CN101845073A - Preparation method and application of 1alpha-dehydroepiandrosterone - Google Patents
Preparation method and application of 1alpha-dehydroepiandrosterone Download PDFInfo
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- CN101845073A CN101845073A CN201010206719A CN201010206719A CN101845073A CN 101845073 A CN101845073 A CN 101845073A CN 201010206719 A CN201010206719 A CN 201010206719A CN 201010206719 A CN201010206719 A CN 201010206719A CN 101845073 A CN101845073 A CN 101845073A
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Abstract
The invention relates to a preparation method of 1alpha-dehydroepiandrosterone, belonging to a preparation method of steroide compounds. The preparation method is characterized by comprising the following steps of: carrying out a dehydrogenated oxidizing reaction on glycol-condensed dehydroepiandrosterone as a raw material under the action of a metallic palladium catalyst, an allyl phosphodiester ligand and alkali to generate conjugated ketene; and carrying out epoxidation and liquid ammonia-metal reduction and deprotecting reaction to obtain the 1alpha-dehydroepiandrosterone. The invention has the advantages of simple process flow, short production cycle, high product yield, low production cost, low price and easy accessibility of the raw material and a reagent, simple operation, no need of column chromatography and other operations and suitability for large-scale preparation and production. In addition, the invention solves the problems of complicated process, long production cycle, low yield and high production cost existing in the method for fermenting microorganisms in the prior art.
Description
Technical field
The present invention is a kind of preparation method of 1 alpha-dehydroepiandrosterone.Belong to the steroide preparation method.
Background technology
1, the 25-dihydroxyvitamin D
3It is vitamins D
3The activity form of performance physiological action, in having control agent the function of alcium and phosphor metabolization, activated vitamin D
3And derivative still is good differentiating inducer and antiblastic, and immunomodulator etc. are commonly used to treat osteoporosis, renal insufficiency, hyperparathyroidism, chronic eczema class skin hyperplasia disease, cancer, diabetes, Immunological diseases etc. clinically.1 alpha-dehydroepiandrosterone is the composite reactive vitamins D
3The key intermediate of class medicine.
1 alpha-dehydroepiandrosterone of the prior art prepares by microbial fermentation processes, and complex process, the production cycle is long, yield is low, production cost is high.
Summary of the invention
The object of the present invention is to provide the preparation method of 1 alpha-dehydroepiandrosterone that a kind of technological process is simple, with short production cycle, product yield is high, production cost is low.
The preparation method of 1 alpha-dehydroepiandrosterone of the present invention; with the ethylene glycol dehydroepiandrosterone that contracts is raw material; under metal palladium catalyst, allyl group phosphodiester part and alkali effect; the reaction of generation dehydrogenation oxidation; generate the conjugation ketenes; make through epoxidation, liquefied ammonia-metallic reducing and deprotection reaction again, comprise the steps and chemical reaction:
A. dehydrogenation oxidation
With the ethylene glycol dehydroepiandrosterone that contracts is the starting raw material I, and the allyl group phosphodiester adopts metal palladium catalyst as the oxygenant part, in the alkali organic solvent medium, under 25 ℃～250 ℃ temperature, the dehydrogenation oxidation reaction takes place, and makes the intermediate compound II;
B. epoxidation
The intermediate compound II under-40 ℃～100 ℃ temperature, is carried out epoxidation reaction with epoxidation reagent in the alkali organic solvent medium, make the intermediate compound III;
C. liquefied ammonia-metallic reducing
The intermediate compound III in the presence of fire-fighting medium, in organic solvent medium, under-80 ℃～150 ℃ temperature, is carried out reduction reaction with liquefied ammonia-metal, makes the intermediate compound IV;
D. deprotection
The intermediate compound IV in alcoholic solvent and water blending agent are arranged, under-40 ℃～150 ℃ temperature, with the deprotecting regent reaction, makes product 1 alpha-dehydroepiandrosterone V;
Among the present invention:
Used oxidising agent is any one in allyl group diethyl phosphoric acid, allyl group dimethyl phosphate or the allyl group di(2-ethylhexyl)phosphate propyl ester among the step a, palladium catalyst is that palladium, four (triphenyl phosphorus) is closed any one in palladium, three (dibenzalacetone) two palladiums or the Palladous chloride, alkali is any one in yellow soda ash, salt of wormwood, cesium carbonate, triethylamine or the pyridine, and reaction solvent is any one in tetrahydrofuran (THF), dioxane, dimethyl formamide or the N,N-DIMETHYLACETAMIDE.
Used epoxidation reagent is any one in hydrogen peroxide, benzoyl hydroperoxide, metachloroperbenzoic acid or the peroxy tert-butyl alcohol among the step b, alkali is sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, calcium hydroxide or 1,8-diazacyclo [5,4,0] any one in the hendecene-7 (DBU), reaction solvent is any one in methyl alcohol, ethanol, Virahol, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, ether or the t-butyl methyl ether.
Used liquefied ammonia-metallic reducing reagent is Li/NH among the step c
3Or Na/NH
3, reaction solvent is any one in tetrahydrofuran (THF), dioxane, ether or the t-butyl methyl ether, used quencher is any one in ammonium chloride, Neutral ammonium fluoride, volatile salt or the bicarbonate of ammonia.
In the steps d used protection reagent be tosic acid, camphorsulfonic acid, boron trifluoride diethyl etherate, hydrochloric acid, acetic acid, nitric acid, sulfuric acid or mercury chloride any one; Reaction solvent be methyl alcohol, ethanol, propyl alcohol, Virahol or butanols any one.
The present invention's 1 alpha-dehydroepiandrosterone is applicable to as the composite reactive vitamins D
3The raw material of class medicine, synthetic Maxacalcitol maxacalcitol, calcitriol calcitriol, calcipotriol calcipotriol, Tacalcitol tacacitol, degree ostelin doxercalciferol medicine etc.
The preparation method of the present invention's 1 alpha-dehydroepiandrosterone has following beneficial effect:
Technological process is simple, with short production cycle, product yield is high, production cost is low, and it is raw materials used and reagent is all inexpensive is easy to get, simple to operate, do not need operations such as column chromatography, be fit to mass preparation and production, solved the problem that complex process, production cycle are long, yield is low, production cost is high that prior art exists by the microbial fermentation processes preparation.
Embodiment
Below in conjunction with embodiment the present invention is further described.
Embodiment 1
Prepare 1 alpha-dehydroepiandrosterone according to preparation method of the present invention
A. dehydrogenation oxidation, preparation intermediate compound II:
With the dissolving of 100ml dimethyl formamide, stirring at room 30min adds formula ethylene glycol contract dehydroepiandrosterone 14.5g, yellow soda ash 37.0g with allyl group diethyl phosphoric acid 56.5g and palladium 750mg, under 160 ℃ of temperature, and stirring and refluxing 8h.After adding 10% citric acid, extract with methylene dichloride.Concentrate the back recrystallizing methanol, must the intermediate compound II, promptly 17,17-ethylenedioxy-1,4,6-triolefin-androstane-3-ketone 12.1g, yield 85.0%.
Fusing point: 130～132 ℃, [α]
D:-39 (c=0.55, methyl alcohol).1H-NMR(600MHZ，CDCl
3)δ：7.07(1H，d，J＝10.2Hz)，6.22-6.26(2H，m)，6.05(1H，dd，J＝10.2，1.8Hz)，6.03(1H，s)，3.82-3.90(4H，m)，2.28(1H，t，J＝10.2Hz)，2.04(1H，m)，1.82-1.87(3H，m)，1.60-1.68(3H，m)，1.42-1.50(3H，m)，1.20(3H，s)，0.97(3H，s)。
B. epoxidation prepares 17,17-ethylenedioxy-1 α, 2 α-epoxy-androstane-4,6-diene-3-ketone, i.e. intermediate compound III;
The intermediate compound II 223.2g of step a preparation is dissolved in 640ml methyl alcohol, adds 5%NaOH methanol solution 22ml, drip 30%H
2O
280ml, cryosel bathe i.e.-10 ℃ of thermotonus 18h.After adding saturated sodium bisulfite solution, use ethyl acetate extraction, after concentrating, obtain intermediate compound III 14.6g with methyl alcohol-methylene dichloride recrystallization, yield 60.0%, fusing point: 179～183 ℃, [α]
D:+167 (c=0.5, dioxane).
1H-NMR(600MHZ，CDCl
3)δ：6.11(1H，dd，J＝9.6，2.4Hz)，6.06(1H，d，J＝10.02)，5.65(1H，s)，3.84-3.94(4H，m)，3.59(1H，d，J＝3.6Hz)，3.44(1H，dd，J＝3.6，1.5Hz)，2.25(1H，t，J＝10.2Hz)，2.02-2.08(1H，m)，1.94-1.98(1H，m)，1.83-1.87(2H，m)，1.60-1.72(4H，m)，1.49-1.53(1H，m)，1.41-1.48(1H，m)，1.18(3H，s)，0.96(3H，s)。
C. liquefied ammonia-metallic reducing prepares 17,17-ethylenedioxy-5-alkene-androstane-1 α, and 3 beta-diols, i.e. intermediate compound IV:
Under-80 ℃ of temperature, in 800ml liquefied ammonia, add metallic lithium 12.5g, make reaction soln.The tetrahydrofuran solution of the intermediate compound III of 7g step b preparation is added drop-wise in the above-mentioned reaction soln.Under-80 ℃～0 ℃ temperature, reacted 30～40 minutes.After adding anhydrous ammonium chloride 90g, in reaction mixture, slowly drip water.The reaction solution ethyl acetate extraction.Concentrate the back recrystallizing methanol, get intermediate compound IV 3.0g, yield 42.9%.Fusing point: 195～198 ℃, [α]
D:-89.8 (c=0.5, methyl alcohol).
1H-NMR(600MHZ，CDCl
3)δ：5.60(1H，s)，3.98-3.99(1H，m)，3.90-3.94(4H，m)，3.86-3.87(1H，m)，2.39(1H，d，J＝10.2Hz)，2.30(1H，t，J＝11.4Hz)，2.11(1H，d，J＝12.6Hz)，1.98-2.06(2H，m)，1.22-1.82(12H，m)，1.04(3H，s)，0.87(3H，s)。
D. deprotection, preparation product compound V, i.e. 1 α, 3 beta-dihydroxyies-5-alkene-androstane-17-ketone
The intermediate compound IV 3.0g that step c is made dissolves with the 18ml tetrahydrofuran (THF), stirs to add p-methyl benzenesulfonic acid 18mg down, and under 50 ℃ of temperature, reacting by heating 10h.Use ethyl acetate extraction after adding saturated sodium bicarbonate solution.Concentrate the back recrystallizing methanol, get compound V weight 52.44g, productive rate 92.8%.Fusing point: 261～266 ℃, [α]
D:+24 (c=0.5, methyl alcohol).
Embodiment 2
According to method and the step of embodiment 1, difference only is to replace the allyl group diethyl phosphoric acid to carry out same reaction, the yield 78.6% of a step with the allyl group dimethyl phosphate.
Embodiment 3
According to method and the step of embodiment 1, difference only is to replace yellow soda ash to carry out same reaction, the yield 71.6% of a step with salt of wormwood.
Embodiment 4
According to method and the step of embodiment 1, difference only is to replace yellow soda ash to carry out same reaction, the yield 61.1% of a step with cesium carbonate
Embodiment 5
According to method and the step of embodiment 1, difference only is to replace yellow soda ash to carry out same reaction, the yield 64.6% of a step with triethylamine.
Embodiment 6
According to method and the step of embodiment 1, difference only is to close palladium, allyl group diethyl phosphoric acid and yellow soda ash with four triphenyl phosphorus, reacts the yield 46.5% of a step in tetrahydrofuran (THF).
Embodiment 7
According to method and the step of embodiment 1, difference only is to close palladium, allyl group diethyl phosphoric acid and yellow soda ash with four triphenyl phosphorus, reacts the yield 54.8% of a step in dimethyl formamide.
Embodiment 8
According to method and the step of embodiment 1, difference only is to react the yield 57.6% of a step with Palladous chloride, allyl group diethyl phosphoric acid and yellow soda ash in dimethyl formamide.
Embodiment 9
According to method and the step of embodiment 1, difference only is to react the yield 63.2% of a step with three (dibenzalacetones), two palladiums, allyl group diethyl phosphoric acid and yellow soda ash in dimethyl formamide.
Claims (6)
1. the preparation method of an alpha-dehydroepiandrosterone; it is characterized in that with the ethylene glycol dehydroepiandrosterone that contracts be raw material; under metal palladium catalyst, allyl group phosphodiester part and alkali effect; the reaction of generation dehydrogenation oxidation; generate the conjugation ketenes; make through epoxidation, liquefied ammonia-metallic reducing and deprotection reaction again, comprise the steps and chemical reaction:
A. dehydrogenation oxidation
With the ethylene glycol dehydroepiandrosterone that contracts is the starting raw material I, and the allyl group phosphodiester adopts metal palladium catalyst as the oxygenant part, in the alkali organic solvent medium, under 25 ℃～250 ℃ temperature, the dehydrogenation oxidation reaction takes place, and makes the intermediate compound II;
B. epoxidation
The intermediate compound II under-40 ℃～100 ℃ temperature, is carried out epoxidation reaction with epoxidation reagent in the alkali organic solvent medium, make the intermediate compound III;
C. liquefied ammonia-metallic reducing
The intermediate compound III in the presence of fire-fighting medium, in organic solvent medium, under-80 ℃～150 ℃ temperature, is carried out reduction reaction with liquefied ammonia-metal, makes the intermediate compound IV;
D. deprotection
The intermediate compound IV in alcoholic solvent and water blending agent are arranged, under-40 ℃～150 ℃ temperature, with the deprotecting regent reaction, makes product 1 alpha-dehydroepiandrosterone V;
2. the preparation method of 1 alpha-dehydroepiandrosterone according to claim 1, it is characterized in that used oxidising agent is the allyl group diethyl phosphoric acid among the step a, in allyl group dimethyl phosphate or the allyl group di(2-ethylhexyl)phosphate propyl ester any one, palladium catalyst is a palladium, four (triphenyl phosphorus) close palladium, in three (dibenzalacetones), two palladiums or the Palladous chloride any one, alkali is yellow soda ash, salt of wormwood, cesium carbonate, in triethylamine or the pyridine any one, reaction solvent are tetrahydrofuran (THF), dioxane, in dimethyl formamide or the N,N-DIMETHYLACETAMIDE any one.
3. the preparation method of 1 alpha-dehydroepiandrosterone according to claim 1, it is characterized in that used epoxidation reagent among the step b is any one in hydrogen peroxide, benzoyl hydroperoxide, metachloroperbenzoic acid or the peroxy tert-butyl alcohol, alkali is sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, calcium hydroxide or 1,8-diazacyclo [5,4,0] any one in the hendecene-7 (DBU), reaction solvent is any one in methyl alcohol, ethanol, Virahol, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, ether or the t-butyl methyl ether.
4. the preparation method of 1 alpha-dehydroepiandrosterone according to claim 1 is characterized in that used liquefied ammonia-metallic reducing reagent is Li/NH among the step c
3Or Na/NH
3, reaction solvent is any one in tetrahydrofuran (THF), dioxane, ether or the t-butyl methyl ether, used quencher is any one in ammonium chloride, Neutral ammonium fluoride, volatile salt or the bicarbonate of ammonia.
5. the preparation method of 1 alpha-dehydroepiandrosterone according to claim 1, it is characterized in that in the steps d used protection reagent be tosic acid, camphorsulfonic acid, boron trifluoride diethyl etherate, hydrochloric acid, acetic acid, nitric acid, sulfuric acid or mercury chloride any one; Reaction solvent be methyl alcohol, ethanol, propyl alcohol, Virahol or butanols any one.
6.1 alpha-dehydroepiandrosterone is used for the composite reactive vitamins D
3The class medicine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102386441A (en) * | 2011-10-21 | 2012-03-21 | 厦门大学 | Double-functional lithium battery electrolyte additive and preparation method thereof |
| CN108752409A (en) * | 2018-07-10 | 2018-11-06 | 武汉工程大学 | The method for preparing epiandrosterone as raw material using androstenedione |
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| CN101250211A (en) * | 2008-04-02 | 2008-08-27 | 中国科学院上海有机化学研究所 | Pregna-16-ene-20S-acetate compound and method for synthesizing same |
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| ANDOR FURST ET AL.: ""Eine ergiebige Herstellung von 1α,3β-Dihydroxy-Δ5-steroiden durch Reduktion von 1α,2α-Epoxy-4,6-dien-3-onen mit Lithium in Ammoniak"", 《HELVETICA CHIMICA ACTA》, vol. 64, no. 6, 31 December 1981 (1981-12-31), pages 1870 - 1892 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102386441A (en) * | 2011-10-21 | 2012-03-21 | 厦门大学 | Double-functional lithium battery electrolyte additive and preparation method thereof |
| CN108752409A (en) * | 2018-07-10 | 2018-11-06 | 武汉工程大学 | The method for preparing epiandrosterone as raw material using androstenedione |
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Denomination of invention: Preparation method and application of 1alpha-dehydroepiandrosterone Effective date of registration: 20161027 Granted publication date: 20140827 Pledgee: Agricultural Bank of China, Limited by Share Ltd, Yiyuan county subbranch Pledgor: Reyoung Pharmaceutical Co., Ltd. Registration number: 2016990000912 |
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Address after: 256100 No. 6 Erlang Road, Yiyuan County, Zibo, Shandong Patentee after: Ruiyang Pharmaceutical Co., Ltd Address before: 256100 No. 6 Erlang Road, Yiyuan County, Zibo, Shandong Patentee before: REYOUNG PHARMACEUTICAL Co.,Ltd. |
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Date of cancellation: 20201228 Granted publication date: 20140827 Pledgee: Agricultural Bank of China Limited by Share Ltd. Yiyuan county subbranch Pledgor: REYOUNG PHARMACEUTICAL Co.,Ltd. Registration number: 2016990000912 |