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Патент USA US3052703

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3,®5Z,593
Patented Sept. 4, 1962
2
1
‘of the radicals R1 and R4 being an ethinyl radical-contain
3,052,693
STEROID ALKYL ETHERS AND
PROCESS THEREFOR
Otto Eugelfried,‘ Berlin-Wittenau, and Martin Schenek,
Berlin-Brahman, Germany, ,assignojrs to Schering Alr
tiengesellschaft, Berlin, Germany
ing group, and wherein R6 is selected from the group
consisting of H, OH, O, halogen and lower alkyl radicals.
5
In the above formula the substituent Rgmay be any
lower alkyl radical of up to 5 carbon atoms. Preferably,
the substituent R5 is either the methyl or ethyl radical.
The compounds‘ of the present invention may be pro
duced by subjecting the starting compound, that is com
pound of the above general formula wherein _R5 is hydro
gen to alkylation of the tertiary hydroxyl group of the
No Drawing. Filed Mar. 13, 1959, Ser. No. 799,079
8 Claims. (Cl. 260—397.4)'
The present invention relates to steroid alkyl ethers, 10
ethinyl radical-containing group by means of a lower
and more particularly to alkyl ethers of tertiary steroid
alkyl radical-containing alkylating agent such as methyl
iodide ‘after; if necessary, blocking any other radicals
alcohols which on the same carbon atoms as that to
which the tertiary hydroxyl group is linked is also linked
an ethinyl group.
'
‘
which maybe reactable with the alkylating agent. Where
'
It is an object of the present invention to provide for 15 such blocking is necessary, the ?nal product is obtained
by subsequently removing the blocking agent. The reac
tion with the alkylating agent can be in general carried
the production of such alkyl ethers of tertiary steroid
alcohols which carry an ethinyl group on the same carbon
atom as the one which carries the tertiary hydroxyl group.
out according to known methods.
’
It is another object of the present invention to provide
Thus, in accordance with the present invention, the
a new series of compounds of the above type, which com
starting material, that is a compound vof the above'genera1
formula wherein R5 hydrogen (‘hereinafter referred to as
pound has in general a greater progesterone-like activity
than the non-etheri?ed (i.e. free hydroxyl-group con
taining) steroids.
tertiary steroid alcohol) is ?rst converted to the corre
sponding alcoholate with metallic sodium ‘by reaction in
'
liquid ammonia, preferably in the presence of a trace
of ferric nitrate, and then etherli?ed to the chosen alkyl
ether by reaction with an alkylating agent such as methyl
It is yet another object of the present invention to pro
vide a method of producing the new compounds of the
present invention.
‘Other objects and advantages of the present invention
will be apparent from a further reading of ‘the speci?ca
tion and of the appended claims.
‘With the above objects in View, the present invention
mainly comprises a compound having the following gen~
eral formula:
iodide, preferably dissolved in an inert organic solvent
such as tetrahydrofurane. The produced alkyl ether ‘is
then separated from the reaction mixture ‘in the usual
manner.’
Other groups in the tertiary steroid alcohol, such as
secondary hydroxyl group, keto groups, and the like,
which are reaotable with the alkylating agent are ‘blocked
in known manner by conversion into non-reaetable func
35 tional derivatives such as esters, semicarbazones, or the
like in order ‘to protect these groups from the action of
the alkylating agent. After the alkylation of the tertiary
alcohol group the resulting compound is reconverted into
a compound in which the blocked groups are reintro
This is also done in known
40 duced into the molecule.
manner.
'
According to .the preferred embodiment of the pres
Ru
ent invention the alkyl ethers thereof are the lower 17
wherein the rings A and B contain between 0 and 3 double
alkyl ethers ‘of 17ethinyl-testosterones, particularly, the
bonds, wherein R1 is a radical selected from the class 45 17-methyl ethers. These compounds, as is the :case with
consisting of =0 and the ethinyl-containing group
all of the compounds of the present invention, are thera
peutically valuable with respect to the progesterone-like
0R5
activity ‘thereof. The progesterone-like activity com
‘050E
pounds of the present invention are greater than that of
wherein R5 is a lower alkyl radical, wherein R2 is selected
from the group consisting of H and CH3; wherein R3 is
selected from the group consisting ,of H and CH3, and‘
wherein R4 is a radical selected ‘from the class consisting
of :0, the ethinyl radical-containing group
the initial ethinyletertiary steroid (alcohols. Thus, the
progesterone-like activity of ethinyl-testosterone is in
creased by about ten times in accordance with the present
invention by etheri?cation of the tertiary hydroxyl group
thereof. Similarly, increased activity occurs by etheri?ca
55 tion of the tertiary hydroxyl group of the already strong
\ozon
ly active l71ethinyl-19-nQr-testosterone.
'
'
The following examples are given to further illustrate
and the ethinyl radical-containing group
the present invention. The scope of the invention is not,
however, meant to be limited to the speci?c ,details'of the
60
wherein R5 has the same de?nition as above, at least one
examples.
’
'
'
’
Example I
0.46 g. of metallic sodium are added in portions in
small pieces to approximately 1750 cc. of ammonia at
3,052,693
3
4
a temperature of between -80 and —60° C., after the
addition thereto of a trace of ferric nitrate. After the
Example IV
After the addition of a trace of ferric nitrate to- approxi
mately 200 to 250 cc. of liquid ammonia, 0.83 g. of small
pieces of metallic sodium are added thereto at a temper
ature of —80 to —60° C. After the disappearance of
the blue color 9.45 g. of 17a-ethinyl-A5-androstene-3/3,17
blue color disappears, 6.3 g. of l7-ethinyl-androstene
3,17-diol in 100 ‘cc. of tetrahydrofurane are added drop
wise during a time period of 10 minutes, and the mixture
is subsequently stirred for one to two hours. Thereafter,
1.25 cc. of methyl iodide dissolved in 10 cc. of tetrahy
drofurane are added and the stirring is continued for an
diol in 150 cc. of tetrahydrofurane are added. After one
hour 3 cc. of ethyl iodide in 15 cc. of tetrahydrofurane are
additional 3 hours. The reaction mixture is then poured
onto ice and acidi?ed with acetic acid. The separated
solid substance is ?ltered off and washed until neutral.
The crude reaction product, preferably after prior acet
ylation, is subjected to alumina-chromatography in or
der to remove the non-reacted starting material. There
is in this manner obtained 3-acetoxy-17—methoxy-17
ethinyl-androstene having a melting point of 166-168° C.
added and the mixture is stirred for approximately ‘?fteen
hours. The reaction mixture is then poured onto ice, acdi
tied, and the precipitated product ?ltered off and washed
until neutral. 1For the separation of the main portion of
non-reacted poorly soluble starting material the crude
reaction product is extracted under mild warmth with
15 benzene and the benzene solution subjected to chroma
tography on alumina (according to the method of Brock
mann). The main product which is obtained in prepon
derant amount is 17a-ethinyl-17-ethoxy-A5-androstene-3?
Instead of tetrahydrofurane another solvent can be
used, as for example dimethylformamide.
The 3-acetoxy-17-methoxy-l7-ethinyl—androstene ob
01 having a melting point of 161-1645 ° C. As side prod
tained in the above manner is, after saponi?cation to the
uct in small amount there is obtained the 3,17-diethyl ether
having a melting point of 113-1145 ° C.
3-hydroxyl compound (melting point equals 1685-1705“
C.) in known manner oxidized according to the method
The isolation ‘of the mono-ethyl ether can be accom
of Oppenauer to the l7-ethinyl-testosterone~17~methyl
plished through the production of the 3-acetate analo
ether. After several recrystallizations, the melting point
gously to the method described in Example I. There is
of the compound is found to be 129-131u C.
25
obtained in this manner the 3-acetoxy-17u-ethinyl-17
ethoxy-As-androstene having a melting point of 124.5
(a)n=+l5 °
(in dioxane).
Absorption in ultraviolet light: e241=l6,30()
125.5 ° C.
Ethyl bromide can be used in the above process in
30
Infra-red spectrum:
~No OH-band is discernible
Ethinyl bands at 3.10 and 4.77“
A4-3-keto bands at 5.98 and 6.17p
Ether band at 9.12;»
place of ethyl iodide iodide. By Oppenauer oxidation in
known manner the above compound can be converted (af
ter formation of the 3-hydroxy compound) to form ?nally
the 17-ethinyl-testosterone-ethyl ether having a melting
point of 105—108° C.
35
Example 11
Absorption in ultraviolet light:
5240:
Infra-red spectrum:
Ethinyl bands at 3.1 and 4.78,u
0.23 g. of sodium in small pieces are introduced gradu
ally into approximately 70 to 80 cc. of liquid ammonia
3-keto band at 6.0a
A4-band at 6.2a
Ether band at 9.25,“
containing ‘a trace of ferric nitrate at a temperature of
——70° C. After the blue color disappears, a suspension
of 3.12 g. of ethinyl-testosterone in 50 cc. of tetrahydro“
furane are added and a reaction mixture is stirred for
Upon subcutaneous application of the 17-ethinyl
one hour. Subsequently, 0.63 cc. of methyl iodide in 5
testosterone-ethyl ether the activity thereof in the Clau
cc. of tetrahydrofurane are added dropwise and the re 45 berg test is found to be ten times as great as the corre
action mixture stirred for an additional three hours.
sponding non-etheri?ed free 17-hydroxyl compound.
The reaction mixture is then poured onto ice, acidi?ed
Example V
with acetic acid, and the precipitated product ?ltered off
and washed until neutral. The product is separated from
After addition of a trace of ferric nitrate to approxi
non-converted starting material by extraction with ether 50 mately 150 cc. of liquid ammonia, 0.441 g. of small pieces
and fractional crystallization of the portion which is
of cut metallic sodium are added slowly thereto at a tem
easily soluble in ether from methylene chloride-hexane.
perature of -80 to —60° C. After disappearance of
There is thus obtained the ethinyl~testosterone-methyl
the blue color, 4.96 g. of 17a-ethinyl-A1,4~androstadiene
' ether having a melting point of 124-128“ C. No melting
17-01-3 -one in 100 cc. of tetrahydrofurane are added drop
wise. After one and one-half hours 1.5 cc. of methyl
- point depression occurs with the substance obtained from
Example 1.
iodide in 10 cc. of tetrahydrofurane are added to the reac
Example III
17-ethinyl-19-nor-andros-tene-3,17-diol is reacted under
tion mixture and the reaction mixture is stirred an addi
tion three hours. It is thereupon poured onto ice, acidi
tied with acetic acid, and the precipitated reaction product
taken up in ether. The neutral-washed ether solution af
ter ‘drying over sodium sulfate is evaporated, the residue
taken up in benzene and subjected to chromatography on
aluminum oxide (according to the method of Brockmann).
There is thus obtained 17ot-ethinyl-AlA-androstadiene-17
- the conditions set forth in Example I and then worked
up in the same manner. The obtained oily, crude prod
uct is oxidized in known manner according to the method
of Oppenauer. After chromatography on alumina the
compound 17-ethinyl-19-nor-testosterone-methyl ether is
obtained having the following characteristics:
65
Melting point: 122.5-124.5° C.
Absorption in ultraviolet light: e240=16,650
Infra-red spectrum:
Ethinyl band at 3.04pi
A4-3-ket-o bands at 6.010 and 6.l9,u
Ether band at 9.17M
This compound given subcutaneously in the Clauberg
_test is found to have six times the activity of the non
etheri?ed 17-ethinyl-19-nor=testosterone.
ol-3-one-methyl ether which after recrystallization from
hexane melts at 1345-1355” C.
Absorption in ultraviolet light:
70
€203=4,16O
€243:16,020
Infra-red spectrum:
“All known characteristics present.”
The activity of the produced compound by the Clau
berg test upon subcutaneous administration is found to
53052693
5
be three to four times greater than the compared non
‘
etheri?ed steroid alcohol.
Example VI
17rx-ethinyl-A‘ite-androstadiene-17-ol-3-one is reacted
ozon
Loom
I.
and worked up under analogous ‘condition to those de
scribed in Example V. The oily separated crude product
RO-
is taken up in ether, the ether solution washed with water
and dried over sodium sulfate. The non-reacted, di?i
,
i ,/
O
culty soluble starting material separates upon concentra
tion of the ether solution. The easily soluble portion re
maining in the ether solution is the reaction product.
This is separated from the ether by evaporation of the
ether, taken up in ‘benzene and subjected to chromatog
ozon
Loon3
raphy on aluminum oxide (according to the method of 15
Brock-mann). There is thus obtained 17¢x-ethinyl-l7~
methoxy-A‘i'6-androstadiene-3-one having a melting point
'_?
HO——
of 96.5—98.5° C.
:
on out
Absorption in ultraviolet light:
20
A
e234=26,420
c2011
'—0 CH3
Infra-red spectrum:
Ethinyl bands at 3.09 and 4.75;»
3-keto band at 6.00/1.
A‘l-band at 6.17M
AG-band at 629p.
Ether ‘band at 9.12M
-———r
0:
CH3
This compound is found to have three to four times the
050E
30
activity of the non-etheri?ed compound.
The same compound can be produced in better yield
uoona
from 17ot-ethinyl-17-methoxy-A5-androstene-3?-ol (pro
duced according to Example I) by dehydration by means
of quinone in boiling toluene in the presence of aluminum
isopropylate.
35
The analogous 17ot-ethinyl-l7-ethoxy-A416-androstadiene
3-one having a melting point of 125—l27° C. can be pro
duced from 17a-ethinyl-17-ethoxy-A5-androstene-3/3 _ 01
O:
t
on3
(produced according to Example IV). This ether is found
The 17-ethinyl-6a-methyl-testosterone-methyl ether of
Example V11
Example VIII
S-ethinyl-androstane-B‘,17,8-diol is etheri?ed analogously
to have three to four times the activity of the non~etheri?ed 40 this example is found to be active in the Clauberg test
in an amount of 0.2 mg. subcutaneously.
compound.
1706 - ethinyl - 61x - methyl - A4-androstene-l7-ol-3~one is
etheri?ed and Worked up in an ‘analogous manner to that 4:5 to Example I. The crude reaction product is acetylated
described in Example V. The crude product is extracted
and subjected to chromatography on aluminum oxide
(according to the method of Brockmann). There is thus
obtained 3 - ethinyl - 3-methoxy-androstane-17B-ol-acetate
which is only poorly soluble therein. The ether solution
having a melting point of 160-162” C. The correspond
is evaporated and the residue dissolved in benzene is sub—
jected to chromatography on aluminum oxide (according 50 ing 17-OH-compound (having a melting point of 158
159° C.) is produced by alkaline saponi?cation, and the
to the method of Brockmann). There is thus obtained
hydroxyl compound is then oxidized according to the
17-ethinyl~6a-methyl-testosterone-methyl ether having a.
method of Oppenauer to the 3-ethinyl-3-methoxy-andro
melting point of l33—l35° C.
stane-17-one having a melting point of 125 .5—l27° C.
Absorption in ultraviolet light: e241:15,370
55 Infra-red spectrum:
Infra-red spectrum:
Ethinyl bands at 3.00 and 4.74”
Ethinyl bands at 3.06 and 4.75,:1.
l7-keto band at 5.74”
3-keto band at 5.98/1.
Ether band at 9.1711.
A4-band at 6.20M
Example IX
Ether band at 9.14/1.
with ether to remove the non—reacted sarting material
After the addition of the trace of a ferric salt to 250
cc. of liquid ammonia, 1.01 g. of sodium is introduced
ethinyl - 17 - methoxy - 5,6-oxido»androstane-3,8-ol Whose
thereto under stirring at a temperature of -—80 to -—70°
acetate (obtainable from 17a-ethinyl-l7-rnethoxy-A5—
C. After the disappearance of the blue color 7.61 g. of
androstene-3B-ol or acetate (see Example I) is obtained 65 17a-ethinyl-estradiol-3~tetrah'ydropyranyl ether in 150 cc.
The same compound can also be produced from 170:
in known reaction sequence through the following steps:
of tetrahydrofurane is added dropwise during a time period
of 1—2 hours. After an additional hour 2.75 cc. of methyl
iodide in 10cc. of tetrahydrofurane are added and the
reaction mixture is further stirred for several hours (max
70 imum of ?fteen hours). The [reaction mixture is poured
onto ice and acidi?ed with concentrated ‘acetic acid. The
‘reaction product is extracted with ether and the ether
RO
R=H or ACYL
solution is Washed with water until neutral. The solution
is dried over sodium sulfate and then evaporated. The
75 reaction product in crude form which precipitates in the
3,052,693
8
test in an amount of 0.3 mg. administered subcutaneously.
form of a foamy residue is, without puri?cation, treated
to split oil? the tetrahydropyranyl ether, as follows:
Without further analysis, the foregoing will so fully re
veal the gist of the present invention that others can by
The product is dissolved in 240 cc. of methylene chlo
ride, mixed with 80 cc. of methanol and about 25-30
applying current knowledge readily adapt it for various
applications without omitting ‘features that, ‘from the
drops of concentrated hydrochloric acid is added thereto.
action solution is washed with water and dried over
standpoint of prior art, fairly constitute essential charac
teristics of the generic or speci?c aspects of this invention
sodium sulfate. After evaporation of the solvent there is
obtained 17a-ethinyl-estradiol-17-monomethyl ether which
and, therefore, such adaptations should and are intended
to be comprehended within the meaning and range of
After standing for one hour at room temperature the re
star-ts to sinter at 162° C. and then melts at 167—171° C. 10 equivalence of the following claims.
What is claimed as new and desired to be secured by
Letters Patent is:
melts at 1705-172“ C.
After recrystallization from methanol the pure substance
1. The
Absorption in ultraviolet light:
15
€280=2,
£285:
5205': 1 8,
l7-ethinyl- l9-nor-testosterone- l7
3. The compound l7cr-ethinyl-l7 - methoxy - A416 - an
Example X
drostadiene-B-one.
4. The compound l7cc-etlinyl-17-ethoxy-A4-6-andros
After the addition of a small amount of a crystalline
ferric salt to 150 cc. of liquid ammonia, 0.45 g. of sodium
are slowly added under stirring at a temperature of —~80—
60° C. After disappearance of the blue color a solution
of 6.85 g. of 2Oa-ethinyl-A5-pregnene-3,B-ZO-diol ‘having a
melting point of’ 240.5—243° C. (obtained from A5-preg
nene-3?-ol-ZO-one-acetate by ethinylation according to the
compound
methyl ether.
2. The compound 17a-ethinyl-A1A-androstadiene-17-ol
3-one-17-methyl ether.
tadiene-3-one.
5. The compound 17ethinyl-6u-methyl-testosterone
17-methyl ether.
6. The compound 20a-ethinyl-ZO-methoxy-M-pregnene
3-one.
25
7. The
compound
Hot-ethinyl-17-methoxy-A1’4’6-an
usual methods) in 200 cc. of tetrahydrofurane are added
dropwise and the reaction mixture is stirred for an addi
drostatriene-3-one.
tional hour. The reaction mixture is subsequently reacted
steroid alcohols which carry an ethinyl group on the same
with a solution of 1.25 cc. of methyl iodide in 10 cc. of
carbon atom as the one which carries the tertiary hy
8. The method of producing alkyl ethers of tertiary
ltetrahydrofurane, after the addition of which the reaction 30 droxyl group, which comprises subjecting a compound of
the ‘formula:
mixture is stirred for three hours at the above mentioned
temperature. The reaction mixture is then poured onto
ice and acidi?ed with concentrated acetic acid. The pre
cipitated reaction product is ?ltered and washed until neu
tral. For the removal of the non-reacted starting mate
rial the crude product precipitated in benzene is subjected
to chomato-graphy on an aluminum oxide column. There
is thus obtained 20ix-ethinyl-2O-methoxy-A5-pregnene-3?
ol, which after recrystallization from acetic ester melts
at 182—184° C. By Oppenauer oxidation (conditions
analogous to Example I) there is obtained the compound
2Oa-ethinyl-2O-methoxy-A4-pregnene~3-one, which after
Ru
wherein the rings A and B are selected from the group
consisting of rings which are free of double bonds and
recrystallation from acetic ester melts at 213—215° C.
Absorption in ultraviolet light: €241=l6,43O
Example XI
17a-ethinyl-testosterone-methyl ether is dehydrogenated
by chloranil by several hours of heating in amyl alcohol.
45
rings containing double bonds in position selected from
the group consisting of
A4’ A5(10), AM, AM and A1,4.6
wherein R1 is selected from the group consisting of =0
and the ?rst ethinyl radical-containing group
After the end of the reaction the reaction mixture is 50
evaporated under vacuum, the residue taken up in methyl
(
5
ene chloride, the solution washed repeatedly with sodium
XCECHz
dithiosul?te solution (Na2S2O4) and two times with 0.1
wherein R5 is hydrogen, wherein when R1 is said ?rst
normal sodium hydroxide solution and subsequently with
ethinyl radical-containing group R4 is =0 and when R1
water. The methylene solution is evaporated, the residue 55 is =0 R; is selected from the group consisting of the
taken up in benzene and then subjected to chromatog
second ethinyl radical-containing group
raphy on silica gel which was subjected to a calcining
treatment and then mixed with 10% water. The benzene
RCFCHE:
eluate was discarded, the material is washed with chloro
form and the chloroform eluate is then evaporated. The 60 and the third ethinyl radical-containing group
residue is taken up in benzene, puri?ed and subjected to
H
chromatography on aluminum oxide (according to the
method of Brockmann). The crystallized fractions are
recrystallized from hexane. There is obtained in this
manner 170a - ethinyl - l7-methoxy-A1A?-androstatriene-3
one having a melting point of 168~170° C.
< O /CH3
65
0R5
/
CECHs
wherein R5 is hydrogen, wherein when R.,, is said second
ethinyl radical-containing group R2 is selected from the
group consisting of H and CH3, R3 is CH3 and R6 is
€206=11,090
selected from the group consisting of H and lower alkyl
6223:11,340
70 radicals, and when R; is said third ethinyl radical-con
taining group R2 and R3 are both CH3 and R6 is H, to
€302=11,930
6256:
etheri?cation of the tertiary hydroxyl group of said ethinyl
radical-containing group with a lower alkyl alkylating
The same substance can be produced starting from 17a
agent after blocking any other radical reactable with said
ethinyl-17-methoxy-A1A-androstadieneQ-one. The com
pound produced in this example is active in the Clauberg 75 alkylating agent by forming with said radical a group
Absorption in ultraviolet light:
3,052,693
9
which is not reactable with said alkylating agent, and
subsequently reconverting such formed group after said
etheri?cation of said tertiary hydroxyl group to the origi
nal radical, thereby forming said compound wherein R5
is a lower alkyl radical.
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,280,236
2,305,727
2,318,105
2,374,369
2,837,464
Inhoffen et a1. ________ __
Miescher et a1. _______ -_
Ruzicka _____________ __
Miescher et a1. _______ _..
Nobile ______________ __
Apr. 21,
Dec. 22,
May 4,
Apr. 24,
June 3,
10
FOREIGN PATENTS
1,010,963
Germany ____________ __ June 27, 1957
OTHER REFERENCES
Djerassi et al.: J. Am. Chem. Soc. 76, 4092-4094
(1954).
Mancera et al.: J. Am. Chem. Soc. 77, 5673-5676
(1955).
1942
Ringold et al.: J. Am. Chem. Soc. 78, 2477-2479
10
1942
(1956).
1943
Ackroyd et al.: J. Chem. Soc. (Gr. Br.) 1957, pages
1945
4099-4111.
1958
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