CN102887934B - 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 the preparation method that one take 3 β, 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone as 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.Compared with the progestogen obtained by synthesizing mean equally with other, drospirenone has the effect of anti mineralocorticoid and antiandrogen, but pharmacologically active is not had to adrenocortical hormone and estrogen receptor, the long-term pharmaceutical composition of oral administration for the preparation of having contraceptive efficacy of drospirenone, wide market.
European patent EP 0076189 discloses a kind of method of synthesizing drospirenone, side chain introduced by the method propiolic alcohol, need high-pressure catalytic hydrogenation, to processing condition and equipment requirements high, and the method has used the oxygenant containing heavy metal chromium in the step being oxidized to volution, can produce more by product, and chromium toxicity is larger, environmental pollution is serious, makes the method be 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 this method avoid the oxygenant of containing metal chromium, but the drospirenone that purity is not high can only be obtained, finally also need the purity being improved drospirenone by chromatography, in addition, the place to go of the transition metal ruthenium element in production process and process are also comparatively difficult, and the method is not suitable for suitability for industrialized production equally.
In addition; China Patent Publication No.: CN101503455A; publication date on August 12nd, 2009; disclose a kind of method preparing drospirenone, the method is with 3-hydroxy-androstane-5-alkene-15 β available on market, and 16 β-methylene radical-17-ketone is starting raw material; through hydroxyl protection; addition-hydrolysis, becomes volution while oxidation, finally becomes the steps such as triatomic ring to obtain drospirenone.The method adopts first introducing side chain to become volution again; and used on market be difficult to obtain and the propylene chlorohydrin addition-hydrolysis of expensive hydroxyl protection when introducing side chain; secondly be oxidized under palladium catalyst catalysis and become volution; yield low (only having 34%); the method production cost is high, same and be not suitable for suitability for industrialized production.
Summary of the invention
The object of the invention is to solve that production cost existing for existing drospirenone preparation method is high, product yield is low, the problem of poor product quality, provides a kind of preparation method of drospirenone, this preparation method is efficient, production cost is low, by product is few, and to production unit without particular requirement, reaction conditions is gentle, process stabilizing, convenient operation and harmless environment, be applicable to large-scale industrial production, and by constant product quality that the method obtains, yield and purity high, without the need to 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, first react obtained formula II compound with methylene iodide and zinc copper couple, then formula II compound carries out condensation reaction and obtains formula III compound in the THF solution of metallic lithium and 3-methyl bromide c, then formula III compound carries out lactonization reaction and obtains formula IV compound in the DMF solution of sodium ethylate, last IV compound uses hypochlorite oxidation successively, obtained formula V compound after tosic acid dehydration, i.e. drospirenone, described preparation method's reaction stream formula is as follows:
Wherein, type 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-hydroxy-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 drospirenone be obtained by four-step reaction, preparation process is short, method is efficient, in addition, present invention employs environmental friendliness, clorox with low cost is as oxygenant, do not use costliness, and the heavy metal oxidation agent that toxicity is larger, not only reduce production cost, and avoid discharge and the process of heavy metal, the harmless environment of reaction, simultaneously, the present invention's by product in reaction process is few, to production unit without particular requirement, reaction conditions is gentle, process stabilizing, convenient operation, be applicable to large-scale industrial production.
As preferably, the concrete steps of described preparation method are as follows:
(1) 3 β are prepared, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17-ketone
By the THF of 220 ~ 230ml, the cuprous chloride of 13 ~ 17g and the zinc powder of 58 ~ 62g add in reaction flask, be heated to 65 ~ 75 DEG C and keep back flow reaction 3 ~ 4h, 3 β of 14.5 ~ 15.5g are added again after being cooled to room temperature, 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone, then in reactor, 63 ~ 65g methylene iodide is dripped, controlling 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 the acetum of 33 ~ 36%, collect the solid of separating out, namely 3 β are obtained after drying, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17-ketone.
(2) 3 β are prepared, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxy-21-methyl-formiate
Under nitrogen protection, 142 ~ 162ml is added in reaction flask, concentration is the THF solution of the metallic lithium of 1.4 ~ 1.6mol/L, 3 β of 7.8 ~ 8.2g are added after being cooled to 0 ~ 2 DEG C, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17-ketone also stirs 30 ~ 40min, then 48 ~ 52ml is dripped, containing the THF solution of the 3-methyl bromide c of 3.5 ~ 3.7g, controlling rate of addition makes temperature of reaction maintain 0 ~ 2 DEG C, dropwise rear reaction solution at stirring at room temperature 8 ~ 12h, finally reaction solution is poured in the water of 250 ~ 350ml, filter after stirring 1 ~ 3h, filtrate is washed to pH in neutral rear dry, obtain 3 β, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxy-21-methyl-formiate.
(3) 3 β are prepared, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21,17-carboxylic acid lactone
The sodium ethylate of 13.2 ~ 15.6g is dissolved in after in the DMF of 110 ~ 130ml and adds reaction flask, then 3 β of 14.5 ~ 16g are added, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxy-21-methyl-formiate, after being warming up to 75 ~ 80 DEG C, insulation reaction is to the completely dissolve of TLC detection display substrate point, is then down to room temperature, the solid of add water analysis of material collection precipitation, obtain 3 β, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21,17-carboxylic acid lactone.
(4) drospirenone is prepared
The THF of 190 ~ 210ml and 3 β of 9 ~ 11g is added in reaction flask, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21, 17-carboxylic acid lactone, be stirred in being cooled to 8 ~ 12 DEG C after emulsus, then 118 ~ 122g is dripped, mass concentration is the chlorine bleach liquor of 4.8 ~ 5.1%, controlling rate of addition makes temperature of reaction maintain 13 ~ 15 DEG C, chlorine bleach liquor dropwises rear insulation reaction to the completely dissolve of TLC detection display substrate point, add quencher cancellation reaction immediately, extract with methylene dichloride after stirring 30 ~ 40min, 2 ~ 3g toluenesulphonic acids is added and in stirred at ambient temperature 8 ~ 10h after organic phase drying, underpressure distillation is except desolventizing, obtain drospirenone crude product, to drospirenone crude product recrystallizing methanol, obtain drospirenone.
As preferably, in step (4), the consumption of methylene dichloride is 200 ~ 230ml, and extraction times 2 ~ 3 times, merges organic phase after extraction.Extract 2 ~ 3 times to improve product yield, extraction times too much can reduce production efficiency.
As preferably, in step (4), organic phase adopts anhydrous magnesium sulfate or anhydrous sodium sulfate drying.
As preferably, in step (4), during recrystallization, the consumption of methyl alcohol is 2 ~ 4 times of drospirenone crude product quality.
As preferably, in step (4), quencher add-on becomes colorless be as the criterion to add to reaction solution color.Before adding quencher, reaction solution color is faint yellow, and after adding quencher, reaction solution color is decorporated gradually until colourless, as long as quencher add-on controls to become colourless making the color of reaction solution decorporate.
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) present invention employs environmental friendliness, clorox with low cost as oxygenant, do not use costliness, and the heavy metal oxidation agent that toxicity is larger, not only reduce production cost, and avoid discharge and the process of heavy metal, the harmless environment of reaction;
(4) the present invention's by product in reaction process is few, and to production unit without particular requirement, reaction conditions is gentle, process stabilizing, convenient operation, is applicable to large-scale industrial production;
(5) constant product quality, yield and purity high, without the need to 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-cent is weight unit, all devices and raw material all can be buied from market or the industry is conventional, wherein, and 3 β, 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone is purchased from Hangzhou Fu Shitang Bioisystech Co., Ltd.
Method in following embodiment, if no special instructions, is this area ordinary method.
Embodiment 1
(1) 3 β are prepared, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17-ketone
By the THF of 220ml, the cuprous chloride of 13g and the zinc powder of 58g add in reaction flask, be heated to 65 DEG C and keep back flow reaction 4h, 3 β of 14.5g are added again after being cooled to room temperature, 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone, then in reactor, 63g methylene iodide is dripped, controlling 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 60g, mass concentration is the acetum of 36%, collect the solid of separating out, 3 β of 13.1g are obtained after 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) 3 β are prepared, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxy-21-methyl-formiate
Under nitrogen protection, 142ml is added in reaction flask, concentration is the THF solution of the metallic lithium of 1.6mol/L, 3 β of 7.8g are added after being cooled to 2 DEG C, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17-ketone also stirs 30min, then 48ml is dripped, containing the THF solution of the 3-methyl bromide c of 3.5g, controlling rate of addition makes temperature of reaction maintain 0 ~ 2 DEG C, dropwise rear reaction solution at stirring at room temperature 8h, finally reaction solution is poured in the water of 250ml, filter after stirring 1h, filtrate is washed to pH in neutral rear dry, obtain 3 β of 7.2g, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxy-21-methyl-formiate.TLC shows essentially no impurity.TLC: methylene dichloride: methyl alcohol=4:1.
(3) 3 β are prepared, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21,17-carboxylic acid lactone
The sodium ethylate of 13.2g is dissolved in after in the DMF of 110ml and adds reaction flask, then add 3 β of 14.5g, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxy-21-methyl-formiate, after being warming up to 75 DEG C, insulation reaction is to the completely dissolve of TLC detection display substrate point, is then down to room temperature, the solid of add water analysis of material collection precipitation, obtain 3 β of 9.8g, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21,17-carboxylic acid lactone.TLC: sherwood oil: ethyl acetate=1:2.
(4) drospirenone is prepared
3 β of THF and 9g of 190ml are added in reaction flask, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21, 17-carboxylic acid lactone, be stirred in being cooled to 8 DEG C after emulsus, then 118g is dripped, mass concentration is the chlorine bleach liquor of 5.1%, controlling rate of addition makes temperature of reaction maintain 13 ~ 15 DEG C, chlorine bleach liquor dropwises rear insulation reaction to the completely dissolve of TLC detection display substrate point, add V-Brite B cancellation reaction immediately, V-Brite B add-on becomes colorless be as the criterion to add to reaction solution, extraction is carried out 2 times with the methylene dichloride of 200ml after stirring 30min, organic phase is merged after extraction, organic phase adds 2g toluenesulphonic acids and in stirred at ambient temperature 8h after anhydrous magnesium sulfate drying, underpressure distillation is except desolventizing, obtain drospirenone crude product, by the recrystallizing methanol that quality is drospirenone crude product quality 2 times, obtain 4.2g, the drospirenone that purity is greater than 99%.TLC: sherwood oil: ethyl acetate=2:1.
Embodiment 2
Other steps of the present embodiment are all identical with embodiment 1, and difference is 3 β of step (1), 5-dihydroxyl-6 β, 7 β, the preparation of 15 β, 16 β-dimethylene-5 β-androstane-17-ketone:
By the THF of 225ml, the cuprous chloride of 15g and the zinc powder of 60g add in reaction flask, be heated to 70 DEG C and keep back flow reaction 3h, 3 β of 15g are added again after being cooled to room temperature, 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone, then in reactor, 64g methylene iodide is dripped, controlling 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 64g, mass concentration is the acetum of 34%, collect the solid of separating out, 3 β of 13.3g are obtained after 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 the present embodiment are all identical with embodiment 1, and difference is 3 β of step (1), 5-dihydroxyl-6 β, 7 β, the preparation of 15 β, 16 β-dimethylene-5 β-androstane-17-ketone:
By the THF of 230ml, the cuprous chloride of 17g and the zinc powder of 62g add in reaction flask, be heated to 75 DEG C and keep back flow reaction 3.5h, 3 β of 15.5g are added again after being cooled to room temperature, 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone, then in reactor, 65g methylene iodide is dripped, controlling 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 65g, mass concentration is the acetum of 33%, collect the solid of separating out, 3 β of 13.4g are obtained after 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 the present embodiment are all identical with embodiment 1, and difference is 33 β of step (2), 5-dihydroxyl-6 β, 7 β, the preparation of 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxy-21-methyl-formiate:
Under nitrogen protection, 150ml is added in reaction flask, concentration is the THF solution of the metallic lithium of 1.5mol/L, 3 β of 8g are added after being cooled to 0 DEG C, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17-ketone also stirs 35min, then 50ml is dripped, containing the THF solution of the 3-methyl bromide c of 3.6g, controlling rate of addition makes temperature of reaction maintain at 0 ~ 2 DEG C, dropwise rear reaction solution at stirring at room temperature 10h, finally reaction solution is poured in the water of 300ml, filter after stirring 2h, filtrate is washed to pH in neutral rear dry, obtain 3 β of 7.5g, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxy-21-methyl-formiate.TLC shows essentially no impurity.TLC: methylene dichloride: methyl alcohol=4:1.
Embodiment 5
Other steps of the present embodiment are all identical with embodiment 1, and difference is 33 β of step (2), 5-dihydroxyl-6 β, 7 β, the preparation of 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxy-21-methyl-formiate:
Under nitrogen protection, 162ml is added in reaction flask, concentration is the THF solution of the metallic lithium of 1.4mol/L, 3 β of 8.2g are added after being cooled to 1 DEG C, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17-ketone also stirs 40min, then 52ml is dripped, containing the THF solution of the 3-methyl bromide c of 3.7g, controlling rate of addition makes temperature of reaction maintain at 0 ~ 2 DEG C, dropwise rear reaction solution at stirring at room temperature 12h, finally reaction solution is poured in the water of 350ml, filter after stirring 3h, filtrate is washed to pH in neutral rear dry, obtain 3 β of 7.7g, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxy-21-methyl-formiate.TLC shows essentially no impurity.TLC: methylene dichloride: methyl alcohol=4:1.
Embodiment 6
Other steps of the present embodiment are all identical with embodiment 1, and difference is 3 β of step (3), 5-dihydroxyl-6 β, 7 β, the preparation of 15 β, 16 β-dimethylene-5 β-androstane-21,17-carboxylic acid lactone:
The sodium ethylate of 14.4g is dissolved in after in the DMF of 120ml and adds reaction flask, then add 3 β of 15g, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxy-21-methyl-formiate, after being warming up to 78 DEG C, insulation reaction is to the completely dissolve of TLC detection display substrate point, is then down to room temperature, the solid of add water analysis of material collection precipitation, obtain 3 β of 10.5g, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21,17-carboxylic acid lactone.TLC: sherwood oil: ethyl acetate=1:2.
Embodiment 7
Other steps of the present embodiment are all identical with embodiment 1, and difference is 3 β of step (3), 5-dihydroxyl-6 β, 7 β, the preparation of 15 β, 16 β-dimethylene-5 β-androstane-21,17-carboxylic acid lactone:
The sodium ethylate of 15.6g is dissolved in after in the DMF of 130ml and adds reaction flask, then add 3 β of 16g, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxy-21-methyl-formiate, after being warming up to 80 DEG C, insulation reaction is to the completely dissolve of TLC detection display substrate point, is then down to room temperature, the solid of add water analysis of material collection precipitation, obtain 3 β of 11.7g, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21,17-carboxylic acid lactone.TLC: sherwood oil: ethyl acetate=1:2.
Embodiment 8
Other steps of the present embodiment are all identical with embodiment 1, and difference is the preparation of the drospirenone of step (4):
3 β of THF and 10g of 200ml are added in reaction flask, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21, 17-carboxylic acid lactone, be stirred in being cooled to 10 DEG C after emulsus, then 120g is dripped, mass concentration is the chlorine bleach liquor of 5%, controlling rate of addition makes temperature of reaction maintain 13 ~ 15 DEG C, chlorine bleach liquor dropwises rear insulation reaction to the completely dissolve of TLC detection display substrate point, add V-Brite B cancellation reaction immediately, V-Brite B add-on becomes colorless be as the criterion to add to reaction solution color, extraction is carried out 2 times with the methylene dichloride of 210ml after stirring 35min, organic phase is merged after extraction, organic phase adds 2.5g toluenesulphonic acids and in stirred at ambient temperature 9h after anhydrous sodium sulfate drying, underpressure distillation is except desolventizing, obtain drospirenone crude product, by the recrystallizing methanol that quality is drospirenone crude product quality 2 ~ 4 times, obtain 4.5g, the drospirenone that purity is greater than 99%.TLC: sherwood oil: ethyl acetate=2:1.
Embodiment 9
Other steps of the present embodiment are all identical with embodiment 1, and difference is the preparation of the drospirenone of step (4):
3 β of THF and 11g of 210ml are added in reaction flask, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21, 17-carboxylic acid lactone, be stirred in being cooled to 12 DEG C after emulsus, then 125g is dripped, mass concentration is the chlorine bleach liquor of 4.8%, controlling rate of addition makes temperature of reaction maintain 13 ~ 15 DEG C, chlorine bleach liquor dropwises rear insulation reaction to the completely dissolve of TLC detection display substrate point, add V-Brite B cancellation reaction immediately, V-Brite B add-on becomes colorless be as the criterion to add to reaction solution color, extraction is carried out 3 times with the methylene dichloride of 230ml after stirring 40min, organic phase is merged after extraction, organic phase adds 3g toluenesulphonic acids and in stirred at ambient temperature 10h after anhydrous magnesium sulfate drying, underpressure distillation is except desolventizing, obtain drospirenone crude product, by the recrystallizing methanol that quality is drospirenone crude product quality 2 ~ 4 times, obtain 5.7g, the drospirenone that purity is greater than 99%.TLC: sherwood oil: ethyl acetate=2:1.
Although contriver has done comparatively detailed elaboration to technical scheme of the present invention and has enumerated, be to be understood that, for one, this area those skilled in the art, above-described embodiment to be modified and/or flexible or adopt equivalent replacement scheme to be obvious, all can not depart from the essence of spirit of the present invention, the term occurred in the present invention, for the elaboration of technical solution of the present invention and understanding, can not be construed as limiting the invention.
Claims (6)
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, first react obtained formula II compound with methylene iodide and zinc copper couple, then formula II compound carries out condensation reaction and obtains formula III compound in the THF solution of metallic lithium and 3-methyl bromide c, then formula III compound carries out lactonization reaction and obtains formula IV compound in the DMF solution of sodium ethylate, last IV compound uses hypochlorite oxidation successively, obtained formula V compound after tosic acid dehydration, i.e. drospirenone, described preparation method's reaction stream formula is as follows:
Concrete steps are as follows:
(1) 3 β are prepared, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17-ketone
By the THF of 220 ~ 230ml, the cuprous chloride of 13 ~ 17g and the zinc powder of 58 ~ 62g add in reaction flask, be heated to 65 ~ 75 DEG C and keep back flow reaction 3 ~ 4h, 3 β of 14.5 ~ 15.5g are added again after being cooled to room temperature, 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone, then in reactor, 63 ~ 65g methylene iodide is dripped, controlling 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 the acetum of 33 ~ 36%, collect the solid of separating out, namely 3 β are obtained after drying, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17-ketone,
(2) 3 β are prepared, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxy-21-methyl-formiate
Under nitrogen protection, 142 ~ 162ml is added in reaction flask, concentration is the THF solution of the metallic lithium of 1.4 ~ 1.6mol/L, 3 β of 7.8 ~ 8.2g are added after being cooled to 0 ~ 2 DEG C, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17-ketone also stirs 30 ~ 40min, then 48 ~ 52ml is dripped, containing the THF solution of the 3-methyl bromide c of 3.5 ~ 3.7g, controlling rate of addition makes temperature of reaction maintain 0 ~ 2 DEG C, dropwise rear reaction solution at stirring at room temperature 8 ~ 12h, finally reaction solution is poured in the water of 250 ~ 350ml, filter after stirring 1 ~ 3h, filtrate is washed to pH in neutral rear dry, obtain 3 β, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxy-21-methyl-formiate,
(3) 3 β are prepared, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21,17-carboxylic acid lactone
The sodium ethylate of 13.2 ~ 15.6g is dissolved in after in the DMF of 110 ~ 130ml and adds reaction flask, then 3 β of 14.5 ~ 16g are added, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17 beta-hydroxy-21-methyl-formiate, after being warming up to 75 ~ 80 DEG C, insulation reaction is to the completely dissolve of TLC detection display substrate point, is then down to room temperature, the solid of add water analysis of material collection precipitation, obtain 3 β, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21,17-carboxylic acid lactone;
(4) drospirenone is prepared
The THF of 190 ~ 210ml and 3 β of 9 ~ 11g is added in reaction flask, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-21, 17-carboxylic acid lactone, be stirred in being cooled to 8 ~ 12 DEG C after emulsus, then 118 ~ 122g is dripped, mass concentration is the chlorine bleach liquor of 4.8 ~ 5.1%, controlling rate of addition makes temperature of reaction maintain 13 ~ 15 DEG C, chlorine bleach liquor dropwises rear insulation reaction to the completely dissolve of TLC detection display substrate point, add quencher cancellation reaction immediately, extract with methylene dichloride after stirring 30 ~ 40min, 2 ~ 3g toluenesulphonic acids is added and in stirred at ambient temperature 8 ~ 10h after organic phase drying, underpressure distillation is except desolventizing, obtain drospirenone crude product, to drospirenone crude product recrystallizing methanol, obtain drospirenone.
2. the preparation method of a kind of drospirenone according to claim 1, is characterized in that, in step (4), during extraction, the consumption of methylene dichloride is 200 ~ 230ml, and extraction times 2 ~ 3 times, merges organic phase after extraction.
3. the preparation method of a kind of drospirenone according to claim 1, is characterized in that, in step (4), organic phase adopts anhydrous magnesium sulfate or anhydrous sodium sulfate drying.
4. the preparation method of a kind of drospirenone according to Claims 2 or 3, is characterized in that, in step (4), during recrystallization, the consumption of methyl alcohol is 2 ~ 4 times of drospirenone crude product quality.
5. the preparation method of a kind of drospirenone according to claim 1, is characterized in that, quencher add-on becomes colorless be as the criterion to add to reaction solution color in step (4).
6. the preparation method of a kind of drospirenone according to claim 1 or 5, it is characterized in that, described quencher is V-Brite B.
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| CN103408628B (en) * | 2013-08-19 | 2015-12-02 | 江苏佳尔科药业集团有限公司 | 3 β, 5-dihydroxyl-6 β, 7 β; The preparation method of 15 β, 16 β-dimethylene-5 β-androstane-17-ketone |
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