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

4-trifluoromethyl-3-ketosteroid compound and synthesizing method thereof Download PDF

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CN1061983C
CN1061983C CN96116595A CN96116595A CN1061983C CN 1061983 C CN1061983 C CN 1061983C CN 96116595 A CN96116595 A CN 96116595A CN 96116595 A CN96116595 A CN 96116595A CN 1061983 C CN1061983 C CN 1061983C
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trifluoromethyl
ketone
alkene
steroidal compounds
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CN1161972A (en
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费向曙
田伟生
陈庆云
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Shanghai Institute of Organic Chemistry of CAS
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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-ketosteroid compound and synthetic method thereof
The present invention relates to a kind of fluorine-containing steroidal compounds.Be 4-trifluoromethyl-3-ketosteroid compound and synthetic, comprise its female steroid, androstane, pregnant steroid or spiral shell steroid compound.
At first,, in the organic active molecule, introduce fluorine, can cause noticeable change [P.Goldman, Science, 1969,64,1123 of molecular chemistry, physics and physiologically active because the fluorine element element has unique character; Biomedical Aspects of Fluorine Chemistry, R.Filler and Y.Kobayashi, Kodansha Ltd., Tokyo, 1980.].In the steroidal molecule, introduce the noticeable change that fluorine can cause physiologically active equally, as the high 10-12 of specific activity nonfluorinated cortisone that fluoridizes cortisone [J.Fried and E.F.Sabo doubly, J.Am.Chem.Soc., 1954,76,1455], therefore introducing fluorine in the steroidal molecule is an important channel seeking the steroidal new drug.Because trifluoromethyl has very high electronegativity, stability and lipotropy, therefore change of properties is more obvious after introducing trifluoromethyl usually in the steroidal molecule, as trifluoro angular methyl(group) steroidal is a kind of good aromatization enzyme inhibitor [Hideo Nemoto etal, J.Org.Chem., 1,995 60,594], the activity of 17-trifluoromethyl-testosterone be three times of anti-early pregnancy drug RU486 (Wang Zhongqi, Lu Shoufu, ZL93112563.4).But synthetic trifluoromethyl steroidal is than a synthetic fluorine, the more difficult [J.Fried of difluoro steroidal, N.A.Abraham, Organic Reaction in Steroid Chemistry, New York, 1972, Vol.1, pp423-493], particularly on heterocycle, introduce the steroidal synthetic of trifluoromethyl group and report seldom.Generally be photoresponse [A.F.Pascual and M.E.Wolff, J.Med.Chem., 1971 of adopting CF3I and steroidal, 14,164], be illustrated in fig. 1 shown below photoresponse [the G.H.Rasmusson et al J.Org.Chem. that has reported CF3I and steroidal, 1975,40,672]
Figure 9611659500051
A, R=β-OAc, α-H b, R=β-COCH3, α-OAc
But transformation efficiency has only 32-42%.Therefore the method for bibliographical information not only the time long, operational difficulty, and productive rate is very low.Secondly also have the CF3SiMe3 of employing and carbonyl reaction [J.Fluorine Chem., Z.Q.Wang, etal, 1994,69,1), but be subjected to steric influence bigger.The 3-ketosteroid compound is a known drug, introduce bromine or iodine at C4, with 3-carbonyl-4-en steroids in the mixed solvent of acetate, ether, with the trimethylpyridine is proton acceptor, can only generate 4-bromine or iodine-3-ketone-4-en steroids compound (D.N.Kirk, etal, J.Chem.Soc., 1956,627).We on this basis, obtain the product that halogen is replaced by trifluoromethyl under the suitable condition by experiment, promptly obtain more high reactivity new class compound: the 4-trifluoromethyl-3-ketosteroid compound, and, find out efficient, easy synthetic method at the deficiency of aforesaid method.
Purpose of the present invention just provides the highly active new steroidal compounds of a class: the 4-trifluoromethyl-3-ketosteroid compound, and a kind of method of synthetic 4-trifluoromethyl-3-ketosteroid compound simply, efficiently is provided.
4-trifluoromethyl-3-ketosteroid compound provided by the invention has following general molecular formula:
Figure 9611659500061
R wherein 1=H or CH 3, R 2=H or O, R 3=H, CH 3Or C 2H 5, R 4=OH, CH 3CO, CH 3COO, CONR7R8 or C 1-10Alkyl, R 5=H, CH 3Or CH 3COO, R 4And R 5=O, OCH 2CH 2O or R 6=H or CH 3, R 5And R 6=O, R 7Or R 8=H, C 1-10Alkyl, cycloalkyl, R 7And R 8=(CH 2) n, n=1-6,
Figure 9611659500063
Figure 9611659500064
It can be female steroid, androstane, pregnant steroid or the spiral shell steroid compound of 4-alkene, 1,4-diene or 4,6-diene.As 4-Trifluoromethyl-1 7 beta-hydroxy androstane-4-alkene-3-ketone, 4-Trifluoromethyl-1 7 beta-hydroxyl-17 alphas-methyl androstane-4-alkene-3-ketone-17-acetic ester, 4-trifluoromethyl androstane-4-alkene-3,11, the 17-triketone, 4-trifluoromethyl-N-sec.-propyl androstane-4-alkene-3-ketone-17 β-methane amide, 4-Trifluoromethyl-1 3-ethyl androstane-4-alkene-3, the 17-diketone, 4-Trifluoromethyl-1 3-ethyl androstane-1,4-alkene-3, the 17-diketone, 4-Trifluoromethyl-1 7 beta-hydroxies female steroid-4-alkene-3-ketone, 4-Trifluoromethyl-1 7 beta-hydroxyl-17 alphas-methyl female steroid-3-ketone, 4-Trifluoromethyl-1 6 α, the pregnant steroid of 17 α-epoxy-4-alkene-3-ketone, the pregnant steroid of 4-Trifluoromethyl-1 7 beta-hydroxies-16 Alpha-Methyl-4-alkene-3-ketone-17-acetic ester, the pregnant steroid of 17 beta-hydroxies-4-trifluoromethyl-4-alkene-3-ketone-21-hydroxy acid lactone, 4-trifluoromethyl androstane-4,6-diene-3, the 17-diketone-, 4-trifluoromethyl-N-sec.-propyl androstane-1,4-diene-3-ketone-17 β-methane amide, 4-Trifluoromethyl-1 3-ethyl androstane-4,6-diene-3, the 17-diketone, 4-trifluoromethyl androstane-4,6-diene-3, the 17-diketone, 4-trifluoromethyl female steroid-1,4-diene-3, the 17-diketone, 4-trifluoromethyl androstane-1,4-diene-3, the 17-diketone, 4-trifluoromethyl-N-(1, the 1-dimethyl ethyl) androstane-4,6-diene-3-ketone-17 β-methane amide, 4-trifluoromethyl-N-sec.-propyl androstane-4,6-diene-3-ketone-17 β-methane amide, 4-trifluoromethyl-N-sec.-propyl female steroid-1,4-diene-3-ketone-17 β-methane amide, (25R)-4-trifluoromethyl spiral shell steroid-4-alkene-3-ketone etc.
The method that the present invention also provides a kind of simple and effective to prepare above-mentioned 4-trifluoromethyl-3-ketosteroid compound promptly with molecular formula is:
Figure 9611659500071
4-bromine or iodine-3-ketone-4-alkene-sterides compound raw material, wherein R 1=H, CH 3, R 2=H or O, R 3=H, CH 3Or C 2H 5, R 4=OH, CH 3CO, CH 3COO, CONR 7R 8Or C 1-10Alkyl, R 5=H, CH 3Or CH 3COO, R 4And R 5=O, OCH 2CH 2O or, R 6=H or CH 3, R 5And R 6=O, R 7Or R 8=H, C 1-10Alkyl or cycloalkyl, R 7And R 8=(CH2) n, n=1-6,
Figure 9611659500072
In solvent, with CuI or Cu powder is catalyzer, with 4-bromine or iodine-3-ketone-4-alkene-steroidal and trifluoromethyl reagent reaction, because trifluoromethyl reagent can generate corresponding trifluoromethylation product with alkene halogen, fragrant halogen and allyl halide reaction, therefore get product: 4-trifluoromethyl-3-ketone-4-en steroids, productive rate good (yield is 70～93%).Reaction formula is as shown in Figure 2:
A: trifluoromethyl reagent, CuI or Cu powder, solvent, 40-80 ℃ of .R=C 2H 5, CH 3, H
B: benzene or dioxane, tetrachlorobenzoquinone.
C: the trimethyl carbinol, dichloro dinitrile benzoquinones.
Wherein solvent is ether, sherwood oil, benzene, tetracol phenixin, ethyl ketone, dimethyl sulfoxide (DMSO), hexamethylphosphoramide HMPA, N, dinethylformamide DMF, N,N-dimethylacetamide DMA.Recommending solvent is hexamethylphosphoramide HMPA, N, dinethylformamide DMF, N,N-dimethylacetamide DMA.The mole ratio of 4-bromine or iodine-3-ketone-4-alkene-steroidal, CuI or Cu powder and trifluoromethyl reagent is 1: 0.1-5: 0.5-5, reaction times is 1-10 hour, heating is to help the carrying out that react in the method for the invention, and temperature of reaction depends on reactant and solvent, the temperature of reaction of this reaction is controlled at 30-120 ℃ usually, and the recommendation response temperature is 40-80 ℃.
4-trifluoromethyl-3-ketone-4-en steroids generates 4-trifluoromethyl-3-ketone-1 with dichloro dinitrile benzoquinones reacting by heating in t-butanol solvent, 4-two en steroids, wherein 4-trifluoromethyl-3-ketone-4-en steroids and dichloro dinitrile benzoquinones the reaction mole ratio 1: 0.8-5, the reacting by heating time is 2-8 hour in t-butanol solvent.
4-trifluoromethyl-3-ketone-4-en steroids generates 4-trifluoromethyl-3-ketone-4 with the tetrachlorobenzoquinone reacting by heating in benzene or dioxane solvent, 6-diene steroidal compounds. wherein 4-trifluoromethyl-3-ketone-4-en steroids and tetrachlorobenzoquinone the reaction mole ratio 1: 0.8-5, the reacting by heating time is 2-15 hour in benzene or dioxane solvent.
In the method for the present invention, key is that trifluoromethylation reaction, the used trifluoromethyl reagent of the present invention can represent with general formula, i.e. X (CF 2CF 2O) m(CF 2) kCO 2Y, wherein X=Cl, Br, I or FO 2S, Y=H, CH 3, C 2H 5Or K, m=0 or 1, k=1 or 2.As FO 2SCF 2CO 2CH 3, FO 2SCF 2CO 2C 2H 5, FO 2SCF 2CF 2OCF 2CO 2CH 3, FO 2SCF 2CF 2OCF 2CO 2K, FO 2SCF 2CF 2OCF 2CF 2CO 2CH 3, XCF 2CO 2CH 3, XCF 2CO 2C 2H 5, XCF 2CO 2K etc.
In sum, trifluoro-methyl steroid of the present invention has been compared following significant effect with existing steroidal compounds with method, at first has high physiologically active, carrying out the bioactive Ki value comparison that the enzyme kinetics method is measured as androstane-4-trifluoromethyl-4-alkene-3-ketone-17 beta-diketon and known steroid drugs Proscar, is respectively 28.8 and 54.7.Secondly needn't by with CF 3I carries out photoresponse and expends the plenty of time, and it is brief that yield can be brought up to the 70-93% method steps from 32-42%, easy to operate, and productive rate is good.Required trifluoromethyl reagent is easy to preparation, does not need special conversion unit and reagent.
Following embodiment will help to understand the present invention, but be not limited to content of the present invention:
Embodiment 1
Get 0.43mmol4-bromine courage steroid-4-alkene-3-ketone
Figure 9611659500091
0.05-2mmol Cu powder or CuI, 0.2-2mmol FO 2SCF 2CO 2Me, FO 2SCF 2CF 2OCF 2CO 2K or BrCF 2CO 2CH 3, in 20ml benzene, acetonitrile or DMF solvent, at N 2Following 60-80 ℃ of reaction 4-8 hour, after reaction finished, reactant diluted with ether, and with silicon bath soil elimination solid, filtrate is poured in the 50ml water and is told organic layer, and water layer is used 3 * 30mml extracted with diethyl ether again, merges organic phase, washes with water three times.The anhydrous MgSO of ether layer 4After the drying, pressure reducing and steaming solvent, head product get white solid 4-trifluoromethyl courage steroid-4-alkene-3-ketone after separating with flash column chromatography
Figure 9611659500092
176mg, yield is 90%.m.p.：111.0～112.0℃。IR(KBr?pellet)：2980，2800，2690，1600，1468，1370，1346，1160，1124cm -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。
19F?NMR(60MHz，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)。
Ultimate analysis C 28H 43OF 3Calculated value: C:74.30, H:9.57
Measured value: C:74.59, H:9.97.
Embodiment 2
Get 0.50mmol 4-bromine androstane-4-alkene-3,17-diketone, 0.05-2mmol CuI, 0.3-2.5mmolFO 2SCF 2CO 2C 2H 5, in 20ml N,N-dimethylacetamide DMA solvent, at N 2Following 50-75 ℃ of reaction 6 hours, after reaction finished, reactant diluted with ether, and with silicon bath soil elimination solid, filtrate is poured in the 40ml water and is told organic layer, and water layer is used extracted with diethyl ether again, merges organic phase, washes with water three times.The anhydrous MgSO of ether layer 4After the drying, pressure reducing and steaming solvent, head product get white solid 4-trifluoromethyl androstane-4-alkene-3 after separating with flash column chromatography, the 17-diketone, and yield is 81%,
m.p.：150.0～151.0℃。
IR(KBr?pellet)：3000，1750，1600，1350，1160，1120cm -1。
1H?NMR(300MHz，CDCl 3)d：0.93(s，3H，C 18-H)，1.29(s，C 19-H)，3.12(d，br，J=14.82Hz，1H)ppm。
19F?NMR(60MHz，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)。
Ultimate analysis: C 20H 25O 2F 3Calculated value: C:67.78, H:7.11
Measured value: C:67.54, H:7.37.
Embodiment 3
Get the pregnant steroid of 0.50mmol 4-bromine-4-alkene-3,21-diketone, 1mmol Cu powder, 2mmolFO 2SCF 2CF 2OCF 2CO 2CH 3, in 20ml hexamethylphosphoramide HMPA solvent, at N 2Following 90-110 ℃ of reaction 2 hours, after reaction finished, reactant diluted with ether, and with silicon bath soil elimination solid, filtrate is poured in the 50ml water and is told organic layer, and water layer is used extracted with diethyl ether again, merges organic phase, washes with water three times.The anhydrous MgSO of ether layer 4After the drying, pressure reducing and steaming solvent, head product get the pregnant steroid of white solid 4-trifluoromethyl-4-alkene-3, the 21-diketone after separating with flash column chromatography.Yield is 74%,
m.p.：124.5～125.5℃。
IR(KBr?pellet)：2950，2800，1700，1600，1460，1364，1120cm -1。
1H?NMR(300MHz，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。
19F?NMR(60MHz，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).
Ultimate analysis: C 22H 29O 2F 3Calculated value: C:69.09, H:7.64
Measured value: C:69.00, H:8.11.
Embodiment 4
Get the pregnant steroid of 0.40mmol 17b-hydroxyl-4-bromine-4-alkene-3-ketone-21-carboxylic acid lactone, 2mmol Cu powder, 0.2mmol BrCF 2CO 2K is in 20ml hexamethylphosphoramide HMPA solvent, at N 2Following 40-60 ℃ of reaction 8 hours, after reaction finished, reactant diluted with ether, and with silicon bath soil elimination solid, filtrate is poured in the 50ml water and is told organic layer, and water layer is used extracted with diethyl ether again, merges organic phase, washes with water three times.The anhydrous MgSO of ether layer 4After the drying, pressure reducing and steaming solvent, head product get the pregnant steroid of solid 17b-hydroxyl-4-trifluoromethyl-4-alkene-3-ketone-21-carboxylic acid lactone after separating with flash column chromatography, and yield is 70%,
m．p.：124.0～125.0℃。
IR(KBr?pellet)：2900，1770，1700，1638，1600，1340，1180，1120cm -1。
1H?NMR(300MHz，CDCl 3)d：1.00(s，C 18-H)，1.28(s，C 19-H)，2.21(s，C 21-H)ppm。
19F?NMR(60MHz，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 C 22H 29O 2F 3Calculated value: 410.2069
Measured value: 410.2082.
Embodiment 5
Get 0.60mmol (25R)-4-bromine spiral shell steroid t-4-alkene-3-ketone, 0.06mmol CuI, 2mmolClCF 2CO 2K is in the 30ml dimethyl sulfoxide solvent, at N 2Following 100-120 ℃ of reaction 3 hours, after reaction finished, reactant diluted with ether, and with silicon bath soil elimination solid, filtrate is poured in the 60ml water and is told organic layer, and water layer is used extracted with diethyl ether again, merges organic phase, washes with water three times.The anhydrous MgSO of ether layer 4After the drying, pressure reducing and steaming solvent, head product get solid (25R)-4-trifluoromethyl spiral shell steroid-4-alkene-3-ketone after separating with flash column chromatography. and yield is 71%.
m．p.：218.0～219.0℃。
IR(KBr?pellet)：2900，1780，1600，1456，1346，1120，1056，980cm -1。
1H?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。
19F?NMR(60MHz，CDCl 3)d：-21.6(s)ppm。
MS?m/z：382(M +，1.2)，450(0.86)，421(4.21)，411(M +-CF 3，6.74)，408(10.56)，366(18.95)，366(18.95)，351(6.44)，337(25.76)，139(100)，69(37.38)。
Ultimate analysis: C 28H 39O 3F 3Calculated value: C:69.97, H:8.18
Measured value: C:69.47, H:8.27.
Embodiment 6
Get 0.80mmol 4-bromine female steroid-4-alkene-3,17-diketone, 4mmol Cu powder, 2mmolClCF 2CO 2CH 3, in the 40ml carbon tetrachloride solvent, at N 2Following 70-80 ℃ of reaction 5 hours, after reaction finished, reactant diluted with ether, and with silicon bath soil elimination solid, filtrate is poured in the 40ml water and is told organic layer, and water layer is used extracted with diethyl ether again, merges organic phase, washes with water three times.The anhydrous MgSO of ether layer 4After the drying, pressure reducing and steaming solvent, head product get solid 4-trifluoromethyl female steroid-4-alkene-3 after separating with flash column chromatography, the 17-diketone, and yield is 82%,
m.p.：185.6～187.0℃。
IR(KBr?pellet)：2800，1740，1690，1600，1100，1040cm -1。
1H?NMR(300MHz，CDCl 3)d：0.94(s，C 18-H)，3.48(m)ppm。
19F?NMR(60MHz，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 C 19H 23O 2F 3Calculated value: 340.1650;
Measured value: 340.1638.
Embodiment 7
Get 0.20mmol 4-bromo-N-(1, the 1-dimethyl ethyl) androstane-4-alkene-3-ketone-17b-methane amide, 0.2mmol Cu powder, lmmol FO 2SCF 2CF 2OCF 2CF 2CO 2CH 3, in 30ml hexamethylphosphoramide HMPA solvent, at N 2Following 70-80 ℃ of reaction 6 hours, after reaction finished, reactant diluted with ether, and with silicon bath soil elimination solid, filtrate is poured in the 40ml water and is told organic layer, and water layer is used extracted with diethyl ether again, merges organic phase, washes with water three times.The anhydrous MgSO of ether layer 4After the drying, pressure reducing and steaming solvent, head product get solid 4-trifluoromethyl-N-(1, the 1-dimethyl ethyl) androstane-4-alkene-3-ketone-17b-methane amide after separating with flash column chromatography. and yield is 91%
m.p.：158.0～159.0℃。
IR(KBr?pellet)：3499(br，N-H)，2900，1680(br)，1590，1510，1450，1360，1260，1230，1120cm -1。
1H?NMR(300MHz，CDCl 3)d：0.74(s，C 18-H)，1.26(s，C 19-H)，1.35(s，t-Bu)，5.08(s，N-H)ppm。
19F?NMR(60MHz，CDCl 3)d：-20.8(s)ppm。
MS?m/z：439(M +，30.73)，424(M +-CH 3，11.6)，404(22.75)，384(11.05)，368(7.5)，339(7.95)，248(19.67)，149(51.94)，69(63.88)，57(100)。
Ultimate analysis: C 25H 36O 2NF 3Calculated value: C:68.31, H:8.25, N:3.19.
Measured value: C:68.22, H:8.31, N:2.98.
Embodiment 8
Get 0.55mmol 4-iodo-13-ethyl androstane-4-alkene-3,17-diketone, 1mmol Cu powder, 2mmol BrCF 2CO 2C 2H 5, at 30ml N, in the dinethylformamide DMF solvent, at N 2Following 30-50 ℃ of reaction 8 hours, after reaction finished, reactant diluted with ether, and with silicon bath soil elimination solid, filtrate is poured in the 40ml water and is told organic layer, and water layer is used extracted with diethyl ether again, merges organic phase, washes with water three times.The anhydrous MgSO of ether layer 4After the drying, pressure reducing and steaming solvent, head product get solid 4-Trifluoromethyl-1 3-ethyl androstane-4-alkene-3, the 17-diketone after separating with flash column chromatography.Yield is 93%
IR(KBr?pellet)：3000，1750，1600，1346，1160，1120cm -1。
1H?NMR(300MHz，CDCl 3)d：1.00(t，J=8.0Hz，CH 3-)，1.29(s，C 19-H)ppm。
19F?NMR(60MHz，CDCl 3)d：-21.8(s)ppm。
MS?m/z：368(M +，42.7)，353(M +，11.5)，324(17.2)，299(M +-CF 3，28.4)，270(16.7)，194(100)。
Ultimate analysis: C 21H 27O 2F 3Calculated value: C:68.46, H:7.38.
Measured value: C:68.14, H:7.20.
Embodiment 9
Get 0.5mmol 4-iodo-13-ethyl-17 beta-hydroxyl-17 alphas-methyl androstane-4-alkene-3 ketone, 1mmol Cu powder, 2mmol ClCF 2CO 2C 2H 5, at 30ml N, in the dinethylformamide DMF solvent, at N 2Following 50-60 ℃ of reaction 6 hours, after reaction finished, reactant diluted with ether, and with silicon bath soil elimination solid, filtrate is poured in the 50ml water and is told organic layer, and water layer is used extracted with diethyl ether again, merges organic phase, washes with water three times.The anhydrous MgSO of ether layer 4After the drying, pressure reducing and steaming solvent, head product get solid 4-Trifluoromethyl-1 3-ethyl-17 beta-hydroxyl-17 alphas-methyl androstane-4-alkene-3 ketone after separating with flash column chromatography. and yield is 83%
IR(KBr?pellet)：3300(br)，1690，1600，1340，1120cm -1。
1H?NMR(300MHz，CDCl 3)d：1.00(t，J=8.0Hz，CH 3-)，1.29(s，C 19-H)，1.40(s，C 20-H)ppm。
19F?NMR(60MHz，CDCl 3)d：-20.6(s)ppm。
MS?m/z：384(M +，1?7.6)，369(M +-CH 3，4.5)，366(M +-H 2O，19.2)，297(43.5)，194(100)。
Ultimate analysis: C 22H 31O 2F 3Calculated value: C:68.73, H:8.13.
Measured value: C:69.00, H:8.03.
Embodiment 10
Get 0.3mmol 4-iodo-N-sec.-propyl androstane-4-alkene-3-ketone-17 β-methane amide, 1mmol Cu powder, 2mmol FO 2SCF 2CF 2OCF 2CO 2CH 3, at 30ml N, in the dinethylformamide DMF solvent, at N 2Following 50-60 ℃ of reaction 6 hours, after reaction finished, reactant diluted with ether, and with silicon bath soil elimination solid, filtrate is poured in the 50ml water and is told organic layer, and water layer is used extracted with diethyl ether again, merges organic phase, washes with water three times.The anhydrous MgSO of ether layer 4After the drying, pressure reducing and steaming solvent, head product get solid 4-trifluoromethyl-N-sec.-propyl androstane-4-alkene-3-ketone-17 β-methane amide after separating with flash column chromatography, and yield is 83%
IR(KBr?pellet)：3500(br，N-H)，2900，1680，1594，1510，1455，1356，1260，1210cm -1。
1H?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) 2CH-)，4.50(q，J=6.1Hz，(CH 3) 2CH-N)，5.09(s，N-H)ppm。
19F?NMR(60MHz，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)。
Ultimate analysis: C 24H 34O 2NF 3Calculated value: C:67.74, H:8.05, N:3.29.
Measured value: C:67.68, H:7.96, N:3.32.
Embodiment 11
Get 0.6mmol 4-iodo-17 beta-hydroxy androstane-4-alkene-3-ketone, 0.06mmol Cu powder, 3mmol FO 2SCF 2CF 2OCF 2CO 2CH 3, in 30ml ethyl ketone or acetone solvent, at N 2Following 70-80 ℃ of reaction 7 hours, after reaction finished, reactant diluted with ether, and with silicon bath soil elimination solid, filtrate is poured in the 50ml water and is told organic layer, and water layer is used extracted with diethyl ether again, merges organic phase, washes with water three times.The anhydrous MgSO of ether layer 4After the drying, pressure reducing and steaming solvent, head product get solid 4-Trifluoromethyl-1 7 beta-hydroxy androstane-4-alkene-3-ketone after separating with flash column chromatography, and yield is 78%
IR(KBr?pellet)：3300(br，-OH)，2900，1680，1600，1110，1040cm -1。
1H?NMR(300MHz，CDCl 3)d：0.86(s，C 18-H)，1.28(s，C 19-H)，4.62(t，J=8.5Hz，C 17-H)ppm。
19F?NMR(60MHz，CDCl 3)d：-21.8(s)ppm。
MS?m/z：356(M +，16.4)，341(M +-CH 3，23.2)，338(M +-H 2O，8.6)，294(78.5)，192(100)。
Ultimate analysis: C 20H 27O 2F 3Calculated value: C:67.40, H:7.63.
Measured value: C:67.62, H:7.80.
Embodiment 12
Get 0.2mmol 4-bromo-17 beta-hydroxyl-17 alphas-methyl androstane-4-alkene-3-ketone-17-acetic ester, 0.8mmol Cu powder, 3mmol FO 2SCF 2CF 2OCF 2CO 2K is at 30ml N, in the dinethylformamide DMF solvent, at N 2Following 80 ℃ of reactions 4 hours, after reaction finished, reactant diluted with ether, and with silicon bath soil elimination solid, filtrate is poured in the 50ml water and is told organic layer, and water layer is used extracted with diethyl ether again, merges organic phase, washes with water three times.The anhydrous MgSO of ether layer 4After the drying, pressure reducing and steaming solvent, head product get solid 4-Trifluoromethyl-1 7 beta-hydroxyl-17 alphas-methyl androstane-4-alkene-3-ketone-17-acetic ester after separating with flash column chromatography, and yield is 70%
IR(KBr?pellet)：2950，1750，1680，1600，1340，1110cm -1。
1H?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 3CO-)ppm
19F?NMR(60MHz，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)。
Ultimate analysis: C 23H 31O 3F 3Calculated value: C:66.97, H:7.57.
Measured value: C:66.60, H:7.46.
Embodiment 13
Get 0.6mmol 4-bromine androstane-4-alkene-3,11,17-triketone, 3mmol CuI, 3mmolFO 2SCF 2CF 2OCF 2CF 2CO 2CH 3, at 30mlN, in the dinethylformamide DMF solvent, at N 2Following 40 ℃ of reactions 4 hours, after reaction finished, reactant diluted with ether, and with silicon bath soil elimination solid, filtrate is poured in the 50ml water and is told organic layer, and water layer is used extracted with diethyl ether again, merges organic phase, washes with water three times.The anhydrous MgSO of ether layer 4After the drying, pressure reducing and steaming solvent, head product get solid 4-trifluoromethyl androstane-4-alkene-3 after separating with flash column chromatography, and 11,17-triketone yield is 82%
IR(KBr?pellet)：3000，1750，1600，1340，1160，1120cm -1。
1H?NMR(300MHz，CDCl 3)d：0.96(s，C 18-H)，1.30(s，C 19-H)ppm。
19F?NMR(60MHz，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)。
Ultimate analysis: C 20H 23O 3F 3Calculated value: C:65.21, H:6.29.
Measured value: C:65.36, H:5.90.
Embodiment 14
Reaction conditions gets product 4-Trifluoromethyl-1 7 beta-hydroxyl-17 alphas-methyl female steroid-3-ketone with embodiment 13.Yield is 75%.
IR(KBr?pellet)：3300(br)，1680，1600，1320，1120cm -1。
1H?NMR(300MHz，CDCl 3)?d：0.90(s，C 18-H)，1.39(s，C 20-H)ppm。
19F?NMR(60MHz，CDCl 3)d：-21.0(s)ppm。
MS?m/z：356(M +，17.8)，355(M +-1，26.3)，338(M +-H 2O，36.5)，310(76.4)，270(90)，107(100)。
Ultimate analysis: C 20H 27O 2F 3Calculated value: C:67.40, H:7.63.
Measured value: C:67.02, H:7.70.
Embodiment 15
Reaction conditions gets product 4-Trifluoromethyl-1 7 beta-hydroxies female steroid-4-alkene-3-ketone with embodiment 12.Yield is 87%.
IR(KBr?pellet)：3300(br，-OH)，2800，1686，1600，1106，1050cm -1。
1H?NMR(300MHz，CDCl 3)d：0.85(s，C 18-H)，4.62(t，J=8.5Hz，C 17-H)ppm。
19F?NMR(60MHz，CDCl 3)d：-21.0(s)ppm。
MS?m/z：343(M ++1，16.4)，342(M +，5?4.6)，324(M +-H 2O，18.0)，297(65.4)，271(82.0)，107(100)。
12
Ultimate analysis: C 19H 25O 2F 3Calculated value: C:66.65, H:7.36.
Measured value: C:66.90, H:7.30.
Embodiment 16
Reaction conditions gets product 4-Trifluoromethyl-1 6 α with embodiment 2, the pregnant steroid of 17 α-epoxy-4-alkene-3-ketone, and yield is 88%.
IR(KBr?pellet)：3000，2900，1760，1700，1600，1440，1116cm -1。
1H?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.，
19F?NMR(60MHz，CDCl 3)d：-20.8(s)ppm。
MS?m/z：396(M +，26.3)，381(M +-CH 3，6.32)，378(M +-H 2O，28.9)，327(M +-CF 3，5.42)，284(17.4)，197(100)。
Ultimate analysis: C 22H 27O 3F 3Calculated value: C:66.65, H:6.86.
Measured value: C:66.98, H:6.66.
Embodiment 17
Reaction conditions gets the pregnant steroid of product 4-Trifluoromethyl-1 7 beta-hydroxies-16 Alpha-Methyl-4-alkene-3-ketone-17-acetic ester with embodiment 3.Yield is 85%.
IR(KBr?pellet)：2950，2800，1760，1700，1600，1460，1120cm -1。
1H?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 3COO-)，2.21(s，C 21-H)ppm。
19F?NMR(60MHz，CDCl 3)d：-21.6(s)ppm。
MS?m/z：454(M +，22.4)，439(M +-CH 3，5.6)，394(M +-H 2O，84.0)，325(43.6)，147(100)。
Ultimate analysis: C 25H 33O 4F 3Calculated value: C:66.06, H:7.32.
Measured value: C:66.31, H:7.40.
Embodiment 18
Get 0.1mmol 4-trifluoromethyl androstane-4-alkene-3, the 17-diketone, the 0.5mmol tetrachlorobenzoquinone, in 20ml dioxane solvent, reflux 2 hours is filtered, after filtrate decompression is steamed and is desolventized, solid CH 2Cl 2After the dissolving, use 5% NaHCO respectively 3Solution and water washing, after the organic phase drying, pressure reducing and steaming solvent, rapid column chromatography separate product 4-trifluoromethyl androstane-4,6-diene-3, the 17-diketone, yield is 85%.
IR(KBr?pellet)：2900，1750，1660，1600，1270，1160，1110cm -1。
1H?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。
19F?NMR(60MHz，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)。
Ultimate analysis: C 20H 23O 2F 3Calculated value: C:68.17, H:6.58.
Measured value: C:68.07, H:6.46.
Embodiment 19
Get 0.4mmol 4-trifluoromethyl female steroid-4-alkene-3, the 17-diketone, the 1mmol tetrachlorobenzoquinone, in 30ml dioxane solvent, reflux 6 hours is filtered, after filtrate decompression is steamed and is desolventized, solid CH 2Cl 2After the dissolving, use 5% NaHCO respectively 3Solution and water washing, after the organic phase drying, pressure reducing and steaming solvent, rapid column chromatography separate product 4-trifluoromethyl female steroid-4,6-diene-3, the 17-diketone, yield is 87%.
IR(KBr?pellet)：2850，1740，1680，1600，1100，1040cm -1。
1H?NMR(300MHz，CDCl 3)d：0.94(s，C 18-H)，6.30(Complexdoublet，J=11Hz，C 6-H)，6.71(Complex?doublet，J=11Hz，C 7-H)ppm。
19F?NMR(60MHz，CDCl 3)d：-23.0(s)ppm。
MS?m/z：339(M ++1，28.7)，338(M +，86.5)，320(17.6)，269(100)。
Ultimate analysis: C 19H 23O 2F 3Calculated value: C:67.49, H:6.86.
Measured value: C:67.30, H:7.02.
Embodiment 20
Get 1mmol 4-trifluoromethyl-N-(1, the 1-dimethyl ethyl) androstane-4-alkene-3-ketone-17 β-methane amide, the 0.8mmol tetrachlorobenzoquinone, in the 30ml benzene solvent, reflux 15 hours is filtered, after filtrate decompression is steamed and is desolventized, solid CH 2Cl 2After the dissolving, use 5% NaHCO respectively 3Solution and water washing, after the organic phase drying, pressure reducing and steaming solvent, rapid column chromatography separate product 4-trifluoromethyl-N-(1, the 1-dimethyl ethyl) androstane-4,6-diene-3-ketone-17 β-methane amide, yield is 75%.
IR(KBr?pelle1)：3450(br，N-H)，2900，1680，1580，1260，1180，1120cm -1。
1H?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=11Hz，C 7-H)ppm。
19F?NMR(60MHz，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)。
Ultimate analysis: C 25H 34O 2NF 3Calculated value: C:68.63, H:7.83, N:3.20.
Measured value: C:68.70, H:7.90, N:3.35.
Embodiment 21
Get 0.5mmol 4-Trifluoromethyl-1 3-ethyl androstane-4-alkene-3, the 17-diketone, the 2mmol tetrachlorobenzoquinone, in the 30ml benzene solvent, reflux 10 hours is filtered, after filtrate decompression is steamed and is desolventized, solid CH 2Cl 2After the dissolving, use 5% NaHCO respectively 3Solution and water washing, after the organic phase drying, pressure reducing and steaming solvent, rapid column chromatography separate product 4-Trifluoromethyl-1 3-ethyl androstane-4,6-diene-3, the 17-diketone, yield is 90%.
IR(KBr?pellet)：3000，1750，1580，1340，1160，1110cm -1。
1H?NMR(300MHz，CDCl 3)d：1.00(t，J=8.0Hz，CH 3CH 2-)，1.28(s，C 19-H)，6.30(Complex?doublet，J=11Hz，C 6-H)，6.71(Complex?doublet，J=11Hz，C 7-H)ppm。
19F?NMR(60MHz，CDCl 3)d：-24.0(s)ppm。
MS?m/z：366(M +，28.2)，351(M +-CH 3，7.4)，337(M +-Et，4.4)，297(M +-CF 3，32.5)，194(100)。
Ultimate analysis: C 21H 25O 2F 3Calculated value: C:68.83, H:6.88.
Measured value: C:69.10, H:7.02.
Embodiment 22
Get 0.4mmol 4-trifluoromethyl-N-sec.-propyl androstane-4-alkene-3-ketone-17 β-methane amide, the 1.2mmol tetrachlorobenzoquinone, in 30ml dioxane solvent, reflux 12 hours is filtered, after filtrate decompression is steamed and is desolventized, solid CH 2Cl 2After the dissolving, use 5% NaHCO respectively 3Solution and water washing, after the organic phase drying, pressure reducing and steaming solvent, rapid column chromatography separate product 4-trifluoromethyl-N-sec.-propyl androstane-4,6-diene-3-ketone-17 β-methane amide, yield is 85%.
IR(KBr?pellet)：3500(br)，2900，1690，1600，1340，1160cm -1。
1H?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) 2CH-)，4.50(q，J=6.0Hz，(CH 3) 2CH-N)，5.10(s，N-H)，6.30(dm，J=11Hz，C 6-H)，6.71(dm，J=11Hz，C 7-H)ppm。
19F?NMR(60MHz，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)。
Ultimate analysis: C 24H 32O 2NF 3Calculated value: C:28.06, H:7.16, N:3.31.
Measured value: C:27.98, H:7.40, N:3.11.
Embodiment 23
Get 0.1mmol 4-trifluoromethyl androstane-4-alkene-3, the 17-diketone, 0.5mmol dichloro dinitrile benzoquinones, in the 20ml t-butanol solvent, reflux 2 hours is filtered, and after filtrate decompression was steamed and desolventized, solid was used 5% NaHCO respectively after dissolving with EtOAc 3Solution and water washing, after the organic phase drying, pressure reducing and steaming solvent, rapid column chromatography separate product 4-trifluoromethyl androstane-1,4-diene-3, the 17-diketone, yield is 82%.
IR(KBr?pellet)：3000，1750，1600，1596，1340，1110cm -1。
1H?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。
19F?NMR(60MHz，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)。
Ultimate analysis: C 20H 23O 2F 3Calculated value: C:68.17, H:6.58.
Measured value: C:68.39, H:6.34.
Embodiment 24
Get 0.4mmol 4-trifluoromethyl female steroid-4-alkene-3, the 17-diketone, 1mmol dichloro dinitrile benzoquinones, in the 30ml t-butanol solvent, reflux 4 hours is filtered, and after filtrate decompression was steamed and desolventized, solid was used 5% NaHCO respectively after dissolving with EtOAc 3Solution and water washing, after the organic phase drying, pressure reducing and steaming solvent, rapid column chromatography separate product 4-trifluoromethyl female steroid-1,4-diene-3, the 17-diketone, yield is 77%.
IR(KBr?pellet)：2810，1740，1660，1600，1100，1020cm -1。
1H?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。
19F?NMR(60MHz，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)。
Ultimate analysis: C 19H 21O 2F 3Calculated value: C:67.44, H:6.26.
Measured value: C:67.40, H:6.28.
Embodiment 25
Get 0.5mmol 4-trifluoromethyl-N-(1, the 1-dimethyl ethyl) androstane-4-alkene-3-ketone-17 β-methane amide, 0.4mmol dichloro dinitrile benzoquinones, in the 30ml t-butanol solvent, reflux 8 hours is filtered, after filtrate decompression is steamed and desolventized, solid is used 5% NaHCO respectively after dissolving with EtOAc 3Solution and water washing, after the organic phase drying, pressure reducing and steaming solvent, rapid column chromatography separate product 4-trifluoromethyl-N-(1, the 1-dimethyl ethyl) androstane-1,4-diene-3-ketone-17 β-methane amide, yield is 71%.
IR(KBr?pellet)：3500(br，N-H)，2900，1680(br)，1590，1500，1440，1230，1120cm -1。
1H?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=10Hz，C 1-H)ppm。
19F?NMR(60MHz，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)。
Ultimate analysis: C 25H 34O 2NF 3Calculated value: C:68.63, H:7.83, N:3.20.
Measured value: C:68.40, H:7.51, N:3.10.
Embodiment 26
Get 1mmol 4-Trifluoromethyl-1 3-ethyl androstane-4-alkene-3, the 17-diketone, 4mmol dichloro dinitrile benzoquinones, in the 30ml t-butanol solvent, reflux 3 hours is filtered, and after filtrate decompression was steamed and desolventized, solid was used 5% NaHCO respectively after dissolving with EtOAc 3Solution and water washing, after the organic phase drying, pressure reducing and steaming solvent, rapid column chromatography separate product 4-Trifluoromethyl-1 3-ethyl androstane-1,4-diene-3, the 17-diketone, yield is 73%.
IR(KBr?pellet)：3000，1750，1680，1600,1340，1120cm -1。
1H?NMR(300MHz，CDCl 3)d：1.00(t，J=8.0Hz，CH 3CH 2-)，1.50(s，C 19-H)，6.30(d，J=10Hz，C 2-H)，7.46(d，J=10Hz，C 1-H)ppm。
19F?NMR(60MHz，CDCl 3)d：-25.0(s)ppm。
MS?m/z：366(M +，32.3)，351(M +-CH 3，8.6)，337(M +-Et，6.8)，297(M +-CF 3，26.7)，194(100)。
Ultimate analysis: C 21H 25O 2F 3Calculated value: C:68.83, H:6.88.
Measured value: C:68.70, H:6.90.
Embodiment 27
Get 0.4mmol 4-trifluoromethyl-N-sec.-propyl androstane-4-alkene-3-ketone-17 β-methane amide, 1.2mmol dichloro dinitrile benzoquinones is in the 30ml t-butanol solvent, reflux 6 hours is filtered, after filtrate decompression is steamed and desolventized, solid is used 5% NaHCO respectively after dissolving with EtOAc 3Solution and water washing, after the organic phase drying, pressure reducing and steaming solvent, rapid column chromatography separate product 4-trifluoromethyl-N-sec.-propyl androstane-1,4-diene-3-ketone-17 β-methane amide, yield is 81%.
IR(KBr?pellet)：3500(br)，2900，1690，1600，1340，1120cm -1。
1H?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) 2CH-)，4.50(q，J=6.0Hz，(CH 3) 2CH-N)，5.09(s，N-H)，6.45(d，J=10Hz，C 2-H)，7.46(d，J=10Hz，C 1-H)ppm。
19F?NMR(60MHz，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)。
Ultimate analysis: C 24H 32O 2NF 3Calculated value: C:28.06, H:7.16, N:3.31.
Measured value: C:28.43, H:7.46, N:3.10.

Claims (8)

1, a kind of 4-trifluoromethyl-3-ketone-steroidal compounds is characterized in that having following molecular formula:
R wherein 1=H or CH 3, R 2=H or O, R 3=H, CH 3Or C 2H 5, R 4=OH, CH 3CO, CH 3COO, CONR 7R 8Or C 1-10Alkyl, R 5=H, CH 3Or CH 3COO, R 4And R 5=O, OCH 2CH 2O or
Figure 9611659500022
R 6=H or CH 3, R 5And R 6=O, R 7Or R 8=H, C 1-10Alkyl, cycloalkyl, R 7And R 8=(CH 2) n, n=1-6,
Figure 9611659500023
Figure 9611659500024
2, a kind of 4-trifluoromethyl as claimed in claim 1-3-ketone-steroidal compounds, it is characterized in that it being the 4-trifluoromethyl-3-ketone-4-alkene, 4-trifluoromethyl-3-ketone-1,4-diene or 4-trifluoromethyl-3-ketone-4, the female steroid of 6-diene, androstane, pregnant steroid or spiral shell steroid compound.
3, the preparation method of a kind of 4-trifluoromethyl as claimed in claim 1-3-ketone-steroidal compounds is characterized in that it being to carry out with the step of following method respectively:
(1), adopt molecular formula to be:
Figure 9611659500025
4-bromine or iodine-3-ketone-4-alkene-sterides compound raw material, wherein R 1=H, CH 3, R 2=H or O, R 3=H, CH 3Or C 2H 5, R 4=OH, CH 3CO, CH 3COO, CONR 7R 8Or C 1-10Alkyl, R 5=H, CH 3Or CH 3COO, R 4And R 5=O, OCH 2CH 2O or R 6=H or CH 3, R 5And R 6=O, R 7Or R 8=H, C 1-10Alkyl or cycloalkyl, R 7And R 8=(CH 2) n, n=1-6, In the presence of solvent and catalyzer, make 4-trifluoromethyl-3-ketone-4-alkene-steroidal compounds with the trifluoromethyl reagent reaction, the mole ratio of 4-bromine or iodine-3-ketone-4-alkene-steroidal compounds, catalyzer and trifluoromethyl reagent is 1: 0.1-5: 0.5-5, reaction times is 1-10 hour, and temperature of reaction is 30-120 ℃;
(2), 4-trifluoromethyl-3-ketone-4-alkene-steroidal compounds and dichloro dinitrile benzoquinones obtained 4-trifluoromethyl-3-ketone-1,4-diene steroidal compounds in reacting by heating 2-8 hour in t-butanol solvent, wherein the mole ratio of 4-trifluoromethyl-3-ketone-4-alkene-steroidal compounds and dichloro dinitrile benzoquinones is 1: 0.8-5
Figure 9611659500033
(3), 4-trifluoromethyl-3-ketone-4-alkene-steroidal compounds and tetrachlorobenzoquinone are in benzene or dioxane solvent reacting by heating 2-15 hour, obtain 4-trifluoromethyl-3-ketone-4,6-diene steroidal compounds, wherein the mole ratio of 4-trifluoromethyl-3-ketone-4-alkene-steroidal compounds and tetrachlorobenzoquinone is 1: 0.8-5
Figure 9611659500034
4, the preparation method of a kind of 4-trifluoromethyl as claimed in claim 3-3-ketone-steroidal compounds, it is characterized in that solvent used in the reaction of (1) is ether, sherwood oil, benzene, tetracol phenixin, ethyl ketone, dimethyl sulfoxide (DMSO), hexamethylphosphoramide, N, dinethylformamide, N,N-dimethylacetamide.
5, a kind of preparation method as claim 3 or 4 described 4-trifluoromethyl-3-ketone-steroidal compounds is characterized in that solvent used in the reaction of (1) is hexamethylphosphoramide, N, dinethylformamide, N,N-dimethylacetamide.
6, the preparation method of a kind of 4-trifluoromethyl as claimed in claim 3-3-ketone-steroidal compounds is characterized in that methylating reagent used in the reaction of (1) is X (CF 2CF 2O) m(CF 2) kCO 2Y, wherein X=Cl, Br, I or FO 2S, Y=H, CH 3, C 2H 5Or K, m=0 or 1, k=1 or 2.
7, the preparation method of a kind of 4-trifluoromethyl as claimed in claim 3-3-ketone-steroidal compounds is characterized in that catalyzer used in the reaction of (1) is Cu powder or CuI.
8, the preparation method of a kind of 4-trifluoromethyl as claimed in claim 3-3-ketone-steroidal compounds is characterized in that temperature of reaction is 40-80 ℃.
CN96116595A 1996-11-29 1996-11-29 4-trifluoromethyl-3-ketosteroid compound and synthesizing method thereof Expired - Fee Related CN1061983C (en)

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CN101775055B (en) * 2009-12-30 2012-10-24 中国科学院上海有机化学研究所 Method for synthesizing 4-trifluoromethyl-4-olefine-3-steroidal ketone compound
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EP0231671A1 (en) * 1985-12-26 1987-08-12 Mitsubishi Kasei Corporation Gonatriene derivatives and process for preparing them
US4753932A (en) * 1985-01-14 1988-06-28 Roussel Uclaf Novel 10-substituted steroids

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Publication number Priority date Publication date Assignee Title
US4753932A (en) * 1985-01-14 1988-06-28 Roussel Uclaf Novel 10-substituted steroids
EP0231671A1 (en) * 1985-12-26 1987-08-12 Mitsubishi Kasei Corporation Gonatriene derivatives and process for preparing them

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