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Патент USA US3040046

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United States Patent O?tice
3,040,036
Patented June 19, 1962
2
1
tioned objects can be ‘achieved by treating a 3-keto-1, 4
diene steroid compound having the ‘above-described For
3,040,036
PROCESS FOR THE AROMATIZATION 0F RING A
OF STEROH) COMPDUNDS
mula II with zinc in an alcohol selected from the group
consisting of aliphatic alcohols having 2 to 6 carbon
Kyosnke Tsuda, Urawa City, Eiji Oki, Tokyo, Shigeo
Nozoe, Kamakura City, and Yutaka Okada, Tokyo,
Japan, assignors to Sankyo Company, Limited, Tokyo,
Japan
No Drawing. Filed Sept. 12, 1961, Ser. No. 137,526
Claims priority, application Japan Sept. 19, 1960
atoms, such as ethanol, propanol, butanol, tertiary amyl
‘alcohol, n-amyl alcohol, isoamyl alcohol and hexanol,
dihydric alcohols, such as ethylene glycol and propylene
glycol, and benzyl alcohol to form the corresponding
19-nor steroid compound with aromatized ring A hav
ing the above-described Formula I.
In carrying out the present invention, it is preferable
4 Claims. (Cl. 260—239.55)
This invention relates to a process for effecting aroma
tization of ring A and demethylation of the methyl group
at 19 position of steroid compounds. More particularly,
it relates to a process for preparing 19-nor steroid com
pounds With aromatized ring A having the formula
to dissolve a starting steroid compound in an alcohol as
described above, add zinc to the solution, and heat the
resulting mixture under reflux for about 1 to 5 hrs. The
15 reaction time may vary depending upon the relative
amount of zinc added base on that of the starting steroid
0
E0
compound, activity of the Zinc and temperature.
The
‘amount of zinc used may be sufficient to convert the
starting steroid compound to the desired product, but the
20 preferred range is vfrom about 5 to 50 g. per gram of
the starting steroid compound.
After completion of the reaction, the desired product
Al E
(I)
insofar as rings A, B and C of the steroid nucleus are
may be isolated from the reaction mixture by conven~
tional methods. For example, after completion of the
concerned, said compounds having one double bond be 25 reaction, the reaction mixture is cooled, the zinc is re
moved by ?ltration, the ?ltrate is evaporated to dryness
tween two carbon atoms of the steroid nucleus at one
in vacuo and then the resulting residue is recrystallized
of 6(7), 8(9) and 9(11) positions, by aromatization
from acetone, methanol, diethyl ether or ethyl acetate
of the ring A and demethylation of the methyl group
to obtain the desired product. Alternatively, the desired
at 19 position of the corresponding 3 keto-l, 4-diene
30 product is obtained by adding water to the ?ltrate after
steroid compounds having the formula
removal of the zinc, extracting the resulting mixture with
a water-immiscible organic solvent such as chloroform,
diethyl ether or ethyl acetate, washing the extract with
water, removing the solvent from the Washed extract, and
35 then recrystallizing the residue from acetone, methanol,
ethanol or ethyl acetate.
Representative of the 3-keto-1.4-diene steroid com
0
pounds used as the starting material in the process ac
(II)
insofar as rings A, B and C of the steroid nucleus are 40 cording to the present invention are
concerned.
17/3-hydroxyandrosta-1,4,6-triene-3-one
It has been heretofore proposed to produce steroid
compounds with aromatized ring A from the correspond
17B-acetoxy-androsta-1,4,6etriene-3-one
andro sta-1,4,6-triene-3 ,17-dione
ing steroid compounds by thermal degradation (HI-I.
pregna-1,4,6,16-tetraene~3 ,ZO-dione
Inhotfen: Angew. Chem., 53, 471 (1940)) or by heat
17a,21-dihydroxypregna~1,4,6-triene-3,20-dione 2 l-acetate
ing in mineral oil (C. Djerassi et al.: I . Am. Chem. Soc.,
androsta-1,4,9( 1-1)-triene-3 , 1 7-dione
73, 1523 (1951); ibid. 72, 4543 (1950); E. B. Hershberg,
M. Rubin, E. Schwenck: J. Org. Chem., 15, 292 (1950)).
17rx,21-dihydroxypregna-1,4,9( 1 1)-triene-3 ,ZO-dione
However, use of these methods is very limited because
1 l?-hydroxyandrosta-l,4,8~triene-3,17-dione
1 118,17,8-dihydroxyandrosta-1,4,8-triene-3-one
they cannot be applied to steroid compounds having
substituents unstable to heat on the steroid nucleus owing
to the use of high temperature such as about 600° C.
11B,17a,21-t1ihydroxypregna-1,4,8-triene-3,2O-dione
Moreover, it is disadvantageous that low yield of the
desired product and complicated procedures are associ
1 l?-hydroxypregna-1,4,8-triene-3 ,20-dione
ated with these methods.
21
acetate
21
acetate
55
17,3-hydroxyandrosta-1,4,9 ( 1 1 ) -triene-3 -one
17/3-acetoxyandrosta-1,4,9( 1 1 ) -triene-3-one
Furthermore, method of ring A arom'atization of steroid
pregnan-1,4,9(l1)-t1iene-3 ,20-dione
compounds by means of acid is known. However, there
17a,21-dihydroXypregnan-1,4,9r(11) - triene - 3,20 - dione
occurs in this method migration of the angular methyl
BMD
group to ring A with the result that such compounds
11B,17/3-dihydroxyandrosta-1,4,8-triene-3-one 17-acetate
as having the Formula I cannot be prepared by this 60 1 l?-hydroxyandrosta-l,4,6-triene-3,17-dione
method.
cholesta-l ,4,6-triene-3 -one
It is an object of this invention to provide a process
ergosta-l ,4,6,22-tetraene-3 -one
for converting 3-keto-1, 4-diene steroid compounds hav
ing the above-described Formula II insofar as rings A,
stigmasta-1,4,6,22-tetraene-3-one
spirosta-l,4,9(11)-triene-3-one
B and C of the steroid nucleus are concerned to the 65 1 1 B-hydroxyspirosta-l ,4,8-triene-3-one, and
corresponding 19-nor steroid compounds with aromatized
ring A having the above-described Formula I insofar
17u-methyl-androsta-1,4,9 ( 1 1 ) -triene- 175-01-3 -one
as rings A, B and C of the steroid nucleus are concerned
The above-mentioned 3-keto-1,4-diene steroid com
without the above-mentioned disadvantages in an economi
pounds are converted by the process according to the
cally advantageous Way. Other objects of this invention 70 present invention to the corresponding compounds as
will be apparent herein below.
follows: A6-estradiol, A6-estradiol 17-acetate, A6-estrone,
According to the present invention, the above-men
19-norpregna-1,3,5(10),6,16-pentaene-3-ol - 20 - one,
19
3,040,036
3
4
benzene and to the solution is added petroleum ether.
The resulting solution is chromatographed on 30 g. of
acetate, estra-1,3 ,5 ( 10) ,9 ( 1 l ) —tetraene-3-ol-17-one (A9
silica gel for puri?cation. 'Elution is ?rst made with
(11)-estrone) , 19-norpregna-1,3,5(10),9(11)-tetraene-3,
benzene-petroleum ether (1:1) and then with the same
17a, 21-triol-20-one 2l-acetate, 3,11,8-dihydroxyestra-1,3,
5(l0),8-tetraen-17-one(11/3-hydroxy-A8-estrone), 3,115, 5 solvent with increased ratio of benzene.
17B-trihydroxyestra-1,3,5 ( 1O ) ,8-tetraene( 1 1/8-hydroxy-A8
The solvent is removed from fraction eluted with ben
zene-petroleum ether (99:1) and to the residue is added
estradiol) , 19-norpregna-1,3,5(10),8-tetraene-3,11?,17o¢,
norpregna,1,3,5(10),6-tetraene-3,17u,21-triol-2O - one 21
2 l-tetr-aol-ZO-one 21-acetate, 19-norpregna-1,3,5 ( 1 0) ,8
a small amount of methanol.
tetraene-3,11?-diol-20-one,3,17?-dihydroxyestra-1,3,5(10),
precipitate crystals, which are recrystallized from meth
9(11) - tetraene,3,17/3 - dihydroxyestra - 1,3,5(10),9(11)
10 anol.
tetraene 17-acetate, 19-norpregnan-1,3 ,5 ( 10) ,9 ( 1 1 ) -tetra
19 - norpregna - l,3,5(10),6,16 - pentaene - 3 - ol - 20
ene-3-ol-20-one, 19-norpregnan- l ,3,5 ( 10) ,9 ( 11)-tetraene
3,17a,21-triol-20-one BMD, 3,11,8,17,6-trihydroxyestra-L3,
5 ( 10),8-tetraene
one is obtained as prisms melting at 240—241° C., 110
mg.
Analysis.—Calc’d for CZOHZQOZ: C, 8.60; H, 7.53.
17-acetate,3,11[3 - dihydroxyestra — 1,3,5
( 10) ,6-tetraene-17-one, 19-norcholesta-l,3,5 ( 10) ,6-tetra
ene-3-ol, 19-norergosta—1,3,5 ( 10) ,6,22-pentaene-3-ol, 19
norstigmasta-1,3,5 ( 10) ,6,22-pentaene-3-ol, 19-norspirosta
1,3,5 (10) ,9( 1 1 ) -tetraene-3-o1, 19-norspirosta-1,3,5(10),8
15
Found: C, 81.69; H, 7.60.
£13911 224 my (6 38000)
270 mpt (@6800), 304 mp (62700).
tetraene-3 ,1 l?-diol, 17a—methylestra-1,3 ,5 ( 10) ,9 ( 1 1 ) ~tet
raene-3,17,8-diol.
The mixture is chilled to
Example 3
20
The following examples are given as illustrative of our
05
process, but are not intended to be limitative upon the
scope thereof.
Example 1
25
d
.93 _» .0
30
To a solution of 500 mg. of androsta-1,4,9(11)-triene
3,17-dione in 50 ml. of ethylene glycol is added 10 g. of
zinc dust. The mixture is heated under re?ux with stir
ring. After cooling, the zinc is removed by ?ltration and
the ?ltrate is poured into a large amount of water fol
To a suspension of 1 g. of 17-acet0xyandrosta-1,4,6
trien-3-one, M.P. 151° C., in 75 ml. of ethylene glycol 35 lowed by extraction with diethyl ether. The diethyl ether
layer is washer with water, dried. The ether is then dis
are added 15 g. of zinc dust washed successively with
tilled off and the residual oily substance is dissolved in
hydrochloric acid, water and acetone. The resulting mix
a small amount of methanol. The solution is chilled to
ture is heated under re?ux with stirring for 3 hrs. After
be
crystallized. The crystals are separated by ?ltration
cooling the supernatant is poured into water, followed 40
and recrystallized from methanol to give 250 mg. of
by extraction of the separated oil with ethyl acetate.
A9(1l)-estrone.
The zinc is washed with several portions of ethyl
Example 4
acetate containing 10% acetic acid. The combined ex
tract and washings are washed with aqueous sodium bi
carbonate and dried over sodium sulfate.
The solvent is then removed and the residue is mixed 45
with a small amount of methanol. The mixture is al
lowed to stand at a cold place to precipitate crystals. The
crystals are separated by ?ltration and recrystallized from
methanol to give 120 mg. of A6-estradiol-17-acetate, M.P.
250—251‘‘ C., Amax 262 m,“ (68900), 303m,“ (E2700)
Example 2
ode
50
To a solution of 282 mg. of androsta-1,4,9(11)-triene
3,17-dione in 20 ml. of ethanol is added 10 g. of zinc
dust washed successively with diluted by hydrochloric
55 acid and water.
The mixture is heated under re?ux with
stirring for 4 hrs. The reaction mixture is cooled and
the zinc is removed ‘by ?ltration. The ethanol is re
moved from the ?ltrate by evaporation in vacuo and the
residue is recrystallized from acetone-diethyl ether to give
60 190 mg. of A9(11)-estrone melting at 254~258° C.;
A mixture of 1.2 g. of pregna-1,4,6,l6-tetraene-3,20
dione and 90 ml. of ethylene glycol is heated at 120° C.
to a complete solution.
of) IQ m5
To the solution are added 30 65
g. of zinc dust washed successively with 10% hydro
chloric ‘acid, water and acetone. The reaction tempera
ture is then gradually raised to 190° C. in 20 min. with
vigorous stirring. Heating under re?ux is continued for
additional 3 hrs.
70
After cooling, the zinc is removed from the reaction
mixture by ?ltration and the ?ltrate is poured into a large
amount of Water. The crystals formed are separated by
?ltration, washed thoroughly with water and dried to
give 700 mg. of the crude product. It is dissolved in 75
AS35393 263 my. (6 18000)
229 Inn (63200).
Example 5
n5
0?
i313 ~ ..
The same procedures are repeated as those in Example
3,040,036
5
6
4 except that 20 m1. of propanol are used in place of
the ethanol to give 210 mg. of A9(1l)-estrone.
zinc is removed by ?ltration. The ethanol is distilled off
in vacuum from the ?ltrate and the residue is allowed to
stand at a cold place after admixed with a small amount
Example 6
diethyl ether. The crystals precipitated are separated by
‘?
?ltration and recrystallized from acetone-diethyl ether to
give 200 mg. of 3,11?-dihydroxyestra-1,3,5(10),8-tetraen
l7-one, M.P. 184-187° (3.;
Hi
it)
W?
£53911 279 my (6 18000)
Example 10
The same procedures are repeated as those in Example
9 except that 30 ml. of tertiary butanol are used in place
of the ethanol to give 220 mg. of 3,1lB-dihydroxyestra
1,3,5(10),8-tetraen-17-one.
The same procedures are repeated as those in Example
4 except that 30 ml. of tertiary butanol are used in place
of the ethanol to give 210 mg. of A9(l1)-estrone.
Example 11
Example‘ 7
20
m5 (I95
The same procedures are repeated as those in Example
9 except that 30 ml. of n-amyl alcohol are used in place
of the ethanol to give 200 mg. of 3,11B-dihydroxyestra
1,3,5 (10) ,8-tetraen-17-one.
We claim:
1. A process for preparing 19-n0r steroid compounds
with aromatized ring A having the formula
433 g
The same procedures are repeated as those in Example
4 except that 30 ml. of n-amyl alcohol are used in place 30
of the ethanol to give 168 mg. of A9(l1)-estrone.
Example 8
HO
insofar as rings A, B and C of the steroid nucleus are
concerned, said compounds having one double bond be
M
tween two carbon atoms of the steroid nucleus at one of
'
.03 g -
6(7), 8(9) and 9(11) positions which comprises treating
the corresponding 3-keto-1,4-diene steroid compound hav
ing the formula
40
To a solution of 282 mg. of androsta-1,4,9(l1)-triene
3,17-dione in 30 ml. of benzyl alcohol are added 10 g. of
A
B
zinc dust washed successively with diluted hydrochloric
acid and water. The mixture is heated under re?ux with
stirring for 4 hrs. The reaction mixture is cooled and
the zinc is removed therefrom by ?ltration. To the ?ltrate
are added 60 ml. of diethyl ether and the resulting solu
tion is shaken with 5% aqueous potassium hydroxide to
dissolve the phenolic compound in the alkali solution.
The alkali solution layer is then washed with ether and
acidi?ed with 1% hydrochloric acid followed by extrac
with zinc in an alcohol selected from the group consisting
of aliphatic alcohols having two to six carbon atoms, di
hydric alcohols and benzyl alcohol.
2. A process for preparing 19-nor steroid compounds
with aromatized ring A having the formula.
tion with ethyl acetate. The extract is washed succes
sively with diluted aqueous sodium bicarbonate and water
and dried. The solvent is removed from the extract by
distillation and the residue is recrystallized from acetone
diethyl ether to give 170 mg. of A9(l1)-estrone, M.P.
256—258° C.
Example 9
HO
60
insofar as rings A, B and C of the steroid nucleus are
raj/F1- T ‘i
concerned which comprises treating the corresponding
3-keto-1,4-diene steroid compound having the formula
5
70
To a solution of 298 mg. of lIB-hydroxyandrosta-1,4,8
triene-3,17-dione in 30 ml. of ethanol is added 10 g. of
0
with zinc in an alcohol selected from the group consisting
zinc dust washed successively with diluted hydrochloric
of aliphatic alcohols having two to six carbon atoms, di
acid and water. The mixture is heated under re?ux with
stirring for 4 hrs. The reaction mixture is cooled and the 75 hydric alcohols and benzyl alcohol.
7
8
3. A process for preparing l9-nor steroid compounds
with aromatized ring A having the formula
4. A process for preparing 19-nor steroid compound
with aromatized ring A having the formula
m
HO
insofar as rings A, B and C of the steroid nucleus are con
cerned Which comprises treating the corresponding 3-keto
1,4-diene steroid compound having the formula
HO 4W
insofar as rings A, B and C of the steroid nucleus are
concerned Which comprises treating the corresponding
3-keto-1,4-diene steroid compound having the formula
C
with zinc in an alcohol selected from the group consisting
of aliphatic alcohols having two to six carbon atoms, di
hydric alcohols ‘and benzyl alcohol.
with zinc in an alcohol selected from the group consisting
of aliphatic alcohols having two to six carbon atoms.
No references cited.
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