CN101845073B - Preparation method and application of 1alpha-dehydroepiandrosterone - Google Patents
Preparation method and application of 1alpha-dehydroepiandrosterone Download PDFInfo
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- CN101845073B CN101845073B CN201010206719.2A CN201010206719A CN101845073B CN 101845073 B CN101845073 B CN 101845073B CN 201010206719 A CN201010206719 A CN 201010206719A CN 101845073 B CN101845073 B CN 101845073B
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- dehydroepiandrosterone
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- OFNXJEMTSIJRAV-LLGJDXCXSA-N C[C@](CCC1[C@@]2(C)C3OC33)(C(CC4)C1C=CC2=CC3=O)C41OCCO1 Chemical compound C[C@](CCC1[C@@]2(C)C3OC33)(C(CC4)C1C=CC2=CC3=O)C41OCCO1 OFNXJEMTSIJRAV-LLGJDXCXSA-N 0.000 description 1
- NHEVYNJDQIWZAO-OQPPHWFISA-N C[C@](CCC1[C@@]2(C)C=C3)(C(CC4)C1C=CC2=CC3=O)C41OCCO1 Chemical compound C[C@](CCC1[C@@]2(C)C=C3)(C(CC4)C1C=CC2=CC3=O)C41OCCO1 NHEVYNJDQIWZAO-OQPPHWFISA-N 0.000 description 1
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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 steroide preparation method.
Background technology
1,25-dihydroxyvitamin D
3it is vitamins D
3the activity form of performance physiological action, in thering is control agent the function of alcium and phosphor metabolization, activated vitamin D
3and derivative or good differentiating inducer and antiblastic, immunomodulators 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 composite reactive vitamins D
3the key intermediate of class medicine.
1 alpha-dehydroepiandrosterone of the prior art is prepared 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; taking ethylene glycol contracting dehydroepiandrosterone as raw material; under metal palladium catalyst, allyl group phosphodiester part and alkali effect; the reaction of generation dehydrogenation oxidation; generate conjugation ketenes; make through epoxidation, liquefied ammonia-metallic reducing and deprotection reaction again, comprise the steps and chemical reaction:
A. dehydrogenation oxidation
Taking ethylene glycol contracting dehydroepiandrosterone as starting raw material I, allyl group phosphodiester, as oxygenant part, adopts metal palladium catalyst, in alkali organic solvent medium, at 25 DEG C～250 DEG C temperature, dehydrogenation oxidation reaction occurs, and makes intermediate compound II;
B. epoxidation
Intermediate compound II, in alkali organic solvent medium, at-40 DEG C～100 DEG C temperature, is carried out epoxidation reaction with epoxidation reagent, makes intermediate compound III;
C. liquefied ammonia-metallic reducing
Intermediate compound III, under fire-fighting medium exists, in organic solvent medium, at-80 DEG C～150 DEG C temperature, carries out reduction reaction with liquefied ammonia-metal, makes intermediate compound IV;
D. deprotection
Intermediate compound IV, having in alcoholic solvent and water blending agent, at-40 DEG C～150 DEG C temperature, reacts with deprotecting regent, makes product 1 alpha-dehydroepiandrosterone V;
In the present invention:
In step a, oxidising agent used is any one in allyl group diethyl phosphoric acid, allyl group dimethyl phosphate or allyl group di(2-ethylhexyl)phosphate propyl ester, palladium catalyst is that palladium, four (triphenyl phosphorus) is closed any one in palladium, three (dibenzalacetone) two palladiums or Palladous chloride, alkali is any one in sodium carbonate, salt of wormwood, cesium carbonate, triethylamine or pyridine, and reaction solvent is any one in tetrahydrofuran (THF), dioxane, dimethyl formamide or N,N-DIMETHYLACETAMIDE.
In step b, epoxidation reagent used is any one in hydrogen peroxide, benzoyl hydroperoxide, metachloroperbenzoic acid or peroxy tert-butyl alcohol, alkali is sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, calcium hydroxide or 1,8-diazacyclo [5,4,0] any one in hendecene-7 (DBU), reaction solvent is any one in methyl alcohol, ethanol, Virahol, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, ether or t-butyl methyl ether.
In step c, liquefied ammonia-metallic reducing reagent used is Li/NH
3or Na/NH
3, reaction solvent is any one in tetrahydrofuran (THF), dioxane, ether or t-butyl methyl ether, quencher used is any one in ammonium chloride, Neutral ammonium fluoride, volatile salt or bicarbonate of ammonia.
In steps d protection reagent used 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 composite reactive vitamins D
3the raw material of class medicine, synthetic Maxacalcitol maxacalcitol, calcitriol calcitriol, calcipotriol calcipotriol, Tacalcitol tacacitol, doxercalciferol 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 raw materials used and reagent is all cheap and easy to get, simple to operate, do not need the operations such as column chromatography, be applicable to extensive preparation and produce, having solved prior art and prepared the problem that complex process, production cycle are long, yield is low, production cost is high existing by microbial fermentation processes.
Embodiment
Below in conjunction with embodiment, the invention will be further described.
Embodiment 1
Prepare 1 alpha-dehydroepiandrosterone according to preparation method of the present invention
A. dehydrogenation oxidation, prepare intermediate compound II:
Allyl group diethyl phosphoric acid 56.5g and palladium 750mg are dissolved with 100ml dimethyl formamide, and stirring at room temperature 30min, adds formula ethylene glycol contracting dehydroepiandrosterone 14.5g, sodium carbonate 37.0g, at 160 DEG C of temperature, and stirring and refluxing 8h.Add after 10% citric acid, extract with methylene dichloride.After concentrated, by recrystallizing methanol, obtain intermediate compound II, 17,17-ethylenedioxy-Isosorbide-5-Nitrae, 6-triolefin-androstane-3-ketone 12.1g, yield 85.0%.
Fusing point: 130～132 DEG C, [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, preparation 17,17-ethylenedioxy-1 α, 2 α-epoxy-androstane-4,6-diene-3-ketone, i.e. intermediate compound III;
Intermediate compound II 223.2g prepared by step a is dissolved in 640ml methyl alcohol, adds 5%NaOH methanol solution 22ml, drips 30%H
2o
280ml, cryosel is bathed i.e.-10 DEG C of thermotonus 18h.Add after saturated sodium bisulfite solution, extract by ethyl acetate, concentrated after, obtain intermediate compound III 14.6g with methyl alcohol-methylene dichloride recrystallization, yield 60.0%, fusing point: 179～183 DEG C, [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, preparation 17,17-ethylenedioxy-5-alkene-androstane-1 α, 3 beta-diols, i.e. intermediate compound IV:
At-80 DEG C of temperature, in 800ml liquefied ammonia, add metallic lithium 12.5g, make reaction soln.The tetrahydrofuran solution of intermediate compound III prepared by 7g step b is added drop-wise in above-mentioned reaction soln.At-80 DEG C～0 DEG C temperature, react 30～40 minutes.Add after anhydrous ammonium chloride 90g, in reaction mixture, slowly drip water.Reaction solution extracts by ethyl acetate.After concentrated, by recrystallizing methanol, obtain intermediate compound IV 3.0g, yield 42.9%.Fusing point: 195～198 DEG C, [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, prepares product compound V, i.e. 1 α, 3 beta-dyhydroxyl-5-ens-androstane-17-ketone
The intermediate compound IV 3.0g that step c is made dissolves with 18ml tetrahydrofuran (THF), adds p-methyl benzenesulfonic acid 18mg under stirring, at 50 DEG C of temperature, and reacting by heating 10h.Add after saturated sodium bicarbonate solution and extract by ethyl acetate.After concentrated, by recrystallizing methanol, obtain compound V weight 52.44g, productive rate 92.8%.Fusing point: 261～266 DEG C, [α]
d:+24 (c=0.5, methyl alcohol).
Embodiment 2
According to the method for embodiment 1 and step, difference is only to replace allyl group diethyl phosphoric acid to carry out same reaction, the yield 78.6% of a step with allyl group dimethyl phosphate.
Embodiment 3
According to the method for embodiment 1 and step, difference is only to replace sodium carbonate to carry out same reaction, the yield 71.6% of a step with salt of wormwood.
Embodiment 4
According to the method for embodiment 1 and step, difference is only to replace sodium carbonate to carry out same reaction, the yield 61.1% of a step with cesium carbonate
Embodiment 5
According to the method for embodiment 1 and step, difference is only to replace sodium carbonate to carry out same reaction, the yield 64.6% of a step with triethylamine.
Embodiment 6
According to the method for embodiment 1 and step, difference is only to close palladium, allyl group diethyl phosphoric acid and sodium carbonate with four triphenyl phosphorus, reacts the yield 46.5% of a step in tetrahydrofuran (THF).
Embodiment 7
According to the method for embodiment 1 and step, difference is only to close palladium, allyl group diethyl phosphoric acid and sodium carbonate with four triphenyl phosphorus, reacts the yield 54.8% of a step in dimethyl formamide.
Embodiment 8
According to the method for embodiment 1 and step, difference is only, with Palladous chloride, allyl group diethyl phosphoric acid and sodium carbonate, to react the yield 57.6% of a step in dimethyl formamide.
Embodiment 9
According to the method for embodiment 1 and step, difference is only, with three (dibenzalacetone) two palladiums, allyl group diethyl phosphoric acid and sodium carbonate, to react the yield 63.2% of a step in dimethyl formamide.
Claims (5)
1. the preparation method of an alpha-dehydroepiandrosterone, it is characterized in that taking ethylene glycol contracting dehydroepiandrosterone as raw material, under metal palladium catalyst, allyl group phosphodiester part and alkali effect, the reaction of generation dehydrogenation oxidation, generate conjugation ketenes, then make through epoxidation, liquefied ammonia-metallic reducing and deprotection reaction; Described metal palladium catalyst is that palladium, four (triphenyl phosphorus) is closed any one in palladium, three (dibenzalacetone) two palladiums, Palladous chloride; Comprise the steps and chemical reaction:
A. dehydrogenation oxidation
Taking ethylene glycol contracting dehydroepiandrosterone as starting raw material 1, allyl group phosphodiester, as oxygenant part, adopts metal palladium catalyst, in alkali organic solvent medium, at 25 DEG C～250 DEG C temperature, dehydrogenation oxidation reaction occurs, and makes intermediate compound 2
B. epoxidation
Intermediate compound 2 prepared by step a, in alkali organic solvent medium, at-40 DEG C～100 DEG C temperature, carries out epoxidation reaction with epoxidation reagent, makes intermediate compound 3
C. liquefied ammonia-metallic reducing
Step b makes intermediate compound 3, under quencher exists, in organic solvent medium, at-80 DEG C～150 DEG C temperature, carries out reduction reaction with liquefied ammonia-metal, makes intermediate compound 4
D. deprotection
The intermediate compound 4 that step c makes, having in alcoholic solvent and water blending agent, at-40 DEG C～150 DEG C temperature, reacts with deprotecting regent, makes target product 1 alpha-dehydroepiandrosterone 5
2. according to the preparation method of 1 alpha-dehydroepiandrosterone of claim 1, it is characterized in that oxidising agent described in step a is any one choosing from allyl group diethyl phosphoric acid, allyl group dimethyl phosphate, allyl group di(2-ethylhexyl)phosphate propyl ester, described alkali is any one in sodium carbonate, salt of wormwood, cesium carbonate, triethylamine, pyridine, and described reaction solvent is any one in tetrahydrofuran (THF), dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE.
3. according to the preparation method of 1 alpha-dehydroepiandrosterone of claim 1, it is characterized in that epoxidation reagent described in step b is any one in hydrogen peroxide, benzoyl hydroperoxide, metachloroperbenzoic acid, peroxy tert-butyl alcohol, described alkali is sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, calcium hydroxide, 1,8-diazacyclo [5,4,0] hendecene-7(DBU) in any one, described reaction solvent is any one in methyl alcohol, ethanol, Virahol, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, ether, t-butyl methyl ether.
4. according to the preparation method of 1 alpha-dehydroepiandrosterone of claim 1, it is characterized in that the liquefied ammonia-metallic reducing reagent described in step c is Li/NH3 or Na/NH3, reaction solvent is any one in tetrahydrofuran (THF), dioxane, ether, t-butyl methyl ether, and quencher used is any one in ammonium chloride, Neutral ammonium fluoride, volatile salt, bicarbonate of ammonia.
5. according to the preparation method of 1 alpha-dehydroepiandrosterone of claim 1, it is characterized in that deprotecting regent described in steps d be tosic acid, camphorsulfonic acid, boron trifluoride diethyl etherate, hydrochloric acid, acetic acid, nitric acid, sulfuric acid, mercury chloride any one; Reaction solvent be methyl alcohol, ethanol, propyl alcohol, Virahol, butanols any one.
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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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