CN103408628B - 3 β, 5-dihydroxyl-6 β, 7 β; The preparation method of 15 β, 16 β-dimethylene-5 β-androstane-17-ketone - Google Patents
3 β, 5-dihydroxyl-6 β, 7 β; The preparation method of 15 β, 16 β-dimethylene-5 β-androstane-17-ketone Download PDFInfo
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Abstract
The invention discloses a kind of 3 β, 5-dihydroxyl-6 β, 7 β; 15 β, the preparation method of 16 β-dimethylene-5 β-androstane-17-ketone, it is by 3 β, 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone and methylating reagent, under the existence of organic solvent and diethylzinc catalyst, react 0.5 ~ 3h and obtain at the temperature of 50 ~ 70 DEG C.Wherein methylating reagent is methylene bromide, methylene iodide or chloroiodomethane; The mol ratio of diethylzinc catalyst and methylating reagent and 3 β, 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone is 1: 1 ~ 5: 1.Method of the present invention adopts zinc ethyl to substitute Zn-Cu reagent as catalyzer, not only simple to operate, and product yield and purity all higher, be suitable for suitability for industrialized production.
Description
Technical field
The present invention relates to a kind of preparation method of medicine intermediate, be specifically related to a kind of drospirenone intermediate 3 beta, 5-dihydroxy-6 β, 7 β; The preparation method of 15 β, 16 β-dimethylene-5 β-androstane-17-ketone.
Background technology
The chemical name of drospirenone (Drospirenone) is 6 β, 7 β; 15 β, 16 β-dimethylene-3-oxo-17 α-pregnant steroid-4-alkene-21,17-carboxylic lactone, it is a kind of efficient, low toxicity, the steroid contraceptive bian of new generation that has no side effect.
3 β, 5-dihydroxyl-6 β, 7 β; 15 β, 16 β-dimethylene-5 β-androstane-17-ketone is then the important intermediate preparing drospirenone.
Chinese patent literature CN102887934A discloses a kind of preparation method of drospirenone, and wherein namely the first step adopts 3 β, and 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone and methylene iodide are obtained by reacting 3 β, 5-dihydroxyl-6 β, 7 β, 15 β, 16 β-dimethylene-5 β-androstane-17-ketone, concrete grammar is: 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(namely to prepare Zn-Cu reagent), 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, it is 90.34% that molar product yield is up to 86.5%(weight yield).The deficiency of the method is: (1) Zn-Cu reagent needs in situ preparation and uses as early as possible, and its activity affects comparatively large by zinc powder quality and preparation condition, and Zn-Cu reagent dosage is comparatively large, requires high to the stirring system of conversion unit.(2), after reaction terminates, have a large amount of unreacted Zn-Cu reagent and remain, and have zinc salt solid to produce, like this difficulty is caused to post-processing operation, product yield and purity on the low side.
In addition, american documentation literature US4435327A and Chinese patent literature CN101343306A all discloses the method for a kind of synthesis 6,7-methylene sterides, also namely 3 β are prepared by 3 β, 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone, 5-dihydroxyl-6 β, 7 β; The method of 15 β, 16 β-dimethylene-5 β-androstane-17-ketone, and all adopt Zn-Cu reagent as catalyzer.The methylene iodide that wherein american documentation literature US4435327A employing price is higher is as methylating reagent, and large usage quantity, cause cost higher, and molar yield only has 60.00%(weight yield to be 62.69%).Chinese patent literature CN101343306A is then initiator with iodine, and with relatively cheap methylene bromide as methylating reagent, it is 76% that molar yield has brought up to 73%(weight yield), HPLC purity can reach 91%.Still there is the defect that Chinese patent literature CN102887934A adopts Zn-Cu reagent in these two sections of documents.
Summary of the invention
The object of the invention is to solve the problem, a kind of simple to operate, yield and higher drospirenone intermediate 3 beta, 5-dihydroxy-6 β of purity, 7 β are provided; The preparation method of 15 β, 16 β-dimethylene-5 β-androstane-17-ketone.
The technical scheme realizing the object of the invention is: a kind of 3 β, 5-dihydroxyl-6 β, 7 β; The preparation method of 15 β, 16 β-dimethylene-5 β-androstane-17-ketone, it is obtained by reacting under the existence of organic solvent and diethylzinc catalyst by 3 β, 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone and methylating reagent.
Reaction formula is as follows:
。
Described diethylzinc catalyst and 3 described β, the mol ratio of 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone is 1: 1 ~ 5: 1, preferably 3: 1.
Described methylating reagent is methylene bromide, methylene iodide or chloroiodomethane, preferred methylene bromide.
Described methylating reagent and 3 described β, the mol ratio of 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone is 1: 1 ~ 5: 1, preferably 3: 1.
Described organic solvent is tetrahydrofuran (THF).
Above-mentioned temperature of reaction is 50 ~ 70 DEG C, preferably 65 DEG C.
The above-mentioned reaction times is 0.5 ~ 3h, preferred 1.5h.
The positively effect that the present invention has: method of the present invention adopts zinc ethyl to substitute Zn-Cu reagent as catalyzer, not only simple to operate, and product yield and purity all higher, be suitable for suitability for industrialized production.
Embodiment
(embodiment 1)
Under protection of inert gas; by 3 β of 10.00g; 5-dihydroxyl-15 β; 16 β-methylene radical-5 β-androstane-6-alkene-17-ketone (0.032mol) is dissolved in the tetrahydrofuran (THF) of 200mL; add the zinc ethyl (0.096mol) of 11.86g, stir and be warming up to 50 DEG C, drip the methylene bromide (0.096mol) of 16.69g; control time for adding is 45min, is warming up to 65 DEG C of insulation reaction 1.5h after dripping off.
After reaction terminates, reaction system is cooled to room temperature (20 DEG C ± 5 DEG C, lower same), the semi-saturation ammonium chloride solution that 50mL has been cooled to 0 DEG C is added in reaction system, after abundant stirring reaction, leave standstill, layering, the isopropyl acetate of aqueous phase 250mL divides three extractions, merge organic layer, be washed till neutrality with saturated sodium-chloride water solution, then use anhydrous sodium sulfate drying, be evaporated to a large amount of solid to separate out, place fridge overnight.Filter, with the isopropyl acetate washing leaching cake of a small amount of freezing mistake, dry 3 β obtaining 9.62g, 5-dihydroxyl-6 β, 7 β; 15 β, 16 β-dimethylene-5 β-androstane-17-ketone, weight yield is 96.2%, and purity is 98.72%(HPLC).
(embodiment 2 ~ embodiment 9)
The preparation method of each embodiment is substantially the same manner as Example 1, and difference is in table 1.
Table 1
| Zinc ethyl | Methylating reagent | Temperature of reaction/time | Products weight/weight yield/purity | |
| Embodiment 1 | 11.86g（0.096mol） | 16.69g methylene bromide (0.096mol) | 65℃/1.5h | 9.62g/96.2%/98.72% |
| Embodiment 2 | 11.86g（0.096mol） | 25.71g methylene iodide (0.096mol) | 65℃/1.5h | 9.55g/95.5%/98.50% |
| Embodiment 3 | 11.86g（0.096mol） | 16.93g chloroiodomethane (0.096mol) | 65℃/1.5h | 9.50g/95.0%/98.61% |
| Embodiment 4 | 3.95g（0.032mol） | 5.56g methylene bromide (0.032mol) | 65℃/1.5h | 9.54g/95.4%/96.54% |
| Embodiment 5 | 19.76g（0.16mol） | 27.81g methylene bromide (0.16mol) | 65℃/1.5h | 9.58g/95.8%/98.02% |
| Embodiment 6 | 11.86g（0.096mol） | 16.69g methylene bromide (0.096mol) | 50℃/1.5h | 9.38g/93.8%/93.57% |
| Embodiment 7 | 11.86g（0.096mol） | 16.69g methylene bromide (0.096mol) | 70℃/1.5h | 9.51g/95.1%/98.54% |
| Embodiment 8 | 11.86g（0.096mol） | 16.69g methylene bromide (0.096mol) | 65℃/0.5h | 9.58g/95.8%/92.33% |
| Embodiment 9 | 11.86g（0.096mol） | 16.69g methylene bromide (0.096mol) | 65℃/3h | 9.47g/94.7%/98.34% |
As can be seen from Table 1:
When other condition is identical, adopt methylene bromide as methylating reagent time, product yield and purity the highest.
When other condition is identical, when the mol ratio of methylating reagent and catalyzer and 3 β, 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6-alkene-17-ketone is 3: 1, product yield and purity the highest.
When other condition is identical, when temperature of reaction is 65 DEG C, product yield and purity the highest.
When other condition is identical, when the reaction times is 1.5h, product yield and purity the highest.
Claims (9)
1. 3 β, 5-dihydroxyl-6 β, 7 β; The preparation method of 15 β, 16 β-dimethylene-5 β-androstane-17-ketone, it is obtained by reacting under the existence of organic solvent and diethylzinc catalyst by 3 β, 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone and methylating reagent;
Described diethylzinc catalyst and 3 described β, the mol ratio of 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone is 1: 1 ~ 5: 1.
2. 3 β, 5-dihydroxyl-6 β, 7 β according to claim 1; The preparation method of 15 β, 16 β-dimethylene-5 β-androstane-17-ketone, is characterized in that: described diethylzinc catalyst and 3 described β, and the mol ratio of 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone is 3: 1.
3. 3 β, 5-dihydroxyl-6 β, 7 β according to claim 1 and 2; The preparation method of 15 β, 16 β-dimethylene-5 β-androstane-17-ketone, is characterized in that: described methylating reagent is methylene bromide, methylene iodide or chloroiodomethane; Described methylating reagent and 3 described β, the mol ratio of 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone is 1: 1 ~ 5: 1.
4. 3 β, 5-dihydroxyl-6 β, 7 β according to claim 3; The preparation method of 15 β, 16 β-dimethylene-5 β-androstane-17-ketone, is characterized in that: described methylating reagent is methylene bromide.
5. 3 β, 5-dihydroxyl-6 β, 7 β according to claim 3; The preparation method of 15 β, 16 β-dimethylene-5 β-androstane-17-ketone, is characterized in that: described methylating reagent and 3 described β, and the mol ratio of 5-dihydroxyl-15 β, 16 β-methylene radical-5 β-androstane-6 alkene-17-ketone is 3: 1.
6. 3 β, 5-dihydroxyl-6 β, 7 β according to claim 1 and 2; The preparation method of 15 β, 16 β-dimethylene-5 β-androstane-17-ketone, is characterized in that: above-mentioned temperature of reaction is 50 ~ 70 DEG C.
7. 3 β, 5-dihydroxyl-6 β, 7 β according to claim 6; The preparation method of 15 β, 16 β-dimethylene-5 β-androstane-17-ketone, is characterized in that above-mentioned temperature of reaction is 65 DEG C.
8. 3 β, 5-dihydroxyl-6 β, 7 β according to claim 1 and 2; The preparation method of 15 β, 16 β-dimethylene-5 β-androstane-17-ketone, is characterized in that: the above-mentioned reaction times is 0.5 ~ 3h.
9. 3 β, 5-dihydroxyl-6 β, 7 β according to claim 8; The preparation method of 15 β, 16 β-dimethylene-5 β-androstane-17-ketone, is characterized in that: the above-mentioned reaction times is 1.5h.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4435327A (en) * | 1981-09-21 | 1984-03-06 | Schering, Aktiengesellschaft | 3β,7β,15α-Trihydroxy-5-androsten-17-one, its 3,15-dipivalate, and their preparation |
| CN101343306A (en) * | 2007-07-12 | 2009-01-14 | 上海迪赛诺医药发展有限公司 | Method for synthesis of 6,7-methylene sterides |
| CN101735300A (en) * | 2009-12-17 | 2010-06-16 | 西安科技大学 | Method for preparing 6beta,7beta-methylene-steride-3beta,5beta-diol |
| CN102887934A (en) * | 2012-09-20 | 2013-01-23 | 杭州福斯特药业有限公司 | Preparation method of drospirenone |
-
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- 2013-08-19 CN CN201310361076.2A patent/CN103408628B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4435327A (en) * | 1981-09-21 | 1984-03-06 | Schering, Aktiengesellschaft | 3β,7β,15α-Trihydroxy-5-androsten-17-one, its 3,15-dipivalate, and their preparation |
| CN101343306A (en) * | 2007-07-12 | 2009-01-14 | 上海迪赛诺医药发展有限公司 | Method for synthesis of 6,7-methylene sterides |
| CN101735300A (en) * | 2009-12-17 | 2010-06-16 | 西安科技大学 | Method for preparing 6beta,7beta-methylene-steride-3beta,5beta-diol |
| CN102887934A (en) * | 2012-09-20 | 2013-01-23 | 杭州福斯特药业有限公司 | Preparation method of drospirenone |
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