CN102633642A - Method for preparing pleuromutilin crystal - Google Patents
Method for preparing pleuromutilin crystal Download PDFInfo
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- CN102633642A CN102633642A CN2012101120849A CN201210112084A CN102633642A CN 102633642 A CN102633642 A CN 102633642A CN 2012101120849 A CN2012101120849 A CN 2012101120849A CN 201210112084 A CN201210112084 A CN 201210112084A CN 102633642 A CN102633642 A CN 102633642A
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Abstract
The invention relates to a method for preparing pleuromutilin crystal. The method comprises the following steps of: extracting dry pleuromutilin hyphae by using acetone; concentrating extract till acetone almost does not exist; when crystal is precipitated, cooling, crystallizing, centrifuging and drying till the drying weight loss is less than 1 percent so as to obtain a crude pleuromutilin product; and dissolving the crude product by using a methanol solution, decolorizing with active carbon, concentrating until the crystal is precipitated, cooling, crystallizing, separating, washing with cold petroleum ether, and drying till the drying weight loss is less than 1 percent to obtain the pleuromutilin crystal. According to the invention, methyl isobutyl ketone is substituted by acetone for extracting, so that the production cost is reduced, the extraction yield is improved, and the problems about solvent consumption and recovery difficulty are solved; and the method is mild in process conditions and easy to implement, and reduces environmental pollution. Proper solvent consumption is selected in the preparation process, so that introduction of pleuromutilin impurities is reduced, and the purity of the product reaches over 98 percent.
Description
Technical field
The invention belongs to biological medicine intermediate preparation technical field, particularly relate to a kind of thiamutilin synthetic intermediate pleuromutilin crystalline preparation method.
Background technology
Pleuromutilin (Pleuromutilin) is by the pick up the ears diterpene carbapenem antibiotic of one type of wide spectrum that bacterium produces of bacterium of picking up the ears (Pleurotus mutilus) and Pa Shi, is the precursor of synthetic fumaric acid tiamulin.It has good antibacterial activity, can effectively suppress most of gram positive organism and part Gram-negative bacteria, be widely used in veterinary drug clinical in.In recent years, the researchist carries out structural modification to pleuromutilin C ~ 14, obtained the bacteriostatic activity of bacterium and mycoplasma enhanced verivate to some extent, as: thiamutilin, valnemulin, Rui Tamolin etc.Therefore, pleuromutilin being extracted purifying is the committed step of producing said product.
At present, the acquisition of pleuromutilin is to adopt the pleuromutilin in the fermented liquid is extracted purifying mostly, then through the centrifugal pleuromutilin product that obtains.The method of the extraction pleuromutilin of relevant document and disclosed patent report also has following several kinds: (1) dried mycelia is adopted MIBK (hexone) leaching, handle bullion; Bullion is used dissolve with methanol, the last pleuromutilin finished product that gets of thickening and washing; (2) dried mycelia is directly adopted the MIBK extraction, concentrates, and it is synthetic that liquid concentrator directly changes thiamutilin over to; (3) behind the mycelia dry filter, with N-BUTYL ACETATE extraction, condensing crystal to pleuromutilin finished product; (4) take methyl alcohol or extraction using alcohol, concentrate, decrease temperature crystalline is to finished product.
Above-mentioned technology is all comparatively simple, but the final product foreign matter content that obtains is higher, and purity is lower, and is bigger to back process product influence.
Summary of the invention
Intermediate product foreign matter content to above-mentioned fumaric acid tiamulin is higher, problems such as detection difficult, and the present invention provides a kind of preparation method simple, and product yield is high, and purity is high, the pleuromutilin crystalline preparation method who realizes easily.
The technical scheme that the present invention adopted is following:
A kind of pleuromutilin crystalline preparation method is characterized in that: the dried mycelia of pleuromutilin is used acetone extraction, and vat liquor is concentrated into does not have acetone basically; Decrease temperature crystalline when crystal to be had is separated out, centrifugal, vacuum-drying to weight loss on drying are lower than 1%, the pleuromutilin bullion, then bullion is used dissolve with methanol solution; Activated carbon decolorizing, decrease temperature crystalline when being concentrated into crystal and separating out, spinning; Use cold petroleum ether, vacuum-drying to weight loss on drying is lower than 1%, gets the pleuromutilin crystal.
Wherein pleuromutilin crystal bullion extracts and may further comprise the steps:
(1) lixiviate
With acetone leaching twice, leaching back spinning is with the leaching liquid merging of twice gained with the dried mycelia of pleuromutilin.The dried mycelia of the every 1g pleuromutilin of lixiviate for the first time adds the acetone of 5 ~ 7L, and extraction time is 3 ~ 4 hours; The dried mycelia of the every 1g pleuromutilin of lixiviate for the second time adds the acetone of 2 ~ 4L, and extraction time is 1 hour;
(2) concentrate
Vat liquor changes vacuum concentrator over to, 50 ~ 60 ℃ of following vacuum stirring to there not being acetone basically, vacuum degree control-0.04 ~-0.06MPa;
(3) decrease temperature crystalline, centrifugal, dry
Change liquid concentrator over to crystallizer, slowly be cooled to 0 ~ 5 ℃, separate out a large amount of yellow crystal particles this moment, continue insulation 5 hours, behind the sufficient crystallising, spinning, 50 ~ 55 ℃ of vacuum-drying to weight loss on drying are lower than 1%, get the pleuromutilin bullion.
The preparation of pleuromutilin crystal comprises the steps:
(1) dissolving
The pleuromutilin bullion is used dissolve with methanol, and the volume that adds methyl alcohol is 4 ~ 5 times of bullion quality, is heated to dissolving fully;
(2) decolouring
1 ~ 2% of adding bullion weight gac decoloured 0.5 ~ 1 hour in lysate, filtered;
(3) concentrate
Change filtrating over to vacuum concentrator, vacuum concentration is evaporated to 30 ~ 40% of original volume, and have crystal to separate out this moment;
(4) decrease temperature crystalline separates, and uses cold petroleum ether, drying
Change liquid concentrator over to crystallizer, slowly cool to 0 ~ 5 ℃, separate out white crystal; Insulation reaction 5 hours, sufficient crystallising is used the whizzer spinning; Add the cold petroleum ether of 10 times of crystal mass, 60 ~ 70 ℃ of vacuum-drying to weight loss on drying are lower than 1%, get the pleuromutilin crystal.
Compared with prior art, beneficial effect of the present invention is following:
(1) market value of domestic acetone is 6
～7 yuan/kg; And the market value of MIBK is 60～70 yuan/kg; The market value of N-BUTYL ACETATE is 9～10 yuan/kg; The present invention adopts acetone extraction to prepare the pleuromutilin bullion to have replaced the MIBK of original technology or N-BUTYL ACETATE lixiviate to prepare bullion, greatly reduced the use cost of solvent, improved economic benefit of enterprises.Simultaneously, adopt MIBK or N-BUTYL ACETATE lixiviate, its extract yield is 80～90%; And employing acetone, its extract yield＞90%, detailed data is seen embodiment.
(2) extraction and purification process mild condition of the present invention realizes easy handling easily.
(3) solvent of the present invention's employing is less, simple to operate, has not only reduced the introducing of impurity, makes product purity be higher than 98%, and has reduced energy consumption to a great extent, has reduced the difficulty that solvent reclaims, and has reduced the discharging of refuse.
(4) the present invention is the extraction and purification process of environment-friendly type, and the solvent that is adopted can recycle, has fewer environmental impacts, and the certain development prospect is arranged.
Embodiment
With instance the present invention is described below, it should be understood that instance is to be used to explain the present invention rather than limitation of the present invention.Scope of the present invention and core content are confirmed according to claims.
Embodiment 1
The pleuromutilin bullion extracts:
(1) lixiviate: in the dried mycelia of every gram pleuromutilin, add the acetone of 5L, slowly stir, lixiviate is after 3 hours; Centrifugal with whizzer, the mycelia after the centrifugal treating is used the acetone secondary lixiviate of 3L again, and lixiviate is after 1 hour; Centrifugal, merge twice vat liquor and change vacuum concentrator over to.
(2) concentrate: after vat liquor changed vacuum concentrator over to, 50 ~ 60 ℃ of stirrings, concentration and evaporation when crystal is separated out, changed liquid concentrator over to crystallizer rapidly to not having acetone basically.
(3) crystallization: under slow stirring condition, slowly lower the temperature, reduce to 0 ~ 5 ℃ with the speed of 5 ~ 8 ℃/h, insulation reaction 5 hours, crystal is separated out fully.Centrifugal, 50 ~ 55 ℃ of vacuum-drying to weight loss on drying are lower than 1%, get the pleuromutilin bullion.Centrifugate concentrates once more, decrease temperature crystalline, dry pleuromutilin bullion, merges the gained bullion twice, reclaims acetone, recycles.
The preparation of pleuromutilin crystal:
(1) dissolving: add the methyl alcohol of 4 times of bullion quality, heated and stirred is dissolved the pleuromutilin bullion fully;
(2) decolouring: 1 ~ 2% of adding bullion weight gac in lysate, decoloring reaction 0.5 hour filters, and changes destainer over to vacuum concentrator;
(3) concentrate: with solution for vacuum concentration, 40% of concentration and evaporation to original volume, begin to have crystal to separate out this moment, changes crystallizer rapidly over to;
(4) crystallization: slowly stir, and slowly be cooled to 0 ~ 5 ℃, separate out a large amount of crystal this moment with the speed of 5 ~ 8 ℃/h; Insulation reaction 5 hours; The cold petroleum ether complete until crystallization, centrifugal, that the adding crystal mass is 10 times; 60 ~ 70 ℃ of vacuum-drying to weight loss on drying are lower than 1%, get the pleuromutilin finished product.Centrifugate repeats to concentrate, and operations such as decrease temperature crystalline merge the pleuromutilin crystal of twice gained.Reclaim solvent and washings, recycle.
Final extract yield reaches 90%, product purity 99.1%.
Embodiment 2
Method steps is with embodiment 1, and different is that the solvent add-on is different, and data are following:
The pleuromutilin bullion extracts:
In the dried mycelia of every gram pleuromutilin, add the acetone of 6L, slowly stir, lixiviate is after 3 hours, and is centrifugal with whizzer, and the mycelia after the centrifugal treating is used the acetone secondary lixiviate of 3L again, and lixiviate is after 1 hour, and is centrifugal, merges twice vat liquor and changes vacuum concentrator over to.
Concentrate with crystallization with embodiment 1.
The preparation of pleuromutilin crystal:
Add the methyl alcohol of 4 times of bullion quality, heated and stirred is dissolved the pleuromutilin bullion fully; Other like decolouring, concentrate, crystallization is with embodiment 1.
Final extract yield reaches more than 90% product purity 98%.
Embodiment 3
Method steps is with embodiment 1, and different is that the solvent add-on is different, and data are following:
The pleuromutilin bullion extracts:
Lixiviate: in the dried mycelia of every gram pleuromutilin, add the acetone of 6L, slowly stir, lixiviate is after 3 hours; Centrifugal with whizzer, the mycelia after the centrifugal treating is used the acetone secondary lixiviate of 4L again, and lixiviate is after 1 hour; Centrifugal, merge twice vat liquor and change vacuum concentrator over to.
Concentrate with crystallization with embodiment 1.
The preparation of pleuromutilin crystal:
Dissolving: add the methyl alcohol of 5 times of bullion quality, heated and stirred is dissolved the pleuromutilin bullion fully; Other like decolouring, concentrate, crystallization is with embodiment 1.
Final extract yield reaches more than 90% product purity 98.8%.
Embodiment 4
Method steps is with embodiment 1, and different is that the solvent add-on is different, and data are following:
The pleuromutilin bullion extracts:
Lixiviate: in the dried mycelia of every gram pleuromutilin, add the acetone of 7L, slowly stir, lixiviate is after 3 hours; Centrifugal with whizzer, the mycelia after the centrifugal treating is used the acetone secondary lixiviate of 2L again, and lixiviate is after 1 hour; Centrifugal, merge twice vat liquor and change vacuum concentrator over to.Concentrate with crystallization with embodiment 1.
The preparation of pleuromutilin crystal:
Dissolving: add the methyl alcohol of 5 times of bullion quality, heated and stirred is dissolved the pleuromutilin bullion fully; Other like decolouring, concentrate, crystallization is with embodiment 1.
Final extract yield reaches more than 90% product purity 98.2%.
Embodiment 5
Method steps is with embodiment 1, and different is that extraction time is different, and data are following:
The pleuromutilin bullion extracts:
Lixiviate: in the dried mycelia of every gram pleuromutilin, add 5L acetone, slowly stir, lixiviate is after 4 hours; Centrifugal with whizzer, the mycelia after the centrifugal treating is used the acetone secondary lixiviate of 3L again, and lixiviate is after 2 hours; Centrifugal, merge twice vat liquor and change vacuum concentrator over to.Concentrate with crystallization with embodiment 1.
Pleuromutilin crystal preparation method step is identical, and final extract yield reaches more than 90% product purity 98.9%.
Comparative Examples adopts MIBK (hexone) to extract pleuromutilin
The pleuromutilin bullion extracts:
(1) lixiviate: in the dried mycelia of every gram pleuromutilin, add the MIBK of 5L, slowly stir, lixiviate is after 3 hours; Centrifugal with whizzer, the mycelia after the centrifugal treating is used the MIBK secondary lixiviate of 3L again, and lixiviate is after 1 hour; Centrifugal, merge twice vat liquor and change vacuum concentrator over to.
(2) concentrate: after vat liquor changed vacuum concentrator over to, 50 ~ 60 ℃ of stirrings, concentration and evaporation when crystal is separated out, changed liquid concentrator over to crystallizer rapidly to not having MIBK basically.
(3) crystallization: under slow stirring condition, slowly lower the temperature, reduce to 0 ~ 5 ℃ with the speed of 5 ~ 8 ℃/h, insulation reaction 5 hours, crystal is separated out fully.Centrifugal, 50 ~ 55 ℃ of vacuum-drying to weight loss on drying are lower than 1%, get the pleuromutilin bullion.Centrifugate concentrates once more, decrease temperature crystalline, dry pleuromutilin bullion.
The preparation of pleuromutilin crystal:
(1) dissolving: add the methyl alcohol of 4 times of bullion quality, heated and stirred is dissolved the pleuromutilin bullion fully.
(2) decolouring: 1 ~ 2% of adding bullion quality gac in lysate, decoloring reaction 0.5 hour filters, and changes destainer over to vacuum concentrator.
(3) concentrate: with solution for vacuum concentration, 40% of concentration and evaporation to original volume, begin to have crystal to separate out this moment, changes crystallizer rapidly over to;
(4) crystallization: slowly stir, and slowly be cooled to 0 ~ 5 ℃, separate out a large amount of crystal this moment with the speed of 5 ~ 8 ℃/h; Insulation reaction 5 hours; The cold petroleum ether complete until crystallization, centrifugal, that the adding crystal mass is 10 times; 60 ~ 70 ℃ of vacuum-drying to weight loss on drying are lower than 1%, get the pleuromutilin finished product.Centrifugate repeats to concentrate, and operations such as decrease temperature crystalline merge the pleuromutilin crystal of twice gained.
Final extract yield reaches 90%, product purity 97%.
Claims (13)
1. pleuromutilin crystalline preparation method, it is characterized in that: the dried mycelia of pleuromutilin is used acetone extraction, and vat liquor is concentrated into does not have acetone basically; Decrease temperature crystalline when crystal to be had is separated out, centrifugal, be dried to weight loss on drying and be lower than 1%, the pleuromutilin bullion, then bullion is used dissolve with methanol solution; Activated carbon decolorizing, decrease temperature crystalline when being concentrated into crystal and separating out, spinning; Use cold petroleum ether, be dried to weight loss on drying and be lower than 1%, get the pleuromutilin crystal.
2. according to the described pleuromutilin crystalline of claim 1 preparation method, it is characterized in that: the dried mycelia of above-mentioned pleuromutilin is leached the back spinning with acetone extraction twice, merges the vat liquor of twice gained.
3. according to claim 1 or 2 described pleuromutilin crystalline preparing methods, it is characterized in that: the dried mycelia lixiviate of above-mentioned pleuromutilin, the dried mycelia of the every 1g pleuromutilin of lixiviate for the first time adds the acetone of 5 ~ 7L, and extraction time is 3 ~ 4 hours; The dried mycelia of the every 1g pleuromutilin of lixiviate for the second time adds the acetone of 2 ~ 4L, and extraction time is 1 hour.
4. according to the described pleuromutilin crystalline of claim 1 preparation method, it is characterized in that: above-mentioned vat liquor concentrate to adopt vacuum concentration, and controlled temperature is 50 ~ 60 ℃, and vacuum tightness is-0.04 ~-0.06MPa.
5. according to the described pleuromutilin crystalline of claim 1 preparation method, it is characterized in that: the decrease temperature crystalline of said vat liquor is to change liquid concentrator over to crystallizer, slowly is cooled to 0 ~ 5 ℃, is incubated to crystal to separate out fully.
6. according to the described pleuromutilin crystalline of claim 1 preparation method, it is characterized in that: said bullion whiz treating processes is to adopt the whizzer centrifugal treating, and the dry vacuum drying oven that adopts is dry, and 50 ~ 55 ℃ of vacuum-drying to weight loss on drying are lower than 1%.
7. according to the described pleuromutilin crystalline of claim 1 preparation method, it is characterized in that: the said volume that adds methyl alcohol when bullion is used dissolve with methanol solution is 4 ~ 5 times of the bullion quality.
8. according to the described pleuromutilin crystalline of claim 1 preparation method, it is characterized in that: to add quality be 1 ~ 2% of bullion quality to gac during above-mentioned activated carbon decolorizing, decoloured 0.5 ~ 1 hour.
9. according to the described pleuromutilin crystalline of claim 1 preparation method, it is characterized in that: the concentrated employing vacuum concentration of above-mentioned dissolving crude product liquid, controlled temperature is 60 ~ 70 ℃, vacuum tightness is-0.04 ~-0.06MPa.
10. according to the described pleuromutilin crystalline of claim 1 preparation method, it is characterized in that: the decrease temperature crystalline of said bullion liquid concentrator is to change liquid concentrator over to crystallizer, slowly cools to 0 ~ 5 ℃, is incubated to crystallization complete.
11. according to the described pleuromutilin crystalline of claim 1 preparation method, it is characterized in that: said crystal separation adopts whizzer to separate.
12. according to the described pleuromutilin crystalline of claim 1 preparation method, it is characterized in that: said crystal is used cold petroleum ether, the adding volume of sherwood oil is 9 ~ 10 times of crystal mass.
13. according to the described pleuromutilin crystalline of claim 1 preparation method, it is characterized in that: the dry vacuum drying oven that adopts of said crystal is dry, and 60 ~ 70 ℃ of vacuum-drying to weight loss on drying are lower than 1%.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104592023A (en) * | 2015-01-20 | 2015-05-06 | 山西新源华康化工股份有限公司 | Refining technology of pleuromutilin |
| CN110294697A (en) * | 2019-06-23 | 2019-10-01 | 天津瑞普生物技术股份有限公司 | Valnemulin hydrochloride hydrate crystal forms and preparation method thereof with contain the pharmaceutical composition of the crystal form |
| CN113354538A (en) * | 2020-03-03 | 2021-09-07 | 新疆上昵生物科技有限公司 | Extraction method of high-purity pleuromutilin |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104592023A (en) * | 2015-01-20 | 2015-05-06 | 山西新源华康化工股份有限公司 | Refining technology of pleuromutilin |
| CN110294697A (en) * | 2019-06-23 | 2019-10-01 | 天津瑞普生物技术股份有限公司 | Valnemulin hydrochloride hydrate crystal forms and preparation method thereof with contain the pharmaceutical composition of the crystal form |
| CN113354538A (en) * | 2020-03-03 | 2021-09-07 | 新疆上昵生物科技有限公司 | Extraction method of high-purity pleuromutilin |
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