CN1182091A - Fluoric steroid 5Alpha-reductase inhibitor and its synthesis process and use - Google Patents

Fluoric steroid 5Alpha-reductase inhibitor and its synthesis process and use Download PDF

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CN1182091A
CN1182091A CN 96116596 CN96116596A CN1182091A CN 1182091 A CN1182091 A CN 1182091A CN 96116596 CN96116596 CN 96116596 CN 96116596 A CN96116596 A CN 96116596A CN 1182091 A CN1182091 A CN 1182091A
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steroidal
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inhibitor
trifluoromethylation
bromo
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CN1064368C (en
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田伟生
费向曙
陈庆云
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Shanghai Institute of Organic Chemistry of CAS
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Shanghai Institute of Organic Chemistry of CAS
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Abstract

The said inhibitor is 4-trifluoromethyl-17-(N-tertbutylcarbaminoyl)androst-4-en-3-one. It has high steroid-5 alpha-reductase inhibiting biological activity, so that it is possible to further develop it to become medicine for curing prostatauxe and prostate tumor. It may be prepared from commercially available steroid compound (androsterone, progesterone and their derivatives) and through halogenating, trifluoromethylating and other key reaction. The present invention provides three ways to synthesize the said inhibitor.

Description

A kind of fluorine-containing steroidal 5 inhibitor, preparation method and use
The present invention relates to a kind of fluorine-containing steroidal 5 inhibitor, be 4-Trifluoromethyl-1 7-(N-tertiary butyl carbamyl) androstane-4-alkene-3-ketone, synthesize and uses thereof.
Along with science and technology development, the human life-span constantly prolongs, and society progressively tends to aging.Some geriatric diseases as prostatomegaly etc., more and more are subjected to science personnel's care and attention.For male senile patient, (Benign Prostatic Hyperplasia BPH) is modal multiple disease to benign prostate hyperplasia.It is reported that prostatomegaly can appear in the man at age in various degree more than 50 years old; In the 70-79 man at age in year, sickness rate is 70%; The man's at age sickness rate is up to 90% (Ren Guoquan, foreign medical science geriatrics fascicle, 1991,12 (5), 222) more than 80 years old.Therefore, design, synthesize and carry out bioactivity screening and have very big necessity and significance with the medicine of seeking ideal treatment hyperplasia of prostate.Up to now, the drug main of treatment benign prostate hyperplasia will comprise: short sexual hormoue releasing hormone LH-RH, androgen antagonist and steroidal 5 inhibitor.Preceding two kinds of medicines are when treatment, with the side effect of hypoandrogenism symptom.Further studies show that: benign prostatic hyperplasia is mainly relevant with dihydrotestosterone in the body.Steroidal 5 inhibitor can suppress in the body testosterone to the bio-transformation of dihydrotestosterone by suppressing the steroidal 5, and have the testosterone that do not influence in the normal circulation with and
Figure A9611659600041
Physiological action.Therefore, steroidal 5 inhibitor just becomes the medicine (Hu Haifeng etc., foreign medical science microbiotic fascicle, 1995,16 (6), 462) of good treatment hyperplasia of prostate.The 5 inhibitor that investigation has been found that is not difficult to find that they are the derivative of steroidal A/B ring through modifying, as MK 906 (Proscar 1) (Scripp, 1993,18,15), SK﹠amp; F 105657 (Epristeride 2) (M.A.Levy et al, Bioorg.Chem., 1991,19,245) and 4-itrile group steroidal 3 (M.Haase-Held et al, JChem.Soc Perkin I, 1992,2999).As shown in Figure 1.Studies show that in a large number in recent years: in bioactive molecule, introduce the biological activity that fluorine atom or trifluoromethyl could significantly improve or change original parent molecule.On the basis of summing up existing 5 inhibitor structure activity relationship, we have designed the steroidal compounds 4 among Fig. 1 that trifluoromethyl replaces.And the analogue of estimating it and other can have the activity of certain inhibition steroidal 5.
Purpose of the present invention just provides a kind of highly active fluorine-containing steroidal 5 inhibitor: 4-Trifluoromethyl-1 7-(N-tertiary butyl carbamyl) androstane-4-alkene-3-ketone, and simple and effective preparation method and use is provided.
The molecular formula of fluorine-containing steroidal 5 inhibitor provided by the present invention is as follows:
Figure A9611659600051
Be 4-Trifluoromethyl-1 7-(N-tertiary butyl carbamyl) androstane-4-alkene-3-ketone.
The present invention also provides a kind of method of synthesizing above-mentioned 4-Trifluoromethyl-1 7-(N-tertiary butyl carbamyl) androstane-4-alkene-3-ketone simple and effectively, with molecular formula is exactly:
Figure A9611659600052
R wherein 1=CH 3COO, OH, O, R 2=COCH 3, COOH, O, CONHC (CH 3) 3,
Figure A9611659600053
Figure A9611659600054
Steroidal enol ketone make through oxidation, bromo or iodo, the method for taking off the combination of step in bromine or iodine and trifluoromethylation, carboxylation, degraded, the amination or polystep reaction.Be synthetic 4-Trifluoromethyl-1 7-(the N-tertiary butyl of raw material wherein with the Vitarrine compounds
Figure A9611659600061
A.NaOBr; B, H +, CH 3OH; The c.Oppenauer oxidation; D.10%NaOH/EtOH, H +E.SOCl 2, t-Butylamine; F.Br 2G.Collidine; G. trifluoromethyl reagent, 40-80 ℃.Carbamyl) reactions steps of androstane-4-alkene-3-ketone is to make through Oppennauer oxidation, degraded amination, bromo or iodo, the polystep reaction of taking off bromine or iodine and trifluoromethylation.Reaction formula as shown above.
In the reactions steps that with the pregnene ketone compounds is synthetic 4-Trifluoromethyl-1 7-(the N-tertiary butyl carbamyl) androstane-4-alkene-3-ketone of raw material,, be through bromo or iodo, take off bromine or iodine and trifluoromethylation, degraded, aminating polystep reaction make reaction formula as shown in the figure:
Figure A9611659600071
A. bromo or iodo.B. dehydrobromination or hydrogen iodide.C. trifluoromethylation (solvent, Cu powder or, CuI, trifluoromethyl reagent, 40-80 ℃).D.I 2, Py.CH 3ONa/CH 3OH.e. (COCl) 2, TERTIARY BUTYL AMINE.
In the reactions steps that with dehydroepiandros-sterone, androstenone compounds is synthetic 4-Trifluoromethyl-1 7-(the N-tertiary butyl carbamyl) androstane-4-alkene-3-ketone of raw material, be through Oppenauer oxidation, bromo or iodo, take off bromine or iodine and trifluoromethylation, carboxylation, aminating polystep reaction make, reaction formula as shown in the figure:
Figure A9611659600081
The a.Oppenauer oxidation.B. bromo or iodo.C. dehydrobromination or hydrogen iodide.D. trifluoromethylation (solvent, Cu powder or CuI, trifluoromethyl reagent, 40-80 ℃).E. carboxylation.F. amination.
Oxidation in the synthetic method of the present invention, bromo or iodo, to take off bromine or iodine, carboxylation, degraded, amination all be known technology, its key is the trifluoromethylation reaction, be steroidal enol ketone after a step or multistep composite reaction make bromo or iodo product, in the presence of solvent and catalyzer, bromo or iodo product and trifluoromethyl reagent reaction, wherein solvent is ether, sherwood oil, benzene, tetracol phenixin, dimethyl sulfoxide (DMSO), hexamethylphosphoramide (HMPA), N, dinethylformamide (DMF), N,N-dimethylacetamide (DMA).Recommending solvent is hexamethylphosphoramide (HMPA), N, dinethylformamide (DMF), N,N-dimethylacetamide (DMA).Catalyzer is CuI or Cu powder, and the mole ratio of bromo or iodo product, catalyzer and trifluoromethyl reagent is 1: 0.1-5: 1-5, and the reaction times is 1-10 hour, temperature of reaction is 30-120 ℃.Recommended temperature is 40-80 ℃.The reaction yield is 70-92%, wherein the reagent of trifluoromethylation 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.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 3XCF 2CO 2C 2H 5, XCF 2CO 2K etc.
Novel steroid drugs 5 inhibitor of the present invention can further develop the medicine that becomes treatment hyperplasia of prostate disease.4-Trifluoromethyl-1 7-(N-tertiary butyl carbamyl) androstane-4-alkene-3-ketone shows that through preliminary biological activity determination they have the activity that suppresses the steroidal 5.Its biologically active data is shown in Table 1.Table 1 compound 4 and allied compound suppress steroidal 5 (Ki value) sample * isotope method enzyme kinetics method
[ 3H]-T→[ 3H]-DHT NADPHProscar 88.2nM 54.7nMCompounds?1 20.9nM 20.2nMCompounds?2 95.2nM 28.8nMCompounds?3 ＞1000nM ＞1000nM
* Proscar is as the steroidal 5 inhibitor of medicine; Compounds 1, and 4-three
Methyl fluoride-17-(N-tertiary butyl carbamyl) androstane-4-alkene-3-ketone; Compounds 2,
Androstane-4-trifluoromethyl-4-alkene-3, the 17-diketone; Compounds, pregnant steroid-4-trifluoro
Methyl-4-alkene-3, the 20-diketone.
In sum, the novel fluorine-containing steroid drugs 5 inhibitor of the present invention is compared with existing steroid drugs 5 inhibitor and is had distinguishing feature:
1, high physiologically active, its Ki value is respectively 20.9nM and 20.2nM as can be seen from Table 1, and known medicine Proscar is 88.2nM and 54.7nM.
2, reaction conditions gentleness, high yield.Needn't pass through photoresponse and carbonylation reaction, the low shortcoming of yield that overcomes long reaction time and cause greatly owing to the reaction steric hindrance.
Following embodiment will help to understand the present invention, but be not limited to content of the present invention: embodiment 1
1, (9 grams 25mmol.) in 180 milliliters of dioxane (containing 50 ml waters), are cooled to below 10 ℃ dissolving Vitarrine acetic ester, and (dissolving 13 gram NaOH at 0-5 ℃, drip 13 gram bromines in 100 milliliters to drip NaOBr solution.After being added dropwise to complete, add 75 milliliters of dioxane dilutions.Be kept at 0 ℃ standby).After being added dropwise to complete, continue reaction 1 hour, add 50 milliliters of 10%NaHSO 3Solution, back flow reaction 15 minutes.After adding 10 milliliters of concentrated hydrochloric acids, be evaporated to 1/2,0 ℃ of standing over night of original volume.Filter and collect the throw out of separating out, and wash with water, the dry 7.2 gram 3-hydroxy-androstane-5-alkene-17-carboxylic acids that get to neutrality.Yield 92%.Fusing point 276-278 ℃.The yield of gained carboxylic acid about reacting with 75% with methanol eddy in the presence of the catalytic amount tosic acid obtains 3-hydroxy-androstane-5-alkene-17-carboxylate methyl ester.
2, dissolving 18.5 gram 3-hydroxy-androstane-5-alkene-17-carboxylate methyl esters, 10.2 gram aluminum isopropylates and 48 milliliters of cyclopropanones are in 260 milliliters of toluene.Back flow reaction 1 hour adds 1 gram activated carbon and stirred 15 minutes, filters, and filtrate to neutrality, adds anhydrous Na with the saturated common salt water washing 2SO 4Drying, removal of solvent under reduced pressure obtain 13.7 gram androstane-5-alkene-3-ketone-17-carboxylate methyl esters.Yield 74.5%.Fusing point 128-131 ℃.
3, dissolving 13.7 gram androstane-5-alkene-3-ketone-17-carboxylate methyl esters add 40 milliliters of 10%KOH aqueous solution, back flow reaction 4 hours in 80 milliliter of 95% ethanol.Ethanol is removed in decompression, and remaining aqueous solution is regulated pH=3 with 6N HCl.Filter the collecting precipitation thing, washing, drying provides 12.7 gram androstane-5-alkene-3-ketone-17-carboxylic acids.Yield 96%.Fusing point 245-256 ℃.
4, dissolving 5 gram androstane-5-alkene-3-ketone-17-carboxylic acids add 1.6 milliliters of pyridines in 50 milliliters of toluene.Under the ice bath cooling, drip 1.75 milliliters of oxalyl chlorides (through 1.75 milliliters of dilution with toluene), stirring at room reaction 1 hour.Keep temperature of reaction below 40 ℃, drip 8.5 milliliters of TERTIARY BUTYL AMINE (in 10 milliliters of toluene), after dripping, stirring at room reaction 1 hour.In 70 milliliters of frozen water of reaction soln impouring, tell toluene layer, the water layer ethyl acetate extraction.Merge organic phase, use 2N HCl, saturated NaHCO successively 3Solution and saturated common salt water washing, drying, removal of solvent under reduced pressure, residue gets the 5.5 gram N-tertiary butyl-androstane-4-alkene-3-ketone-17-methane amides through toluene/sherwood oil recrystallization.Yield 93.7%.Fusing point 214-217 ℃.
5, dissolving 1.86 gram (3mmol) N-tertiary butyl-androstane-4-alkene-3-ketone-17-methane amides drip 1.2 milliliters of bromines (in 10 milliliters of acetate) at 30 milliliters of anhydrous diethyl ethers (containing 4.5 milliliters of trimethylpyridines).After the reaction of reaction mixture stirring at room.Behind the ether dilute reaction solution, use saturated inferior league matches hydrogen sodium solution, 2N hydrochloric acid, saturated NaHCO successively 3Solution and saturated common salt solution washing, drying, removal of solvent under reduced pressure get the N-tertiary butyl-androstane-4-bromo-4-alkene-3-ketone-17-methane amide crude product.Through obtaining the N-tertiary butyl-androstane-4-bromo-4-alkene-3-ketone-17-methane amide with 64% yield behind the silica gel column chromatography fast.Fusing point 106-107 ℃.Infrared spectra (KBr): 3400,2900,1690,1680,1580,1510,1450,1390,1360,1260,1120cm -1Hydrogen nuclear magnetic resonance spectrum (300MHz, CDCl 3): 0.73 (s, 3H, 18-CH 3), 1.24 (s, 3H, 19-CH 3), 1.35 (s, 9H, C (CH 3) 3), 5.09 (s, NH) ppm; Mass spectrum m/z:452,45,449,434,387,370,369,354,313,298,269 253,57.Ultimate analysis C 24H 36O 2NBr calculated value: C 63.99, H 8.05, and N 3.11.
Measured value: C 69.81, H 8.05, and N 3.00
6, the tertiary butyl-androstane-(methane amide among the dinethylformamide DMF, adds 100mgCuI and 1ml methoxyl group formyl difluoromethyl sulfonic acid fluoride at 80ml exsiccant N to 4-bromo-4-alkene-3-ketone-17 to dissolving 0.9g N-.Under nitrogen protection, 60-80 (C reaction 8 hours.After reaction mixture dilutes with ether, through diatomite filtration.The filtrate washing, drying, the reacting coarse product of removal of solvent under reduced pressure.Obtain 4-three oxygen methyl-17s-(N-tertiary butyl carbamyl) androstane-4-alkene-3-ketone through purification by silica gel column chromatography with 91% yield.Fusing point 158-159 ℃.Infrared spectra (KBr): 3499,2900,1680,1590,1510,1450,1360,1260,1230,1120cm -1Hydrogen nuclear magnetic resonance spectrum (300MHz), CDCl 3): 0.74 (s, 3H, 18-CH 3), 1.26 (s, 3H, 19-CH 3), 1.35 (s, 9H, C (CH 3) 3), 5.08 (s, NH) ppm.Fluorine nmr (60MHz, CDCl 3) :-20.8ppm mass spectrum m/z:439,424,404,384,368,339,248,149,69,57 ultimate analysis C 25H 36O 2NF 3Calculated value: C 68.31, H 8.25, and N 3.19
Measured value: C 68.22, H 8.31, and N 2.98.Embodiment 2
1, press the operational condition reaction of embodiment 1 the 5th step reaction, from the pregnant steroid of raw material-4-alkene-3, the 20-diketone is with synthetic pregnant steroid-4-bromo-4-alkene-3, the 20-diketone of obtaining of 70% yield.162 ℃ of fusing points.
2, the pregnant steroid of dissolving 0.04mmol-4-bromo-4-alkene-3, the 20-diketone adds 0.2mmol Cu powder and 0.1mmol trifluoromethyl reagent (FO in 60ml exsiccant N,N-dimethylacetamide (DMA) 2SCF 2CO 2CH 3, FO 2SCF 2CO 2C 2H 5Or FO 2SCF 2CF 2OCF 2CO 2CH 3).Under nitrogen protection, 80-120 ℃ was reacted 2 hours.After reaction mixture dilutes with ether, through diatomite filtration.The filtrate washing, drying, the reacting coarse product of removal of solvent under reduced pressure.Through purification by silica gel column chromatography, the yield with 74% obtains pregnant steroid-4-trifluoromethyl-4-alkene-3,20-diketone.124 ℃ of fusing points.
3, press the schedule of operation conditioned response of the 1st step of embodiment and the reaction of the 3rd step, from pregnant steroid-4-trifluoromethyl-4-alkene-3, the 20-diketone obtains pregnant steroid-4-trifluoromethyl-4-alkene-3-ketone-17-carboxylic acid with 70% yield
4, press the schedule of operation conditioned response of embodiment the 4th step reaction, (carboxylic acid is a raw material, obtains product 4-Trifluoromethyl-1 7-(N-tertiary butyl carbamyl)-androstane-4-alkene-3-ketone with 85% yield with pregnant steroid-4-trifluoromethyl-4-alkene-3-ketone-17.158 ℃ of fusing points.Infrared spectra (KBr): 3500,2900,1680,1590,1510,1450,1360,1260,1230,1120cm -1Hydrogen nuclear magnetic resonance spectrum (300MHz), CDCl 3): 0.74 (s, 3H, 18-CH 3), 1.25 (s, 3H, 19-CH 3), 1.35 (s, 9H, C (CH 3) 3), 5.08 (s, NH) ppm.Fluorine nmr (60MHz, CDCl 3) :-20.8ppm mass spectrum m/z:437,424,400,384,368,339,248,149,69,57 ultimate analysis C 25H 36O 2NF 3Calculated value: C 68.31, H 8.25, and N 3.19
Measured value: C 68.29, H 8.30, N 3.08 embodiment 3
1, press the 5th step reaction conditions operation of embodiment 1, wherein replace corresponding bromine reaction with iodo, from androstane-4-alkene-3, the 17-diketone obtains androstane-4-iodo-4-alkene-3,17-diketone with 80% yield.152 ℃ of fusing points.
2, dissolving 0.1mmol androstane-4-bromo-4-alkene-3, the 17-diketone adds 0.01mmol Cu powder and 0.05mmol trifluoromethyl reagent (FO in 60ml exsiccant hexamethylphosphoramide (HMPA) 2SCF 2CF 2OCF 2CO 2K, FO 2SCF 2CF 2OCF 2CF 2CO 2CH 3, XCF 2CO 2CH 3, XCF 2CO 2C 2H 5Or XCF 2CO 2K).Under nitrogen protection, 30-50 ℃ was reacted 10 hours.After reaction mixture dilutes with ether, through diatomite filtration.The filtrate washing, drying, the reacting coarse product of removal of solvent under reduced pressure.Through purification by silica gel column chromatography, obtain androstane-4-trifluoromethyl-4-alkene-3,17-diketone with 81%.150 ℃ of fusing points
3, dissolving androstane-4-trifluoromethyl-4-alkene-3, and the 17-diketone (710mg, 2mmol) in 15 ml acetic anhydride, the p-methyl benzenesulfonic acid of catalytic amount.Reaction mixture carried out 2 hours at 60 ℃, handle 3-acetoxyl group androstane-4-trifluoromethyl-3,5-alkene-17-ketone.Dissolving gained 3-acetoxyl group androstane-4-trifluoromethyl-3,5-alkene-17-ketone is in 10 milliliters of anhydrous tetrahydro furans, at-78 (C, drip 4 millimole amounts 1, (dissolve 4 millimoles 1,3-two sulphur six rings are in 5 milliliters of anhydrous tetrahydro furans, at 0 ℃ for 3-two sulphur six cyclic group lithiums, the butyllithium of millimoles such as dropping, stirring reaction 1 hour).After being added dropwise to complete, carried out stirring reaction 10 hours, the room temperature standing over night, aftertreatment obtains crude reaction.With obtaining androstane-4-trifluoromethyl-4-alkene-3-ketone-17-carboxylic acid with 50% total recovery after the NBS oxidation.Crude product is not purified to be directly used in next step reaction.
4, press the 4th step reaction conditions operation of embodiment 1, obtain product 4-Trifluoromethyl-1 7-(N-tertiary butyl carbamyl) androstane-4-alkene-3-ketone with 82% yield from androstane-4-trifluoromethyl-4-alkene-3-ketone-17-carboxylic acid.159 ℃ of fusing points.Infrared spectra (KBr): 3500,2890,1680,1590,1500,1450,1360,1260,1250,1120cm -1. hydrogen nuclear magnetic resonance spectrum (300MHz), CDCl 3): 0.72 (s, 3H, 18-CH 3), 1.25 (s, 3H, 19-CH 3), 1.36 (s, 9H, C (CH 3) 3), 5.08 (s, NH) ppm.Fluorine nmr (60MHz, CDCl 3) :-20.6ppm.Mass spectrum m/z:435,427,400,384,368,339,248,148,69,57 ultimate analysis C 25H 36O 2NF 3Calculated value: C 68.31, H 8.25, and N 3.19
Measured value: C 68.25, H 8.20, and N 3.27

Claims (10)

1. a novel steroidal 5 inhibitor is characterized in that it being fluorine-containing steroidal compounds 4-Trifluoromethyl-1 7-(N-tertiary butyl carbamyl) androstane-4-alkene-3-ketone, and molecular formula is as follows:
Figure A9611659600021
2. the synthetic method of a steroidal 5 inhibitor as claimed in claim 1 is characterized in that it being to be by molecular formula: R wherein 1=CH 3COO, OH, O, R 2=COCH 3, COOH, O, CONHC (CH 3) 3,
Figure A9611659600024
Steroidal enol ketone make through oxidation, bromo or iodo, the method for taking off the combination of step in bromine or iodine and trifluoromethylation, carboxylation, degraded, the amination or polystep reaction.
3. the synthetic method of a steroidal 5 inhibitor as claimed in claim 2, it is characterized in that with the Vitarrine compounds be raw material, is to make through Oppenauer oxidation, degraded amination, bromo or iodo, the polystep reaction of taking off bromine or iodine and trifluoromethylation.
4. the synthetic method of a steroidal 5 inhibitor as claimed in claim 2 is characterized in that with the pregnene ketone compounds be raw material, is through bromo or iodo, takes off bromine or iodine and trifluoromethylation, the aminating polystep reaction of degraded make.
5. the synthetic method of a steroidal 5 inhibitor as claimed in claim 2, it is characterized in that with dehydroepiandros-sterone, androstenone compounds be raw material, be through Oppenauer oxidation, bromo or iodo, take off bromine or iodine and trifluoromethylation, carboxylation, aminating polystep reaction make.
6. synthetic method as claim 2,3,4 or 5 described steroidal 5 inhibitor, it is characterized in that the trifluoromethylation reaction is in the presence of solvent and catalyzer, bromo or iodo product and trifluoromethyl reagent reaction, wherein solvent is for being ether, sherwood oil, benzene, tetracol phenixin, dimethyl sulfoxide (DMSO), hexamethylphosphoramide (HMPA), N, dinethylformamide (DMF), N,N-dimethylacetamide (DMA).Catalyzer is CuI or Cu powder, and the mole ratio of bromo or iodo product, catalyzer and trifluoromethyl reagent is 1: 0.1-5: 1-5, and the reaction times is 1-10 hour, temperature of reaction is 30-120 ℃.
7. the synthetic method of a steroid drugs 5 inhibitor as claimed in claim 6 is characterized in that the recommended temperature of reaction of trifluoromethylation is 40-80 ℃.
8. the preparation method of 4-trifluoromethyl as claimed in claim 6-3-ketone-steroidal compounds, used solvent is hexamethylphosphoramide (HMPA), N in it is characterized in that reacting, dinethylformamide (DMF), N,N-dimethylacetamide (DMA).
9. the synthetic method of steroidal as claimed in claim 6-5 inhibitor, the reagent that it is characterized in that trifluoromethylation is X (CF2CF2O) m (CF2) kCO2Y, wherein X=Cl, Br, I or FO 2S, Y=H, CH 3, C 2H 5Or K, m=0 or 1, k=1 or 2.
10. the purposes of a steroidal 5 inhibitor as claimed in claim 1 is characterized in that further developing the medicine that becomes treatment hyperplasia of prostate disease.
CN 96116596 1996-11-29 1996-11-29 Fluoric steroid 5Alpha-reductase inhibitor and its synthesis process and use Expired - Fee Related CN1064368C (en)

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CN102532236A (en) * 2012-01-05 2012-07-04 中国药科大学 Steroid 5Alpha-reductase inhibitors, preparation methods thereof and medical applications thereof
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CN105017363A (en) * 2015-06-25 2015-11-04 湖南科瑞生物科技股份有限公司 Synthesis methods of 4-androsten-3-one-17-beta-carboxylic acid and methyl 4-androsten-3-one-17-beta-carboxylate

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CN102532236B (en) * 2012-01-05 2014-04-16 中国药科大学 Steroid 5Alpha-reductase inhibitors, preparation methods thereof and medical applications thereof
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
CN105017363A (en) * 2015-06-25 2015-11-04 湖南科瑞生物科技股份有限公司 Synthesis methods of 4-androsten-3-one-17-beta-carboxylic acid and methyl 4-androsten-3-one-17-beta-carboxylate

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