a protection product solution;

[0011] 2) Oxidation reaction: adding dimethyl sulfoxide to the protected product solution, and then adding an oxidizing agent to carry out an oxidation reaction to obtain an oxidized product solution;

[0012] 3) Amination reaction: adding glacial acetic acid and methylamine methanol to the oxidation product solution, and keeping the temperature to react to obtain the amination product solution;

[0013] 4) Reduction reaction: methanol is added to the amination product solution, and sodium borohydride is slowly added to react to obtain a reduction product solution;

[0014] 5) Deprotection reaction: adding methanol and a catalyst to the reduction product solution to carry out a deprotection reaction to obtain a deprotection product solution;

[0015] 6) Salt formation: Add benzoic acid to the deprotected product solution, desolventize and dry to obtain emamectin benzoate.

[0016] Preferably, in step 5), the method for preparing the catalyst comprises the following steps:

[0017] a) dissolving diphenylphosphine in anhydrous THF to prepare a diphenylphosphine solution, and then adding n-butyllithium dropwise to the diphenylphosphine solution, maintaining the reaction temperature below -70°C, to prepare a lithium diphenylphosphine solution;

[0018] b) dispersing the bromine-functionalized PS-PEG resin in anhydrous THF to prepare a suspension, then dropping a lithium diphenylphosphine solution into the suspension, stirring the suspension for reaction, adding a quencher to terminate the reaction, filtering and washing the suspension, and then refluxing the suspension in an ethanol / toluene solution, filtering and drying the suspension to obtain a carrier;

[0019] c) The carrier and allylpalladium chloride dimer are dissolved in THF, mixed and stirred, filtered, washed and dried to obtain a catalyst.

[0020] Preferably, in a), the molar ratio of diphenylphosphine to n-butyllithium is (1.05-1.1): 1. In some embodiments, the molar ratio of diphenylphosphine to n-butyllithium is 1.05: 1 or 1.1: 1. In a more preferred embodiment, the molar ratio of diphenylphosphine to n-butyllithium is 1.09: 1.

[0021] Preferably, in c), the mass ratio of the support to the allyl palladium chloride dimer is 1:(9-12). In some embodiments, the mass ratio of the support to the allyl palladium chloride dimer may be 1:9, 1:9.5, 1:10.5, 1:11, 1:11.5, 1:12. In a more preferred embodiment, the mass ratio of the support to the allyl palladium chloride dimer is 1:10.

[0022] Preferably, the amount of the catalyst is 1%-1.5% of the quality of Avermectin. In some embodiments, the amount of the catalyst is 1.2% or 1.5% of the quality of Avermectin. In a more preferred embodiment, the amount of the catalyst is 1% of the quality of Avermectin.

[0023] Preferably, the step 1) further includes at least one of the following technical features:

[0024] 11) The reaction is carried out in a solvent, and the solvent is a halogenated hydrocarbon solvent;

[0025] 12) The reaction temperature is kept below -30°C;

[0026] 13) The hydroxyl protecting agent is at least one of allyl chloroformate, ethyl chloroformate, trimethylsilyl chloride, and tert-butyldimethylsilyl chloride.

[0027] Preferably, the halogenated hydrocarbon solvent is one of dichloromethane, chloroform and dichloroethane.

[0028] Preferably, in step 2), the method for preparing the oxidizing agent comprises the following steps:

[0029] S1: dissolving the hydroxylated polystyrene resin in dichloromethane, then adding 3-methyl-3-hydroxymethyloxazolidine and stirring for 30 minutes, then dropping 3-methyl-3-hydroxy-methyloxypropane, stirring for reaction, adding methanol to quench the reaction, finally filtering the reaction mixture, washing with saturated sodium carbonate solution, water, methanol and dichloromethane, and vacuum drying to obtain the modified hydroxylated polystyrene resin;

[0030] S2: Add Escherichia coli to the modified hydroxylated polystyrene resin solution and mix well, then apply it on a glass substrate by a scraper method, dry it naturally, and then heat treat and crush it to obtain a porous hydroxylated polystyrene resin;

[0031] S3: Disperse the porous hydroxylated polystyrene resin into the tetramethylethylenediamine solution, mix evenly and place for a period of time, then dry to obtain the porous dendritic solid carrier encapsulating the tetramethylethylenediamine acid binding agent, then immerse it in the copper acetate solution, filter and dry to obtain the oxidizing agent.

[0032] Preferably, in step S3, the mass ratio of the porous hydroxylated polystyrene resin to tetramethylethylenediamine is 1:(4-6). In some embodiments, the mass ratio of the porous hydroxylated polystyrene resin to tetramethylethylenediamine is 1:4 or 1:6. In a more preferred embodiment, the mass ratio of the porous hydroxylated polystyrene resin to tetramethylethylenediamine is 1:5.

[0033] Preferably, in step S2, the heat treatment is performed at 100°C, 150°C, 200°C, and 350°C for half an hour each.

[0034] In summary, this application has the following beneficial effects:

[0035] 1. This application uses avermectin (B1a or B1b) as the starting material, and the catalyst used for the deprotection of the C5 hydroxyl group is a catalyst that loads the palladium active component onto a bromine-functionalized PS-PEG resin compared to the traditional tetrakis(triphenylphosphine)palladium homogeneous catalyst. It not only has high catalytic activity, few side reaction products, and high product purity, but also can be recycled after the reaction is completed, thereby reducing production costs. At the same time, it also reduces the palladium residue in the emamectin benzoate product, which is more environmentally friendly and green.

[0036] 2. In the oxidation reaction, the traditional oxidant phenyl dichloride phosphate is expensive, easily oxidized and requires a reaction at a lower temperature. In order to allow the oxidation reaction stage to be carried out at room temperature, low energy consumption is achieved while reducing costs and increasing yields, while reducing the amount of solvent used, which is conducive to subsequent purification. The oxidizing agent prepared in this application is a porous dendritic copper acetate / tetramethylethylenediamine solid carrier. This design combines an efficient oxidant (copper acetate) and an acid binding agent (tetramethylethylenediamine) to promote the oxidation reaction while neutralizing the byproduct hydrochloric acid in the protection reaction. Here, copper acetate is used as an oxidant, and the divalent copper ions in copper acetate may be reduced to a monovalent copper state to form cuprous compounds, which can then be oxidized back to divalent copper ions again, thereby achieving recycling. In addition, porosity is achieved by adding a microbial template, and the porous structure increases the contact area, effectively adsorbs excess water, and creates a drier reaction environment. Dry conditions are conducive to improving the selectivity, yield and purity of the oxidation reaction, because water may react with copper acetate to form inactive products, reducing its oxidation ability. In addition, the porous structure can accommodate more active ingredients, thereby increasing the loading capacity and making the reaction more economical and efficient.

[0037] 3. In order to reduce production costs and effectively reduce by-products, the present application forms a carrier with high-density hydroxyl sites by grafting linear polyoxyl alcohol onto hydroxylated polystyrene resin, which not only increases the reaction sites, but also increases the loading capacity, which means that less carrier material can be used at the same reaction scale, thereby reducing costs. The porosity of this carrier increases the surface area, which helps the oxidant to contact the reactant more fully and promotes the oxidation reaction. At the same time, the carrier and by-products can be easily separated by filtration, which simplifies the post-processing process of the product, reduces the cost of by-product treatment, and improves the purity of the product. In addition, since the carrier can be reused, further cost savings are achieved.

[0038] 4. In order to improve the reaction medium and reduce the addition of solvent, the porous dendritic resin material prepared here has a certain hydrophilicity. The hydrophilicity of this material improves the solubility and diffusivity of the reactants, thereby improving the reaction rate and efficiency. During the oxidation reaction stage, there is no need to continue to add additional organic solvents (such as dichloromethane, that is, the amount of the original organic solvent can also be appropriately reduced), which reduces the use and treatment of solvents, which is both environmentally friendly and economical. In addition, the reaction system with a low amount of solvent reduces the steps of solvent recovery and treatment, simplifies the process flow, and improves the overall production efficiency. In this way, by using a porous dendritic resin material as a solid phase carrier, combined with the loading of an oxidant and an acid-binding agent, precise control of the oxidation reaction can be achieved, the yield can be improved, the cost can be reduced, and the post-processing process can be simplified. The porosity and hydrophilicity of this material, as well as its high density of reaction sites, provide an ideal environment for the reaction medium, promote the reaction, and reduce the demand for organic solvents, meeting the requirements of green chemistry. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 It is the high performance liquid chromatogram of the deprotected product in Example 1 of the present application.

[0040] Figure 2 It is the high performance liquid chromatogram of the deprotected product in Example 2 of the present application.

[0041] Figure 3 It is the high performance liquid chromatogram of the deprotected product in Example 3 of the present application.

[0042] Figure 4 It is the high performance liquid chromatogram of the deprotected product in Example 4 of the present application.

[0043] Figure 5 It is the high performance liquid chromatogram of the deprotected product in Example 5 of the present application.

[0044] Figure 6 It is the high performance liquid chromatogram of emamectin benzoate in Example 1 of the present application.

[0045] Figure 7 It is the high performance liquid chromatogram of emamectin benzoate in Example 2 of the present application.

[0046] Figure 8 It is the high performance liquid chromatogram of emamectin benzoate in Example 3 of the present application.

[0047] Fig. 9 It is the high performance liquid chromatogram of emamectin benzoate in Example 4 of the present application.

[0048] Fig.10 It is the high performance liquid chromatogram of emamectin benzoate in Example 5 of the present application.

[0049] Fig.11 It is the synthesis route of emamectin benzoate in the examples of the present application. DETAILED DESCRIPTION

[0050] The present application is further described in detail below with reference to the embodiments.

[0051] Unless otherwise specified, the raw materials used in the examples and comparative examples of the present application are all commercially available.

[0052] The synthetic route of the emamectin benzoate of the present application is detailed in Fig.11 .

[0053] The avermectin of this embodiment consists of avermectin B1a and avermectin B1b, with avermectin B1a accounting for 95wt% and avermectin B1b accounting for 5wt%.

[0054] Example 1

[0055] The synthetic method of emamectin benzoate of the present embodiment comprises the following steps:

[0056] 1) Protection reaction: dissolve avermectin (30 g) in dichloroethane (70 g), add to a three-necked flask that has been dried, put into a -40°C cold trap to cool, add ethyl chloroformate (4 g) when the temperature drops below -30°C, add tetramethylethylenediamine (2.5 g) and dichloromethane (2.5 g) into a constant pressure dropping funnel, and drip into the three-necked flask when the temperature drops below -35°C, keep the dropping temperature below -30°C for protection reaction, and obtain a protection product liquid;

[0057] 2) Oxidation reaction: add dimethyl sulfoxide (4 g) and tetramethylethylenediamine (4.5 g) to the protected product solution, add phenyl dichlorophosphate (7 g) and dichloromethane (7 g) into the constant pressure dropping funnel, and start dropping when the temperature rises to -15°C, keep the dropping temperature below -10°C, and keep the temperature for 180 minutes after the dropping to carry out oxidation reaction to obtain the oxidation product solution;

[0058] 3) Amination reaction: Add glacial acetic acid (2.5 g) and 40% methylamine methanol (10 g) to the oxidation product solution, heat to 8°C and keep warm for 180 min to obtain an amination product solution;

[0059] 4) Reduction reaction: add methanol (30 g) to the amination product solution, cool to -15°C, slowly add sodium borohydride (1 g), and keep the temperature for 60 min to obtain the reduction product solution;

[0060] 5) Deprotection reaction: add methanol (30 g) and tetrakis(triphenylphosphine)palladium (500 mg) to the reduction product solution, cool to -15°C, slowly add sodium borohydride (2 g), and keep warm for 60 min to obtain a deprotection product solution;

[0061] 6) Salt formation: Add benzoic acid (3.5 g) to the deprotected product solution, desolventize and dry to obtain emamectin benzoate.

[0062] Example 2

[0063] The synthetic method of emamectin benzoate of the present embodiment comprises the following steps:

[0064] 1) Protection reaction: Avermectin (30 g) was dissolved in dichloromethane (70 g), added to a three-necked flask that had been dried, placed in a -40°C cold trap to cool, and when the temperature dropped to below -30°C, allyl chloroformate (4 g) was added, and tetramethylethylenediamine (2.5 g) and dichloromethane (2.5 g) were added to a constant pressure dropping funnel. When the temperature dropped to below -35°C, the mixture was dropped into the three-necked flask, and the dropping temperature was kept below -30°C for protection reaction to obtain a protection product liquid;

[0065] 2) Oxidation reaction: add dimethyl sulfoxide (4 g) and tetramethylethylenediamine (4.5 g) to the protected product solution, add phenyl dichlorophosphate (7 g) and dichloromethane (7 g) into the constant pressure dropping funnel, and start dropping when the temperature rises to -15°C, keep the dropping temperature below -10°C, and keep the temperature for 180 minutes after the dropping to carry out oxidation reaction to obtain the oxidation product solution;

[0066] 3) Amination reaction: Add glacial acetic acid (2.5 g) and 40% methylamine methanol (10 g) to the oxidation product solution, heat to 8°C and keep warm for 180 min to obtain an amination product solution;

[0067] 4) Reduction reaction: add methanol (30 g) to the amination product solution, cool to -15°C, slowly add sodium borohydride (1 g), and keep the temperature for 60 min to obtain the reduction product solution;

[0068] 5) Deprotection reaction: add methanol (30 g) and catalyst (300 mg) to the reduction product solution, add diethylamine (6 g) dropwise at room temperature, keep warm for 120 min after the addition is completed, take samples for testing, and obtain the deprotection product solution after deprotection without residue. Filter the catalyst and apply it to the next batch;

[0069] 6) Salt formation: Add benzoic acid (3.5 g) to the deprotected product solution, desolventize and dry to obtain emamectin benzoate.

[0070] The preparation method of the catalyst of this embodiment comprises the following steps:

[0071] a) Dissolve diphenylphosphine (11.171 g, 60 mmol) in anhydrous THF (50 mL), add to a three-necked flask that has been dried, stir magnetically, protect with nitrogen throughout the process, put into a -78°C cold trap to cool, use a syringe to draw 22 mL (2.5 mol / L) of n-butyl lithium and drip it into the prepared diphenylphosphine solution, the dripping time is 15 min, the highest temperature is below -70°C, stir the red solution at -78°C for 60 min, then heat to room temperature and stir for 120 min to obtain a diphenylphosphine lithium solution;

[0072] b) Use a syringe to suck out the lithium diphenylphosphine solution and add it dropwise to a suspension of 5g of bromine-functionalized PS-PEG resin (manufacturer: Rapp Polymere, model: TentaGel® S Br 90μm) dissolved in 50mL of anhydrous THF (anhydrous and oxygen-free), stir at room temperature for 6h, add acetone / water (3:1, 50mL) to quench the reaction, filter and wash with water, acetone, and chloroform. Then place it in 50mL of ethanol / toluene (2:1) and reflux for 24h, filter, and vacuum dry at 70℃ to obtain the carrier;

[0073] c) 1 g of the obtained support and 0.1 g of allylpalladium (II) chloride dimer were dissolved in 20 mL of THF, mixed and stirred for 3 h, filtered, washed three times with THF and ethanol respectively, and then dried in vacuum at 60° C. to obtain a catalyst.

[0074] Example 3

[0075] The synthetic method of emamectin benzoate of the present embodiment comprises the following steps:

[0076] 1) Protection reaction: Avermectin (30 g) was dissolved in dichloromethane (70 g), added to a three-necked flask that had been dried, placed in a -40°C cold trap to cool, and when the temperature dropped to below -30°C, allyl chloroformate (4 g) was added, and tetramethylethylenediamine (2.5 g) and dichloromethane (2.5 g) were added to a constant pressure dropping funnel. When the temperature dropped to below -35°C, the mixture was dropped into the three-necked flask, and the dropping temperature was kept below -30°C for protection reaction to obtain a protection product liquid;

[0077] 2) Oxidation reaction: add dimethyl sulfoxide (4 g), oxidizing agent (1 g) and dichloromethane (7 g) to the protected product solution, mix thoroughly and keep warm for 180 min at room temperature to carry out oxidation reaction, and obtain an oxidized product solution;

[0078] 3) Amination reaction: Add glacial acetic acid (2.5 g) and 40% methylamine methanol (10 g) to the oxidation product solution, heat to 8°C and keep warm for 180 min to obtain an amination product solution;

[0079] 4) Reduction reaction: add methanol (30 g) to the amination product solution, cool to -15°C, slowly add sodium borohydride (1 g), and keep the temperature for 60 min to obtain the reduction product solution;

[0080] 5) Deprotection reaction: add methanol (30 g) and catalyst (300 mg) to the reduction product solution, add diethylamine (6 g) dropwise at room temperature, keep warm for 120 min after the addition is completed, take samples for testing, and obtain the deprotection product solution after deprotection without residue. Filter the catalyst and apply it to the next batch;

[0081] 6) Salt formation: Add benzoic acid (3.5 g) to the deprotected product solution, desolventize and dry to obtain emamectin benzoate.

[0082] The preparation method of the catalyst in this embodiment is the same as that in Example 2.

[0083] The preparation method of the oxidizing agent of this embodiment comprises the following steps:

[0084] S1: Dissolve 1g of hydroxylated polystyrene resin in 50mL of dichloromethane, add 0.9g of 3-methyl-3-hydroxymethyloxazolidine, stir for 30min, then add 13mL of 3-methyl-3-hydroxy-methyloxypropane dropwise, and stir at room temperature for 24 hours. Then add 30mL of methanol to quench the reaction. Filter the reaction mixture, wash with saturated sodium carbonate solution, water, methanol and dichloromethane, and vacuum dry to obtain a modified hydroxylated polystyrene resin (dendritic composite resin solution);

[0085] S2: Add 3 mL of deionized water to 1 mL of Escherichia coli cells, centrifuge and wash at 7000 r / min for 5 min, repeat 3 times, then dilute the washed Escherichia coli with 2 mL of deionized water, add to the modified hydroxylated polystyrene resin solution and mix evenly, apply on the glass substrate by scraper method, dry naturally, and then heat treat at 350°C for 1 h, and crush to obtain porous hydroxylated polystyrene resin;

[0086] S3: Disperse 1g of porous hydroxylated polystyrene resin into 5g of tetramethylethylenediamine solution, then mix well and place for 2h, and vacuum dry for 5h to obtain a porous dendritic solid support encapsulating tetramethylethylenediamine acid-binding agent. Then, the solid support prepared in the previous step is implanted into 30mL of copper acetate solution by impregnation method, stirred evenly, stirred at room temperature for 5h, filtered out the loaded solid support, and vacuum dried for 7h to obtain the oxidizing agent.

[0087] Example 4

[0088] The difference between this embodiment and embodiment 3 is that:

[0089] In the method for preparing the oxidizing agent of this embodiment, the heat treatment in step S2 is performed at 100° C., 150° C., 200° C., and 350° C. for half an hour each, and the rest is the same as in Example 3.

[0090] Example 5

[0091] The synthetic method of emamectin benzoate of the present embodiment comprises the following steps:

[0092] 1) Protection reaction: Avermectin (30 g) was dissolved in dichloromethane (70 g), added to a three-necked flask that had been dried, placed in a -40°C cold trap to cool, and when the temperature dropped to below -30°C, allyl chloroformate (4 g) was added, and tetramethylethylenediamine (2.5 g) and dichloromethane (2.5 g) were added to a constant pressure dropping funnel. When the temperature dropped to below -35°C, the mixture was dropped into the three-necked flask, and the dropping temperature was kept below -30°C for protection reaction to obtain a protection product liquid;

[0093] 2) Oxidation reaction: add dimethyl sulfoxide (4 g), oxidizing agent (1 g) and dichloromethane (7 g) to the protected product solution, mix thoroughly and keep warm for 180 min at room temperature to carry out oxidation reaction, and obtain an oxidized product solution;

[0094] 3) Amination reaction: Add glacial acetic acid (2.5 g) and 40% methylamine methanol (10 g) to the oxidation product solution, heat to 8°C and keep warm for 180 min to obtain an amination product solution;

[0095] 4) Reduction reaction: add methanol (30 g) to the amination product solution, cool to -15°C, slowly add sodium borohydride (1 g), and keep the temperature for 60 min to obtain the reduction product solution;

[0096] 5) Deprotection reaction: add methanol (30 g) and tetrakis(triphenylphosphine)palladium (500 mg) to the reduction product solution, cool to -15°C, slowly add sodium borohydride (2 g), and keep warm for 60 min to obtain a deprotection product solution;

[0097] 6) Salt formation: Add benzoic acid (3.5 g) to the deprotected product solution, desolventize and dry to obtain emamectin benzoate.

[0098] The preparation method of the oxidizing agent in this embodiment is the same as that in Example 3.

[0099] Performance testing

[0100] According to the synthesis method of emamectin benzoate in Examples 1-5, the deprotected product and emamectin benzoate in the synthesis process of Examples 1-5 were respectively subjected to high performance liquid chromatography test. The test results are as follows: Figure 1-Figure 10 As shown. Figure 1-Figure 5 is a high performance liquid chromatogram of the deprotected product of Examples 1-5 of the present application, Figure 6-Figure 10 It is the high performance liquid chromatogram of emamectin benzoate in Examples 1-5 of the present application.

[0101] Among them, the chromatographic test conditions of the deprotected product are:

[0102] Detection wavelength: 245nm;

[0103] Chromatographic column: Agilent Extend-C18, 4.6×150mm, 5μm or equivalent;

[0104] The injection volume was 10 μL, the column temperature was 40°C, the flow rate was 1 mL / min, and the time was 20 min.

[0105] The chromatographic test conditions of emamectin benzoate are:

[0106] Chromatographic column: C18 column, 250mm×4.6mm, 5μm or equivalent;

[0107] The column temperature was 40°C, the detection wavelength was 245 nm, the flow rate was 2 mL / min, and the injection volume was 10 μL.

[0108] Analyze Examples 1-5 and combine Figure 1-Figure 11 It can be seen that the synthesis method of emamectin benzoate of the present application uses an oxidizing agent prepared by a porous dendritic copper acetate / tetramethylethylenediamine solid support, which helps the oxidant to fully contact the reactant, improve the purity of the reaction product, and reduce the generation of side reactions. In addition, the catalyst used in the deprotection reaction can reduce the generation of by-products during the reaction process and improve the purity of the deprotection product and the emamectin benzoate product compared to the traditional tetrakis(triphenylphosphine)palladium homogeneous catalyst.

[0109] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make modifications to the present embodiment without any creative contribution as needed, but such modifications are protected by the patent law as long as they are within the scope of the claims of the present application.

Claims

1. A method for synthesizing emamectin benzoate, characterized in that, The steps include: 1) Protection reaction: A protection reaction is carried out between avermectin and a hydroxyl protective agent in a halogenated hydrocarbon solvent, and the reaction temperature is maintained below -30°C to obtain a protection product liquid; the chemical structure of the avermectin is as follows: ; The avermectin is composed of avermectin B1a and avermectin B1b, avermectin B1a accounts for 95wt%, avermectin B1b accounts for 5wt%, wherein avermectin B1a: R = CH3CH2, avermectin B1b: R = CH3; the hydroxyl protective agent is allyl chloroformate; the chemical structure of the protective product is as follows: ; 2) Oxidation reaction: adding dimethyl sulfoxide to the protected product solution, and then adding an oxidizing agent to carry out an oxidation reaction to obtain an oxidized product solution; the preparation method of the oxidizing agent comprises the following steps: S1: dissolving the hydroxylated polystyrene resin in dichloromethane, then adding 3-methyl-3-hydroxymethyloxazolidine and stirring for 30 minutes, then dropping 3-methyl-3-hydroxy-methyloxypropane, stirring for reaction, adding methanol to quench the reaction, finally filtering the reaction mixture, washing with saturated sodium carbonate solution, water, methanol and dichloromethane, and vacuum drying to obtain the modified hydroxylated polystyrene resin; S2: Add Escherichia coli to the modified hydroxylated polystyrene resin solution and mix well, then apply it on a glass substrate by a scraper method, dry it naturally, and then heat treat and crush it to obtain a porous hydroxylated polystyrene resin; S3: dispersing a porous hydroxylated polystyrene resin into a tetramethylethylenediamine solution, mixing and placing the mixture for a period of time, and then drying the mixture to obtain a porous dendritic solid support encapsulating a tetramethylethylenediamine acid-binding agent, and then immersing the solid support in a copper acetate solution, filtering and drying the solid support to obtain an oxidizing agent; 3) Amination reaction: adding glacial acetic acid and methylamine methanol to the oxidation product solution, and keeping the temperature to react to obtain the amination product solution; 4) Reduction reaction: methanol is added to the amination product solution, and sodium borohydride is slowly added to react to obtain a reduction product solution; 5) Deprotection reaction: adding methanol and a catalyst to the reduction product solution to carry out a deprotection reaction to obtain a deprotection product solution; the preparation method of the catalyst comprises the following steps: a) dissolving diphenylphosphine in anhydrous THF to prepare a diphenylphosphine solution, and then adding n-butyllithium dropwise to the diphenylphosphine solution, maintaining the reaction temperature below -70°C, to prepare a lithium diphenylphosphine solution; b) dispersing the bromine-functionalized PS-PEG resin in anhydrous THF to prepare a suspension, then dropping a lithium diphenylphosphine solution into the suspension, stirring the suspension for reaction, adding a quencher to terminate the reaction, filtering and washing the suspension, and then refluxing the suspension in an ethanol / toluene solution, filtering and drying the suspension to obtain a carrier; c) dissolving the support and allylpalladium chloride dimer in THF, mixing and stirring, filtering, washing and drying to obtain a catalyst; 6) Salt formation: Add benzoic acid to the deprotected product solution, desolventize and dry to obtain emamectin benzoate.

2. A synthetic method for emamectin benzoate according to claim 1, characterized in that, In the step a), the molar ratio of diphenylphosphine to n-butyllithium is (1.05-1.1):

1.

3. A synthetic method for emamectin benzoate according to claim 1, characterized in that, In the step c), the mass ratio of the carrier to the allylpalladium chloride dimer is 1:(9-12).

4. A synthetic method for emamectin benzoate according to claim 1, characterized in that, The dosage of the catalyst is 1%-1.5% of the quality of Avermectin.

5. A synthetic method for emamectin benzoate according to claim 1, characterized in that, The halogenated hydrocarbon solvent is one of dichloromethane, chloroform and dichloroethane.

6. A synthetic method for emamectin benzoate according to claim 1, characterized in that, In the step S3, the mass ratio of the porous hydroxylated polystyrene resin to tetramethylethylenediamine is 1:(4-6).

7. A synthetic method for emamectin benzoate according to claim 1, characterized in that, In step S2, the heat treatment is performed at 100°C, 150°C, 200°C, and 350°C for half an hour each.

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