CN106905406A - A kind of preparation technology of Triamcinolone acetonide - Google Patents
A kind of preparation technology of Triamcinolone acetonide Download PDFInfo
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- CN106905406A CN106905406A CN201710012439.XA CN201710012439A CN106905406A CN 106905406 A CN106905406 A CN 106905406A CN 201710012439 A CN201710012439 A CN 201710012439A CN 106905406 A CN106905406 A CN 106905406A
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- triamcinolone acetonide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/0026—Oxygen-containing hetero ring cyclic ketals
- C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
- C07J71/0015—Oxiranes at position 9(11)
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Abstract
A kind of preparation technology of Triamcinolone acetonide, uses intermediate III to be prepared for raw material, using following preparation technology：Using hydrofluoric acid acetone mixed solvent as solvent, intermediate III is slowly added at subzero 40 DEG C to subzero 30 DEG C, reacted 48 hours after the completion of charging, risen again to subzero 50 DEG C, continue to react 10 30min, after completion of the reaction, reaction solution is slowly added into solution of potassium carbonate, pH value 7.0 7.5, filtering and discharging is adjusted, after drying, Triamcinolone acetonide is obtained.This preparation technology shortens the production cycle；Avoid using substantial amounts of high mixture ratio acetone, it is more environment-friendly.
Description
Technical field
The present invention relates to chemicals synthesis, more particularly to a kind of preparation technology of Triamcinolone acetonide belongs to chemical pharmacy skill
Art field.
Background technology
The chemical name of Triamcinolone acetonide is：16 α, 17- [（1- methyl ethylidene）It is double（Oxygen）] -11 β, 21- dihydroxy -9- fluorine
Pregnant steroid-Isosorbide-5-Nitrae-diene -3,20- diketone is efficient fluorine-containing corticosteroid, it is adaptable to various skin diseases (such as neurodermatitis,
Eczema, psoriasis etc.), arthralgia, bronchial astehma, shoulder enclose inflammation, tenosynovitis, acute sprain, slow pain in waist and lower extremities and ophthalmic inflammation
Deng.Its chemical structural formula is：
Triamcinolone acetonide is, with 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate as substrate, to obtain intermediate III, then pass through via the oxidation of double hydroxyls, the hydrolysis of bromine hydroxyl, epoxy
Cross the processes such as fluorine, ketal and obtain Triamcinolone acetonide, wherein fluoride reaction is as molten with hydrofluoric acid (70%HF)-DMF mixed solvents
Agent, carries out fluoride reaction under cryogenic；After completion of the reaction, reaction solution is slowly added to molten to configured good potassium carbonate
In liquid, pH value 7.0-7.5 is adjusted, filtering and discharging obtains intermediate IV, intermediate IV thrown into acetone system, room temperature after drying
Lower dropwise addition perchloric acid（70%）, reacting, triethylamine is neutralized, concentration, cooling, and discharging obtains Triamcinolone acetonide.Intermediate III, centre
Shown in the structure of body IV is specific as follows：
At present there is following defect in the above-mentioned preparation method of application：One be from IV → Triamcinolone acetonide of intermediate be in high mixture ratio amount
Acetone in react, acetone is noxious material easily processed, by national management and control, concentration needs a large amount of energy consumptions, operation step after reaction completely
Rapid cumbersome, the production cycle is more long；Two is that the waste water containing DMF is more intractable, increased environmental protection pressure.
The content of the invention
It is an object of the invention to overcome drawbacks described above present in current Triamcinolone acetonide preparation process, there is provided a koji is pacified
How the preparation technology of moral.
To realize the purpose of the present invention, following technical schemes are employed：A kind of preparation technology of Triamcinolone acetonide, using tool
There is formula intermediate III to be prepared for raw material,
Using following preparation technology：It is slow at subzero 40 DEG C to subzero 30 DEG C using hydrofluoric acid-acetone mixed solvent as solvent
Intermediate III is added, is reacted 4-8 hours after the completion of charging, risen again to subzero 5-0 DEG C, continue to react 10-30min, reaction is finished
Afterwards, reaction solution is slowly added into solution of potassium carbonate, adjusts pH value 7.0-7.5, how filtering and discharging after drying, obtains Qu An
Moral, further, the mass concentration of described hydrofluoric acid is 70%, and hydrofluoric acid is 10 with the volume ratio of acetone:1.
Positive Advantageous Effects of the invention are：One is that this preparation technology is produced using one kettle way, effective to simplify
Production stage, shortens the production cycle；Two are avoided using substantial amounts of high mixture ratio acetone, and consumption is substantially reduced；Three is not
DMF is reused, it is more environment-friendly.
Specific embodiment
In order to more fully explain implementation of the invention, there is provided embodiment of the invention, these embodiments are only
To elaboration of the invention, do not limit the scope of the invention..
A kind of preparation method of intermediate of the present invention III is provided first.The preparation method of intermediate III is as follows：
A：Using the 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate shown in following formula（21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate chemical name：21- monohydric pregnants -1,4,9 (11), 16（17）-
Tetraene -3,20- diketone -21- acetates）For raw material prepares the intermediate I shown in following formula, 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate can be bought by city
Arrive；
Preparation method is as follows：
21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate is added in acetone, -5-0 DEG C is cooled to, formic acid is added, 5min is stirred, liquor potassic permanganate is added,
- 5-0 DEG C of reaction 10min of temperature control, adds sodium sulfite solution, is warming up to 40 DEG C, and filtering is concentrated filtrate to without acetone,
It is cooled to less than 10 DEG C, centrifugal discharge, 60 DEG C dry 12h, obtain intermediate I；
B：The intermediate II shown in following formula is prepared using intermediate I；
Intermediate I is added in DMF, stirring is cooled to -5 DEG C, adds 2.1ml perchloric acid, -5-0 DEG C of temperature control to add in three times
11.2g C5H6Br2N2O2s, add in 30min.- 5-0 DEG C of reaction 1h of insulation, reaction solution is poured into sodium sulfite solution, is stirred
30min, centrifugal discharge, 35 DEG C dry 24h, obtain intermediate II；
C：Intermediate III is prepared using intermediate II；
Intermediate II is added in the mixed solvent of dichloromethane and methyl alcohol, nitrogen displacement three times, stirring is cooled to -5-0 DEG C,
Sodium hydroxide solution is added dropwise, -5-0 DEG C of reaction 20min of temperature control, to glacial acetic acid is added dropwise in reaction solution, adjusts PH to 6.0-7.0, decompression
Concentration dichloromethane and methyl alcohol pour drinking water to sticky, stir 30min, centrifugal discharge, and 60 DEG C dry 12h, obtain intermediate
Ⅲ。
Embodiment 1：The preparation of intermediate III
A：Intermediate I is prepared by 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate；
8.5g potassium permanganate is added in 105ml water, 40 DEG C are warming up to, stirring and dissolving potassium permanganate has dissolved addition 300ml
Acetone, stirring is cooled to -15--20 DEG C, standby.9.5g sodium sulfites are added in 80ml water, stirring and dissolving is standby；Will
20g 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetates are added in 750ml acetone, are cooled to -5-0 DEG C, add 6ml formic acid, stir 5min, what addition was prepared
Liquor potassic permanganate, -5-0 DEG C of reaction 10min of temperature control, the sodium sulfite solution that addition is prepared is warming up to 40 DEG C, and filtering will
Filtrate decompression is concentrated into without acetone, is cooled to less than 10 DEG C, centrifugal discharge, and 60 DEG C dry 12h, obtain intermediate I, 19.2g, color
Spectral purity：97.9%, yield 96.0%；
B：Intermediate II is prepared by intermediate I；
19gN-1 is added in 95mlDMF, stirring is cooled to -5 DEG C, adds 2.5ml perchloric acid, -5-0 DEG C of temperature control to add in three times
Enter 13.2g C5H6Br2N2O2s, added in 30min.- 5-0 DEG C of reaction 1.5h of insulation, reaction solution is poured into the sodium sulfite for preparing molten
In liquid, stirring 30min, centrifugal discharge, 35 DEG C dry 24h, obtain intermediate II, 23.0g, chromatographic purity：97.5%, yield
121.0%；
C：Intermediate III is prepared by intermediate II；
5.7g NaOH is added in 11.4ml water, stirring and dissolving is standby.22gN-2 is added to 110ml dichloromethane
In the mixed solvent of 125ml methyl alcohol, nitrogen displacement three times, stirring is cooled to -5-0 DEG C, and sodium hydroxide solution, 30min is added dropwise
Inside drip off, -5-0 DEG C of reaction 30min of temperature control, to 15ml glacial acetic acids are added dropwise in reaction solution, adjusts PH to 6.0-7.0, concentrated under reduced pressure two
Chloromethanes and methyl alcohol pour 90ml drinking water to sticky, stir 30min, centrifugal discharge, and 60 DEG C dry 12h, obtain intermediate
III, 17.3g, chromatographic purity：98.2%, yield 78.5%.
Embodiment 2：The preparation of Triamcinolone acetonide
200g potassium carbonate is dissolved into 600ml water, stirs molten clear, it is standby.By 75ml hydrofluoric acid（70%HF）Add with 10ml acetone
Enter in the plastic bottle of 250ml, stir, be cooled to -40--30 DEG C, in -40--30 DEG C of temperature of control, 15g is added in 1h
Substrate intermediate III, is added, -35--30 DEG C of reaction 5h of temperature control, rises again to -5-0 DEG C, reacts 10min, and reaction solution is slowly added to
Into configured good solution of potassium carbonate, below 10 DEG C of temperature of control, added in 1h, regulation pH value 7.0-7.5, filtering and discharging,
After drying, Triamcinolone acetonide crude product 14.28g, chromatographic purity are obtained：95.8% .
Embodiment 3：The preparation of Triamcinolone acetonide
200g potassium carbonate is dissolved into 600ml water, stirs molten clear, it is standby.By 70ml hydrofluoric acid（70%HF）Add with 15ml acetone
Enter in the plastic bottle of 250ml, stir, be cooled to -40--30 DEG C, in -40--30 DEG C of temperature of control, 10g is added in 1h
Substrate intermediate III, is added, -35--30 DEG C of reaction 5h of temperature control, rises again to -5-0 DEG C, reacts 10min, and reaction solution is slowly added to
Into configured good solution of potassium carbonate, below 10 DEG C of temperature of control, added in 1h, regulation pH value 7.0-7.5, filtering and discharging,
After drying, Triamcinolone acetonide crude product 14.41g, chromatographic purity are obtained：96.2% .
Embodiment 4：The preparation of Triamcinolone acetonide
200g potassium carbonate is dissolved into 600ml water, stirs molten clear, it is standby.By 75ml hydrofluoric acid（70%HF）With 7.5ml acetone
It is added in the plastic bottle of 250ml, stirs, be cooled to -40--30 DEG C, in -40--30 DEG C of temperature of control, is added in 1h
10g substrates intermediate III, adds, -35--30 DEG C of reaction 5h of temperature control, rises again to -5-0 DEG C, reacts 20min, and reaction solution is slow
Add into configured good solution of potassium carbonate, below 10 DEG C of temperature of control, added in 1h, adjust pH value 7.0-7.5, filter out
Material, after drying, obtains Triamcinolone acetonide crude product 14.39g, chromatographic purity：96.1% .
Embodiment 5：The preparation of Triamcinolone acetonide
200g potassium carbonate is dissolved into 600ml water, stirs molten clear, it is standby.By 75ml hydrofluoric acid（70%HF）Add with 10ml acetone
Enter in the plastic bottle of 250ml, stir, be cooled to -40--30 DEG C, in -40--30 DEG C of temperature of control, 10g is added in 1h
Substrate intermediate III, is added, -35--30 DEG C of reaction 5h of temperature control, rises again to -5-0 DEG C, reacts 20min, and reaction solution is slowly added to
Into configured good solution of potassium carbonate, below 10 DEG C of temperature of control, added in 1h, regulation pH value 7.0-7.5, filtering and discharging,
After drying, Triamcinolone acetonide crude product 14.46g, chromatographic purity are obtained：96.5% .
Embodiment 6：The preparation of Triamcinolone acetonide
200g potassium carbonate is dissolved into 600ml water, stirs molten clear, it is standby.By 75ml hydrofluoric acid（70%HF）Add with 10ml acetone
Enter in the plastic bottle of 250ml, stir, be cooled to -40--30 DEG C, in -40--30 DEG C of temperature of control, 10g is added in 1h
Substrate intermediate III, is added, -35--30 DEG C of reaction 5h of temperature control, rises again to -5-0 DEG C, reacts 30min, and reaction solution is slowly added to
Into configured good solution of potassium carbonate, below 10 DEG C of temperature of control, added in 1h, regulation pH value 7.0-7.5, filtering and discharging,
After drying, Triamcinolone acetonide crude product 14.36g, chromatographic purity are obtained：96.5% .
After embodiments of the present invention are described in detail, one of ordinary skilled in the art is clearly understood that, is not taking off
Various change and modification can be carried out under above-mentioned claim with spirit, it is all real to more than according to technical spirit of the invention
Any simple modification, equivalent variations and modification that example is made are applied, the scope of technical solution of the present invention is belonged to, and the present invention is also not
It is limited to the implementation method of example in specification.
Claims (2)
1. a kind of preparation technology of Triamcinolone acetonide, uses with formula intermediate III for prepared by raw material, and conversion type is as follows：
It is characterized in that using following preparation technology：Using hydrofluoric acid-acetone mixed solvent as solvent, at subzero 40 DEG C to zero
Lower 30 DEG C are slowly added to intermediate III, are reacted 4-8 hours after the completion of charging, rise again to subzero 5-0 DEG C, continue to react 10-
30min, after completion of the reaction, reaction solution is slowly added into solution of potassium carbonate, regulation pH value to 7.0-7.5, and filtering and discharging is done
After dry, Triamcinolone acetonide is obtained.
2. the preparation technology of a kind of Triamcinolone acetonide according to claim 1, it is characterised in that：The mass concentration of hydrofluoric acid is
70%, hydrofluoric acid is 10 with the volume ratio of acetone:1.
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| CN201710012439.XA CN106905406A (en) | 2017-01-09 | 2017-01-09 | A kind of preparation technology of Triamcinolone acetonide |
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| CN201710012439.XA CN106905406A (en) | 2017-01-09 | 2017-01-09 | A kind of preparation technology of Triamcinolone acetonide |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021184502A1 (en) * | 2020-03-20 | 2021-09-23 | 浙江神洲药业有限公司 | Method for preparing 16alpha-hydroxyprednisolone |
| CN114478681A (en) * | 2021-12-24 | 2022-05-13 | 河南利华制药有限公司 | Preparation method of triamcinolone acetonide |
| CN115322243A (en) * | 2022-09-20 | 2022-11-11 | 山东赛托生物科技股份有限公司 | Method for preparing triamcinolone acetonide key intermediate by one-pot method |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1469575A (en) * | 1974-05-17 | 1977-04-06 | Lark Spa | Preparation of 16,17-cyclic acetals and ketals of 9alpha-halo steroids |
-
2017
- 2017-01-09 CN CN201710012439.XA patent/CN106905406A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1469575A (en) * | 1974-05-17 | 1977-04-06 | Lark Spa | Preparation of 16,17-cyclic acetals and ketals of 9alpha-halo steroids |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021184502A1 (en) * | 2020-03-20 | 2021-09-23 | 浙江神洲药业有限公司 | Method for preparing 16alpha-hydroxyprednisolone |
| US11618766B2 (en) | 2020-03-20 | 2023-04-04 | Zhejiang Shenzhou Pharmaceutical Company Limited | Method for preparing 16Alpha-hydroxyprednisolone |
| CN114478681A (en) * | 2021-12-24 | 2022-05-13 | 河南利华制药有限公司 | Preparation method of triamcinolone acetonide |
| CN115322243A (en) * | 2022-09-20 | 2022-11-11 | 山东赛托生物科技股份有限公司 | Method for preparing triamcinolone acetonide key intermediate by one-pot method |
| CN115322243B (en) * | 2022-09-20 | 2023-10-03 | 山东赛托生物科技股份有限公司 | Method for preparing triamcinolone acetonide key intermediate by one-pot method |
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Application publication date: 20170630 |