Catalyst for synthesizing methylamino abamectin intermediate
By using boron-containing compound catalysts in the preparation process of methylamino avermectin, the problems of large amount of methylamine and incomplete reaction are solved, and efficient ammonia reduction reaction and the preparation of high-purity products are achieved, which reduces environmental pressure and production costs.
Patent Information
- Application Number
- CN202411175579.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-08-26
- Publication Date
- 2025-02-25
AI Technical Summary
The current methylammonium avermectin is used in large amounts of methylamine, incomplete reaction, low product yield, resulting in high environmental pressure and high production costs.
Boron-containing compounds are used as catalysts to synthesize methylamino avermectin intermediates to improve the conversion and selectivity of ammonia reduction reaction.
It improves the conversion rate of raw materials and the selectivity of reactions, reduces the amount of methylamine and the ammonia nitrogen in the three wastes, reduces environmental protection treatment costs, and improves the yield and purity of the product.
Smart Images
Figure CN119500086A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of avermectin preparation, and in particular relates to a catalyst for synthesizing an avermectin intermediate. Background Art
[0002] Emamectin benzoate is a highly effective antibiotic insecticide obtained by chemical synthesis using the biological fermentation product avermectin B1 as the starting material. Emamectin benzoate has the characteristics of super high efficiency, low toxicity, no residue, and no pollution. It has a wide insecticide spectrum and low toxicity to humans and animals. It is one of the most cost-effective pesticides at present and has been widely used in the prevention and control of pests and diseases in vegetables, fruits, fruit trees, field crops, etc.
[0003] At present, the synthesis technology of emamectin benzoate mainly uses avermectin B1 or B2a as raw material, and is prepared by six steps of protection, oxidation, amination, reduction, deprotection and salt formation, and the crude product content is about 73%; in order to reduce costs, technicians use methylamine methanol with lower price as amination reagent instead of heptamethyldisilazane with higher price to prepare imine intermediates, but because water is constantly generated during the amination process, the originally unstable imine returns to the oxide state. In order to improve the conversion rate of the oxide, the amount of methylamine has to be increased to ensure that the reaction proceeds in the positive direction, resulting in a large excess of methylamine. When the reaction is finished and processed, the excess methylamine enters the waste gas and wastewater, and the extremely high ammonia nitrogen content not only increases the difficulty of processing the three wastes, but also pollutes the environment, greatly increasing the environmental protection pressure of enterprises. Therefore, it is of great significance to provide a catalyst for synthesizing avermectin intermediates and improve the selectivity of the main reaction. Summary of the invention
[0004] The invention provides a catalyst for synthesizing an avermectin intermediate, which is used to solve the technical problems of large amount of methylamine, incomplete reaction and low product yield in the existing avermectin preparation process.
[0005] In view of this, the present invention provides a catalyst for synthesizing an avermectin intermediate, wherein the catalyst is a boron-containing compound, boron oxide, trimethyl borate, triethyl borate, propyl borate, isopropyl borate, boron tribromide, boron trichloride, etc.; the avermectin structure is 5-protected-4"-avermectin B1a / B1b or 5-protected-4"-avermectin B2a / B2b, as shown in Formula 1:
[0006]
[0007] Optionally, the oxide shown in formula II is dissolved in an inert solvent, and methylamine methanol, acetic acid, the catalyst, sodium borohydride or potassium borohydride are added to obtain the avermectin derivative of formula I. The reaction equation is as follows:
[0008]
[0009] The inert solvent is dichloromethane, dichloroethane, toluene, ethyl acetate, sec-butyl acetate, n-butyl acetate, etc., preferably dichloromethane, dichloroethane, toluene, and the mass of the solvent is 2-5 times the mass of the raw material.
[0010] Optionally, the amount of the catalyst is 1%-20% by weight of the raw material oxide, calculated by mass fraction;
[0011] Furthermore, the amount of the catalyst is 5-15% by weight of the raw material oxide.
[0012] Optionally, the molar addition ratio of the oxide, methylamine methanol, acetic acid, sodium borohydride or potassium borohydride is 1:(3-15):(1-10):(0.1-2.0).
[0013] More preferably, the molar feed ratio of the oxide, methylamine methanol, acetic acid, sodium borohydride or potassium borohydride is 1:(5-10):(2-8):(0.4-1.5).
[0014] Optionally, the reaction temperature is -10 to 20°C, and the reaction time is 1 to 6 hours.
[0015] Furthermore, the reaction temperature is -10 to 20°C, and the reaction time is 2 to 3 hours.
[0016] Optionally, the hydroxy protecting group in Formula I is an allyloxycarbonyl or silicon protecting group, and Formula I without the protecting group is avermectin B1a / B1b or avermectin B2a / B2b.
[0017] Optionally, the boron content in the prepared crude emamectin benzoate is greater than 3 ppm as detected by plasma emission spectroscopy.
[0018] The addition of the catalyst can make the oxide amination reduction proceed simultaneously, which not only improves the conversion rate of the raw materials but also increases the selectivity of the reaction. The residual raw materials are reduced from more than 3% to 0.5%, and the reaction is more thorough. The relative content of the main product avermectin intermediate, 5-protected-4"-avermectin, is increased from 86% to more than 90%.
[0019] The addition of the catalyst improves the reaction yield. The molar yield of the crude emamectin benzoate can reach more than 90% based on the oxide. Further crystallization can obtain emamectin benzoate with a content of more than 95%.
[0020] With the addition of the catalyst, characteristic components can be detected in the final product. Using plasma emission spectrometry, the boron content in the product is greater than 3 ppm, while the boron content in the product without the catalyst is 1 ppm.
[0021] The 5-position protecting group of the avermectin intermediate can be an allyloxycarbonyl group or a silicon-based protecting group. After removing the protecting group, avermectin B1a / B1b or avermectin B2a / B2b can be obtained, and avermectin B1a / B1b benzoate or avermectin B2a / B2b benzoate can be obtained by forming a salt with benzoic acid. If allyl chloroformate is used as a hydroxyl protecting agent, tetrakistriphenylphosphine palladium or other palladium catalysts need to be added during deprotection to remove it; if a silicon-based compound is used as a protecting agent, after the amination reduction reaction is completed, no catalyst needs to be added, and post-treatment is directly performed, and the protecting group can be removed by itself during post-treatment.
[0022] It can be seen from the above technical scheme that the catalyst for synthesizing the avermectin intermediate provided by the present invention solves the practical problems in production and achieves obvious effects:
[0023] 1. The catalyst provided by the present invention increases the conversion rate and selectivity of the reaction. The avermectin benzoate prepared by amination, reduction, deprotection and salt formation using the oxide as the raw material has a molar yield of more than 90% based on the oxide. After further purification, avermectin benzoate with a content of more than 95% can be obtained, i.e., the avermectin derivative shown in Formula 1.
[0024] 2. The catalyst provided by the present invention is stable, convenient and easy to obtain, safe to use, cheap, and reduces the cost of raw materials; no solids are generated during the post-treatment process, which reduces material losses, reduces the labor intensity of workers, and greatly reduces the production cost of avermectin.
[0025] 3. The catalyst provided by the present invention is used in the ammoniation reduction reaction, which greatly reduces the amount of methylamine used, reduces the ammonia nitrogen in the three wastes, and reduces the cost of environmental protection treatment. DETAILED DESCRIPTION
[0026] In order to make the technical scheme of the present invention better understood by the personnel of the technical field, the technical scheme in the embodiment of the present invention is clearly and completely described below. Obviously, the described embodiment is only a part of the embodiment of the present invention, rather than all the embodiments. Based on the embodiment in the present invention, all other embodiments obtained by ordinary technicians in the field without making creative work are within the scope of protection of the present invention. Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or can be prepared by existing methods.
[0027] Example
[0028] Example 1
[0029] 100 g of 96.0% 4"-carbonyl-5-allyloxycarbonylavermectin B1 (0.1 mol) was dissolved in 300 g of dichloromethane, and 10 g of boron oxide was added for later use.
[0030] 54.0g (0.6mol) of methylamine methanol was cooled to -10°C, 18g (0.3mol) of glacial acetic acid was added, and the above solution was added dropwise. After the addition, the temperature was kept at 0-5°C. Samples were taken after 2h. The content of 4"-carbonyl-5-allyloxycarbonylavermectin B1 was less than 0.5% (the reaction had already occurred at this time. When the reaction reached this value, the subsequent reaction could continue). The temperature was cooled to -5-0°C, 0.04g of tetrakistriphenylphosphine palladium was added, nitrogen was protected, and 5.0g (0.13mol) of sodium borohydride was added in batches. The reaction was completed in 2-3 hours, and 10% hydrochloric acid was added to adjust the pH value. to 2-3, and then adjust the pH value to 7-8 with 12% sodium hydroxide, separate the layers, add 11.5g benzoic acid to the organic phase, dissolve it, and evaporate the solvent to obtain 115.0g of a yellow solid with a benzoate content of 79.3% for avermectin B1, a molar yield of 90.5% based on 4"-carbonyl-5-allyloxycarbonylavermectin B1, and a boron content of 0.04% in the solid; add 242g of sec-butyl acetate to dissolve, slowly add 150g of n-hexane dropwise, filter, and dry to obtain 90.6g of a white solid with a benzoate content of 96.0%.
[0031] Example 2
[0032] 98.0 g 96.2% 4"-carbonyl-5-trimethylsilyloxyavermectin B1 (0.1 mol) was dissolved in 300 g dichloromethane, and 10 g trimethyl borate was added for later use.
[0033] 54.0g (0.6mol) of methylamine methanol was cooled to -10°C, 18g (0.3mol) of glacial acetic acid was added, and the above solution was added dropwise. After the addition, the temperature was kept at 0-5°C. Samples were taken after 2h. The content of 4"-carbonyl-5-trimethylsilyloxyavermectin B1 was less than 0.5%. The temperature was cooled to -5-0°C, and 2.0g (0.05mol) of sodium borohydride was added in batches. The reaction was completed in 2-3 hours. 10% hydrochloric acid was added to adjust the pH value to 2-3, and then 12% sodium hydroxide was used to adjust the pH value to 7-8. The layers were separated. layer, 11.5g of benzoic acid was added to the organic phase, and after dissolution, the solvent was evaporated to obtain 114.5g of a yellow solid with a benzoate content of 80.0% for avermectin B1, a molar yield of 90.9% based on 4"-carbonyl-5-allyloxycarbonylavermectin B1, and a boron content of 0.06% in the solid; 242g of sec-butyl acetate was added to dissolve, 150g of n-hexane was slowly added dropwise, filtered, and dried to obtain 89.2g of a white solid with a benzoate content of 96.5% for avermectin B1.
[0034] Example 3
[0035] 100 g of 97.3% 4"-carbonyl-5-allyloxycarbonyl avermectin B2 (0.1 mol) was dissolved in 300 g of dichloromethane, and 15 g of triethyl borate was added for later use.
[0036] 72.0g (0.8mol) methylamine methanol was cooled to -10°C, 24g (0.4mol) glacial acetic acid was added, the above solution was added dropwise, and the temperature was kept at 0-5°C after addition. Samples were taken after 2h. The content of 4"-carbonyl-5-allyloxycarbonylavermectin B2 was less than 0.5%. The temperature was cooled to -5-0°C, 0.04g tetrakistriphenylphosphine palladium was added, nitrogen was protected, 3.8g (0.1mol) of sodium borohydride was added in batches, the reaction was completed in 2-3 hours, 10% hydrochloric acid was added to adjust the pH to 2-3, and then 12% sodium hydroxide was used to adjust the pH. When the H value reaches 7-8, separate the layers, add 11.5g of benzoic acid to the organic phase, dissolve it, and evaporate the solvent to obtain 116.0g of a yellow solid with an emamectin B2 benzoate content of 80.4%, a molar yield of 90.9% based on 4"-carbonyl-5-allyloxycarbonyl emamectin B2, and a boron content of 0.05% in the solid; add 240g of n-butyl acetate to dissolve, slowly add 180g of n-hexane, filter, and dry to obtain 94.0g of a white solid with an emamectin B2 benzoate content of 95.0%.
[0037] Example 4
[0038] 100 g of 96.0% 4"-carbonyl-5-allyloxycarbonylavermectin B1 (0.1 mol) was dissolved in 500 g of toluene, and 15 g of boron tribromide was added for later use.
[0039] 90.0g (1.0mol) methylamine methanol was cooled to -10°C, 36g (0.6mol) glacial acetic acid was added, the above solution was added dropwise, and the temperature was kept at 0-5°C after addition. Samples were taken after 1h. The content of 4"-carbonyl-5-allyloxycarbonylavermectin B1 was less than 0.3%. The temperature was cooled to -5-0°C, 0.04g tetrakistriphenylphosphine palladium was added, nitrogen was protected, 5.0g (0.13mol) of sodium borohydride was added in batches, the reaction was completed in 2-3 hours, 10% hydrochloric acid was added to adjust the pH to 2-3, and 12% sodium hydroxide was used to adjust the pH. When the H value reaches 7-8, separate the layers, add 11.5g of benzoic acid to the organic phase, dissolve it, evaporate the solvent, and obtain 115.0g of yellow solid, with a benzoate content of 79.4% for avermectin B1, a molar yield of 90.6% based on 4"-carbonyl-5-allyloxycarbonylavermectin B1, and a boron content of 0.06% in the solid; add 260g of sec-butyl acetate to dissolve, slowly add 160g of n-hexane, filter, and dry to obtain 91.0g of white solid, with a benzoate content of 96.0% for avermectin B1.
[0040] Example 5
[0041] 98.0 g of 96.2% 4"-carbonyl-5-trimethylsilyloxyavermectin B1 (0.1 mol) was dissolved in 500 g of toluene, and 15 g of tripropyl borate was added for later use.
[0042] 36.0g (0.4mol) of methylamine methanol was cooled to -10°C, 12g (0.2mol) of glacial acetic acid was added, and the above solution was added dropwise. After the addition, the temperature was kept at 0-5°C. Samples were taken after 3h. The content of 4"-carbonyl-5-allyloxycarbonylavermectin B1 was less than 0.5%. The temperature was cooled to -5-0°C, and 5.6g (0.15mol) of sodium borohydride was added in batches. The reaction was completed in 2-3 hours. 10% hydrochloric acid was added to adjust the pH value to 2-3, and then 12% sodium hydroxide was used to adjust the pH value to 7-8. The layers were separated. layer, 11.6g of benzoic acid was added to the organic phase, and after dissolution, the solvent was evaporated to obtain 114.0g of a yellow solid with a benzoate content of 80.5% for avermectin B1, a molar yield of 91.0% based on 4"-carbonyl-5-allyloxycarbonylavermectin B1, and a boron content of 0.07% in the solid; 242g of sec-butyl acetate was added to dissolve, 150g of n-hexane was slowly added dropwise, filtered, and dried to obtain 89.8g of a white solid with a benzoate content of 96.3% for avermectin B1.
[0043] Example 6
[0044] 100.0 g of 94.8% 4"-carbonyl-5-trimethylsilyloxyavermectin B2 (0.1 mol) was dissolved in 500 g of dichloromethane, and 12 g of boron oxide was added for later use.
[0045] 36.0g (0.4mol) of methylamine methanol was cooled to -10°C, 12g (0.2mol) of glacial acetic acid was added, and the above solution was added dropwise. After addition, the temperature was kept at 0-5°C, and samples were taken after 3 hours. The content of 4"-carbonyl-5-trimethylsilyloxy avermectin B1 was less than 0.5%. The temperature was cooled to -5-0°C, and 5.6g (0.15mol) of sodium borohydride was added in batches. The reaction was completed in 2-3 hours, 10% hydrochloric acid was added to adjust the pH value to 2-3, and then 12% sodium hydroxide was used to adjust the pH value to 7-8, and the layers were separated. , add 11.6g of benzoic acid to the organic phase, dissolve it, evaporate the solvent to obtain 115.5g of a yellow solid, the content of avermectin B2 benzoate is 80.5%, the molar yield is 90.6% based on 4"-carbonyl-5-trimethylsilyloxyavermectin B2, and the boron content in the solid is 0.05%; add 242g of sec-butyl acetate to dissolve, slowly add 150g of n-hexane, filter, and dry to obtain 91.0g of a white solid, the content of avermectin B2 benzoate is 95.0%.
[0046] Example 7
[0047] 100 g of 96.0% 4"-carbonyl-5-allyloxycarbonylavermectin B1 (0.1 mol) was dissolved in 300 g of dichloromethane, and 100 g of 10% dichloromethane solution of boron trichloride was added and set aside.
[0048] 54.0g (0.6mol) of methylamine methanol was cooled to -10°C, 18g (0.3mol) of glacial acetic acid was added, and the above solution was added dropwise. After the addition, the temperature was kept at 0-5°C. Samples were taken after 2h. The content of 4"-carbonyl-5-allyloxycarbonylavermectin B1 was less than 0.5%. The temperature was cooled to -5-0°C, 0.04g of tetrakistriphenylphosphine palladium was added, nitrogen was protected, and 5.0g (0.13mol) of sodium borohydride was added in batches. The reaction was completed in 2-3 hours. 10% hydrochloric acid was added to adjust the pH to 2-3, and then 12% sodium hydroxide was used to adjust the pH. When the H value reaches 7-8, separate the layers, add 11.5g of benzoic acid to the organic phase, dissolve it, evaporate the solvent, and obtain 120.0g of yellow solid, with a benzoate content of 80.2% for avermectin B1, a molar yield of 95.2% based on 4"-carbonyl-5-allyloxycarbonylavermectin B1, and a boron content of 0.06% in the solid; add 242g of sec-butyl acetate to dissolve, slowly add 150g of n-hexane, filter, and dry to obtain 91.0g of white solid, with a benzoate content of 96.0% for avermectin B1.
[0049] Comparative Example
[0050] Comparative Example 1
[0051] A catalyst for synthesizing an avermectin intermediate, which differs from Example 1 in that no catalyst is added to oxidize boron, the final avermectin B1 benzoate content is 74.6%, the yield based on 4"-carbonyl-5-allyloxycarbonyl avermectin B1 is 80.5%, and the boron content in the product is 0.01%.
[0052] Comparative Example 2
[0053] A catalyst for synthesizing an avermectin intermediate, which differs from Example 2 in that the catalyst trimethyl borate is not added, the final avermectin B2 benzoate content is 75.8%, the yield based on 4"-carbonyl-5-allyloxycarbonyl avermectin B1 is 82.0%, and the boron content in the product is 0.01%.
[0054] Comparative Example 3
[0055] A catalyst for synthesizing an avermectin intermediate, which differs from Example 3 in that the catalyst triethyl borate is not added, the final avermectin B1 benzoate content is 73.8%, the yield based on 4"-carbonyl-5-allyloxycarbonyl avermectin B1 is 81.5%, and the boron content in the product is 0.01%.
[0056] It can be seen from Examples 1-7 that the catalyst for synthesizing avermectin intermediates of the present application increases the conversion rate and selectivity of the reaction. The avermectin benzoate prepared by amination, reduction, deprotection and salt formation with an oxide as the raw material has a yield of more than 90% based on the oxide, and further purification can obtain avermectin benzoate with a content of more than 95%.
[0057] Combining Example 1 and Comparative Example 1, it can be seen that in Example 1, the molar yield of 4"-carbonyl-5-allyloxycarbonyl avermectin B1 is 90.5%, and the benzoate content of avermectin B1 is 96.0%, which is better than Comparative Example 1, indicating that adding a catalyst boron oxide is more appropriate and can further improve the yield of avermectin.
[0058] Combining Example 2 and Comparative Example 2, it can be seen that in Example 2, the molar yield of 4"-carbonyl-5-allyloxycarbonyl avermectin B1 is 90.9%, and the benzoate content of avermectin B1 is 96.5%, which is better than Comparative Example 2, indicating that adding the catalyst trimethyl borate is more appropriate and can further improve the yield of avermectin.
[0059] Combining Example 3 and Comparative Example 3, it can be seen that in Example 3, the molar yield of 4"-carbonyl-5-allyloxycarbonyl avermectin B2 is 90.9%, and the benzoate content of avermectin B2 is 95.0%, which is better than Comparative Example 3, indicating that adding the catalyst triethyl borate is more appropriate and can further improve the yield of avermectin.
[0060] As described above, the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features thereof may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims
1. A catalyst for synthesizing an avermectin intermediate, characterized in that: The catalyst is a boron-containing compound, boron oxide, trimethyl borate, triethyl borate, propyl borate, isopropyl borate, boron tribromide, boron trichloride, etc.; the structure of avermectin is 5-protected-4"-avermectin B1a / B1b or 5-protected-4"-avermectin B2a / B2b, as shown in Formula 1:
2. The catalyst for synthesizing an avermectin intermediate according to claim 1, characterized in that: The oxide represented by formula II is dissolved in an inert solvent, and methylamine methanol, acetic acid, the catalyst, sodium borohydride or potassium borohydride are added to obtain the avermectin derivative represented by formula I. The reaction equation is as follows:
3. The catalyst for synthesizing an avermectin intermediate according to claim 2, characterized in that: Calculated by mass fraction, the amount of the catalyst used is 1%-20% of the weight of the raw material oxide.
4. The catalyst for synthesizing an avermectin intermediate according to claim 2, characterized in that: The molar addition ratio of the oxide, methylamine methanol, acetic acid, sodium borohydride or potassium borohydride is 1:(3-15):(1-10):(0.1-2.0).
5. The catalyst for synthesizing an avermectin intermediate according to claim 2, characterized in that: The reaction temperature is -10 to 20°C, and the reaction time is 1 to 6 hours.
6. The catalyst for synthesizing an avermectin intermediate according to claim 1, characterized in that: The addition of the catalyst can make the amination and reduction of the oxide proceed simultaneously, and the reaction selectivity is greatly improved. The 100 molar yield of crude avermectin benzoate can reach more than 90% based on the oxide.
7. The catalyst for synthesizing an avermectin intermediate according to claim 2, characterized in that: The inert solvent is any one of dichloromethane, dichloroethane, toluene, ethyl acetate, sec-butyl acetate, n-butyl acetate, etc.
8. The catalyst for synthesizing an avermectin intermediate according to claim 1, characterized in that: The hydroxy protecting group in formula I is an allyloxycarbonyl or silicon protecting group, and formula I without the protecting group is avermectin B1a / B1b or avermectin B2a / B2b.
9. The catalyst for synthesizing an avermectin intermediate according to claim 1, characterized in that: The boron content in the crude product of avermectin benzoate obtained was greater than 3 ppm as detected by plasma emission spectrometry.