CN1061983C - 4-trifluoromethyl-3-ketosteroid compound and synthesizing method thereof - Google Patents

Abstract

The present invention relates to compounds 4-trifluoromethyl-3-ketone-steroid and a preparation method thereof. The compounds are androsteroid, progesteroid or spirosteroid compounds of 4-olefine, 1, 4-diolefine or 4, 6-diolefine; a trifluoromethylation reaction of 4-bromine or iodine-3-ketone-4-olefine-steroid produces an intermediate product 4-trifluoromethyl-3-ketone-4-alkene-steroid; the intermediate product further reacts with benzoquinone compounds to produce 4-trifluoromethyl-3-ketone-1, 4 or 4, 6-olefine-steroid. The method for synthesizing trifluoromethyl steroids provided by the present invention is convenient and effective.

Description

A kind of 4-trifluoromethyl-3-ketone steroid compound and its synthetic method

The present invention relates to a fluorine-containing steroid compound. That is, 4-trifluoromethyl-3-keto steroid compounds and their synthesis, including their estrogen, androster, pregnane or spiro steroid compounds.

a，R=β-OAc，α-H b，R=β-COCH3，α-OAcFirst of all, due to the unique properties of fluorine element, the introduction of fluorine into organic active molecules can cause significant changes in molecular chemical, physical and physiological activities [P. Goldman, Science, 1969, 64, 1123; Biomedical Aspects of Fluorine Chemistry, R. Filler and Y. Kobayashi, Kodansha Ltd., Tokyo, 1980.]. The introduction of fluorine into steroid molecules can also cause significant changes in physiological activity, such as the activity of fluorinated cortisone is 10-12 times higher than that of non-fluorinated cortisone [J. Fried and E． F.Sabo, J.Am.Chem.Soc., 1954,76,1455], so introducing fluorine in steroid molecules is an important way to find new steroid drugs. Because the trifluoromethyl group has high electronegativity, stability and lipophilicity, the property change is more obvious after introducing the trifluoromethyl group in the steroid molecule, such as the trifluoromethyl steroid is a good Aromatase inhibitor [Hideo Nemoto et al, J.Org.Chem., 1995 60,594], the activity of 17-trifluoromethyl-testosterone is three times that of anti-early pregnancy drug RU486 (Wang Zhongqi, Lu Shoufu, ZL93112563. 4). However, it is more difficult to synthesize trifluoromethyl steroids than monofluoro and difluoro steroids [J.Fried, NAAbraham, Organic Reaction in Steroid Chemistry, New York, 1972, Vol.1, pp423-493], especially in heterogeneous There are few reports on the synthesis of steroids with trifluoromethyl groups introduced into the ring. Generally, the photoreaction of CF3I and steroid [AFPascual and ME. Wolff, J.Med.Chem., 1971, 14, 164], as shown in Figure 1 below, reported the photoreaction of CF3I and steroids [GHRasmusson et al J.Org.Chem., 1975, 40, 672]

a, R=β-OAc, α-H b, R=β-COCH3, α-OAc

The convertibility is only 32-42%. Therefore, the method reported in the literature not only takes a long time, is difficult to operate, but also has a low yield. Secondly, there is also the use of CF3SiMe3 and carbonyl reaction [J. Fluorine Chem., Z.Q.Wang, et al, 1994, 69, 1), but it is greatly affected by steric hindrance. 3-keto steroids are known drugs. Bromine or iodine is introduced at C4, and 3-carbonyl-4-ene steroids are used in a mixed solvent of acetic acid and ether, with collidine as the proton acceptor, and can only generate 4-Bromo or iodo-3-keto-4-ene steroids (D.N. Kirk, et al, J. Chem. Soc., 1956, 627). On this basis, under appropriate conditions, we obtained a product in which the halogen was substituted by trifluoromethyl, that is, obtained a new class of compounds with higher activity: 4-trifluoromethyl-3-ketone steroid compounds, and aimed at the above-mentioned Insufficiency of the method, to find out an efficient and simple synthetic method.

The purpose of the present invention is to provide a class of highly active new steroids: 4-trifluoromethyl-3-ketone steroids, and to provide a simple and efficient way to synthesize 4-trifluoromethyl-3-ketone steroids method for compound compounds.

The 4-trifluoromethyl-3-ketone steroid compound provided by the invention has the following general molecular formula:

Wherein R ₁ =H or CH ₃ , R ₂ =H or O, R ₃ =H, CH ₃ or C ₂ H ₅ , R ₄ =OH, CH ₃ CO, CH ₃ COO, CONR7R8 or C _1-10 alkane group, R ₅ =H, CH ₃ or CH ₃ COO, R ₄ and R ₅ =O, OCH ₂ CH ₂ O or R ₆ =H or CH ₃ , R ₅ and R ₆ =O, R ₇ or R ₈ =H, C _1-10 alkyl, cycloalkyl, R ₇ and R ₈ =(CH ₂ ) _n , n= 1-6,

It may be an estroster, androster, pregnane or spirosteroid of a 4-ene, 1,4-diene or 4,6-diene. Such as 4-trifluoromethyl-17β-hydroxyandrost-4-en-3-one, 4-trifluoromethyl-17β-hydroxy-17α-methylandrost-4-en-3-one-17- Acetate, 4-trifluoromethylandrost-4-ene-3,11,17-trione, 4-trifluoromethyl-N-isopropylandrost-4-en-3-one-17β- Formamide, 4-trifluoromethyl-13-ethylandrost-4-ene-3,17-dione, 4-trifluoromethyl-13-ethylandrost-1,4-ene-3,17- Diketone, 4-trifluoromethyl-17β-hydroxyestr-4-en-3-one, 4-trifluoromethyl-17β-hydroxy-17α-methylestr-3-one, 4-trifluoro Methyl-16α, 17α-epoxypregna-4-en-3-one, 4-trifluoromethyl-17β-hydroxy-16α-methylpregna-4-en-3-one-17-acetic acid Esters, 17β-hydroxy-4-trifluoromethylpregna-4-en-3-one-21-hydroxyacidolactone, 4-trifluoromethylandrost-4,6-diene-3,17- Diketo-, 4-trifluoromethyl-N-isopropylandrost-1,4-dien-3-one-17β-carboxamide, 4-trifluoromethyl-13-ethylandrost-4,6 -Diene-3,17-dione, 4-trifluoromethylandrosta-4,6-diene-3,17-dione, 4-trifluoromethylestra-1,4-diene- 3,17-dione, 4-trifluoromethylandrost-1,4-diene-3,17-dione, 4-trifluoromethyl-N-(1,1-dimethylethyl) Androst-4,6-dien-3-one-17β-carboxamide, 4-trifluoromethyl-N-isopropylandrost-4,6-dien-3-one-17β-carboxamide, 4 -Trifluoromethyl-N-isopropylestr-1,4-dien-3-one-17β-carboxamide, (25R)-4-trifluoromethylspirosta-4-en-3-one wait.

                                的4-溴或碘-3-酮-4-烯-甾体化合物原料，其中R₁=H、CH₃，R₂=H或O，R₃=H、CH₃或C₂H₅，R₄=OH、CH₃CO、CH₃COO、CONR₇R₈或C_1-10的烷基，R₅=H、CH₃或CH₃COO，R₄和R₅=O、OCH₂CH₂O或，R₆=H或CH₃，R₅和R₆=O，R₇或R₈=H、C_1-10的烷基或环烷基，R₇和R₈=(CH2)_n，n=1-6，

在溶剂中，以CuI或Cu粉为催化剂，将4-溴或碘-3-酮-4-烯-甾体与三氟甲基化试剂反应，由于三氟甲基化试剂能与烯卤、芳香卤和烯丙基卤反应生成相应的三氟甲基化产物，因此得产物：4-三氟甲基-3-酮-4-烯甾体，产率良好(得率为70～93％)。反应式如图2所示： The present invention also provides a simple and efficient method for preparing the above-mentioned 4-trifluoromethyl-3-ketone steroid compound, that is, the molecular formula is:

4-bromo or iodo-3-one-4-ene-steroid compound starting material, wherein R ₁ =H, CH ₃ , R ₂ =H or O, R ₃ =H, CH ₃ or C ₂ H ₅ , R ₄ = OH, CH ₃ CO, CH ₃ COO, CONR ₇ R ₈ or C _1-10 alkyl, R ₅ = H, CH ₃ or CH ₃ COO, R ₄ and R ₅ = O, OCH ₂ CH ₂ O Or, R ₆ =H or CH ₃ , R ₅ and R ₆ =O, R ₇ or R ₈ =H, C _1-10 alkyl or cycloalkyl, R ₇ and R ₈ =(CH2) _n , n =1-6,

In a solvent, CuI or Cu powder is used as a catalyst to react 4-bromo or iodo-3-one-4-ene-steroids with trifluoromethylation reagents, since trifluoromethylation reagents can react with alkenyl halides, Aromatic halide and allyl halide react to generate corresponding trifluoromethylation product, so product: 4-trifluoromethyl-3-keto-4-ene steroid, good yield (yield is 70～93% ). The reaction formula is shown in Figure 2:

a: Trifluoromethylation reagent, CuI or Cu powder, solvent, 40-80°C. R=C ₂ H ₅ , CH ₃ , H

b: Benzene or dioxane, chloranil.

c: tert-butanol, dichlorodicyanobenzoquinone.

The solvents are diethyl ether, petroleum ether, benzene, carbon tetrachloride, ethyl ketone, dimethyl sulfoxide, hexamethylphosphoramide HMPA, N, N-dimethylformamide DMF, N, N-dimethyl ethyl Amide DMA. Recommended solvents are hexamethylphosphoramide HMPA, N,N-dimethylformamide DMF, N,N-dimethylacetamide DMA. The molar ratio of 4-bromo or iodo-3-one-4-ene-steroid, CuI or Cu powder and trifluoromethylation reagent is 1:0.1-5:0.5-5, and the reaction time is 1-10 hours In the method of the present invention, heating is beneficial to the reaction, and the reaction temperature depends on the reactant and the solvent. The reaction temperature of this reaction is usually controlled at 30-120° C., and the recommended reaction temperature is 40-80° C.

4-trifluoromethyl-3-keto-4-ene steroid reacts with dichlorodicyanobenzoquinone in tert-butanol solvent to generate 4-trifluoromethyl-3-keto-1,4-diene Steroid, wherein the molar ratio of 4-trifluoromethyl-3-keto-4-ene steroid and dichlorodicyanobenzoquinone reaction is 1: 0.8-5, and the heating reaction time in tert-butanol solvent is 2 -8 hours.

4-trifluoromethyl-3-keto-4-ene steroid reacts with tetrachlorobenzoquinone in benzene or dioxane solvent to generate 4-trifluoromethyl-3-keto-4,6-diene Steroid compound. Wherein the molar ratio of 4-trifluoromethyl-3-keto-4-ene steroid and tetrachlorobenzoquinone reaction is 1: 0.8-5, and the heating reaction time in benzene or dioxane solvent is 2-15 hours.

In the method of the present invention, the key lies in the trifluoromethylation reaction. The trifluoromethylation reagent used in the present invention can be represented by the general formula, that is, X(CF ₂ CF ₂ O) _m (CF ₂ ) _k CO ₂ Y, Wherein X=Cl, Br, I or FO ₂ S, Y=H, CH ₃ , C ₂ H ₅ or K, m=0 or 1, k=1 or 2. Such as FO ₂ SCF ₂ CO ₂ CH ₃ , FO ₂ SCF ₂ CO ₂ C ₂ H ₅ , FO ₂ SCF ₂ CF ₂ OCF ₂ CO ₂ CH ₃ , FO ₂ SCF ₂ CF ₂ OCF ₂ CO ₂ K, FO ₂ SCF ₂ CF ₂ OCF ₂ CF ₂ CO ₂ CH ₃ , XCF ₂ CO ₂ CH ₃ , XCF ₂ CO ₂ C ₂ H ₅ , XCF ₂ CO ₂ K, etc.

In summary, compared with existing steroidal compounds and methods, trifluoromethyl steroidal compounds of the present invention have the following remarkable effects, first of all, they have high physiological activity, such as androsta-4-trifluoromethyl- The Ki values of 4-en-3-one-17β-dione and the known steroid drug Proscar are 28.8 and 54.7, respectively, as measured by the enzyme kinetics method. Secondly, there is no need to spend a lot of time through photoreaction with _CF3I , and the yield can be increased from 32-42% to 70-93%. The method has short steps, convenient operation and good yield. The required trifluoromethylation reagent is easy to prepare without special reaction equipment and reagents.

Following examples will help to understand the present invention, but are not limited to content of the present invention:

Example 1

0.05-2mmol Cu粉或CuI，0.2-2mmol FO₂SCF₂CO₂Me、FO₂SCF₂CF₂OCF₂CO₂K或BrCF₂CO₂CH₃，在20ml苯、乙腈或DMF溶剂中，在N₂下60-80℃反应4-8小时，反应结束后，反应物用乙醚稀释，用硅澡土滤去固体，滤液倒入50ml水中分出有机层，水层再用3×30mml乙醚萃取，合并有机相，用水洗涤三次。乙醚层用无水MgSO₄干燥后，减压蒸去溶剂，初产物用快速柱色谱分离后，得白色固体4-三氟甲基胆甾-4-烯-3-酮

176mg，得率为90％。m.p.：111.0～112.0℃。IR(KBr pellet)：2980，2800，2690，1600，1468，1370，1346，1160，1124cm^-1。Take 0.43mmol 4-bromocholest-4-en-3-one

0.05-2mmol Cu powder or CuI, 0.2-2mmol FO ₂ SCF ₂ CO ₂ Me, FO ₂ SCF ₂ CF ₂ OCF ₂ CO ₂ K or BrCF ₂ CO ₂ CH ₃ in 20ml benzene, acetonitrile or DMF solvent, in N _2. React at 60-80°C for 4-8 hours. After the reaction, dilute the reactant with diethyl ether, filter the solid with silica gel, pour the filtrate into 50ml water to separate the organic layer, and extract the aqueous layer with 3×30mml diethyl ether. The combined organic phases were washed three times with water. After the ether layer was dried with anhydrous MgSO ₄ , the solvent was evaporated under reduced pressure, and the initial product was separated by flash column chromatography to obtain a white solid 4-trifluoromethylcholest-4-en-3-one

176mg, the yield is 90%. mp: 111.0-112.0°C. IR (KBr pellet): 2980, 2800, 2690, 1600, 1468, 1370, 1346, 1160, 1124 cm ^-1 .

1H NMR (300MHz, CDCl ₃ )d: 0.71(s, 3H, C ₁₈ -H), 0.86(dd, J=6.85, 1.13Hz, 6H, C ₂₆ -H, C ₂₇ -H), 0.91(d, J=6.49Hz, 3H, C ₂₁ -H), 1.25(s, C ₁₉ -H), 3.30(d,br, J=14.69Hz, 1H) ppm.

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -21.7 (s) ppm.

MS m/z: 454 (M ⁺ +2, 7.07), 453 (M ⁺ +1, 25.62), 452 (M ⁺ , 17.27), 437 (M ⁺ -CH ₃ , 7.667), 383 (M ⁺ -CF ₃ , 12.35), 367 (7.14), 339 (8.88), 297 (31.25), 260 (64.29), 247 (334.44), 192 (61.29), 95 (66.47), 69 (47.91), 43 (100).

Elemental analysis _Calcd for _C28H43OF3 : C: _74.30 , H: 9.57

Measured values: C: 74.59, H: 9.97.

Example 2

Take 0.50mmol 4-bromoandrost-4-ene-3,17-dione, 0.05-2mmol CuI, 0.3-2.5mmol FO ₂ SCF ₂ CO ₂ C ₂ H ₅ in 20ml N,N-dimethylacetamide In DMA solvent, react at 50-75°C under _N2 for 6 hours. After the reaction, dilute the reactant with ether, filter the solid with silica gel, pour the filtrate into 40ml water to separate the organic layer, and extract the water layer with ether , combined the organic phases and washed three times with water. The ether layer was dried with anhydrous MgSO ₄ , and the solvent was evaporated under reduced pressure. After the initial product was separated by flash column chromatography, a white solid 4-trifluoromethylandrost-4-ene-3,17-dione was obtained. was 81%,

m.p.: 150.0-151.0°C.

IR (KBr pellet): 3000, 1750, 1600, 1350, 1160, 1120 ^{cm -1} .

¹ H NMR (300 MHz, CDCl ₃ ) d: 0.93 (s, 3H, C ₁₈ -H), 1.29 (s, C ₁₉ -H), 3.12 (d, br, J=14.82 Hz, 1H) ppm.

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -21.7 (s) ppm.

MS m/z: 355 (M ⁺ +1, 7.22), 354 (M ⁺ , 30.31), 339 (M ⁺ -CH ₃ , 7.72), 310 (16.16), 285 (M ⁺ -CF ₃ , 25.44), 268 (15.88), 241 (17.87), 192 (100), 107 (78.92), 69 (17.69).

Elemental Analysis: Calculated _{for C20H25O2F3} : C: _67.78 , _H : 7.11

Measured values: C: 67.54, H: 7.37.

Example 3

Take 0.50mmol 4-bromopregna-4-ene-3,21-dione, 1mmol Cu powder, 2mmol FO ₂ SCF ₂ CF ₂ OCF ₂ CO ₂ CH ₃ in 20ml hexamethylphosphoramide HMPA solvent, in N _2. React at 90-110°C for 2 hours. After the reaction, dilute the reactant with ether, filter the solid with silica gel, pour the filtrate into 50ml water to separate the organic layer, extract the aqueous layer with ether, combine the organic phases, and water Wash three times. After the ether layer was dried with anhydrous MgSO ₄ , the solvent was evaporated under reduced pressure, and the initial product was separated by flash column chromatography to obtain 4-trifluoromethylpregna-4-ene-3,21-dione as a white solid. The yield was 74%,

m.p.: 124.5-125.5°C.

IR (KBr pellet): 2950, 2800, 1700, 1600, 1460, 1364, 1120 ^{cm -1} .

¹ H NMR (300 MHz, CDCl ₃ ) d: 0.68 (s, 3H, C ₁₈ -H), 1.26 (s, C ₁₉ -H), 2.21 (s, C ₂₁ -H), 3.05 (d, br, J =14.65Hz, 1H)ppm.

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -21.3 (s) ppm.

MS m/z: 382 (M ⁺ , 5.97), 367 (M ⁺ -Me, 10.78), 364 (4.26), 339 (4.29), 192 (49.85), 190 (59.01), 173 (27.37), 147 ( 64.39), 133(37.37), 43(100).

Elemental analysis: Calculated _{for C22H29O2F3} : C: _69.09 , _H : 7.64

Measured values: C: 69.00, H: 8.11.

Example 4

Take 0.40mmol 17b-hydroxy-4-bromopregn-4-en-3-one-21-carboxylactone, 2mmol Cu powder, _{0.2mmol BrCF2CO2K} in 20ml hexamethylphosphoramide HMPA solvent , reacted at 40-60°C for 8 hours under N ₂ , after the reaction, the reactant was diluted with diethyl ether, the solid was filtered out with silica gel, the filtrate was poured into 50ml of water to separate the organic layer, the aqueous layer was extracted with diethyl ether, and the organic layer was combined. phase, washed three times with water. After the ether layer was dried with anhydrous MgSO ₄ , the solvent was evaporated under reduced pressure, and the initial product was separated by flash column chromatography to obtain solid 17b-hydroxy-4-trifluoromethylpregn-4-en-3-one-21- Carboxylic acid lactone, the yield is 70%,

m. p.: 124.0-125.0°C.

IR (KBr pellet): 2900, 1770, 1700, 1638, 1600, 1340, 1180, 1120 cm ^-1 .

¹ H NMR (300 MHz, CDCl ₃ ) d: 1.00 (s, C ₁₈ -H), 1.28 (s, C ₁₉ -H), 2.21 (s, C ₂₁ -H) ppm.

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -21.3 (s) ppm.

MS m/z: 410 (M ⁺ , 5.10), 341 (M ⁺ -CF ₃ , 3.95), 337 (7.90), 310 (6.96), 219 (12.31), 203 (30.74), 149 (15.35), 134 (100), 55 (64.44).

High resolution mass spectrum Calculated for C ₂₂ H ₂₉ O ₂ F ₃ : 410.2069

Measured value: 410.2082.

Example 5

Take 0.60mmol (25R)-4-bromospiroster-4-en-3-one, 0.06mmol CuI, _2mmol ClCF2CO2K, in _30ml DMSO solvent, 100-120°C under _N2 React for 3 hours. After the reaction is over, the reactants are diluted with ether, and the solids are filtered out with silica gel. The filtrate is poured into 60 ml of water to separate the organic layer, and the aqueous layer is extracted with ether. The combined organic phases are washed with water three times. After the ether layer was dried with anhydrous _MgSO4 , the solvent was evaporated under reduced pressure, and the initial product was separated by flash column chromatography to obtain solid (25R)-4-trifluoromethylspirosta-4-en-3-one. Yield was 71%.

m. p.: 218.0-219.0°C.

IR (KBr pellet): 2900, 1780, 1600, 1456, 1346, 1120, 1056, 980 ^{cm -1} .

¹ H NMR (300MHz, CDCl ₃ )d: 0.79 (d, J=6.18, 3H, CH ₃ ), 0.83 (s, 3H, C ₁₈ -H), 0.94 (d, J=9.91Hz, CH ₃ ), 1.27(s, C ₁₉ -H), 2.40～2.48(m, 2H), 3.05(d, br, J=14.85Hz, IH), 3.35～3.50(m, 2H), 4, 42(dd, J= 14, 72, 7.48Hz, 1H) ppm.

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -21.6 (s) ppm.

MS m/z: 382(M ⁺ , 1.2), 450(0.86), 421(4.21), 411(M ⁺ _-CF3 , 6.74), 408(10.56), 366(18.95), 366(18.95), 351 (6.44), 337 (25.76), 139 (100), 69 (37.38).

Elemental Analysis: Calculated _{for C28H39O3F3} : C: _69.97 , _H : 8.18

Measured values: C: 69.47, H: 8.27.

Example 6

Take 0.80mmol of 4-bromoestr-4-ene-3,17-dione, 4mmol of Cu powder, 2mmol of ClCF ₂ CO ₂ CH ₃ in 40ml of carbon tetrachloride solvent, and react at 70-80°C under N ₂ for 5 Hours, after the reaction was over, the reactants were diluted with ether, and the solids were filtered off with silica gel. The filtrate was poured into 40ml of water to separate the organic layer, and the aqueous layer was extracted with ether. The organic phases were combined and washed three times with water. The ether layer was dried with anhydrous MgSO ₄ , and the solvent was evaporated under reduced pressure. After the initial product was separated by flash column chromatography, solid 4-trifluoromethylestr-4-ene-3,17-dione was obtained. The yield was 82%,

m.p.: 185.6-187.0°C.

IR (KBr pellet): 2800, 1740, 1690, 1600, 1100, 1040 ^{cm -1} .

¹ H NMR (300 MHz, CDCl ₃ ) d: 0.94 (s, C ₁₈ -H), 3.48 (m) ppm.

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -20.8 (s) ppm.

MS m/z: 341 (M ⁺ +1, 26.76), 340 (M ⁺ , 79.37), 322 (16.98), 296 (46.73), 281 (30.71), 271 (80.69), 254 (78.03), 227 ( 32.69), 215 (51.37), 145 (64.81), 107 (100).

High resolution mass spectrum Calculated value for C ₁₉ H ₂₃ O ₂ F ₃ : 340.1650;

Measured value: 340.1638.

Example 7

Take 0.20mmol 4-bromo-N-(1,1-dimethylethyl)androst-4-en-3-one-17b-carboxamide, 0.2mmol Cu powder, 1mmol FO ₂ SCF ₂ CF ₂ OCF ₂ CF ₂ CO ₂ CH ₃ , in 30ml hexamethylphosphoramide HMPA solvent, react at 70-80°C under N ₂ for 6 hours, after the reaction, dilute the reactant with ether, filter the solid with silica gel, pour the filtrate Add 40ml of water to separate the organic layer, then extract the aqueous layer with ether, combine the organic phases, and wash with water three times. After the ether layer was dried with anhydrous MgSO ₄ , the solvent was evaporated under reduced pressure, and the initial product was separated by flash column chromatography to obtain solid 4-trifluoromethyl-N-(1,1-dimethylethyl)androster- 4-en-3-one-17b-carboxamide. Yield 91%

m.p.: 158.0-159.0°C.

IR (KBr pellet): 3499 (br, NH), 2900, 1680 (br), 1590, 1510, 1450, 1360, 1260, 1230, 1120 ^{cm -1} .

¹ H NMR (300 MHz, CDCl ₃ ) d: 0.74 (s, C ₁₈ -H), 1.26 (s, C ₁₉ -H), 1.35 (s, t-Bu), 5.08 (s, NH) ppm.

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -20.8 (s) ppm.

MS m/z: 439(M ⁺ , 30.73), 424(M ⁺ _-CH3 , 11.6), 404(22.75), 384(11.05), 368(7.5), 339(7.95), 248(19.67), 149 (51.94), 69 (63.88), 57 (100).

Elemental analysis: _{Calcd .} for _C25H36O2NF3 : _C : 68.31, H: 8.25, N: 3.19.

Measured values: C: 68.22, H: 8.31, N: 2.98.

Example 8

Take 0.55mmol 4-iodo-13-ethylandrost-4-ene-3,17-dione, 1mmol Cu powder, 2mmol BrCF ₂ CO ₂ C ₂ H ₅ in 30ml N,N-dimethylformamide DMF In a solvent, react at 30-50°C _under N for 8 hours. After the reaction, dilute the reactant with diethyl ether, filter the solid with silica gel, pour the filtrate into 40ml of water to separate the organic layer, and extract the water layer with diethyl ether. The combined organic phases were washed three times with water. After the ether layer was dried with anhydrous _MgSO4 , the solvent was evaporated under reduced pressure, and the initial product was separated by flash column chromatography to obtain solid 4-trifluoromethyl-13-ethylandrost-4-ene-3,17-dione . 93% yield

IR (KBr pellet): 3000, 1750, 1600, 1346, 1160, 1120 ^{cm -1} .

¹ H NMR (300 MHz, CDCl ₃ ) d: 1.00 (t, J=8.0 Hz, CH ₃ -), 1.29 (s, C ₁₉ -H) ppm.

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -21.8 (s) ppm.

MS m/z: 368 (M ⁺ , 42.7), 353 (M ⁺ , 11.5), 324 (17.2), 299 (M ⁺ _-CF3 , 28.4), 270 (16.7), 194 (100).

Elemental analysis: Calcd _{. for C21H27O2F3} : C: _68.46 , H: 7.38.

Measured values: C: 68.14, H: 7.20.

Example 9

Take 0.5mmol 4-iodo-13-ethyl-17β-hydroxyl-17α-methylandrost-4-en-3one, 1mmol Cu powder, 2mmol ClCF ₂ CO ₂ C ₂ H ₅ , in 30ml N,N- In dimethylformamide DMF solvent, react at 50-60°C under _N for 6 hours. After the reaction, the reactant is diluted with ether, and the solid is filtered with silica gel. The filtrate is poured into 50ml of water to separate the organic layer, and the water The layer was extracted with ether, and the organic phases were combined and washed three times with water. After the ether layer was dried with anhydrous MgSO ₄ , the solvent was evaporated under reduced pressure, and the initial product was separated by flash column chromatography to obtain solid 4-trifluoromethyl-13-ethyl-17β-hydroxyl-17α-methylandroster- 4-en-3-one. Yield 83%

IR (KBr pellet): 3300 (br), 1690, 1600, 1340, 1120 cm ^-1 .

¹ H NMR (300 MHz, CDCl ₃ ) d: 1.00 (t, J=8.0 Hz, CH ₃ -), 1.29 (s, C ₁₉ -H), 1.40 (s, C ₂₀ -H) ppm.

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -20.6 (s) ppm.

MS m/z: 384 (M ⁺ , 17.6), 369 (M ⁺ -CH ₃ , 4.5), 366 (M ⁺ -H ₂ O, 19.2), 297 (43.5), 194 (100).

Elemental analysis: Calcd _{. for C22H31O2F3} : C: _68.73 , H: 8.13.

Measured values: C: 69.00, H: 8.03.

Example 10

Take 0.3mmol 4-iodo-N-isopropylandrost-4-en-3-one-17β-carboxamide, 1mmol Cu powder, 2mmol FO ₂ SCF ₂ CF ₂ OCF ₂ CO ₂ CH ₃ in 30ml N,N - In dimethylformamide DMF solvent, react at 50-60°C for 6 hours under N ₂ , after the reaction, dilute the reactant with ether, filter the solid with silica gel, pour the filtrate into 50ml water to separate the organic layer, The aqueous layer was extracted with ether, and the combined organic phases were washed three times with water. After the ether layer was dried with anhydrous _MgSO4 , the solvent was evaporated under reduced pressure, and the initial product was separated by flash column chromatography to obtain solid 4-trifluoromethyl-N-isopropylandrost-4-en-3-one-17β -formamide, yield 83%

IR (KBr pellet): 3500 (br, NH), 2900, 1680, 1594, 1510, 1455, 1356, 1260, 1210 ^{cm -1} .

¹ H NMR (300MHz, CDCl ₃ )d: 0.75(s, C ₁₈ -H), 1.26(s, C ₁₉ -H), 1.36(d, J=6.0Hz, (CH ₃ ) ₂ CH-), 4.50 (q, J = 6.1 Hz, (CH ₃ ) ₂ CH-N), 5.09 (s, NH) ppm.

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -20.9 (s) ppm.

MS m/z: 425 (M ⁺ , 42.6), 410 (M ⁺ -CH ₃ , 15.3), 390 (20.7), 38 (12.0), 366 (7.6), 337 (8.0), 43 (100).

Elemental _{analysis: Calcd. for C24H34O2NF3 : C :} 67.74, H: 8.05, N: 3.29.

Measured values: C: 67.68, H: 7.96, N: 3.32.

Example 11

Take 0.6mmol 4-iodo-17β-hydroxyandrost-4-en-3-one, 0.06mmol Cu powder, 3mmol FO ₂ SCF ₂ CF ₂ OCF ₂ CO ₂ CH ₃ in 30ml of ethyl ketone or acetone solvent, in Under _N2 , react at 70-80°C for 7 hours. After the reaction, dilute the reactant with ether, filter the solid with silica gel, pour the filtrate into 50ml water to separate the organic layer, extract the aqueous layer with ether, and combine the organic phases. Wash three times with water. The ether layer was dried with anhydrous MgSO ₄ , and the solvent was evaporated under reduced pressure. After the initial product was separated by flash column chromatography, solid 4-trifluoromethyl-17β-hydroxyandrost-4-en-3-one was obtained. 78%

IR (KBr pellet): 3300 (br, -OH), 2900, 1680, 1600, 1110, 1040 cm ^-1 .

¹ H NMR (300 MHz, CDCl ₃ ) d: 0.86 (s, C ₁₈ -H), 1.28 (s, C ₁₉ -H), 4.62 (t, J=8.5 Hz, C ₁₇ -H) ppm.

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -21.8 (s) ppm.

MS m/z: 356 (M ⁺ , 16.4), 341 (M ⁺ -CH ₃ , 23.2), 338 (M ⁺ -H ₂ O, 8.6), 294 (78.5), 192 (100).

Elemental analysis: Calcd _{. for C20H27O2F3} : C: _67.40 , H: 7.63.

Measured values: C: 67.62, H: 7.80.

Example 12

Take 0.2mmol 4-bromo-17β-hydroxy-17α _{- methylandrost} -4- _en -3-one-17 _- acetate, 0.8mmol Cu powder, 3mmol _{FO2SCF2CF2OCF2CO2K} , In 30ml of N,N-dimethylformamide DMF solvent, react at 80°C under _N for 4 hours. After the reaction, the reactant is diluted with ether, and the solid is filtered with silica gel, and the filtrate is poured into 50ml of water to separate The organic layer and the aqueous layer were extracted with ether, and the combined organic phases were washed with water three times. After the ether layer was dried with anhydrous _MgSO4 , the solvent was evaporated under reduced pressure, and the initial product was separated by flash column chromatography to obtain solid 4-trifluoromethyl-17β-hydroxyl-17α-methylandrost-4-ene-3 - Keto-17-acetate, 70% yield

IR (KBr pellet): 2950, 1750, 1680, 1600, 1340, 1110 ^{cm -1} .

¹ H NMR (300MHz, CDCl ₃ )d: 0.85(s, C ₁₈ -H), 1.29(s, C ₁₉ -H), 1.40(s, C ₂₀ -H), 2.04(s, CH ₃ CO-) ppm

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -21.8 (s) ppm.

MS m/z: 412 (M ⁺ , 13.4), 397 (M ⁺ -CH ₃ , 4.0), 352 (M ⁺ -HOAc, 24.2), 283 (32.0), 197 (100).

Elemental analysis: Calcd _{. for C23H31O3F3} : C: _66.97 , H: 7.57.

Measured values: C: 66.60, H: 7.46.

Example 13

Take 0.6mmol 4-bromoandrost-4-ene-3,11,17-trione, 3mmol CuI, 3mmol FO ₂ SCF ₂ CF ₂ OCF ₂ CF ₂ CO ₂ CH ₃ in 30ml N,N-dimethylformamide In DMF solvent, react at 40°C _under N for 4 hours. After the reaction, dilute the reactant with diethyl ether, filter the solid with silica gel, pour the filtrate into 50ml water to separate the organic layer, extract the aqueous layer with diethyl ether, and combine The organic phase was washed three times with water. After the ether layer was dried with anhydrous _MgSO4 , the solvent was evaporated under reduced pressure, and the initial product was separated by flash column chromatography to obtain solid 4-trifluoromethylandrost-4-ene-3,11,17-trione. Yield 82%

IR (KBr pellet): 3000, 1750, 1600, 1340, 1160, 1120 ^{cm -1} .

¹ H NMR (300 MHz, CDCl ₃ ) d: 0.96 (s, C ₁₈ -H), 1.30 (s, C ₁₉ -H) ppm.

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -22.0 (s) ppm.

MS m/z: 368 (M ⁺ , 32.4), 353 (M ⁺ -CH ₃ , 11.4), 324 (23.6), 366 (M ⁺ -CF ₃ , 28.7), 282 (23.4), 204 (100).

Elemental analysis: Calcd _{. for C20H23O3F3} : C: _65.21 , H: 6.29.

Measured values: C: 65.36, H: 5.90.

Example 14

The reaction conditions were the same as in Example 13 to obtain the product 4-trifluoromethyl-17β-hydroxyl-17α-methylestr-3-one. The yield was 75%.

IR (KBr pellet): 3300 (br), 1680, 1600, 1320, 1120 cm ^-1 .

¹ H NMR (300 MHz, CDCl ₃ ) d: 0.90 (s, C ₁₈ -H), 1.39 (s, C ₂₀ -H) ppm.

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -21.0 (s) ppm.

MS m/z: 356 (M ⁺ , 17.8), 355 (M ⁺ -1, 26.3), 338 (M ⁺ _-H2O , 36.5), 310 (76.4), 270 (90), 107 (100).

Elemental analysis: Calcd _{. for C20H27O2F3} : C: _67.40 , H: 7.63.

Measured values: C: 67.02, H: 7.70.

Example 15

The reaction conditions were the same as in Example 12 to obtain the product 4-trifluoromethyl-17β-hydroxyestr-4-en-3-one. The yield was 87%.

IR (KBr pellet): 3300 (br, -OH), 2800, 1686, 1600, 1106, 1050 cm ^-1 .

¹ H NMR (300 MHz, CDCl ₃ ) d: 0.85 (s, C ₁₈ -H), 4.62 (t, J=8.5 Hz, C ₁₇ -H) ppm.

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -21.0 (s) ppm.

MS m/z: 343(M ⁺⁺ 1, 16.4), 342(M ⁺ , 54.6), 324(M ⁺ _-H2O , 18.0), 297(65.4), 271(82.0), 107(100) .

12

Elemental analysis: Calcd _{. for C19H25O2F3} : C: _66.65 , H: 7.36.

Measured values: C: 66.90, H: 7.30.

Example 16

The reaction conditions were the same as in Example 2, and the product 4-trifluoromethyl-16α, 17α-epoxypregn-4-en-3-one was obtained with a yield of 88%.

IR (KBr pellet): 3000, 2900, 1760, 1700, 1600, 1440, 1116 ^{cm -1} .

¹ H NMR (300MHz, CDCl ₃ )d: 0.70(s, C ₁₉ -H), 1.26(s, C ₁₉ -H), 2.22(s, C ₂₁ -H), 4.90(d, J=4.0Hz, C ₁₆ -H)ppm.,

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -20.8 (s) ppm.

MS m/z: 396 (M ⁺ , 26.3), 381 (M ⁺ -CH ₃ , 6.32), 378 (M ⁺ -H ₂ O, 28.9), 327 (M ⁺ -CF ₃ , 5.42), 284 (17.4 ), 197(100).

Elemental analysis: _{Calcd. for C22H27O3F3 : C} : _66.65 , H: 6.86.

Measured values: C: 66.98, H: 6.66.

Example 17

The reaction conditions were the same as in Example 3 to obtain the product 4-trifluoromethyl-17β-hydroxyl-16α-methylpregn-4-en-3-one-17-acetate. The yield was 85%.

IR (KBr pellet): 2950, 2800, 1760, 1700, 1600, 1460, 1120 ^{cm -1} .

¹ H NMR (300MHz, CDCl ₃ )d: 0.70(s, C ₁₈ -H), 1.08(d, J=6.0Hz, C ₁₆ -CH ₃ ), 1.26(s, C ₁₉ -H), 2.13(s , CH ₃ COO-), 2.21 (s, C ₂₁ -H) ppm.

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -21.6 (s) ppm.

MS m/z: 454 (M ⁺ , 22.4), 439 (M ⁺ -CH ₃ , 5.6), 394 (M ⁺ -H ₂ O, 84.0), 325 (43.6), 147 (100).

Elemental analysis: Calcd _{. for C25H33O4F3} : C: _66.06 , H: 7.32.

Measured values: C: 66.31, H: 7.40.

Example 18

Take 0.1mmol 4-trifluoromethylandrost-4-ene-3,17-dione, 0.5mmol tetrachlorobenzoquinone in 20ml dioxane solvent, heat and reflux for 2 hours, filter, and evaporate the filtrate under reduced pressure After removing the solvent, the solid was dissolved with _CH2Cl2 , washed with 5% _NaHCO3 solution and water respectively, after _the organic phase was dried, the solvent was evaporated under reduced pressure, and the product 4-trifluoromethylandrogen was separated by flash column chromatography. Steta-4,6-diene-3,17-dione, 85% yield.

IR (KBr pellet): 2900, 1750, 1660, 1600, 1270, 1160, 1110 ^{cm -1} .

¹ H NMR (300MHz, CDCl ₃ )d: 0.92 (s, C ₁₈ -H), 1.30 (s, C ₁₉ -H), 6.31 (Complex doublet, J=11Hz, C ₆ -H), 6.71 (Complex doublet , J=11Hz, C ₇ -H)ppm.

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -22.6 (s) ppm.

MS m/z: 352 (M ⁺ , 40.6), 337 (M ⁺ -CH ₃ , 10.0), 308 (26.6), 283 (M ⁺ -CF ₃ , 35.3), 266 (18.0), 190 (100).

Elemental analysis: Calcd _{. for C20H23O2F3} : _C : 68.17, H: 6.58.

Measured values: C: 68.07, H: 6.46.

Example 19

Take 0.4mmol 4-trifluoromethylestr-4-ene-3,17-dione, 1mmol tetrachlorobenzoquinone in 30ml dioxane solvent, heat to reflux for 6 hours, filter, and evaporate the filtrate under reduced pressure After the solvent, the solid was dissolved with _CH2Cl2 , washed with 5% _NaHCO3 solution and water respectively, and after _the organic phase was dried, the solvent was evaporated under reduced pressure, and the product 4-trifluoromethylestradiol was separated by flash column chromatography -4,6-diene-3,17-dione, the yield was 87%.

IR (KBr pellet): 2850, 1740, 1680, 1600, 1100, 1040 ^{cm -1} .

¹ H NMR (300MHz, CDCl ₃ )d: 0.94 (s, C ₁₈ -H), 6.30 (Complex doublet, J=11Hz, C ₆ -H), 6.71 (Complex doublet, J=11Hz, C ₇ -H) ppm .

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -23.0 (s) ppm.

MS m/z: 339 (M ⁺ +1, 28.7), 338 (M ⁺ , 86.5), 320 (17.6), 269 (100).

Elemental analysis: Calcd _{. for C19H23O2F3} : C: _67.49 , H: 6.86.

Measured values: C: 67.30, H: 7.02.

Example 20

Take 1mmol 4-trifluoromethyl-N-(1,1-dimethylethyl)androst-4-en-3-one-17β-carboxamide, 0.8mmol tetrachlorobenzoquinone, in 30ml benzene solvent , heated to reflux for 15 hours, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure. After the solid was dissolved with CH ₂ Cl ₂ , it was washed with 5% NaHCO ₃ solution and water respectively. After the organic phase was dried, the solvent was evaporated under reduced pressure, and the flash column The product 4-trifluoromethyl-N-(1,1-dimethylethyl)androst-4,6-dien-3-one-17β-carboxamide was separated by chromatography with a yield of 75%.

IR (KBr pelle1): 3450 (br, NH), 2900, 1680, 1580, 1260, 1180, 1120 cm ^-1 .

¹ H NMR (300MHz, CDCl ₃ )d: 0.74 (s, C ₁₈ -H), 1.30 (s, C ₁₉ -H), 1.35 (s, t-Bu), 6.31 (Complex doublet, J=11Hz, C ₆ -H), 6.71 (Complex doublet, J=11 Hz, C ₇ -H) ppm.

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -23.5 (s) ppm.

MS m/z: 437 (M ⁺ , 52.0), 422 (M ₊ -CH ₃ , 23.5), 402 (27.0), 384 (10.5), 346 (23.8), 57 (100).

Elemental _{analysis: Calcd. for C25H34O2NF3 : C :} 68.63, H: 7.83, N: 3.20.

Measured values: C: 68.70, H: 7.90, N: 3.35.

Example 21

Take 0.5mmol 4-trifluoromethyl-13-ethylandrost-4-ene-3,17-dione, 2mmol tetrachlorobenzoquinone in 30ml benzene solvent, heat and reflux for 10 hours, filter, and evaporate the filtrate under reduced pressure After removing the solvent, the solid was dissolved with _CH2Cl2 , washed with 5% _NaHCO3 solution and water respectively, after _the organic phase was dried, the solvent was evaporated under reduced pressure, and the product 4-trifluoromethyl- 13-Ethylandrost-4,6-diene-3,17-dione, the yield is 90%.

IR (KBr pellet): 3000, 1750, 1580, 1340, 1160, 1110 ^{cm -1} .

¹ H NMR (300MHz, CDCl ₃ )d: 1.00(t, J=8.0Hz, CH ₃ CH ₂ -), 1.28(s, C ₁₉ -H), 6.30 (Complex doublet, J=11Hz, C ₆ -H ), 6.71 (Complex doublet, J=11 Hz, C ₇ -H) ppm.

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -24.0 (s) ppm.

MS m/z: 366 (M ⁺ , 28.2), 351 (M ⁺ _-CH3 , 7.4), 337 (M ⁺ -Et, 4.4), 297 (M ⁺ _-CF3 , 32.5), 194 (100).

Elemental analysis: Calcd _{. for C21H25O2F3} : C: _68.83 , H: 6.88.

Measured values: C: 69.10, H: 7.02.

Example 22

Take 0.4mmol 4-trifluoromethyl-N-isopropylandrost-4-en-3-one-17β-carboxamide, 1.2mmol tetrachlorobenzoquinone in 30ml dioxane solvent, heat and reflux for 12 hours , filtered, the filtrate _was evaporated to remove the solvent under reduced pressure, the solid was dissolved in _CH2Cl2 , washed with 5% _NaHCO3 solution and water respectively, after the organic phase was dried, the solvent was evaporated under reduced pressure, and the product was separated by flash column chromatography 4-Trifluoromethyl-N-isopropylandrost-4,6-dien-3-one-17β-carboxamide, the yield was 85%.

IR (KBr pellet): 3500 (br), 2900, 1690, 1600, 1340, 1160 cm ^-1 .

¹ H NMR (300MHz, CDCl ₃ )d: 0.75(s, C ₁₈ -H), 1.28(s, C ₁₉ -H) 1.35(d, J=6.0Hz, (CH ₃ ) ₂ CH-), 4.50( q, J=6.0Hz, (CH ₃ ) ₂ CH-N), 5.10(s, NH), 6.30(dm, J=11Hz, C ₆ -H), 6.71(dm, J=11Hz, C ₇ -H )ppm.

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -24.8 (s) ppm.

MS m/z: 423 (M ⁺ , 62.3), 408 (M ⁺ -CH ₃ , 14.2), 388 (2.10), 365 (18.0), 337 (21.5), 43 (100).

Elemental _{analysis: Calcd. for C24H32O2NF3 : C :} 28.06, H: 7.16, N: 3.31.

Measured values: C: 27.98, H: 7.40, N: 3.11.

Example 23

Get 0.1mmol 4-trifluoromethylandrost-4-ene-3,17-dione, 0.5mmol dichlorodicyanobenzoquinone, in 20ml tert-butanol solvent, heat and reflux for 2 hours, filter, and the filtrate reduces After pressure evaporation to remove the solvent, the solid was dissolved with EtOAc, washed with 5% _NaHCO3 solution and water respectively, after the organic phase was dried, the solvent was evaporated under reduced pressure, and the product 4-trifluoromethylandroster was separated by flash column chromatography -1,4-diene-3,17-dione, yield 82%.

IR (KBr pellet): 3000, 1750, 1600, 1596, 1340, 1110 ^{cm -1} .

¹ H NMR (300MHz, CDCl ₃ )d: 0.92(s, C ₁₈ -H), 1.48(s, C ₁₉ -H), 6.40(d, J=10Hz, C ₂ -H), 7.54(d, J =10Hz, C ₁ -H)ppm.

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -25.0 (s) ppm.

MS m/z: 352 (M ⁺ , 72.5), 337 (M ⁺ -CH ₃ , 8.5), 307 (18.0), 283 (M ⁺ -CF ₃ , 32.6), 190 (100).

Elemental analysis: Calcd _{. for C20H23O2F3} : C: _68.17 , H: 6.58.

Measured values: C: 68.39, H: 6.34.

Example 24

Take 0.4mmol 4-trifluoromethylestr-4-ene-3,17-dione, 1mmol dichlorodicyanobenzoquinone in 30ml tert-butanol solvent, heat to reflux for 4 hours, filter, and depressurize the filtrate After the solvent was evaporated, the solid was dissolved with EtOAc, washed with 5% _NaHCO3 solution and water respectively, after the organic phase was dried, the solvent was evaporated under reduced pressure, and the product 4-trifluoromethylestro- 1,4-diene-3,17-dione, 77% yield.

IR (KBr pellet): 2810, 1740, 1660, 1600, 1100, 1020 ^{cm -1} .

¹ H NMR (300MHz, CDCl ₃ )d: 0.93(s, C ₁₈ -H), 6.38(d, J=10Hz, C ₂ -H), 7.48(dd, J=10, 5.2Hz, C ₁ -H )ppm.

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -24.2 (s) ppm.

MS m/z: 339 (M ⁺ +1, 32.0), 338 (M ⁺ , 86.4), 320 (23.4), 269 (92.0) 107 (100).

Elemental analysis: Calcd _{. for C19H21O2F3} : C: _67.44 , H: 6.26.

Measured values: C: 67.40, H: 6.28.

Example 25

Take 0.5mmol 4-trifluoromethyl-N-(1,1-dimethylethyl)androst-4-en-3-one-17β-carboxamide, 0.4mmol dichlorodicyanobenzoquinone, in In 30ml of tert-butanol solvent, heat and reflux for 8 hours, filter, evaporate the solvent under reduced pressure from the filtrate, dissolve the solid with EtOAc, wash with 5% _NaHCO3 solution and water respectively, dry the organic phase, and evaporate the solvent under reduced pressure , separated by flash column chromatography to obtain the product 4-trifluoromethyl-N-(1,1-dimethylethyl)androsta-1,4-dien-3-one-17β-carboxamide, the yield is 71%.

IR (KBr pellet): 3500 (br, NH), 2900, 1680 (br), 1590, 1500, 1440, 1230, 1120 cm ^-1 .

¹ H NMR (300MHz, CDCl ₃ )d: 0.74 (s, C ₁₈ -H), 1.35 (s, t-Bu) 1.90 (s, C ₁₉ -H), 6.66 (dd, J=4.0, 2.0Hz, C ₂ -H), 7.70 (d, J=10 Hz, C ₁ -H) ppm.

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -24.6 (s) ppm.

MS m/z: 437 (M ⁺ , 42.7), 422 (M ⁺ -CH ₃ , 16.6), 402 (24.6), 382 (10.5), 246 (22.0), 57 (100).

Elemental _{analysis: Calcd. for C25H34O2NF3 : C :} 68.63, H: 7.83, N: 3.20.

Measured values: C: 68.40, H: 7.51, N: 3.10.

Example 26

Take 1mmol 4-trifluoromethyl-13-ethylandrost-4-ene-3,17-dione, 4mmol dichlorodicyanobenzoquinone in 30ml tert-butanol solvent, heat to reflux for 3 hours, filter, After the filtrate was evaporated to remove the solvent under reduced pressure, the solid was dissolved with EtOAc, washed with 5% _NaHCO3 solution and water respectively, after the organic phase was dried, the solvent was evaporated under reduced pressure, and the product 4-trifluoromethyl was separated by flash column chromatography -13-Ethylandrost-1,4-diene-3,17-dione, the yield was 73%.

IR (KBr pellet): 3000, 1750, 1680, 1600, 1340, 1120 ^{cm -1} .

¹ H NMR (300MHz, CDCl ₃ )d: 1.00(t, J=8.0Hz, CH ₃ CH ₂ -), 1.50(s, C ₁₉ -H), 6.30(d, J=10Hz, C ₂ -H) , 7.46 (d, J=10Hz, C ₁ -H) ppm.

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -25.0 (s) ppm.

MS m/z: 366 (M ⁺ , 32.3), 351 (M ⁺ _-CH3 , 8.6), 337 (M ⁺ -Et, 6.8), 297 (M ⁺ _-CF3 , 26.7), 194 (100).

Elemental analysis: Calcd _{. for C21H25O2F3} : C: _68.83 , H: 6.88.

Measured values: C: 68.70, H: 6.90.

Example 27

Take 0.4mmol 4-trifluoromethyl-N-isopropylandrost-4-en-3-one-17β-carboxamide, 1.2mmol dichlorodicyanobenzoquinone, in 30ml tert-butanol solvent, heat to reflux After 6 hours, filter, after the filtrate was evaporated to remove the solvent under reduced pressure, after the solid was dissolved with EtOAc, it was washed with 5% _NaHCO3 solution and water respectively, after the organic phase was dried, the solvent was evaporated under reduced pressure, and the product 4 was obtained by flash column chromatography. -Trifluoromethyl-N-isopropylandrost-1,4-dien-3-one-17β-carboxamide, yield 81%.

IR (KBr pellet): 3500 (br), 2900, 1690, 1600, 1340, 1120 cm ^-1 .

¹ H NMR (300MHz, CDCl ₃ )d: 0.75(s, C ₁₈ -H), 1.50(s, C ₁₉ -H) 1.36(d, J=6.0Hz, (CH ₃ ) ₂ CH-), 4.50( q, J=6.0Hz, (CH ₃ ) ₂ CH-N), 5.09(s, NH), 6.45(d, J=10Hz, C ₂ -H), 7.46(d, J=10Hz, C ₁ -H )ppm.

¹⁹ F NMR (60 MHz, CDCl ₃ ) d: -25.2 (s) ppm.

MS m/z: 423 (M ⁺ , 58.6), 408 (M ⁺ -CH ₃ , 23.2), 388 (22.80), 368 (80.0), 339 (23.6), 43 (100).

Elemental _{analysis: Calcd. for C24H32O2NF3 : C :} 28.06, H: 7.16, N: 3.31.

Measured values: C: 28.43, H: 7.46, N: 3.10.

Claims (8)

1. A 4-trifluoromethyl-3-ketone-steroid compound, characterized in that it has the following molecular formula: Wherein R ₁ =H or CH ₃ , R ₂ =H or O, R ₃ =H, CH ₃ or C ₂ H ₅ , R ₄ =OH, CH ₃ CO, CH ₃ COO, CONR ₇ R ₈ or C _{1- 10} alkyl, R ₅ =H, CH ₃ or CH ₃ COO, R ₄ and R ₅ =O, OCH ₂ CH ₂ O or

R ₆ =H or CH ₃ , R ₅ and R ₆ =O, R ₇ or R ₈ =H, C _1-10 alkyl, cycloalkyl, R ₇ and R ₈ =(CH ₂ ) _n , n= 1-6,

2. A 4-trifluoromethyl-3-ketone-steroid compound as claimed in claim 1, characterized in that it is 4-trifluoromethyl-3-ketone-4-ene, 4-trifluoromethyl Estrogen, androster, pregnane or spirosteroids of yl-3-keto-1,4-diene or 4-trifluoromethyl-3-keto-4,6-diene. 3, a kind of preparation method of 4-trifluoromethyl-3-keto-steroid compound as claimed in claim 1, it is characterized in that be to carry out with the step of following method respectively: (1), the molecular formula is adopted as:

4-bromo or iodo-3-one-4-ene-steroid compound starting material, wherein R ₁ =H, CH ₃ , R ₂ =H or O, R ₃ =H, CH ₃ or C ₂ H ₅ , R ₄ = OH, CH ₃ CO, CH ₃ COO, CONR ₇ R ₈ or C _1-10 alkyl, R ₅ = H, CH ₃ or CH ₃ COO, R ₄ and R ₅ = O, OCH ₂ CH ₂ O or R ₆ =H or CH ₃ , R ₅ and R ₆ =O, R ₇ or R ₈ =H, C _1-10 alkyl or cycloalkyl, R ₇ and R ₈ =(CH ₂ ) _n , n= 1-6, In the presence of a solvent and a catalyst, reaction with a trifluoromethylating reagent yields 4-trifluoromethyl-3-keto-4-ene-steroids, 4-bromo or iodo-3-keto-4-ene- The molar ratio of the steroid compound, the catalyst and the trifluoromethylation reagent is 1:0.1-5:0.5-5, the reaction time is 1-10 hours, and the reaction temperature is 30-120°C; (2), 4-trifluoromethyl-3-ketone-4-ene-steroid compound and dichlorodicyanobenzoquinone were reacted by heating in tert-butyl alcohol solvent for 2-8 hours to obtain 4-trifluoromethyl- 3-keto-1,4-diene steroid compound, wherein the molar ratio of 4-trifluoromethyl-3-keto-4-ene-steroid compound to dichlorodicyanobenzoquinone is 1:0.8- 5,

(3), 4-trifluoromethyl-3-keto-4-ene-steroid compound and chloranil were reacted by heating in benzene or dioxane solvent for 2-15 hours to obtain 4-trifluoromethyl -3-keto-4,6-diene steroid compound, wherein the molar ratio of 4-trifluoromethyl-3-keto-4-ene-steroid compound to chloranil is 1:0.8-5,

4, a kind of preparation method of 4-trifluoromethyl-3-ketone-steroid compound as claimed in claim 3, it is characterized in that the solvent used in the reaction of (1) is ether, sherwood oil, benzene, four Carbon chloride, ethyl ketone, dimethylsulfoxide, hexamethylphosphoramide, N,N-dimethylformamide, N,N-dimethylacetamide. 5. A preparation method of 4-trifluoromethyl-3-ketone-steroid compound as claimed in claim 3 or 4, characterized in that the solvent used in the reaction of (1) is hexamethylphosphoramide, N,N-dimethylformamide, N,N-dimethylacetamide. 6. A preparation method of 4-trifluoromethyl-3-keto-steroid compound as claimed in claim 3, characterized in that the methylation reagent used in the reaction of (1) is X(CF ₂ CF ₂ O) _m (CF ₂ ) _k CO ₂ Y, where X=Cl, Br, I or FO ₂ S, Y=H, CH ₃ , C ₂ H ₅ or K, m=0 or 1, k=1 or 2. 7. A method for preparing 4-trifluoromethyl-3-keto-steroid compound as claimed in claim 3, characterized in that the catalyst used in the reaction of (1) is Cu powder or CuI. 8. A method for preparing 4-trifluoromethyl-3-keto-steroid compound as claimed in claim 3, characterized in that the reaction temperature is 40-80°C.