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Патент USA US3069450

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3,009,440
United States Patent 0 ”
Patented Dec. 18, 1962
1
2
and
3,069,440
CH;
NEW 17-OXYGENATED-A"-PROGESTERONES
Joseph P. Joseph, Cliffside Park, N.J., and John P. Dusza,
Nanuet, and Seymour Bernstein, New City, N.Y., as
signors to American Cyanamid Company, New York,
/CH \ '/
i /
6
C
N.Y., a corporation of Maine
No Drawing. Filed Oct. 27, 1961, Ser. No. 148,057
6 Claims. (Cl. 260-39145)
//c-\CH// C \ on? CH
O
This invention relates to new steroid compounds. More 10
particularly, it relates to nuclear unsaturated progesterones
and methods of preparing the same.
The novel progesterones of the present invention can
radicals.
The compounds of the present invention are, in gen
eral, crystalline solids. They are insoluble in water and
somewhat soluble in the usual organic solvents such as
chloroform or alcohol.
be illustrated by the following formula:
The present compounds are prepared, for example,
starting with pregn-1l-ene-3,20-dione (I) which is de
scribed by P. Hegner and T. Reichstein, Helv. Chim. Acta.
26, 721 (1943). The above compounds are treated with
selenium dioxide in the presence of a lower alkanol such
as, for example, methyl alcohol. The product obtained
This com
20 is 3,3-bismethoxypregn-1l-en-ZO-one (II).
pound is treated in solution with oxygen to produce the
corresponding Noe-peroxide (III). Without puri?cation
the peroxide (III) is dissolved in glacial acetic acid and
in which R is a member of the group consisting of hydro
treated with zinc dust. The product obtained is 171x
gen and lower alkanoyl and X is a member of the group 25 hydroxypregn-ll-ene-3,20-dione (VI). The latter com
consisting of divalent radicals having the formula:
pound can also be prepared by starting with 16o¢,17ot
epoxy-3a,l2a-dihydroxypregnan-20-one (XII) which is
dissolved in a solvent and treated with ethylchloroformate.
The product resulting is 3tX-C3I‘bOethOXy-160t,170t-CPOXY
30 12a-hydroXypregnan-20-one (XIII).
l
The latter com
pound is treated with p~toluenesulfonyl chloride to pro
CH2
20-one (XIV). This compound, heated with s-collidine,
duce 3 oc-carboethoXy-l 60c, l7u-epoxy-l2u-tosyloxypregnan
produces 30: - carboethoxy-16:»,17a-epoxy-1l-pregnen-ZO
one (XV). The latter compound, when heated with so
dium methoxide, gives 16a,17u-epoXy-3u-hydroxypregn
11-en-20-one (XVI). On treating the latter compound
with chromium trioxide in pyridine the compound 16oz,
l7a-epoxypregn-1l-ene-3,20-dione (IV) is obtained. The
40 latter compound when treated with hydrogen bromide in
l
glacial acetic acid produces 16B-brorno-l7a-hydroxypregn
11-ene-3,20-dione (V). This compound heated with
Raney nickel produces 17a-hydroxypregn-11-ene-3,20
CH;
/CH2 \‘ /
ca,
(I:
I
.
45
CH
O//c\CH// C \CH//
produces
CH
c‘:
O
/
// \ CH/
(in
/
(VIII).
pregna-4,ll-diene-3,20-dione (VII); l7a-acetoxypregna
4,6,1l-triene-3,20-dione (IX); 17a-acetoXypregna-1,4,l1
I
CH,
17a-acetoXypregn-1l-ene-3,20-dione
This compound when heated with 2,3-dichloro-5,6-di
cyanobenzoquinone in a solvent produces four compounds
‘
50 which are separated by chromatography: l7a-acetoxy
ca,
éGH\I /
dione (VI) which is identical with compound VI pre~
pared above. The latter compound when treated with
acetic anhydride in the presence of p-toluenesulfonic acid
on2
triene-3,20-dione (X) and l7a-acetoxypregna-1,4,6,11
5 tetraene-3,20-dione. These reactions are shown in the
following ?owsheet.
0
FLOWSHEET
OH
I
(‘3H5
can
CH5
‘RH ‘=0
- ~ ‘,0
__
__p
>
i
no ’
V XII
if
C; H5 060 /
1
XIII
3,069,440
5
FLOWSHEET—C0ntinued
V
CH;
l
C=O
.15
i- OH
% 9H
H
VII
coca;j
i
.. - 0A9
/.
XI
The compounds of the present invention are physiologi
resulting solution is allowed to remain at room tempera
cally active as progestational agents. As such, they are
ture for 24 hours. Crystals of II (10.7 g., melting point
useful for the treatment of threatened and habitual abor 65 135-137“ C.) which separate during this time are col—
tion, amenorrhea, dysmenorrhea, premenstrual tension
lected and Washed with methanol. The methanol wash
and related gynecological disorders.
is combined with the mother liquors and concentrated
The following examples describe in detail the prepara~
under reduced pressure. To this solution is added 18 g.
tion of representative substituted progesterones of the
of potassium hydroxide in 360 ml. of methanol. After
present invention.
70 adding 2 liters of water, tan crystals separate from the
EXAMPLE 1
solution which are collected by ?ltration and immediately
are
recrystallized from methanol containing a few drops
3,3-Bism ethoxypregn-Z 1 -En-20-One (II)
of pyridine to give an additional 5.7 g. of II, melting point
To 500 m1. of methanol is added 18.0 g. of pregn-ll
136—138° C. A sample is recrystallized from methanol
ene-3,20-dione (I) and 18.0 g. of selenium dioxide. The
and melts at 137-139“ C.
3,069,440
S
6’
EXAMPLE 2
gum which crystallizes on trituration with petroleum
ether (50—70° C.) to give 48 mg. of l7a-acetoxypregn
1 7 oz-Hydroxypregn-I 1 -En e~3,20-Di0ne (VI)
A solution of 320 mg. of 3,3-bismethoxypregn-1l-en
1l-ene-3,20-dione (VIII), melting point l65—171° C.
Several recrystallizations from aqueous methanol raises
the melting point to 185—l87° C.
EXAMPLE 5
1 7 a-A cetoxypregna-4J 1-Diene-3,Z0~Dione (VII)
20-one (II) is stirred while oxygen is admitted from a
calibrated burette. After a slight excess of the theoretical
amount of oxygen (21.4 ml.) is consumed the reaction
is terminated and neutralized with glacial acetic acid. The
mixture is extracted from an aqueous solution with
methylene chloride. After drying over magnesium sul 10
fate the solvent is removed under reduced pressure to
give 265 mg. crude 170t-PEI'OXld6 (III). Without puri?ca
tion III is dissolved in 26.5 ml. of glacial acetic acid and
2.65 g. of zinc dust is added with vigorous stirring. After
stirring 2 hours at room temperature the reaction mixture
is ?ltered and the zinc residue is washed with glacial
acetic acid. The combined ?ltrate and acid Wash are
1 7cc-A cet0xypregna-4,6,1 .7 -Triene-3,20-Di0ne (IX)
1 7a-A cet0xypregna-1,4,1 1-Triene-3,20-Di0ne (X)
1 7u-Acet0xypregna-1,4,6,1 1-Tetraene-3,20-Di0ne (XI)
In 5 ml. of dioxane 585 mg. of 17a-acetoxypregn-l1
ene-3,20-dione (VIII) and 600 mg. of 2,3-dichloro-5,6
dicyanobenzoquinone are dissolved and re?uxed for 18
hours. The reaction mixture is evaporated under re—
duced pressure. The residue is suspended in benzene and
the insoluble hydroquinone removed by ?ltration. The
?ltrate is concentrated under reduced pressure and added
to a column of hydrated magnesium silicate (30 g.). By
gradient elution chromatography 0—20% dioxane in
petroleum ether (60-70° C.) the column is fractionated
(10 ml. cuts taken) and product detected by ultraviolet
evaporated under reduced pressure (bath temperature
30° C.). To the residue is added methylene chloride and
water. The organic layer is separated and is washed with
excess sodium bicarbonate solution and water until neu
tral. After drying and evaporation under reduced pres
sure a gummy residue results which on trituration with
ether gives 10 mg. of crystalline l7a-hydroxypregn-11
25 and infrared analyses.
ene-3,20-dione (VI).
Cuts #241-280 contain com
pounds VII and IX (44 mg.) and cuts #281-350 contain
EXAMPLE 3
compounds IX, X and XI (77 mg).
I 7oc-Hydr0xypregn-1 1-Ene-3,20-Di0ne (VI)
Partition chromatography on a diatomaceous earth
column of cuts 281-350 with methanolsheptane gives 31
epoxy-pregn-ll-ene-3,20-dione (IV) in 5 ml. of methylene 30 mg. of pure l7a-acetoxypregna-1,4,11-triene-3,20-dione
(X)
chloride is added 0.5 ml. of glacial acetic acid. T0 this
To a cooled (18° C.) solution of 400 mg. of 160:,1704
is added dropwise over ?ve minutes, 0.4 ml. of 32%
kgtif‘m‘ 246 mu
hydrogen bromide in glacial acetic acid. After stirring
for an additional 20 minutes the solution is poured on
and 17a-acetoxypregna-1,4,6,l1-tetraene-3,20-di0ne (XI)
ice Water and is extracted with methylene chloride. The
methylene chloride extracts are washed with Water and
dried over magnesium sulfate. Evaporation under re
Partition chromatography on
duced pressure (bath temperature 25° C.) gives the
diene-3,20-dione (VII)
AMethsnol
223, 255 and 300 ml‘
max.
bromohydrin (V) a gum which crystallizes on tritura
tion with ether, melting point 204—206° C. This material
gives a positive Beilstein halogen test. The crude crystal
line (V) is suspended in 10 ml. of methanol containing
0.4 ml. of water and 2 gm. of Raney nickel [prepared
according to P. L. Julian et al., I. Am. Chem. Soc. 78,
3153 (1956)] is added. The mixture is stirred under
re?ux for 4 hours and the nickel is removed while hot
and washed with methanol. The combined methanol
solutions are evaporated under reduced pressure to give
a diatomaceous earth
column of cuts 241-280 gives l7a-acetoxypregna-4,ll
40
and 170s - acetoxypregna - 4.6.11 - triene-3,20-dione (IX)
R35???“ 285 mu
EXAMPLE 6
Preparation of 3oc-Carb0clh0xy-16a,17ot-Ep0xy-12a
HydrOxypregrzan-ZO-One (XIII)
In 3 ml. of reagent pyridine 500 mg. of 160:,170c-6POXY
3a,l2a-dihydrOXypregnan-ZO-one (XII) is dissolved and
a gum. This is dissolved in methylene chloride and is
dried over magnesium sulfate. Evaporation of solvent 50 the solution is cooled to 5° C. To this is added 0.42 ml.
of ethyl chloroformate and the reaction mixture is al
under reduced pressure gives 93 mg. of crystalline 17a
lowed to remain at room temperature for 4 hours. It is
hydroxypregn-l1-ene-3,20-dione (VI), melting point
then poured into 30 m1. of ice Water and the mixture is
191—l94° C. identical by infrared analysis with material
extracted with ether several times. The combined ether
obtained in Example 2 above. Recrystallization of a sam
ple raises melting point to 204—206° C.
EXAMPLE 4
1 70t-A cetoxypregn-l 1-Ene-3,20-Di0ne (VIII)
55 extracts are washed with excess saturated aqueous sodium
bicarbonate followed by Water until neutral. After drying
and evaporation pyridine is removed from the residual
gum by repeated evaporation with benzene. A glass re
sulted which crystallizes on the addition of ether, melt~
Under a nitrogen atmosphere to a solution of 100 mg. 60 ing point l89~191° C. Recrystallization from acetone
of 17a-hydroxypregn-11-ene-3,20-dione (VI) in 3 ml. of
acetic acid and 1 ml. acetic anhydride is added 100 mg.
of p-toluenesulfonic acid. After 18 hours under nitrogen
at room temperature the reaction mixture is poured on
ice and water and extracted with methylene chloride. The
extract is washed with excess sodium bicarbonate, dried
over magnesium sulfate and evaporated under reduced
petroleum ether gives XIII, melting point 198—200° C.
EXAMPLE 7
Preparation of 3ct-Carb0eth0xy-1 6a,] 7a-Ep0xy-12ot
T05y loxypregnan-ZO-One (XIV)
A solution of 1.4 g. of 3a-carboethoxy-l6a,17a-epoxy
pressure leaving a glass (30 mg.). To an aiiquot (70
12a-hydroxypregnan-20'one (XIII) and 2.0 g. of p-tolu
mg.) of this glass in 1.5 ml. of methanol is added 0.06
enesulfonyl chloride in 10 ml. of pyridine is allowed to
ml. of 3.15 N sodium methoxide in methanol. After 20 70 remain at 37° C. for 4 days, sealed from atmospheric
minutes the solution is neutralized with acetic acid and
moisture. The clear yellow solution is poured into 100
evaporated under reduced pressure (bath temperature
ml. of water, and the resulting white gum solidi?es on
20~25° C.) The residue is dissolved in methylene
standing. The solid is collected by ?ltration and dis~
chloride and ?ltered to remove inorganic salts. The
solved in methylene chloride. This solution is washed
?ltrate on evaporation under reduced pressure gives a 75 with excess aqueous saturated sodium bicarbonate and
3,069,440
10
then water until neutral. After drying over magnesium
sulfate and evaporation, XIII is obtained as a glass
143-146° C.
Recrystallization of a sample from acetone
petroleum ether raises the melting point to 147~l49° C.
( 1.99 g.).
In another experiment, the l2cc-tosyloxy steroid XIV is
obtained in crystalline form, melting point 176—177‘’ C.,
We claim:
1. A compound of the formula:
which did not change on recrystallization from acetone
petroleum ether.
EXAMPLE 8
Preparation 0f 3 a-Carboethoxy-I 6 at, I 7 rx-Epoxypregn
II-En-ZO-One (XV)
10
In 66 ml. of s-collidine 27.0‘ g. of crude 3-carboethoxy_
16a,l7a-epoxy-12tx-tosyloxypregnan-20-one (XIV) is re
31
?uxed for 24 hours. This is cooled and added to 7 liters
of 2 N hydrochloric acid. The mixture is then extracted
with chloroform several times.
in which R is a member of the group consisting of hydro
gen and lower alkanoyl and X is a member of the group
The extracts are com
consisting of divalent radicals having the formula:
bined and washed with water until neutral, dried and evap
orated leaving a black gum. This is dissolved in 500 ml.
CH;
of ether and washed with 100 ml. of N hydrochloric acid
and then water. Evaporation of the dried solution gives 20
a dark gum.
This is dissolved in 100 ml. of benzene and added to a
column of 500 g. of silica gel (>200 mesh). Elution with
benzene:ether (98:2) gives 12.6 g. of crude 3a~carbo
ethoxy-16a,17a-epoxypregn-1l~en-20-one (XV) which on 25
trituration with methanol gives 11.3 g. of product, melting
point 147-149° C. Further elution of the column with
benzene:ether (9:1) gives 4.6 g. of starting material,
i
1‘ \
0% ‘cm/lH
I
/CH2
on;
/
\ v/
CH2 (i
I
/ CH
01/G we” \ea/
XIV, melting point 172-175° C.
EXAMPLE 9
‘it
C
30
Preparation of 160517a-Ep0xy-3a-Hydr0xypregn-11
\
_._\‘
En-ZO-One (XVI)
CH;
911m /
In 60 ml. of 0.1 N sodium methoxide in methanol, 1.0
g. of 3a-carboethoxy-16a,17a-epoxypregn - 11 - en-ZO-one 35
CH
(XV) is dissolved and re?uxed for one hour. After evap
oration the residue is dissolved in methylene chloride and
washed twice with water (neutral to litmus). The meth
ylene chloride solution is dried and evaporated to give a
I
C
|
l
o4.G \cn" C‘ \cnz/
‘
and
mixture of solid and gum. This is crystallized from ace
CH;
tone-petroleum ether to give 711 mg. of XVI, melting point
169~170° C. Further recrystallization does not alter the
melting point.
EXAMPLE 10
Preparation of 16:1,] 7u~Epoxypregn-11-Ene
or?’
CH\I /
45
04/’ \OH 9
3,20-Di0ne (IV)
c
t
I
H
9c
radicals.
To an ice-cold solution of 1.7 g. of 16a,l7a-epoxy-3u
_
2. The compound 17a-hydroxypregn-11-ene-3,20-d1one.
3. The compound 17ot-acetoxypregn-1l-ene-3,20-dione.
is added a solution of 1.62 g. of chromium trioxide in 18.7 50
4. The compound 17u-acetoXypregna-4,6-11-triene-3,
ml. of cold pyridine. The resulting dark brown mixture is
ZO-dione.
stirred for 20 hours at room temperature. To the mix
hydroxy-ll-pregnen-ZO-one (XVI) in 36 ml. of pyridine
5. The compound l7ot-acetoxypregna - 1,4,11 - triene-3,
ture is added about 50 ml. of methanol and then it is evap
orated to give a gum. Benzene is added to remove the last
20-dione.
traces of pyridine by evaporation. After the addition of
water, methylene chloride is used for extraction. The
6. The compound 17a-acetoxypregn-1,4,6,1l-tetraene
3,20-dione.
combined extracts are washed successively with dilute so
dium bicarbonate and then water. After drying over mag
References Cited in the ?le of this patent
nesium sulfate, the methylene chloride solution is passed
through a column of magnesium silicate which on evap
oration the dione (IV)
(1.52 g.), melting point
60
UNITED STATES PATENTS
2,782,211
2,969,304
Wettstein et al. _______ __ Feb. 19, 1957
Wettstein et al. _____ __,___ Jan. 24, 1961
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