CN103664989A - Method used for preparing moxidectin using nemadectin fermentation broth - Google Patents
Method used for preparing moxidectin using nemadectin fermentation broth Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
Abstract
The invention discloses a method used for preparing moxidectin using nemadectin fermentation broth, and belongs to the synthesis technology field of compounds with condensed rings containing 4 or more heterocyclic rings. The method comprises following steps: the nemadectin fermentation broth is subjected to solid-liquid separation so as to obtain mycelium; the mycelium is immersed in ethanol so as to obtain an ethanol immersion liquid; the ethanol immersion liquid is condensed, an organic solvent with low polarity is added for extraction, and an obtained product is condensed; methanamide or a mixed solvent of methanamide and a polar solvent is added for extraction so as to obtain an extract liquor; dichloromethane is added for extraction, and an obtained mixture is condensed, and is subjected to chromatography using macroporous resin or silicagel column so as to obtain nemadectin with a purity of more than 85%; and nemadectin is subjected to upper protection, oxidation, oximation, crystallization, deprotection, and chromatography using macroporous resin or silicagel column so as to obtain moxidectin with a purity of more than 93%. The method processes advantages such as short operation time, simple operation, high overall yield, and low cost.
Description
Technical field
The present invention relates to condense the synthesis technical field of the compound that contains 4 or more heterocycles in ring system.
Background technology
Mosictin, claim again moxidectin (Moxidectin, MXD), be for No. CAS 113507-06-5, being the macrolide antibiotics of the semi-synthetic single component of a kind of streptomycete (Streptomyces.cyanneogrisens noncyanogenus) fermentation generation, is the derivative of nimoctin (Nemadectin).
Mosictin and other Macrolide antiparasitic ivermectins (Ivermetin, IVM) and Avrmectin (Avermectin, AVM) difference, be that it is single component, there are wider anthelmintic activity and the characteristic such as long-acting, safe, and under very low dose, just have the endoparasite and ectoparasite such as very strong nematicide and arthropods active, 20th century the mid-80 just start to use as insect repellent for animals, in now commercialization of Japan.
Chinese patent Granted publication CN101372492B; on August 25 2010 day for announcing, the name of innovation and creation is called a kind of method of preparing high-purity moxidectin, and this application case discloses the method for preparing high-purity moxidectin; the method is to pass through solid-liquid separation; after leaching, obtain nimoctin, then by purification with macroreticular resin nimoctin, obtain purity after 40～50% nimoctin; again by the directly upper protection of above-mentioned purification liquid; oxidation, deprotection, oximate.Wherein, upper protection has increased the step of macroporous adsorption resin chromatography purifying protection thing afterwards.Finally by crossing macroporous adsorption resin chromatography, obtain the more than 93% mosictin solution of purity, by conventional condensing crystal, mosictin is separated from solution as required.The method is used resin chromatography three times, well-known, during chromatography the parsing time long, yield is low, causes total cost higher.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of method of preparing mosictin with nimoctin fermented liquid, has advantages of that required time is short, simple to operate, total recovery is high and cost is low.
For solving the problems of the technologies described above, the technical solution used in the present invention is: a kind of method of preparing mosictin with nimoctin fermented liquid, comprises the steps:
(1) nimoctin fermented liquid is obtained to mycelium after solid-liquid separation, add alcohol immersion, obtain nimoctin alcohol immersion liquid, after concentrated removal ethanol, obtain the enriched material of nimoctin alcohol immersion liquid;
(2) in the enriched material of above-mentioned nimoctin alcohol immersion liquid, add low polar organic solvent extraction, obtain the low polar organic solvent extraction liquid of nimoctin, after concentrated this low polar organic solvent of removal, obtain the enriched material of the low polar organic solvent extraction liquid of nimoctin;
(3) in the enriched material of the low polar organic solvent extraction liquid of above-mentioned nimoctin, add the mixed solvent of methane amide or methane amide and polar solvent to extract, obtain nimoctin methane amide extraction liquid or nimoctin mixed solvent extraction liquid;
(4) in above-mentioned nimoctin methane amide extraction liquid or in nimoctin mixed solvent extraction liquid, add dichloromethane extraction, obtain nimoctin dichloromethane extraction liquid, after concentrated removal methylene dichloride, obtain the enriched material of nimoctin dichloromethane extraction liquid;
(5) by the enriched material of above-mentioned nimoctin dichloromethane extraction liquid through macroporous adsorption resin chromatography or silica gel column chromatography, obtain more than 85% nimoctin of purity;
(6) by above-mentioned purity, more than 85% nimoctin carries out upper protection, oxidation, oximation reaction; obtain oxime compounds, oxime compounds is carried out to deprotection reaction after by the Methods For Purification of crystallization, obtain mosictin; through macroporous adsorption resin chromatography or silica gel column chromatography, obtain highly purified mosictin.
Preferably, the low polar organic solvent in step (2) is normal hexane, Skellysolve A, normal heptane or sherwood oil.
Further preferred, the low polar organic solvent in step (2) is normal hexane.
The milliliter number of the low polar organic solvent volume used in step (2) be nimoctin alcohol immersion liquid enriched material grams 5-10 doubly.
Preferably, the polar solvent in step (3) is ethanol, methyl alcohol or acetonitrile.
Further preferred, the polar solvent in step (3) is ethanol.
In the mixed solvent of the middle methane amide of step (3) and polar solvent, the volume ratio of methane amide and polar solvent is 10:1～50:1.
The milliliter number of the methane amide in step (3) or the mixed solvent volume used of methane amide and polar solvent be the low polar organic solvent extraction liquid of nimoctin enriched material grams 5-20 doubly.
Preferably, in step (4), nimoctin methane amide extraction liquid or nimoctin mixed solvent extraction liquid, with after activated carbon decolorizing, add dichloromethane extraction.
The 1-5 that the middle methylene dichloride volume used of step (4) is nimoctin methane amide extraction liquid or nimoctin mixed solvent extraction liquid volume doubly.
The source of nimoctin fermented liquid of the present invention can be for adopting the conventional bacterial classification in this area to carry out resulting fermented liquid after normal fermentation; In the enriched material of nimoctin alcohol immersion liquid, add low polar organic solvent to extract, can the large impurity of remove portion polarity after separatory; In the enriched material of the low polar organic solvent extraction liquid of nimoctin, add the mixed solvent of methane amide or methane amide and polar solvent to extract, can the little impurity of remove portion polarity after separatory; Nimoctin methane amide extraction liquid or nimoctin mixed solvent extraction liquid can be removed a lot of foreign pigments with activated carbon decolorizing; In nimoctin methane amide extraction liquid or in nimoctin mixed solvent extraction liquid, add methylene dichloride to extract, after separatory, can remove impurity and some foreign pigments of being dissolved in methane amide, through the inventive method, nimoctin fermented liquid be purified and can be obtained the more than 85% high purity nimoctin of purity.By high purity nimoctin, start synthetic mosictin, the side reaction that each step chemical reaction is followed is few, does not therefore need resin chromatography to come purifying intermediate product can obtain highly purified mosictin.
The beneficial effect that adopts technique scheme to produce is:
(1) the present invention by solvent extraction, obtains the more than 85% high purity nimoctin of purity, and solvent used easily reclaims, and the extraction yield of each step is all more than 90%.
(2) the present invention starts synthetic mosictin by high purity nimoctin; the side reaction that each step chemical reaction is followed is few; do not need resin chromatography to carry out purifying intermediate product, the Methods For Purification of oxime compounds by crystallization is by deprotection, and resin or silica gel column chromatography can obtain highly purified mosictin.
(3) the present invention has advantages of that required time is short, simple to operate, total recovery is high and cost is low.
Embodiment
In following examples, the model of big pore adsorption resin is HP-20,40 orders, and Mitsubishi chemical production, market is on sale; Used silica gel is 100 orders, and Shanghai the May 4th chemical reagent company limited produces, and market is on sale.
Embodiment 1
A method of preparing mosictin with nimoctin fermented liquid, comprises the steps:
(1) nimoctin fermented liquid 26L is obtained to filter cake (mycelium) after vacuum filtration solid-liquid separation, then add 15L alcohol immersion filter cake, obtain nimoctin alcohol immersion liquid, after concentrated removal ethanol, obtain the enriched material of nimoctin alcohol immersion liquid, wherein contain nimoctin 38g, purity 15%.
(2) in the enriched material of above-mentioned nimoctin alcohol immersion liquid, add normal hexane to stir extraction, the milliliter number of normal hexane volume used is 5 times of enriched material grams of nimoctin alcohol immersion liquid, obtain nimoctin n-hexane extract, after concentrating under reduced pressure removal normal hexane, obtain the enriched material of nimoctin n-hexane extract, wherein contain nimoctin 36g, purity 56%.
(3) methane amide that is 10:1 to the volume ratio that adds methane amide and ethanol in the enriched material of above-mentioned nimoctin n-hexane extract and the mixed solvent of ethanol, extract, the milliliter number of mixed solvent volume used is 5 times of enriched material grams of nimoctin n-hexane extract, obtains nimoctin mixed solvent extraction liquid.
(4) in above-mentioned nimoctin mixed solvent extraction liquid, add dichloromethane extraction, methylene dichloride volume used is 1 times of nimoctin mixed solvent extraction liquid volume, obtain nimoctin dichloromethane extraction liquid, after concentrating under reduced pressure removal methylene dichloride, obtain the enriched material of nimoctin dichloromethane extraction liquid, wherein contain nimoctin 33g, purity 70%.
(5) by the enriched material of above-mentioned nimoctin dichloromethane extraction liquid upper macroporous adsorption resin chromatography after 70% dissolve with ethanol, use respectively the ethanol elution of different concns, during wash-out, collect more than 94% elutriant of purity and merge, be evaporated to dry, in enriched material, contain nimoctin 28g, purity 86%.
(6) nimoctin of above-mentioned purity 86% is carried out to upper protection, oxidation, oximation reaction (popular response), obtain oxime compounds, oxime compounds is passed through to ordinary method crystallization (system of second alcohol and water, V
ethanol: V
water=3:2), obtain oxime compounds 23g after purification, purity is 90%.Oxime compounds is carried out to deprotection reaction (popular response); obtain mosictin; with 70% dissolve with ethanol process macroporous adsorption resin chromatography; use respectively the ethanol elution of different concns; during wash-out, collect the elutriant merging that purity is greater than 94%; after concentrating under reduced pressure, obtain mosictin 15g, content is 93%, and total recovery is 39%.
Embodiment 2
A method of preparing mosictin with nimoctin fermented liquid, comprises the steps:
(1) nimoctin fermented liquid 30L is obtained to filter cake (mycelium) after vacuum filtration solid-liquid separation, then add 18L alcohol immersion, obtain nimoctin alcohol immersion liquid, after concentrated removal ethanol, obtain the enriched material of nimoctin alcohol immersion liquid, wherein contain nimoctin 40g, purity 15%.
(2) in the enriched material of above-mentioned nimoctin alcohol immersion liquid, add normal heptane to stir extraction, the milliliter number of normal heptane volume used is 10 times of enriched material grams of nimoctin alcohol immersion liquid, obtain nimoctin normal heptane extraction liquid, after concentrating under reduced pressure removal normal heptane, obtain the enriched material of nimoctin normal heptane extraction liquid, wherein contain nimoctin 37g, purity 58%.
(3) in the enriched material of above-mentioned nimoctin normal heptane extraction liquid, add methane amide to extract, the milliliter number of methane amide volume used is 20 times of enriched material grams of nimoctin normal heptane extraction liquid, obtains nimoctin methane amide extraction liquid.
(4) by above-mentioned nimoctin methane amide extraction liquid with after activated carbon decolorizing, add dichloromethane extraction, methylene dichloride volume used is 3 times of nimoctin methane amide extraction liquid volume, obtain nimoctin dichloromethane extraction liquid, after concentrating under reduced pressure removal methylene dichloride, obtain the enriched material of nimoctin dichloromethane extraction liquid, wherein contain nimoctin 34g, purity 71%.
(5) by the enriched material of above-mentioned nimoctin dichloromethane extraction liquid upper macroporous adsorption resin chromatography after 65% dissolve with ethanol, use respectively the ethanol elution of different concns, during wash-out, collect more than 94% elutriant of purity and merge, be evaporated to dry, in enriched material, contain nimoctin 25g, purity 85%.
(6) nimoctin of above-mentioned purity 85% is carried out to upper protection, oxidation, oximation reaction (popular response), obtain oxime compounds, oxime compounds is passed through to ordinary method crystallization (system of second alcohol and water, V
ethanol: V
water=3:2), obtain oxime compounds 19g after purification, purity is 90%.Oxime compounds is carried out to deprotection reaction (popular response); obtain mosictin; dissolve with ethanol with 70% is through macroporous adsorption resin chromatography; use respectively the ethanol elution of different concns; during wash-out, collect the elutriant merging that purity is greater than 94%; after concentrating under reduced pressure, obtain mosictin 17g, content is 93%, and total recovery is 42%.
Embodiment 3
A method of preparing mosictin with nimoctin fermented liquid, comprises the steps:
(1) nimoctin fermented liquid 27L is obtained to filter cake (mycelium) after vacuum filtration solid-liquid separation, then add 16L alcohol immersion, obtain nimoctin alcohol immersion liquid, after concentrated removal ethanol, obtain the enriched material of nimoctin alcohol immersion liquid, wherein contain nimoctin 40g, purity 15%.
(2) in the enriched material of above-mentioned nimoctin alcohol immersion liquid, add petroleum ether and stirring extraction, the milliliter number of sherwood oil volume used is 8 times of enriched material grams of nimoctin alcohol immersion liquid, obtain nimoctin petroleum ether extraction liquid, after concentrating under reduced pressure removal sherwood oil, obtain the enriched material of nimoctin petroleum ether extraction liquid, wherein contain nimoctin 38g, purity 55%.
(3) methane amide that is 50:1 to the volume ratio that adds methane amide and methyl alcohol in the enriched material of above-mentioned nimoctin petroleum ether extraction liquid and the mixed solvent of methyl alcohol, extract, the milliliter number of mixed solvent volume used is 10 times of enriched material grams of nimoctin petroleum ether extraction liquid, obtains nimoctin mixed solvent extraction liquid.
(4) by above-mentioned nimoctin mixed solvent extraction liquid with after activated carbon decolorizing, add dichloromethane extraction, methylene dichloride volume used is 4 times of nimoctin mixed solvent extraction liquid volume, obtain nimoctin dichloromethane extraction liquid, after concentrating under reduced pressure removal methylene dichloride, obtain the enriched material of nimoctin dichloromethane extraction liquid, wherein contain nimoctin 34g, purity 71%.
(5) by the enriched material of above-mentioned nimoctin dichloromethane extraction liquid upper macroporous adsorption resin chromatography after 65% dissolve with ethanol, use respectively the ethanol elution of different concns, during wash-out, collect more than 94% elutriant of purity and merge, be evaporated to dry, in enriched material, contain nimoctin 23g, purity 86%.
(6) nimoctin of above-mentioned purity 86% is carried out to upper protection, oxidation, oximation reaction (popular response), obtain oxime compounds, oxime compounds is passed through to ordinary method crystallization (system of second alcohol and water, V
ethanol: V
water=3:2), obtain oxime compounds 20g after purification, purity is 90%.Oxime compounds is carried out to deprotection reaction (popular response); obtain mosictin; dissolve with ethanol with 70% is through macroporous adsorption resin chromatography; use respectively the ethanol elution of different concns; during wash-out, collect the elutriant merging that purity is greater than 94%; after concentrating under reduced pressure, obtain mosictin 15g, content is 93%, and total recovery is 37%.
Embodiment 4
A method of preparing mosictin with nimoctin fermented liquid, comprises the steps:
(1) nimoctin fermented liquid 35L is obtained to filter cake (mycelium) after vacuum filtration solid-liquid separation, then add 20L alcohol immersion, obtain nimoctin alcohol immersion liquid, after concentrated removal ethanol, obtain the enriched material of nimoctin alcohol immersion liquid, wherein contain nimoctin 50g, purity 15%.
(2) in the enriched material of above-mentioned nimoctin alcohol immersion liquid, add Skellysolve A to stir extraction, the milliliter number of Skellysolve A volume used is 6 times of enriched material grams of nimoctin alcohol immersion liquid, obtain nimoctin Skellysolve A extraction liquid, after concentrating under reduced pressure removal Skellysolve A, obtain the enriched material of nimoctin Skellysolve A extraction liquid, wherein contain nimoctin 47g, purity 55%.
(3) methane amide that is 30:1 to the volume ratio that adds methane amide and acetonitrile in the enriched material of above-mentioned nimoctin Skellysolve A extraction liquid and the mixed solvent of acetonitrile, extract, the milliliter number of mixed solvent volume used is 8 times of enriched material grams of nimoctin Skellysolve A extraction liquid, obtains nimoctin mixed solvent extraction liquid.
(4) by above-mentioned nimoctin mixed solvent extraction liquid with after activated carbon decolorizing, add dichloromethane extraction, methylene dichloride volume used is 3 times of nimoctin mixed solvent extraction liquid volume, obtain nimoctin dichloromethane extraction liquid, after concentrating under reduced pressure removal methylene dichloride, obtain the enriched material of nimoctin dichloromethane extraction liquid, wherein contain nimoctin 43g, purity 72%.
(5) by the enriched material of above-mentioned nimoctin dichloromethane extraction liquid upper silica gel column chromatography after petroleum ether dissolution, the sherwood oil of different ratios and ethyl acetate are carried out wash-out, during wash-out, collecting more than 94% elutriant of purity merges, be evaporated to dry, in enriched material, contain nimoctin 32g, purity 88%.
(6) nimoctin of above-mentioned purity 88% is carried out to upper protection, oxidation, oximation reaction (popular response), obtain oxime compounds, oxime compounds is passed through to ordinary method crystallization (system of second alcohol and water, V
ethanol: V
water=3:2), obtain oxime compounds 25g after purification, purity is 90%.Oxime compounds is carried out to deprotection reaction (popular response), obtain mosictin reaction solution.After mosictin reaction solution is concentrated, with petroleum ether dissolution, through silica gel column chromatography, the sherwood oil of different ratios and ethyl acetate are carried out wash-out, collect the elutriant merging that purity is greater than 94%, obtain mosictin 21g after concentrating under reduced pressure, and content is 93%.Total recovery is 42%.
Embodiment 5
A method of preparing mosictin with nimoctin fermented liquid, comprises the steps:
(1) nimoctin fermented liquid 55L is obtained to filter cake (mycelium) after vacuum filtration solid-liquid separation, then add 32L alcohol immersion, obtain nimoctin alcohol immersion liquid, after concentrated removal ethanol, obtain the enriched material of nimoctin alcohol immersion liquid, wherein contain nimoctin 80g, purity 16%.
(2) in the enriched material of above-mentioned nimoctin alcohol immersion liquid, add normal hexane to stir extraction, the milliliter number of normal hexane volume used is 10 times of enriched material grams of nimoctin alcohol immersion liquid, obtain nimoctin n-hexane extract, after concentrating under reduced pressure removal normal hexane, obtain the enriched material of nimoctin n-hexane extract, wherein contain nimoctin 77g, purity 58%.
(3) methane amide that is 50:1 to the volume ratio that adds methane amide and ethanol in the enriched material of above-mentioned nimoctin n-hexane extract and the mixed solvent of ethanol, extract, the milliliter number of mixed solvent volume used is 15 times of enriched material grams of nimoctin n-hexane extract, obtains nimoctin mixed solvent extraction liquid.
(4) by above-mentioned nimoctin mixed solvent extraction liquid with after activated carbon decolorizing, add dichloromethane extraction, methylene dichloride volume used is 5 times of nimoctin mixed solvent extraction liquid volume, obtain nimoctin dichloromethane extraction liquid, after concentrating under reduced pressure removal methylene dichloride, obtain the enriched material of nimoctin dichloromethane extraction liquid, wherein contain nimoctin 73g, purity 75%.
(5) by the enriched material of above-mentioned nimoctin dichloromethane extraction liquid upper silica gel column chromatography after petroleum ether dissolution, the sherwood oil of different ratios and ethyl acetate are carried out wash-out, during wash-out, collecting more than 94% elutriant of purity merges, be evaporated to dry, in enriched material, contain nimoctin 55g, purity 88%.
(6) nimoctin of above-mentioned purity 88% is carried out to upper protection, oxidation, oximation reaction (popular response), obtain oxime compounds, oxime compounds is passed through to ordinary method crystallization (system of second alcohol and water, V
ethanol: V
water=3:2), obtain oxime compounds 48g after purification, purity is 90%.Oxime compounds is carried out to deprotection reaction (popular response), obtain mosictin reaction solution.After mosictin reaction solution is concentrated, with petroleum ether dissolution, through silica gel column chromatography, the sherwood oil of different ratios and ethyl acetate are carried out wash-out, collect the elutriant merging that purity is greater than 94%, obtain mosictin 36g after concentrating under reduced pressure, and content is 93%.Total recovery is 45%.
Claims (10)
1. with nimoctin fermented liquid, prepare a method for mosictin, it is characterized in that, comprise the steps:
(1) nimoctin fermented liquid is obtained to mycelium after solid-liquid separation, add alcohol immersion, obtain nimoctin alcohol immersion liquid, after concentrated removal ethanol, obtain the enriched material of nimoctin alcohol immersion liquid;
(2) in the enriched material of above-mentioned nimoctin alcohol immersion liquid, add low polar organic solvent extraction, obtain the low polar organic solvent extraction liquid of nimoctin, after concentrated this low polar organic solvent of removal, obtain the enriched material of the low polar organic solvent extraction liquid of nimoctin;
(3) in the enriched material of the low polar organic solvent extraction liquid of above-mentioned nimoctin, add the mixed solvent of methane amide or methane amide and polar solvent to extract, obtain nimoctin methane amide extraction liquid or nimoctin mixed solvent extraction liquid;
(4) in above-mentioned nimoctin methane amide extraction liquid or in nimoctin mixed solvent extraction liquid, add dichloromethane extraction, obtain nimoctin dichloromethane extraction liquid, after concentrated removal methylene dichloride, obtain the enriched material of nimoctin dichloromethane extraction liquid;
(5) by the enriched material of above-mentioned nimoctin dichloromethane extraction liquid through macroporous adsorption resin chromatography or silica gel column chromatography, obtain more than 85% nimoctin of purity;
(6) by above-mentioned purity, more than 85% nimoctin carries out upper protection, oxidation, oximation reaction; obtain oxime compounds, oxime compounds is carried out to deprotection reaction after by the Methods For Purification of crystallization, obtain mosictin; through macroporous adsorption resin chromatography or silica gel column chromatography, obtain highly purified mosictin.
2. a kind of method of preparing mosictin with nimoctin fermented liquid according to claim 1, is characterized in that the low polar organic solvent in described step (2) is normal hexane, Skellysolve A, normal heptane or sherwood oil.
3. a kind of method of preparing mosictin with nimoctin fermented liquid according to claim 2, is characterized in that the low polar organic solvent in described step (2) is normal hexane.
4. according to a kind of method of preparing mosictin with nimoctin fermented liquid described in claim 1,2 or 3, the milliliter number that it is characterized in that the low polar organic solvent volume used in described step (2) be nimoctin alcohol immersion liquid enriched material grams 5-10 doubly.
5. a kind of method of preparing mosictin with nimoctin fermented liquid according to claim 1, is characterized in that the polar solvent in described step (3) is ethanol, methyl alcohol or acetonitrile.
6. a kind of method of preparing mosictin with nimoctin fermented liquid according to claim 5, is characterized in that the polar solvent in described step (3) is ethanol.
7. according to a kind of method of preparing mosictin with nimoctin fermented liquid described in claim 1,5 or 6, it is characterized in that in the mixed solvent of methane amide and polar solvent in described step (3), the volume ratio of methane amide and polar solvent is 10:1～50:1.
8. a kind of method of preparing mosictin with nimoctin fermented liquid according to claim 7, the milliliter number that it is characterized in that the mixed solvent volume used of methane amide in described step (3) or methane amide and polar solvent be the low polar organic solvent extraction liquid of nimoctin enriched material grams 5-20 doubly.
9. a kind of method of preparing mosictin with nimoctin fermented liquid according to claim 1, it is characterized in that the middle nimoctin methane amide extraction liquid of described step (4) or nimoctin mixed solvent extraction liquid, with after activated carbon decolorizing, add dichloromethane extraction.
10. according to a kind of method of preparing mosictin with nimoctin fermented liquid described in claim 1 or 9, it is characterized in that methylene dichloride volume used in described step (4) be nimoctin methane amide extraction liquid or nimoctin mixed solvent extraction liquid volume 1-5 doubly.
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| CN104193760A (en) * | 2014-08-29 | 2014-12-10 | 宁夏泰瑞制药股份有限公司 | Method for extracting crude nemadectin product from nemadectin fermentation liquor |
| CN104628740A (en) * | 2015-02-13 | 2015-05-20 | 河北圣雪大成制药有限责任公司 | Method for chemical synthesis and purification of moxidectin |
| CN105272992A (en) * | 2014-07-26 | 2016-01-27 | 海正药业(杭州)有限公司 | Method for extracting nemadectin from fermentation liquor |
| CN105418631A (en) * | 2015-12-07 | 2016-03-23 | 苏州纳微科技有限公司 | Method for separating and purifying nemadectin by using HPLC (high performance liquid chromatography) |
| CN105624229A (en) * | 2014-10-30 | 2016-06-01 | 牡丹江佰佳信生物科技有限公司 | Method for improving nemadectin yield |
| CN106701860A (en) * | 2015-07-13 | 2017-05-24 | 牡丹江佰佳信生物科技有限公司 | Fermentation culture medium and method for preparing moxidectin |
| CN107815477A (en) * | 2016-09-12 | 2018-03-20 | 牡丹江佰佳信生物科技有限公司 | A kind of method of fermenting and producing moxidectin |
| CN114956451A (en) * | 2022-05-13 | 2022-08-30 | 新宇药业股份有限公司 | Moxidectin wastewater treatment method |
| CN115707706A (en) * | 2022-11-14 | 2023-02-21 | 丽珠集团新北江制药股份有限公司 | Method for recovering moxidectin protector intermediate from crystallization mother liquor |
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| CN105272992A (en) * | 2014-07-26 | 2016-01-27 | 海正药业(杭州)有限公司 | Method for extracting nemadectin from fermentation liquor |
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| CN105624229B (en) * | 2014-10-30 | 2019-01-08 | 牡丹江佰佳信生物科技有限公司 | A method of improving nimoctin yield |
| CN104628740A (en) * | 2015-02-13 | 2015-05-20 | 河北圣雪大成制药有限责任公司 | Method for chemical synthesis and purification of moxidectin |
| CN104628740B (en) * | 2015-02-13 | 2017-06-16 | 河北圣雪大成制药有限责任公司 | A kind of chemical synthesis and the method for purifying moxidectin |
| CN106701860A (en) * | 2015-07-13 | 2017-05-24 | 牡丹江佰佳信生物科技有限公司 | Fermentation culture medium and method for preparing moxidectin |
| CN105418631A (en) * | 2015-12-07 | 2016-03-23 | 苏州纳微科技有限公司 | Method for separating and purifying nemadectin by using HPLC (high performance liquid chromatography) |
| CN105418631B (en) * | 2015-12-07 | 2017-12-26 | 苏州纳微科技有限公司 | A kind of high performance liquid chromatography separation purify how the method for horse rhzomorph |
| CN107815477A (en) * | 2016-09-12 | 2018-03-20 | 牡丹江佰佳信生物科技有限公司 | A kind of method of fermenting and producing moxidectin |
| CN114956451A (en) * | 2022-05-13 | 2022-08-30 | 新宇药业股份有限公司 | Moxidectin wastewater treatment method |
| CN115707706A (en) * | 2022-11-14 | 2023-02-21 | 丽珠集团新北江制药股份有限公司 | Method for recovering moxidectin protector intermediate from crystallization mother liquor |
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