CN113354695A - Continuous production process of emamectin benzoate B1/B2 - Google Patents
Continuous production process of emamectin benzoate B1/B2 Download PDFInfo
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- CN113354695A CN113354695A CN202110580357.1A CN202110580357A CN113354695A CN 113354695 A CN113354695 A CN 113354695A CN 202110580357 A CN202110580357 A CN 202110580357A CN 113354695 A CN113354695 A CN 113354695A
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- emamectin benzoate
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- 238000000034 method Methods 0.000 title claims abstract description 23
- 230000008569 process Effects 0.000 title claims abstract description 22
- 238000010924 continuous production Methods 0.000 title claims abstract description 21
- CXEGAUYXQAKHKJ-NSBHKLITSA-N emamectin B1a Chemical compound C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](NC)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 CXEGAUYXQAKHKJ-NSBHKLITSA-N 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 92
- 239000005660 Abamectin Substances 0.000 claims abstract description 40
- -1 methylamino avermectin B1 Chemical compound 0.000 claims abstract description 34
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 32
- 239000002994 raw material Substances 0.000 claims abstract description 31
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000002904 solvent Substances 0.000 claims abstract description 29
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 26
- 238000005576 amination reaction Methods 0.000 claims abstract description 23
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 23
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims abstract description 23
- 238000006722 reduction reaction Methods 0.000 claims abstract description 22
- RRZXIRBKKLTSOM-XPNPUAGNSA-N avermectin B1a Chemical compound C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 RRZXIRBKKLTSOM-XPNPUAGNSA-N 0.000 claims abstract description 21
- 238000004519 manufacturing process Methods 0.000 claims abstract description 20
- 239000012442 inert solvent Substances 0.000 claims abstract description 17
- GZKHDVAKKLTJPO-UHFFFAOYSA-N ethyl 2,2-difluoroacetate Chemical compound CCOC(=O)C(F)F GZKHDVAKKLTJPO-UHFFFAOYSA-N 0.000 claims abstract description 16
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000012046 mixed solvent Substances 0.000 claims abstract description 10
- 230000009467 reduction Effects 0.000 claims abstract description 8
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 7
- 230000020477 pH reduction Effects 0.000 claims abstract description 4
- ZPAKHHSWIYDSBJ-QDXJZMFISA-N avermectin b2 Chemical compound O1C(C)C(O)C(OC)CC1OC1C(OC)CC(O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O[C@@H]([C@@H](C)C(O)C4)C(C)C)O3)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)OC1C ZPAKHHSWIYDSBJ-QDXJZMFISA-N 0.000 claims abstract description 3
- 230000003647 oxidation Effects 0.000 claims abstract description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 29
- 238000002425 crystallisation Methods 0.000 claims description 20
- 230000008025 crystallization Effects 0.000 claims description 20
- 238000001914 filtration Methods 0.000 claims description 20
- 229950008167 abamectin Drugs 0.000 claims description 18
- IBSREHMXUMOFBB-JFUDTMANSA-N 5u8924t11h Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O3)C=C[C@H](C)[C@@H](C(C)C)O4)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 IBSREHMXUMOFBB-JFUDTMANSA-N 0.000 claims description 16
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 16
- 238000001816 cooling Methods 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 13
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical group CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 12
- 150000007530 organic bases Chemical class 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical group [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000012074 organic phase Substances 0.000 claims description 9
- 239000005711 Benzoic acid Substances 0.000 claims description 8
- 238000006859 Swern oxidation reaction Methods 0.000 claims description 8
- 235000010233 benzoic acid Nutrition 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 6
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 6
- CMPQUABWPXYYSH-UHFFFAOYSA-N phenyl phosphate Chemical compound OP(O)(=O)OC1=CC=CC=C1 CMPQUABWPXYYSH-UHFFFAOYSA-N 0.000 claims description 6
- 239000011592 zinc chloride Substances 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- ZSMNRKGGHXLZEC-UHFFFAOYSA-N n,n-bis(trimethylsilyl)methanamine Chemical group C[Si](C)(C)N(C)[Si](C)(C)C ZSMNRKGGHXLZEC-UHFFFAOYSA-N 0.000 claims description 5
- 230000001590 oxidative effect Effects 0.000 claims description 5
- CAEWJEXPFKNBQL-UHFFFAOYSA-N prop-2-enyl carbonochloridate Chemical group ClC(=O)OCC=C CAEWJEXPFKNBQL-UHFFFAOYSA-N 0.000 claims description 5
- 235000005074 zinc chloride Nutrition 0.000 claims description 5
- 239000012452 mother liquor Substances 0.000 claims description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical group [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims description 2
- 239000005894 Emamectin Substances 0.000 claims description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 238000005406 washing Methods 0.000 abstract description 10
- 239000002699 waste material Substances 0.000 abstract description 5
- 239000007810 chemical reaction solvent Substances 0.000 abstract description 4
- 238000004134 energy conservation Methods 0.000 abstract description 3
- 238000005265 energy consumption Methods 0.000 abstract description 3
- 239000000575 pesticide Substances 0.000 abstract description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 abstract 1
- GCKZANITAMOIAR-XWVCPFKXSA-N dsstox_cid_14566 Chemical compound [O-]C(=O)C1=CC=CC=C1.C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H]([NH2+]C)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 GCKZANITAMOIAR-XWVCPFKXSA-N 0.000 description 40
- 238000003756 stirring Methods 0.000 description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 238000004321 preservation Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 6
- 229940011051 isopropyl acetate Drugs 0.000 description 6
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000000110 cooling liquid Substances 0.000 description 3
- 239000000498 cooling water Substances 0.000 description 3
- 238000004807 desolvation Methods 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000003825 pressing Methods 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000011085 pressure filtration Methods 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000002920 hazardous waste Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000010829 isocratic elution Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000004383 yellowing Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- 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
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- 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 relates to the technical field of pesticide production, and particularly discloses a continuous production process of emamectin benzoate B1/B2 benzoate. The production process comprises the following steps: under the condition of an inert solvent, taking avermectin shown in a formula (I) as a raw material, and sequentially and continuously carrying out 5-position hydroxyl protection, 4' -position hydroxyl oxidation, amination reduction, deprotection and acidification salt-forming reaction to obtain methylamino avermectin B1/B2 benzoate shown in a formula (II); wherein the inert solvent is a mixed solvent of ethyl difluoroacetate and dichloroethane; the reducing agent of the amination reduction reaction is sodium triacetoxyborohydride. The invention realizes the emamectin benzoate by selecting a specific reaction solvent and a reducing agent for amination reduction reactionThe continuous production of formate avoids the complex operations of desolventizing, redissolving, washing and the like, improves the yield of the product, uses a small amount of solvent in the reaction, reduces the three-waste treatment, meets the requirements of energy conservation and consumption reduction, and has wide application prospect.
Description
Technical Field
The invention relates to the technical field of pesticide production, in particular to a continuous production process of emamectin benzoate B1/B2 benzoate.
Background
The emamectin benzoate B1 and the emamectin benzoate B2 are used as mature insecticides, are widely used and have large annual yield. The currently reported preparation process of emamectin benzoate mainly comprises the following steps: taking avermectin as a raw material, carrying out esterification reaction on 5-hydroxyl of the avermectin in a dichloromethane solvent under the conditions of low temperature and no water, and protecting active hydroxyl of the avermectin to obtain protected avermectin; then performing Swern oxidation reaction on the protected abamectin and an oxidant, oxidizing 4' hydroxyl of the abamectin into carbonyl, and after the reaction is finished, washing with water, drying and desolventizing to obtain an abamectin ketone compound; then dissolving the avermectin ketone compound in isopropyl acetate to obtain ZnCl2Or Zn (CF)3COO)2As a catalyst, NaBH4As a reducing agent, carrying out amination and reduction reaction at the 4 'position, converting the carbonyl at the 4' position into methylamino, and adding excessive NaBH after the reaction is finished4Removing a protecting group from the 5 th position, washing, drying and desolventizing after the reaction is finished to obtain a crude product of the emamectin benzoate, dissolving the crude product of the emamectin benzoate by using an isopropyl acetate solvent, adding benzoic acid for salifying, and adding n-hexane or petroleum ether solvent for crystallization to obtain the emamectin benzoate.
The preparation process involves twice water washing and twice desolventizing operations, and the repeated water washing can cause product loss, so that the yield of emamectin benzoate is low; moreover, the properties of the reaction intermediate and the product are close to those of saccharides, the reaction solution becomes viscous after being concentrated to a certain degree, so that the desolvation is extremely difficult, the solvent can be removed only by prolonging the desolvation time, but the intermediate or the product is decomposed and the color of the product is yellowed due to the overlong desolvation time, so that the yield and the appearance of the final product are influenced. In addition, the number of equipment is increased in the desolventizing and redissolving step, the operation difficulty is increased, the production period is prolonged, more solvents are applied, the production operation and management are not facilitated, the difficulty of the post-treatment of the solvents is increased, and the potential safety hazard of the actual production is increased. Therefore, the development of the production process of the emamectin benzoate B1/B2, which has the advantages of simple process, high product yield and high quality, has very important significance.
Disclosure of Invention
Aiming at the problems of poor yield and quality, complex operation and low production efficiency of the production process of emamectin benzoate B1/B2 in the prior art, the invention provides a continuous production process of emamectin benzoate B1/B2.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
a continuous production process of emamectin benzoate B1/B2 comprises the following steps:
under the condition of an inert solvent, taking avermectin shown in a formula (I) as a raw material, and sequentially and continuously carrying out 5-position hydroxyl protection, 4' -position hydroxyl oxidation, amination reduction, deprotection and acidification salt-forming reaction to obtain methylamino avermectin B1/B2 benzoate shown in a formula (II); wherein the inert solvent is a mixed solvent of ethyl difluoroacetate and dichloroethane; the reducing agent of the amination reduction reaction is sodium triacetoxyborohydride;
r is CH3Or CH2CH3(ii) a X-Y is CH ═ CH or CH2-CH(OH)。
Compared with the prior art, the production process of emamectin benzoate B1/B2 shown in formula (II) provided by the invention selects a mixed solvent of ethyl difluoroacetate and dichloroethane as a reaction solvent, and selects sodium triacetoxyborohydride as a reducing agent for amination reduction reaction, so that all reaction raw materials can be fully dissolved in a reaction system, the aim of reaching reaction conditions required by each step of reaction can be ensured, and the full progress of each step of reaction is ensured, thereby realizing the continuous progress of 5-bit hydroxyl reaction, oxidation reaction, amination reduction reaction, deprotection and acidification salt formation in the same solvent, avoiding the operations of desolventizing, redissolving, washing and the like, improving the product yield and improving the appearance of the product; in addition, the reaction solvent provided by the invention has lower solubility to the organic base hydrochloride, can effectively avoid the influence of the organic base hydrochloride formed in the reaction on the amination reaction, reduces the generation of impurities in the amination reaction, and improves the purity of the product. The production process of methylamino B1/B2 benzoate provided by the invention not only reduces the variety of raw materials, but also avoids operations such as desolventizing, redissolving, washing and the like, simplifies the operation process, improves the yield and purity (the purity can reach more than 97 percent and the yield can reach more than 85 percent) of methylamino abamectin B1/B2 benzoate products, is more suitable for industrial large-scale production, and has very important significance for the development of abamectin pesticides.
The emamectin benzoate B1/B2 comprises emamectin B1a/1bBenzoate and emamectin B2a/2bA benzoate salt. When R is CH2CH3X-Y is CH ═ CH, and the compound shown in the formula (II) is emamectin benzoate B1a benzoate; when R is CH3X-Y is CH ═ CH, and the compound shown in the formula (II) is emamectin benzoate B1B benzoate; when R is CH2CH3X-Y is CH2-CH (OH), wherein the compound shown in the formula (II) is emamectin benzoate B2a benzoate; when R is CH3X-Y is CH2-CH (OH), wherein the compound shown in the formula (II) is emamectin benzoate B2B benzoate.
Preferably, the content of ethyl difluoroacetate in the inert solvent is 10-20 wt%.
The optimized proportion of ethyl difluoroacetate can increase the solubility of sodium triacetoxyborohydride in a system, ensure the reaction temperature required by the amination reaction to be reached and improve the conversion rate of the amination reaction.
Preferably, the continuous production process of emamectin benzoate B1/B2 specifically comprises the following steps:
s101, dissolving abamectin shown in a formula (I) in an inert solvent, cooling, adding a hydroxyl protecting reagent and organic base to perform 5-bit hydroxyl protecting reaction, after the reaction is completed, adding an oxidant and the organic base into a reaction liquid to perform Swern oxidation reaction, and filtering after the reaction is completed to obtain an oxidation reaction liquid;
s102, adding an aminating agent and a catalyst into the oxidation reaction liquid, carrying out amination reaction, cooling after reaction is completed, adding alcohol and sodium triacetoxyborohydride for reduction reaction, adding a deprotection catalyst and sodium triacetoxyborohydride after reaction is completed, carrying out 5-site deprotection reaction, and filtering after reaction is completed to obtain deprotection reaction liquid;
s103, adding benzoic acid and a crystallization solvent into the deprotection reaction solution, and cooling and crystallizing to obtain the emamectin benzoate B1/B2 shown in the formula (II).
The production process of emamectin benzoate B1/B2 provided by the invention realizes the continuous production of emamectin benzoate, avoids the complex operations of desolventizing, redissolving, washing and the like, improves the yield of products, reduces the three-waste treatment, meets the requirements of energy conservation and consumption reduction, and has wide application prospect.
Preferably, in the step S101, the mass ratio of the inert solvent to the avermectin raw material shown in the formula (i) is 5-10: 1.
Preferably, in step S101, the hydroxyl protecting reagent is allyl chloroformate, the organic base is tetramethylethylenediamine or triethylamine, and the oxidizing agent is dimethyl sulfoxide and phenyl phosphate diacid chloride.
Preferably, in step S101, the adding amount of the hydroxyl protecting reagent is 13.8 to 14.2 wt% of the weight of the avermectin raw material, the adding amount of the phenyl phosphate diacid chloride is 27 to 28 wt% of the weight of the avermectin raw material, and the adding amount of the dimethyl sulfoxide is 9 to 11 wt% of the weight of the avermectin raw material.
Preferably, in the step S101, in the 5-position hydroxyl protection reaction, the amount of the organic base added is 10 to 11 wt% of the abamectin raw material; in the Swern oxidation reaction, the adding amount of the organic base is 3.5-4.2 wt% of the mass of the avermectin raw material.
Preferably, in step S101, the temperature is reduced to-25 ℃, a hydroxyl protecting reagent and an organic base are added to perform a 5-position hydroxyl protecting reaction, and the temperature in the hydroxyl protecting reaction process is controlled not to exceed-20 ℃.
Preferably, in step S101, the temperature of the Swern oxidation reaction is between-10 and-5 ℃.
The preferable reaction conditions can ensure that the 5-position hydroxyl protection reaction and the oxidation reaction are carried out more fully, reduce the occurrence of side reactions and improve the conversion rate of reaction raw materials.
Preferably, in step S102, the aminating agent is heptamethyldisilazane, the catalyst is zinc chloride, and the deprotection catalyst is palladium acetate or tetrakis (triphenylphosphine) palladium.
Preferably, in the step S102, in the reduction reaction, the addition amount of the sodium triacetoxyborohydride is 30 to 35 wt% of the mass of the avermectin raw material; in the deprotection reaction, the addition amount of the sodium triacetoxyborohydride is 20-25 wt% of the mass of the avermectin raw material.
The sodium triacetoxyborohydride has higher solubility in a mixed solvent of ethyl difluoroacetate and dichloroethane, can promote the reduction and deprotection reactions, and improves the yield of the emamectin benzoate B1/B2.
Preferably, in step S102, the adding amount of the amination agent is 25 to 30 wt% of the mass of the avermectin raw material, the adding amount of the catalyst is 2 to 2.5 wt% of the mass of the avermectin raw material, and the adding amount of the deprotection catalyst is 0.5 to 0.6 wt% of the mass of the avermectin raw material.
Preferably, in the step S102, the adding amount of the alcohol is 3-4 wt% of the mass of the avermectin raw material.
Optionally, the alcohol is absolute ethyl alcohol or absolute methyl alcohol.
Preferably, in step S102, the temperature of the amination reaction is 60-65 ℃ and the reaction time is 6-7 h.
Preferably, in step S102, the temperature of the reduction reaction is-5 to 0 ℃ and the reaction time is 1 to 1.5 hours.
Preferably, in step S102, the temperature of the 5-position deprotection reaction is 0-5 ℃, and the reaction time is 2-3 h.
The preferable reaction conditions of the step S102 are favorable for promoting the amination reduction reaction and the 5-position deprotection reaction, and the yield and the purity of the emamectin benzoate B1/B2 are improved.
Preferably, in step S103, the crystallization solvent is cycloheptane.
The preferable crystallization solvent is matched with the preferable inert solvent, so that the emamectin benzoate B1/B2 can be fully separated out in the crystallization process, and reaction byproducts are guaranteed to be always dissolved in a system and cannot be separated out in the crystallization process, so that the purity and the yield of the product are improved.
Preferably, the mass ratio of the crystallization solvent to the abamectin raw material shown in the formula (I) is 1-5: 1.
Preferably, in step S103, the temperature for cooling crystallization is 0 to 5 ℃, and the time for cooling crystallization is 25 to 35 min.
The preferable crystallization condition can further improve the yield and the purity of the product.
Optionally, in step S103, the adding amount of benzoic acid is the same as the molar amount of the avermectin raw material.
Preferably, step S103 further includes: and (3) cooling the crystallization mother liquor obtained by filtering to-25 to-30 ℃, carrying out solid-liquid separation to obtain an organic phase, separating the organic phase, removing cycloheptane, and returning the organic phase to the step (S101) to be used as a solvent for dissolving the abamectin raw material.
Optionally, the organic phase is optionally rectified in a rectification column to remove the cycloheptane.
The invention also has a remarkable advantage in selecting the mixed solvent of ethyl difluoroacetate and dichloroethane: the crystallization mother liquor can be frozen to remove moisture, ethyl difluoroacetate and dichloroethane can be recycled to the first step after the moisture is removed to be used as solvents for dissolving the abamectin raw materials, the 5-position hydroxyl protection reaction and the oxidation reaction are not influenced, the raw material cost is reduced, the generation of three wastes is reduced, the treatment cost of the three wastes is reduced, and the requirements of energy conservation and consumption reduction are met.
In the invention, each step of reaction is carried out under the protection of inert atmosphere.
The invention provides a production process of emamectin benzoate B1/B2, which realizes continuous production of the emamectin benzoate, the yield of the product can reach more than 85%, the purity can reach more than 97%, the solvent after reaction is convenient to separate, the solvent is convenient to recycle, no hazardous waste polluting the environment is generated, and the production process is green and environment-friendly and is suitable for large-scale industrial production.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
In the prior art, the emamectin benzoate preparation needs multiple desolventizing, and the steps of adding other solvents again for dissolution and multiple washing after desolventizing, so that the operation is complicated, and continuous operation cannot be realized. And the problems of yellowing of products, low yield and the like are easily caused by the steps of desolventizing and washing. In addition, in the prior art, dichloromethane is mainly used as a solvent for 5-hydroxyl protection reaction and oxidation reaction to promote the 5-hydroxyl protection reaction and the oxidation reaction to be fully performed, but dichloromethane cannot achieve good reaction effect when being used as a solvent for subsequent amination reaction, so that more impurities are generated, the yield of emamectin benzoate is low, and therefore, desolventization is required to be replaced by an isopropyl acetate solvent. However, isopropyl acetate as a solvent also has a series of problems: the water generated by the reductive amination reaction can be mixed and dissolved with isopropyl acetate, and can be recycled after being dehydrated by adopting dehydrating agents such as calcium chloride or magnesium sulfate, and the like, thereby increasing the three wastes and the treatment cost. In addition, the organic base (triethylamine, tetramethylethylenediamine, etc.) in the 5-position hydroxyl group protecting reaction and the Swern oxidation reaction reacts with HCl removed from the allyl chloroformate hydroxyl group protecting reagent to convert into an organic base hydrochloride, which is partially dissolved in isopropyl acetate and cannot be removed even by filtration, and the generated organic base hydrochloride competes with the aminating agent, thereby generating impurities and lowering the yield.
In order to effectively simplify the production process of the emamectin benzoate, improve the production efficiency and improve the product quality, the invention improves the existing production process of the emamectin benzoate: the mixed solvent of ethyl difluoroacetate and dichloroethane is selected as a reaction solvent, and sodium triacetoxyborohydride is selected as a reducing agent for amination reduction reaction, so that all reaction raw materials can be fully dissolved in a reaction system, reaction conditions required by all steps can be ensured to be met, and the reactions in all steps can reach a better reaction effect, thereby realizing the continuous production of the emamectin benzoate. In addition, the mixed solvent of ethyl difluoroacetate and dichloroethane has low solubility to the organic alkali hydrochloride, and the organic alkali hydrochloride generated by the reaction can be removed by filtering, so that the influence of the organic alkali hydrochloride on the amination reaction is avoided; in addition, after the mixed solvent of ethyl difluoroacetate and dichloroethane is doped with moisture, the mixed solvent can be simply frozen and removed to meet the requirements of 5-position hydroxyl protection reaction and Swern reaction on the moisture in the solvent, thereby realizing the recycling of the solvent.
The process for continuously producing emamectin benzoate B1/B2 provided by the embodiment of the application specifically comprises the following steps:
s101, dissolving abamectin shown in a formula (I) in an inert solvent, cooling, adding a hydroxyl protecting reagent and organic base to perform 5-bit hydroxyl protecting reaction, after the reaction is completed, adding an oxidant and the organic base into a reaction liquid to perform Swern oxidation reaction, and filtering after the reaction is completed to remove suspended organic base hydrochloride to obtain an oxidation reaction liquid;
s102, adding an aminating agent and a catalyst into the oxidation reaction liquid, carrying out amination reaction, cooling after the reaction is completed, adding methanol and sodium triacetoxyborohydride for reduction reaction, adding a deprotection catalyst and sodium triacetoxyborohydride after the reaction is completed, carrying out 5-site deprotection reaction, filtering after the reaction is completed, and removing suspended acetate to obtain deprotection reaction liquid;
s103, adding benzoic acid and a crystallization solvent into the deprotection reaction solution, and cooling and crystallizing to obtain the emamectin benzoate B1/B2 shown in the formula (II).
In order to detect the purity of the prepared emamectin benzoate B1/B2, the content of the product is detected by adopting high performance liquid chromatography, and the specific method comprises the following steps:
a chromatographic column: a stainless steel column of 150mm × 3.9mm filled with a filler of Nova-Pak C18 with a particle size of 5 μm;
mobile phase: methanol: acetonitrile: 0.03% ammonia solution 42:42: 16;
flow rate: 1.0 mL/min;
column temperature: room temperature;
detection wavelength: 245 nm;
sample introduction volume: 5 mu L of the solution;
and (3) an elution mode: isocratic elution.
In order to better illustrate the invention, the following examples are given by way of further illustration.
Example 1
A continuous production process of emamectin benzoate B1 comprises the following steps:
under the protection of nitrogen, 100.0kg of abamectin B1 (content: 95%) is added into a No. 1 reaction kettle of 1000L, then closing the kettle cover, adding 500kg of inert solvent (400.0kg of 1, 2-dichloroethane and 100.0kg of ethyl difluoroacetate) into the reaction kettle through a feeding pipeline, opening a stirring and jacket cooling liquid valve to cool, after about 30min, the temperature reaches-25 ℃, adding 13.8kg of allyl chloroformate into a high-level tank, stirring for 15min, opening a valve of tetramethylethylenediamine, dropwise adding 10.0kg of tetramethylethylenediamine into the reaction kettle, controlling the reaction temperature to be not more than-20 ℃, keeping the temperature and stirring for 15min after dropwise adding is finished for about 20min, adjusting the temperature in the reaction kettle to be-10 to-5 ℃, adding 9.0kg of dimethyl sulfoxide and 3.5kg of tetramethylethylenediamine, stirring for 10min, dropwise adding 27.0kg of phenyl phosphate diacyl chloride, keeping the temperature and stirring for reacting for 60min after dropwise adding is finished for about 30 min. And opening a filter pressing pump and a plate frame filter at the bottom of the kettle, filtering the oxidation reaction liquid, and introducing the oxidation reaction liquid into a No. 2 1000L reaction kettle.
And (2) carrying out nitrogen replacement in advance, adding 25.0kg of heptamethyldisilazane and 2.0kg of zinc chloride after all the oxidation reaction liquid enters, opening a steam valve to control the temperature in the kettle to be 60-65 ℃, carrying out heat preservation stirring for 6 hours, closing the steam valve, opening cold water circulation, controlling the temperature in the kettle to be 0 ℃, adding 3.0kg of anhydrous methanol, adding 30.0kg of sodium triacetoxyborohydride in the kettle under the protection of nitrogen, carrying out heat preservation stirring for 1 hour, then adding 0.5kg of palladium acetate and 25.0g of sodium triacetoxyborohydride, controlling the temperature in the kettle to be 0-5 ℃, carrying out heat preservation stirring for 2 hours, opening a pressure filtration pump and a plate and frame filter at the bottom of the kettle, and filtering the deprotection reaction liquid and then directly introducing the deprotection reaction liquid into a No. 3 1000L reaction kettle.
And (3) after all the deprotection reaction liquid enters a No. 3 reaction kettle, adding 14.0kg of benzoic acid into the reaction kettle, stirring at room temperature for 30min, dropwise adding 100.0kg of cycloheptane into the reaction kettle, completing the addition for about 30min, starting cooling water to control the temperature in the reaction kettle to be 0-5 ℃, preserving heat, stirring for 30min, performing centrifugal filtration by using a centrifugal machine, and drying to obtain 100.5kg of white solid with the yield of 90.0% and the content of 98.0%.
Example 2
A continuous production process of emamectin benzoate B1 comprises the following steps:
under the protection of nitrogen, 100.0kg of abamectin B1 (content: 95%) is added into a No. 1 reaction kettle 2000L, then closing the kettle cover, adding 1000kg of inert solvent (900.0kg of 1, 2-dichloroethane and 100.0kg of ethyl difluoroacetate) into the reaction kettle through a feeding pipeline, starting a stirring and jacket cooling liquid valve to cool, after about 40min, the temperature reaches-25 ℃, adding 14.0kg of allyl chloroformate into a high-level tank, stirring for 15min, opening a valve of tetramethylethylenediamine, dropwise adding 11.0kg of tetramethylethylenediamine into the reaction kettle, controlling the reaction temperature to be not more than-20 ℃, keeping the temperature and stirring for 15min after dropwise adding is finished for about 20min, adjusting the temperature in the reaction kettle to be-10 to-5 ℃, adding 11.0kg of dimethyl sulfoxide and 3.6kg of tetramethylethylenediamine, stirring for 10min, dropwise adding 28.0kg of phenyl phosphate diacyl chloride, keeping the temperature and stirring for reacting for 60min after dropwise adding is finished for about 30 min. And opening a filter pressing pump and a plate frame filter at the bottom of the kettle, filtering the oxidation reaction liquid, and introducing the oxidation reaction liquid into a No. 2 2000L reaction kettle.
And (2) carrying out nitrogen replacement in advance, adding 25.0kg of heptamethyldisilazane and 2.0kg of zinc chloride after all the oxidation reaction liquid enters, opening a steam valve to control the temperature in the kettle to be 60-65 ℃, carrying out heat preservation stirring for 6 hours, closing the steam valve, opening cold water circulation, controlling the temperature in the kettle to be 0 ℃, adding 4.0kg of anhydrous methanol, adding 32.0kg of sodium triacetoxyborohydride into the kettle under the protection of nitrogen, carrying out heat preservation stirring for 1.5 hours, then adding 0.5kg of tetrakis (triphenylphosphine) palladium and 22.0g of sodium triacetoxyborohydride, controlling the temperature in the kettle to be 0-5 ℃, carrying out heat preservation stirring for 2 hours, opening a pressure filter pump and a plate frame filter at the bottom of the kettle, and directly introducing the deprotection reaction liquid into a No. 3 2000L reaction kettle after filtration.
And (3) after all the deprotection reaction liquid enters a No. 3 reaction kettle, adding 14.0kg of benzoic acid into the reaction kettle, stirring at room temperature for 30min, dropwise adding 500.0kg of cycloheptane into the reaction kettle, completing addition for about 60min, starting cooling water to control the temperature in the reaction kettle to be 0-5 ℃, preserving heat, stirring for 30min, performing centrifugal filtration by using a centrifugal machine, and drying to obtain 98.4kg of white solid with the yield of 89.0% and the content of 99.0%.
Example 3
A continuous production process of emamectin benzoate B2 comprises the following steps:
under the protection of nitrogen, 100.0kg of abamectin B2 (with the content of 97%) is added into a No. 1 reaction kettle of 1000L, then closing the kettle cover, adding 600kg of inert solvent (510.0kg of 1, 2-dichloroethane and 90.0kg of ethyl difluoroacetate) into the reaction kettle through a feeding pipeline, opening a stirring and jacket cooling liquid valve to cool, after about 30min, the temperature reaches-25 ℃, adding 14.2kg of allyl chloroformate into a high-level tank, stirring for 15min, opening a tetramethylethylenediamine valve, delivering 10.5kg of tetramethylethylenediamine into a reaction kettle, controlling the reaction temperature to be not more than-20 ℃, keeping the temperature and stirring for 15min after dropwise addition is finished for about 20min, adjusting the temperature in the reaction kettle to be-10 to-5 ℃, adding 10.0kg of dimethyl sulfoxide and 4.2kg of tetramethylethylenediamine, stirring for 10min, dropwise adding 27.0kg of phenyl phosphate diacyl chloride, keeping the temperature and stirring for reaction for 60min after dropwise addition is finished for about 30 min. And opening a filter pressing pump and a plate frame filter at the bottom of the kettle, filtering the oxidation reaction liquid, and introducing the oxidation reaction liquid into a No. 2 1000L reaction kettle.
And (2) carrying out nitrogen replacement in advance, adding 25.0kg of heptamethyldisilazane and 2.0kg of zinc chloride after all the oxidation reaction liquid enters, opening a steam valve to control the temperature in the kettle to be 60-65 ℃, carrying out heat preservation stirring for 6 hours, closing the steam valve, opening cold water circulation, controlling the temperature in the kettle to be 0 ℃, adding 3.0kg of anhydrous methanol, adding 35.0kg of sodium triacetoxyborohydride in the kettle under the protection of nitrogen, carrying out heat preservation stirring for 1 hour, then adding 0.5kg of palladium acetate and 20.0g of sodium triacetoxyborohydride, controlling the temperature in the kettle to be 0-5 ℃, carrying out heat preservation stirring for 3 hours, opening a pressure filtration pump and a plate and frame filter at the bottom of the kettle, and filtering the deprotection reaction liquid and then directly introducing the deprotection reaction liquid into a No. 3 1000L reaction kettle.
And (3) after all the deprotection reaction liquid enters a No. 3 reaction kettle, adding 14.0kg of benzoic acid into the reaction kettle, stirring at room temperature for 30min, dropwise adding 300.0kg of cycloheptane into the reaction kettle, completing addition for about 40min, starting cooling water to control the temperature in the reaction kettle to be 0-5 ℃, preserving heat, stirring for 30min, performing centrifugal filtration by using a centrifugal machine, and drying to obtain 99.5kg of white solid with the yield of 87% and the content of 97.5%.
After the crystallization mother liquor in the above embodiment 1-3 is cooled to-25 to-30 ℃, the solid-liquid separation is carried out to obtain an organic phase, and the organic phase can be recycled as a solvent for dissolving the raw material of avermectin after the cycloheptane is separated and removed in a rectifying tower.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. A continuous production process of emamectin benzoate B1/B2 is characterized by comprising the following steps:
under the condition of an inert solvent, taking avermectin shown in a formula (I) as a raw material, and sequentially and continuously carrying out 5-position hydroxyl protection, 4' -position hydroxyl oxidation, amination reduction, deprotection and acidification salt-forming reaction to obtain methylamino avermectin B1/B2 benzoate shown in a formula (II); wherein the inert solvent is a mixed solvent of ethyl difluoroacetate and dichloroethane; the reducing agent of the amination reduction reaction is sodium triacetoxyborohydride;
r is CH3Or CH2CH3(ii) a X-Y is CH ═ CH or CH2-CH(OH)。
2. The continuous production process of emamectin benzoate B1/B2 as claimed in claim 1, wherein the content of ethyl difluoroacetate in the inert solvent is 10-20 wt%.
3. The continuous production process of emamectin benzoate B1/B2 as claimed in claim 1 or 2, which is characterized by comprising the following steps:
s101, dissolving abamectin shown in a formula (I) in an inert solvent, cooling, adding a hydroxyl protecting reagent and organic base to perform 5-bit hydroxyl protecting reaction, after the reaction is completed, adding an oxidant and the organic base into a reaction liquid to perform Swern oxidation reaction, and filtering after the reaction is completed to obtain an oxidation reaction liquid;
s102, adding an aminating agent and a catalyst into the oxidation reaction liquid, carrying out amination reaction, cooling after reaction is completed, adding alcohol and sodium triacetoxyborohydride for reduction reaction, adding a deprotection catalyst and sodium triacetoxyborohydride after reaction is completed, carrying out 5-site deprotection reaction, and filtering after reaction is completed to obtain deprotection reaction liquid;
s103, adding benzoic acid and a crystallization solvent into the deprotection reaction solution, cooling, crystallizing and filtering to obtain emamectin benzoate B1/B2 shown in the formula (II).
4. The continuous production process of emamectin benzoate B1/B2 as claimed in claim 3, wherein in the step S101, the mass ratio of the inert solvent to the raw material of the abamectin shown in the formula (I) is 5-10: 1.
5. The continuous emamectin benzoate production process according to claim 3, wherein in step S101, the hydroxyl protecting reagent is allyl chloroformate, the organic base is tetramethylethylenediamine or triethylamine, and the oxidizing agent is dimethyl sulfoxide and phenyl phosphate diacid chloride; and/or
In step S102, the aminating agent is heptamethyldisilazane, the catalyst is zinc chloride, and the deprotection catalyst is palladium acetate or tetrakis (triphenylphosphine) palladium.
6. The continuous production process of emamectin benzoate B1/B2 as claimed in claim 3, wherein in the step S102, in the reduction reaction, the addition amount of the sodium triacetoxyborohydride is 30-35 wt% of the mass of the raw material of the abamectin; in the deprotection reaction, the addition amount of the sodium triacetoxyborohydride is 20-25 wt% of the mass of the avermectin raw material.
7. The continuous emamectin B1/B2 benzoate production process of claim 3, wherein in step S103, the crystallization solvent is cycloheptane.
8. The continuous production process of emamectin benzoate B1/B2 as claimed in claim 7, wherein the mass ratio of the crystallization solvent to the raw material of the emamectin benzoate shown in formula (I) is 1-5: 1.
9. The continuous production process of emamectin benzoate B1/B2 as claimed in claim 3, wherein in the step S103, the temperature for cooling and crystallization is 0-5 ℃, and the time for cooling and crystallization is 25-35 min.
10. The continuous emamectin benzoate production process according to claim 3, wherein the step S103 further comprises the following steps: and (3) cooling the crystallization mother liquor obtained by filtering to-25 to-30 ℃, carrying out solid-liquid separation to obtain an organic phase, separating the organic phase, removing cycloheptane, and returning the organic phase to the step (S101) to be used as a solvent for dissolving the abamectin raw material.
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