CN1055930C - Steroalkenol polyfluohydrocarbyl sulfonate compound and its deriv., use and preparing process - Google Patents

Abstract

The invention relates to a steroid enol polyfluoroalkyl sulfonate compound and its derivatives, application and preparation method. This compound is similar to enol triflate, can react with various nucleophiles, and is an important intermediate of steroid drugs. Steroid-3-ketone compounds can be prepared by reacting with polyfluorosulfonyl fluoride in the presence of nitrogen-containing compounds with arc pairs of electrons on nitrogen atoms. Not only the yield is high, but also the polyfluorosulfonyl fluoride used is cheap, convenient and easy to obtain, the property of the reagent is stable, the reaction operation is convenient, and it has good chemical selectivity.

Description

Steroid enol polyfluoroalkyl sulfonate compound and its derivatives, use and preparation method

The invention relates to a steroid enol polyfluoroalkyl sulfonate compound and its derivatives, application and preparation method. This steroidal enol polyfluoroalkyl sulfonate compound and its derivatives can be obtained by reacting polyfluorosulfonyl halides with carbonyl compounds. This method is especially suitable for 3-perfluoroalkyl or alkoxysulfonyl substituted steroids. The synthesis of body compounds, the products are important intermediates of steroid drugs.

这不仅降低了反应产物2的收率，也增加了分离得到产物2纯样品的难度，最终不仅增加了烯醇三氟甲基磺酸酯的成本，而且也限制了它们的应用。为使烯醇磺酸酯能与各种亲核试剂的反应能在工业生产上获得应用，寻找价格便宜的甾体烯醇多氟烷基磺酸酯及其衍生物，性质稳定、价廉、具有较高反应选择性的烯醇磺酰化试剂和用烯醇磺酰化试剂选择性制备甾体烯醇多氟烷基磺酸酯及其衍生物的方法是非常必要的。Enol triflate can react with various nucleophiles in the form of alkenyl cations, and is applied to the synthesis of alkenes with various substituents (PJstang et al., Synthesis, 1982, 85; WJScott et al., Acc.Chem.Res, 1988,21,47.), as applied to the synthesis of steroidal 5α-reductase inhibitors-3-carboxy steroids (DAHolt et al., J.Med.Chem, 1990,33,943 ). Although in the chemical laboratory, enol trifluoromethanesulfonate can be easily prepared by the reaction of carbonyl compound and trifluoromethanesulfonic anhydride, but trifluorosulfonic anhydride is not only expensive, but also unstable, and the reaction The selectivity is low, thus limiting its practical application in industrial production. For example, when the steroidal compound 1 is converted into the corresponding enol trifluoromethylsulfonate 2, due to the lack of good reaction selectivity of trifluoromethanesulfonic anhydride, in addition to generating the expected enol trifluoromethyl In addition to sulfonate, it is also accompanied by the generation of unwanted by-product 3:

This not only reduces the yield of reaction product 2, but also increases the difficulty of isolating a pure sample of product 2, which ultimately not only increases the cost of enol triflate, but also limits their application. In order to enable the reaction of enol sulfonate with various nucleophilic reagents to be applied in industrial production, it is necessary to look for cheap steroid enol polyfluoroalkyl sulfonate and its derivatives, which are stable in nature, cheap and An enol sulfonylating reagent with high reaction selectivity and a method for selectively preparing steroidal enol polyfluoroalkyl sulfonate and its derivatives using the enol sulfonylating reagent are very necessary.

The object of the present invention is to provide a cheap, high-purity enol polyfluoroalkyl sulfonate and derivatives thereof.

Another object of the present invention is to provide a method for synthesizing enol polyfluoroalkyl sulfonate and derivatives thereof with higher selectivity, which is especially suitable for 3-substituted perfluoroalkyl sulfonate and derivatives thereof Synthesis of steroidal compounds.

Another object of the present invention is to provide the use of such steroidal enol polyfluoroalkylsulfonate and its derivatives.

其中 或 ，R₁＝H或CH₃，R₂＝H、CH₃或C₂H₅，R₃＝CONR′R″、

C_1-10的烷基、CO₂CH₃、CN或OH，R′、R″＝H、CH₃、C₂H₅、(CH₃)₂CH、(CH₃)₃C、-(CH₂)-、-(CH₂)₃-、-(CH₂)₄-、-(CH₂)₅-、

或

，R₄＝H、C₂H₅、CH₃C≡C-、HC≡C-、CF₃，R₅或R₆＝H、F、Cl、OH、CH₃、CF₃、CH₂＝或O，

Y＝X(CF₂CF₂O)n、CF₃(CF₂)m，X＝F、Cl、Br、I、H，n＝0、1或2，m＝0-5。N-叔丁基-3-[(5-氢-3-氧代八氟戊烷)磺酰氧基]-雄甾-3，5-二烯-17β甲酰胺，3-[(5-氢-3-氧代八氟戊烷)磺酰氧基]-5α-雄甾-3-烯-17-酮，3-[(5-氢-3-氧代八氟戊烷)磺酰氧基]-5α-甾-3-烯16β，20-二醇缩丙酮，17α-甲基-3-[(5-氢-3-氧代八氟戊烷)磺酰氧基]-雄甾-3，5-烯-17β-醇，3-[(5-氢-3-氧代八氟戊烷)磺酰氧基]-6-氧代-5α-胆甾-3-烯-24羧酸甲酯，3-[(5-氢-3-氧代八氟戊烷)磺酰氧基]-孕甾-3，5-二烯-酮-20，N-叔丁基3-[(5-氢-3-氧代八氟戊烷)磺酰氧基]-雄甾-3，5-二烯-17β-甲酰胺，N-叔丁基-3-[(全氟辛烷)磺酰氧基]-雄甾-3，5-二烯-17β-甲酰胺，N-叔丁基-3-(甲氧酰基)-雄甾-3，5-二烯-17β-甲酰胺，3-[(5-氢-3-氧代八氟戊烷)磺酰氧基]-雄甾-3，5-二烯-17-酮，3-[(全氟丁烷)磺酰氧基]-孕甾-3，5-二烯-20-酮，17α-炔基-18-甲基-19-去甲基-3-3(5-氢-3-氧代八氟戊烷)磺酰氧基-雄甾-3，5-二烯-17β-醇，3-[(5-氢-3-氧代八氟戊烷)磺酰氧基]-16-甲基-5α-孕甾-3，16-二烯-20-酮，N-叔丁基-3-[(8-氢-3，6-二氧代全氟辛烷磺酰氧基]-雄甾-3，5-二烯-17β-甲酰胺等。A kind of enol polyfluoroalkyl sulfonate and its derivatives provided by the present invention have the following molecular formula:

in or , R ₁ =H or CH ₃ , R ₂ =H, CH ₃ or C ₂ H ₅ , R ₃ =CONR'R",

C _1-10 alkyl, CO ₂ CH ₃ , CN or OH, R′, R″=H, CH ₃ , C ₂ H ₅ , (CH ₃ ) ₂ CH, (CH ₃ ) ₃ C, -(CH ₂ )-, -(CH ₂ ) ₃ -, -(CH ₂ ) ₄ -, -(CH ₂ ) ₅ -,

or

, R ₄ =H, C ₂ H ₅ , CH ₃ C≡C-, HC≡C-, CF ₃ , R ₅ or R ₆ =H, F, Cl, OH, CH ₃ , CF ₃ , CH ₂ = or O,

Y=X(CF ₂ CF ₂ O)n, CF ₃ (CF ₂ )m, X=F, Cl, Br, I, H, n=0, 1 or 2, m=0-5. N-tert-butyl-3-[(5-hydrogen-3-oxoctafluoropentane)sulfonyloxy]-androst-3,5-diene-17βcarboxamide, 3-[(5-hydro -3-oxoctafluoropentane)sulfonyloxy]-5α-androst-3-en-17-one, 3-[(5-hydrogen-3-oxoctafluoropentane)sulfonyloxy ]-5α-ster-3-ene 16β,20-diol acetonide, 17α-methyl-3-[(5-hydro-3-oxoctafluoropentane)sulfonyloxy]-androst-3 , 5-en-17β-ol, 3-[(5-hydro-3-oxoctafluoropentane)sulfonyloxy]-6-oxo-5α-cholest-3-ene-24 carboxylate Ester, 3-[(5-hydro-3-oxoctafluoropentane)sulfonyloxy]-pregna-3,5-dien-one-20, N-tert-butyl 3-[(5- Hydrogen-3-oxoctafluoropentane)sulfonyloxy]-androst-3,5-diene-17β-carboxamide, N-tert-butyl-3-[(perfluorooctane)sulfonyloxy Base]-androst-3,5-diene-17β-carboxamide, N-tert-butyl-3-(methoxyyl)-androst-3,5-diene-17β-carboxamide, 3-[ (5-Hydro-3-oxoctafluoropentane)sulfonyloxy]-androst-3,5-dien-17-one, 3-[(perfluorobutane)sulfonyloxy]-pregnant Ste-3,5-dien-20-one, 17α-alkynyl-18-methyl-19-desmethyl-3-3(5-hydro-3-oxoctafluoropentane)sulfonyloxy -Androst-3,5-dien-17β-ol, 3-[(5-hydro-3-oxoctafluoropentane)sulfonyloxy]-16-methyl-5α-pregna-3, 16-Diene-20-one, N-tert-butyl-3-[(8-hydro-3,6-dioxoperfluorooctanesulfonyloxy]-androst-3,5-diene- 17β-formamide, etc.

5-iodo-3-oxoctafluoropentanesulfonyl fluoride is a synthetic intermediate of fluorosurfactant polyfluoroalkylsulfonate, which can be easily obtained (Perfluorosulfonic Acid Group, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences , Acta Chemica Sinica, 1979,37,317; Scientia Sinica, 1978,21,773), it and its analogues can react with phenol, polyfluorinated alkyl alcohols and amine compounds thereof (Chen Qingyun, Acta Chemica Sinica , 1982, 40, 33; Huang Weiyuan et al., Acta Chim. Sinica, 1983, 1, 58; Chen Lifo, Acta Chemical Sinica, 1983, 9, 860). We have found that 5-iodo-3-oxooctafluorosulfopentanoyl fluoride and its related sulfonyl fluorides can be conveniently converted from carbonyl compounds to the corresponding enol polyfluoroalkyl or alkyl or alkoxy sulfonates. The enolsulfonylating reagent used in the present invention may have the following molecular formula: YCF ₂ CF ₂ SO ₃ F, wherein Y=X(CF ₂ CF ₂ O)n or CF ₃ (CF ₂ )m, X=F, Cl , Br, I or H, n=0, 1 or 2, m=0-5.

The method for preparing steroid enol polyfluoroalkyl sulfonate of the present invention can conveniently prepare enol polyfluoroalkyl sulfonate and its derivatives from steroid 3-keto compound by reacting with the above-mentioned sulfonyl fluoride.

的甾体-3-酮化合物为起始原料，其中

或

R₁＝H或CH₃，R₂＝H，CH₃或C₂H₅，R₃＝CONR’R”、

C_1-10的烷基、CO₂CH₃或OH等，R’、R”＝H、CH₃、C₂H₅、(CH₃)₂CH、(CH₃)₃C、-(CH₂)₂-、-(CH₂)₃-、-(CH₂)₄-、-(CH₂)₅-、 或

，R₄＝H、C₂H₅、CH₃C≡C-、HC≡C-、CF₃、-CN等，R₅或R₆＝H、F、Cl、OH、CH₃、CF₂Cl、CF₃、CH₂＝或O，，采用磺酰化试剂YCF₂CF₂SO₃F，其中Y＝X(CF₂CF₂O)n、CF₃(CF₂)m，X＝F、Cl、Br、I、H，n＝0、1或2，m＝0-5。在氮原子上带有弧对电子的含氮化合物存在下与上述烯醇磺化试剂反应制得甾体烯醇多氟磺酰氟化合物及其衍生物。甾体-3-酮化合物、 氮原子上带弧对电子的含氮化合物与烯醇磺酰化试剂的克分子比为1∶1-20∶1-20。更多的氮原子上带有弧对电子的含氮化合物、磺酰化试剂对反应是有利的。从经济上考虑，三者克分子比例以1∶2-8∶2-8为佳。The method of the present invention can be from molecular formula as

The steroid-3-one compound is the starting material, wherein

or

R ₁ =H or CH ₃ , R ₂ =H, CH ₃ or C ₂ H ₅ , R ₃ =CONR'R",

C _1-10 alkyl, CO ₂ CH ₃ or OH, etc., R', R"=H, CH ₃ , C ₂ H ₅ , (CH ₃ ) ₂ CH, (CH ₃ ) ₃ C, -(CH ₂ ) ₂ -, -(CH ₂ ) ₃ -, -(CH ₂ ) ₄ -, -(CH ₂ ) ₅ -, or

, R ₄ =H, C ₂ H ₅ , CH ₃ C≡C-, HC≡C-, CF ₃ , -CN, etc., R ₅ or R ₆ =H, F, Cl, OH, CH ₃ , CF ₂ Cl , CF ₃ , CH ₂ = or O, , using the sulfonylation reagent YCF ₂ CF ₂ SO ₃ F, where Y=X(CF ₂ CF ₂ O)n, CF ₃ (CF ₂ )m, X=F, Cl, Br, I, H, n=0 , 1 or 2, m=0-5. In the presence of a nitrogen-containing compound with arc pair electrons on the nitrogen atom, react with the above-mentioned enol sulfonating reagent to prepare steroid enol polyfluorosulfonyl fluoride compound and its derivatives. The molar ratio of the steroid-3-one compound, the nitrogen-containing compound with arc pair electrons on the nitrogen atom and the enol sulfonylation reagent is 1:1-20:1-20. More nitrogen-containing compounds and sulfonylation reagents with arc pair electrons on nitrogen atoms are beneficial to the reaction. Considering the economy, the molar ratio of the three is preferably 1:2-8:2-8.

The nitrogen-containing compound with arc pair electrons on the nitrogen atom adopted in the method of the present invention can be diethylamine, triethylamine, diisopropylethylamine, collidine, lutidine, 1,5 - Diazabicyclo[4,3,0]nonene-5(DBN), 1,8-diazabicyclo[5,4,0]undecene-7(DBU), 1-butylimidazole, etc. .

The method of the present invention preferably carries out in solvent, and described solvent is preferably polar solvent or aromatic hydrocarbon, as benzene, methylene dichloride, chloroform, acetonitrile, toluene, xylene, dimethylformamide, dioxygen Hexacyclic and ethylene glycol dimethyl ether, etc.

In the method of the present invention, the reaction temperature is usually from room temperature to 160° C., and the reaction can also proceed if the reaction temperature is further increased. The reaction time is 0.5-20 hours, usually 2-8 hours.

The product of the present invention is steroid enol polyfluorosulfonate and its derivatives, its reactivity is similar to that of enol trifluoromethylsulfonate, and it can react with various nucleophiles to synthesize desired target molecules. The steroidal enol polyfluoroalkylsulfonate compound and its derivatives of the present invention can be easily converted into 3-position carboxylate groups, carboxyl groups, cyano groups, and hydrogen groups by using common methods on the 3-position substituents. Steroidal compounds such as or amide groups, especially as important intermediates of steroidal drugs. Such as N-tert-butyl-3-[(5-hydro-3-oxoctafluoropentane)sulfonyloxy]-androst-3,5-diene-17βcarboxamide, catalyzed by pd(0) Next, it reacts with carbon monoxide in methanol solution to obtain the corresponding 3-carboxylate steroid compound, which is then hydrolyzed into a steroidal 5α-reductase inhibitor.

The method of the present invention not only has a high yield, usually 40-90%, but also has the advantages of convenient and easy access to polyfluorosulfonyl fluoride reagents, low price, The reagent is stable in nature, the reaction operation is convenient, and it has the advantages of good chemical selectivity and the like.

The contents of the present invention will be further understood through the following examples, but the contents of the present invention are not limited.

Example 1, N-tert-butyl-3-[(5-hydrogen-3-oxoctafluoropentane)sulfonyloxy]-androst-3,5-diene-17βcarboxamide (4) synthesis

Dissolve 742mg of 17β-tert-butylformyl-androst-4-en-3-one in 5ml of toluene, and slowly add DBU and 5-hydrogen-3-oxo-octane under heating and stirring (temperature 80-90°C) Fluoropentanesulfonyl fluoride. After 6 hours of reaction, the reaction was cooled to room temperature, filtered through a short silica gel column, and the filtrate and eluate were collected. The solvent was removed under reduced pressure to obtain the product. Yield 77%.

Compound analysis results: mp78.5-80.7°C ¹ HNMR (DCCl ₃ , 300MH ₂ ): 0.73 (3H, S, 18-H ₂ ), 0.97 (3H, S, 19-H ₃ ),

1.36 (9H, S, N ⁺ ), 5.09 (1H, brs, NH),

5.57(1H, m, 6-H),

5.86 (1H, tt, J = 3, 52.4H ₂ , HCF ₂ ), 6.0 (1H, S, 4-H) ppm ¹⁹ FNMR (DCCl ₃ ): 3.5 (S, 2F, -OCF ₂ -), 10.4 ( S, 2F, -CF ₂ O-),

_35.9 (S, 2F, _-CF2SO2- ),

60.0 (d, 2F, J = 53.0 H ₂ , HCF ₂ -) ppm MS m/e: 651 (M ⁺ ), 370, 314, 57,

Example 2, 3-[(5-Hydro-3-oxoctafluoropentane)sulfonyloxy]-5α-androst-3-en-17-one (5)

Dissolve 1mmol of androst-3,17-dione in 6ml of benzene, add 5mmol of triethylamine and 5-hydrogen-3-oxo-octafluoropentanesulfonyl fluoride dropwise under constant stirring at 60-80°C, and react After 3 hours, it was cooled to room temperature, filtered through a silica gel column, and the filtrate was desolventized to obtain the product with a yield of 91%.

Compound analysis results: mp50.0-51.0°C IR υ(KCl): 1760, 1704, 1200cm ^{-1 1} HNMR (DCCl ₃ , 300MH ₂ ): 0.83, 0.88, 5.67, 5.87ppm ¹⁹ FNMR (TFA is 0, high field Positive): 60.0, 36.0, 3.5, 10.3ppmC ₂₃ H ₂₈ O ₅ SF ₈ Calculated value C48.59 H4.93 Measured value C48.52 H4.96

Example 3, 3-[(5-Hydro-3-oxoctafluoropentane)sulfonyloxy]-5α-pregna-3-ene-16β,20-diol acetonide (6)

Dissolve 2mmol of 3-oxopregna-16,20-diol acetone in 10ml of dichloroethane, add dropwise 10mmol of lutidine and 5-hydrogen-3-oxo-octafluoro at reflux temperature with stirring Sulfonyl fluoride was reacted for 5 hours, cooled, filtered through a silica gel column, and the filtrate was desolventized to obtain the product with a yield of 76%.

Compound analysis results: mp92.4-93.4°C IRυ(KCl): 1680, 1100-1220cm ^{-1 1} HNMR(DCCl ₃ , 300MH ₂ ): 0.82, 0.89, 1.19, 1.33, 3.85, 4.15, 5.65,

5.86ppm ¹⁹ FNMR (CDCl ₃ ): 3.5, 10.1, 36, 59.5ppm MS m/e: 639 (M ⁺ -CH ₃ ), 579 (M ⁺ -CH ₃ -HOAC), 315, 297, 246C ₂₈ H ₃₈ O ₆ SF ₈ Calculated value C51.38 H5.81 F23.24 S4.89 Measured value C51.45 H5.69 F23.61 S5.17

Example 4, Preparation of 17α-methyl-3-[(5-hydrogen-3-oxoctafluoropentane)sulfonyloxy]-androst-3,5-diene-17β-alcohol (7)

The 17α-methyl-17β-hydroxyandrost-4-en-3-one raw material was synthesized according to the method in Example 1 to obtain an oily product. Yield 44%.

Compound analysis results: IRυ(KCl): 3500(OH), 1680(C=C)cm ^{-1 1} HNMR(CDCl ₃ , 300MH ₂ ): 0.9(3H), 0.99(3H), 1.23(3H), 5.57( 1H),

5.87(1H), 5.67(1H)ppmMS m/e _: 564(M ⁺ -H2O), 549(M ⁺ _-H2O - _CH3 ),

283(M ⁺ -H ₂ O-HCF ₂ CF ₂ OCF ₂ CF ₂ SO ₃ )

Example 5, 3-[(5-hydrogen-3-oxoctafluoropentane)sulfonyloxy]-6-oxo-5α-cholest-3-ene-24 carboxylate methyl ester (8) synthesis

Dissolve 1mmol of 3,6-dioxobutanoic acid methyl ester in 10ml of acetonitrile solvent, and react with 10mmol of diethylamine and 5-hydrogen-3-oxo-octafluorosulfonyl bromide under stirring at 60°C for 10 hours , treated the same as above to obtain the product with a yield of 32%.

Compound analysis results: mp89.6-91.3°C IR: 1730 (C=O), 1700 (C=O) cm ^{-1 1} HNMR (CDCl ₃ , 300MH ₂ ): 0.68 (3H), 0.78 (3H), 0.93 ( 3H), 3.67(3H)

5.67(1H), 5.87(1H)ppm ¹⁹ FNMR(CDCl ₃ ): 3.5(S, 2F), 10.3(S, 2F), 36(S, 2F), 60.0(d, 2F)ppm MS m/e: 667 (M ⁺ -15), 633, 609, 525, 401C ₂₉ H ₃₈ O ₇ SF ₈ Calculated C51.0 H5.57 Found C51.07 H5.59

Example 6, Preparation of 3[(5-hydrogen-3-oxoctafluoropentane)sulfonyloxy]-pregna-3,5-dienone-20(9)

The raw material of pregna-4-ene-3,20-dione was prepared according to the method in Example 2, and the yield was 77%.

Compound analysis results: mp72.7-73.9°C IRυ(KCl): 1760(C=O)cm ^{-1 1} HNMR(CDCl ₃ , 300MH ₂ ): 0.67(S, 3H), 0.97(S, 3H), 2.13( S, 3H),

5.58(m, 1H), 6.00(d, 1H), 5.86(tt, 1H) MS m/e: 594(M ⁺ ), 313, 295

Example 7, Preparation of N-tert-butyl-3-[(perfluorooctane)sulfonyloxy]-androst-3,5-diene-17β-carboxamide (10)

Dissolve 1mmol of 17β-tert-butylformyl-androst-4-en-3-one in 6ml of toluene, add 8mmol of DBU and perfluorooctanesulfonyl fluoride dropwise under stirring at 80°C, react for 8 hours, and treat it according to the previous method to obtain Compound in 41% yield.

Compound analysis results: mp129.2-131.4°C ¹ HNMR (CDCl ₃ , 300MH ₂ ): 0.72 (3H, S), 0.97 (3H, S), 1.35 (9H, S),

5.07(1H,S), 5.58(1H,m), 6.01(1H,d)ppmMS m/e: 853(M ⁺ ), 370, 57C ₃₂ H ₃₆ O ₄ SFN Calculated C45.02 H4.22 Found C49.05 H4.15

Example 8, the preparation of N-tert-butyl 3-(methoxyl)-androst-3,5-diene-17β-carboxamide (11)

Dissolve the steroidal polyfluorosulfonate compound (2) in dry methanol and dimethylformamide, add an equivalent amount of triethylamine and catalyst-bis(triphenylphosphine)palladium diacetate, in a carbon dioxide atmosphere Under 60-80°C, the reaction was stirred for 4 hours. The insoluble impurities were removed by filtration, the filtrate was concentrated, and the crude product was processed by column chromatography to obtain the product with a yield of 92%.

Compound analysis results: mp145.0-145.7°C IRυmax: 3350(NH), 1720(C=O), 1260(CO), 1660(C=O), 720cm ^{-1 1} HNMR: 0.72(3H, S), 0.91 (3H,S), 1.36(9H,S), 3.75(3H,S),

5.13(1H,S), 5.80(1H,m), 7.04(1H)ppmMS m/e: 413(M), 414(M ⁺¹ ), 398(413-CH ₃ ), 366(MC ₃ H ₇ ) , 381, 310,

248,57

Example 9, Preparation of 3-[(5-fluoro-3-oxoctafluoropentane)sulfonyloxy]-androst-3,5-dien-17-one (12)

The raw material of androst-4-ene-3,17-dione was synthesized according to the method in Example 1 to obtain the product. Yield 49%.

Compound analysis results: mp71.7-73.5°C IRυ (thin film): 1740 (C=O), 1640 (C=O) cm ^{-1 1} HNMR (DCCl ₃ , 300MH ₂ ): 0.92 (3H, S), 0.995 ( 3H,S), 5.61(1H,m),

6.02 (1H, d), 5.88 (tt) ppm MS m/e: 566 (M ⁺ ), 285, 267, 243, 225, 213, 57

Example 10, Preparation of 3-[(5-hydrogen-3-oxoctafluoropentane)sulfonyloxy]-cholest-3-ene (13)

Using cholestan-3-one as raw material and the method of Example 1, an oily product was obtained with a yield of 80%.

Compound analysis results: IRυ (thin film): 1680 (C=C), 1120-1190 (-SO ₃ -) cm ^{-1 1} HNMR (DCCl ₃ , 300MH ₂ ): 0.66 (3H, S), 0.79 (3H, S ), 0.85(3H,d),

0.87 (3H, d), 0.90 (3H, d) ppm ¹⁹ FNMR: 4.3 (2F, S), 11 (2F, S), 36.5 (2F, S), 60 (2F, S) ppm MS m/e: 667 (M ⁺ +1), 511, 497, 443C ₃₁ H ₄₆ O ₄ F ₈ S Calculated C55.86 H6.91 Found C56.30 H7.11

Example 11, Synthesis of 3-[(perfluorobutane)sulfonyloxy]-pregna-3,5-dien-20-one (14)

Dissolve 1mmol pregna-4-ene-3,20-dione in 10ml ethylene glycol dimethyl ether solvent, and react with 2mmol perfluorobutanesulfonyl iodide and DBU at reflux temperature for 5 hours, and the product is passed through the column After chromatographic separation and purification, the yield was 60%.

Compound analysis results: IRυ(KCl): 1710(C=O)cm ^{-1 1} HNMR(COCl ₃ , 300MH ₂ ): 0.68(3H,S), 0.97(3H,S), 2.12(3H,S),

5.56 (1H, m), 6.01 (1H, d) ppmMS m/e: 596 (M ⁺ ), 313, 295, 149, 43, calculated for C ₂₅ H ₂₉ O ₄ SF ₉ C50.34 H4.87 found C50.08 H4.77

Example 12, 17α-alkynyl-18-methyl-19-desmethyl-3-[(5-hydrogen-3-octafluoropentane)sulfonyloxy]-androst-3,5-di Synthesis of En-17β-ol (15)

Dissolve 2mmol of 17α-alkynyl-17β-alcohol-18-methyl-19-desmethyl-androst-4-en-3-one in toluene and mix with 5mmol of 5-hydrogen-3-oxoctafluoropentanesulfonate Acyl fluoride and triethylamine were reacted at reflux temperature for 6 hours to obtain a 45% yield.

Compound analysis results: IRυ(KCl): 3500(OH), 2100(C=C)cm ^{-1 1} HNMR(CDCl ₃ , 300MH ₂ ) 5.54(1H, m), 5.86(1H, tt), 5.68(1H, d) ppmMS m/e: 576(M ⁺ ), 558(M ⁺ -H ₂ O)C ₂₅ H ₂₈ O ₄ SF ₈ Calculated C52.08 H4.86 Found C53.05 H4.81

Example 13, 3-[(5-Hydro-3-oxoctafluoropentane)sulfonyloxy]-16-methyl-5α-pregna-3,16-dien-20-one (16) Synthesis

After reacting 2mmol of 16-methyl-pregna-3,20dione, 20mmol of 5-hydrogen-3-oxoctafluoropentanesulfonyl fluoride and DBU at 60°C for 10 hours, they were separated and purified by column chromatography to obtain 78% Yield product.

Compound analysis results: IRυ(KCl): 1690(C=O), 1640(C=C)cm ^{-1 1} HNMR(CDCl ₃ , 300MH ₂ ): 0.78(3H,S), 0.98(3H,S), 2.13 (3H,S),

1.80 (3H, S), 5.54 (1H, m) _, 5.86 (1H, tt), ppmMS m/e: 592 (M ⁺ ), _{313 , 295} Calcd for C26H32O4SF8 C52.70 H5.41 Measured value C51.50 H5.35

Example 14, N-tert-butyl-3-[(8-hydrogen-3,6-dioxoperfluorooctane)sulfonyloxy]-androsta-3,5-diene-17β-carboxamide Synthesis of (17)

React 1mmol of 17β-tert-butylformyl-androst-4-en-3-one, 15mmol of 8-hydrogen-3,6-dioxosperfluorooctanesulfonyl fluoride and acetonitrile at 30-40°C for 20 hours. After purification, 40% product was obtained.

Compound analysis results: IRυ (KCl): 1690 (CONH ⁺ ) cm ^{-1 1} HNMR (CDCl ₃ , 300MH ₂ ): 0.74 (3H, S), 0.96 (3H, S), 1.35 (9H, S),

5.08(1H, brs), 5.58(1H, m), 5.88(12H, tt),

6.0(1H,S)ppm

Example 15, N-tert-butyl-3-[(5-hydrogen-3-octafluoropentane)sulfonyloxy]-androst-3,5-diene-17β-carboxamide (4) synthesis

Dissolve 17β-tert-butylformyl-androst-4-en-3-one in toluene, add DBU and 5-iodo-3-oxyoctafluoropentanesulfonyl fluoride dropwise at 80-90°C with stirring, and react After 10 hours, the solvent was removed under reduced pressure, and then separated by silica gel column chromatography with a yield of 28%. The analysis of the compound by IR, ¹ HNMR and mp is the same as that in Example 1.

Claims (10)

1. a steroid enol polyfluoroalkyl sulfonate compound is characterized in that its molecular formula is:

in

or , R ₁ =H or CH ₃ , R ₂ =H, CH ₃ or C ₂ H ₅ , R ₃ =CONR'R", C _1-10 alkyl, CO ₂ CH ₃ or OH, R', R"=H, CH ₃ , C ₂ H ₅ , (CH ₃ ) ₂ CH, (CH ₃ ) ₃ C, -(CH ₂ ) ₂ -, -(CH ₂ ) ₃ -, -(CH ₂ ) ₄ -, -(CH ₂ ) ₅ -,

or , R ₄ =H, C ₂ H ₅ , CH ₃ C≡C-, HC≡C-, CF ₃ , R ₅ or R ₆ =H, F, Cl, OH, CH ₃ , CF ₃ , CH ₂ = or O, R ₃ R ₅ =

Y=X(CF ₂ CF ₂ O)n, CF ₃ (CF ₂ )m, X=F, Cl, Br, I, H, n=0, 1 or 2, m=0-5. 2. a steroidal enol polyfluoroalkyl sulfonate compound as claimed in claim 1, characterized in that said compound is N-tert-butyl-3-[(5-hydrogen-3-oxoocta fluoropentane)sulfonyloxy]-androst-3,5-diene-17βcarboxamide. 3. a steroid enol polyfluoroalkyl sulfonate compound as claimed in claim 1, characterized in that said compound is 3-[(5-hydrogen-3-oxoctafluoropentane) sulfonyl Oxy]-pregna-3,5-dien-one-20. 4. a preparation method of a steroid enol polyfluoroalkyl sulfonate compound as claimed in claim 1, comprising in the presence of a nitrogen-containing compound with an arc pair of electrons on a solvent and a nitrogen atom, the steroid-3- The ketone compound reacts with a sulfonylation reagent, and is characterized in that the molecular formula of the steroid-3-ketone compound is:

in or

R ₁ =H or CH ₃ , R ₂ =H, CH ₃ or C ₂ H ₅ , R ₃ =CONR'R",

, C _1-10 alkyl, CO ₂ CH ₃ or OH, R ₄ =H, C ₂ H ₅ , CH ₃ C≡C-, HC≡C-, CF ₃ , R', R"=H, CH ₃ , C ₂ H ₅ , (CH ₃ ) ₂ CH, (CH ₃ ) ₃ C, -(CH ₂ ) ₂ -, -(CH ₂ ) ₃ -, -(CH ₂ ) ₄ -, -(CH ₂ ) ₅ -,

or

R ₅ or R ₆ =H, F, Cl, OH, CH ₃ , CF ₃ , CH ₂ = or O,

, The sulfonylation reagent is YCF ₂ CF ₂ SO ₃ F, wherein Y=X(CF ₂ CF ₂ O)n, CF ₃ (CF ₂ )m, X=F, Cl, Br, I, H, n=0, 1 or 2, m=0-5, the molar ratio of the steroid-3-ketone compound, the sulfonylation reagent and the nitrogen-containing compound with arc pair electrons on the nitrogen atom is 1:1-20 : 1-20. 5. a preparation method as claimed in claim 4, is characterized in that described steroid-3-ketone compound, sulfonylation reagent and the nitrogen-containing compound molar ratio of band arc pair electron are 1: 2-8: 2-8. 6. A preparation method as claimed in claim 4, characterized in that nitrogen-containing compound diethylamine, triethylamine, diisopropylethylamine, collidine with arc pair electrons on the nitrogen atom , lutidine, 1,5-diazabicyclo[4,3,0]-nonene-5 or 1,8-diazabicyclo[5,4,0]undecene-7. 7. A preparation method as claimed in claim 4, 5 or 6, characterized in that the reaction temperature is 160°C at room temperature. 8. A preparation method as claimed in claim 4, 5 or 6, characterized in that the reaction time is 0.5-20 hours. 9. A preparation method as claimed in claim 4, 5 or 6, characterized in that said solvent is a polar solvent or an aromatic hydrocarbon. 10. A use of the steroidal enol polyfluoroalkylsulfonate compound as claimed in claim 1, 2 or 3, characterized in that it is an intermediate for synthesizing steroidal drugs.