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Патент USA US3092638

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United States Patent 0
3,092,628
Patented June 4, 1953
1
2
and
3,092,628
ALDOSTERONE ANTAGONISTS
Arthur E. Oberster, Garwood, Roger E. Beyler, West?eld,
and Lewis H. Sarett, Princeton, NJ., assignors to Merck
& Co., Inc., Rahway, N.J., a corporation of New Jersey
No Drawing. Filed May 29, 1959, Ser. No. 816,693
1 Claim. (Cl. 260-23957)
CH3
This invention relates to steroids having aldosterone
antagonist activity, to intermediates prepared in the forma 10
0
tion of the same, and to processes for making the novel ' '
aldosterone antagonists.
Aldosterone is a powerful agent for maintaining elec
0_
trolyte balance in adrenalectomized patients and in pa
tients su?ering ‘from adrenal hypofunction. .Aldosterone 15 where R2 is as previously de?ned. These compounds are
promotes water retention and retention of sodium and
also especially useful in forming 9a-ha1o compounds of
chloride ions and tends to promote excretion of potas
this invention.
sium. Over-secretion of aldosterone can threfore be seen
The process of this invention may he illustrated with
to cause electrolyte imbalance. It is therefore necessary
respect to the ‘formation of 3-(17?-hydroxy-l6u-methy1
in those cases to administer an aldosterone antagonist in 20
order to restore the balance. ‘
The aldosterone antagonist compounds ofthis invention
' .
3,11-dioxo-4-androsten-l7a-yl)propionic acid gamma-lac
tone from 3a,17u-dihydroXy-1Ga-methyl-I1,20-pregnane
dione. This process proceeds according to the ?ow sheet
have a general formula selected from the group consist.
below:
ing of
CH3
25
CH3
(5:0
I
0
ll
C
6 ‘FE:
"""CHg
NWRZ
30
H5100
HO
I
35
O.
and
CH3
40
0
H
9
I
0 EH:
R1/\
0%/E
with
MR,
OH
45
I o-Al?igf
50
X
0_
-
where R1 is selected from the group consisting of ?-hy
.00 x
7
‘
droxyl and 70x0, R2 is a lower alkyl radical, and X is se
III
on
Imago-o 0 on
lected from the group consisting of hydrogen ?uorine, 55
Ito-1A: Ton,
chlorine and bromine.
Other novel aldosterone ‘antagonists have a ‘general ton
mula of the group consisting of
.
CH;
60
65
70
Q
HO
‘
Hi
r.
3,092,628
4
This reaction can also be carried
.out using lithium and ammonia in lieu of hydrogen in
'
gamma-lactone '(V) .
the presence of a catalyst.
-
The compound 3-(3a,l1p,17B-t1'ihydroxy-1Got-methyl
etiocholan-lh-yDpropionic acid gamma-lactone (V) is
oxidized with chromium trioxide to form 3-( 17 ?-hydroxy
16¢ a‘ methyl - 3,11 - dioxoetiocholan - 17o: - yl)propionvic
{acid gamma-lactone (VI).
7
'
'
, _, _'
The compound 3-(17?-hy ’ oxy-16u-methyl-3,1‘1#dioxo¢
10
etiocholan117a-yl)propionie acid gamma-lactone (V1) is
reacted with one mole of bromine to form 3~(4-bromo
175 - hydroxy - 16a - methyl - 3,11 - dioxoetiocholan
':17a-y1)propi'onicacid gammadactone (VI‘I). Reach'on of
this compound with semicarbazide results inthe tor-ma;
15 tion .1 of," 3 ; (17B - hydroxy 4160: - methyl - ‘1'1 - oxo'-l3
semicarbazido-4-androsten-17a-yl);propionic acidi gam~
ma-lactone ’ ('VI'I-I)." Removal of the _i 3-semicarbazride
group can be accomplished by means such as hydrolysis
in an aqueous mixture of pyruvic acid and acetic acid,
20
thereby forming thewaldosterone ‘antagonist 3-‘(17p-hy-.
droxy - 160:. - methyl - 3,11 - dioxo- 4 ‘- androsten --17a
yl)propionic acid gamma-laetone (IX) .
'
-
‘ The aldosterone antagonist 3-(1~15,1713,dihydroxy-16¢
__
25
methyl 3 3 - oxo - 4 - androsten - 17a -' y1)propionic acid
gamma-lactone (XI) can be prepared from 3-(l7?-hy
droxy -i'16’u‘-'methy1 -'11 - oxo - 3 - semicarbazido - 4-_
androsten-lh-ynpropionic acid gamma-lactone'. (VIII),
the preparation of which has been previously described,
9 i by reaction with sodium borohydride or other suitable re
30
ducing agent, thereby ‘forming 3-'(l1}3,17?-dihydroxy-16u- f
methyl - 3 - semicarbazido - 4 - androsten - 17a - yl)pro-.
pionic acid gamma-lactone (X) which is hydrolyzed, for
example with pyruvic acid in aqueous acetic acid, to form
3 - (1119,1713 - dihyd-roxfy -. 16oz - methyl - 3 - oxo-4-andro
35
sten-17a-yl)propionic acid' gamma-lactone (X[). This
conversion is illustrated as follows:
CH;
0
0H,
l
The starting material 3a,_17qsdihydroxyél'6a-methyl
11,20-pregnanedione (I) is reacted" with periodic acid
45
’
HzNO0NHN_
‘ O=(|J—CH:
’,
o
H,
3a-hydroxy-16a-methyl-11,17-etiocholanedione (H) is re
covered from the reaction mixture by-extraction with ethyl 50
acetane followed by chromatography on a suitable ad
sorbent such as alumina. ‘7 This compound is reacted with
no
acetylenemagnesium bromide in tetrahydrofuran :to form
'
I 01130000011
55
lanone
The acetylenemagnesium' bromide, which has
the formula HC-zOMgBr, is prepared by ?rst making
ethylmagnesium bromide according to the conventional
in tetrahydrofuran, and then adding the ethylmagnesium
bromide solution to a saturated solution of ‘acetylene in
Torr,
‘
a Grignardgcompl'ex, which is hydrolyzed to form 170:
procedure of adding excess ethyl bromide to magnesium
NaBH4
——-->
vrn
in aqueous methanol at room temperature. The product
ethynyl - 30:,173 - dihydroxy - 1611; methyl - 1_1.- etiocho
‘
.
____.____,
HaNCONHN_
o=o—0m.
l
0
..
‘on,
CH!
tetrahydrofuran. The 3m-hydroxy4'16bt-methyl-11,17-etio
cholanedione (VII) in tetrahydrofuran is; added to the acet
ylenemagnesium bromide solutionland.‘acetylenegis there
after continuously bubbled into ‘the’ solution. When the 65
reaction is complete, the acetylene is stopped, water is
added, and the mixture after ?ltration is extracted with
ethyl acetate to recover-the product.
,
(
(Q
XI
The Qa-?LIOIO compounds of the present invention may
be formed according tothe following sequence of re
The product 17a-etl1ynyl-3a,17?-dihydroxy-16u—methy1
'
1,
1 l-etiocholanone (-111) ‘of the; previous "step is reacted with 70 actions:
The compound 3:(11,9,17l3-dihydroxy-16a-methyl-3
ethylmagnesium bromide, followed by carbon dioxide to
oxo-4-androsten-17a-yl)propionic .acid gamma-lactone
torm '3 - (311,115,175 itrihydroxy {16a - methyl - etio
cholandh-yD-Z-propynoic acid '(IV). This compound
q (X1) is reacted with methanesulfonyl chloride or p-toluene
is catalytically ‘hydrogenated to form 3-(73a,11}3,17,8-tri~
l- sulfonyl chloride to form 3-[l7?-hyd-roxy-l6a-methyl-3
hydroxy - 16a - methyletiocholal'r-v 1-71» :yl) propionic acid 75 0x0 - 4,9(11) — androstadien’ {117a - yl]propionic acid
3,092,628
5
gamma-lactone (XII), which is reacted with a reagent
which furnishes hypobromous acid in solution, ‘as for ex
ample N-bromosuccinimide, thereby forming 3-(9a-b1'0
mo - 115,175 - dihydroxy - 16a - methyl - 3 - oxo - 4
androsten-17a-yl)propionic ‘acid gamma-lactone (XIII).
Reaction of this compound with an alkaline reagent such
5
as potassium carbonate yields 3-(9?,11?-epoxy-17B-hy
droxy - 16¢ - methyl - 3 - oxo - 4 - androsten - 17a - yl)
propionic acid gamma-lactone (XIV). This compound,
when reacted with hydro?uoric or hydrochloric acid, 10
yields 3-(9a-?l101‘0-1 1p,17,8-dihydroxy-16a-methyl-3-oxo
XVI
4-androsten-17a-yl) propionic acid gamma-lactone (XV),
The 9oz-Ohl01‘0 compounds ‘are made in the same way,
or 3 - (90c - chloro - 115,175 - dihydroxy - 16oz -methyl-3~
substituting hydrogen chloride for hydrogen ?uoride in
oxo-4-androsten-17a-yl)propionic acid gamma-‘lactone re
the reaction with the 9,11~epoxy compound (XIV).
Aldosterone antagonists having the 1,4-conjugated diene
spectively, which are novel active aldosterone antagonists. 15
These compounds can be oxidized with chromic anhydride
structure in the A-ring can also be prepared according to
to form 3-(9a-?uoro-17,8;hydroxy-16a-rnethyl-3,1l-dioxo
this invention. For example 3-(17B-hydroxy-16a-methyl
4-androsten-17u-yl)pr0pionic acid gamma-lactone (XVI),
and
3,11~dioxo-4-androsten-17a-y1)prop-ionic acid gamma-lac
3-(9a-chloro-17B-hydroxy-16u-methyl-3, 1 1-diOXO-4
tone (IX') can be dehydrogenated at the 1 and 2 positions
androsten-17a-yl)-propionic acid galrnna-lactone respec 20 by various known means such as reaction with selenium
dioxide or microbial dehydrogenation with microorgan
tively, which are also novel taldosterone antagonists.
isms of the species Bacillus sphaericus, thereby a?ording
the novel aldosterone ‘antagonist 3-(17B-hydroxy-16a
methyl-3,1 l-dioxo-l ,4-androstadien-17a-yl) propionic acid
Preparation of the 9ad?uoro compounds may he illus
trated as follows:
25 gamma-lactone (XVII), which can be reduced if desired
O=C—-CHg
with an equivalent quantity of sodium horohydride to 3
O X'ZH:
no
(11?,l7,3 - dihydroxy - 16oz - methyl - 3 - 0X0 - 1,4
androstadien - 17oz - yl)propionic
CH3
acid
gamma-lactone
(XVIII). This transformation is indicated by the vfollow
ing equation:
0:
cl
CHsSOzCl
o=('3——0H1
——>
O
I
0=o—oH,
H:
O
'
H7
XI
O
,
H/\
o'—/\
35
O=C—CH2
“0H3
'
H:
on,
o:
o=l/\
-on.
l
Nan]:
0_,
IX
.
O
‘Q’
_
(cnaconnnr
0=o—0rr,
——-—->
XII
0
HO
O ‘41H:
I
O=C—.CH2
\,
XVII
45
HO
CH:
éH:
time
Q XVIII
O_ . i
The corresponding 9a-?uoro compounds, i.e. 3-(‘901
?uoro-l7B-hydroxy - 16a - methyl-3,1l-dioxo-lA-androsfj
55
tadien-17a-yl)propionic acid gamma-lactone ‘and 3—.(9a-.‘
?uoro - =1 15,175 - dihydroxy-16u-methyl-3 -oXo-1,4-andros—
tadien-17a-yl)propionic acid gamma-lactone can be
formed in the same way from 3-(9a-?uoro-17B-hydroxy
16a-methyl-3,11-dioXo-4eandrosten-17a-yl_)propionic acid
60 gamma-lactone (XVI).
Y
' The ‘foregoing equations and reagents represent pre
ferred embodiments of the invention for formation of
novel compounds of the 16a-1ower alkyl series. Other re
agents than those indicated may be used as is evident from
65
the foregoing portion of the speci?cation. Lower alkyl
substituents other than methyl rat the 16lX-POSIIIOI1 may
also be introduced as will be evident to those skilled in the
art.
.
In addition to the 16a-methyl compounds illustrated
70
above, 165-lower alkyl compounds and particularly 16B
methyl compounds can be formed according to this inven
tion using the procedures illustrated in the foregoing equa
tions starting with 3a,l7a-dihydroxy-l6/8-methyl-l1,20
pregnane-dione, which is the 16?-methyl epimer of com
75 pound I. Novel aldosterone antagonists which ‘can he thus
£3,092,628
8
sis solution in vacuo, and the residual oil is extracted from
‘formed include 3-( l7p-hydroxy-16B-methyl-3,l1-dioxo-4
the resulting aqueous solution with’ chloroform. The
androsten-17a-yl)propionic acid gamma-lactone, 3-(11/3,
chloroform extract is washed with water to neutrality,
l7?fr-dihydroxy - 16,8 - methyl-3-oxo-4-androsten-17u-yl)
dried, and the chloroform isv evaporatednnder reduced
propionic acid gamma-lactone, 3-(9a-?uO1'O-11B,17?~dih¥
pressure. The residual oil is triturated with ether, and the
droxy-16/8-methyl’3-oxo-4-androsten - 17oz - yl)propionic
crystalline material thus formed is recrystallized from
ethyl acetate-petroleum ether to give 3u,17u-dihydroxy
acid gamma-lactone, 3~(9a-?uoro¢17/S-hydroxy-16?-meth
yl-3,11-dioxo-4~androsten-17a-yl)propionic acid gamma
lactone, 3-(17t3~hydroxy-1618-methyl - 3,11 - dioxo-l,4-an
16a-methyl-1LZO-pregnanedione (I).
..
v
.
~
'
.
The 16-lower alkyl homologs of (I) can be prepared
17?-dihydroxy g 165 - methyl-3-oxo-1,4-androstadien-17a 10' by substituting the appropriate lower alkyl iodide for
methyl iodide in the above procedure.
;
yl)propionic acid gamma-lactone, 3-(9a-?uoro-11B,17?
_ The starting material 3a,17a-dihydroxy-16B-methyl¢l1,
dihydroxy-16p-m'ethyl-3-oxo - 1,4 - androstadien-17a-yl)
20~pregnanedione can also be prepared from the known
propionic acid ‘gamma-lactone, 3-(9a-?uoro-l7?-hydroxy
compound 3a-acetoxy-16-pregnene-11,20-dione. A- pro<
16B - methyl-3,1l-dioxoelAaandrostadien - 17cc - yl) propi
drostadien-l7ot-yl)propionic acid gamma-lactone, 3-(115,
cedure for carrying out this synthesis is as follows:
In a 500 ml. three-necked ?ask equipped withcom
onic acid gamma-lactone, and the 16?-lower alkyl homo
logs thereof.
‘
denser, dropping funnel and nitrogen inlet are placed 20 g.
of potassium hydroxide in 90 ml. of water, 100 ml. of
methanol, and 100 ml. of ether. A solution of 10 g. of
known compound 3-acetoxy-16-pregnene-11,20-dione can
20 N-methyl-N-nitroso-p-toluenesulfonamide in 50 ml. of
be carried out as follows:
ether is placed in the dropping funnel. Diazomethane is
' A solution of 10.22 g. of methyl iodide in '50 ml. of
- The preparation of the starting material 3a,17a-'dihy
droxy-l6a-methyl - 11,20 - pregnanedione v(I) from the
generated by warming the ?ask to 40° to 45° C. and con- I
ether is added to 1.73 g. of magnesium in 50 m1. of ether.
tinuously adding the N-methyl-N-nitroso-p-toluenesulfon7
To the resulting ethereal solution of methyl magnesium
amide solution from the dropping tunnel. Nitrogen is uti
iodide, maintained under a nitrogen atmosphere, is added
0.045 g. of anhydrous cuprous chloride. To this mixture 25 lized to sweep the diazomethane into a solution of 20 g.
isadded, over a period of about one hour, during which
i of 3u-acetoxy-l6-pregnene-11,20-dione in 100 ml. of tetra
hydrofuran and 120 ml. of ether. The'process is con
period the reaction mixture is stirred vigorously’ and main
tinued until the steroid solution remains‘yellowrfor sev
eral hours. The product, 3a~acetoxy-l6oc,Not-methylene
about 5.6 g. of 3-acetoxy-16-pregnene-11,20-dione in 175
m1. of ether. A white granular solid separates during this 301 azo-11,20-pregnanedione, largely precipitates from the re
action mixture. After 16 hours the mixture isf?ltered,
addition. The resulting mixture isheated under gentle
washed with ether and dried‘ in air; M.P. 1862190“, C.
re?ux for two hours after which the reaction mixture is
cooled,_ and 125 ml. of saturated aqueous ammonium
Diazoethane, diazopropane, or the like is substituted in
chloridejsolution is added followed by 200 m1. of ether.
The layers'are separated, and the ethereal layer is washed 35; the above step for diazomethanewhere a l6?-lower alkyl
homolog of 3u-acetoxy416p-methyl-11,20-pregnanedione
with three 50 ml. portions of water. The washed ethereal
is to be produced.
.1
_ ,
layer is dried, andthe solvent evaporated in vacuo to give
Into a 500 ml. round-bottomed ?ask heated by an oil
. a brown viscous oil. This oil, which is essentially 3a-hy
bath is placed 37.4 g. of 3a-acetoxy-16u,Una-methylene
droxy-l6a-methyl-11,20-pregnanedione, is heated for '15
minutes at 609-70“ C. with a mixture of 25 ml.- of pyrié 40. razo-l1,20-pregnanedione. A manometer and a 12-1iter,
tained at approximately room temperature; a solution of
(decomposes).
' '
'
‘
surge ?ask are in the line between the reaction ?ask and
the vacuum pump ‘trap. The ?ask contents are heated in
vacuo atan initial pressure of 0.6 mm. until the bath tem-_
perature reaches 180° C. The maximum pressure de
veloped is about 83 mm. After 10 minutes at 180° to
dine and'acetic anhydride. The acetylated product is puri
?ed-by chromatography on acid-washed alumina followed
by crystallization from petroleum ether to give approxi
mately 1.5g. of substantially pure 3-acetoxy-16m-methy1
1 1,20-pregnanedione.
182° C. the melt is cooled. ' The product, which has
~‘A v‘solution of 22 g. of 3oc~acetoxy-l6a-methyl-l1,20
pregnanedione and 1 g. of p-toluene sulfonic acid in 250
ml. of acetic anhydride is heated at re?ux under nitrogen
for a period of approximately three days. Two grams of
xggaP? 249, E% 191
is taken up in about 150ml; of acetone, ?ltered through
anhydrous potassium acetate is added, and the volatile 50, diatomaceous earth and concentrated to about 100 ml.
while ether is slowly added to the boiling solution until
solvents are separated by distillation in vacuo. The resid
crystallization occurs. These crystals were 3u-acetoxy-16
ual material is extracted with benzene, and the benzene
rnethyl-lG-pregnene-l1,20-dione;= M.P. 165° to 167° C.,
extract is ?ltered to remove insoluble material. The ben
zene extracts are evaporated to a volume of 100 ml. and
(0.)?“ +75". xiii.“ 249’ Ea 930°
petroleum ether is added to the cloud point. The result 55,
ing solution is adsorbed on 660 g. of acid-washed alumina,
To a solution of 200 mg. of '3a-acetoxy-16-methyl-16
the alumina adsorbate is then washed with 2 liters of pe
pregnene-l1,20-dione in 20 ml. of methanol is ‘added 200
troleum ether. The adsorbate is then eluted with'85 :15
mg. of 25% palladium on a calcium carbonate catalyst.
petroleum ether-ether mixture, and the ?rst four liters of
The mixture is stirred in hydrogen at atmospheric pres
elute is collected, and evaporated tordryness in vacuo to 60 sure and a temperature of 25° C. untilhydrogen uptake is
give a mixture of enol acetates containing 3a,20-diacetoxy
complete. The mixtureis ?ltered, the ?ltrate evaporated
16a-methyl-1’7(20)-pregnene-1l-one. This mixture of,
to dryness, and the residue crystallized to form ether-hex
enolates, weighing approximately 14 g., is dissolved in 50
ane to give needles of pure 3a-acetoxy-16?-methyL11,20
ml. of benzene and treated with an ‘excess of perbenzoic
pregnanedione; M.P. 160° to163° C.‘,
acid, over a 16-hour period. The reaction mixture is, 65
shaken with dilute aqueous potassium hydroxide solution“
until the benzene layer is free of perbenzoic acid; the_ben-.
zene layer is then washed with water until neutral, dried;
and the solvent evaporated in vacuo to give a'crystalline
material, 3oz,21-diacetoxy - 170:,20 -' epoxy-16m-methylr1L
The latter material is dissolved, without»
puri?cation, in 200 ml. of methanol, 120 ml. of‘water,
and 1,0 g. of potassium bicarbonate; and the resulting so‘-v
lution is heated, at re?ux under nitrogen for a period of
pregnanone.
16 hou_rs.- The methanol is evaporated from the hydroly-f
.
To a stirred solution of 1.63 g. of 3a-acetoxy-16?-meth
yl-11,20-pregnanedione in5ml. of chloroform and 25 ml.
of carbon tetrachloride cooled to 0°~
. C(is added a mixture
' of 2.60 ml. of cold acetic anhydride and 0.13 ml. of 60%
70‘
perchloric acid. This mixture is held at 25° C. ‘for two
hours and then at 0° C. for 17 hours, and then is suc
cessively washed‘with cold 5% aqueous sodium carbonate
and cold water, and dried over sodium sulfate. The sol
3,092,628
9
10
vents are removed in vacuo, leaving a colorless residue
3oz, 17,8-dihydroxy-16a-methyl - 11 - etiocholanone (IH).
of 3a,20-diacetoxy-l65-methyl-17 (20) pregnene-l l-one;
Mm, 5.75, 5.85, 8.0;;
M.P. 244°—247° C.
To 1.86 g. of 3a,20-diacetoxy-16?~methyl-l7(20)-preg
Analysis-Calculated: C, 76.70%; H, 9.36%. Found:
C, 76.44%; H, 9.11%.
nene-l l-one and 3 ml. of vbenzene is added 25 ml. of 2.5
M perbenzoic acid in benzene. After 16 hours at 25° C.
uptake of perbenzoic acid is complete. Additional ben
EXAMPLE 3
zene and ether are added, and the mixture washed with
3-(30:,11,3,17,8-Trihydroxy-16a-Methyletiocholanh
aqueous sodium sul?te, sodium carbonate, and water.
The organic layer is dried over sodium sulfate and taken
17a-Yl) -2-Propynoic Acid
-
T060 g. of magnesium in 400 ml. of tetrahydrofuran
was added ethyl bromide until all the magnesium was
consumed. A solution of 4 ‘g. of 17a-ethynyl-3u,17[3
to dryness to yield 3a,20-diacetoxy-l7,20-epoxy-l65
methyl-l l-pregnanone. This compound is dissolved in 70
ml. of ethanol, and 1.20 g. of sodium hydroxide in 35 ml.
dihydroxy-16u-methyl-1l-etiocholanone (III) in 50 ml. of
of Water is added. After two hours at 25° C., 4 ml. of 15
tetrahydrofuran
was added. The mixture was re?uxed
acetic acid is added and the mixture concentrated to a
small volume in vacuo. Chloroform and water are added.
for 40 minutes and stirred at room temperature ‘for an
The chloroform layer is washed with aqueous potassium
bicarbonate, saturated with sodium chloride, and dried
through the reaction mixture overnight. The tetrahydro~
and benzene-ethyl acetate give pure 3a,17a-dihydroxy
16,8-methyl-11,20-prepnanedione; M.P. 192° to 197° C.;
reagent. The aqueous solution was extracted with ethyl
additional hour.
Dry carbon dioxide was bubbled
over magnesium sulfate. Removal of the solvents in 20 furan was blown oil with a strong stream of carbon
dioxide, and Water was added to decompose the Grignard
vacuo and successive crystallization from acetone-ether
Analysis-Found: C, 72.97; H, 9.95.
This invention will now be described in detail with ref
erence to speci?c ‘examples thereof:
EXAMPLE 1
3a-Hydr0xy-1 6oc-Methyl-1 1,1 7-Eti0ch0lanedione
acetate and the aqueous layer was treated with 2.5 N
hydrochloric acid until acidic. The acidic aqueous solu
tion was extracted four times with benzene, and the ben
25 zene extract was washed with water until neutral and then
discarded. The wash water was combined with the ‘acidic
aqueous solution, which was extracted twice with ethyl
acetate. The ethyl acetate was washed with water until
neutral and dried over anhydrous sodium sulfate and
30 concentrated to dryness. The product obtained ‘was 3
(3u,11/3,17/8-trihydroxy - 16a-methyletiocholan-l7a-yl) -2
propynoic acid (IV). The product was recrystallized
To 2 g. of 3a,l7a,dihydroxy-l6u-methyl-l1,20-preg
from ether. M.P. 198°-211°C. (decomposes).
nanedione' (I) in'40 ml. of methanol is added 5.9 g. of
periodic acid, H5106, in 4.8 ml. of water. The resulting
A2321 2.81;, 4.40% 5.84;‘; Ailgphuline 2.81”, 450p, 6.35;;
homogeneous solution was allowed to stand 65 hours at 35
room temperature. The reaction mixture was worked up
These infra-red spectra indicate that reduction took place
by adding water and extracting twice with ethyl acetate.
at the 11 position.
The ethyl acetate extract was washed with aqueous so
Analysis-Calculated: C, 70.74%; H, 8.78%.
dium bicarbonate and then with water until neutral and
dried over anhydrous sodium sulfate. The crude product 40 served: C, 70.33%; H, 8.67%.
weighed 1.767 g. This product was chromatographed on
EXAMPLE 4
a column of acid-washed alumina. The column was
eluted with ether-chloroform mixtures starting with pure
chloroform and increasing the amount of ether in incre
ments of 10% of the total mixture. The product 3a-hy 45
The 3-( 3a, 111 5,17B-trihydroxy - 16a - methyletiocholan
droxy-16a-methy1-11,17-etiocholanedione (II) was recov
ered from the fractions containing 80% chloroform and
20% ether. The product was recrystallized from ether
methylene chloride. M.P. 159 °—l62° C.;
1515813 2.8, 5.69, 5.81,.
17a-yl)-2-propynoic acid (IV), obtained in Example 3,
was dissolved in 160 ml. of methanol and catalytically
hydrogenated at a pressure of 40 lbs. per square inch in
the presence of 1.6 g. of palladium oxide catalyst. The
50
reaction product was ?ltered and concentrated. Upon
the addition of ether the product 3~(3a,l1,B,17/9-trihy
droxy-1Ga-methyletiocholan-17u-yl)propionic acid gam
AnaIysis.—-Calculated: C, 75.43%; H, 9.50%. Found:
C, 75.00%; H, 9.40%.
EXAMPLE 2
ma-lactone (V) was obtained.
55
This compound has a
double melting point at l40°-142° C. and i195°-l98° C.
l 7a-EthynyZ-3a,1 7B-Dihydroxy-J 6oc-Methyl
1 1 -Eti0cholanone
' Analysis-Calculated: c, 73.36% H, 9.64%. Ob
To 1.02 g. of magnesium in 24 ml. of tetrahydrofuran
served: C, 72.83%; H, 9.59%.
was added excess ethyl bromide until all the magnesium 60
disappeared. The ethylmagnesium bromide was trans
EXAMPLE 5
ferred under pressure in a nitrogen atmosphere to a drop
3-(] 7?-Hydroxy-1 6u-Methyl-3,1 1 -Di0x0eti0cholan-1 7a
ping funnel and was added dropwise over a two~hour pe
Yl) Propionic Acid Gamma-Lactone
_ "
riod to 30 ml. of tetrahydrofuran saturated with acetylene.
To this solution was added 300 mg. of 3a-hydroxy-l6a 65
To 100 mg. of 3-(3a,11/3,l7B-trihydroxy-16a~methyl
methyl-l1,17-etiocho1anedione (H) in 5 ml. of tetrahy
drofuran over a 20-minute period. Acetylene was contin
uously bubbled through the solution overnight. Water
was added until a gelatinous precipitate appeared. The
etiocholan-l7u-yl)propionic acid gamma-lactone (V) in
1.6 ml. in glacial acetic acid was added 100 mg. of chromic
anhydride in 3.0 ml. of 90% acetic acid. The reaction
mixture was stirred for 80 minutes at room temperature.
mixture was ?ltered through “Supercel” (diatomaceous 70 The reaction mixture was diluted with four volumes .of
earth) and the ?ltrate was extracted with ethyl acetate.
water and the solution
extracted with ethyl acetate.
The ethyl acetate extract was washed with water until
neutral, dried over anhydrous sodium sulfate ‘and concen
The ethyl acetate extract was washed with sodium bi
carbonate and then with water until neutral, dried over
trated. A crude product weighing 320 mg. wasobtained.
anhydrous sodium sulfate, ‘and concentrated to obtain the
Recrystallization from acetone yielded pure 17a-ethynyl 75 product 3-( 1718 - hydroxy - 16a - methyl — 3,11-dioxoetio-.
3,092,628.
11
cholan --17 a ‘- yl)propionic
acid 7 gamma'lactone
12
is ‘added, with stirring,‘ 60 mg. of sodium borohydride;
(VI);
The reaction mixture was stirred at room temperature ‘for
16 hours. Dilutehydrochloric acid was added until the
solution was slightly acid.
The resultant solution was
extracted with ethyl acetate, and the extracts washed with
water, dried and evaporated under reduced pressure.’ The
resulting residue was taken up'in methanol and concené
trated. Methylene chloride and ether were added; and
.= Analysis.-—Calculated:j C,j74,1_6%; H, 8.66%‘. Found:
C, 73.52%; H, 8.75%.
'
‘
‘
‘
EXAMPLE 6
3 -(4jBr0_mo-1‘7?-Hydroxy-l 6oz-Methy [-3 ,1 1 -D ioxoezfio
ch olane-I 7a-Yl ) Propionic Acid Gamma-Lactone
the product 3-(1118,17ft-hydroxy-16a-methyl-3-semicar;
bazido-4-androsten-17u-yl)propionic acid gamma-lactone
(X) precipitated ‘out and collected. M.P. 250°~280° .C.
. To 90 mg. of 3-(17/8-hydroxy-16a-methyl—3,-l'1-dioxo
etiocholan-17u-yl)propionic acid gamma-lactone (V),
dissolved in 3 m1. of dimethylformamide was added 2.2
ml. of a solution containing 18 mg. of bromine permilli
liter ofdimethylformamide, and about 5 mg. of p-toluene
(decomposes) ;
15,’
sulfonic. acid. The solution was allowed to stand at
room temperature until the bromine color disappeared,
which required about three and one-half hours. The re
action mixture was then diluted with 40 m1. of ether and
extracted with four 10-ml. portions of water. The ether
solution was then dried and then evaporated. The prod
i
'
EXAMPLE l0
3-(1113,]7a-Dihydroxy-16a-Methyl-3-Ox0-4-Andrasten; V
Y
17oc-Yl) Propionic Acid Gamma-Lactonc
One hundred and forty-?ve milligrams of 3-(115, 17B
dihydroxy-l6aémethyl-3-semicarbazido - 4-a'ndrosten-l7a
uct, 3-(4 - bromo - 17B - hydroxy - 16a-methyl-3,l1-dioxo
yl)-propionic acid gamma-lactone (X), 1.5 ml. of 98%‘
pyruvic acid, 1.5 ml. of glacial aceticacid, and 1.5 ml.
etiochol-an-17 a-yl)propionic acid gamma-lactone' (VII),
was: crystallized from methylenechloride-ether. M.P.
of water are mixed at room temperature- The reaction
mixture allowed to stand at room temperature for 16
240°~245° C. (decomposes).
-
25. hours, diluted with about 30ml. of water, and extracted
with ethyl acetate. The extracts were washed with satu
rated sodium'bicarbon-ate solution and water and dried
EXAMPLE 7
3-(i7?-Hydroxy-16a-Methyl-1I-Oxo-d-Semicarbazido-li
over sodium sulfate. Removal of the solvent resulted in
crystallization of 3-(11B,17a-dihydroxy-l6a-methyl-3
’ Androsten-l 7u-Yl)Pr0pionic Acid Gamma-Lactone
oxo-4-androsten-17a-yl)propionic acid gamma-lactone '
30
r fFifty milligrams of 3-(4-bromoa17?-hydroxy-17a
(X[); 'The ‘product is' recrystallized from methylene‘
methyl-3,11-dioxoetiocholan-17a-yl)propionic acid gam
chloride-ether.
ma-l'actone (VIII), 11 mg. of semicarbazide hydrochlo
thoroughly in a ?ask which
purged with nitrogen. To
the mixture was added 1.5 ml. of dimethylformamide. 35
The solution turned yellow almostimmediately. The re
action mixture was stirred at room temperature for two
and one-half hours.
M.P. 251°—258° C.
1
-
_,
I
» r
. Analysis.—.-Calcula.ted f0]? »C23H3204I C,
ride and 19 ml. of semicarbazide free base were mixed
8.66%.
. diluted with about 20 ml. of water and extracted with 40
ethyl acetate. The ethyl ‘acetate extracts were washed
with water, dried over anhydrous sodium sulfate, and‘
H,‘
-
-
EXAMPLE '11
3[17B-HydroxyJ6a-Mcthyl<3-Oxo-4,9(11)Androsiadien-I
'
The reaction mixture was then
Observed: C, 74.21%; H.72%.
l7a-Yl]Propionic Acid Gamma-Lactone V
' To a, solution of 100 mg; of 3-(1lp,-17;8-dihydroxy-16a
methyl-3-oxo-4-androsten-l7a-yl)propionic acid gamma
lactone (XI) in 4.8 ml. of dimethylformamide was added
0.8
evaporated to dryness under reduced pressure. The prod
of pyridine and 0.4 ml. ‘of methanes‘ulfonyl chlo~
ride. The reaction mixture washeated at 80“ (to-85° C.
uct 34(17):? - hydroxy-l?a-methyl-l l-oxo-3-semicarbazido
for one hour. The solution became red in color ‘after
4-androsten-l7u-yl)propionic acid gamma-lactone (VIII)
was crystallized from methylene chloride-ether; M.P. 45 aboutv 15 minutes and almost black by the end of the
hour. The reaction mixture was poured into about 10_ ml.
245°-265° C. (decomposed);
of ice water, and extracted with ethyl acetate. The ex
tract was washed with water, dilute hydrochloric acid,
saturated aqueous sodium bicarbonate and water again,
50 and dried over anhydrous sodium sulfate. The solution
h2g5? 271 mIz;Em°125,200
EXAMPLE 8
i
1 3-(17?-Hydroxy-16a-Methyl-3,11-Di0xo-4-Androsten
'
H ;I7u-YZ)Propi0nic Acid Gamma-Lactone
; A solutionrof 40 mg. of 3-(17/8-hydroxy-16m-methyl
l‘1ioxo-3-semicarbazido-4-androsten - 17a - yl)propionic
was evaporated, leaving a red’ oil. This oil was acid
washed. alumina. 'Ihe alumina was elutedwithether and
the product 3- [ 17,8-hydroxy-16a-methyl-3-oxo-4,9(|1 1 ) -
androstadien-lh-yl]propionic acid gamma-lactone (XII)
acid gamma-lactone (VIH) in 0.5 ml. of pyruvic acid, 55 was crystallized from ether. M.P. 18l°~185° C. 'Re
peated recrystallization from ether yielded an analytical
0.5 ml. of acetic acid, and 0.5 ml. of water was prepared.
sample; M.P. 188° ‘to 191° C.;
The reaction mixture was allowed to stand at room tem
perature for 16 hours and then’ diluted with 20 ml. of
rggyH 239 my; Ema 16,700 _
water and extracted with- ethyl acetate. The extracts
were washed with water, sodiurrrbicarbonate solution 60 . Analysis.r—oalcul'aited for (3231-13003:
and again with wateryand dried over anhydrous sodium
sulfate. Evaporation under reduced pressure resulted in
35 mg. of crude product of 3-(l7?-hydroxy-l6u-methyl
3,11-dioxo-4-androsten-l7a-yl)propionic acid gamma-lac
tone (IX). ‘The crude product was recrystallized from 65
methylene chloride-ether.
>
M.P. 237°—244° C.;
‘ '
0, 77.93%, A H;
8.53%. Found: C, 78.18%; H, 8.46%.
EXAMPLE 12
' 3-(9a-Brom0-11BJ7I8-Dihydr0xy-16a-Methyl-3-0x0-4- ’
Androsten-I 7a-Yl )Propio'nic Acid Gamma-Lactone
» One hundred and forty milligrams of 3-[17l3-hydroxy
l 6a-methyl -’ 3-oxo-4,9 ( l 1 ) androstadien-17a-yl]propionic
238 m; Ema 13,400
3-(115,17?@Dihydroxy-16a-Methyl-3-Semicarbazid0-4
acid gamma-lactone (XII) was dissolved in '2 ml.v of
acetone and cooled with stirring to 0° C. To this solu;
tion were added 109mg. of N-bromosuccinimide and 0.4
i -_Andr0sten-1-7a~_Yl)PropionicrAcid Gamma-Lactone
ml. of aqueous perchloric acid, prepared by diluting 0.32
' To a solution of 150 mg. of 3.-(17?-hydroxy-16a-methyl.
ml. of 60% perchloric acid with 16 ml. of wate'r/ After
;
‘ I
EXAMPLE 9
-
11'-'oxo-.3'-semicarbazido - 4 - androsten-17a-yl) propionic
acid ‘gamma-lactone' (VIII) in 15 ml. of tetr'ahydrofuran,
about ?ve' minutes at 0° 'C. a precipitate formed int-he
reaction ?ask. Stirring was continuedat 0° C. for two
3,092,628
13
14
hours. The precipitate was separated by ?ltration, washed
to dryness. The product 3-(9a-?uoro-11,6,17B-dihydroxy_
with cold acetone and cold ether and dried. The crude
product weighed 116 mg. ‘and 'had a melting point of
202°—206° C. (decomposes). Extraction of the mother
16o: - methyl - 3 - oxo - 4-and-rosten-Hot-yl)propionic
liquors with methylene chloride, followed by evapora
tion yielded a second crop.
M.P. 201 °-205° C.
acid
gamma-‘lactone (XV) was taken up in Iacetone, concen
trated and crystallized out upon cooling. Yield 30 mg.
M.P. 298°—305° C. (decomposes). A sample was re
A
crystallized for analysis from acetone. M.P. 303 °—306°
C. (placed on Ko?er hot stage at 270° C.).
sample of the product 3-(9a-bromo-11B,=l7,8-dihydroxy
16a. - methyl, - 3-oxo-4-androsten-Hot-yl)propionic acid
ACHaOH
2,380; E...l 16,770
gamma-lactone (XHI) was recrystallized for analysis
max.
from acetone. M.P. 204°—206° C. (decomposes).
10
Analysis-Calculated for C23H31O4F: C, 70.75%; H,
8.00%; F, 4.86%. Found: C, 70.71%; H, 7.87%; F,
CHKOH
243 m,.; Ema 16,200
EX.
4.90%.
Analysis.—Calculated for C23H31O4Br: C, 61.20% ;H,
6.93%. Found: C, 61.27%;H, 6.92%.
EXAMPLE 13
EXAMPLE 15
15 3-(175 - Hydr0xy-16a - Methyl-3,11-Dioxo-1,4-Andr0sta
dien-17u-Yl)Pr0pi0nic Acid Gamma-Lactone
3- (9,8,1 16-Epoxy-J 7B-Hydr0xy-1 6 a-Methyl-3-Ox0-4
Androsteln-l 7a-Yl )Propionic Acid Gamma-Lactone
To a solution of 100 mg. ‘of 3-(1713-hydroxy-16a-meth
yl-3,'ll1~dioxo~4-andros-ten-l7a-yl)propionic acid gamma
lactone (IX) in 2 ml. of tert.-butanol are added 0.1 ml.
dihydroxy 416a - methyl - 3 - oxo‘4-androsten-l7a-yl) 20 of glacial acetic acid, 100 mg. of mercury, and 74 mg.
of selenium dioxide in 3.3 ml. of tert.-butanol. The reac
propionic acid gamma-lactone (XII'I) in 8 ml. of tetra—
tion mixture is stirred at room temperature for sixteen
hydrofuran was added 187 mg. of potassium carbonate
hours and then ?ltered. The ?ltrate is diluted with about
in 3.25 ml. of water. The reaction mixture was stirred
20 ml. of ethyl acetate and extracted with 12'0-24% aque
at room temperature for about 16 hours, and was then
ous ammonium sul?de solution saturated aqueous sodium
extracted with three 50-ml. portions of ethyl acetate. The
bicarbonate, and 2.5 N hydrochloric acid, and water, and
extracts were combined, washed with water until the
dried over anhydrous sodium sulfate. Removal of the
washings were neutral, dried over anhydrous sodium
To a suspension of 100 mg. of 3-(9a-bromo-1l?,l7?
drying agent and solvents results in 3-(1'7?-hydroxy-16u
sulfate, and evaporated to dryness under reduced pres
sure, resulting in 87 mg. of crude product. Upon tritura
methyl-3,ll-dioxo-1,4-androstadien-Hot-yl)propionic acid
tion with ether, the product 3~(9B,1lB-epoxy-l7B-hydroxy 30 gamma-lactone (XVII).
‘ 16a - methyl - 3-oxo-4-androsten-17a-yl)propionic
acid
EXAMPLE ‘l6
gamma-lactone (XIV) crystallized and was separated by
3-(1116,175-Dihya‘roxy-loa-Methyl-3-Ox0-1,4-Andros
?ltration. M.P. 198°~206° C. A sample was recrystal~
lized for analysis from ether-methylene chloride. M.P.
35
211°~213° C.
tadien-17a-Yl)Propionic Acid Gamma-Lactone
A solution of ‘100 mg. of 3-(17/3-hydroxy416a-methyl
3,-11 - dioxo -|1,4 - androstad-ien - 17a - yl)propionic acid
gamma-lactone (XVI-I) in 2.7 ml. of tetrahydrofuran is
Analysis.—Calculated for C23H30O4: C, 74.56%; H,
8.16%. Found: C, 74.38%; H, 8.22%.
EXAMPLE 14
3- (9a-Flll0r0-1 1,3,17B-Dihydr0xy-16a-Methyl-3-Ox0-4
cooled to 10° C. To this solution is added with stirring
40 0.8 ml. of an aqueous solution of sodium borohydride
containing .17.5 mg. of sodium borohydride per milliliter.
The reaction mixture is stirred at 0° C. for three hours,
dilute hydrochloric acid is then added, and the solution
Androsten-I 7cc-Yl) Propionic Acid Gamma-Laclone
is extracted with ethyl acetate. The extracts are washed
A solution of 50 mg. of 3-(9?,11B~epoxy-l7B-hydroxy 45 with water, dried, and evaporated. Crystallization from
16cc - methyl - 3 - oxo - 4 - randrosten _ 17m -> yl)propionic
methylene chloride-ether results in the product 3-(11?,
t17?-dihydroxy-1'6a-methyl - 3 - oxo-‘l,4-androstadien-l7u
acid gamma-lactone (XIV) in 2 ml. of chloroform was
yl)propionic gamma-lactone (XVIII).
added to 2 ml. of a solution prepared by mixing 7.45 ml.
What is claimed is:
of a 6% (by weight) solution of hydrogen ?uoride in
3~(tl7|3-hydroxy-16m-methyl-3,~l.1-dioxo - 4 - androsten
tetrahydrofuran with 5 ml. of tetrahydrofuran and 3.75 50
Una-yl)propionic acid gamma-lactone.
ml. of chloroform. The reaction mixture was cooled to
—40° C., allowed to stand at this temperature for four
References Cited in the ?le of this patent
hours, and then poured into a mixture of 8 g. of potas
UNITED STATES PATENTS
sium carbonate in ‘15 g. of ice water and 15 ml. of chloro
Cella ________________ .._ Apr. 5, 1955
form. The chloroform layer was separated and the aque 55 2,705,712
2,875,199
Cella ________________ __ Feb. 24, 1959
ous layer was washed with two l5-ml. portions of chloro
form. The chloroform extracts were combined and washed
with water until .the washings were neutral. The solution
was dried over anhydrous sodium sulfate and evaporated
2,925,416
Brown et a1 ___________ __ Feb. 16, 1960
OTHER REFERENCES
Marker et al.: J.A.C.S., 64, 1280 (.1942).
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