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Патент USA US3094532

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United States Patent 0 " "Ice
3,094,522
Patented June 18, 1963
2
1
acted with methyl acrylate in the presence of base to
give 3a-acetoxy-17a-[2'-methoxycarbonylethyl]~17/3-nitro
3,094,522
ALKANOYLTI-IIO AND PYRAZOLO ANDROSTANE
DERIVATIVES
Arthur A. Patchett, Metuchen, and Glen E. Arth, Cran
SB-androstane-ll?-ol.
The latter compound is treated
with methane sulfonyl chloride in the presence of an
organic base such as pyridine to a?ord 3a-acetoxy-17u
ford, N.J., and Harvey Schwam, Woodside, N.Y., as
[2'—methoxycarbonylethyl]-17?-nitro - 9(11) - 5,8 - andro
signors to Merck & Co., Inc., Rahway, N.J., a corpora
tion of New Jersey
No Drawing. Filed July 25, 1961, Ser. No. 126,509
24 Claims. (Cl. 260-2395)
stene. Reduction of 3u-acetoxy-17a-[2’-methoxycarbon—
ylethyl]-17;8-nitro-9(15)-5/8-androstene with zinc dust in
acid solution forms 3-(3’a-acetoxy-l7’B-amino-9'(11')
10 5'B-androstene-l7'a-yl)-propionic acid lactam. The latter
This invention is concerned generally with novel ste
roids and processes of preparing the same. More par
compound is converted into 3-(l7’B-amino-3’a-hydroxy
9’( 11’)-5’?-androstene-l7'a-yl) -propionic acid lactam, for
ticularly, it relates to novel compounds having the fol
example, by heating with an auqeous methanolic solution
lowing structure:
15
of alkali metal bicarbonate. The 3-(17’?-amino-3'a-hy
droxy-9'(11’)-5’;3-androstene-17’a-yl)-propionic acid lac~
tam is oxidized to 3-(17'?-amino-9’(11’)-5’B-androstene
3’-one-17’a-yl)~propionic acid lactam, for example, with
chromium trioxide in the presence of an organic base
such as pyridine. The 3-(17’p-amino-9'(11’)-5',8-andro
20 stene-3'-one-l7’a-yl)-propionic acid lactam is converted
into 3-( 17';8-4a1rrrino~"4’,‘9"‘(11’)-andro-stadiene-3 ’-one~l7’u~
yl)—propionic acid lactam by treatment sequentially with
bromine in hydrogen bromide and acetic anhydride and
then with a mixture of lithium bromide and lithium car
25 bonate in an organic solvent.
and wherein R stands for
' 17’a-yl)-propionic acid lactam is converted into 3-(3'a
hydroxy-l7’,8~methylamino-9'( 11')-5’? - androstene- 17’a
-—i-IJ—— 01' "“CHF
and wherein R’ is hydrogen or alkyl when R is
0
_<Ԥ_
yl)-propionic acid lactam by reaction ?rst with dihydro
30 pyran in the presence of an acidic catalyst ‘to form 3-(17'5
amino-3 'a-hydroxy-9’( 1 1 ’ ) -5 '13-androstene- 17’a-yl) -propi
onic acid lactam 3u-tetrahydropyranyl ether. The latter
compound is methylated, for example, using methyl iodide
and sodium hydride and then treated with acid to give
and R’ is hydrogen or acyl when R is —CH2-—, and
wherein X is halogen. This invention also concerns 35 3- (3 'a-hydroxy-17’}9Jmethylamino-9’( 1 1’ ) -5 'B-androstene
17'a-yl) ~pnopionic acid lactam. The 3-( 3'a-hydroxy-17'B
closely related compounds, and in particular the 7a-alkan
methylarnino-9’(11’)-5’?-androstene-l7'a-yl) - propionic
oylthio and the pyrazolo derivatives, and the A1»4- and
acid lactam is then oxidized to 3-(l7’?-methylamino-9’
ALB-analogues of the above compounds.
( 111’) -5'?-androstene-3’-one-17’a-yl) -propionic acid lac
The above described compounds possess useful thera
peutic properties as aldosterone inhibitors. These novel 40 tam using chromium trioxide in pyridine. The 3-(17'B—
steroids block the salt-retaining effects of aldosterone and
inethylamino-9' ( 1l’)-5’;9-androstene-3’-one - l7’a-yl) -pro
pionic acid lactam is converted into 3-(17'B-methylamino
other salt retaining steroids so as to be useful in the
treatment of diseases such 'as congestive heart failure,
4’,9"(ll')-androstadiene-3'-one-17’u - yl) - propionic acid
l'actam by treatment sequentially with bromine in a hy
nephrosis and cirrohis of the kidney in which aldosterone
45 drogen bromide-acetic anhydride reagent and then with a
secretion is increasedr
V In preparing our novel chemical compounds the start
mixture of lithium bromide and lithium carbonate in an
ing material utilize-d is 3u-acetoxy-lo-pregnene-l1,20
organic solvent.
The 3 -( l7'B-amino-3'a-hydroxy8’ ( 1 1’ ) -5 'B-androstene
dione (see Flow Sheet A). This compound is heated
‘17'a-yl)-propionic acid lactam is reduced with lithium
with hydroxylamine hydrochloride and ‘an organic base
50
aluminum hydride, in a solvent such as dioxane to give
such as pyridine to give 3u-acetoxy-16-pregnene-11,20‘
dione 20~oxime. The latter compound is treated with
an aryl sulfonyl halide such as p-acetylaminobenzene
sulfonyl chloride and an organic base followed by acid
3a-hydr0xy-9(11)-5/8-androstene-17-spiro-2'- (1’ - 2')/8
pyrrolidene (see Flow Sheet B). The latter compound is
converted into a 3 a-acyloxy-9'( 1 1 ) -5,8-androstane-17-spiro
hydrolysis and reactylation to form 3a-acetoxy-5B-andro
2’-(1'-2')?-1'-acylpyrrolidene by treating with an acylating
stane-11,l7-dione. This forms the 3a-acetoxy-5?-andro 55 agent, tag. a lower hydrocarbon carboxylic acid acylating
stane-l1,17~dione 17-oxime on heating with hydroxyl
agent such as benzoic anhydride or tertiary butyl acetyl
amine hydrochloride and an organic base.
chloride; a lower alkanoic anhydride or lower alkanoyl
The 3a-acetoxy-518-androstane-11,17-dione 17-oxime is
‘halide such as acetic anhydride, propionic anhydride or
converted to 3a-acetoxy-l7?-nitro-5?-androstane-115-01
acetyl chloride; or a polybasic anhydride such as 18,5-di
by treating with N-bromosuccinimide in aqueous dioxane 60 methylglu-taric anhydride, succinic anhydride ‘and the like,
under oxidizing conditions, for example, with vigorous
stirring over ‘an extended period, to form the 3a-‘acetoxy
17a-bromo-17/8-nitro-5B-androstane-ll-one. The latter
compound is then converted into 3a-acetoxy-175-nitro
5B—androstane-l 15-01 by reacting with sodium borohydride
in aqueous tetrahydrofuran solution.
The 3aaacetoxy-l7?-nitro-5p-androstane-ll?-ol is re
in the presence of an organic base such as pyridine.
The 3 a-acyloxy-9 ( 11)-5/3 - androstene-17-spiro-2’-( 1'
2’) ,8-1’-acylpyrrolidene is re?uxed with an auqueous meth
65 anolic solution of alkali metal bicarbonate to give SOL-hy
droxy-9( 1 1 ) -5/i-androstene-17-spiro-2'-( 1'-2' ) ,B-l ' - acyl
pyrrolidene.
3,094,522
3
3u-hydr0xy-9(1-1)-5? - androstene-17-spiro-2’-(1'-2')B
1'-acylpyrrolidene can be converted to 4,9'(1l)-androsta
driene-3-one-17-spiro-2'-(1'-2’)?-1’ - acylpyrrolidene in the
methylarnino - [3’,2' - c]pyrazolo-4’-androstene-11'-one
same manner as that indicated above for the conversion of
3-(17’?-amino-3'a-hydroxy-9'( 11’)-5’? - androstene-lT-a
zolo - 4-androstene-3,11-dione-17~spiro-2'-(1’-2’);3-1'-ac
the corresponding 3-(17'?-amino-[3',2'-c]pyrazo1o—4’-an
drostene-l1’-one-17'u-yl)-pr0pionic iacid lactam, 3-(17’5
l7’a-yl)-propionic acid lactam and 9a-?uoro-[3,2-¢]PYra
yl)-propionic acid lactam to 3-(17'?-arnino-4',9’(11')~
ylpyrrolidene by ?rst reacting with an alkyl formate and
strong base in an inert atmosphere to form the correspond
androstadiene-3’-one-17’a-yl)-p~ropionic acid lactarn.
The 3-(17’?-arnino-4',9’( 11')-androstadiene-3’-one-17'
a-yl)-propionic acid lactam, 3-(17’B-methyla1nino-4’,9'
(11’)-androstadiene~3’-one-17'a-yl)-propionic acid lactarin
ing 2-‘hydroxymethylene derivative, and then reacting the
latter compound with hydrazine, or a monosubstituted
and 4,9 ( l l ) -androstadiene-3-0ne-17-spiro#2'—( 1 ’-2’) 5-1’;
acylpyrrolidene may be converted into the corresponding
hydrazine, to give the corresponding pyrazolo compound,
10
which is exempli?ed in Flow Sheet D‘ as compound'28, , K
The structure of the pyrazolo-compound designated in
3 - (17'13-amino-9’a-?uoro-4'-androstene-3',l1’-dione-17’
the ?ow sheet is based upon an interpretation of data ac
a-yD-propionic acid lactam, 3-(9'a-fluoro-l7’?aniethyl
cording to the state of the art presently known to organic
However, it is to be understoodthat no part
of the ‘speci?cation will be materially defective if it shoiild
later be ‘established that the correct structure‘ of any of
these compounds with respect to the position‘ of the double
bonds and the R” substituent in the pyrazole- ring-is
amino - 4’-androstene-3',11'-dione-17'a-yl)-propionic acid 15 chemists.
lactarn, or 9a-?uoro-44androstene-3,l1-dione-17-spiro-2’
(1’-2’) ,B-1’-acylpyrrolidene (‘see Flow Sheet C) by react;
ing ?rst with N-bromo'succinimide in dioxane to fonrn the
corresponding 9a-bromo-1l?-hydroxy-derivative; heating
the latter compound with potassium acetate in absolute 20 isoijneric to the structure shown, and in particular’ ifthe
ethanol to obtain the corresponding 9,8,l1/3-‘oxide; then
following structure exists‘:
converting the 95,11/3-o'xidé into the corresponding 9a
halo-11 ?-hydroxy-der'ivative and in particular the 9d
RT
?uoro-'1l?ihydroxy-derivative, forf example, by treating
with anhydrous hydrogen ?uoride in tetrah'ydrofuran; and
?nally oxidizing the 9ix-?uo'ro-1l?-hydroxy-derivative to‘
25
obtain the corresponding 9oi-?uoro-1LketO-ctimpoiind.
9o: - ?uoro-‘4-‘androstene43,l 1‘-dione-1"7-‘spiro'-2’-( l'-2’)?-‘
pyrrolidene may be‘prep‘a‘red by mineral acid’ hydrolysis of
9d~?uoro-4w'androstene-3, l l-dione -l7-sp‘iro-2"-(1'-2’),B-1'
\acylpyrrolidene, ‘especially when the acyl {group ‘is readily
hydrolyzed, as for example, when the acyl group is forrnyl.
30
The 3 - (17'p-aminoeammo-4'-androjstene-s',11'-di
wherein R stands for
one-17'a-yl)-propionic acid lactain, 3-(9'q-?naro-17'p';
methylamino - 4"-androst‘ene-‘3’,11'-dione;17'a-yl)-propi 35
onic acid lactam and 9a-?uoro'-4+androstene-3,1l-dione
17-spiro-2'-(l'-2’)?-l’acylpyrfolidene are converted into
R’ is hydrogen or alkyl when R is
the corresponding Alr‘i-‘analogues on treatment with se=
leniuni dioxide (see Flow Sheet D).
‘
_‘ _
i
The 3 - (17'?4amino-9’oz-?uoro;4'-androstene-3',11'-di 40
one-17'a-yl)lpropionic acid :lactarn, a-(9'a-?uoro-17'p
and R’ is acyl when R is —_CH2-—, and R" is hydrogen,
elk'yl,» cycloalkyl', aryl or aralkyl and wherein Xir's'halog‘ei?
methylamino - 4'-andro'ste,ne13',l1';dione>17'a-yl)-propi
onic acid 'lactam and 9ot-?uorol4-an‘drostene-3Jl-dione
17‘-spiro‘-2'-( 112’),B-1'-acylpyrrolidene are ‘converted in
to the corresponding 3-(7’béalk-anoylthio-l7'B-amino-9’a
?uoro-4'-androstene‘-3 ',1 1'-dione‘-17'ot-yl) fp'ropioni'c acid
To form the pyrazolo compound the 2-hydroxyif1eth4
45
lactam, 3- ( 7 'walkano'ylthio-9 admire-17 ' ,B;methy1'a\_inin'o
4"-androstene‘-'3’,l1'-dione417'bi1yl)-propionic ‘acid lactatn
and 7e2-alkanoylthio-4-androstene;3,11-dione#17-spirci-2'
ylene-steroid is dissolved in a solvent such as absolute
ethanol, and'he'ated with hydrazine-or ‘an alkyLcycloalk-yl;
aralkyl, or aryl s‘iibstitute'd hydrazine in- an inert-rati'no'se
phere. A’ hydrazine salt may he used-inthe presence of
a buffering agent’ such as sodium acetate; Among the
(1’ - 2’)B-1'-acylpyrrolidene by dehydrogenation with 50 substituted hydrazines which {may be used for reaction
With’ the above described 2-hydroxymethyle'ne-steroid
compoundsiin the process of our invention are: Alk'ylhyé
drazines, such as methyl-hydrazine, ethylhydr'aziiie,l propylé
chloranil to form the corresponding‘ M's-analogue and
then reacting the latter compound with a thioalkanoie
acid. Among the radicals comprehended by the expres
sion alkanoyl are for-myl, acetyl, propionyl, butyryl,
valeryl, hexanoyl, he'p'ta'noyl, octanoyl and branched-chain
isomers thereof, saidyalkanoyl radicals being the acyl
(radicals ‘of alkanoic acids containing ‘fewer than nine car
bon
atoms.
,
,
,_
p
‘ hydrazines, butylhydrazines, ‘19 - hydro
55
ethylh‘ydr'azine,
cycloallkylhydr'aziiie's‘j arylhydrazines suehv as phe‘hylhyj
drazine, 0-, 611-, and p—halophenylhydrazines, o“-, 111:, and
p-tolylh'ydra'z'iries, 6-, in‘, and p-alkoxyphenylhydrazines';
0-, m-, and pmitroplienylhydrazines, l-hyd'ra'z'inonaph
thalene; 2-hyd‘razinopyridine, 3'-hydra7zinopyridine_; any:
drazinopyridine, 4-hydrazinopyridine oxide, and ~2"-h‘y-'
drazinopyrir'nidine; ‘and aralkylhydrazines such as Be?zyt
hydrazine and phenyl'ethylenehydrazine.
Flow‘ Sheet A
(I111;
o=o
A00
cm
=Noii
Ac-N
Ac-N
V
y ._.,
H
18
wherein Ac represents a‘cyl.
5
Flbw Sheet C
I 53
5
2a
25 wherein fR stands for
R’ is hydrogen or alkyl when R is
o
‘a
and'R! is acyl when R is
and x is halogen.
Flow Sheet D
3,094,522
9
10
ture is stirred for 2.5 hours and 80 g. of hydroxylamine
hydrochloride in 1.2 liters of water is added slowly. The
solution is extracted with ether and the ether extract is
wherein R stands for
0
-—g— or -—CH3—
R’ is hydrogen or alkyl when R is
washed successively with Water, ferrous sulfate, water,
sodium bisul?te and water. Concentration of the ether
extract a?ords 13 g. of 3a-acetoxy¢l7/3-nitro-5B-andro
i
and R’ is acyl when R is —CI-I2--, R” is hydrogen, alkyl,
cycloalkyl, aryl or aralkyl, and wherein X is halogen.
The following examples illustrate methods of carrying
stane-lLB-ol. Chromatography over acid washed alumina
yields an additional 7 g. of product. The analytical
sample has a M.P. of ISO-183° C.
10
EXAMPLE 5
To 19.2 g. of 3a-acetoxy-17/3-nitro-518-androstane-l1B
01 in 290 ml. of methyl acrylate and 145 ml. of t-butanol
there is added 29‘ ml. of methanolic tetramethylammo
nium hydroxide. The solution is left overnight in a
EXAMPLE 1
15 stoppered ?ask and it is then poured into 100 ml. of 2.5
A solution of 192 g. of 3a-acetoxy-l6-pregnene-11,20-di
N hydrochloric acid and an equal volume of ice. The
one, 45 g. of hydroxylamine hydrochloride and 204 ml. of
organic materials are extracted into ether which is washed
pyridine in 770 ml. of ethyl alcohol are re?uxed for 0.5
once with 50 ml. of a saturated potassium bicarbonate
out the present invention but it is to be understood that
these examples are given for purposes of illustration and
not of limitation.
hour. Then 195 ml. of hot Water is added to the hot reac
solution and two times with water. The dried solvent is
tion mixture and the solution is allowed to cool slowly to 20 evaporated
in vacuo until crystallization begins. The crys
room temperature. The crystalline precipitate is collected
tals are collected on a ?lter, washed with cold ether, and
on a ?lter, washed with 400‘ ml. of 50% methanol-water
air dried to yield 20.7 g. of 3a-acetoxy-l7a-[2’-methoxy
solution and air dried to yield 187 g. of crude 3a-acetoxy
l6-pregnene-1l,20~dione 20-oxime.
carbonylethyl]~17B-nitro-5?-androstane-llp-ol, M.P. 214
220" C. A sample for analysis, after crystallization from
25 ethyl acetate, melts at 220~222° C.
EXAMPLE 2
A solution of 215 g. of crude 3a-acetoxy-16-pregnene
11,20-dione 20-oxime in 580 ml. of dry pyridine is cooled
to between —5 and —10° C. To this is added dropwise
and with stirring 258 g. of p-acetylaminobenzenesulfonyl
EXAMPLE 6
A solution consisting of 17.1 g. of 3a-aC6tOXY-l7ot-[2'~
methoxycarbonylethyl]-17,3-nitro-5?-androstane - 11p - 01,
102 ml. of dimethylformamide and 51 ml. of collidine is
chloride in 515 ml. of pyridine. This addition requires 30 cooled to +10° C. Twenty ml. of methanesulfonylchlo
one and one-quarter hours. Stirring is continued at O~5°
ride is added and the reaction ?ask is immersed immedi
C. for one hour, and then at 10-20“ C. for three hours.
ately in an oil bath maintained at 35° C. After 20 min
One liter of water is added, and then 1.4 liters of mixed
utes the reaction mixture is poured into 1.5 liters of cold
solvent is distilled from the mixture under reduced pres
water and the solid is collected by ?ltration. Crystalliza
35
sure. A solution of three hundred and ?fty ml. of con~
tion from methanol yields 11.7 g. of 3u-acetoxy-17a-[2’
centrated sulfuric acid in 2.6 liters of water is added and
methoxycarbonylethyl]-l7,B-nitro-9(11) - 5,8 - androstene,
this mixture is heated and stirred vigorously at 80° C. for
M.P. 127-130° C. The mother liquor is chromato
one hour. The brown oil is extracted four times with
graphed over acid washed alumina and the 50% petro
ether, Washed once with aqueous ‘sodium bicarbonate and
leum ether-ether eluates yields an additional 2.8 g. The
then two times With water. After distillation of the dried 40 analytical sample from methanol has a M.P. of 129
ether, the residue is made crystalline by trituration with
130 C.
petroleum ether. Filtration affords 168 g. of a mixture
EXAMPLE 7
of 3u-hydroxy-S/S-androstane-l1,17-dione and 3a-acetoxy
5 ?-androstane-l 1,17-dione.
To 12.2 g. of 3a-acetoxy-17a-[2'-methoxycarbonyleth
A solution consisting of 74 g. of the above mixture, 360 45 yl]-l7,8-nitro-9(ll)-5?-androstene in 300 ml. of glacial
acetic acid there is added 12.2 g. of zinc dust in small por
ml. of pyridine and 80 ml. of acetic anhydride is heated on
the steam bath for twenty minutes.
Water is added cau
tiously to the cooled mixture to afford 75 g. of 3a-acetoxy
5,8-androstane-11,17-dione.
EXAMPLE 3
A solution of 75 g. of 3wacetoxy-iB-androstane-11,17
dione, 17.3 g. of hydroxylamine hydrochloride and 500
ml. of pyridine is heated on a steam cone at 90° C. for
2.5 hours. the solution is cooled and diluted with 300 ml. 55
of water. The precipitate is collected on a ?lter, rinsed
well with water and air dried to yield 68 g. of 3m-acetoxy
tions over a 65 minute period. After 1 hour, 12.2 g. more
of zinc is added and the mixture is stirred for 18 hours.
The mixture is ?ltered and the ?ltrate is evaporated under
reduced pressure. Dilution with water and ?ltration yields
9.74 g. of 3-(3'a-acetoxy-17'?-amino-9'(11’)S’?-andro
stene-17'a-yl)~propionic acid lactam, M.P. 230-235” C.
(crystal change at 220° C.). A sample for analysis melts
at 238-240° C. after crystallization from ethyl acetate.
EXAMPLE 8
To a solution of 3 g. of 3-(3'a-acetoxy-17'?-amino
9’(11')-5'?-androstene-lTa-yl)-propionic acid lactam in
SB-androstane-l1,17-dione-17-oxime. A sample for anal
94 ml. of methanol there is added a solution of 6.5 g. of
sis melts at 190-193" C. after crystallization from meth
potassium bicanbonate in 36 ml. of water. The solution
anol.
60 is re?uxed for four hours, cooled, poured into water and‘
EXAMPLE 4
extracted with ethyl acetate. The ethyl acetate solution
To a slurry of 110 g. of N-bromosuccinirnide in 350 ml.
is washed with water, dried over anhydrous sodium sul
of dioxane and 350 ml. of Water there is added simulta
fate and concentrated in vacuo. The crude product is
neously 65 g. of 3ot-acetoxy-5B-androstane-11,17-dione-l7
oxime in 700 ml. of dioxane and 61 g. of potassium bicar 65 crystallized from ethyl acetate to yield 2.71 ‘g. of 3-(17’5
amino ~ 3'18 - hydroxy - 9’(l1’) - 5'5 - androstene - 17'ec bonate in 350 m1. of Water. The mixture is stirred for
yl)-propionic acid lactam, M.P. 179-183° C.
18 hours, diluted with water and extracted with ethyl
EXAMPLE 9
acetate. The ethyl acetate extract is washed successively
A solution of 3.5 g. of 3-(l7’l3-arnino-3’?-hydroxy
with a saturated ferrous sulfate solution (2 times), water,
10% sodium bisul?te (2 times) and again with water. 70 9'(1l’)-5’[i-androstene-l7'a-yl)-propionic acid lactam in
20 :ml. of pyridine is added slowly with stirring to a pyri
After drying over anhydrous sodium sulfate, the ethyl
dine-chromic acid complex prepared from 3.5 g. of chro
acetate is removed under vacuum leaving a solid residue.
mium trioxide and 20 ml. of pyridine. After 18 hours.
This is dissolved in 1.8 liters of an 80% tetrahydrofuran
at room temperature the dark brown solution is poured
water solution and 31 g. of sodium borohydride is added
over a 40 minute period with vigorous stirring. The mix 75 into water and extracted two times with ethyl acetate.
3,094,522?»
11
12
"mean-Y1 ‘acetate is-was’h‘e'd‘two‘times- with dilute hydro
into water and extracted two times with ethyl acetate.
chloric-acid, threetii'nes withwater and‘ dried over 'so—‘
The ethyl acetate is washed two times with dilute hydro
diur'i'rsulfate. The solvent is evaporated'in vacuo and
chloric acid, three times with water and dried over sodium
the residue is crystallized from ethyl acetate to yield 2.412
sulfate. The solvent is evaporated in vacuo ‘and the resi
g‘. of 3 -'(17'?#amino-9'(11’);5’?~androstene-3’-one-17’ot an,- due is crystallized from ethyl acetate to give 3-(17’/3—
ylyprcpiunie acid lactam, M.P. 245—250° C. The ana
methylamino - 9’(11') - 5’?-androstene-3'-one-l7’ot-yl)
propionic acid lactam.
sample is ‘crystallized from methanol, M.P. 255
258"
'
‘
,
,
EXAMPLE 1s
EXAM'PLE 10
A solution of L26 g. of 3-(l7’?-methylamino-9’U1')
A solution of 1.265g-. of 3-(l7’?-amino-9’(11’)-5'? 10' S'B-androstene-S’-one-17’a-yl)-propionic acid lactam, 21
andtostene-S’-one-'17'a-yl)-propionic acid lactam, 21 ml.
ml. of chloroform, 5 ml. of glacial acetic acid and 0.5
of'chlo‘roform', 5 m1. of glacial ‘acetic acid and 0.5 ml.
ml. of HBr-ace'tic anhydride reagent is stirred at '0" C.
of HBr-acetic ‘anhydride reagent is stirred ‘at 0° C. The
The latter solution is prepared by adding 0.5 ml. of 48%
latter solution is prepared by adding 0.5 ml. of 48%
. hydrobromic acid to 2 ml. of cold acetic anhydride. To
hydrobromict-acid to 2 ml. of cold acetic anhydride. To
the reaction mixture there is added dropwise over a one
the reaction mixture there is ‘added dropwise over a one
hour period 14 ml. of glacial acetic acid containing 670
hou'r'period 14 ml. of glacial acetic acid containing 670
mg. of bromine and 2 ml. of the HBr-acetic anhydride re
mg‘.- of bromine and. 2 ml. of the HBr-acetic anhydride
agent. After stirring for an additional forty-?ve minutes,
reagent. After stirring'for ‘an additional forty-?ve min
the reaction is quenched by the addition of 4 g. of potas
utes,- the reaction is'quen'che'd by the addition of 4 g. of 20 sium acetate. The mixture is poured into water, extracted
acetate. The mixture is poured into water,
with chloroform and the chloroform layer is washed with
extracted with-chloroform and the chloroform layer is
washed with Water, dried over sodium sulfate and con
water, dried over sodium sulfate and concentrated in
vacuo.
V
I
The crude product (1.6 g.) is heated in an oil bath at
The crude product ‘((1.6 g.) is heated in an oil bath at 25 120° C. for two hours with 30 ml. of dimethylformamide,
120° C. for two hours with 30 ml. of dimethylformamide,
1.6 g. ‘of lithium bromide and 1.6 g. of lithium carbonate.
116 :g. of lithium bromide and 1.6 g. of lithium carbonate.
The reaction mixture is cooled, diluted with water and
The reaction mixture is cooled, diluted with water ‘and
extracted with ethyl acetate. The organic layer is washed
extracted
ethyl acetate. The organic layer is
with water, dried over sodium sulfate and concentrated
washed with water, dried'over sodium- sulfate and con
in vacuo. Crystallization from ethyl acetate yields 3
ceiitif'ated invaciios'
centrated in vacuo.‘ Crystallization from ethyl acetate
yields 560 mg. of 3=(17’/3-amino-4’,9’(11’)~androstad1
ene- 3'-one'-17'w-y1)-propionic acid lactam, M.P. (de
comp.) 288-294" C. The analytical sample is crystal
lized-frommethanol,
(decomp.) 294—298° 0., ultra
violet absorption kmax 238 mu, 6 15,640.
’
EXAMPLE 11;
Five-hundred mg. vof V3-(l7'18eamino-3'?-hydroxy-9'—
(11’)-5'?=androstene=17’ot=yl)epropionic acid lactam 1s re
acted at'room temperature for eighteen hours with 50 m1.
of \dry dihydropyran and 150 mg. of p-toluenesulfonyl
chloride. This mixture is their‘ diluted With 5% sodium
bicarbonate solution'and‘ a‘ crystalline precipitate of the
yl)-propionic acid’lactam 3’B-tet‘rahydropyranyl other is
collected.
' A‘solutio'n is prepared-of 250 mg. of this tetrahydropy
ranyl ether in 8~m1. of dimethylformamide and 16 ml.
(17',8 - methylamino - 4’,9’( 1 1’) - androstadiene - 3’ - one
17’a-yl)-propionic acid lactam.
EXAMPLE 14
35
One gram of 3-('17'?-amino-3'?-hydroxy-9'(11')-5';8
androstene-17’u-yl)-propionic acid lactam is re?uxed with
three‘ grams of lithium‘ aluminum hydroide in 400 ml. of
puri?ed dioxane for ninety hours. Ether and saturated
aqueous sodium potassium tartrate are added carefully
to the cooled solution. This mixture is ?ltered through
Supercel (an infusorial earth) and then concentrated in
vacuo to remove most of the dioxane.
Dilute sodium
hydroxide is added and the desired amine is brought into
ethyl acetate with several extractions. Removal of the
45 ‘washed and dried solvent leaves 3ot-hy1droxy-9(11)-5l3
androsten'e-l 7-spiro-2’-( 1’-2’ ) ,B-pyrrolidene.
EXAMPLE 15‘
The diac'etylation of 250 mg. of 3ot-hydroxy-9(1l)-5?
of benzene. Eight ml. of benzene is distilled off to in 50 androstene - l7 - spiro-2’-(1'-2’),9-pyrrolidene is accom
plished with 2.5 ml. of acetic anhydride and 2.5 ml. of
sure dryness. After they addition of 80 mg. of sodium
pyridine. This mixture is heated ‘on the steam bath under
hydride; a yellow anion developed. Two ml. of methyl
nitrogen for one and oneehalf hours. It is then taken to
iodide is“ addediand the mixture-is stirred overnight under
dryness on the rotating evaporator and the residue is
nitroge‘n'and. then refluxed for one hour. The mixture is
diluted with benzene, washed with Water, ‘dried and evapo 55 crystallized from methylene chloride-ether to give 3w.
rated to, yield crude 3-(3’ot-hydroxy-17’?-methylamino_
9’(11’)-5'B-androstene-17’u-yl)-propionic acid lactarn 3'5
tetrahydropyranyl ether.
‘
acetoxy - 9(11)‘ - 5e - androstene ~ 17 — spiro - 2' - (1’
2’ ) )6- 1 ’-acetylpyrrolidene.
The diformylation of 250 mg. of 3u-hydroxy-9(l1)-5B
The reversal of‘ the ether at C-3’ is accomplished by.
androstene - 171 spiro-2’-(1’-2’)p-pyrrolidene is accom
adding the steroid to a mixture of 20 mg. of p-toluene sul
fonic acid in 10 ml. of ethanol. After eighteen hours at
plished by vadding the compoundat 0° C. to 2 ml. of
acetic anhydride in 5 ml. of 98% formic acid. The mix
room temperature, some of the ethanol is removed on the
ture is allowed to come to room temperature and after
eighteen hours, excess reagent is removed at room tem
perature on the rotating evaporator. The residue is crys
rotator, water is ‘added and the product is extracted into
ethyl ‘acetate. The solvent is washedwith dilute sodium
talliz'ed from methylene chloride-ether to give 3ot-formyl
bicarbonate, dried and evaporated. Recrystallization of
the residue fromvmethylene. chloride-‘ether yields 3-(3'—cc~ 65 oxy - 9(11) -' 5B '- androstene- 17 - spiro - 2' - (1' - 2')?
1 ’-formylpyrrolidene.
hydroxy 417’3- methylamino - 9'(11’)-5’/3-androstene-'
I‘7'a-YD-PI'OP1OI11C acid lactam.
'
EXAMPLE 16
EXAMPLE 12
A solution ofv 3.5 g. of 3-(3'a-hydroxy-17’?-methyl
amino-9’( 11')-5',8-androstene417'a-yl)-propionic acid lac
tam in 20ml; of pyridine is added slowly with stirring to
a pyridine chromic'acid complex prepared from 3.5 g. of
chromium trioxide and 20 ml. of pyridine. After 18 hours
at room temperature the dark brown solution is poured
To a solution of 3 g. of 3ot-acetoxy-9(11)-5}3-andro
70 stene'-17-spiro-2'-(1’-2')?-Y-acetylpyrrolidene in 94 ml.
of methanol there is added a solution of 6.5 g. of potas
sium bicarbonate in 36 ml. of water. The solution is re
?uxed for four hours; cooled, poured into water and ex
tracted with ethyl acetate. The ethyl acetate solution is
Washed with water, dried over anhydrous sodium sulfate
3,094,522
14
13
and concentrated in vacuo. The crude product is crystal
nated by the addition of glacial acetic acid and ice-water.
lized from ethyl acetate to yield 3u-hydroxy-9(11)-5;3-an~
drostene-17-spiro~2’-( 1 '-2' ) B~1’-acetylpyrrolidene.
In accordance with the above procedure, but starting
washed with water and dried in vacuo to yield 120 mg.
of 3-(17'?-arnino-9’,11' - epoxy-4'-andros-tene-3Lone-17%;
After cooling, the crystalline precipitate is collected,
with the corresponding 3u-formyloxy-9(11)-5?-andro
stene—17-spiro-2’-( 1’-2')e-1'-formylpyrrolidene, there is
obtained the corresponding 3a-hydroxy-9(11)-5?-andro'
yl)-propionic acid lactam. Two crystallizations from
ethyl acetate affords the analytical sample, M.P. (decomp)
282—286° C. ultraviolet absorption at xmax 243 mu,
stene-17-spiro-2’-( 1’-2' ) ;3-1’-formylpyrrolidene.
514,240.
EXAMPLE 1“?
A solution of 3.5 g. of 3a-hydroxy-9(11)-5/8-andro
stene-17-spiro-2’-(1'-2')?-1’-acetylpyrrolidene in 20 m1.
of pyridine is added slowly with stirring to a pyridine
chromic acid complex prepared from 3.5 g. of chromium
A hydrogen ?uoride solution is prepared at ---60° C.
10 from 10.4 g. of anhydrous hydrogen ?uoride, 14.3 ml.
of tetrahydrofuran and 7.5 m1. of chloroform. One and
one-half cc. of this solution is kept at ~60° C. and to it
is added 54 mg. of 3-(l7’?-amino-9’,l1’-epoxy-4'-andro.
stene-3’-one-l7'a-yl)-propionic acid lactam in 0.75 ml. of
trioxide and 20 ml. of pyridine. After 18 hours at room 15 chloroform likewise chilled at —60° C. The reaction
temperature, the dark brown solution is poured into
mixture is maintained at —-40° C. for two and one-half
water and extracted two times with ethyl acetate. The
hours and then it is added to a well agitated mixture of
ethyl acetate is washed two times with dilute hydrochloric
aqueous potassium carbonate, chloroform and ice. The
acid, three times with water and dried over sodium sul
organic layer is washed two times with water, dried over
fate. The solvent is evaporated in vacuo and the residue
sodium sulfate and concentrated in vacuum. Crystalliza
is crystallized from ethyl acetate to yield 9(11)~5}9~andro
tion from ethyl acetate yields 30‘ mg. of 3-(l7'l3-amino
stene—3¢one-17-spiro-2’-( 1’-2’ ) IS-pyrrolidene.
9’a-?uoro-1l’,B-hydroxy-4'-androstene - 3' - one-17'a-yl)
'In'accordance with the above procedure, but starting
propionic acid lactam, M.P. (decomp) 310-320“ C. with
with 3a-hydroxy - 9(11) - 5B - androstene-17-spiro-2’-(1'
2’)B-1’-formylpyrrolidene in place of 3a-hydroxy-9(11)
ultraviolet absorption at Amax 238 ma, 6 15,980.
25
A solution of 400 mg. of 3-(17'B-amino-9’a-?uoro-l 1'5
5/3 - androstene - 17 - spiro - 2' - (1’ - 2’);8 - 1' - acetyl
hydroxy-4'-androstene-3’-one-17’a-yl)-propionic acid lac
pyrrolidene ‘there is obtained the 9(11)-55-androstene-3
tam in 4 ml. of pyridine is added to the complex formed
by the addition of 400 mg. of chromium trioxide to 4 m1.
one-17-spiro-2'-( 1 ’-2’ ) [3-1 ’-formylpyrrolidene.
of pyridine.
EXAMPLE 18
The mixture is swirled until thoroughly
mixed and then allowed to stand at room temperature
A solution of 1.26 g. of 9(11)-5?-androstene~3-one-17
overnight. The reaction mixture is poured into water,
spiro-2’(1'~2’),B-1'-acetylpyrrolidene, 21 ml. of chloro
form, 5 ml. of glacial acetic acid and 0.5 ml. of HBr
and the aqueous mixture is extracted with ether and then
twice with ethyl acetate. The combined ether and ethyl
acetic anhydride reagent is stirred at 0° C. The latter
acetate extracts are washed with dilute aqueous sulfuric
solution is prepared by adding 0.5 ml. of 48% hydro
acid at about 0° C., and then with water until neutral.
bromic acid to 2 ml. of cold acetic anhydride. To the re 35 The organic solvent layer is then dried, the solvents are
action mixture there is added dropwise over a one-hour
evaporated therefrom in vacuo, and the residual crystal
period 14 ml. of glacial acetic acid containing 670 mg.
of bromine and 2 ml. of the HBr-anhydride reagent.
line material is puri?ed by crystallization from a mixture
of ethyl acetate and ether to give 3-(17’j3-amil'10'9'd-?l1OI'O
After stirring for an additional forty-?ve minutes, the re
4’~androstene-3’,11’-dione~17’a-yl)-propionic acid lactam.
action is quenched by the addition of 4 g. of potassium
acetate. The mixture is poured into Water, extracted with
chloroform and the chloroform layer is washed with
In accordance with all of the above procedures, but
starting with 3~(17'5-methylamino-4',9'(1l')-androstadi
ene-3’-one-l7'a-yl)-propionic acid lactam, or 4,9-(1l)~an
water, dried ‘over sodium sulfate and concentrated in
drostadiene-3-one-l7-spiro-2'-(1'-2’)18-1'-acylpyrrolidene in
vacuo.
place of 3-(17'B-amino-4’,9’(11') - androstadiene-3'-one
The crude product (1.6 g.) is heated on an oil bath at
120° C. for two hours with 30‘ ml. of dimethylformamide,
1.6 g. of lithium bromide and 1.6 g. of lithium carbonate.
The reaction mixture is cooled, ‘diluted with water and ex
l7'a-yl)-propionic acid lactam, there is obtained the cor
responding 3-(9’a-?uoro-17'j8-methylamino-4'-androstene
3',11'-dione-17'a-yl)-propionic acid lactam, 9a-?u0r0-4
androstene - 3,11-dione-17-spiro-2'-(1'-2’)B-1’-acylpynroli
tracted with ethyl acetate. The organic layer is washed
dene.
with water, dried over sodium sulfate and concentrated 50 4 A solution of 250 mg. of 9ot-?uoro-4-androstene-3,11
in vacuo. Crystallization from ethyl acetate yields 4,9
dione-l7-spiro~2'-(1’-2’)B-1'-formylpyrrolidene in 10 cc. of
(11) - androstadiene - 3 - one - 17 - spiro - 2’ - (1' - 2’)?—
ethanol containing 2 cc. of concentrated hydrochloric acid
is re?uxed for 4 hours. Evaporation of the solvent under
reduced pressure leaves the hydrochloride of 9a-?uoro-4
l’-acetylpyrroliclene.
In accordance with the above procedure, but starting
with the 9(ll)-5,8-androstene-3-one-17-spiro-2’-(1’-2’)13
androstene - 3,11 - dione-17-spiro-2’-(1’-2’)p-pyrrolidene.
1'-acetylpyrrolidene, there is obtained the corresponding
The hydrochloride is treated with alkali in an inert solvent
and is chromatographed on basic alumina to yield the
4,9(11) - androstadiene - 3 - one - 17 - spiro - 2’ - (1'
2' ) B-1'-formylpyrrolidene.
EXAMPLE 19‘
puri?ed free base.
60
0.71 milliliters of 0.2 N perchloric acid is added with
stirring to a suspension of 200 mg. of 3-(17’,B~amino‘4’,9’
(1 l')-androstadiene-3’-one~17 'ct-Y1)—PFOP1OH1C acid lactam,
EXAllIPLE 20
To 100 mg. of 3-(17',8-amino-9’a-?uoro-4'-androstenc
3’,11'-dione-l7’a-yl)Jpropionic acid lactarn in 5 ml. of t
butanol and 0.1 ml. of‘acetic acid is added 50 mg. of
selenium dioxide. The mixture is re?uxed under nitrogen
135 mg. of N-bromosuccinimide and 4 ml. of dioxane at
5° C. This mixture is left in the refrigerator for three 65
‘for 18 hours; then 50 mg. of selenium dioxide is added
and one-half hours and is then diluted carefully with
and the mixture is re?uxed for an additional 24 hours.
water until a precipitate occurs. The crystals are col
The mixture is ?ltered and the ?ltrate evaporated to dry
lected on a ?lter, washed two times with water and dried
ness. The residue is extracted with ethyl acetate and the
to yield 176 mg. of crude 3-(17'?-amino-9'a-bromo-1l'B
'hydroxy-4’-androstene-3’~one-17’a-yl)-propionic acid lac 70 extract is washed successively with aqueous sodium bicar
tam.
To a suspension of 176 mg. of the above compound in
5 ml. of dry methanol there is added 0.5 ml. of a 1 N
sodium methoxide solution, and the mixture is stirred at
room temperature for 10 minutes. The reaction is termi 75
bonate, ammonium sul?de, dilute ammonia water, Water,
dilute hydrochloric acid and water, and then dried over
magnesium sulfate. The extract is treated with activated
charcoal and then concentrated to dryness. Crystalliza
tion of the residue from a mixture of acetone and ether
15
3,094,522
1'6‘
gives 3-(17'?-amino-9'a-?uoro4’,4’-androstadiene~3 ’,l l’
dione-17'a-yD-propionic acid lactam.
separated and the aqueous phase is extracted with ether,
with ethyl actate andwith methylene chloride. The
combined organic layers are extracted‘with sodium bi
In accordance with the above procedure, but starting
with 3-(9’a-?uoro-17’,B-methylamino-4’-androstene-3', l 1’
carbonate to remove impurities.
dione-l7'a-yD-propionic acid lactam or 9a-?uoro-4-andro
The product is then
UL extracted into a 2% aqueous solution of sodium hy->
stem-3,1l~dione-l7-spiro-2'-(1'-2')p~l’ - acetylpyrrolidene
droxide. Acidi?cation of the alkaline extracts with dilute
hydrochloric acid- gives a product which is taken up in
methylene chloride. The solution is ?ltered and evap
orated to ‘dryness, to give l3-(l7’B-amino-[3’,2’-c]pyra
inplace of 3-(l7’?-aminor9’a-?uoro-4’~androstene~3',l1'
dione-l7'a-yD-propionic acid lactam, there is obtained the
corresponding 3-(9'a-?uoro-l7'p - methylamino-1',4'-an
drostadiene-3",ll’-dione-l7'u-yl)-propionic acid lactam or
zolo-4’-androstene-ll'-one-17'ot - yl) - propionic acid lac
9a-?uoro-1,4-androst2idiene-3,11 - dione-l7-spiro~2’-(l’-2')
tam.
p-1'-ace.tylpyrrolidene.
’
In accordance with the above procedures, but start
ing with 3 - (9'a-?uoro-17'l8-methylamino-4'-androstene
EXAMPLE 21
A solution of 200‘ mg. of 3-(17’£-amino-9'a-?u0ro-4’ 15
androstene-3',1l'-dione-17'a-yl)-propionic acid lactam and
3’,11’~dione-17'a-yl)~propionic acid lactam or 9u-?uoro
4-androstene-3,11-dione - 17 - spiro~2,'-(1’-2’),8~l'-acetyl
pyrrolidene in place of 3-(17’,8-amino-9'oc-?uoro-4’-andro—
stene-3’,11’-dione-17’a-yl)-propionic acid lactam there is
400 mg. of chloranil in 30 ml. of t~butanol are re?uxed
overnight. The mixture is then taken down to dryness in
vacuoland chromatographed on silica gel. Elution with
obtained as product the corresponding 3-(17',8-methyl
amino - [3',2'-c]pyrazolo-4'-androstene-1l’ - one - 17'u
chloroform-acetone (1:1) a?ords 3-(l7’B-amino-9’w?uoro
yl)-propionic acid lactam or 9a-?uoro-[3,2-c]pyrazolo
4’,6'-androstadiene-3',11’-dione-17'a-yl) - propionic acid 20.
4-androstene-3,11-dione-17-spiro - 2' - (1'—2'),B-l'-acetyl
lactam.
pyrrolidene.
To 10"- ml. of freshly distilled thioacetic acid there is
added 150 mg. of 3-(1736-arnino-9’a-?uoro-4’,6'-androsta
Various changesand modi?cations may be made in
This 25 carrying out the present invention without departing from
the spirit and scope thereof. Insofar as these changes
solution islheated on the steam bath under nitrogen for
and modi?cations are within the purview ‘of the annexed
diene—3',ll’-dione-17’u-yl)-propionic acid lactam.
one-half hour and excess thioacet-ic acid is blown'oif with
claims, they are to ‘be considered as part of our invention.
nitrogen. The residue is taken up in ethyl acetate and
We claim:
washed with sodium bicarbonate and Water. Removal of
1. A compound of the formula
the dried solvent and trituration with methanol gives 3 30
(7’u-acetylthio- l7'?-amino-9'a-?uoro-4'-androstene-3’,1 1'
dione-17’oz-yD-propionic acid lactam.
In accordance with the above procedures, but starting
with the 3-(9'a-?uoro-l7’p - methylamino-4’-androstene
3',11’-dione-17'a-yl)-propionic acid lactam or 9ot-?uoro-4-v 35
androstene - 3,11 - dione-l7-spiro~2'-( l'-2’)?-l"-acetylpyr
rolidene in- place- of 3~(17’,8-amino-9'u-?uoro-4'-andro—
stene~3?,11i-dione-17'a-yl)-propionic acid lactam there is
obtained as product the corresponding 3-(7’a-acetylthio
'
l
Rs-k/ \/i-Rz
9'0: - ?uoro-l7’,B-methylamino-4’-androstene-3',11’-dione
l7"u-yl)-propionic acid lactam or 7a-acetylthio-4-andro
Sterne-3,1l-dione-17-spiro-2'-(1’-2’)?-1'-acetylpyr-rolidene.
in which
EXAMPLE 22
A suspension of 610 mg. of 3-(17'p-amino-9'a-?uoro
4’-androstene-3',11',~dione-17'u - yl) - propionic acid lac
Y?y
45
tam in 50 ml. of dry benzene is stirred in a nitrogen
atmosphere with 1 ml. of ethyl formate and 450 mg.
of a suspension of about 54% sodium hydride in
mineral oil at room temperature for 19 hours. Stirring
is continued for 2 more hours after the addition of 1 50
ml. of ethyl formate and 350 mg. of sodium hydride.
The reaction mixture is chilled in an icebath and acidi?ed
R1 is selected from the group consisting of hydrogen,
methyl, and carboxylic acyl,
A is selected ‘from the group consisting of carbonyl and
methylene,
R2 is selected from the group consisting of hydrogen
and lower alkanoylthio,
R3 is selected from‘ the group consisting of at-hydroxyl,
keto, and, together with R4, a group-—
CH
with an excess of an ‘aqueous solution of sodium di
hydrogen phosphate. The layers are separated and the
aqueous phase is extracted with ether, with ethyl acetate 55
and with methylene chloride. The combined organic
in which
layers are extracted with sodium bicarbonate to remove
impurities. The product is then extracted into a 2%
aqueous solution of sodium hydroxide. Acidi?cation of
the alkaline extracts with dilute hydrochloric gives 60
a product which is taken up in methylene chloride. The
solution is ?ltered and evaporated to dryness, to give
3-(l7’B-amino-9'a -. ?uoro - 2’ - hydroxymethylene - 41'
androstene-3',11'-di0ne-l7’a-yl)-propionic acid lactam.
A suspension of 610 mg. of 3-(l7’li-amino-9'a-?uoro 65
2' - hydroxymethylene - 4’ - androstene - 3’,11' - dione
17'a-yl),-propionic acid lactam in 50 ml. of dry benzene
is stirred in a nitrogen atmosphere with 1 ml. of ethyl
formate and 450 mg. of a suspension of about 54%
sodium hydride in mineral oil at room temperature for
19 hours. Stirring is continued for 2 more hours after
the addition of 1 ml. of ethyl formate and 350 mg. of
sodium hydride. The reaction mixture is chilled in an
icebath and acidi?ed with an excess of an aqueous solu
tion of‘ sodium dihydrogen phosphate. The layers are 75
R5 is selected from the group consisting of lower alkyl,
hydroxyalkyl, cycloalkyl, phenyl, tolyl, alkoxy~
phenyl, nitrophenyl, naphthyl pyridyl, N-oxidopyri
dyl, pyrimidyl, benzyl and phenethyl,
R4 is selected from the group consisting of hydrogen
and, together with R3, a pyrazolo group’ as de?ned
above,
X is selected vfro mthe group consisting of hydrogen,
halogen and, together with Y, 9 (11) double bonds
and epoxy groups,
Y is selected from the group consisting of keto. oxygen,
?-hydroxyl and, together with X, 9 (11) double
bonds and epoxy groups, and the dotted lines in the
1, 2, and 3 and 5, 6 positions show that each of
these bonds is selected from the ‘group consisting of
single and double bonds.
3. Ba-acetoxy - 17a-['2.’-methoxycarbonylethyl] - 175
nitro-9(11)-5?-androstene.
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