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Патент USA US3088958

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3,088,946
United States Patent 0 "ice
Patented May 7, 1963
2
1
benzoate, trimethylacetate, phenoxyacetate, phenylpropio
3,083,946
natc, cyclopentylpropionate, tri?uoroacetate and ?-chloro
propionate. When A is 1741-10WBI' alkin(l)yl-17?-hy
droxy in a A4-3-ketone, the compounds exhibit progesta
tional activity.
STEROIDAL C-6 ALKINYL OR ALKENYL DERIVA
TIVES AND PROCESS FOR THE PREPARATION
THEREOF
John A. Zderic and Howard J. Ringold, Mexico City,
Mexico, assignors, by mesne assignments, to Syntex
Corporation, a corporation of Panama
No Drawing. Filed Jan. 19, 1960, Ser. No. 3,277
Claims priority, application Mexico Jan. 20, 1959
33 Claims. (Cl. 260-43955)
The present invention relates to cyclopentanophenan
The novel compounds of this invention which are also
progestational type agents having anti-estrogenic, anti
androgenic and anti-pituitary activity may be character
ized by the following formulae:
10
threne compounds and to a novel process for the pro
duction thereof.
More particularly the invention relates to novel steroid
compounds which have an alkinyl or alkenyl substituent 15
at 0-6.
The novel compounds of the present invention are
valuable hormones as Well as valuable intermediates for
the production of other valuable steroids as hereinafter
20
described.
The novel compounds of the present invention which
are valuable androgenic-type hormones having anabolic,
anti-estrogenic and anti-gonadotropic activity may be
In the above formulae R, R1, Y and E represent the
characterized by the following formulae:
A
R.
R--
A
l
l
R.
R"
QE
!
6:011,
same groups as heretofore set forth; R5 represents hydro
gen, hydroxy or ocyloxy, the acyl being derived from a
hydrocarbon carboxylic acid containing from 1 to 12
carbon atoms as described hereinabove. X represents
hydrogen, chlorine, bromine or ?uorine and when Y
is hydrogen, X must be hydrogen.
M0
Similarly the novel C-6 substituted derivatives of the
diesters of ‘hydrocarbon carboxylic acids of the same type
as above stated of Reichstein’s Compound “S” exhibit
the same biological activity, in ‘addition to being useful
intermediates for the preparation of cortical hormones
35 by introducing an oxygen function at 0-11 by known
means.
Cl
The novel compounds of the present invention which
exhibit anti-in?ammatory, thymolytic and glycogenic ac
tivity may be illustrated by the following formulae:
ClIrOR°
0:0
'---0 RT
Rt
45
In the above formulae, R represents hydrogen or lower
alkyl containing 1 to 5 carbon atoms; R1 represents hydro
gen or methyl; A represents ?-hydroxy, ?-acyloxy, 17a
lower alkyl-??-hydroxy, 17a-lower alltin(1)yl-17,6-hy
droxy,l7a-lower alken(l)yl-17B-hydroxy; Y represents
u-hydroxy, ,B-hydroxy, keto or hydrogen. E represents
?-lower alkinyl and B-lower alkenyl groups containing 1
to 8 carbon atoms and may be of straight, branched, cyclic 55
or mixed straight or branched cyclic and may also be
substituted by hydroxy, alkoxy or halogen as chlorine,
bromine and ?uorine. R‘ represents ?-hy-droxy, keto or
cyclic alkylene dioxy. The aforesaid ,acyl groups are de
rived from a hydrocarbon carboxylic ‘acid containing from 60
1 to 12 carbon atoms, saturated or unsaturated, straight
chain or branched chain aliphatic, cyclic, cycliceliphatic,
aromatic and may be substituted by, for example, halo
gen.
Typical ester groups are the formate, acetate,
propionate, butyrate, hemisuccinate, enanthate, caproate,
0:1
i TR!
3,088,946
3
4
In the above formulae, R, R4, and E have the same mean
ing as hereinabove set forth. R6 represents hydrogen or
When starting with a 3?-hydroxy compound, the process
acyl; Y represents keto, a-hydroxy or ?-hydroxy. X
represents hydrogen, chlorine, bromine or ?uorine. R8
represents hydrogen, u-methyl or ?-methyl. When R8 5
represents hydrogen, R'I represents hydrogen; when R8
represents acyl, R7 represents hydrogen or acyl. The acyl
group in each instance is derived from a hydrocarbon
carboxylic acid containing 1 to 12 carbon atoms of the
character as heretofore stated.
1O
Certain novel compounds of the present invention are
proceeds in a similar manner, as follows:
,
H0
Grignard
_
ylation of the ??-lower alkenyl, particularly the tS?-vinyl
_,
HO—
i
I
no
0
/
also valuable intermediates for the preparation of 6;?
(dihydroxy lower alkylene) derivatives of androstane and
pregnane compounds which may be prepared by hydrox
compounds of the present invention with osmium tetroxide.
The preparation of the C—6 substituted cyclopentano
__..
,
1/
.
EC R°
.
/Reduet1on
O xidation
15
HO
polyhydrophenanthrene compounds which form the sub
ject of the present invention may be illustrated by the
‘
0_
H=CHR°
following equation, insofar as rings A and B are con
cerned. When a A4-3-keto compound is used as the start
\Oxidation
\
ing material; the process proceeds in the following
l Reduction
manner:
/
‘l
Dehydration
<________
l
‘
/
Ketallzatlon and
0_
O
~___-_>
O:
0:
(hH=0HR°
epoxidatlon
/
0
:
; ,.
‘
HO
11:01am
30
In the above equations, R9 represents hydrogen or lower
o
alkyl.
In practicing the processes above outlined, a 511,60;
oxido compound of the androstane or pregnane series,
lalkinyl Mg B r
35 substituted at C-3 by hydroXy or 3-cyclic alkylene dioxy,
preferably 3-ethylenedioxy, is reacted with an alkinyl
Grignard reagent, preferably acetylenic magnesium halide
reduction
[ "Q
0
r“ [ °
'
0
n6
no
and more particularly ethinyl magnesium bromide under
re?ux conditions in a solvent such as tetrahydrofurane to
40 form a 6?-ethinyl-5a-hydroxy compound,
The latter can
then be converted to the 3~keto<6?~ethinyl ia-hydroxy
compound by hydrolysis of the 3-ketal group with an
(J H=G H R"
acid such as dilute perchloric acid in tctrahydrofurane, p
toluenesulfonic acid in aqueous acetone, or hydrochloric
or sulfuric acid in aqueous lower alkanols, or by oxida
l hydrolysis
tion of the SB-hydroxy group by treatment with an oxid
izing agent as for example, chromic acid. The GB-ethinyl
Sa-hydroxy compound substituted at C~3 by keto, B-hy
droxy or ethylenedioxy is reduced to the corresponding
O=
0 6,8-vinyl-5a-hydroxy compound either by catalytic hydro
,
genation in the presence of a hydrogenation catalyst such
Ho
H=OH It“
as palladium on calcium carbonate in a solvent such as
pyridine or by the use of lithium in liquid ammonia in
the absence of alcohol. Where a 6,8,l7a-di-ethinyl com
ldchydration
55
pound is hydrogenated, reduction of the l7a-ethinyl group
to l7a-vinyl is effected at the same time.
at.
Catalytic
hydrogenation
a.__h__
Prior to the reduction step, the 3-keto-6?-ethinyl-5a-hy
droxy compounds may be dehydrated as by treatment with
potassium acetate and methyl alcohol under re?ux con
60 ditions or with thionyl chloride in pyridine solution at low
temperature, to yield the corresponding 6t9-ethinyl-A4-3
keto compound, which may then subsequently be reduced
to the 6?-vinyl-A4-3-keto derivative. It is also within the
scope of the present invention to effect dehydration sub
a _)1 sequent to the reduction step.
The alkenyl moiety may also be introduced directly at
only
CIOR“
C-6 by the use of an alkenyl magnesium halide in an
inert solvent such as dioxane under re?ux conditions, or
lower temperatures for a long period of time.
70
Alternatively the 6?-ethinyl-A4-3-keto compound may
be treated with hydrochloric acid which results in the ad
dition of the elements of hydrogen and halogen to the
acetylenic bond with simultaneous inversion of the steric
con?guration at C-6 to form the ?u-[l-Ci'liOl"O'Vinyi)-A4'3—
keto compound.
8,088,946
5
are not intended to limit the present invention.
The organic phase was separated, washed with water, dried
Example I
over anhydrous sodium sulfate and the solvent was evapo~
rated. Chromatography of the residue on neutral alumina
A stream of acetylene was introduced into a cooled mix
ture of 250 cc. of 4 N methylmagnesium bromide in
ether and 1000 cc. of tetrahydrofurane, for 3 hours and
taking care that the temperature did not rise over 10° C.
There were then added 10 g. of 3-ethylenedioxy-5a,6a
oxido-androstan-??-ol dissolved in 100 cc. of tetrahydro
6
of the reagent; the mixture was kept for 12 hours in the
dark at room temperature and then diluted with water.
The following speci?c examples serve to illustrate but
yielded 3-ethylenedioxy-5a,6a-oxido~androstan-17?-ol.
10
furane and the mixture was re?uxed for 20 hours under
an atmosphere of nitrogen. It was then cooled, poured
into 5 l. of ice cold aqueous 20% ammonium chloride
solution; the product was extracted with several portions
of ethyl acetate, the combined extract was washed with
sively 6,8-ethinyl-17a-methyl-3-ethylenedioxy-androstane
5a,l7B-diol and 6B~ethinyl-l'Ia-methyl-androstane-Sa,17,3
diol~3-one.
A solution of l g. of the above compound in 30 cc. of
methanol was treated with l g. of potassium acetate and
the mixture was re?uxed for 1 hour. It was then cooled,
poured into ice water and the formed precipitate col
water, dried over anhydrous sodium sulfate and the sol
vent was evaporated. Chromatography of the residue on
neutral alumina afforded the pure GB-ethinyl-S-ethylenedi
oxy-androstane-5a,17p-diol, M.P. l08—110° C., [0:]5 —47
(pyridine).
Example 2
By following the procedure described in Example 1, 5
g. of 17DL-lTlBthYl-3-BthyiEI1€dlOXy-5OL,60t-OXidO-3l'ldl‘05t3?
175-01. obtained from 17u-methyl-testosterone by apply
ing the preparation method of Example 1, yielded succes
20
A solution of 5 g. of the above compound in 100 cc. of
acetone was treated with 500 mg. of p-tolucnesulfonic acid
and kept for 4 hours at room temperature. It was then
diluted with water and the precipitate formed was col
lected by ?ltration, washed with water, dried, chromato
graphed on neutral alumina and ?nally recrystallized from
lected. Crystallization from methylene chloride-ether gave
the pure é?-ethinyl-l7a-methyl-testosterone.
The later compound was hydrogenated in pyridine solu
tion and the using 2% palladium on calcium carbonate as
catalyst, in accordance with the hydrogenation method
25
of Example 1, thus affording 613-vinyl-17a-methyl-testos
terone.
Example 3
By following the procedure described in Example 1, 5 g.
acetone. There was thus obtained 6?-ethinylandrostane
5a,l7l3-diol-3-one with M.P. 240-245", raised to 258
260“ C. after several recrystallizations, [411D — l9 (chloro
of l7a-ethinyl-3~ethylenedioxy-5a,6a-oxido-androstan-17b
form).
ol, obtained from 17a-ethinyl-testoster0ne by applying the
A solution of 1 g. of the above compound in 15 cc. of
pyridine was cooled to 0” C. and treated with 1 cc. of
preparation method of Example 1, was converted succes
thionyl chloride for 8 minutes while cooling in an ice bath.
The mixture was poured into 40 cc. of water, the product
was extracted with several portions of ethyl acetate and
the combined extract was washed with dilute hydrochloric
acid and water, dried over anhydrous sodium sulfate and
511,173 - diol; 6B,l7a-bis-ethinyl-androstane-Sa,17,8-diol-3
one and 65,l7a-bis-ethinyl-testosterone.
the ethyl acetate was evaporated. The residue was dis
solved in acetone, decolorized with charcoal and then puri
?ed by repeated recrystallization from acetone, thus af
fording G?-ethinyl-testosterone.
A suspension of 900 mg. of 2% palladium on calcium
carbonate in 150 cc. of pure pyridine was treated with
hydrogen at room temperature for 3 hours to pre-reduce
the catalyst. There was then added 3 g. of GB-ethinyl
testosterone and the mixture was hydrogenated under
continuous stirring at room temperature until the absorp
tion of hydrogen practically ceased, which occurred when
1 molar equivalent of hydrogen had been absorbed. The
catalyst was removed by ?ltration washing the filter with
a little pyridine and the combined ?ltrate and washings
was evaporated to dryness under reduced pressure. The
residue was dissolved in ether, the ether solution was con
secutively washed with dilute hydrochloric acid, water, sat
urated aqueous sodium bicarbonate solution and ?nally
again with water, dried over anhydrous sodium sulfate
and the ether was evaporated. Recrystallization of the
residue from acetone-hexane yielded ??-vinyl-testosterone.
sively into 6,9,l7a-bis-ethinyl-3-ethylenedioxy-androstane
A solution of 1 g. of the latter compound in 20 cc.
of pyridine was added to a suspension of 500 mg. of 2%
palladium on calcium carbonate in 100 cc. of pyridine,
that have been previously reduced. The mixture was
hydrogenated under continuous stirring at room tempera
ture until 2 molar equivalents of hydrogen were absorbed.
The catalyst was removed by ?ltration and the solution
was worked up in accordance with the method described
in Exampie 1. There was thus obtained 6p,l7a-di-vinyl
testosterone.
Example 4
By following the procedure described in Example 1,
but substituting the ethinylmagnesium bromide for vinyl
rnagnesiurn bromide, l7wethinyl-3-ethylenedioxy-5a,6a
oxido-androstan-??-ol was converted successively into
6,8-vinyl-l7a-ethinyl-3-ethylenedioxy - androstane-5a,l7?
diol;
op-vinyl-l’la-ethinyl - androstane-Sa, 17 p-diol-B-one
and 6,8-vinyl-1Methinyl-testosterone.
Example 5
5 g. of 3-ethylenedioxy-5a,6a-oxido-9-nor-androstan
175-01, obtained from l9-nor-ethinyl-testosterone, by the
preparation method described in Example 1, was proc
essed in accordance with the method described also in
The starting material, namely 3-ethylenedioxy-5a,6a
Example 1, but substituting the stream of acetylene for
oxido-androstan-UB-ol was obtained by the following 60 butine-l, there were thus successively obtained ti?-butin
method of preparation:
( l )yl-3-ethylenedioxy-l9-nor»androstane-5ot,l7B-diol; 6e
A mixture of 5 g. of testosterone, 300 cc. of anhydrous
butin(1)yl-l9-nor-androstane-5a,l7?-diol-3-one and 618
benzene, 35 cc. of ethyleneglycol and 500 mg. of p-toluene
tbutin( l )yl- l Q-nQr-testosterone.
sulfonic acid monohydrate was re?uxed for 24 hours, with
the use of a water separator for removing the water
Example 6
formed during the reaction; the cooled mixture was treated
A
solution
of
5
g.
of 3-ethylenedioxy-5a,6a-oxido
wlth 50 cc. of 5% aqueous sodium carbonate solution and
androstan-l7,6~o1-ll-one, obtained from ll-keto-testos
200 cc. of water and the benzene layer was separated,
terone by the preparation method described in Example
washed with water, dried over anhydrous sodium sulfate,
filtered and the benzene was evaporated. By chromatog 70 1, in 100 cc. of tetrahydrofurane was treated with ethinyl
magnesium bromide, in accordance with the method de
raphy on neutral alumina there was obtained 3-ethylene
dioxy-M-androsten-l75-01.
To a cooled solution of 5 g. of the above compound
in 100 cc. of chloroform was added an ether solution
of monoperphthalic acid containing 1.2 molar equivalents
scribed in Example 1, and the resulting 6?-ethinyl-3-eth
ylenedioxy-androstane-Sa,l7?-diol-ll-one was hydrolized
with p-toluenesulfonic acid in acetone solution, thus yield
ing 6p-ethinyl-androstan-5a,17B-diol-ll-one.
3,088,946
7
8
A mixture of 1 g. of the above compound, 5 cc. of
pyridine and 3 cc. of acetic anhydride was kept at room
temperature for 4 hours, it was poured into water, the
formed precipitate was ?ltered, washed with water and
Example 1'1
A solution of 5 g. of 3,ZO-bis-ethylenedioxy-Sa,6a
oxido-pregnane obtained from progesterone by the prepa
ration method of Example 1, was treated with ethinyl
dried, thus producing the 17-acetate of GB-ethinyl-andro
magnesium bromide in accordance with the method of
stan-5u,17/3-diol-1l-one.
Example 1, to afford 6?-ethinyl-3,ZO-bis-ethylenedioxy
pregnan-Sa-OI, M.P. 144-146" C.; [1119 —35‘’ (chloro
The above crude compound was treated with thionyl
chloride in pyridine solution, by following the dehydra
tion method of Example 1, to produce the acetate of
6;.3-ethinyl-1l-keto-testosterone.
Hydrogenation of the latter compound in pyridine solu
form). The ketal groups were then hydrolized with
p'toluenesulfonic acid in acetone, to afford 6?-ethinyl
10 pregnan-5a-ol-3,20-dione, M.P. 288-290° C. (dec.);
[MD +51.4° (chloroform). Dehydration of the above
compound with thionyl chloride in pyridine gave 65
ethinyl-progesterone, M.P. ISO-184° C.; [ab +46°
tion, and using 2% palladium on calcium carbonate as
catalyst, in accordance with the method of Example 1,
gave the acetate of 618-vinyl-1l-keto-testosterone.
15
Example 7
Hydrogenation of the latter compound in pyridine solu
tion, using 2% palladium on calcium carbonate as cata
A solution of 5 g. of 2a,17a-dlmethy1-5a,6a-0Xld0
lyst, in accordance with the method of Example 1, gave
androstan-17,B-ol, obtained from 20:,l7ot-Cll1‘IlCIhYl-1CSIOS
6?-vinyl-progesterone.
terone by ketalization followed by epoxidation, in ac
cordance with the preparation method of Example 1, was
Example 12
By following the procedure described in Example 1, but
treated with ethinylmagnesium bromide, and the resulting
2m,17a-dimethyl-65-ethinyl - 3 - ethylenedioxy-androstane,
using 3,20-bis-ethy1enedioxy-5a,6a~oxido-pregnan-17a-ol
5a,17;3-diol was hydrolyzed with p-toluenesulfonic acid in
as starting material, obtained from l7u-hydroxy-proges
terone by the preparation method described in Example
1, there were obtained successively, 6?-ethinyl-3,20-bis
acetone solution, in accordance with the method de
scribed in Example 1 to produce 20:,17wdlt116thYl-613-8th
inyl-androstane-Sa,17?-diol-3-one.
ethylenedioxy-pregnan-Sa,l7a-diol, MAP. 210—213° C.;
The above compound was dehydrated with potassium
acetate in methanol by following the procedure described
[ab-48 (chloroform); SB-ethinyI-pregnan-Sa,17a-diol
3,20~dione and 6,8-ethinyl-17a-ol-3,20~dione, i.e. GB-ethin
in Example 2, thus giving 2a,17a-dimethyl-6B-ethinyl
testosterone.
(dioxane).
30
Example 8
In accordance with the hydrogenation method of Ex
ample 1, 2 g. of 2a,17a-dimethyl-6l3-ethinyl-androstane
5a,17;S-diol-3-one, intermediate in the preceding exam
ple, was converted into 211,17rx-dimethyl-??-vinyl-andro
yl-17a-hydroxy-progesterone.
A mixture of 1 g. of the above compound, 40 cc. of
acetic acid, 20 cc. of acetic anhydride and 1 g. of p
toluenesulfonic acid was kept at room temperature for
1 hour. The resulting dark solution was poured into ice
water and heated on the steam bath for 30 minutes. It
was then extracted with ethyl acetate, and the organic
extract washed with water, 5% sodium bicarbonate solu
tion and again with water, dried over anhydrous sodium
sulfate and evaporated to dryness under reduced pressure.
Chromatography of the residue gave G?-ethinyl-l'la-ace
stane-5a,17B-diol-3-one.
Dehydration of the latter compound with potassium
acetate in methanol, by applying the method described
in Example 2, gave 2a,17a-dimethyl-o?-vinyl-testosterone.
toxy-progesterone.
Hydrogenation of the latter compound in accordance
with the method described in Example 1, afforded 6,3—
Example 9
vinyl~17a-acetoxy-progesterone.
10 g. of 5a,6a-oxido-17u-methyLandrostan-3B,l7u-diol
3—monoacetate, described by H. J. Ringold et al. in J.O.C.,
22, 99 (1957) was treated with ethinylmagnesium bro
mide, in accordance with the method described in Ex
Example 13
To a solution of ethylmagnesium bromide, prepared
from 3.63 g. of magnesium, 16.3 g. of ethyl bromide and
350 cc. of ether, was added 10.52 g. of ethoxyacetylene
dissolved in 175 cc. of ether, under continuous stirring
A solution of 3 g. of the above compound in 120 cc.
of acetone was cooled to 0° C., ?ushed with nitrogen and 50 and in the course of 30' minutes. The mixture was
stirred for 1 hour further and to the ether solution of
treated with an 8 N solution of chromic acid, under
ethoxyacetylene bromide thus obtained there was then
stirring at 0° C. and under an atmosphere of nitrogen
added a solution of 5 g. of 3,20~bis-ethylenedioxy-5u,6a
until the color of chromium trioxide persisted in the mix
oxido-pregnane in 100 cc. of benzene. The mixture was
ture (the 8 N solution of chromic acid had been pre
re?uxed for 5 hours under an atmosphere of nitrogen,
pared by dissolving 26.7 g. of chromium trioxide in 23 cc.
poured into 450 cc. of 20% aqueous ammonium chlo
of concentrated sulfuric acid and diluting with distilled
ride solution and the organic layer was separated, washed
water to 100 cc.). The mixture was stirred for 5 min
with water to neutral, dried over anhydrous sodium
utes more at 0° C. under an atmosphere of nitrogen,
sulfate and the solvent was evaporated. By chromatog
then diluted with ice water and the precipitate was col
raphy of the residue on neutral alumina there was ob
lected, washed with water, dried and recrystallized from
ample 1, to produce GB-ethinyl-17a-methyl-androstane
3;3,5a,17a-triol.
tained 6/i-ethoxyethinyl-3,20-bis-ethylenedioxy-pregnan
acetone-ether, to produce ??-ethinyl-l7lx-methyl-andro
Soc-01, which was then treated with p‘toluenesulfonic acid
in acetone solution, in accordance with the method of
stan-5a,l7j3-diol-3-one, identical with that obtained in
Example 2. Dehydrogenation of the above compound
Example 1, to produce 6/3-ethoxyethinyl~pregnan-5a-ol
with potassium acetate in methanol, as described in Ex
ample 2, gave 6,8-ethinyl-17or-methyl-testosterone.
65
Example 10
In accordance with the method of Example 1, 2 g. of
3,20-dione. Dehydration of the above compound with
thionyl chloride in pyridine afforded 6(3-ethoxyethinyl
progesterone.
Example 14
To 20 cc. of acetic acid containing 1 g. of 65-ethinyl
5a,6a-oxido-androstane-3,8,l7?-diol diacetate, described 70 progesterone, obtained as described in Example 10, was
by Bowers et al. in Tetrahedron 1958, p. 14, was con
verted into 6?-ethinyl-androstane-3i3,5a,17B-triol.
Hy
drogenation of the above compound in accordance with
the method of Example 1, afforded ??-vinyl-androstan
3?,5a,l7;9-triol.
added 2 cc. of concentrated hydrochloric acid. The reac
tion mixture was kept at room temperature for 2 hours,
water was added and the mixture was extracted with
ethyl acetate. The extract was then washed with water,
dried over anhydrous sodium sulfate and evaporated to
3,088,946
dryness under vacuo. The residue was chromatographed
on neutral alumina, the ?rst fractions eluted gave, after
10
Example
I
I1
recrystallization from ether. 600 mg. of 6a—(l-chloro
vinyl)-progesterone, M.P. 158-161“I C.; [adv-+94” (di
19-nor~progestcrone _________ _ _
oxane) Am,‘ 240 my. log :1 4.16.
2O _______ -_ ga-?noro-ll?-hydroxy-
hydroxy-prc esterone.
21 _______ _. Qa-chloro-ll-keto-
Example 15
??-etlilnyl~9a~c lore-ll
progcsterone.
By following the procedure described in the previous
example, but using é?-ethinyl-testosterone as starting ma
terial, there was obtained 6a-(l-chloro-vinyl)-testoster
progesterone.
GB-cthinyLQw?uOro-ll?
progesterone.
hem-progesterone.
Cortisone _________________ __
??-ethinyl-eortisonc.
l?q-methylcortisoue ______ __
6t§~othlny1-l6a-mcthyl~
ll-koto-progcstcronc ....... __
??eethlnyl-ll-kcto
cortisone.
one.
progesterone.
Example 25
By following the hydrogenation method described in
Example 16
Example 1, 6,8-ethinyl-lda-methyl-cortisone was con
In accordance with the method described in Example
verted into 6?-vinyl-16a-rnethyl-cortisone.
Example 26
into 6l8-ethinyl-3,20~bis-ethylenedioxy-5a,l7a,2l-triol-2l
By following the hydrogenation method described in
monoacetate; G?-ethinyl-pregnan-Sa,l7a,2l-triol-3,20-di 20 Example 1, GB-ethinylwortisone was converted into 648
one-21-rnonoacetate and o?-ethinyl-d‘i-pregnane-l7a,2l
vinyl-cortisone.
1, 5 g. of 3,20-bis-ethylenedioxy-5a,6a-oxido-pregnan
l7a,2l-diol-2l-monoacetate were converted successively
diol-3,20-dione.
We claim:
1. A compound of the ‘following formula:
l g. of the above compound was acetylated at C-17
with acetic anhydride-acetic acid, in the presence of p
toluenesulfonic acid, in accordance with the method de
scribed in Example 9, thus producing 6?-ethinyl-A4-preg
nene-17a,2l-diol-3,20-dione diacetate.
The latter compound was hydrogenated by following
the procedure of Example 1, thus producing 6,3-vinyl
A4-pregnene-l7a,2l-diol-3,20-dione diacetate. Treatment
of the latter compound with concentrated hydrochloric
25
l
YAQ
Rt
30
acid in acetic acid, in accordance with the method of
E
Example 14, gave 6a-(l-chloro-vinyl)-A4-pregnene-17a,
2l~di0l-3,20»dione diacetate.
The starting material, namely 3,20-bis-ethylenedioxy
wherein R is selected from the group consisting of hydro
gen and lower alkyl; R’ is selected from the group consist
ing of hydrogen and methyl; Y is selected from the group
5a,6a-oxido-pregnan-17a,2l-diol-Zl-monoacetate, was ob
consisting of hydrogen,
tained from Ad-pregnen-l'la,2l-diol-3,20-dione by ketal
/0
ization at C-3 and C—20, acetylation at C-21 and ep
:0, x
oxidation of the resulting Sa,6a-oxido-A5-pregnene-l7a,
21-diol'3,20~dione Zl-acetate.
‘OH
and
"
)1
\OH
A is selected from the group consisting of
Example 17
(H
,H
'lower alkyl
\OH \OAcyl \OH
To a solution of l g. of sodium metal in 500 cc. of
liquid ammonia was added 2 g. of 6?-ethinyl-3,20-bis
ICH=CHR2
\OH
\OH
was stirred for 2 hours, 5 g. of ammonium chloride was
in which R2 is selected from the group consisting of hy
drogen and lower alkyl, and acyl is derived from a hydro
carbon carboxylic acid containing 1 to 12 carbon atoms;
E is selected from the group consisting of ---CH-—-CHR3
then added, the ammonia was allowed to evaporate and
and —*CECR3 wherein R3 is selected from the group con
the residue was subjected to chromatographic puri?cation
on neutral alumina. Recrystallization of the solid frac
sisting of hydrogen, lower alkyl and lower alkoxy.
2. ??-ethinyl-testosterone.
3. 66-vinyl-testosterone.
ethylenedioxy-pregnan-Six-01, intermediate in Example 11,
dissolved in 20 cc. of tetrahydrofurane. The mixture
tions from acetone-hexane yielded 6B-vinyl-3,20-bis-eth
4. 65-ethinyl-l7a-methyl-testosterone.
5. 6iB-vinyl-17a-ethinyl-testosterone.
ylenedioxy-pregnan~5a-ol.
Hydrolysis and dehydration of the above compound in
accordance with the procedure of Example ll, gave 6B~
6. A compound of the following formula:
vinyl-progesterone.
Example 18
By following the procedure of Example 11, 5 g. of
51,611 - oxido - 20 - ethylenedioxy - pregnan - 3B - ol - ace
tate, obtained from A5~pregnen-3?-ol-20-one acetate by
ketalization at C-ZO followed by epoxidation, in accord
ance with the preparation method of Example 1, were con
verted successively into 6,8-ethinyll?-ethylenedioxy-preg
nane - 35,51: - diol; 6B - ethinyl - pregnane - 35,5a-diol
60
R at
l1
wherein R is selected from the group consisting of hydro
gen and lower alkyl; R’ is selected from the group con
20-one and 6?-vinyl-pregnane-3?,5a-diol-20-one.
In accordance with the preparation method described 70
sisting of hydrogen and methyl; Y is selected from the
in Example 1, the ‘following compounds listed under I
group consisting of hydrogen,
were converted into the corresponding 5a,6ot-OXid0—3,20—
diethylenedioxy derivatives, which in turn, ‘by following
the procedure described in Example 11 gave the ??-eth
OH
OH
inyl-compounds listed under ll.
75
3,088,946
12
A is selected from the group consisting of
‘H
‘H
[lower alkyl
carbon earboxylic acid containing from I to 12 carbon
‘CH=CHR2
atoms.
’CI—ICRT
.
.
.
.
.
and
in which R2 is selected from the group consisting of hy
drogen and lower alkyl, and acyl is derived from a hydro
carbon carboxylic acid containing 1 to 12 carbon atoms.
6B-ethinyl-progesterone.
6?-vinvyl-progesterone.
GB-ethoxyethinyl-progresterone.
6/3~ethinyl-17a-acetoxy-progesterone.
6.;8~viny1-17a-acetoxy-progesterone.
. 6/i-ethinyl-9a-?uoro-1IB-hydroxy-progesterone.
7. A compound of the following formula:
. A compound of the following formula:
10
A
" U
R1
R_ _
R4
,
11-
Ho
E
O:
wherein R is selected from the group consisting of hydro
gen and lower alkyl; R’ is selected from the group con
sisting of ‘hydrogen and methyl; Y is selected from the
group consisting of hydrogen,
H
:0,
OH
"
\OH
from 1 to 12 carbon atoms and E is selected from the
A is selected from the group consisting of
H
11
i 0H ' i OAcyl
[lower alkyl
'
wherein R is lower alkyl; R’ is selected from the group
consisting of hydrogen and methyl; R6 and R’1 are each
selected from the group consisting of hydrogen and the
acyl radical of a hydrocarbon carboxylic acid containing
'H
and
icHzoHR‘l‘
'
Egg,
and
0 II
group consisting of -CH=CHR3 and ——-CECR3 where
in R3 is selected from the group consisting of hydrogen,
30 lower alkyl and lower alkoxy.
19. A compound of the following formula:
in which R2 is selected from the ‘group consisting of hy
drogen and lower alkyl, and acyl is derived from a hydro 35
carbon carboxylic acid containing 1 to 12 carbon atoms;
E is selected from the group consisting of —CH=CHR3
and ——CECR3 wherein ‘R3 is selected from the group con~
sisting of hydrogen, lower alkyl and lower ‘alkoxy; R4 is
selected from the group consisting of ?-hydroxy, keto, and 40
lower alkylenedioxy.
9. 6B - ethinyl - 17a - methyl - ‘androstane - 5a,l7;9
diol-3-0ne.
1
l0. 6?,l7a - diethinyl - androstane - 511,173 - diol - 3
one.
11. A compound of the following formula:
wherein R is selected from the group consisting of hydro
gen and lower alkyl; R’ is methyl; Y is selected from
the group consisting of hydrogen,
n
=0,
‘
n
and
oH
OH
X is selected from the group consisting of hydrogen,
chlorine, bromine and ?uorine, and when Y is hydrogen,
X is hydrogen and R5 is selected from the group con
sisting of hydrogen, hydroxy and hyrocarbon carboxylic
acyl containing from 1 to 12 carbon atoms.
60
wherein R is selected from the group consisting of hydro
gen and lower alkyl; R’ is methyl; Y is selected ‘from the
20. 6oc-( 1)-chlorovinyl-progesterone.
21. A compound of the following formula:
group consisting of hydrogen,
'H
and
"
\OH
X is selected from the group consisting of hydrogen, chlo
rine, bromine and ?uorine and when Y is hydrogen, X is
hydrogen; E is selected from the group consisting of
-—CH:CHR3 and --CECR3 wherein R3 is selected from
the group consisting of hydrogen, lower alkyl and lower
nlkoxy; and R5 is selected from the group consisting of
hydrogen, hyd'roxy and acyloxy derived from a hydro 75
i: lg?
3,088,946
13
14
31. A compound of the following formula:
wherein R is selected from the group consisting of hydro
gen and lower alkyl; R’ is methyl; and R‘3 and R’ are each
selected from the group consisting of hydrogen and the
acyl radical of a hydrocarbon carboxylic acid contain
ing from 1 to 12 carbon atoms.
22. A compound of the following formula:
10
' --0R1
HQ
(']=CH|
15 wherein R is selected from the group consisting of hydro
R__
gen and lower alkyl; Y is selected from the group con
RI
sisting of keto, ?-hydroxy and a-hydroxy; X is selected
from the group consisting of hydrogen, chlorine, bromine
Ha
and ?uorine; R‘3 and R’7 are each selected from the group
20 consisting of hydrogen and a hydrocarbon carboxylic acyl
E
group containing from 1 to 12 carbon atoms; R8 is selected
from the group consisting of hydrogen, a-methyl and
wherein R is selected from the group consisting of hydro
gen and lower alkyl; R’ is methyl; E is selected from
the group consisting of —-CH-—--CHR3 and —-CECR3 25
wherein R3 is selected from the group consisting of hydro
gen, lower alkyl and lower alkoxy; R2 and R3 are each
selected from the group consisting of hydrogen and the
acyl radical of a hydrocarbon carboxylic acid contain
ing from 1 to 12 carbon atoms; R4 is selected from the 30
group consisting of B-hydroxy, keto and lower alkylene
?-methyl.
32. A compound of the following formula:
CHgORu
=0
R- —
dioxy.
23. GB-ethinyl-pregnane-5u-ol-3,20-dione.
24. 6?-ethinyl-3,ZO-bis-ethylenedioxy-pregnane-Su-ol.
25. 6?-vinyl-pregnane-Sa-o1-3,20-dione.
0
35
x
.
110
26. A compound of the following formula:
wherein R is selected from the group consisting of hydro
gen and lower alkyl; E is selected from the group con
sisting of —CH=CHR3 and -—CECR3 wherein R3 is
selected from the group consisting of hydrogen, lower
alkyl and lower alkoxy; Y is selected from the group con
(EH10 R5
sisting of keto, ?-hy-droxy, ot-hydroxy and d-hydI'U'CBIbOn
carboxylic acyloxy containing from 1 to 12 carbon atoms;
45 X is selected from the group consisting of hydrogen,
chlorine, bromine and ?uorine; R6 and R‘7 are selected
from the group consisting of hydrogen and a hydrocar
bon carboxylic acyl group containing from 1 to 12. car
bon atoms; R8 is selected from the group consisting of
50
hydrogen, u-methyl and ?-methyl.
33. A process for the production of 6|B-1ower alkinyl
A4-3-keto steroids selected from the class consisting of the
androstane series and the pregnane series which com
wherein R is selected from the group consisting of hydro
prises reacting a compound selected from the group con
gen and lower alkyl; E is selected from the group consist 55 sisting of a 5a,6a-oxido~androstane and a 50:,6ut-0Xid0
ing of —CH=CHR3 and —C;.CR3 wherein R3 is selected
pregnane having an alkylenedioxy substituent at C-3
from the group consisting of hydrogen, lower alkyl and
with an alkinyl magnesium halide in an inert solvent, hy
lower alkoxy; Y is selected from the group consisting of
drolyzing the thus formed 3-alkylenedioxy~5m-hydroxy
keto, ?-hydroxy and e-hydroxy; X is selected from the
G?-alkinyl-steroid with an acid to obtain the corresponding
group consisting of hydrogen, chlorine, bromine and 60 3-keto-5a-hydroxy-G?-alkinyl-steroid and treating with a
?uorine; R6 and R’I are each selected from the group con
dehydrating agent to obtain the corresponding 6B-alkiny1
sisting of hydrogen and a hydrocarbon carboxylic acyl
A4-3-lteto-steroid.
group containing from 1 to 12 carbon atoms and R5 is
selected from the group consisting of hydrogen, tit-methyl
and B-rnethyl.
27. o?-ethinyl-lopqnethyl-cortisone.
28. 66-ethinyl-cortisone.
29. 6?-vinyl-cortisone.
30. d?-vinyl-l6?-methyl-cortisone.
65
References Cited in the ?le of this patent
Burn et al.: “Journal Chem. Soc," December 19-59,
pages 3808-3811.
Ellis: “Journal Chem. Soc," June 1960, pages 2596
2602.
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