CN101418032A - Method for synthesizing deflazacort - Google Patents
Method for synthesizing deflazacort Download PDFInfo
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- CN101418032A CN101418032A CNA2008102027427A CN200810202742A CN101418032A CN 101418032 A CN101418032 A CN 101418032A CN A2008102027427 A CNA2008102027427 A CN A2008102027427A CN 200810202742 A CN200810202742 A CN 200810202742A CN 101418032 A CN101418032 A CN 101418032A
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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
- C07J71/0036—Nitrogen-containing hetero ring
- C07J71/0057—Nitrogen and oxygen
- C07J71/0068—Nitrogen and oxygen at position 16(17)
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Abstract
The invention provides a method for synthesizing deflazacort. The method comprises the following steps: dissolving 11 belta-hydroxy-pregna-1, 4-diene-3 and 20-diketone[17 alpha, 16 alpha-d]-2'-methyl oxazoline in solvent, reacting the solvent with a bromization reagent under the catalysis of ammonium salt, performing solid-liquid separation, collecting liquid phase, volatilizing the solvent, obtaining 21-bromization-11 belta-hydroxy-pregna-1, 4-diene-3 and 20-diketone[17 alpha, 16 alpha-d]-2'-methyl oxazoline, reacting the 21-bromization-11 belta-hydroxy-pregna-1, 4-diene-3 and 20-diketone[17 alpha, 16 alpha-d]-2'-methyl oxazoline in the solvent in the presence of acetate and catalytic amount phase-transfer catalyst, and collecting target products from reaction products. The method has the advantages of using the low-priced bromization reagent, lowering production cost, simultaneously solving the problems that the used reagent and intermediate products are unstable and have high toxicity, and the by-products can cause serious environmental pollution, and the like, having high reaction yield and mild reaction conditions, reclaiming the solvent and facilitating the industrialized production.
Description
Technical field
The present invention relates to prepare the method for deflazacort.
Background technology
Deflazacort, English Deflazacort by name.Be a kind of white crystalline powder.Belong to adrenocortical hormone and Actrope.This product has anti-inflammatory, anti-allergic effects, and its effect is equivalent to 10～20 times of prednisolones.Be applicable to hypocorticoidism, autoimmune disorder, anaphylactic disease and disease in the blood system etc.Its structural formula is as (1):
At present, in the existing technology, committed step is 11 beta-hydroxies-pregnant steroid-1, and 4-diene-3,20-diketone [17a, 16a-d]-2 '-Jia oxazolins (2) are through 21 iodos, and the Potassium ethanoate displacement obtains the process of final product deflazacort.Its reaction formula is as follows:
As US Patent 3413286, a kind of method for preparing deflazacort is provided, at its committed step 11 beta-hydroxies-pregnant steroid-1,4-diene-3,20-diketone [17a, 16a-d]-2 '-first oxazolin (2) used expensive iodine when 21 iodos, need bimolecular iodine to obtain two iodo things (3) simultaneously, with after the Potassium ethanoate displacement obtains final product.So elemental iodine is because the uneconomical large usage quantity of its atom causes with high costs, two iodo things (3) must be preserved down by lucifuge nitrogen, can not place for a long time, otherwise this compound decomposes easily, and iodine has limited its use in suitability for industrialized production to the corrosion and the problems such as storage and transportation of equipment simultaneously.
Summary of the invention
The synthetic method that the purpose of this invention is to provide a kind of deflazacort is to overcome the above-mentioned defective that prior art exists.
The method of present method comprises the steps:
(1) general's compound as the formula (2) is under ammonium salt in catalysis, in solvent, react 0.5～24h with brominated reagent, temperature of reaction is 20～100 ℃, liquid phase is collected in liquid-solid then separation, flings to solvent, get the compound shown in the formula (4), the not purified the next step that is directly used in, yield is 80～99.5%, reaction equation is as follows:
The chemical name of compound as the formula (2) is 11 beta-hydroxies-pregnant steroid-1,4-diene-3, and 20-diketone [17a, 16a-d]-2 '-Jia oxazolins (2) can adopt the method for US Patent 3413286 bibliographical informations to be prepared;
Described ammonium salt is selected from ammonium acetate, ammonium formiate, propionic acid ammonium, ammonium chloride, brometo de amonio or Neutral ammonium fluoride etc., and preferred ammonium salt is ammonium formiate or ammonium acetate;
Described brominated reagent is selected from N-bromosuccinimide or 1,3-dibromo 5,5-dimethyl hydantion etc.;
Described solvent does not have special requirement, preferred tetrahydrofuran (THF), ether, 2-methyl furan, isopropyl ether, 1,4-dioxane, glycol dimethyl ether, glycol ether dme, methylene dichloride, 1, more than one of 2-ethylene dichloride, Skellysolve A, normal hexane, acetonitrile, dimethyl sulfoxide (DMSO), toluene or dimethylbenzene;
The mol ratio of compound shown in the formula (2) and brominated reagent is 1:1～2.5;
The mol ratio of compound shown in the formula (2) and ammonium salt is 1:0.001～0.1;
In the solvent, the content of the compound shown in the formula (2) is 0.1～1.0mol/L;
(2) with the compound shown in the formula (4) in solvent, the phase-transfer catalyst of acetate and catalytic amount exists down, reacts 2～48 hours, temperature of reaction is 50～120 ℃, collect target product then from reaction product, yield is 75～99%, and reaction equation is as follows:
Described acetate is selected from Potassium ethanoate, sodium-acetate or Lithium Acetate;
Described solvent is selected from methyl alcohol, ethanol, N, dinethylformamide, methyl-sulphoxide, acetone, acetonitrile, methylene dichloride or 1, more than one in the 2-ethylene dichloride;
The general structure of described phase-transfer catalyst is R
4N
+X
-
Wherein R is C
1～C
8Straight chained alkyl, C
1～C
8Branched-chain alkyl or phenyl etc.;
X is fluorine, chlorine, bromine or iodine;
Described catalyzer is commercial chemicals.
Compound (4) is 1: 1～4 with the mol ratio of acetate;
Compound (4) is 1: 0.01～0.1 with the mol ratio of phase-transfer catalyst;
In the solvent, the content of the compound shown in the formula (4) is 0.1～1.0mol/L.
Method of the present invention has used low-cost brominated reagent to replace iodine, still transports the traditional technology that angle all is better than using iodine greatly from storing from atom economy angle and Costco Wholesale angle.What the people was surprised in addition is the use of catalyzer ammonium salt, when not using the catalyzer ammonium salt, compound (2) and brominated reagent do not have any reaction or by product more, but after adding the ammonium salt of catalytic amount, product yield and reaction preference improve greatly, the compound (3) that the compound that obtains (4) prepares than traditional technology is more stable, can preserve for a long time.In the reaction of compound (4) and acetate, a small amount of its yield that obtains target product (1) of phase-transfer catalyst cheap and easy to get of adding is also not a halfpenny the worse than using traditional technology subsequently.The intermediate product purification difficult that we's bright institute reported method has been avoided being run in this compounds traditional synthesis, use problems such as a large amount of costlinesses and acrid iodine, with the our bright intermediate product for preparing (4) Stability Analysis of Structures, greatly reduce production cost.Avoided simultaneously big, unstable, the problem such as the by product environmental pollution is serious of the reagent that uses and intermediate product toxicity." three wastes " discharging reduces significantly in its production technique.This is that additive method is beyond one's reach.With of the present invention and the deflazacort for preparing of method because its reaction conditions gentleness reacts more complete, can reach more than 99% through its purity after the simple purification.Employed reagent all comparatively is easy to get in entire reaction, while reaction yield height, and the reaction conditions gentleness, solvent can be recycled, thereby is convenient to industrializing implementation.
Embodiment
To help to understand the present invention by following specific implementation method, but not limit content of the present invention.
Embodiment 1
21-bromo-11 beta-hydroxy-pregnant steroid-1,4-diene-3, the preparation of 20-diketone [17a, 16a-d]-2 '-Jia oxazolins (4):
In being equipped with the 250mL there-necked flask of thermometer, reflux condensing tube, magnetic agitation, an exsiccant adds compound (2) (19.17g; Fw:383.48; 50mmol), N-bromosuccinimide (9.79g; Fw:178.00; 55mmol), ether is 150 milliliters; Subsequently with ammonium acetate (0.39g; Fw:77.08; 0.005mmol) the adding system.System continues to stir 0.5h at 20 ℃, and reaction finishes.Reaction finishes and uses methylene dichloride 50mL washing leaching cake after after-filtration is removed white precipitate, merges organic phase and gets faint yellow clear liquid, and concentrating under reduced pressure removes and desolvates, and gets faint yellow solid 21.27g, yield: 92%, and HPLC content is greater than 95%.
Embodiment 2
21-bromo-11 beta-hydroxy-pregnant steroid-1,4-diene-3, the preparation of 20-diketone [17a, 16a-d]-2 '-Jia oxazolins (4):
In being equipped with the 250mL there-necked flask of thermometer, reflux condensing tube, magnetic agitation, an exsiccant adds compound (2) (19.17g successively; Fw:383.48; 50mmol), N-bromosuccinimide (9.79g; Fw:178.00; 55mmol), toluene is 150 milliliters; Subsequently with ammonium acetate (0.39g; Fw:77.08; 0.005mmol) the adding system.System continues to stir 5h at 110 ℃, and reaction finishes.Reaction finishes postcooling to room temperature, removes by filter behind the white precipitate with methylene dichloride 50mL washing leaching cake, merge organic phase and get faint yellow clear liquid, concentrating under reduced pressure remove desolvate faint yellow solid 19.65g, yield: 85%, HPLC content is greater than 95%.
Embodiment 3
21-bromo-11 beta-hydroxy-pregnant steroid-1,4-diene-3, the preparation of 20-diketone [17a, 16a-d]-2 '-Jia oxazolins (4):
In being equipped with the 250mL there-necked flask of thermometer, reflux condensing tube, magnetic agitation, an exsiccant adds compound (2) (19.17g successively; Fw:383.48; 50mmol), 1,3-dibromo 5,5-dimethyl hydantion (35.74g; Fw:285.94; 125mmol), ether is 150 milliliters; Subsequently with ammonium acetate (0.39g; Fw:77.08; 0.005mmol) the adding system.System continues to stir 3h under refluxing, and reaction finishes.The reaction after-filtration that finishes is removed behind the white precipitate with ether 50mL washing leaching cake, merge organic phase and get faint yellow clear liquid, concentrating under reduced pressure remove desolvate faint yellow solid 16.18g, yield: 70%, HPLC content is greater than 92%.
Embodiment 4
21-bromo-11 beta-hydroxy-pregnant steroid-1,4-diene-3, the preparation of 20-diketone [17a, 16a-d]-2 '-Jia oxazolins (4):
In being equipped with the 250mL there-necked flask of thermometer, reflux condensing tube, magnetic agitation, an exsiccant adds compound (2) (19.17g successively; Fw:383.48; 50mmol), 1,3-dibromo 5,5-dimethyl hydantion (35.74g; Fw:285.94; 125mmol), methylene dichloride is 150 milliliters; Subsequently with ammonium acetate (0.039g; Fw:77.08; 0.0005mmol) the adding system.System continues to stir 24h under refluxing, and reaction finishes.The reaction after-filtration that finishes is removed behind the white precipitate with ether 50mL washing leaching cake, merge organic phase and get faint yellow clear liquid, concentrating under reduced pressure remove desolvate faint yellow solid 16.41g, yield: 71%, HPLC content is greater than 92%.
Embodiment 5
The preparation of deflazacort:
In being full of the 100mL there-necked flask that is equipped with thermometer, magnetic agitation and reflux condensing tube of nitrogen, an exsiccant adds compound (4) (11.56g; Fw:462.38; 25mmol), add sodium-acetate (8.20g subsequently; Fw:82.03; 100mmol), with in the methyl alcohol 50mL adding system.
Subsequently with Tetrabutyl amonium bromide (0.81g; Fw:322.38; 2.5mmol).Be warmed up to 50 ℃ and stir 48h.After finishing, question response is cooled to room temperature.After reaction finishes, system temperature is added chloroform 50mL after being cooled to room temperature in system, filter, and filter cake washs molten thing with the no product of conclusive evidence, merging organic phase with minimum of chloroform again, with 10% aqueous sodium carbonate washing 3 times, saturated sodium-chloride washs once organic phase again.Organic phase with anhydrous sodium sulfate drying, remove inorganic salt and get weak yellow liquid, be concentrated into dried, ethyl acetate refining product 9.93g, yield 90%, HPLC content〉99%.
Embodiment 6
The preparation of deflazacort:
In being full of the 100mL there-necked flask that is equipped with thermometer, magnetic agitation and reflux condensing tube of nitrogen, an exsiccant adds compound (4) (11.56g; Fw:462.38; 25mmol), add Glacial acetic acid potassium (3.68g subsequently; Fw:98.14; 37.5mmol), in acetone 50mL adding system.Subsequently with tetrabutylammonium iodide (0.10g; Fw:369.37; 0.25mmol).Being warmed up to refluxes stirs 2h.After finishing, question response is cooled to room temperature.After reaction finishes, system temperature is added chloroform 50mL after being cooled to room temperature in system, filter, and filter cake washs molten thing with the no product of conclusive evidence, merging organic phase with minimum of chloroform again, with 10% aqueous sodium carbonate washing 3 times, saturated sodium-chloride washs once organic phase again.Organic phase with anhydrous sodium sulfate drying, remove inorganic salt and get weak yellow liquid, be concentrated into dried, ethyl acetate refining product 10.93g, yield 99%, HPLC content〉99%.
Embodiment 7
The preparation of deflazacort:
In being full of the 100mL there-necked flask that is equipped with thermometer, magnetic agitation and reflux condensing tube of nitrogen, an exsiccant adds compound (4) (11.56g; Fw:462.38; 25mmol), add Glacial acetic acid potassium (3.68g subsequently; Fw:98.14; 37.5mmol), in acetonitrile 50mL adding system.Subsequently with tetrabutylammonium iodide (0.10g; Fw:369.37; 0.25mmol).Being warmed up to refluxes stirs 2h.After finishing, question response is cooled to room temperature.After reaction finishes, system temperature is added chloroform 50mL after being cooled to room temperature in system, filter, and filter cake washs molten thing with the no product of conclusive evidence, merging organic phase with minimum of chloroform again, with 10% aqueous sodium carbonate washing 3 times, saturated sodium-chloride washs once organic phase again.Organic phase with anhydrous sodium sulfate drying, remove inorganic salt and get weak yellow liquid, be concentrated into dried, ethyl acetate refining product 10.93g, yield 99%, HPLC content〉99%.
Embodiment 8
The preparation of deflazacort:
In being full of the 100mL there-necked flask that is equipped with thermometer, magnetic agitation and reflux condensing tube of nitrogen, an exsiccant adds compound (4) (11.56g; Fw:462.38; 25mmol), add Glacial acetic acid potassium (2.45g subsequently; Fw:98.14; 25mmol), with N, in the dinethylformamide 50mL adding system.Subsequently with tetrabutylammonium iodide (0.10g; Fw:369.37; 0.25mmol).Be warmed up to 120 ℃ and stir 2h.After finishing, question response is cooled to room temperature.After reaction finishes, system temperature is added chloroform 50mL after being cooled to room temperature in system, filter, and filter cake washs molten thing with the no product of conclusive evidence, merging organic phase with minimum of chloroform again, with 10% aqueous sodium carbonate washing 3 times, saturated sodium-chloride washs once organic phase again.Organic phase with anhydrous sodium sulfate drying, remove inorganic salt and get weak yellow liquid, be concentrated into dried, ethyl acetate refining product 10.93g, yield 99%, HPLC content〉99%.
Claims (10)
1. the synthetic method of deflazacort is characterized in that, comprises the steps:
(1) general's compound as the formula (2) is under ammonium salt in catalysis, and with the brominated reagent reaction, liquid phase is collected in liquid-solid then separation, flings to solvent, gets the compound shown in the formula (4) in solvent, and reaction equation is as follows:
(2) with the compound shown in the formula (4) in solvent, the phase-transfer catalyst of acetate and catalytic amount exists down, target product is collected in reaction then from reaction product.
The general structure of described phase-transfer catalyst is R
4N
+X
-
Wherein R is C
1～C
8Straight chained alkyl, C
1～C
8Branched-chain alkyl or phenyl etc.;
X is fluorine, chlorine, bromine or iodine.
2. method according to claim 1 is characterized in that, the reaction times of step (1) is 0.5～24h, and temperature of reaction is 20～100 ℃.
3. method according to claim 1 is characterized in that, described ammonium salt is selected from ammonium acetate, ammonium formiate, propionic acid ammonium, ammonium chloride, brometo de amonio or Neutral ammonium fluoride.
4. method according to claim 1 is characterized in that described brominated reagent is selected from N-bromosuccinimide or 1,3-dibromo 5,5-dimethyl hydantion.
5. method according to claim 1, it is characterized in that, the solvent of step (1) is tetrahydrofuran (THF), ether, 2-methyl furan, isopropyl ether, 1,4-dioxane, glycol dimethyl ether, glycol ether dme, methylene dichloride, 1, more than one of 2-ethylene dichloride, Skellysolve A, normal hexane, acetonitrile, dimethyl sulfoxide (DMSO), toluene or dimethylbenzene.
6. method according to claim 1 is characterized in that, the mol ratio of compound shown in the formula (2) and brominated reagent is 1:1～2.5; The mol ratio of compound shown in the formula (2) and ammonium salt is 1:0.001～0.1; In the solvent, the content of the compound shown in the formula (2) is 0.1～1.0mol/L.
7. method according to claim 1 is characterized in that, in the step (2), the reaction times is 2～48 hours, and temperature of reaction is 50～120 ℃.
8. method according to claim 1 is characterized in that described acetate is selected from Potassium ethanoate, sodium-acetate or Lithium Acetate.
9. method according to claim 1 is characterized in that, in the step (2), described solvent is selected from methyl alcohol, ethanol, N, dinethylformamide, methyl-sulphoxide, acetone, acetonitrile, methylene dichloride or 1, more than one in the 2-ethylene dichloride.
10. method according to claim 1 is characterized in that, compound (4) is 1:1～4 with the mol ratio of acetate; Compound (4) is 1:0.01～0.1 with the mol ratio of phase-transfer catalyst; In the solvent, the content of the compound shown in the formula (4) is 0.1～1.0mol/L.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008102027427A CN101418032A (en) | 2008-11-13 | 2008-11-13 | Method for synthesizing deflazacort |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008102027427A CN101418032A (en) | 2008-11-13 | 2008-11-13 | Method for synthesizing deflazacort |
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| CN101418032A true CN101418032A (en) | 2009-04-29 |
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| CNA2008102027427A Pending CN101418032A (en) | 2008-11-13 | 2008-11-13 | Method for synthesizing deflazacort |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102746358A (en) * | 2011-04-22 | 2012-10-24 | 天津金耀集团有限公司 | Novel technology for synthesis of pregnane 21-bit bromide |
| CN102936274A (en) * | 2012-11-12 | 2013-02-20 | 浙江仙居君业药业有限公司 | Preparation method for [17alpha, 16alpha-d] methyl oxazoline |
| JP2015509493A (en) * | 2012-02-23 | 2015-03-30 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | New method for producing ciclesonide |
| CN106397532A (en) * | 2016-08-30 | 2017-02-15 | 江西宇能制药有限公司 | Preparation method of deflazacort |
-
2008
- 2008-11-13 CN CNA2008102027427A patent/CN101418032A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102746358A (en) * | 2011-04-22 | 2012-10-24 | 天津金耀集团有限公司 | Novel technology for synthesis of pregnane 21-bit bromide |
| CN102746358B (en) * | 2011-04-22 | 2016-02-10 | 天津金耀集团有限公司 | A kind of technique of synthesizing pregnant steroid 21 bromides |
| JP2015509493A (en) * | 2012-02-23 | 2015-03-30 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | New method for producing ciclesonide |
| CN102936274A (en) * | 2012-11-12 | 2013-02-20 | 浙江仙居君业药业有限公司 | Preparation method for [17alpha, 16alpha-d] methyl oxazoline |
| CN102936274B (en) * | 2012-11-12 | 2015-04-01 | 江西君业生物制药有限公司 | Preparation method for [17alpha, 16alpha-d] methyl oxazoline |
| CN106397532A (en) * | 2016-08-30 | 2017-02-15 | 江西宇能制药有限公司 | Preparation method of deflazacort |
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Open date: 20090429 |