close

Вход

Забыли?

вход по аккаунту

?

Патент USA US3067228

код для вставки
3,967,218
ice
United States Patent
Patented Dec. 4, 1952
d?)
5.
i
3,667,218
200,17oc-DHa/EETHYL DERIVATIVES OF THE
CH3
ANDRGSTANE SERIES
Raymond L. Pederson, Kaiamazoo, John {3. Babe-och,
Portage Township, Kaiamazoo County, and .‘lohn A.
Hogg, Kalamazoo, Mich.
No Drawing. Filed June 9, 1958, Ser- No. 740,517
2 Claims. (£1. 260-69145)
0:/\
CH3
(‘)H--~bweralkyl
HO_/\
F
(3115-
This invention is a continuation-in-part of our applica 10
tion Serial No. 547,309, ?led November 16, 1955, now
US. Patent 2,883,401 and relates to novel steroid com
(|)H"lower
alkyl
F
OH;
0113-
CH:
'
‘__.
O=
VII
O:
VI
pounds, more particularly to novel synthetic hormones of
wherein the lower-alkyl groups each contain from one to
the androstane series, and to novel intermediates in their
eight carbon atoms, inclusive, and are preferably methyl,
15
preparation and to the process for their production.
and X is a halogen having an atomic Weight from 35 to
The novel compounds of this invention, 9ct~?uoro-11
127, inclusive, i.e., chlorine, bromine or iodine, and R
oxygenated 2a-methyl-l7a-lower-alkyltestosterones (VI
is selected from the group consisting of hydrogen, car
and VII below), especially those wherein the lower-alkyl
group is methyl, possess pronounced oral anabolic activity
bonyl lower-alkoxy, lower-alkoxy and tri?uoromethyl.
dering them effective in therapy requiring an anabolic
other Object is the provision of steroid intermediates read
ily convertible to these synthetic steroid hormones. Still
another object is to furnish a process for the production
of these steroid compounds. Other objects will be ap‘
It is an object of the present invention to supply novel
with little androgenic activity or salt retention, thus ren 20 synthetic steroid hormones of the androstane series. An
agent where accompanying androgenic activity is undesir
able, e.g., in the treatment of osteoporosis in females. The
absence of androgenic activity is in sharp contrast to the
pronounced androgenic activity of 9a-?uoro-ll-oxygen
25 parent to those skilled in the art to which this invention
ated-l7a-methyltestosterones. These novel compounds
pertains.
(VI and VII) of the present invention are also effective
According to the present invention a 9(11)-dehydro
in inhibiting pituitary gonadotropins Without exhibiting
17ot-lower-alkyltestosterone represented by Formula I, is
estrogenic effects and therefore ?nd use in the manage
converted to the novel physiologically active steroid com
ment of menopausal problems.
In addition the novel
pounds (VI) of the present invention by the following
(\
alkyl
t I
40 hydrochlorination or hydro?uorination to convert the
reactions: ?rst, glyoxylation, formylation, carboxylation
compounds (VI and VII) are effective anti-in?ammatory
or tri?uoroacetylation to produce a 2-carbonyl derivative
agents.
(II); second, alkylation to produce the corresponding 2
The novel products and processes of the present inven
methyl Z-carbonyl compound; third, removal of the 2
tion may be represented by the following formulae:
35 carbonyl group to produce the Z-methyl compound (III);
fourth, halohydrination, e.g., bromohydrination to pr0~
ona
ona
OH
on
duce a 9a-br0m0-1 1 B-hydroxy-2a-methyl-17 a-lower-alkyl
CHa
L.__1Ower_
OH“
I --lower
derivative (IV); ?fth, dehydrohalogenation to produce the
(\
alkyl
l ,
\
Oll
—*
0:
R-C
epoxy structure to the corresponding 9OL-Chl0l‘0 or 90c
?uoro compound (VI). If desired the Qa-?uoro-llB
l
O:
I
corresponding 95,11?-epoxy-compound (V); and sixth,
I
II
45
hydroxy derivatives represented by Formulae IV and VI or
the corresponding 9u-chloro compounds can be converted
to the corresponding ll-keto compounds by oxidation with
chromium trioxide dissolved in acetic acid.
The starting 9(11)-dehydro-l7a-lower-alkyltestoster
on,
'
on
on
|__..10wer_
HO_/\
l
on;
one (I) can be prepared as described in Preparation 1A.
This starting steroid is converted to 9(ll)-dehydro-2a
CH3
CH3
alkyl
l———1ower- 50 methyl-17a-lower-alkyltestosterone (III) in the manner
(\
l
onr-
alkyl
be readily converted to 9?,1l?-epoXy-2a-methyl-17zx-low
55 er-alkyltestosterone (V) in the manner described in Ex
amples 6 and 7.
0:
IV
(I) can also be utilized
tosterone (see Preparation 1B and 1C), which in turn can
/
on?
0-
described in Examples 1 and 2.
for the production of 9,8,11B-epoxy-17u-lower-alkyltes
in
In addition to the route indicated in the above ?ow
sheet for the production of 9(11)-dehydro-2a-methyl-17a
i
x‘
60
CH3
CH:
on
alkyl
0:
|"?ower
0__/\
CH3 "X
CH3-
6'5 but are not to be construed as limiting.
PREPARATION 1A
CH3“
Iva
O:
The following preparations and examples are illustra
tive of the process and products of the present invention,
alkyl
H30
/
the starting steroid 1ll8-hydroxy-2a-methyl-Not-lower
alkyltestosterone (see Preparation 2).
OH
Lnhweb
O=
lower-alkyl testosterone (III), this compound can also be
prepared in the manner described in Preparation 4 from
9(11 ) -Dehydr0-17ot-Methyltest0ster0ne
V
70
A warm solution of one gram of 11u-hydroXy-l7
methyltestosterone (I, US. Patent 2,660,586) vin'tw'o
milliliters of dry pyridine was mixed with one gram ‘of
4
para-toluenesulfonyl chloride. The mixture was main
tained at room temperature for eighteen hours and then
poured into 25 milliliters of Water.
minutes, 150 milliliters of ether was added and stirring
was continued for an additional ?fteen minutes. Then
the mixture was ?ltered and the collected precipitate was
The mixture was
stirred until the precipitated oil solidi?ed. The solid
washed with ether and dried at 25 degrees centigrade at
was ?ltered, washed with water and dried to give 1.41
reduced pressure. The dried precipitate was dissolved in
forty milliliters of water to which was then added ?fteen
grams of lla-p-toluenesulfonyloxy-17u-methyl-17/8-hy
droxy-4~androsten-3-one which melted at 144 to 148
milliliters of ten percent hydrochloric acid with stirring
and cooling. The resulting precipitate was collected by
?ltration, washed with Water and dried to give 3.57
degrees centigrade with decomposition and, after crys—
tallization from a mixture of methylene chloride and
hexane hydrocarbons, melted at 141 to 144 degrees cen 10 grams, a yield of 85 percent of the theoretical of Z-meth
tigrade with decomposition and had an [@113 of plus
41 degrees in chloroform and the analysis below.
oxyoxalyl-l l?-hydroxy-17a-methyltestosterone melting at
120 to 123 degrees centigrade.
Anal.—Calculated for C2qH36O5S: C, 68.61; H, 7.68;
S, 6.78. Found: C, 68.86; H, 7.86; S, 6.89.
‘ B. 2MBTHOXYOXALYL-2-METHYL-1l?-HYDROXY
l7a-METHYLTESTOSTERONE
A mixture of one gram of the thus~produced Ila-p 15
toluenesulfonyloxy -17a-methyl -17;3~hydroxy ~4-androsten
To a cold solution of 3.4 grams of 2-methoxy0xalyl
1l?-hydroxy-17a-methyltestosterone and ?fteen milliliters
3-one, 0.2 gram of sodium formate, 0.57 milliliter of
of methyl iodide in thirty milliliters of acetone was added
water and fourteen milliliters of absolute ethanol was
twenty grams of anhydrous potassium carbonate and the
heated at its re?ux temperature for a period of nineteen
resulting mixture was stirred for 64 hours. The mixture
hours. The solution was cooled and then poured onto 20 was diluted with 300 milliliters of water and then
?fty grams of a mixture of ice and water with stirring.
extracted with three 100-milliliter portions of methylene
The resulting procipitate was ?ltered and dried to give
chloride. The combined extracts were washed with water
0.59 gram of 9(11)-dehydro-l7a-methyltestosterone
and dried. The methylene chloride solution was evapo
Which melted at 156 to 160 degrees centigrade and, after
rated leaving a glassy residue of 2-methoxyoxalyl-2
crystallization from a mixture of methylene chloride 25 methyl-1 1 B-hydroxy- l 7e-methyltestosterone.
and hexane hydrocarbons, melted at 167 to 170 degrees
C. 2a-METHYL-1 IB-HYDROXY-l 7(1-METHYL
centigrate and had an [MD of plus 57 degrees in chloro
TESTOSTERONE
form and the analysis below:
The glassy residue of 2-methoxyoxalyl-Z-methyl-1118
Anal.—Calculated for C20H28O2: C, 79.96; H, 9.39.
Found: C, 79.59; H, 9.08.
30 hydroxy-17-methyltestosterone described above was dis
solved in twenty milliliters of methanol to which was then
PREPARATION 1B
added two milliliters of a 24 percent solution of methano
9a-Bromo-1 1 fi-Hydroxy-J 7a-Methyltestosterone
lic sodium methoxide and the mixture then allowed to
stand for three hours at 25 degrees centigrade. The mix
To a solution of one gram of 9(11)-dehydro-l7u
ture was then diluted with 100 milliliters of water and
methyltestosterone (Preparation 1A) in ?fty milliliters
extracted with ‘three 50-milliliter portions of methylene
chloride. The methylene chloride was evaporated leaving
of acetone was added dropwise, with stirring, at ?fteen
degrees centigrade, one gram of N-bromoacetamide
dissolved in 25 milliliters of water. A solution of twenty
milliliters of 0.8 normal perchloric acid was then slowly
added at the same temperature. After twenty minutes,
2.8 grams of residue which was redissolved in ?fty milli
liters of methylene chloride. The solution was then di
luted with ?fty milliliters of Skellysolve B hexane hydro‘
carbons and then poured over a chromatographic column
there was added a sul?cient amount of a saturated
of 120 grams of Florisil synthetic magnesium silicate.
The column was developed with 250-milliliter portions
aqueous solution of sodium sul?te to discharge the yellow
color of the solution. The resulting mixture was then
diluted with 100 milliliters of water thereby precipitating
one gram of 9a-bromo-1l?-hydroxy-l7a-methyltestoster
of solvent of the following fractions, composition and
order: four of Skellysolve B plus ?ve percent acetone,
fourteen of Skellysolve B plus six percent acetone, ?ve of
Skellysolve B plus seven percent acetone and eight of
Skellysolve B plus eight percent acetone. The solvent was
evaporated ‘from last Skellysolve B plus seven percent
acetone eluate and all but the last Skellysolve B plus eight
percent acetone eluates and the combined residual solid,
one as needles melting at 153 to 155 degrees centigrade.
PREPARATION 1C
95,1][3-Ep0xy-1 7a-Methyltest0sterone
A suspension of one gram of 9a-bromo-l1B-hydroxy
l7a-methyltestosterone (Preparation 1B) in thirty milli
which weighed 1.004 grams, was redissolved in five milli
liters of methanol, was titrated with one molar equivalent
of 0.1 normal aqueous sodium hydroxide. The resulting
liters of warm acetone to which was then added twelve
milliliters of Skellysolve B and the mixture distilled until
crystallization commenced. There was thus obtained
0.587 gram of 2a-methyl-l1?-hydroxy-l7a-methyltestos
terone melting at 217 to 219 degrees centigrade, having
an [ab of plus 125 degrees (C, 1.0323 in chloroform)
and the analysis below.
mixture was diluted with ?fty milliliters of water and
then chilled to about zero degrees centigrade thereby
precipitating 0.64 gram of 95,1lB-epoxydM-methyltes
tosterone melting at 170 to 176 degrees centigrade which,
after crystallization from dilute methanol, melted at
165 to 172 degrees centigrade (with sublimation) and
had an [a]D of minus forty degrees in chloroform and
the analysis below.
60
Anal.—Calculated for C20H28O3: C, 75.92; H, 8.92.
Found: C, 75.60; H, 8.96.
PREPARATION 2
Zu-Methy [-1 1 ?-Hydroxy-I 7 a-M'ethy [testosterone
A. -2-METHOXYOXALYL-1 1 ?-HYDROXY-l 7a~METHYL~
AnaI.—Calculated for C21H32O3: C, 75.86; H, 9.70.
Found: C, 75.44; H, 9.78.
Following the procedure of Preparation 2, but sub
stituting ethyl iodide for the methyl iodide, there is thus
produced 2-methoxyalyl-2-ethyl-1 l?-hydroxy- 17a-methy1
65
testosterone and 2a-ethyl-ll?-hydroxy-17ot-methyltestos
terone. Substituting another lower-alkyl halide, e.g., meth
yl bromide, ethyl bromide, allyl chloride, n-propyl iodide
or other alkyl halide wherein the alkyl group contains
from
one to eight carbon atoms, inclusive, for the methyl
To a solution of 3.18 grams (0.01 mole) of 11B~hy 70 iodide, there are produced other Z-methoxyoxalyl-Z-low
droxy-l7a-methyltestosterone (US. 2,735,854) and 2.9
er-alkyl-l1,6-hydroxy-17a-methyltestosterones and Za-lOW
milliliters of diethyl oxalate dissolved in 45 milliliters of
TE STO STERONE
er-alkyl-l1,8-hydroxy-l7a-methyltestosterones, e.g., Za-eth
tertiary butyl alcohol at ?fty degrees centigrade was
yl-l 1 ,B-hyclroxy-17a-methyltestosterone, 2tx-n-propyl-1 1,8
added, with stirring, 3.4 milliliters of a 24 percent solution
hydroxy-17a-methyl
testosterone, 2u-a1lyl-11p~hydroxy
of sodium methoxide in absolute methanol. After twelve 75 l7a-methyltestosterone, possessing anabolic gonadotropic
3,067,218
5
cooled to ten degrees centigrade. Anhydrous sulfur di
oxide gas was then bubbled into the cooled mixture until
inhibiting, central nervous system modifying and anti
in?amrnatory activity.
the mixture gave a negative test with acidi?ed starch
iodide paper. The stirred mixture was then mixed with
ten milliliters of water followed by cold dilute hydro
I Substituting another 1lfi-hydroxy-l7ut-lower-alkyltes
tosterone, e.g., l1,8-hydroxy-l7“ethyltestosterone, 11(3
hydroxy'17tum-propyltestosterone, or other 11,8-hydroxy
chloric acid prepared by mixing ?fteen milliliters of con
centrated hydrochloric acid with 25 grams of ice. The
precipitated solid was collected, washed with water, dried
and then crystallized from a mixture of methylene chlo
duced other 2-methoxyoxalyl-2~methyl-1lB-hydroxy-lh
and Skellysolve B hexane hydrocarbons and then
lower-alkyltestosterones and Za-methyl-l1,8-hydroxy-l7u 10 ride
from
dilute acetone to give 2a,17a-dimethyl-9(11)-dehy
lower-alkyltestosterones, e.g., 2a-methyl-l 1/3-hydroxy-l7oc
17rx-lower-alkyltestosterone wherein the 17or-lower-alkyl
group contains from one to eight carbon atoms, inclusive,
as the starting steroid in Preparation 2 there are thus pro
drotestosterone 17-acetate.
ethyltestosterone and 2a - methyl - 11B - hydroxy - 17a -
n-propyl-testosterone and other 2or-methyl-11B-hydroxy
17a-lower-alkyl testosterones wherein the 17oc-l0W?f-2llkYl
PREPARATION 5
group contains from one to eight carbon atoms, inclusive. 15
Similarly, by selection of the appropriate 11 ,5’-hydroxy
17a-lower-alkyltestosterone as the starting steroid and the
appropriate lower-alkyl halide as the alkylating agent,
2a,] 7oc-Dimethyl-9(11 )-Dehydr0test0ster0ne
To a solution of 0.5 gram of 2a,l7u-dimethyl-9(ll)
dehydrotestosterone acetate in 15 milliliters of methanol
1 gram of potassium hydroxide in ?ve milliliters of water
was added. The mixture was refluxed for one hour under
combinations of the above compounds, e.g., 2a l7a-di
lower-alkyl-llB-hydroxytestosterones are prepared ac
cording to ‘the method of Preparation 2 wherein both of
the lower-alkyl groups are other than methyl, e.g., ethyl,
propyl, or other lower-alkyl group.
Following the procedure of Preparation 2 but substitut
nitrogen then quenched with water. The product thus
obtained was recrystallized from a mixture of methylene
chloride and Skellysolve B (hexane hydrocarbons) to
yield pure 20¢,l7oL-di1116ihYl-9 ( 1 l ) -dehydrotest-osterone.
EXAMPLE 1
ing another di-lower-alkyl oxalate for the di-ethyl oxalate,
e.g., dimethyl oxalate, dipropyl oxalate, methyl propyl
oxalate, methyl butyl oxalate, the same 2-methyl-2-lower
2 - Methoxyoxalyl - 9(11) - Dehydro - 17a - Methyl
testosterone (17B - Hydroxy - 2 - Methoxyoxalyl -__17oc
Methyl - 4,9(11) - Androstadien - 3 - One)
alkoxyoxalyl-ll?-hydroxy-l7ot-methyltestosterone is pre
pared and converted to Za-methy-ll?-hydroxy-Ua-meth- _
yltestosterone.
10.5 grams of 9(11)-dehydro-17ot~methy1testosterone
(17,8 - hydroxy - 17a - methyl - 4,9(11) - androstadiene
Substituting a lower-alkyl formate for the diethyl oxa
3 - one) (Preparation 1A) was dissolved in 150 milliliters
late employed in Preparation 2, e.g., methyl formate,
of tertiary-butyl alcohol, ten milliliters of diethyl oxalate
ethyl formate, there are thus produced 2-formyl-l-l/3
i1B-hydroxy-l7ot-methyltestosterone which is also con
verted to 2ot-methyl-l1?-hydroxy-l7a-methyltestosterone
was added and the solution warmed to about 55 degrees
centigrade. Eleven milliliters of a 25 percent solution of
sodium methoxide in methanol was added and after ?fteen
minutes the reaction mixture was cooled to 25 degrees
in the manner described in Preparation 2. Similarly, sub
stituting a lower-alkyl tri?uoroacetate, e.g., methyl or
centigrade and 450 milliliters of ether added with stirring.
After ?fteen minutes the mixture was ?ltered and the
ethyl tri?uoroacetate, for the diethyl oxalate of Prepara
tion 2 is productive of 2-tri?uoromethylacetyl-ll?-hy
precipitate washed with ether and dried. The dry pre
hydroxy-17u-methyltestosterone and 2-formyl-2-methyl
droxy - 17a - methyltestosterone
cipitate was dissolved in 100 milliliters of water and
acidi?ed with ten percent hydrochloric acid. The product
and 2-tri?uoroacety1-2
was washed with water to yield 5.5 grams of Z-methoxy
methyl-1l?-hydroxy-17a-methyltestosterone which is also
converted to Za-methyI-l l?-hydroxy-l7ct-methyltestoster
one. A Z-carbonyl-lower-alkoxy-1l?-hydroxy-lh-meth
ioxalyl-9(11)-dehydro-17a-methyltestosterone. The ether
?ltrate previously set aside was concentrated to approxi
mately 100 milliliters and ?fty milliliters of ?ve percent
aqueous sodium carbonate solution added and the layers
separated. The aqueous layer was acidi?ed to give an oil
which yielded an additional 5.3 grams of 2-methoxy
yltestosterone, which is similarly converted to a Zea-methyl
1l?-hydroxy-17a-methyltestosterone, is prepared by sub
stituting a lower-alkyl carbonate e.g., ethyl carbonate, for
the diethyl oxalate of Freparation 2.
PREPAMTION 3
Za-MethyZ-J 1/3-Hydroxy-1 7a-l'vlethylteslosl'erone
50
1 7-Acetate
A solution of one gram of 2a-methyl-11B-hydroxy-17
ioxalyl-9(1 l ) -dehydro-17a-methyltestosterone.
Substituting another 9( 1l)-dehydro-17a-lower-‘alkyl
testosterone, e. g.,
9(11)-dehydro-?ea-ethyltestosterone,
9(1l)-dehydro-17a-n-propyltestosterone, or other 9(11)
dehydro-17ot-lower-alkyltestosterone wherein the 170:
lower-alkyl group contains from one to eight carbon
methyltestosterone in 25 milliliters of acetic anhydride
atoms, inclusive, as the starting steroid in Example 1,
was re?uxed under nitrogen for one hour, cooled and di 55 there are thus produced other 2-methoxyoxalyl-9(11)-de
luted with 100 milliliters of ice water. The product was
extracted with ether, washed with water, ?ve percent so
dium hydroxide solution, and water. The ether solution
hydro-17a-lower-alkyltestosterones, e.g., Z-methoxyoxalyle
9(11) - dehydro - 17a - ethyltestosterone, 2 - methoxy
roxalyl - 9(11) - dehydro - 17a - n - propyltestosterone and
was dried with sodium sulfate and evaporated to dryness.
other 2 - methoxyoxalyl - 9(11) - dehydro - 17a - lower
The residue was dissolved in 25 milliliters of methylene 60 alkyltestosterones wherein the l7a-lower-alkyl group con~
chloride, poured onto a column containing forty grams
tains from one to eight carbon atoms, inclusive.
of Florisil, and eluted with increasing proportions of ace
Substituting a lower-alkyl formate for the diethyl
tone in Skellysolve B. The ?rst substance thus eluted was
oxalate employed in Example 1, e.g., methyl or ethyl
crystallized from alcohol-Skellysolve B to give Zea-methyl
65 formate, there is thus produced 2ot-formyl-9(11)-dehydro
1 1 ?-hydroxy-l7-methyltestosterone 17-acetate.
17a-methyltestosterone which is converted to 2a,l7a-di
PREPARATION 4
2a-17a-Dimethyl-9(11 ) -Dehydrotestoster0ne 1 7-Acetate
methyl-9(1l)-dehydrotestosterone in the manner de
scribed in Example 2. Similarly, substituting a lower
alkyl tri?uoroacetate, e.g., methyl or ethyl triiluoroacetate,
To a solution of one gram of 2ot-methyl-11?-hydroxy 70 for the diethyl oxalate of Example 1, is productive of 2
l7a-methyltestosterone 17-acetate dissolved in ten mil
liliters of dry pyridine was added, with stirring at 25 de—
grees centigrade in a nitrogen atmosphere, 0.5 gram of
N-bromoacetamide portionwise. The stirring was con
tinued for ?fteen minutes and the mixture was then 75
tri?uoroacetyl-9( l 1 ) -l7a~methyltestosterone which is also
converted to 206,170t-dl1116ihY1-9 ( 1 1 ) -dehydrotestosterone
in the manner described in Example 2. A Z-carbonyl
lower - alkoxy' - 9(11) - dehydro - 17a - methyltestos-
terone which is similarly converted to 2a,1-7a-dimetl1yl
3,067,218
"I.
l
.
9(11)-dehydrotestosterone, is prepared by substituting a
lower-alkyl carbonate, e.g., ethyl carbonate, for the diethyl
8
EXAMPLE 4
9rx-Br0m0 - 206,1706 - Dimethy'l = 11 ~Ket0test0ster0ne (90c
oxalate of Example 1.
Bromo - 11 - Keto - 175 - Hydroxy — 2m,17cc—Dim8?lyl-4
Androsten-S-One)
EXAMPLE 2
20:,170: - Dimethyl - 9(1'1) - Dehydrotefstosterone (1713
Hydroxy - 2a,]706 - Dimethyl ‘- 4,9(11)Andr0stadieiz
A solution of 0.5 gram of chromium trioxide and one
milliliter of water in twenty milliliters of acetic acid was
3-One)
added to a solution or" one gram of 9a-bromo-2u,17a-di
A mixture containing 5.5 grams of Z-methoxyoxalyle
methyl- ll?-hydroxytestosterone in ?fty milliliters of
glacial acetic acid. The mixture was maintained at room
9(11)-dehydro-17a-methyltestosterone (Example 1), ?fty
temperature for ?ve hours and then mixed with ten mil-'
liters of methanol. The solvent was removed by distil;
lation at reduced pressure and the almost dry residue‘
mixed with ?fty milliliters of water. The precipitate was
?ltered, washed with water and then dried to give 0.85
milliliters of acetone, twenty milliliters of methyl iodide
and 25 grams ‘of anhydrous potassium carbonate was
stirred for 54 hours.
300 milliliters of water was added
and the resulting mixture extracted with three 100 mil
liliter portions of methylene chloride. The extract was
gram of 9Ct-b1'OII10-2OC,17OL-dlm6thyl-1l-k?tOtBStOSteI'One.
Following the procedure described in Example 4, but
substituting as starting steroid other 9ix-bromo-2a,l7a-di_
lower-alkyl l1,B—hydroxytestosterones is productive of the
washed, dried ‘and evaporated to dryness. The residue
was dissolved in ?fty milliliters of absolute methanol and
3.5 milliliters of a 25 percent solution of sodium meth
exide in methanol added. The solution was allowed to
stand for four hours, then diluted with 300 milliliters of
water and extracted with ether. The ether extract was
corresponding 9a-bl‘Ol'I10-20c,170L-dl-1OW8f-3lkYl - 11 - keto
testosterones.
EXAMPLE 5
9j6,1]?-Ep0xy-2a,1 7a-Dimethyltestosterone (913,115 - Ep
washed with water, dried over sodium sulfate and evap
orated to yield 4.14 grams of crude 2a,17u-dimethyl
9(1 1)-dehydrotestosterone ( 17?-hyd1'OXy-20t,170t~dlf?€lhi
oxy-Z 75-Hydr0xy-2aJ 7a-Dz'methyl4-Androsten-3-0ne)
yl-4,9(l1)-androstadien~3-one), an oral anabolic‘ com
pound possessing a high ratio of anabolic to androgenic
activity.
114 milliliters of a 0.1 normal solution of sodium‘.
hydroxide was added slowly to a stirred suspension of
_
4.68 grams (0.0114 mole) of 9a=bromo‘-11?-'hydroxy-2a,
17ot-dimethyltestosterone in 140 milliliters of methanol
containing
one drop of phenolphthalein'. The volume of
30
and eluted with 250 milliliter fractions of a mixture of
sodium hydroxide solution added was enough to render
acetone and Skellysolve B (hexane hydrocarbons):?
the steroid suspension just alkaline. After one hour the
The product was chromatographed over a column of
160 grams of Florisil (a synthetic‘magnesium silicate)
Fractions 1 to 17_—acetone:'Skellysolve B‘—6':94 v
Fractions 18 to 2l-acetonezSkellysolvé B—15:'85
reaction mixture was acidi?ed with six drops of acetic
acid and diluted with 150 milliliters of Water. The mix
Fractions ?ve to seven contained 2.47 grams of prod= 35 ture was extracted three times with 100 milliliters of
methylene chloride and the extract washed, dried and
uct. They were combined and recrystallized from ace
evaporated to give 3.99 grams of crude crystalline 918,115“
tonetskellysolve B to give 1.78 grams of crystalline 2a,
epoxy-2a,17u-dimethyltestosterone.
17a-dimethyl-9‘(l1)-dehydrotestosterone with a melting
point of 150 to 153 degrees centigrade.
To purify the product it was dissolved in ?fty milliliters
V
Anal.-——Calculated for C21H30O2: C, 80.21;‘ H, 9.62‘.
Found: C, 80.34; H, 9.66.
Similarly, by selection of the appropriate 2-lower-al
kyloxyoxalyl-9( l1 )-dehydro-l7a-lower - alkyltestosterone
as the starting steroid and the appropriate lower-alkyl
halide as the alkylating agent, combinations of the above
compounds, e.g., 2a,17a-di-lower alkyl-9(l1) -dehydro
testosterones are prepared according to the method of
Example 2 wherein one or both of the lower-alkyl groups
are other than methyl, e.g., ethyl, propyl or other lower
alkyl group.
EXAMPLE 3
9a-Br0m0-2uJ 7u-Dimethyl-11[i-Hydroxytesiosterone (9a
40
of methylene chloride, ?fty milliliters of Skellysolve B
added and the steroid chromatographed over a column of
160 grams of Florisil. Elution was as follows using 180
milliliter fractions of a mixture of acetone and Skelly
solve B:
Fractions 2 to 6—acetone:Skellysolve B—-5:95
Fractions 7 to 17—acetone:Skellysolve B——9:91
Fractions 18 to 24—acetone:Skellysolve B—10:90
Fractions 11 to 19 were combined to give 2.57 grams
50 of product with a melting point of 150 to 170 degrees
centigrade. Recrystallization from a mixture of acetone
and Skellysolve B yielded 1.70 grams of 9B,11/8-epoxy
2a,17a-climethyltestosterone with a melting point of 175
Br0m0-115,1 7,8-Dihydr0xy-2a,] 7ot-Dimethyl-4 - Andro
to 176 degrees centigrade.
sten-3-Onc)
tive and rotation [a1]; minus ten degrees (chloroform).
Infrared absorption maxima were: OH, 3390 centime
4.81 grams of 2a,17et-dimethyl-9(1l)-dehydrotestoster
one (Example 2) was dissolved in 150 milliliters of
acetone and cooled to ?fteen degrees centigrade. 2.3
grams of N-bromoacetamide dissolved in 45 milliliters of
The Beilstein test was nega
ters—1; conjugated ketone, 1668 centimeterrl; conjugated
C=C, 1623 centimeters-1.
Anal.—Calculated for C21H30O3: C, 76.32; H, 9.15.
water was added with stirring. In the course of ?ve min 60 Found: C, 76.86; H, 9.52.
Following the procedure described in Example 5, but
utes 92 milliliters of a solution of 0.8 normal perchloric
substituting as starting steroid other 9a-bromo-11B-hy
acid that had been chilled to ten degrees centigrade was
droxy-2a,17or-di-lower-alkyltestosterones is productive of
slowly added to the reaction mixture and stirring con
the corresponding 9,8 - ll? - epoxy-2a,17a-di-lower-alkyl
tinued for twenty minutes. Seven milliliters of a saturated
testosterones.
aqueous solution of sodium sul?te was added and the 65
EXAMPLE 6
mixture diluted with 500 milliliters of water, cooled and
?ltered to yield 4.69 grams of crystalline Qua-bIOmO-Zoc,
Z-Methoxyoxalyl-QBJI?-Epoxy - 17a - Methyltestosterone
17a-dimethyl - ll?-hydroxytestosterone, with a melting
point of 125—140 degrees centigrade.
Following the procedure described in Example 3, but
substituting as starting steroid other 2a,l7a-di-loWer-alkyl
9(11)-del1ydrotestosterones is productive of the corre
sponding 9ix-bromo-2ot,17a-di-lower-alkyl - 11,8 - hydroxy
testosterones.
Ten grams of 95,11?-epoxy-17ot-methyltestoster0ne
(Preparation 10) was dissolved in 150 milliliters of ter
tiary butyl alcohol, ten milliliters of diethyl oxalate was
added and the solution warmed- to about 55 degrees centi~
grade. Eleven milliliters of a 25 percent solution of
8,067,218
pound was identical with that obtained from the product
sodium methoxide in methanol was added and after ?fteen
minutes the reaction mixture was cooled to 25 degrees
centigrade and 450 milliliters of ether added with stirring.
After ?fteen minutes the mixture was ?ltered and the
precipitate washed with ether and dried. The dry pre
cipitate was dissolved in 100 milliliters of water and
acidi?ed with ten percent hydrochloric acid. The prod
of Example 5.
EXAMPLE 8
9a-Flll0r0-1 1 ?-Hydroxy-Z a,] 7a-Dimethyltestosterone
A solution containing 1.2 grams of 9B,11,8-epoxy-2a,
l7a-dimethyltestosterone in 25 milliliters of methylene
chloride in a polyethylene bottle was cooled to minus
uct was washed with water to yield 10.5 grams of 2
?fteen degrees centigrade and 1.8 milliliters of 48 percent
aqueous hydro?uoric acid added. The reaction mixture
Substituting another 913,11B-epoxy-lower-alkyltestostcr 10 was stirred at plus ?ve degrees centigrade for 42 hours
one, e.g., 918,1l?-epoxy-17u-ethyltestosterone, 9/3,11?
and then poured slowly into a mixture containing ?ve
epoxy-l7a-n-propyltestosterone, or other 95,11/3-epoxy
grams of sodium bicarbonate in ?fty milliliters of ice
methoxyoxalyl-95,l 1,8-epoxy-l7ot-methyltestosterone.
17u-lower-alkyltestosterone wherein the 17a-lower-a1ky1
water. The layers were separated and the aqueous stra
group contains from one to eight carbon atoms, inclusive,
as the starting steroid in Example 6, there are thus pro
duced other 2-methoxyoxalyl-9/3-11B-epoxy-17a-lower
alkyltestosterones, e.g., 2-methoxyoxalyl-9?,11/8-epoxy
17a-ethyltestosterone, 2-methoxyoxalyl-9?, l l ?-epoxy- 17a
n—propyltestosterone and other 2-methoxyoxalyl-9/3,1l;8
epoxy-17a-lower-alkyltestosterones wherein the 17a
tum extracted with two 25 milliliter portions of methyl
ene chloride. The combined extract was washed with
water, dried over sodium sulfate and concentrated to
dryness to yield 1.18 grams of residue. The dried prod
20
lower-alkyl group contains one to eight carbon atoms,
inclusive.
uct was dissolved in methylene chloride and chromato
graphed over a column of forty grams of Florisil and
elutedwith ?fty milliliter fractions consisting of a mix
ture of nine percent acetone and 91 percent Skellysolve
B. Fractions 14 to 21, inclusive, contained 569 milli—
Substituting 21 lower-alkyl formate for the diethyl oxa
grams of sold and were combined and recrystallized from
late employed in Example 6, e.g., methyl or ethyl formate,
ether to give 370 milligrams of solvated product. Dry
there is thus produced 2ot-formyl-9B,llB-epoxy-lh 25 ing at 110 degrees centigrade for three hours in vacuo
methyl-testosterone which is converted to 2a,l7u-dimeth
yielded 904 - ?uoro - ll?-hydroxy-2ot,I7a-dimethyltestos
yl-9,8,1l?-epoxytestosterone in the manner described in
terone with a melting point of 179 to 181 degrees centi
Example 7. Similarly, substituting a lower-alkyl tri?uoro
grade, a [a]D of plus 100 degrees (in chloroform) and
acetate, e.g., methyl or ethyltri?uoroacetate, for the di
the
analysis below.
ethyl oxalate of Example 6, is productive of 2-tri?uoro
AnaI.—-Calculated for C21H31FO3: C, 71.97; H,
methylacetyl-9,8,llp-epoxy-17ot-methyltestosterone which
8.92; F, 5.42. Found: C, 72.07; H, 9.28; F, 5.29.
is also converted to 2a,l7a-dimethyl 95,11?-epoxytestos
In addition to the principal product, 9on-?L1OIO-ll?
terone in the manner described in Example 7.
A 2
hydroxy-2ot,l7ot-dimethyltestosterone, a by-product, 2,17
carbonyl-lower-alkoxy-9?,1l?-epoxy - 17a - methyltestos
dimethyl-4,l6-androstadien-3-one is also recovered as de~
scribed in the following procedure. A solution con
taining 169 grams of 95,115, epoxy-2a,l’la-dimethyltes
terone which is similarly converted to 2a,l7a-dimethyl—
95,1l?-epoxytestosterone, is prepared by substituting a
lower-alkyl carbonate, e.g., ethyl carbonate, for the di
ethyl oxalate of Example 6.
40 of anhydrous hydrogen fluoride in 140 milliliters of
EXAMPLE 7
96,11B-Ep0xy - 2a,17a - Dimethyltestosz‘erone
tosterone in 100' milliliters of methylene chloride cooled to
minus seventy degrees centigrade was added to 268 grams
methylene chloride and 568 milliliters of tetrahydrofuran.
(95,116
The red solution was maintained at minus ?fteen degrees
centigrade for four hours then poured into a stirred so
lution of 1880 grams of potassium carbonate in 6700
milliliters of water containing 5000 milliliters of crushed
ice. The product was extracted with methylene chloride
which was washed with water, dried, concentrated to
a small volume and diluted with benzene. Concentration
Epoxy-J7?-Hydr0xy-2a,17a-Dimethyl-4-Andr0sten - 3
One)
A mixture containing 9.5 grams of Z-methoxyoxalyl
95,11,8-epoxy-l7ot-methyltestosterone (Example 6), 100
milliliters of acetone, forty milliliters of methyl iodide
and ?fty grams of anhydrous potassium carbonate was
stirred for 54 hours. 600 milliliters of water was added
of this solution yielded crystals if the benzene solvate of
and the resulting mixture extracted with three 200-milli
9a-?luoro-l1?~hydroxy-2oc,17a - dimethyltestosterone with
liter portions of methylene chloride. The extract was 50 a melting point of 105 to 115 degrees centigrade (ac
washed, dried and evaporated to dryness. 'The residue
companied by evolution of gas). The solvate resolidi
was dissolved in 100 milliliters of absolute methanol and
?ed and had a melting point of 145 to 200 degrees centi
seven milliliters of a 25 percent solution of sodium meth
grade. [04],; plus 99 degrees (chloroform; A max. 238.5
oxide in methanol added. The solution was allowed to
(Am=16,000).
stand for four hours, then diluted with 600 milliliters 55 mgConcentration
of the ?ltrate gave 8.6 grams of the
of water and extracted with ether. The ether extract
dehydrated by-product, 90c -.fluoro— 11B-hydroxy-2,l7-di
was washed with water, dried over sodium sulfate and
methyl-4,l-6-androstadien43-one, with a melting point of
240 degrees centigrade, [MD plus 91 degrees (chloro
evaporated to yield 9.5 grams of crude 9,8,1l/3-epoxy-2a,
17ot—.dimethyltestosterone (93,1l{3—epoxy-l7?-hydroxy-2a,
17a-dimethyl-4-androsten-3-one ) .
The crude product dissolved in 100 milliliters of meth
ylene chloride and 100 milliliters of Skellysolve B was
form). This compound exhibits gonadotropin inhibiting,
60 central nervous system modifying and anabolic proper
ties with improved therapeutic ratios. The benzene sol
vate was converted into non-solvated product by re
chromatographed over a column of 300 grams of Florisil
peated crystallization from methylene chloride-Skelly
and eluted with 250 milliliter fractions of a mixture of
solve B hexane hydrocarbons to give 9ot-?uoro-llri
acetone and Skellysolve B.
hydroxy-Za,l7a-dimethyltestosterone with a melting point
Fractions 1 to l1--aceto11e:Skellysolve B—-7:93
of 128 to 133 degrees centigrade; [aJD plus 116 de
Fractions 12 to 23—acetone:Skellysolve B-8z92
grees (chloroform; kmxalc- 238 mg (Am=l5,000). The
non-solvated product forms an ether solvate on crystal
Fractions 14 to 22, inclusive, were combined and
yielded 2.2 grams of product which had a melting point 70 lization from ether, which, like the benzene solvate and
non-solvated product, is converted on heating at 110
of 148 to 170 degrees Centigrade. Recrystallization from
degrees centigrade for three to 24 hours into the de~
a mixture of methylene chloride, acetone and Skellysolve
hydrated compound, 9a - ?uoro - llB-hydroxy - 2,17-di
B gave 1.66 grams of 96,1IB-epoxy-Za,17a-dimethyltes
methyl-4,16-androstadien-3-one.
tosterone with a melting point of 170 to 172 degrees
Following the procedure described in Example 8, but
centigrade. The infrared spectrum of the steroid com 75
65
ll
12
substituting as starting steroid other 9B,11/3-epoxy-2<x,l7u
due mixed with ?fty milliliters of water. The precipi
di-lower-ialkyltestosterones is productive of the corre
tate was ?ltered, washed with water and then dried to
sponding git-?llOI‘O- 1 lB-hydroxy-2a,17a-di-lower—alkytes
yield 0.95 grams of 9ow?uoro-2a,17a-dimethyl-1l-ketotes
tosterones.
tosterone.
In the same manner as described in Example 8, re
acting 9[>’,11?-epoxy-2a,17a-dimethyltestosterone with hy
5
Following the procedure described in Example 9, but
substituting as starting steroid other 9a-?uoro-2a,17:x
drochloric acid or hydro‘oromic acid is productive of
di-lower-alkyl-lIB-hydroxytestosterones is productive of
9cx-Ch10rO-l1B-hYdr0XY - 20¢,17oc - dimethyltestosterone
the corresponding 9a-?uoro - 205,17a - di-lower-alkyl-ll
or
9a-bromo-11B-hydroxy-2a,17a ~ dimethyltestosterone pos
sessing physiologic properties similar to those of the
corresponding 9a-?uoro compounds but of somewhat
different potencies and therapeutic ratios. Similarly,
9ca-Chl0i‘0- 1 I?-hydrOXy-Za,17a-di-lower-alkyltestosterones
tor 9a-1bromo-11[3-hydroxy-2a,17a-di - lower - alkyltestos
terones are prepared by substituting 9B,11,8-epoxy-2u,17<z
di-lower-alkyltestosterone as the starting steroid.
It is to be understood that the invention is not to
be limited to the exact details of operation or exact
compounds shown and described, as obvious modi?ca
tions and equivalents will be apparent to one skilled in
the art to which this invention pertains, and the inven
tion is therefore to be limited only by the scope of the
appended claims.
EXAMPLE 9
Qa-FILIOJ‘O ~Zot-17o4 - Dimethyl-lI-Ketotestosterone
ketotestosterones possessing the same type of activity
as the corresponding ,1 l?-hydroxy compounds.
(9a
Fluoro-JI-Keto-IZB - Hydr0xy-2a,17oc - Dimelizyl - 4
Androsten-B-One)
A solution of 0.5 gram of chromium trioxide and
one milliliter of water in twenty milliliters of acetic
acid was added to a solution of one gram of 9<x~?uoro
We claim:
1. 9a~?uoro-l1?-hydroxy-2a,17a-dimethyl-4,16 - andro
stadien-3-one.
2. 17/3-hydroxy-2a,17u-dimethyl-4,9(11)-androstadien
3-one.
References Cited in the ?le of this patent
2a,17a-dimethy1-1l?-hydroxytestosterone in ?fty milli~
liters of 'glacial acetic acid‘ The mixture was main
tained at room temperature for ?ve hours and then mixed
with ten milliliters of methanol. The solvent was re
moved by distillation in vacuo and the nearly dry resi 30
UNITED STATES PATENTS
2,793,218
2,837,464
2,842,573
2,883,401
Herr ________________ _._ May 21,
Nobile _______________ __ June 3,
Herr et al. ____________ __ July 8,
Babcock et al. ________ __ Apr. 21,
1957
1958
1958
1959
Документ
Категория
Без категории
Просмотров
0
Размер файла
921 Кб
Теги
1/--страниц
Пожаловаться на содержимое документа