CN1161972A - 4-trifluoromethyl-3-ketosteroid compound and synthesizing method thereof - Google Patents
4-trifluoromethyl-3-ketosteroid compound and synthesizing method thereof Download PDFInfo
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- CN1161972A CN1161972A CN 96116595 CN96116595A CN1161972A CN 1161972 A CN1161972 A CN 1161972A CN 96116595 CN96116595 CN 96116595 CN 96116595 A CN96116595 A CN 96116595A CN 1161972 A CN1161972 A CN 1161972A
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Abstract
This invention is a kind of A-trifluoromethyl-3- ketone-steroid compound and its preparation method. The said compounds are androsteroid, progesteroid or spirosteroid compounds of 4-olefine, 1,4-diolefine or 4,6-diolefine. They are intermediate products 4-trifluoromethyl-3-ketone-steroid compound obtained by trifluoromethylation reaction of 4-bromine or iodine-3-ketone-4-olefine-steroid compound, and the resultant further reacts with benzoquinone compounds to obtain 4-trifluoromethyl-3-ketone-4-olefine-steroid compound.
Description
The present invention relates to a kind of 4-trifluoromethyl-3-ketosteroid compound and synthetic, comprise androstane, pregnant steroid or spiral shell steroid compound.
In the steroidal molecule, introduce biological activity and biological activity intensity thereof that fluorine atom, trifluoromethyl can significantly change original parent molecule.Activity as the fluoro cortisone is 10-12 times [J Fried and E.F.Sabo, J.Am.Chem.Soc., 1954,76,1455] of cortisone.Therefore introducing fluorine atom or trifluoromethyl in the steroidal molecule is an important channel seeking new steroid drugs.But still lack the method for synthetic trifluoromethyl steroidal effectively at present.Especially lack the method for on steroid backbone, directly introducing trifluoromethyl.Though CF
3The photoresponse of I and steroidal can be used for the synthetic of trifluoro-methyl steroid, but long reaction time, operational difficulty, reaction yield low (transformation efficiency 32-42%) [A.F.Pascual and M.E.Wolff J.Med.Chem., 1971,14,164; G.H.Rasmusson et al J.Org.Chem., 1975,40,672].Steroidal-4-alkene-3-ketone is common steroidal compounds, they can obtain 4-bromo (or iodo) steroidal-4-alkene-3-ketone compound (D.N.Kirk through adding the reaction of bromine (iodine) and dehydrobromination (or hydrogenchloride), etal, J.Chem.Soc., 1956,627) halogen is promptly obtained 4-trifluoromethyl steroidal-4-alkene-3-ketone compound by the trifluoromethyl replacement under appropriate reaction conditions.They can be used for synthetic and screen novel steroid drugs.
The purpose of this invention is to provide a class 4-trifluoromethyl steroidal-3-ketone compound.
4-trifluoromethyl steroidal provided by the invention-3-ketone compound has following general 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
, R
6=H or CH
3, R
5And R
6=O, R
7Or R
8=H, C
1-10Alkyl, cycloalkyl, aryl or heterocycle, R
7And R
8=(CH
2) n, n=1-6,
Or
It can be the androstane of 4-alkene, 1,4-diene or 4,6-diene, pregnant steroid or spiral shell steroid compound.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 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-tertiary butyl 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:
The sterides compound raw material, R wherein
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 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 follows:
A: trifluoromethyl reagent, CuI or Cu powder, solvent, 40-80 ℃ of .R=C
2H
5, CH
3, Hb: benzene or dioxane, tetrachlorobenzoquinone.C: the trimethyl carbinol, dichloro dinitrile benzoquinones.Wherein solvent is ether, sherwood oil, benzene, tetracol phenixin, dimethyl sulfoxide (DMSO), hexamethylphosphoramide (HMPA), N, dinethylformamide (DMF), N,N-dimethylacetamide (DMA).The recommendation solvent is hexamethylphosphoramide (HMPA), N, dinethylformamide (DMF), N,N-dimethylacetamide (DMA).The mole ratio of 4-bromine (or iodine) steroid-4-alkene-3-ketone, CuI or Cu powder and trifluoromethyl reagent is 1: 0.1-5: 1-5, the 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, and 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: 1-5, the reacting by heating time is 2-8 hour in t-butanol solvent.
4-trifluoromethyl-3-ketone bucket en steroids generates 4-trifluoromethyl-3-ketone-4,6-diene steroidal compounds with the tetrachlorobenzoquinone reacting by heating in benzene or dioxane solvent.Wherein 4-trifluoromethyl-3-ketone-4-en steroids and tetrachlorobenzoquinone the reaction mole ratio 1: 1-5, 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 (CF2CF2O) m (CF2) 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 is expected to have certain biological activity, and becomes the potential medicine.The synthetic method method reactions steps that the present invention relates to is brief, easy to operate, and productive rate is good.Required trifluoromethyl reagent is easy to preparation.
Following embodiment will help to understand the present invention, but be not limited to content of the present invention:
Example I
Get compound 4-bromine courage steroid-4-alkene-3-ketone (200mg, 0.43mmol), Cu powder or CuI (0.05-2mmol), FO
2SCF
2CO
2Me or FO
2SCF
2CF
2OCF
2CO
2K or BrCF
2CO
2CH
3(0.2-2mmol), in benzene or acetonitrile or DMF solvent (20ml), 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 extracted with diethyl ether (30ml * 3) again, merges organic phase, washes with water three times.The anhydrous MgSO of ether layer
4After the drying, the pressure reducing and steaming solvent, (petrol ether/ethyl acetate: 50/1), get white solid 4-trifluoromethyl courage steroid-4-alkene-3-ketone 176mg, yield is 90% to head product with the flash column chromatography separation.M.p.:111.0~112.0 ℃ .IR (KBr pellet): 2980,2800,2690,1600,1468,1370,1346,1160,1124cm
-1.
1H NMR (300MHz, CDCl
3) δ: 0.71 (s, 3H, C
18-H), 0.85 (d, J=6.85, Hz, 3H, C
26-H or C
27-H), 0.86 (d, J=6.85, Hz, 3H, C
26-H or 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) δ :-21.7 (s) ppm.MS m/z: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 compound 4-bromine androstane-4-alkene-3,17-diketone (0.50mmol), CuI (0.05-2mmol), FO
2SCF
2CO
2C
2H
5(0.3-2.5mmol), in N,N-dimethylacetamide (DMA) solvent (20ml), 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 (30m * 3) again, merges organic phase, washes with water three times.The anhydrous MgSO of ether layer
4After the drying, the pressure reducing and steaming solvent, head product with flash column chromatography separate (petrol ether/ethyl acetate: 50/1), white solid 4-trifluoromethyl androstane-4-alkene-3, the 17-diketone. yield is 81%.M.p.:150.0~151.0 ℃ .IR (KBr pellet): 3000,1750,1600,1350,1160,1120cm
-1.
1HNMR (300MHz, CDCl
3) δ: 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) δ :-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 compound 4-bromine-4-alkene-3,21-diketone (0.50mmol), Cu powder (1mmol), FO
2SCF
2CF
2OCF
2CO
2CH
3(2mmol), in hexamethylphosphoramide (HMPA) solvent (20ml), 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 (30ml * 3) again, merges organic phase, washes with water three times.The anhydrous MgSO of ether layer
4After the drying, the pressure reducing and steaming solvent, head product separates (petrol ether/ethyl acetate: 5/1), get the pregnant steroid of white solid 4-trifluoromethyl-4-alkene-3, the 21-diketone with flash column chromatography.Yield is 74%m.p.:124.5~125.5 ℃ .IR (KBr pellet): 2950,2800,1700,1600,1460,1364, and 1120cm
-1.
1HNMR (300MHz, CDCl
3) δ: 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) δ :-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). and 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 17-hydroxyl-4-bromine-4-alkene-3-ketone-21-carboxylic acid lactone (0.40mmol), Cu powder (2mmol), BrCF
2CO
2K (0.2.mmol) is in hexamethylphosphoramide (HMPA) solvent (20ml), 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 (30ml * 3) again, merges organic phase, washes with water three times.The anhydrous MgSO of ether layer
4After the drying, the pressure reducing and steaming solvent, head product with flash column chromatography separate (petrol ether/ethyl acetate: 5/1), the pregnant steroid of solid 17-hydroxyl-4-trifluoromethyl-4-alkene-3-ketone-21-carboxylic acid lactone. yield is 70%.M.p.:124.0~125.0 ℃. IR (KBr pellet): 2900,1770,1700,1638,1600,1340,1180,1120cm
-1.
1HNMR (300MHz, CDCl
3) δ: 1.00, s, C
18-H), 1.28 (s, C
19-H), 2.21 (s, C
21-H) ppm.
19F NMR (60MHz, CDCl
3) :-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 4-bromine spiral shell steroid-4-alkene-3-ketone (0.60mm.), CuI (0.06mm.), ClCF
2CO
2K (2.mmol) is in dimethyl sulfoxide solvent (30ml), 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 (30ml * 3) again, merges organic phase, washes with water three times.The anhydrous MgSO of ether layer
4After the drying, the pressure reducing and steaming solvent, head product separates (petrol ether/ethyl acetate: 50/1), get solid 4-trifluoromethyl spiral shell steroid-4-alkene-3-ketone with flash column chromatography.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) δ: 0.79 (s, 3H, C
18-H), 0.83 (d, J=7Hz, 3H, C
21-H), 0.94 (d, J=6.9Hz, 3H, C
26-H), 1.27 (s, 3H, C
19-H), 2.40~2.48 (m, 2H), 3.05 (d, br, J=14.85Hz, 1H), 3.35~3.50 (m, 2H), 4,42 (dd, J=14,72,7.48Hz, 1H) ppm.
19F NMR (60MHz, CDCl
3): δ :-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 4-bromine androstane-4-alkene-3,17-diketone 0.80mmol), Cu powder (4mmol), anhydrous K F (2mmol), ClCF
2CO
2CH
3(2.mmol), in carbon tetrachloride solvent (40ml), 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 (40ml * 3) again, merges organic phase, washes with water three times.The anhydrous MgSO of ether layer
4After the drying, the pressure reducing and steaming solvent, head product separates (petrol ether/ethyl acetate: 5/1), get solid 4-trifluoromethyl androstane-4-alkene-3, the 17-diketone with flash column chromatography.Yield is 82%.Data are identical with embodiment 2.Embodiment 7
Get the N-tertiary butyl-4-bromine androstane-4-alkene-3-ketone-17-methane amide (0.20mmol), Cu powder (0.2mmol), FO
2SCF
2CF
2OCF
2CF
2CO
2CH
3(1.mmol), in hexamethylphosphoramide (HMPA) solvent (30ml), at N
2Following 80-100 ℃ 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 (30ml * 3) again, merges organic phase, washes with water three times.The anhydrous MgSO of ether layer
4After the drying, the pressure reducing and steaming solvent, head product separates (petrol ether/ethyl acetate: 4/1), get solid N-(tertiary butyl)-4-trifluoromethyl-androstane-4-alkene-3-ketone-17-methane amide with flash column chromatography.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): δ: 0.74 (s, 3H, C
18-H), 1.26 (s, 3H, C
19-H), 1.35 (s, 9H, t-Bu), 5.08 (s, NH) ppm.
19F NMR (60MHz, CDCl
3) δ :-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 4-iodo-13-ethyl androstane-4-alkene-3,17-diketone (0.55mmol), Cu powder (1mmol), BrCF
2CO
2C
2H
5(2.mmol), at N, in dinethylformamide (DMF) solvent (30ml), at N
2Following 50-80 ℃ 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 (30ml * 3) again, merges organic phase, washes with water three times.The anhydrous MgSO of ether layer
4After the drying, the pressure reducing and steaming solvent, head product separates (petrol ether/ethyl acetate: 5/1), get solid 4-Trifluoromethyl-1 3-ethyl androstane-4-alkene-3, the 17-diketone with flash column chromatography.Yield is 93%.IR(KBr?pellet):3000,1750,1600,1346,1160,1120cm
-1.
1H?NMR(300MHz,CDCl
3)δ:1.00(t,3H,J=8.0Hz,C
18-CH
3),1.29(s,3H,C
19-H)ppm.
19F?NMR(60MHz,CDCl
3)δ:-21.8(s)ppm.MS?m/z:368(M
+,42.7),353(M
+-CH
3,11.5),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 4-iodo-13-ethyl-17 beta-hydroxyl-17 alphas-methyl androstane-4-alkene-3 ketone (0.5mmol), Cu powder (1mmol), ClCF
2CO
2C
2H
5(2mmol), at N, in dinethylformamide (DMF) solvent (30ml), at N
2Following 60-100 ℃ 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 (30ml * 3) again, merges organic phase, washes with water three times.The anhydrous MgSO of ether layer
4After the drying, the pressure reducing and steaming solvent, head product separates (petrol ether/ethyl acetate: 3/1), get solid 4-Trifluoromethyl-1 3-ethyl-17 beta-hydroxyl-17 alphas-methyl androstane-4-alkene-3 ketone with flash column chromatography.Yield is 83%.IR(KBr?pellet):3300(br),1690,1600,1340,1120cm
-1.
1HNMR(300MHz,CDCl
3)δ:1.00(t,3H,J=8.0Hz,C
18-CH
3),1.29(s,3H,C
19-H),1.40(s,3H,C
20-H)ppm.
19F?NMR(60MHz,CDCl
3)δ:-20.6(s)ppm.MS?m/z:384(M
+,17.6),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 4-iodo-N-sec.-propyl androstane-4-alkene-3-ketone-17 β-methane amide (0.3mmol), Cu powder (1mmol), FO
2SCF
2CF
2OCF
2CO
2CH
3(2.mmol), at N, in dinethylformamide (DMF) solvent (30ml), at N
2Following 80-100 ℃ 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 (30ml * 3) again, merges organic phase, washes with water three times.The anhydrous MgSO of ether layer
4After the drying, the pressure reducing and steaming solvent, head product with flash column chromatography separate (petrol ether/ethyl acetate: 5/1), solid 4-trifluoromethyl-N-sec.-propyl androstane-4-alkene-3-ketone-17 β-methane amide. yield is 83%.IR(KBr?pellet):3500(br,N-H),2900,1680,1594,1510,1455,1356,1260cm
-1。
1HNMR(300MHz,CDCl
3)δ:0.75(s,3H,C
18-H),1.26(s,3H,C
19-H),1.36(d,6H,J=6.0Hz,(CH
3)
2CH-),4.50(q,1H,J=6.1Hz,(CH
3)
2CH-N),5.09(s,N-H)ppm。
19F?NMR(60MHz,CDCl
3)δ:-20.9(s)ppm。MS m/z:425 (M+, 42.6), 410 (M+-CH3,15.3), 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 4-iodo-17 beta-hydroxy androstane-4-alkene-3-ketone (0.6mmol), Cu powder (0.6mmol), FO
2SCF
2CF
2OCF
2CO
2CH
3(3.0mmol), in ethyl ketone or acetone solvent (30ml), 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 (30ml * 3) again, merges organic phase, washes with water three times.The anhydrous MgSO of ether layer
4After the drying, the pressure reducing and steaming solvent, head product separates (petrol ether/ethyl acetate: 2/1), get solid 4-Trifluoromethyl-1 7 beta-hydroxy androstane-4-alkene-3-ketone with flash column chromatography.Yield is 78%.IR(KBr?pellet):3300(br,OH),2900,1680,1600,1110,1040cm
-1.
1HNMR(300MHz,CDCl
3)δ:0.86(s,3H,C
18-H),1.28(s,3H,C
19-H),4.62(t,J=4.5Hz,C
17-H)ppm。
19F?NMR(60MHz,CDCl
3)(:-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 4-bromo-17 beta-hydroxyl-17 alphas-methyl androstane-4-alkene-3-ketone-17-acetic ester (0.2mmol), Cu powder (0.3mmol), FO
2SCF
2CF
2OCF
2CO
2K (1mmol) is at N, in dinethylformamide (DMF) solvent (30ml), 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 (30ml * 3) again, merges organic phase, washes with water three times.The anhydrous MgSO of ether layer
4After the drying, the pressure reducing and steaming solvent, head product separates (petrol ether/ethyl acetate: 3/1), get solid 4-Trifluoromethyl-1 7 beta-hydroxyl-17 alphas-methyl androstane-4-alkene-3-ketone-17-acetic ester with flash column chromatography.Yield is 70%.IR(KBr?pellet):2950,1750,1680,1600,1340,1110cm
-1。
1HNMR (300MHz, CDCl
3) δ: 0.85 (s, 3H, C
18-H), 1.29 (s, 3H, C
19-H), 1.40 (s, 3H, C
20-H), 2.04 (s, 3H, CH
3CO) ppm
19F NMR (60MHz, CDCl
3) δ :-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). and 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 4-bromine androstane-4-alkene-3,11,17-triketone (0.6mmol), CuI (0.6mmol), FO
2SCF
2CF
2OCF
2CF
2CO
2CH
3(3.mmol), at N, in the dinethylformamide DMF solvent (30ml), at N
2Following 100 ℃ 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 (30ml * 3) again, merges organic phase, washes with water three times.The anhydrous MgSO of ether layer
4After the drying, the pressure reducing and steaming solvent, head product with flash column chromatography separate (petrol ether/ethyl acetate: 3/1), solid 4-trifluoromethyl androstane-4-alkene-3,11, the 17-triketone.Yield is 82%.IR(KBr?pellet):3000,1750,1600,1340,1160,1120cm
-1。
1H?NMR(300MHz,CDCl
3)δ:0.96(s,3H,C
18-H),1.30(s,3H,C
19-H)ppm.
19F?NMR(60MHz,CDCl
3)δ:-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 obtains from 4-bromo-17 beta-hydroxyl-17 alphas-methyl androstane-3-ketone with embodiment 13.4-Trifluoromethyl-1 7 beta-hydroxyl-17 alphas-methyl androstane-3-ketone.Yield is 75%.μ is 75%.IR (KBr pellet): 3300 (br), 1680,1600,1320,1120cm
-1.
1H NMR (300MHz, CDCl
3) δ: 0.90 (s, 3H, C
18-H), 1.30 (s, 3H, C
19-H), 1.39 (s, 3H, C
20-H) ppm.
19F NMR (60MHz, CDCl
3) δ :-21.0 (s) ppm.MSm/z:356 (M
+, 17.8), 355 (M
+-1,26.3), 338 (M+-H
2O, 36.5), 310 (76.4), 270 (90), 107 (100). and 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 4-Trifluoromethyl-1 7 beta-hydroxy androstane-4-alkene-3-ketone with embodiment 12 from 4-bromo-17 beta-hydroxy androstane-4-alkene-3-ketone.Yield is 87%.IR(KBr?pellet):3300(br,-OH),2800,1686,1600,1106,1050cm
-1.
1HNMR(300MHz,CDCl
3)δ:0.85(s,3H,C
18-H),1.30(s,3H,C
19-H),4.62(t,1H,J=8.5Hz,C
17-H)ppm.
19F?NMR(60MHz,CDCl
3)δ:-21.0(s)ppm.MS?m/z:343(M
++1,16.4),342(M
+,4.6),324(M
+-H
2O,18.0),297(65.4),271(82.0),107(100)。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 is with embodiment 2, and from 4-bromo-16 α, the pregnant steroid of 17 α-epoxy-4-alkene-3-ketone gets product 4-Trifluoromethyl-1 6 α, the pregnant steroid of 17 α-epoxy-4-alkene-3-ketone, and yield is 58%.IR (KBr pellet): 3000,2900,1760,1700,1600,1440,1116cm
-1.
1HNMR (300MHz, CDCl
3) δ: 0.70 (s, 3H, C
18-H), 1.26 (s, 3H, C
19-H), 2.22 (s, 3H, C
21-H), 4.0 (d, J=4.0Hz, C
16-H) ppm.,
19F NMR (60MHz, CDCl
3) δ :-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 obtains the pregnant steroid of 4-Trifluoromethyl-1 7 beta-hydroxies-16 Alpha-Methyl-4-alkene-3-ketone-17-acetic ester with embodiment 3 from the pregnant steroid of 4-bromo-17 beta-hydroxies-16 Alpha-Methyl-4-alkene-3-ketone-17-acetic ester.Yield is 85%.IR(KBr?pellet):2950,2800,1760,1700,1600,1460,1120cm
-1。
1HNMR(300MHz,CDCl
3)δ:0.70(s,3H,C
18-H),1.08(d,3H,J=6.0Hz,C
16-CH
3),1.26(s,3H,C
19-H),2.13(s,3H,CH
3COO-),2.21(s,3H,C
21-H)ppm。
19F?NMR(60MHz,CDCl
3)δ:-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 4-trifluoromethyl androstane-4-alkene-3,17-diketone (0.1mmol), tetrachlorobenzoquinone (0.5mmol), in dioxane (20ml) 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.
1HNMR(300MHz,CDCl
3)δ:0.92(s,3H,C
18-H),1.30(s,3H,C
19-H),6.31(d,J=11Hz,1H,C
6-H),6.71(d,J=11Hz£1H,C
7-H)ppm.
19F?NMR(60MHz,CDCl
3)δ:-22.6(s)ppm.MS?m/z:352(M
+,40.6),337(M
+-CH3,10.0),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 the 4-trifluoromethyl-N-tertiary butyl-androstane-4-alkene-3-ketone-17 β-methane amide (1mmol), tetrachlorobenzoquinone (0.8mmol), in benzene (30ml) 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-tertiary butyl androstane-4,6-diene-3-ketone-17 β-methane amide, yield is 75%.IR(KBr?pdlet):3450(br,N-H),2900,1680,1580,1260,1180,1120cm
-1.
1H?NMR(300MHz,CDCl
3)δ:0.74(s,3H,C
18-H),1.30(s,3H,C
19-H),1.35(s,9H,t-Bu),6.31(d,J=11Hz,1H,C
6-H),6.71(d,J=11Hz,1H,C
7-H)ppm。
19F?NMR(60MHz,CDCl3)δ:-23.5(s)ppm。MS m/z:437 (M
+, 52.0), 422 (M
+-CH3,23.5), 402 (27.0), 384 (10.5), 346 (23.8), 57 (100). and 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 20
Get 4-Trifluoromethyl-1 3-ethyl androstane-4-alkene-3,17-diketone (0.5mmol), tetrachlorobenzoquinone (2mmol), in benzene (30ml) 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.
1HNMR(300MHz,CDCl
3)δ:1.00(t,J=8.0Hz,3H,C
18-CH
3),1.28(s,3H,C
19-H),6.30(d,J=11Hz,C
6-H),6.71(d,J=11Hz,C
7-H)ppm。
19F NMR (60MHz, CDCl
3) δ :-24.0 (s) ppm.MS m/z:366 (M
+, 28.2), 351 (M
+-CH3,7.4), 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 21
Get 4-trifluoromethyl-N-sec.-propyl androstane-4-alkene-3-ketone-17 β-methane amide (0.4mmol), tetrachlorobenzoquinone (1.2mmol), in dioxane (30ml) 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.
1HNMR(300MHz,CDCl
3)δ:0.75(s,3H,C
18-H),1.28(s,3H,C
19-H)1.35(d,6H,J=6.0Hz,(CH
3)
2CH),4.50(q,J=6.0Hz£1H,(CH
3)
2CH-N),5.10(s,N-H),6.30(d,J=11Hz,1H,C
6-H),6.71(d,J=11Hz,1H,C
7-H)ppm。
19F?NMR(60MHz,CDCl
3)δ:-24.8(s)ppm。MS?m/z:423(M
+,62.3),408(M
+-CH3,14.2),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 22
Get 4-trifluoromethyl androstane-4-alkene-3,17-diketone (0.1mmol), dichloro dinitrile benzoquinones (0.5mmol) is in the trimethyl carbinol (20ml) solvent, reflux 2 hours, filter, filtrate decompression liquid and water washing are after the organic phase drying, the 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.
1HNMR(300MHz,CDCl
3)δ: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(d,J=11Hz,C
6-H),6.71(d,J=11Hz,C
7-H)ppm。
19F?NMR(60MHz,CDCl
3)δ:-24.8(s)ppm。MS?m/z:423(M
+,62.3),408(M
+-CH3,14.2),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 4-trifluoromethyl androstane-4-alkene-3,17-diketone (0.1mmol), dichloro dinitrile benzoquinones (0.5mmol), in the trimethyl carbinol (20ml) solvent, reflux 2 hours is filtered, 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-three oxygen methyl androstanes-1,4-diene-3, the 17-diketone, yield is 82%.IR(KBr?pellet):3000,1750,1600,1596,1340,1110cm
-1.
1HNMR(300MHz,CDCl
3)δ: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)δ:-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 4-trifluoromethyl androstane-4-alkene-3,17-diketone (0.4mmol), dichloro dinitrile benzoquinones (1mmol), in the trimethyl carbinol (30ml) 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.
1HNMR(300MHz,CDCl
3)δ: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)δ:-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 4-trifluoromethyl-N-tertiary butyl androstane-4-alkene-3-ketone-17 β-methane amide (0.5mmol), dichloro dinitrile benzoquinones (0.4mmol).In the trimethyl carbinol (30ml) 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-tertiary butyl 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。
1HNMR (300MHz, CDCl
3) δ: 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-Hppm
19F NMR (60MHz, CDCl
3) δ :-24.6 (s) ppm.MS m/z:437 (M+, 42.7), 422 (M
+-CH
3, 16.6) and .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 4-Trifluoromethyl-1 3-ethyl androstane-4-alkene-3,17-diketone (1mmol), dichloro dinitrile benzoquinones (4mmol), in the trimethyl carbinol (30ml) solvent, reflux 3 hours is filtered, 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.
1HNMR(300MHz,CDCL
3)δ:1.00(t,J=8.0Hz,CH
3CH
2-),1.50(s,C
19-H),6.30(dJ=10Hz,C
2-H),7.46(d,J=10Hz,C
1-H)ppm。
19F NMR (60MHz, CDCl3) δ :-25.0 (s) ppm.MS m/z:366 (M
+, 32.3), 351 (M
+-CH
3, 8.6), 337 (M
+-Et, 6.8), 297 (M
+-CF3,26.7), 194 (100). and 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 4-trifluoromethyl-N-sec.-propyl androstane-4-alkene-3-ketone-17 β-methane amide (0.4mmol), dichloro dinitrile benzoquinones (1.2mmol) is in the trimethyl carbinol (30ml) 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.
1HNMR(300MHz,CDCl
3)δ: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)δ:-25.2(s)ppm。MS?m/z:423(M
+,58.6),408(M
+-CH3,23.2),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 (7)
1, a kind of 4-trifluoromethyl-3-ketone-steroidal compounds is characterized in that having following minute flat:
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
, R
6=H or CH
3, R
5And R
6=O, R
7Or R
8=H, C
1-10Alkyl, cycloalkyl aryl or heterocycle, R
7And R
8=(CH
2) n, n=1-6,
Or
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 androstane of 6-diene, 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:
The sterides compound raw material, R wherein
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: 1-5, 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: 1-5
(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: 1-5
4, the preparation method of a kind of 4-trifluoromethyl as claimed in claim 3-3-ketone-steroidal compounds, used solvent is ether, sherwood oil, benzene, tetracol phenixin, dimethyl sulfoxide (DMSO), hexamethylphosphoramide (HMPA), N in it is characterized in that reacting, dinethylformamide (DMF), N,N-dimethylacetamide (DMA).
5, the preparation method of a kind of 4-trifluoromethyl as claimed in claim 3-3-ketone-steroidal compounds, used methylating reagent is X (CF2CF2O) m (CF2) kCO2Y in it is characterized in that reacting, wherein X=Cl, Br, I or FO2S, Y=H, CH3, C2H5 or K, m=0 or 1, k=1 or 2.
6, the preparation method of a kind of 4-trifluoromethyl as claimed in claim 3-3-ketone-steroidal compounds, used catalyzer is Cu powder or CuI in it is characterized in that reacting.
7, 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 30-120 ℃.
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Cited By (3)
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CN100440277C (en) * | 2001-06-07 | 2008-12-03 | 株式会社瑞萨科技 | Display device and drive circuit for displaying |
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 |
CN104045585A (en) * | 2013-03-11 | 2014-09-17 | 中国科学院上海有机化学研究所 | New trifluoro methylation reagent and preparation and application thereof |
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FR2576025B1 (en) * | 1985-01-14 | 1987-01-23 | Roussel Uclaf | NOVEL SUBSTITUTED STEROIDS IN POSITION 10, THEIR PROCESS AND THE PREPARATION INTERMEDIATES, THEIR APPLICATION AS MEDICAMENTS, THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
HU201091B (en) * | 1985-12-26 | 1990-09-28 | Mitsubishi Chem Ind | Process for producing gonatriene derivatives and pharmaceutical compositions comprising same |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN100440277C (en) * | 2001-06-07 | 2008-12-03 | 株式会社瑞萨科技 | Display device and drive circuit for displaying |
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 |
CN104045585A (en) * | 2013-03-11 | 2014-09-17 | 中国科学院上海有机化学研究所 | New trifluoro methylation reagent and preparation and application thereof |
CN104045585B (en) * | 2013-03-11 | 2016-06-29 | 中国科学院上海有机化学研究所 | Novel trifluoromethyl reagent and preparation thereof and application |
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