WO2022134385A1 - Purification method for 4"-(s)-methylamino abamectin b2a benzoate - Google Patents
Purification method for 4"-(s)-methylamino abamectin b2a benzoate Download PDFInfo
- Publication number
- WO2022134385A1 WO2022134385A1 PCT/CN2021/086469 CN2021086469W WO2022134385A1 WO 2022134385 A1 WO2022134385 A1 WO 2022134385A1 CN 2021086469 W CN2021086469 W CN 2021086469W WO 2022134385 A1 WO2022134385 A1 WO 2022134385A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- benzoate
- purification method
- butyl ether
- methylamino abamectin
- methylamino
- Prior art date
Links
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 title claims abstract description 62
- 239000005660 Abamectin Substances 0.000 title claims abstract description 39
- 229950008167 abamectin Drugs 0.000 title claims abstract description 39
- 238000000034 method Methods 0.000 title claims abstract description 25
- 238000000746 purification Methods 0.000 title claims abstract description 17
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims abstract description 33
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims abstract description 20
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims abstract description 15
- -1 methylamino abamectin Chemical compound 0.000 claims abstract description 15
- 238000002425 crystallisation Methods 0.000 claims abstract description 14
- 230000008025 crystallization Effects 0.000 claims abstract description 14
- 239000000047 product Substances 0.000 claims abstract description 14
- 238000001816 cooling Methods 0.000 claims abstract description 13
- 239000012043 crude product Substances 0.000 claims abstract description 13
- 239000011259 mixed solution Substances 0.000 claims abstract description 11
- 238000001914 filtration Methods 0.000 claims abstract description 8
- 239000000706 filtrate Substances 0.000 claims abstract description 6
- 238000010438 heat treatment Methods 0.000 claims abstract description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 claims description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 claims description 6
- 238000005481 NMR spectroscopy Methods 0.000 claims description 6
- 238000005100 correlation spectroscopy Methods 0.000 claims description 5
- 238000001052 heteronuclear multiple bond coherence spectrum Methods 0.000 claims description 3
- 238000000990 heteronuclear single quantum coherence spectrum Methods 0.000 claims description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 5
- 239000002904 solvent Substances 0.000 abstract description 5
- 239000003905 agrochemical Substances 0.000 abstract description 2
- 230000000749 insecticidal effect Effects 0.000 abstract description 2
- 238000001228 spectrum Methods 0.000 description 6
- CWGATOJEFAKFBK-PDVFGPFMSA-N 5-o-demethyl-22,23-dihydro-23-hydroxy-(13r,23s)-avermectin a1a Chemical compound C1[C@H](O)[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 CWGATOJEFAKFBK-PDVFGPFMSA-N 0.000 description 5
- 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 description 5
- CWGATOJEFAKFBK-UHFFFAOYSA-N Ac-(E)-8-Tridecen-1-ol Natural products C1C(O)C(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 CWGATOJEFAKFBK-UHFFFAOYSA-N 0.000 description 4
- SHURRSUZDBDBMX-JLSLGBNPSA-N avermectin B2a Natural products CC[C@H](C)[C@H]1O[C@@]2(C[C@@H]3C[C@@H](CC=C(/C)[C@@H](O[C@H]4C[C@H](OC)[C@@H](O[C@H]5C[C@H](OC)[C@@H](O)[C@H](C)O5)[C@H](C)O4)[C@@H](C)C=CC=C6/OC[C@@H]7[C@H](O)C(=C[C@@H](C(=O)O3)[C@]67O)C)O2)C[C@@H](O)[C@@H]1C SHURRSUZDBDBMX-JLSLGBNPSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000005570 heteronuclear single quantum coherence Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 108010062877 Bacteriocins Proteins 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000010189 synthetic method Methods 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
- C07H1/06—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- 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
Definitions
- the present scheme relates to a purification method of 4"-(s)-methylaminoabamectin B2a benzoate, belonging to the field of agricultural chemicals and preparation.
- Abamectin is a mixture of fermentation components, with 8 components: A1a, A1b, A2a, A2b, B1a, B1b, B2a, B2b.
- Abamectin B2a/2b can be obtained by separating and purifying abamectin for many times.
- the structures of Abamectin B2a and Abamectin B2b are shown in formula (II) and formula (III):
- Avermectin B2a/2b has been paid more and more attention.
- a large number of literatures have reported the synthesis method of Avermectin B2a/2b, related derivatives of Avermectin B2a/2b, and related preparation methods.
- Avermectin B2a benzoate is one of the most widely used substances.
- the methylaminoavermectin B2a benzoate prepared by the current synthesis method has a relatively low purity and contains many impurities, thus affecting the insecticidal activity of the subsequent preparation. Therefore, it is necessary to seek a method for separating and purifying methylaminoavermectin B2a benzoate isomers with higher yield and purity.
- this scheme provides a purification of 4"-(s)-methylaminoavermectin B2a benzoate method.
- a kind of purifying method of 4 "-(s)-methylamino abamectin B2a benzoate comprises the following steps:
- the S configuration in this scheme means that the methylamino group at the 4" position of the reactive site is the S configuration.
- the mass ratio of the methyl tert-butyl ether, tert-butanol and n-butyl ether is 1:1 ⁇ 1.5:1.5 ⁇ 4.
- the mass ratio of the methylamino abamectin B2a/2b benzoate crude product to methyl tert-butyl ether, tert-butyl alcohol and n-butyl ether total amount is 1:3 ⁇ 5.
- the temperature of the cooling filtration is 0-5°C.
- the temperature of above-mentioned cooling filtration is conducive to fully removing the methylaminoavermectin B2b benzoate and other impurities in the methylaminoavermectin B2a/2b benzoate crude product, thereby helping to obtain high-purity 4" -(s)-Methylaminoavermectin B2a benzoate.
- the temperature of cooling and crystallization is -10 ⁇ -5°C.
- the time for cooling and crystallization is 2-3 hours.
- the dropping time of the mixed solution of tert-butanol and n-butyl ether is 1.5-2.5h.
- the content of methylaminoabamectin B2a benzoate in the methylaminoabamectin B2a/2b benzoate crude product is not less than 70%.
- the temperature for heating and dissolving is 35-45°C.
- the above-mentioned heating temperature is conducive to fully dissolving the Avermectin B2a/2b benzoate crude product, thereby helping to remove impurities by cooling and filtration.
- the 1 H-NMR, 13 C-NMR, DEPT135, DEPT90, COSY, HSQC and HMBC spectrograms obtained by nuclear magnetic resonance characterization are used for the obtained 4"-(s)-methylaminoavermectin B2a benzene. Structural identification of formate products.
- This scheme adopts the 1 H-NMR, 13 C-NMR, DEPT135, DEPT90, COSY, HSQC and HMBC spectra in nuclear magnetic resonance for comprehensive analysis, which proves that the purified methylaminoabamectin B2a benzoate is S. -structure.
- the method for purifying methylamino abamectin B2a benzoate provided in this scheme is to select a mixed solution of methyl tert-butyl ether, tert-butyl alcohol and n-butyl ether as a crystallization solvent, and cooperate with two cooling methods for crystallization , to obtain 4"-(s)-methylaminoabamectin B2a benzoate product with a content of more than 98% in a single configuration, the product yield can reach more than 62%, and the purification method is simple, which is developed for subsequent R&D personnel.
- a highly active methylaminoavermectin B2a benzoate product offers the possibility.
- Fig. 1 is the NOESY spectrum of 4 "-(s)-methylamino abamectin B2a benzoate prepared in Example 1 of this scheme;
- FIG. 2 is a partial enlarged view of the NOESY spectrum in FIG. 1 .
- the content of the used methylamino abamectin B2a/2b benzoate crude product in the following examples is 70%.
- a kind of purifying method of 4 "-(s)-methylamino abamectin B2a benzoate comprises the following steps:
- 50g methylamino abamectin B2a/2b benzoate crude product was added in 50g methyl tert-butyl ether, heated to 40 ° C to make it completely dissolved, then slowly added dropwise the mixed solution of 50g tert-butanol and 150g n-butyl ether , the dropwise addition time is 2h, after the dropwise addition is completed, the temperature is lowered to 0°C for filtration, the obtained filtrate is cooled to -5°C, stirred and crystallized for 3h, filtered, and dried to obtain off-white 4"-(s)-Averbacter methylamino. 22.24g of benzoate product of B2a, HPLC content of 98.5% and yield of 62.6%.
- Test conditions at normal temperature, get the prepared 4 "-(s)-methylaminoabamectin B2a benzoate and dissolve it in an appropriate amount of CDCl 3 , at 303K temperature, to the sample 1 H-NMR, 13 C-NMR , DEPT135, DEPT90, COSY, HSQC, HMBC spectra were tested, and the results are shown in Figure 1- Figure 2.
- ⁇ 3.398 and delta The integral value of 3.395 is 3, and the peak position is in the range of methoxy chemical shift, so it is assigned to C-3 and C-4.
- nitrogen has a slightly weaker deshielding effect, that is, the methyl group connected to N should be in the high field of the methoxy group, ⁇ 36.35 attributable to H-4", ⁇ 1.355 and ⁇ 1.218 has a COSY correlation, is coupled to a doublet by the adjacent CH, and has a weak HMBC remote correlation with the methoxy group, which should be attributed to H-5" and H-5'.
- ⁇ 55.62 and ⁇ 56.43 are negative peaks in DEPT135 and disappear in DEPT90 spectrum, which are proved to be methyl carbon peaks, which are related to H-3" and H-3'.
- HSQC is closely related, so it belongs to C-3" and C-3'.
- ⁇ 17.56, ⁇ 18.05 and ⁇ 36.35 are negative peaks in DEPT135 and disappear in DEPT90, which are proved to be methyl carbon peaks, and have HSQC short-ranges with H-5", H-5' and H-4" It is related, so it belongs to C-5", C-5' and C-4' in turn.
- H-4" and H-3" have correlation peaks
- H-4" and H-5" have correlation peaks, indicating that the spatial distance between them is less than 5 ⁇ , indicating that these three groups are in space
- the above is the same direction, which further proves that the methylamino group at the 4" position is in the s configuration.
- a kind of purifying method of 4 "-(s)-methylamino abamectin B2a benzoate comprises the following steps:
- a kind of purifying method of 4 "-(s)-methylamino abamectin B2a benzoate comprises the following steps:
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Crystallography & Structural Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to the technical field of agricultural chemicals and preparation. Specifically, disclosed is a purification method for 4"-(s)-methylamino abamectin B2a benzoate. The purification method comprises the following steps: adding a crude product of methylamino abamectin B2a/2b benzoate to methyl tert-butyl ether, heating and dissolving, dropwise adding a mixed solution of tert-butanol and n-butyl ether, cooling and filtering after the dropwise adding, and cooling and crystallizing an obtained filtrate to obtain a product of 4"-(s)-methylamino abamectin B2a benzoate. According to the purification method provided by the present invention, by selecting the mixed solution of methyl tert-butyl ether, tert-butanol and n-butyl ether as a crystallization solvent, and in coordination with twice cooling and crystallization, the product of 4"-(s)-methylamino abamectin B2a benzoate having S-configured methylamino at bit 4" and having a content of 98% or more is obtained, thereby facilitating improvement of the insecticidal activity of related preparations, and achieving a wide application prospect.
Description
本方案要求于2020年12月25日提交的中国专利申请CN202011568862.6的优先权。在先申请的公开内容通过整体引用并入本申请。This proposal claims the priority of Chinese patent application CN202011568862.6 filed on December 25, 2020. The disclosures of the earlier applications are incorporated by reference into this application in their entirety.
本方案涉及4"-(s)-甲氨基阿维菌素B2a苯甲酸盐的纯化方法，属于农用化学品及制备领域。The present scheme relates to a purification method of 4"-(s)-methylaminoabamectin B2a benzoate, belonging to the field of agricultural chemicals and preparation.
阿维菌素为发酵组分的混合物，共有8个组分：A1a、A1b、A2a、A2b、B1a、B1b、B2a、B2b。通过对阿维菌素进行多次分离纯化可得到阿维菌素B2a/2b。阿维菌素B2a与阿维菌素B2b结构如式（II）和式（III）所示：Abamectin is a mixture of fermentation components, with 8 components: A1a, A1b, A2a, A2b, B1a, B1b, B2a, B2b. Abamectin B2a/2b can be obtained by separating and purifying abamectin for many times. The structures of Abamectin B2a and Abamectin B2b are shown in formula (II) and formula (III):
近年来甲氨基阿维菌素B2a/2b逐渐被重视，大量文献报道了甲氨基阿维菌素B2a/2b的合成方法、阿维菌素B2a/2b相关衍生物、以及相关制剂方法。甲氨基阿维菌素B2a苯甲酸盐是其中应用较多的一种物质。但是，目前合成方法制备所得的甲氨基阿维菌素B2a苯甲酸盐的纯度较低，含有较多的杂质，因此，影响后续制剂的杀虫活性。因此，有必要寻求一种收率和纯度较高的甲氨基阿维菌素B2a苯甲酸盐异构体的分离纯化方法。In recent years, Avermectin B2a/2b has been paid more and more attention. A large number of literatures have reported the synthesis method of Avermectin B2a/2b, related derivatives of Avermectin B2a/2b, and related preparation methods. Avermectin B2a benzoate is one of the most widely used substances. However, the methylaminoavermectin B2a benzoate prepared by the current synthesis method has a relatively low purity and contains many impurities, thus affecting the insecticidal activity of the subsequent preparation. Therefore, it is necessary to seek a method for separating and purifying methylaminoavermectin B2a benzoate isomers with higher yield and purity.
针对目前合成方法制备所得的甲氨基阿维菌素B2a苯甲酸盐的纯度较低的问题，本方案提供一种4"-(s)-甲氨基阿维菌素B2a苯甲酸盐的纯化方法。Aiming at the problem that the purity of the methylaminoavermectin B2a benzoate prepared by the current synthetic method is relatively low, this scheme provides a purification of 4"-(s)-methylaminoavermectin B2a benzoate method.
一种4"-(s)-甲氨基阿维菌素B2a苯甲酸盐的纯化方法，包括以下步骤：A kind of purifying method of 4 "-(s)-methylamino abamectin B2a benzoate, comprises the following steps:
将甲氨基阿维菌素B2a/2b苯甲酸盐粗品加入甲基叔丁基醚中，加热溶解，然后滴加叔丁醇和正丁醚混合溶液，滴加结束后降温过滤，将所得滤液降温析晶，得到4"-(s)-甲氨基阿维菌素B2a苯甲酸盐产品。Add methylamino abamectin B2a/2b benzoate crude product to methyl tertiary butyl ether, heat to dissolve, then dropwise add tert-butanol and n-butyl ether mixed solution, drop the temperature and filter after finishing, and cool the gained filtrate Crystallization to obtain 4"-(s)-methylaminoabamectin B2a benzoate product.
4"-(s)-甲氨基阿维菌素B2a苯甲酸盐的结构式如式（I）所示：The structural formula of 4"-(s)-methylaminoabamectin B2a benzoate is shown in formula (I):
本方案中所述S构型指的是反应活性位点4"位的甲胺基是S构型。The S configuration in this scheme means that the methylamino group at the 4" position of the reactive site is the S configuration.
作为一种实施例，所述甲基叔丁基醚、叔丁醇和正丁醚的质量比为1:1~1.5:1.5~4。As an embodiment, the mass ratio of the methyl tert-butyl ether, tert-butanol and n-butyl ether is 1:1~1.5:1.5~4.
作为一种实施例，所述甲氨基阿维菌素B2a/2b苯甲酸盐粗品与甲基叔丁基醚、叔丁醇和正丁醚总量的质量比为1:3~5。As an embodiment, the mass ratio of the methylamino abamectin B2a/2b benzoate crude product to methyl tert-butyl ether, tert-butyl alcohol and n-butyl ether total amount is 1:3～5.
上述结晶溶剂以及溶剂的加入量，有利于去除甲氨基阿维菌素B2a/2b苯甲酸盐粗品中的杂质，并有利于获得高纯度的4"-(s)-甲氨基阿维菌素B2a苯甲酸盐产品。The add-on of above-mentioned crystallization solvent and solvent is conducive to removing the impurity in the crude benzoate of methylamino abamectin B2a/2b, and is conducive to obtaining high-purity 4"-(s)-methylamino abamectin B2a benzoate product.
作为一种实施例，降温过滤的温度为0~5℃。As an embodiment, the temperature of the cooling filtration is 0-5°C.
上述降温过滤的温度有利于充分去除甲氨基阿维菌素B2a/2b苯甲酸盐粗品中的甲氨基阿维菌素B2b苯甲酸盐和其他杂质，从而有利于后续得到高纯度的4"-(s)-甲氨基阿维菌素B2a苯甲酸盐。The temperature of above-mentioned cooling filtration is conducive to fully removing the methylaminoavermectin B2b benzoate and other impurities in the methylaminoavermectin B2a/2b benzoate crude product, thereby helping to obtain high-purity 4" -(s)-Methylaminoavermectin B2a benzoate.
作为一种实施例，降温析晶的温度为-10~-5℃。As an embodiment, the temperature of cooling and crystallization is -10~-5°C.
作为一种实施例，降温析晶的时间为2~3h。As an embodiment, the time for cooling and crystallization is 2-3 hours.
作为一种实施例，所述叔丁醇和正丁醚混合溶液的滴加时间为1.5~2.5h。As an embodiment, the dropping time of the mixed solution of tert-butanol and n-butyl ether is 1.5-2.5h.
上述降温析晶温度和时间，以及叔丁醇和正丁醚混合溶液的滴加时间，有利于增大4"-(s)-甲氨基阿维菌素B2a苯甲酸盐与其他物质在体系中的溶解度差异，从而获得高纯度的单一构型的4"-(s)-甲氨基阿维菌素B2a苯甲酸盐产品。Above-mentioned cooling crystallization temperature and time, and the dropping time of tert-butanol and n-butyl ether mixed solution, are beneficial to increase 4"-(s)-methylamino abamectin B2a benzoate and other substances in the system The solubility difference of 4"-(s)-methylaminoavermectin B2a benzoate of single configuration of high purity is obtained thereby.
作为一种实施例，所述甲氨基阿维菌素B2a/2b苯甲酸盐粗品中甲氨基阿维菌素B2a苯甲酸盐的含量不小于70%。As an embodiment, the content of methylaminoabamectin B2a benzoate in the methylaminoabamectin B2a/2b benzoate crude product is not less than 70%.
作为一种实施例，加热溶解的温度为35~45℃。As an example, the temperature for heating and dissolving is 35-45°C.
上述加热温度有利于使甲氨基阿维菌素B2a/2b苯甲酸盐粗品充分溶解，从而有利于通过降温过滤除去杂质。The above-mentioned heating temperature is conducive to fully dissolving the Avermectin B2a/2b benzoate crude product, thereby helping to remove impurities by cooling and filtration.
作为一种实施例，采用核磁共振表征所得的
1H-NMR、
13C-NMR、DEPT135、DEPT90、COSY、HSQC和HMBC谱图对所得4"-(s)-甲氨基阿维菌素B2a苯甲酸盐产品进行结构鉴定。
As an example, the 1 H-NMR, 13 C-NMR, DEPT135, DEPT90, COSY, HSQC and HMBC spectrograms obtained by nuclear magnetic resonance characterization are used for the obtained 4"-(s)-methylaminoavermectin B2a benzene. Structural identification of formate products.
本方案采用核磁共振中的
1H-NMR、
13C-NMR、DEPT135、DEPT90、COSY、HSQC和HMBC谱图进行综合分析，证明了纯化所得的甲氨基阿维菌素B2a苯甲酸盐为S-构型。
This scheme adopts the 1 H-NMR, 13 C-NMR, DEPT135, DEPT90, COSY, HSQC and HMBC spectra in nuclear magnetic resonance for comprehensive analysis, which proves that the purified methylaminoabamectin B2a benzoate is S. -structure.
本方案提供的甲氨基阿维菌素B2a苯甲酸盐的纯化方法，通过选择甲基叔丁基醚、叔丁醇和正丁醚的混合溶液作为结晶溶剂，并配合两次降温析晶的方式，得到单一构型的含量98%以上的4"-(s)-甲氨基阿维菌素B2a苯甲酸盐产品，产品收率可达62%以上，且纯化方法简单，为后续研发人员开发高活性的甲氨基阿维菌素B2a苯甲酸盐产品提供了可能。The method for purifying methylamino abamectin B2a benzoate provided in this scheme is to select a mixed solution of methyl tert-butyl ether, tert-butyl alcohol and n-butyl ether as a crystallization solvent, and cooperate with two cooling methods for crystallization , to obtain 4"-(s)-methylaminoabamectin B2a benzoate product with a content of more than 98% in a single configuration, the product yield can reach more than 62%, and the purification method is simple, which is developed for subsequent R&D personnel. A highly active methylaminoavermectin B2a benzoate product offers the possibility.
图1为本方案实施例1制备的4"-(s)-甲氨基阿维菌素B2a苯甲酸盐的NOESY谱；Fig. 1 is the NOESY spectrum of 4 "-(s)-methylamino abamectin B2a benzoate prepared in Example 1 of this scheme;
图2为图1中NOESY谱的局部放大图。FIG. 2 is a partial enlarged view of the NOESY spectrum in FIG. 1 .
本方案的实施方式Implementation of this scheme
以下实施例中所用甲氨基阿维菌素B2a/2b苯甲酸盐粗品的含量为70%。The content of the used methylamino abamectin B2a/2b benzoate crude product in the following examples is 70%.
实施例1Example 1
一种4"-(s)-甲氨基阿维菌素B2a苯甲酸盐的纯化方法，包括以下步骤：A kind of purifying method of 4 "-(s)-methylamino abamectin B2a benzoate, comprises the following steps:
将50g甲氨基阿维菌素B2a/2b苯甲酸盐粗品加入50g甲基叔丁基醚中，加热至40℃使其完全溶解，然后缓慢滴加50g叔丁醇和150g正丁醚的混合溶液，滴加时间为2h，滴加结束后降温至0℃过滤，将所得滤液降温至-5℃搅拌析晶3h，过滤，烘干，得到类白色4"-(s)-甲氨基阿维菌素B2a苯甲酸盐产品22.24g，HPLC含量98.5%，收率62.6%。50g methylamino abamectin B2a/2b benzoate crude product was added in 50g methyl tert-butyl ether, heated to 40 ° C to make it completely dissolved, then slowly added dropwise the mixed solution of 50g tert-butanol and 150g n-butyl ether , the dropwise addition time is 2h, after the dropwise addition is completed, the temperature is lowered to 0°C for filtration, the obtained filtrate is cooled to -5°C, stirred and crystallized for 3h, filtered, and dried to obtain off-white 4"-(s)-Averbacter methylamino. 22.24g of benzoate product of B2a, HPLC content of 98.5% and yield of 62.6%.
制备所得4"-(s)-甲氨基阿维菌素B2a苯甲酸盐的核磁谱图解析过程如下：The NMR spectrum analysis process of the prepared 4"-(s)-methylaminoabamectin B2a benzoate is as follows:
仪器：AVIII-500兆核磁共振仪，德国BRUKER公司，产地：瑞士。Instrument: AVIII-500 mega nuclear magnetic resonance apparatus, Germany BRUKER company, origin: Switzerland.
溶剂：氘代氯仿。Solvent: deuterated chloroform.
测试条件：常温下，取制备所得4"-(s)-甲氨基阿维菌素B2a苯甲酸盐溶于适量CDCl
3中，在303K温度下，对样品
1H-NMR、
13C-NMR、DEPT135、DEPT90、COSY、HSQC、HMBC谱进行测试，结果如图1-图2所示。
Test conditions: at normal temperature, get the prepared 4 "-(s)-methylaminoabamectin B2a benzoate and dissolve it in an appropriate amount of CDCl 3 , at 303K temperature, to the sample 1 H-NMR, 13 C-NMR , DEPT135, DEPT90, COSY, HSQC, HMBC spectra were tested, and the results are shown in Figure 1-Figure 2.
4"-(s)-甲氨基阿维菌素B2a苯甲酸盐核磁共振氢谱数据：1H NMR data of 4"-(s)-methylaminoabamectin B2a benzoate:
lH
NMR (400.0 MHz): 8.13(s, 1H),
7.55(d, J = 6.1, 2H), 7.45(d, J = 7.5, 2H), 5.43 (m, 3H), 5.00 (m, lH), 4.76
(br d, J = 3.0, lH), 4.69 (m, 2H), 4.30 (br d, J = 6.1, lH), 4.03 (br q, J =
6.7, lH), 3.98 (d, J = 6.2, lH), 3.94 (br s, lH), 3.88 (m, 2H), 3.85(s,
1H),3.82 (dq, J = 9.1, 6.2, lH), 3.74 (ddd, J = 11.5, 5.0, 3.8, lH), 3.68 (s,
lH), 3.58 (m, lH), 3.48 (dd, J= 9.9, 1.3, lH), 3.398(s,3H), 3.395(s, 3H),
3.38 (m, lH), 3.32(s,1H), 3.30 (q, J = 2.2, lH), 3.23 (dd, J = 9.1, 8.7, lH),
2.87 (br d, J = 3.8, lH), 2.67 (s,3H), 2.52 (m, lH), 2.31-2.25 (m, 3H), 2.21
(dd, J = 12.7, 5.0, lH), 2.05-1.90 (m, 2H), 1.87 (br s, 3H),1.78 (m, lH),
1.72 (d, J = 4.1, 2H), 1.63-1.46(m,6H),1.49(brs,3H), 1.369(d, J=6.7, 3H),
1.355(d, J=6.7, 3H), 1.230(d, J=6.2,3H), 1.218(d,J=7.0,3H), 1.11(d, J=7.6, 3H),
0.96-0.91 (m, 9H), 0.89 (m, 1H)。
l H NMR (400.0 MHz): 8.13(s, 1H), 7.55(d, J = 6.1, 2H), 7.45(d, J = 7.5, 2H), 5.43 (m, 3H), 5.00 (m, lH) , 4.76 (br d, J = 3.0, lH), 4.69 (m, 2H), 4.30 (br d, J = 6.1, lH), 4.03 (br q, J = 6.7, lH), 3.98 (d, J = 6.2, lH), 3.94 (br s, lH), 3.88 (m, 2H), 3.85(s, 1H), 3.82 (dq, J = 9.1, 6.2, lH), 3.74 (ddd, J = 11.5, 5.0, 3.8, lH), 3.68 (s, lH), 3.58 (m, lH), 3.48 (dd, J= 9.9, 1.3, lH), 3.398(s, 3H), 3.395(s, 3H), 3.38 (m, lH), 3.32(s,1H), 3.30 (q, J = 2.2, lH), 3.23 (dd, J = 9.1, 8.7, lH), 2.87 (br d, J = 3.8, lH), 2.67 (s, 3H), 2.52 (m, lH), 2.31-2.25 (m, 3H), 2.21 (dd, J = 12.7, 5.0, lH), 2.05-1.90 (m, 2H), 1.87 (br s, 3H), 1.78 (m, lH), 1.72 (d, J = 4.1, 2H), 1.63-1.46(m, 6H), 1.49(brs, 3H), 1.369(d, J=6.7, 3H), 1.355(d, J= 6.7, 3H), 1.230(d, J=6.2, 3H), 1.218(d, J=7.0, 3H), 1.11(d, J=7.6, 3H), 0.96-0.91 (m, 9H), 0.89 (m , 1H).
4"-(s)-甲氨基阿维菌素B2a苯甲酸盐核磁共振碳谱数据：Carbon NMR data of 4"-(s)-methylaminoabamectin B2a benzoate:
13C
NMR(400.0 MHz): 174.98, 170.30, 139.56, 138.15, 136.31, 135.15, 133.90, 130.50,
130.30, 130.20,130.10, 128.60, 128.40, 126.03, 120.57, 118.42, 118.13, 98.68,
95.90, 95.33, 81.39, 80.99, 80.53, 79.18, 74.99, 74.20, 71.10, 68.62, 68.48,
68.46, 67.83, 67.35, 65.65, 60.58, 56.43, 55.62, 47.50, 45.82, 41.60, 40.55,
36.80, 36.35, 35.20, 34.63, 34.44, 30.83, 30.70, 27.61, 26.27, 20.11, 18.05,
17.56, 16.50, 15.20, 13.11, 12.33, 12.32。
13 C NMR(400.0 MHz): 174.98, 170.30, 139.56, 138.15, 136.31, 135.15, 133.90, 130.50, 130.30, 130.20,130.10, 128.60, 128.40, 126.03, 120.57, 118.42, 118.13, 98.68, 95.90, 95.33, 81.39, 80.99, 80.53, 79.18, 74.99, 74.20, 71.10, 68.62, 68.48, 68.46, 67.83, 67.35, 65.65, 60.58, 56.43, 55.62, 47.50, 45.82, 41.60, 40.55, 36.80, 36.35, 35.20, 34.63, 34.44, 30.83, 30.70, 27.61, 26.27, 20.11, 18.05, 17.56, 16.50, 15.20, 13.11, 12.33, 12.32.
核磁共振氢谱（
1H-NMR）中，由于分子式中氢质子个数较多，造成许多氢质子峰交叉重叠。为了验证甲氨基阿维菌素B2a苯甲酸盐结构式中4"-甲胺基所在的含氧六元环中三个甲基的成键方向，下面只归属了相关联的甲基氢和甲基碳，以便确定相关甲基的成键方向，结果如表1-表2所示。
In the hydrogen nuclear magnetic resonance spectrum ( 1 H-NMR), due to the large number of hydrogen protons in the molecular formula, many hydrogen proton peaks overlap. In order to verify the bonding direction of the three methyl groups in the oxygen-containing six-membered ring where the 4"-methylamino group is located in the structural formula of methylaminoavermectin B2a benzoate, only the associated methyl hydrogen and methyl group are assigned below. In order to determine the bonding direction of the relevant methyl groups, the results are shown in Table 1-Table 2.
表1 氢谱测试结果Table 1 Hydrogen spectrum test results
表2 碳谱测试结果
Table 2 Carbon spectrum test results
上表中，δ
3.398和δ
3.395的积分值为3，出峰位置为甲氧基化学位移范畴，故归属为C-3和C-4。氮与氧相比，氮的去屏蔽效应稍弱，即与N相连的甲基应处在甲氧基的高场，δ
36.35归属为H-4"，
δ 1.355和δ
1.218均有COSY相关，被相邻CH偶合为双峰，分别与甲氧基有较弱HMBC远程相关，应归属于H-5"和H-5'。In the above table, δ
3.398 and delta
The integral value of 3.395 is 3, and the peak position is in the range of methoxy chemical shift, so it is assigned to C-3 and C-4. Compared with oxygen, nitrogen has a slightly weaker deshielding effect, that is, the methyl group connected to N should be in the high field of the methoxy group, δ
36.35 attributable to H-4",
δ 1.355 and δ
1.218 has a COSY correlation, is coupled to a doublet by the adjacent CH, and has a weak HMBC remote correlation with the methoxy group, which should be attributed to H-5" and H-5'.
核磁共振碳谱（
13C-NMR）中，δ
55.62和δ
56.43在DEPT135为负峰，并在DEPT90谱图中消失，证明为甲基碳峰，且与H-3"和H-3'有HSQC近程相关，故归属C-3"和C-3'。同理δ
17.56、δ
18.05和δ
36.35均在DEPT135为负峰，并在DEPT90中消失，证明为甲基碳峰，且与H-5"、H-5'和H-4"有HSQC近程相关，故依次归属C-5"、C-5'和C-4'。
In the carbon nuclear magnetic resonance spectrum ( 13 C-NMR), δ 55.62 and δ 56.43 are negative peaks in DEPT135 and disappear in DEPT90 spectrum, which are proved to be methyl carbon peaks, which are related to H-3" and H-3'. HSQC is closely related, so it belongs to C-3" and C-3'. Similarly, δ 17.56, δ 18.05 and δ 36.35 are negative peaks in DEPT135 and disappear in DEPT90, which are proved to be methyl carbon peaks, and have HSQC short-ranges with H-5", H-5' and H-4" It is related, so it belongs to C-5", C-5' and C-4' in turn.
在二维NOESY谱中，H-4"与H-3"有相关峰、H-4"与H-5"有相关峰，说明他们之间空间距离小于5Å，表明这三个基团在空间上为同一方向，进而证明4"位甲胺基为s构型。In the two-dimensional NOESY spectrum, H-4" and H-3" have correlation peaks, and H-4" and H-5" have correlation peaks, indicating that the spatial distance between them is less than 5Å, indicating that these three groups are in space The above is the same direction, which further proves that the methylamino group at the 4" position is in the s configuration.
综合上述分析，证明了本实施例制备所得的产品为4"-(s)-甲氨基阿维菌素B2a苯甲酸盐。在谱图中并未发现R构型相关出峰。Comprehensive above-mentioned analysis, it is proved that the product prepared by the present embodiment is 4 "-(s)-methylamino abamectin B2a benzoate. R configuration correlation peak is not found in the spectrogram.
实施例2Example 2
一种4"-(s)-甲氨基阿维菌素B2a苯甲酸盐的纯化方法，包括以下步骤：A kind of purifying method of 4 "-(s)-methylamino abamectin B2a benzoate, comprises the following steps:
将50g甲氨基阿维菌素B2a/2b苯甲酸盐粗品加入23g甲基叔丁基醚中，加热至45℃使其完全溶解，然后缓慢滴加35g叔丁醇和92g正丁醚的混合溶液，滴加时间为2h，滴加结束后降温至2℃过滤，将所得滤液降温至-8℃搅拌析晶2.5h，过滤，烘干，得到类白色4"-(s)-甲氨基阿维菌素B2a苯甲酸盐产品21.97g，HPLC含量98.9%，收率62.1%。Add 50g methylamino abamectin B2a/2b benzoate crude product in 23g methyl tert-butyl ether, be heated to 45 ℃ and make it dissolve completely, then slowly drip the mixed solution of 35g tert-butanol and 92g n-butyl ether , the dropwise addition time is 2h, after the dropwise addition is completed, the temperature is lowered to 2°C for filtration, the obtained filtrate is cooled to -8°C and stirred for crystallization for 2.5h, filtered and dried to obtain off-white 4"-(s)-methylaminoavidin Bacteriocin B2a benzoate product 21.97g, HPLC content 98.9%, yield 62.1%.
实施例3Example 3
一种4"-(s)-甲氨基阿维菌素B2a苯甲酸盐的纯化方法，包括以下步骤：A kind of purifying method of 4 "-(s)-methylamino abamectin B2a benzoate, comprises the following steps:
将50g甲氨基阿维菌素B2a/2b苯甲酸盐粗品加入54g甲基叔丁基醚中，加热至35℃使其完全溶解，然后缓慢滴加65g叔丁醇和81g正丁醚的混合溶液，滴加时间为2h，滴加结束后降温至5℃过滤，将所得滤液降温至-10℃搅拌析晶2h，过滤，烘干，得到类白色4"-(s)-甲氨基阿维菌素B2a苯甲酸盐产品22.34g，HPLC含量98.2%，收率62.7%。Add 50g methylamino abamectin B2a/2b benzoate crude product in 54g methyl tertiary butyl ether, be heated to 35 ℃ and make it dissolve completely, then slowly drip the mixed solution of 65g tert-butanol and 81g n-butyl ether , the dropwise addition time is 2h, after the dropwise addition is completed, the temperature is lowered to 5°C for filtration, the obtained filtrate is cooled to -10°C and stirred for crystallization for 2h, filtered and dried to obtain off-white 4"-(s)-Averbacter methylamino. 22.34g of benzoate product of B2a, HPLC content of 98.2% and yield of 62.7%.
Claims (10)
- 一种4"-(s)-甲氨基阿维菌素B2a苯甲酸盐的纯化方法，其特征在于，包括以下步骤：A kind of purification method of 4 "-(s)-methylamino abamectin B2a benzoate, is characterized in that, comprises the following steps:将甲氨基阿维菌素B2a/2b苯甲酸盐粗品加入甲基叔丁基醚中，加热溶解，然后滴加叔丁醇和正丁醚混合溶液，滴加结束后降温过滤，将所得滤液降温析晶，得到4"-(s)-甲氨基阿维菌素B2a苯甲酸盐产品。Add methylamino abamectin B2a/2b benzoate crude product to methyl tertiary butyl ether, heat to dissolve, then dropwise add tert-butanol and n-butyl ether mixed solution, drop the temperature and filter after finishing, and cool the gained filtrate Crystallization to obtain 4"-(s)-methylaminoabamectin B2a benzoate product.
- 如权利要求1所述的4"-(s)-甲氨基阿维菌素B2a苯甲酸盐的纯化方法，其特征在于，所述甲基叔丁基醚、叔丁醇和正丁醚的质量比为1:1~1.5:1.5~4。The purification method of 4 "-(s)-methylamino abamectin B2a benzoate as claimed in claim 1, is characterized in that, the quality of described methyl tertiary butyl ether, tert-butanol and n-butyl ether The ratio is 1:1~1.5:1.5~4.
- 如权利要求2所述的4"-(s)-甲氨基阿维菌素B2a苯甲酸盐的纯化方法，其特征在于，所述甲氨基阿维菌素B2a/2b苯甲酸盐粗品与甲基叔丁基醚、叔丁醇和正丁醚总量的质量比为1:3~5。The purification method of 4 "-(s)-methylamino abamectin B2a benzoate as claimed in claim 2, is characterized in that, described methylamino abamectin B2a/2b benzoate crude product and The mass ratio of the total amount of methyl tert-butyl ether, tert-butanol and n-butyl ether is 1:3~5.
- 如权利要求1所述的4"-(s)-甲氨基阿维菌素B2a苯甲酸盐的纯化方法，其特征在于，降温过滤的温度为0~5℃。The purification method of 4 "-(s)-methylamino abamectin B2a benzoate as claimed in claim 1, is characterized in that, the temperature of cooling filtration is 0～5 ℃.
- 如权利要求4所述的4"-(s)-甲氨基阿维菌素B2a苯甲酸盐的纯化方法，其特征在于，降温析晶的温度为-10~-5℃。The purification method of 4 "-(s)-methylamino abamectin B2a benzoate as claimed in claim 4, is characterized in that, the temperature of cooling and crystallization is-10～-5 ℃.
- 如权利要求5所述的4"-(s)-甲氨基阿维菌素B2a苯甲酸盐的纯化方法，其特征在于，降温析晶的时间为2~3h。The purification method of 4 "-(s)-methylamino abamectin B2a benzoate as claimed in claim 5, is characterized in that, the time of cooling and crystallization is 2～3h.
- 如权利要求1所述的4"-(s)-甲氨基阿维菌素B2a苯甲酸盐的纯化方法，其特征在于，所述叔丁醇和正丁醚混合溶液的滴加时间为1.5~2.5h。The purification method of 4 "-(s)-methylamino abamectin B2a benzoate as claimed in claim 1, is characterized in that, the dropping time of described tert-butyl alcohol and n-butyl ether mixed solution is 1.5 ~ 2.5h.
- 如权利要求1所述的4"-(s)-甲氨基阿维菌素B2a苯甲酸盐的纯化方法，其特征在于，所述甲氨基阿维菌素B2a/2b苯甲酸盐粗品中甲氨基阿维菌素B2a苯甲酸盐的含量不小于70%。The purification method of 4 "-(s)-methylamino abamectin B2a benzoate as claimed in claim 1, is characterized in that, in the described methylamino abamectin B2a/2b benzoate crude product The content of methylaminoavermectin B2a benzoate is not less than 70%.
- 如权利要求1所述的4"-(s)-甲氨基阿维菌素B2a苯甲酸盐的纯化方法，其特征在于，加热溶解的温度为35~45℃。The purification method of 4 "-(s)-methylamino abamectin B2a benzoate as claimed in claim 1, is characterized in that, the temperature of heating and dissolving is 35～45 ℃.
- 如权利要求1所述的4"-(s)-甲氨基阿维菌素B2a苯甲酸盐的纯化方法，其特征在于，采用核磁共振表征所得的 1H-NMR、 13C-NMR、DEPT135、DEPT90、COSY、HSQC和HMBC谱图对所得4"-(s)-甲氨基阿维菌素B2a苯甲酸盐产品进行结构鉴定。 The purification method of 4 "-(s)-methylamino abamectin B2a benzoate as claimed in claim 1, is characterized in that, adopts nuclear magnetic resonance to characterize gained 1 H-NMR, 13 C-NMR, DEPT135 , DEPT90, COSY, HSQC and HMBC spectra were used to identify the structure of the obtained 4"-(s)-methylaminoabamectin B2a benzoate product.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011568862.6A CN112707939B (en) | 2020-12-25 | 2020-12-25 | Purification method of 4' -(s) -emamectin benzoate B2a |
| CN202011568862.6 | 2020-12-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2022134385A1 true WO2022134385A1 (en) | 2022-06-30 |
Family
ID=75546795
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2021/086469 WO2022134385A1 (en) | 2020-12-25 | 2021-04-12 | Purification method for 4"-(s)-methylamino abamectin b2a benzoate |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN112707939B (en) |
| WO (1) | WO2022134385A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116444582A (en) * | 2023-04-18 | 2023-07-18 | 河北兴柏农业科技股份有限公司 | Emamectin benzoate purification process |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112707939B (en) * | 2020-12-25 | 2022-06-24 | 河北威远生物化工有限公司 | Purification method of 4' -(s) -emamectin benzoate B2a |
| CN113912659A (en) * | 2021-12-01 | 2022-01-11 | 河北威远生物化工有限公司 | Emamectin benzoate crystal and amorphous crystal of emamectin B2a and preparation method thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0351923A2 (en) * | 1988-07-22 | 1990-01-24 | Merck & Co. Inc. | Alkyl avermectin derivatives |
| CN103497226A (en) * | 2013-10-11 | 2014-01-08 | 齐鲁晟华制药有限公司 | Refinement method of methylamino abamectin benzoate |
| CN104876990A (en) * | 2015-06-02 | 2015-09-02 | 宁夏泰瑞制药股份有限公司 | Method for purifying crude emamectin benzoate |
| CN106243174A (en) * | 2015-06-08 | 2016-12-21 | 龙灯农业化工国际有限公司 | The method of purification emamectin-benzoate and the compositions containing described emamectin-benzoate |
| CN108191935A (en) * | 2018-01-10 | 2018-06-22 | 武汉回盛生物科技股份有限公司 | A kind of process for purification of emamectin-benzoate |
| CN112707939A (en) * | 2020-12-25 | 2021-04-27 | 河北威远生物化工有限公司 | Purification method of 4' -(s) -emamectin benzoate B2a |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103333214B (en) * | 2013-07-03 | 2015-08-12 | 大庆志飞生物化工有限公司 | A kind of Avrmectin B 2athe preparation method of fine powder |
| CN104650167B (en) * | 2015-03-10 | 2018-01-12 | 齐鲁制药（内蒙古）有限公司 | A kind of preparation method of avermectin B2a |
-
2020
- 2020-12-25 CN CN202011568862.6A patent/CN112707939B/en active Active
-
2021
- 2021-04-12 WO PCT/CN2021/086469 patent/WO2022134385A1/en active Application Filing
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0351923A2 (en) * | 1988-07-22 | 1990-01-24 | Merck & Co. Inc. | Alkyl avermectin derivatives |
| CN103497226A (en) * | 2013-10-11 | 2014-01-08 | 齐鲁晟华制药有限公司 | Refinement method of methylamino abamectin benzoate |
| CN104876990A (en) * | 2015-06-02 | 2015-09-02 | 宁夏泰瑞制药股份有限公司 | Method for purifying crude emamectin benzoate |
| CN106243174A (en) * | 2015-06-08 | 2016-12-21 | 龙灯农业化工国际有限公司 | The method of purification emamectin-benzoate and the compositions containing described emamectin-benzoate |
| CN108191935A (en) * | 2018-01-10 | 2018-06-22 | 武汉回盛生物科技股份有限公司 | A kind of process for purification of emamectin-benzoate |
| CN112707939A (en) * | 2020-12-25 | 2021-04-27 | 河北威远生物化工有限公司 | Purification method of 4' -(s) -emamectin benzoate B2a |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116444582A (en) * | 2023-04-18 | 2023-07-18 | 河北兴柏农业科技股份有限公司 | Emamectin benzoate purification process |
| CN116444582B (en) * | 2023-04-18 | 2024-03-08 | 河北兴柏农业科技股份有限公司 | Emamectin benzoate purification process |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112707939B (en) | 2022-06-24 |
| CN112707939A (en) | 2021-04-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2022134385A1 (en) | Purification method for 4"-(s)-methylamino abamectin b2a benzoate | |
| CA2722496C (en) | Crystalline minocycline base and processes for its preparation | |
| TR201816203T4 (en) | Method for producing substituted (z) -alpha-fluoro-beta-amino-acrylaldehydes. | |
| US11180449B2 (en) | Crystal form of key intermediate of bruton tyrosine kinase (BTK) inhibitor and preparation method thereof | |
| CN109678840B (en) | Preparation method of pomalidomide | |
| CN108440447A (en) | The preparation method of -1,1 (2H)-dioxide of 1,2,3,4- Ben Bing Evil triazines | |
| CN108752415B (en) | Synthesis and purification method of finasteride chiral impurity (5 β -finasteride) | |
| CN101260126B (en) | Crystallization method for trichlorosucrose | |
| CN111423424B (en) | Preparation method of high-purity mangiferin crystal | |
| CN103319548B (en) | A kind of method of purification of cane sugar-6-acetic ester | |
| CN113185423B (en) | Refining method of chloroprocaine hydrochloride | |
| CN107033114B (en) | Method for separating and purifying dihydromyricetin | |
| CN112300222B (en) | Azacitidine refining method with high purity and low solvent residue | |
| CN111454170B (en) | Acetanilide compound and preparation method and application thereof | |
| CN102351775A (en) | Preparation method of levo-5-hydroxytryptophan | |
| WO2021134921A1 (en) | Flazasulfuron crystal form and preparation method therefor | |
| CN114685383B (en) | Preparation method of dexrazoxane | |
| CN116589463A (en) | High-purity apixaban and preparation method thereof | |
| CN101024646B (en) | Method for purifying methoxyfuran-furan-2-one | |
| CN113698377B (en) | Method for extracting dihydromethysticin from alpinia japonica leaves | |
| CN111072546B (en) | Synthesis method of 5-ethynylindoline-2, 3-diketone | |
| CN118165001A (en) | Thienopyrimidine compound, intermediate and preparation method thereof | |
| CN117304050A (en) | Preparation method of N- (3-bromo-5-fluoro-4-methylphenyl) acetamide | |
| CN117720451A (en) | Preparation method of hydroxy pinacolone retinoic acid ester | |
| CN112645942A (en) | Novel crystal form of compound for treating bacterial infection and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 21908397 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 21908397 Country of ref document: EP Kind code of ref document: A1 |