CN1097763A - Trifluoro-methyl steroid, preparation and uses thereof - Google Patents

Abstract

The invention provides a 13-methyl or ethyl-3,3-dimethoxy or carbonyl-17-hydroxyl or trimethylsilyloxy-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 steroid compounds. Can use trifluoromethylation reaction, or again By demethylation or detrimethylsilyloxy, or transposition of olefinic bonds in the steroidal ring or Conversion reaction synthesis. Not only the synthetic route is short, the operation is convenient and the yield is high, Moreover, intermediates and anti-early pregnancy drugs for the synthesis of anti-early pregnancy drugs are provided things.

Description

Trifluoromethyl steroid compound, preparation and use thereof

The present invention relates to a steroidal organic compound, specifically a 17-trifluoromethyl steroidal compound with physiological activity, its preparation and use.

The rapid growth of the world's population will bring many problems to the self-development balance of human beings. In order to effectively control the population, finding effective, safe and reliable contraceptive methods is the subject that scientists are striving to explore. Anti-conception drugs are the implementation of family planning and control One of the important measures for population growth, however, the currently widely used steroidal anti-pregnancy drugs have certain shortcomings and deficiencies, and the search for steroidal drugs with unique curative effect, small side effects, high biological potency and convenient use has become a research topic for family planning in various countries. common goal.

According to the long-term research on steroidal anti-pregnancy drugs, there is a close relationship between molecular structure and biological potency. When the 10-position methyl group is removed from the steroid molecule, the flexibility of the molecule is increased and different charge distributions are caused, which increases the molecular weight. And progesterone receptor affinity, so as to achieve the purpose of anti-pregnancy. In addition, when the steroid extends the conjugated double bond from 4(5) double bond to 4(5), 9(10) diene, it can deform the A ring, resulting in a decrease in affinity with the androgen receptor, When 4(5), 9(10) dienes become 4(5), 9(10), 11(12) trienes, the conformation of the A ring is more stable, and the affinity with the progesterone receptor is increased. At the same time, it also increases the affinity with the androgen receptor and so on.

Chinese Academy of Sciences Shanghai Institute of Organic Chemistry once reported the synthetic method of 18-norethindrone, norethindrone and 18-methylnorethindrone [Acta Chemicals, 33 (2), 139 (1975); 37 (1), 1 (1979)], norethindrone and 18-methyl ketone are all oral contraceptives commonly used at home and abroad at present, norethindrone and 18-methyl norethindrone are very Good contraceptives, the latter compatible with prostaglandins for anti-early pregnancy have long been identified in Shanghai, but they all have certain shortcomings, either they need to be taken every day, or they may cause abnormal liver function during the medication.

During the research and development of new drugs from the structure-activity relationship of molecules, chemists and pharmacologists have found that many compounds introduced with fluorine atoms have greatly changed their activities (physical, chemical, biological, etc.), especially in the molecules. The changes in their properties are particularly obvious after the introduction of trifluoromethyl groups, so both synthetic chemists and pharmacologists have conducted long-term and in-depth studies on the synthesis and pharmacology of trifluoromethyl-introduced molecules.

It is more difficult to introduce a trifluoromethyl group into a molecule than a single fluorine atom. So far, people have made great efforts in this area, and many effective methods and reagents have been found. Various methods, reagents They all have their own characteristics. The addition reaction of trifluoromethylation reagents to carbonyl groups to introduce trifluoromethyl groups is Me ₃ SiCF ₃ (TMSCF ₃ ), which is the most effective. Carbonyl compounds undergo addition reactions, and the reagent can also undergo coupling reactions with aryl and alkenyl halides. In the addition reaction to carbonyls, the conditions are mild, side reactions are few, and the yield is high, and the reagent is easy Preservation and other advantages, so it becomes a very useful trifluoromethylation tool in synthesis. People such as Xu Yuanyao use trifluoromethyl block method to introduce trifluoromethyl [CN90106105] on the side chain of steroid conveniently, also once reported to use TMSCF ₃ to introduce trimethyl to synthesize steroid compound [Bioorganic Chem, 21,330 (1993)]. Wang Zhongqi et al. have reported a trifluoromethyl steroid compound with trifluoromethyl and hydroxyl on the same carbon atom on the C17 position or its extendable side chain and its preparation method [CN93112563.4] that is, at the 17 position or Steroidal compounds with carbonyl groups on their side chains undergo addition reactions with Me ₄ NF and CF ₃ SiMe ₃ at a molar ratio of 1:0.5-5:0.5-10 to generate trifluoromethylsilyl ether steroidal compounds. The temperature is -10-80 ° C, the reaction time is 1 minute to 10 hours, and then the trifluoromethyl silicon ether steroid compound is hydrolyzed with 10-50% HF aqueous solution and a polar solvent miscible with water, and the solvent and HF aqueous solution The volume ratio can be 1:0.2-5, the hydrolysis temperature is 0-80°C, and the reaction time is 0.5-20 hours. This method provides an important way for the synthesis of new drugs containing trifluoromethyl steroids. So far, the synthesis of trifluoromethyl steroid analogues, the exploration of their physiological activities, and the search for and development of valuable new drugs are still topics of concern to chemists from all over the world.

The object of the present invention is to provide a trifluoromethyl steroid compound, its preparation and its use.

The trifluoromethyl steroid compound provided by the present invention is a kind of 13-methyl or ethyl-3,3-bismethoxy or carbonyl-17-hydroxyl or trimethylsilyloxy-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 ) dienes or -4(5), 9(10), 11(12) triene steroids.

其中R₁＝CH₃或C₂H₅，R₂＝OH或OSi(CH₃)₃，R₃＝R₄或R₃或R₄＝CH₃O，R₃R₄＝0

或

Trifluoromethyl steroids of the present invention have the following structural formula:

wherein R ₁ =CH ₃ or C ₂ H ₅ , R ₂ =OH or OSi(CH ₃ ) ₃ , R ₃ =R ₄ or R 3 or _{R 4 =} CH ₃ O, R ₃ R ₄ =0

or

Such as 13-methyl-17-hydroxyl-17-trifluoromethyl-4(5)estren-3-one (1), 13-ethyl-17-hydroxyl-17-trifluoromethyl-4( 5) Steren-3-one (2), 13-methyl-17-trimethylsilyloxy-17-trifluoromethyl-5(10)estren-3-one-3,3- Dimethyl ether (3), 13-ethyl-17-trimethylsilyloxy-17-trifluoromethyl-5(10)steren-3-one-3,3-dimethyl ether (4) , 13-methyl-17-hydroxyl-17-trifluoromethyl-5(10)estren-3-one (5), 13-ethyl-17-hydroxyl-17-trifluoromethyl-5( 10) sex steten-3-one (6), 13-methyl-17-trimethylsilyloxy-17-trifluoromethyl-5 (10) estroten-3-one (7), 13 -Ethyl-17-trimethylsilyloxy-17-trifluoromethyl-5(10)steren-3-one (8), 13-methyl-17-trimethylsilyloxy-17 -Trifluoromethyl-4(5), 9(10)-estradien-3-one(9), 13-ethyl-17-trimethylsilyloxy-17-trifluoromethyl-4 (5), 9(10)-osteradien-3-one (10), 13-methyl-17-hydroxy-17-trifluoromethyl-4(5), 9(10) estradiene -3-ketone (11), 13-ethyl-17-hydroxyl-17-trifluoromethyl-4 (5), 9 (10) steroid-3-one (12), 13-methyl- 17-trimethylsilyloxy-17-trifluoromethyl-5(10), 9(11)estradien-3-one-3,3-dimethylether(13), 13-ethyl- 17-trimethylsilyloxy-17-trifluoromethyl-5(10), 9(11)-steradien-3-one-3,3-dimethylether(14), 13-methyl- 17-trimethylsilyloxy-17-trifluoromethyl-5(10), 9(11)estradien-3-one(15), 13-ethyl-17-trimethylsilyloxy -17-trifluoromethyl-5(10), 9(11)steradien-3-one(16), 13-methyl-17-trimethylsilyloxy-17-trifluoromethyl- 4(5), 9(10), 11(12) estratrien-3-one(17), 13-ethyl-17-trimethylsilyloxy-17-trifluoromethyl-4(5 ), 9(10), 11(12) stertriene-3-one (18), 13-methyl-17-hydroxyl-17-trifluoromethyl-4(5), 9(10), 11 (12) Estratrien-3-one (19), 13-ethyl-17-hydroxyl-17-trifluoromethyl-4(5), 9(10), 11(12)- 3-keto (20) etc.

或

The trifluoromethyl steroid compound provided by the invention may also have the following structural formula: wherein R ₁ =CH ₃ or C ₂ H ₅ , R ₂ =OH or OSi(CH ₃ ) ₃ , R ₃ =R ₄ or R 3 or R ₄ =CH ₃ O, R _{3 R 4 =} 0,

or

The above-mentioned 17-trimethylsilyloxy-17-trifluoromethyl steroid compound provided by the present invention is an important intermediate, which can become 17-hydroxyl-17-trifluoromethyl steroid-3-one after hydrolysis Compound, and this kind of compound has physiological activity, is a kind of anti-early pregnancy drug.

The present invention also provides a method for synthesizing the above-mentioned trifluoromethyl steroid compound. The method of the present invention is mainly to use TMSCF ₃ and TMAF reagent to introduce trifluoromethyl and trimethyl at the 17-position to the 17-ketosteroid compound protected by methyl ether, dimethyl ether or tetrahydropyrrolyl at the 3-position of industrial semi-finished products Siloxyl to give steroidal compounds of 17-trimethylsilyloxy-17-trifluoromethyl-3-methyl ether or 3,3-dimethyl ether. It can be hydrolyzed to remove -3-methyl ether or 3,3-dimethyl ether to form the corresponding 17-trimethylsilyloxy-17-trifluoromethyl steroid 3-one compound, and can also remove 3- Methyl ether or 3,3-dimethyl ether and 17-trimethylsiloxy to 17-hydroxyl-17-trifluoromethyl steroid 3-ketone compound. The ethylenic bond in the steroidal ring can be transferred or the monoene can be converted into a diene, which in turn can be converted into a triene. It is also possible to carry out the conversion of the steroidal ringene before the hydrolysis, or to carry out the hydrolysis afterwards. The 17-hydroxyl-17-trifluoromethyl steroid anti-early pregnancy drug in the present invention can be produced by hydrolysis of 17-trimethylsiloxy-17-trifluoromethyl steroid compound.

The process of the invention can start from industrial semi-finished products. The simple method is described as follows: with 13-methyl or ethyl-5 (10) estrogen or sex sterene-3,17-dione-3,3-dimethyl ether (21) or 13-methyl or ethyl Base-2(3), 5(10)-estradiene or sexosteradien-17-one-3-methyl ether (22) as raw materials, introduce trifluoromethyl through trifluoromethylation reaction, generate Steroidal compound (3), (4) or 13-methyl or ethyl-17-trimethylsilyloxy-17-trifluoromethyl-2(3), 5(10)-estradiene ( 23) Orthosteroid (24)-3-methyl ether, steroidal compound (3), (4), (23) or (24) is produced after removing monomethyl ether or dimethyl ether and trimethyl silicon Steroidal compound (5), (6) or (1), (2). Steroidal compounds (5) and (6) can be converted into steroidal compounds (1) and (2) with concentrated hydrochloric acid.

Steroidal compounds (3), (4) or (23), (24) can also be reacted with demethylated ether or dimethyl ether to generate steroidal compounds (7) or (8). Steroids (7) and (8) can be transformed into steroids (9) and (10) through olefin transposition.

Steroidal compounds (9) and (10) are detrimethylsilylated to generate steroidal compounds (11) and (12).

13-methyl or ethyl-5(10), 9(11) estrodiene (25) or sex stediene (26)-3,17-dione-3,3-dimethyl ether for industrial semi-finished products Generate steroid compound (13) and (14) for raw material through trifluoromethylation reaction, (13) or (14) can obtain steroid compound (11) or (12) through dedimethyl ether and trimethyl silicon reaction ). (13) or (14) can also be dedimethylated to obtain steroidal compound (15) or (16).

Steroidal compound (9) or (10) can obtain 13-methyl or ethyl-17-trimethylsilyloxy-17-trifluoromethyl-3,5(10),9 (11) Estratriene (27) or estratriene (28)-3-(1-tetrahydropyrrolyl), steroidal compound (27) or (28) can be obtained by detetrahydropyrrole protecting group Compound (15) or (16).

Steroidal compound (15) or (16) can generate triene steroidal compound (17) or (18) through transposition reaction.

Steroidal compound (17) or (18) is detrimethylsilylated to obtain steroidal compound (19) or (20).

The reaction pathway can be represented by the following formula:

The trifluoromethylation reaction in the method of the present invention is that the steroid compound with 17-keto group and (CH ₃ ) ₄ NF and CF ₃ Si(CH ₃ ) ₃ are respectively in a molar ratio of 1:0.5-5: 0.5-10 for addition reaction, the reaction temperature is -10-80°C, and the reaction time is 1 minute to 10 hours. The recommended molar ratio is 1:0.5-1.5:0.5-2, the addition reaction temperature is 0-40°C, and the reaction time is 1 minute to 5 hours.

In the present invention, the condition for removing trimethylsilicon or simultaneous removal of trimethylsilicon and mono- or dimethyl ether is that the steroid compound containing the above groups is carried out with 10-50% HF aqueous solution and a water-miscible polar solvent. hydrolysis. The volume ratio of solvent and HF aqueous solution can be 1:0.2-5, the hydrolysis temperature is 0-80°C, and the reaction time is 0.5-20 hours. The recommended corresponding volume ratio is 1:0.5-2, the temperature is 10-30°C, and the reaction time is 0.5-5 hours. Usually the molar ratio of HF to steroid is equivalent or 0.8-50:1.

甾体化合物用水和与水互溶的极性溶剂在有机酸存在下室温反应，反应时间5-200分钟，有机酸与甾体化合物克分子比为2-10∶1。该反应中还可以加入硅胶，有利于反应进行。硅胶加入量为甾体原料重量比0.5-2倍。所述的有机酸通常采用草酸、丙二酸。The condition of demethyl ether, dimethyl ether or tetrahydropyrrole among the present invention is to have the above-mentioned group

The steroid compound is reacted with water and a water-miscible polar solvent at room temperature in the presence of an organic acid, the reaction time is 5-200 minutes, and the molar ratio of the organic acid to the steroid compound is 2-10:1. Silica gel can also be added in this reaction, which is beneficial to the reaction. The amount of silica gel added is 0.5-2 times the weight ratio of steroid raw materials. Described organic acid usually adopts oxalic acid, malonic acid.

The reaction condition for protecting 3-ketosteroid compound with tetrahydropyrrole in the present invention is that the molar ratio of 3-ketosteroid compound to tetrahydropyrrole is 1:1-10, preferably 1:1-5. The reaction time is 0.1-1 hour. Typically the reaction is refluxed in the presence of a polar solvent.

In the present invention, the reaction condition that 5 (10) monoene steroid compound is changed into 4,9 (10) diene steroid compound is in polar solvent, with perbrominated pyridinium hydrobromide heating reaction 1-10 Hour. The weight ratio of 5(10) monoene steroid compound to perbrominated pyridinium hydrobromide is 1:1-3.

In the present invention, 5(10), 9(11) diene steroid compound is converted into 4,9(10), 11(12) The reaction condition of triene steroid compound is in the presence of polar solvent or mixed solvent, Reacting with dichlorodicyanoquinone at room temperature for 1-3 days, the molar ratio of dien steroid compound to dichlorodicyanoquinone is 1:1-5.

In the present invention, the steroid compound (5) or (6) can be conveniently converted into (1) or (2) under acidic conditions. Typically a mineral acid such as hydrochloric acid is used. The reaction time is 0.5-5 hours.

The trifluoromethyl steroid compound synthesized by the invention has the advantages of short synthesis route, convenient operation, mild conditions and high yield. Moreover, the 17-hydroxyl-17-trifluoromethyl steroid-3-one compound of the present invention has physiological activity and is a class of anti-early pregnancy drugs, and other steroid compounds of the present invention are important drug intermediates. For example, the anti-early pregnancy effect of the steroid compound (1) is three times higher than that of RU486 in vitro, which provides strong evidence for the development of a new generation of contraceptives.

The present invention can be further understood through the following examples, but the content of the present invention is not limited. Compound test method is as follows in the embodiment:

Melting point: measured by Buchi535 melting point apparatus, all melting points of compounds are not corrected.

Optical rotation: determined by a Perkin Elmer241MC polarimeter, the solvent is CHCl ₃ and the concentration unit is g/100ml.

Infrared: measured by Shimadazu IR-440 infrared spectrometer, the absorption unit is cm ^-1 , unless otherwise stated, it is KBr tablet method.

Ultraviolet: measured by HP8451A fast ultraviolet spectrophotometer, the solvent is EtOH.

Fluorine nuclear magnetic resonance spectrum: determined by Jeol FX-90Q, EM360 nuclear magnetic resonance instrument, CF ₃ COOH as external standard, chemical shift in ppm, J value in Hz, solvent in CDCl ₃ .

Proton nuclear magnetic resonance spectrum: TMS was determined by Bruker AM-300 nuclear magnetic resonance instrument as the internal standard, the chemical shift was ppm, and the solvent was CDCl ₃ .

Carbon nuclear magnetic resonance spectrum: measured by Bruck AM-300 nuclear magnetic resonance instrument, chemical shift unit is ppm, CDCl ₃ is solvent.

Mass spectrum: measured by HP-5989A mass spectrometer.

Elemental analysis: determined by the analysis room of our institute.

Column chromatography: silica gel H (10-40μ) from Qingdao Ocean Chemical Factory, the eluent is petroleum ether (60-90) and ethyl acetate.

X-Ray Crystal Diffraction: X-Ray Test Group of Xiamen University.

Example 1

Synthesis of 13-methyl-17-trimethylsilyloxy-17-trifluoromethyl-5(10)-estren-3-one-3,3-dimethylether (3):

In a dry 25ml reaction bottle, dissolve 104mg (21-1) 13-methyl-5(10)estra-3,7-dione-3,3-dimethylether in 0.5ml THF, add 5mgTMAF.4H ₂ O, under an ice-water bath, add 0.5mlTMSCF ₃ , rise to room temperature and stir to react, the system rapidly darkens and releases gas, after stirring for 1 hour, add 0.2mlTMSCF ₃ and 5mgTMAF.4H ₂ O, stir for another 0.5 hour, pump Remove THF, dissolve the residue with 20ml _CH2Cl2 , filter with a small amount of silica gel, remove the solvent from _the organic phase, and separate by column chromatography [petroleum ether (pet): EtOAc: _Et3 N=100:1:1] to obtain 136mg Colorless flaky solid 3, yield: 90%.

mp: 77.6-79.7℃

[α] ²⁰ D +94.3° (C.0.8, CHCl ₃ )

¹⁹ FNMR: (Py-D ₆ ): -4.0 (S, CF ₃ ) ppm

¹ HNMR (Py-D ₆ ): 3.14 (S, 3H, CH ₃ O), 3.11 (S, 3H, CH ₃ O),

0.76 (S, 3H, 18-CH ₃ ),

0.11(S, 9H, Si(CH ₃ ) ₃ )ppm

IR(KBr): 1600, 1160cm ^-1

MS: 460 (M ⁺ , 8), 445 (M ⁺ -CH ₃ , 1),

428(M ⁺ _-CH3OH , 100), 396(M ⁺ _-2CH3OH , 17)

Elemental analysis: C ₂₄ H ₃₉ F ₃ O ₃ Si

Calculation: C.62.57% H.8.53% F.12.37%

Solid side: C.62.55% H.8.75% F.12.34%

Example 2

Synthesis of 13-methyl-17-hydroxy-17-trifluoromethyl-4(5)-estren-3-one (1):

At room temperature, in a 50ml egg-shaped flask, dissolve 1.785g 3 (3.88mmol) in 8ml THF, inject 6ml 40% HF (aq), stir and react overnight, then add 1.5ml concentrated HCl, continue stirring for 3.5 hours, and put it in an ice-water bath , neutralized to alkaline with 3N NaOH aqueous solution, THF was removed under reduced pressure, the residual aqueous solution was extracted with EtOAc (50ml×3), and the combined organic phases were separated by column chromatography (petroleum ether:ethyl acetate=7:1) to obtain 1.227g white columnar crystal 1, yield: 92%.

mp: 225.5-227℃

[α] ²⁰ D +48.3° (C.0.27, CHCl ₃ )

IR(KBr): 3350, 1620, 1160cm ^-1

UV(EtOH) λmax=242nm (εmax=1.04×10 ⁴ )

¹⁹ FNMR: -2.6 (S, CF ₃ ) ppm

¹ HNMR 5.84 (S, 1H, 4-H), 1.01 (S, 3H, 18-CH ₃ ) ppm

MS: 342 (M ⁺ , 7.5), 324 (M ⁺ _-H2O , 2)

Elemental analysis: C ₁₉ H ₂₅ F ₃ O ₂

Calculation: C.66.65% H.7.36% F.16.65%

Real side: C.66.34% H.7.31% F.17.28%

Example 3

Synthesis of 13-methyl-17-hydroxy-17-trifluoromethyl-5(10)-estren-3-one (5):

At 25°C, 735mg of 3 (1.60mmol) was dissolved in 1ml of acetone and 2ml of THF, injected into 2ml of 40% HF aqueous solution, and stirred at this temperature for 2 hours, the mixture was neutralized to alkaline with 3M NaOH (aq), and depressurized Acetone and THF were removed under vacuum, 5ml H ₂ O was added to the residue, and extracted with CH ₂ Cl ₂ (20ml×3), the organic phases were combined, filtered once with a small amount of silica gel, and the organic phase was separated by column chromatography (Pet:EtOAc=7 : 1) 163 mg and 241 mg of colorless columnar crystals 1 and 5 were obtained, respectively. Yield: 1, 30% 5, 44%. Compound 5:

mp: 202.9-204.9℃

[α] ²⁰ D +135.9° (C.0.91, CHCl ₃ )

IR: 3400, 1710, 1150cm ^-1

¹⁹ FNMR: -2.2 (S, CF ₃ ) ppm

¹ HNMR: 0.97 (S, 3H, 18-CH ₃ ) ppm

MS: 342 (M ⁺ , 100)

Elemental analysis: C ₁₉ H ₂₅ F ₃ O ₃

Calculation: C.66.65% H.7.36% F.16.65%

Measured: C.66.58% H.7.31% F.16.95%

Example 4

Synthesis of 13-methyl-17-trimethylsilyloxy-17-trifluoromethyl-5(10)-estren-3-one (7):

At room temperature, in a 25ml reaction bottle, dissolve 342mg 3 (0.74mmol) in 4ml acetone-H ₂ O (75:15) solution, add 189mg malonic acid (1.82mmol), stir for 2.5 hours, under ice-water bath, Neutralize to slightly alkaline with saturated NaHCO ₃ , remove acetone, extract the aqueous solution with Et ₂ O (15ml×3), combine the organic phases, wash with saturated NaCl(aq) until neutral, dry (NaSO ₄ ), filter, The solvent was removed and separated by column chromatography (petroleum ether: ethyl acetate = 100:1) to obtain 269 mg of colorless flaky crystal 7. Yield: 87.4%.

mp: 106.2-106.5℃

[α] ²⁰ D +135.9° (C.0.38, CHCl ₃ )

IR(KBr): 1730, 1170cm ^-1

¹⁹ FNMR: -4.2 (S, CF ₃ ) ppm

¹ HNMR 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)

Elemental analysis: C ₂₂ H ₃₃ F ₃ O ₂ Si

Calculation: C.63.37% H.8.02% F.13.75%

Measured: C.63.66% H.8.09% F.13.54%

Example 5

Synthesis of 13-methyl-17-trimethylsilyloxy-17-trifluoromethyl-4,9(10)-estradien-3-one (9):

At 16°C, in a dry 50ml reaction flask, dissolve 1.174g 7 (2.84mmol) in 8ml Py (dry), drop into C ₅ H ₅ N.Br ₂ .HBr/Py (1g/8ml), in 15 minutes After the internal drop is completed, continue to stir and react at this temperature for 3.5 hours, then rise to 100°C and stir for 1 hour, remove Py under reduced pressure, and neutralize with 5% HCl aqueous solution to slightly acidic under ice-water bath, and then use EtOAc to neutralize the aqueous solution. Extract (30ml * 3), combine organic phase, use saturated NaCl solution successively, 5%NaHCO ₃ solution, saturated NaCl solution wash, dry, filter, remove solvent under reduced pressure, column chromatography separates (petroleum ether: ethyl acetate= 100:3) to obtain 869 mg of colorless flaky crystal 9, yield: 74.4%. Compound 9:

mp: 113.0-115.2℃

[α] ¹⁶ D: -181.2° (C.0.44, CHCl ₃ )

IR(KBr): 1670, 1170cm ^-1

UV(EtOH) λmax=302nm (εmax=1.92×10 ⁴ )

¹⁹ FNMR: -3.33 (S, CF ₃ ) ppm

¹ HNMR 5.68 (S, 1H, 4-H), 1.00 (S, 3H, 18-CH ₃ ),

0.15(S, 9H, Si(CH ₃ ) ₃ )ppm

MS: 412(M ⁺ , 61), 397(M ⁺ _-CH3 , 6),

343 (M ⁺ _-CH3 , 15),

322(M ⁺ -(CH ₃ ) ₃ SiOH, 68)

Elemental analysis: C ₂₂ H ₃₁ F ₃ O ₃ Si

Calculation: C.64.04% H.7.57% F.13.02%

Measured: C.63.97% H.7.48% F.13.08%

Example 6

Synthesis of 13-methyl-17-hydroxy-17-trifluoromethyl-4(5), 9(10)-estradien-3-one (11):

At room temperature, in a 25ml egg-shaped flask, dissolve 1.230g 9 (2.98mmol) in 3mlTHF, add 4ml 40% HF aqueous solution (84.22mmol), and stir the reaction at this temperature for 1.5 hours. NaOH(aq) was neutralized to slightly alkaline, the mixed solution was extracted with EtOAc (50ml×3) and the combined organic phase was washed with saturated NaCl(aq) until neutral, the organic phase was dried (NaSO ₄ ), filtered, and pumped under reduced pressure Desolvated column chromatography (Pet:EtOAc:EtOH=70:30:0.3) gave colorless columnar crystals (Pet-EtOAc) 11, 950mg. Yield: 93%.

mp: 202.9-204.9℃

[α] ¹⁶ D -224.3° (C.0.37, CHCl ₃ )

IR(KBr): 3350, 1640, 1595, ^1150cm-1

UV(EtOH) λmax=304nm (εmax=1.36×10 ⁴ )

¹⁹ FNMR: -2.3 (S, CF ₃ ) ppm

¹ HNMR: 5.69 (S, 1H, 4-H), 1.12 (S, 3H, 18-CH ₃ ) ppm

MS: 340(M ⁺ , 70), 325(M ⁺ _-CH3 , 6),

322 (M ⁺ -H ₂ O, 7)

Elemental analysis: C ₁₉ H ₂₃ F ₃ O ₂

Calculation: C.66.92% H.6.80% F.16.72%

Measured: C.66.94% H.6.66% F.16.36%

Example 7

13-methyl-17-trimethylsilyloxy-17-trifluoromethyl-3-(1-tetrahydropyrrolyl)-3,5(10),9(11)-estratriene ( 27) Synthesis:

In 25ml of dry egg shape, dissolve 134mg 9 (0.32mmol) in 1.5ml of anhydrous methanol, heat to boiling and reflux, inject 0.2ml (2.4mmol) tetrahydropyrrole, after 1min, a yellow solid appears, continue to stir and reflux Reaction 1 hours, cooled in an ice-water bath, filtered the solid, washed with ice-cold CH ₃ OH, and dried in vacuo to give 132 mg of 27 as a yellow solid. Yield: 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 )

¹⁹ FNMR: -3.6 (S, CF ₃ ) ppm

¹ HNMR: 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-tetrahydropyrrole),

0.87 (S, 3H, 18-CH ₃ ),

0.13(S, 9H, Si(CH ₃ ) ₃ )ppm

MS: 467 (M ⁺ , +2, 100)

Example 8

Synthesis of 13-methyl-17-trimethylsilyloxy-17-trifluoromethyl-5(10), 9(11)-estradien-3-one (15):

In a 25ml egg-shaped bottle, add 85mg of malonic acid ( _0.81mmol , 3eq) and 100mg of 200-300 Target silica gel, stirred and reacted at 20°C for 1 hour, poured the mixture into 50ml of ice water under stirring, extracted with EtOAc (100ml×3), removed a large amount of solvent (EtOAc) under reduced pressure, and the remaining organic phase was successively washed with saturated NaHCO ₃ (aq) was washed with saturated NaCl (aq), dried, the solvent was removed, and column chromatography (Pet:EtOAc=100:3, V/V) gave colorless columnar crystals (Pet/EtOAc) 15, 92mg. Yield: 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 )

¹⁹ FNMR: -3.3 (S, CF ₃ ) ppm

¹ HNMR: 5.63 (t, J=2.68, 2.58Hz, 1H, 11-H)

2.87(S, 2H, 4-H), 0.87(S, 3H, 18- _CH3 ),

0.15(S, 9H, Si(CH ₃ ) ₃ )ppm

MS: 412(M ⁺ , 88), 397(M ⁺ _-CH3 , 5),

343 (M ⁺ -CF ₃ , 4), 322 (M ⁺ -[(CH ₃ ) ₃ ]SiOH, 26),

307(M ⁺ -[(CH ₃ ) ₃ SiOH-CH ₃ , 14)

High resolution mass spectrum: C ₂₂ H ₃₁ F ₃ O ₂ Si

Calculation: 412.2046

Measured: 412.2077

Example 9

Synthesis of 13-methyl-17-trimethylsilyloxy-17-trifluoromethyl-4(5), 9(10), 11(12)-estratrien-3-one (17):

At 25°C, under N2 flow, in a dry 250ml reaction flask with a branch tube, dissolve 431mg15 (1.04mmol) in 20ml anhydrous ethyl acetate and 5ml anhydrous benzene, add 620mgDDQ (2.58mmol, 2.5eq), room temperature, N ₂ Stir the reaction under protection for 3 days, remove ethyl acetate and benzene under reduced pressure, recrystallize the residue with EtOAc-Pet (60-90°C) (secondary) to remove solid DDQ and DDQH ₂ , combine the organic phase of the mother liquor (200ml) , washed with saturated NaHCO ₃ aqueous solution until the alkali layer was colorless, washed with saturated aqueous NaCl solution until neutral, dried, removed the solvent, and separated by column chromatography (Pet:EtOAc=100:1) to obtain 343 mg of colorless needle crystals (Prt /EtOAc) 17. Yield: 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 )

¹⁹ FNMR: -2.3 (S, CF ₃ ) ppm

¹ HNMR: 6.48 (d, 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), 1.00(S, 3H, 18- _CH3 ),

0.16(S, 9H, Si(CH ₃ ) ₃ )ppm

MS: 410(M ⁺ 25.52), 395(M ⁺ _-CH3 2.45),

320 (M ⁺ -HOSi(CH ₃ ) ₃ , 12.51),

305 (M ⁺ -CH ₃ -HOSi(CH ₃ ) ₃ , 5.80)

Elemental Analysis: C ₂₂ H ₂₉ F ₃ O ₂ Si

Calculation: C.64.36% H.7.12% F.13.89%

Measured: C.64.37% H.7.13% F.13.94%

Example 10

Synthesis of 13-methyl-17-hydroxy-17-trifluoromethyl-4(5), 9(10), 11(12)-estratrien-3-one (19):

189mg of 17 (0.4mmol) was dissolved in 1.2ml of THF solvent, 1.0ml of 40% HF aqueous solution (21.05mmol, 4aq) was added, and the reaction was stirred at room temperature for 16 hours, and the mixture was neutralized to slightly alkaline with 3M NaOH (aq), Extract with EtOAc (50ml×3), combine the organic phases, wash with saturated NaCl (aq) until neutral, dry, filter, remove EtOAc, and separate by column chromatography (Pet:EtOAc=7:1) to obtain 132 mg of light yellow column Crystalline (Pet/EtOAc) 19 . Yield: 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 )

¹⁹ FNMR: -1.6 (S, CF ₃ )

¹ HNMR: 6.48 (S, 2H, 11, 12-H), 5.80 (S, 1H, 4-H),

1.09 (S, 3H, 18-CH ₃ )ppm

¹³ CNMR: 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, 123.84pp, 1q, 9＝m( CF ₃ ), 127.614, 139.357, 140.828, 156.4, 199.488

MS: 338 (M ⁺ , 100), 320 (M ⁺ -H ₂ O, 13),

296 (M ⁺ -CF ₃ , 6.69)

Elemental analysis: C ₁₉ H ₂₁ F ₃ O ₂

Calculation: C.67.44% H.6.26% F.16.85%

Measured: C.67.45% H.6.33% F.16.86%

Example 11

Synthesis of 13-ethyl-17-trimethylsilyloxy-17-trifluoromethyl-2(3), 5(10)-osteradien-3-methyl ether (24):

Dissolve 1 g of 13-ethyl-2(3), 5(10)-steradien-17-one-3-methyl ether (22) in 35 ml of freshly distilled anhydrous THF, add 180 mg of TMAF under cooling in an ice-water bath, 2.3ml (CH ₃ ) ₃ SiCF ₃ , stirred at room temperature for 10 hours, the solvent was concentrated to dryness, and column chromatography gave 24: 1.367g, yield: 92.8%.

mp: 143.8-144.5℃

IR(KBr): 1250, 1170cm ^-1

MS: 442(M ⁺ ₎ , 427(M ⁺ _-CH3 ), 413(M ⁺ _-C2H5 )

¹ HNMR: 3.48 (S, 3H, -OMe),

0.98(t, 3H, J=7Hz, C ₁₃ -CH ₂ CH ₃ ),

0.17(S,9H,-Si(CH ₃ ) ₃ )ppm

¹⁹ FNMR: +73.0ppm

Elemental analysis: C ₂₄ H ₃₇ F ₃ O ₂ Si

Calculation: C.65.12% H.8.43% F.12.88%

Measured: C.65.44% H.9.00% F.12.64%

Example 12

Synthesis of 13-ethyl-17-hydroxy-17-trifluoromethyl-4(5)-steren-3-one (2):

Take 250 mg of (24) and dissolve in 3ml THF, add 2.5ml 40% HF aqueous solution, stir at room temperature for 10 hours, then add 2ml of concentrated HCl, stir at room temperature for 2 hours, treat in the same way (3→1), and get (2 ): 165 mg, yield: 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 ⁺ _-C2H5 )

¹ HNMR: 5.8 (S, 1H, 4-H),

1.02 (t, 3H, J=7Hz, C ₁₃ -CH ₂ CH ₃ ) ppm

¹⁹ FNMR: +74.4ppm

Elemental analysis: C ₂₀ H ₂₇ F ₃ O ₂

Calculation: C.67.40% H.7.64% F.15.99%

Measured: C.67.60% H.7.79% F.16.21%

Example 13:

Synthesis of 13-ethyl-17-trimethylsilyloxy-17-trifluoromethyl-5(10)-stem-3-one (8):

Take 1g of (24) and add 60ml CH ₃ COCH ₃ , 12ml H ₂ O, 1g oxalic acid, and stir at room temperature for 6 hours. After the solution is clear, add saturated NaHCO ₃ solution under cooling in an ice-water bath to neutralize to slightly alkaline, filter, and use the filter residue CH ₂ Cl ₂ washed, the filtrate was extracted with CH ₂ Cl ₂ after most of the solvent was removed under reduced pressure, the CH ₂ Cl ₂ liquid was combined, dried, and the solvent was removed under reduced pressure. Column chromatography gave (8): 870mg, yield : 89.8%.

mp: 136-137℃

IR(KBr): 1720, 1250, 1165cm ^-1

MS _: 428(M ⁺ ), 399(M ⁺ _-C2H5 )

¹ HNMR: 0.95 (t, 3H, J=7Hz, C ₁₃ -CH ₂ CH ₃ ),

0.18(S, 9H, SiMe ₃ )ppm

¹⁹ FNMR: +72.3ppm

Elemental analysis: C ₂₃ H ₃₅ F ₃ O ₂ Si

Calculation: C.64.45% H.8.23% F.13.30%

Measured: C.64.40% H.8.65% F.13.38%

Example 14

Synthesis of 13-ethyl-17-trimethylsilyloxy-17-trifluoromethyl-4(5), 9(10)-osteradien-3-one (10):

Take 870 mg of (8), add 4 ml of anhydrous pyridine, add dropwise 4 ml of anhydrous pyridine solution containing 630 mg of pyridinium perbromide hydrobromide under stirring, and process in the same way (7→9), and obtain (9) by column chromatography 810 mg, yield 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 ⁺ _-C2H5 )

¹ HNMR: 5.65 (S, 1H, 4-H),

1.0 (t, 3H, J = 7Hz, C ₁₃ -CH ₂ CH ₃ ),

0.16(S, 9H, SiMe ₃ )ppm

¹⁹ FNMR: +72.5ppm

Elemental analysis: C ₂₃ H ₃₃ F ₃ O ₂ Si

Calculation: C.64.70% H.7.87% F.13.35%

Measured: C.64.96% H.8.05% F.13.02%

Example 15:

Synthesis of 13-ethyl-17-hydroxy-17-trifluoromethyl-4(5), 9(10)-osteradien-3-one (12):

190mg (10) was dissolved in 1.5ml THF, 2ml 40% HF aqueous solution was added, stirred at room temperature for 10 hours, treated in the same way (9→11), column chromatography gave (12): 125mg, yield: 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 ⁺ _-H2O ), 325(M ⁺ _-C2H5 )

¹ HNMR: 5.65 (S, 1H, C ₄ -H),

1.05 (S, 3H, J=7Hz, C ₁₃ -CH ₂ CH ₃ ) ppm

¹⁹ FNMR: +74.2ppm

Elemental analysis: C ₂₀ H ₂₅ F ₃ O ₂

Calculation: C.67.78% H.7.11% F.16.08%

Measured: C.67.96% H.7.18% F.16.17%

Example 16:

13-Ethyl-17-trimethylsilyloxy-17-trifluoromethyl-3-(1-tetrahydropyrrolyl)-3,5(10),9(11)-sterotriene (28) synthesis:

Add 5ml of treated anhydrous methanol to 800mg (10), add 1.3ml of tetrahydropyrrole after heating to boiling, continue to reflux for half an hour, the bath temperature is about 80°C, filter after cooling, wash twice with frozen methanol, and dry to obtain ( 28): 839 mg, yield: 93.27%.

Example 17

Synthesis of 13-ethyl-17-trimethylsilyloxy-17-trifluoromethyl-5(10), 9(11)-osteradien-3-one (16):

Put (28) 800mg into a 150ml flask, add CH ₃ COCH ₃ 60ml, H ₂ O 12ml, malonic acid 550mg, 200-300 mesh silica gel 1g, stir at room temperature for 40 minutes, remove the silica gel after the solution is clear, and cool in an ice-water bath Neutralize to slightly alkaline with saturated NaHCO ₃ , remove most of the solvent under reduced pressure, extract with EtOAc, dry, and obtain (16) by column chromatography: 481 mg, yield: 67.6%.

IR(KBr): 1720, 1258, 1160cm ^-1

UV(EtOH): 240nm (εmax=1.35×10 ⁴ )

MS _: 426(M ⁺ ), 397(M ⁺ _-C2H5 )

¹ HNMR: 5.65 (d, 1H, J=5.6Hz, C ₁₁ -H),

0.91 (t, 3H, J=7.2Hz, C ₁₃ -CH ₂ CH ₃ ) ppm

¹⁹ FNMR: +73.1ppm

High resolution mass spectrum: C ₂₃ H ₃₃ F ₃ O ₂ Si

Calculation: 426.2202

Measured: 426.2212

Example 18

Synthesis of 13-ethyl-17-trimethylsilyloxy-17-trifluoromethyl-4(5), 9(10), 11(12)-sterotrien-3-one (18):

Add 8.7ml of anhydrous EtOAc and 11.6ml of anhydrous benzene to 400mg (16), add 560mg of dichlorodicyanoquinone under _N2 atmosphere, stir at room temperature for 20 hours under _N2 atmosphere, dilute the reaction solution with EtOAc, wash it with saturated _NaHCO3 to alkali The aqueous layer was basically colorless, the organic layer was dried with anhydrous Na ₂ SO ₄ , the solvent was removed under reduced pressure, and (18) was obtained by column chromatography: 262 mg, yield: 65.8%.

IR(KBr): 1670, 1580, 1258, ^1170cm-1

UV(EtOH): 338nm (εmax=2.36×10 ⁴ )

MS: 424(M ⁺ ) _, 395(M ⁺ _-C2H5 ), 409(M ⁺ _-CH3 )

¹ HNMR: 6.52 (m, 2H, C ₁₁ and C ₁₂ -H), 5.78 (S, 1H, 4-H),

1.0 (t, 3H, J=7.3Hz, C ₁₃ -CH ₂ CH ₃ ),

0.18(S, 9H, SiMe ₃ )ppm

¹⁹ FNMR: +73.2ppm

High resolution mass spectrum: C ₂₃ H ₃₁ F ₃ O ₂

Calculation: 424.2045

Measured: 424.2043

Example 19

1 Synthesis of 3-ethyl-17-hydroxyl-17-trifluoromethyl-4(5), 9(10), 11(12)-sterotriene-3-one (20):

Dissolve (18) 200mg in 2.5ml THF at 20°C, add 2.5ml 40% HF aqueous solution, stir for 10 hours, neutralize to basicity with 3N NaOH, extract with EtOAc, dry with anhydrous Na ₂ HO ₄ , remove the solvent under reduced pressure , column chromatography (20): 130 mg, yield: 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 ⁺ _-C2H5 )

¹ HNMR: 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 ₂ CH ₃ ) ppm

¹⁹ FNMR: +74.7ppm

High resolution mass spectrum: C ₂₀ H ₂₈ F ₃ O ₂

Calculation: 352.1650

Measured: 352.1652

Example 20

The Absolute Configuration of Compound 11 Determined by Single Crystal X-Ray Diffraction

Example 21

Affinity of three compounds for rat uterine cytosolic progesterone receptors.

The experiment adopts low temperature, ultracentrifugation, and DCC method. According to the characteristics of [ ³ H]R ₅₀₂₀ and Pre with high specific affinity, the competition test is used to compare compounds 1, 11, 19 and RU486 with rat uterine cytoplasmic progesterone receptors binding activity. If the affinity between RU486 and progesterone receptor is 100, compared with RU486, their relative affinities are 1:291.6, 11:77.8, 19:38.9 respectively. From the above data, it can be seen that the activity of compound 1 is 3% of that of RU486. times, and the activities of 11, 19 were only slightly worse than RU486.

Claims (11)

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=0,

Or

2. trifluoro-methyl steroid as claimed in claim 1 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=0,

Or

3. a trifluoro-methyl steroid as claimed in claim 1 is characterized in that 13-methyl-17-hydroxyl-17-trifluoromethyl-4 (5)-female steroid alkene-3-ketone.

4. a trifluoro-methyl steroid as claimed in claim 1 is characterized in that 13-ethyl-17-hydroxyl-17-trifluoromethyl-4 (5)-property steroid alkene-3-ketone.

5. a trifluoro-methyl steroid as claimed in claim 1 is characterized in that 13-methyl-17-hydroxyl-17-trifluoromethyl-4 (5), 9 (10)-estradienes-3-ketone.

6. a trifluoro-methyl steroid as claimed in claim 1 is characterized in that 13-ethyl-17-hydroxyl-17-trifluoromethyl-4 (5), 9 (10)-property steroid diene-3-ketone.

7. a trifluoro-methyl steroid as claimed in claim 1 is characterized in that 13-methyl-17-hydroxyl-17-trifluoromethyl-4 (5), 9 (10), and 11 (12)-female steroids triolefin-3-ketone.

8. a trifluoro-methyl steroid as claimed in claim 1 is characterized in that 13-ethyl-17-hydroxyl-17-trifluoromethyl-4 (5), 9 (10), 11 (12)-property steroid triolefin-3-ketone.

9. 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 (10)-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 of 3-(25, or 26).Described trifluoromethyl silicon ether compound is 13-methyl or ethyl-17-trimethylsiloxy group-17-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-trimethylsiloxy group-17-trifluoromethyl-2 (3), 5 (10)-estradienes or property steroid diene-3-methyl ether (23 or 24), 13-methyl or ethyl-17-trimethylsiloxy group-17-trifluoromethyl-5 (10), 9 (11)-estradienes or property steroid diene-3-ketone-3, the two methyl ethers (13 or 14) of 3-;

Or b. is 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-hydroxyl-17-trifluoromethyl-4 (5)-female steroid alkene or the property steroid alkene-3-ketone (1 or 2) of getting respectively, 13-methyl or ethyl-17-hydroxyl-17-trifluoromethyl-5 (10)-female steroid alkene or property steroid alkene-3-ketone (5 or 6), 13-methyl or ethyl-17-hydroxyl-17-trifluoromethyl-4 (5), 9 (10)-estradienes or property steroid diene-3-ketone (11 or 12);

Or c. is with above-mentioned steroidal compounds (3), (4), (23), (24), (13), (14) through piptonychia ether or the resulting 13-methyl of two methyl ether or ethyl-17-trimethylsiloxy group-17-trifluoromethyl-5 (10)-female steroid alkene or property steroid alkene-3-ketone (7 or 8), 13-methyl or ethyl-17-trimethylsiloxy group-17-trifluoromethyl-5 (10), 9 (11)-estradienes or property steroid diene-3-ketone (15 or 16);

Or d. is with above-mentioned steroidal compounds (7), (8) or (15), (16) get 13-methyl or ethyl-17-trimethylsiloxy group-17-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-trimethylsiloxy group-17-trifluoromethyl-4 (5), 9 (10), 11 (12)-female steroid triolefins or property steroid triolefin-3-ketone (17 or 18);

Or e. is with above-mentioned steroidal compounds (9), (10), (17), (18) get 13-methyl or ethyl-17-hydroxyl-17-trifluoromethyl-4 (5) through taking off the trimethyl silicane radical reaction, 9 (10)-estradienes or property steroid diene-3-ketone (11 or 12), 13-methyl or ethyl-17-hydroxyl-17-trifluoromethyl-4 (5), 9 (10), 11 (12)-female steroid triolefins or property steroid triolefin-3-ketone (19 or 20)

Or f. is with above-mentioned steroidal compounds (9), (10) through Pyrrolidine protect 13-methyl or ethyl-17-trimethylsiloxy group-17-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. is above-mentioned steroidal compounds (5), and (6) are carried out the cyclic olefinic bond translocation reaction with concentrated hydrochloric acid and obtained steroidal compounds (1), (2).

10. purposes as claim 3,4,5,6,7 or 8 described trifluoro-methyl steroids is characterized in that a kind of medicine of antiearly pregnancy.

11. the purposes of a trifluoro-methyl steroid as claimed in claim 1 or 2 is characterized in that 13-methyl or ethyl-17-hydroxyl-17-trifluoromethyl-4 (5)-female steroid alkene or property steroid alkene-3-ketone are a kind of medicines of antiearly pregnancy.