CN106589035A - Preparation process of prednisolone acetate - Google Patents
Preparation process of prednisolone acetate Download PDFInfo
- Publication number
- CN106589035A CN106589035A CN201610973712.0A CN201610973712A CN106589035A CN 106589035 A CN106589035 A CN 106589035A CN 201610973712 A CN201610973712 A CN 201610973712A CN 106589035 A CN106589035 A CN 106589035A
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- CN
- China
- Prior art keywords
- prednisolone
- prednisolone acetate
- reaction
- pyridine
- acetic anhydride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
Abstract
The invention relates to a preparation process of prednisolone acetate. The preparation process comprises the steps that under the action of 4-dimethylamino-pyridine, no solvent needs to be additionally added, prednisolone and acetic anhydride directly react, the materials are flushed into water for separation, filtering and drying are carried out, and prednisolone acetate is prepared. The technical prejudice that in the prior art of the reaction process, pyridine or a pyridine-substituted solvent is generally used is overcome, the lot production capacity of a reaction still is greatly improved, and it is avoided that a large amount of industrial waste water hard to treat is generated. The process is simple in process, beneficial to environmental protection, low in cost and suitable for industrial large-scale production.
Description
Technical field
The invention belongs to chemical pharmacy field, and in particular to a kind of preparation technology of prednisolone acetate chemosynthesis.
Background technology
Prednisolone acetate（Pregnant steroid-Isosorbide-5-Nitrae-diene -3 of 11 β, 17 α, 21- trihydroxies, 20- diketone -21- acetates）Knot
Structure formula is：
Prednisolone acetate is glucocorticoid medicine, can be used for outward treating anaphylaxis, non-infectious dermatosiss and some hypertrophy
Property dermatopathy, it can also be used to treat anaphylaxis and autoimmune inflammation disease, collagenosis etc..Prednisolone acetate is
The important intermediate of synthesis prednisolone and other steroid drugss, in steroid drugss field using extremely wide.
The traditional preparation method of prednisolone acetate is divided into two clock of bioconversion and chemosynthesis, specially：
(1), with hydrocortisone acetate as conversion of substrate, arthrobacterium fermentation method prepares prednisolone acetate, and conversion reaction formula is：
Chinese patent CN200710060202.5, CN200810152878.1 etc. are prepared using mentioned microorganism conversion method.
It is low to there are substrate hydrocortisone acetate high cost, substrate feed concentrations in the preparation method（Feed concentrations are 5～8g/L）, production
Cycle is long（Spawn culture and transformation period are 58～84 hours）, last handling process isolate and purify the deficiencies such as difficulty.
(2), with 17 Alpha-hydroxies-Isosorbide-5-Nitrae, 9- triolefins-pregnant steroid -3,20- diketone are raw material, and Jing brominations, debrominate, upper iodine, displacement are made
It is standby to obtain prednisolone acetate.Synthesis route is：
Chinese patent CN200710061258.2 prepares prednisolone acetate using above-mentioned process route.The preparation method exists de-
Crome metal is arrived used in bromine reaction, heavy metal is easily introduced in the product；Upper Iod R needs to use valuable raw material iodine, and
, in production process, there is the drawbacks such as stock risk in upper iodine unstable products.
(3), with 17 Alpha-hydroxies-Isosorbide-5-Nitrae, 9- triolefins-pregnant steroid -3,20- diketone are raw material, and Jing brominations, reduction, bromo, displacement are made
It is standby to obtain prednisolone acetate.Synthesis route is：
Chinese patent CN 201310348285.3 prepares prednisolone acetate using above-mentioned process route, and the preparation method is avoided
Crome metal and iodine, intermediate stability has been used also to be improved；But metallic zinc, same meeting are arrived used in reduction reaction
Heavy metal is introduced in the product, and needs to use low boiling solvent ether in the multistep reactions such as reduction, bromo, displacement, no
Beneficial to being produced in temperature higher summer, there is larger potential safety hazard.
(4) with prednisolone acetate as raw material, the protection of 3 and 20 ketone group semicarbazones of Jing, 11 ketone group reduction, 3 and 20
Position deprotection, 21- bit esterified method prepares prednisolone acetate.Synthesis route is：
Chinese patent CN00136583.5 prepares prednisolone acetate intermediate reduction thing, the system using above-mentioned process route
Standby technique is adopted semicarbazones protection and reduces two-step reaction and completed in " one kettle way " mode, but patented method does not refer to whole work
The committed step deprotection reaction of skill route.In 3 and 20 deprotection reactions of critical process, conventional fabrication techniques be prior to
The system of sodium nitrite solution and hydrochloric acid solution carries out reaction and obtains nitrous compound, then carries out resin hydrolyzing and be further purified removal
Prednisolone is obtained after impurity.Why the deprotection reaction mode combined using nitrosation and resin hydrolyzing, is due to strong
It is stronger to the destruction of steroidal ring structure under acid condition, need by adding the reactive mode removal nitrosation of resin hydrolyzing anti-
Should during a large amount of impurity for producing and improve product appearance.
(5) with prednisolone acetate as raw material, 3 and 20 ketone group semicarbazones protections of Jing, 11 ketone group reduction, 21 hydroxyls
Base ester, the method for 3 and 20 deprotections prepare prednisolone acetate.Synthesis route is：
Chinese patent CN201510787710.8 prepares prednisolone acetate using above-mentioned process route, and the preparation method is improved
Process route, by way of adopting and formerly carrying out carrying out deprotection reaction again after esterification by 21- positions hydroxyl, increases remove-insurance
Shield reaction substrate and product reduce deprotection reaction product in acid flux material system in the stability of acid flux material system
Dissolubility, reacts and resin hydrolyzing reactions steps so as to eliminate being quenched for deprotection operation.But still need in deprotection reaction
To carry out under strong acid system, it is impossible to avoid destruction and solution loss to steroidal ring structure under strong acidic condition.
(6), with prednisolone as raw material, prednisolone acetate is prepared with acetic anhydride esterification reaction.Synthetic route is：
Prednisolone adopts pyridine as solvent and the catalyst of reaction with the traditional handicraft of acetic anhydride esterification.Its defect exists
In：Pyridine toxicity is larger, is pungent unpleasant, easily causes human injury；Pyridine in production waste liquid is difficult to reclaim, and environmental pollution is big,
Sewage environmental protection treatment high cost；Relatively large expensive raw material --- the use of pyridine, it is impossible to cause with avoiding product solution loss,
Cause product appearance to be turned to be yellow, need to carry out multiple refinement treatment, the yield of the traditional handicraft is low, and production cost is high.
Chinese patent 201510115790.2 substitutes pyridine using dipolar aprotic solvent, using alkali salt acetate as urging
Agent, prepares prednisolone acetate by prednisolone and acetic anhydride reaction.The preparation method realizes low poison solvent and substitutes pyridine, contracting
The short response time；But dipolar aprotic solvent dimethylformamide in the technique（DMF）Or the use of dimethyl sulfoxide (DMSO)
Amount is larger, and directly in water, the mode of analysis of material causes a large amount of solvents reclaim for reaction end.So can not only produce substantial amounts of
Industrial wastewater, and cannot can bring the solution loss of product with avoiding.Due to the stable chemical nature of DMF and DMSO, it is difficult to
Degraded with conventional biological processes, it is necessary to waste water is processed using expensive membrane separation technique, quantity of wastewater effluent is still suffered from excessive, industrial
The deficiencies such as cost for wastewater treatment height.
The content of the invention
The present invention is directed to the deficiencies in the prior art, there is provided a kind of preparation technology of prednisolone acetate.What the present invention was provided
Method significantly reduces the consumption of liquid supplementary material in reaction system, and product yield is high, and amount of industrial wastewater is greatly decreased, and effectively drops
Low cost of material and environmentally friendly cost, are adapted to industrial scale production.
It is that, up to above-mentioned purpose, the measure that the present invention takes is as follows：
A kind of preparation technology of prednisolone acetate, is prepared with acetic anhydride reaction by prednisolone, it is characterised in that：
In the presence of the DMAP of 0.08-0.2 weight portions, be not required to increase solvent in addition, by the prednisolone of 1 weight portion with
The acetic anhydride of 1.5-4 weight portions is reacted in 10-80 DEG C, pours analysis of material in water, and filtration drying prepares prednisolone acetate
Dragon.
Prednisolone ranges preferably from 1 with the ratio of weight and number of DMAP：0.1-0.15.
Prednisolone ranges preferably from 1 with the ratio of weight and number of acetic anhydride：2-3.
Range of reaction temperature of the prednisolone with acetic anhydride under DMAP effect is preferably 60-65 DEG C.
The invention has the beneficial effects as follows：Under DMAP effect, prednisolone is directly reacted with acetic anhydride
Prepare prednisolone acetate.In technical process, substantial amounts of solvent --- the pyrrole arrived used in conventional art need not be added
The replacement solvent of pyridine and pyridine（Dipolar aprotic solvent etc.）, so as to the prior art for overcoming the course of reaction generally needs
Use pyridine or pyridine substitutes the technology prejudice of solvent.It is not required to increase solvent in addition using present invention process, not only significantly carries
The high batch production capacity of reactor, and generation is avoided because solvent is using bringing a large amount of reluctant industrial wastewaters, keep away
The strip loss of solvent in last handling process is exempted from.Present invention process has technical process simple, is conducive to environmental conservation, cost
Advantage that is low, being suitable for industrialized great production.
Specific embodiment
For purposes of simplicity and clarity, the description of known conventional production process is hereafter rightly eliminated, in order to avoid those
Unnecessary details affects the description to the technical program.
The present invention is illustrated with example below, these examples are intended to the technological means for helping understand the present invention.But
It should be understood that these embodiments are exemplary, this is the invention is not limited in.
Embodiment one
90g acetic anhydride, 30g prednisolones are added in reaction bulb successively, the DMAP of 3g is added, stirring heat up in
60-65 DEG C is reacted 6 hours.TLC shows that reaction is complete, reactant liquor is poured into and be cooled in 0-10 DEG C of frozen water in advance, stirs 30 points
Zhong Hou, stands more than 2 hours, filters, is dried to obtain 33g prednisolone acetates, HPLC purity 99.0%.
Embodiment two
80g acetic anhydride, 40g prednisolones are added in reaction bulb successively, the DMAP of 6g is added, stirring heat up in
60-65 DEG C is reacted 5 hours.TLC shows that reaction is complete, reactant liquor is poured into and be cooled in 0-10 DEG C of frozen water in advance, stirs 30 points
Zhong Hou, stands more than 2 hours, filters, is dried to obtain 44.2g prednisolone acetates, HPLC purity 99.1%.
Embodiment three
125g acetic anhydride, 50g prednisolones are added in reaction bulb successively, the DMAP of 6g is added, stirring heats up
React 6 hours in 60-65 DEG C.TLC shows that reaction is complete, reactant liquor is poured into and be cooled in 0-10 DEG C of frozen water in advance, stirring 30
After minute, more than 2 hours are stood, filter, be dried to obtain 55.1g prednisolone acetates, HPLC purity 99.1%.
Claims (4)
1. a kind of preparation technology of prednisolone acetate, is prepared with acetic anhydride reaction by prednisolone, it is characterised in that：
In the presence of the DMAP of 0.08-0.2 weight portions, be not required to increase solvent in addition, by the prednisolone of 1 weight portion with
The acetic anhydride of 1.5-4 weight portions is reacted in 10-80 DEG C, pours analysis of material in water, and filtration drying prepares prednisolone acetate
Dragon.
2. the preparation technology of a kind of prednisolone acetate according to claim 1, it is characterised in that：Described prednisolone
Ratio of weight and number scope with DMAP is 1：0.1-0.15.
3. the preparation technology of a kind of prednisolone acetate according to claim 1, it is characterised in that：Described prednisolone
Ratio of weight and number scope with acetic anhydride is 1：2-3.
4. the preparation technology of a kind of prednisolone acetate according to claim 1, it is characterised in that：Prednisolone and acetic anhydride
Range of reaction temperature under DMAP effect is 60-65 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610973712.0A CN106589035A (en) | 2016-11-07 | 2016-11-07 | Preparation process of prednisolone acetate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610973712.0A CN106589035A (en) | 2016-11-07 | 2016-11-07 | Preparation process of prednisolone acetate |
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| CN106589035A true CN106589035A (en) | 2017-04-26 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201610973712.0A Pending CN106589035A (en) | 2016-11-07 | 2016-11-07 | Preparation process of prednisolone acetate |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110540569A (en) * | 2018-05-28 | 2019-12-06 | 江苏佳尔科药业集团有限公司 | Preparation method of tetraene acetate |
| CN113563402A (en) * | 2021-06-11 | 2021-10-29 | 佳尔科生物科技南通有限公司 | Synthetic method for preparing prednisolone by one-pot method |
| CN114807286A (en) * | 2022-05-10 | 2022-07-29 | 华中药业股份有限公司 | Method for refining prednisone acetate based on resting cell transformation |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104761607A (en) * | 2015-03-17 | 2015-07-08 | 河南利华制药有限公司 | Preparation of prednisolone acetate |
| CN105566146A (en) * | 2016-03-10 | 2016-05-11 | 济宁市化工研究院 | Preparation method of D-panthenyl triacetate |
-
2016
- 2016-11-07 CN CN201610973712.0A patent/CN106589035A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104761607A (en) * | 2015-03-17 | 2015-07-08 | 河南利华制药有限公司 | Preparation of prednisolone acetate |
| CN105566146A (en) * | 2016-03-10 | 2016-05-11 | 济宁市化工研究院 | Preparation method of D-panthenyl triacetate |
Non-Patent Citations (4)
| Title |
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| RIM SALAME 等: "Questions about the structures of nitraraine and nitraraidine", 《TETRAHEDRON LETTERS》 * |
| 廖联安 等: "4-二甲氨基吡啶的合成及其催化的有机反应", 《合成化学》 * |
| 焦德权 等: "DMAP催化合成O-乙酰基乳酸丁酯", 《天津师范大学学报（自然科学版）》 * |
| 肖海鸿 等: "应用4-DMAP催化合成乙酸薄荷酯的新方法", 《香料香精化妆品》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110540569A (en) * | 2018-05-28 | 2019-12-06 | 江苏佳尔科药业集团有限公司 | Preparation method of tetraene acetate |
| CN113563402A (en) * | 2021-06-11 | 2021-10-29 | 佳尔科生物科技南通有限公司 | Synthetic method for preparing prednisolone by one-pot method |
| CN114807286A (en) * | 2022-05-10 | 2022-07-29 | 华中药业股份有限公司 | Method for refining prednisone acetate based on resting cell transformation |
| CN114807286B (en) * | 2022-05-10 | 2023-09-15 | 华中药业股份有限公司 | Method for refining prednisone acetate based on resting cell transformation |
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Application publication date: 20170426 |