CN104356140A - Method for separating and preparing high-purity Moxidectin membrane - Google Patents
Method for separating and preparing high-purity Moxidectin membrane Download PDFInfo
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- CN104356140A CN104356140A CN201410525928.1A CN201410525928A CN104356140A CN 104356140 A CN104356140 A CN 104356140A CN 201410525928 A CN201410525928 A CN 201410525928A CN 104356140 A CN104356140 A CN 104356140A
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Abstract
The invention discloses a method for separating and preparing a high-purity Moxidectin membrane, and belongs to the technical field of pharmaceutical chemistry. The method comprises the following steps: performing membrane filtration on a pre-purified Nemadectin solution; after extraction with dichloromethane, removing solvents by using conventional concentration; successively performing a protection feeding reaction, an oxidation reaction, an oximation reaction and a protection removing reaction on concentrate to obtain a Moxidectin crude solution; filtering to remove impurities through a membrane separation technique; obtaining a high-purity Moxidectin concentrated solution through a membrane concentration technique. The method disclosed by the invention uses the membrane separation technique to replace column chromatography and a macroporous resin adsorption and separation method, the technique is stable, controllable, simple and practical, the industrialization is easy, the dosage of the solvents is reduced, and a high-temperature solvent removing process of a material solution is omitted, so that the degradation risk of products is reduced, the product purity, the product quality and the product yield are improved, at the same time, the energy resources are saved, and the production cost is reduced.
Description
Technical field
The present invention relates to field of pharmaceutical chemistry technology, be specifically related to a kind of membrane sepn preparation method of high-purity moxidectin.
Background technology
Mosictin (INN:Moxidectin) is a kind of agricultural antibiotic of Macrolide, be mainly used in treating the parasitosis in the animal bodies such as cattle and sheep, nimoctin (INN:Nemadectin) is produced by streptomycete fermentation, obtained by chemical reaction, the structural formula of nimoctin and mosictin is such as formula (1) again.
US Patent No. 4916154A discloses a kind of method preparing mosictin, by the fermented liquid produced after streptomycete fermentation through solid-liquid separation, the nimoctin solution obtained after leaching is by extraction, silica gel column chromatography, gel chromatography obtains the nimoctin of purity more than 90% (HPLC), by the nimoctin of purification by upper protection, oxidation, deprotection and oximation reaction obtain mosictin, obtaining through silica gel column chromatography, but the method complex process, need operation and control all loaded down with trivial details hi-sil chromatography, this solvent system large usage quantity, to the upper prop thing entering silicagel column anhydrous require high, Reusability is low, this chromatography yield is caused to reduce, cost is higher.Application number be 200810126358.3 Chinese patent disclose a kind of macroporous adsorptive resins be separated mode replace hi-sil chromatography scheme, but the method that resin absorption is separated still needs to use a large amount of organic solvent, also need a large amount of organic solvent reprocessing, program complexity, cost of investment and production cost are higher simultaneously.Above-mentioned two kinds of methods, the feed liquid after purification needs vacuum removal organic solvent, and energy consumption is high, and product yield is low.
Summary of the invention
For overcoming the weak point that present technology exists, the object of the present invention is to provide a kind of membrane sepn preparation method of high-purity moxidectin, the method is owing to employing membrane separation technique, replace silica gel column chromatography to be separated with macroporous resin adsorption, the method is simple and easy to do, energy consumption is low, improve product purity, quality and yield, reduce production cost and cost of investment simultaneously.
For achieving the above object, technical solution of the present invention is as follows:
A membrane sepn preparation method for high-purity moxidectin, the method comprises the steps:
(1) by the nimoctin solution of purifying in advance successively through microfiltration membrane and ultrafiltration membrance filter, remove carbohydrate, protein and most of oil-soluble impurities in nimoctin solution; Nimoctin strength of solution after filtration is 50 ~ 60wt.%; In this step, microfiltration membrane used is that nonionic exchanges, nonpolar film, and select the hollow fiber microfiltration membrane of 1-2 ten thousand molecular weight cut-off (to refer to that microfiltration membrane used should select the hollow fiber microfiltration membrane of 1-2 ten thousand molecular weight cut-off, this microfiltration membrane can not be ion-exchange membrane simultaneously, can not be Polar Crystal Slab); Or described microfiltration membrane is nonionic exchange membrane, and select the rolling microfiltration membrane (refer to that microfiltration membrane used should select the rolling microfiltration membrane of 1500-3000 molecular weight cut-off, this microfiltration membrane is nonionic exchange membrane simultaneously) of 1500-3000 molecular weight cut-off; Described ultra-filtration membrane is that nonionic exchanges, nonpolar film, and select the tubular fibre of 2000-20000 molecular weight cut-off or rolling ultrafiltration membrane (to refer to that ultra-filtration membrane used should select tubular fibre or the rolling ultrafiltration membrane of 2000-20000 molecular weight cut-off, this ultra-filtration membrane can not be ion-exchange membrane simultaneously, can not be Polar Crystal Slab).
(2) adopt nanofiltration membrane to be concentrated by the nimoctin solution after step (1) filtration, obtain nimoctin concentrated solution; In this step, described nanofiltration membrane is nonionic exchange membrane, and is the rolling nanofiltration membrane of 200 molecular weight cut-offs.
(3) step (2) gained nimoctin concentrated solution is passed through dichloromethane extraction, by underpressure distillation concentrated removing dichloromethane solvent after extraction, obtain nimoctin enriched material;
(4) by described nimoctin enriched material successively by upper protective reaction, oxidizing reaction and oximation reaction post crystallization, then obtain mosictin crude product through protective reaction;
(5) described mosictin crude product is joined in the mixed solvent of polar organic solvent and water, be mixed with the solution of mosictin crude product, then by the solution of mosictin crude product through ultrafiltration membrance filter (its objective is byproduct of reaction removing in step (4)), obtain mosictin sterling solution; In this step, ultra-filtration membrane used is that nonionic exchanges, nonpolar film, and is the rolling ultrafiltration membrane of 600-800 molecular weight cut-off.
(6) described mosictin sterling solution nanofiltration membrane concentrated, after concentrated, strength of solution is 20 ~ 40wt.%; In this step, nanofiltration membrane used is that nonionic exchanges, nonpolar film, and is the rolling nanofiltration membrane of 200-500 molecular weight cut-off.
(7) namely the mosictin sterling solution after step (6) is concentrated is obtained described high-purity moxidectin by convection drying, or adopt condensing crystal technology from solution, isolate described high-purity moxidectin the mosictin sterling solution after step (6) is concentrated.
Described in above-mentioned steps (1), pre-nimoctin solution of purifying refers to the nimoctin solution obtained after solid-liquid separation and leaching successively by the fermented liquid produced after streptomycete fermentation.
In above-mentioned steps (1), (2) and (6), before solution employing microfiltration membrane, ultra-filtration membrane and nanofiltration membrane containing mosictin is filtered or is concentrated, first add the mixed solvent of polar organic solvent and water in containing the solution of mosictin, be made into the polar organic solvent of mosictin, and then it filtered or concentrates; Described polar organic solvent is methyl alcohol, ethanol, acetone or ethyl acetate; In described mixed solvent, polar organic solvent content is 45 ~ 75vol.%, is preferably 40-60vol.%; In the polar organic solvent of described mosictin, mosictin content is 0.1 ~ 20wt.%.
In above-mentioned steps (5), described polar organic solvent is methyl alcohol, ethanol, acetone or ethyl acetate; In described mixed solvent, polar organic solvent content is 45 ~ 75vol.%, is preferably 40-60vol.%; In the solution of described mosictin crude product, mosictin content is 0.1 ~ 20wt.%.
Design philosophy of the present invention is as follows:
Membrane technique is a kind of purification technique emerging in recent years, document [Pobert J.Petersen.Compositereverse osmosis and nanofiltration membranes.J.Membrane Sci.1993, 83:81] point out, membrane separation technique is compared with conventional isolation techniques, there is operating process simple, without being separated, separation factor is large, energy-conservation, efficiently, non-secondary pollution, can normal-temperature continuous operate, without the need to advantages such as other materials additional, cleaner production can be realized, can directly amplify, it is a new and high technology, at biotechnology, be used widely in field of medicaments.
The nimoctin extracting solution that after the present invention is directed to leaching, solid-liquid separation obtains, first remains carbohydrate, protein and most of oil-soluble impurities thereof and removes through micro-filtration, ultra-filtration membrane by most of fermented liquid.The nimoctin purity of preliminary purification is at 50 ~ 60wt.%.This component through paranitrobenzoyl chloride is protected, oxidation, oximate chemically modified and routine crystallization method after, protective reaction thing purity is at 40 ~ 60wt.%.Some residual small molecular weight impurity material in reaction and solution is removed again through micro-filtration, obtain the mosictin solution of 93 ~ 95wt.%, eventually pass nanofiltration membrane and obtain mosictin product strong solution at cryoconcentration, by conventional drying or condensing crystal, mosictin is separated from solution, the purity of gained mosictin product is 90-95% again.
The preparation method of the pre-purification nimoctin that the present invention relates to is see THE JOURNAL OFANTIBIOTICS (4,1988,519-528), nimoctin 3 ~ 25wt.% contained by its solid substance.The chemical modification method that the present invention relates to is see CN90107676.7.
Compared with method of the prior art, advantage of the present invention and beneficial effect as follows:
The inventive method, owing to employing membrane separation technique, replaces silica gel column chromatography to be separated with macroporous resin adsorption, the method is simple and easy to do, energy consumption is low, improves product purity, quality and yield, reduces production cost and cost of investment simultaneously.
Embodiment
The present invention is further illustrated below by embodiment.It should be understood that the preparation method of the embodiment of the present invention is only used for the present invention being described, instead of limitation of the present invention, in following examples each material concentration (content) without particular limitation of time refer to weight percentage.
In following examples, in step (1), (2) and (6), before solution employing microfiltration membrane, ultra-filtration membrane and nanofiltration membrane containing mosictin is filtered or is concentrated, first add the mixed solvent of polar organic solvent and water in containing the solution of mosictin, be made into the polar organic solvent of mosictin, and then it filtered or concentrates; Described polar organic solvent is methyl alcohol, ethanol, acetone or ethyl acetate; In described mixed solvent, polar organic solvent content is 45 ~ 75vol.%, is preferably 40-60vol.%; In the polar organic solvent of described mosictin, mosictin content is 0.1 ~ 20wt.%.
In following examples, in step (5), in the solution of described mosictin crude product, mosictin content is 0.1 ~ 20wt.%.
Embodiment 1:
The method steps that the present embodiment prepares high-purity moxidectin is as follows:
(1) the streptomycete fermentation fermentation liquor solid-liquid separation of producing, the nimoctin obtained after leaching is purified liquid in advance, purity 15.6%, and the solid 80g wherein containing 1.5% concentration, pumps into Polyethersulfone Hollow Fiber Plasma micro-filtrate membrane filtration, control pump pressure 0.1-0.7MP.Receive membrane filtration liquid, obtain the filtrate that purity is 20%.
Above-mentioned filtrate pumps into the spiral wound membrane filtration of 3000 molecular weight cut-offs, control pump pressure 0.5-0.9MP, receives filtrate, obtains the filtrate that purity is 52.5%.
(2) the rolling nanofiltration membrane that the nimoctin solution after step (1) ultrafiltration pumps into 200 molecular weight cut-offs concentrates, and obtains nimoctin concentrated solution.
(3) step (2) gained nimoctin concentrated solution is added methylene dichloride (nimoctin concentrated solution/methylene dichloride=1/10 (V/V)), be evaporated to dry after extraction.Obtain nimoctin enriched material 85.1g, nimoctin content 52%.
(4) above-mentioned nimoctin enriched material is through upper protection, oxidation, oximation reaction post crystallization, then obtains mosictin crude product 80.1g, mosictin content 69.5% through protective reaction (being popular response and conventional crystallization methods).
(5) above-mentioned mosictin crude product joins preparation in the mixed solvent (in mixed solvent, ethanol contend ratio is 50%) of second alcohol and water becomes the solution of mosictin crude product, mosictin content 10% in the solution of mosictin crude product, enters the spiral wound membrane filtration of 600 molecular weight cut-offs.Collection obtains mosictin sterling solution, mosictin 42g, purity 94.2%.
(6) above-mentioned mosictin sterling solution, pumps into the nanofiltration membrane of 200 molecular weight cut-offs, control pump pressure 1-10MPa, and collect concentrated rear solution, mosictin concentration is 30wt.%, wherein mosictin 42g, purity 94.2%.
(7) above-mentioned concentrated solution adds dehydrated alcohol to mosictin concentration 40%, put into after dissolution filter refrigerator after 48 hours filtration drying obtain the mosictin of solid, mosictin content 93.2% (giving money as a gift) after measured.
Embodiment 2:
The method steps that the present embodiment prepares high-purity moxidectin is as follows:
(1) the streptomycete fermentation fermentation liquor solid-liquid separation of producing, the nimoctin obtained after leaching is purified liquid in advance, purity 18.2%, and the solid 90g wherein containing 1.8% concentration, pumps into Polyethersulfone Hollow Fiber Plasma micro-filtrate membrane filtration, control pump pressure 0.1-0.7MP.Receive membrane filtration liquid, obtain the filtrate that purity is 20%.
Above-mentioned filtrate pumps into the spiral wound membrane filtration of 2000 molecular weight cut-offs, control pump pressure 0.7-1.2MP, receives filtrate, obtains the filtrate that purity is 52%.
(2) the rolling nanofiltration membrane that the nimoctin solution after step (1) ultrafiltration pumps into 200 molecular weight cut-offs concentrates, and obtains nimoctin concentrated solution.
(3) step (2) gained nimoctin concentrated solution is added methylene dichloride (nimoctin concentrated solution/methylene dichloride=1/10 (V/V)), be evaporated to dry after extraction.Gained nimoctin enriched material 85g, nimoctin content 52%.
(4) above-mentioned nimoctin enriched material is through upper protection, oxidation, oximation reaction post crystallization, then (is popular response and conventional crystallization methods through protective reaction.) obtain mosictin crude product 83.5g, mosictin content 70.2%.
(5) above-mentioned mosictin crude product joins preparation in the mixed solvent (in mixed solvent, ethanol contend ratio is 50%) of second alcohol and water becomes the solution of mosictin crude product, mosictin content 10% in the solution of mosictin crude product, enters the spiral wound membrane filtration of 600 molecular weight cut-offs.Collection obtains mosictin sterling solution, mosictin 45g, purity 93.8%.
(6) above-mentioned mosictin sterling solution, pumps into the nanofiltration membrane of 200 molecular weight cut-offs, control pump pressure 1-10MP, and solution after concentrated, mosictin concentration is 30wt.%, wherein mosictin 42g, purity 94.2%.
(7) above-mentioned concentrated solution adds dehydrated alcohol to mosictin concentration 40%, put into after dissolution filter refrigerator after 48 hours filtration drying obtain the mosictin of solid, mosictin content 93.2% (giving money as a gift) after measured.
Embodiment 3:
The method steps that the present embodiment prepares high-purity moxidectin is as follows:
(1) the fermentation liquor solid-liquid separation of streptomycete fermentation production, the nimoctin obtained after leaching is purified liquid in advance, purity 13.2%, the solid 100g wherein containing 1.4.8% concentration, pump in polyethersulfone and control fiber micro-filtrate membrane filtration, control pump pressure 0.1-0.7MP.Receive membrane filtration liquid, obtain the filtrate that purity is 18.6%.
Above-mentioned filtrate pumps into the spiral wound membrane filtration of 1500 molecular weight cut-offs, control pump pressure 0.7-1.2MP, receives filtrate, obtains the filtrate that purity is 51.4%.
(2) the rolling nanofiltration membrane that the nimoctin solution after step (1) ultrafiltration pumps into 200 molecular weight cut-offs concentrates, and obtains nimoctin concentrated solution.
(3) step (2) gained nimoctin concentrated solution is added methylene dichloride (nimoctin concentrated solution/methylene dichloride=1/10 (V/V)), be evaporated to dry after extraction.Gained nimoctin enriched material 82g, nimoctin content 51.2%.
(4) above-mentioned nimoctin enriched material is through upper protective reaction post crystallization (being popular response and conventional crystallization methods), then through peroxidation, go protection and oximation reaction, obtain mosictin crude product 85.5g, mosictin content 66.2%.
(5) above-mentioned mosictin crude product joins preparation in the mixed solvent (in mixed solvent, ethanol contend ratio is 50%) of second alcohol and water becomes the solution of mosictin crude product, mosictin content 10% in the solution of mosictin crude product, enters the spiral wound membrane filtration of 600 molecular weight cut-offs.Collection obtains mosictin sterling solution, mosictin 43.3g, purity 92.8%.
(6) above-mentioned mosictin sterling solution, pumps into the nanofiltration membrane of 200 molecular weight cut-offs, control pump pressure 1-10MP, and collect concentrated rear solution, mosictin concentration is 35wt.%, wherein, and mosictin 41g, purity 92.3%.
(7) above-mentioned concentrated solution adds dehydrated alcohol to mosictin concentration 40%, put into after dissolution filter refrigerator after 48 hours filtration drying obtain the mosictin of solid, mosictin content 93.2% (giving money as a gift) after measured.
Claims (9)
1. a membrane sepn preparation method for high-purity moxidectin, is characterized in that: the method comprises the steps:
(1) by the nimoctin solution of purifying in advance successively through microfiltration membrane and ultrafiltration membrance filter, remove carbohydrate, protein and most of oil-soluble impurities in nimoctin solution; Nimoctin strength of solution after filtration is 50 ~ 60wt.%;
(2) adopt nanofiltration membrane to be concentrated by the nimoctin solution after step (1) filtration, obtain nimoctin concentrated solution;
(3) step (2) gained nimoctin concentrated solution is passed through dichloromethane extraction, by underpressure distillation concentrated removing dichloromethane solvent after extraction, obtain nimoctin enriched material;
(4) by described nimoctin enriched material successively by upper protective reaction, oxidizing reaction and oximation reaction post crystallization, then obtain mosictin crude product through protective reaction;
(5) described mosictin crude product is joined in the mixed solvent of polar organic solvent and water, is mixed with the solution of mosictin crude product, then by the solution of mosictin crude product through ultrafiltration membrance filter, obtain mosictin sterling solution;
(6) described mosictin sterling solution nanofiltration membrane concentrated, after concentrated, strength of solution is 20 ~ 40wt.%;
(7) namely the mosictin sterling solution after step (6) is concentrated is obtained described high-purity moxidectin by convection drying, or adopt condensing crystal technology from solution, isolate described high-purity moxidectin the mosictin sterling solution after step (6) is concentrated.
2. the membrane sepn preparation method of high-purity moxidectin according to claim 1, is characterized in that: described in step (1), pre-nimoctin solution of purifying refers to the nimoctin solution obtained after solid-liquid separation and leaching successively by the fermented liquid produced after streptomycete fermentation.
3. the membrane sepn preparation method of high-purity moxidectin according to claim 1, is characterized in that: in step (1), and described microfiltration membrane is that nonionic exchanges, nonpolar film, and selects the hollow fiber microfiltration membrane of 1-2 ten thousand molecular weight cut-off; Or described microfiltration membrane is nonionic exchange membrane, and select the rolling microfiltration membrane of 1500-3000 molecular weight cut-off; Described ultra-filtration membrane is that nonionic exchanges, nonpolar film, and selects tubular fibre or the rolling ultrafiltration membrane of 2000-20000 molecular weight cut-off.
4. the membrane sepn preparation method of high-purity moxidectin according to claim 1, is characterized in that: in step (2), and described nanofiltration membrane is nonionic exchange membrane, and is the rolling nanofiltration membrane of 200 molecular weight cut-offs.
5. the membrane sepn preparation method of high-purity moxidectin according to claim 1, is characterized in that: in step (5), and ultra-filtration membrane used is that nonionic exchanges, nonpolar film, and is the rolling ultrafiltration membrane of 600-800 molecular weight cut-off.
6. the membrane sepn preparation method of high-purity moxidectin according to claim 1, is characterized in that: in step (6), and nanofiltration membrane used is that nonionic exchanges, nonpolar film, and is the rolling nanofiltration membrane of 200-500 molecular weight cut-off.
7. the membrane sepn preparation method of high-purity moxidectin according to claim 1, it is characterized in that: in step (1), (2) and (6), before solution employing microfiltration membrane, ultra-filtration membrane and nanofiltration membrane containing mosictin is filtered or is concentrated, first add the mixed solvent of polar organic solvent and water in containing the solution of mosictin, be made into the polar organic solvent of mosictin, and then it filtered or concentrates.
8. the membrane sepn preparation method of high-purity moxidectin according to claim 7, is characterized in that: described polar organic solvent is methyl alcohol, ethanol, acetone or ethyl acetate; In described mixed solvent, polar organic solvent content is 45 ~ 75vol.%; In the polar organic solvent of described mosictin, mosictin content is 0.1 ~ 20wt.%.
9. the membrane sepn preparation method of high-purity moxidectin according to claim 1, is characterized in that: in step (5), and described polar organic solvent is methyl alcohol, ethanol, acetone or ethyl acetate; In described mixed solvent, polar organic solvent content is 45 ~ 75vol.%; In the solution of described mosictin crude product, mosictin content is 0.1 ~ 20wt.%.
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Cited By (3)
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| CN104846030A (en) * | 2015-05-07 | 2015-08-19 | 芜湖福民生物药业有限公司 | Preparation method of moxidectin |
| CN105001232A (en) * | 2015-07-08 | 2015-10-28 | 安徽省皖北药业股份有限公司 | Purification method for moxidectin |
| CN107686489A (en) * | 2017-11-29 | 2018-02-13 | 江苏威凌生化科技有限公司 | A kind of high-purity moxidectin isolates and purifies method |
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