CN106893753A - A kind of method that prednisolone is prepared by the step of biofermentation one - Google Patents
A kind of method that prednisolone is prepared by the step of biofermentation one Download PDFInfo
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- CN106893753A CN106893753A CN201510976860.3A CN201510976860A CN106893753A CN 106893753 A CN106893753 A CN 106893753A CN 201510976860 A CN201510976860 A CN 201510976860A CN 106893753 A CN106893753 A CN 106893753A
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P33/00—Preparation of steroids
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P33/00—Preparation of steroids
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Abstract
The present invention relates to one kind with hydrocortisone acetate as raw material, the preparation method of prednisolone is directly generated by the step of biofermentation one by using Arthrobacter simplex Arthrobacter Simple ATCC 21032.
Description
Technical field：
It is that 1,2 dehydrogenations and 21 acetic acid are carried out by biofermentation the present invention relates to a kind of preparation method of prednisolone
Ester hydrolysis reaction, prednisolone is prepared from the step of hydrocortisone acetate one.
Background technology：
A kind of common cortin of prednisolone, both can be as corticosteroid therapy medicine, it is also possible to used as other
The raw material of corticosteroid drug, is with a wide range of applications, particularly significant.The preparation research for the product continues both at home and abroad
Constantly.
The conventional initiation material of domestic production prednisolone is the mold oxide from diene, and it first passes through C11
Again by C1,2 dehydrogenations after oxidation, in side chain modify that to obtain 21 bit esterified again afterwards.The difficult point of this technique is C11
The introducing of carbonyl and C1,2 double bonds, because around C11, no activity functional groups play influence on it, under normal condition
It is difficult to C11 hydroxyl is oxidized into C11 carbonyl；And fertile formula oxide is after C11 aoxidizes, the C1 of next step, 2 it is de-
Hydrogen is difficult to carry out, and there is a problem that yield is low, high cost.
Xiao Jun et al. reports (prednisolone manufacture experimently and analysis research, University Of Nanchang's journal (industry science version), volume 24 the
4 phases, 63-65) with prednisone acetate as starting material, it is obtained by ketone group and urea condensation, sodium borohydride reduction, hydrolysis.Certainly protect
The means for protecting ketone group also have a lot, and for example spent glycol is condensed, it is also possible to carry out similar reaction.
Sun Xinyu et al. reports (the bioconversion research of steroid 6- hydrogenated methyl cortisones in double-aqueous phase system,
Zhejiang Polytechnical University's journal, volume 35 the 6th phase, 617-620) report that 1,2 dehydrogenations are carried out to 6- hydrogenated methyls cortisone to be prepared
6- methylprednisolones.
The structure of prednisolone is that have 1 and 4 double bonds, 11 hydroxyls, 21 hydroxyls, 17 hydroxyls on pregnant steroid parent nucleus
Quito group, and hydrocortisone acetate by two unit processes of 1,2 dehydrogenations and 21 hydrolysis formed 1,2 double bonds and
21 hydroxyls.Common preparation method, is to draw 1,2 double bonds, such as long-range Xian Le pharmaceutcal corporation, Ltds in Jiangsu by bioanalysis
The invention CN201510076695.6 of application；21 hydroxyls, such as the Tianjin day medicine limited public affairs of medicine company share are obtained by basic hydrolysis again
Take charge of the CN200510016229.5 inventions of application.And have been generally acknowledged that directly make initiation material with hydrocortisone acetate, carry out C1,
The biofermentation of 2, obtains Econopred, and the shortcoming of this technique is that the yield of biofermentation is low, causes high cost.
In fact, Isosorbide-5-Nitrae position double bond, 21 hydroxyls are the conventional basic structure of current anti-inflammatory steroid hormone.Due to last century
Since the fifties, scientist gropes above-mentioned group synthetic method repeatedly, has formd the preparation technology of maturation, usually
1,2 double bonds, and 21- hydroxyls are prepared by the way that 21 are carried out with iodate by biological dehydrogenation, then is replaced and is drawn 21 acetates,
Hydrolysis draws hydroxyl.The unit process of this process route is groped by several generations's, it is considered to be the most rational to prepare road
Line, has formd the common recognition of industry.In recent years scientific research personnel hardy direction is reformed for single-step process
And improvement, but it is limited to Conventional wisdom thinking, there is presently no the adjustment for carrying out process route.
The content of the invention
In order to improve yield, experimenter is had surprisingly found that can with acetic acid hydrogenation by constantly studying under study for action
Pine be raw material, by using the Arthrobacter simplex Arthrobacter Simple ATCC 21032 can be with one by biofermentation
Step directly generates prednisolone,
It is a kind of with hydrocortisone acetate as raw material, by using Arthrobacter simplex Arthrobacter Simple
ATCC 21032 directly generates the preparation method of prednisolone by the step of biofermentation one.
Above-mentioned preparation method, it is characterized in that hydrocortisone acetate being crushed or being dissolved with solvent, input has been cultivated
Bioconversion is carried out in the fermentation tank of arthrobacterium, is extracted after conversion and is obtained prednisolone.
Above-mentioned preparation method, it is characterized in that the solvent of the dissolving substrate is selected from methyl alcohol, ethanol, tetrahydrofuran, dioxy
One or more in six rings, DMF, the minimum multiple that substrate can be dissolved under the dissolving preferred normal temperature of multiple.
Above-mentioned preparation method, it is characterized in that：The preferred micro mist of described substrate turns to D90≤ 30 μm of particulate.
Above-mentioned preparation method, it is characterized in that being≤4% as the feed concentrations of the compound (1) of substrate.
Above-mentioned preparation method, it is characterized in that as the hydrocortisone acetate of substrate feed concentrations preferably 1%~
3%, fermentation temperature is 29 DEG C~32 DEG C, and the reaction time is 36~72 hours.
Above-mentioned biological dehydrogenation method, it is characterized in that described biological dehydrogenation reaction can use following zymotechnique.
Above-mentioned preparation method, it is characterized in that the slant medium culture medium that methods described is used uses following proportioning：Portugal
The distilled water of grape sugar 1.3%, yeast extract 1.3%, agar 2.0%, and surplus, pH7.0-7.2 is adjusted to inorganic alkali solution, is used
In inclined-plane culture.
Above-mentioned preparation method, it is characterized in that the slant medium culture medium that methods described is used is matched using following %：
Yeast extract 0.5%, peptone 0.5%, grape wards off 1%, and agar 2%, running water is prepared, and pH to 7.0- is adjusted to inorganic alkali solution
7.2, for inclined-plane culture.
Above-mentioned preparation method, it is characterized in that the fermentation medium that methods described is used is following proportioning：Glucose 1.0,
Yeast extract 0.16%, KH2PO40.25%, corn pulp 1%, and surplus distilled water, be adjusted to pH 7.0- with inorganic alkali solution
7.2, in one-level, two grades of cultures and final biological respinse.
Above-mentioned preparation method, it is characterized in that the fermentation medium that methods described is used is following proportioning：Peptone
0.4%, glucose 0.6%, corn pulp 0.6%, potassium dihydrogen phosphate 0.07%, dipotassium hydrogen phosphate 0.05%, and surplus steaming
Distilled water, pH 7.0-7.2 are adjusted to inorganic alkali solution, in one-level, two grades of cultures and final biological respinse.
Above-mentioned preparation method, it is characterized in that the inorganic base that methods described is used is NaOH, potassium hydroxide, bicarbonate
One or more in sodium, saleratus, sodium carbonate, potassium carbonate.
Preparation method as described in claim 8-11, it is characterized in that the inorganic base that uses of methods described for NaOH,
One or more in potassium hydroxide.
Above-mentioned preparation method, it is characterized in that methods described is crushed before hydrocortisone acetate feeds intake to zymotic fluid in use
0.01~3% (v/v) chaotropic agent of middle addition.Above-mentioned preparation method, it is characterized in that described chaotropic agent is preferred Tween-80.
Hydrocortisone acetate is crushed or complete molten or semi-soluble with solvent, input has cultivated arthrobacterium or Arthrobacter simplex
Fermentation tank in carry out biological dehydrogenation reaction, after conversion extract obtain prednisolone.The solvent be selected from but be not limited only to methyl alcohol,
Ethanol, tetrahydrofuran, dioxane, one or more in DMF (DMF) are described to crush the acetic acid for feeding intake
Hydrocortisone is preferably micronized D90The particulate of (90% pass through particle diameter)≤40 μm.It is preferred that being added in zymotic fluid when crushing feeds intake
0.01~3% (v/v) chaotropic agent, described chaotropic agent is preferred Tween-80.
The feed concentrations of hydrocortisone acetate are≤4% (relative to zymotic fluid volume)；It is preferred that feed concentrations be 1%~
3%, 30~34 DEG C of fermentation temperature, preferably chaotropic agent addition are 0.2~0.5% (v/v).The biological dehydrogenation reaction time 30~72
Hour.
Biological respinse terminates rear terminating reaction, it is preferred to use zymotic fluid is warming up into 70~90 DEG C and makes the side of thalline inactivation
Method, is used after terminating reaction and prednisolone is extracted preferably in the form of solvent extraction zymotic fluid.The extraction preferred second of solvent
Acetoacetic ester.
The biological respinse uses Arthrobacter simplex, and (Latin is named：Arthrobacter simplex) preferred following bacterium
Strain Arthrobacter Simple ATCC 21032.
Arthrobacter simplex (name by Latin：Arthrobacter simplex) AS 1.754, AS 1.94* be (by Chinese section
Institute of microbiology of institute provides).
Described biological dehydrogenation reaction can use following zymotechnique：
Inclined-plane culture → one-level culture → one-level culture → addition compound (1) fermentation carries out biological dehydrogenation reaction → termination
Reaction.
Described bio-fermentation process can also such as be referred to using any known bio-fermentation process method《Biosynthesis
Materia medica》(Chemical Industry Press, publishes for 2000, Chu Zhiyi chief editors；Page 666~675) disclosed in bio-fermentation process.
Culture medium used by described biological dehydrogenation preferably uses following proportioning：
Slant medium (%)：The distilled water of glucose 1.3, yeast extract 1.3, agar 2.0, and surplus, pH7.0-
7.2, for inclined-plane culture
Fermentation medium (%)：Glucose 1.0, yeast extract 0.16, KH2PO40.25, corn pulp 1, and surplus distillation
Water, pH 7.0-7.2, in one-level, two grades of cultures and final biological dehydrogenation reaction.
Embodiment
The measure of substrate conversion efficiency：The substrate quality that product is converted into conversion ratio course of reaction accounts for the total matter of initial substrate
The percentage of amount is represented.Determined using HPLC, splitter is C18 posts, and Detection wavelength is 240nm, and mobile phase is acetonitrile：Water
(volume ratio)=60：40 flow velocity that is dissolved in is 1.5mL/min.Substrate conversion efficiency is calculated using area normalization method.
Inclined-plane culture：Slant medium is sub-packed in the test tube of 20 × 200mm, inclined-plane is put into after sterilizing 30min.Inclined-plane
2d is placed in 37 DEG C of incubators, observation can be inoculated with without microbiological contamination situation.Back bevel is inoculated with 2d is cultivated at 30 DEG C, then
It is placed in 4 DEG C of refrigerators and preserves.
One-level culture：Thalline is taken from well-grown Arthrobacter simplex inclined-plane, the 250mL equipped with 30ml culture mediums is accessed
In triangular flask, 30~34 DEG C, 180r/min shaken cultivations, 24 hours
Two grades of cultures：The zymotic fluid after one-level culture will be completed to be accessed equipped with 150ml cultures with 5%~10% inoculum concentration
In the 1000mL secondary seed culture triangular flasks of base, two grades of cultures are carried out with same condition, two grades of incubation times are 24 hours
Biological dehydrogenation and hydrolysis：In two grades of culture identical inoculum concentrations access 5L fermentation tanks, 29~32 DEG C of cultivation temperature,
Speed of agitator 150r/min, throughput 2.0L/min, add substrate to carry out biological dehydrogenation reaction after cultivating 24 hours.
Slant medium 1 uses following proportioning：Glucose 1.3%, yeast extract 1.3%, agar 2.0%, and surplus
Distilled water, pH7.0-7.2 is adjusted to inorganic alkali solution, for inclined-plane culture.
Slant medium 2 uses following proportioning：Yeast extract 0.5%, peptone 0.5%, grape wards off 1%, agar 2%, from
Water is prepared, and pH to 7.0-7.2 is adjusted to inorganic alkali solution, for inclined-plane culture.
Fermentation medium 1 is following proportioning：Glucose 1.0, yeast extract 0.16%, KH2PO40.25%, corn pulp 1%, with
And the distilled water of surplus, pH 7.0-7.2 are adjusted to inorganic alkali solution, for one-level, two grades of cultures and final biological respinse
In.
Fermentation medium 2 is following proportioning：Peptone 0.4%, glucose 0.6%, corn pulp 0.6%, potassium dihydrogen phosphate
0.07%, dipotassium hydrogen phosphate 0.05%, and surplus distilled water, be adjusted to pH 7.0-7.2 with inorganic alkali solution, for one-level,
In two grades of cultures and final biological respinse.
DMF：DMF
Embodiment 1：
Arthrobacter simplex (Arthrobacter Simple ATCC 21032) is carried out successively to use inclined-plane culture respectively
Base culture, one-level culture and two grades of cultures, cultivation temperature is 29-32 DEG C, and the hydrocortisone acetate that will be dissolved in organic solvent is thrown
Enter in the 5L fermentation tanks of fermentation medium, feed concentrations see the table below, reaction temperature is 31 ± 1 DEG C.Reaction time see the table below, reaction
After the completion of be warming up to 70 DEG C of terminating reactions, adopt and be extracted with ethyl acetate extraction zymotic fluid, organic phase is concentrated, measure prednisolone
Conversion ratio.
Embodiment 2：
Specific preparation method culture medium, feed concentrations, with embodiment 1, are trained in fermentation before cortisone acetate input
Tween 80 is added in the 5L fermentation tanks for supporting base.
Comparative examples 1：
Arthrobacter simplex (AS 1.94*) is carried out successively to use slant medium culture, one-level culture and two grades of trainings respectively
Support, cultivation temperature is 29-32 DEG C, the hydrocortisone acetate that will be dissolved in organic solvent puts into the 5L fermentation tanks of fermentation medium
In, feed concentrations see the table below, and reaction temperature is 31 ± 1 DEG C.Reaction time see the table below, and 70 DEG C is warming up to after the completion of reaction and terminates anti-
Should, adopt and be extracted with ethyl acetate extraction zymotic fluid, organic phase is concentrated, it is 4.5% to measure prednisolone conversion ratio.
Comparative examples 2：
Arthrobacter simplex (AS 1.754) is carried out successively to use slant medium culture, one-level culture and two grades of trainings respectively
Support, cultivation temperature is 29-32 DEG C, the hydrocortisone acetate that will be dissolved in organic solvent puts into the 5L fermentation tanks of fermentation medium
In, feed concentrations see the table below, and reaction temperature is 31 ± 1 DEG C.Reaction time see the table below, and 70 DEG C is warming up to after the completion of reaction and terminates anti-
Should, adopt and be extracted with ethyl acetate extraction zymotic fluid, organic phase is concentrated, measure prednisolone conversion ratio.
After testing, comparative examples are obtained substantially Econopred (more than 70%) and minimal amount of cellulose acetate hydrogen
Change cortisone, and prednisolone is few.
Claims (10)
1. one kind is with hydrocortisone acetate as raw material, by using Arthrobacter simplex Arthrobacter Simple ATCC
21032 preparation methods that prednisolone is directly generated by the step of biofermentation one.
2. preparation method as claimed in claim 1, it is characterized in that hydrocortisone acetate being crushed or being dissolved with solvent, puts into
Cultivate and carry out bioconversion in the fermentation tank of arthrobacterium, extracted after conversion and obtain prednisolone.
3. preparation method as claimed in claim 1, it is characterized in that the solvent of the dissolving substrate is selected from methyl alcohol, ethanol, tetrahydrochysene
One or more in furans, dioxane, DMF, the minimum multiple that substrate can be dissolved under the dissolving preferred normal temperature of multiple.
4. preparation method as claimed in claim 1, it is characterized in that：The preferred micro mist of described substrate turns to D90≤ 30 μm micro-
Grain.
5. preparation method as claimed in claim 1, it is characterized in that being≤4% as the feed concentrations of the compound (1) of substrate.
6. preparation method as claimed in claim 1, it is characterized in that excellent as the feed concentrations of the hydrocortisone acetate of substrate
1%~3% is selected, fermentation temperature is 29 DEG C~32 DEG C, the reaction time is 36~72 hours.
7. biological dehydrogenation method as claimed in claim 1, it is characterized in that described biological dehydrogenation reaction can use to issue
Ferment technique.
8. preparation method as claimed in claim 1, it is characterized in that the slant medium culture medium that methods described is used use with
Lower proportioning：The distilled water of glucose 1.3%, yeast extract 1.3%, agar 2.0%, and surplus, is adjusted to inorganic alkali solution
PH7.0-7.2, for inclined-plane culture.
9. the preparation method as described in claim 8-11, it is characterized in that the inorganic base that methods described is used is NaOH, hydrogen
One or more in potassium oxide, sodium acid carbonate, saleratus, sodium carbonate, potassium carbonate.
10. preparation method as claimed in claim 1, it is characterized in that methods described is being fed intake using crushing hydrocortisone acetate
0.01~3% (v/v) chaotropic agent is added in forward direction zymotic fluid.
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Cited By (5)
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| CN110157764A (en) * | 2019-05-29 | 2019-08-23 | 浙江仙琚制药股份有限公司 | A kind of preparation method of Dexamethasone Intermediate |
| CN112143771A (en) * | 2019-06-26 | 2020-12-29 | 河南利华制药有限公司 | Method for producing prednisolone by microorganism one-step fermentation method |
| CN112342261A (en) * | 2020-11-12 | 2021-02-09 | 湖南新合新生物医药有限公司 | Preparation method of prednisone acetate |
| CN112608970A (en) * | 2020-12-25 | 2021-04-06 | 河南利华制药有限公司 | Production method of methylprednisolone dehydrogenation product |
| CN115433756A (en) * | 2022-08-30 | 2022-12-06 | 山东新华制药股份有限公司 | Preparation method of prednisolone |
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| CN115433756A (en) * | 2022-08-30 | 2022-12-06 | 山东新华制药股份有限公司 | Preparation method of prednisolone |
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