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Патент USA US3094531

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United States Patent 0 ” "ice
2
1
drostene with zinc dust in acid solution gives 3-(3’5
3,094,521
acetoxy-l7’B-amino-5'~androstene-17’u-yl)-propionic acid
ALKANOYLTHIO AND PYRAZOLO ANDROSTANE
DERIVATIVES
Arthur A. Patchett, Metuchen, Glen E. Arth, Crawford,
and Frances G. Hoifman, Newark, N.J., assignors to
Merck & Co., Inc., Rahway, NJ., a corporation of
New Jersey
lactam.
The latter compound is converted into 3-(3'5
hydroxy-l7’B-amino-5'-androstene-l7’a-yl)~propionic acid
lactam for example, by heating with an aqueous metha
nolic solution of alkali metal bicarbonate. The 3-(3’?
hydroxy-17'?-amino - 5’ - androstene-l7'a-yl)-propionic
N0 Drawing. Filed July 25, 1961, Ser. No. 126,508
13 Claims. (Cl. zen-239.5)
This invention is concerned generally with novel
steroids and processes of preparing the same.
3,094,521
Patented June 18, 1963
acid lactam is oxidized to 3-(3’-oxo-l7'?eamino-4’-an
.drostene-17’a-yl)-propi0nic acid lactam, vfor example, 'by
using aluminum isopropoxide and cyclohexanone (or ace
More
tone) in a hydrocarbon solvent such as toluene.
particularly, it relates to novel compounds having the
following structure:
The 3-(3'?-hydroxy-17'?-amino - 5’ - androstene - 17'oc
yl)~propionic acid lactam is converted to 3-(I3’-'hydroxy
l7’,B-methylamino-5’-androstene-l7’a-yl)-propionic acid
15 lactam by reaction ?rst with dihydropyran in the pres
ence of an acidic catalyst to form 3-(3'B-hydroxy-17'B
amino-5’-androstene-17’u-yl)-propionic acid lactam 3B
tetrahydropyranyl ether, and then methylating the latter
compound, for example, using methyl iodide and sodium
20 hydride followed by acid treatment to give 3-(3'18-hy
droxy - 17’5 - methylamino - 5' - androstene - 17'“ - yl)
propionic acid lactam. The 3-(3’?-hydroxy-l7’j3-methyl
amino-S'androstene-l7'u-yl)-propionic acid lactam is
then oxidized to 3-(3’eoxo-17’,B-methylamino_4’-andro
in which R1 may be hydrogen or alkanoyl of less than
nine carbons, R2 may be hydrogen or lower alkanoyl 25 stene-17’a-yl)-propionic acid lactam. The oxidation may
be brought about by using aluminum isopropoxide and
thio, R3 may ‘be ,B-hydroxyl, keto, or together with R,
cyclohexanone (or acetone) in a hydrocarbon solvent
a pyrazolo ring, R; is hydrogen or together with R3 a
such as toluene.
pyrazolo ring, at least one of R2 and R4 being other than
The 3-(3’l3-hydroxy-l7’;3-amino-5'-androstene-17'a-yl)
hydrogen and the dotted lines in the 1, 2 and 6, 7 posi
tions shows that these bonds may be single or ‘double 30 propionic acid lactam is converted into 3-oxo-4-andro
stene-17-spiro~2’-(l'-2’)?-pyrrolidene (see Flow Sheet
bonds, only one of them being a double bond at any
C) by ?rst reducing 3-(3'B-hydroxy-17”,6-amino-5'
one time.
androstene-l7'm‘yl)-propionic acid lactam with lithium
aluminum hydride in a solvent such as dioxane to give
alk-anoylthio and pyrazolo derivatives and the Al-‘l- and
Abe-analogues thereof possess useful therapeutic prop 35 3,3-hydroxy-5-androstene-17-spiro-2'-(1' - 2’),s - pyrroli
dene and then oxidizing 3?-hydroxy-5-androstene-17
erties as aldosterone inhibitors. These novel steroids
spiro-2’-(1'-2’)?-pyrrolidene to 3-oxo-4-andro-stene-17
block the salt-retaining e?ects of aldosterone and other
The above-described compounds, as well as the 70:
salt-retaining steroids so as to be useful in the treatment
spiro~2’-(1'-2’),8-pyrrolidene, for example, by using alu
ing material utilized is 3B-acetoxy-5-androstene-17-one
(See Flow Sheet A.) The preparation of the
l7-spiro-2’-(1’-2’)IS-Y-acylpyrrolidene by treating with
article by E. B. Hershberg in J. Org. Chem, 13, 542
(1948). This compound is ?rst brominated to give the
lower alkanoyl halide such as acetic anhydride, propionic
minum isopropoxide and cyclohexanone (or acetone) in
of diseases such as congestive heat failure, nephrosis
and cirrhosis of the kidney in which aldosterone secre 40 a hydrocarbon solvent such as toluene.
The 3B-hydroxy~5-androstene-17-spiro - 2' - (1’ - 2’)B—
tion is increased.
pyrrolidene is converted into 3/3-acyloxy-5-androstene
In preparing our novel chemical compounds, the start
an acylating agent, e.g. a lower hydrocarbon carboxylic
3 ;8~acetoxy-5 -androstene-17-oneeoxime, also known as de 4.5 acid acylating agent such as 'benzoic anhydride or terti
ary butyl acetyl chloride; a lower alkanoic anhydride or
hydroisoandrosterone acetate oxime, is described in an
oxime.
3B-acetoxy-17a-bromo-l7?-nitro-5-androstene - 3 - acetate,
anhydride or acetyl chloride; or a polybasic anhydride
such as [3,;3-dimethylglutaric anhydride, succinic anhy
for example, by treating sequentially with N-bromosuc 50 dride and the like, in the presence of an organic base
cinimide in aqueous dioxane, and then with concentrated
nitric acid. The bromine is then removed from the 3B
such as pyridine.
'Ihe 3,8-acyloxy-5-androstene-17-spiro-2’-(l'-2');8 - 1’
give 3,8-acetoxy-175-nitro~5-androstene. This can be ac-
acylpyrrolidene is re?uxed with an aqueous methanolic
solution of alkali metal bicarbonate to give S?-hydroxy
re?uxing with an aqueous methanolic solution of an
tone) in a hydrocarbon solvent such as toluene.
acetoxy-l7a-bromo-17B-nitro-5eandrostene compound to
complished by re?uxing with sodium borohydride in 55 5 -androstene-17-spiro-2’- (‘l’-2’ ) [3- l '-.acylpyrro1idene. The
latter compound is then oxidized to 3-oxo-4-androstene—
aqueous tetrahydrofuran solution.
l7-spiro-2’-(1’-2’)B-Y-acylpyrrolidene, for example, us
The 3B-acetoxy-l7?-nitro-5-androstene is converted
ing aluminum isopropo-Xide and cyclohexanone (or am
into 3,8-hydroxy-17/3-nitro-5-androstene, for example, by
alkali metal bicarbonate and then treating with hydroxyl
amine hydrochloride.
The 3?-hydr0xy-‘175-nitro-5-an
, drostene is oxidized to 17/8-nitro-4-androstene-3-one, for
The
3-(3'~oxo-17',B-amino-4’-androstene-17’a-yl) -pro
pionic acid lactam, 3-(3’-oxo-17’/3-methylamino-4’-andro~
stene-l7'a-yl)-propionic acid lactam and 3-oxo-4-andro~
are con
verted into the corresponding ALz-analogues on treatment
anone (‘or acetone) in a hydrocarbon solvent such as
65 with selenium dioxide under the conditions described in
toluene.
example, by using aluminum isopropoxide and cyclohex
stene~17-spiro-2’~(1'-2’)B-Y-acetylpyrrolidene
3-(3’-oxo~17’,8~amino - 4’ - androstene-17'u-yl)-propionic
Example 12. (See Flow Sheet C.)
The 3J( 3’-oxo-17’5-amino-4’-androstene--17’a-yl) ~pno~
methyl acrylate to give 3/8-acetoxy-17a-[2’-methoxycar
bonylethyl]-17/3-nitro-S-androstene. Reduction of 3,8
verted into the corresponding 3-(7’a-alkanoyl-3'-oxo-17’
,B-amino-4'-androstene-l7'a-yl)-propionic acid lactam, 3
acetoxy - 17a - [2’-methoxycarbonylethyl]-17,B-nitro-5-an
(7’a-alkanoylthio-3'-oxo-l7’,B-methylamino - 4’ - ‘andro
The 3?-acetoxy-17?-nitro-S-androstene is converted to
pionic acid 'lactam, 3-(3'-oxo-17’{3~methylamino-4’-andno
acid lactam by the following series of reactions (see
stene-17’u-yl)-propionic acid lactam and 3-oxo-4-andro
Flow Sheet B):
The B?-acetcxy-l7?-nitro-5~androstene is reacted with 70 stene~l7-spiro-2’~(l'-2')? - 1’ - acylpyrrolidene are con
3,094,521
3
4
stene-l7'ot-yl)-propionic acid lactam and 7u-a1kan0ylthio
a bu?ering agent such as sodium acetate. Among the
substituted hydrazines which may be used for reaction
3 - OX0 - 4 - andnostene - 17 - spiro - 2' - (1’ - 2')? —
1’-acylpyrrolidene by ‘dehydrogenation with chloranil to
with the above-described 2-hydroxymethylene-steroid
form the A‘l's-analogue, and then reacting the latter com
pound with a thioalkanoic acid. Among the radica?s
compounds in the process of our invention are: alkyl
hydrazines, Such as butylhydrazines, ?-hydroxyethyl
hydrazine and cyclohexylhydrazine; arylhydrazines such
comprehended by the expression alkanoyl are formyl,
acetyl, propionyl, buty-ryl, valeryl, hexanoyl, heptanoyl,
as phenylhydrazine, o-, m-, and p-halophenylhydrazines,
o-, m-, and p-tolylhydrazines, 0-, m-, and p-alkoxyphenyl
ootanoyl and branched-chain isomers thereof, said ‘al
kanoyl radicals being the acyl radicals of alkanoic acids
hydrazines, o-, m-, and p-nitrophenylhydrazine, l-hydra
containing fewer than nine carbon atoms.
10 zinonaphthalene, '2 - hydrazinopyridine, 3 - hydrazino
The addition of thioa‘lkanoic acids to the 6,7-double
pyridine, 4-hydrazinopyridine, 4-hydrazinopyridine oxide,
bond of the intermediates employed in the practice of
and Z-hydrazinopyrimidine; and aralky?hydrazines, such
this invention proceeds under steric in?uences such that
as benzylhydrazine and phenylethylenehydrazine.
of the ‘stereoisomers formed, one is obtained in predomi
Flow Sheet A
nant amount, which, in each case, has been character 15
NOH
NO:
ized herein as possessing the u-con?guration of the 7
acylthio-group. However, the designated con?guration of
the 7-acylthio group is based upon data presently ap
peering in the chemical literature, and is therefore not to
be interpreted except in relation to the state ‘of the art
presently known to organic chemists. It will be appar
ent that no part of the speci?cation will be materially de
fective if it should later be established that the con?gura
tion is the opposite of that deducible from data presently
available to workers in the ?eld.
The 3-( 3 ’-oXo-17’B-amino~4'-androstene—l7’ot-yl)-pro
25
stene-l7'a-yl)-propionic acid lactam and 3-oxo-4-andro
stene - r17 - spiro - 2' - (l' - 2')B - 1' - acylpyrrolidene
are converted into the corresponding 3-( [3’,2'-c]pyr~azoio 3 O
l7’?-amino-4'-androstene-17'a-yl)~propionic acid lactam,
3 - ([3’,‘2’ - c]pyrazolo - l7’l8 - methylamino - 4’ - an
drostene-l7'u-yl)-propionic acid lactam, and [3,2-c]pyr
azollo - 4 - tandrostene - l7 - spiro - 2' - (1' - ‘2’)? - 1’ -
acrylpyrrolidene by ?rst reacting with an alkyl formate 35
and sodium hydride in an inert atmosphere to form the
corresponding 2~hydroxymethylene-derivative, and then
reacting the latter compound with hydrazine or a mono‘
substituted hydrazine to form the corresponding pyrazolo
compound which is exempli?ed in Flow Sheet C as com
3-( [3’,2’-c]pyrazolo-17',8-methylamino-4’-andro
stene-l7’a-yl)-propi0nic acid lactam. The structure of
the pyrazolo-compound designated in the flow sheet is
based upon an interpretation of data according to the
state of the art presently known to organic chemists. 45
However, it is to be understood that no part of the speci?
cation will be materially defective if it shou‘ld 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 iso 50
meric to the structure shown, and in particular if the fol
lowing structure exists:
RT
I
/
55
/\ ’ I
R stvcty
60
wherein R stands for
—(!L,— or —CI'Ia
R’ is hydrogen ‘or alkyl when R is
on
An”
5
,o - Moj
pionic acid lactam, 3J(3’-oxo-l7’?-methylamino-4’-andro
pound
1
65
0
—("J—— and R’
is acyl when R is —CH2—-, R" is hydrogen, alkyl, cy
cloalkyl, aryl or aralkyl.
70
To form the pyrazolo compound the 2-hydroxymethyl
ene-steroid is ‘dissolved in a solvent such as absolute eth
anol, and heated with hydrazine or an alkyl, cycloalkyl,
aralkyl, or aryl substituted hydrazine in ‘an inert atmos
phere. A hydrazine salt may be used in the presence of 75
,Qj -—» 0Q
Flow Sheet B
3,094,521
@5/
is acyl when R is -—CH;—, R" is hydrogen, alkyl, cyclo
alkyl, aryl ‘or aralkyl.
9
Flow Sheet C
US
sm m
Qm
Q
A.
i
W
Flow Sheet D
3,094,521
M‘.\x
/\
I /
H0
19
20
wherein R’ is acyl.
Most of the methanol is removed in vacuo, aqueous hy
The following examples illustrate methods of carry
droxylamine hydrochloride is added and the product is
ing tout ‘the present invention but it is to be understood
extracted into ethyl acetate. Removal of the dried solvent
that these examples are given for purposes of illustra 35 leaves 3l8-hydroxy-l7?-nitro-5-androstene of su?icient pu
tion and not of limitation.
rity for the next step.
About 15 ml. of toluene is distilled from a solution of
EXAMPLE 1
1 g. of 3,6-hydroxy-17,8-nitro-5-androstene in 16 ml. of
A slurry of 16.35 g. of N-bromosuccinimide in 45 ml.
cyclohexanone and 150 ml. of toluene. Then 5 ml. is
water and 60 ml. dioxane is stirred vigorous in 500 ml. 3
added of a 20% solution of aluminum isopropoxide in
necked ?ask. To it is added simultaneously at a rapid
toluene and the mixture is re?uxed for one and one-half
drop-wise rate a slurry of 7.59 g. of sodium bicarbonate
hours in an apparatus protected from atmospheric mois
in 45 ml. of Water and 10.41 g. ‘of '3?-acetoxy-5-andro
ture with an anhydrous calcium sulfate tube. Some water
stene-17-o11e oxi-me in 90 cc. of dioxane. The resultant
bluish-green reaction mixture is stirred an additional ?f 45 is added and the organic layer is decanted o?, ?ltered
and concentrated in vacuo. Chromatography on neu
teen minutes at room temperature. Water is then added
tral alumina altords 300 mg. of product from the ether
and the bromo-nitroso intermediate is extracted into pe
and ether-chloroform (9:1) fractions. Recrystallization
troleum ether. The washed and dried solvent is removed
on the rotator at room temperature to give 10.95 g. of
product.
from methanol-ether gives analytically pure 17;3-nitro-4
androstene-3-one of M.P. 152-5 ° C., U.V. xmax 240 mp,
50 E% 448 and [a]D.
Five grams of this crude bromo-nitroso intermediate
'
is dissolved in 200 ml. of petroleum ether. To the vigor
ously stirred solution there is added slowly 40 ml. of con
centrated nitric acid. Stirring is continued at room tem
perature for ?fteen minutes and then water and ethyl ace
EXAMPLE 3
A partial suspension is prepared of 20 g. of 3B-acetoxy
17,6-nitro-5-androstene in 150 cc. of t-butanol and 75 cc.
of methyl vacrylate. Thirty cc. of methanolic tetramethyl
55 ammonium hydroxide is added slowly with magnetic stir
tate are added. The solvent is washed with water and
ring whereupon all of the steriod goes into solution. After
dilute sodium bicarbonate and then dried and removed in
eighteen hours at room temperature, the reaction mixture
vacuo to give 4.3 g. of crude 17u-bromo-3?-hydroxy-l7?
is poured onto iced dilute HCl. ‘It is then extracted with
nitro-S-androstene-3-acetate.
ethyl acetate. Removal of the washed and dried solvent,
Removal of the bromine from this latter compound is
accomplished by re?uxing it in 100 ml. of tetrahydrofuran 60 ?nally at high vacuum, leaves a semicrystalline residue.
Crystallization from ether and petroleum ether altords
and 10 ml. of water with 2.0 g. of sodium borohydride.
12.86 g. of 3?-acetoxy-17a-[2’-methoxycarbony1ethyl]
After an hour the mixture is cooled and 5.0 g. of hy
17?-nitro-5-androstene. The analytical sample from the
droxylamine hydrochloride in 100 ml. of water is added.
same solvent has a M.P. of 133~4° C., [a]D-—57° C. (di
The steroid is extracted into ethyl acetate. The solvent
is removed and the residue is reacetylated by heating it 65 oxane).
?fteen minutes on the steam bath with 15 ml. of acetic
anhydride and 15 ml. of pyridine. The crude 3/3-acetoxy
17?-nitro-5-androstene weighs 4.07 g. Several recrystal
lizations from ethanol affords a pure sample, M.P. 208—
EXAlllPLE 4;
Two grams of 3B-acetoxy-17a [2'-methoxycarbonyl
ethyl]-17?-nitro-5-androstene are dissolved in 150 ml. of
glacial acetic acid and heated under re?ux with stirring
70 with 2 g. of zinc dust for seventy-two hours.
An addi
tional 1 g. of zinc dust is added at each twenty-four hour
interval of heating. The reaction mixture is then ?ltered,
A solution of 1.5 g. of 3?-acetoxy-17?-nitro-5-andr‘o
Washed with warm glacial acetic acid and concentrated to
stene in 120 ml. of methanol and 12 m1. of Water are re
dryness in vacuo. The residue is extracted with ethyl
?uxed for three hours with 3 g. of potassium bicarbonate. 75 acetate and water, and the solvent is dried and evaporated
212° C., [a]D—-29.7° C.
EXAMPLE 2
3,094,521
‘.9
to yield 1.9 g. of crude 3-(3'?-acetoxy-17'?-amino-5'
androstene-17’ot-yl)-propionic acid lactam. Recrystalli
i0
frared absorption ‘at 5.95, 6.0 ‘and 6.2,u and U.V. hmax
240, E% 448.
EXAMPLE 8
zation from acetone-ether gives 1.6 g. of product, Ml’.
300—305° C.; infrared absorption occurs at 3.16, 5.78, 5.85
One gram of -3 - (3'5 - hydroxy - 17'5 ~amino - 5'
androstene-17’a-yl)-propionic acid lactam is re?uxed
and 8.1,u.
with 3 g. of lithium aluminum hydride in 400 ml. of
EXAMPLE 5
puri?ed dioxane for ninety hours. Ether and saturated
1.6 grams of 3-(3'?-acetoxy-l7’§-amino-5’-androstene
aqueous sodium potassium tartrate are added carefully to
the cooled solution. This mixture is ?ltered through
l7'a-YD-PIOPlOHlC acid lactam is re?uxed for two hours
with 3 g. of potassium bicarbonate in 300 ml. of methanol
Supercel (an infusorial earth) and then concentrated in
and 30 ml. of Water. Most of the solvent is then removed
in vacuo, Water is added and the crystalline product is
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
amino-5’-androstene-l7’a-yl) -propionic acid lactam, MP.
washed ‘and dried solvent leaves 820 mg. of 3/3-hydroxy
285—295° C. (from methylene chloride-methanol) and
infrared absorption at 2.95, 3.10 and 586p.
15 5-androstene—17-spiro-2'-(1’-2')B-pyrro1idene which is re
crystallized from methanol-ethyl acetate to Md’. 194—
A solution of 500 mg. of 3-(3’B~hydroxy-17’B-amino-5’
5° C., infrared absorption at 3.18/L.
androstene-l'7'a-yl)~propionic acid lactam in 8 ml. of cy
clohexanone and 75 ml. of toluene is dried by distilling
EXAMPLE 9
off 10 ml. Then 2.5 ml. of a 20% aluminum isopropoxide‘
A solution of 500 mg. ‘of 3?-hydroxy-S-androstene-17
solution in toluene is added. After re?uxing for a five 20 spiro-2’-(1'-2’),B-pyrrolidene in 8 ml. ‘of cyclohexanone
hour period, a small amount of Water is added to the
and 75 ml. of toluene is dried by distilling off 10 ml.
cooled solution and the toluene is ?ltered off and taken to
Then 2.5 ml. of a 20% aluminum isopropoxide solution
dryness. Most of the excess cyclohexanone is removed
in toluene is added. After re?uxing ‘for 5 hours, a small
at the oil pump at 100° C. The desired 3-(3’-oxo-17’(>’
amount of water is added to the cooled solution and
amino-4’-androstene-lWot-yl)-propioni.c acid lactam. is 25 the
toluene is ?ltered off and taken to dryness. Most
eluted from silica gel with chloroform-acetone 1:1. The
of the excess cyclohexanone is removed at the oil pump
crude yield is 250 mg. which is recrystallized from methyl
at 100° C. The residue is eluted from silica gel with
ene chloride/ether to give a product M.P. 270—275° C.,
chloroform-acetone (1:1) to give 310 mg. of 3-oxo-4~
infrared absorption at 2.9, 3.1, 5.9, 6.0 and 6.2a and U.V.
androstene-17-spiro-2'-(1’-2’)f3-pyrrolidene from 500 mg.
30
Amax 240, 13% 448.
of alcohol. A hydrochloride is prepared thy dissolving
?ltered off.
The yield is 1.2 g. ‘of 3-(3’B-hydroxy-17’?
EXAMPLE 6
the free base in a small amount of methanol to which a
Five-hundred mg. of 3-(3'?-hydroxy-17’,8-amin0-5’- an
drostene-17’a-yl)-prcpionic acid lactam is reacted at room
20-40 fold quantity of ether is added. After centrifuging
oif impurities, HCl gas is added to precipitate the salt.
This salt is recrystallized several times from methanol
‘methyl ethyl ketone to give a product with melting point
greater than 350° C., infrared absorption at 3.69, 3.81,
temperature for eighteen hours with 50 ml. of dry dihydro~
,pyran and 150 mg. of p-toluenesulfonyl chloride. This
mixture is then diluted with 5% sodium bicarbonate solu
tion and 300 mg. of a crystalline precipitate of the 3-(3’3
4.05, 5.98, 6.21 and 630p and U.V. Am). 239.5, E% 446.
hydroxy-17’6-amino-5'-androstene-1i7’ayl) -propionic acid
EXAMPLE 10
lactam 3’B-tetrahydropyranyl ether is collected.
The diacetylation of 250 mg. ‘of 3y3~hydroxy-5-andro
A solution is prepared of 250 mg. of this tetrahydro 40
stene-17-spiro-2’-(1'-2')-13-pyrrolidene is accomplished
pyranyl ether in 8 ml. of dimethylfonnamide and 16 ml.
with 2.5 ml. of acetic anhydride and 2.5 ml. of pyridine.
of benzene. Eight ml. of benzene is distilled off to in
This mixture is heated on the steam bath under nitrogen
sure dryness. After the addition of 80 mg. of sodium
for one and one-half hours. It is then taken to dryness
hydride, a yellow ‘anion developed. Two ml. of methyl
iodide is added ‘and the mixture is stirred overnight under 45 on the rotating evaporator and the residue is crystallized
nitrogen and then re?uxed for ‘one hour.
from methylene chloride-ether. The analytical sample
The mixture is
diluted with benzene, washed with water, dried and
evaporated to yield 192 mg. of crude 3-(3’?-hydroxy
of 3?-acetoxy-S-androstene-17-spiro-2’-(1’-2')\B-1'-acetyl
, 17’B - methylamino - 5’ - androstene - 17'a - yl) - propi
sorption at 5.78 and 6.10/1"
pyrrolidene has a M.P. 208.5-210° C. and infrared ab
50
onic acid lactam 3’/3—tetrahydropyranyl ether.
The reversal of the other at 0-3’ is accomplished by
adding .the steroid to a mixture of 20 mg. of p-toluene
sulfonic acid in 10 ml. of ethanol. After eighteen hours
at room temperature, some of the ethanol is removed on
the rotator, water is added and the product is extracted
into ethyl ‘acetate. The solvent is washed with dilute
sodium bicarbonate, dried and evaporated. Recrystalli
EXAMPLE 11
A solution of 298 mg. of 3B-acetoxy-5-androstene-17
ispiro-2’-(1’-2’);8-1'-acetylpyrrolidene in 35 ml. of meth
anol, 3.5 ml. of Water and 600 mg. of potassium bicar
55 bonate is re?uxed for three hours. iMost of the methanol
is removed in vacuo, water is added and essentially pure
3,8-hydroxy-5-androstene - 17 - spiro-2'-i(1’-2’)B-1’-acetyl
'pyrrolidene is recovered by ethyl acetate extraction. The
zation of the residue from methylene chloride-ether
product weighs about 200 mg. and has infrared absorp
yields 140 mg. of 3-(3'?-hydroxy-17’B-methylamino~5'
at 2.91u and 6.14;/..
androstene-lTu-yl)propionic acid lacta-rn, MP. 255 60 tion
This material is azeotropically [dried in a solution of
260° C.
EXAMPLE 7
About 10 ml. of solvent is distilled from a solution of
i 16 ml. of toluene, 8 ml. ‘of idioxane, 8 ml. of benzene and
3.2 ml. of cyclohexanone. After most of the benzene
has been distilled off, 1 ml. of a 20% aluminum isopro
500 mg. of 3-(3'B-hydroxy-l7’B-methylamino-5’-andro
poxide solution in toluene is added. Re?ux is maintained
stene-l7’a-yl)-propionic ‘acid lactmn in 8 ml. of cyclo 65 for three hours and then a small amount of water is
hexanone and 75 ml. of toluene. Then 2.5 ml. of a 20%
solution of aluminum isopropoxide in toluene is added
and the mixture is re?uxed for three hours. A small
added to the cooled solution.
Filtration and removal
‘ of solvent under vacuum affords a crystalline residue of
3-oxo-4-androstene - l7 - spiro‘-2'-(1’-2’)?-1’-acetylpyr
amount of water is added to the cooled solution which 70 rolidene. An analytical sample is prepared from ethyl
is ?ltered and evaporated to dryness. Elution from neu
acetate, M.P. 223.5—225.5° C., [a]D=+23° C. infrared
absorption at 6.00, 6.11 and 6.20m and U.V. Am“ 240,
tral alumina with ether and ether-chloroform (1:1) af
E% 419.
fords 311 mg. of 3-‘(3’-oxo-l7’?-methyl-amino-4?androa
EXAMPLE 12
stene17'a-yl) -propionic acid lactam. It is recrystallized
To 100 mg. of 3-(3'-oxo-17'?-amino-4'-androstene
from methylene chloride-ether to give a product with in 75
3,094,521
11
12
17'u-y1)-propionic acid lactam in 5 ml. of t-butanol and
aqueous solution of sodium dihydrogen phosphate. The
layers ‘are separated and the aqueous phase is extracted
with ether, with ethyl acetate and with methylene chlo
0.1 ml. of acetic acid is added 50 mg. of selenium dioxide.
The mixture is re?uxed under nitnogen for 18 hours; then
50 mg. of selenium ‘dioxide is added and the mixture
is re?uxed for an additional 24 hours. The mixture is
ride. The combined organic 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 acid gives a product which is taken
up in methylene chloride. The solution is ?ltered and
?ltered, and the ?ltrate evaporated to dryness. The
residue is extracted with ethyl acetate and the extract is
washed successively with aqueous sodium bicarbonate,
ammonium sul?de, tdilute ammonia water, water, dilute
hydrochloric acid and Water, and then dried over mag
nesium sulfate. The extract is treated with activated
evaporated to dryness, to give 3-(2'—hydroxymethylene~
3'—oxo-17'B-amino-4’-androstene-17'a-yl) - propionic acid
charcoal and then concentrated to dryness. Crystalliza
lactam.
In accordance with the above procedure, but starting
tion of the residue from a mixture \Of acetone and ether
gives 3-( 3 '-oxo~17 'B-amino-1’,4’-androstadiene- 17 'ot-yl) -
with the 3-(3’-oxo-17'B-methylamino-4'-androstene-17'a
propionic acid lactam.
15 yl)-propionic acid lactam or the 3-oxo-4-androstene-17
In ‘accordance with the above procedure, but starting
spiro-2'-(1’-2’)B-1'—acetylpyrrolidene in place of the 3-(3’
with the 3-(3'-oxo-17'?-methylamino-4’-androstene-17’ot
oxo-l7'B-amino-4’-androstene - 17'“ - yl) — propionic acid
yl)-ptropionic acid lactam or the 3-oxo-4-androstene-17
spiro-2'-(1’-2’-)?-T-acetylpyrrolidene in place of the 3
(3'-oxo-l7',8-amino-4'-androstene-l7’u-yl)-propionic acid
lactam, there is obtained the corresponding 3-(3'-oxo
lactam, there is obtained the corresponding 3-(2'-hy
droxymethylene-3’-oxo-17’B-methylamino - 4'-androsteue
20 l7'ot-yl)-propionic acid lactam or 2-hydroxymethylene-3~
oxo - 4 - androstene-17-spiro-2'-(1’-2')16-1’aacetylpyrroli
17’B-methylamino-1’,4'-androstadiene-17'a-yl) - propionic
dene.
acid lactam or 3-oxo-l,4-androstadiene-l7-spiro-2'-(1’
EXAMPLE 16
2’-) ,8-1’-acetylpyrrolidene.
A 25 mg. aliquot of 3-(2’-hydroxymethylene-3’-oxo
25
EXAMPLE 13
17’?-'amino-4'-androstene-17’a-yl)propionic acid lactam
is dissolved in 0.6 ml. of ethanol. An 0.032 ml. aliquot
of a reagent, prepared by dissolving 0.48 ml. of hydrazine
hydrate in 0.96 ml. of ethanol, is added and the mixture
is re?uxed under nitrogen for 45 minutes. The volatiles
A solution of 200 mg. of 3-(3’-oxo-17',B-arnino-4'-an_
dr0stene-17'u-yl)-propionic acid lactam and 400 mg. of
chloranil in 30 ml. of t-‘butanol are re?uxed overnight.
The mixture is then‘ taken down to dryness in vacuo and
chromatographed on silica gel. Elution with chloroform
acetone (1:1) .a?ords 60 mg. of 3-(3’-oxo-l7'?-amino-4’,
are removed in vacuo and the residue is extracted with
hot methylene chloride. The methylene chloride solution
6’-androstadiene-l7'a-yl)-propionic ‘acid lactam, M.P.
3104315o C. (from acetone), U.V. Am“ 279, E% 650.
In accordance with the above procedure, but starting
with the 3-(3'-oxo-17'?-methylamino-4'-androstene-l7’a
is ?ltered to remove insolubles and taken to dryness. The
residue is ?ushed two times with n-hexane and dried to
give 3-( [3',2’-c]pyrazolo-17'B-amino-4’-androstene-l7’a—
yl)-propionic acid lactam.
yl)-propionic acid lactam or the 3-oxo-4-androstene-17
A mixture of 90 mg. of 3-(2'-hydroxymethylene-3'-oxo
spiro-2'-(1’-2’) B-Y-acetylpyrrolidene in place of the 3-(3’
17’?-amino-4’-androstene-17'ot-y1)-propionic acid lactam
oxo-17',B-amino-4'-androstene - 17 'ct - yl) - propionic acid
lactam, there is obtained the corresponding 3-(3'-oxo
17 '?-methylarnino-4’,6’-androstadiene~17’a-yl) - propionic
40
‘and 0.028 ml. of phenylhydrazine are re?uxed under ni
trogen in 1.2 ml. of absolute ethanol for 50 minutes.
The reaction mixture is taken to dryness. Water is added
and the product is ?ltered to give an amorphous solid,
which is washed successively with water, dilute acid,
water, and petroleum ether. The product is crystallized
from methanol to give 3-(1"-phenyl-[3”,2"-c]pyrazolo
acid lactam or 3-oxo-4,6-androstadiene-l7-spiro-2'-(1’
2’ ) ?- 1 ’-acetylpyrrolidene.
EXAMPLE 14
To 10 ml. of freshly distilled thioacetic acid there is 45 l7'5-amino-4'~androstene-17’a-yl)propionic ‘acid lactam.
added 150 mg. of 3-(3'-0xo-17’?-amino-4’,6'-androsta
In accordance with the above procedure, but starting
diene-17’a-yl)-propionic :acid lactam. This solution is
with the 3 - (2' - hydroxymethylene-3'-oxo-l7',8-methyl
heated on the steam bath under nitrogen for one-half
amino-4'-androstene-17'a-yl)~propionic acid lactam, 2
hour ‘and excess thioacetic acid is blown off with nitro
hydroxymethylene-B-oxo-4<androstene-17-spiro-2’-( 1’-2’ ) ‘gen. The residue is taken up in ethyl acetate and Washed 50 B-Y-aCetylp'yrrolidene in place of the 3-(2'-hydroxymeth
with sodium bicarbonate and water. Removal of the
ylene-3’-oxo-l7'?-am?no—4'-andros>tene-17'a-yl)-propionie
dried solvent and trituration with methanol gives 50 mg.
of
acid lactam there is obtained the corresponding 3-([3',
3-(7'ot - acetylthio - 3’ - oxo-17',6-amino-4’-androstene—
17’a-yl)-propionic acid lactam, M.P. 244—8° C., U.V.
Amx 238, E %440.
In accordance with the above procedure, but starting
with the 3-(3'-oxo-17’?-methylamino-4'-6’-androstadiene
2’-c]Pyrazolo-17'?-methylamino-4’-androstene-17’a - yl)
propionic acid lactam or [3",2”-c]pyrazolo-4-androstene
55
17-spiro-2'-(1’-2’)B-Y-acetylpyrrolidene, or the 1”-phen'~
yl-derivatives thereof.
Various changes and modi?cations may be made in car
17'a-yl)-propionic acid lactam or the 3-oxo-4,6-andro
rying out the present invention without departing from
stadiene—17-spiro-2'-(1'-2')-;8-1’-acetylpyrrolidene in place
of the 3-(3'—oxo-17'[3-amino-4’,6’-androstadiene-17’oa-yl) 60 the spirit and scope thereof. Insofar as these changes
and modi?cations are within the purview of the annexed
propionic acid lactam there is obtained the corresponding
claims, they are to be considered as part of our invention.
3 - (7’ - 0o - acetylthio-3'-oxo-17'B—methylamino-4’»andro
We claim:
stene-17'a-yl)~propionic acid lactam or 7u-acetylthio-3
1. A compound of the formula—
oxo-4 ~androstene -17 - spiro - 2' - (1' - 2’)? - 1’ - acet
ylpyrroliden'e.
_
~
65
EXAMPLE 15
A suspension of 61-0 mg. of 3-(3’-oxo—17’B-amino-4'
androstene-17'wyl)-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 70
about 54% sodium hydride in mineral oil at room tem
perature for 19 hours. Stirring is continued for 2 more
hours after the addition of 1 m1. 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 75
3,094,521
13
14
5. 2 - hydroxymethylene - 3-oXo-4-androstene-17-spiro
R1 is selected from the group consisting of hydrogen
and alkanoyl of less than nine carbons,
R2 is selected from the group consisting of hydrogen
‘and lower alkancylthio,
R3 is selected from the group consisting of ?-hydroxyl,
keto and, together with R4, pyrazolo in which one
2'-( 1'-2’) ?-Y-acetylpyrrolidine.
7. 3B - hydroxy - 5 - androstene-17-spiro-2’-(l’-2’)?—
pyrrolidine.
8. 3-oxo-4-androstene- 17 -spiro-2’-( 1’-2’ ) ?-pyrrolidine.
of the nitrogen carries a substituent selected from
9.v 3B - acyloxy - S-androstene-l7-spiro-2'-(1'-2’)B-1'
the group consisting of hydrogen, alkyl, cyclohexyl,
acylpyrrolidine.
phenyl, halophenyl, tolyl, alkoxyphenyl, nitrophenyl,
naphthyl, pyridyl, oxidopyridyl, pyrimidyl, benzyl
10. 3,8 - hydroxy-S-androstene-l7-spiro-2’~(l’-2');3-1’
acylpyrrolidine.
and phenylethyl,
11. 3 - oxo - 4-androstene—17-spiro-2’-(1'-2’)[3-1'-acy1
R4 is selected from the group consisting of hydrogen
and, together with R3, pyrazolo ‘of the above de
pyrrolidine.
12. The process for the preparation of 3?-hydroXy-5
androstene-l7-spiro-2'-(1’-2’);8~pyrrolidine which com
scription, and
the dotted line between carbons 1 and 2 and 6 and 7
indicates that the bonds joining these carbons is
selected from the group consisting of single and
double bonds, only one of said bonds being a double
prises redncing 3-(3',B=hydroxy-17'5-amin0-5’~androstene
17’u-y1-)-propionic Iacid lactam with lithium aluminum
hydride.
13. The process for the preparation of 3B~hydroxy~5~
bond,
in which at least one of R2 and R4 is other than 20 ‘androstene - 17-spiro-2’—(1'-2’),B-Y-acylpyrrolidine which
comprises heating an aqueous solution of S?-acyloxy-S
androstene-17-spiro-2'-(1'-2')B-Y-acylpyrrolidine and an
alkali metal bicarbonate.
hydrogen.
2. 3 - oXo - 1,4-androstadiene-17-spiro-2’-(1'-2')?-1’
acetylpyrrolidine.
3. 3 - 0X0 - 4,6-androstadiene-17-spiro-2’-(1’-2’)18-1'
acetylpyrrolidine.
4. 7oz - alkanoylthio - 3-oxo-4-androstene-17-spiro-2’
(1'-2’)5-1’-acylpyrrolicline.
25
References Cited in the ?le of this patent
UNITED STATES PATENTS
3,001,986
Burtner et a1. ________ __ Sept. 26, 1961
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