CN1727494A - Method for preparing 11 alpha bydroxy canrenone through conversion method of batch fermentation of microbe - Google Patents
Method for preparing 11 alpha bydroxy canrenone through conversion method of batch fermentation of microbe Download PDFInfo
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Abstract
A process for preparing the 11 alpha-hydroxy canrenone by microbial fermen in batches features used of the ochraspergillus as bacterial seed and the canrenone as substrate, and includes such steps as generating spores, preparing slant, preparing spore suspension, culturing seeds, fermenting culturing and substrate conversion. Its advantages are short period and high conversion rate.
Description
Technical field
The invention belongs to the microorganism technology of preparing.Relating to a kind of microbe transformation method and produce the preparation technology of 11 alpha hydroxy-canrenones, is bacterial classification with the Aspergillus ochraceus particularly, and canrenone is a substrate, takes the batch fermentation technology to prepare the method for 11 alpha hydroxy-canrenones.
Background technology
11 alpha hydroxy-canrenones (11 α OH Canrenone), chemical name pregnant steroid-4,6-diene-21-carboxylic acid, 11,17-dihydroxyl-3-oxygen-gamma lactone.It is the important medicine intermediate of synthesizing eplerenone (Eplerenone).Eplerenone is to be set out by 11 alpha hydroxy-canrenones finally to synthesize via six step chemical reactions, is mainly used in treatment congestive heart failure (CHF).
11 alpha hydroxy-canrenones are obtained by microbial transformation hydroxyl on 11 by canrenone.Because market potential is huge, the report of canrenone 11 α hydroxylation reactions has been arranged very early.
1971, B.lunt etc. just attempted producing 11 alpha hydroxy-canrenones with canrenone.When the canrenone charging capacity was 0.5g/l, transformation efficiency reached 90%.
Deshayes in 1980 is under the condition after the optimization, and the 1.5g/l canrenone can obtain 95% transformation efficiency.This is considered to the great advance in this field, but its charging capacity is not high, is unsuitable for large-scale industrial production.
1996, Ng; John S. etc. adopt fed-batch, though charging capacity greatly improves, owing to intermittently mend carbon source, nitrogenous source, microbiotic (example hydrochloric acid tsiklomitsin, sulphuric acid kanamycin etc.), cost are improved greatly; And biomass constantly increases in the process, thalline even can be exposed in the air, and mixing speed 500-1000rpm brings suitable difficulty to production control; Transformation time 140-180h because transformation time is long, has strengthened production cost virtually.
In sum, existing Production by Microorganism Fermentation 11 alpha hydroxy-canrenone production technique still exist the production cycle long, the cost height, and problems such as complex process have limited the popularization and the application of this product.So researching and developing 11 simple, economical and practical alpha hydroxy-canrenone production technique of a kind of technology is task of top priority.
Summary of the invention
The problem that solves:
At the problems referred to above, the present invention seeks to solve existing microorganism intermittent fed-batch fermentation method, prepare long, problems such as cost is high, complex process of 11 alpha hydroxy-canrenone production cycles; Provide that a kind of technology is simple, charging capacity is high, do not need feed supplement in the conversion process, the batchwise technology of preparing of economical and practical, 11 alpha hydroxy-canrenones that are suitable for scale operation.
Technical scheme:
The technology of preparing that microorganism batch fermentation conversion method is produced 11 alpha hydroxy-canrenones is to serve as to produce bacterial classification with Aspergillus ochraceus (AS3.4411), canrenone is a substrate, spore and production inclined-plane prepare through producing, spore suspension prepares, first order seed is cultivated, second order fermentation is cultivated, the batch fermentation technology of substrate conversion finally obtains target product, and concrete grammar is as follows:
(1) producing spore prepares with the inclined-plane with producing
The production bacterial classification is Aspergillus ochraceus (AS 3.4411), this bacterium is placed on glucose murphy juice inclined-plane PDA substratum or the millet inclined-plane, the 25-28 ℃ of born yellowly spore of constant temperature culture 4-7, cover on the inclined-plane, color is a lark, can observe red pigments in the back side, PDA inclined-plane, transfer then on yeast extract paste soy peptone glucose slant medium YPDA inclined-plane, cultivated 7-10 days for 25～28 ℃, can generate golden yellow spore, promptly produce and use the inclined-plane, preservation in 4 ℃ of refrigerators, the preservation time is in 15 days;
(2) spore suspension preparation
5ml2% tween 80 solution is added in the production inclined-plane, wash spore, it is 4-8 * 10 that counting is adjusted spore suspension concentration
8Individual/100ml;
(3) first order seed is cultivated
Seed culture medium is made up of carbon source, nitrogenous source, uses 10%H
3PO
4(w/v) regulate 5.0～6.0,120～125 ℃ of sterilizations of pH, 15～25min, every 100ml seed culture medium inserts the 1ml spore suspension, under shaking speed 150-200r/min, cultivates 18～24h for 25-30 ℃ and promptly obtains the inoculum that is suitable for inoculating;
(4) second order fermentation is cultivated
Fermention medium is made up of carbon source, nitrogenous source, phosphorus source, regulates pH to 4.0～6.0,120～125 ℃ sterilization 15～25min with 10%HCl (w/v).The inoculum size of well-grown seed culture fluid by 2%～5% (v/v) is linked in the fermentor tank, and initial speed is 100～200r/min during the fermentation, and air flow is 70～100L/h, and tank pressure is 0.05～0.1Mpa, 25～28 ℃ of culture temperature.Control by air flow, rotating speed and the tank pressure of regulating fermentor tank that dissolved oxygen level remains on 20%～30% in the fermented liquid, cultivate after 18-22 hour, when residual sugar is reduced to 10-14g/L, promptly get the bacterial culture fluid that is suitable for transforming;
(5) conversion of substrate
Fermentation
Employing dry powder feeds intake, substrate is carried out pre-treatment, substrate will be pulverized in advance, require granularity less than 100 μ, in 50～100 ℃ of baking 4h, charging capacity 10～20g/L controls by air flow, rotating speed and the tank pressure of regulating fermentor tank in conversion process that dissolved oxygen level transforms 60-70h 10～30% in the fermented liquid;
Detect
Transform after the 60h, detect its transformation efficiency by thin-layer chromatography TLC and high performance liquid phase HPLC, when wherein adopting the TLC methods analyst, selecting development system for use is benzene: acetone=3～5: 1～4 or chloroform: ethyl acetate=2～4: 1～5, when adopting HPLC to analyze, select the C18 post for use, the detection wavelength is 280nm, select for use 70-90% methanol-water or acetonitrile water as moving phase, after transformation efficiency is higher than 90%, put jar.
Need to prove:
Seed culture medium is formed compound nitrogen source by peptone and yeast extract paste, and glucose is as carbon source, and its composition content is:
Glucose 16～26g/L;
Peptone 15～23g/L;
Yeast extract paste 16～24g/L;
pH 5.0～6.0。
Fermention medium is by glucose, peptone, yeast extract paste and KH
2PO
4Constitute.It forms content:
Glucose 16～26g/L;
Peptone 15～23g/L;
Yeast extract paste 16～24g/L;
KH
2PO
4?1～5g/L；
pH 4.0～6.0；
The substrate grinding particle size is recommended as 10-20 during conversion.60 ℃ of substrate storing temperatures, transformation time 60-70h are advisable.
When adopting the TLC methods analyst during conversion, select for use development system to be recommended as benzene: acetone=4: 1 (v/v) or chloroform: ethyl acetate=3: 2 (v/v); When adopting HPLC to analyze, recommend to select for use 80% methanol-water (v/v) as moving phase.
Canrenone 11 α hydroxylation reactions are as follows:
Canrenone 11 alpha hydroxy-canrenones
Beneficial effect:
The invention provides and do not need feed supplement, the economical and practical production technology that is suitable for the preparing 11 alpha bydroxy canrenone through conversion method of batch fermentation of scale operation in a kind of charging capacity height, the conversion process.This technology is compared with fed-batch fermentative Production technology in the past, and technology is simple, thereby has reduced production cost.The thalline biomass reaches and continues behind the peak value to descend, do not exist thalline to be exposed to airborne phenomenon, has solved the shortcoming that fermented liquid upper strata thalline can not participate in conversion reaction.Because process is simple, the probability of microbiological contamination is very low, and transformation time is short.The end of a period transformation efficiency still is higher than 90%.The present invention be a kind of new, economical and practical, produce 11 alpha hydroxy-canrenone methods with biotechnology, lay a good foundation for large-scale industrial production, have than the large economy benefit.
Embodiment
Embodiment 1:
The production bacterial classification is Aspergillus ochraceus (AS 3.4411), and (glucose murphy juice slant medium) places 25 ℃ of constant temperature culture, 7 born yellowly spores to this bacterium on the PDA inclined-plane.Cover on the PDA inclined-plane, color is a lark, can observe red pigments in the back side, inclined-plane.Transfer then on the YPDA inclined-plane, cultivated 5 days, and can generate golden yellow spore for 28 ℃.Preservation in 4 ℃ of refrigerators, preservation were used after 10 days.5ml2% tween 80 solution is added in the production inclined-plane, wash spore, it is 4 * 10 that counting is adjusted spore suspension concentration
8Individual/100ml.Seed culture medium is made up of carbon source, nitrogenous source, that is:
Glucose 20g/L;
Peptone 20g/L;
Yeast extract paste 20g/L;
pH 6.0；
Use 10%H
3PO
4(w/v) regulate pH=6,120～125 ℃ of sterilization 15min.Every 100ml seed culture medium inserts 1ml spore suspension (4 * 10
8Individual), under shaking speed 150r/min, cultivate 18h for 28 ℃ and promptly obtain the inoculum that is suitable for inoculating.
Fermention medium is formed:
Glucose 20g/L;
Peptone 20g/L;
Yeast extract paste 20g/L;
KH
2PO
4 3.3g/L；
pH 4.5；
Adopt the 7L fermentor tank, liquid amount is 4.5L.Regulate pH to 4.5 with 10%HCl (w/v), 120～125 ℃ of sterilization 20min.The inoculum size (135ml) of well-grown seed culture fluid by 3% (v/v) is linked in the above-mentioned fermention medium.Initial speed is 100r/min, and air flow is 70L/h, and tank pressure is 0.05Mpa, 28 ℃ of cultivations, and by regulating rotating speed, air flow, tank pressure are kept dissolved oxygen about 30% in the process.Cultivate 18h, remaining sugar concentration can obtain being fit to the fermenting culture that transforms during for 10g/L.Employing dry powder feeds intake, and requires the substrate granularity at 30-50 μ, feeds intake after the baking 3h in 80 ℃ of baking ovens before feeding intake.Throw 67.5g substrate canrenone, regulate rotating speed in the conversion process, air flow, tank pressure are kept dissolved oxygen about 20%.Transform after the 60h, sampling detects transformation efficiency by TLC and HPLC, TLC methods analyst wherein, and selecting development system for use is benzene: acetone=4: 1 (v/v).HPLC selects for use 80% methanol-water (v/v) as moving phase when analyzing.The detection wavelength is 280nm, selects the C18 post for use.After being higher than 90%, rate to be transformed puts jar.
Embodiment 2:
The production bacterial classification is Aspergillus ochraceus (AS 3.4411), and this bacterium places 28 ℃ of constant temperature culture, 5 born yellowly spores on the millet inclined-plane.Cover on the PDA inclined-plane, color is a lark, can observe red pigments in the back side, inclined-plane.Transfer then on the YPDA inclined-plane, cultivated 7 days, and can generate golden yellow spore for 26 ℃.Preservation in 4 ℃ of refrigerators, preservation were used after 15 days.5ml2% tween 80 solution is added in the production inclined-plane, wash spore, it is 8 * 10 that counting is adjusted spore suspension concentration
8Individual/100ml.
Seed culture medium is made up of carbon source, nitrogenous source, that is:
Glucose 24g/L;
Peptone 23g/L;
Yeast extract paste 16g/L;
pH 6.0；
Use 10%H
3PO
4(w/v) regulate pH, 120～125 ℃ of sterilization 15min.Every 100ml seed culture medium inserts 1ml spore suspension (8 * 10
8Individual spore), under shaking speed 180r/min, cultivate 18h for 28 ℃ and promptly obtain the inoculum that is suitable for inoculating.
Fermention medium is formed:
Glucose 24g/L;
Peptone 17g/L;
Yeast extract paste 22g/L;
KH
2PO
4 2g/L；
pH 4.0；
108g glucose is dissolved in is mixed with 40% solution in the 270ml water.110 ℃ of sterilization 10～15min.With peptone 76.5g, yeast extract paste 99g, KH
2PO
49g is dissolved in the 4.23L water.With being loaded in the 7L jar behind 10%HCl (w/v) the adjusting pH 4.0.120～125 ℃ of sterilization 25min.The inoculum size (225ml) of well-grown seed culture fluid by 5% (v/v) is linked in the above-mentioned fermention medium together with glucose.Initial speed is 200r/min, and air flow is 100L/h, and tank pressure is 0.1Mpa, 26 ℃ of cultivations, and by regulating rotating speed, air flow, tank pressure are kept dissolved oxygen about 30% in the process.Cultivate 24h, remaining sugar concentration can obtain being fit to the fermenting culture that transforms during for 14g/L.Employing dry powder feeds intake, and requires the substrate granularity at 10-20 μ, feeds intake after the baking 4h in 60 ℃ of baking ovens before feeding intake.Throw 90g substrate canrenone.Feed intake the back by adding 20% (w/v) NaOH solution adjusting pH to 6.0, keep pH about 6.0 by adding NaOH or HCl in the conversion process.Keep dissolved oxygen in the conversion process about 20%.Transform after the 70h, sampling detects transformation efficiency by TLC and HPLC, and it is chloroform that TLC selects development system for use when analyzing: ethyl acetate=3: 2 (v/v).HPLC selects for use 70% methanol-water (v/v) as moving phase when analyzing.The detection wavelength is 280nm, selects the C18 post for use.After being higher than 90%, rate to be transformed puts jar.
Embodiment 3:
The production bacterial classification is Aspergillus ochraceus (AS 3.4411), and this bacterium places 28 ℃ of constant temperature culture, 7 born yellowly spores on PDA inclined-plane (glucose murphy juice slant medium).Cover on the PDA inclined-plane, color is a lark, can observe red pigments in the back side, inclined-plane.Transfer then on the YPDA inclined-plane, cultivated 7 days, and can generate golden yellow spore for 28 ℃.Preservation in 4 ℃ of refrigerators, preservation were used after 20 days.5ml2% tween 80 solution is added in the production inclined-plane, wash spore, it is 6 * 10 that counting is adjusted spore suspension concentration
8Individual/100ml.
Seed culture medium is made up of carbon source, nitrogenous source, that is:
Glucose 16g/L;
Peptone 22g/L;
Yeast extract paste 15g/L;
pH 5.0；
Use 10%H
3PO
4(w/v) regulate pH=5,120～125 ℃ of sterilization 15min.Every 100ml seed culture medium inserts 1ml spore suspension (6 * 10
8Individual spore), under shaking speed 200r/min, cultivate 20h for 28 ℃ and promptly obtain the inoculum that is suitable for inoculating.
Fermention medium is formed:
Glucose 16g/L;
Peptone 17g/L;
Yeast extract paste 22g/L;
KH
2PO
4 4g/L；
pH 5.5；
7L fermentor tank liquid amount is 4.5L.Regulate pH with 10%HCl (w/v), 120～125 ℃ of sterilization 20min.The inoculum size (225ml) of well-grown seed culture fluid by 5% (v/v) is linked in the above-mentioned fermention medium.Initial speed is 150r/min, and air flow is 80L/h, and tank pressure is 0.1Mpa, 26 ℃ of cultivations, and by regulating rotating speed, air flow, tank pressure are kept dissolved oxygen about 30% in the process.Cultivate 20h, remaining sugar concentration can obtain being fit to the fermenting culture that transforms during for 13g/L.Employing dry powder feeds intake, and requires the substrate granularity at 20-30 μ, feeds intake after the baking 4h in 70 ℃ of baking ovens before feeding intake.Throw 90g substrate canrenone.Keep dissolved oxygen in the conversion process about 20%.Transform after the 70h, sampling detects transformation efficiency by TLC and HPLC, and selecting development system for use is chloroform: ethyl acetate=4: 1 (v/v).HPLC selects for use 85% methanol-water (v/v) as moving phase when analyzing.The detection wavelength is 280nm, selects the C18 post for use.After being higher than 90%, rate to be transformed puts jar.
Claims (6)
1, the method for preparing 11 alpha bydroxy canrenone through conversion method of batch fermentation of microbe, it is characterized in that with Aspergillus ochraceus (AS 3.4411) serving as to produce bacterial classification, canrenone is a substrate, spore and production inclined-plane prepare through producing, spore suspension prepares, first order seed is cultivated, second order fermentation is cultivated, the batch fermentation technology of substrate conversion finally obtains target product, and concrete grammar is as follows:
(1) producing spore prepares with the inclined-plane with producing
The production bacterial classification is Aspergillus ochraceus (AS 3.4411), this bacterium is placed on glucose murphy juice inclined-plane PDA substratum or the millet inclined-plane, the 25-28 ℃ of born yellowly spore of constant temperature culture 4-7, cover on the inclined-plane, color is a lark, can observe red pigments in the back side, PDA inclined-plane, transfer then on yeast extract paste soy peptone glucose slant medium YPDA inclined-plane, cultivated 7-10 days for 25～28 ℃, can generate golden yellow spore, promptly produce and use the inclined-plane, preservation in 4 ℃ of refrigerators, the preservation time is in 20 days;
(2) spore suspension preparation
5ml2% tween 80 solution is added in the production inclined-plane, wash spore, it is 4-8 * 10 that counting is adjusted spore suspension concentration
8Individual/100ml;
(3) first order seed is cultivated
Seed culture medium is made up of carbon source, nitrogenous source, uses 10%H
3PO
4(w/v) regulate 5.0～6.0,120～125 ℃ of sterilizations of pH, 15～25min, every 100ml seed culture medium inserts the 1ml spore suspension, under shaking speed 150-200r/min, cultivates 18～24h for 25-30 ℃ and promptly obtains the inoculum that is suitable for inoculating;
(4) second order fermentation is cultivated
Fermention medium is by carbon source, nitrogenous source, the phosphorus source is formed, regulate pH4.0～6.0 with 10%HCl (w/v), 120～125 ℃ of sterilization 15～25min, the inoculum size of well-grown seed culture fluid by 2%～5% (v/v) is linked in the fermentor tank, initial speed is 100～200r/min during the fermentation, air flow is 70～100L/h, tank pressure is 0.05～0.1Mpa, 25～28 ℃ of culture temperature, by regulating the air flow of fermentor tank, rotating speed and tank pressure control that dissolved oxygen level remains on 20%～30% in the fermented liquid, cultivate after 18-22 hour, when residual sugar is reduced to 10-14g/L, promptly get the bacterial culture fluid that is suitable for transforming;
(5) conversion of substrate
Fermentation
Employing dry powder feeds intake, substrate is carried out pre-treatment, substrate will be pulverized in advance, require granularity less than 100 μ, in 50～100 ℃ of baking 4h, charging capacity 10～20g/L controls by air flow, rotating speed and the tank pressure of regulating fermentor tank in conversion process that dissolved oxygen level transforms 60-70h 10～30% in the fermented liquid;
Detect
Transform after the 60h, detect its transformation efficiency by thin-layer chromatography TLC and high performance liquid phase HPLC, wherein during the TLC methods analyst, selecting development system for use is benzene: acetone=3～5: 1～4 or chloroform: ethyl acetate=2～4: 1～5, HPLC selects the C18 post for use when analyzing, the detection wavelength is 280nm, selects for use 70-90% methanol-water or acetonitrile water as moving phase, puts jar after transformation efficiency is higher than 90%.
2, the side of preparing 11 alpha bydroxy canrenone through conversion method of batch fermentation of microbe according to claim 1 is characterized in that seed culture medium forms compound nitrogen source by peptone and yeast extract paste, and glucose is as carbon source, and it is formed content and is:
Glucose 16～26g/L;
Peptone 15～23g/L;
Yeast extract paste 16～24g/L;
pH 5.0～6.0。
3, the method for preparing 11 alpha bydroxy canrenone through conversion method of batch fermentation of microbe according to claim 1 is characterized in that fermention medium is by glucose, peptone, yeast extract paste and KH
2PO
4Constitute, its composition content is:
Glucose 16～26g/L;
Peptone 15～23g/L;
Yeast extract paste 16～24g/L;
KH
2PO
4 1～5g/L；
pH 4.0～6.0。
4, the method for preparing 11 alpha bydroxy canrenone through conversion method of batch fermentation of microbe according to claim 1, when it is characterized in that transforming, the substrate grinding particle size is 10-20 μ.
5, the method for preparing 11 alpha bydroxy canrenone through conversion method of batch fermentation of microbe according to claim 1, the substrate storing temperature is 60 ℃ when it is characterized in that transforming, transformation time is 60-70h.
6, according to the method for the described preparing 11 alpha bydroxy canrenone through conversion method of batch fermentation of microbe of claim 1-6, TLC methods analyst when it is characterized in that transforming, selecting development system for use is benzene: acetone=4: 1 (v/v) or chloroform: ethyl acetate=3: 2 (v/v); HPLC selects for use 80% methanol-water (v/v) as moving phase when analyzing.
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| CN102061320A (en) * | 2010-12-02 | 2011-05-18 | 浙江仙琚制药股份有限公司 | Preparation method of 11 alpha,17 alpha-dyhydroxyl-androst-4-ene-3,20-dione |
| CN103255192A (en) * | 2013-03-25 | 2013-08-21 | 天津科技大学 | Method for producing 11 alpha-hydroxycarvenone by efficient conversion of canrenone |
| CN103255194A (en) * | 2013-03-25 | 2013-08-21 | 天津科技大学 | Method for raising conversion rate of 15 alpha, 17 alpha-epoxyprogesterone |
| CN104046675A (en) * | 2014-06-13 | 2014-09-17 | 江苏大学 | Method for producing 11 alpha-hydroxycarvenone by using fermentation liquor containing hydroxylase |
| CN103665083B (en) * | 2013-12-02 | 2015-12-02 | 江苏大学 | A kind of method of separation and purification 11 Alpha-hydroxy canrenone |
| CN108085359A (en) * | 2016-11-22 | 2018-05-29 | 保定九孚生化有限公司 | A kind of production method of 11 alpha-hydroxy-4-ene -3,17- androstanediones |
| CN112980910A (en) * | 2021-03-19 | 2021-06-18 | 上海应用技术大学 | Method for microbial transformation of 11 alpha-hydroxy canrenone in phase transfer catalyst system |
| CN115505537A (en) * | 2022-10-12 | 2022-12-23 | 江苏佳尔科药业集团股份有限公司 | High-activity 11 alpha-hydroxylated aspergillus ochraceus and application thereof |
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| CN102409067B (en) * | 2011-12-10 | 2013-12-04 | 福州大学 | Culture medium for producing kojic acid by fermenting aspergillus oryzae, and fermentation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| NZ325276A (en) * | 1995-12-12 | 1999-11-29 | Akzo Nobel Nv | Microbial method of in vitro transformation of a steroid into the 11a-hydroxy analogue using oxygen and a micro-organism |
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| CN102061320B (en) * | 2010-12-02 | 2013-04-03 | 浙江仙琚制药股份有限公司 | Preparation method of 11 alpha,17 alpha-dyhydroxyl-androst-4-ene-3,20-dione |
| CN102061320A (en) * | 2010-12-02 | 2011-05-18 | 浙江仙琚制药股份有限公司 | Preparation method of 11 alpha,17 alpha-dyhydroxyl-androst-4-ene-3,20-dione |
| CN103255194B (en) * | 2013-03-25 | 2015-04-15 | 天津科技大学 | Method for raising conversion rate of 15 alpha, 17 alpha-epoxyprogesterone |
| CN103255192A (en) * | 2013-03-25 | 2013-08-21 | 天津科技大学 | Method for producing 11 alpha-hydroxycarvenone by efficient conversion of canrenone |
| CN103255194A (en) * | 2013-03-25 | 2013-08-21 | 天津科技大学 | Method for raising conversion rate of 15 alpha, 17 alpha-epoxyprogesterone |
| CN103665083B (en) * | 2013-12-02 | 2015-12-02 | 江苏大学 | A kind of method of separation and purification 11 Alpha-hydroxy canrenone |
| CN104046675A (en) * | 2014-06-13 | 2014-09-17 | 江苏大学 | Method for producing 11 alpha-hydroxycarvenone by using fermentation liquor containing hydroxylase |
| CN104046675B (en) * | 2014-06-13 | 2016-08-17 | 江苏大学 | Utilize the method that the fermentation liquid containing hydroxylase produces 11 Alpha-hydroxy canrenones |
| CN108085359A (en) * | 2016-11-22 | 2018-05-29 | 保定九孚生化有限公司 | A kind of production method of 11 alpha-hydroxy-4-ene -3,17- androstanediones |
| CN108085359B (en) * | 2016-11-22 | 2020-07-24 | 保定九孚生化有限公司 | Production method of 11 α -hydroxy-4-ene-3, 17-androstenedione |
| CN112980910A (en) * | 2021-03-19 | 2021-06-18 | 上海应用技术大学 | Method for microbial transformation of 11 alpha-hydroxy canrenone in phase transfer catalyst system |
| CN112980910B (en) * | 2021-03-19 | 2024-01-05 | 上海应用技术大学 | Method for microbial conversion of 11 alpha-hydroxy canrenone in phase transfer catalyst system |
| CN115505537A (en) * | 2022-10-12 | 2022-12-23 | 江苏佳尔科药业集团股份有限公司 | High-activity 11 alpha-hydroxylated aspergillus ochraceus and application thereof |
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