close

Вход

Забыли?

вход по аккаунту

?

Патент USA US3096363

код для вставки
3,096,353
United States Patent 0
Patented July 2, 1963
2
1
androstadiene-l?one which has the following structural
formula:
3,096,353
A9-DEHYDRO-2l-HALOETHISTERONES AND THE
PROCESS FOR THE PRODUCTION THEREOF
John Fried, Plaintield, and Thomas S. Bry, Elizabeth,
NJ., assignors to Merck & Co., Inc, Rahvvay, N.J., a
corporation of New Jersey
No Drawing. ‘Filed Aug. 3, 1961, Ser. No. 128,977 ~
9 Claims. (Cl. 260—-397.4)
mol i
This invention is concerned genenally with novel deriv 10
atives of 21-halonorethisterones and their Mum-isomers.
More particularly, it relates to A9-dehydro ‘21- halonor
This 3-methoxy-19-nor-2,5 ( l0)-androstadiene - 17 -one is
ethisterones ‘and their l7-esters; to 3-enol ethers of 2'l-halo
reacted with a haloethyne to form the corresponding 17a
norethisterone's, their Mum-isomers and A9-dehydro de~
- l9 - nor-2,5(lOt)-androstadiene
rivatives, ‘and 17-esters thereof; and to novel processes for 15 haloethynyl-Ii-methoxy
1713-01, which has the following structural formula:
preparing these new compounds starting with 3-methoxy
2,5 ( 10)~androstadiene-17-one. The A9-dehydro-21-halo
H0
.norethisterones and their 17-esters; ‘and the 3-eno1 ethers
and the 3-enol ether-17-esters of 21-halonorethisterones,
their Mum-isomers and A9~dehydro derivatives, subject of 20
the present invention, possess useful therapeutic properties
as orally and parenterally active progestational agents.
This {application is a continuation-in-part of applica
tion Serial No. 99,668, ?led March 31, 1961, which, in 25
turn, is a continuation-in-part of application Serial No.
88,575, ?led March 2, 1961, now Patent No. 3,072,646.
The 3-enol ethers of 21-halonorethisterone and their
A5<1°)-isomers (i.e., l7a-halocthynyl-l9-nor-3,S-androsta
diene-3,17?-diol 3-ether ‘and 17oc-haloethynyl-l9-nor-3,
5(10)-andnostadiene-3,17,6-di0l 3-ether) may be chemi
30
cally represented ‘as follows:
fl
,ozox
IA
wherein X stands for chloro, bromo, or ?uoro.
In a preferred embodiment of this procedure, the halo
ethyne is formed in situ by the reaction of a. 1,2-dihalo
ethylene (preferably the cis form) and methyl lithium.
For example, the l7a-chlonoethynyl-3-methoxy-19-nor
2,5(10)~androstadiene-l7B-ol is prepared by adding a so
H0
‘0502:
lution of cis-l,2~dichloroethylene in ether to a solution
of methyl lithium at about 0° C. in ether. The reaction
35
mixture is stirred under nitrogen for 1-2 hours, and to
the resulting solution containing the chloroethyne is added
3-methoxy-19-nor-2,5( l0)eandrostadiene-17-one, and stir
ring is continued d?or several hours longer.
R10
40
I
The l7a~haloethynyl-3~methoxy-19-nor-2,5 (10)-andros
tadiene-l7?-ol is converted into the l7a-haloethynyl-l7?
hydroxy-l9-nor-4-androstene-3one (i.e., the ZI-halonor
no
ethisterone) which has the following formula:
‘0202:
HO
R10
50
0.
wherein X stands for chloro, bromo or ?uoro, and R1 is
a hydrocarbon or substituted hydrocarbon substituent as,
for example, an aliphatic or substituted aliphatic nadical 55 wherein X stands for chloro, bromo or ?uoro, by reaction
with a strong acid, such as p-toluenesulfonic acid. For
such as alkyl or aralkyl, more particularly, methyl, ethyl,
example, a mixture of the steroid and p-toluenesulfonic
butyl, amyl, benzyl, a cycloaliphatic or cycoalkyl group
acid in acetone solution is left standing at room tempera
ing such as cyclopentyl, cyclohexyl, land the like.
ture overnight.
These 3-enol ethers of 21-halono-rethisterones and their
The 17a-haloethynyl-17l3-hydroxy-l9-nor-4dandrostene
Mum-isomers as well
the intermediate 3-ketones (i.e., 60
3-ones,
their Mum-isomers, and l7-esters thereof, may be
l7a-haloethynyl-19-nor-4-androstene-l7?-ol - 3 - ones and
converted into the corresponding 3-enol ethers (i.e., the
17oa-ha1oethynyl - 19 - nor - 5(10) - androstene-17B-ol-3
17a-haloethyinyl-19-nor - 3,5 - iandrostadiene ~ 3,1713 - diol
ones), are prepared, in accordance with the presently in
vented process, starting with 3-methoxy-19-nor-2,5(10)
3-ethers and l7oc-haloethynyl-l9-nor - 3,5 ( 10) - androsta
3,096,353
4%
diene; 3-hexyloxy-l7ot-chloroethynyl-17/3-acetoxy-19-nor
3,5-androstadiene; 3~aralkoxy-17ot-haloethynyl-17B-alka
diene-3,17;3-dio1 B-ethers, and their 17-esters) which have
the following formulae:
R20
/
noyloxy-l9-nor-3,5-androstadiene, such as 3-benzlyoxy
CECX
17a-chloroethynyl - 17B-propionoxy - 19-nor-3,5-androsta
OX
diene; 3-benzyloxy-17a-?uoroethyny1-17?-acetoxy-l9-nor
3,5-androstadiene; and the like, are recovered from the
neutralized reaction mixture.
H
The 17a-haloethynyl-l7;8-hyrdoxy'l9-nor-4-androstene
/
3-one 3-enol ethers, other than the 3-enol ethyl ethers,
are conveniently prepared starting with said 3-enol ethyl
R10
ether (e.g., 3-ethoxy-17a-haloethyny1-19-nor-3,5-androsta
diene-l7?-ol) by mixing together the latter compound and
RBO
/
CEOX
an inert hydrocarbon solvent such as isoctane and an al
cohol such as, for example, an aliphatic alcohol such as
15
propanol, n-butyl alcohol, amyl alcohol, a cycloaliphatic
alcohol, as for example, a cycloalkanol such as cyclohex
anol, cyclopentanol, an araliphatic alcohol, as, for ex
ample, an aralkanol such as benzyl alcohol, and the like,
and an acidic catalyst such as p-toluenesulfonic acid, and
:/
R10
I
20
heating the resulting mixture, preferably under re?ux, in
an apparatus equipped with means for removing the
wherein X stands for chloro, bromo, or ?uoro, R1 is a
hydrocarbon or substituted hydrocarbon substituent as,
Water from the distillate and returning the dry distillate
to the reaction mixture. The acid catalyst is then neutral
ized with a base such as pyridine, and the resulting neutral
such as ‘alkyl, or aralkyl, more particularly,‘ methyl, ethyl, 25 solution is evaporated to dryness in vacuo to give the 170:
for example, an aliphatic or substituted aliphatic radical
"butyl, amyl, benzyl, a cycloaliphatic or cycloalkyl group
ing such as cyclopentyl, cyclohexyl, and the like, and R2
vhaloethynyl-17,6-hydroxy-l9-nor-4-androstene 3-enol eth
er, which is conveniently puri?ed by crystallization from
methanol containing traces of pyridine, or by chromotog
stands for an acyl radical, for example, a lower hydro~
carbon carboxylic acyl radical such as benzoyl, a lower
raphy.
alkanoyl radical such as acetyl, propionyl, butyryl, and the 30 The 6-chloro- 17 a-haloethynyl- 17 ?-hydroxy- 19-nor-4,6
like, by stirring together a mixture of the steroid and an
androstadiene-Ii-one may be prepared in a multiple-step
alkyl, cycl-oalkyl or aralkyl orthoforrnate in diox-ane solu
process from the 3-enol ethers of the 17ot-haloethynyl-17B
tion in the presence of a strong acid catalyst, for exam
hydroxy-l9-nor-4-androstene-3-one by reaction ?rst with
ple, organic sulfonic acid.
N-bromosuccinimide to give '6?-bromo-l7a-haloethynyl
‘In a preferred procedure, the novel l7a-haloethynyl 35 17,8-hydroxy-l9-nor-4-androstene-3-one which has the fol
17,3-hydroxy-19-nor-4-androstene-3-one 3-enol ethers and
lowing formula:
l7u-haloethynyl-l7/3-acyloxy - 19-nor-4-androstene - 3-one
110
3-enol ethers are prepared by adding an alkyl ortho
formate, a cycloalkyl orthoformate, or aralkyl ortho
{050x
3,
formate, such as ethyl orthoformate, propyl orthoformate, 40
.n-butyl orthoformate, cyclopentyl orthoformate, cyclo
pentyl orthoformate, cyclohexyl orthoformate, benzyl or
.thoformate, and the like, and an acidic catalyst such as
2,4-dinitrobenzene sulfonic acid, p-toluene-sulfonic acid,
and the like, to a solution of the steroid in an organic
solvent such as dioxane or preferably the alcohol corre 45
sponding to the particular alkyl orthoformate, cycloalkyl
The acidic cataylst is then neutralized with a base such as
pyridine, and the l7a-haloethynyl-17B-hydroxy-19-nor-4
The 17?-lower alkanoyl esters of 17?-hydroxy-17ot
haloethynyl-3~keto-steroids, such as l7?-hydroxy-17a
chloroethynyl - 19-nor-4-androstene-3-one, 17/8-hydroxy~
androstene-3-one 3-enol ether or 17a-haloethynyl-17B
acyloxy-l9enor-4-androstene-3-one 3-enol ether, as for ex
ample,
3-alkoxy - l7a-haloethynyl ~ l9-n0r-3,5-androsta
diene-17/3-ol, such as S-ethoxy-17ot-chloroethynyl-19-nor
3,5-androstadiene-17?-ol; 3-propoxy-17u-?uoroethynyl-19—
Br
wherein X is chloro, bromo or ?uoro. In a preferred pro
cedure, a solution of the steroid and sodium acetate in
aqueous acetone is stirred with N-bromosuccinimide and
acetic acid at about 0° C.
onthoformate, or aralkyl orthoformate employed, and stir
ring the resulting mixtures together at room temperature.
l7a-bromoethynyl - 19-nor-4-androstene - 3-one,
17B-hy
55 droxy-lh-chloroethynyl - 19-nor-4,9-androstadiene-3-one,
nor-3,5-androstadiene-175-01; 3-n-butoxy-17a-cholr0eth
17?-hydroxy - 17a-bromoethyny1 - 19-nor - 4,9-androsta
ynyl~19-nor-3,5-androstadiene-1713-01; 3 - cycloalkoxy-17a
diene-3-one, are prepared by the reaction of the 17,8-hy
droxy-17a-haloethynyl-3-keto—steroid with a lower alka~
haloethynyl-19-nor-3,5-androstadiene-17,8-01, such as 3
noic acid anhydride in the presence of an organic base
diene-17B-ol; 3-benzy1oxy-17a~?uoroethynyl - 19-nor-3,5 60 such as pyridine. The lower acid anhydrides which are
cyclopentyloxy ~ 17u-ch1oroethynyl - 19-nor-3,5-androsta
androstadiene-U?-ol; 3-hexyloxy-17a-chloroethynyl-l9
nor-3,5-andr0stadiene-17,8-01; 3-aral‘koxy-17ot-haloethynyl
l9-nor-3,5-androstadiene-1718-ol, such as 3-benzyloxy-17a
chloroethynyl-l9-nor-3,S-androstadiene-175-01; 3-benzyl
oxy-17a-?uoroethynyl-19-nor-3,5-androstadiene-l7?-ol; 3
ordinarily used include acetic anhydride, propionic anhy
dride, butyric anhydride, and the like.
' The d-bromo-derivative is then dehydrobrominated to
65
alkoxy - 17a-haloethynyl-17/8-alkanoyloxy - 19-nor-3,5-an
drostadiene, such as 3-ethoxy-l7a-chloroethynyl-l7B-ace
toxy-19-nor-3,5-androstadiene; 3-propoxy-17a-?uoroeth
ynyl-17B-acetoxy - l9-nor-3,5-androstadiene; 3-n-butoxy 70
17a-chloroethyny1- 17;9-propionoxy-l9-nor - 3,5-androsta
diene; 3-cyc1oalkoxy-17a-haloethynyl-l7p-alkanoyloxy-19
nor-3,5-androstadiene, such as S-cyclopentyloxy-l7a-chlo
roethynyl-l7?-acetoxy-l9-nor-3,5--androstadiene; 3-benzyl
oxy-17w?uoroethynyl-17,6-hutyroxy - 19~nor-3,5-androsta
introduce a A6 bond thus forming the 17u-haloethynyl
17/8-hydroxy-19-nor-4,6-androstadiene-3-one Which has
the following formula:
3,096,353
5
.
wherein X is chloro, bromo, or ?uoro.
6
out the present invention, but it is to be understood that
these examples are given for purposes of illustration and
not of limitation.
The dehydro
biomination is conveniently brought about by heating
a solution of the steroid in a solvent such as dirnethylform
Example I
A solution consisting of 1.7 g. (1.32 cc.) of cis-1,2-di
chloroethylene in 10 cc. of sodium-dried ether is added
amide with lithium bromide and lithium carbonate for
several hours at about 120° C.
The above compound is then oxidized to the 605,70:
epoxy-lh-haloethynyl - 17,8-hydroxy - 19-nor-4-andr0
over 0.5 hour at 0° C. to 3 cc. of a 1.4 ‘N-solution of
stene-3-one which has the following formula:
methyl lithium (prepared by adding lithium to methyl
no
iodide in dry ether solution under nitrogen at about 10°
,ozox
10 C.) in 25 cc. of sodium-dried ether. The reaction mixture
is stirred at room temperature under nitrogen for an addi
.63
tional 11/2 hours, followed by the addition, over a 15
minute period, of 100 mg. of 3-rnethoxy-l9-nor-2,5(10)
androstadiene-l7-one in 4 cc. of sodium-dried ether. The
mixture is left stirring at room temperature overnight,
poured into ice water and extracted with ether. The ether
extracts are Washed with water, dried over sodium sulfate
and concentrated in vacuo. The residue is chromato
graphed on 10 g. of basic alumina. The product is
wherein X is chloro, bromo, or ?uoro, conveniently by
treating a solution of the steroid in a solvent such as ben
20 eluted with petroleum etherzether 8:2.
ethynyl-S-methoxy - 19-nor-2,5 ( 10 ) -androstadiene-l7p-ol,
M.P. 112-115” C.
A solution of the 6a,7a-epoxy-17a-haloethynyl-17?-hy
droxy-19-nor-4-androstene-3-one in an organic solvent is
treated with CHCls at room temperature to form 6-chloro
Crystallization
from acid-free methanol aifords 48 mg. of 17a-chloro
zone with perbenzoic acid in the dark at room tempera~
ture for about 60-70 hours.
25
17a-haloethynyl - 17,8-hydroxy - 19-nor-4,6-androstadiene
3-one which has the following formula:
LR. my? 2.80, 4.48, 6.02, 6.12;‘
Analysis: (Calculated for C21H27O2Cl): C, 72.71; H,
7.85. Found: C, 72.85; H, 8.13. [a]D26°+618.6° (0:1
in dioxane).
in accordance with the above procedures, but using 1,2
30 dibromoethylene in place of 1,2-dichloroethylene, there is
obtained the 17a-bromoethynyl-3-methoxy-l9-nor-2,5
10504:
a
( 10) -androstadiene-17?~ol.
In accordance with the above procedure, but using 1
chloro-Z-?uoroethylene in place of 1,2-dichloroethylene,
35 there is obtained a mixture of the 17ot-ch1oroethynyl and
the 17u-?uoroethynyl-3~methoxy-19-nor-2,5 ( 10)-androsta
diene-l7B-ol, which compounds are separated by chroma
tography.
Example 2
wherein X is chloro, bromo, or ?uroro.
The 17a-haloethynyl-3~methoxy-19-nor-2,5 ( l0) -andros
A solution consisting of 10 mg. of 17a-ch-loroethynyl
3-methoxy-19-nor-2,5(110)-androstadiene-l7B-ol, 2 cc. of
has‘ acetone and 2 mg. of p~toluenesulfonic acid is left stand
ing at room temperature overnight. The reaction mix
ture is then poured into ice water and extracted with
45 ether. The ether extract is Washed with aqueous sodium
bicarbonate solution, ‘dried over sodium sulfate and con
centrated in vacuo. Crystallization from ethyl acetate
tadiene-l'l?-ol may be converted into 17a-haloethynyl
17?-hydroxy-l9-nor-5(l0)-androstene-3-one which
the following formula:
no
pzo-x
iafr’ords 17a - chloroethynyl-l7B-hydroxy;19-nor-4-andro
50
stene-3-one, M.P. 185—l90° C.,
LR. A531?‘ 2.95, 4.50, 6.10, 6.21;;
For ex
upon further recrystallization, M.P. 198-201" C.
In accordance with the above procedure, but starting
with the l7a-bromoethynyl- or 17a-?uoroethynyl-3
The 17u-haloethynyl-17r3-hydroxy-19‘-nor-4,9-androsta
sponding 17a-bromoethynyl- or 17a-?uoroethynyl-17B_
wherein X stands for chloro, bromo, or ?uoro, by reaction
with a Weak organic acid such as acetic acid.
ample, a mixture of the steroid and glacial acetic acid in 55 methoxy-l9-nor-2,5(10)-androstadiene-l7B-ol in place of
the 17ot-chloroethynyl-3-rnethoxy-l 9-no-r-2, 5 ( 10 ) eandros
‘an aqueous solution of absolute ethanol ‘and dioxane is
tadiene-l7B-ol there is obtained as products the corre
left standing at room temperature for several hours.
diene-3-one which has the following formula:
HO
hydroxy-1§-nor-4-androstene-3-one.
Example 3
,ozo-oc
/
To a solution of 100 mg. of 17a-chloroethynyl-17?
hydroxy-19-nor-4-androstene-3-one in 3 cc. of dioxane
is added 2 cc. of ethyl orthoformate and 101 mg. of p
toluenesulfonic acid. The reaction mixture is stirred
at room temperature for 3 hours and 1 cc. of pyridine is
added, followed by the dropwise addition of 5 cc.of water.
The aqueous phase is separated and extracted with ben
zene.
The organic extracts are washed with a sodium
wherein X stands for chloro, bromo or fluoro, may be 70 bicarbonate solution ‘and then with water until the wash
prepared by treatment of l7a-haloethynyl-17,8-hydroxy
ings are neutral. The ‘organic phase is dried over sodium
sulfate and concentrated in vacuo to give 3-6thOXy-17OL
'19-nor-5(10)-androstene-3-one with approximately one
equivalent of bromine in pyridine solution, or with pyri
dine perbromide hydrobromide.
The following examples illustrate methods of carrying 75
chloroethynyl-l9-nor-3,5-androstadiene-17/3-ol.
LR. 7&3‘? 2.86, 4.50, 6.05, 6.15;:
3,096,353
7
%
In accordance ‘with the above procedure, but starting
with the 17a-bromoethynyl- or the 17ot-?uoroethynyl-17/3
hydroxy-19-nor-4-androstene-3-one in place of the 170L
Example 6
To a solution of 160 mg. of 17a-chloroethynyl-3-me
thoxy~l9-nor-2,5(l0)-androstadiene-17p-ol in 1.6 cc. of
chloroethynyl - 17,8 - hydroxy-l9-nor-4-androstene-3-one
dioxane and 7.2 cc. of absolute ethanol is added 3.2 cc.
there are obtained as products the corresponding 17oz
of glacial acetic acid, and immediately thereafter, 1.6 cc.
bromoethynyl-‘or the 17ot-?uoro-ethynyl-3-ethoxy-l9-nor—
3,5-androstadiene-17?-ol.
Example 4
of water. This reaction mixture is left standing at room
temperature for 5 hours.
-It is then poured into an ice/
sodium bicarbonate solution, allowed to stand until the
mixture is basic and extracted with benzene. The benzene
A mixture of 100 mg. of l7a-chloroethynyl-17?-hy~
droxy-19-nor-4<androstene-3~one, 0.06 g. of 2,4-dinitro
benzenesulfonic acid, 3 ml. of dry dioxane and 10.25 ml.
extracts are washed with water until the washings are only
slightly basic and then dried over anhydrous potassium
carbonate, ?ltered and concentrated in vacuo using a water
of freshly distilled n-butyl orthoformate are stirred over
bath at 30—50° C. By crystallization of the residual
night at 30° C. The acid catalyst is then neutralized by
addtiion of 0.1 ml. of pyridine. The reaction mixture is 15 material from ether, about 910 mg. of l7a-chloroethynyl
1718-hydroxy-19-nor-5 ( l0)-androstene-3-one is obtained.
diluted with water and extracted with ether. The com
U.V. no m'ax.;
bined ether extracts are washed with water, dried and
evaporated under reduced pressure. The residue is
LR. k213i" 2.98, 4.50, 5.9044
chromatographed over ‘alumina (alkaline) and eluted with
In accordance with the above procedures, but starting
mixtures of ether and petroleum ether to separate 3 20 with the 17a-bromoethynyl- or the 17a-?uoroethynyl-3
butoxy-17u-chloroethynyl-l9-nor-3,5-androstadiene - 17 ,8
methoxy-19-nor-2,5(10)-androstadiene-17p-ol in place of
the 17a-ch1oroethynyl-3-methoxy-19~nor-2,5'( l0) -andros—
01.
In accordance with the above procedure, but starting
with the 17a-bromoethyny1- or the 17a-?uoroethynyl-17B
hydroxy-19-nor-4-androstene-3-one in place of the 17er
tadiene-IZB-ol there are obtained as products the corre
sponding l7a-bromoethynyl- or l7u-chloroethynyl-l7/3
hydroxy-l9-nor-5 ( 10 ) -androstene-3~one.
Example 7
chloroethynyl - 175 - hydroxy-19-nor-4-androstene-3-one
there are obtained as products the corresponding 17a
bromoethynyl- or the r17e-fluoroethynyl-3-butoxy-19-nor
To 100 mg. of 17a-chloroethynyl-17?-hydroxy-l9-nor
3,5Jandrostadiene-17?-ol.
5(10)-androstene-3-one in 5 cc. of pyridine is ‘added one
30 equivalent of bromine. The ‘reaction mixture is stirred for
Example 5
A solution consisting of 1 g. of 3-ethoxy-17a-chloro
ethynyl-19-nor-3,5-androstadiene-173-01, 700 mg. of so
dium acetate, 5 ml. of water and 40 ml. of acetone is
cooled to 0° C. ‘and 1.07 g. of N-bromosuccinimide and 35
0.83 ml. of acetic acid is added. The mixture is stirred
for 3 hours at 0.5 ° C. and then poured into water to
yield the 6(3-bromo-17a-chloroethynyl-17?-hydroxy-l9
nor-4-androstene-3-one.
two hours at room temperature, poured into ice water and
the aqueous mixture extracted with ether. The ether
extract is washed with water, dried over sodium sulfate,
1and concentrated in vacuo to yield 17a-chloroethyny1~l7?
hydroxy-19=nor-4,9-androstadiene-3-one.
‘In accordance with the above procedures, but starting
with the 17a-bromoethynyl~ or the 170c-?lt01‘06thYDY1-17/8
hydroxy-19-nor-5'(10)-androstene-3-one in place of the
17u-chloroethynyl-171i-hydroxy-19-nor-5 ( l0‘) ~androstene
Treatment of 6B-bromo-17u-chloroethynyl-17/8-hy 40 3-one
there ‘are obtained as products the corresponding
idroxy-19-nor-4-androstene-3~one (1.0 g.) with 1.0 g. of
17a-bromoethynylor the 17a-?uoroethynyl-17,8-hydroxy
‘lithium bromide, 500 mg. of lithium carbonate and 20
19~nor-4,9-androstadiene-3-one.
ml. of dimethylformamide for 5 hours at 120° C., fol
lower by dilution with ice water and ?ltration affords 17a
Example 8
chloroethynyl - 17,8 - hydroxy-19-nor-4,6-androstadiene-3
To 100 mg. of 17a~chloroethynyl-17e-hydroxy-19-nor
one.
A solution consisting of 675 mg. of 17a-chloroethyny1
17?-hydroxy-19-nor-4,6-androstadiene-3aone, 30 ml. of
0.2 N-perbenzoic acid dissolved in benzene and 30 ml.
of ether is allowed to stand at room temperature in the
dark for 68 hours. The resulting benzene-ether solution
is washed with acidi?ed sodium bisul?te solution, water,
2.5 N-potassium hydroxide solution, and again with
water. The washed benzene-ether reaction solution is
dried and evaporated in vacuo to give 6oz,7oc—€pOXy—17a.
chloroethynyl-17,8-hydroxy-19-nor-4-androstene-3-one.
The 60¢,70L-6POXY - 17a - chloroethynyl-17?-hydroxy-19
nor-4eandrostene-3-one is dissolved in 20 ml. of a 0.4 N
solution of hydrogen chloride in chloroform, and the re
sulting solution is allowed to stand for 5.5 hours at room 60
temperature. The reaction solution is then poured into
iced sodium bicarbonate solution. The aqueous mixture
is extracted with chloroform, and the chloroform extract
is evaporated to dryness in vacuo. The residual material
is chromatographed on acid-washed alumina (20 g.) and
eluted with ether-petroleum ether mixtures to give 6
5'(10)-androstene-3-one in 5 cc. of pyridine is added one
equivalent of bromine. The reaction mixture is stirred
for ?fteen hours at room temperature, poured into ice
water and the aqueous mixture extracted with ether. The
ether extract is washed with water, dried over sodium
sulfate, and concentrated in vacuo to yield l7a-chloro~
ethynyl-17?-hydroxy~19-nor-4,9-androstadiene-3-one.
In accordance with the "above procedures, but starting
with the 17a-bromoethynyl- or the 17u-?uoroethynyl-17?
hydroxy-19-nor-5(10)-androstene-3-one in place of the
17a-chloroethyny1-l713-hydroxy-19-nor-5 ( 10) Jandrostene
3-one there are obtained as products the corresponding
17a-brcmoethynyl- or the l7a-?uor-oethynyl-175-hydroxy
19-nor-4,9-androstadiene-3-one.
Example 9
A mixture of 50 mg. of 3-ethoxy-l7a-chloroethynyl
19-nor-3,5-androstadiene-175-01, 5.5 ml. of isooctane, 25
mg. of cyclohexanol and 2.5 mg. of p-toluenesulfonic acid
is heated under re?ux for a period of approximately 32
chloro - 17cc - chloroethynyl - 17/8 - hyd-roxy - 19 - nor-4,6
hours in an apparatus providing for the separation of water
androstadiene-El-one.
from the condensate before return to the re?uxing mix
In accordance with the above procedures, but starting
ture. The reaction mixture is cooled, 0.1 ml. of pyridine
with the 3-ethoxy-(17or-bromoethynyl- or 17oc-?t101‘0 70 is added to neutralize the p-t-oluenesulfonic acid catalyst,
ethynyl)-19-nor-3,S-androstadiene-U?-ol in place of the
S-ethoxy-17a-chloroethynyl-19-nor-3,5-androstadiene-17/3
01 there are obtained as products the corresponding
6-chloro-(17a-bromo-ethynyl- or 17a-?uoroethynyl)-17?
hydroxy-19-nor~4,6-androstadiene-3~one.
.
and the liquid is completely evaporated in vacuo to dry
ness to give as the residual product 3-CYClOl'l6XYlOXY-17oc
chloroethynyl-l9-nor-3,5-androstadiene-175-01.
In accordance with the above procedure, but starting
with 3-ethoxy-17a - bromoethynyl - l9 - nor - 3,5 - andros~
3,096,353
'
9
10
tadiene-l7p-ol in place of the 3 - etlroxy - 17a - chloro
as starting material in the foregoing procedure, there is
ethynyl-l9-nor-3,S-androstadiene-175-01, there is obtained
as product the corresponding 3-cyclohexyloxy-17a-bromo
?uoroethynyl-19-nor-3,5-androstadiene-17B-ol.
obtained as product the corresponding 3-benzyloxy-l7u
ethynyl-l9enor-3,5-androstadiene-175-01. Similarly, when
Example 13
One-hundred mg. of 17ot-chloroethynyl-Uri-hydroxy
3-ethoxy-17ct~?uoroethynyl - 19 - nor ~ 3,5 - androstadiene
17/3-01 is utilized as starting material in the foregoing
procedure, there is obtained as product the corresponding
19-nor-4,9-androstadiene-3-one is heated with 1 cc. of ace
tic anhydride ‘and 1.2 cc. of pyridine on the steam bath
3-cyclohexyloxy~'17ot-?uoroethynyl - l9 - nor - 3,5 — andros
tadiene-l7i6-ol.
overnight. The reaction mixture is then poured onto ice
The extract is washed
with Water and concentrated. The concentrate is chromat
ographed over acid-Washed alumina and eluted with mix
tures of ether and petroleum ether to give 17B-acetoxy
10 and extracted with chloroform.
Example 10
A mixture of 50 mg. of 3-ethoxy-17u-chloroethynyl
19-nor-3,5-androstadiene-17p-ol, 5.5 ml. of isooctane, 25
17a-chloroethynyl-19-nor-4,9-androstadiene-3-one.
mg. of n-butanol and 2.5 mg. of p-toluenesulfonic acid is
heated under re?ux for a period of approximately 32 hours
in an 'apparatus providing for the separation of water from
the condensate before return to the re?uxing mixture.
The reaction mixture is cooled, l0.1 ml. of pyridine is
added to neutralize the p-toluenesulfonic catalyst, and the
cc. of acetic anhydride and 1.2 cc. of pyridine on the steam
19-nor-3,5-androstadiene-17?-ol.
chromatographed over acid-Washed alumina and eluted
with mixtures of ether and petroleum ether to give 3-cyclo
with 3-ethoxy - 17cc - bromoethynyl-l9-nor-3,5-androstadi
pentyloxy - 17B — acetoxy-17a-chloroethylnyl-19-nor - 3,5
Example 14
One-hundred mg. of 3-cyclopentyloxy-Not-chloro
ethynyl-l9-nor-3,5~androstadiene-17?-o1 is heated with 1
liquid is completely evaporated to dryness in vacuo to give 20 bath overnight. The reaction mixture is then poured onto
ice and extracted with chloroform. The extract is
as the residual product 3-n-butoxy-17a-chloroethynyl
In accordance with the above procedure, but starting
ene-17?-ol in place of the 3-ethoxy-17wchloroethynyl-19 25 androstadiene.
nor-3,5-androstadiene-17,8-01, there is obtained as product
Example 15
the corresponding 3-n-butoxy-l7a-bromoethynyl-l9-nor
3,5-androstadiene-175-01. Similarly, when 3-ethoxy-17a
A mixture of 736 mg. of 17ot-chloroethynyl-19-nor-4
androstene-l7p3-ol-3-one, 2.1 g. of cyclopentyl ortho
?uoroethynyl-l9-n0r-3,S-androstadiene-175-01 is utilized
formate, 7.4 ml. of cyclopentanol and 30 mg. of
as starting material in the foregoing procedure, there is 30 p-toluenesulfonic acid is stirred under an ‘atmosphere of
obtained as product the corresponding 3-n-‘butoxy-17a
nitrogen for a period of 3.5 hours. The reaction mixture
?uoroethynyl-l9-nor-3,5-androstadiene-1718-01.
poured into ice-cold aqueous sodium bicarbonate solu
tion, and the aqueous mixture extracted with ethyl ether.
Example 11
The ethyl ether extract is separated, dried, and evaporated
A mixture of 50 mg. of 3-ethoxy-17a-chloroethynyl-19 35 to dryness in high vacuum at a temperature not exceeding
nor-3,5-androstadiene-17B-ol, 5 .5 ml. of isooctane, 25 mg.
50° C. to give 3-cyclopentyloxy-17a-chloroethynyl-19
of cyclopentanol and 2.5 mg. of p-toluenesulfonic acid is
nor-3,5-androstadiene-l7(3-01 which is puri?ed by chroma
heated under re?ux for a period of approximately 32
tography on silicia gel.
hours in an apparatus providing for the separation of
In accordance with the above procedure, but starting
water from the condensate before return to the re?uxing 40
mixture. The reaction mixture is cooled, 0.1 ml. of pyri
dine is added to neutralize the p-toluenesulfonic catalyst,
and the liquid is completely evaporated in vacuo to dry
ness to give as the residual product 3-cyclopentyloxy-l7a
with 17a-bromoethynyl-19-nor-4-androstene-17/8-ol-3-one
in place of the 17a-c‘hloroethynyl-19-nor-4-androstene
17B-ol-3-one, there is obtained as product the correspond
ing
3-cyclopentyloxy - 17a - brorn'oethynyl-19-nor-3,5-an
drostadiene-17p-ol.
chloroethynyl-l9-nor-3,5-androstadiene-17/3-ol.
And similarly, when 17a-?uoro
ethynyl-l9-nor-4-androstene-l7?-ol-3-one is utilized as
In accordance with the above procedure, but starting 45 starting material in the foregoing procedure, there is ob
with 3-ethoxy - 170a - bromoethynyl-19-nor-3,S-androstadi
tained as product the corresponding 3-cyclopentyloxy-l7a
ene-17?-ol in place of the 3-ethoxy-17a-chloroethynyl-19
?uoroethynyl-19-nor-3,S-androstadiene-1713-01.
Example 16
nor-3,5-androstadiene-17,8-01, there is obtained as product
the corresponding 3~cyclopentyloxy-17a-brornoethynyl
19-n0r - 3,5 - androstadiene-17/3-ol.
Similarly, when 3- r
ethoxy-l7a-?uoroethynyl-l9-nor-3,5-andr0stadiene-175-01
is utilized as starting material in the foregoing procedure,
there is obtained as product the corresponding 3-cyclo
pentyloxy - 17a - ?uoroethynyl-19-nor-3,5-androstadiene
17,8-01.
sulfonic acid is stirred under an atmosphere of nitrogen
55 for a period of 3.5 hours. The reaction mixture is poured
Example 12
A mixture of 50 mg. of 3-ethoxy-17a-chloroethynyl-19
nor-3,5-androstadiene-175-01, 5.5 ml. of isooctane, 25 mg.
of ‘benzyl alcohol and 2.5 mg. of p-toluenmulfom'c acid is 60
heated under re?ux for a period of approximately 32
hours in an apparatus providing for the separation of
Water from the condensate before return to the re?uxing
mixture. The reaction mixture is cooled, ‘0.1 ml. of
A mixture of 736 mg. of 17ot-chloroethynyl-19-nor-4,9
androstadiene-17B-ol-3-one, 2.1 g. of cyclopentyl ortho
formate, 7.4 ml. of cyclopentanol and 30 mg. of p-toluene
into ice-cold aqueous sodium bicarbonate solution, and
the aqueous mixture extracted with ethyl ether. The
ethyl ether extract is separated, dried, and evaporated
to dryness in high vacuum at a temperature not exceeding
50° C. to give 17ot-chloroethynyl-l9-nor-4,9-androsta
diene-17,8-ol-3-one-3-cyclopentyl enol ether which is puri—
?ed by chromatography on silica gel.
Various changes and modi?cations may be made in
carrying out the present invention without departing from
pyridine is added to neutralize the p-toluenesulfonic 65 the spirit and scope thereof. Insofar as these changes
and modi?cations are within the purview of the annexed
catalyst, and the liquid is completely evaporated in vacuo
claims, they are to be considered as part of our inven
to dryness to give as the residual product 3-benzyloxy
tion.
17ot-chloroethynyl-l9-nor-3,5-androstadiene-175-01.
We claim:
In accordance with the above procedure, but starting
with
3-ethoxy-l7a-bromoethynyl~19-nor-3,5-androstadi
ene-17?-ol in place of the 3-ethoxy-l7a-chloroethynyl-19
nor-3,5-androstadiene-175-01, there is obtained as product
1. 170a - haloethynyl - 17,8 - hydroxy - 19-nor-4,9'(10)
androstadiene-3-one.
2. 17a - haloethynyl - 17B - acyloxy - l9‘ - nor-4,9( 10)
androstadiene-3—cne.
the corresponding 3-benzyloxy-l7a-bromoethynyl-19-nor
3. 170: - haloethynyl - 175 - hydroxy 3,5~androstadiene-175-01. Similarly, when 3-ethoxy-17a
?uoroethynyl-l9-nor-3,S-androstadiene-175-01 is utilized 75 androstadiene-3-one 3-enol ether.
19 - nor-49(10)
3,096,353
11
4. 170a - haloethynyl - 175 - acyloxy - 19 - nor-4,9i(10)-
androstadiene-B-one 3-eno1 ether.
5. 17oz - chloroethynyl - 17E - hydroxy - 19-11or-4,9(10)androstadjene-3.one_
12
8. 1700 - chloroethynyl - 17B - acetoxy-19-nor-4,9(10)
androstadiene-3-one 3-cyc1openty1 enol ether.
9. The process for the preparation of 17ot-ha1oethyny1
17,8 - hydroxy - 19 - nor - 4,9(10) - androstadiene-‘S-one
6- 1706 _ chloroethynyl _ 17,3 _ acetOXy_19_nor_4,9(1O)_ 5 which comprises reacting 17¢x-haloethyny1-17/8-hydroXy
androstadieneswne‘
7_ 17“ _ chloroethynyl _ 17B _ hydmXy_19_nOr_ 4,9(10)_
androstadiene-3-one 3-cyclopentyl enol ether.
19-nor-5(10)-androstene-3-one with approximately one
equivalent Weight of bromine in pyridine solution.
No references cited.
Документ
Категория
Без категории
Просмотров
0
Размер файла
771 Кб
Теги
1/--страниц
Пожаловаться на содержимое документа