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Патент USA US3068257

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United States Patent O?ice
3,068,247
Patented Dec. 11, 1962
1
2
the androstane, 19-nor-androstane, and 17a-hydroxy-preg
3,068,247
nane series. Those of the normal series yield 4-hydroxy~
PROCESS 0F PREPARING 4-HYDRQXY-3
3-keto-A4-6-steroids from which the corresponding 4-hy
KETO-M-STEROIDS
droxy-3-keto-A4-steroid is obtained by catalytic hydro
Bruno (Iamerino, Bianca Patelli, and Roberto Sciaky, all 5
genation while those of the 19-nor-series ‘yield the cor
of Milan, Italy, assignors to Societa Farmaceutici
responding 4-hydroxy-3-keto-A4-steroids directly.
Italia, Milan, Italy, a corporation of Italy
No Drawing. Fitted Jan. 29, 1962, Ser. No. 169,628
Claims priority. application Italy Feb. 10, 1961
13 Claims. ((31. 260-—397.4)
According to our invention, 4-chloro-3-keto-A4-steroids
(prepared according to B. Camerino et al., Belgian pat
ent applications No. 549,701, No. 552,152, No. 552,153
Our invention relates to a new process of obtaining
10 and No. 557,735), of the series of androstane, 19-nor
androstane and 17a-hydroxy-pregnane, are dissolved in
4-hydroxy-S-keto-M-steroids, of the series of androstane,
of 19-nor-androstane and of 17u-hydroxy-pregnane.
tertiary aliphatic alcohols, such as tertiary buty alcohol
or tertiary amyl alcohol, and reacted either with oxygen
or air in the presence of the potassium salt of a tertiary
Our invention has as an object, the transformation of
4-chloro-3-ket0-A4-steroids to 4~hydroxy - 3 - keto-A‘Lste
15
roids by reaction either with oxygen or air in the presence
aliphatic alcohol, such as potassium, t.butylate or potas
sium tamylate.
of the potassium salt of a tertiary aliphatic alcohol. In
the U.S. patent application Serial No. 129,478, ?led Au
The reaction is carried out at a tem
perature ranging from 10° to 50° C., preferably at room
temperature over a period of time from a few hours to
gust 4, 1961, a process was described and claimed for
several days. When the treatment is over, the reaction
obtaining 4-hydroxy-3-keto-A4-steroids (C), of the nor 20 mixture is neutralized with acids, such as acetic acid
mal series and of the 19-nor-series from the correspond
or a dilute inorganic acid, and then diluted with water.
ing 3-keto-5?-steroids (B) by reaction with oxygen in the
The steroid is extracted with a usual water-immiscible
presence of the potassium salt of a tertiary aliphatic alco
organic solvent.
hol. The 3-keto-5i8-steroids are obtained by catalytic hy
The resulting crude products, i.e. 4-hydroxy-3—keto
drogenation of the corresponding 3-keto-A4-steroids (A). 25 Abs-steroids of the normal‘ series and 4-hydroxy-3-keto
A‘i-steroids of the 19-nor-series may be puri?ed either
R |
by crystallization from an organic solvent or by chro
Catalytic
Oxygen
hydrogenation O_
matography 0n resins such as Florisil (an activated mag
silicate) and subsequent elution and crystalliz
30 nesium
ation. They may be transformed into their acylates by
acylation of the present primary and secondary hydroxy
twigs???)
.a o o a e
H
groups with the chloride or anhydride of an organic acid
in the optional presence of a tertiary amine.
(B)
R
R
(\
R I
/ Oata-
Oxygen
O:
(potas- O:
alco-
V
holate)
OH
/
alcoholate)
gena-
I
OH
(E)
(F)
( otas
_
D
-
_
hydro- 0
‘
between 1:5 and 1:10.
/
-——>
(potas‘ O_
\H I /
Oxygen
0'
containers. The molar ratio of potassium t.alcoholate
and steroid may range from 1:1 to 1:30 and is preferably
|
/ Catalytic
Oxygen
-————>
C,
4o surface of the steroid solution standing in large and open
(0)
I
sium t.
case it is preferred to remove any carbon dioxide and
moisture present, or reaction may be carried out at the
tion
(D)
4:)
_
tion
(G)
H I
I
alcoholate)
(H)
_
The transformation of 4-hydroxy-3-keto~A4-6-steroids of
the normal series into the corresponding 4-hydroxy-3
keto-A‘Lsteroids is carried out by hydrogenation in the
presence of catalysts, such as 540% palladium on char
coal or platinum dioxide until one mol of hydrogen is
absorbed at room temperature and atmospheric pressure,
OH
said 4-hydroxy-3-keto-A4-steroids being thereafter puri?ed
50 according
to the usual procedures.
4-hydroxy-3-keto-A‘*~steriods are useful in therapy in
particular as anabolic, androgenic and progestative prod
a
sium t. O“
O1
The process of our invention. may be carried out either
with atmospheric oxygen or with pure oxygen. Air or
oxygen may be either blown into the solution, in which
gena‘
OH
(A)
/
35
hydro- O:
slum t.
\/
/
lytic
'—————>
ucts as disclosed in Belgian Patents No. 588,348, No.
I
OH
(I)
579,383, No. 588,005, No. 588,006 and U.S. patent ap
O plication Serial No. 79,960, ?led January 3, 1961.
on August 4, 1961, a process was described and claimed
The following examples serve to illustrate, but are not
intended to limit, the present invention.
in which 3-keto-A4-steroids of (A) of the normal series
EXAMPLE 1
In the U.S. patent application Serial No. 129,255, ?led
and of the 19-nor-series were treated with oxygen, in the 60
presence of the potassium salt of a tertiary aliphatic al
cohol to produce the corresponding 4-hydroxy-3-keto
NIB-steroids (D) which in turn, by catalytic hydrogen
ation of A6, yield the corresponding 4-hydroxy-3-keto
A4-steroids (C).
We have found, and this is the object of the present
invention, that 4-halo-3-keto-A4-steroids by a similar treat
ment in a tertiary aliphatic alcoholic solution with oxy
4-Hydroxy-Test0sterone
2 g. of 4-chloro-testosterone-acetate were dissolved in
80 cc. of t.butanol. A potassium t.butylate solution, pre
pared from 0.90 g. of potassium and 30 cc. of t.butanol,
65 was added thereto.
The reaction was allowed to proceed
at room temperature and the course thereof was followed
by UV. spectroscopic examination. After about 18
hours, the maximum at 256 mu had. completely disap
gen in the presence of an alkali metal salt of a tertiary
peared and a new maximum appeared at 300-305 mg.
aliphatic alcohol at from 10° to 50° C. can be converted 70 The solution was neutralized with acetic acid, diluted
into the corresponding 4-hydroxy-3-keto—A4,6-steroids.
The steroids treated are preferably 4-chloro-steroids of
with ethyl acetate, and then poured into salty water. The
organic extract waswashed with a 5% solutionof sodium
8,068,247
3
bicarbonate and then with water to neutrality. The ex
tract was dried over Na2SO4 and evaporated to dryness
under vacuum. The crude product absorbed U.V. radia
tion at 318 my and gave a violet coloration with ferric
chloride. The residue was dissolved in benzene and
chromatographed on Florisil. The fractions, after being
eluted with benzene-ether 9:1 and 8:2 by volume mix
tures, were recrystallized from ether. A halogen-free
4
.
280 mg. The solution was neutralized with acetic acid,
diluted with ethyl acetate, and poured into salty water.
The organic extract was washed with a 5% solution of
NaHCOa and then with H2O to neutrality. The extract
was then dried over anhydrous Na2SO4 and evaporated
to dryness under vacuum. The crude product absorbed
U.V. radiation at 278 mu and gave a green coloration
with ferric chloride. The residue was dissolved in ben
zene and chromatographed on Florisil. The fractions
product was obtained which melted at 210-215 ° C. with
x max. 318 mm, which is identical to 4-hydroxy-A6-de 10 eluted with benzene-ether 9:1 and 8:2 volume mixtures
were rercystallized from ether-petroleum ether. A prod
hydro-testosterone in every respect.
Acetylation of 4-hydroxy-A6-dehydro-testosterone with
acetic anhydride and pyridine yielded the corresponding
uct was obtained which melts at 185-190“ C. with a A
max. at 287 mg and is identical to 4-hydroxy-l9-nor
4,17-diacetate (M.P. ISO-153° C.). Hydrogenation of
testosterone in every respect.
4-hydroxy-A6-dehydro-testosterone in the presence of pal
ladium on charcoal or platinum dioxide PtOz), yielded
4-hydroxy-testosterone (M.P. 221—223° C.).
EXAMPLE 2
4-Hydroxy-l 7a-Methyltest0ster0ne
2 g. of 4-chloro-17a-methyltestosterone were dissolved
‘1.5 g. of 4-chloro-19-nor-17a-methyl-testosterone were
dissolved in 60 cc. of t.butanol. A solution of potas
sium t.butylate, prepared from °.67 g. of potassium in
22.5 cc. of t.butanol, was added thereto. The reaction
was allowed to proceed at room temperature and the
prepared from 0.90 g. of K and 30 cc. of t.butanol was
course thereof followed by U.V. spectroscopic examina
added thereto. The reaction was allowed to proceed at
room temperature and its course was followed by U.V. 25 tion. After about 3 hours, the maximum at 256 me had
disappeared and a new maximum appeared at 278-280
spectroscopic examination. After about 18 hours, the
I'D/.4.
The solution was neutralized with acetic acid, di
maximum at 256 mg had completely disappeared and a
luted with ethyl acetate, and then poured into salty water;
new maximum appeared at 300-305 mg. The solution
the extract was washed with a 5% solution of NaHCO3,
,was neutralized with acetic acid, diluted with ethyl ace
tate, and then poured in salty water. The organic ex 30 with H2O to neutrality, dried over Na2SO4 and evapo
rated to dryness under vacuum. The crude product ab’
tract was washed with a 5% solution of NaHCOa and
sorbed U.V. radiation at 278 lTl/L and gave a green colora
then with water to neutrality. The extract was then dried
tion with ferric chloride. The residue was dissolved in
over Na2SO4 and evaporated to dryness under vacuum.
chloroform and passed through a little column of Florisil
The crude pro-duct absorbed U.V. radiation at 318 mg
and gave a violet coloration with ferric chloride. The 35 by elution with chloroform. The eluates Were recrystal
in 80 cc. of t.butanol. A potassium t-butylate solution
residue was dissolved in benzene and chromatographed
,on Florisil. The fractions, after being eluted with ben
zene-ether 9:1 volume mixture, were recrystallized from
ether. A halogen-free product was thereby obtained,
lized from ether-petroleum ether. A crystalline product,
melting at 145-155 ° C., was obtained, with a A max. 278
mu, which is identical to 4-hydroxy-17ot-methyl-19-nor
testosterone in every respect.
Obviously many modi?cations and variations of the
which melted at 195-205 ° C. with )t max. 318 mu, which 40
present invention are possible in the light of the above
is identical to 4-hydroxy~A5-dehydro-17or-methyltestoster
teachings. It is therefore to be understood that within the
one in every respect.
scope of the appended claims, the invention may be prac
Hydrogenation of 4-hydr0xy-A6-dehydro-17a-methyl
ticed otherwise than as speci?cally described.
testosterone in the presence of palladium on charcoal or
platinum dioxide (Pt02) yielded 4-hydroxy-17a-methyl 45 We claim:
1. A process of preparing a compound selected from
testosterone (M.P. 170—l72° C.).
EXAMPLE 3
the group consisting of 4-hydroxy-3-keto-A4-steroids of
the androstane series, and of the l7ot-hydroxv-pregnane
4 ,1 7u-Dihydroxy-Progesterone
0.5 g. of 4-chloro-4-pregnen-l7a-ol-3,20-dione (melting
series, which comprises reacting the corresponding 4-halo
at 223-225 ° C.) were dissolved in 20 cc. of t.butanol,
phatic alcohol and transforming the resulting 4-hydroxy
then warmed to 35° C. and reacted with 0.35 g. of potas
sium dissolved in 10 cc. of t.butanol in an oxygen stream
for 40 minutes. The solution was acidi?ed with acetic
acid, diluted with water and extracted with ethyl acetate.
The extract was washed wih a 10% solution of sodium
bicarbonate and with water. After distillation of the sol
vent, a residue remained which had A max. 318 mg and,
crystallized from aqueous methanol, yielded 4,6-pregna
3-keto-A4-steroid with oxygen in a tertiary aliphatic alco
hol in the presence of the potassium salt of a tertiary ali
3-keto-A4'6-steroid by catalytic hydrogenation with a cata
lyst selected from the group consisting of palladium on
charcoal and platinum dioxide to the resulting 4-hydroxy
3-keto-A4-steroid.
'
2. A process of preparing a compound selected from
the group consisting of 4-hydroxy-3-keto-A4-steroids of
the androstane series, and of the 17a-hydroxy-pregnane
diene-4,17u-diol-3,20-dione melting at 260—262° C. The 60 series, which comprises reacting the corresponding 4
chloro-3-keto-A4-steroid with oxygen in a tertiary aliphatic
above-mentioned product was transformed into 4,17oc-dl
alcohol in the presence of the potassium salt of a tertiary
hydroxy-progesterone (M.P. 229-231" C.) by hydrogena
aliphatic alcohol and transforming the resulting 4-hy
tion in the presence of palladium on charcoal or platinum
droxy-3-keto-A416-steroid by catalytic hydrogenation with
dioxide.
65 a catalyst selected from the group consisting of palladium
EXAMPLE 4
on charcoal and platinum dioxide to the resulting 4-hy
4-Hydroxy-I 9-Nor-Testosterone
1.5 g. of 4-chloro-19-nor-testosterone acetate were dis
solved in 60 cc. of t.butanol, and a solution of potassium
droxy~3-keto-A4-steroid.
3. A process of preparing a compound selected from
the group consisting of 4-hydroxy-3-keto-A4-steroids of
t.butylate, prepared from 0.67 g. of potassium and 22.5 70 the androstane series, and of the 17oc-hydroxy-pregnane
series, which comprises dissolving the corresponding 4
cc. of t.butanol, was added thereto. The reaction was
chloro-3-keto-A4-steroid in a tertiary aliphatic alcohol,
allowed to proceed at room temperature and the course
reacting the steroid solution with oxygen in the presence
thereof followed by U.V. spectroscopic examination.
‘of the potassium salt of a tertiary alcohol, in a molar
After about 5 hours, the maximum at 256 mp. had dis
appeared and a new maximum appeared at about 278
75 ratio of base to steroid from 1:1 to 1:30, at atmospheric
5
‘3,068,247
pressure and a temperature between 10 to 50° C., and
transforming the resulting 4-hydroxy-3-keto-A4-6-steroids
6
steroid from 1:5 to 1:10, at atmospheric pressure and
room temperature, and transforming the resulting 4-hy
droXy-AB-dehydro-testosterone by a catalytic hydrogena
by catalytic hydrogenation with a catalyst selected from
the group consisting of palladium on charcoal and plati
num dioxide to the resulting 4-hydroxy-3-keto-A4-steroids.
4. A process of preparing 4-hydroxy-3-keto-A4-steroids
of the series of l9-nor-androstane, which comprises dis
tion with a catalyst selected from the group consisting of
palladium on chracoal and platinum dioxide to 4-hy
solving the corresponding 4-chloro-3-keto-A4-steroid in
a tertiary aliphatic alcohol, reacting the steroid solution
tosterone, which comprises reacting 4-chloro-17a-meth~
yl-testosterone dissolved in a tertiary aliphatic alcohol,
droxy-testosterone.
9. A process of preparing 4-hydroxy-Il7a-methyl-tes
with oxygen in the presence of the potassium salt of a ter 10 selected from the group consisting of tertiary butyl and
tiary alcohol, in a molar ratio of base to steroid from 1:1
tertiary butyl alcohol, reacting the steroid solution with
to 1:30, at atmospheric pressure and a temperature be
oxygen in the presence of the potassium salt of a tertiary
tween 10 to 50° C., to yield the resulting 4-hydroxy-3
keto-M-steroid.
5. A process of preparing a compound selected from
the group consisting of 4-hydroxy-3-keto-A4-steroids of
the androstane series and of the 17a-hydroxy-pregnane
series, which comprises dissolving the corresponding 4
alcohol selected from the group consisting of potassium
t.butylate and potassium t.amylate, in a molar ratio of
potassium alcoholate to steroid from 1:5 to 1:10, at at
mospheric pressure and room temperature, and catalyti
cally hydrogenating with a catalyst selected from the group
consisting of palladium on charcoal and platinum dioxide
chloro-3-keto-A4-steroid in a tertiary aliphatic alcohol, se—
lected from the group consisting of tertiary butyl and ter
the resulting 4~hydroxy-A6-dehydro-17ot-methyl-testoster
tiary butyl alcohol, reacting the steroid solution with
oxygen by blowing carbon dioxide-and-moisture-free oxy
10. A process of preparing 4,l7a-dihydroxy-progester
one, which comprises reacting 4-chloro-4-pregnen-17a-ol~
gen in said steroid solution, in the presence of the potas
sium salt of a tertiary alcohol selected from the group
3,20-dione dissolved in a tertiary aliphatic alcohol, se
lected from the group consisting of tertiary butyl and ter
consisting of potassium t.butylate and potassium t.amyl
ate, in a molar ratio of base to steroid from 1:5 to 1:10,
at atmospheric pressure and room temperature for about
1 to 2 days, transforming the resulting 4-hydroxy-3-keto
M's-steroids by catalytic hydrogenation with a catalyst
selected from the group consisting of palladium on char
coal and platinum dioxide to the resulting 4-hydroxy-3
keto-A‘i-steroids.
6. A process of preparing a compound selected from
one to 4-hydroxy~17a-methyl-testosterone.
tiary butyl alcohol, reacting the steroid solution with oxy
gen in the presence of the potassium salt of a tertiary
alcohol selected from the group consisting of potassium
t.butylate and potassium t.amylate, in a molar ratio of
potassium alcoholate to steroid from 1:5 to 1:10, at at
mospheric pressure and room temperature, and catalyti
cally hydrogenating with a catalyst selected from the group
consisting of palladium on charcoal and platinum dioxide
the resulting 4,6-pregnediene-4,17ot-diol-3,20-dione to 4,
the group consisting of 4-hydroxy-3-keto-A4-steroids of
the androstane series and of the 17u-hydroxy pregnane
l7a-dihydroxyprogesterone.
series, which comprises dissolving the corresponding 4
one, which comprises reacting 4-chloro-19-nor-testoster~
chloro-3-keto-A4-steroid in a tertiary aliphatic alcohol,
selected from the group consisting of tertiary butyl and
tertiary butyl alcohol, reacting the steroid solution with
11. A process of preparing 4'hydroxy~19-nor-testoster
one dissolved in a tertiary aliphatic alcohol, selected from
the group coonsisting of tertiary butyl and tertiary butyl
alcohol, reacting the steroid solution with oxygen in the
oxygen in the presence of the potassium salt of a tertiary 40 presence of the potassium salt of a tertiary alcohol se
alcohol selected from the group consisting of potassium
t.butylate and potassium t.amylate, in a molar ratio of
potassium alcoholate to steroid from 1:5 to 1:10, at at
mospheric pressure and room temperature for about 1 to
2 days, transforming the resulting 4-hydroxy-3-keto-A4-6
steroids by catalytic hydrogenation with a catalyst selected
from the group consisting of palladium on charcoal and
platinum dioxide to the resulting 4-hydroxy~3-keto-A4
steroids.
lected from the group consisting of potassium t.butylate
and potassium t.amylate, in a molar ratio of potassium
alcoholate to steroid from 1:5 to 1:10, at atmospheric
pressure and room temperature, to yield 4-hydroxy-19
nor-testosterone.
12. A process of preparing 4-hydroxy-19-nor-17a
methyl-testosterone which comprises reacting 4-chloro-19
nor~17a-methyl-testosterone dissolved in a tertiary ali
phatic alcohol, selected from the group consisting of ter
7. A process of preparing 4-hydroxy-3-keto-A4-steroids 50 tiary butyl and tertiary butyl alcohol, reacting the steroid
of the series of 19-nor-androstane, which comprises dis
solution with oxygen in the presence of the potassium
solving the corresponding 4~chloro~3-keto-A4-steroid in a
tertiary aliphatic alcohol, selected from the group consist
ing of tertiary butyl and tertiary butyl alcohol, reacting the
salt of a tertiary alcohol selected from the group consist
ing of potassium t.butylate and potassium t.amylate, in
a molar ratio of potassium alcoholate to steroid from 1:5
steroid solution with oxygen by blowing carbon dioxide 55 to 1:10, at atmospheric pressure and room temperature,
and-moisture-free oxygen in said steroid solution, in the
to yield 4-hydroxy-19-nor-17ot-methyltestosterone.
presence of the potassium salt of a tertiary alcohol selected
13. A process of preparing 4,17-diacetate-M-testoster
from the group consisting of potassium t.butylate and po
one, which comprises reacting 4-chloro~testosterone~ace
tassium t-amylate, in a molar ratio of base to steroid from
tate dissolved in a tertiary aliphatic alcohol, selected from
60
1:5 to 1:10, at atmospheric pressure and room tempera
ture for about 1 to 2 days, to give the corresponding 4
hydroxy-3-keto-A4-steroids.
8. A process of preparing 4-hydroxy-testosterone, which
comprises reacting 4-chloro-testosteroneacetate dissolved
the group consisting of tertiary butyl and tertiary butyl
alcohol, reacting the steroid solution with oxygen in the
presence of the potassium salt of a tertiary alcohol se~
lected from the group consisting of potassium t.butylate
and potassium t.amylate, in a molar ratio of potassium
in a tertiary aliphatic alcohol, selected from the the group 65 alcoholate to steroid from 1:5 to 1:10, at atmospheric
consisting of tertiary butyl and tertiary butyl alcohol, re
acting the steroid solution with oxygen in the presence of
the potassium salt of a tertiary alcohol selected from the
group consisting of potassium t.butylate and potassium
t.amylate, in a molar ratio of potassium alcoholate to 70
pressure and room temperature, and transforming the re
sulting 4-hydroxy-A6-dehydro-testosterone by acetylation
to 4,17-diacetate-A6-testosterone.
No references cited.
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