Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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; The invention relates to a process for producing
~ '5'(10)-steroids from corresponding ~1'3'5(10)-steroids by
; electrochemical reduction.
It is known that the electrolys:is of unsaturated
aromatic steroids in liquid ammonia in an undivided cell in
the presence of alkali or alkaline earth rnetal salts does ;~
indeed lead to the reduction of unsaturated ~roups, but the
aromatic part of the steroid molecule is not attacked (see
German Patent Publication No. 2,063llOl, published 22nd June
1972 to Dr. Klaus Junghans).
; The electrochemical reduction of aromatic steroids
to form the corresponding Q2r5(10)-steroids is also known (see
' German Patent Specification No. 1,266,300). In such process,
;l the electrolysis is carried out in methylamine or in another
alkylamine solvent. Ilowever, the process has the dlsadvantage
that the amine used as the solvent must, after the electrolysis,
~ be separated from the product by distillation under reduced
`~ pressure or precipitation with other liquids.
Because of the low conductivity of the reaction mix- `
- 20 ture, the consumption of current is very high, and there is a
correspondingly strong evolution of heat. ~owever, in carrying
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~' out the process on an industrial scaie the heat must be removed.
The present invention is based on the problem of dis-
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;l covering a process for the electrochèmical reduction of aromatic
steroids, in which the solvent can be separated from the product, ~;~
without great technical expenditure and less current consumption,
and thus no great evolution of heat.
The above problem is solved by carrying out the elec-
trolysis with a liquid ammonia solvent in a divided cell in the
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presence of an alkali metal salt of a strong acid having a pK
value of less than 5 as the conductive salt, or in an undivided
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cell in the presence of an a]kali me-tal salt containing anions
of a weak acid having a pK value of 5 to 32 as the con~uctive
salts.
Electrochemical reduction in liquid ammonia is des-
cribed for simple aromatic substances (see, Eor example, U.S. -
Patents Nos. 3,493,477 and 3,488,266), but the smooth electrolysis
of steroids having a complex structure and optionally substituted
by functional groups could not have been expected~ Is is also
surprising that the aromatic ring is reduced by working in
accordance with the process of German ~atent Publication ~o.
2/063,101, but in a divided cell ins-tead of an undivided cell,
or by using in an undivided cell, as conductive salts, alkali
metal salts having anions of acids that are weak acids in liquid
ammonia, optionally with the addition of alkali metal salt of
strong acids.
W'nen the elec-trolysis of the invention is carried out
in a divided cell, there are used as conductive salts alkali
metal salts, for example, lithium, sodium or potassium salts.
The anions necessary for charge equalization are derived from
strong acids and are, for example, halides such as a chloride or
bromide, or complex anions such as a tetrafluoborate, sulphate
or perchlorate.
When the electrolysis is carried out in an undivided
cell, there are used as conductive salts alkali salts of weak
` acids, for example, aniline, hydrazine~ alcohol or water in
liquid ammonia, i.e. alkali metal anilides, hydrazides, alcohol- ;
ates, and hydroxides.
The concentration ratio of electrolyte salt to the
steroid to be reduced has no influence on -the reduction and may
vary within wide limits. The reduction is also not disturbed if
; a portion of the reactants is present as solid at the bottom
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of the liquid (saturated solution).
In accordance with the invention, ammonia is used as
solvent. Small amounts of other solvents may be added, provided
they are inert with respect to the reac-tants. Such other sol-
vents serve as a solubiliser between the ammonia and the steroid
to be reduced. The other solvents include, for example, ethers
such as diethyl ether, tetrahydrofuran and dioxane, acid deriva-
- tives such as ethyl acetate, acetonitrile and dimethylformamide,
and dimethyl sulphoxide.
The divided cell is of conventional construction, the
electrode compartments being separated by porous m~terial, for
example, glass frit, a clay diaphragm or asbestos wool, or by
an ion-exchange membrane.
The electrolysis may be carried out with an~ type of
current such as alternating current, rectified unsmoothed alter-
nating current, direct current or modulated direct current. The
;, conditions of the electrolysis, such as voltage, amperage, cur-
rent density, electrode area, pressure and temperature, can be
varied widely. It is advantageous to operate at a current den-
20 sity of 0.1 to 5 amperes/cm2 and a temperature of from -50C up
to the boiling point of the reaction mixture. ~Iowever, it is
also possible to operate under pressure. The nature of the
electrode material is not critical. It only has to conduct the
current and to be stable under the conditions of the electrolysis,
as are, for example, gold, silver, mercury, platinum, aluminium,
tungsten carbide and graphite. The process of electrolysis may
be carried out in a continuous or discontinuous manner. -
The starting compounds used in accordance with the
invention are ~1~3~5(1)-3-hydroxy-trienes of oestrane, 18-methyl-
30 oestrane, l9-nor-pregnane or l9-nor-cholestane in the form of
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their 3-alkyl, 3-cycloalkyl or 3-aralkyl ethers. They may con-
tain, in addition -to the double bonds in the aromatic A-ring,
one or more conjugated carbon-to-carbon bonds such as, for
example, ~6_, ~8_, or a9 (11)_ and/or other reducible groupings,
for example, carbonyl groups in the 6-, 11- or 20-position,
nitro or imino groups ~C=N~, wherein R represents hydrogen,
hydroxyl, alkyl, aryl or aralkyl. The double bonds are co-
reduced during the process of the invention, and an exo-cyclic
multiple bond, such as the 17~-ethinyl group, is reduced to a
double bond. Such an isolated carbon-to-carbon double bond is
not further reduced. The steroid structure may contain addi-
tional alkyl groups, for example, methyl in the 1-, 6-, 7- or
16-position, and free or functionally convertedhydroxyl groups
in the 1-, 3-, 6-, 7-, 11-, 15-, 16-, 17-, or 21-position. A
17-alkyl group may be ~-or ~-positioned.
The starting steroids include, for example, oestrone
methyl ether; 3-methoxy-~1'3'5(1)'3-oestratetraen-17~-ol; 3-
methoxy-18-methyl-~1'3'5(1)'3-oestratetraen-17-one; 3-methoxy-
~ '3'5(1)-pregnatrien-17~-ol-20-ethylene-ketal; 3-methoxy-
~1~3'5'(10)'9(11)-oestratetraen-17~-ol; 3-ethoxy-17a-methyl-
oestra-~1'3'5(1)-trien-17~-ol; 3-cyclohexyloxy-17~-vinyl-
~1'3'5(1)-oestratrien-173-ol; 3-methoxy-19-nor-~1'3'5(1)-
chloestatriene; 3-methoxy-1-methyl-19-nor-20-cycloethylenedioxy-
'3'5(10)-pregnatriene; 3-methoxy-17~,20;20,21-bis-methylene-
dioxy-pregna-l9-nor-~1'3'5(10)-pregnatriene; 3-methoxy-17-
ethylene-diOxy-~1'3'5(10)-oestratriene and 3-methoxy-17~-t-
b t ~1,3,5(10),9(11)_Oestratetraene.
The compounds obtained by the process of the present
invention are often intermediate products fot the preparation of
i 30 valuable pharmaceutical products.
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The present invention will be further illustrated by
way of the followiny Examples in which Examples 1, 4, 6, and 7
relate to divided cells.
Example 1
1.0 g of oestrone methyl ether is dissolved in 50 ml of
tetrahydrofuran and 200 ml of liquid ammonia, and the solution is
electrolyzed in the presence of 2.5 g of lithium perchlorate in a
cell divided by a glass frit for 1.5 hours at 1 ampere (cathode
of stainless steel and anode of graphite). After evaporating the
solvent, water is added, and the mixture is filtered. There is
thus obtained 0.9 g of 3-methoxy-~ ' (1)-oestradien-17~--ol melt-
ing at 114-116C (methanol~.
Example 2
2.0 g of 3-methoxy-~1'3'5(1)'3-oestratetraene-17~-ol
are eleckrolyzed in 200 ml of liquid ammonia and 20 ml of ethanol
in the presence of 2 g of lithium ethylate and 0.5 g of lithium C
anilide for 3 hours in an undivided cell between an aluminium
cathode and a platinum anode at a current density of 2.5 amperes/
cm . After working up, there are isolated 1.8 g of 3-methoxy-
~ '5(1~-oestradien-17~-ol melting at 110C.
Example 3 l~
0-5 g of d~l-3-methoxy-lg-methyl-~l~3~5(lo)~8 oest
; tetraen-17-one in 250 ml of liquid ammonia is electrolyzed in an
autoclave at 30C between a stainless steel cathode and a
graphite anode in the presence of 2.0 g of sodium chloride and
` 2.0 g of sodium ethylate at 2 amperes. When the reaction has
;, terminated, the solvent is evaporated by cautious pressure
equilization, water is added to the residue, and the mixture is L
filtered. There is thus obtained 0.4 g of _,1-3-methoxy-18-
methyl-h ' (1)-oestradien-17~-ol melting at 98-100C.
Example 4
- 1.0 g of 3-methoxy-hl'3'5(1)-pregnatrien-17a-ol-20-
ethylene-ketal is electrolyzed in a cell divided by a cation
-5-
exchange membrane in 200 ml of liquid ammonia in the presence
of 2.5 g of sodium perchlorate with an aluminium cathode. After
; working up, 1.0 g of 3-methoxy-Q2'5(1)-pregnadien-17~-ol-20- -
ethylene-ketal melting at 172-175C.
Example 5
1.0 g of 3-methoxy-~l~3~5(lO)~9(ll)-oestratetraen-17~-
-ol is dissolved in 25 ml of dioxane, and the solution is intro-
duced into a decolorized mixture of 0.5 g of lithium in 200 ml
of liquid ammonia, 5 g of lithium chloride, 15 ml of ethanol and
5 ml of aniline. When electrolysis at 1 ampere between two
platinum electrodes has terminated and the ammonia has been
evaporated, a large amount of water is added, and the mixture
; is filtered. 0.8 g of 3-methoxy-~2'5(1)-oestradien-173-ol
melting at 108-112C is isolated.
Example 6
1.0 g oE 3-methoxy-17-ethylene-dioxy-~1'3'5(1)-oestra-
triene in 10 ml of ethanol is added to 200 ml of liquid ammonia
and 2 g of lithium chloride, and electrolyzed for 1 hour at 1
ampere with a tungsten carbide electrode in a cell divided by
- 20 a cation exchange membrane. After working up, 0.9 g of 3-
methoxy-17-ethylene-dioxy-~2'5(1)-oestradiene melting at
115-120C is obtained.
Example 7
1.0 g of 3-methoxy-17 -t-butoxy-~1~3~5(10)~9(11) oe t
t~traen:i~sdissolved in 4 ml of aniline and 3 ml of ethanol,
added to 150 ml of liquid ammonia and 5 g of lithium perchlor~
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ate, and electrolyzed for 2 hours at 1 ampere with a merecury
~ electrode in a cell divided by a glass frit. After working up,
;, the crude product (1.1 g) is dissolved in ethanol and heat~d
-~ 30 with 3 ml of concentrated hydrochloric acid. By the cautious
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: addition of water and after cooling, 0.~ y of nor-testosterone ;:
is obtained which, after recrystallization from isopropyl ether, ;~
melts at 108-110C.
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