Note: Descriptions are shown in the official language in which they were submitted.
1410
The invention relates to the manufacture of new polyhalogenated
steroids, especially 9~,21-dihalogeno-11~,17~-dihydroxy-6~-fluoro-16~-methyl-
pregna-1,4-diene-3,20-dione compounds of the formula
l~2_x2
CH3 C=0
H0 ~ ~ 0-R ~I)
1 ~ H3
o
F
in which Xl represents chlorine or fluorine, X2 represents bromine or chlorine,
Rl represents hydrogen or chlorine and R2 represents a straight-chain lower
alkanoyl group, as well as to 2-unsubstituted 1,2-dihydro derivatives of these
compounds.
Carbon-containing compounds and radicals designated throughout this
specification as "lower" preferably contain not more than 7 carbon atoms.
A straight-chain lower alkanoyl is~ for example, acetyl, propionyl,
butyryl, valeryl, hexanoyl or heptanoyl.
The compounds of the present invention have valuable pharmacological
properties. Thus they are distinguished by a pronounced anti-antiflammatory
action, whilst having a reduced systemic action. Accordingly, for example,
when applied locally in the raw cotton wool granuloma test on rats, inhibition
of the inflammator~v processes can be observed in the dosage range between about
0.001 and about 0.10 mg per cotton wool pellet. The first indications of a
systemic action, however, are only apparent at, or even above, the upper limit
C '
,~ --1--
.. . . .
of this dosage range, namely in the decrease in weight of the thymus at a
dose above 0.03 mg per cotton wool pellet, of the adrenals at a dose above
0.1 mg per cotton wool pellet, and of the entire body only at a dose of 1 mg
per cotton wool pellet. On topical administration ~rat's ear test of Tonelli),
ED50 is approx. 10 to 30 mcg/ml.
On account of these biological properties, the new compounds can be
used in all indications for which glucocorticoid steroids with anti-inflamma-
tory properties are suitable. In particular, they are suitable for use as
anti-inflammatory glucocorticoids for topical application, for example for the
treatment of inflammatory dermatoses) such as eczemas, or dermatides, or
dermatoses which are partially corticoid-resistant, for example psoriasis.
They can also be used as useful intermediate products for obtaining other
useful substances, especially other pharmacologically active steroids.
The invention preferably relates to those compounds of the formula I
in which Xl represents fluorine or chlorine, X2 represents chlorine, R
represents hydrogen and R2 represents propionyl.
The invention above all relates st particularly to the compounds
of the formula I mentioned in the examples.
The compounds according to the invention of the formula I can be
manufactured in a manner which is known per se, for example by treating a
compound of the formula
ICH2 -X2
CH3 C=O
~\ \ ~~ ~ O-R2 (II)
1 ~ CH3
O ~`
F
J -2-
with a hydrogen halide of the formula H-Xl ~III).
Cleavage of the 9~ -oxido group in a starting material of the
formula II by treatment with a hydrogen halide of the formula III, that is
to say with hydrogen chloride or hydrogen fluoride, is carried out in a
manner which is known per se, advantageousl-y using an anhydrous hydrogen
halide, optionally in the presence of an inert solvent, such as chloroform,
tetrahydrofurane or, in particular, dimethylformamide, or also hydrogen
fluoride in aqueous solution.
In place of the hydrogen halide of the formula III, it is also
possible to use an agent which releases hydrogen fluoride or hydrogen
chloride, such as the salt of such an
"i ;, i
. ,~ ,1
" .", :=:`, J
,
1 lQ 14 1 0
acid with a tertlary organic base, for example pyridine, or,
especially if hydrogen fluoride is used, a similar suitable
addition compound. A particularly advantageous process is
described in U.S. paten~ 3,~11,758, wherein hydrogen
fluoride is used in the form of an adduct with a carbamic
acid derivative or thiocarbamic acid derivative, especially
with urea.
The starting materials of the formula II can be ob-
tained in a manner which is known per se, for example by
eliminating water from a 6a-fluoro-11~-hydroxy-16~-methyl-2-
Rl-17a-GR2-21-X2-pregna-1,4-diene-3,20-dione compound, for
example by treatment with a suitable acid chloride, such as
phosphorus oxychloride or methanesulphonyl chloride, in the
presence of a base, for example pyridine, adding hypo-
bromous acid (which, for example, is used in the form of N-
bromoacetamide or N-bromosuccinimide) onto the 9,11-double bond
of the 6a-fluoro-16~-methyl-2-Rl-17a-OR2-21-X2-pregna-1,4,9
(ll)-triene-3,20-dione compound which is thus obtainable and
eliminating hydrogen bromide from the corresponding 9a,11~-
bromohydrin compound by treatment with a base, for example an
alkali metal carbonate or alkali metal hydroxide, for example
potassium carbonate or potassium hydroxide, with formation of
the desired starting material of the formula II. In the
above intermediate products 9 Rl, R2 and X2 have the above-
` mentioned meanings.
_.
G~
~10~L4~ (~
The new compounds of the for~ula I can also be obtained by convert-
ing the group XO in a compound of the general formula
Cl H2-Xo
CH, C=O
~ O R2 (IV~
o
F
in which XO represents the group ~O~Ra, in which Ra represents the acyl
radical of an organic sulphonic acid, (i.e. a sulphonyloxy group), is treated
in a manner which is known per se with an alkaline salt of the halogen X2.
The acyl radical Ra of an organic sulphonic acid is, in particular, the acyl
radical of an aliphatic or carboxylic, optionally unsaturated sulphonic acid
or of an aromatic sulphonic acid. Such acids are, inter alia, unsubstituted
or substituted, for example halogenated, lower alkanesulphonic acids,
cycloalkanesulphonic acids, in which the cycloalkyl radical can be monocyclic
or polycyclic, or benzenesulphonic acids which are unsubstituted or substituted
by lower alkyl, for example methyl, lower alkoxy, for example methoxy,
halogen, for example chlorine or bromine, and/or nitro.
~ -5-
0
Typical examples o~ such acids are trifluoromethanesulphonic
acid, (~)-camphor-10-sulphonic acid, 4-bromob~nzenesulphonic
acid and 3-nitrobenzenesulphonic acid and especially p-toluene-
sulphonic acid and, in particular, methanesulphonic acid.
The substitution reaction is usually carried out by
treating the starting material with an alkali metal halide of
the formula M-X2 (V), in which M represents an alkali metal,
in the presence of an aprotic organic s~lvent which has a
dielectric constant of 29 or higher. An alkali metal M
which can be used is, preferably, lithium. Aprotic organ-
ic solvents which can be used are, in particular, di-lower
alkyl sulphoxides, for example dimethyl sulphoxide, N,N-di-lower
alkylamides of lower aliphatic carboxylic acids, for example
.
N,N-dimethylformamide or N,N-dimethylacetamide, lower alkane-
nitriles or lower alkenenitriles, for example acetonitrile,
hexa-lower alkylphosphoramides, for example hexamethylphosphor-
triamide, or, above all when using starting materials of the
formula IV in which R2 represents hydrogen, also ketones,
especially aliphatic or cycloaliphatic ketones conta~ng up to ~nd
inclu~g lOcarbcn atoms such as corresponding alkanones, for
example acetone, 2-butanone, 2- or 3-pentanone, 2-hexanone or
4-decanone, or cycloalkanones~contau~ngupto and inclu~ 8~gc~xn
atoms, for example cyclopentanone or cyclohexanone, or mixtures
of such solvents.
The reaction is appropriately carried out between
room temperature and the boiling point of the reaction mixture
11~141(;~
and is effected with at least one equivalent of the alkali metal halide of
the formula V.
The starting materials of the formula IV are known or can be
manufactured in a manner which is known per se, for example by converting
the 2l-hydroxylgroup in a 6~-fluoro-ll~,2l-dihydroxy-l6~-methyl-2-Rl-9~-Xl-
l7~-OR2-pregna-l,4-diene-3,20-dione compound into the desired organic
sulphonyloxy group ~ORa by treatment with a reactive derivative of an organic
sulphonic acid of the formula Ra-OH (VI), especially with a corresponding
sulphonic acid chloride of the formula Ra-Cl (VIa), in the presence of a
; lO base, for example pyridine.
The new compounds of the formula I in which Xl represents chlorine
can also be obtained by adding hypochlorous acid onto the 9,ll-double bond
of a compound of the formula
CIH2-X2
Cl13 C=O
21 ~ ~ -~2 (VII)
O
F
in which Rl, R2 and X2 have the above meanings.
According to the above reaction, the elements of hypochlorous acid
are added onto the 9,ll-double bond of the starting materials of the
formula VII in a manner which is known per se. The reaction is carried out,
for example, with aqueous hypochlorous acid, or a hypochlorous acid donor,
such as a N-chlorocarboxylic acid amide or imide (cf. U.S. patent
~ -7-
.
.
~10~41(:~
specification 3,057,886), can be used. The reaction is carried out in an
inert solvent, such as a tertiary alcohol, for example tert. butanol, an
ether, for example diethyl ether, methyl isopropyl ether, dioxane or tetra-
hydrofurane, or a ketone, for example acetone, in the presence of water and
optionally of a strong acid.
The addition of hypochlorous acid to the 9,11-double bond of the
starting material of the formula VII can also be carried out in a non-aqueous
medium. A particularly advantageous embodiment of this modification is the
use of lower alkyl hypochlorites, above all tert.-butyl hypochlorite, in an
-8_
, ~ :
11~141(~
inert, wa.ter-imm.iscible solvent, for example a nitro~
hydrocarbon, usually in the presence of perchloric acid
(cf. ~erman patent specification 2,011,559).
The starting materials of the formula VII can be manu-
factured in a manner which is known per se, for example by
eliminating water from a 6a-fluoro-ll~-hydroxy-16~-methyl-2-Rl-
17a-OR2-21-X2-pregna-1,4-diene-3,20-dione compound, for exarnple
by treatment with a suitable acid chloride, such as phorphorus
oxychloride or methanesulphonyl chloride, in the presence of a
base, for example pyridine.
The new compounds of the formula I in which Rl repres-
ents hydrogen can also be obtained by introducing the l,2-
double bond into a compound of the formula
.
fH2 -X2
CH ~=0
-0-R2 (VIII)
U3
l?
.
and, if desired, carrying out;the additional measures.
me introduction of the 1,2-double bond can be carried
out by dehydrogenation, for example by treatment with a suit-
able dehydrogenating quinone, such as 2,3-dichloro-5,6-dicyano-
l,4-benzoquinone.
, I
.
.
., ~ .
11014~0
The 1,2-dehydrogenation of starting materials of the formula VIII
can also be effected by treatment with selenium dioxide or microbiologically,
for example with suitable microorganisms, such as Corynebacterium simplex or
Septomyxa affinis.
The starting materials of the formula VIII have valuable pharma-
ceutical properties analogous to those of end products of the formula I and
can also be used in the same way as these latter. The compounds of the
formula VIII, in which Xl, X2 and R2 have the above meanings, also form an
object of the present invention. They are obtained by means of the process
described above, starting in each case from 1,2-saturated, 2-unsubstituted
compounds of the type of formula II, IV or VII, and carrying out the
corresponding reaction. Thus they can be obtained for example by converting
the 21-hydroxyl group of a 6a-fluoro-11~,21-dihydroxy-16~-methyl-9a-Xl-17a-
OR2-pregn-4-ene-3,20-dione compound (i.e. a compound of the formula IV type)
for example by treatment with a suitable sulphonic acid derivative, such as
methanesulphonyl chloride, into a 21-organic sulphonyloxy group, and treating
the intermediate with a lithium halide, for example lithium chloride.
A compound of the formula I, wherein Rl represents hydrogen, and
which is obtainable according to the process can be converted into an
analogous compound of the formula I, wherein Rl represents chlorine, in a
manner which is known per se.
For this purpose it is possib]e to add one molecule of chlorine
onto the 1,2-double bond in such a compound and to split off one mole of
hydrogen chloride from the intermediate 1,2-dichloro-pregn-4-ene-3,20-dione.
The addition of chlorine to the 1,2-double bond can be effected by treatment
with elementary chlorine or with a mixture of two different chlorine-
containing compounds, one of which releases positive chlorine and the other
~ ~ -10-
.
. ~
~ .
releases negative chlorine.
The treatment with elementary chlorine can be carried out in an
inert organic solvent, for example an ether, such as dioxane or tetrahydro-
furane, a halogenated hydrocarbon, for example methylene chloride, or a
carboxylic acid, especially a lower aliphatic carboxylic acid, such as acetic
acid or propionic acid, or a derivative thereof, such as an acid amide, for
example dimethylformamide, or a nitrile, such as a lower alkanenitrile, for
example acetonitrile. Advantageously, it is also possible to use mixtures
of such solvents, especially mixtures of an ether, such as dioxane, with one
of the lower alkanecarboxylic acids mentioned. The chlorination is usually
carried out using the stoichiometric amount of chlorine at low temperature,
say between -50 and +30, for example at between -20 and +10, and with the
exclusion of light.
In a particularly preferred embodiment, the compound of the
formula I in which Rl represents hydrogen, is dissolved in one of the above
solvents, for example dioxane,
~ ..1;
~ 4 10
and treated with a solution of chlorine in a lower aliphatic
carboxylic acid, for example propionic acid, and this solution
is then left to stand, for example at the indicated temperature.
In a mixture of two different chlorinating agents,
reagents which call set free positive chlorine are chlorinated
acid amides or acid imides, such as chlorosuccinimide or chloro-
acetamide, and reagents which yield negative chlorine are, for
example, hydrogen chloride and also alkali metal chlorides.
The elimination of hydrogen chloride from the
intermediate 1,2-dichloro-pregn~4-ene-3,20-dione is advantage-
ously effected by treatment with a base. Ex-
amples of suitable bases are tertiary organic nitrogen
bases, such as lower aliphatic amines, for example a tri-lower
alkylamine, such as triethylamine, hetero-aromatic bases, for
example pyridine or collidine, or mixed aliphatic-aromatic
bases, such as N,N-di-lower alkyl-aniline, for example N,N-
dimethylaniline, The reaction is preferably carried out
with an excess of the base, which at the same -time can be
used as solvent. Howe~er, it is also possible to use in-
organic bases, such as, in particular~ the alkali metal salts
or alkaline ear-th metal salts which are also used for hydroly-
sis of the ll~-trifluoroacetate described below, for example
potassium acetate or bicarbonate or sodium acetate or bicarbon
ate, in aqueous-alcoholic solution, as well as the corresponding
hydroxides. The dehydrochlorination is preferably carried
out in a temperature range between about 20Cand about 100C.
C i 1 ~
- ,~6 - ,
~ 4 1~
Advantageouslys those agents and reaction conditions are
chosen which have no influence on the other f~mctional groups,
especially those in the 17-position and/or 21-position.
Before adding chlorine onto the 1,2-double bond in a
compound of the formula I, in which Rl represen-ts hydrogen,
the ll~-hydroxyl group is advantagecusly protected, for example
by esterification, preferably in the form of a trifluoroacetoxy
group, a compound of the formula I in which Rl represents
hydrogen being reacted in a manner which is kno~n per se
with a suitable reactive derivative o~ an acid, for example
with trifluoroacetyl chloride or trifluoroacetic anhydride.It is
known that the trifluoroacetyl group can be split off easily
by solvolysis, for example by hydrolysis or alcoholysis, for
example by treatment with alkali metal hydroxides, carbonates,
bicarbonates or acetates or alkaline earth metal hydroxides,
carbonates, bicarbonates or acetates, in a suitable medium, for
example an alcoholic, such as methanolic, or aqueous-alcoholic
medium. A particular method of carrymg out the solvolysis of the
ll-tri~luoroacetoxy group is described in German patent spec-
ification 1,593,519. This procedure can be used mainly because it
leaves intact any esterified hydroxyl group which may be
present in the 17a-position an~d consists in treating the 11~-
trifluoroacetoxy compound, in a lower- alkanol, with
the salt of an acid which has a pKa value in the range of
from about 2.3 to about 7.3,for eæamp~ with an alkali metal azide,
for example sodium aæide or potassium azide, or an alkali metal
.
/3
141~
formate, for example sodium formate or potassium formate. If appropriate,
this salt can also be used only in catalytic amounts. Furthermore, the 11~-
trifluoroacetyl group can also be removed by treatment with other bases, for
example with amines and especially with hetero-aromatic bases, such as
pyridine or collidine. Finally, the cleavage of the trifluoroacetoxy group
by treatment with silica gel according to the process described in German
Offenlegungsschrift 2,144,405 is also possible.
Liberation of the ll~-hydroxyl group from the protected form can be
effected immediately after the addition of chlorine to the 1,2-double bond or
at the same time as the dehydrochlorination by means of a base, but if
desired, it can also be effected only subsequently to this step as a separate
- operation.
- The starting materials used in the above process steps are prefer-
ably those which result in the compounds described above as being particularly
preferred.
The compounds of the present invention are especially useful for
the manufacture of pharmaceutical compositions which contain, as active
ingredient, a compound according to the invention of the formula I, or a
2-unsubstituted 1,2-dehydro derivative thereof.
Suitable pharmaceutical compositions are in particular those for
topical application, such as creams, ointments, pastes, foams, tinctures and
solutions, which contain from about 0.005% to about 0.1% of the active
compound.
The pharmaceutical compositions for topical application are
obtained in known manner, for example by dissolving or suspending the active
substance in the base or in a part thereof, if necessary. When processing
the active substance in the form of a solution, it is usually dissolved in
O.i,. ~
~ ~ -14-
- , .,. ' - ' ' .. , ~
one of the two phases before the emulsification, and when processing the
active substance in the form of a suspension, it is mixed with a part of the
base before the emulsification and then added to the remainder of the
formulation.
In addition to the pharmaceutical compositions which can be applied
topically, other suitable preparations are those for enteral, for example
oral, and parenteral administration to warm-blooded animals and which contain
the active substance as sole ingredient or together with a pharmaceutically
acceptable carrier. These pharmaceutical compositions contain about 0.01% to
about 10% of active substance and are in dosage unit form, such as coated
tablets, tablets, capsules, suppositories or ampoules. They are obtained in
known manner, for example by conventional mixing, granulating, coating,
dissolving or lyophilising methods.
~ -15-
.,
141~
The dosage of active substance depends on the
species of warm-blooded animal, the age, and the individual
conditioll as well as on the mode of application.
The present invention also relates ~o the use of the
new compounds the formula I and of the salts of such compounds
with salt-forming properties, preferably for treating
inflammations, chiefly as antiinfla~matory glucocorticoids for
local application, normally in the form of pharmaceutical
compositions, especially in the form of pharmaceutical composi
tions for topical application.
The following Examples describe the invention in more
detail, without in any way restricting the scope thereof,
- .. ~5 -
4~.1)
Example 1
230 mg of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) are added to a solution oE 228 mg of 21-chloro-6~,9~-
difluoro-ll,B~l7~-dihydroxy-l6~-methyl-pregn 4-ene-3,20-dione-
17-propionate in 11.4 ml of dioxane, which is then refluxed
for 20 hours in a nitrogen atmosphere, The reaction mixture
is concentrated in a water jet vacuum and the amorphous residue
i5 chromatographed on 100 times its weight of silica gel
(stepped column). The fractions eluted with a 99:1 mixture of
methylene chloride/methanol yield the pure 21-chloro-6a,9a-
difluoro-ll,B,170;-dihydroxy-16~-methyl-pregna-1,4-diene-3,20-
dione-17-propionate which melts at 220-221C after recrys-
tallisation from methylene chloride/e~her.
The 17-monopropionate used as starting material is
prepared as follows:
A suspension of 1 g of 21-chloro-9~ epoxy-17~-
hydroxy-16~-methyl-pregn-4-ene-3,20-dione-17-propionate in
5.4 ml of dioxane and 1.4 ml of triethyl orthoformate is
treated with 0.9 ml of a solution consisting of 277 mg of
p-toluenesulphonic acid, 2.7 ml of dioxane and 0.55 ml of
ethyl alcohol and stirred for` 90 minutes at room temperatureO
After addition of 3.8 ml of pyridine, the reaction mixture
is diluted with ethyl acetate, washed 3 times with a saturated
solution of sodium chloride, dried and concentrated in a water
jet vacuum. The crude 3-ethyl-enol ether (3-ethoxy-21-chloro-
.~ /1
.~ - ~ _
llGl~O
9~ epoxy-17~-hydroxy-16~-methyl pregna-3~5-~iene-20-one-17-
propionate) is dissolved in a mixture of 50 ml of tetrahydro-
furane and 10 ml of water and the solution is treated for 40
minutes at room temperature with gaseous perchloroyl fluoride.
After nitrogen has subsequently been introduced over the
course of 10 minutes~ the reaction solution is diluted with
ethyl acetate, washed successively with 10% potassium iodide
solution, 10% sodium thiosulphate solution and 3 times with
a saturated solution of sodium chloride, then dried and
concentrated in a water jet vacuum. The crude product is
chromatographed on 100 times its weight of silica gel (stepped
column).
The colulnn is eluted with a 90:10 mixture of toluene/
ethyl acetate. Recrystallisation from methylene chloride/ether
of the fractions obtained yield 21-chloro-6~-fluoro-9~
epoxy-17~-hydroxy-16~-methyl-pregn-4-ene-3,20-dione-17-
propionate which melts at 174-177C.
14.5 ml of a reagent prepared by mixing 10 g of urea
with 13.25 g of anhydrous liquid hydrogen fluoride are poured
over 720 mg of the above compound in à plastic vessel. The
reaction mixture is stirred for 3 hours with ice cooling, then
poured onto 55 ml of an ice-cold saturated solution of ammonia,
weakly acidiied with acetic acid and extracted twice with
chloroform. The organic phases are combined, washed with the
ice-cold sodium hydroxide solution, dried and concentrated in
~ 4 1~
a water je~ vacuum. The crude product is chromatograplled on
100 times its weight of silica gel (stepped column). The
column is eluted with 90:10 mixture of toluene/ethyl acetate.
Recrystallisation from methylene chloride/ether of the fractions
obtained yields 21~chloro-6a,9a-difluoro-11~,17a-dihydroxy-16~-
methyl-pregn-4-ene-3~20-dione-17-propionate which melts at
212-213C.
Example 2
A solution of 370 g of 21-chloro-6a,9a-difluoro~ ,17a-
dihydroxy-16~-methylpregna-1,4-diene-3,20-dione 17-propionate
in 30 ml of dioxane is treated with 1.85 ml of a solution which
is prepared by introducing 7.7 g of chlorine gas into 100 ml
of propionic acid. The reaction mixture is allowed to stand
for 5 days at 3~4C. It is then diluted with chloroform,
washed successively with a 10% potassium iodide solution, a
10% sodium thiosulphate solution, dilute sodium hydroxide
solution and water, dried, and concentrated n a water jet
vacuum~ The crude 1~,2~,21-trichloro-6a,9a-difluoro~ ,17a-
dihydroxy-16~-methylpregn-4-ene-3,20-dione-17-propionate
is dissolved in methylene chloride to remove HCl and filtered
through a column of 37 g of basic alumina (activity 2). The
eluted solution is concentrated and recrystallised from
methylene chloride to yield 2,21-dichloro-6a,9a-difluoro-11~,
17a-dihydroxy-16~-methylpregna-1,4-diene-3,20-dione-17-
propionatc which melts at 202-204C.
4~0
.
Example 3
A solution of 350 mg of 9a,21-dichloro-6~-fluoro-
11~,17-dihydroxy-16,B-methyl-pregn-4-ene-3,20-dione-17-
propionate and 525 mg o 2,3-dichloro-5,6-dicyano~1,4-benzo-
quinone in 17.5 ml of dioxane is refluxed for 20 hours in an
atmosphere of nitrogen. The cooled mixture is filtered and the
filtrate is evaporated. The residue is dissolved in methylene
chloride and filtered through lS times its weight of neutral
alumina ~activity 2), The filtrate is concentrated and purified
by preparative thin-layer chromatography (on silica gel, 3
developings by a 9:1 mixture of toluene/methanol as eluant).
The desired zone is localised by ultra-violet light having a
wavelength of 254 nm, eluted from the adsorbent with ethyl
acetate and recrystallised from methylene chloride/ether,
affording the desired 9a,21-dichloro-6a-fluoro-11~,17-dihydroxy-
16~-methyl-pregna-1,4-diene-3,20-dione-17-propionate which
melts, with decomposition, at 212-213C.
The starting steroid is obtained as follows:
Hydrogen chloride gas is introduced at 0C in the course
of 30 minutes into a solution of 400 mg of 21-chloro-6~-fluoro-
9,B,ll-epoxy-17-hydroxy-16~-me~thyl-pregn-4-ene-3,20-dione-
propionate in 20 ml of chloroform. The mixture is allowed to
stand for a further 30 minutes at 0C, diluted with chloroform,
washed with an ice~cold saturated sodium hydrocarbonate
solution dried and concentrated in vacuo. The crude 9c;,21-
_~ _
...,, .~
,
11~141~
dichloro-6~-fluoro-11~,17-dihydroxy-16~-methyl-pregn-4-ene
3,20-dione-17-propionate can be used without purification for
the dihydrogenation reaction.
Example 4
Hydrogen chloride gas is introduced at 0C in the
course of 30 minutes into a solution of 2.8 g of 21-chloro-6a-
fluoro-9~ epoxy-17-hydroxy-16~-methyl pregna 1,4-diene~3,20-
dione-propionate in 140 ml of chloroo~rm. The mixture is
allowed to stand for a further 30 minutes at 0C, diluted with
chloroform, washed with an ice-cold saturated sodium hydro-
carbonate solution, dried and evapora~ed in vacuo. The crude
product is chromatographed on 100 times its weight of silica
gel (stepped column). The desired product is eluted with a
99:1 mixture of toluene/methanol. Crystallisation from
methylene chloride/ether yields 9~,21-dichloro-6~-iluoro-
11~,17-dihydroxy-16~-methyl-pregna-1,4-diene-3,20-dione-17-
propionate which melts, with decomposition, at 212-213C and
is identical with the product of Example 3.
The starting steroid is obtained as ollows:
A mixture of 3 g of 21-chloro-6~-fluoro-9~,11-epoxy-
17-hydroxy-16~-methyl-pregn-4-ene-3,20-dione-propionate and
3 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 150 ml of
dioxane is reflu~ed for 20 hours in an atmosphere of nitrogen.
The cooled mixture is filtered, and the filtrate concentratedO
~f
.
The resi.due is dissolved in methylene chloride and
filtered through 15 times its weight of neutral alumina
(activity II). The filtrate is concentrated, af:Eording the
crude 21-chloro-6~-fluoro-9,B-ll-epoxy-17~hydroxy-16~-methyl-
pregna-1,4-diene-3,2û-dione-propionate which can be treated
with hydrogen chloride without further puri:Eication.
Example 5
An ointment containing 0.1% of 21-chloro-6c~,9~-
difluoro~ll,3~17~-dihydroxy-16~-methyl-pregna-1,4-diene-3,20-
dione 17-propionate can be prepared as follows:
Composition
21-chloro-6a,9~x-difluoro~ ,17~-dihydroxy-
16~-methyl-pregna-1,4 diene-3,20-dione 17-propionate0.1%
white petroleum jelly 45.0%
liquid paraf:Ein 19.6%
cetyl alcohol 5.0%
beeswax 5.0%
sorbitane sesquioleate 5.0%
p-hydroxybenzoic acid ester 0.2%
perfwne ~ 0.1%
water 20.0%
,
llQ1410
The ~at-ty substances and emulsifiers are melted to-
gether, The preserva-tive is dissolved in water and the
solution is emulsi~ied into the fatty melt at elevated tempera-
ture. After cooling, a suspension of the active compound
in part of the fatty melt is incorporated into the emulsion and
the perfume is then added.
~ ,;2 3
,~.,.,i ~
