CN101875681A - Synthetic method of 16alpha-hydroxy prednisonlone - Google Patents
Synthetic method of 16alpha-hydroxy prednisonlone Download PDFInfo
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- CN101875681A CN101875681A CN 201010205878 CN201010205878A CN101875681A CN 101875681 A CN101875681 A CN 101875681A CN 201010205878 CN201010205878 CN 201010205878 CN 201010205878 A CN201010205878 A CN 201010205878A CN 101875681 A CN101875681 A CN 101875681A
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Abstract
The invention discloses a synthetic method of 16alpha-hydroxy prednisonlone as shown in formula (III), comprising the following steps: taking the prednisonlone as shown in formula (I) as a raw material; carrying out dehydration reaction to generate a double bond in acidic ionic liquid as shown in formula (II); adding hydrogen peroxide aqueous solution to react; and adding water for further hydrolyzation after full reaction to finally obtain the 16alpha-hydroxy prednisonlone. The synthetic method of the invention adopts the property of the acidic ionic liquid as a reaction medium as well as a catalyst and changes technological conditions such as reaction time, reaction temperature and the like, thus achieving the purpose of reduced cost, energy conservation and emission reduction, and being applicable to industrial production.
Description
(1) technical field
The present invention relates to a kind of synthetic method of 16 alpha-hydroxy prednisonlones.
(2) background technology
16 alpha-hydroxy prednisonlones, chemical formula: C
21H
28O
6, molecular weight: 376.44.It is a kind of important intermediate for the treatment of the medicine-ciclesonide of asthma.About synthesizing of 16 alpha-hydroxy prednisonlones; reported method all is to be raw material with the prednisolone at present; under the katalysis of tosic acid pyridinium salt, become ring with triethly orthoacetate; selective opening gets acetylate under the solutions of weak acidity; after generating the diacetylation thing with acetic anhydride reaction again under alkaline condition, the acetic acid that Potassium ethanoate exists heating down to slough a part gets (11 β)-hydroxyl-21-acetoxyl group-1,4; the pregnant steroid triolefin-3 of 16-, the 20-dione compounds.With this compound selectivity bishydroxy under the potassium permanganate effect, deacetylated product 16 alpha-hydroxy prednisonlones that get under the existence of sodium hydroxide.In existing synthetic route, synthesis step is long, product aftertreatment complexity.
In recent years, we just are being devoted to the applied research of all kinds of ionic liquids in hormone medicine and intermediate are synthetic.Ionic liquid is by organic cation and inorganic or organic anion two portions are formed, the ionic system that is in a liquid state under room temperature and adjacent temperature.Ionic liquid has the incomparable advantage of many other materials, as the liquid temperature wide ranges, there is not significant vapour pressure, Heat stability is good, have acidity or superpower acidity, and acidity can be carried out modulation as required, many mineral compound and organic compound etc. had good solubility, the separation that electrochemical window is wide, can overcome homogeneous catalyst, reclaim difficulty and environment is polluted, have homogeneous catalyst high reaction activity and heterogeneous catalyst simultaneously concurrently easily and the isolating advantage of product.Based on these characteristics, ionic liquid has a wide range of applications at aspects such as extracting and separating, catalyzed reaction, electrochemistry.The acidity of acidic ion liquid is by anionic essence decision.Acidic ion liquid is divided into " Lewis acidic ion liquid " and " Br ō nsted acidic ion liquid ".The advantage of acidic ion liquid is an ionic liquid as the friendly type acid catalyst of a kind of novel environmental, and it is little to have corrodibility; Reaction conditions relaxes; Acidity can be regulated; Can recycle.Overcome the problem of environmental pollution that traditional Lewis acid catalyst brings, and in acid catalyzed reaction, shown good activity and selectivity.Be expected to become 21 century the most promising green solvent and one of catalyzer.
(3) summary of the invention
The technical problem to be solved in the present invention is to provide a kind of method of utilizing the acidic ion liquid while as reaction medium and synthetic 16 alpha-hydroxy prednisonlones of catalyzer, this technology is easy to operate, the production capacity height, excellent in efficiency, the three wastes are few, convenient post-treatment, ionic liquid is reusable, has economical and practical characteristics.
For solving the problems of the technologies described above, the present invention adopts following technical scheme:
A kind of structure is suc as formula the synthetic method of 16 alpha-hydroxy prednisonlones shown in (III), comprise the steps: that be raw material with structure suc as formula the prednisolone shown in (I), in suc as formula the acidic ion liquid shown in (II), carry out dehydration reaction earlier and generate two keys, adding aqueous hydrogen peroxide solution then reacts, fully add the further hydrolysis of entry again after the reaction, obtain described 16 alpha-hydroxy prednisonlones at last;
In the formula (II), R is the substituted alkyl of C1～C10, and the substituting group of described substituted alkyl is sulfonic group or carboxyl, and L is HSO
4, COO, CH
3COO, BF
4, PF
6Or CF
3SO
3Perhaps R is the alkyl of C1～C10, and L is HSO
4, COO or CF
3SO
3
In the technical scheme of the present invention, the dehydration earlier of raw material prednisolone generates two keys, is that oxygenant carries out oxidizing reaction then with the hydrogen peroxide, carries out hydrolysis reaction after the oxidation, obtains target product at last.
Further, the acidic ion liquid shown in the described formula (II), preferred: R is the substituted alkyl of C1～C10, and the substituting group of described substituted alkyl is a sulfonic group; Further, preferred L is HSO
4, CH
3COO or BF
4
Further, described dehydration reaction is preferably carried out under 100～150 ℃ temperature condition, more preferably 110～130 ℃.By TLC tracking monitor reaction process, disappear until raw material point, recommend with hexanaphthene: the mixed solvent of acetone (volume ratio)=5: 5 is as developping agent.
Further, described oxidizing reaction and hydrolysis reaction preferably carry out under 10～60 ℃ temperature condition, and more preferably oxidizing reaction and hydrolysis reaction carry out under 40～60 ℃ temperature condition.Behind the preferred adding aqueous hydrogen peroxide solution, reacted 5～50 hours, add the further hydrolysis of entry then; After more preferably adding aqueous hydrogen peroxide solution, reacted 10～40 hours, add the further hydrolysis of entry then.The present invention recommends with hexanaphthene by the above-mentioned reaction process of TLC tracking monitor: the mixed solvent of acetone (volume ratio)=5: 5 is as developping agent.
Further, the mass ratio that feeds intake of prednisolone of the present invention and acidic ion liquid is 1: 1～20, be preferably 1: 8～and 15, more preferably 1: 10.
Further, the mol ratio of prednisolone of the present invention and hydrogen peroxide is 1: 1～10, preferred 1: 3～5.The present invention does not have special requirement for the concentration of the aqueous hydrogen peroxide solution that uses, and all is applicable to the present invention such as the aqueous hydrogen peroxide solution of mass concentration 30～70%.
The present invention does not have special requirement for the consumption in order to the water of further hydrolysis that adds in the reaction process yet, and those skilled in the art can adjust according to practical situation.The general further hydrolysis of water that adds 40～60 times of prednisolone quality among the present invention.
The present invention is concrete to recommend described synthetic method to carry out according to following steps: prednisolone is added in the acidic ion liquid, under 100～150 ℃, react, TLC tracks to raw material point and disappears, be cooled to room temperature, add aqueous hydrogen peroxide solution, react 5～50h down, add the further hydrolysis of entry again at 10～60 ℃, TLC follows the tracks of reaction process, and reaction finishes back gained reaction solution and obtains described 16 alpha-hydroxy prednisonlone products through aftertreatment; The mass ratio that feeds intake of described prednisolone and acidic ion liquid is 1: 1～20; The molar ratio of described prednisolone and hydrogen peroxide is 1: 1～10.
Following steps are adopted in described aftertreatment: reaction solution extracts with toluene, gets toluene layer, uses distilled water wash, with the anhydrous magnesium sulfate drying toluene layer, removes toluene under reduced pressure, obtains 16 alpha-hydroxy prednisonlone products.Toluene extraction back gained raffinate can directly add reaction system and be used for reaction, reuses 3～5 times after, wash with water, dichloromethane extraction, dry reusable again after concentrated.
Compared with prior art, synthetic method of the present invention utilizes acidic ion liquid not only as reaction medium but also as the character of catalyzer, by changing processing condition such as reaction times and temperature of reaction, realized reducing cost, the purpose of energy-saving and emission-reduction, be suitable for suitability for industrialized production.Particularly, the technology of the present invention is easy to operate, the production capacity height, and excellent in efficiency, the three wastes are few, convenient post-treatment, ionic liquid is reusable, is economical and practical green environmental protection technique.
(4) embodiment
The present invention is described further below in conjunction with specific embodiment, but protection scope of the present invention is not limited in this.
Hydrogen peroxide described in the embodiment of the invention adds with the form of the aqueous hydrogen peroxide solution of mass concentration 30%, and quality among the embodiment and amount of substance are all in hydrogen peroxide itself.
Embodiment 1
With prednisolone (I) 0.1g (2.77 * 10
-4Mol) and methyl butyl sulfonic group imidazole bisulfate acidic ion liquid 1g add in the reaction flask, maintain the temperature at 120 ℃, reaction process TLC tracking monitor, with hexanaphthene: the mixed solvent of acetone (volume ratio)=5: 5 disappears until raw material point as developping agent.Then, be cooled to room temperature, add hydrogen peroxidase 10 .028g (8.31 * 10
-4Mol), 50 ℃ of down reactions 20 hours, add 5 ml waters again, after thin layer plate (with hexanaphthene: the mixed solvent of acetone (volume ratio)=5: 5 is as developping agent) is followed the tracks of reaction and finished, add and extract with 3 * 5mL toluene, combining extraction liquid behind 3 * 5mL distilled water wash, is told organic layer, behind the anhydrous magnesium sulfate drying, underpressure distillation obtains suc as formula 16 alpha-hydroxy prednisonlone product 0.09g shown in (III) to constant weight, and yield is 90%.Mp：238～241℃。H
1NMRδ：0.98(s，3H)，1.49(s，3H)，4.24-4.68(dd，2H，J＝20.1，Hz).4.50(d，1H，J＝2.5Hz)，5.08(d，1H，J＝8.2Hz)，6.03(s，3H)，6.28(d，1H，9.3Hz)，7.25(d，1H，J＝10.1Hz)。
Embodiment 2
With prednisolone (I) 0.1g (2.77 * 10
-4Mol) and the acid ionic liquid 1g of methyl butyl sulfonic group imidazoles acetate add in the reaction flask, maintain the temperature at 150 ℃, reaction process TLC tracking monitor, with hexanaphthene: the mixed solvent of acetone (volume ratio)=5: 5 disappears until raw material point as developping agent.Then, be cooled to room temperature, add hydrogen peroxidase 10 .009g (2.77 * 10
-4Mol), 50 ℃ of down reactions 10 hours, add 5 ml waters again, after thin layer plate (with hexanaphthene: the mixed solvent of acetone (volume ratio)=5: 5 is as developping agent) is followed the tracks of reaction and finished, add and extract with 3 * 5mL toluene, combining extraction liquid behind 3 * 5mL distilled water wash, is told organic layer, behind the anhydrous magnesium sulfate drying, underpressure distillation obtains suc as formula 16 alpha-hydroxy prednisonlone product 0.08g shown in (III) to constant weight, and yield is 80%.
Embodiment 3
With prednisolone (I) 0.1g (2.77 * 10
-4Mol) and methyl butyl sulfonic group tetrafluoroborate acidic ion liquid 1g add in the reaction flask, maintain the temperature at 100 ℃, reaction process TLC tracking monitor, with hexanaphthene: the mixed solvent of acetone (volume ratio)=5: 5 disappears until raw material point as developping agent.Then, be cooled to room temperature, add hydrogen peroxidase 10 .094g (2.77 * 10
-3Mol), 50 ℃ of down reactions 20 hours, add 5 ml waters again, after thin layer plate (with hexanaphthene: the mixed solvent of acetone (volume ratio)=5: 5 is as developping agent) is followed the tracks of reaction and finished, add and extract with 3 * 5mL toluene, combining extraction liquid behind 3 * 5mL distilled water wash, is told organic layer, behind the anhydrous magnesium sulfate drying, underpressure distillation obtains suc as formula 16 alpha-hydroxy prednisonlone product 0.092g shown in (III) to constant weight, and yield is 92%.
Embodiment 4
With prednisolone (I) 0.1g (2.77 * 10
-4Mol) and methyl butyl sulfonic group imidazole bisulfate acidic ion liquid 0.8g add in the reaction flask, maintain the temperature at 120 ℃, reaction process TLC tracking monitor, with hexanaphthene: the mixed solvent of acetone (volume ratio)=5: 5 disappears until raw material point as developping agent.Then, be cooled to room temperature, add hydrogen peroxidase 10 .047g (13.85 * 10
-4Mol), 10 ℃ of down reactions 30 hours, add 5 ml waters again, after thin layer plate (with hexanaphthene: the mixed solvent of acetone (volume ratio)=5: 5 is as developping agent) is followed the tracks of reaction and finished, add and extract with 3 * 5mL toluene, combining extraction liquid behind 3 * 5mL distilled water wash, is told organic layer, behind the anhydrous magnesium sulfate drying, underpressure distillation obtains suc as formula 16 alpha-hydroxy prednisonlone product 0.089g shown in (III) to constant weight, and yield is 89%.
Embodiment 5
With prednisolone (I) 0.1g (2.77 * 10
-4Mol) and methyl butyl sulfonic group imidazole bisulfate acidic ion liquid 1.5g add in the reaction flask, maintain the temperature at 120 ℃, reaction process TLC tracking monitor, with hexanaphthene: the mixed solvent of acetone (volume ratio)=5: 5 disappears until raw material point as developping agent.Then, be cooled to room temperature, add hydrogen peroxidase 10 .038g (11.08 * 10
-4Mol), 40 ℃ of down reactions 25 hours, add 5 ml waters again, after thin layer plate (with hexanaphthene: the mixed solvent of acetone (volume ratio)=5: 5 is as developping agent) is followed the tracks of reaction and finished, add and extract with 3 * 5mL toluene, combining extraction liquid behind 3 * 5mL distilled water wash, is told organic layer, behind the anhydrous magnesium sulfate drying, underpressure distillation obtains suc as formula 16 alpha-hydroxy prednisonlone product 0.09g shown in (III) to constant weight, and yield is 90%.
Claims (10)
1. a structure is suc as formula the synthetic method of 16 alpha-hydroxy prednisonlones shown in (III), comprise the steps: that be raw material with structure suc as formula the prednisolone shown in (I), structure suc as formula the acidic ion liquid shown in (II) in, carry out dehydration reaction earlier and generate two keys, adding aqueous hydrogen peroxide solution then reacts, fully add the further hydrolysis of entry after the reaction, obtain described 16 alpha-hydroxy prednisonlones at last;
In the formula (II), R is the substituted alkyl of C1～C10, and the substituting group of described substituted alkyl is sulfonic group or carboxyl, and L is HSO
4, COO, CH
3COO, BF
4, PF
6Or CF
3SO
3Perhaps R is the alkyl of C1～C10, and L is HSO
4, COO or CF
3SO
3
2. the synthetic method of 16 alpha-hydroxy prednisonlones as claimed in claim 1 is characterized in that the acidic ion liquid shown in the described formula (II), and R is the substituted alkyl of C1～C10, and the substituting group of described substituted alkyl is a sulfonic group, and L is HSO
4, CH
3COO or BF
4
3. the synthetic method of 16 alpha-hydroxy prednisonlones as claimed in claim 1 or 2 is characterized in that described dehydration reaction carries out under 100～150 ℃ temperature condition.
4. the synthetic method of 16 alpha-hydroxy prednisonlones as claimed in claim 3 is characterized in that described dehydration reaction carries out under 110～130 ℃ temperature condition.
5. the synthetic method of 16 alpha-hydroxy prednisonlones as claimed in claim 1 or 2 is characterized in that: add behind the aqueous hydrogen peroxide solution in 10～60 ℃ and react, fully add entry again in 10～60 ℃ of further hydrolysis after the reaction.
6. the synthetic method of 16 alpha-hydroxy prednisonlones as claimed in claim 2 is characterized in that: in 10～60 ℃ of reaction 5～50h, add the further hydrolysis of entry again behind the adding aqueous hydrogen peroxide solution.
7. the synthetic method of 16 alpha-hydroxy prednisonlones as claimed in claim 1 or 2 is characterized in that the mass ratio that feeds intake of described prednisolone and acidic ion liquid is 1: 1～20.
8. the synthetic method of 16 alpha-hydroxy prednisonlones as claimed in claim 1 or 2, the molar ratio that it is characterized in that described prednisolone and hydrogen peroxide is 1: 1～10.
9. the synthetic method of 16 alpha-hydroxy prednisonlones as claimed in claim 1 or 2, it is characterized in that described synthetic method carries out according to following steps: prednisolone is added in the acidic ion liquid, under 100～150 ℃, react, TLC tracks to raw material point and disappears, be cooled to room temperature, add aqueous hydrogen peroxide solution, react 5～50h down at 10～60 ℃, add entry then and continue reaction, TLC follows the tracks of reaction process, and reaction finishes back gained reaction solution and obtains described 16 alpha-hydroxy prednisonlone products through aftertreatment; The mass ratio that feeds intake of described prednisolone and acidic ion liquid is 1: 1～20; The molar ratio of described prednisolone and hydrogen peroxide is 1: 1～10.
10. the synthetic method of 16 alpha-hydroxy prednisonlones as claimed in claim 9, it is characterized in that described aftertreatment employing following steps: reaction solution extracts with toluene, get toluene layer, use distilled water wash, with the anhydrous magnesium sulfate drying toluene layer, the evaporated under reduced pressure solvent obtains 16 alpha-hydroxy prednisonlone products.
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| CN101875681B CN101875681B (en) | 2012-08-08 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102850423A (en) * | 2012-09-26 | 2013-01-02 | 仙居县力天化工有限公司 | Synthesis method of 16alpha-hydroxy prednisolone |
| CN104788469A (en) * | 2015-04-14 | 2015-07-22 | 临海市利民化工有限公司 | Preparation method of clopidogrel bisulfate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4404141A (en) * | 1981-03-09 | 1983-09-13 | Schering Aktiengesellschaft | Δ9(11) - And Δ16 -21-chloro-20-keto steroids of the pregnane and D-homopregnane series, their preparation and use as intermediates for the synthesis of highly effective corticoids |
| WO2007054974A2 (en) * | 2005-09-28 | 2007-05-18 | Arch Pharmalab Limited | A green chemistry process for the preparation of pregnadiene esters |
| CN101279997A (en) * | 2008-05-29 | 2008-10-08 | 鲁南制药集团股份有限公司 | Novel preparation of budesonide |
-
2010
- 2010-06-22 CN CN2010102058780A patent/CN101875681B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4404141A (en) * | 1981-03-09 | 1983-09-13 | Schering Aktiengesellschaft | Δ9(11) - And Δ16 -21-chloro-20-keto steroids of the pregnane and D-homopregnane series, their preparation and use as intermediates for the synthesis of highly effective corticoids |
| WO2007054974A2 (en) * | 2005-09-28 | 2007-05-18 | Arch Pharmalab Limited | A green chemistry process for the preparation of pregnadiene esters |
| CN101279997A (en) * | 2008-05-29 | 2008-10-08 | 鲁南制药集团股份有限公司 | Novel preparation of budesonide |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102850423A (en) * | 2012-09-26 | 2013-01-02 | 仙居县力天化工有限公司 | Synthesis method of 16alpha-hydroxy prednisolone |
| CN102850423B (en) * | 2012-09-26 | 2014-07-09 | 仙居县力天化工有限公司 | Synthesis method of 16alpha-hydroxy prednisolone |
| CN104788469A (en) * | 2015-04-14 | 2015-07-22 | 临海市利民化工有限公司 | Preparation method of clopidogrel bisulfate |
| CN104788469B (en) * | 2015-04-14 | 2017-03-01 | 临海市利民化工有限公司 | A kind of preparation method of Clopidogrel Bisulfate |
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| CN101875681B (en) | 2012-08-08 |
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Effective date of registration: 20201214 Address after: 251909 East Chengkou Town, Wudi County, Binzhou City, Shandong Province Patentee after: Wudi Xinyue Chemical Group Co.,Ltd. Address before: Hangzhou City, Zhejiang province 310014 City Zhaohui District Six Patentee before: ZHEJIANG University OF TECHNOLOGY |
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Granted publication date: 20120808 |