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Патент USA US3088966

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United States Patent O?ice
3,083,953
Patented May 7, 1963
2
l
For the preparation of the novel compounds of the
present invention we started from 53,10B-oxido-estran
3,083,953
l7/3-ol-3-one, substituted at C-17OL with a lower alkyl or
lower alkinyl group (I) or from a 5a-halo-estrane-105,
l7?-diol-3-one, substituted at C—170L with a lower alkyl,
alkenyl or alkinyl group (II) described in our US. patent
M-ESTRENE-10,8,l'7?-DIGL-3-0NE C(IMPUUNDS
AND PROCESS THEREFUR
Carl Diernssi, Fred Allan Kincl, and Jose Iriarte, all of
Mexico City, Mexico, assignors, by mesne assignments,
to Syntex Corporation, a corporation of Panama
No Drawing. Filed Mar. 18, I959, Ser. No. 800,093
Claims priority, application Mexico Mar. 19, 1958
11 Claims. (Cl. zen-397.4)
application Serial No. 800,085, ?led simultaneously here
with.
We subjected any of such starting compounds to an
10
‘alkaline treatment, preferably by re?uxing with potas
sium hydroxide in methanol solution, and thus we ob
The present invention relates to novel cyclopentano
tained the A4-estrene-10?,17B-diol-3-one correspondingly
phenanthrene derivatives and to a method for the prep
aration thereof.
substituted vat C-17a (III; R=alkyl, alkenyl or alkinyl,
R1=H).
In particular, it relates to novel A4-estrene-l0B,17?-diol
3-one compounds substituted at C-17u with a residue of
an aliphatic hydrocarbon, saturated or unsaturated, having
up to 5 carbon atoms, and which may further have an
additional double bond between C-1 and 0-2, as well
as to their C—l0, 17-diesters of hydrocarbon carboxylic
20
acids of up to 12 carbons.
This reaction has already been described in the litera
ture for the transformation of 55,IOB-oxido-estran-lHR-ol
S-one, unsubstituted at C-17a, into A4-estrene-105,17,8
diol-S-one.
Alternatively, we also converted I into III
by reaction with perchloric acid in aqueous acetone
solution.
In the resulting novel A4-estrene-105,17i3-diol-3-one sub
The novel compounds, for example the novel 17a-eth
stituted at (3-17“, there can be introduced an additional
inyl-A4-estrene-l0?,17,8-diol-3-one and its diesters, are
double
bond between (3-1 and C~2 by chemical or micro
anabolic drugs having a favorable anabolic-androgenic
biological methods, well known for effecting such dehy
ratio and also show anti-estrogenic e?ect.
The novel compounds of the present invention are illus 25 drogenation. Preferably we esteri?ed the two hydroxyl
groups of a 17u~substituted A‘i-est-rene-l05,17?-diol-3-one
trated by the following formula:
by reaction with the anhydride of a hydrocarbon car
boxylic acid in the presence of an acid catalyst, such as
p-toluenesultonic acid, and the resulting diester (III;
30 R=allkyl, alkenyl or alkinyl; R1=acyl) was refluxed with
selenium dioxide in mixture with t-butanol and in the
presence of pyridine. Thus we obtained the respective
Y
10,17-diester of A1,4-estradiene-10,B,l7?-diol-3-one, corre
spondingly substituted at C-17a with a hydrocarbon resi
35
Q:
due (IV; R=alkyl, alkenyl or alkinyl; R1=acyl). By
conventional methods, for example by treatment with
methanolic potassium hydroxide, we hydrolyzed these di
In the above formula Y represents a double bond at
04(2) or a saturated linkage, R represents lower alkyl,
esters to produce the free 170t-Sllb5tltllt6d A1,4—estradiene
lower alkenyl or lower alkinyl, and R1 represents hydro
l0,B,l7?-diol-3-one (IV; R=alkyl, alkenyl or alkinyl;
gen or a hydrocarbon carboxylic acyl group of up to 12 40 R1=H); for the reesteri?cation of these compounds we
carbon atoms of straight or branched chain aliphatic,
employed the method mentioned above for the esteri?ca
cyclic or mixed cyclic-aliphatic which may be conven
tion of the A4-compounds.
tionally substituted as for example acetate, propionate,
cyclopentylpropionate, benzoate, B-chloropropionate, ace
For converting a l7a-alkinyl-A4-estrene-l0'?,17B-diol-3~
one, obtained by alkaline treatment of the corresponding
45 oxide-compound I, into a l7ot-alkenyl-A4-estrene-10B,17B
toxypropionate, etc.
The following equation illustrates the process for pre
diol-3-one, We hydrogenated the triple bond of the former
paring the above compounds:
to a double bond. This hydrogenation can be conducted
either before or after the esteri?cation of the hydroxyl
groups at 0-10 and 0-17; in the latter case there is
obtained the diester of the corresponding alkenyl-corn
pound of Formula III.
For the esteri?cation of the hydroxyl groups of III and
IV we used the anhydride of a carboxylic acid having
up to 12 carbon atoms, of straight or branched chain,
cyclic or mixed cyclicaliphatic, substituted or not with
methoxy, halogen or other groups to produce diesters
such as the acetates, propionates, butyrates, hemisucci
nates, enanthates, caproates, benzoates, trimethylacetates,
cyclopentylpropionates, phenylpropionates,v acetoxypropi
onates and ?-chloropropionates.
The following speci?c examples serve to illustrate but
are not intended to limit the present invention.
Example I
A mixture of 5 g. of 17a-rnethyl-5B,10?-oxido-estran
17B-0l-3-one and 100 cc. of a 5% solution of potassium
hydroxide in methanol was re?uxed for 1 hour, poured
into ice water and the reaction product was extracted with
III
70 ethyl acetate.
In the above equation R and R1 represent the same
groups as heretofore.
‘
The extract was washed with water to
neutral, dried over anhydrous sodium sulfate and the ethyl
acetate was evaporated. The residue crystallized from
aosaoas
3
4i
ethyl acetate to furnish 17a-methyl-A4-estrene-10p,17B
diol-3-one.
when the equivalent of 1 mo! of hydrogen had been ab
sorbed. The catalyst was removed by ?ltration, washing
the ?lter with ethyl acetate, and the combined ?ltrate and
washings was washed dilute hydrochloric acid and water,
dried over anhydrous sodium sulfate and evaporated to
dryness. The residue was puri?ed by recrystallization
3 g. of the above compound was dissolved in 301 cc. of
acetic anhydride, treated with 300 mg. of p-toluenesul
tonic ‘acid and the mixture was stirred at room tempera
ture for 12 hours. It was then poured into ice water,
heated on the steam bath for half an ‘hour and cooled;
from acetone-hexane, thus affording 17oz~vinyl-A4-estrene
the precipitate was collected by ?ltration, washed with
10,8,175-di0l-3-one.
Example V
waten-dried and redissolved in 300v cc. of 1% methanolic
potassium hydroxide previously cooled to 5° C. The 10
A mixture of 300 mg. of 17oi-ethinyl-A4-estrene
mixture was kept at this temperature for 1 hour, acidi
10,5,17B-diol-3-one,
3 cc. of acetic anhydride and 30 mg.
tied with acetic acid, concentrated to a small volume
of p-toluenesulfonic acid was treated under the condi
under reduced pressure and diluted with water. The
tions described in Example I, thus giving rise to the forma
precipitate was collected, washed with water, dried and
tion
the 10,17-diacetate; the latter was hydrogenated
recrystallized from acetone-hexane. There was thus ob 15 underofthe
conditions described in the previous example.
tained 17a-methyl-A4-estrene-105,17B-diol-3-one diacetate.
There was thus obtained 17ot-vinyl-A4-estrene-10,6,17,6
A mixture of 2 g. of the above compound, 100 cc. of
diol-3-one 10,17-diacetate.
anhydrous t-butanol, 0.8 g. of selenium dioxide and 0.5 cc.
Example VI
of pyridine was re?uxed under an atmosphere of nitro
gen for 72 hours and then ?ltered through celite, washing 20
A solution of 200 mg. of 17ot-ethinyl-5,6,10,6-oxido
the ?lter with hot tebutanol. The combined ?ltrate and
estran-17/3-ol~3-one in 20 cc. of acetone was treated with
washings was evaporated to dryness under reduced pres
1.5 cc. of 1.5 N perchloric acid and the mixture was kept
sure and the residue was redissolved in acetone, decolor
for 16 hours at room temperature; after pouring into
ized with charcoal under re?ux, ?lter and the solution
water, the reaction product was extnacted with ethyl
was evaporated to dryness. The residue was puri?ed
acetate, washed with water to neutral, dried over anhy
by chromatography on neutral alumina, thus yielding
drous sodium sulfate and evaporated to dryness. Crystal
17-a-methyl-A1A-estradiene-l05,17,8-diol-3-one diacetate.
lization of the residue from acetone-hexane furnished 17a
By re?uxing with 5% methanolic potassium hydroxide,
exactly ‘as described above, there was obtained the free
17a-rnethy1-A1A-estradiened 0,8, 17,8-diol-3-one.
Example 11'
In another experiment the intermediate l7a-methyl-A4
estrene-IOB,17?-diol-3-one was obtained by re?uxing 17a
methyl-Son-?uoroestnahe-10,8,17,8-diol-3-one with metha
ethinyl-A‘l-estrene-106,17B-diol-3-one, identical with the
compound described in Example Ill.
30
Example VII
By re?uxing 5a-?uoro-estrane-10?,17B-diol-3-one with
potassium hydroxide, by the method described in EX
ample I, there was obtained the already known A‘i-estrene
10?,1'/?-diol-3-one, Ml’. 208-212" 0., [a1]; +80.3°
(methanol), Amax, 236 mu, log E 4.2.
nolic potassium hydroxide solution, following the method
described in the previous example.
Example III
We claim:
1. A process for the production of a compound of the
By following the same methods described in the pre 40
following formula:
vious examples, all of the l7a-alkyl and 17a-alkinyl
5e,1OB-oxido-estran-l7,8-ol-3-ones and 17a-a1kyl, 17a
OR1
OR1
on
alkenyl and 17ot-a1kinyl-5a-?uoro-estrane-10p,17?-diol-3
ones were converted into the respective d‘l-estrene
10,6,17B-diol-3-ones, correspondingly substituted at C—17oc. 45
By the aforementioned acetylation there were obtained
the 10,17-diacetates of suchcompounds, and by subse
quent dehydrogenation there were obtained the 10,17
diacetates of the respective 17et-substitutedAli‘i-estra
diene-IQB,17,8-diol-3-ones. By substituting for acetic an
hydride, the anhydride of another carboxylic acid having
where R is selected from the group consisting of lower
alkyl, lower alkenyl and lower alkinyl and R1 is selected
from the group consisting of hydrogen and a hydrocarbon
carboxylic acyl group of up to 12 carbon atoms com
up to 12 carbon ‘atoms, there were obtained the respective
diesters, including the dibenzoates ‘and dicyclopentylpro
prising heating a corresponding compound selected from
pionates.
Thus, from the 17a-ethinyl analogs of SdIO?-oxido 55 the group consisting of a 55,10l6-oxido compound and a
5a-?uoro-10e-hydroxy compound with a strong alkali in
estran-17,8~ol-3-one and of 5 a-?uoro-estrane-ltl?,l7B-diol
methanol.
3-one, there was obtained 17ct-ethiny1-A4-estrene-l0,8,17,8
2. A compound of the following formula:
diol-3-one, then its dipropionate, and by dehydrogenation
of the latter there was obtained 17ot-ethinyl-A114-estra—
diene-10[>’,17,6-diol-3-one dipro-pion-ate, which was saponi
OR1
OR1
60
|___R
?ed to the free diolone. All of the compounds thus ob
tained were well de?ned by their constants.
'
For example, 17ct-ethinyl-A4-estrene-10p,l7?-diol-3-one
was obtained ‘by crystallization from acetone in the form
of prisms having a melting point of 263-265 ° 0.;
.
WI/
[a1]; +4.5° (methanol); Am“ 236 my, log E 4.08; 71mm
(KBr) 3380, 3280, 1655 cmfl.
Example IV
wherein Y is selected from the group consisting of a double
bond at C—1(2) and a saturated linkage at C—l(2), R is
To a prereduced suspension of 20 mg. of 2% palladium 70 selected from the group consisting of lower alkyl, lower
on calcium carbonate catalyst in 5 cc. of pyridine there
alkenyl and lower alkinyl and R1 is selected from the
was added 200 mg. of 17a-ethinyl-A4-estrene-10/3,17o
group consisting of hydrogen and a hydrocarbon car
diol-3-one, obtained in accordance with the previous ex
boxylic acyl group of up to 12 carbon atoms.
ample, and the mixture was hydrogenated until the ab
sorption of hydrogen practically ceased, which occurred 75
3,088,953
5
6
ing heating a corresponding compound selected from the
group consisting of a 55,10f3-oxido compound and a 5m
?uoro-ltl?-hydroxy compound with a strong alkali in
methanol and thereafter dehydrogenating at C-1,2.
. 17a-lower alkinyl-Mestren-10B,175-diol-3—one.
. 17LX-1OW6I alkyl-A114-estradien-1018,17B-diol-3-one.
. 17oc-1OWCI‘ alkeny1-A114-estradien-105,l7?-diol-3-one.
17a-lower alkinyl-Al?-estradien-l03,17?-diol-3-one.
. A process for the production of a compound of the 5
following formula:
v11. A process for the production of a compound of
the following formula:
0R1 l
OR1
OR!
I
10
0:
15
wherein R is selected from the group consisting of lower
wherein R is selected from the group consisting of lower
alkyl, lower alkenyl and lower alkinyl and R1 is selected
aikyi, lower alkenyl and lower alkinyl and R1 is selected
from the group consisting of hydrogen and a hydrocarbon
from the group consisting of hydrogen and a hydrocarbon
carboxylic acyl group of up to 12 carbon atoms com
carboxylic acyl group of up to 12 carbon atoms compris 20 prising
treating a corresponding 55,10?-oxido compound
ing treating a corresponding 55,10f3-oxido compound with
with perchloric acid and thereafter dehydrogenating at
perchloric acid.
C-1,2.
10. A process for the production of a compound of
the following formula:
References Cited in the ?le of this patent
25
UNITED STATES PATENTS
2,721,871
2,729,654
30
wherein R is selected from the group consisting of lower
Colton _____________ __ Oct. 25, 1955
Colton ______________ __ Jan. 3, 1956
2,806,862
Pederson et al. _______ __ Sept. 17, 1957
‘2,845,381
2,871,245
Tindall _____________ __ July 29, 1958
Wettstein et a1. _______ __ Jan. 27, 1959
OTHER REFERENCES
Ringold et al.: J. Org. Chem, vol. 23, pages 239-240
1956).
alkyl, lower alkenyl and lower alkinyl and R1 is selected 35 (February
Ruelas et al.: J. Org. Chem, vol. 23, pages 1744-47
from the group consisting of hydrogen and a hydrocarbon
carboxylic acyl group of up to 12 carbon atoms compris
(November 1958).
,
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