CN1072678C - Trifluoro-methyl steroid, preparation and its application - Google Patents

Trifluoro-methyl steroid, preparation and its application Download PDF

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CN1072678C
CN1072678C CN 94112181 CN94112181A CN1072678C CN 1072678 C CN1072678 C CN 1072678C CN 94112181 CN94112181 CN 94112181 CN 94112181 A CN94112181 A CN 94112181A CN 1072678 C CN1072678 C CN 1072678C
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methyl
steroid
trifluoromethyl
ketone
ethyl
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CN1097763A (en
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王钟麒
卢寿福
张建蓉
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Shanghai Institute of Organic Chemistry of CAS
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Shanghai Institute of Organic Chemistry of CAS
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Abstract

The present invention provides a steroid 13-methyl or ethyl-3, 3-dimethyl or carbonyl-17-hydroxyl or trimethylsiloxyl-17-trifluoromethyl-4(5) monoene or 5(10) monoene or 2(3), 5(10) diene or 4(5), 9(10) diene or 5(10), 9(11) diene or 4(5), 9(10), 11(12) triene. The steroid can be synthesized by trifluoromethylation or methyl ether removing or trimethylsiloxy removing or olefinic bond transposition or conversion reaction in steroid ring. The synthetic route is short; the operation is convenient, and the yield is high; the present invention provides an intermediate for synthesizing medicines for terminating early pregnancy as well as medicines for terminating early pregnancy.

Description

Trifluoro-methyl steroid, preparation and uses thereof
The present invention relates to the steroidal organic compound, specifically a kind of 17-trifluoro-methyl steroid with physiologically active, preparation and uses thereof.
The hurried growth of world population, to bring many problems to human self-development balance, be effective control population, the searching effect is remarkable, safe and reliable contraceptive device is exactly the problem that scientist makes great efforts to seek, the contraceptive thing then is one of important measures that practice family planning and bring the growth of population under control, but, all there is certain shortcoming and defect in present widely used steroidal contraceptive thing, seek special effect, side effect is little, and biological value height, steroid drugs easy to use become various countries' birth control investigator common target.
According to studies show that of steroidal contraceptive thing for a long time, molecular structure and biological value have close contact.In the steroidal molecule, remove 10 methyl, the flexibility that has increased molecule with cause different charge distribution, make molecule increase avidity with progesterone receptor, thereby reach anti-pregnant purpose.In addition, when steroidal prolongs conjugated double bond, become 4 (5) from 4 (5) two keys, 9 (10) dienes then can make the A annular strain, cause reducing with the avidity of androgen receptor, when 4 (5), 9 (10) dienes become 4 (5), 9 (10), 11 (12) triolefins, then make A ring conformation more stable, increase the avidity with progesterone receptor again, simultaneously, also increased avidity with androgen receptor or the like.
Shanghai Organic Chemistry Institute, Chinese Academy of Sciences had once reported the 18-methylnorethindron, the synthetic method of norgestrienone and 18-methylnorgestrienon [chemical journal, 33 (2), 139 (1975), 37 (1), 1 (1979)], Norethisterone and 18-methyl acetylenic ketone all are oral contraceptives commonly used both at home and abroad at present, norgestrienone and 18-methylnorgestrienon all are good contraceptive bians, the latter and prostaglandin(PG) compatibility are used for antiearly pregnancy and identify in Shanghai that already still, all there is certain weak point in they, or need take, or during medication, can cause dysfunction of liver everyday.
Chemist and medicine scholars are from the structure activity study and development new drug process of molecule, find the compound that a lot of fluorine atoms are introduced, its activity (physics, chemistry, biology etc.) all has very big change, it is especially obvious particularly to introduce behind the trifluoromethyl their change of properties in molecule, so synthetic chemistry man and medicine scholar introduce the synthetic of molecule to trifluoromethyl and carried out long-term and deep research with pharmacology.
Introducing trifluoromethyl in molecule has bigger difficulty than introducing single fluorine atom, up to the present, people have paid painstaking efforts to the research of this respect, a lot of effective meanss and reagent have been found, the whole bag of tricks, reagent all have their characteristics separately, utilize trifluoromethyl reagent to the addition reaction effect of carbonyl and introduce trifluoromethyl and surely belong to Me 3SiCF 3(TMSCF 3) the most effective, it can not only with sterically hindered less carbonyl compound generation addition reaction, and this reagent can also with aryl and thiazolinyl halides generation linked reaction, in addition reaction to carbonyl, have mild condition, side reaction is few, the productive rate height, and advantages such as the easy preservation of this reagent are so become a kind of trifluoromethylation instrument of great use on synthetic.Human trifluoromethyl building block methods such as Xu Yuanyao are introduced trifluoromethyl [CN90106105] easily on the steroidal side chain, also once reported and use TMSCF 3Introduce trimethylammonium and synthesized steroidal compounds [Bioorganic Chem, 21,330 (1993)].It is a kind of there to be trifluoro-methyl steroid of trifluoromethyl and hydroxyl and preparation method thereof [CN93112563.4] promptly to have the steroidal compounds and the Me of carbonyl on the same carbon atom on C17 position or its extendible side chain on 17 or its side chain that Wang Zhongqi etc. have reported 4NF and CF 3SiMe 3Be 1 with mol ratio respectively: 0.5-5: 0.5-10 carries out addition reaction and generates trifluoromethyl silicon ether steroidal compounds, temperature of reaction is-10-80 ℃, 1 minute to 10 hours reaction times, trifluoromethyl silicon ether steroidal compounds is hydrolyzed with the HF aqueous solution of 10-50% with polar solvent that water dissolves each other then, the volume ratio of the solvent and the HF aqueous solution can be 1: 0.2-5, hydrolysis temperature is 0-80 ℃, and the reaction times is 0.5-20 hour.This method contains trifluoromethyl steroidal new drug an important channel is provided for synthetic.So far synthesize trifluoromethyl steroidal analogue, and explore their physiologically active, seek valuable each kind new medicine of exploitation, be still the problem that the various countries chemists pay close attention to.
The purpose of this invention is to provide a kind of trifluoro-methyl steroid, preparation and uses thereof.
Trifluoro-methyl steroid provided by the invention is a kind of 13-methyl or ethyl-3,3-bi-methoxy or carbonyl-17 beta-hydroxies or trimethylsiloxy group-17 α-trifluoromethyl-4 (5) monoene or 5 (10) monoene or-2 (3), 5 (10) diene or-4 (5), 9 (10) diene or-5 (10), 9 (11) diene or-4 (5), 9 (10), 11 (12) triolefin steroidal compounds.
Trifluoro-methyl steroid of the present invention has following structural formula: R wherein 1=CH 3Or C 2H 5, R 2=OH or OSi (CH 3) 3, R 3=R 4Or R 3Or R 4=CH 3O, R 3R 4=O
Figure C9411218100062
As 13-methyl-17 beta-hydroxyl-17 alpha-trifluoromethyl-4 (5) female steroids alkene-3-ketone (1), 13-ethyl-17 beta-hydroxyl-17 alphas-trifluoromethyl-4 (5) property steroid alkene 3-ketone (2).13-methyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-5 (10) female steroids alkene-3-ketone-3, the two methyl ethers (3) of 3-, 13-ethyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-5 (10) property steroid alkene-3-ketone-3, the two methyl ethers (4) of 3-, 13-methyl-17 beta-hydroxyl-17 alpha-trifluoromethyl-5 (10) female steroids alkene-3-ketone (5), 13-ethyl-17 beta-hydroxyl-17 alphas-trifluoromethyl-5 (10) property steroid alkene-3-ketone (6), 13-methyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-5 (10) female steroid alkene 3-ketone (7), 13-ethyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-5 (10) property steroid alkene 3-ketone (8), 13-methyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-4 (5), 9 (10)-estradienes-3-ketone (9), 13-ethyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-4 (5), 9 (10)-property steroid diene-3-ketone (10), 13-methyl-17 beta-hydroxyl-17 alpha-trifluoromethyl-4 (5), 9 (10) estradienes-3-ketone (11), 13-ethyl-17 beta-hydroxyl-17 alphas-trifluoromethyl-4 (5), 9 (10) property steroid diene-3-ketone (12), 13-methyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-5 (10), 9 (11) estradienes-3-ketone-3, the two methyl ethers (13) of 3-, 13-ethyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-5 (10), 9 (11) property steroid diene-3-ketone-3, the two methyl ethers (14) of 3-, 13-methyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-5 (10), 9 (11) estradienes-3-ketone (15), 13-ethyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-5 (10), 9 (11) property steroid diene-3-ketone (16), 13-methyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-4 (5), 9 (10), 11 (12) female steroid triolefins-3-ketone (17), 13-ethyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-4 (5), 9 (10), 11 (12) property steroid triolefin-3-ketone (18), 13-methyl-17 beta-hydroxyl-17 alpha-trifluoromethyl-4 (5), 9 (10), 11 (12) female steroid triolefins-3-ketone (19), 13-ethyl-17 beta-hydroxyl-17 alphas-trifluoromethyl-4 (5), 9 (10), 11 (12) property steroid triolefin-3-ketone (20) etc.
The steroidal compounds of above-mentioned 17 β provided by the invention-trimethylsiloxy group-17 α-trifluoromethyl is important intermediate, can become 17 beta-hydroxyl-17 alphas-trifluoromethyl steroidal-3-ketone compound through hydrolysis, and this compounds is to have physiologically active, is a kind of medicine of antiearly pregnancy.
The present invention also provides synthetic above-mentioned trifluoro-methyl steroid method.Method of the present invention mainly is that industry is closed finished product at 3 17-ketosteroid compound TMSCF with methyl ether, two methyl ether or the protection of Pyrrolidine base 3Introduce trifluoromethyl and trimethylsiloxy group with TMAF reagent at 17, obtain 17 β-trimethylsiloxy group-17 α-trifluoromethyl-3-methyl ether or 3, the steroidal compounds of the two methyl ethers of 3-.Hydrolysis is removed-3-methyl ether or 3 again, the two methyl ethers of 3-form corresponding 17 β-trimethylsiloxy group-17 α-trifluoromethyl steroidal 3-ketone compound, also can remove 3-methyl ether or 3 simultaneously, the two methyl ethers of 3-and 17 β-trimethylsiloxy group become 17 beta-hydroxyl-17 alphas-trifluoromethyl steroidal 3-ketone compound.Steroidal intra-annular ethylene linkage can shift or monoene changes into diene, and then can change into three alkene.Also can before hydrolysis, carry out the conversion of alkene in the steroidal ring, or be hydrolyzed again.17 beta-hydroxyl-17 alphas among the present invention-trifluoromethyl steroidal anti-early pregnancy drug can be formed by 17 β-trimethylsiloxy group-17 α-trifluoro-methyl steroid hydrolysis.
Method of the present invention can be from industrial work in-process as starting raw material.Simple and direct method is described below: with 13-methyl or ethyl-5 (10) female steroids or property steroid alkene-3,17-diketone-3, the two methyl ethers (21) of 3-or 13-methyl or ethyl-2 (3), 5 (10)-estradienes or property steroid diene-17-ketone-3-methyl ether (22) are raw material, introduce trifluoromethyl through the trifluoromethylation reaction, generate steroidal compounds (3), (4) or 13-methyl or ethyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-2 (3), 5 (10)-estradienes (23) or property steroid diene (24)-3-methyl ether, steroidal compounds (3), (4), (23) or (24) after taking off monomethyl ether or two methyl ether and trimethyl silicane, generate steroidal compounds (5), (6) or (1), (2).Steroidal compounds (5) and (6) can change into steroidal compounds (1) and (2) with the concentrated hydrochloric acid reaction.
Steroidal compounds (3), (4) or (23), (24) are also available to generate steroidal compounds (7) and (8) through piptonychia ether or the reaction of two methyl ether.Steroidal compounds (7) and (8) can generate steroidal compounds (9) and (10) by the alkene transposition.
Steroidal compounds (9) and (10) generate steroidal compounds (11) and (12) through taking off the trimethyl silicane reaction.
With industrial work in-process 13-methyl or ethyl-5 (10), 9 (11) estradienes (25) or property steroid diene (26)-3,17-diketone-3, the two methyl ethers of 3-are that raw material generates steroidal compounds (13) and (14) through the trifluoromethylation reaction, and (13) can (14) can obtain steroidal compounds (11) or (12) through taking off the reaction of pair methyl ethers and trimethyl silicane.(13) or (14) also can get steroidal compounds (15) or (16) through taking off two methyl ethers.
Steroidal compounds (9) or (10) can protect carbonyl to obtain 13-methyl or ethyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-3 through Pyrrolidine; 5 (10); 9 (11) female steroid triolefins (27) or property steroid triolefin (28)-3-(1-Pyrrolidine base), steroidal compounds (27) or (28) get steroidal compounds (15) or (16) through taking off the Pyrrolidine protecting group.
Steroidal compounds (15) or (16) can generate triolefin steroidal compounds (17) or (18) by translocation reaction.
Steroidal compounds (17) or (18) take off trimethyl silicane react steroidal compounds (19) or (20).
Reaction path can be represented by the formula:
The reaction of trifluoromethylation described in the inventive method has the steroidal compounds and (CH of 17-ketone group 3) 4NF and CF 3Si (CH 3) 3Be 1 with mol ratio respectively: 0.5-5: 0.5-10 carries out addition reaction, and temperature of reaction is-10-80 ℃, 1 minute to 10 hours reaction times.Recommend mol ratio to be followed successively by 1: 0.5-1.5: 0.5-2, the addition reaction temperature is 0-40 ℃, the reaction times is 1 minute to 5 hours.
Take off trimethyl silicane reaction among the present invention or take off trimethyl silicane simultaneously and the condition of single or the two methyl ethers polar solvent that to be the steroidal compounds that will contain above-mentioned group dissolve each other with the HF aqueous solution and the water of 10-50% is hydrolyzed.The volume ratio of the solvent and the HF aqueous solution can be 1: 0.2-5, hydrolysis temperature are 0-80 ℃, and the reaction times is 0.5-20 hour.Recommending the respective volume ratio is 1: 0.5-2, and temperature is 10-30 ℃, the reaction times is 0.5-5 hour.Usually the mol ratio of HF and steroidal compounds is equivalent or 0.8-50: 1.
The condition of piptonychia ether, two methyl ether or Pyrrolidine is the steroidal compounds water of the above-mentioned group of tool and the polar solvent room temperature reaction in the presence of organic acid that dissolves each other with water among the present invention, reaction times 5-200 minute, organic acid and steroidal compounds mol ratio were 2-10: 1.Can also add silica gel in this reaction, help reaction and carry out.The silica gel add-on is that the steroidal raw material weight is than 0.5-2 times.Described organic acid adopts oxalic acid, propanedioic acid usually.
The 3-ketosteroid compound is that 3-ketosteroid compound and Pyrrolidine mol ratio are 1 with the reaction conditions of Pyrrolidine protection among the present invention: 1-10 is recommended as 1: 1-5.Reaction times 0.1-1 hour.Usually reaction is to reflux in the presence of polar solvent.
The reaction conditions that among the present invention 5 (10) monoene steroidal compounds is changed into 4,9 (10) diene steroidal compounds is in polar solvent, uses pyridinium bromide hydrobromate reacting by heating 1-10 hour.5 (10) monoene steroidal compounds are 1 with crossing pyridinium bromide hydrobromate weight ratio: 1-3.
Among the present invention with 5 (10), 9 (11) diene steroidal compounds change into 4,9 (10), the reaction conditions of 11 (12) triolefin steroidal compounds is in the presence of polar solvent or mixed solvent, at room temperature reacted 1-3 days with dichlorodicyanobenzoquinone, the mole ratio of diene steroidal compounds and dichlorodicyanobenzoquinone is 1: 1-5.
Steroidal compounds among the present invention (5) or (6) can convert (1) or (2) easily under acidic conditions, use mineral acid usually, example hydrochloric acid.Reaction times 0.5-5 hour.
The synthetic route of synthetic trifluoro-methyl steroid of the present invention is short, easy to operate, mild condition, yield height.And 17 beta-hydroxyl-17 alphas of the present invention-trifluoromethyl steroidal-3-ketone compounds has physiologically active, is the medicine of a class antiearly pregnancy, and other steroidal compounds of the present invention is important pharmaceutical intermediate.As steroidal compounds (1) than RU486 Senior Three doubly, for the Development of New Generation contraceptive bian provides strong evidence at its interceptive effect of in vitro tests.
Can further understand the present invention by following embodiment, but not place restrictions on content of the present invention.The compound testing method is as described below among the embodiment:
Fusing point: measured by Buchi 535 fusing point instrument, all melting point compounds are not all proofreaied and correct.
Optically-active: measured by Perkin Elmer 241MC type polarimeter, solvent is CHCl 3Concentration unit is g/100ml.
Infrared: Shimadazu IR-440 determination of infrared spectroscopy is arranged, and absorbance units is cm -1, unexplained reference is the Kbr pressed disc method.
Ultraviolet: measured by the quick ultraviolet spectrophotometer of HP 8451A type, solvent is EtOH.
Nucleus magnetic resonance fluorine spectrum: by Jeol FX-90Q type, EM360 nmr determination, CF 3COOH is an external standard, and chemical shift is ppm, and J value unit is Hz, and solvent is CDCl 3
Proton nmr spectra: TMS is interior mark by Bruker AM-300 type nmr determination, and chemical shift is ppm, and solvent is CDCl 3
Carbon-13 nmr spectra: by Bruck AM-300 type nmr determination, chemical shift unit is ppm, CDCl 3Be solvent.
Mass spectrum: measure by HP-5989A type mass spectrograph.
Ultimate analysis: measure by this institute analyzer room.
Column chromatography: the silica gel H of Haiyang Chemical Plant, Qingdao (10-40 μ), eluent are sherwood oil (60-90) and ethyl acetate.
The X-Ray crystalline diffraction, the X-Ray of Xiamen University test group.
Embodiment 1
13 methyl-17 β-trimethylsiloxy group-17 α-trifluoromethyls-5 (10)-female steroid alkene-3-ketone-3, the two methyl ethers (3) of 3-synthetic.
In the exsiccant 25ml reaction flask, with 104mg (21-1) 13-methyl-5 (10) female steroids-3,7-diketone-3, the two methyl ethers of 3-are dissolved among the 0.5mlTHF, add 5mgTMAF.4H 2O under the ice-water bath, adds 0.5mlTMSCF 3, rise to the stirring at room reaction, the rapid color burn of system, and emit gas, and stir after 1 hour, add 0.2mlTMSCF 3And 5mgTMAF.4H 2O, restir 0.5 hour is taken out THF, remaining thing 20mlCH 2Cl 2A small amount of filtered through silica gel is used in dissolving, and organic phase is taken out and desolvated, column chromatography for separation [sherwood oil (pet): EtOAc: Et 3N=100: 1: 1] the colourless chip solid 3 of 136mg, productive rate: 90%.
mp: 77.6-79.7℃ [α] 20 D +94.3(C.0.8,CHCl 3 19FNMR:(Py-D 6): -4.0(S,CF 3)ppm 1HNMR(Py-D 6): 3.14(S,3H,CH 3O),3.11(S,3H,CH 3O),
0.76(S,3H,18-CH 3),
0.11(S,9H,Si(CH 3) 3ppmIR(KBr): 1600,1160cm -1MS: 460(M +,8),445(M +-CH 3,1),
428 (M +-CH 3OH, 100), 396 (M +-2CH 3OH, 17) ultimate analysis: C 24H 39F 3O 3Si calculates: C.62.57% H.8.53% F.12.37% implement: C.62.55% H.8.75% F.12.34%
Embodiment 2
Synthesizing of 13-methyl-17 beta-hydroxyl-17 alpha-trifluoromethyl-4 (5)-female steroid alkene-3-ketone (1):
Under the room temperature, in the 50ml egg type bottle, 1.785g 3 (3.88mmol) is dissolved among the 8mlTHF, inject 6ml40%HF (aq), stirring reaction spends the night, and adds the dense HCl of 1.5ml then, continues to stir 3.5 hours, under the ice-water bath, be neutralized to alkalescence with the 3N NaOH aqueous solution, take out THF under the decompression, residuary water solution extracts (50ml * 3) with EtOAc, merge organic phase and use column chromatography (sherwood oil: ethyl acetate=7: 1) get 1.227g white styloid 1, productive rate: 92%.
Mp:225.5-227 ℃ [α] 20 D+ 48.3 (C.0.27, CHCl 3) IR (KBr): 3350,1620,1160cm -1UV (EtOH) λ max=242nm (ε max=1.04 * 10 4) 19FNMR:-2.6 (S, CF 3) ppm 1HNMR 5.84 (S, 1H, 4-H), 1.01 (S, 3H, 18-CH 3) ppm MS:342 (M +, 7.5), 324 (M +-H 2O, 2) ultimate analysis: C 19H 25F 3O 2Calculate: C.66.65% H.7.36% F.16.65% real side: C.66.34% H.7.31% F.17.28%
Embodiment 3
Synthesizing of 13-methyl-17 beta-hydroxyl-17 alpha-trifluoromethyl-5 (10)-female steroid alkene-3-ketone (5).
In the time of 25 ℃, 735mg3 (1.60mmol) is dissolved among 1ml acetone and the 2mlTHF, injects the 2ml40%HF aqueous solution, and under this temperature stirring reaction 2 hours, mixture with 3M NaOH (aq) or and to alkalescence, decompression is down taken out acetone and THF, adding 5ml H in the residue 2O, and use CH 2Cl 2Extract (20ml * 3), merge organic phase, with a small amount of silica gel filter once, organic phase uses column chromatography (Pet: EtOAc=7: 1) get colorless prismatic crystal 1 and 5 and be respectively 163mg and 241mg.Productive rate: 1,30% 5,44%.
Compound 5:
Mp:202.9-204.9 ℃ [α] 20 D+ 135.9 (C.0.91, CHCl 3)
Figure C9411218100121
IR:3400,1710,1150cm -1 19FNMR:-1.2 (S, CF 3) ppm 1HNMR:0.97 (S, 3H, 18-CH 3) ppmMS:342 (M +, 100) and ultimate analysis: C 19H 25F 3O 3Calculate: C.66.65% H.7.36% F.16.65% actual measurement: C.66.58% H.7.31% F.16.95%
Embodiment 4
Synthesizing of 13-methyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-5 (10)-female steroid alkene-3-ketone (7):
During room temperature, in the 25ml reaction flask, 342mg 3 (0.74mmol) is dissolved in 4ml acetone-H 2In O (75: the 15) solution, add 189mg propionic acid acid (1.82mmol), stirring reaction 2.5 hours under the ice-water bath, is used saturated NaHCO 3Be neutralized to slight alkalinity, take out acetone, aqueous solution Et 2O extracts (15ml * 3), merges organic phase, is washed till neutrality with saturated NaCl (aq), dry (NaSO 4), filter, take out and desolvate, column chromatography for separation (sherwood oil: ethyl acetate=100: 1) get the colourless tabular crystal 7 of 269mg.Productive rate: 87.4%.
mp: 106.2-106.5℃ [α] 20 D +135.9(C.0.38,CHCl 3) IR(KBr): 1730,1170cm -1 19FNMR: -4.2(S,CF 3)ppm 1HNMR 2.750(d,1H,4-H),2.747(d,1H,4-H),
0.88(S,3H,18-CH 3),
0.14 (S, 9H, Si (CH 3) 3) ppm MS:414 (M +, 31) and ultimate analysis: C 22H 33F 3O 2Si calculates: C.63.37% H.8.02% F.13.75% actual measurement: C.63.66% H.8.09% F.13.54%
Embodiment 5
Synthesizing of 13-methyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-4,9 (10)-female steroid diene-3-ketone (9):
In the time of 16 ℃, in the exsiccant 50ml reaction flask, 1.174g 7 (2.84mmol) is dissolved in the 8ml pyridine (doing), splashes into C 5H 5N.Br 2.HBr/ pyridine (1g/8ml), in 15 minutes, drip off, under this temperature, continue stirring reaction 3.5 hours, rise to 100 ℃ of following stirring reactions 1 hour then, take out pyridine under the decompression, under the ice-water bath, be neutralized to subacidity with the 5%HCl aqueous solution, the aqueous solution extracts (30ml * 3) with EtOAc, merges organic phase, use saturated NaCl solution successively, 5%NaHCO 3Solution, saturated NaCl solution washing, drying is filtered, and decompression is taken out and is desolvated, column chromatography for separation (sherwood oil: ethyl acetate=100: 3) get the colourless tabular crystal 9 of 869mg, productive rate: 74.4%.Compound 9:mp:113.0-115.2 ℃ [α] 16 D-181.2 (C.0.44, CHCl 3) IR (KBr): 1670,1170cm -1UV (EtOH) λ max=302nm (ε max=1.92 * 10 4) 19FNMR:-3.33 (S, CF 3) ppm 1HNMR 5.68 (S, 1H, 4-H), 1.00 (S, 3H, 18-CH 3),
0.15(S,9H,Si(CH 3) 3)ppmMS: 412(M +,61),397(M +-CH 3,6),
343(M +-CH 3,15),
322 (M +-(CH 3) 3SiOH, 68) ultimate analysis: C 22H 31F 3O 3Si calculates: C.64.04% H.7.57% F.13.02% actual measurement: C.63.97% H.7.48% F.13.08%
Embodiment 6
Synthesizing of 13-methyl-17 beta-hydroxyl-17 alpha-trifluoromethyl-4 (5), 9 (10)-estradienes-3-ketone (11):
Under the room temperature, in 25ml egg type bottle, 1.230g 9 (2.98mmol) is dissolved among the 3ml THF, add the 4ml 40%HF aqueous solution (84.22mmol), stirring reaction is 1.5 hours under this temperature, under ice-water bath, be neutralized to slight alkalinity with 3M NaOH (aq), mixed liquid extracts (50ml * 3) with EtOAc and merges organic phase, is washed till neutrality with saturated NaCl (aq), organic phase drying (NaSO 4), filter, take out the column chromatography for separation of desolvating (Pet: EtOAc: EtOH=70: 30: 0.3) under the decompression and obtain colorless prismatic crystal (Pet-EtOAc) 11,950mg.Productive rate: 93%.
mp: 202.9 204.9℃[α] 16 D -224.3·(C.0.37,CHCl 3)IR(KBr): 3350,1640,1595,1150cm -1UV(EtOH) λmax=304nm(εmax=1.36×10 4) 19FNMR: -2.3(S,CF 3)ppm 1HNMR 5.69(S,1H,4-H),1.12(S,3H,18-CH 3)ppm,MS: 340(M +,70),325(M +-CH 3,6),
322 (M +-CH 3, 7), ultimate analysis: C 19F 23F 3O 2Calculate: C.66.92% H.6.80% F.16.72% actual measurement: C.66.94% H.6.66% F.16.36%
Embodiment 7
Synthesizing of 13-methyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-3-(1-Pyrrolidine base)-3,5 (10), 9 (11)-female steroid triolefins (27):
In the dry egg shape of 25ml, 134mg 9 (0.32mmol) is dissolved in the 1.5ml anhydrous methanol, is heated to boiling reflux, inject 0.2ml (2.4mmol) Pyrrolidine, behind the 1min, yellow solid occurs, continue stirring and refluxing reaction 1 hour,, cross the freezing CH of filter solid with the ice-water bath cooling 3The OH washing, vacuum-drying gets 132mg yellow solid 27.Productive rate: 90%.
mp: 153.6-155.4℃ [α] 20 D -49.3·(C.0.367,CHCl 3) IR(KBr): 1660,1620,1170cm -1 UV(EtOH) λmax=342nm(εmax=1.41×10 4) 19FNMR: -3.6(S,CF 3)ppm 1HNMR 5.12(t,J=2.37,2.53Hz,1H,11-H),
4.87(S,1H,4-H),
(3.13 t, J=6.66,6.62Hz, 4H, 2.5-H-Pyrrolidine)
0.87(S,3H,18-CH 3)
0.13(S,9H,Si(CH 3) 3)ppm MS: 467(M +,+2,100)
Embodiment 8
Synthesizing of 13-methyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-5 (10), 9 (11)-estradienes-3-ketone (15):
In the 25ml egg type bottle, to 132mg 27 (0.29mmol) at 2ml acetone/H 2O (v/v, 75/15) in the suspension liquid, add 85mg propanedioic acid (0.81mmol, 3eq) with 100mg 200-300 purpose silica gel, 20 ℃ of following stirring reactions 1 hour, mixture pulled to tremble down pour in the 50ml frozen water, extract (100ml * 3) with EtOAc, take out a large amount of solvents (EtOAc) under the decompression, remaining organic phase is used saturated NaHCO successively 3(aq) saturated NaCl (aq) washing, drying is taken out and is desolvated, column chromatography for separation (Pet: EtOAc=100: 3, V/V) obtain colorless prismatic crystal (Pet/EtOAc) 15,92mg.Productive rate: 76%.
mp: 95.0-96.1℃ [α] 20 D +103.05(C.0.16,CHCl 3) IR(KBr): 1720,1660,1160cm -1 UV(EtOH) λmax=240nm(εmax=1.47×10 4) 19FNMR: -3.3(S,CF 3)ppm 1HNMR 5.63(t,J=2.68,2.58Hz,1H,11-H),
2.87(S,2H,4-H),0.87(S,3H,18-CH 3),
0.15(t,9H,Si(CH 3) 3)ppm MS: 412(M +,88),397(M +-CH 3,5),
343(M +-CF 3,4),322(M +-[(CH 3) 3]SiOH,26),
307 (M +-[(CH 3) 3SiOH-CH 3, 14) and high resolution mass spectrum: C 22H 31F 3O 2Si calculates: 412.2046 actual measurements: 412.2077
Embodiment 9
13-methyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-4 (5), 9 (10), 11 (12)-female steroids triolefin-3-ketone (17) synthetic:
In the time of 25 ℃, N 2Flow down, in the exsiccant 250ml band arm reaction flask, 431mg 15 (1.04mmol) is dissolved in 20ml anhydrous ethyl acetate and the 5ml dry-out benzene, and adding 620mg DDQ (2.58mmol, 2.5eq), room temperature, N 2Stirring reaction is 3 days under the protection, and ethyl acetate and benzene are taken out in decompression, and residue removes solid DDQ and DDQH with EtOAc-Pet (60-90 ℃) recrystallization (secondary) 2, merge mother liquor organic phase (200ml), use saturated NaHCO 3It is colourless that the aqueous solution is washed till the alkali layer, is washed till neutrality with the saturated NaCl aqueous solution, and drying is taken out and desolvated, column chromatography for separation (Pet: EtOAc=100: 1) get the colourless needle crystal of 343mg (Prt/EtOAc) 17.Productive rate: 74.98%.
mp: 112.9-114.0℃
[α] 15 D -19.2(C.0.14,CHCl 3)
IR(KBr): 1660,1580,1170cm -1
UV(EtOH) λmax=338nm(εmax=2.91×10 4)
19FNMR: -2.3(S,CF 3)ppm
1HNMR 6.48(t,J=11.87,1H,11-H?or?12-H),
6.43(d,J=10,20,1H,11-H?or?12-H),
5.78(S,1H,4-H),100(S,3H,18-CH 3)
0.16(S,9H,Si(CH 3) 3)ppm
MS: 410(M +,25.52),395(M +-CH 32.45),
320(M +-HOSi(CF 3) 3,12.51,
305(M +-CH 3-HOSi(CH 3) 3,5.80)
Ultimate analysis: C 22H 29F 3O 2Si
Calculate: C.64.36% H.7.12% F.13.89%
Actual measurement: C.64.37% H.7.13% F.13.94%
Embodiment 10
13-methyl-17 beta-hydroxyl-17 alpha-trifluoromethyl-4 (5), 9 (10), 11 (12)-female steroids triolefin-3-ketone (19) synthetic:
189mg 17 (0.4mmol) is dissolved in the 1.2mlTHF solvent, the adding 1.0ml 40%HF aqueous solution (21.05mmol, 4aq), at room temperature stirring reaction is 16 hours, mixture is neutralized to slight alkalinity with 3M NaOH (aq), extract (50ml * 3) with EtOAc, merge organic phase, be washed till neutrality with saturated NaCl (aq), dry, filter, take out EtOAc, column chromatography for separation (Pet: EtOAc=7: 1) obtain 132 light yellow styloids (Pet/EtOAc) 19.Productive rate: 85%.
mp: 196.1-197.2℃ [α] 15 D -56.3(C.0.28,CHCl 3) IR 3350,1660,1570,1160cm -1 UV(EtOH) λmax=340nm(εmax=3.42×10 5) 19FNMR: 1.6(S,CF 3)
1HNMR 6.48(S,2H,11,12-H),5.80(S,1H,4-H.),
1.09(S,3H,18-CH 3)ppm
13CNMR: 17.656,23.459,24.328,27.094?31.397,33.883,36.586,38.185,48.374,48.760,?82.983(q,2J=0.34ppm,17-C),123.711,123.844,?126.792(q,1J=3.79ppm,CF 3),127.614,139.357,140.828,?156.4,199.488
MS: 338(M +,100),320(M +-H 2O,13),
296(M +-CF 3,6.69)
Ultimate analysis: C 19H 21F 3O 2
Calculate: C.67.44% H.6.26% F.16.85%
Actual measurement: C.67.45% H.6.33% F.16.86%
Embodiment 11
Synthesizing of 13-ethyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-2 (3), 5 (10)-property steroid diene-3-methyl ether (24):
1g 13-ethyl-2 (3), 5 (10)-property steroid diene-17-ketone-3-methyl ether (22) is dissolved among the new anhydrous THF of steaming of 35ml, and the ice-water bath cooling adds 180mgTMAF, 2.3ml (CH down 3) 3SiCF 3, stirring at room reaction 10 hours, solvent is concentrated into dried, and column chromatography gets 24:1.367g, productive rate: 92.8%.
mp: 143.8-144.5℃
IR(KBr): 1250,1170cm -1
MS: 442(M +),427(M +-CH 3),413(M +-C 2H 5)
1HNMR: 3.48(S,3H,-Ome),
0.98(t,3H,J=7Hz,C 13-CH 2CH 3),
0.17(S,9H,-Si(CH 3) 3)ppm
19FNMR: +73.0ppm
Ultimate analysis: C 24H 37F 3O 2Si
Calculate: C.65.12% H.8.43% F.12.88%
Actual measurement: embodiment 12 F.12.64% H.9.00% C.65.44%
Synthesizing of 13-ethyl-17 beta-hydroxyl-17 alphas-trifluoromethyl-4 (5)-property steroid alkene-3-ketone (2):
Get (24) 250mg and be dissolved among the 3mlTHF, add the 2.5ml 40%HF aqueous solution, stirring at room 10 hours adds the dense HCl of 2ml again, and stirring at room 2 hours is handled by same procedure (3 → 1), and column chromatography gets (2), 165mg, productive rate: 81.94%.
mp: 168-170℃
IR(KBr): 3430,1660,1615,1150cm -1
UV(EtOH): 240nm(εmax=1.66×10 4)
MS: 356(M +),327(M +-C 2H 5)
1HNMR: 5.8(S,1H,4-H),
1.02(t,3H,J=7Hz,C 13-CH 2CH 3)ppm
19FNMR: +74.4ppm
Ultimate analysis: C 20H 27F 3O 2
Calculate: C.67.40% H.7.64% F.15.99%
Actual measurement: C.67.60% H.7.79% F.16.21%
Embodiment 13:
Synthesizing of 13-ethyl-17 β-three silyloxy-17 α-trifluoromethyl-5 (10)-property steroid alkene-3-ketone (8):
Get (24) 1g and add 60ml CH 3COCH 3, 12ml H 2O, 1g oxalic acid, stirring at room 6 hours treats that the limpid back of solution adds saturated NaHCO under the ice-water bath cooling 3Liquid is neutralized to slight alkalinity, filters filter residue CH 2Cl 2Wash, filtrate is used CH after under reduced pressure taking out most of solvent 2Cl 2Extraction merges CH 2Cl 2Liquid, drying, removal of solvent under reduced pressure, column chromatography gets (8): 870mg, productive rate: 89.8%.
mp: 136-137℃
IR(KBr): 1720,1250,1165cm -1
MS: 428(M +),399(M +-C 2H 5)
1HNMR: 0.95(t,3H,J=7Hz,C 13-CH 2CH 3),
0.18(S,9H,SiMe 3)ppm
19FNMR: +72.3ppm
Ultimate analysis: C 23H 35F 3O 2Si
Calculate: C.64.45% H.8.23% F.13.30%
Actual measurement: C.64.40% H.8.65% F.13.38%
Embodiment 14
Synthesizing of 13-ethyl-17 β-three silyloxy-17 α-trifluoromethyl-4 (5), 9 (10)-property steroid diene-3-ketone (10):
Get (8) 870mg, add the 4ml anhydrous pyridine, drip 4ml under stirring and contain the anhydrous pyridine solution that 630mg crosses the pyridinium bromide hydrobromate, handle by same procedure (7 → 9), column chromatography gets (9) 810mg, productive rate 93.54%.
mp: 123-124℃
IR(KBr): 1665,1660,1250,1170cm -1
UV(EtOH): 304nm(εmax=1.98×10 4)
MS: 426(M +),397(M +-C 2H 5)
1HNMR: 5.65(S,1H,4-H),
1.0(t,3H,J=7Hz,C 13-CH 2CH 3),
0.16(S,9H,SiMe 3)ppm
19FNMR: +72.5ppm
Ultimate analysis: C 23H 33F 3O 2Si
Calculate: C.64.70% H.7.87% F.13.35%
Actual measurement: C.64.96% H.8.05% F.13.02%
Embodiment 15
Synthesizing of 13-ethyl-17 beta-hydroxyl-17 alphas-trifluoromethyl-4 (5), 9 (10)-property steroid diene-3-ketone (12):
190mg (10) is dissolved among the 1.5mlTHF, adds the 2ml 40%HF aqueous solution, and stirring at room 10 hours is handled by same procedure (9 → 11), and column chromatography gets (12): 125mg, productive rate: 79.17%.
mp: 168.6-169.2℃
IR(KBr): 3400,1640,1660,1150cm -1
UV(EtOH): 302nm(εmax=2.12×10 4)
MS: 354(M +),336(M +-H 2O),325(M +-C 2H 5)
1HNMR: 5.65(S,1H,C 4-H),
1.05(S,3H,J=7Hz,C 13-CH 2CH 3)ppm
19FNMR: +74.2ppm
Ultimate analysis: C 20H 25F 3O 2
Calculate: C.67.78% H.7.11% F.16.08%
Actual measurement: C.67.96% H.7.18% F.16.17%
Embodiment 16
Synthesizing of 13-ethyl-17 β-three silyloxy-17 α-trifluoromethyl-3-(1-Pyrrolidine base)-3,5 (10), 9 (11)-property steroid triolefins (28):
Add the anhydrous methanol that 5ml handled among the 800mg (10), be heated to the back adding 1.3ml Pyrrolidine that boils, continue the half an hour of refluxing, bathe about 80 ℃ of temperature, cold after-filtration washes twice with freezing methyl alcohol, dry (28): 839mg, the productive rate: 93.27% of getting.
Embodiment 17
Synthesizing of 13-ethyl-17 β-three silyloxy-17 α-trifluoromethyl-5 (10), 9 (11)-property steroid diene-3-ketone (16):
(28) 800mg is put into the 150ml flask, add CH 3COCH 360ml, H 2O 12ml, propanedioic acid 550mg, 200-300 order silica gel 1g, stirring at room 40 minutes, the limpid back of solution is divided and is removed silica gel, and ice-water bath is cold to remove down to use saturated NaHCO 3Be neutralized to slight alkalinity, most of solvent is taken out in decompression, and EtOAc extracts, drying, and column chromatography gets (16): 481mg, productive rate: 67.6%.
IR(KBr): 1720,1258,1160cm -1
UV(EtOH): 240nm(εmax=1.35×10 4)
MS: 426(M +),397(M +-C 2H 5)
1HNMR: 5.65(d,1H,J=5.6Hz,C 11-H)
0.91(t,3H,J=7.2Hz,C 13-CH 2CH 3)ppm
19FNMR: +73.1ppm
High resolution mass spectrum: C 23H 33F 3O 2Si
Calculate: 426.2202
Actual measurement: 426.2212
Embodiment 18
13-ethyl-17 β-three silyloxy-17 α-trifluoromethyl-4 (5), 9 (10), 11 (12)-property steroid triolefins-3-ketone (18) synthetic:
Add the anhydrous FtOAc11.6ml dry-out benzene of 8.7ml, N among the 400mg (16) 2Add dichlorodicyanobenzoquinone 560mg, N 2Stirring at room is 20 hours under the atmosphere, EtOAc dilute reaction solution, saturated NaHCO 3It is colourless substantially that it is washed till the buck layer, the no Na of organic layer 2SO 4Drying, decompression is taken out and is desolvated, and column chromatography gets (18): 262mg, productive rate: 65.8%.
IR(KBr): 1670,1580,1258,1170cm -1
UV(EtOH): 338nm(εmax=2.36×10 4)
MS: 424(M +),395(M +-C 2H 5),409(M +-CH 3)
1HNMR:6.52 (m, 2H, C 11And C 12-H), 5.78 (S, 1H, 4-H),
1.0(t,3H,J=7.3Hz,C 13-CH 2CH 3),
0.18(S,9H,SiMe 3)ppm
19FNMR: +73.2ppm
High resolution mass spectrum: C 23H 31F 3O 2
Calculate: 424.2045
Actual measurement: 424.2043
Embodiment 19
13-ethyl-17 beta-hydroxyl-17 alphas-trifluoromethyl-4 (5), 9 (10), 11 (12)-property steroid triolefins-3-ketone (20) synthetic:
20 ℃ are dissolved in (18) 200mg among the 2.5mlTHF, add the 2.5ml 40%HF aqueous solution, stirring reaction 10 hours, and 3NNaOH is neutralized to alkalescence, and EtOAc extracts, anhydrous Na 2HO 4Drying, control is taken out in decompression, and column chromatography gets (20): 130mg, productive rate: 78.3%.
mp: 180.2-181℃
IR(KBr): 3360,1650,1570,1162cm -1
UV(EtOH): 340nm(εmax=2.49×10 4)
238nm(εmax=6.89×10 3)
MS: 352(M +),323(M +-C 2H 5)
1HNMR: 6.55(m,2H,C 11,C 12-H),5.8(S,1H,C 4-H),
1.02(S,3H,J=7.35Hz,C 13-CH 2CH 3)ppm
19FNMR: +74.7ppm
High resolution mass spectrum: C 20H 23F 3O 2
Calculate: 352.1650
Actual measurement: 352.1652
Embodiment 20
The absolute configuration that the monocrystalline X-Ray crystalline diffraction method of compound 1 is measured
Figure C9411218100231
Embodiment 21
Three kinds of compounds are to the avidity of rat uterus cytosol PgR:
Low temperature is adopted in experiment, ultracentrifugation, and the DCC method, according to [ 3H] R 5020Have the highly feature of specificity avidity with Pre, it is active with combining of rat uterus cytosol PgR to use competition experiments comparative compound 1,11,19 and RU486.As the avidity with RU486 and PgR power is 100, and then they are compared with RU486, and its relative affinity was respectively 1: 291.6,11: 77.8,19: 38.9, from above-mentioned data as can be known, the activity of compound 1 is 3 times of RU486, and 11,19 activity is only poor slightly than RU486.

Claims (10)

1. trifluoro-methyl steroid is characterized in that having following structural formula: R wherein 1=CH 3Or C 2H 5, R 2=OH or OSi (CH 3) 3, R 3=R 4Or R 3Or R 4=CH 3O, R 3R 4=O,
Figure C9411218100022
2. a trifluoromethyl steroid compound as claimed in claim 1 is characterized in that 13-methyl-17 beta-hydroxyl-17 alpha-trifluoromethyl-4 (5)-female steroid alkene-3-ketone.
3. a trifluoro-methyl steroid as claimed in claim 1 is characterized in that 13-ethyl-17 beta-hydroxyl-17s-α-trifluoromethyl-4 (5)-property steroid alkene-3-ketone.
4. a trifluoro-methyl steroid as claimed in claim 1 is characterized in that 13-methyl-17 beta-hydroxyl-17-α-trifluoromethyl-4 (5), 9 (10)-estradienes-3-ketone.
5. a trifluoro-methyl steroid as claimed in claim 1 is characterized in that 13-ethyl-17 beta-hydroxyl-17 beta-hydroxyl-17 alpha-trifluoromethyl-4 (5), 9 (10)-property steroid diene-3-ketone.
6. a trifluoro-methyl steroid as claimed in claim 1 is characterized in that 13-methyl-17 beta-hydroxyl-17 alpha-trifluoromethyl-4 (5), 9 (10), 11 (12)-female steroids triolefin-3-ketone.
7. a trifluoro-methyl steroid as claimed in claim 1 is characterized in that 13-ethyl-17 beta-hydroxyl-17s-α-trifluoromethyl-4 (5), 9 (10), 11 (12)-property steroid triolefin-3-ketone.
8. the preparation of a trifluoro-methyl steroid as claimed in claim 1 comprises having carbonyl steroidal compounds and Me 4NF and CF 3SiMe 3Carry out the trifluoromethylation reaction, perhaps the trifluoromethyl silicon ether steroidal compounds of Sheng Chenging is hydrolyzed with the polar solvent that the HF aqueous solution and the water of 10-50% dissolves each other, perhaps trifluoromethyl silicon ether steroidal compounds water and the polar solvent piptonychia ether or the two methyl ether in the presence of organic acid that dissolve each other with water.Perhaps used pyridinium bromide hydrobromate or dichlorodicyanobenzoquinone to carry out ethylene linkage conversion in the steroidal ring through the trifluoromethyl silicon ether steroidal compounds of piptonychia ether or two methyl ethers, perhaps the steroidal compounds after ethylene linkage transforms is hydrolyzed with the polar solvent that the HF aqueous solution and the water of 10-50% dissolves each other again, it is characterized in that and can make respectively with following step:
A, described carbonyl steroidal compounds is 13-methyl or ethyl-5 (10)-female steroid alkene or property steroid alkene-3,17-diketone-3, the two methyl ethers (21) of 3-, 13-methyl or ethyl-2 (3), 5 (0)-estradienes or property steroid diene-17-ketone-3-methyl ether (22), 13-methyl or ethyl-5 (10), 9 (11) estradienes or property steroid diene-3,17-diketone-3, the two methyl ethers (25 of 3-, or 26), described trifluoromethyl silicon ether compound is 13-methyl or ethyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-5 (10)-female steroid alkene or property steroid alkene-3-ketone-3, the two methyl ethers (3 or 4) of 3-, 13-methyl or ethyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-2 (3), 5 (10)-estradienes or property steroid diene-3-methyl ether (23 or 24), 13-methyl or ethyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-5 (10), 9 (11)-estradienes or property steroid diene-3-ketone-3, the two methyl ethers (13 or 14) of 3-;
Or b, with above-mentioned steroidal compounds (3), (4), (23), (24), (13), (14) through piptonychia ether or two methyl ether and trimethyl silicon based 13-methyl or ethyl-17 beta-hydroxyl-17 alphas-trifluoromethyl-4 (5)-female steroid alkene or the property steroid alkene-3-ketone (1 or 2) of getting respectively, 13-methyl or ethyl-17 beta-hydroxyl-17 alphas-trifluoromethyl-5 (10)-female steroid alkene or property steroid alkene-3-ketone (5 or 6), 13-methyl or ethyl-17 beta-hydroxyl-17 alphas-trifluoromethyl-4 (5), 9 (10)-estradienes or property steroid diene-3-ketone (11 or 12);
Or c, with above-mentioned steroidal compounds (3), (4), (23), (24), (13), (14) are through piptonychia ether or the resulting 13-methyl of two methyl ether or ethyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-5 (10)-female steroid alkene or property steroid alkene-3-ketone (7 or 8), 13-methyl or ethyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-5 (10), 9 (11)-estradienes or property steroid diene-3-ketone (15 or 16);
Or d, with above-mentioned steroidal compounds (7), (8) or (15), (16) get 13-methyl or ethyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-4 (5) through being converted into diene or triolefin respectively, 9 (10)-estradienes or property steroid diene-3-ketone (9 or 10), 13-methyl or ethyl-17 β-trimethylsiloxy group-17 α-trifluoromethyl-4 (5), 9 (10), 11 (12)-female steroid triolefins or property steroid triolefin-3-ketone (17 or 18);
Or e, with above-mentioned steroidal compounds (9), (10), (17), (18) get 13-methyl or ethyl-17 beta-hydroxyl-17 alphas-trifluoromethyl-4 (5) through taking off the trimethyl silicane radical reaction, 9 (10) ,-estradiene or property steroid diene-3-ketone (11 or 12), 13-methyl or ethyl-17 beta-hydroxyl-17 alphas-trifluoromethyl-4 (5)-9 (10), 11 (12)-female steroid triolefins or property steroid triolefin-3-ketone (19 or 20);
Or f, with above-mentioned steroidal compounds (9), (10) through Pyrrolidine protect 13-methyl or ethyl-17 β-trimethylsiloxy group 17 α-trifluoromethyl-3 (4), 5 (10), 9 (11)-female steroid triolefins or property steroid triolefin-3-Pyrrolidine base, get steroidal compounds (15), (16) through taking off the Pyrrolidine protecting group again;
Or g, with above-mentioned steroidal compounds (5), (6) are carried out the cyclic olefinic bond translocation reaction with concentrated hydrochloric acid and are obtained steroidal compounds (1), (2).
10. purposes as claim 3,4,5,6,7 or 8 described trifluoro-methyl steroids is characterized in that being used to prepare the medicine of antiearly pregnancy.
11. the purposes of a trifluoro-methyl steroid as claimed in claim 1 or 2 in the medicine of preparation antiearly pregnancy, it is characterized in that described compound is 13-methyl or ethyl-17 beta-hydroxyl-17 alphas-trifluoromethyl-4 (5)-female steroid alkene or property steroid alkene-3-ketone.
CN 94112181 1994-05-30 1994-05-30 Trifluoro-methyl steroid, preparation and its application Expired - Fee Related CN1072678C (en)

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