CN1061983C - 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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- 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
- steroid compound
- keto
- reaction
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- 238000000034 method Methods 0.000 title claims abstract description 14
- 150000001875 compounds Chemical class 0.000 title abstract description 18
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 13
- -1 trifluoromethyl steroids Chemical class 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 238000006692 trifluoromethylation reaction Methods 0.000 claims abstract description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 96
- 239000002904 solvent Substances 0.000 claims description 60
- 229910052799 carbon Inorganic materials 0.000 claims description 53
- 238000006243 chemical reaction Methods 0.000 claims description 47
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 22
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 18
- 239000000843 powder Substances 0.000 claims description 14
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 claims 4
- 125000000217 alkyl group Chemical group 0.000 claims 4
- 239000003054 catalyst Substances 0.000 claims 3
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 claims 2
- JWMFYGXQPXQEEM-NUNROCCHSA-N 5β-pregnane Chemical compound C([C@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](CC)[C@@]2(C)CC1 JWMFYGXQPXQEEM-NUNROCCHSA-N 0.000 claims 1
- 229940011871 estrogen Drugs 0.000 claims 1
- 239000000262 estrogen Substances 0.000 claims 1
- 230000011987 methylation Effects 0.000 claims 1
- 238000007069 methylation reaction Methods 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract description 11
- 239000013067 intermediate product Substances 0.000 abstract 2
- 150000004057 1,4-benzoquinones Chemical class 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 49
- 239000007787 solid Substances 0.000 description 36
- 239000000047 product Substances 0.000 description 30
- 239000010410 layer Substances 0.000 description 26
- 239000008188 pellet Substances 0.000 description 26
- 238000004458 analytical method Methods 0.000 description 25
- 238000001035 drying Methods 0.000 description 23
- 239000000706 filtrate Substances 0.000 description 23
- 239000012074 organic phase Substances 0.000 description 23
- 238000010025 steaming Methods 0.000 description 23
- 150000003431 steroids Chemical class 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000000376 reactant Substances 0.000 description 14
- 230000003637 steroidlike Effects 0.000 description 14
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 13
- 230000008030 elimination Effects 0.000 description 13
- 238000003379 elimination reaction Methods 0.000 description 13
- 238000003818 flash chromatography Methods 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- 229910052710 silicon Inorganic materials 0.000 description 13
- 239000010703 silicon Substances 0.000 description 13
- 239000002689 soil Substances 0.000 description 13
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 10
- 230000006837 decompression Effects 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 8
- 150000004054 benzoquinones Chemical class 0.000 description 8
- 125000003963 dichloro group Chemical group Cl* 0.000 description 8
- 229910052731 fluorine Inorganic materials 0.000 description 8
- 239000011737 fluorine Substances 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- QZLYKIGBANMMBK-UGCZWRCOSA-N 5α-Androstane Chemical compound C([C@@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CCC[C@@]2(C)CC1 QZLYKIGBANMMBK-UGCZWRCOSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- VPAYJEUHKVESSD-UHFFFAOYSA-N trifluoroiodomethane Chemical compound FC(F)(F)I VPAYJEUHKVESSD-UHFFFAOYSA-N 0.000 description 2
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- JGZVUTYDEVUNMK-UHFFFAOYSA-N 5-carboxy-2',7'-dichlorofluorescein Chemical compound C12=CC(Cl)=C(O)C=C2OC2=CC(O)=C(Cl)C=C2C21OC(=O)C1=CC(C(=O)O)=CC=C21 JGZVUTYDEVUNMK-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 238000005899 aromatization reaction Methods 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 150000001887 cortisones Chemical class 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 229940072254 proscar Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 1
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- Steroid Compounds (AREA)
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
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]
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:
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,
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:
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,
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
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
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)
Priority Applications (1)
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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 |
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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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 |
-
1996
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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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