Note: Descriptions are shown in the official language in which they were submitted.
i7;i~S~)
K592
--1--
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
KS92
-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
S-X3
,~
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
X5
~,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
-4- K592
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
K592
--5--
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~
-6- K592
The steroids of formula I having a
17~-substituent can be prepared from the
corresponding androstene having the formula
II o
HO ~ ~v~R2
//~
0
R3
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
R3
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
~.
R3
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
;
R3
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,~
-8- K592
VIII O S-Rl .
CH3 ~ R2
o
R3
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
. ~.
R3
~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
KS92
_g_
XI Y2
O=S=O
CH3-~-O
~ R2
R3
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~
K592
--10--
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~
KS92
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~
K592
-12-
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~
-13- K592
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
KS92
-14-
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~
K592
-15-
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~
K592
-16-
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~
K592
-17-
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~
K592
-18-
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~
K592
--19--
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~
K592
-20-
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
K592
-21-
(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.
