Note: Descriptions are shown in the official language in which they were submitted.
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4-HALOGENATED 17-METHYLENE STEROIDS, METHOD FOR THE PRODUCTION
THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE
COMPOUNDS
The invention relates to 17-methylene steroids,. process for
their production and pharmaceutical compositions that contain
these compounds.
The compounds according to the invention have a hybrid-type
profile of action in.the sense that they act as inhibitors of 5a-
reductase and simultaneously as gestagens. They are therefore
~ suitable for.treating diseases that are the result of elevated
androgen levels in certain organs and tissues in men and.women.
Together with other hormonal substances, such as an estrogen,,
testosterone or a strong androgen., the compounds according to the
invention are suitable as contraceptive agents for women and for-,
men.
In women, elevated levels of 5a-dihydroprogesterone can
contribute to serious feelings of ill-health during the
premenstrual syndrome. These disruptions can also be
advantageously affected by inhibition of 5a-reductase. The
simultaneous presence of a gestagenic action results in an
inhibition.of gonadal function in males and females.. This effect
is then desired if an antifertile action or else an inhibition of
the hormone secretion of the gonads is to be achieved with the
treatment. Since the inhibition of 5a-reductase can irreversibly
disrupt.the sexual development of the fetus in the case of a
woman pregnant with a male fetus, an elimination of fertility
accompanied by an antiandrogenic therapy is very desirable.
2
Possible indications are prostate diseases, alopecia of the=male
type, acne, and hirsutism. The symptoms during the premenstrual
syndrome can be.alleviated in correspondingly disposed women.
It was found, surprisingly enough, that 17-methylene
steroids of general formula I act both as inhibitors of 5a=
reductase and as gestagens.
This invention consequently.relates to 17-methylene steroids
of general formula I
~ ~ . - - - . Rzoa
Rzo
Rio
O ~ I
R4
in which
R4 stands for.a halogen atom or a pseudohalogen,
R10 stands for a hydrogen atom or a straight-chain or
branched C1-C4 alkyl group,
' R20 and R20a, independently of one another, represent a
hydrogen atom, a straight-chain or branched Cl.4 alkyl or hydroxy-
Cj_4 alkyl group, or
one of radicals R20 and R20a means a hydrogen atom, a
straight-chain or branched C1_4 alkyl or hydroxy-Cl_4 alkyl group,
and the other radical means a halogen atom-or a pseudohalogen.
R4 can mean a halogen atom, such as a fluorine, chlorine,
bromine or iodine atom, or a-pseudohalogen,.such as a cyanate,
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3
thiocyanato, cyano or azide group, whereby a bromine atom or a cyano
group is preferred, and a chlorine atom is especially preferred.
R10 can stand for a hydrogen atom or a straight-chain or
branched Ct_4 alkyl group, whereby examples of straight-chain or
branched C1_4 alkyl groups are methyl, ethyl, propyl, isopropyl,
butyl, isobutyl and tert-butyl. Rt0 preferably means a hydrogen
atom or a methyl group.
On the one hand, R20 and R20a, independently of one another,
can represent a hydrogen atom, a straight-chain or branched C1_4
alkyl or hydroxy-C1_4 alkyl group. In this case, R20 and R20a~
independently of one another, preferably mean a hydrogen atom, a
methyl group or a group -CHZOH.
In addition, one of radicals R20 and R20a can mean a hydrogen
atom, a straight-chain or branched C1_4 alkyl or hydroxy-C1_4 alkyl
group, and the other radical can mean a halogen atom, such as a
fluorine, chlorine, bromine or iodine atom, or a pseudohalogen,
such as a cyanate, rhodanid, cyano or azide group. Examples of
straight-chain or branched C7_4 alkyl groups are the groups cited
for R10. Straight-chain or branched hydroxy-C~_4 alkyl groups are
derived from the above-mentioned straight-chain or branched C1_4
alkyl groups, whereby one or more hydrogen atoms are replaced by
hydroxy groups.
In this case, one of radicals R20 and R20a preferably means a
hydrogen atom or a methyl group, and the other radical means a
halogen atom, preferably-a fluorine atom, especially preferably a
chlorine or bromine atom, or a pseudohalogen, preferably an azido
or thiocyanato group, especially preferably a cyano group.
4
In the case of R20 and RZOa, examples of straight-chain or
branched Cl_4 alkyl groups are the groups that are cited for R10.
Straight-chain or branched hydroxy-Cl_G alkyl groups are derived
from these C1_4 alkyl groups, whereby one or more hydrogen atoms
are replaced by hydroxy groups, such as especially a group
=(CHZ)n-OH with n 1 to 4.
Especially preferred are the following compounds:
1) E-17-Chloromethylene-4-chloro-estr-4-en-3-one,
2) E-17-Cyanomethylene-4-chloro-estr-4-en-3-one,
~ 3) Z-17-Cyanomethylene-4-chloro-estr-4-en-3-one,
4) Z-17-(1')-Cyanoethylidene-4-chloro-estr-4-en-3-one,
5) Z-17-Ethylidene-4-chloro-estr-4-en-3-one,
6) E-17-Ethylidene-4-chloro-estr-4-en-3-one,
7) E-17-Bromomethylene-4-chloro-estr-4-en-3-one,
8) Z-17-Chloroethylidene-4-chloro-estr-4-en-3-one,
9) Z-17-Bromoethylidene-4-chloro-estr-4-en-3-one,
10) E-17-Chloromethylene-4-cyano-androst-4-en-3-one,
11) E-.17-Chloromethylene-4-chloro-androst-4-en-3-one,
12) E-17-(2')-Hydroxyethylidene-4-chloro-estr-4-en-3-one.and
13) Z-17-(2')-Hydroxyethylidene-4-chloro-estr-4-en-3-one.
Subjects of this invention are also pharmaceutical
compositions that contain at least one 17-methylene steroid of
general formula I as active ingredient, whereby these
compositions also contain suitable adjuvants and vehicles, and
the use of these compounds for the production of pharmaceutical
agents, especially for the indications below.
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5
The compounds according to the invention are suitable for
the production of pharmaceutical compositions and.preparations.
The pharmaceutical compositions or pharmaceutical agents contain
as active ingr-edient one or more of the compounds according to
the invention, optionally mixed with other pharmacologically or
pharmaceutically active substances. The production of the
pharmaceutical agents is carried out in a known way, whereby the.
known and commonly used pharmaceutical adjuvants and other
commonly used vehicles and-diluents can be used.
~ As such.vehicles and adjuvants, for example, those are
suitable that are recommended or indicated in the following,
bibliographic references as adjuvants for pharmaceutics,
cosmetics and related fields: Ulimans Encyklopadie der
technischen Chemie [Ullman's Encyclopedia of Technical
Chemistry], Volume 4 (1953), pages 1 to 39; Journal of
.Pharmaceutical Sciences, Volume 52 (1963), page,918 ff., H. v.
Czetsch-Lindenwald, Hilfsstoffefur Pharmazieund angrenzende
Gebiete [Adjuvants for Pharmaceutics and Related Fields], Pharm.
Ind., No. 2, 1961, pages 72 and ff.: Dr. H. P. Fiedler, Lexikon
der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete
[Dictionary of Adjuvants for Pharmaceutics, Cosmetics and Related
Fields], Cantor KG, Aulendorf in Wurttemberg 1971.
The compounds can be administered orally or parenterally,
for example intraperitoneally, intramuscularly, subcutaneously or
percutaneously. The compounds can also be implanted in the
tissue.
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6
For oral administration, capsules, pills, tablets, coated
tablets, etc. are suitable. In addition to the active
ingredient, the dosage units can contain a pharmaceutically
compatible vehicle, such as, for example, starch, sugar,
sorbitol, gelatin, lubricant, silicic acid, talc, etc.
For parenteraI administration, the active ingredients can be
dissolved or suspended in a physiologically compatible diluent.
As diluents, very frequently oils with or without the addition of
a solubilizer, a surfactant, a suspending agent or emulsifier can.
be used. Examples of oils that are used are olive oil, peanut
oil, cottonseed oil, soybean oil, castor oil and sesame oil.
The compounds can also be used in the form of a depot
injection or an implant preparation that can be formulated in
such a way that a delayed release of active ingredient is made
possible.
Implants can contain as inert materials, for example,
biodegradable polymers or synthetic silicones such as,.for
example, silicone gum. In-addition, the active ingredients can
be added to a patch for percutaneous administration, for example.
For the production of intravaginal systems (e.g., vaginal
rings) or intrauterine systems (e.g., pessaries, coils, IUDs,
Mirena(R)) that are charged with active compounds of general
formula I for local administration, various polymers,-such as;
for example, silicone polymers, ethylenevinyl acetate,
polyethylene or polypropylene, are suitable.
To achieve a better bio-availability of the active
ingredient, the compounds can also be formulated as cyclodextrin
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7
clathrates. In this connection, the compounds are reacted with
a-, 8- or y-cyclodextrin or derivatives of the latter
(WO 96/002277).
According to the invention, - the compounds of general formula
I can also be encapsulated with liposomes.
The compounds according to the invention have a hybrid-type
profile of action. They are inhibitors of 5a-reductase and,
moreover, also act as gestagens. They are therefore suitable for
treating diseases that are the result, of elevated androgen levels
in certain organs and tissues-in men and women. In women,
elevated levels of 5a-dihydroprogesterone can contribute to
serious feelings of ill-health during the premenstrual syndrome.
This can be advantageously influenced by inhibition of the 5a-
reductase.
The simultaneous presence of a gestagenic action in
compounds according to the invention results in an inhibition of
gonadal function in males and females. This effect is desirable.
if an antifertile action or else an inhibition of the hormone
secretion of the gonads is to be achieved with the treatment.
This is frequently the case in diseases of the prostate (benign
prostate hyperplasia). In addition to prostate diseases,
possible indications are contraception in both sexes, alopecia of
the male type, acne and hirsutism. Together with other hormonal
substances, such as an estrogen, testosterone or a strong
androgen, the compounds according to the invention are suitable
as contraceptive agents for women or for men. In the latter
case, the action of testosterone in the prostate by inhibition of
8
the 5a-reductase is reduced, while the gestagenic activity
enhances the action in the male gonads, i.e., the inhibition of
spermatogenesis.
If the compounds according to the invention are used for
female contraception, they can be used by themselves or together
with an estrogen. As estrogens, basically all estrogen-active
compounds are suitable: estrogens that can be used are, for
example;-ethinylestradiol, 1713-estradiol as well as its esters,
such as estradiol-3-benzoate, estradiol-17-valerate, -cyprionate,
~ -undecylate, -enanthate and/or other estradiol esters, (US-A-
2,611,773, US-A-2,990,414, US-A-2,054,271, US-A-2,225,419 and US-
A-2,156,599) and conjugated estrogens.
Estradiol-, ethinylestradiol- and estrone-3-sulfamates, for
example estrone-N,N-dimethylsulfamate, estrone-N,N-
diethylsulfamate, ethinylestradiol-3-N,N-dimethylsulfamate,
ethinylestradiol-3-N,N-diethylsulfamate, ethinylestradiol-3-N,N-
tetraniethylenesulfamate, estrone sulfamate, estradiol-3-
sulfamate, estradiol-3-N,N-dimethylsulfamate, estradiol-3-N,N-
diethylsulfamate, and ethinylestradiol-3-sulfamate, which produce
all prodrugs of the corresponding 3-hydroxy.compounds (W. Elger
et al., in J. Steroid Biochem. Molec. Biol., Vol. 55, No. 3/4,
395-403, 1995, DE 44 29 398 Al and DE 44 29 397 A1),.can also be
used according to the invention.
If the compounds according to the invention are used for
male contraception, they can be used by themselves or together
with an androgen, such as, for example, testosterone and
testosterone esters.
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9
Data for 5o-reductase-type 2-activity in genital.dermal
homogenates and in vivo data for gestagenic activity are
presented by way of example in Tables 1 and 2 below.
Table 1
5a-Reductase-Type 2-Activity in Genital Dermal Homogenates
under Optimized Conditions at pH 5.5 (IC50("))
~ Progesterone-receptor binding to uterus-cytosol, rabbits, primed
Tracer: 3H-ORG 2058/incubation conditions.0-4 C; 18 hours
Reference substance: progesterone = 100%
Compound ICSO(nM) PR
Progesterone = 100%
(1) E-17-Chloromethylene-4- 250 . 60
chloro-estr-4-en-3-one
Table 2
In-vivo Data for Gestagenic Activity
z__~
Mouse pregnancy maintenance test after s.c: administration
Compound Dosage Pregnancy
mg/animal/day rate achieved
S.C.
(1) E-17-Chloromethylene-4- 1.0 5/5
chloro-estr-4-en-3-one 0.1 0/5
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10
The data presented in Tables 1 and 2 confirm the hybrid-type
profile of action of the compounds.according to the invention
that act as inhibitors of 5a-reductase and as gestagens.
The 17-methylene steroids of general formula I according to
the invention are available from compounds of general formula II-
(K. Ponsold et al., Pharmazie [Pharmaceutics] 33, 792 (1978)) and
general formula V.
The com.pounds of general formula V are.obtained from the
corresponding 17a-epoxy compounds (G. Drefahl et al., Ber. 98,
~ 604 (1965)) by reaction with a halide, such as, for example,
hydrogen chloride or hydrogen bromide, or pseudohalide, such as;
for example, hydrogen_thiocyanate or hydrogen nitride, iri a
dipolar aprotic solvent, preferably DMSO or DMPU.
Ho
Rzo
R2o HO
Rio
Rio Rioa
, ~ ~' ,II =
O_
The compounds.of Formula I are obtained by a compound of
general formula II being reacted in an aprotic solvent,
preferably in pyridine or triethylamine, with an acid chloride,
preferably thionyl chloride or phosphoroxy chloride, to a
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11
compound of general formula III,
Rio
Rl0
o . ~ zlr
the latter being subjected in a way that isknown in the art to
an epoxidation with HZ02/NaOH in an alcohol, preferably methanol
or ethanol, the resulting 4,5-epoxide being opened with
nucleophiles, such as halide, such as for example, hydrogen
chloride or hydrogen bromide or pseudohalide, such as,.for
example, hydrogen thiocyanate or hydrogen nitride, in a dipolar
aprotic solvent, preferably DMSO or DMPU, dioxane or acetone, to
halogen= or pseudohalogen hydrins, and the latter being
dehydrated with catalytic mediation by mineral acid, carboxylic
acid or sulfonic acid, such as hydrochloric acid, oxalic acid or
p-toluenesulfon.ic acid, in a protic or aprotic solvent, such as
methanol or acetone, to a compound of general formula IV
R20
~
R'
O ~ IV R
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12
in which R4 stands for a halogen atom or pseudohalogen, whereby
R10 has the above-indicated meaning, and R20 means a C1_4 alkyl or
hydroxy-C1_4 alkyl group, a halogen atom or a pseudohalogen.
In addition, 17-methylene steroids of general formula I are
obtained by a compound of general formula V being reacted in an
aprotic solvent, preferably in pyridine or triethylamine, with an
acid chloride, preferably thionyl chloride or phosphoroxy
chloride, to a compound of general formula VI
~ R20a '
R20
Rio
vi
the latter being subjected in a way.that is known in the art to
an epoxidation with HzOZ/NaOH in an alcohol, preferably methanbl
~~ .
or ethanol, the resulting 4,5-epoxide being opened with a'
nucleophile, such as a halide, such as, for example, hydrogen
chloride or hydrogen bromide or pseudohalide, such as, for
example, hydrogen thiocyanate or hydrogen nitride, in a dipolar
aprotic solvent, preferably DMSO or DMPU, dioxane or acetone-to a
halogen- or pseudohalogen hydrin, and the latter then being
dehydrated with catalytic mediation by mineral acid, carboxylic
acid or sulfonic acid, such as hydrochloric acid, oxalic acid or.
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13
p-toluenesulfonic acid, in a protic or aprotic solvent, such as
methanol or acetone, to a compound of general formula VII.
R20a
ViI
R4
Finally, other 17-methylene steroids of general formula I
can be obtained by compounds of general formulas III and VI
R R20 Rzoa
Rzo
Rlo
Rio
o / III i VI
being reacted in a way that is known in the art (M. Haase-Held,
M. Mattis and J. Mann, J. Chem. Soc. Perkin Trans. 1, 2999, 1992)
with Na104/KMnO4 in alcohols, preferably in t-BuOH to the 3,5-
seco-keto acids, the latter being converted with AcZO/AcC1 into
unsaturated lactones and the latter being reacted with n-
BuLi/CH3CN in a-dipolar aprotic solvent, such as tetrahydrofuran
(THF), into compounds of general formulas VIII and IX.
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14
H
R 20 Rzoa
R10 /
Rio
VITI
CN 0 LX
CN
~ E-17-Chloromethylen-estr-4-en-3-one can also be produced by
WITTIG reaction with chloromethyltriphenylphosphonium chloride
(S. Miyano et al., J. C. S. Chem. Comm., 446 (1978)). The
isomeric 17-cyanomethylen-estr-4-en-3-ones can also be obtained
by carbonyl olefination according to HORNER with cyanomethylene
diethyl phosphonate or by PETERSON olefination with
trimethylsilylacetonitrile (EP-A-O 077 040 or I. Ojima et al.,
Tetrahedron Lett. 46 (1974) 4005-4008).
Z-20-Cyano-19-norpregna-4,17(20)-dien-3-one is synthesized.
by PO-activated carbonyl activation with 2-dietYiylphosphono-
propionitrile (R. W. Freerksen et al., Journal American Chemical
Society (1977) 1536).
The invention is explained in.more detail by the examples
below.
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15
Example 1
Z-17-(1'-Chloroethylidene-4-chloro-estr-4-en-3-one
A) Z-17-(1')-Chloroethyliden-estr-4-en-3-one
9.74 mmol (3.28.g) of 17J3-(1')-chloroethyl-17-hydroxy-estr-
4-en-3-one (see compounds of general formula V) is dissolved in
34 ml of pyridine. While being cooled slightly, 12.66 mmol (0.92
ml) of thionyl chloride is added in drops while being stirred.
It is stirred for about 1 hour under a cover gas..(argon), and the
reaction solution is then added to ice-cooled, dilute
hydrochloric acid with a pH = 3-4. The sticky precipitation
product is extracted with methylene chloride, the combined,
neutral-washed extracts are dried with sodium sulfate and.
concentrated by evaporation. The accumulating solid product is
purified by chromatography on silica gel (eluant: toluene/ethyl
acetate = 95/5) and optionally recrystallization from methanol.
0.6 g of a solid product is obtained.
Flash point = 138-141 C; [a]pZ0 _ +104 (CHC13)
B) Z-17-(1')-Chloroethylidene-4E 5E-epoxy-estran-3-one
~
2.80 mmol (894 mg) of Z-17-(1'-(chloroethyliden-estr-4-en-3-
one is dissolved in a mixture of 9 ml of methanol and 7.3 ml of
methylene chloride and cooled to 0 C: 6.31 mmol (0.63 ml) of
hydrogen peroxide (30%) and 1.26 mmol (0.3 ml) of sodium
hydroxide solution (c = 4 mol/1) are added in drops in succession
to the cooled solution while being stirred and under a cover.gas
(argon). After dropwise addition is completed, the temperature
is slowly increased to room temperature. After about 1.5 hours
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16
of reaction time, the mixture is added to ice water and then
extracted with methylene chloride. The combined extracts are
dried with sodium sulfate and concentrated by evaporation. 926
mg of a light yellow solid is obtained.
'H-NMR/d (CDC13/PPm) 0.94(18-H), 199(21-H), 3.04 (4-H)
C) Z-17-(1')-Chloroethylidene-4-chloro-estr-4-en-3-one
2..71 mmol (896 mg) of Z-17-(1')-chloroethyliden-4E,5E.,epoxy-
estran-3-one is dissolved in 25 ml of 1,3-dimethyltetrahydro-
2(1H)-pyrimidinone.(DMPU), and 26.54 mmol (2.2 ml) of
~ .
hydrochloric acid (37%) is slowly added in drops. After 1 hour
of stirring under a cover gas (argon), the reaction solution is
added to ice-cooled,.aqueous sodium bicarbonate solution, the
precipitation is suctioned off, and it is finally dried in a
desiccator with potassium hydroxide. By flash-chromatography on
silica gel (eluant.: toluene/ethyl acetate = 99/1) and subsequent
recrystallization from methanol/acetone, 353 mg of solid product
is obtained.
Flash point = 182-185 C; [a)o20 = +137 (CHC13)
_.~ . .
Example 2
Z-17-(1')-Bromoethylidene-4-chloro-estr-4-en-3-one
Starting from 1713-(1')-bromoethy1-17-hydroxy-estr-4-en-3-one
(see compounds of general formula V), Z-17-(1')-bromoethylidene-
4-chloro-estr-4-en-3-one is obtained analogously to 1713-(1')-
chloroethyl-estr-4-en-3-one.
Flash point = 164-173 C; [aJo20 = +138 (CHC13)
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17
Example 3
E-17-Chloromethylene-4-chloro-estr-4-en-3-one
A) E-17-Chloromethylen-estr-4-en-3-one
18.27 mmol (5.9 g) of 17a-chloromethyl-17-hydroxy-estr-4-en-.
3-one is dissolved in 60 ml of pyridine. While being cooled
slightly, 21.9 mnmol (1.56 ml) of thionyl chloride is added in
drops while being stirred. It-is stirred under a cover gas
(argon) for about 1 hour, and the reaction solution is then added
to ice-cooled, dilute hydrochloric ac.id with a pH = 3-4. The
~ sticky precipitation product is extracted with methylene
chloride, the combined, neutral-washed extracts are dried on
sodium sulfate and concentrated by evaporation. The accumulating
solid product is purified by chromatography on silica gel
(eluant: n-hexane/ethyl acetate = 85/15). After
recrystallization from acetone, 1.6 g of product is obtained.
Flash point = 143-146 C; [a]p20 _ +20 (CHC13)
B) E-17-Chloromethylene-4k,5E-epoxy-estran-3-one_.
3.93 mmol (1.2 g) of E-17-chloromethylen-estr-4-en-3-one is
dissolved in a mixture of 12 ml of methanol and 10 ml of
methylene chloride under a cover gas (argon) and cooled to.0 C.
9.2 mmol (0.94 ml.) of hydrogen peroxide (30%) and 1.65 mmol (0.4
ml) of sodium hydroxide solution (c = 4 mol/1) are added in drops
in succession to the cooled solution while being stirred. After
dropwise addition is completed, the temperature is slowly
increased to room temperature. After about 1.5 hours of reaction
time, the mixture is added to ice water and extracted with
CA 02421302 2003-03-03
18
methylene chloride. The combined extracts are dried on sodium
sulfate and concentrated by evaporation. 1.1 g of a white,
sticky foam is obt.ained.
'H-NMR/b (CDC13/ppm) 0.87(18-H), 3.04(4-H), 5.70(20-H)
C) E-17-Chloromethylene-4-chloro-estr-4-en-3-one
3.42 mmol (1.1 g) of E-17-.chloromethylene-4E,5E-epoxy-
estran-3-one is dissolved in 26 ml of DMPU, and 33 mmol (2.74 ml)
of hydrochloric acid (37%) is slowly added in drops. After 1
hour, the reaction solution is added to ice-cooled, aqueous
sodium.bicarbonate solution, the precipitation is suctioned off
and dried in a desiccator on potassium hydroxide. 'After.
recrystallization from acetone, 760 mg of white crystals is
.obtained.
Flash point = -182-194 C; [cz]p2 _ +63 (CHC13)
Example 4
E-17-Brot~omethylene-4-chloro-estr-4-en-3-one
-Starting from E-17-bromomethyl-.178-hydroxy-estr-4-en-3-.one
~ =
(see compounds of general formula II), E-17-bromomethylene-4-
chloro-estr-4-en-3-one is obtained analogously to 17a-
chloromethyl-17-hydroxy-estr-4-en-3-one.
Flash point = 169-176 C; [a]p20 _ +45 . (CHC13)
CA 02421302 2003-03-03
