CN103601776A - Preparation method of emamectin benzoate midbody - Google Patents
Preparation method of emamectin benzoate midbody Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 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 abstract 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 52
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- 150000003839 salts Chemical class 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 31
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 27
- 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 26
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 21
- 239000007787 solid Substances 0.000 claims description 21
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 20
- 238000009413 insulation Methods 0.000 claims description 16
- 238000010792 warming Methods 0.000 claims description 14
- CAEWJEXPFKNBQL-UHFFFAOYSA-N prop-2-enyl carbonochloridate Chemical compound ClC(=O)OCC=C CAEWJEXPFKNBQL-UHFFFAOYSA-N 0.000 claims description 13
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 10
- 238000001556 precipitation Methods 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 238000005265 energy consumption Methods 0.000 abstract description 3
- 239000005894 Emamectin Substances 0.000 abstract 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 abstract 2
- TXFOLHZMICYNRM-UHFFFAOYSA-N dichlorophosphoryloxybenzene Chemical compound ClP(Cl)(=O)OC1=CC=CC=C1 TXFOLHZMICYNRM-UHFFFAOYSA-N 0.000 abstract 1
- 239000012467 final product Substances 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 24
- 238000004811 liquid chromatography Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 238000010606 normalization Methods 0.000 description 5
- FSDYDBAXNANUQE-UHFFFAOYSA-N tris(2,4-dichlorophenyl) phosphate Chemical compound ClC1=CC(Cl)=CC=C1OP(=O)(OC=1C(=CC(Cl)=CC=1)Cl)OC1=CC=C(Cl)C=C1Cl FSDYDBAXNANUQE-UHFFFAOYSA-N 0.000 description 5
- 241000238631 Hexapoda Species 0.000 description 4
- 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 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 230000000749 insecticidal effect Effects 0.000 description 3
- 239000005660 Abamectin Substances 0.000 description 2
- ZFUKERYTFURFGA-UHFFFAOYSA-N Avermectin B1b Natural products O1C(C)C(O)C(OC)CC1OC1C(OC)CC(OC2C(=CCC3CC(CC4(O3)C=CC(C)C(C(C)C)O4)OC(=O)C3C=C(C)C(O)C4OCC(C34O)=CC=CC2C)C)OC1C ZFUKERYTFURFGA-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- RRZXIRBKKLTSOM-UHFFFAOYSA-N avermectin B1a Natural products C1=CC(C)C(C(C)CC)OC11OC(CC=C(C)C(OC2OC(C)C(OC3OC(C)C(O)C(OC)C3)C(OC)C2)C(C)C=CC=C2C3(C(C(=O)O4)C=C(C)C(O)C3OC2)O)CC4C1 RRZXIRBKKLTSOM-UHFFFAOYSA-N 0.000 description 2
- ZFUKERYTFURFGA-PVVXTEPVSA-N avermectin B1b 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 ZFUKERYTFURFGA-PVVXTEPVSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000002574 poison Substances 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- 230000000895 acaricidal effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- -1 ester compounds Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000010887 waste solvent Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a preparation method of an emamectin benzoate midbody. The preparation method has the advantages that low-cost triphosgene is used for replacing phenyl dichlorophosphate, the operating environments adopting the triphosgene are mild, the energy consumption is low, the production cost is reduced, the content and the yield of the midbody oxide of the emamectin are increased, the yield is above 95%, the content of the midbody oxide is above 92%, the color of the final product tends to be colorless and crystalline, and a good foundation is laid for the preparation of the high-purity emamectin.
Description
Technical field
The present invention relates to a kind of preparation method of pharmaceutical intermediate, be specifically related to a kind of preparation method of intermediate oxide of first dimension salt.
Background technology
First dimension salt, full name methylamino avermectin benzoate, chemical name: 4'-table-methylamino-4'-deoxidation AVERMECTIN B1 benzoate, it is a kind of insecticidal/acaricidal agent, a kind of new and effective semisynthetic antibiotics sterilant that starts to synthesize from leavened prod AVERMECTIN B1, it has ultra-high efficiency, low toxicity (preparation is closely nontoxic), low residue, the nuisanceless feature that waits biological pesticide, with AVERMECTIN B1 first insecticidal activity improved 3 orders of magnitude, activity to the larva of lepidopterous insects and other many insects is high, existing stomach poison function is double action of contace poison again, under low-down dosage (0.084～2g/ha), there is good effect, and in the process of pest control, beneficial insect is not injured, be conducive to the integrated control to insect, expanded in addition insecticidal spectrum, reduced the toxicity to people and animals.
Existing production technique is by AVERMECTIN B1, to react with chloro-formic ester compounds to generate 5 AVERMECTIN B1s that have chloro-formic ester class protecting group; then add Tetramethyl Ethylene Diamine, dimethyl sulfoxide (DMSO); drip the dichloromethane solution of dichloro-phenyl phosphate, it is intermediate oxide 4 " Biao-4 "-carbonyl-5-allyl formiate base-AVERMECTIN B1 of first dimension salt that reaction obtains 4 " the oxidized generation 4 of OH " position carbonyl again.Its weak point is: (1) temperature of reaction is all below-15 ℃, and its energy consumption is high; (2) dichloro-phenyl phosphate adopting is expensive, very easily oxidized, causes the production cost of first dimension salt higher.
Summary of the invention
For the deficiencies in the prior art, the invention provides a kind of preparation method of first dimension salt intermediate, adopt the dichloro-phenyl phosphate of the solid phosgene replacement cost costliness that cost is lower, carry out intermediate oxide 4 " Biao-4 "-carbonyl-5-allyl formiate base-AVERMECTIN B1 of production first dimension salt.The method processing condition are gentle, and production cost is low, improved content and the yield of the intermediate oxide of first dimension salt, for preparing highly purified first dimension salt, have laid a good foundation.
A preparation method for first dimension salt intermediate, described first dimension salt intermediate is 4 " Biao-4 "-carbonyl-5-allyl formiate base-AVERMECTIN B1, its chemical structural formula is as follows:
The preparation method of described first dimension salt intermediate, reaction scheme is as follows:
Wherein, in above-mentioned reaction equation, the name of chemical compounds I is called AVERMECTIN B1, is to be mixed by Avermectin B1a and avermectin B1b, and wherein Avermectin B1a is not less than 90%, and avermectin B1b is no more than 5%; The name of compound ii is called 4 " Biao-5-allyl formiate base-AVERMECTIN B1, compound ii is the substituent of 5 OH of AVERMECTIN B1; The name of compound III is called 4 " Biao-4 "-carbonyl-5-allyl formiate base-AVERMECTIN B1.
The preparation method of first dimension salt intermediate of the present invention, concrete steps are as follows:
(1) AVERMECTIN B1 and methylene dichloride are added in reactor, after stirring and dissolving, be cooled to below-15 ℃, then drip respectively allyl chlorocarbonate and Tetramethyl Ethylene Diamine;
(2) after step (1) is added dropwise to complete, be warming up to-5 ℃～-15 ℃, add respectively dimethyl sulfoxide (DMSO) and Tetramethyl Ethylene Diamine, then drip the dichloromethane solution that is dissolved with solid phosgene;
(3), after step (2) is added dropwise to complete, is warming up to-5 ℃～5 ℃ and carries out insulation reaction;
(4) after the described insulation reaction of step (3) completes, in reaction solution, add aqueous sodium carbonate to regulate pH value, oil phase is got in layering, and precipitation is dry, obtains product 4 " Biao-4 "-carbonyl-5-allyl formiate base-AVERMECTIN B1.
The present invention adopts cold salt, and liquid calcium chloride is lowered the temperature, and its objective is that the 5-OH in AVERMECTIN B1 is generated 5-OCOA by allyl chlorocarbonate protection.
The weight ratio 1:5-7 of AVERMECTIN B1 and methylene dichloride described in step (1), this is optimum weight ratio scope.If weight ratio is excessive, can affect normally carrying out of reaction, if weight ratio is too small, can waste solvent, increase production cost.
Described in step (1), the mol ratio of AVERMECTIN B1, allyl chlorocarbonate and Tetramethyl Ethylene Diamine is AVERMECTIN B1: allyl chlorocarbonate: Tetramethyl Ethylene Diamine=1:1-3:2-6.Allyl chlorocarbonate, as protective material, protects 5-OH in AVERMECTIN B1 to form 5-OCOA, produces HCl simultaneously; Tetramethyl Ethylene Diamine is as acid binding agent, and absorption HCl forms Tetramethyl Ethylene Diamine hydrochloride, impels reaction forward to carry out, and generates compound ii 4 " Biao-5-allyl formiate base-AVERMECTIN B1.
Described in step (2), the weight ratio of solid phosgene and methylene dichloride is 0.2-0.25:1.Because the boiling point of methylene dichloride is 39.8 ℃, when surpassing 30 ℃, temperature easily volatilizees, so control temperature during the dichloromethane solution that configuration contains solid phosgene, be 10 ℃-30 ℃.
The AVERMECTIN B1 that step (1) is described and the mol ratio of dimethyl sulfoxide (DMSO), Tetramethyl Ethylene Diamine and the solid phosgene described in step (2) are AVERMECTIN B1: dimethyl sulfoxide (DMSO): Tetramethyl Ethylene Diamine: solid phosgene=1:2-3:1.5-4:0.6-3.Described step (2) is solid phosgene to be reacted to generation with dimethyl sulfoxide (DMSO)
thereby " OH is oxidized to 4 of AVERMECTIN B1.
Tetramethyl Ethylene Diamine described in step (2) is not only as acid binding agent, and absorption HCl forms Tetramethyl Ethylene Diamine hydrochloride, impels reaction forward to carry out, and solid phosgene is depolymerized to ClCOCl, further impels reaction forward to carry out.
The time of the described insulation reaction of step (3) is 1.5h-5h.
The massfraction of the described aqueous sodium carbonate of step (4) is 2%-10%.If massfraction is excessive, can destroy the structure of product, affect the quality of product; If massfraction is too small, can cause water consumption excessive, make the waste water of generation too much, not only bad for environment, and cause post-processed cost excessive.
The described pH value of step (4) is 6-8.Why adopt aqueous sodium carbonate to regulate pH value, its objective is and remove to greatest extent remaining solid phosgene, improve the quality of product.
Compared with prior art, the present invention adopts the dichloro-phenyl phosphate of the solid phosgene replacement cost costliness that cost is lower, carrys out intermediate oxide 4 " Biao-4 "-carbonyl-5-allyl formiate base-AVERMECTIN B1 of production first dimension salt.The method processing condition are gentle, and production cost is low, improved content and the yield of the intermediate oxide of first dimension salt, yield is more than 95%, content is all more than 92%, and the sample look of its finished product is tending towards colourless crystalline, for preparing highly purified first dimension salt, haves laid a good foundation.
Embodiment
Below in conjunction with embodiment, further illustrate the present invention, can make those skilled in the art more fully understand the present invention.
Embodiment 1
A preparation method for first dimension salt intermediate, described first dimension salt intermediate is 4 " Biao-4 "-carbonyl-5-allyl formiate base-AVERMECTIN B1, concrete steps are as follows:
(1) by 20g(0.023mol) AVERMECTIN B1 and 100g methylene dichloride add in reactor, after stirring and dissolving, be cooled to-20 ℃, then drip respectively 5.5g(0.046mol) allyl chlorocarbonate and 13.0g(0.092mol) Tetramethyl Ethylene Diamine 0.5h;
(2) after step (1) is added dropwise to complete, be warming up to-15 ℃, add respectively 3.6g(0.046mol) dimethyl sulfoxide (DMSO) and 9.7g(0.069mol) Tetramethyl Ethylene Diamine, then drip be dissolved with 6.8g(0.023mol) the dichloromethane solution 34g of solid phosgene;
(3) after step (2) is added dropwise to complete, is warming up to 5 ℃ and carries out insulation reaction 3h;
(4) after the described insulation reaction of step (3) completes, to adding massfraction in reaction solution, be that 6% aqueous sodium carbonate regulates pH value to 6, oil phase is got in layering, 68 ℃ of precipitations are dry, obtain product 4 〞-Biao-4 〞-carbonyl-5-allyl formiate base-AVERMECTIN B1, yield is 95.0%, and adopting liquid chromatography normalization method to measure its content (massfraction) is 92.5%.
Embodiment 2
A preparation method for first dimension salt intermediate, described first dimension salt intermediate is 4 " Biao-4 "-carbonyl-5-allyl formiate base-AVERMECTIN B1, concrete steps are as follows:
(1) by 20g(0.023mol) AVERMECTIN B1 and 120g methylene dichloride add in reactor, after stirring and dissolving, be cooled to-17 ℃, then drip respectively 2.8g(0.023mol) allyl chlorocarbonate and 16.2g(0.115mol) Tetramethyl Ethylene Diamine 1h;
(2) after step (1) is added dropwise to complete, be warming up to-10 ℃, add respectively 5.4g(0.069mol) dimethyl sulfoxide (DMSO) and 13.0g(0.092mol) Tetramethyl Ethylene Diamine, then drip be dissolved with 20.5g(0.069mol) the dichloromethane solution 82g of solid phosgene;
(3) after step (2) is added dropwise to complete, is warming up to 3 ℃ and carries out insulation reaction 5h;
(4) after the described insulation reaction of step (3) completes, to adding massfraction in reaction solution, be that 4% aqueous sodium carbonate regulates pH value to 8, oil phase is got in layering, 68 ℃ of precipitations are dry, obtain product 4 〞-Biao-4 〞-carbonyl-5-allyl formiate base-AVERMECTIN B1, yield is 95.3%, and adopting liquid chromatography normalization method to measure its content (massfraction) is 93%.
Embodiment 3
A preparation method for first dimension salt intermediate, described first dimension salt intermediate is 4 " Biao-4 "-carbonyl-5-allyl formiate base-AVERMECTIN B1, concrete steps are as follows:
(1) by 20g(0.023mol) AVERMECTIN B1 and 140g methylene dichloride add in reactor, after stirring and dissolving, be cooled to-18 ℃, then drip respectively 8.3g(0.069mol) allyl chlorocarbonate and 6.5g(0.046mol) Tetramethyl Ethylene Diamine 1.5h;
(2) after step (1) is added dropwise to complete, be warming up to-8 ℃, add respectively 4.5g(0.058mol) dimethyl sulfoxide (DMSO) and 9.7g(0.069mol) Tetramethyl Ethylene Diamine, then drip be dissolved with 4.1g(0.014mol) the dichloromethane solution 18.6g of solid phosgene;
(3), after step (2) is added dropwise to complete, is warming up to-5 ℃ and carries out insulation reaction 1.5h;
(4) after the described insulation reaction of step (3) completes, to adding massfraction in reaction solution, be that 2% aqueous sodium carbonate regulates pH value to 7, oil phase is got in layering, 65 ℃ of precipitations are dry, obtain product 4 〞-Biao-4 〞-carbonyl-5-allyl formiate base-AVERMECTIN B1, yield is 95.5%, and adopting liquid chromatography normalization method to measure its content (massfraction) is 92.6%.
Embodiment 4
A preparation method for first dimension salt intermediate, described first dimension salt intermediate is 4 " Biao-4 "-carbonyl-5-allyl formiate base-AVERMECTIN B1, concrete steps are as follows:
(1) by 100kg(0.115kmol) AVERMECTIN B1 and 550kg methylene dichloride add in reactor, after stirring and dissolving, be cooled to-16 ℃, then drip respectively 27.7kg(0.230kmol) allyl chlorocarbonate and 97.3kg(0.690kmol) Tetramethyl Ethylene Diamine 1.2h;
(2) after step (1) is added dropwise to complete, be warming up to-12 ℃, add respectively 17.9kg(0.23kmol) dimethyl sulfoxide (DMSO) and 24.3kg(0.173kmol) Tetramethyl Ethylene Diamine, then drip be dissolved with 68.3kg(0.23kmol) the dichloromethane solution 325.2kg of solid phosgene;
(3) after step (2) is added dropwise to complete, is warming up to 0 ℃ and carries out insulation reaction 2h;
(4) after the described insulation reaction of step (3) completes, to adding massfraction in reaction solution, be that 10% aqueous sodium carbonate regulates pH value to 6.5, oil phase is got in layering, 65 ℃ of precipitations are dry, obtain product 4 〞-Biao-4 〞-carbonyl-5-allyl formiate base-AVERMECTIN B1, yield is 95.1%, and adopting liquid chromatography normalization method to measure its content (massfraction) is 93.1%.
Embodiment 5
A preparation method for first dimension salt intermediate, described first dimension salt intermediate is 4 " Biao-4 "-carbonyl-5-allyl formiate base-AVERMECTIN B1, concrete steps are as follows:
(1) by 125kg(0.143kmol) AVERMECTIN B1 and 812.5kg methylene dichloride add in reactor, after stirring and dissolving, be cooled to-15 ℃, then drip respectively 17.2kg(0.143kmol) allyl chlorocarbonate and 60.5(0.429kmol) Tetramethyl Ethylene Diamine 0.8h;
(2) after step (1) is added dropwise to complete, be warming up to-5 ℃, add respectively 33.5kg(0.429kmol) dimethyl sulfoxide (DMSO) and 40.3kg(0.286kmol) Tetramethyl Ethylene Diamine, then drip be dissolved with 42.4kg(0.143kmol) the dichloromethane solution 184.5kg of solid phosgene;
(3) after step (2) is added dropwise to complete, is warming up to 1 ℃ and carries out insulation reaction 4h;
(4) after the described insulation reaction of step (3) completes, to adding massfraction in reaction solution, be that 8% aqueous sodium carbonate regulates pH value to 7.5, oil phase is got in layering, 66 ℃ of precipitations are dry, obtain product 4 " Biao-4 "-carbonyl-5-allyl formiate base-AVERMECTIN B1, yield is 95.4%, and adopting liquid chromatography normalization method to measure its content (massfraction) is 93.5%.
From embodiment 1-5, can find out, adopt the method for the invention to prepare the intermediate oxide of first dimension salt, adopt cheap solid phosgene to replace dichloro-phenyl phosphate, it adopts the operating environment of solid phosgene gentle, and energy consumption is low, reduced production cost, the content and the yield that have improved the intermediate oxide of first dimension salt, yield is more than 95%, and content is all more than 92%, the sample look of its finished product is tending towards colourless crystalline, for preparing highly purified first dimension salt, haves laid a good foundation.
Claims (8)
1. first is tieed up a preparation method for salt intermediate, and described first dimension salt intermediate is 4 " Biao-4 "-carbonyl-5-allyl formiate base-AVERMECTIN B1, it is characterized in that: concrete steps are as follows:
(1) AVERMECTIN B1 and methylene dichloride are added in reactor, after stirring and dissolving, be cooled to below-15 ℃, then drip respectively allyl chlorocarbonate and Tetramethyl Ethylene Diamine;
(2) after step (1) is added dropwise to complete, be warming up to-5 ℃～-15 ℃, add respectively dimethyl sulfoxide (DMSO) and Tetramethyl Ethylene Diamine, then drip the dichloromethane solution that is dissolved with solid phosgene;
(3), after step (2) is added dropwise to complete, is warming up to-5 ℃～5 ℃ and carries out insulation reaction;
(4) after the described insulation reaction of step (3) completes, in reaction solution, add aqueous sodium carbonate to regulate pH value, oil phase is got in layering, and precipitation is dry, obtains product 4 〞-Biao-4 〞-carbonyl-5-allyl formiate base-AVERMECTIN B1.
2. the preparation method of first dimension salt intermediate according to claim 1, is characterized in that: the weight ratio 1:5-7 of AVERMECTIN B1 and methylene dichloride described in step (1).
3. the preparation method of first dimension salt intermediate according to claim 1, is characterized in that: described in step (1), the mol ratio of AVERMECTIN B1, allyl chlorocarbonate and Tetramethyl Ethylene Diamine is AVERMECTIN B1: allyl chlorocarbonate: Tetramethyl Ethylene Diamine=1:1-3:2-6.
4. the preparation method of first dimension salt intermediate according to claim 1, is characterized in that: described in step (2), the weight ratio of solid phosgene and methylene dichloride is 0.2-0.25:1.
5. the preparation method of first dimension salt intermediate according to claim 1, is characterized in that: the AVERMECTIN B1 that step (1) is described and the mol ratio of dimethyl sulfoxide (DMSO), Tetramethyl Ethylene Diamine and the solid phosgene described in step (2) are AVERMECTIN B1: dimethyl sulfoxide (DMSO): Tetramethyl Ethylene Diamine: solid phosgene=1:2-3:1.5-4:0.6-3.
6. the preparation method of first dimension salt intermediate according to claim 1, is characterized in that: the time of the described insulation reaction of step (3) is 1.5h-5h.
7. the preparation method of first dimension salt intermediate according to claim 1, is characterized in that: the massfraction of the described aqueous sodium carbonate of step (4) is 2%-10%.
8. the preparation method of first dimension salt intermediate according to claim 1, is characterized in that: the described pH value of step (4) is 6-8.
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| CN103012525A (en) * | 2013-01-05 | 2013-04-03 | 哈尔滨理工大学 | Method for synthesizing emamectin benzoate |
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