CN101560237A - 14beta-hydro6beta,7beta,15beta,16beta-dimethylene-3-oxo-17beta-pregn-4-ene-21,17-carbolactone and synthesis method thereof - Google Patents
14beta-hydro6beta,7beta,15beta,16beta-dimethylene-3-oxo-17beta-pregn-4-ene-21,17-carbolactone and synthesis method thereof Download PDFInfo
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Abstract
The invention relates to 14beta-hydro6beta,7beta,15beta,16beta-dimethylene-3-oxo-17beta-pregn-4-ene-21,17-carbolactone and a synthesis method thereof. The compound has a structural formula shown on the right. The method starts from cheap and readily available material dehydroepiandros-sterone and can obtain the target product through totally eight steps. In the method, all materials are from China and cheap and readily available and the yield is high. The method synthesizes a14beta-hydro-17beta isomer of drospirenone, which is slightly different from the drospirenone in structure. At present, no report on the 14beta-hydro-17beta isomer of the drospirenone and the synthesis method thereof is available in any document. Meanwhile, in consideration that steroids generally have physiological activity, the 14beta-hydro-17beta isomer of the drospirenone is expected to be a new medicament having the same effect as the drospirenone or other unique effects and has high development value.
Description
Technical field:
The present invention relates to a kind of 14 β-hydrogen-6 β, 7 β, 15 β, 16 β-dimethylene-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone and synthetic method thereof.
Background technology:
Steroid compound is a class living matter that plays peculiar effect in the animals and plants vital process, doctor R.F.Witzmann once was called it " key of life ", steroidal compounds can activate transcribing of karyomit(e), transmission information, regulation and control sex and control of heredity material, also can regulate and control the activity of central nervous system, in the human intelligence activity, play important effect.
Drospirenone (Drospirenone) and analogue thereof, the steroidal class contraceptive bian of new generation that is a kind of efficient, low toxicity, has no side effect, be by the of new generation oral contraceptive of Schering Corp the earliest in exploitation in 2000, surpassed 100 countries in the whole world and used, it is by suppressing ovulation, make the retrogradation of uterine cervix mucus, stop sperm to penetrate fertilization, change uterine endometrium shape, making zygote be difficult for approach such as implantation to reach the contraception purpose.Its exclusive novel progestogen be to derive and the drospirenone that comes from 17-α spironolactone, owing to have pharmacological characteristics near the natural progesterone of women be different from before the progestogen of synthetic, have anti mineralocorticoid and androgen antagonist effect simultaneously, water-sodium retention and weight increase be can effectively resist, acne and premenstrual tension syndrome improved.Gondola one studies show that the oral contraceptive that contains the progestogen drospirenone has desirable influence to bone metabolism.According to another in September, 2006 " U.S.'s hypertension magazine " report, after the climacteric of accepting the enalapril treatment among the hypertension women, drospirenone (drospirenone) and 17-times he-estradiol (E2) combined utilization has tangible hypotensive promoter action.In view of drospirenone in the wide application prospect in drug research field, countries in the world are furtherd investigate the synthetic method of this medicine.The large-scale investigation that relevant this medicine user's quality of life is improved shows, uses weight loss and constant person behind this medicine to account for 78%, and negative feeling has clear improvement with symptoms such as the breast tenderness relevant with water-sodium retention, four limbs distending pains simultaneously.The security that result of study has also proved this medicine life-time service is surveyed in Europe oral contraception woman medicine inspection, and later becoming pregnant had no adverse effects.The wide medical value of drospirenone has attracted the extensive interest in the world.
Summary of the invention:
One of purpose of the present invention is to provide a kind of new compound 14 β-hydrogen-6 β, 7 β, 15 β, 16 β-dimethylene-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone.
Two of purpose of the present invention is to provide this compound and synthetic method thereof.
For achieving the above object, the synthetic route that the inventive method has adopted is:
According to said synthesis route, the present invention adopts following technical scheme:
A kind of 14 β-hydrogen-6 β, 7 β, 15 β, 16 β-dimethylene-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone is characterized in that the structural formula of this compound is:
A kind of 14 above-mentioned β-hydrogen-6 β for preparing, 7 β, 15 β, 16 β-dimethylene-3-oxo-17 β-pregnant steroid-4-alkene-21, the method for 17-carboxylic lactone is characterized in that this method has following steps:
A. with dehydroepiandros-sterone and cupric bromide by 1: the mol ratio of (2.2～3.8) is dissolved in the anhydrous methanol, back flow reaction 20～30 hours; Filtered while hot, filtrate is washed with deionized water, dichloromethane extraction, organic layer with anhydrous magnesium sulfate drying after, filter, the solvent that spins off in the filtrate gets yellow dope, and this dope is 16-bromo-3 beta-hydroxies-androstane-5-alkene-17-ketone with ethyl alcohol recrystallization white needles solid again; The structural formula of this compound is:
Molecular formula: C
19H
27BrO
2
Molecular weight: 366.12
Chinese named: 16-bromo-3 beta-hydroxies-androstane-5-alkene-17-ketone
Outward appearance: white solid
Fusing point: 165.4～165.9 degree
Specific rotation :-22 degree (concentration=2.5, chloroform)
Infrared spectra (Potassium Bromide, centimetre
-1) v
Maximum: 1741,1634.
Proton nmr spectra (500 megahertzes, deuterochloroform, ppm) δ: 0.928 (s, 3H, 18-or 19-CH
3), 1.039 (s, 3H, 18-or 19-CH
3), 3.543 (m, 1H, 3-H), 4.542 (m, 1H, 16-H), 5.381 (m, 1H, 6-H).Carbon-13 nmr spectra (125 megahertzes, deuterochloroform, ppm) δ: 14.02,19.50,20.33,30.68,30.80,31.56,32.32,34.25,36.69,37.18,42.19,46.39,47.64,48.35,50.10,71.56,120.69,141.14,213.65.
B. under the inert atmosphere, with above-mentioned 16-bromo-3 beta-hydroxies-androstane-5-alkene-17-ketone, lithiumbromide and Quilonum Retard are by 1: (3.5～7.5): (4.2～6.5) are dissolved in N,N-DIMETHYLACETAMIDE, back flow reaction 5～10 hours, cooled reactant solution is used ethyl acetate extraction after using the acetum cancellation, organic layer is washed with 5% sodium hydrogen carbonate solution, wash with saturated nacl aqueous solution again, anhydrous magnesium sulfate drying, filter, the solvent that spins off in the filtrate gets the red-brown dope, get white crystal 14 β-hydrogen-3 beta-hydroxies-androstane-5 with re-crystallizing in ethyl acetate again, 16-diene-17-ketone; The structural formula of this compound is:
Molecular formula: C
19H
26O
2
Molecular weight: 286.19
Chinese named: 14 β-hydrogen-3 beta-hydroxies-androstane-5,16-diene-17-ketone
Outward appearance: white solid
Fusing point: 216.1～216.7 degree
Specific rotation :+307 degree (concentration=2.3, chloroform)
Infrared spectra (Potassium Bromide, centimetre
-1) v
Maximum: 1686,1583;
Proton nmr spectra (500 megahertzes, deuterochloroform, ppm) δ: 0.993 (s, 3H, 18-or 19-CH
3), 1.090 (s, 3H, 18-or 19-CH
3), 3.492 (m, 1H, 3-H), 5.410 (m, 1H, 6-H), 6.269 (dd, J
16H-15H=6 hertz, J
14F-15H=2.25 hertz, 1H, 15-H), 7.799 (dd, J
15H-16H=6 hertz, J
14H-16H=2 hertz, 1H, 16-H); Carbon-13 nmr spectra (125 megahertzes, deuterochloroform, ppm) δ: 17.71,19.11,22.84,29.75,30.27,31.18,33.52,36.43,38.54,41.94,42.38,47.63,53.69,71.64,120.87,134.59,141.36,165.43,216.49.
C. under the inert atmosphere, sodium hydrogen and Trimethylsulfoxonium Iodide are pressed 1: after mix (1～2.2), drip dimethyl sulfoxide (DMSO) under the room temperature, be stirred to that no bubble is emerged and reactant solution clarification back adds above-mentioned 14 β-hydrogen-3 beta-hydroxies-androstane-5,16-diene-17-ketone, Trimethylsulfoxonium Iodide and 14 β-hydrogen-3 beta-hydroxies-androstane-5 wherein, 16-diene-17-ketone mol ratio is 1: (0.5～2.5), stirred 15～25 hours; Use extracted with diethyl ether, the organic layer anhydrous magnesium sulfate drying filters, and spins off the solvent in the filtrate, and column chromatography for separation gets white solid 14 β-hydrogen-3 beta-hydroxy-15 β, 16 β-methylene radical-androstane-5-alkene-17-ketone; The structural formula of this compound is:
Molecular formula: C
20H
28O
2
Molecular weight: 300.21
Chinese named: 14 β-hydrogen-3 beta-hydroxy-15 β, 16 β-methylene radical-androstane-5-alkene-17-ketone
Outward appearance: white solid
Fusing point: 167.5～168.4 degree,
Specific rotation :+129 degree (concentration=2.5, methylene dichloride)
Infrared spectra (Potassium Bromide, centimetre
-1) v
Maximum: 3028,1705;
Proton nmr spectra (500 megahertzes, deuterochloroform, ppm) δ: 0.978 (s, 3H, 18-or 19-CH
3), 0.999 (s, 3H, 18-or 19-CH
3), 3.541 (m, 1H, 3-H), 5.439 (m, 1H, 6-H); Carbon-13 nmr spectra (125 megahertzes, deuterochloroform, ppm) δ: 16.55,17.91,19.57,19.95,23.58,29.19,29.25,29.70,31.22,33.92,36.58,37.88,41.35,41.96,49.69,51.25,71.53,121.23,140.95,220.47.
D. under the inert atmosphere, magnesium sheet, iodine grain are dissolved in the tetrahydrofuran (THF), reflux and slowly drip the tetrahydrofuran solution of 3-bromine propionic aldehyde dimethylacetal down, wherein the mol ratio of magnesium and 3-bromine propionic aldehyde dimethylacetal is: (1.0～2.5): 1, begin during to the color fade of iodine grain to stir, refluxed again after dropwising 2～4 hours; Be cooled to room temperature, add 14 above-mentioned β-hydrogen-3 beta-hydroxy-15 β again, the tetrahydrofuran solution reaction of 16 β-methylene radical-androstane-5-alkene-17-ketone 10～15 hours, wherein, 3-bromine propionic aldehyde dimethylacetal and 14 β-hydrogen-3 beta-hydroxy-15 β, the mol ratio of 16 β-methylene radical-androstane-5-alkene-17-ketone is: (2.5～6.5): 1; With sodium hydrogen carbonate solution cancellation reaction, dichloromethane extraction, organic layer Anhydrous potassium carbonate dried overnight, filter to get filtrate, use the methylene dichloride recrystallization, get white solid 14 β-hydrogen-15 β, 16 β-methylene radical-3 β, 17-dihydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene; The structural formula of this compound is:
Molecular formula: C
25H
40O
4
Molecular weight: 404.29
Chinese named: 14 β-hydrogen-15 β, 16 β-methylene radical-3 β, 17-dihydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene
Outward appearance: white solid
Infrared spectra (Potassium Bromide, centimetre
-1) v
Maximum: 3457,3070,3030,1632,1131,1054,1019 proton nmr spectras (500 megahertzes, deuterochloroform, ppm) δ: 0.677 (s, 3H, 18-or 19-CH
3), 0.900 (s, 3H, 18-or 19-CH
3), 3.204 (s, 3H, two OCH
3One of them), 3.209 (s, 3H, two OCH
3One of them), 3.274 (m, 1H, 3-H) 4.053 (s, 1H, 17-OH), 4.318 (t, J=5.5 hertz, 1H, CH
2CH
2 CH(OCH
3 )
2), 4.600 (d, J
3H-(3-OH)=4.5 hertz, 1H, 3-OH), 5.289 (m, 1H, 6-H) carbon-13 nmr spectra (125 megahertzes, deuterochloroform, ppm) δ: 16.09,18.95,19.29,20.10,20.96,25.79,26.73,28.64,29.21,29.33,29.96,31.40,35.83,36.66,42.24,43.80,52.17,52.43,52.56,54.99,69.98,82.68,104.90,120.79,140.66
E. with 14 above-mentioned β-hydrogen-15 β, 16 β-methylene radical-3 β, 17-dihydroxyl-17-(3 ', 3 '-dimethoxy) propyl group androstane-5-alkene and pimelinketone are by 1: the mol ratio of (1.1～2.5) is dissolved in the dry toluene, drips the toluene solution of aluminum isopropylate again, wherein, 14 β-hydrogen-15 β, 16 β-methylene radical-3 β, the mol ratio of 17-dihydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene and aluminum isopropylate is (1.5～4.5): 1; Dropwise the back concentrated reaction solution, again reaction soln cooling back is diluted with ether, add aqueous sulfuric acid again, the organic layer dried over mgso, filter to get filtrate, spin off the solvent in the filtrate, residuum is again through steam distillation, dichloromethane extraction, the organic layer dried over mgso filters to get filtrate, the solvent that spins off in the filtrate gets yellow dope, this dope gets white crystal 14 β-hydrogen-15 β with recrystallizing methanol, 16 β-methylene radical-3 oxos-17-hydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene, the mother liquor resistates can be through column chromatographic isolation and purification, also get white solid 14 β-hydrogen-15 β, 16 β-methylene radical-3 oxos-17-hydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene; The structural formula of this compound is:
Molecular formula: C
25H
38O
4
Molecular weight: 402.28
Chinese named: 14 β-hydrogen-15 β, 16 β-methylene radical-3 oxos-17-hydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene
Outward appearance: white solid
Fusing point: 143.7～144.6 degree
Infrared spectra (Potassium Bromide, centimetre
-1) v
Maximum: 3559,1659,1123,1036
Proton nmr spectra (500 megahertzes, deuterochloroform, ppm) δ: 0.705 (s, 3H, 18-or 19-CH
3), 1.114 (s, 3H, 18-or 19-CH
3), 3.207 (s, 3H, two OCH
3One of them), 3.212 (s, 3H, two OCH
3One of them), 4.073 (s, 1H, 17-OH), 4.318 (t, J=5.5 hertz, 1H, CH
2CH
2 CH(OCH
3 )
2), 4.322 (m, 1H, 4-H)
F. with 14 above-mentioned β-hydrogen-15 β, 16 β-methylene radical-3 oxos-17-hydroxyl-17-(3 ', the 3 '-dimethoxy) propyl group-androstane-5-alkene and the catalyzer vitriol oil are dissolved in the acetone back flow reaction 15～45 minutes; Be cooled to 0～15 degree, in 5～15 minutes, drip Jones reagent while stirring; After 25～55 minutes, reaction mixture adds the ethyl acetate dilution, organic layer is respectively with saturated acetic acid sodium solution and saturated nacl aqueous solution washing, the organic layer anhydrous magnesium sulfate drying, filter, spin off the solvent in the filtrate, thin-layer chromatography separate purify white solid compound 14 β-hydrogen-15 β, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone; The structural formula of this compound is:
Molecular formula: C
23H
30O
3
Molecular weight: 354.22
Chinese named: 14 β-hydrogen-15 β, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone
Outward appearance: white solid
Proton nmr spectra (500 megahertzes, deuterochloroform, ppm) δ: 0.881 (s, 3H, 18-or 19-CH
3), 1.173 (s, 3H, 18-or 19-CH
3), 5.765 (s, 1H, 4-H);
Carbon-13 nmr spectra (125 megahertzes, deuterochloroform, ppm) δ: 15.45,17.82,19.68,20.82,21.01,26.92,28.16,29.44,29.70,29.91,31.99,32.94,33.50,33.88,38.40,47.26,53.99,55.53,96.91,124.02,170.99,176.78,199.48.
G. with 14 above-mentioned β-hydrogen-15 β, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone and tetrachlorobenzoquinone are by 1: the mol ratio of (0.5～2.5) is dissolved in the trimethyl carbinol, reflux 2～6 hours; Dissolve with methylene dichloride after spinning off solvent, water, 5% sodium hydroxide solution, washing successively again, the organic layer dried over mgso, filter, spin off the solvent in the filtrate, re-crystallizing in ethyl acetate gets pale yellow crystals 14 β-hydrogen-15 β, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4,6-diene-21,17-carboxylic lactone; The structural formula of this compound is:
Molecular formula: C
23H
28O
3
Molecular weight: 352.20
Chinese named: 14 β-hydrogen-15 β, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4,6-diene-21,17-carboxylic lactone
Outward appearance: light yellow solid
Proton nmr spectra (500 megahertzes, deuterochloroform, ppm) δ: 0.881 (s, 3H, 18-or 19-CH
3), 1.173 (s, 3H, 18-or 19-CH
3), 5.765 (s, 1H, 4-H)
Carbon-13 nmr spectra (125 megahertzes, deuterochloroform, ppm) δ: 15.45,17.82,19.68,20.82,21.01,26.92,28.16,29.44,29.70,29.91,31.99,32.94,33.50,33.88,38.40,47.26,53.99,55.53,96.91,124.02,170.99,176.78,199.48.
H. under the inert atmosphere, sodium hydrogen and Trimethylsulfoxonium Iodide are pressed 1: after the mixed in molar ratio of (0.5～1.5), drip methyl-sulphoxide under the room temperature, be stirred to that no bubble is emerged and reactant solution clarification back adds above-mentioned 14 β-hydrogen-15 β, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4,6-diene-21,17-carboxylic lactone, Trimethylsulfoxonium Iodide and 14 β-hydrogen-15 β wherein, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4,6-diene-21, the mol ratio of 17-carboxylic lactone is (0.5～2.5), stirring at room 15～25 hours; Extracted with diethyl ether, the organic layer anhydrous magnesium sulfate drying filters, and spins off the solvent in the filtrate, gets white solid 14 β-hydrogen-6 β through column chromatography for separation again, 7 β, 15 β, 16 β-dimethylene-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone.The structural formula of this compound:
Molecular formula: C
24H
30O
3
Molecular weight: 366.22
Chinese named: 14 β-hydrogen-6 β, 7 β, 15 β, 16 β-dimethylene-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone
English name: 14 β-hydro-6 β, 7 β, 15 β, 16 β-Dimethylen-3-oxo-17 β-pregn-4-ene-21,17-carbolactone
Outward appearance: colourless crystal formation solid
Proton nmr spectra (500 megahertzes, deuterochloroform, ppm): 0.885 (s, 3H, 18-or 19-CH
3), 1.062 (s, 3H, 18-or 19-CH
3), 6.016 (s, 1H, 4-H)
Carbon-13 nmr spectra (125 megahertzes, deuterochloroform, ppm): 17.13,18.03,18.19,19.62,19.94,20.00,21.11,21.14,27.82,29.05,29.20,30.19,33.48,33.96,37.10,37.39,45.93,54.14,55.98,96.43,125.74,171.12,171.04,198.17.
The present invention is from dehydroepiandros-sterone cheap and easy to get, and reacting completely through eight steps to obtain target product, and whole raw materials is all from domestic, and the cheap and easy to get and method productive rate height of raw material is fit to scale operation.
The present invention has synthesized 14 β-hydrogen-17 beta isomer of drospirenone, and this isomer is structurally compared with drospirenone only small difference.14 β of drospirenone-hydrogen-17 beta isomer and synthetic method thereof are not seen so far bibliographical information, generally all has physiologically active in view of steroide simultaneously, believe that it may become and has equal or other the new drug of unique drug effect with drospirenone, has higher development and is worth.
Embodiment:
Embodiment one: concrete steps are as follows:
1. in 50 ml flasks, add dehydroepiandros-sterone 0.8 gram, 30 milliliters of bromination ketone 1.9 grams and anhydrous methanols, about 20～30 hours of reflux.Stopped reaction, filtered while hot.Remaining part adds deionized water and dichloromethane extraction 3 times again.Tell organic layer, anhydrous magnesium sulfate drying filters, and Rotary Evaporators pressure reducing and steaming solvent gets yellow dope, and this dope is used ethyl alcohol recrystallization white needles solid again, 16-bromo-3 beta-hydroxies-androstane-5-alkene-17-ketone, productive rate 62%.
2. under the protection of inert gas; with 0.31 gram 16-bromo-, the 3 beta-hydroxies-androstane-5-alkene-17-ketone for preparing previously; 0.44 gram lithiumbromide and 0.38 gram Quilonum Retard are dissolved in N,N-DIMETHYLACETAMIDE; refluxed 5～10 hours; cooled reactant solution is used ethyl acetate extraction after using the acetum cancellation; organic layer is washed with 5% sodium hydrogen carbonate solution; wash with saturated nacl aqueous solution again; anhydrous magnesium sulfate drying; filter, get filtrate, Rotary Evaporators pressure reducing and steaming solvent; get the red-brown dope; re-crystallizing in ethyl acetate gets orange crystal 14 β-hydrogen-3 beta-hydroxies-androstane-5,16-diene-17-ketone, productive rate 43%.
3. under the protection of inert gas; in 10 milliliters of three-necked bottles, add 0.1 gram sodium hydrogen and 0.37 gram Trimethylsulfoxonium Iodide; drip 6 milliliters of methyl-sulphoxides under the room temperature; be stirred to 14 β-hydrogen-3 beta-hydroxies-androstane-5 that no bubble is emerged and reactant solution clarification back adding prepares previously; 16-diene-17-ketone 0.45 gram stirred 15～25 hours.After the stopped reaction, use extracted with diethyl ether, the organic layer anhydrous magnesium sulfate drying of telling, filter, get filtrate, Rotary Evaporators pressure reducing and steaming ether, column chromatography gets white solid 14 β-hydrogen-3 beta-hydroxy-15 β, 16 β-methylene radical-androstane-5-alkene-17-ketone, productive rate 85%.
4. under the protection of inert gas; in 100 milliliters of there-necked flasks, add magnesium sheet 0.44 gram; 15 milliliters of several iodine grains and tetrahydrofuran (THF)s; slowly drip 30 milliliters of tetrahydrofuran solutions of 3-bromine propionic aldehyde dimethylacetal under the reflux; begin during the color fade of iodine to stir, refluxed again after dropwising three hours.Remove oil bath and be cooled to room temperature, add 0.9 gram 14 β-hydrogen-3 beta-hydroxy-15 β for preparing previously again, 7.5 milliliters of tetrahydrofuran solution reactions of 16 β-methylene radical-androstane-5-alkene-17-ketone 10～15 hours.With sodium hydrogen carbonate solution cancellation reaction, dichloromethane extraction, the salt of wormwood drying is spent the night, and filters to get filtrate, the methylene dichloride recrystallization gets white solid 14 β-hydrogen-15 β, 16 β-methylene radical-3 β, 17-dihydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene, productive rate 75%.
5. in 10 milliliters of there-necked flasks, add 0.14 gram 14 β-hydrogen-15 β, 16 β-methylene radical-3 β, 17-dihydroxyl-1 (3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene and 3.5 milliliters of dry toluenes stir and make its dissolving, and it adds 0.70 milliliter of pimelinketone again.Steam the 0.54 milliliter of toluene solution that drips 0.38 gram aluminum isopropylate behind a part of toluene.Steam some toluene after dropwising again, stopped reaction, dilute with ether reactant solution cooling back, add aqueous sulfuric acid again, the layering of vibrating in the separating funnel is told the upper strata organic layer, dried over mgso, filter to get filtrate, Rotary Evaporators pressure reducing and steaming ether revolves not dried residuum again through steam distillation, and dichloromethane extraction is told organic layer, dried over mgso, filter to get filtrate, Rotary Evaporators pressure reducing and steaming methylene dichloride gets yellow dope, and this dope gets white crystal 14 β-hydrogen-15 β with recrystallizing methanol, 16 β-methylene radical-3 oxos-17-hydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene, the mother liquor resistates gets white solid 14 β-hydrogen-15 β through column chromatography again, 16 β-methylene radical-3 oxos-17-hydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene, productive rate 60%.
6. in 100 milliliters of round-bottomed flasks, add the 0.15 gram vitriol oil and 60 milliliters of acetone, add 0.58 gram 14 β-hydrogen-15 β that compound prepares previously again, 16 β-methylene radical-3 oxos-17-hydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene, reflux 15～45 minutes.Be cooled to 0～15 degree, in 5～15 minutes, drip 2.25 milliliters of Jones reagents while stirring.After 25～55 minutes, reaction mixture adds the ethyl acetate dilution, tells organic layer, and it is inferior to give a baby a bath on the third day after its birth with saturated acetic acid sodium solution and saturated nacl aqueous solution respectively again, the organic layer anhydrous sodium sulfate drying, filter to get filtrate, Rotary Evaporators pressure reducing and steaming organic solvent, thin-layer chromatography separates purify (petrol ether/ethyl acetate=2: 1), get white solid compound 14 β-hydrogen-15 β, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone, productive rate 80%.
7. in 10 ml flasks, add 0.21 gram 14 β-hydrogen-15 β for preparing previously, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone and 0.18 gram tetrachlorobenzoquinone add 6 milliliters of trimethyl carbinols, reflux 2～6 hours again.Stop reaction, dissolve with methylene dichloride behind the Rotary Evaporators pressure reducing and steaming solvent, water, 5% sodium hydroxide solution, washing successively again, the organic layer dried over mgso is filtered, Rotary Evaporators pressure reducing and steaming methylene dichloride, re-crystallizing in ethyl acetate gets pale yellow crystals 14 β-hydrogen-15 β, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4,6-diene-21,17-carboxylic lactone, productive rate 38%.
8. under the protection of inert gas; in there-necked flask, add 0.06 gram sodium hydrogen and 0.28 gram Trimethylsulfoxonium Iodide; drip dimethyl sulfoxide (DMSO) under the room temperature; be stirred to that no bubble is emerged and reactant solution clarification back adds 14 β-hydrogen-15 β of above-mentioned preparation; 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4; 6-diene-21,17-carboxylic lactone 0.12 gram, stirring at room 15～25 hours.Stopped reaction, extracted with diethyl ether is told ether layer, and anhydrous magnesium sulfate drying filters, get filtrate, Rotary Evaporators pressure reducing and steaming ether gets white solid 14 β-hydrogen-6 β, 7 β through column chromatography again, 15 β, 16 β-dimethylene-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone, productive rate 40%.
Embodiment two: concrete steps are as follows:
1. in 500 ml flasks, add dehydroepiandros-sterone 8 grams, 300 milliliters of bromination ketone 19 grams and anhydrous methanols, about 20～30 hours of reflux.Stopped reaction, filtered while hot.Remaining part adds deionized water and dichloromethane extraction 3 times again.Tell organic layer, anhydrous magnesium sulfate drying filters, and Rotary Evaporators pressure reducing and steaming solvent gets yellow dope, and this dope is used ethyl alcohol recrystallization white needles solid again, 16-bromo-3 beta-hydroxies-androstane-5-alkene-17-ketone, productive rate 60%.
2. under the protection of inert gas; with 3.1 gram 16-bromo-, the 3 beta-hydroxies-androstane-5-alkene-17-ketone for preparing previously; 4.4 gram lithiumbromide and 3.8 gram Quilonum Retards are dissolved in N,N-DIMETHYLACETAMIDE; refluxed 5～10 hours; cooled reactant solution is used ethyl acetate extraction after using the acetum cancellation; organic layer is washed with 5% sodium hydrogen carbonate solution; wash with saturated nacl aqueous solution again; anhydrous magnesium sulfate drying; filter, get filtrate, Rotary Evaporators pressure reducing and steaming solvent; get the red-brown dope; re-crystallizing in ethyl acetate gets orange crystal 14 β-hydrogen-3 beta-hydroxies-androstane-5,16-diene-17-ketone, productive rate 40%.
3. under the protection of inert gas; in 250 milliliters of three-necked bottles, add 1 gram sodium hydrogen and 4.7 gram Trimethylsulfoxonium Iodides; drip 75 milliliters of methyl-sulphoxides under the room temperature; be stirred to 14 β-hydrogen-3 beta-hydroxies-androstane-5 that no bubble is emerged and reactant solution clarification back adding prepares previously; 16-diene-17-ketone 4.48 grams stirred 15～25 hours.After the stopped reaction, use extracted with diethyl ether, the organic layer anhydrous magnesium sulfate drying of telling, filter, get filtrate, Rotary Evaporators pressure reducing and steaming ether, column chromatography gets white solid 14 β-hydrogen-3 beta-hydroxy-15 β, 16 β-methylene radical-androstane-5-alkene-17-ketone, productive rate 85%.
4. under the protection of inert gas; in 500 milliliters of there-necked flasks, add magnesium sheet 2.2 grams; 75 milliliters of several iodine grains and tetrahydrofuran (THF)s; slowly drip 150 milliliters of tetrahydrofuran solutions of 3-bromine propionic aldehyde dimethylacetal under the reflux; begin during the color fade of iodine to stir, refluxed again after dropwising three hours.Remove oil bath and be cooled to room temperature, add 4.5 gram 14 β-hydrogen-3 beta-hydroxy-15 β that prepare previously again, 75 milliliters of tetrahydrofuran solution reactions of 16 β-methylene radical-androstane-5-alkene-17-ketone 10～15 hours.With sodium hydrogen carbonate solution cancellation reaction, dichloromethane extraction, the salt of wormwood drying is spent the night, and filters to get filtrate, the methylene dichloride recrystallization gets white solid 14 β-hydrogen-15 β, 16 β-methylene radical-3 β, 17-dihydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene, productive rate 75%.
5. in 100 milliliters of there-necked flasks, add 1.36 gram 14 β-hydrogen-15 β, 16 β-methylene radical-3 β, 17-dihydroxyl-1 (3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene and 35 milliliters of dry toluenes stir and make its dissolving, and it adds 7.0 milliliters of pimelinketone again.Steam 54 milliliters of toluene solutions that drip 3.8 gram aluminum isopropylates behind a part of toluene.Steam some toluene after dropwising again, stopped reaction, dilute with ether reactant solution cooling back, add aqueous sulfuric acid again, the layering of vibrating in the separating funnel is told the upper strata organic layer, dried over mgso, filter to get filtrate, Rotary Evaporators pressure reducing and steaming ether revolves not dried residuum again through steam distillation, and dichloromethane extraction is told organic layer, dried over mgso, filter to get filtrate, Rotary Evaporators pressure reducing and steaming methylene dichloride gets yellow dope, and this dope gets white crystal 14 β-hydrogen-15 β with recrystallizing methanol, 16 β-methylene radical-3 oxos-17-hydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene, the mother liquor resistates gets white solid 14 β-hydrogen-15 β through column chromatography again, 16 β-methylene radical-3 oxos-17-hydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene, productive rate 60%.
6. in 1000 milliliters of round-bottomed flasks, add the 1.5 gram vitriol oil and 600 milliliters of acetone, add 5.8 gram 14 β-hydrogen-15 β that compound prepares previously again, 16 β-methylene radical-3 oxos-17-hydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene, reflux 15～45 minutes.Be cooled to 0～15 degree, in 5～15 minutes, drip 22.5 milliliters of Jones reagents while stirring.After 25～55 minutes, reaction mixture adds the ethyl acetate dilution, tells organic layer, and it is inferior to give a baby a bath on the third day after its birth with saturated acetic acid sodium solution and saturated nacl aqueous solution respectively again, the organic layer anhydrous sodium sulfate drying, filter to get filtrate, Rotary Evaporators pressure reducing and steaming organic solvent, thin-layer chromatography separates purify (petrol ether/ethyl acetate=2: 1), get white solid compound 14 β-hydrogen-15 β, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone, productive rate 80%.
7. in 100 ml flasks, add 2.09 gram 14 β-hydrogen-15 β that prepare previously, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone and 1.8 gram tetrachlorobenzoquinones add 60 milliliters of trimethyl carbinols, reflux 2～6 hours again.Stop reaction, dissolve with methylene dichloride behind the Rotary Evaporators pressure reducing and steaming solvent, water, 5% sodium hydroxide solution, washing successively again, the organic layer dried over mgso is filtered, Rotary Evaporators pressure reducing and steaming methylene dichloride, re-crystallizing in ethyl acetate gets pale yellow crystals 14 β-hydrogen-15 β, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4,6-diene-21,17-carboxylic lactone, productive rate 37%.
8. under the protection of inert gas; in there-necked flask, add 0.51 gram sodium hydrogen and 2.8 gram Trimethylsulfoxonium Iodides; drip dimethyl sulfoxide (DMSO) under the room temperature; be stirred to that no bubble is emerged and reactant solution clarification back adds 14 β-hydrogen-15 β of above-mentioned preparation; 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4; 6-diene-21,17-carboxylic lactone 1.2 grams, stirring at room 15～25 hours.Stopped reaction, extracted with diethyl ether is told ether layer, and anhydrous magnesium sulfate drying filters, get filtrate, Rotary Evaporators pressure reducing and steaming ether gets white solid 14 β-hydrogen-6 β, 7 β through column chromatography again, 15 β, 16 β-dimethylene-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone, productive rate 40%.
Embodiment three: concrete steps are as follows:
1. in 50 liters of reactors, add dehydroepiandros-sterone 800 grams, 30 liters of 1.9 kilograms of bromination ketone and anhydrous methanols, about 20～30 hours of reflux.Stopped reaction, filtered while hot.Remaining part adds deionized water and dichloromethane extraction 3 times again.Tell organic layer, anhydrous magnesium sulfate drying filters, and Rotary Evaporators pressure reducing and steaming solvent gets yellow dope, and this dope is used ethyl alcohol recrystallization white needles solid again, 16-bromo-3 beta-hydroxies-androstane-5-alkene-17-ketone, productive rate 55%.
2. under the protection of inert gas; with 310 gram 16-bromo-, the 3 beta-hydroxies-androstane-5-alkene-17-ketone for preparing previously; 440 gram lithiumbromides and 380 gram Quilonum Retards are dissolved in N,N-DIMETHYLACETAMIDE; refluxed 5～10 hours; cooled reactant solution is used ethyl acetate extraction after using the acetum cancellation; organic layer is washed with 5% sodium hydrogen carbonate solution; wash with saturated nacl aqueous solution again; anhydrous magnesium sulfate drying; filter, get filtrate, Rotary Evaporators pressure reducing and steaming solvent; get the red-brown dope; re-crystallizing in ethyl acetate gets orange crystal 14 β-hydrogen-3 beta-hydroxies-androstane-5,16-diene-17-ketone, productive rate 39%.
3. under the protection of inert gas; in 25 liters of reactors, add 100 gram sodium hydrogen and 470 gram Trimethylsulfoxonium Iodides; drip 7.5 liters of methyl-sulphoxides under the room temperature; be stirred to 14 β-hydrogen-3 beta-hydroxies-androstane-5 that no bubble is emerged and reactant solution clarification back adding prepares previously; 16-diene-17-ketone 448 grams stirred 15～25 hours.After the stopped reaction, use extracted with diethyl ether, the organic layer anhydrous magnesium sulfate drying of telling, filter, get filtrate, Rotary Evaporators pressure reducing and steaming ether, column chromatography gets white solid 14 β-hydrogen-3 beta-hydroxy-15 β, 16 β-methylene radical-androstane-5-alkene-17-ketone, productive rate 81%.
4. under the protection of inert gas; add magnesium sheet 110 grams in 25 liters of reactors, 3.8 liters of several iodine grains and tetrahydrofuran (THF)s slowly drip 7.5 liters of tetrahydrofuran solutions of 3-bromine propionic aldehyde dimethylacetal under the reflux; begin during the color fade of iodine to stir, refluxed again after dropwising three hours.Remove oil bath and be cooled to room temperature, add 225 gram 14 β-hydrogen-3 beta-hydroxy-15 β that prepare previously again, 75 milliliters of tetrahydrofuran solution reactions of 16 β-methylene radical-androstane-5-alkene-17-ketone 10～15 hours.With sodium hydrogen carbonate solution cancellation reaction, dichloromethane extraction, the salt of wormwood drying is spent the night, and filters to get filtrate, the methylene dichloride recrystallization gets white solid 14 β-hydrogen-15 β, 16 β-methylene radical-3 β, 17-dihydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene, productive rate 74%.
5. in 10 liters of there-necked flasks, add 136 gram 14 β-hydrogen-15 β, 16 β-methylene radical-3 β, 17-dihydroxyl-1 (3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene and 3.5 liters of dry toluenes stir and make its dissolving, and it adds 700 milliliters of pimelinketone again.Steam 5.4 liters of toluene solutions that drip 380 gram aluminum isopropylates behind a part of toluene.Steam some toluene after dropwising again, stopped reaction, dilute with ether reactant solution cooling back, add aqueous sulfuric acid again, the layering of vibrating in the separating funnel is told the upper strata organic layer, dried over mgso, filter to get filtrate, Rotary Evaporators pressure reducing and steaming ether revolves not dried residuum again through steam distillation, and dichloromethane extraction is told organic layer, dried over mgso, filter to get filtrate, Rotary Evaporators pressure reducing and steaming methylene dichloride gets yellow dope, and this dope gets white crystal 14 β-hydrogen-15 β with recrystallizing methanol, 16 β-methylene radical-3 oxos-17-hydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene, the mother liquor resistates gets white solid 14 β-hydrogen-15 β through column chromatography again, 16 β-methylene radical-3 oxos-17-hydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene, productive rate 56%.
6. in 20 liters of round-bottomed flasks, add the 30 gram vitriol oil and 12 liters of acetone, add 116 gram 14 β-hydrogen-15 β that compound prepares previously again, 16 β-methylene radical-3 oxos-17-hydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene, reflux 15～45 minutes.Be cooled to 0～15 degree, in 5～15 minutes, drip 112.5 milliliters of Jones reagents while stirring.After 25～55 minutes, reaction mixture adds the ethyl acetate dilution, tells organic layer, and it is inferior to give a baby a bath on the third day after its birth with saturated acetic acid sodium solution and saturated nacl aqueous solution respectively again, the organic layer anhydrous sodium sulfate drying, filter to get filtrate, Rotary Evaporators pressure reducing and steaming organic solvent, thin-layer chromatography separates purify (petrol ether/ethyl acetate=2: 1), get white solid compound 14 β-hydrogen-15 β, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone, productive rate 80%.
7. in 3 liters of flasks, add 62.7 gram 14 β-hydrogen-15 β that prepare previously, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone and 54 gram tetrachlorobenzoquinones add 1.8 liters of trimethyl carbinols, reflux 2～6 hours again.Stop reaction, dissolve with methylene dichloride behind the Rotary Evaporators pressure reducing and steaming solvent, water, 5% sodium hydroxide solution, washing successively again, the organic layer dried over mgso is filtered, Rotary Evaporators pressure reducing and steaming methylene dichloride, re-crystallizing in ethyl acetate gets pale yellow crystals 14 β-hydrogen-15 β, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4,6-diene-21,17-carboxylic lactone, productive rate 35%.
8. under the protection of inert gas; in there-necked flask, add 15.3 gram sodium hydrogen and 84 gram Trimethylsulfoxonium Iodides; drip dimethyl sulfoxide (DMSO) under the room temperature; be stirred to that no bubble is emerged and reactant solution clarification back adds 14 β-hydrogen-15 β of above-mentioned preparation; 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4; 6-diene-21,17-carboxylic lactone 36 grams, stirring at room 15～25 hours.Stopped reaction, extracted with diethyl ether is told ether layer, and anhydrous magnesium sulfate drying filters, get filtrate, Rotary Evaporators pressure reducing and steaming ether gets white solid 14 β-hydrogen-6 β, 7 β through column chromatography again, 15 β, 16 β-dimethylene-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone, productive rate 38%.
Embodiment four: concrete steps are as follows:
1. in 250 liters of reactors, add 8 kilograms of dehydroepiandros-sterones, 100 liters of 19 kilograms of bromination ketone and anhydrous methanols, about 20～30 hours of reflux.Stopped reaction, filtered while hot.Remaining part adds deionized water and dichloromethane extraction 3 times again.Tell organic layer, anhydrous magnesium sulfate drying filters, and Rotary Evaporators pressure reducing and steaming solvent gets yellow dope, and this dope is used ethyl alcohol recrystallization white needles solid again, 16-bromo-3 beta-hydroxies-androstane-5-alkene-17-ketone, productive rate 50%.
2. under the protection of inert gas; with the 3.1 kilograms of 16-bromo-3 beta-hydroxies-androstanes-5-alkene-17-ketone for preparing previously; 4.40 kilogram lithiumbromide and 3.80 kilograms of Quilonum Retards are dissolved in N,N-DIMETHYLACETAMIDE; refluxed 5～10 hours; cooled reactant solution is used ethyl acetate extraction after using the acetum cancellation; organic layer is washed with 5% sodium hydrogen carbonate solution; wash with saturated nacl aqueous solution again; anhydrous magnesium sulfate drying; filter, get filtrate, Rotary Evaporators pressure reducing and steaming solvent; get the red-brown dope; re-crystallizing in ethyl acetate gets orange crystal 14 β-hydrogen-3 beta-hydroxies-androstane-5,16-diene-17-ketone, productive rate 38%.
3. under the protection of inert gas; in 100 liters of reactors, add 500 gram sodium hydrogen and 2.35 kilograms of Trimethylsulfoxonium Iodides; drip 35 liters of methyl-sulphoxides under the room temperature; be stirred to 14 β-hydrogen-3 beta-hydroxies-androstane-5 that no bubble is emerged and reactant solution clarification back adding prepares previously; 2.24 kilograms of 16-diene-17-ketone stirred 15～25 hours.After the stopped reaction, use extracted with diethyl ether, the organic layer anhydrous magnesium sulfate drying of telling, filter, get filtrate, Rotary Evaporators pressure reducing and steaming ether, column chromatography gets white solid 14 β-hydrogen-3 beta-hydroxy-15 β, 16 β-methylene radical-androstane-5-alkene-17-ketone, productive rate 81%.
4. under the protection of inert gas; add magnesium sheet 550 grams in 100 liters of reactors, iodine grain and tetrahydrofuran (THF) are 15 liters on a small quantity, slowly drip 30 liters of tetrahydrofuran solutions of 3-bromine propionic aldehyde dimethylacetal under the reflux; begin during the color fade of iodine to stir, refluxed again after dropwising three hours.Remove oil bath and be cooled to room temperature, add 1.12 kilograms of 14 β-hydrogen-3 beta-hydroxy-15 β that prepare previously again, 800 milliliters of tetrahydrofuran solution reactions of 16 β-methylene radical-androstane-5-alkene-17-ketone 10～15 hours.With sodium hydrogen carbonate solution cancellation reaction, dichloromethane extraction, the salt of wormwood drying is spent the night, and filters to get filtrate, the methylene dichloride recrystallization gets white solid 14 β-hydrogen-15 β, 16 β-methylene radical-3 β, 17-dihydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene, productive rate 74%.
5. in 50 liters of reactors, add 680 gram 14 β-hydrogen-15 β, 16 β-methylene radical-3 β, 17-dihydroxyl-1 (3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene and 15 liters of dry toluenes stir and make its dissolving, and it adds 3.5 liters of pimelinketone again.Steam 25 liters of toluene solutions that drip 1.9 kilograms of aluminum isopropylates behind a part of toluene.Steam some toluene after dropwising again, stopped reaction, dilute with ether reactant solution cooling back, add aqueous sulfuric acid again, the layering of vibrating in the separating funnel is told the upper strata organic layer, dried over mgso, filter to get filtrate, Rotary Evaporators pressure reducing and steaming ether revolves not dried residuum again through steam distillation, and dichloromethane extraction is told organic layer, dried over mgso, filter to get filtrate, Rotary Evaporators pressure reducing and steaming methylene dichloride gets yellow dope, and this dope gets white crystal 14 β-hydrogen-15 β with recrystallizing methanol, 16 β-methylene radical-3 oxos-17-hydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene, the mother liquor resistates gets white solid 14 β-hydrogen-15 β through column chromatography again, 16 β-methylene radical-3 oxos-17-hydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene, productive rate 55%.
6. in 100 liters of reactors, add the 150 gram vitriol oil and 60 liters of acetone, add 580 gram 14 β-hydrogen-15 β that compound prepares previously again, 16 β-methylene radical-3 oxos-17-hydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene, reflux 15～45 minutes.Be cooled to 0～15 degree, in 5～15 minutes, drip 560 milliliters of Jones reagents while stirring.After 25～55 minutes, reaction mixture adds the ethyl acetate dilution, tells organic layer, and it is inferior to give a baby a bath on the third day after its birth with saturated acetic acid sodium solution and saturated nacl aqueous solution respectively again, the organic layer anhydrous sodium sulfate drying, filter to get filtrate, Rotary Evaporators pressure reducing and steaming organic solvent, thin-layer chromatography separates purify (petrol ether/ethyl acetate=2: 1), get white solid compound 14 β-hydrogen-15 β, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone, productive rate 75%.
7. in 15 liters of flasks, add 310 gram 14 β-hydrogen-15 β that prepare previously, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone and 270 gram tetrachlorobenzoquinones add 9 liters of trimethyl carbinols, reflux 2～6 hours again.Stop reaction, dissolve with methylene dichloride behind the Rotary Evaporators pressure reducing and steaming solvent, water, 5% sodium hydroxide solution, washing successively again, the organic layer dried over mgso is filtered, Rotary Evaporators pressure reducing and steaming methylene dichloride, re-crystallizing in ethyl acetate gets pale yellow crystals 14 β-hydrogen-15 β, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4,6-diene-21,17-carboxylic lactone, productive rate 35%.
8. under the protection of inert gas; in there-necked flask, add 80 gram sodium hydrogen and 420 gram Trimethylsulfoxonium Iodides; drip dimethyl sulfoxide (DMSO) under the room temperature; be stirred to that no bubble is emerged and reactant solution clarification back adds 14 β-hydrogen-15 β of above-mentioned preparation; 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4; 6-diene-21,17-carboxylic lactone 180 grams, stirring at room 15～25 hours.Stopped reaction, extracted with diethyl ether is told ether layer, and anhydrous magnesium sulfate drying filters, get filtrate, Rotary Evaporators pressure reducing and steaming ether gets white solid 14 β-hydrogen-6 β, 7 β through column chromatography again, 15 β, 16 β-dimethylene-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone, productive rate 36%.
Embodiment five: concrete steps are as follows:
1. in 500 liters of reactors, add 40 kilograms of dehydroepiandros-sterones, 350 liters of 95 kilograms of bromination ketone and anhydrous methanols, about 20～30 hours of reflux.Stopped reaction, filtered while hot.Remaining part adds deionized water and dichloromethane extraction 3 times again.Tell organic layer, anhydrous magnesium sulfate drying filters, and Rotary Evaporators pressure reducing and steaming solvent gets yellow dope, and this dope is used ethyl alcohol recrystallization white needles solid again, 16-bromo-3 beta-hydroxies-androstane-5-alkene-17-ketone, productive rate 50%.
2. under the protection of inert gas; with the 31 kilograms of 16-bromo-3 beta-hydroxies-androstanes-5-alkene-17-ketone for preparing previously; 44 kilograms of lithiumbromides and 38 kilograms of Quilonum Retards are dissolved in N,N-DIMETHYLACETAMIDE; refluxed 5～10 hours; cooled reactant solution is used ethyl acetate extraction after using the acetum cancellation; organic layer is washed with 5% sodium hydrogen carbonate solution; wash with saturated nacl aqueous solution again; anhydrous magnesium sulfate drying; filter, get filtrate, Rotary Evaporators pressure reducing and steaming solvent; get the red-brown dope; re-crystallizing in ethyl acetate gets orange crystal 14 β-hydrogen-3 beta-hydroxies-androstane-5,16-diene-17-ketone, productive rate 38%.
3. under the protection of inert gas; in 100 liters of reactors, add 750 gram sodium hydrogen and 3.5 kilograms of Trimethylsulfoxonium Iodides; drip 50 liters of methyl-sulphoxides under the room temperature; be stirred to 14 β-hydrogen-3 beta-hydroxies-androstane-5 that no bubble is emerged and reactant solution clarification back adding prepares previously; 33.6 kilograms of 16-diene-17-ketone stirred 15～25 hours.After the stopped reaction, use extracted with diethyl ether, the organic layer anhydrous magnesium sulfate drying of telling, filter, get filtrate, Rotary Evaporators pressure reducing and steaming ether, column chromatography gets white solid 14 β-hydrogen-3 beta-hydroxy-15 β, 16 β-methylene radical-androstane-5-alkene-17-ketone, productive rate 81%.
4. under the protection of inert gas; add 11 kilograms in magnesium in 100 liters of reactors, iodine grain and tetrahydrofuran (THF) are 20 liters on a small quantity, slowly drip 40 liters of tetrahydrofuran solutions of 3-bromine propionic aldehyde dimethylacetal under the reflux; begin during the color fade of iodine to stir, refluxed again after dropwising three hours.Remove oil bath and be cooled to room temperature, add 22.4 kilograms of 14 β-hydrogen-3 beta-hydroxy-15 β that prepare previously again, 15 liters of tetrahydrofuran solution reactions of 16 β-methylene radical-androstane-5-alkene-17-ketone 10～15 hours.With sodium hydrogen carbonate solution cancellation reaction, dichloromethane extraction, the salt of wormwood drying is spent the night, and filters to get filtrate, the methylene dichloride recrystallization gets white solid 14 β-hydrogen-15 β, 16 β-methylene radical-3 β, 17-dihydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene, productive rate 74%.
5. in 100 liters of reactors, add 13.6 kilograms of 14 β-hydrogen-15 β, 16 β-methylene radical-3 β, 17-dihydroxyl-1 (3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene and 25 liters of dry toluenes stir and make its dissolving, and it adds 40 liters of pimelinketone again.Steam 55 liters of toluene solutions that drip 38 kilograms of aluminum isopropylates behind a part of toluene.Steam some toluene after dropwising again, stopped reaction, dilute with ether reactant solution cooling back, add aqueous sulfuric acid again, the layering of vibrating in the separating funnel is told the upper strata organic layer, dried over mgso, filter to get filtrate, Rotary Evaporators pressure reducing and steaming ether revolves not dried residuum again through steam distillation, and dichloromethane extraction is told organic layer, dried over mgso, filter to get filtrate, Rotary Evaporators pressure reducing and steaming methylene dichloride gets yellow dope, and this dope gets white crystal 14 β-hydrogen-15 β with recrystallizing methanol, 16 β-methylene radical-3 oxos-17-hydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene, the mother liquor resistates gets white solid 14 β-hydrogen-15 β through column chromatography again, 16 β-methylene radical-3 oxos-17-hydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene, productive rate 55%.
6. in 100 liters of reactors, add 1.50 kilograms of vitriol oils and 60 liters of acetone, add 11.6 gram 14 β-hydrogen-15 β that compound prepares previously again, 16 β-methylene radical-3 oxos-17-hydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene, reflux 15～45 minutes.Be cooled to 0～15 degree, in 5～15 minutes, drip 11.2 liters of Jones reagents while stirring.After 25～55 minutes, reaction mixture adds the ethyl acetate dilution, tells organic layer, and it is inferior to give a baby a bath on the third day after its birth with saturated acetic acid sodium solution and saturated nacl aqueous solution respectively again, the organic layer anhydrous sodium sulfate drying, filter to get filtrate, Rotary Evaporators pressure reducing and steaming organic solvent, thin-layer chromatography separates purify (petrol ether/ethyl acetate=2: 1), get white solid compound 14 β-hydrogen-15 β, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone, productive rate 75%.
7. in 50 liters of flasks, add 6.2 kilograms of 14 β-hydrogen-15 β that prepare previously, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone and 5.4 kilograms of tetrachlorobenzoquinones add 30 liters of trimethyl carbinols again, reflux 2～6 hours.Stop reaction, dissolve with methylene dichloride behind the Rotary Evaporators pressure reducing and steaming solvent, water, 5% sodium hydroxide solution, washing successively again, the organic layer dried over mgso is filtered, Rotary Evaporators pressure reducing and steaming methylene dichloride, re-crystallizing in ethyl acetate gets pale yellow crystals 14 β-hydrogen-15 β, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4,6-diene-21,17-carboxylic lactone, productive rate 35%.
8. under the protection of inert gas; in there-necked flask, add 3.2 kilograms of sodium hydrogen and 16.8 kilograms of Trimethylsulfoxonium Iodides; drip 50 liters of dimethyl sulfoxide (DMSO) under the room temperature; be stirred to that no bubble is emerged and reactant solution clarification back adds 14 β-hydrogen-15 β of above-mentioned preparation; 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4; 6-diene-21,7.2 kilograms of 17-carboxylic lactones, stirring at room 15～25 hours.Stopped reaction, extracted with diethyl ether is told ether layer, and anhydrous magnesium sulfate drying filters, get filtrate, Rotary Evaporators pressure reducing and steaming ether gets white solid 14 β-hydrogen-6 β, 7 β through column chromatography again, 15 β, 16 β-dimethylene-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone, productive rate 36%.
Claims (2)
1. 14 β-hydrogen-6 β, 7 β, 15 β, 16 β-dimethylene-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone is characterized in that the structural formula of this compound is:
2. one kind prepares 14 β according to claim 1-hydrogen-6 β, 7 β, and 15 β, 16 β-dimethylene-3-oxo-17 β-pregnant steroid-4-alkene-21, the method for 17-carboxylic lactone is characterized in that this method has following steps:
A. with dehydroepiandros-sterone and cupric bromide by 1: the mol ratio of (2.2～3.8) is dissolved in the anhydrous methanol, back flow reaction 20～30 hours; Filtered while hot, filtrate is washed with deionized water, dichloromethane extraction, organic layer with anhydrous magnesium sulfate drying after, filter, the solvent that spins off in the filtrate gets yellow dope, and this dope is 16-bromo-3 beta-hydroxies-androstane-5-alkene-17-ketone with ethyl alcohol recrystallization white needles solid again;
B. under the inert atmosphere, with above-mentioned 16-bromo-3 beta-hydroxies-androstane-5-alkene-17-ketone, lithiumbromide and Quilonum Retard are by 1: (3.5～7.5): (4.2～6.5) are dissolved in N,N-DIMETHYLACETAMIDE, back flow reaction 5～10 hours, cooled reactant solution is used ethyl acetate extraction after using the acetum cancellation, organic layer is washed with 5% sodium hydrogen carbonate solution, wash with saturated nacl aqueous solution again, anhydrous magnesium sulfate drying, filter, the solvent that spins off in the filtrate gets the red-brown dope, get white crystal 14 β-hydrogen-3 beta-hydroxies-androstane-5 with re-crystallizing in ethyl acetate again, 16-diene-17-ketone;
C. under the inert atmosphere, sodium hydrogen and Trimethylsulfoxonium Iodide are pressed 1: after mix (1～2.2), drip dimethyl sulfoxide (DMSO) under the room temperature, be stirred to that no bubble is emerged and reactant solution clarification back adds above-mentioned 14 β-hydrogen-3 beta-hydroxies-androstane-5,16-diene-17-ketone, Trimethylsulfoxonium Iodide and 14 β-hydrogen-3 beta-hydroxies-androstane-5 wherein, 16-diene-17-ketone mol ratio is 1: (0.5～2.5), stirred 15～25 hours; Use extracted with diethyl ether, the organic layer anhydrous magnesium sulfate drying filters, and spins off the solvent in the filtrate, and column chromatography for separation gets white solid 14 β-hydrogen-3 beta-hydroxy-15 β, 16 β-methylene radical-androstane-5-alkene-17-ketone;
D. under the inert atmosphere, magnesium sheet, iodine grain are dissolved in the tetrahydrofuran (THF), reflux and slowly drip the tetrahydrofuran solution of 3-bromine propionic aldehyde dimethylacetal down, wherein the mol ratio of magnesium and 3-bromine propionic aldehyde dimethylacetal is (1.0～2.5): 1, begin during to the color fade of iodine grain to stir, refluxed again after dropwising 2～4 hours; Be cooled to room temperature, add 14 above-mentioned β-hydrogen-3 beta-hydroxy-15 β again, the tetrahydrofuran solution reaction of 16 β-methylene radical-androstane-5-alkene-17-ketone 10～15 hours, wherein, 3-bromine propionic aldehyde dimethylacetal and 14 β-hydrogen-3 beta-hydroxy-15 β, the mol ratio of 16 β-methylene radical-androstane-5-alkene-17-ketone is (2.5～6.5): 1; With sodium hydrogen carbonate solution cancellation reaction, dichloromethane extraction, organic layer Anhydrous potassium carbonate dried overnight, filter to get filtrate, use the methylene dichloride recrystallization, get white solid 14 β-hydrogen-15 β, 16 β-methylene radical-3 β, 17-dihydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene;
E. with 14 above-mentioned β-hydrogen-15 β, 16 β-methylene radical-3 β, 17-dihydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene and pimelinketone are by 1: the mol ratio of (1.1～2.5) is dissolved in the dry toluene, drips the toluene solution of aluminum isopropylate again, wherein, 14 β-hydrogen-15 β, 16 β-methylene radical-3 β, the mol ratio of 17-dihydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene and aluminum isopropylate is: (1.5～4.5): 1; Dropwise the back concentrated reaction solution, again reaction soln cooling back is diluted with ether, add aqueous sulfuric acid again, the organic layer dried over mgso, filter to get filtrate, spin off the solvent in the filtrate, residuum is again through steam distillation, dichloromethane extraction, the organic layer dried over mgso filters to get filtrate, the solvent that spins off in the filtrate gets yellow dope, this dope gets white crystal 14 β-hydrogen-15 β with recrystallizing methanol, 16 β-methylene radical-3 oxos-17-hydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene, the mother liquor resistates can be through column chromatographic isolation and purification, also get white solid 14 β-hydrogen-15 β, 16 β-methylene radical-3 oxos-17-hydroxyl-17-(3 ', 3 '-dimethoxy) propyl group-androstane-5-alkene;
F. with 14 above-mentioned β-hydrogen-15 β, 16 β-methylene radical-3 oxos-17-hydroxyl-17-(3 ', the 3 '-dimethoxy) propyl group-androstane-5-alkene and the catalyzer vitriol oil are dissolved in the acetone back flow reaction 15～45 minutes; Be cooled to 0～15 degree, in 5～15 minutes, drip Jones reagent while stirring; After 25～55 minutes, reaction mixture adds the ethyl acetate dilution, organic layer is respectively with saturated acetic acid sodium solution and saturated nacl aqueous solution washing, the organic layer anhydrous magnesium sulfate drying, filter, spin off the solvent in the filtrate, thin-layer chromatography separate purify white solid compound spiral shell 14 β-hydrogen-15 β, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone;
G. with 14 above-mentioned β-hydrogen-15 β, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone and tetrachlorobenzoquinone are by 1: the mol ratio of (0.5～2.5) is dissolved in the trimethyl carbinol, reflux 2～6 hours; Dissolve with methylene dichloride after spinning off solvent, water, 5% sodium hydroxide solution, washing successively again, the organic layer dried over mgso, filter, spin off the solvent in the filtrate, re-crystallizing in ethyl acetate gets pale yellow crystals 14 β-hydrogen-15 β, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4,6-diene-21,17-carboxylic lactone;
H. under the inert atmosphere, sodium hydrogen and Trimethylsulfoxonium Iodide are pressed 1: after the mixed in molar ratio of (0.5～1.5), drip methyl-sulphoxide under the room temperature, be stirred to that no bubble is emerged and reactant solution clarification back adds above-mentioned 14 β-hydrogen-15 β, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4,6-diene-21,17-carboxylic lactone, Trimethylsulfoxonium Iodide and 14 β-hydrogen-15 β wherein, 16 β-methylene radical-3-oxo-17 β-pregnant steroid-4,6-diene-21, the mol ratio of 17-carboxylic lactone is (0.5～2.5), stirring at room 15～25 hours; Extracted with diethyl ether, the organic layer anhydrous magnesium sulfate drying filters, and spins off the solvent in the filtrate, gets white solid 14 β-hydrogen-6 β through column chromatography for separation again, 7 β, 15 β, 16 β-dimethylene-3-oxo-17 β-pregnant steroid-4-alkene-21,17-carboxylic lactone.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102887934A (en) * | 2012-09-20 | 2013-01-23 | 杭州福斯特药业有限公司 | Preparation method of drospirenone |
| CN102964411A (en) * | 2012-12-03 | 2013-03-13 | 华中药业股份有限公司 | Synthesis method of androstane-4,6-diene-17 alpha-methyl-17 beta-alcohol-3-ketone |
| JP2014515391A (en) * | 2011-06-01 | 2014-06-30 | エステトラ エス アー | Process for producing estetrol intermediates |
| 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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2009
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014515391A (en) * | 2011-06-01 | 2014-06-30 | エステトラ エス アー | Process for producing estetrol intermediates |
| CN102887934A (en) * | 2012-09-20 | 2013-01-23 | 杭州福斯特药业有限公司 | Preparation method of drospirenone |
| CN102887934B (en) * | 2012-09-20 | 2015-05-27 | 杭州福斯特药业有限公司 | Preparation method of drospirenone |
| CN102964411A (en) * | 2012-12-03 | 2013-03-13 | 华中药业股份有限公司 | Synthesis method of androstane-4,6-diene-17 alpha-methyl-17 beta-alcohol-3-ketone |
| CN102964411B (en) * | 2012-12-03 | 2015-04-22 | 华中药业股份有限公司 | Synthesis method of androstane-4,6-diene-17 alpha-methyl-17 beta-alcohol-3-ketone |
| 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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