CN107573362A - A kind of method of the separating-purifying sirolimus from zymotic fluid - Google Patents
A kind of method of the separating-purifying sirolimus from zymotic fluid Download PDFInfo
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- CN107573362A CN107573362A CN201711050054.9A CN201711050054A CN107573362A CN 107573362 A CN107573362 A CN 107573362A CN 201711050054 A CN201711050054 A CN 201711050054A CN 107573362 A CN107573362 A CN 107573362A
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- sirolimus
- organic solvent
- eluent
- concentrate
- zymotic fluid
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Abstract
The invention provides a kind of method of the separating-purifying sirolimus from zymotic fluid, it uses freezing broken wall, mycelium after organic solvent heating extraction freezing broken wall treatment, and dynamic axial high pressure chromatographic column is carried out to sirolimus crude product and separated, eluent gradient elutes, collect eluent, eluent concentrated after concentrate, and obtain sirolimus using twice organic solvent is dissolving crystallized.A kind of method of disclosed separating-purifying sirolimus from zymotic fluid, reduce the production cost that sirolimus is separated and purified from zymotic fluid, avoid silica gel column chromatography twice, so as to simplify the purifying process of sirolimus, the defects of post loss liquid is big is greatly reduced, therefore is relatively more suitable for industrial volume production.
Description
Technical field
The present invention relates to biopharmaceutical technology, more particularly to a kind of side of the separating-purifying sirolimus from zymotic fluid
Method.
Background technology
Sirolimus (Sirolimus) is also referred to as rapamycin (Rapamycin), is 1975 isolated by Veniza etc.
The macrolide antibiotic that is produced of streptomyces hygroscopicus.By years of researches, sirolimus, which has been developed into clinic, to be made
Potent immunosuppressant suppresses.Simultaneously using sirolimus as precursor, some structure novel derivatives of chemical modification synthesis, it is found
In immunosupress, anticancer, antiparkinsonism and AIDS etc., there is new therapeutic action, wherein its synthetic
Temsirolimus, Everolimus, AP23573 carry out clinical research as antineoplastic target novel drugs, and sirolimus exists
Medical applications field has extensive prospect.
Poplar state newly waits《Strait Pharmaceutical Journal》Disclosed in (2007, the 17th phase of volume 19,25-26 pages) document：Zymotic fluid passes through
Mycelium is obtained after centrifugation, mycelium is soaked 2 times respectively with 95% alcohol of doubling dose volume, and mycelia slag is abandoned in centrifugation, merges wine
Smart soak, it is concentrated under reduced pressure and removes alcohol.Liquid Residue is extracted 2 times respectively with isometric ethyl acetate, combined ethyl acetate layer,
And washed 1 time with saturation NaCl solution, through anhydrous Na2SO4After drying 1h, filtering, the removing ethyl acetate that is concentrated under reduced pressure obtains upper prop
Thing.Upper prop thing is dissolved in the eluant, eluent (ethyl ester-petroleum ether elution system) of proper volume, and the segmentation of 200~300 mesh silica gel column chromatographies is received
Collection, HPLC detections, merges the eluent containing sirolimus, is concentrated under reduced pressure, and concentrate is washed crystalline substance, crystallized, through above-mentioned through crystallizing from ether
The sirolimus crystallization of preparation is dissolved in a small amount of eluant, eluent, silica gel (200~300 mesh) column chromatography for separation, Fraction collection, separates
Journey efficient liquid phase tracing detection.Merge the eluent containing sirolimus, be concentrated under reduced pressure, concentrate washes crystalline substance, weight through crystallizing from ether
Crystallization obtains the sirolimus sample of high-purity.
From the technique extracted from zymotic fluid and purify sirolimus disclosed in above-mentioned documents and materials, we can see
Rough purity to sirolimus brings up to 95%, and refined purity has brought up to more than 99.8%, or single miscellaneous and total miscellaneous
Content also fall below 0.1% and less than 1%, but its extraction purification process handling process is cumbersome, time cycle length, especially
Silica gel column chromatography twice is undergone, the defects of separating-purifying cost is higher, post loss liquid is big be present, so as to greatly reduce Xi Luomo
The yield of department.
Therefore it provides a kind of low production cost, the production method for the purification sirolimus for being suitable for industrialized production are compeled
In the eyebrows and eyelashes.
The content of the invention
It is an object of the invention to disclose a kind of method of the separating-purifying sirolimus from zymotic fluid, to reduce from hair
Separated in zymotic fluid and purify the production cost of sirolimus, to simplify the purifying process of sirolimus, and propose that one kind is suitable to work
The method of industry volume production.
For achieving the above object, the invention provides a kind of method of the separating-purifying sirolimus from zymotic fluid,
Comprise the following steps：
(1) after into sirolimus zymotic fluid, addition filter aid is stirred 30~45 minutes, plate-frame filtering collects mycelia
Body；
(2) mycelium is placed in freezing environment and freezes broken wall 3~5 hours；
(3) using the mycelium 1~2 time after organic solvent heating extraction freezing broken wall treatment, extract 4~6 hours every time,
Filtering merges leaching liquor, and concentrate is obtained after being concentrated under reduced pressure under conditions of -0.06MPa~0.1MPa；
(4) concentrate obtained by step (3) is adsorbed using non-polar macroporous resin, eluent gradient elution, collection is washed
De- liquid；
(5) eluent is transferred in concentration tank, and adds organic solvent into concentration tank and extracted, collect extraction
Liquid；
(6) activated carbon is added into extract, stirring is filtered after 30~60 minutes and collects filtered fluid；
(7) filtered fluid is concentrated under reduced pressure, until the filtrate steamed is free of organic solvent, collects concentrate；
(8) concentrate obtained by step (7) is dissolved using organic solvent, inhales crystalline substance after being sufficiently stirred under cryogenic,
Brilliant liquid must be inhaled, to obtaining sirolimus crude product after inhaling brilliant liquid filtering；
(9) carry out dynamic axial high pressure chromatographic column to sirolimus crude product to separate, eluent gradient elution, collection is washed
De- liquid, eluent concentrated after concentrate；
(10) concentrate obtained by step (9) is dissolved using organic solvent, crystallization obtains sirolimus semi-finished product；
(11) sirolimus semi-finished product obtained by step (10) are dissolved using organic solvent, crystallization obtain sirolimus into
Product.
As a further improvement on the present invention, the organic solvent of the step (3) is selected from ethyl acetate, ethanol or acetone
In one or two kinds of any of the above ratio mixture；Organic solvent in the step (5) be selected from ethyl acetate or
Chloroform；The step (8) is selected from petroleum ether or hexamethylene with the organic solvent in step (10)；Having in the step (11)
Solvent is selected from ethyl acetate or ether.
As a further improvement on the present invention, the non-polar macroporous resin is selected from X-5, D1300 or HZ818.
As a further improvement on the present invention, the eluant, eluent in the step (4) is to contain 20wt%~60wt% acetone
The aqueous solution or the aqueous solution containing 30wt%~70%wt ethanol；Eluant, eluent in the step (9) be containing 25wt%~
The n-hexane mixed liquor of 40wt% acetone or the petroleum ether mixed liquor containing 30wt%~50wt% ethyl acetate.
As a further improvement on the present invention, 0.01~0.02 kilogram of activity is added by liter extract in the step (6)
The ratio addition activated carbon of charcoal.
As a further improvement on the present invention, the activated carbon is selected from medical needle-like activated carbon or 864 activated carbons.
As a further improvement on the present invention, in the step (8) organic solvent addition for the volume of concentrate 1~
3 times.
As a further improvement on the present invention, the sieve plate particle diameter 10um in the dynamic axial high pressure chromatographic column, pillar height
100cm, diameter 10cm, blade diameter length ratio 1:10.
As a further improvement on the present invention, the filter aid in the step (1) is in diatomite or perlite
A kind of or its mixture.
As a further improvement on the present invention, the addition of filter aid is sirolimus zymotic fluid in the step (1)
The 1~4% of volume.
Compared with prior art, the beneficial effects of the invention are as follows：Disclosed one kind separates from zymotic fluid to be carried
The method of pure sirolimus, the production cost that sirolimus is separated and purified from zymotic fluid is reduced, avoid silica gel twice
Column chromatography, so as to simplify the purifying process of sirolimus, the defects of post loss liquid is big is greatly reduced, therefore be relatively more suitable for
Industrial volume production.
Brief description of the drawings
The separated high-efficient liquid phase chromatogram for purifying obtained sirolimus of Fig. 1 embodiments one；
The separated high-efficient liquid phase chromatogram for purifying obtained sirolimus of Fig. 2 embodiments two；
The separated high-efficient liquid phase chromatogram for purifying obtained sirolimus of Fig. 3 embodiments three.
Embodiment
With reference to each embodiment, the present invention is described in detail, but it should explanation, these embodiments are simultaneously
Non- limitation of the present invention, those of ordinary skill in the art are according in these embodiment institute work energy, method or structures
Equivalent transformation or replacement, belong within protection scope of the present invention.
Unless there is specified otherwise in specification, the component in each embodiment, raw material in the present invention are pure using analyzing
Rank.In addition, " g " in each embodiment is unit of weight " gram "；" ml " is volume unit " milliliter "；" room temperature " is 23 DEG C.
" wt% " is concentration unit " mass percent ".
Embodiment one：
A kind of method of the separating-purifying sirolimus from zymotic fluid, comprises the following steps：
(1) after into sirolimus zymotic fluid, addition filter aid is stirred 30~45 minutes, plate-frame filtering collects mycelia
Body.Filter aid is selected from diatomite, and the addition of filter aid is the 1% of the volume of sirolimus zymotic fluid.
(2) mycelium is placed in freezing environment and freezes broken wall 3~5 hours.
(3) using the mycelium 1~2 time after organic solvent heating extraction freezing broken wall treatment, extract 4~6 hours every time,
Filtering merges leaching liquor, and concentrate is obtained after being concentrated under reduced pressure under conditions of -0.06MPa~0.1MPa.Step (3) have
Solvent is selected from ethyl acetate.
(4) concentrate obtained by step (3) is adsorbed using non-polar macroporous resin, eluent gradient elution, collection is washed
De- liquid.Specifically, the non-polar macroporous resin is selected from D1300.Eluant, eluent in the step (4) be containing 20wt%~
The aqueous solution of 60wt% acetone, and the more preferably aqueous solution of 30wt% acetone.
(5) eluent is transferred in concentration tank, and adds organic solvent into concentration tank and extracted, collect extraction
Liquid.Organic solvent in step (5) is ethyl acetate.
(6) activated carbon is added into extract, stirring is filtered after 30~60 minutes and collects filtered fluid.It is specifically, described
In step (6) activated carbon is added in the ratio for rising extract 0.01 kilogram of activated carbon of addition.Wherein, activated carbon is selected from medical needle-like
Activated carbon.
(7) filtered fluid is concentrated under reduced pressure, until the filtrate steamed is free of organic solvent, collects concentrate.
(8) concentrate obtained by step (7) is dissolved using organic solvent, inhales crystalline substance after being sufficiently stirred under cryogenic,
Brilliant liquid must be inhaled, to obtaining sirolimus crude product after inhaling brilliant liquid filtering.The addition of organic solvent is concentrate in the step (8)
2 times of volume.Organic solvent is selected from petroleum ether.
(9) carry out dynamic axial high pressure chromatographic column to sirolimus crude product to separate, eluent gradient elution, collection is washed
De- liquid, eluent concentrated after concentrate.Sieve plate particle diameter 10um in the dynamic axial high pressure chromatographic column, pillar height
100cm, diameter 10cm, blade diameter length ratio 1:10.Eluant, eluent in the step (9) for the acetone containing 25wt%~40wt% just oneself
Alkane mixed liquor, and be most preferably the n-hexane mixed liquor of the acetone containing 35wt%.
(10) concentrate obtained by step (9) is dissolved using organic solvent, crystallization obtains sirolimus semi-finished product.Step
(10) organic solvent in is selected from hexamethylene.
(11) sirolimus semi-finished product obtained by step (10) are dissolved using organic solvent, crystallization obtain sirolimus into
Product.Organic solvent in step (11) is selected from ether.
Join shown in Fig. 1, in the present embodiment, the sample solution that the sirolimus obtained by purifying is configured is in liquid chromatogram
By sequentially eluting in post, wherein, it is within 16 minutes sirolimus, is within 18 minutes sirolimus dynamic isomer, sirolimus change
Isomers is active princlple, sirolimus purity 95.5%, and dynamic isomer is into purity 4.4%.
Embodiment two：
A kind of method of the separating-purifying sirolimus from zymotic fluid, comprises the following steps：
(1) after into sirolimus zymotic fluid, addition filter aid is stirred 30~45 minutes, plate-frame filtering collects mycelia
Body.Filter aid is selected from perlite, and the addition of filter aid is the 4% of the volume of sirolimus zymotic fluid.
(2) mycelium is placed in freezing environment and freezes broken wall 3~5 hours.
(3) using the mycelium 1~2 time after organic solvent heating extraction freezing broken wall treatment, extract 4~6 hours every time,
Filtering merges leaching liquor, and concentrate is obtained after being concentrated under reduced pressure under conditions of -0.06MPa~0.1MPa.In the step (3)
Organic solvent is ethanol.
(4) concentrate obtained by step (3) is adsorbed using non-polar macroporous resin, eluent gradient elution, collection is washed
De- liquid.Specifically, non-polar macroporous resin is selected from X-5.Eluant, eluent in the step (4) is to contain 30wt%~70%wt second
The aqueous solution of alcohol, and the specially aqueous solution of 45wt% ethanol.
(5) eluent is transferred in concentration tank, and adds organic solvent into concentration tank and extracted, collect extraction
Liquid.Organic solvent in step (5) is chloroform.
(6) activated carbon is added into extract, stirring is filtered after 30~60 minutes and collects filtered fluid.The step (6)
In in the ratio for rising extract and adding 0.02 kilogram of activated carbon add activated carbon.Wherein, activated carbon is selected from 864 activated carbons.
(7) filtered fluid is concentrated under reduced pressure, until the filtrate steamed is free of organic solvent, collects concentrate.
(8) concentrate obtained by step (7) is dissolved using organic solvent, inhales crystalline substance after being sufficiently stirred under cryogenic,
Brilliant liquid must be inhaled, to obtaining sirolimus crude product after inhaling brilliant liquid filtering.The addition of organic solvent is concentrate in the step (8)
1 times of volume.Organic solvent is selected from hexamethylene.
(9) carry out dynamic axial high pressure chromatographic column to sirolimus crude product to separate, eluent gradient elution, collection is washed
De- liquid, eluent concentrated after concentrate.Sieve plate particle diameter 10um in the dynamic axial high pressure chromatographic column, pillar height
100cm, diameter 10cm, blade diameter length ratio 1:10.Eluant, eluent in the step (9) for the acetone containing 25wt%~40wt% just oneself
Alkane mixed liquor.
(10) concentrate obtained by step (9) is dissolved using organic solvent, crystallization obtains sirolimus semi-finished product.Step
(10) organic solvent in is selected from petroleum ether.
(11) sirolimus semi-finished product obtained by step (10) are dissolved using organic solvent, crystallization obtain sirolimus into
Product.Organic solvent in step (11) is selected from the mixed solution of ethyl acetate and ether arbitrary proportion.
Join shown in Fig. 2, in the present embodiment, the sample solution that the sirolimus obtained by purifying is configured is in liquid chromatogram
By sequentially eluting in post, wherein, sirolimus purity 94.1%, dynamic isomer 5.8%.
Embodiment three：
A kind of method of the separating-purifying sirolimus from zymotic fluid, comprises the following steps：
(1) after into sirolimus zymotic fluid, addition filter aid is stirred 30~45 minutes, plate-frame filtering collects mycelia
Body.Filter aid is selected from the mixture of diatomite and perlite, and the addition of filter aid is the volume of sirolimus zymotic fluid
2%.
(2) mycelium is placed in freezing environment and freezes broken wall 3~5 hours.
(3) using the mycelium 1~2 time after organic solvent heating extraction freezing broken wall treatment, extract 4~6 hours every time,
Filtering merges leaching liquor, and concentrate is obtained after being concentrated under reduced pressure under conditions of -0.06MPa~0.1MPa.In the step (3)
Organic solvent is selected from the mixed solution of ethanol and acetone.
(4) concentrate obtained by step (3) is adsorbed using non-polar macroporous resin, eluent gradient elution, collection is washed
De- liquid.The non-polar macroporous resin is selected from HZ818.Eluant, eluent in the step (4) is to contain the water-soluble of 60wt% acetone
Liquid.
(5) eluent is transferred in concentration tank, and adds organic solvent into concentration tank and extracted, collect extraction
Liquid.Organic solvent in step (5) is ethyl acetate and the mixed solution of chloroform arbitrary proportion.
(6) activated carbon is added into extract, stirring is filtered after 30~60 minutes and collects filtered fluid.The step (6)
In in the ratio for rising extract and adding 0.015 kilogram of activated carbon add activated carbon.Wherein, activated carbon is selected from medical needle-like activity
Charcoal.
(7) filtered fluid is concentrated under reduced pressure, until the filtrate steamed is free of organic solvent, collects concentrate.
(8) concentrate obtained by step (7) is dissolved using organic solvent, inhales crystalline substance after being sufficiently stirred under cryogenic,
Brilliant liquid must be inhaled, to obtaining sirolimus crude product after inhaling brilliant liquid filtering.The addition of organic solvent is concentrate in the step (8)
3 times of volume.Organic solvent is selected from petroleum ether.
(9) carry out dynamic axial high pressure chromatographic column to sirolimus crude product to separate, eluent gradient elution, collection is washed
De- liquid, eluent concentrated after concentrate.Sieve plate particle diameter 10um in the dynamic axial high pressure chromatographic column, pillar height
100cm, diameter 10cm, blade diameter length ratio 1:10.Eluant, eluent in the step (9) contains 30wt%~50wt% acetic acid second for person
The petroleum ether mixed liquor of ester.
(10) concentrate obtained by step (9) is dissolved using organic solvent, crystallization obtains sirolimus semi-finished product.Step
(10) organic solvent in is selected from petroleum ether.
(11) sirolimus semi-finished product obtained by step (10) are dissolved using organic solvent, crystallization obtain sirolimus into
Product.Organic solvent in step (11) is selected from ethyl acetate.
Join shown in Fig. 3, in the present embodiment, the sample solution that the sirolimus obtained by purifying is configured is in liquid chromatogram
By sequentially eluting in post, wherein, sirolimus purity 93.9%, dynamic isomer 5.8%.
Those listed above is a series of to be described in detail only for feasibility embodiment of the invention specifically
Bright, they simultaneously are not used to limit the scope of the invention, all equivalent implementations made without departing from skill spirit of the present invention
Or change should be included in the scope of the protection.
It is obvious to a person skilled in the art that the invention is not restricted to the details of above-mentioned one exemplary embodiment, Er Qie
In the case of without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of which point, embodiment all should be regarded as exemplary, and be nonrestrictive, the scope of the present invention is by appended power
Profit requires rather than described above limits, it is intended that all in the implication and scope of the equivalency of claim by falling
Change is included in the present invention.
Moreover, it will be appreciated that although the present specification is described in terms of embodiments, not each embodiment is only wrapped
Containing an independent technical scheme, this narrating mode of specification is only that those skilled in the art should for clarity
Using specification as an entirety, the technical solutions in the various embodiments may also be suitably combined, forms those skilled in the art
It is appreciated that other embodiment.
Claims (10)
- A kind of 1. method of the separating-purifying sirolimus from zymotic fluid, it is characterised in that comprise the following steps：(1) after into sirolimus zymotic fluid, addition filter aid is stirred 30~45 minutes, plate-frame filtering collects mycelium；(2) mycelium is placed in freezing environment and freezes broken wall 3~5 hours；(3) using the mycelium 1~2 time after organic solvent heating extraction freezing broken wall treatment, extract 4~6 hours every time, filtering Merge leaching liquor, concentrate is obtained after being concentrated under reduced pressure under conditions of -0.06MPa~0.1MPa；(4) concentrate obtained by step (3) is adsorbed using non-polar macroporous resin, eluent gradient elution, collects eluent；(5) eluent is transferred in concentration tank, and adds organic solvent into concentration tank and extracted, collect extract；(6) activated carbon is added into extract, stirring is filtered after 30~60 minutes and collects filtered fluid；(7) filtered fluid is concentrated under reduced pressure, until the filtrate steamed is free of organic solvent, collects concentrate；(8) concentrate obtained by step (7) is dissolved using organic solvent, inhales crystalline substance after being sufficiently stirred under cryogenic, must inhale Brilliant liquid, to obtaining sirolimus crude product after inhaling brilliant liquid filtering；(9) carry out dynamic axial high pressure chromatographic column to sirolimus crude product to separate, eluent gradient elution, collect elution Liquid, eluent concentrated after concentrate；(10) concentrate obtained by step (9) is dissolved using organic solvent, crystallization obtains sirolimus semi-finished product；(11) sirolimus semi-finished product obtained by step (10) are dissolved using organic solvent, crystallization obtains sirolimus finished product.
- 2. according to the method for claim 1, it is characterised in that the organic solvent of the step (3) is selected from ethyl acetate, second The mixture of one or two kinds of any of the above ratio in alcohol or acetone；Organic solvent in the step (5) is selected from second Acetoacetic ester or chloroform；The step (8) is selected from petroleum ether or hexamethylene with the organic solvent in step (10)；The step (11) organic solvent in is selected from ethyl acetate or ether.
- 3. according to the method for claim 1, it is characterised in that the non-polar macroporous resin be selected from X-5, D1300 or HZ818。
- 4. according to the method for claim 1, it is characterised in that eluant, eluent in the step (4) be containing 20wt%~ The aqueous solution of 60wt% acetone or the aqueous solution containing 30wt%~70%wt ethanol；Eluant, eluent in the step (9) is The n-hexane mixed liquor of the acetone containing 25wt%~40wt% or the petroleum ether mixing containing 30wt%~50wt% ethyl acetate Liquid.
- 5. according to the method for claim 1, it is characterised in that in the step (6) by rise extract addition 0.01~ The ratio addition activated carbon of 0.02 kilogram of activated carbon.
- 6. according to the method for claim 5, it is characterised in that the activated carbon is selected from medical needle-like activated carbon or 864 Activated carbon.
- 7. according to the method for claim 1, it is characterised in that the addition of organic solvent is concentration in the step (8) 1~3 times of liquid product.
- 8. according to the method for claim 1, it is characterised in that the sieve plate particle diameter in the dynamic axial high pressure chromatographic column 10um, pillar height 100cm, diameter 10cm, blade diameter length ratio 1:10.
- 9. according to the method for claim 1, it is characterised in that filter aid in the step (1) be selected from diatomite or One kind or its mixture in perlite.
- 10. according to the method for claim 9, it is characterised in that the addition of filter aid is Xi Luomo in the step (1) Take charge of the 1~4% of the volume of zymotic fluid.
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| CN201711050054.9A CN107573362A (en) | 2017-10-31 | 2017-10-31 | A kind of method of the separating-purifying sirolimus from zymotic fluid |
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| CN201711050054.9A CN107573362A (en) | 2017-10-31 | 2017-10-31 | A kind of method of the separating-purifying sirolimus from zymotic fluid |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113087723A (en) * | 2020-01-09 | 2021-07-09 | 鲁南制药集团股份有限公司 | Separation and purification method of sirolimus |
| CN114315860A (en) * | 2021-12-27 | 2022-04-12 | 无锡福祈制药有限公司 | Preparation method of sirolimus crude product |
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| CN102433364A (en) * | 2011-11-10 | 2012-05-02 | 中科医药行业生产力促进中心有限公司 | Process for preparing rapamycin by using microbial fermentation method |
| CN102443012A (en) * | 2010-10-13 | 2012-05-09 | 山东新时代药业有限公司 | Method for purifying rapamycin from broth |
| CN106749329A (en) * | 2016-11-28 | 2017-05-31 | 无锡福祈制药有限公司 | A kind of method that ascosin is isolated and purified in the liquid from streptomycete fermentation |
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2017
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| CN102443012A (en) * | 2010-10-13 | 2012-05-09 | 山东新时代药业有限公司 | Method for purifying rapamycin from broth |
| CN102433364A (en) * | 2011-11-10 | 2012-05-02 | 中科医药行业生产力促进中心有限公司 | Process for preparing rapamycin by using microbial fermentation method |
| CN106749329A (en) * | 2016-11-28 | 2017-05-31 | 无锡福祈制药有限公司 | A kind of method that ascosin is isolated and purified in the liquid from streptomycete fermentation |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113087723A (en) * | 2020-01-09 | 2021-07-09 | 鲁南制药集团股份有限公司 | Separation and purification method of sirolimus |
| CN113087723B (en) * | 2020-01-09 | 2023-07-28 | 鲁南制药集团股份有限公司 | Separation and purification method of sirolimus |
| CN114315860A (en) * | 2021-12-27 | 2022-04-12 | 无锡福祈制药有限公司 | Preparation method of sirolimus crude product |
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