CN102887934A - Preparation method of drospirenone - Google Patents
Preparation method of drospirenone Download PDFInfo
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Abstract
The invention discloses a preparation method of drospirenone, which aims at solving the problems of high production cost, low yield, and poor product quality in the existing preparation method of the drospirenone. The preparation method comprises the steps of: taking 3beta, 5-dyhydroxy-15beta, 16beta-methylene-5beta-androstane-6 alkene-17-ketone as materials, firstly, reacting with diiodomethane and zinc-copper couple, introducing 6beta and 7beta cyclopropane structures, then orderly carrying out condensation reaction and esterification reaction in THF (tetrahydrofuran) solution of lithium metal and 3-methyl bromopropionate and DMF (dimethyl formamide) solution of sodium ethoxide, finally oxidizing by sodium hypochlorite, and dewatering the toluenesulfonic acid to obtain the drospirenone. According to the preparation method, the efficiency is high, the production cost is low, by-products are few, special demands on production equipment do not exist, the reaction condition is mild, the process is stable, the operation is convenient, the environment is prevented from being damaged, and the large-scale industrial production is facilitated. The product obtained by the method is stable in quality, high in yield and purity and free of purification.
Description
Technical field
The present invention relates to chemosynthesis technical field, especially relate to a kind of with 3 β, 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone is the preparation method of the drospirenone of raw material.
Background technology
The steroid contraceptive bian of new generation that drospirenone (Drospirenone, 6 β, 7 β, 15 β, 16 β-dimethylene-3-oxo-17 α-pregnant steroid-4-alkene-21,17-carboxylic lactone) is a kind of efficient, low toxicity, have no side effect.Compare by the progestogen that synthesizing mean obtains equally with other, drospirenone has the effect of anti mineralocorticoid and antiandrogen, but adrenocortical hormone and estrogen receptor there is not pharmacologically active, for the preparation of the pharmaceutical composition of the oral administration with contraceptive efficacy, market outlook are wide for a long time for drospirenone.
European patent EP 0076189 discloses a kind of method of synthetic drospirenone, the method will be introduced side chain with propiolic alcohol, need the high pressure catalytic hydrogenation, high to processing condition and equipment requirements, and the method used the oxygenant that contains heavy metal chromium in being oxidized to the step of volution, can produce more by product, and chromium toxicity is larger, environmental pollution is serious, so that the method is not suitable for suitability for industrialized production.
European patent EP 918791 discloses a kind of ruthenium salt that adopts as the drospirenone synthetic method of oxygenant, although the method has been avoided the oxygenant of containing metal chromium, but can only obtain the not high drospirenone of purity, also need to improve by chromatography at last the purity of drospirenone, in addition, the place to go of the transition metal ruthenium element in the production process and processing are also comparatively difficult, and the method is not suitable for suitability for industrialized production equally.
In addition; China Patent Publication No.: CN101503455A; open day on August 12nd, 2009; disclose a kind of method for preparing drospirenone, the method is with available 3-hydroxy-androstane-5-alkene-15 β on the market, and 16 β-methylene radical-17-ketone is starting raw material; through hydroxyl protection; addition-hydrolysis becomes volution in the time of oxidation, become at last the step such as triatomic ring to obtain drospirenone.The method employing is introduced first side chain and is become volution again; market is difficult to obtain and the propylene chlorohydrin addition of expensive hydroxyl protection-hydrolysis and used when introducing side chain; secondly oxidation and become volution under palladium catalyst catalysis; yield low (only having 34%); the method production cost is high, and is same and be not suitable for suitability for industrialized production.
Summary of the invention
The object of the invention is to solve that the existing production cost of existing drospirenone preparation method is high, product yield is low, the problem of poor product quality, a kind of preparation method of drospirenone is provided, this preparation method is efficient, production cost is low, by product is few, and without particular requirement, reaction conditions is gentle to production unit, process stabilizing, convenient operation and harmless environment are fit to large-scale industrial production, and the constant product quality that obtains by the method, yield and purity are high, need not purifying.
To achieve these goals, the present invention is by the following technical solutions:
A kind of preparation method of drospirenone, adopt 3 β, 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone is raw material, make formula II compound with methylene iodide and zinc copper couple reaction first, then formula II compound carries out condensation reaction and makes formula III compound in the THF solution of metallic lithium and 3-methyl bromide c, then formula III compound carries out lactonization reaction and makes formula IV compound in the DMF of sodium ethylate solution, last IV compound is used hypochlorite oxidation successively, make formula V compound after the tosic acid dehydration, be drospirenone, described preparation method's reaction stream formula is as follows:
Wherein, formula I compound is 3 β, 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone; Formula II compound is 3 β, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17-ketone; Formula III compound is 3 β, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxies-21-methyl-formiate; Formula IV compound is 3 β, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21,17-carboxylic acid lactone; Formula V compound is drospirenone.The present invention adopts commercially available, it is domestic that generally to hold facile compound be raw material, cost is low, and can obtain drospirenone by four-step reaction, preparation process is short, and method is efficient, in addition, the present invention has adopted environmental friendliness, clorox with low cost does not use costliness as oxygenant, and the larger heavy metal oxygenant of toxicity, not only reduced production cost, and avoided discharging and the processing of heavy metal, the harmless environment of reaction, simultaneously, the present invention's by product in reaction process is few, without particular requirement, reaction conditions is gentle, process stabilizing to production unit, convenient operation is fit to large-scale industrial production.
As preferably, described preparation method's concrete steps are as follows:
(1) preparation 3 β, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17-ketone
THF with 220 ~ 230ml, the cuprous chloride of 13 ~ 17g and the zinc powder of 58 ~ 62g add in the reaction flask, be heated to 65 ~ 75 ℃ and keep back flow reaction 3 ~ 4h, be cooled to 3 β that add again 14.5 ~ 15.5g after the room temperature, 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone, then in reactor, drip 63 ~ 65g methylene iodide, the control rate of addition makes temperature of reaction maintain room temperature, methylene iodide dropwises rear insulation reaction to the completely dissolve of TLC detection display substrate point, drip 60 ~ 65g, mass concentration is 33 ~ 36% acetum, collects the solid of separating out, and namely gets 3 β after the drying, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17-ketone.
(2) preparation 3 β, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxies-21-methyl-formiate
Under nitrogen protection; in reaction flask, add 142 ~ 162ml; concentration is the THF solution of the metallic lithium of 1.4 ~ 1.6mol/L; be cooled to 3 β that add 7.8 ~ 8.2g after 0 ~ 2 ℃; 5-dihydroxyl-6 β; 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17-ketone also stirs 30 ~ 40min; then drip 48 ~ 52ml; the THF solution that contains the 3-methyl bromide c of 3.5 ~ 3.7g, the control rate of addition makes temperature of reaction maintain 0 ~ 2 ℃, dropwises afterreaction liquid at stirring at room 8 ~ 12h; at last reaction solution is poured in the water of 250 ~ 350ml; filter after stirring 1 ~ 3h, filtrate is washed to pH is neutral rear dry, get 3 β; 5-dihydroxyl-6 β; 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxies-21-methyl-formiate.
(3) preparation 3 β, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21,17-carboxylic acid lactone
Add reaction flask after the sodium ethylate of 13.2 ~ 15.6g being dissolved among the DMF of 110 ~ 130ml, then add 3 β of 14.5 ~ 16g, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxies-21-methyl-formiate, insulation reaction then is down to room temperature to the completely dissolve of TLC detection display substrate point after being warming up to 75 ~ 80 ℃, adds the elutriation material and collects the solid of separating out, get β, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21, the 17-carboxylic acid lactone.
(4) preparation drospirenone
In reaction flask, add the THF of 190 ~ 210ml and the β of 9 ~ 11g, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21, the 17-carboxylic acid lactone, be stirred to and be cooled to 8 ~ 12 ℃ after being emulsus, then drip 118 ~ 122g, mass concentration is 4.8 ~ 5.1% chlorine bleach liquor, and the control rate of addition makes temperature of reaction maintain 13 ~ 15 ℃, the chlorine bleach liquor dropwises rear insulation reaction to the completely dissolve of TLC detection display substrate point, add immediately quencher cancellation reaction, extract with methylene dichloride behind stirring 30 ~ 40min, add 2 ~ 3g toluenesulphonic acids after the organic phase drying and under room temperature, stir 8 ~ 10h, the underpressure distillation desolventizing, get the drospirenone crude product, to drospirenone crude product recrystallizing methanol, get drospirenone.
As preferably, the consumption of methylene dichloride is 200 ~ 230ml in the step (4), and extraction times 2 ~ 3 times merges organic phase after the extraction.Extract 2 ~ 3 times to improve product yield, extraction times too much can reduce production efficiency.
As preferably, organic phase adopts anhydrous magnesium sulfate or anhydrous sodium sulfate drying in the step (4).
As preferably, in the step (4) during recrystallization the consumption of methyl alcohol be 2 ~ 4 times of drospirenone crude product quality.
As preferably, the quencher add-on becomes colorless and is as the criterion to add to the reaction solution color in the step (4).Add before the quencher, the reaction solution color is faint yellow, add quencher after, the reaction solution color is decorporated gradually until colourless, as long as the quencher add-on be controlled at the color that makes reaction solution decorporate become colourless.
As preferably, described quencher is V-Brite B.
Therefore, the present invention has following beneficial effect: (1) adopts that commercially available, domestic generally to hold facile compound be raw material, and cost is low;
(2) can obtain drospirenone by four-step reaction, preparation process is short, and method is efficient;
(3) the present invention has adopted environmental friendliness, clorox with low cost as oxygenant, does not use costliness, and the larger heavy metal oxygenant of toxicity, has not only reduced production cost, and has avoided discharging and the processing of heavy metal, the harmless environment of reaction;
(4) the present invention's by product in reaction process is few, and without particular requirement, reaction conditions is gentle to production unit, process stabilizing, and convenient operation is fit to large-scale industrial production;
(5) constant product quality, yield and purity are high, need not purifying.
Embodiment
Below by specific embodiment, technical scheme of the present invention is described in further detail.
In the present invention, if not refer in particular to, all per-cents are weight unit, all devices and raw material all can be buied from market or the industry is commonly used, wherein, and 3 β, 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone is available from Hangzhou good fortune generation hall Bioisystech Co., Ltd.
Method among the following embodiment if no special instructions, is this area ordinary method.
Embodiment 1
(1) preparation 3 β, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17-ketone
THF with 220ml, the cuprous chloride of 13g and the zinc powder of 58g add in the reaction flask, be heated to 65 ℃ and keep back flow reaction 4h, be cooled to 3 β that add again 14.5g after the room temperature, 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone, then drip the 63g methylene iodide in reactor, the control rate of addition makes temperature of reaction maintain room temperature, and methylene iodide dropwises rear insulation reaction to the completely dissolve of TLC detection display substrate point, drip 60g, mass concentration is 36% acetum, collects the solid of separating out, and gets 3 β of 13.1g after the drying, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17-ketone.TLC: sherwood oil: ethyl acetate=1:2.
(2) preparation 3 β, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxies-21-methyl-formiate
Under nitrogen protection; in reaction flask, add 142ml; concentration is the THF solution of the metallic lithium of 1.6mol/L; be cooled to 3 β that add 7.8g after 2 ℃; 5-dihydroxyl-6 β; 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17-ketone also stirs 30min; then drip 48ml; the THF solution that contains the 3-methyl bromide c of 3.5g, the control rate of addition makes temperature of reaction maintain 0 ~ 2 ℃, dropwises afterreaction liquid at stirring at room 8h; at last reaction solution is poured in the water of 250ml; filter after stirring 1h, filtrate is washed to pH is neutral rear dry, get 3 β of 7.2g; 5-dihydroxyl-6 β; 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxies-21-methyl-formiate.TLC shows essentially no impurity.TLC: methylene dichloride: methyl alcohol=4:1.
(3) preparation 3 β, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21,17-carboxylic acid lactone
Add reaction flask after the sodium ethylate of 13.2g being dissolved among the DMF of 110ml, then add 3 β of 14.5g, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxies-21-methyl-formiate, insulation reaction then is down to room temperature to the completely dissolve of TLC detection display substrate point after being warming up to 75 ℃, adds the elutriation material and collects the solid of separating out, get the β of 9.8g, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21, the 17-carboxylic acid lactone.TLC: sherwood oil: ethyl acetate=1:2.
(4) preparation drospirenone
In reaction flask, add the THF of 190ml and the β of 9g, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21, the 17-carboxylic acid lactone, be stirred to and be cooled to 8 ℃ after being emulsus, then drip 118g, mass concentration is 5.1% chlorine bleach liquor, and the control rate of addition makes temperature of reaction maintain 13 ~ 15 ℃, and the chlorine bleach liquor dropwises rear insulation reaction to the completely dissolve of TLC detection display substrate point, add immediately V-Brite B cancellation reaction, the V-Brite B add-on becomes colorless and is as the criterion to add to reaction solution, stirs that the methylene dichloride with 200ml extracts merging organic phase after the extraction 2 times behind the 30min, organic phase is through adding the 2g toluenesulphonic acids and stir 8h under room temperature behind the anhydrous magnesium sulfate drying, the underpressure distillation desolventizing gets the drospirenone crude product, is the recrystallizing methanol of 2 times of drospirenone crude product quality with quality, 4.2g, purity is greater than 99% drospirenone.TLC: sherwood oil: ethyl acetate=2:1.
Embodiment 2
Other steps of present embodiment are all identical with embodiment 1, and difference is 3 β of step (1), 5-dihydroxyl-6 β, and 7 β, 15 β, the preparation of 16 β-dimethylene-5 β-androstane-17-ketone:
THF with 225ml, the cuprous chloride of 15g and the zinc powder of 60g add in the reaction flask, be heated to 70 ℃ and keep back flow reaction 3h, be cooled to 3 β that add again 15g after the room temperature, 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone, then drip the 64g methylene iodide in reactor, the control rate of addition makes temperature of reaction maintain room temperature, and methylene iodide dropwises rear insulation reaction to the completely dissolve of TLC detection display substrate point, drip 64g, mass concentration is 34% acetum, collects the solid of separating out, and gets 3 β of 13.3g after the drying, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17-ketone.TLC: sherwood oil: ethyl acetate=1:2.
Embodiment 3
Other steps of present embodiment are all identical with embodiment 1, and difference is 3 β of step (1), 5-dihydroxyl-6 β, and 7 β, 15 β, the preparation of 16 β-dimethylene-5 β-androstane-17-ketone:
THF with 230ml, the cuprous chloride of 17g and the zinc powder of 62g add in the reaction flask, be heated to 75 ℃ and keep back flow reaction 3.5h, be cooled to 3 β that add again 15.5g after the room temperature, 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone, then drip the 65g methylene iodide in reactor, the control rate of addition makes temperature of reaction maintain room temperature, and methylene iodide dropwises rear insulation reaction to the completely dissolve of TLC detection display substrate point, drip 65g, mass concentration is 33% acetum, collects the solid of separating out, and gets 3 β of 13.4g after the drying, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17-ketone.TLC: sherwood oil: ethyl acetate=1:2.
Embodiment 4
Other steps of present embodiment are all identical with embodiment 1, and difference is 33 β of step (2), 5-dihydroxyl-6 β, and 7 β, 15 β, the preparation of 16 β-dimethylene-5 β-androstane-17 beta-hydroxies-21-methyl-formiate:
Under nitrogen protection; in reaction flask, add 150ml; concentration is the THF solution of the metallic lithium of 1.5mol/L; be cooled to 3 β that add 8g after 0 ℃; 5-dihydroxyl-6 β; 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17-ketone also stirs 35min; then drip 50ml; the THF solution that contains the 3-methyl bromide c of 3.6g, the control rate of addition maintains at 0 ~ 2 ℃ temperature of reaction, dropwises afterreaction liquid at stirring at room 10h; at last reaction solution is poured in the water of 300ml; filter after stirring 2h, filtrate is washed to pH is neutral rear dry, get 3 β of 7.5g; 5-dihydroxyl-6 β; 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxies-21-methyl-formiate.TLC shows essentially no impurity.TLC: methylene dichloride: methyl alcohol=4:1.
Embodiment 5
Other steps of present embodiment are all identical with embodiment 1, and difference is 33 β of step (2), 5-dihydroxyl-6 β, and 7 β, 15 β, the preparation of 16 β-dimethylene-5 β-androstane-17 beta-hydroxies-21-methyl-formiate:
Under nitrogen protection; in reaction flask, add 162ml; concentration is the THF solution of the metallic lithium of 1.4mol/L; be cooled to 3 β that add 8.2g after 1 ℃; 5-dihydroxyl-6 β; 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17-ketone also stirs 40min; then drip 52ml; the THF solution that contains the 3-methyl bromide c of 3.7g, the control rate of addition maintains at 0 ~ 2 ℃ temperature of reaction, dropwises afterreaction liquid at stirring at room 12h; at last reaction solution is poured in the water of 350ml; filter after stirring 3h, filtrate is washed to pH is neutral rear dry, get 3 β of 7.7g; 5-dihydroxyl-6 β; 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxies-21-methyl-formiate.TLC shows essentially no impurity.TLC: methylene dichloride: methyl alcohol=4:1.
Embodiment 6
Other steps of present embodiment are all identical with embodiment 1, and difference is 3 β of step (3), 5-dihydroxyl-6 β, and 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21,17-carboxylic acid lactone's preparation:
Add reaction flask after the sodium ethylate of 14.4g being dissolved among the DMF of 120ml, then add 3 β of 15g, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxies-21-methyl-formiate, insulation reaction then is down to room temperature to the completely dissolve of TLC detection display substrate point after being warming up to 78 ℃, adds the elutriation material and collects the solid of separating out, get the β of 10.5g, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21, the 17-carboxylic acid lactone.TLC: sherwood oil: ethyl acetate=1:2.
Embodiment 7
Other steps of present embodiment are all identical with embodiment 1, and difference is 3 β of step (3), 5-dihydroxyl-6 β, and 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21,17-carboxylic acid lactone's preparation:
Add reaction flask after the sodium ethylate of 15.6g being dissolved among the DMF of 130ml, then add 3 β of 16g, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxies-21-methyl-formiate, insulation reaction then is down to room temperature to the completely dissolve of TLC detection display substrate point after being warming up to 80 ℃, adds the elutriation material and collects the solid of separating out, get the β of 11.7g, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21, the 17-carboxylic acid lactone.TLC: sherwood oil: ethyl acetate=1:2.
Embodiment 8
Other steps of present embodiment are all identical with embodiment 1, and difference is the preparation of the drospirenone of step (4):
In reaction flask, add the THF of 200ml and the β of 10g, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21, the 17-carboxylic acid lactone, be stirred to and be cooled to 10 ℃ after being emulsus, then drip 120g, mass concentration is 5% chlorine bleach liquor, and the control rate of addition makes temperature of reaction maintain 13 ~ 15 ℃, and the chlorine bleach liquor dropwises rear insulation reaction to the completely dissolve of TLC detection display substrate point, add immediately V-Brite B cancellation reaction, the V-Brite B add-on becomes colorless and is as the criterion to add to the reaction solution color, stirs that the methylene dichloride with 210ml extracts merging organic phase after the extraction 2 times behind the 35min, organic phase is through adding the 2.5g toluenesulphonic acids and stir 9h under room temperature behind the anhydrous sodium sulfate drying, the underpressure distillation desolventizing gets the drospirenone crude product, is the recrystallizing methanol of 2 ~ 4 times of drospirenone crude product quality with quality, 4.5g, purity is greater than 99% drospirenone.TLC: sherwood oil: ethyl acetate=2:1.
Embodiment 9
Other steps of present embodiment are all identical with embodiment 1, and difference is the preparation of the drospirenone of step (4):
In reaction flask, add the THF of 210ml and the β of 11g, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21, the 17-carboxylic acid lactone, be stirred to and be cooled to 12 ℃ after being emulsus, then drip 125g, mass concentration is 4.8% chlorine bleach liquor, and the control rate of addition makes temperature of reaction maintain 13 ~ 15 ℃, and the chlorine bleach liquor dropwises rear insulation reaction to the completely dissolve of TLC detection display substrate point, add immediately V-Brite B cancellation reaction, the V-Brite B add-on becomes colorless and is as the criterion to add to the reaction solution color, stirs that the methylene dichloride with 230ml extracts merging organic phase after the extraction 3 times behind the 40min, organic phase is through adding the 3g toluenesulphonic acids and stir 10h under room temperature behind the anhydrous magnesium sulfate drying, the underpressure distillation desolventizing gets the drospirenone crude product, is the recrystallizing methanol of 2 ~ 4 times of drospirenone crude product quality with quality, 5.7g, purity is greater than 99% drospirenone.TLC: sherwood oil: ethyl acetate=2:1.
Although the contriver has done comparatively detailed elaboration to technical scheme of the present invention and has enumerated, be to be understood that, for the those skilled in the art in this area, modify and/or flexible or to adopt the replacement scheme that is equal to be obvious for above-described embodiment, the essence that all can not break away from spirit of the present invention, the term that occurs among the present invention is used for elaboration and the understanding to technical solution of the present invention, can not be construed as limiting the invention.
Claims (7)
1. the preparation method of a drospirenone, it is characterized in that, adopt 3 β, 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone is raw material, make formula II compound with methylene iodide and zinc copper couple reaction first, then formula II compound carries out condensation reaction and makes formula III compound in the THF solution of metallic lithium and 3-methyl bromide c, then formula III compound carries out lactonization reaction and makes formula IV compound in the DMF of sodium ethylate solution, last IV compound is used hypochlorite oxidation successively, make formula V compound after the tosic acid dehydration, be drospirenone, described preparation method's reaction stream formula is as follows:
Wherein, formula I compound is 3 β, 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone; Formula II compound is 3 β, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17-ketone; Formula III compound is 3 β, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxies-21-methyl-formiate; Formula IV compound is 3 β, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21,17-carboxylic acid lactone; Formula V compound is drospirenone.
2. the preparation method of a kind of drospirenone according to claim 1 is characterized in that, described preparation method's concrete steps are as follows:
(1) preparation 3 β, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17-ketone
THF with 220 ~ 230ml, the cuprous chloride of 13 ~ 17g and the zinc powder of 58 ~ 62g add in the reaction flask, be heated to 65 ~ 75 ℃ and keep back flow reaction 3 ~ 4h, be cooled to 3 β that add again 14.5 ~ 15.5g after the room temperature, 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone, then in reactor, drip 63 ~ 65g methylene iodide, the control rate of addition makes temperature of reaction maintain room temperature, methylene iodide dropwises rear insulation reaction to the completely dissolve of TLC detection display substrate point, drip 60 ~ 65g, mass concentration is 33 ~ 36% acetum, collects the solid of separating out, and namely gets 3 β after the drying, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17-ketone;
(2) preparation 3 β, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxies-21-methyl-formiate
Under nitrogen protection, in reaction flask, add 142 ~ 162ml, concentration is the THF solution of the metallic lithium of 1.4 ~ 1.6mol/L, be cooled to 3 β that add 7.8 ~ 8.2g after 0 ~ 2 ℃, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17-ketone also stirs 30 ~ 40min, then drip 48 ~ 52ml, the THF solution that contains the 3-methyl bromide c of 3.5 ~ 3.7g, the control rate of addition makes temperature of reaction maintain 0 ~ 2 ℃, dropwises afterreaction liquid at stirring at room 8 ~ 12h, at last reaction solution is poured in the water of 250 ~ 350ml, filter after stirring 1 ~ 3h, filtrate is washed to pH is neutral rear dry, get 3 β, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxies-21-methyl-formiate;
(3) preparation 3 β, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21,17-carboxylic acid lactone
Add reaction flask after the sodium ethylate of 13.2 ~ 15.6g being dissolved among the DMF of 110 ~ 130ml, then add 3 β of 14.5 ~ 16g, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxies-21-methyl-formiate, insulation reaction then is down to room temperature to the completely dissolve of TLC detection display substrate point after being warming up to 75 ~ 80 ℃, adds the elutriation material and collects the solid of separating out, get β, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21, the 17-carboxylic acid lactone;
(4) preparation drospirenone
In reaction flask, add the THF of 190 ~ 210ml and the β of 9 ~ 11g, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21, the 17-carboxylic acid lactone, be stirred to and be cooled to 8 ~ 12 ℃ after being emulsus, then drip 118 ~ 122g, mass concentration is 4.8 ~ 5.1% chlorine bleach liquor, and the control rate of addition makes temperature of reaction maintain 13 ~ 15 ℃, the chlorine bleach liquor dropwises rear insulation reaction to the completely dissolve of TLC detection display substrate point, add immediately quencher cancellation reaction, extract with methylene dichloride behind stirring 30 ~ 40min, add 2 ~ 3g toluenesulphonic acids after the organic phase drying and under room temperature, stir 8 ~ 10h, the underpressure distillation desolventizing, get the drospirenone crude product, to drospirenone crude product recrystallizing methanol, get drospirenone.
3. the preparation method of a kind of drospirenone according to claim 2 is characterized in that, the consumption of methylene dichloride is 200 ~ 230ml when extracting in the step (4), and extraction times 2 ~ 3 times merges organic phase after the extraction.
4. the preparation method of a kind of drospirenone according to claim 2 is characterized in that, organic phase adopts anhydrous magnesium sulfate or anhydrous sodium sulfate drying in the step (4).
5. according to claim 2 or the preparation method of 3 or 4 described a kind of drospirenones, it is characterized in that, in the step (4) during recrystallization the consumption of methyl alcohol be 2 ~ 4 times of drospirenone crude product quality.
6. the preparation method of a kind of drospirenone according to claim 2 is characterized in that, the quencher add-on becomes colorless and is as the criterion to add to the reaction solution color in the step (4).
7. according to claim 2 or the preparation method of 6 described a kind of drospirenones, it is characterized in that described quencher is V-Brite B.
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| CN104163846A (en) * | 2013-05-17 | 2014-11-26 | 上海创诺制药有限公司 | Method for preparing drospirenone |
| CN113387993A (en) * | 2021-07-06 | 2021-09-14 | 江西百思康瑞药业有限公司 | Synthesis method of drospirenone |
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