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CN114181267B - Synthesis method of emamectin benzoate - Google Patents

Synthesis method of emamectin benzoate Download PDF

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Publication number
CN114181267B
CN114181267B CN202111544543.6A CN202111544543A CN114181267B CN 114181267 B CN114181267 B CN 114181267B CN 202111544543 A CN202111544543 A CN 202111544543A CN 114181267 B CN114181267 B CN 114181267B
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solution
kettle
formula
oxidation
reaction
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CN114181267A (en
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薛树会
任建海
钟行利
周士珂
罗俊峰
刘文耀
于晓军
徐亚会
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QILU SYNVA PHARMACEUTICAL CO Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/04—Monocyclic monocarboxylic acids
    • C07C63/06—Benzoic acid
    • C07C63/08—Salts thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses a method for synthesizing emamectin benzoate, which comprises a continuous preparation method of a protection procedure, an oxidation procedure, an amination procedure, a deprotection procedure and a salification procedure. In the protection procedure, avermectin (formula II) is dissolved in haloalkane to obtain avermectin solution, and the avermectin solution, alkali and a protective agent are respectively and continuously pumped into a multi-kettle serial device to obtain mixed reaction solution A containing 5-hydroxyl-protected avermectin (formula III); in the deprotection step, inorganic alkali such as sodium hydroxide, potassium hydroxide and the like is added into sodium borohydride alcohol solution; desalting and filtering are carried out before the amination step. Solves the problem that the stable continuous flow production cannot be realized in the whole process in the emamectin benzoate production process in the prior art, has small material quantity in the online reaction, and can realize intrinsic safety.

Description

Synthesis method of emamectin benzoate
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing emamectin benzoate.
Technical Field
Emamectin benzoate (collectively referred to as emamectin benzoate), white or pale yellow crystalline powder, is dissolved in acetone and methanol, slightly water-soluble, and insoluble in hexane. The emamectin benzoate is a novel efficient semisynthetic antibiotic pesticide, and has the characteristics of super-high efficiency, low toxicity (the preparation is near non-toxic), low residue, no public hazard and the like. Is widely used for preventing and controlling various pests on crops such as vegetables, fruit trees, cotton and the like. The emamectin benzoate is synthesized by taking a fermentation product avermectin B1 as a raw material, wherein the natural avermectin contains 8 components, and the total content of the natural avermectin is more than or equal to 80 percent, namely A 1a、A2a、B1a and B 2a are mainly 4 components; the corresponding 4 smaller homologs are A 1b、A2b、B1b and B 2b, the total content of which is less than or equal to 20%.
The traditional method for synthesizing emamectin benzoate is to protect the hydroxyl on the 5 '-position of avermectin by using a reaction kettle, oxidize the carbonyl on the 4' -position, reduce the carbonyl by sodium borohydride, deprotect to generate emamectin benzoate, and further form salt with benzoic acid, but the methods have the defects of large online loading capacity, high risk, no continuity and automation of the whole process, and the like. The traditional process and production equipment have the defects of large carrying capacity, insufficient reaction, lower yield and higher impurity, and influence on the product quality. Meanwhile, the dropping reaction time is controlled to be prolonged due to large heat release. In the protection reaction process, mass transfer is poor, so that the content of local allyl chloroformate is too high, the temperature is too high, the selectivity is poor, C4' -hydroxyl is easy to form, meanwhile, the protection is carried out, the waste of raw materials is caused, and the yield is low. And a great deal of manpower is consumed, and the operation is complex.
When the emamectin benzoate and the intermediate thereof are prepared, the microreactor is adopted, so that the online loading capacity can be reduced, the specific reaction is sufficient, the mass transfer and the heat transfer are good, the produced impurities are few, the product quality is better, and the yield is higher. For example, chinese patent document CN 110627853A (201910902849.0) discloses a method for preparing emamectin benzoate intermediate by using a microreactor, which is characterized by comprising the following steps: 1) Dissolving abamectin and tetramethyl ethylenediamine in dichloromethane, and respectively pumping the dichloromethane and allyl chloroformate into a modularized micro-channel reaction device, wherein the reaction temperature is controlled to be-25-20 ℃ and the reaction residence time is controlled to be 10-20 s, so as to obtain a compound I; 2) Mixing dimethyl sulfoxide with the compound I obtained in the step 1), and respectively pumping the mixture and phenyl dichlorophosphate into a micro-channel reaction device of a next module, wherein the reaction temperature is controlled to be-20 ℃, and the reaction residence time is controlled to be 20-40 s, so as to obtain a compound II; 3) Regulating 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) And (3) distilling the organic phase in the step (3) to remove dichloromethane, thus obtaining the emamectin benzoate intermediate 4 '-epi-4' -carbonyl-5-allyl formate-abamectin B 1. However, in the protection and oxidation step of preparing emamectin benzoate, a microchannel reactor is adopted, and salt is generated and separated out to block a pipeline in the reaction process, so that the operation of equipment is affected.
Chinese patent document CN 113072598A (202110358641.4) discloses a method for continuously preparing emamectin benzoate and an intermediate thereof, wherein the emamectin benzoate intermediate is C4' -methylamino-5-allylformate-avermectin B 1, and the method specifically comprises the following steps: dissolving C4 '-methylimino-5-allyl formate-abamectin B 1 in haloalkane, respectively pumping the solution into a mixer together with alcohol of C 1-4, respectively pumping the mixture into a micro-channel modularized reaction device together with a reducing agent solution, controlling the reaction temperature to be-15-25 ℃ and the reaction residence time to be 3-50 s, and obtaining C4' -methylamino-5-allyl formate-abamectin B 1. However, the reducing agent solution in the patent is unstable, and can degrade to generate bubbles, so that accurate feeding cannot be realized. Due to the problems, the prior art still cannot realize the complete continuous production of emamectin benzoate.
Disclosure of Invention
The invention provides a synthesis method of emamectin benzoate in order to solve the problem that the stable continuous flow production cannot be realized in the whole process in the prior art. According to the invention, the modularized reaction device is adopted to carry out continuous production operation, so that the mass transfer and heat transfer rates are greatly improved, the reaction time is greatly shortened, the byproducts of the product are lower, the quality of the product is better, and the intrinsic safety of the synthesis process is realized.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
The method for synthesizing the emamectin benzoate is characterized by comprising the following steps of:
(1) Dissolving avermectin (formula II) in haloalkane to obtain avermectin solution, continuously pumping the avermectin solution, alkali and protective agent into a multi-kettle serial device respectively to obtain mixed reaction solution A containing 5-hydroxy-protected avermectin (formula III),
R 1 is CH 3 or C 2H5, and X-Y is ch=ch or CH 2 -CH (OH);
R 2 is a protecting group from allyl chloroformate, ethyl chloroformate, trimethylchlorosilane, tert-butyldimethylchlorosilane, preferably allyl chloroformate and tert-butyldimethylchlorosilane;
(2) The mixed reaction liquid A, dimethyl sulfoxide, organic base and oxidation activator solution obtained in the step (1) are respectively pumped into a multi-kettle serial device to generate mixed reaction liquid B containing 4' carbonyl-5-hydroxyl protection abamectin (formula IV);
(3) Filtering the mixed reaction liquid B obtained in the step (2), and respectively and continuously pumping the filtered mixed reaction liquid B, organic acid and methylamine alcohol into an amination process microreactor, wherein the reaction temperature is controlled to be 0-50 ℃, and the reaction residence time is controlled to be 30-200 s, so that a mixed reaction liquid C is obtained;
(4) Pumping the mixed reaction solution C and the sodium borohydride alcohol solution into a reduction process microreactor respectively, controlling the reaction temperature to be-20 ℃ and the reaction residence time to be 20-100 s, and obtaining a mixed reaction solution D containing a compound (formula V);
(5) Mixing the mixed reaction solution D with the catalyst solution, respectively and continuously pumping the mixed reaction solution D and the sodium borohydride alcohol solution into a deprotection process tubular reactor, controlling the reaction temperature to be-20-10 ℃ and the reaction residence time to be 1-15 min, so as to obtain a mixed reaction solution E containing a compound (formula VI);
(6) The mixed reaction solution E containing the compound (formula VI) is fully mixed with an inorganic acid solution and an inorganic alkali solution respectively, and then separated, wherein the lower layer is 4' methylamino avermectin (formula VI); the 4' methylamino avermectin (formula VI) reacts with benzoic acid to produce emamectin benzoate (formula I).
Preferably, the reaction of the reaction solution in the step (1) in the multi-kettle serial device comprises: all avermectin solution and protective agent accounting for 30 percent of the total weight of the protective agent enter a first-stage protective kettle and stay for a certain time; the reactant obtained from the first-stage protective kettle enters a second-stage protective kettle, and simultaneously, a protective agent accounting for 30 percent of the total weight of the protective agent is continuously pumped into the second-stage protective kettle to stay for a certain time; the reactant obtained by the second-stage protective kettle enters the third-stage protective kettle, and simultaneously, the protective agent accounting for 30 percent of the total weight of the protective agent is continuously pumped into the third-stage protective kettle to stay for a certain time; the reactant obtained by the three-stage protective kettle enters the four-stage protective kettle, and simultaneously, the protective agent accounting for 10 percent of the total weight of the protective agent is continuously pumped into the four-stage protective kettle to stay for a certain time.
Further preferably, the reaction temperature in the step (1) is-40-0 ℃, and the single kettle reaction residence time is 5-15 min; the total residence time is 20-60 min.
Preferably, the mass ratio of the compound (formula II) to the haloalkane in the step (1) is 1:3-10. The molar ratio of the avermectin to the haloalkane is 1:3-10, so that the solvent consumption is greatly reduced, and the solvent can be greatly reduced by adopting a multi-kettle serial device, so that the raw materials are prevented from being separated out.
Preferably, the molar ratio of the compound of formula (II) to the base in step (1) is 1:0.5-3. Preferably 1:0.6 to 0.8.
Preferably, the molar ratio of the compound of formula (II) to the protecting agent in step (1) is 1:0.8-3. Preferably 1:1 to 1.2.
Preferably, the base in step (1) is an organic amine, and more preferably one or both of tetramethyl ethylenediamine and triethylamine.
Preferably, the protective agent in the step (1) is a hydroxyl protective agent, and more preferably one of allyl chloroformate, ethyl chloroformate, trimethylchlorosilane and tert-butyldimethylsilyl chloride. The protecting agent provides the R 2 group.
Preferably, the haloalkane in step (1) is selected from one of dichloromethane, chloroform, and 1, 2-dichloroethane.
Preferably, the reaction of the reaction solution in the step (2) in the multi-kettle serial device comprises: all the mixed solution B and the oxidation activator solution accounting for 30 percent of the total weight of the oxidation activator solution enter a first-stage oxidation kettle and stay for a certain time; the reactants obtained from the first-stage oxidation kettle enter a second-stage oxidation kettle, and simultaneously, an oxidation activator solution accounting for 30 percent of the total weight of the oxidation activator solution is continuously pumped into the second-stage oxidation kettle to stay for a certain time; the reactant obtained by the second-stage oxidation kettle enters a third-stage oxidation kettle, and simultaneously, an oxidation activator solution accounting for 30 percent of the total weight of the oxidation activator solution is continuously pumped into the third-stage oxidation kettle for a certain time; the reactants obtained by the three-stage oxidation kettle enter a four-stage oxidation kettle, and simultaneously, the oxidation activator solution accounting for 10 percent of the total weight of the oxidation activator solution is continuously pumped into the four-stage oxidation kettle to stay for a certain time.
It is further preferable that the reaction control temperature in the step (2) is-10 to 30 ℃, the single-kettle reaction residence time is 5 to 15min, and the total residence time is 20 to 60min. The preferred temperature is-10 to 20 ℃.
Preferably, in step (2), the molar ratio of compound (formula III) to dimethylsulfoxide is 1:1.2-4.
Preferably, in the step (2), the molar ratio of the dimethyl sulfoxide to the organic base is 1:0.5-3. Preferably 1:0.9 to 1.2.
Preferably, in the step (2), the oxidation activator is one of phenyl dichlorophosphate and triphosgene.
Preferably, in step (2), the molar ratio of compound (formula III) to oxidation activator is 1:0.2-3. Preferably 1:0.35 to 0.9.
Preferably, in the step (2), the mass ratio of the oxidation activator to the haloalkane is 1:0.5-4.
Preferably, in the step (2), the organic base is selected from one of tetramethyl ethylenediamine and triethylamine. In the invention, organic alkali is added as an acid binding agent, and the pH of the environment is controlled, so that the reaction is normally carried out.
Preferably, in the step (2), the haloalkane is selected from one of dichloromethane, chloroform and 1, 2-dichloroethane.
Further preferably, in step (3), the organic acid is selected from one of formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzoic acid, p-toluenesulfonic acid and methanesulfonic acid. Further preferably, in step (3), the molar ratio of compound (formula iv) to organic acid is 1:0.1 to 4. Preferably, 1:0.5 to 1.2. Preferably, the temperature is 25 to 45 ℃.
Further preferably, in step (3), the alcohol in the methylamine alcohol is one of methanol and ethanol.
Further preferably, in the step (3), the mass fraction of methylamine in the methylamine alcohol is between 10% and 90%.
Further preferably, in step (3), the molar ratio of the organic acid to methylamine is 1:1.5 to 15. Preferably 1:4 to 5.
Preferably, the alcohol in the sodium borohydride alcoholic solution in the step (4) is selected from one of methanol and ethanol.
Preferably, in the step (4), an inorganic base such as sodium hydroxide or potassium hydroxide is added to the sodium borohydride alcoholic solution. Can prevent sodium borohydride from degrading to generate bubbles, has stable feeding metering and realizes continuous production.
Preferably, in the step (4), the mass ratio of the sodium borohydride to the alcohol is 1:1-10.
Preferably, in the step (4), the molar ratio of the sodium borohydride to the inorganic base is 1:0.01-2.
Preferably, the catalyst in the step (5) is a palladium catalyst, and more preferably one of tetrakis (triphenylphosphine) palladium and bis (triphenylphosphine) palladium dichloride.
Preferably, the catalyst solution in the step (5) is a haloalkane solution of a catalyst, and the haloalkane is selected from one of dichloromethane, chloroform and 1, 2-dichloroethane. The concentration of the catalyst in the catalyst solution is 0.5% -2%.
Preferably, the alcohol of the sodium borohydride alcoholic solution in step (5) is selected from methanol and ethanol.
Preferably, in the step (5), an inorganic base such as sodium hydroxide or potassium hydroxide is added to the sodium borohydride alcoholic solution.
Preferably, in the step (5), the mass ratio of the sodium borohydride to the alcohol is 1:1-10.
Preferably, in the step (5), the molar ratio of the sodium borohydride to the inorganic base is 1:0.01-2.
Preferably, the salifying method in the step (6) comprises the following steps: mixing the mixed reaction solution E containing the compound (formula VI) with the benzoic acid solution, pumping into a continuous concentration device, controlling the temperature of the concentration device between 20 and 60 ℃, concentrating until the solid content is between 20 and 70 percent, and then feeding the concentrated solution into a continuous drying device, controlling the drying temperature between 20 and 120 ℃, thus obtaining the compound (formula I).
Further preferably, in step (6), the continuous concentration device is a thin film evaporator.
The invention has the beneficial effects that:
The invention adopts a multi-kettle series device in the protection and oxidation steps, and the generated salt is removed by the parallel filter, so that the condition that the pipeline is blocked by salting out is avoided, and the invention has stable continuous automation.
According to the invention, sodium borohydride is dissolved in methanol to prepare a solution, and a small amount of sodium hydroxide is added to serve as a stabilizer, so that sodium borohydride is prevented from being degraded to generate bubbles, a metering pump can be used for feeding, and feeding accuracy is ensured.
The invention realizes a full-flow continuous production mode through improving the combined device, has high automation level and less material quantity of online reaction (the material quantity is reduced by more than 90 percent compared with kettle reaction), and can realize intrinsic safety.
Drawings
Fig. 1 is a schematic diagram of a multi-tank serial device for a protection process.
FIG. 2 is a schematic diagram of the structure of a multi-tank serial device for the oxidation process.
FIG. 3 is a schematic diagram of a continuous production flow of emamectin benzoate.
FIG. 4 is a liquid chromatogram of the emamectin benzoate obtained in example 1.
Reference numerals: 1. avermectin dichloromethane solution storage tank; 2. a protecting agent storage tank; 3. an organic alkali storage tank; 4. a dimethylsulfoxide storage tank; 5. an oxidation activator solution storage tank; 6. an organic acid storage tank; 7. a methylamine alcohol storage tank; 8. a sodium borohydride solution storage tank; 9. a catalyst storage tank; 10. a hydrochloric acid storage tank; 11. a liquid alkali storage tank; 12. a benzoic acid solution storage tank; 13. a protection procedure multi-kettle serial device; 14. the oxidation process is a multi-kettle serial device; 15. a parallel filter device; 16. an amination process microreactor; 17. a heat exchanger; 18. a reduction process microreactor; 19. a deprotection process tubular reactor; 20. a heat exchanger; 21. a pipe mixer; 22. a heat exchanger; 23. a pipe mixer; 24. a conical knockout; 25. a tube mixer; 26. a continuous evaporator; 27. a continuous belt dryer; 28. a metering pump; A. a section of protection kettle; B. a second-stage protection kettle; C. a three-stage protection kettle; D. a four-stage protection kettle; E. a first-stage oxidation kettle; F. a second-stage oxidation kettle; G. a three-stage oxidation kettle; H. and (3) a four-stage oxidation kettle.
Detailed Description
In order to make the technical scheme and advantages of the present invention more apparent, the present invention will be further described in detail with reference to specific examples, but the scope of the present invention is not limited thereto.
The raw materials and devices used in the invention are all common commercial products, wherein avermectin (formula II) is purchased from Lu Zhiyao (inner Mongolia) and the protection process multi-kettle serial device is purchased from Shanghai Hui and chemical de biotechnology Co., ltd, the oxidation process multi-kettle serial device is purchased from Shanghai Hui and chemical de biotechnology Co., ltd, the parallel filter device is purchased from Shanghai Grignard fluid equipment technology Co., ltd, the amination process microreactor and the reduction process microreactor are purchased from Shanghai Hui and chemical de biotechnology Co., ltd, and the deprotection process tubular reactor is purchased from Shanghai Hui and chemical de biotechnology Co., ltd. In the embodiment of the invention, allyl chloroformate, tetramethyl ethylenediamine, dimethyl sulfoxide, phenyl dichlorophosphate, acetic acid and the like are all pure substances. The mass fraction of methylamine in the methylamine alcohol is 40%.
Example 1
A method for synthesizing emamectin benzoate comprises the following steps:
(1) Mixing avermectin B1 and dichloromethane according to the mass ratio of 1:3, adding into a dissolution kettle, fully stirring and dissolving, cooling to-30 ℃ to obtain an avermectin solution, and transferring into an avermectin solution storage tank (1) for standby.
The reaction temperature in the protective kettle (A/B/C/D) is controlled to be minus 30+/-5 ℃. And (3) feeding the avermectin solution prepared in the step (1) into a kettle A according to the flow rate of 520Kg/h, and simultaneously pumping allyl chloroformate (protective agent) and tetramethyl ethylenediamine (alkali) into the kettle A, wherein the flow rates of the allyl chloroformate and the tetramethyl ethylenediamine are respectively controlled at 5.85Kg/h and 10.38Kg/h. The three materials are fully mixed and reacted in the kettle A; the feed liquid enters the B kettle by self-flowing, allyl chloroformate is pumped in, the flow speed is controlled at 5.85Kg/h, and then the mixture is fully mixed; the material liquid enters the protection series kettle C kettle through self-flowing, allyl chloroformate is pumped in at the same time, the flow speed is controlled to be 5.85Kg/h, then the material liquid is fully mixed, the material liquid enters the protection series kettle D kettle through self-flowing, allyl chloroformate is pumped in at the same time, the flow speed is controlled to be 1.95Kg/h, then the material liquid is fully mixed, the material liquid enters the oxidation series kettle E kettle, and the residence time of the reaction liquid in the A, B, C, D kettle is 10min. In this example, the molar ratio of avermectin to base is 1:0.6, the molar ratio of the avermectin to the allyl chloroformate is 1:1.086.
(2) The reaction temperature in the oxidation series reactor (E/F/G/H) is controlled to be between 13 ℃ below zero and 3 ℃. After the reaction solution enters an oxidation series kettle E kettle, dimethyl sulfoxide, tetramethyl ethylenediamine and phenyl dichlorophosphate solution (prepared methylene dichloride solution with the mass concentration of 50%) are pumped at the same time, the flow rates of the dimethyl sulfoxide, the tetramethyl ethylenediamine and the phenyl dichlorophosphate solution are respectively controlled at 15.59Kg/H, 20.87Kg/H and 17.34Kg/H, the four materials are subjected to full mixing reaction in the oxidation series kettle E kettle, the feed liquid enters the oxidation series kettle F kettle through self flow, the phenyl dichlorophosphate solution is pumped at the flow rate of 17.34Kg/H, the feed liquid enters the oxidation series kettle G kettle through self flow, the phenyl dichlorophosphate solution is pumped at the flow rate of 17.34Kg/H, the feed liquid enters the oxidation series kettle H kettle through self flow, the phenyl dichlorophosphate solution is pumped at the flow rate of 5.78/H, the feed liquid is subjected to full mixing, the solid in the feed liquid is removed through a parallel filtering device (15), and the filtrate enters an amination process microreactor (16 Kg) for amination reaction. The residence time of the reaction solution in the E, F, G, H kettle is 15min.
Specifically, in step (2) of this example, the molar ratio of the compound (formula III) to dimethylsulfoxide was 1:1.34. The molar ratio of dimethyl sulfoxide to organic base was 1:0.9. The molar ratio of compound (formula III) to oxidation activator was 1:0.92.
(3) The temperature of the amination reaction is controlled to be 30+/-5 ℃, the flow rate of the oxide feed liquid entering the micro-reactor in the amination process is controlled to be 600Kg/h, meanwhile, acetic acid and methylamine alcohol are pumped in, and the flow rates of the acetic acid and the methylamine alcohol are respectively controlled to be 10.36Kg/h and 64.79Kg/h. The residence time was controlled to 150s. The reaction liquid of the amination process microreactor (16) enters a heat exchanger (17) through a pump to be cooled to-15+/-5 ℃, and then the discharged material enters a reduction process microreactor module, wherein the flow is 675Kg/h.
Specifically, in the step (3), the molar ratio of the compound (formula iv) to acetic acid is 1:1.16, the mass fraction of methylamine in methylamine alcohol is 40%. The molar ratio of acetic acid to methylamine was 1:4.84.
(4) The reaction temperature in the reduction process microreactor (18) is controlled to be between-15+/-5 ℃. Pumping the amination material into a microreactor of a reduction process, and simultaneously pumping a methanol solution of sodium borohydride containing sodium hydroxide, wherein the flow rate of the sodium borohydride solution is 17.09Kg/h, and the reaction residence time is 100s.
The mass ratio of the sodium borohydride to the methanol is 1:5, and the molar ratio of the sodium borohydride to the sodium hydroxide is 1:0.0625.
(5) The reaction liquid of the micro-reactor in the reduction process enters a tubular reactor (19) in the deprotection process through a pump, the flow rate is controlled to 692Kg/h, and simultaneously sodium borohydride alcohol solution containing sodium hydroxide and catalyst solution are pumped in, and the flow rates of the sodium borohydride alcohol solution and the catalyst solution are respectively controlled to 17.09Kg/h and 34.58Kg/h. The reaction temperature is controlled to be minus 15 plus or minus 5 ℃, and the reaction residence time is controlled to be 200s.
Specifically, the catalyst is tetra (triphenylphosphine) palladium, the catalyst solution is methylene dichloride solution of the catalyst, the alcohol in the sodium borohydride alcohol solution is methanol, the mass ratio of the sodium borohydride to the methanol is 1:5, and the molar ratio of the sodium borohydride to the sodium hydroxide is 1:0.0625.
The reaction liquid of the tubular reactor (19) in the deprotection procedure enters a heat exchanger (20) through a pump to be cooled to-5+/-5 ℃, the discharged material enters a pipeline mixer (21), and is fully mixed with hydrochloric acid (HCl with the mass percentage of 15%) in the mixer, and enters a heat exchanger (22) to be cooled to 0+/-5 ℃ again. Then the mixed solution enters a pipeline mixer (23) again, is fully mixed with alkali liquor (NaOH with the mass percentage of 14%) in the mixer, and enters a conical liquid separator (24) for continuous liquid separation treatment; the upper water phase is continuously layered and enters a wastewater treatment center. The addition of hydrochloric acid is calculated according to the amounts of monomethylamine, organic acid and sodium borohydride, and the excess monomethylamine and sodium borohydride are consumed for 10% more, so as to ensure complete acidification; the alkali liquor is mainly used for neutralizing excessive inorganic acid, ensuring that the reaction solution is in a neutral condition and preventing the degradation of products.
(6) The layered lower layer deprotection reaction solution enters a tubular mixer (25), benzoic acid solution (the pre-prepared concentration is 20%) is pumped at the same time, the flow rate is controlled to be 90.83Kg/h, the two materials are fully mixed in the mixer, then enter a continuous evaporator (26) for concentration, the concentration temperature is 25+/-5 ℃ (the solid content of the outlet is controlled to be 50%), meanwhile, the discharged material enters a continuous belt dryer (27) (the primary control temperature is 115+/-5 ℃, the secondary control temperature is 90+/-5 ℃, the tertiary control temperature is 75+/-5 ℃, the quaternary control temperature is 15+/-5 ℃) for drying operation, and meanwhile, the discharged material is continuously discharged to a material temporary storage bin, and then the packaging operation is carried out.
149.05Kg/h of emamectin benzoate product can be obtained, the content is 78.5%, and the mass yield is 90%. The purity was 87.2%.
Example 2
A method for synthesizing emamectin benzoate comprises the following steps:
The difference from the embodiment 1 is that,
And (3) a protection procedure: the protective agent is ethyl chloroformate, the organic base is triethylamine, and the mol ratio of abamectin to triethylamine is 1:0.8, the molar ratio of the avermectin to the ethyl chloroformate is 1:1.2, the reaction temperature is-20+/-5 ℃.
Oxidation procedure: the organic base is triethylamine, and the molar ratio of the dimethyl sulfoxide to the organic base is 1:1.2.
Amination step: at a temperature of 40+ -5deg.C, acetic acid is replaced by benzoic acid solution, the concentration of the benzoic acid solution is 20%, and the molar ratio of the compound (formula IV) to benzoic acid is 1:1.2.
147.82Kg/h of emamectin benzoate product can be obtained, the content is 78.1 percent, the mass yield is 88.8 percent, and the purity is 85.2 percent.
Example 3
A method for synthesizing emamectin benzoate comprises the following steps:
The difference from the embodiment 1 is that,
And (3) a protection procedure: the organic base is triethylamine, and the mol ratio of the abamectin to the triethylamine is 1:0.8.
Oxidation procedure: the organic base is triethylamine, the mol ratio of dimethyl sulfoxide to the organic base is 1:1.2, the activator is methylene dichloride solution of triphosgene, the concentration of triphosgene is 30%, the mol ratio of the compound (formula III) to triphosgene is 1:0.35, and the reaction temperature is 0+/-5 ℃.
Amination step: at a temperature of 40+/-5 ℃, acetic acid is replaced by a p-toluenesulfonic acid solution, the concentration of the p-toluenesulfonic acid solution is 20%, and the molar ratio of the compound (formula IV) to the p-toluenesulfonic acid is 1:0.5, the molar ratio of the p-toluenesulfonic acid to the methylamine is 1:4.5.
Deprotection process: the temperature is controlled to be 5+/-5 ℃, the reaction residence time is 150s, and the catalyst is bis (triphenylphosphine) palladium dichloride.
151.42Kg/h of emamectin benzoate product can be obtained, the content is 77.9%, the mass yield is 90.73%, and the purity is 88.5%.
Comparative example 1
A method for synthesizing emamectin benzoate comprises the following steps: the difference from example 1 is that step (1) is changed: three kettles are adopted for series connection:
The protective agents added into the three kettles A, B, C respectively account for 40%,30% and 30% of the total amount of the protective agents. Other conditions were the same as in example 1. 146.05kg/h of emamectin benzoate product can be obtained, the content is 71.5 percent, and the mass yield is 80.3 percent. Purity 81.3%.
Therefore, the adoption of three kettles in series can lead to incomplete reaction, incomplete raw material conversion and great reduction of the conversion rate and purity of the product.
Comparative example 2
A method for synthesizing emamectin benzoate comprises the following steps: the difference from example 1 is that sodium hydroxide is not added in the step (4), and the emamectin benzoate product 147.12kg/h, the content of 66.8% and the mass yield of 75.6% can be obtained under the same conditions as in example 1. Purity of 72.8%
Therefore, as sodium hydroxide is not added as a stabilizer, a large amount of bubbles are generated in the sodium borohydride solution, the metering accuracy of a pump is affected, the addition amount is large in part of time, the product generates side reaction, and the incomplete conversion of raw materials is caused by the insufficient addition of part of time. Both cases reduce the yield and purity of the product. In addition, the sodium borohydride can be degraded greatly without adding the stabilizer, the reaction is qualified only by increasing the dosage of the sodium borohydride solution, and meanwhile, the sodium borohydride by-product can degrade the product, so that the yield and purity of the product are affected.
It can be seen that the absence of sodium hydroxide as a stabilizer seriously affects the smooth running of continuous production.
Comparative example 3
A method for synthesizing emamectin benzoate comprises the following steps: the difference from example 1 is that no desalting filtration is carried out before the amination reaction in step (3), and the other conditions are the same as in example 1. 144.14kg/h of emamectin benzoate product can be obtained, the content is 68.7%, and the mass yield is 76.2%. Purity 74.2%.
The method can be carried out for 3.5 hours continuously, while example 1 can be carried out for more than one week continuously. The reason why the continuous production for a long time was impossible in comparative example 1 is that: and the byproduct salt generated in the oxidation process is protected from entering a subsequent process without a filtering process, and is accumulated in the amination microreactor by continuously hanging walls, so that a pipeline is finally blocked, and the production is stopped.
The molar ratio of the abamectin to the haloalkane is 1:3-10, so that the solvent consumption is greatly reduced, and the method adopts a multi-kettle series-connection and parallel-connection filtering device, so that the tolerance of the system to solid precipitation phenomenon is greatly improved, the smoothness of the system is ensured, the continuity of continuous production is further ensured, and the reduction of the solvent is also indirectly realized.

Claims (15)

1. The method for synthesizing the emamectin benzoate is characterized by comprising the following steps of:
(1) Dissolving avermectin (formula II) in haloalkane to obtain avermectin solution, continuously pumping avermectin solution, alkali and protecting agent into multi-kettle serial device respectively, removing the produced salt by parallel filter to obtain mixed reaction solution A containing 5-hydroxy-protected avermectin (formula III),
（Ⅱ）；
（Ⅲ）
R 1 is CH 3 or C 2H5, and X-Y is ch=ch or CH 2 -CH (OH);
R 2 is a protecting group from allyl chloroformate, ethyl chloroformate, trimethylchlorosilane and tert-butyldimethylchlorosilane; the reaction of the reaction liquid in the multi-kettle serial device comprises the following steps: all avermectin solution and protective agent accounting for 30 percent of the total weight of the protective agent enter a first-stage protective kettle and stay for a certain time; the reactant obtained from the first-stage protective kettle enters a second-stage protective kettle, and simultaneously, a protective agent accounting for 30 percent of the total weight of the protective agent is continuously pumped into the second-stage protective kettle to stay for a certain time; the reactant obtained by the second-stage protective kettle enters the third-stage protective kettle, and simultaneously, the protective agent accounting for 30 percent of the total weight of the protective agent is continuously pumped into the third-stage protective kettle to stay for a certain time; the reactant obtained by the three-stage protective kettle enters a four-stage protective kettle, and simultaneously, the protective agent accounting for 10 percent of the total weight of the protective agent is continuously pumped into the four-stage protective kettle to stay for a certain time;
the reaction temperature is-40-0 ℃, and the single-kettle reaction residence time is 5-15 min; the total residence time is 20-60 min;
(2) The mixed reaction liquid A, dimethyl sulfoxide, organic base and oxidation activator solution obtained in the step (1) are respectively pumped into a multi-kettle serial device to generate mixed reaction liquid B containing 4' carbonyl-5-hydroxyl protection abamectin (formula IV);
（Ⅳ）；
The reaction of the reaction liquid in the multi-kettle serial device comprises the following steps: all the mixed solution B and the oxidation activator solution accounting for 30 percent of the total weight of the oxidation activator solution enter a first-stage oxidation kettle and stay for a certain time; the reactants obtained from the first-stage oxidation kettle enter a second-stage oxidation kettle, and simultaneously, an oxidation activator solution accounting for 30 percent of the total weight of the oxidation activator solution is continuously pumped into the second-stage oxidation kettle to stay for a certain time; the reactant obtained by the second-stage oxidation kettle enters a third-stage oxidation kettle, and simultaneously, an oxidation activator solution accounting for 30 percent of the total weight of the oxidation activator solution is continuously pumped into the third-stage oxidation kettle for a certain time; the reactants obtained by the three-stage oxidation kettle enter a four-stage oxidation kettle, and simultaneously, an oxidation activator solution accounting for 10 percent of the total weight of the oxidation activator solution is continuously pumped into the four-stage oxidation kettle to stay for a certain time; the reaction control temperature is-10-30 ℃, the single-kettle reaction residence time is 5-15min, and the total residence time is 20-60 min;
(3) Filtering the mixed reaction liquid B obtained in the step (2), and respectively and continuously pumping the filtered mixed reaction liquid B, the organic acid and the methylamine alcohol into an amination process microreactor, wherein the reaction temperature is controlled to be 0-50 ℃, and the reaction residence time is controlled to be 30-200 s, so that a mixed reaction liquid C is obtained;
(4) Respectively pumping the mixed reaction liquid C and the sodium borohydride alcohol solution into a reduction process microreactor, controlling the reaction temperature to be-20 ℃ and the reaction residence time to be 20-100 s, and obtaining a mixed reaction liquid D containing a compound (formula V); adding inorganic alkali sodium hydroxide or potassium hydroxide into the sodium borohydride alcohol solution, wherein the molar ratio of the sodium borohydride to the inorganic alkali is 1:0.01-2;
（Ⅴ）；
(5) Mixing the mixed reaction solution D and the catalyst solution, respectively and continuously pumping the mixed reaction solution D and the sodium borohydride alcohol solution into a deprotection process tubular reactor, controlling the reaction temperature to be-20-10 ℃ and the reaction residence time to be 1-15 min, and obtaining a mixed reaction solution E containing a compound (formula VI);
（Ⅵ）；
(6) The mixed reaction solution E containing the compound (formula VI) is fully mixed with an inorganic acid solution and an inorganic alkali solution respectively, and then separated, wherein the lower layer is 4' methylamino avermectin (formula VI); reacting 4' methylamino avermectin (formula VI) with benzoic acid to generate emamectin benzoate (formula I);
（Ⅰ）。
2. The method of claim 1, wherein in step (1), R 2 is derived from allyl chloroformate and t-butyldimethylsilyl chloride.
3. The method for synthesizing emamectin benzoate according to claim 1 or 2, wherein the mass ratio of the compound (formula ii) to the haloalkane in the step (1) is 1:3-10;
The molar ratio of the compound in the formula (II) to the alkali in the step (1) is 1:0.5-3;
The molar ratio of the compound in the formula (II) to the protective agent in the step (1) is 1:0.8-3;
the alkali in the step (1) is organic amine.
4. The method for synthesizing emamectin benzoate according to claim 3, wherein the molar ratio of the compound of formula (II) to the base in the step (1) is 1:0.6-0.8; the molar ratio of the compound of the formula (II) to the protective agent is 1:1-1.2; the alkali is one or two of tetramethyl ethylenediamine and triethylamine.
5. The method for synthesizing emamectin benzoate according to claim 4, characterized in that,
The haloalkane in the step (1) is selected from one of dichloromethane, chloroform and 1, 2-dichloroethane.
6. The method for synthesizing emamectin benzoate according to claim 1, wherein the temperature in the step (2) is-10-20 ℃; the molar ratio of the compound (formula III) to the dimethyl sulfoxide is 1:1.2-4;
the molar ratio of the dimethyl sulfoxide to the organic base is 1:0.5-3;
The oxidation activator is one of phenyl dichlorophosphate and triphosgene;
the mol ratio of the compound (formula III) to the oxidation activator is 1:0.2-3;
The mass ratio of the oxidation activator to the haloalkane is 1:0.5-4;
in the step (2), the organic base is selected from one of tetramethyl ethylenediamine and triethylamine; the alkyl halide is selected from one of dichloromethane, chloroform and 1, 2-dichloroethane.
7. The method for synthesizing emamectin benzoate according to claim 6, wherein in the step (2), the molar ratio of the compound (formula iii) to the oxidation activator is 1:0.35-0.9; the molar ratio of the dimethyl sulfoxide to the organic base is 1:0.9-1.2.
8. The method for synthesizing emamectin benzoate according to claim 1, wherein in step (3), the organic acid is selected from one of formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzoic acid, p-toluenesulfonic acid and methanesulfonic acid;
the molar ratio of compound (formula IV) to organic acid is 1:0.1 to 4; the temperature is 25-45 ℃;
the alcohol in the methylamine alcohol is one of methanol or ethanol;
The mass fraction of methylamine in methylamine alcohol is 10% -90%;
the molar ratio of the organic acid to the methylamine is 1: 1.5-15.
9. The method of claim 1, wherein in step (3), the molar ratio of the compound (formula iv) to the organic acid is 1: 0.5-1.2; the mol ratio of the organic acid to the methylamine is 1:4-5.
10. The method for synthesizing emamectin benzoate according to claim 1, wherein the alcohol in the sodium borohydride alcoholic solution in the step (4) is one selected from methanol and ethanol;
And (3) in the step (4), the mass ratio of the sodium borohydride to the alcohol is 1:1-10.
11. The method for synthesizing emamectin benzoate according to claim 1, wherein the catalyst in step (5) is a palladium catalyst.
12. The method for synthesizing emamectin benzoate according to claim 11, wherein the catalyst in step (5) is one of tetrakis (triphenylphosphine) palladium and bis (triphenylphosphine) palladium dichloride.
13. The method for synthesizing emamectin benzoate according to claim 1, wherein the catalyst solution in step (5) is a haloalkane solution of a catalyst, and the haloalkane is selected from one of dichloromethane, chloroform and 1, 2-dichloroethane; the concentration of the catalyst in the catalyst solution is 0.5% -2%;
The alcohol of the sodium borohydride alcohol solution is selected from methanol and ethanol;
Sodium hydroxide and potassium hydroxide are added into the sodium borohydride alcohol solution;
the mass ratio of the sodium borohydride to the alcohol is 1:1-10;
The molar ratio of the sodium borohydride to the inorganic base is 1:0.01-2.
14. The method for synthesizing emamectin benzoate according to claim 1, wherein the salifying method in step (6) is as follows: mixing the mixed reaction solution E containing the compound (formula VI) with a benzoic acid solution, pumping into a continuous concentration device, controlling the temperature of the concentration device to be 20-60 ℃, concentrating until the solid content is 20-70%, and then feeding the concentrated solution into a continuous drying device, controlling the drying temperature to be 20-120 ℃, thereby obtaining the compound (formula I).
15. The method of claim 14, wherein the continuous concentrating device in step (6) is a thin film evaporator.
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