CN108250217A - A kind of method for preparing immunosuppressor sirolimus - Google Patents
A kind of method for preparing immunosuppressor sirolimus Download PDFInfo
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- CN108250217A CN108250217A CN201611244883.6A CN201611244883A CN108250217A CN 108250217 A CN108250217 A CN 108250217A CN 201611244883 A CN201611244883 A CN 201611244883A CN 108250217 A CN108250217 A CN 108250217A
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- sirolimus
- immunosuppressor
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
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Abstract
The present invention relates to a kind of methods for preparing immunosuppressor sirolimus, this method includes decolourizing sirolimus mycelia leaching liquor by macropore decolorizing resin, then sirolimus destainer is imported into large pore resin absorption column and carries out Adsorption and desorption, the crude extract containing sirolimus is obtained after concentration stripping liquid, crude extract is dissolved with polar solvent, chromatography, then the sirolimus product of condensing crystallizing drying to obtain high-purity are carried out to it using polymer nano-microspheres.The preparation high-purity sirolimus of the present invention method is simple for process, reliable in quality, high income can reach more than 70%, and solvent consumption is few, suitable for the production of industrial-scale production pharmaceutical grade sirolimus raw material.
Description
Technical field
Three inventions belong to industrial microbial technology field, are related to the preparation method of pharmaceutical raw material, and in particular to one kind from
The preparation method of immunosuppressor sirolimus is isolated and purified in fermentation mycelium.
Background technology
Sirolimus (sirolimus) also known as rapamycin (rapamycin) are a kind of from streptomyces hygroscopicus
A kind of (Streptomyees hygroscopicus) spontaneous nitrogenous 36 membered macrolide antibiotics of lipophilicity, molecular formula
For C51H79N013, molecular weight 914.17, structural formula is as follows：
Sirolimus is white crystals, 183~184 DEG C of fusing point, -147 °~-157 ° of optical activity (c=l.02, three chloromethanes
Alkane).Methanol, ethyl alcohol, acetone, ethyl acetate, chloroform or ether are dissolved in, is insoluble in hexane or petroleum ether, it is not soluble in water.
Sirolimus is that it can block the late phase reaction of T lymphocyte activations (proliferation) as the mechanism of immunosuppressor
Cell is inhibited to enter the S phases from the G1 phases, the combination of blocking leukocyte interleukin -2 (IL-2) and its receptor, prevent Tc, Td cell from into
For the sensitization T lymphocytes with immune response effect, its immunization is played.
Fujian Microorganism Inst.'s Chen Yuan honor etc. was the 07th phase in 2007《Strait Pharmaceutical Journal》Report high-purity sirolimus
Preparation method, chromatographic column of this method filled with 200-300 mesh silica gel, with ethyl acetate and petroleum ether and acetone and oil
Ether is made eluant, eluent and is chromatographed repeatedly, and after purification with crystallizing from ether, complex crystallization 2-3 times of laying equal stress on, obtaining trans- sirolimus HPLC purity is
97.8%, cis- sirolimus HPLC purity is 2.0%, adds up to the sirolimus that purity is 99.8%, the method is not achieved suitable
Particular/special requirement of the formula sirolimus purity less than 0.5% and method fail to report product yield.
External Wyeth's patent 200680006609.3 reports a kind of rapamycin (sirolimus) purification process, should
Method mainly purifies sirolimus by chemical method, and the related drug that this method uses is especially more, and toxicity is big, and product is pure
Degree is not achieved 99%, and product yield is not achieved 70%, and trans- and cis- sirolimus ratio is 3：1, medicinal west cannot be reached substantially
Luo Mosi quality standards.
Invention content
The technical problem to be solved in the invention is to provide a kind of technique for preparing immunosuppressor sirolimus, this method
Simple for process, reliable in quality, high income, suitable for the production of industrial-scale production pharmaceutical grade sirolimus raw material.
In order to solve the above technical problems, the technical solution used in the present invention is：It is a kind of to prepare immunosuppressor Xi Luomo
The method of department, includes the following steps：
1) with the polar solvent that concentration expressed in percentage by volume is 80~95% to the mycelium obtained by sirolimus separation of fermentative broth
It is impregnated, then carrying out separation of solid and liquid to soak again obtains sirolimus leaching liquor；
2) it is 25%~40% this sirolimus leaching liquor to be diluted with water to polar solvent concentration expressed in percentage by volume again, then
Leaching liquor after dilution is subjected to decolorization by macropore decolorizing resin column, obtains sirolimus destainer；
3) sirolimus destainer importing large pore resin absorption column is adsorbed, then with the mixing of polar solvent and water
Solution carries out gradient desorption to large pore resin absorption column, obtains stripping liquid of sirolimus；
4) stripping liquid is concentrated, and with ethyl acetate or n-butyl acetate extraction, then liquid separation and concentrates ethyl acetate
Phase or butyl acetate phase, obtain sirolimus crude extract；
5) sirolimus crude extract with polar solvent is dissolved, injects nanometer polymer microballoon chromatographic column；
6) gradient desorption is carried out, and be segmented receipts to nanometer polymer microballoon chromatographic column using the mixed liquor of polar solvent and water
Collect his sirolimus stripping liquid, trans- sirolimus and cis- sirolimus are added up into sirolimus solution of the concentration more than 98.5%
Imbibition merges, and obtains the secondary stripping liquid of sirolimus；
7) above-mentioned secondary stripping liquid is concentrated and adds in organic solvent crystallization, then obtain western sieve after separation of solid and liquid drying
Do not take charge of fine powder.
Further improvement of the present invention is：Every kilogram of mycelium adds in 2~4 liter 85 in the soaking process of the step 1)
~95% polar solvent.
Further improvement of the present invention is：Macropore decolorizing resin column used in the step 2) decolorization is
LX-900 LSA-700 macropore decolorizing resin columns；In the step 3) large pore resin absorption column be XF-800, HZ-816 or
D101 large pore resin absorption columns.
Further improvement of the present invention is：Gradient desorption is carried out in the step 3) to large pore resin absorption column to be used
Polar solvent and the concentration expressed in percentage by volume of mixed solution of water be respectively 40~50% and 80%~90%
Further improvement of the present invention is：Gradient desorption is carried out to nanometer polymer microballoon chromatographic column in the step 6)
The concentration expressed in percentage by volume of the mixed solution of used polar solvent and water is respectively 45~55% and 80%~85%.
Further limit of polar solvent of the present invention is：The polar solvent for methanol, ethyl alcohol, isopropanol its
Middle one kind.
Further improvement of the present invention is：Nanometer polymer microballoon in the nanometer polymer microballoon chromatographic column is to receive
Rice polystyrene microsphere or nano pipe/polyhenylethylene derivative microballoon.
The present invention it is above-mentioned technical proposal further improvement lies in that：The polymer nano-microspheres are PS-30 type nanometers
Polymer microballoon or PSA-30 type nanometer polymer microballoons.
Further improvement of the present invention is：Organic solvent in the step 7) is acetone or butyl acetate, acetone or
The addition of butyl acetate is 2~8 times of the secondary stripping liquid volume after concentration.
Further improvement of the present invention is：The sirolimus after the concentration of secondary stripping liquid in the step 7) is a concentration of
100mg/mL~150mg/mL.
By adopting the above-described technical solution, the technological progress acquired by the present invention is：
A kind of method for preparing immunosuppressor sirolimus of the invention is simple for process, reliable in quality, and high income is suitable for
Industrial-scale production pharmaceutical grade sirolimus raw material.By using macropore decolorizing resin to sirolimus in the method for the present invention
Leaching liquor decolourizes, and can effectively remove most pigment in sirolimus leaching liquor, improve leaching liquor clarity and
Quality.Sirolimus is enriched with and is purified by reusing macroporous absorbent resin, has further been abandoned in fermentation process
The interference of generated secondary metabolite improves the quality of purpose product.It is detached again by using nanometer polymer microballoon pure
Change sirolimus, the purity of product can be increased substantially.Macroporous absorbent resin is used with nanometer polymer microballoon desorption process
Discrete gradient desorption method, the strippant of low concentration can remove most of pigment and highly polar impurity, later using high concentration
Strippant desorption, the quality of stripping liquid is made significantly to be improved.Utilize the sirolimus purity obtained by the method for the present invention
Up to more than 99.5%, whole total recovery is more than 70%.
The method of the present invention impregnates sirolimus mycelium by using the polar solvent of quantitative high concentration, makes
The pigment and other impurity of the sirolimus zymotic fluid carried in mycelium are sufficiently separated with mycelium, convenient for subsequent decoloration
And impurity elimination processing.Present invention desorption polar solvent used and the organic solvent of crystallization can use Conventional solvents, it
Small toxicity, be suitable for industrialized production.
Description of the drawings
Fig. 1 is the crude product liquid chromatogram of sirolimus of the present invention；
Fig. 2 is the sterling liquid chromatogram of sirolimus of the present invention.
Specific embodiment
Following embodiments are used merely to explain the method for realizing the present invention, should not be construed as limiting the invention.It is unless special
It does not explain, all percentages are percent by volume in the present invention.
Sirolimus zymotic fluid used in the present invention is trained for Tianjin Ling Shi biotechnologies development corporation, Ltd. with microorganism
What foster means obtained.The reagents such as ethyl alcohol, methanol, ethyl acetate, butyl acetate are commercially available.XF-800, D101 type macroporous absorption
Resin, Shandong Dong great chemical industrial companies, HZ-816 types macroporous absorbent resin are Shanghai Huazhen Science and Technology Co., Ltd..LX-900,
LSA-700 type decolorizing resins, Xi'an Lanxiao Sci-Tech Co., Ltd..Polymer nano-microspheres are produced for Suzhou Na Wei scientific ＆ technical corporation.
The high performance liquid chromatograph that the present invention uses is LC1100 multi-wavelengths (MWD) type detector, and (Agilent is public for four meta analysis pump
Department).
Embodiment 1
It is the sirolimus zymotic fluid 10L that fermentation unit is taken to be 556ug/mL first, sirolimus zymotic fluid is carried out true
Sky filters, and makes sirolimus zymotic fluid separation of solid and liquid, obtains 2.76kg mycelium.The ethyl alcohol of addition 95% is molten in this mycelium
Liquid 6.0L, immersion are filtered by vacuum this solution, and collect sirolimus leaching liquor after stirring 1 hour.Then it is diluted with water
Above-mentioned sirolimus leaching liquor to ethyl alcohol concentration expressed in percentage by volume be 30%, by this diluted leaching liquor by loading amount be 500mL
LX-900 macropore decolorizing resin columns decolourize, the destainer of gained imports XF-800 large pore resin absorption columns and is inhaled again
Attached, the resin loading amount of big pore adsorption resin column is 500mL, the flow velocity 550mL/h of importing.Then sirolimus will be adsorbed with
XF-800 resin columns first by the use of 1100mL volumetric concentrations be 40% (V/V) ethanol water washed as mobile phase, so
Afterwards again by the use of a concentration of 85% ethanol water as mobile phase wash to sirolimus elution finish, second is controlled in washing process
The flow velocity of alcohol solution is 550mL/h, obtains a stripping liquid of sirolimus in this way.
Above-mentioned stripping liquid of sirolimus is concentrated under reduced pressure, is then extracted with ethyl acetate again, liquid separation, Ran Houzai
The ethyl acetate phase of gained is concentrated, obtains sirolimus crude extract 6.92g.Sirolimus crude extract is molten with 35mL ethyl alcohol
Solution, solution is injected into the PS-30 type nanometer polymer microballoon chromatographic columns of 500mL, then uses 1000mL volumetric concentrations first
Ethanol water for 45% is washed as mobile phase, then is washed by the use of volumetric concentration for 80% ethanol water as mobile phase
It washs, until sirolimus desorption finishes；Stripping liquid under Fractional Collections PS-30 columns in desorption process, and be segmented under PS-30 type columns
Liquid carries out HPLC detections, and stripping liquid of the Xi Mosi concentration more than or equal to 98.5% is merged to get secondary stripping liquid.By gained
Secondary stripping liquid is concentrated under reduced pressure into 30mL, at this time a concentration of 142mg/mL of the sirolimus in solution, then into this concentrate
250mL butyl acetates are added in, after mixing, stand still for crystals 8h, it is then filtered, dry to get sirolimus fine powder 3.95g.Instead
Formula sirolimus fine powder HPLC purity is up to 98.12%, and cis- sirolimus fine powder HPLC purity is 0.56%, pros-and-cons type Xi Luomo
Department fine powder HPLC adds up to purity up to 98.68%, and the total recovery in production process is up to 71.04%.
Embodiment 2
The present embodiment is the sirolimus zymotic fluid 30L that fermentation unit is taken to be 582ug/mL first, and sirolimus is fermented
Liquid is filtered by vacuum, and is made sirolimus zymotic fluid separation of solid and liquid, is obtained 9.71kg mycelium.It is added in above-mentioned mycelium
85% isopropyl acetone 29.5L, immersion are filtered by vacuum this solution, and collect sirolimus leaching liquor after stirring 1 hour.
Then it is 25% that above-mentioned sirolimus leaching liquor to isopropyl acetone concentration expressed in percentage by volume, which is diluted with water, this diluted leaching liquor is led to
It crosses the LSA-700 macropore decolorizing resin columns that loading amount is 2000mL to decolourize, the destainer of gained imports the suction of HZ-816 macropores again
Attached resin column is adsorbed, and the resin loading amount of big pore adsorption resin column is 2000mL, the flow velocity 3000mL/ that destainer imports
h.Then the isopropanol water solution for being 45% (V/V) by the HZ-816 resin column 4000mL volumetric concentrations for being adsorbed with sirolimus
It is washed as mobile phase, then the isopropanol again by the use of a concentration of 90% is washed as mobile phase, and sirolimus elution finishes,
It is 2000mL/h that isopropanol flow velocity is controlled in washing process, obtains a stripping liquid of sirolimus in this way.
Above-mentioned stripping liquid of sirolimus is concentrated, n-butyl acetate extraction, liquid separation are then used again, then again by institute
The butyl acetate obtained mutually concentrates, and obtains sirolimus crude extract 22.16g.Sirolimus crude extract is molten with 150mL isopropanols
Solution, solution is injected into the PSA-30 type nano pipe/polyhenylethylene derivative microballoon chromatographic columns of 2000mL, is then used first
The isopropanol of 4000mL a concentration of 50% as mobile phase wash, then by the use of the isopropanol of 85% concentration as mobile phase wash up to
Sirolimus desorption finishes；Stripping liquid under Fractional Collections PSA-30 type columns in desorption process, and be segmented to liquid under PSA-30 type columns
HPLC detections are carried out, stripping liquid of the purity more than or equal to 98% are added up to merge to get secondary solution with cis- sirolimus by trans-
Imbibition.Secondary stripping liquid is concentrated under reduced pressure into 100mL, makes a concentration of 146mg/mL of solution sirolimus, is then concentrated to this
170mL acetone is added in liquid, after mixing, stands still for crystals 8h, it is then filtered, it is dry to get sirolimus fine powder 12.59g.Instead
Formula adds cis- sirolimus fine powder HPLC purity to be 99.11%, and total recovery reaches 72.12%.
Embodiment 3
The present embodiment is the sirolimus zymotic fluid 50L that fermentation unit is taken to be 518ug/mL first, and sirolimus is fermented
Liquid is filtered by vacuum, and is made sirolimus zymotic fluid separation of solid and liquid, is obtained 16.45kg mycelium.It is added in above-mentioned mycelium
90% methanol 65L, immersion are filtered by vacuum this solution, and collect sirolimus leaching liquor after stirring 1 hour.Then
It is 40% that above-mentioned sirolimus leaching liquor to methanol volumn concentration, which is diluted with water, this diluted leaching liquor is passed through loading amount
LX-900 macropore decolorizing resin columns for 2500mL decolourize, the destainer of gained import again D101 large pore resin absorption columns into
Row absorption, the resin loading amount of big pore adsorption resin column is 2500mL, the flow velocity 3750mL/h that destainer imports.Then it will inhale
D101 resin columns with sirolimus first by the use of the methanol aqueous solution that 5000mL volumetric concentrations are 50% (V/V) as mobile phase into
Row washing, then by the use of a concentration of 80% methanol as mobile phase wash to sirolimus elute finish, first is controlled in washing process
Alcohol flow velocity is 2500mL/h, obtains a stripping liquid of sirolimus in this way.
Above-mentioned stripping liquid of sirolimus is concentrated, is then extracted with ethyl acetate again, liquid separation, then again by institute
The ethyl acetate phase concentration obtained, obtains sirolimus crude extract 37.32g.Sirolimus crude extract 160mL methanol is dissolved,
Solution is injected into the PS-30 type nano pipe/polyhenylethylene microballoon chromatographic columns of 2500mL, it is then a concentration of with 6500mL first
55% methanol is washed as mobile phase, then by the use of the methanol of 82% concentration as mobile phase washing until tacrolimus solution sucks
Finish；Stripping liquid under Fractional Collections PS-30 type columns in desorption process, and be segmented and HPLC detections are carried out to liquid under PS-30 type columns, it will be anti-
The stripping liquid of formula and cis- sirolimus purity more than 98% merges to get secondary stripping liquid.Secondary stripping liquid is concentrated under reduced pressure
To 160mL, make a concentration of 153mg/mL of solution sirolimus, 1000mL butyl acetates are then added in into this concentrate, mix
After Uniform, 8h is stood still for crystals, it is then filtered, it is dry to get sirolimus fine powder 18.39g.Trans- and cis- total sirolimus
Fine powder HPLC purity is 99.65%, and total recovery reaches 71.00%.
Mycelium, the weight of sirolimus crude product and fine powder, HPLC purity and the yield that Examples 1 to 3 obtains are shown in Table 1.
Can be 85~95% times to polar solvent in mycelial soaking process in the specific embodiment of the present invention
Leaching liquor is diluted to 25%~40% any concentration range by the polar solvent for concentration of anticipating again after extraction；Ethyl alcohol usage amount can
To be any number that every kilogram of mycelium adds in 2~4 liters；Large pore resin absorption column is carried out used in first gradient desorption
The polar solvent concentration of the mixed solution of polar solvent and water can be any concentration of 40~50% (volumetric concentrations), to macropore
The polar solvent concentration of the mixed solution of polar solvent and water can be used in adsorption resin column the second gradient desorption of progress
Any concentration of 80%~90% (volumetric concentration)；Nanometer polymer microballoon chromatographic column is carried out used in first gradient desorption
The concentration of the mixed solution of polar solvent and water can be any concentration of 45~55% (concentration expressed in percentage by volumes), to nanometer polymerization
The concentration that object microballoon chromatographic column carries out the mixed solution of polar solvent and water used in first gradient desorption can be 80%~
Any concentration of 85% (concentration expressed in percentage by volume)；Sirolimus concentration after the concentration of-secondary stripping liquid can also be 100mg/mL~
Any number of 150mg/mL；The usage amount of organic solvent-acetone or butyl acetate can be the secondary stripping liquid volume after concentration
2~8 times of any number.
Table 1
Claims (10)
- A kind of 1. method for preparing immunosuppressor sirolimus, it is characterised in that：Include the following stepsThe mycelium obtained by sirolimus separation of fermentative broth is soaked with the polar solvent that concentration expressed in percentage by volume is 80~95% Then bubble carries out separation of solid and liquid to soak again and obtains sirolimus leaching liquor；It is 25%~40% that this sirolimus leaching liquor is diluted with water to polar solvent concentration expressed in percentage by volume again, then will dilution Leaching liquor afterwards carries out decolorization by macropore decolorizing resin column, obtains sirolimus destainer；Sirolimus destainer importing large pore resin absorption column is adsorbed, then with polar solvent and the mixed solution pair of water Large pore resin absorption column carries out gradient desorption, obtains stripping liquid of sirolimus；Concentrate a stripping liquid, and with ethyl acetate either n-butyl acetate extraction then liquid separation and concentrate ethyl acetate phase or Butyl acetate phase obtains sirolimus crude extract；Sirolimus crude extract with polar solvent is dissolved, injects nanometer polymer microballoon chromatographic column；Gradient desorption, and western sieve of Fractional Collections are carried out to nanometer polymer microballoon chromatographic column using the mixed liquor of polar solvent and water Stripping liquid is not taken charge of, sirolimus stripping liquid of the concentration more than or equal to 98% is merged, obtains the secondary stripping liquid of sirolimus；Above-mentioned secondary stripping liquid is concentrated and adds in organic solvent crystallization, then obtains sirolimus essence after separation of solid and liquid drying Powder.
- 2. a kind of method for preparing immunosuppressor sirolimus according to claim 1, it is characterised in that：The step 1) every kilogram of mycelium adds in 2~4 liter 85~95% of polar solvent in soaking process.
- 3. a kind of method for preparing immunosuppressor sirolimus according to claim 1, it is characterised in that：The step 2) the macropore decolorizing resin column used in decolorization is LX-900 or LSA-700 macropore decolorizing resin columns；The step 3) Middle large pore resin absorption column be XF-800, HZ-816 D101 large pore resin absorption columns.
- 4. a kind of method for preparing immunosuppressor sirolimus according to claim 1, it is characterised in that：The step 3) concentration expressed in percentage by volume of the mixed solution of polar solvent and water used in gradient desorption is carried out in large pore resin absorption column Respectively 40~50% and 80%~90%.
- 5. a kind of method for preparing immunosuppressor sirolimus according to claim 1, it is characterised in that：The step 6) volume hundred of the mixed solution of polar solvent and water used in gradient desorption is carried out in nanometer polymer microballoon chromatographic column Point concentration is respectively 45~55% and 80%~85%.
- 6. according to claim 1,2,4 or a kind of method for preparing immunosuppressor sirolimus of 5 any one of them, feature It is：The polar solvent is methanol, the one of which of ethyl alcohol, isopropanol.
- 7. according to a kind of method for preparing immunosuppressor sirolimus of 1 or 5 any one of them of claim, feature exists In：Nanometer polymer microballoon in the nanometer polymer microballoon chromatographic column is nano pipe/polyhenylethylene microballoon or nanometer polyphenyl second Ene derivative microballoon.
- 8. a kind of method for preparing immunosuppressor sirolimus according to claim 7, it is characterised in that：The polymerization Object nanoparticle is PS-30 type nanometer polymer microballoons or PSA-30 type nanometer polymer microballoons.
- 9. a kind of method for preparing immunosuppressor sirolimus according to claim 1, it is characterised in that：The step 7) organic solvent in is acetone or butyl acetate, and the addition of acetone or butyl acetate be the secondary stripping liquid volume after concentrating 2~8 times.
- 10. according to a kind of method for preparing immunosuppressor sirolimus of 1 or 9 any one of them of claim, feature It is：A concentration of 100mg/mL~150mg/mL of sirolimus after the concentration of secondary stripping liquid in step 7).
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| CN201611244883.6A CN108250217A (en) | 2016-12-29 | 2016-12-29 | A kind of method for preparing immunosuppressor sirolimus |
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Cited By (1)
| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102070652A (en) * | 2011-02-21 | 2011-05-25 | 西南大学 | Method for separating and extracting Sirolimus from fermentation liquid |
| CN102372726A (en) * | 2011-11-08 | 2012-03-14 | 福建省微生物研究所 | Preparation method for sirolimus coarse crystal |
| CN102936253A (en) * | 2012-11-12 | 2013-02-20 | 华北制药集团新药研究开发有限责任公司 | Preparation method of high-purity tacrolimus |
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2016
- 2016-12-29 CN CN201611244883.6A patent/CN108250217A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102070652A (en) * | 2011-02-21 | 2011-05-25 | 西南大学 | Method for separating and extracting Sirolimus from fermentation liquid |
| CN102372726A (en) * | 2011-11-08 | 2012-03-14 | 福建省微生物研究所 | Preparation method for sirolimus coarse crystal |
| CN102936253A (en) * | 2012-11-12 | 2013-02-20 | 华北制药集团新药研究开发有限责任公司 | Preparation method of high-purity tacrolimus |
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 |
| 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 |
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