CN110627853A - Method for preparing emamectin benzoate intermediate by using microreactor - Google Patents
Method for preparing emamectin benzoate intermediate by using microreactor Download PDFInfo
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Abstract
The invention relates to a method for preparing a emamectin benzoate intermediate by using a microreactor, and particularly discloses a method for preparing a emamectin benzoate intermediate by dissolving abamectin and tetramethylethylenediamine in dichloromethane to form a homogeneous solution, and respectively pumping the homogeneous solution and allyl chloroformate into a microchannel modular reaction device to generate a compound I; mixing dimethyl sulfoxide with the reaction solution of the compound I, and pumping the mixture and phenyl dichlorophosphate into a microreactor of the next module respectively to obtain a compound II; adjusting the pH of the reaction liquid to 6-8 with alkaline water, standing to separate an organic phase, distilling the organic phase, and removing dichloromethane to obtain a emamectin benzoate intermediate 4 '-epi-4' -carbonyl-5-allyl formate-abamectin B1. According to the technical scheme, the modularized microchannel reaction device is adopted, so that the mass transfer efficiency and the heat transfer efficiency are high, the raw materials are instantly and fully mixed, the reaction rate is accelerated, the selectivity is improved, the reaction time is greatly shortened, and the production efficiency is improved; can be continuously operatedThe product quality stability is improved, the equipment integration level is high, and the occupied space can be reduced; the product has high yield and high purity.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing an emamectin benzoate intermediate by using a microreactor.
Background
The emamectin benzoate is a low-toxicity, high-efficiency, green and biogenic insecticide, and solves the problems of high toxicity, resistance and influence on the environment of the traditional pesticide. The emamectin benzoate has incomparable activity to other pesticides, and especially has ultrahigh effect on lepidoptera, diptera and thrips on crops such as vegetables, cotton, rice, potatoes, tobacco and the like. The plant nutrient solution has no systemic property on the safety of crops, but can effectively permeate into the epidermal tissues of the applied crops, thereby having longer residual effect period and being rarely influenced by environmental factors such as wind, rain and the like; the pesticide is easy to degrade in soil, has no pollution and residue, and is safe to beneficial insects, natural enemies of pests, people and livestock within the conventional dosage range for preventing and treating the pests.
The existing technology for producing emamectin benzoate in China mainly takes abamectin as a raw material, and hydroxyl on the 4' -position of the abamectin is reformed into methylamino to prepare the emamectin benzoate. Synthesizing methylamino abamectin, firstly taking methylene chloride as a solvent, protecting 5-hydroxy by allyl chloroformate to produce a compound I, and oxidizing C4' -hydroxy of the abamectin with the protected C5-hydroxy to carbonyl by adopting dimethyl sulfoxide as an oxidant and phenyl dichlorophosphate as a catalyst to generate a compound II. The synthetic route is as follows:
CN102532224A provides a C4' -oxidation reaction method in the production process of emamectin benzoate, which uses di (trichloromethyl) carbonate as a catalyst to replace phenyl dichlorophosphate for oxidation reaction. The bis (trichloromethyl) carbonate (i.e. triphosgene) used in the method is solid and needs to be dissolved in methylene dichloride in advance, the solid feeding has large pungent smell, the dissolving process needs to be heated, the heating is easy to decompose into the virulent phosgene, and the danger coefficient is larger. The dropping process is easy to separate out and block the pipeline, and the operation is complex.
CN105017358A provides a C4' -site hydroxyl to replace oxidation reaction of dimethyl sulfoxide by sulfonylation reaction, but the reaction time is still long within 5-15h, and the sulfonylation reagent has strong corrosivity and strict requirements on reaction equipment and operation environment.
CN103408622B provides a method for preparing 5-O-allyl formate-4' -carbonyl-avermectin B by reacting abamectin with allyl chloroformate and tetramethyl ethylenediamine for 5-hydroxy protection and then reacting with phenyl dichlorophosphate in the presence of dimethyl sulfoxide and triethylamine1The method has long reaction time (3.5 hours are needed), the pH value of the solution needs to be adjusted by phosphoric acid after 5-site hydroxyl protection is finished, the solution is extracted by a solvent and then the organic solvent is removed by decompression, triethylamine and dilute acid are needed to be additionally added in the 4-site hydroxyl oxidation procedure to stop the reaction, and the operation steps are more.
CN103601776A provides a preparation method of emamectin benzoate intermediate, in particular to avermectin B1Reacting with dichloroethane at-15 deg.C with allyl chloroformate and tetramethylethylenediamine, heating, adding dimethyl sulfoxide and tetramethylethylenediamine, dripping dichloromethane solution containing solid phosgene, reacting while maintaining the temperature, regulating pH, collecting oil phase, desolventizing, and drying to obtain 4 '-epi-4' -carbonyl-5-allyl formate-avermectin B1However, the reaction time is at least 3 hours and toxic phosgene solids are required and the solids feed requires premature dissolution, easy plugging of the lines and the use of relatively high amounts of alkaline reagents.
CN105968154A provides a synthesis method of acetamido abamectin, which comprises abamectin B1The 5-hydroxyl comprises the step of oxidizing the 4' -hydroxyl, and particularly, the abamectin is dissolved in dichloromethane and then treated according to abamectin B1: isopropyl chloride: dropwise adding isopropyl chloride and tetramethylethylenediamine at the temperature of-20 to-15 ℃ according to the molar ratio of 1:1:1, dropwise adding dimethyl sulfoxide and tetramethyldiethylamine after the reaction is finished, cooling to-20 ℃, dropwise adding phenyl dichlorophosphate for the reaction is finished, extracting with a solvent, adjusting the pH, drying and vacuum desolventizing to obtain 4' -O-5-O-allyloxy formyl abamectin B1However, it also needs to add tetramethylethylenediamine again in the step of hydroxyl oxidation, which is not suitable for continuous reaction and is not suitable for industrial mass production.
CN105906677B provides a method for preparing emamectin benzoate, in particular to a method for dissolving abamectin B in toluene1Adding a molecular sieve, detecting the moisture content, then carrying out solid-liquid separation, cooling, dropwise adding allyl chloroformate, stirring and reacting for 1h, then slowly dropwise adding allyl chloroformate and tetramethyldiethylamine within half an hour, continuously replenishing allyl chloroformate after the reaction is finished, dropwise adding a mixed solution of dimethyl sulfoxide and tetramethylethylenediamine, slowly adding solid phosgene after stirring, and carrying out heat preservation and reaction for 2h after dropwise adding is finished for 1 h.
The traditional process and production equipment have low yield, and the reaction time is long due to large heat release and dropping time control. In the process of protecting and reflecting the hydroxyl at the C5 position, the mass transfer is poor, so that the content of local allyl chloroformate is over high, the temperature is over high, C4' -hydroxyl is easy to form and simultaneously protected, the raw material waste is caused, and the yield is low. The production cost is high, and the operation is complex. Therefore, a new reaction method is urgently needed, which can solve the problems of mass transfer and heat transfer, improve the product yield, accelerate the reaction speed, reduce the production cost and simplify the operation.
Disclosure of Invention
The invention provides a method for preparing an emamectin benzoate intermediate by adopting a microchannel modular reaction device, aiming at the problems of low selectivity, long reaction time, incapability of continuous production and the like caused by the fact that the traditional equipment has poor mass transfer heat transfer and extremely quick heat release in the synthesis process of a C4' -site oxide in the production process of the emamectin benzoate intermediate.
In order to achieve the technical purpose, the invention provides the following technical scheme: a method for preparing an emamectin benzoate intermediate by using a microreactor comprises the following steps:
1) dissolving abamectin and tetramethylethylenediamine in dichloromethane, and pumping the dichloromethane and allyl chloroformate into a modular microchannel reaction device respectively, controlling the reaction temperature to be-25-20 ℃ and the reaction residence time to be 10-20 s to obtain a compound I;
2) mixing the compound I obtained in the step 1) with dimethyl sulfoxide, pumping the mixture and phenyl dichlorophosphate into a microchannel reaction device of the next module respectively, and controlling the reaction temperature to be-20 ℃ and the reaction residence time to be 20-40 s to obtain a compound II;
3) adjusting the pH value of the compound II obtained in the step (2) to 7-8 by using alkali, and standing to separate an organic phase;
4) distilling the organic phase obtained in the step (3) to remove dichloromethane to obtain the emamectin benzoate intermediate 4 '-epi-4' -carbonyl-5-allyl formate-abamectin B1；
Further, in the step 1), the molar ratio of the abamectin to the dichloromethane is 1: 20-50;
furthermore, the molar ratio of the abamectin to the tetramethylethylenediamine is 1: 1-6;
further, in the step 1), the molar ratio of the abamectin to the allyl chloroformate is 1: 1-1.5;
further, in the step 1), the reaction temperature is-15 ℃, and the reaction residence time is 10-15 s;
further, the modularized microchannel reaction device in the step 1) is a microchannel reaction module a, and comprises an abamectin and tetramethyl ethylenediamine solution precooling heat exchanger, an allyl chloroformate precooling heat exchanger and a microchannel reactor I, wherein a reaction material is conveyed by a metering pump, and each reactant solution storage tank is respectively connected with the abamectin and tetramethyl ethylenediamine solution precooling heat exchanger and the allyl chloroformate precooling heat exchanger through pipelines and then connected with the microchannel reactor I;
specifically, the device is provided with an abamectin and tetramethyl ethylenediamine solution storage tank, an allyl chloroformate storage tank, an abamectin and tetramethyl ethylenediamine solution precooling heat exchanger, an allyl chloroformate precooling heat exchanger and a microchannel reactor I;
further, in the step 2), the microchannel reaction device of the next module is a microchannel reaction module B, and comprises a phenyl dichlorophosphate precooling heat exchanger, a compound I precooling heat exchanger, a microchannel reactor II and a delay tube, wherein the compound I material, dimethyl sulfoxide and phenyl dichlorophosphate are respectively connected with the microchannel reactor II through pipelines, and the microchannel reactor II is connected with the delay tube;
specifically, the system is provided with a dimethyl sulfoxide storage tank, a phenyl dichlorophosphate storage tank, a microstructure mixer, a phenyl dichlorophosphate precooling heat exchanger, a compound I precooling heat exchanger, a microchannel reactor II, a delay tube and a compound II receiving tank, wherein a compound I material and dimethyl sulfoxide are respectively mixed with the microstructure mixer through pipelines, then are respectively connected with the microchannel reactor II through pipelines in series, and finally enter the compound II receiving tank;
further, the above reaction raw materials and products are delivered by a precision metering pump (such as a plunger pump or a diaphragm pump), and the micro-mixer is a micro-mixing unit with a channel size of 10-1000um, including but not limited to one or two of a star mixer, a separation recombination micro-mixer, an impinging stream micro-mixer, a partition wall crossing micro-mixer and a Y-type mixer; the microchannel reactor is a microreactor with a channel size of 10-1000um, a channel depth of 0.5-4mm and a certain liquid holdup (20-1000mL), and the material of the microreactor is silicon carbide;
the reaction raw materials are input into a micro mixer and subsequent equipment through an accurate metering pump, so that the materials can continuously pass through a micro-channel modular reaction device and the residence time of the materials is controlled; a single-pass heat exchanger is arranged between the microreactor and the product collecting bottle and is used for prolonging the reaction residence time;
further, in the step 2), the molar ratio of the abamectin to the dimethyl sulfoxide is 1: 1-3; the molar ratio of the abamectin to the phenyl dichlorophosphate is 1: 0.8-3;
further, in the step 2), the reaction temperature is-10-15 ℃, and the reaction residence time is 20-30 s;
further, the alkali for adjusting the pH in the step 3) is inorganic alkali;
still further, the inorganic base is an inorganic sodium salt or an inorganic potassium salt; specifically, it can be inorganic sodium salt or inorganic potassium salt such as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, etc.; specifically, an alkali solution with the mass concentration of 0.1-1 mol/L can be used;
further, in the step 4), the distillation is performed by firstly performing atmospheric distillation and then performing negative pressure distillation, wherein the atmospheric distillation temperature is 40-60 ℃, and the vacuum degree of the negative pressure distillation is-0.05-0.1 Mpa.
Due to the adoption of the technology, compared with the prior art, the invention has the remarkable advantages that:
1) by adopting the modularized microchannel reaction device, the mass transfer efficiency is high, the raw materials are fully mixed instantly, the reaction rate is accelerated, the reaction time is greatly shortened, and the production efficiency is improved;
2) the continuous production operation can be realized, the product quality stability is improved, the equipment integration level is high, and the occupied space can be reduced;
3) the product has high yield and high purity, and is superior to the traditional method for producing emamectin benzoate intermediate.
Drawings
FIG. 1 is a schematic diagram of the overall structure of the device for preparing emamectin benzoate intermediate.
Wherein, a 1-abamectin and tetramethylethylenediamine solution storage tank, a 2-allyl chloroformate storage tank, a 3-abamectin and tetramethylethylenediamine solution metering pump, a 4-allyl chloroformate metering pump, a 5-abamectin and tetramethylethylenediamine solution precooling heat exchanger, a 6-allyl chloroformate precooling heat exchanger, a 7-temperature display, an 8-microchannel reactor I, a 9-sampling valve, a 10-one-way stop valve, an 11-phenyl dichlorophosphate storage tank, a 12-dimethyl sulfoxide storage tank, a 13-phenyl dichlorophosphate metering pump, a 14-dimethyl sulfoxide metering pump, a 15-microstructure mixer, a 16-phenyl dichlorophosphate precooling heat exchanger, a 17-compound I precooling heat exchanger, an 18-microchannel reactor II, a 19-delay tube, 20-compound II receiving tank, 21-micro reaction module A and temperature control device, 22-micro reaction module B and temperature control device.
Detailed Description
In order to make the technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to specific examples, but the scope of the present invention is not limited thereby.
The micromixer used in the embodiment is a star-type micromixer which is purchased from Shandong Haomai chemical technology Co., Ltd, and is of the model RHSXN095 and made of Hc-276; the used micro-channel reactor is in an umbrella-shaped channel form, is made of silicon carbide, and is purchased from Shandong Haomai chemical technology Co., Ltd, and has the model number of CS 2; according to different flow rates, a plunger type metering pump and a three-pump-head diaphragm pump are selected respectively, the plunger type metering pump is purchased from Shanghai, the third is scientific and technological instrument company, and the three-pump-head diaphragm pump is purchased from Prolate fluid control (Dalian) company, Inc.
Example 1
A method for preparing an emamectin benzoate intermediate by using a microreactor comprises the following specific steps:
1) dissolving abamectin and tetramethyl ethylenediamine in dichloromethane to form a uniform solution, pumping the solution and allyl chloroformate into a micro-reaction module A respectively, and controlling the abamectin: tetramethylethylenediamine: dichloromethane: reacting allyl chloroformate at the molar ratio of 1:5:20:1.3 at the temperature of-15 ℃ for 15s, sampling through a sampling valve to detect the reaction condition, and obtaining a compound I after the reaction is finished;
2) mixing the reaction liquid of the compound I flowing out in the step (1) with pumped dimethyl sulfoxide in a micro mixer, then flowing into a micro reaction module B, carrying out mixing reaction with phenyl dichlorophosphate pumped simultaneously, and controlling abamectin: dimethyl sulfoxide: the molar ratio of phenyl dichlorophosphate to phenyl dichlorophosphate is 1:2:1.3, the reaction temperature is controlled to be-10 ℃, the reaction retention time is 20s, and a sample is taken from a receiving bottle to detect the reaction condition to obtain a compound II;
3) regulating the pH value of the reaction liquid of the compound II in the step (2) to 7 by using a sodium carbonate solution with the concentration of 0.25mol/L, and standing to separate an organic phase; extracting the water phase with dichloromethane for 2 times;
4) the organic phase distillation in the step (3) is firstly desolventized to 60 ℃ under normal pressure, then is changed into negative pressure, the vacuum degree is minus 0.06Mpa, the desolventization is carried out to 50 ℃, and the dichloromethane is removed, thus obtaining the emamectin benzoate intermediate 4 '-epi-4' -carbonyl-5-allyl formate-avermectin B1The product was weighed and the content was determined by HPLC.
The parallel experiment is carried out for 3 groups, the original method is carried out for 2 groups of comparison experiment,
control experiments (traditional method) parallel 2 groups:
1) adding dichloromethane and abamectin into the reaction kettle for dissolving. Firstly, dripping tetramethyl ethylenediamine for 30min, then dripping allyl chloroformate for 60 min; keeping the temperature for reaction (about 2-3 hours) until the reaction solution of the compound I is qualified;
2) and (3) dropwise adding dimethyl sulfoxide into the reaction solution for 60 min. Dropwise adding phenyl dichlorophosphate for 2 hours, and then carrying out heat preservation reaction (about 2-3 hours) until the reaction solution is qualified to obtain a compound II reaction solution;
3) the material proportion, temperature and post-treatment process in the reaction process were the same as in example 1.
The experimental data are shown in table 1:
TABLE 1
Example 2
A method for preparing an emamectin benzoate intermediate by using a microreactor comprises the following specific steps:
1) dissolving abamectin and tetramethyl ethylenediamine in dichloromethane to form a uniform solution, and respectively pumping the uniform solution and allyl chloroformate into a micro-reaction module A simultaneously to control the abamectin: tetramethylethylenediamine: dichloromethane: reacting allyl chloroformate at the molar ratio of 1:2.5:35:1.05 at the temperature of-10 ℃ for 15s, sampling through a sampling valve to detect the reaction condition, and obtaining a compound I after the reaction is finished;
2) mixing the reaction liquid of the compound I flowing out in the step (1) with pumped dimethyl sulfoxide in a micro mixer, then flowing into a micro reaction module B, carrying out mixing reaction with phenyl dichlorophosphate pumped simultaneously, and controlling abamectin: dimethyl sulfoxide: the molar ratio of phenyl dichlorophosphate to phenyl dichlorophosphate is 1:1.95:1.0, the reaction temperature is controlled to be-5 ℃, the reaction retention time is 30s, and a sample is taken from a receiving bottle to detect the reaction condition to obtain a compound II;
3) regulating the pH value of the reaction liquid of the compound II in the step (2) to 7 by using a sodium carbonate solution with the concentration of 0.25mol/L, and standing to separate an organic phase; extracting the water phase with dichloromethane for 2 times;
4) the organic phase distillation in the step (3) is firstly desolventized to 60 ℃ under normal pressure, then is changed into negative pressure, the vacuum degree is minus 0.06Mpa, the desolventization is carried out to 50 ℃, and the dichloromethane is removed, thus obtaining the emamectin benzoate intermediate 4 '-epi-4' -carbonyl-5-allyl formate-avermectin B1The product was weighed and the content was determined by HPLC.
The parallel experiment is carried out for 3 groups, the original method is carried out for 2 groups of comparison experiment,
control experiments (traditional method) parallel 2 groups:
1) adding dichloromethane and abamectin into the reaction kettle for dissolving. Firstly, dripping tetramethyl ethylenediamine for 30min, then dripping allyl chloroformate for 60 min; keeping the temperature for reaction (about 3-5 hours) until the reaction solution of the compound I is qualified;
2) and (3) dropwise adding dimethyl sulfoxide into the reaction solution for 60 min. Dropwise adding phenyl dichlorophosphate for 2 hours, and then carrying out heat preservation reaction (about 3-5 hours) until the reaction solution is qualified to obtain a compound II reaction solution;
3) the material ratio, temperature and post-treatment process in the reaction process were the same as in example 2.
The experimental data are shown in table 2:
TABLE 2
Example 3
A method for preparing an emamectin benzoate intermediate by using a microreactor comprises the following specific steps:
1) dissolving abamectin and tetramethyl ethylenediamine in dichloromethane to form a uniform solution A, respectively pumping the solution A and allyl chloroformate into a micro-reaction module A, and controlling the abamectin: tetramethylethylenediamine: dichloromethane: reacting allyl chloroformate at a molar ratio of 1:3.5:35:1.07 at-15 ℃ for 10s, sampling through a sampling valve to detect the reaction condition, and obtaining a compound I after the reaction is finished;
2) mixing the reaction liquid of the compound I flowing out in the step (1) with pumped dimethyl sulfoxide in a micro mixer, then flowing into a micro reaction module B, carrying out mixing reaction with phenyl dichlorophosphate pumped simultaneously, and controlling abamectin: dimethyl sulfoxide: the molar ratio of phenyl dichlorophosphate to phenyl dichlorophosphate is 1:2.0:1.0, the reaction temperature is controlled to be-10 ℃, the reaction retention time is 30s, and a sample is taken from a receiving bottle to detect the reaction condition to obtain a compound II;
3) adjusting the pH value of the reaction liquid of the compound II in the step (2) to 7 by using a sodium bicarbonate solution with the concentration of 0.4mol/L, and standing to separate an organic phase; extracting the water phase with dichloromethane for 2 times;
4) the organic phase distillation in the step (3) is firstly desolventized to 60 ℃ under normal pressure, then is changed into negative pressure, the vacuum degree is minus 0.06Mpa, the desolventization is carried out to 50 ℃, and the dichloromethane is removed, thus obtaining the emamectin benzoate intermediate 4 '-epi-4' -carbonyl-5-allyl formate-avermectin B1The product was weighed and the content was determined by HPLC.
The parallel experiment is carried out for 3 groups, the original method is carried out for 2 groups of comparison experiment,
control experiments (traditional method) parallel 2 groups:
1) adding dichloromethane and abamectin into the reaction kettle for dissolving. Firstly, dripping tetramethyl ethylenediamine for 30min, then dripping allyl chloroformate for 60 min; keeping the temperature for reaction (about 3-5 hours) until the reaction solution of the compound I is qualified;
2) and (3) dropwise adding dimethyl sulfoxide into the reaction solution for 60 min. Dropwise adding phenyl dichlorophosphate for 2 hours, and then carrying out heat preservation reaction (about 3-5 hours) until the reaction solution is qualified to obtain a compound II reaction solution;
3) the material ratio, temperature and post-treatment process in the reaction process were the same as in example 3.
The experimental data are as follows:
TABLE 3
Example 4
A method for preparing an emamectin benzoate intermediate by using a microreactor comprises the following specific steps:
1) dissolving abamectin and tetramethyl ethylenediamine in dichloromethane to form a uniform solution, pumping the solution and allyl chloroformate into a micro-reaction module A respectively, and controlling the abamectin: tetramethylethylenediamine: dichloromethane: the allyl chloroformate is reacted at the temperature of-15 ℃ for 10s at the molar ratio of 1:5:40:1.07, the reaction condition is detected by sampling through a sampling valve, and a compound I is obtained after the reaction is finished;
2) mixing the reaction liquid of the compound I flowing out in the step (1) with pumped dimethyl sulfoxide in a micro mixer, then flowing into a micro reaction module B, carrying out mixing reaction with phenyl dichlorophosphate pumped simultaneously, and controlling abamectin: dimethyl sulfoxide: the molar ratio of phenyl dichlorophosphate to phenyl dichlorophosphate is 1:2.0:0.9, the reaction temperature is controlled to be-10 ℃, the reaction retention time is 30s, and a sample is taken from a receiving bottle to detect the reaction condition to obtain a compound II;
3) adjusting the pH value of the reaction liquid of the compound II in the step (2) to 7 by using a sodium bicarbonate solution with the concentration of 0.4mol/L, and standing to separate an organic phase; extracting the water phase with dichloromethane for 2 times;
4) the organic phase distillation in the step (3) is firstly desolventized to 60 ℃ under normal pressure, then is changed into negative pressure, the vacuum degree is minus 0.05Mpa, the desolventization is carried out to 60 ℃, and the dichloromethane is removed, thus obtaining the emamectin benzoate intermediate 4 '-epi-4' -carbonyl-5-allyl formate-avermectin B1The product was weighed and the content was determined by HPLC.
The parallel experiment is carried out for 3 groups, the original method is carried out for 2 groups of comparison experiment,
control experiments (traditional method) parallel 2 groups:
1) adding dichloromethane and abamectin into the reaction kettle for dissolving. Firstly, dripping tetramethyl ethylenediamine for 30min, then dripping allyl chloroformate for 60 min; keeping the temperature for reaction (about 5-6 hours) until the reaction solution of the compound I is qualified;
2) and (3) dropwise adding dimethyl sulfoxide into the reaction solution for 60 min. Dropwise adding phenyl dichlorophosphate for 2 hours, and then carrying out heat preservation reaction (about 4-5 hours) until the reaction solution is qualified to obtain a compound II reaction solution;
3) the material proportion, temperature and post-treatment process in the reaction process were the same as in example 4.
The experimental data are as follows:
TABLE 4
Example 5
A method for preparing an emamectin benzoate intermediate by using a microreactor comprises the following specific steps:
1) dissolving abamectin and tetramethyl ethylenediamine in dichloromethane to form a uniform solution, pumping the solution and allyl chloroformate into a micro-reaction module A respectively, and controlling the abamectin: tetramethylethylenediamine: dichloromethane: the allyl chloroformate is reacted at the temperature of 20 ℃ for 10s according to the molar ratio of 1:5:40:1.07, the reaction condition is detected by sampling through a sampling valve, and a compound I is obtained after the reaction is finished;
2) mixing the reaction liquid of the compound I flowing out in the step (1) with pumped dimethyl sulfoxide in a micro mixer, then flowing into a micro reaction module B, carrying out mixing reaction with phenyl dichlorophosphate pumped simultaneously, and controlling abamectin: dimethyl sulfoxide: the molar ratio of phenyl dichlorophosphate to phenyl dichlorophosphate is 1:2.0:0.9, the reaction temperature is controlled to be 20 ℃, the reaction retention time is 20s, and a sample is taken from a receiving bottle to detect the reaction condition to obtain a compound II;
3) adjusting the pH value of the reaction liquid of the compound II in the step (2) to 7 by using a sodium bicarbonate solution with the concentration of 0.4mol/L, and standing to separate an organic phase; extracting the water phase with dichloromethane for 2 times;
4) the organic phase distillation in the step (3) is firstly desolventized to 60 ℃ under normal pressure, then is changed into negative pressure, the vacuum degree is minus 0.05Mpa, the desolventization is carried out to 60 ℃, and the dichloromethane is removed, thus obtaining the emamectin benzoate intermediate 4 '-epi-4' -carbonyl-5-allyl formate-avermectin B1The product was weighed and the content was determined by HPLC.
The parallel experiment is carried out for 3 groups, the original method is carried out for 2 groups of comparison experiment,
control experiments (traditional method) parallel 2 groups:
1) adding dichloromethane and abamectin into the reaction kettle for dissolving. Firstly, dripping tetramethyl ethylenediamine for 30min, then dripping allyl chloroformate for 60 min; keeping the temperature for reaction (about 2-3 hours) until the reaction solution of the compound I is qualified;
2) and (3) dropwise adding dimethyl sulfoxide into the reaction solution for 60 min. Dropwise adding phenyl dichlorophosphate for 2 hours, and then carrying out heat preservation reaction (about 2-3 hours) until the reaction solution is qualified to obtain a compound II reaction solution;
3) the material ratio, temperature and post-treatment process in the reaction process were the same as in example 5.
The experimental data are as follows:
TABLE 5
Example 6
A method for preparing an emamectin benzoate intermediate by using a microreactor comprises the following specific steps:
1) dissolving abamectin and tetramethyl ethylenediamine in dichloromethane to form a uniform solution, pumping the solution and allyl chloroformate into a micro-reaction module A respectively, and controlling the abamectin: tetramethylethylenediamine: dichloromethane: the allyl chloroformate is reacted at the temperature of 15 ℃ for 10s at the molar ratio of 1:5:40:1.07, the reaction condition is detected by sampling through a sampling valve, and a compound I is obtained after the reaction is finished;
2) mixing the reaction liquid of the compound I flowing out in the step (1) with pumped dimethyl sulfoxide in a micro mixer, then flowing into a micro reaction module B, carrying out mixing reaction with phenyl dichlorophosphate pumped simultaneously, and controlling abamectin: dimethyl sulfoxide: the molar ratio of phenyl dichlorophosphate to phenyl dichlorophosphate is 1:2.0:0.9, the reaction temperature is controlled to be 15 ℃, the reaction retention time is 25s, and a sample is taken from a receiving bottle to detect the reaction condition to obtain a compound II;
3) adjusting the pH value of the reaction liquid of the compound II in the step (2) to 7 by using a sodium bicarbonate solution with the concentration of 0.4mol/L, and standing to separate an organic phase; extracting the water phase with dichloromethane for 2 times;
4) the organic phase distillation in the step (3) is firstly desolventized to 60 ℃ under normal pressure, then is changed into negative pressure, the desolventization is carried out under the vacuum degree of minus 0.05Mpa to 60 ℃, and dichloromethane is removed, namelyObtaining the emamectin benzoate intermediate 4 '-epi-4' -carbonyl-5-allyl formate-avermectin B1The product was weighed and the content was determined by HPLC.
The parallel experiment is carried out for 3 groups, the original method is carried out for 2 groups of comparison experiment,
control experiments (traditional method) parallel 2 groups:
1) adding dichloromethane and abamectin into the reaction kettle for dissolving. Firstly, dripping tetramethyl ethylenediamine for 30min, then dripping allyl chloroformate for 60 min; keeping the temperature for reaction (about 2-3 hours) until the reaction solution of the compound I is qualified;
2) and (3) dropwise adding dimethyl sulfoxide into the reaction solution for 60 min. Dropwise adding phenyl dichlorophosphate for 2 hours, and then carrying out heat preservation reaction (about 2-3 hours) until the reaction solution is qualified to obtain a compound II reaction solution;
3) the material ratio, temperature and post-treatment process in the reaction process were the same as in example 6.
The experimental data are as follows:
TABLE 6
Example 7
A method for preparing an emamectin benzoate intermediate by using a microreactor comprises the following specific steps:
1) dissolving abamectin and tetramethyl ethylenediamine in dichloromethane to form a uniform solution, pumping the solution and allyl chloroformate into a micro-reaction module A respectively, and controlling the abamectin: tetramethylethylenediamine: dichloromethane: the allyl chloroformate is reacted at the temperature of 15 ℃ for 10s according to the molar ratio of 1:4.5:35:1.02, the reaction condition is detected by sampling through a sampling valve, and a compound I is obtained after the reaction is finished;
2) mixing the reaction liquid of the compound I flowing out in the step (1) with pumped dimethyl sulfoxide in a micro mixer, then flowing into a micro reaction module B, carrying out mixing reaction with phenyl dichlorophosphate pumped simultaneously, and controlling abamectin: dimethyl sulfoxide: the molar ratio of phenyl dichlorophosphate to phenyl dichlorophosphate is 1:2.0:1.1, the reaction temperature is controlled to be 15 ℃, the reaction retention time is 20s, and a sample is taken from a receiving bottle to detect the reaction condition to obtain a compound II;
3) adjusting the pH value of the reaction liquid of the compound II in the step (2) to 7 by using a sodium bicarbonate solution with the concentration of 0.4mol/L, and standing to separate an organic phase; extracting the water phase with dichloromethane for 2 times;
4) the organic phase distillation in the step (3) is firstly desolventized to 60 ℃ under normal pressure, then is changed into negative pressure, the vacuum degree is minus 0.05Mpa, the desolventization is carried out to 60 ℃, and the dichloromethane is removed, thus obtaining the emamectin benzoate intermediate 4 '-epi-4' -carbonyl-5-allyl formate-avermectin B1The product was weighed and the content was determined by HPLC.
The parallel experiment is carried out for 3 groups, the original method is carried out for 2 groups of comparison experiment,
control experiments (traditional method) parallel 2 groups:
1) adding dichloromethane and abamectin into the reaction kettle for dissolving. Firstly, dripping tetramethyl ethylenediamine for 30min, then dripping allyl chloroformate for 60 min; keeping the temperature for reaction (about 2-3 hours) until the reaction solution of the compound I is qualified;
2) and (3) dropwise adding dimethyl sulfoxide into the reaction solution for 60 min. Dropwise adding phenyl dichlorophosphate for 2 hours, and then carrying out heat preservation reaction (about 2-3 hours) until the reaction solution is qualified to obtain a compound II reaction solution;
3) the material ratio, temperature and post-treatment process in the reaction process were the same as in example 7.
The experimental data are as follows:
TABLE 7
Example 8
A method for preparing an emamectin benzoate intermediate by using a microreactor comprises the following specific steps:
(1) dissolving 100kg (0.12kmol) of abamectin and 40kg (0.34kmol) of tetramethylethylenediamine in 300kg (3.52kmol) of dichloromethane to form a uniform solution (volume of 340L), placing the uniform solution in a raw material storage tank, and pumping the uniform solution into a micro-reaction module A at a flow rate of 3.837L/min; simultaneously, 16kg (0.13kmol, 14L) of allyl chloroformate is pumped into a micro-reaction module I at the flow rate of 0.158L/min to react with abamectin; controlling the reaction module 1 to react at the temperature of-15 ℃, keeping the reaction time for 15s, and sampling through a sampling valve to detect the reaction condition to obtain a compound I;
2) adding 18kg (0.23kmol) of dimethyl sulfoxide into 30kg of dichloromethane for dilution to prepare a uniform solution (the volume is 35L), pumping the uniform solution into a mixer at a rate of 0.177L/min, fully mixing the uniform solution with a reaction solution (the volume is 350L) of the compound I flowing out in the step (1) in a micro mixer, then flowing into a micro reaction module B, pumping 25kg (0.117kmol, the volume is 17L) of phenyl dichlorophosphate into a micro reaction module II and a coil reactor at a rate of 0.859L/min, controlling the total liquid holding capacity of the step to be 3L, controlling the reaction temperature to be-10 ℃ and the reaction retention time to be 25s, sampling from a receiving bottle, and detecting the reaction condition to obtain a compound II;
3) adjusting the pH value of the reaction liquid of the compound II in the step (2) to 7 by using a sodium bicarbonate solution with the concentration of 0.4mol/L, and standing to separate an organic phase; extracting the water phase with dichloromethane for 2 times;
4) the organic phase distillation in the step (3) is firstly desolventized to 60 ℃ under normal pressure, then is changed into negative pressure, the vacuum degree is minus 0.05Mpa, the desolventization is carried out to 60 ℃, and the dichloromethane is removed, thus obtaining the emamectin benzoate intermediate 4 '-epi-4' -carbonyl-5-allyl formate-avermectin B1The product was weighed and the content was determined by HPLC.
The parallel experiment is carried out for 3 groups, the original method is carried out for 2 groups of comparison experiment,
control experiments (traditional method) parallel 2 groups:
1) adding dichloromethane and abamectin into the reaction kettle for dissolving. And firstly, dropwise adding tetramethylethylenediamine for 30min, and then dropwise adding allyl chloroformate for 60 min. Keeping the temperature for reaction (about 4-6 hours) until the reaction solution of the compound I is qualified;
2) and (3) dropwise adding dimethyl sulfoxide into the reaction solution for 60 min. Dropwise adding phenyl dichlorophosphate for 2 hours, and then carrying out heat preservation reaction (about 4-6 hours) until the reaction solution is qualified to obtain a compound II reaction solution;
3) the material ratio, temperature and post-treatment process in the reaction process were the same as in example 5.
The experimental data are as follows:
TABLE 8
It can be seen from the experiments of the above examples that:
the microreactor is used for protecting the hydroxyl at the C5-position and oxidizing the C4-position of the emamectin benzoate intermediate, the conversion rate and the selectivity of two-step reaction are obviously improved, the total yield of two steps is greatly improved compared with the original process, particularly, the reaction is greatly shortened, and the good effect of synthesizing the product by using the microreactor is fully demonstrated.
The above-mentioned embodiments are merely preferred embodiments of the present invention, and should not be construed as limiting the present invention, and the scope of the present invention should be defined by the claims, and equivalents including technical features of the claims, i.e., equivalent modifications within the scope of the present invention.
Claims (10)
1. A method for preparing an emamectin benzoate intermediate by using a microreactor is characterized by comprising the following steps:
1) dissolving abamectin and tetramethylethylenediamine in dichloromethane, and pumping the dichloromethane and allyl chloroformate into a modular microchannel reaction device respectively, controlling the reaction temperature to be-25-20 ℃ and the reaction residence time to be 10-20 s to obtain a compound I;
2) mixing the compound I obtained in the step 1) with dimethyl sulfoxide, pumping the mixture and phenyl dichlorophosphate into a microchannel reaction device of the next module respectively, and controlling the reaction temperature to be-20 ℃ and the reaction residence time to be 20-40 s to obtain a compound II;
3) adjusting the pH value of the compound II obtained in the step (2) to 7-8 by using alkali, and standing to separate an organic phase;
4) distilling the organic phase obtained in the step (3) to remove dichloromethane to obtain the emamectin benzoate intermediate 4 '-epi-4' -carbonyl-5-allyl formate-abamectin B1。
2. The method for preparing the emamectin benzoate intermediate by using the microreactor as claimed in claim 1, wherein in the step 1), the molar ratio of the abamectin to the dichloromethane is 1: 20-50; preferably, the molar ratio of the abamectin to the tetramethylethylenediamine is 1: 1-6.
3. The method for preparing the emamectin benzoate intermediate by using the microreactor as claimed in claim 1, wherein in the step 1), the molar ratio of the abamectin to the allyl chloroformate is 1: 1-1.5.
4. The method for preparing the emamectin benzoate intermediate by using the microreactor as claimed in claim 1, wherein in the step 1), the reaction temperature is-15 ℃, and the reaction residence time is 10-15 s.
5. The method for preparing the emamectin benzoate intermediate by using the microreactor as claimed in claim 1, wherein the modularized microchannel reaction device in the step 1) is a microchannel reaction module A, and comprises an abamectin and tetramethyl ethylenediamine solution precooling heat exchanger, an allyl chloroformate precooling heat exchanger and a microchannel reactor I, wherein a reaction material is conveyed by a metering pump, and each reactant solution storage tank is respectively connected with the abamectin and tetramethyl ethylenediamine solution precooling heat exchanger and the allyl chloroformate precooling heat exchanger through pipelines and then connected with the microchannel reactor I.
6. The method for preparing the emamectin benzoate intermediate by using the microreactor as claimed in claim 1, wherein in the step 2), the molar ratio of the abamectin to the dimethyl sulfoxide is 1: 1-3; the molar ratio of the abamectin to the phenyl dichlorophosphate is 1: 0.8-3.
7. The method for preparing the emamectin benzoate intermediate by using the microreactor as claimed in claim 1, wherein in the step 2), the reaction temperature is-10-15 ℃, and the reaction residence time is 20-30 s.
8. The method for preparing the emamectin benzoate intermediate by using the microreactor as claimed in claim 1, wherein in the step 2), the microchannel reaction device of the next module is a microchannel reaction module B, and comprises a phenyl dichlorophosphate precooling heat exchanger, a compound I precooling heat exchanger, a microchannel reactor II and a delay tube, wherein the compound I material, dimethyl sulfoxide and phenyl dichlorophosphate are respectively connected with the microchannel reactor II through pipelines, and the microchannel reactor II is connected with the delay tube.
9. The method for preparing the emamectin benzoate intermediate by using the microreactor as claimed in claim 1, wherein the base for adjusting the pH in the step 3) is an inorganic base; preferably, the inorganic base is an inorganic sodium salt or an inorganic potassium salt.
10. The method for preparing the emamectin benzoate intermediate by using the microreactor as claimed in claim 1, wherein in the step 4), the distillation is performed by firstly performing atmospheric distillation and then performing negative pressure distillation, the atmospheric distillation temperature is 40-60 ℃, and the negative pressure distillation vacuum degree is-0.05-0.1 MPa.
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