CA1257250A - 17.beta.-(SUBSTITUTED THIO)ANDROSTENES - Google Patents

Abstract

ABSTRACT

The invention relates to novel intermediates of the formula or the 1,2-dehydro derivative thereof, wherein R2 is hydrogen, hydroxy, alkoxy, aryloxy, methylene, alkylthio, arylthio, alkanoyl, alkanoyloxy, or halogen;
R3 is hydrogen, methyl, hydroxy or halogen;
which are used in the preparation of new steroid compounds having the formula or the 1,2-dehydro derivative thereof, wherein R1 is alkyl, alkanoyloxyalkyl, arylcarbonyloxyalkyl, alkenyl, alkynyl, cycloalkyl, aryl or arylalkyl;
R2 and R3 are as defined above; and n is 0, 1 or 2. The latter are useful since they possess topical anti-inflammatory activity.

Description

i7;i~S~) 17~-(SUBSTITUTED THIO)ANDROSTENES
The present invention relates to new steroids having the formula I Rl : ~=)n HO ~ R2 //~
O
R3 , which have topical antiinflammatory activity. In formula I, and throuyhout the specification, the symbols are as defined below.
Rl is alkyl, alkanoyloxyalkyl, arylcarbonyl-oxyàlkyl, alkenyl, alkynyl, cycloalkyl, aryl or axylalkyl;
R2 is hydrogen, hydroxy, alkoxy, aryloxy, - methylene (=CH2), alkylthio, arylthio, alkanoyl, alkanoyloxy, or halogen;
R3 is hydrogen, methyl, hydroxy, or halogen; and n is 0, 1 or 2.
The dotted line in the 1,2-positions of the structural formulas shown i~ this specification indicate the optional presence of ethylenic ~saturation.
The t~rm "aryl", as used throughout ~he specification either individually or as part of a larger group, refers to phenyl or phenyl substituted with one, two or three alkyl, alkoxy or halogen group6.
The term "halogen", as used throughout the specification either individually or as part of a larger group, refers to fluorine, chlorine, bromine and iodine.

~2S7250

-2-The terms "alkyl" and "alXoxy", as used throughout the specification either individually or as part of a larger group, refer to groups having 1 to 12 carbon atoms.
The terms "alkanoyl", "alkenyl" and "alkynyl", as used throughout the specification either individually or as part of a larger group, refer to groups having 2 to 13 carbon atoms.
The disclosures of United States Patents 4,091,036, issued May 23, 1978, 4,094,840, issued June 13, 1978, 4,133,811, issued January 9, 1979, 4,146,538, issued March 27, 1979, 4,265,815, issued May 5, 1981 and 4,397,782, issued August 9, 1983, encompass within their combined disclosures androstene intermediates having the partial structural formula S-~l ~: ~ X2 ,~ , wherein X1 is alkyl, aryl, arylalkyl, or acyloxyalkyl and X2 is chloro, bromo, alkoxy, aryloxy, alkylthio or arylthio.
United States Patent 4,361,559, issued November 30, 1982 discloses androstene intermediates having the partial structural formula l3 S
~ ~,X4 wherein X3 is alkyl, cycloalkyl or aryl, and X4 is hydrogen, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, alkanoyloxy or halogen.

~5725~

_3_ K592 United States Patent 4,420,428, issued December 13, 1983,discloses androstene intermediates having the partial structural formula ,~

wherein X3 is alkyl, cycloalkyl or aryl.
United States Patent 4,427,592, issued January 24, 1984,discloses androstene intermediates having the partial structural formula ~,X6 wherein X5 is alkyl, aryl, arylalkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, mono-, di-, or trifluoroalkyl, cyanoalkyl, alkanoylalkyl or -~C~2)m-~-NX7X8 wherein m is 1, 2, 3 or 4 and X7 and X8 are hydrogen or alkyl, and X6 is hydrogen, hydroxy, alkoxy, aryloxy, oxo, methylene, alkylthio, arylthio, alkanoyl, alkanoyloxy or fluorine.
United States Patent 4,183,924, issued January 15, 1~80, discloses 11-ketoandrostene products (anti-acne agents) having the partial structural formula ~257;~5 ;3 S()m ~ "~Cl ~

wherein m is 1 or 2 and Xg is benzyl, phenethyl, methylbenzyl, dimethylbenzyl, or chlo.robenzyl and an alkyl group, and as intermediates, 11-ketoandro-stenes having the partial structural formula S
~, Green et al., in J. Med. Chem., 26(1):78 (1983), disclose an ll~-hydroxy-androstene having the partial structural formula S-C~
;~

~2572~0 The steroids of formula I, and the 1,2 dehydro and 6,7-dehydro derivatives thereof, are topical antiinflammatory agents that can be used to treat skin conditions such~as dermatitis, psoriasis, sunburn, eczema, neurodermatltis, or anogenital pruritus, and inhalation therapy for topical treatment of allergy and asthma.
Fox the treatment of skin conditions, the topical antiinflammatory steroids of this invention may be administered in a conventional pharmaceutical carrier in the form of a cream, ointment, lotion or the like. The steroids will preferably be used in the range of O.01 to 5.0% by weight of the vehicle, preferably O.OS to 2.0% by weight of the vehicle.
For the ~opical treatment of allergy and asthma the topical antiinflammatory steroids of this invention may be administered in the conventional manner, e.g., as solid medicament which has been atomized. United States Patent

3,948,264 and 4,147,166, are exemplary of the literature which describes devices that can be used to administer solid medicaments for inhalation therapy.

~2572~5~

The steroids of formula I having a 17~-substituent can be prepared from the corresponding androstene having the formula II o HO ~ ~v~R2 //~

The andxostenes of formula II are well known in the art; see, for exampl~, Unites States Patent

4,361,559, issued November 30, 1982.
Reaction of an androstene of formula II with hydrogen sulfide in the presence of an organic amine such as morpholine yields the corresponding steroid having the formula III S~
}IO ~L~I~R2 ` 25 O

The androstenes of formula III are novel in~ermediates, and as such, constitute an integral part of this invention.
Reaction of an intermediate of formula III
with a compound having ~he formula IV Rl-Yl , ~257~;25~

_7_ K592 wherein Y1 is a leaving group such as halogen, yields the corresponding product of formula I
having a 17~ substituent. The reaction is preferably run in the presence of an inorganic base.
The steroids of-formula I having a 17a-substituent can be prepared from the corresponding steroid having the formula V O OH
CH3_~_o~ R2 ~.

Sequential reaction of a steroid of formula V with a phosphine such as ~riphenylphosphine, an azodicarboxylate such as diethylazodicarboxylate and a thiol having the formula VI Rl-SH
yields the corresponding ~teroid having the formula VII S-Rl c~3~ 2 o ;

Deprotection using conventional technigues yields the desired product of formula I having a 17a-substituent.
Alternatively, the steroids of formula I
having a 17~-su~stituent can be prepared from an androstene having the formula S72,~

VIII O S-Rl .
CH3 ~ R2 o Steroids of formula VIII are known in the art;
see, for example, United States Patents 4,361,559 and 4,427,5~2. Treatment of a compound of formula VIII with a silane such as triethylsilane and an acid such as trifluoroacetic acid yields the corresponding compound having the ormula IX ~ ~-Rl C~3 -O ~ ~ R2 . ~.

~eprotection of the }l-hydroxy group using conventional techniques yields the desired product of formula I having a 17~-substituent. It is also possible to utilize the ll~-hydroxy analog of a steroid of formula VIII in this reaction.
Alternatively, the steroids of ormula I
having a 17a-substituent can be prepared by first reacting an androstene of formula V with a compound having the formula X O
Y2-~-Cl, wherein Y2 is alkyl or aryl, to obtain the corresponding steroid having the formula ~L25725E3 _g_ O=S=O
CH3-~-O
~ R2 Reaction of a steroid of formula XI with a metal (e.~., sodium) mercaptide prepared from a thiol of formula VI, yields the corresponding product of formula I having a 17a-substituent.
Alternatively, steroids of formula I
wherein Rl is alXanoyloxyalkyl or arylcarbonyloxy-alkyl can be prepared from the corresponding 17-alkylthio steroid of formula I. Oxidation of the 17-alkylthio steroid wi~h approximately one eguivalent of an oxidizing agent such as m-chloro-pero~ybenzoic acid yield3 the corresponding 17-alkylsulfinyl steroid. Acylation o~ the 17-alkylsulfinyl steroid using, for example, a~
acid anhydride, yields the desired 17-acyloxy-alkylthio steroid.
The steroids of formula I wherein n is 1 or2 can be obtained from the corresponding sulfide of formula I (i.e., n is 0) by oxidizing the sulfide with the appropriate amount of a peracid such as m-chloroperbenzoic acid or periodic acid.
The use of about one eguivalent of the oxidizing agent yields the sulfoxide (n is 1) and the use of excess oxidizing agent yields the sulfone (n is 2 ) .
Preparation of the starting 17~-hydroxy steroid of formula V is described in ~5725~

United States Patent 4,488,985, issued December 18, 1984. U~ing art-recognized acylation techniques, a steroid of formula II can first be converted to the S corresponding ll~-acetyloxy derivative. Reducing an 11~-acetyloxy derivative of a steroid of formula II using, for example, sodium borohydride, yields the desired 17~-hydroxy steroid of formula V.
The following examples are specific embodiments of this invention.

~25725~

Example 1 (11~,17~)-9-Fluoro-ll-hydroxy-17-(2-propenylthio)-androsta-1,4-dien-3-one A ) ( 11~ ,17~)-9-Fluoro-ll-hydroxy-17-mercapto-androsta-1,4-dien-3-one Into a chilled solution (ice bath) of 3g of (11~)-9-fluoro-11-hydroxyandrosta-1,4-dien-3,17-dione in 12 ml of dimethylformamide and 15 ml of morpholine, there was introduced a stream of hydrogen sulfide. Once the exothermic reaction had ceased, the ice bath was removed, the hydrogen sulfide stream was reduced to about one bubble every two seconds and continued overnight. The next day th~ reaction mixture was poured into ice water, the resulting solid filtered off, washed with water, and dried to yield 3g of crude product. EPLC analysis indicated the presence of 11% starting material and 88% product. The above 3g were combined with 2g of crud~ product that had been obtained from two earlier batches and chromatographed on silica gel. Elution with chloro~orm-20% ethyl acetate yielded 2g of the title compound as a white solid. Crystallization rom acetonitrile furnished the analytically pure sample ~l.Sg), melting point 295-297C. Further elution gave lg of the starting st~roid.
Recrystallization of the thiol from acetic acid yielded needles.
B) (11~,17~)-9-Fluoro-11-hydroxy-17-(2-propenyl-thlo)androsta-1,4-dien-3-one To a stirred solution of 1.7g of (11~, 17~)-9-Fluoro~ hydroxy-17-mercaptoandrosta-1,4-dien-3-one dissolved in 100 ml of methanol, ~ :~s725e~

there was added lg of sodium hydroxide followed by 2.5 ml of allyl bromide (nitrogen atmosphere).
The alkylation was complete after 1 hour of stirring at room temperature. The solution was S partly evaporated, water was added and the resulting solid filtered and washed with water.
Crystallization of the solid from ethyl acetate-petroleum ether furnished 1.08g of the analytical sample, melting point 173-175C.
Anal. Calc'd. for C22H29F02S: C, 70.17; H, 7.76;
S, 8.52; F, 5.05.
Found: C, 70.08; ~, 7.74; S, 8.47; F, 5.07.

Exam le 2 (11~,17a)-9-Fluoro-ll-hydroxy-17-(phenylthio)-androsta-1,4-dien-3-one A) (11~,17a)-11-(Acetyloxy)-9-f}uoro-17-(phenyl-thio)androsta-1,4-dien-3-one To a magnetically stirrod solution of triphenylpho~phine (l.OSg) in dry tetrahydrofuran (15.0 ml) maintained at 0C was added diethylazo-dicarboxylate (.488 ml) and the mixture was stirred at 0C for thirty minutes. To this stirrsd solution at 0C was added dropwise, a mixture of (11~,17~)-11-(acetyloxy)-9-fluoro-17-hydroxyandrosta-1,4-dien-3-one ~362 mg, 1 mmole) and thiophenol (.276 ml) dissolved in 5.0 ml of tetrahydrofuran. The solution was added over a ten minute period and then the reaction mixture stirred for 1 hour at 0C, followed by 5.5 hours at room temperature. TLC (silica gel, 7:3 ch}oroform:ethyl acetate) indicated very little reaction taking place so the mixture was refluxed under nitrogen f~r 48.0 hours, followed by ~57~

quenching in water and extraction with chloroform (4x50 ml). The combined chloroform extracts were dried over anhydrous magnesium sulfate and evaporated to a yellow oil. This was dissolved in a mixture of chloroform and hexane (8:2) and preadsorbed on silica~gel. Flash chromatography was performed and the desired produ t was successfully eluted with (9:1) chloroform:hexane.
The product-containing fractions were pooled, evaporated to an oil, taken up in hot ethyl acetate and evaporated to a yellow crystalline material which was vacuum dried.
B) (11~,17~)-9-Fluoro-ll-hydroxy-17-(phenyl~hio)-androsta-1,4-dien-3-one ~
To a stirred mixture of (11~,17~)-11-(acetyloxy)-9-fluoro-17-(phenylthio)androsta-1,4-dien-3-one (300 mg) in tetrahydrofuran (12.0 ml) and methanol (6.0 ml) (in a nitrogen atmosphere) was added 1.5 ml of a 12% sodium hydroxide solution. TLC (7:3, chloroform:ethyl acetate) taken a~ter 1 hour showed the reaction to be complete. ~fter a total of 1.5 hours at room temperature, the reaction was quenched with water and ex~racted with chloroform (3xS0 ml). The chloroform extracts were pooled, dried over anhydrous magnesium sulfate and evaporated to a yellow oil. This was dissolved in 10.0 ml of boiling dichloromethane, cooled, and a ew drops of petroleum ether were added. The solution was left in the freezer overnight, yielding fine, light green needle-like crystals (57 mg) of an analytical spe~imen with consisten~ spectral data and melting point 248-252C (wi~h decomposition).
Anal. Calc'd. for C25~2902SF: C, 72-78; ~, 7.37;
s, 7.77; F, 4.61.

~2~i7~50 Found: C, 72.88; H, 7.15; S, 7.67; F, 4.60.
Exam~le 3 (11~,17~-9-Fluoro-ll-hydroxy-17-(methylthio)-androsta-1,4-dien-3-one S
A~ ,17~ (Acetyloxy)-9-fluoro-17-(methane-sulfonyloxY)androsta-1,4-dien-3-one A solution of (11~,17~)-11-(acetyloxy)-9-fluoro-17-hydroxyandrosta-1,4-dien-3-one ~1.0g;
2.9 mmole) in dry pyridine (12 ml) was stirred in an ice bath and methane~ulfonyl chloride (0.435 ml;
644 mg; 5.6 mmole) was addad. The solution was left standing at 0-5C for 20 hours and then poured into ico-cold 20% hydrochloric acid. The mixture lS was extracted with chloroform, the chloroform solution was washed with water, a dilute sodium bicarbonate solution and water, dried (anhydrous magnesium sulfate) and evaporated to afford a solid (1.20g). One crystallization from ethyl acetate-hexane gave a specimen tl.Og), melting point 210-211C
(dec.), with consistent spectral data.

B) (11~,17~)-9-Fluoro-11-hydroxy-17-(methylthio)-androsta-1,4-dien-3-ona To a s~spension of 50% sodium hydride/
paraffin (100 mg) in dry dimethylformamide ~10 ml), cooled and stirred in an ice bath, a stream of methanethiol was passed until a homogeneous solution resulted. (11~,17~)-11-(Acetyloxy)-9-fluoro-17-(methanesulfonyloxy)androsta-1,~-dien-3-one (280 mg, 0.64 mmole) was added and the solution was heated in an atmosphere of nitrogen in a bath at 100-120C for 5.0 hours. The mixture was then cooled to room temperature and water (1.0 ml) was added. After stirring for 20 minutes, ~25725~

the mixture was poured into water and was extracted with chloroform. ~he chloroform solution was washed with water, dried (anhydrous magnesium sulfate) and evaporated ln vacuo. The residue was dissolved in chloroform-hexane (7:3; 15 ml) And absorbed on a column of silica ~el ~5.0g). The column was first eluted with chloroform to remove the paraffin.
Further elution of the column with chloroform:
hexane (9:1) gave the title compound (179 mg) which had a small amount of a slightly less polar impurity (tlc). One crystallization of this from ethyl acetate followed by drying (110C, 0.3 mm of Hg, 20 hours) gave the analytical specimen ~157 mg), melting point 235-236C with consistent spectral data.
Anal. Calc'd- for C20H27F25 C~ 68-53; H~ 7-77;
F, 5.42; S, 9.15.
Found: C, 68.73; H, 7.87; F, 5.45; S, 8.90.

- 20 ExamPle 4 (11~,17a~-17-(Ethylthio)-9-fluoro-ll-hydroxy-androsta-1,4-dien-3-one A suspension of 50% sodium hydride-paraffin (300 mg, 6.5 mmole) in dry dimethylformamide (20 ml) was cooled and stirred in an ice-water bath and ethanethiol (O.67 ml, 9.0 mmole) was added. The ice bath was then removed and the mixture was stirred at room temperature until a clear solution resulted. Then, (11~,17~
(acetyloxy)-9-fluoro-17-(methanesulfonyloxy)-androsta-1,4-dien-3-one (540 mg, 1.21 mmole) was added. The resulting solution was heated in a bath at 110-120C under an atmosphere of nitrogen for 5.0 hours. After cooling to room temperature, water (1.0 ml) was added and the mixture was 3L;25725~

stirred for 20 minutes. The mixture was then added into water ~150 ml) and was extracted with chloroform (3x50 ml). The extracts were combined, washed with water, dried (anhydrous maqnesium sulfate) and evaporated to afford the title compound as a solid contaminated with paraffin.
It was dissolved in chloroform-hexane (7:3; 20 ml) and absorbed on a column of silica gel (15g). The column was then successively elut~d with chloroform and chloroform:ethyl acetate (85:15) to af~ord the homogeneous (tlc) title compound as a solid (380 mg) from the later fractions. One crystallization from ethyl acetate-hexane followed by drying (110C, 0.3mm of ~g, 6 hour~) gave the analytical specimen ~362 mg), melting point 196-197C with consistent spectral data.
Anal. Calc'd- for ~21~29F25 C~ 69-19; ~ 8-02;
F, 5.22; S, 8.80.
Found: C, 69.40; H, 8.03; F, 5.33; S, 8.52.
Example 5 (11~,17~)-9-Fluoro~ hydroxy-17-(methylthio)-androsta-1,4-dien-3-one Method I
A) (11~,17~)-11-(Acetyloxy)-9-fluoro-17-(methyl-thio~androsta-1,4-dlrn-3-one A solution o~ ,17~)-11-(acetyloxy)-9-fluoro-17-(methylthio)androsta-1,4,16-trien 3-one (3.0g, 7.7 mmole) in dry dichloromethane (60 ml) was stirred with triethylsilane (1.lg) and dry trifluoroacetic acid (0.9g) for 2.0 hours. The same amounts of reagents were again added. After 20 hours, the solution was washed with water, a dilute sodium bicarbonate solution and water, ~:~57ZS~

dried (anhydrous magnesium sulfate) and evaporated to afford the crude product. One crystallization of this from ethyl acetate-hexane gave the title compound (2.4g) melting point 169-170C, with consistent spectral data.
-B) (11~,17~)-9-Fluoro~ hydroxy-17-(methyl-thio)androsta-1,4-dien-3-one A solution of (11~,17~)-11-(acetyloxy)-9-fluoro-17-(methylthio)androsta-1,4-dien-3-one (2.0g; 5.09 mmole) in a mixture of methanol (15 ml) and tetrahydrofuran (15 ml) was flushed well with nitrogen, 3M aqueous sodi~m hydroxide (2.0 ml) was added and the mixture was stirred at room temperature for 45 minutes. A moderate excess of acetic acid was added, the mixture was concentrated in vacuo and was diluted with water.
The steroid that separated was isolated by filtration, washed with water, dried, crystallized from ethyl acetate-hexane and dried (100C, 0.3mm of ~g, 10 hours) to afford ~he homogeneous (tlc) analytical specimen of the title compound ~1.4g), melting point 269-270C with consistent spectral data.
Anal- Calc'd- for C20~21F2S C, 68-53; H~ 7.77;
F, ~.42; S, 9.15.
Found: C, 68.69; H, 7.84; F, 5.28; S, 9.13.

Method II
A solution of 1.8g (5.17 mmole) of 9-fluoro-~ hydroxy-17-(methylthio)andro~ta-1,4,16-trien-3-one, 648 mg (5.7 mmole) of dry trifluoroacetic acid and 722 mg (6.2 mmole) of triethylsilane in 100 ml of dry dichloromethane was stirred at room temperature under a nitrogen atmosphere. The tlc 12~7Z5~

of an aliquot after 2.0 hours showed about 60%
unreacted starting material. More trifluoroacetic acid (972 mg) and triethylsilane (1.083g) were added. The reaction was continued for another 2 hours while the starting steroid disappeared (tlc). The resulting solution was diluted with dichloromethane, washed with saturated sodium bicarbonate and water, dried (anhydrous sodium sulfate) and evaporated ln vacuo. The residue was redissolved in 1:9 hexane-chloroform and chromatographed on a 30g silica gel column.
Elutions successively with l:9 hexane-chloroform, chloroform and 5:95 ethyl acetate-chloroform gave 800 mg of the tlc-homogeneous title compound.
Crystallization from acetone-hexane ~ave 455 mg of an analytical specimen, melting point 268-269C, with consistent spectral data.
Anal. Calc'd. for C20H27FO25: C, 68.53; H, 7.77;
F, 5.42; S, 9.15.
Found: C, 68.72; ~, 8.07; F, 5.18; S, 9.21.

Example 6 (11~,173)-17-(Ethylthio)-9-~luoro-11-hydroxyandrosta-1,4-dien-3-one To a homogeneous solution of 600 mg (1.66 mmole) of 17-~ethylthio)-9-fluoro~
hydroxyandrosta-1,4,16-trien-3-one in a mixture of dry dichloromethane ~60 ml) and trifluoroacetic acid (207 mg) was added triethylsilane (230 mg) and the mixture was stirred at room temperature under a nitrogen atmosphere for 2.5 hours. Since the tlc of an aliquot showed incomplete reaction, more trifluoroacetic acid (207 mg) and triethylsilane (230 mg) were added. After 1.5 hours the starting ma~erial had disappeared by tlc. The resulting ~257~5~

solution was diluted with dichloromethane, washed with saturated sodium bicarbonate solution and water, dried (anhydrous sodium sulfate) and evaporated in vacuo to give a solid. This was S redissolved in 1:4 hexane chloroform and chromato-graphed on a 30g silica gel column. Elution with 1:4 hexane-chloroform, chloroform and 5:95 ethyl acetate-chloroform gave 520 mg of a tlc homogeneous title compound. Crystallization from acetone-hexane gave 410 mg of an analytical specimen, melting point 223-225C, with consistent spectral data.
Anal- Calc'd- for C21~29F2S C~ 69-19; H~ 8-02;
F, 5.21; S, 8.80 Found: C, 69.17; ~, 7.97; F, 5.16; S, 8.80 Example 7 (11~,17~)-9-Fluoro-11-hydroxy-17-(methylsulfinyl)-androsta-l,4-dien-3-one -To a solution of ( 11~,17~)-9-fluoro-11-hydroxy17-(methylthio~androsta-1,4-dien-3-one (701 mg, 2.0 mmole; see example 5) in chloroform (30 ml) was added a solution of 85% m-chloroper-benzoic acid ~398 mg, 2.0 mmole) in chloroform (10 ml). An instantaneou~ reaction was observed (tlc). The solution was then washed with a 10%
potassium carbonate solution and water, dried (anhydrous magnesium sulfate) and evaporated to afford the title compound as a solid (700 mg).
One crystallization of this from acetone-hexane followed by drying (100C, 0.3 mm of Hg, 10 hours) gave the analytical specimen of the title compound (600 mg) melting point 270-272C dec., as a mixture of sulfoxide stereoisomers, with consistent spectral data.

;7~

Anal. Calc'd. for C2aH27F03S: C, 65.54J H, 7.42;
F, 5.18; S, 8.73.
Found: C, 65.69; H, 7.49; F, 5.00; S, 8.87.

ExamPle 8 (11~,17~ [[(Acetyloxy)methyl]thio]-9-fluoro-ll-hydroxyandrosta-1,4-dien-3-one A mixture of 820 mg (2.24 mmole) of (11~,17~)-9-fluoro~ hydroxy-17-(methylsulfinyl)-androsta-1,4-dien-3-one (see example 7), 45 ml of acetic anhydride and 1.0 g of fused sodium acetate was heated at 100C under nitrogen for 3 hours.
The ~olution was cooled and ~he solvent was evapor~ted in vacuo at room temperature. The residue was dissolved in chloroform, washed with saturated sodium bicarbonate and water, dried (anhydrous sodium sulfate) and evaporated ln vacuo to give a solid (800 mg). This was dissolved in 1:9 hexane:chloroform and chromatographed on a 30 gram-silica gel column. Elutions successively with chloroform, chloroform-ethyl acetate (95:5) and chloroform-ethyl acetate (9:1) gave 430 mg of the tlc homogeneous title compound. A crystallization from acetone-hexane gave 370 mg of an ana}ytical specimen, melting point 178-179C, with consistent spectral data.
Anal- Calc'd- for C22~29F4S C, 64-6B; H~ 7-16;
F, 4.65; S, 7.85.
Found: C, 64.63; ~, 7.20; F, 4.52; S, 7.83.
Exam~le 9 ~ 17~ ) ol7~ ~ Ethylsulfinyl)-9-fluoro-11-hydroxy-androsta-1 4-dien-3-one To a solution of (11~,17~)-17-(ethyl-thio)-9-fluoro~11-hydroxyandrosta-1,4-dien-3-one ~ZS7Z5~0 (700 mg, 1.92 mmole; see example f ) in chloroform ~30 ml) was added a solution of 86%
m-chloroperbenzoic acid ~390 mg, 1.95 mmole) in chloroform (15 ml). An instantaneous reaction was noted ~tlc). The solution was then washed with a 10% potassium carbonate solution and water, dried ~anhydrous magnesium sulfate) and evaporated to afford the title compound (697 mg) as a solid.
One crystallization of this from ethyl acetate followed by drying ~100C, 0.3 mm of Hg, 10 hours) gave the analytical specimen of the title compound (600 mg), meltin~ point 247-250C, with consistent spectral data.
Anal. Calc'd. for C21~29FO35: C, 66.28; ~, 7-68;
F, 4.99; S, 8.41.
Found: C, 66.40; H, 7.59; F, 4.92; S, 8.37.

Claims (3)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A compound of the formula or the 1,2-dehydro derivative thereof, wherein R2 is hydrogen,hydroxy, alkoxy, aryloxy, methylene, alkylthio, arylthio, alkanoyl, alkanoyloxy, or halogen; and R3 is hydrogen, methyl, hydroxy or halogen.

2. A compound in accordance with claim 1, which is (11.beta. ,17.beta.)-9-fluoro-11-hydroxy-17-mercapto-androsta-1,4-dien-

3-one.