‘2,901,494
Patented Aug. 25, 1959
'2
androstenediones (e.g. 9a-?uoro-A4-androstene-11,3, 16a
diol -3,17-dione and 9‘a-ch1oro-A4-androstene-1118,16a-dio1
3,17-dione) and the 9a-halo-16a-hydroxyandrostenetriones
(e.g. 9a-?uoro-A4-androstene-16u-ol-3,11,17-trione and
2,901,494
9,16-DIHALO STEROIDS OF THE ANDROSTANE
'
SERIES
.
.
'
9.o¢-chloro-A4-androstene 16a~ol-3,-1 1,17-trione) .
Josef Fried, Princeton, and Gordon H. Thomas, New
The sulfonic acid esters formed are then reacted with
Brunswick, N.J., assignors to Olin Mathieson Chemical
an alkali metal halide (e. g., potassium ?uoride, potassium
Corporation, New York, N.Y., a corporation of V11‘
hydro?uoride, lithium bromide and sodium iodide) or an
ginia =
alkaline earth metal halide (e.g., calcium chloride) to
No Drawing. Application November 25, ‘1957
Serial No. 698,321
10 yield a 16-haloandrostene derivative, wherein the halide
corresponds to the halogen ion of the inorganic reactant.
The reaction is preferably conducted under substantially
'13 Claims. (Cl. ‘260-—397.3)
anhydrous conditions at an elevated temperature.
To form the 16-halo-17-hydroxy steroids of this in
The reduction
may be accomplished by treating with a borohydride
(e.g. sodium borohydride). If an ll-keto steroid is
This application is a continuation-in-part of our par 15 vention, the 17-keto group is reduced.
ent application, Serial No. 638,674, ?led February 7,
1957, now U.S. Patent No. 2,857,403, granted October
21, 1958.
employed as a reactant in this reduction, the ll-keto group
This invention relates to, and has for its object the
is ‘also reduced to the llp-hydroxy derivative. To form,
provision of, a method of preparing 9,16-dihalo steroids 20 therefor, an 1l-keto-l7B-hydroxy derivative, the 115-175
of the androstane (including the androstene) series and
dihydroxy steroid is esteri?ed, in the usual manner, as
to the physiologically active steroids produced thereby.
by treatment with an acyl halide or acid anhydride of
The compounds of this invention are prepared by sul
any desired acid to protect the 17,8-hydroxyl group and
fonating a 9a-ha1o-11-?-hydroxy (or 11-ket0)-16u-hy
the lle-hydroxy group is then oxidized, as by treatment
droxyandrostenedione (which can be prepared as dis 25 with chromium trioxide in aqueous sulfuric acid in a
closed in the U.S. application of Thomas et aL, Serial
solvent such as acetone, to the desired ll-keto analogue.
The 17B-acyloxy group can then be hydrolyzed to the free
No. 693,039, ?led October 29, 1957, now Patent No.
2,853,502, granted September 23, 1958), reacting the
17?-hydroxy compound in the usual manner, as by treat
l6m-sulfonyloxy derivative formed with an alkali metal
ment with an alkali metal hydroxide, such as potassium
halide or alkaline earth metal halide to yield the cor 30 hydroxide, in an organic solvent such as methanol.
responding 16-halo derivative, and, if desired, either re
Among the suitable agents which can be used are the
ducing the 17-keto group to a 17-hydroxy grouping or
acyl chlorides and acid anhydrides of hydrocarbon
treating with a Grignard reagent to yield the correspond
carboxylic ‘acids having less than ten carbon atoms, as
ing 17a-substituted-17B-hydroxy derivative. Furthermore
exempli?ed by the lower alkanoic acids (e.g. acetic and
propionic acid), the monocyclic aromatic carboxylic acids
acyloxy derivative as the ?nal product.
(e.g. benzoic and toluic acid), the monocyclic aralkanoic
The compounds of this invention may be represented
acids (e.g. phenacetic and B-phenylpropionic acid), the
by the general formula:
lower alkenoic acids, the cycloalkane carboxylic acids, and
the cycloalkene carboxylic acids. The acylation step is
40 preferably conducted in the presence of an organic base,
the 17-hydroxy derivatives can be acylated to yield a 17
35
such as pyridine.
This series of steps can be represented by the follow
ing schematic analysis, using 9a-?ll0I‘O-l1,8,16a-dil1Ydl'0XY
45
androstenedione as the starting material:
(I)
wherein individually R is hydroxy or acyloxy, R’ is hy 50
drogen or together R and R’ is keto, R" is hydrogen, R’"
is ?-hydroxy, or together R" and R'” is keto, X is halo
(which may be in either the alpha or beta position) and
X’ is halo (preferably fluoro) .
To prepare the compounds of this invention a 9a-halo
11 e-hydroxy (or 1l-keto)-16u-hydroxyandrostene is treat 65
ed with an organic sulfonating agent such as a lower
alkane sulfonyl halide (e.g., mesyl chloride) or a mono
cyclic aromatic sulfonyl halide (e.g., tosyl chloride).
This reaction is preferably conducted in the cold in the 60
presence of organic base, such as pyridine. The reaction
results in the formation of the new sulfonic acid esters of
9a-halo-1 1 B-hydroxy (or
stenes of this invention.
1 l-keto) -16a-hydroxyandro
_ vAmong the suitable starting materials for this reaction
may be
mentioned the
9oc-halO-l1B,16oc-dihydI'0Xy
i
110?]: Ton HO‘?'A -~OSO:OHa
I
/Y ontsmoi
F
/:
-——>
O:
2,901,494
4
EXAMPLE 3
o
0o_oH,
o ill-CH3
9a-?uor0 - 1619 - chloro - A4 - androstelne - 11/8 - 0l-3,17
dione (IV)
no?’
--F
of]
:\/
r'"
A solution of 200 mg. of 9a-?uoro-A4-androstene4113,
16a-diol-3,17-dione 16u-mesylate and 400 mg. of calcium
chloride in 10 ml. of absolute alcohol is heated under re
?ux ‘for 3 days. Water is added and the steroids ex
tracted with chloroform, the chloroform solution then
being washed with Water, dried over sodium sulfate and
the solvent removed in vacuo. The residue is dissolved
-F
:
-+
O:
i‘
0:
-—->
V
vIn
IX
on
o=(\l
--r
/:
in 2 ml. of benzene and absorbed on 5 g. of acid-washed
alumina. Elution with chloroform in benzene (1:9, 250
ml; 1:4, 350 ml.) followed by crystallization from ace
15 tone-hexane yields about 37 mg. of the 16B-chloro com
pound M.P. about 263-—266° (dec.); [001D +170° (c., 0.94
in CHCl) ;
i
F
0:
20
x
androstenetrione 16-mesylate, (b) 9oc-?llOI'O-16oc-l‘lY
droxy-androstenetrione 16a-mesylate, and (c) 9a-chloro
115, 16adihydroxyandrostenedione 16a-mesylate for the
active substances which possess androgenic activity. Thus,
the compounds of this invention can be used in "lieu of
known androgenic steroids, such as testosterone and
methyltestosterone, in the treatment of menopausal dis
orders, being formulated for such administration in the
same type of preparations as testosterone, for example,
with concentration and/ or dosage based on the activity of
9oz-?t101'0 - 11B - 160a - 'dihydroxyandrostenedione
16a
mesylate in the procedures of Examples 2 and 3, there are
obtained, respectively: (a) 9a-chloro-l6w?uoroandro
stenetrione, 9a-chloro-16B-?uoroandrostenetrione, and
30
9a,16,8-dichloroandrostenetrione;
(b)
9a,16m-di?uoro
androstenetrione, 9a,16,8—di?uoroandrostenetrione, 9a
?uoro-l6,8-chloroandrostenetrione; and (c) 9oz—ClllO1‘O-16oz
?uoro-l 1 (i-hydroxyandrostenedione, 9a-chloro-16B-?uoro
1 1B-hydroxyandrostenedione, and 9u,16?—dichloro-1 1,3
The following examples illustrate the invention (all tem
peratures being in centigrade):
EXAMPLE 1
9a-?uoro-A4-androstene - 1600,1113 - diol - 3,17 - dione 16oz
F, 5.35. Found: Cl. 9.74; F, 5.09.
Similarly, by substituting (a) 9a-ch1oro-16a-hydroxy
The compounds of this invention are physiologically
the particular compound.
A311; 237 my (e=l7,200); NL‘SQ‘ 2.86, 5.72, 6.00, 6.17”
Analysis.—Calcd. for C19H24O3ClF (354.84): Cl, 9.99;
35
tavdroxyandrostenedione.
mesylate (I)
EXAMPLE 4
A solution of 3 g. of 9u-?uoro-11/3,16a-dihydroxy
9a-16l3-di?u0r0-l 1 B-hydroxytestosterone ( VI )
androstene-dione and 3 m1. methanesulfonyl chloride in
A solution of 50 mg. of 9a-16?-di?uoro-A4-androstene
30
of pyridine is allowed to stand at 0° for 18 hours. 40
11,8-o1-3,17-dione in 10 ml. of methanol is stirred with 9
The mixture is then diluted with water, the precipitated
mg. of sodium borohydride for one hour at 0°. After
solid [about 3.18 g., M.P. about 215-2240 (dec.)] col
acidi?cation to pH 6 with 10% acetic acid, the reaction is
lected and washed well with water. Crystallization from
diluted with water and the steroids extracted with chloro~
chloroform-methanol gives the pure 16a-mesylate, M.P.
The chloroform extract is Washed well with water,
about 232—234° (dec.); [alD +134.6° (c., 0.98 in 45 form.
dried over sodium sulfate and evaporated to dryness in
CHClS);
vacuo. Crystallization of the residual solid gives pure
xgg-L 237 III/.L (e=18,100) ; my 3.02,,557, 6.06, 7.33,.
90¢,16?-di?llOI‘O-1 1 ?-hydroxytestosterone.
Analysis.—Calcd. for CzoHgqOsFS (408.43): C, 57.95;
EXAMPLE 5
H, 6.57; F, 4.58; S, 7.74. Found: C, 57.35; H, 6.64; F, 50
9a,16oc-di?u0r0-Z l?-hydroxytestosterone (V)
4.63; S, 7.79.
Similarly, by substituting 9oz-chloro-l1B-16a-dihydroxy
Following the procedure of Example 4, but substituting
androstenedione, 9a - ?uoro-l6a-hydroxyandrostenetrione
50 mg. of 9a,16a-di?uoro-A‘t-androstene-11,B-ol-3,17-dione
(i.e., 9a-?uoro-A4-androstene-16a-ol-3,11,17atrione), and
for the 16,8-?uoro derivative, there is obtained pure 90c,
9u-chloro-16a-hydroxyandrostenetrione for the 9oc-?1101‘0 55 ‘ ’~/~7~di?uoro-1 1 ?-hydroxytestosterone.
11p,16a-dihydroxyandrostenedione in the procedure of
EXAMPLE 6
Example 1, the corresponding 16a-mesylates are formed,
respectively.
Qa-?uoro-l??-chloro-l113~hydroxytestosterone (VII)
EXAMPLE 2
60
A stirred solution of 3 g. of 9a-?uoro-A4-androstene
11?,l6a-diol-3,l7-dione léct-mesylate, and 2.3 g. of an
To a solution of 100 mg. of l6l8-chloro-9a-?uoro-A4
androstene-l1,B-ol-3,17-dione in 20 ml. of methanol is
added at 0° with stirring 18 mg. of sodium borohydride.
The mixture is allowed to remain at 0° for 1 hour and is
then neutralized by the addition of 10% acetic acid.
Water is added and the steroids are extracted with chloro
hydrous potassium ?uoride in 60 ml. of diethylene glycol
is heated at 110° for 18 hours. The mixture is then diluted
with water and extracted with chloroform, the chloroform
extract then being washed with water, dried over sodium
sulfate and evaporated to dryness in vacuo. The resultant
form, the chloroform extract then being washed with
water, dried over sodium sulfate and evaporated to dry—
ness in vacuo. The residual solid after two recrystalliza
tions from acetone-hexane gives pure 16?-ChlOI‘O-9cc
?uoro-l 1 ,B-hydroxytestosterone.
gum is dissolved in 10 ml. of benzene and absorbed on
30g. of acid-washed alumina. Elution with chloroform 70 Similarly, 9a-ch1oro_16a-?uoro-1l?-hydroxyandrostene
benzene (1:4), followed by crystallization ‘from acetone
dione, 9a-ChlOI‘O-l6B-?11OI'O-1 1B-hydroxyandrostenedione,
hexane, gives 9a,16,8-di?uoroandrostene-11B-ol-3,17-dione.
and 9a,16?-dichloro-11B-hydroxyandrostenedione are re
Elution with chloroform-benzene (1:1), followed by crys
tallization from acetone-hexane gives 9a,16u-di?uoro
duced to 9u-chloro-16u-?uoro-1lp-hydroxytestosterone,
androstene-l 1163-01-3, 17~dione.
.
75
9a-chloro-l6p-?uoro-lIB-hydroxytestosterone and 9oc,16?
dichloro-l l?-hydroxytestosterone, respectively.
n
5
2,901,494
6
EXAMPLE 7
Similarly all other 17,8-esters of 9a,16-dihalo-l1-keto
9a, 1 6 oc-di?uoro-J 1,8-hydr0xytest0ster0ne I7B-acetmte
testosterones can be hydrolyzed to the free l7-hydroxyl
derivatives.
(VIII)
The invention may be otherwise variously embodied
A solution of 500 mg. of 90¢,16ot-di?1101'0-1 l?-hydroxy 5 within the scope of the appended claims.
What is claimed is:
testosterone in 10 ml. of anhydrous pyridine and 3 ml. of
1. A steroid of the ‘general formula
acetic anhydride is allowed to stand at room temperature
for 15 hours. The mixture is diluted with water and the
R
R’
precipitated material collected, washed with water and
Rn
dried in vacuo. Crystallization from acetone-hexane 10
gives an analytical sample of 9u,16a-difluoro-ll?-hy
R II
droxytestosterone 17/3-acetate.
Similarly, 9a,16B-di?uoro-1l?-hydroxytestosterone, 9a
?uoro-16?-chloro - 11B - hydroxytestosterone, 9a - chloro
16u-?uoro-1l?-hydroxytestosterone, 9a-chloro-16B-?uoro
15
0:
ll?-hydroxytestosterone and 9a,16/3 - dichloro - 11,8 — hy
droxytestosterone can be 17,3-acetylated. Furthermore,
wherein individually R is selected from the group consist
if another acylating agent such as propionic anhydride and
ing of hydroxy and the acyloxy radical of a hydrocarbon
benzoyl chloride is substituted for the acetic anhydride
in the procedure of Example 7, the corresponding 175 20 carboxylic acid having less than ten carbon atoms and R’
is hydrogen and together R and R’ is keto, individually
propionate and 17/3-benzoate derivatives are formed,
R” is hydrogen, R’” is B-hydroxy, and together R” and
respectively.
R'” is keto, and X and X’ are halo.
2. 9a,‘ l6-dihalo-A4-androstene-1 l?-ol—,-3 , 17-dione.
EXAMPLE 8
9a,16a-di?u0r0-1I-ketotestosterone 1 7?-acetate (IX)
25
To a solution of 250 mg. of 9u,16a-di?uoro-11B-hy
. 9a,16-dihalo-1l?-hydroxytestosterone.
. 9a, l6-dihalo-1 l-ketotestosterone.
droxytestosterone 17B~acetate in 20 ml. of acetone is
added with stirring chromium trioxide in 0.67 N sulfuric
acid (200 mg./ml.) until a permanent brown coloration
is obtained.
. 9a,16-dihalo-A4-androstene-3, 1 1,17-trione.
. 9a,16a-dihalo-1l?-hydroxytestosterone 17,8 - acetate.
. A process for preparing a steroid of claim 1, which
The mixture is then stirred for one hour. 30 comprises treating a 16a-sulfonic acid ester of a steroid
selected from the group consisting of 9a-halo-A4-andro
Dilution with water gives 9a,l6a-difluoro-ll-ketotestos
terone 1718-acetate which is crystallized from acetone
‘stene-l1?,16a-diol-3,17-dione and 9a-halo-A4-androstene
hexane to give a pure sample.
16a-ol-3,11,17-trione with a compound selected from the
group consisting of an alkali metal halide and an alkaline
Similarly all other 17B-esters of 9a,16-dihalo-11?-hy
droxytestosterones can be oxidized to the corresponding 3 earth metal halide.
8. A process for preparing a 9u,16—dihalo—1lB-hy
ll-keto derivatives.
droxytestosterone which comprises treating the corre
sponding l7-ketone derivative with a reducing agent.
EXAMPLE 9
9a,]6a-di?uoro-1l-ketottestosterone (X)
To a solution of 200 mg. of 9a,l6a-di?uoro-l1-keto
4O
9. 9a, 1 6a-di?uoro-A4-androstene-1 l 18-01-3 , l7-dione.
10. 9a,16/3-di?uoro-A4~androstene-11B-ol-3,17-dione.
testosterone 17,8-acetate in 10 ml. of methanol is added,
1 l. 9u,l6a-di?uoro-1 lB-hydroxytestosterone.
under nitrogen, 4 m1. of 2.5% potassium hydroxide solu—
12. 90:,160; - di?uoro-l l?-hydroxytestosterone 17(3-ace~
tion, the mixture then being left at room temperature for
tate.
six hours. The solution is then diluted with water and
13. 9a,16a-di?uoro-l l-ketotestosterone.
the steroids extracted with chloroform. The chloroform 45
extract is washed with water, dried over sodium sulfate
References Cited in the ?le of this patent
and evaporated to dryness in vacuo. Crystallization of
UNITED STATES PATENTS
the residue from acetone-hexane gives 9a,l6a-di?uoro
'll-ketotestosterone.
2,759,929
Farrar et a1. _________ .__ Aug. 21, 1956