Note: Descriptions are shown in the official language in which they were submitted.
The present invention provides a process for the manufacture of
steroid carboxylic acid lactones, in particular of 3-oxo-17~-pregn-4-ene-21,
17-carboxylic acid lactones of the formula
,~0
~f~,~J (I)
O `R
R2
wherein Rl represents an ~-acylthio group and R2 represents hydrogen or R
and R2 together represent a further 6,7-carbon-carbon bond. The acylthio
group is in particular a lower acylthio group, primarily the acetylthio
group.
The compounds are known aldosterone antagonists, such as
spironolactone, the compound of formula I, wherein Rl represents the acetyl-
thio group, which is commercially obtainable under the registered tradename
Aldacton ~. The 17-hydroxy-21-carboxylic acids and salts thereof which are
derived from the ~ 4~6 compounds of the above formula also have the same
anti-aldosterone effects and are likewise used as aldosterone antagonists.
Numerous processes for obtaining compounds of the formula (I)
have been proposed in the literature and patent literature. For example,
the Journal of the American Chemical Society, 79, pa~e 480~ and United
States patent 2,705,712 describe a process for obtaining a compound oE the
formula (~), wherein Rl and R2 to~ether represent a Eurthor 6,7-carbon-carbon
bond, which process can be illustrated as follows tprocess A):
f~
~ - 1 -
;.. . ~ . ~ . . ;
. .~.. ` .:
~ 6~
C -CH
-o CH--CH?~ 0~1 C2H5MgBr C--C-COOH
~` ~, potassaum I t ~ co ,~ OH
~ ~ amylate> ~ ~ ~" 2>~,~ ~ ~"
HO ~II) ~,'~,~ I
HO HO
Pd + C/H ~
chloranil ~ ~ ,H 2 ~ ~ .
O ~ ~ ~,C~J Oppenauer ~ 7
HO
.
To obtain the corresponding compounds, wherein R represents an
acylthîo group, especially the acetylthio group, the abo~e compound ~III) is
reactedwath athiocarboxylic acid, in particular thioacetic acid, according ;
to the process described in German patent 1,121,610. .
The above process for obtaining the 4,6-diene compound of ; ;
formula tIII~ must be regarded as redundant at present because of the
unsatisfactory yields. A better alternative is for example, the process o ::
United States patents 3,738,983 and 3,270,008 ~process B):
~ 2 -
.
.. , ' ,, ,, ' ,',. ' ',' . , ', .; ' ',, . ,' '.. ,,, ,' ' . ~ ', ,, ' ' " ,, " ', ".' ,
C--CH R= alkyl C- CH
HC-OR
RO - CH
CH3 a) CH3Mg Br
b) Co2
c) H
d) N(Et)3 ~:
~Lt)-NH COO
H ~ ~J o ~ a) H2-Pd/CaCO3 ~ DH
HO Br2
Li2C3/LiBr
Gorman O:EEenlogungsschrift 2,237J143 doscrlbos a method o:E
obtaining the spironolactone according to the :~ollowing roaction schomo
~procoss C):
- 3 -
3.~651~4L9
CH~ 0/\ CH~
CH30H / HCl
OC~13
HO
VII VI
chloranil
~ SCOC113
O . SCOCH
VIII 3
CrO3 I X
ac~ ~0
` SCOCH3
,~ .
~ ~65~4~
An alternative thereof is claimed in German Offenlegungsschrift
2,24~,834 ~process D) and another in German Offenlegungsschrift 2,248,835
(process E).
Finally, German Offenlegungsschrit 2,251,476 claims yet another
alternative method according to which a start is made from the 3-oxo-4,6-diene
derivatives which correspond to the above compounds of the formula V,
thioacetic acid is added to these, and the resultant corresponding 3-oxo-7~- .
acetyl-thîo-4-ene derivatives with intact 17~-hydroxy-17a-propionaldehyde-
acetal side-chain are oxidised in acid solution to give spironolactone.
The addition of thioacetic acid to the 6,7-double bond while preserving
intact the substituents contained in the starting material in 17-position
is described in this patent specification as surpri5ing, since acyclisation
of the following kind
/ \ / O~ ~ S-CO-CH3
~f\ , 1 ;~:,
0~1 ~ .
was to be expected in the acid medium of the thioacetic acid.
Experimental verification of this process has now revealed that
the 3-oxo-4,6-di.enes ~i.th 17~-hydroxy-l7~-propionaldehyde-acetal side-chain
referred to above as starting materials are not known at all and also cannot
be obtained according to the particulars of DOS 2,251,476. For i:~ the 3-o~o-
4-enes with 17~-hydroxy-17~-propionaldehyde-acetal side-chain initially
obtainablo according to DOS 2,237,143 and 2,248,834 re:Eorrod to abov~ (citod
on page 4 o~ DOS 2,251,476) are dehydrogenated with chloranil ~as also, for
example, in United States patent 3,137,690, also referred to on page 4 of
DOS 2,251,476 and on page 12 in the experimental part), then the 4,6-dienes
of th0 cyclic deri~atives formed in the above reaction scheme are obtained
and not the corresponding 4,6-dienes, and the ether group which derives
5 _
~J
", ' .
., , . ' , ~ . .
,.
.
~()65~4~1
~rom the alcohol used as ~olv~nt may be present instead of the ac~tylthio
group. The process described and claimed in DOS 2,251,476 therefore cannot be
performed.
From the operational point of view, all the processes referred to
hereinabove for obtaining carboxylic acid lactones of the formula (I) are
unsatisfactory. In the first published process A, reactions are used which
are lit~le suited to the exigencies of practice, for example the protracted
carbon dioxide treatment in the second step and the catalytic hydrogenation
in the second.
Process B affords in the subsequent working up a yield of app.
20 percent, referred to the dehydro-epi-androsterone used as starting material
for obtaining the 17 d~ethinyl-androst-5-en-3~,17~-diol indicated as first
step in the reaction scheme.
According to the experimental part of the respective patent appli-
cations, the yields of processes C to E are between 10 and 23 percent by weight
again referred to the dehydro-epi-androsterone used as starting material.
The present invention provides a process for the manu~acture of
compounds of the above formula I which affords higher yields than those of the
prior art and which from the operational point of view is also simpler, more
convenient, and easier to reproduce.
The process of the present invention for the manufacture of com-
pounds of the formula I comprises treating an acetal of 3~,17-dihydroxy-17~-
pregn-5-en-21-carbaldehyde in basic or neutral medium with a brominating agent
which is suitable ~or adding bromine to the double bond, oxidisin~ the 3-
hydroxy-5J6-dibromo der~vative so ormed with a hexavalent chromium compound
under basic or neutral conditions to conYert the 3-hydroxy group to a 3-oxo
group, dehydrobrominating ~he 3-one compound to obtain a ~,6-dien-3-one com-
pound, reacting the ~,6-dien-3-one with a compound of hexavalent chromium in
~ i - 6 -
J
.
.. .
~ 0~i5849
acid solution and, if a compound in which Rl represents an acylthio group and
R2 is hydrogen is required, reacting the 4,6-dien-3-one compound, either be-
fore or after reaction with the hexavalent chromium compound in acid solution,
with a thiocarboxylic acid to introduce an acylthio group at the 7-position.
The addition of bromine to the 5,6-double bond of the cited start-
ing materials according to the process of this invention can be effected with -
a brominating agent which is generally able to add bromine to double bonds,
while ensuring tha~ the reaction is carried out in basic ~r neutral medium.
This addition can therefore be accomplished in known manner, for example by
using bromine in an inert neutral solvent, for example a halogenated hydro-
carbon, such as ethylene chloride or chloroform, or in a di-lower alkyl-lower
alkanoic amide, for example dimethyl formamide, with or without a buffer, such
as an organic or inorganic baseJ or in an excess of an organic nitrogen base,
for example bromine in a tertiary organic aromatic base, such as pyridine or
the C-methyl homologs thereof, such as the picolines, in particular collidine.
Bromine forms perbromides as intermediates with those nitrogen bases, for
example the perbromides of hydrohalogen salts o the bases, for example the
perbromides of salts of hydrobromic acid. Such perbromides can also be used
with advantage for the bromination according to the invention. In particular,
pyridine hydrobromide perbromide is used. It is advantageous to use a small
excess over the amount of bromine required in theory or brominating a double
bond.
Besides the perbromides of th~ clted nitrogen bases or of other
bascsl lt is nlso possiblo to u9e tho adducts of bromine to ethers, ln parti-
cular cyclic ethers, such as dioxan. A tertiary aromatic base, such as one
.
- . ~
.: , ~ . , .
.. ..
of those referred to above, is also advantageously added in these cases.
The perbromides or bromine addu~ts are reacted in an inert organic
solvent, such as one of those referred to above, or also in an ether, a hydro-
carbon, in alcohols, in particular lower aliphatic univalent or bivalent
alcohols, such as methyl or ethyl alcohol, or n-butanol, or ethylene
glycol.
Other bromine addition complexes, besides those mentioned, can
also effect the addition, for example the addition complex of bromine and
tetramethylammonium bromide.
It is very advantageous to use pyridine hydrobromide perbromide,
which is reacted in pyridine solution and at room temperature or at lower
or elevated temperature~ for example from -10 to +100C, preferably from
0 to ~20C.
The oxidation of the 5,6-dibromo adduct with a compound of hexa-
valent chromium, for example chromium trioxide or chromic acid, will take
place in basic or neutral medium. If appropriate, a suf~icient amount of
the base used beforehand in the bromination is again added during the oxida-
tion, for example pyridine, so as to avoid overstepping the neutral point,
or the bromination reaction mixture obtained in the previous step is
treated with a pyridine chromate solution. This operation is advantageously
carried out at tsmperatures of app, -10 to app, ~30C.
The debromination of thc chromic acid oxidation product to be
then carried out according to the invention can also be accomplished in
known mannor. ~or this purposc thoro are used, for example, inorganic basic
agents, such as lithium salts, in particular lithium halides, primarily
lithium bromide, in the presence of a basic salt of an alkali metal or
alkaliTIe earth metal, such as the carbonates or basic carbonates, for example
oE lithium sodium, calcium or magnesium. The solvent used in this method
is advantageously a dialkylamide of a lower aliphatic carboxylic acid, in
~ - 8 -
.. , ~ , : . . ..
.,, :
,
~ -
5~49
particular a di-lo~er alkyl derivative, for example dimethyl formamide,
at temperatures between 0 and app. 180C, advantageously a~ temperatures
bet~een 80 and 150C. It is also possible to use nitrogen-containing
bases of aromatic character for the dehydrobromination, for example those
cited hereinabove, especially pyridine or collidine.
After hydrogen bromide has been removed in the manner described,
the 4,6 dien-3-one derivative containing the 17~-propionaldehyde-acetal
sidechain is obtained as reaction product. This compound can then be pro-
cessed direct to give the corresponding lactone of the formula ~I), wherein
Rl and R2 represent a further carbon-carbon bond bet~een position 6 and 7
or indirectly to give compounds of the same type with the 7~-acylthio
group, In the first case, the product is oxidised with a compound of hexa-
valent chromium in acid solution, especially in a mineral acid solution.
In doing so, the aldehyde-acetal group is simultaneously deacetalysed,
whereupon cyclisation of the propionaldehyde side-chain with the 17~-hydroxyl
group to give the cyclic hemi-acetal and oxidation thereof to give the
corresponding lactone group take place. The oxidation can be carried out
with chromium trioxide in acid solution, in particular in sulphuric acid,
hydrochloric acid or one of the phosphoric acids, or in a lower carboxylic
acid, such as an alkanecarboxylic acid of 1 to 7 carbon atoms, for example
formic acid, acetic acid or propionic acid or one of the butyric acids or
valeric acids, or in mixtures of these acids, also with or without the
addition of water. The oxidation can also be carried out in organic
solvents, such as ketones or ethers, for example in acetono, dioxan or
tetrahydro~uran, ~ith or without the addition o~ water.
It is advantageously to carry out a preliminary treatment with
one of the cited acids before the oxidation, when the cyclic hemi-acetal is
obtained ~irst, and to e~ect the oxidation in a second step under the condi-
tions just stated.
.~,1 9
349
In the second case, a thioalkane acid is added in known manner to
the 4,6-diene derivative obtained in the dehydrobromination step, i.e. as is
known for compounds of the formula I, wherein Rl and R2 represent a further
carbon-carbon bond between 6- and 7-position, and subsequently as described
above, ~reated in acid solution with a compound of hexavalent chromium.
The above addition of a thiocarboxylic acid to the 4,6-diene deri-
vative can be carried out in known manner as defined herein, for example by
treating the steroid with an excess of thiocarboxylic acid without a solvent
a~ ele~ated temperature. However, the reaction of the 4,6-steroid diene in
a polar solvent, in particular an alcohol, preferably a lower alkanol contain~
ing 1 to 7 carbon atoms, with app. 1.5 to 3.5 moles of thiocarboxylic acid,
if desired with the addition o~ water, gives better yields. The best yields
are obtained at temperatures between O and app. 120C, for example by carry-
ing out the reaction at the boiling point of the cited alcohols, for example
methanol, ethanol, propyl alcohol, isopropyl alcohol, the butanols or penta-
nols, in the absence of water, The most preferred temperatur0 range is that
between 50 and 100C. In this way very good yields o~ the desired 7~acyl-
~hio derivative are obtained without any appreciable formation of the 7~-
isomer, In particular, lower thioalkanoic acids containing 1 to 7 carbon atoms,
such as thioacetic acid, thiopropionic acid or thiovaleric acid, are used as
thiocarboxylic acids.
The acetals to be used as starting materials are derived from
any aliphatic, alicyclic, araliphatic or mixed aliphatic-alicyclic alcoholJ
pr~marily ~rom lower alkanols containing 1 to 7 carbon atoms or lower nlkane-
diols containing 1 to 7 carbon atoms. In particular the ethylene glycol ace-
tal o 3~,17~- dihydroxy-17~pregn-5-en-21-carbaldehyde is used as starting
material.
The process can be illustrated by the following example of the
- 10 -
r^-~ '
~' ~ , ' .
'' . ' ''" '' :.',, ' ' ' '
.
.
.
~;S8~9
manufacture of spiron~lactone or canrenOne C3-oxo-17~-pregna-4,6-diene-21,
17-carbolactone~, ~herein the theoretical yields, referred to the starting
material I', are indicated. As is evident, the total yield of spironolacton0
IV', referred to the starting material I', is 47% of theory, and of
canrenone V', 61% of thcory:
ICH3 !;~~
1~ pyridineperbromide
2~ chromium trioxyde-
pyridine
74,7% 3) Li2CO3 ~ dimethyl
of theory ` formamide
hioa~ tic acid ~J
III ~n. me ~anol IT'
q~ ~ :~ < ~ -~--6~ ~ ..
SCOC~13 ;:
chromic acid 1) H2SO~ .
64% of theory referred to ~ . .
; compound II' 2) chromlc ac d
IV' ~ V' ;
canrenone
SCOChl3 ~aldadiene)
spironolactone 61% of theory referred to 1'
47% of theory referred
to l'
. .
" r -1l-
.Y ~ .
; ' ' ~ ' ' `' '
. . . . , ,,.. ... . : . , :. . ., ~ . .
8~
To make a comparison ~ith earlier processes, for example those of
the German Offenlegung~schriften cited hereinbefore, the manufacture of I'
from dehydro-epi-androsterone by the method used in the~e patent speci~ica-
tions of reacting dehydro-epi-androsterone with a chloropropionaldehyde-
acetal, for example the ethylene acetal, in the presence of lithium, must
be included. This reaction affords a yield of app. 60~ of the theoretical
amount. By converting all yields into percentages by weight, referred to
dehydro-epi-androsterone, then in the manufacture of spironolactone by
the process of the present invention, for example in Examples 2 and 7, the
yield is app. 41 percent by weight, and in the manufacture of canrenone,
for example according to Examples 2 and ~, the yield is app. ~3 percent by
weight. On the other hand, as stated hereinbefore, the yields of the
processes C to E are app. 10 to 23 percent by weight of spironolactone,
referred to dehydro-epi-androsterone.
The process of the present invention can be carried out with a
still higher yield of the desired end products, provided compound I' is
obtained from dehydro-epi-androsterone by addition of chloropropionaldehyde-
ethylsne acetal/Li, by choosing the following novel and invent~ve modifica-
tion which, as particular embodiment of the process of the present inven-
tion, also forms an object thereof. It has been found that, when reactingthe dehydro-epi-androsterone with the chloropropionaldehyde-acetal in the
presence of lithium, a substantial amount of dehydro-epi-androsterone can
be recovered by reacting the reaction product with steam following the
roaction in known manner. Both dehydro-epi-androsterone ~nd the reaction
product, for example the 17~-(3'-ethylenedioxy-propyl)-androst-5-en-3~,17-
diol, can be readily separated from each other from the component which is
not volatile in steam, by means of conventional purification operations,
such as chromatography, for example through aluminium oxideJ and/or
; - 12 -
.~1 1 1
~i
.
" . ~ .. ~: ,
,
.
~o~
crystallisation. On account of this improvement in obtaining the starting
material of the present invention, as illustrated for example in Example 8,
it is possible to increase the yield or example of spironolactone,
among other things as a consequence of the recovery of starting material, `
i.e. of dehydro-epi-androsterone to 50%, and of canrenone to 52%, of the
~eight of reacted dehydro-epi-androsterone.
A particular advantage of the present process also resides in the
fact that in the steps of the reaction of the starting material with the
brominating agent, and of the oxidation thereof and the dehydrobromination,
l~ the 4,6-dien-3-one intermediate is formed as a unitary compound which can be ;~ -
readily obtained pure, for example by mere crystallisation, As against this,
in the processes C to E discussed at the outset, which all proceed via the
4,6-dien-3-one step according to formula VIII, it is difficult to obtain
pure preparations of this constitution, since the products are invariably
mixtures of alkoxy compounds which are epimeric at the 21a-carbon atom.
A consequence thereof is, among other things, that the puriication in the
final step, for example of the spironolactone, is very tedi~us and compli-
cated. In contradistinction thereto, products of such quality are obtained
in the final steps of the present process that normally a simple purifica-
tion, for example crystallisation, suffices to obtain entirely pure products.
T~e advantage o the present proce~s compared wlth that of
process B of United States patents 3,738,983 and 3,270,008, besides ~he ad-
vantages alreacly mentioned regarding the yields, also resides in the fact
that it involves only a eew and technically simple oporations.
If desired, the compounds of the formula I, wherein Rl and R2
represent a further carbon-carbon bond between position 6 and 7, can be
converted in kno~n manner into the salts, in particular the metal salts, of
the corresponding 17~-hydroxy-21-carbox~lic acids, for example b~ treatment
with metal hydroxides, such as potassium or sodium hydroxide, in a~ueous
- 13 -
~.... - . . . . .................. . . , . .:: . , : .... .
. . . . . .
- ~0~ 9
or alcoholic solution.
If desired, the compounds of the formula I obtained by the process
o the present invention, wherein Rl and R2 represent a further carbon-carbon
bond in 6,7-position, can be converted in known manner with a thiocarboxylic
acid, in particular with a lower thioalkanoic acid, for example one of
those referred to hereinbefore, into the compounds of the formula 1, in
which Rl represent~ an acylthio group and R2 represents hydrogen.
The invention also comprises those embodiments of the process
in which a compound obtained in any intermediate stage is used as starting
material and the missing process steps are carried out, or the process is
interrupted in any stage, or in which the starting materials are obtained
in situ. The invention also has for its object the special embodiment
described hereinabove in which the starting material is prepared by
reacting dehydro-epi-androsterone with a chloropropionaldehyde-acetal in
the presence of lithium~ and, following the reaction, the unreacted
dehydro-epi-androsterone is recovered after treating the reaction mixture
beforehand uith steam.
The invention also has for its object the embodiment of the
present process in which compounds of the formula I, wherein R1 and R2
represent a further 6,7-carbon-carbon bond, are obtained first and then
converted in known manner into the compounds of the formula I, wherein R
represents an acylthio group and R2 represents hydrogen.
The Eollowing ~xamples serve to illustrate the invention without
restricting it to what is described thercin.
Example 1
2~ g of dehydro-epi-androsterone are dissolved in 500 ml of abs.
tetrahydr~uran, Then 5.2 g of lithium wire~ cut into small pieces, are
added, ~fter cooling ~ith an ice bath to 0C, 38 g of ~-chloropropionalde-
hyde ethylene acetal in 50 ml of abs, tetrahydrofuran are added dropwise
14 -
~,^?`.¦
. .
,.,' . ~
with stirring in an atmosphere of nitrogen in the course of 15 minutes.
During thi~ addition, the mixture is so intensively cooled ~ice/sodium
chloride mixture) that the reaction temperature does not exceed 10C.
Stirring is subsequently continued for a further 2 1/2 hours at 0 C and `
overnight at room temperature ~under nitrogen). Excess pieces of lithium
are then separated off and the reaction solution is poured into ice water.
Extraction is then performed with ethyl acetate and the extract is washed
with saturated aqueous soaium chloride solution until neutral. The crude
product obtained after drying the organic phase over Na2SO4 and evaporating
it is filtered through 300 g of neutral A1203 of activity IIl unreacted
reagent and nonsteroid impurities being eluted with 3 litres of petroleum
ether/toluene ~1:1) mixture. With CH2C12 as eluant, 19.9 g of 17~-~3'-
ethylenedioxy-propyl)-androst-5-en-3~,17~-diol are obtained in m.p. 181-
182C after one recrystallisation from acetone/petroleum ether. Yield:
16.4 g ~60.6% of theory). IR. 3600, 3~50 cm 1~CH2C12). - NMR.: 0.87,
s, CH3tl8); 1,02, s~, CH3(19); 3.50, m, CH~3); 3.92, m, -OC~l2C~120-; ~.91,t,
J = ~, C~1(3'); 5.34, m, CH~6) ~CDC13).
Example 2
To 6 g of 17~-~3'-ethylenedioxy-propyl)-androst-5-en-3~,17~-diol
in 60 ml of pyridine are added at 0C 5.~ g of solid pyridine hydrobromide
perbromide. The mixture is then stirred for 3 hours at 0C under anhydrous
conditions. One hour ater the start of this reaction, ~1.5 g of Cr03 in
6 ml o~ H20 are added dropwise, with stirring, to ~5 ml of ice-cold pyridine,
the rate of addition be:Lng so chosen that the temperature in ~he flask does
not exceed 10C. The pyridine chromate solution obtained is then stirred
until completion of the parallel bromination reaction at 0C. The pyridine
chromate solution is then poured into the bromination solution and the
reaction mixture is stirred initially for a further 3 hours at ~C and then
- 15 - -
.~ .
. , .
l~S~
additionally overnight at room temperature. The batch is then diluted with a
substantial amount of C~IC13 and washed 4 times in succession with saturated
aqueous NaCl solution ten times with water. The organic phase is subsequent-
ly dried over NA2S04 and evaporated to dryness ln vacuo.
The crude oxidation product is dissolved repeatedly in toluene to
remove residual pyridine as an azeotrope and evaporated to dryness in vacuo.
The product is dissolved in 108 ml of abs. dimethyl formamide, treated with
10.8 g of LiBr and Li2C03 respectively, and heated, with stirring, in an
atmosphere of nitrogen to 1~0C in the course of 15 minutes and kept at this
temperature for a further 1 1/4 hours. The batch is afterwards allowed to
cool, diluted ~ith ethyl acetate, and washed ten times with water and once
with saturated sodium chloride solution. The organic phase is dried over
Na2S0~, then concentrated in vacuo, and the residue is filtered through 100 g
of neutral A1203 ~activity II). The apolar impurities are first eluted with
500 ml of toluene. The subsequent ethyl acetate eluates consist of 4.56 g of
ll@-hydroxy-17~-t3~-ethylenedioxy-propyl)-androsta-4,6-dien-3-one, and melt
at 132C after one recrystallisation from acetone/petroleum ether. Yield
after recrystallisation: 4.44 g (74.7% of theory). IR.: 3570, 3450, 1655,
1620, 1585 cm (CH2C12). - UV.: 287 ~19700~ in C2H50H. - NMR.: 0.95, SJ
CH3(18); 1.10, s, CH3(19), ca. 3.95~ m, -OCH2CH~0-; 4,89, t, J = 4, CH(3');
5.65, s, CH~4~; 6.08, s (2H), CH(6) ~ CH~7) (CDC13). - ~D ~ ~ 6 ~ in
CHC13~.
5 g o~ 17~-hydroxy-17~-~3'-ethylenediox~-prop~l~-androsta-~,6-
dien_3 one are dIssolved at room temperature in 50 ml of methanol. Then
7.5 ml of water and 2.5 ml of thioacetic acid are added in succession and
the mixture is stirred for 3 hours at room temperature. The batch is
thereafter poured into ice-cold 2 normal a~ueous Na~lC03 solution and extrac-
tion is performed with ethyl acetate. The extract is washed neutral with
saturated aqueous NaCl so~ution, dried over sodium sulphate and concentrated
q~ ~
,J ~ 1~ ~
.. ... . .. . . . .
-
'~ ' . ' : , '
65~34~
in vacuo, to yield 5.86 ~ of 7c~-acetrlthio-17~-hydroxy-17-C3'-ethylene-
dioxy-propyl)-androst-4-en-3-one ~IR. 3450 ~wide) 1685, 1670, 1620 cm 1
(CH2C12); NMR. 0.92, s, CH3(18~; 1.22, s, CH3(19); 2.33, s, SCOCH3;
3.94, m, CH(7) ~ - OCH2CH20 -; 4.91, t, J = 4, CH(3'); bs, CH(4) (CDC13)],
which ar0 further processed direct. The 5.86 g of crude product are
dissolved in 200 ml of acetone and the solution is cooled to 0C. Then 10
ml of 8 normal Cr03 in 8 normal H2SO4 are added dropwise, with stirring,
in such a way that the temperature does not exceed 10C. The mixture is
then stirred for 45 minutes at room temperature. Then 5 ml of the above
CrO3 solution are again added dropwise at room temperature and stirring is
continued for a ~urther hour at this same temperature. Thereafter 10 ml
of methanol are added, and the batch is stirred for 10 minutes and subse-
quently diluted with ethyl acetate. The ethyl acetate phase is washed 3
times with saturated aqueous solutions of sodium acetate and sodium
chloride respectively, dried over Na2SO4 and evaporated to dryness in vacuo.
Yield: 5.5 g of a crystalline product from which 2.75 g of spironolactone
(7-acetylthio-3-oxo 17a-preg-4-en-21,17-carbolactone t51% of theory,
referred to the aduct of Example 3), with a double melting point of 135
and 202C) are obtained by crystallisation from methanol at - 10C. [IR.
1770, 1670-1700 wide, 1620 cm 1 (CH2C12). UV. 240 ~19400) iD C2H50H. - MMR.
0,97~ s, CH3(18), 1.20, s, CH3(19); 2.31, s, SCOCH3; 2.84, 8-, I6 6= 15,I67= 4
I4 62, CH~6~):3.97, m, CH(7): 5,68) d.I - 2. CH(4~ (CDC13).
~xample 4
1 g o~ 17~-hydroxy-17a-~3'-ethyl0n0dioxy-propyl)-androsta-4,6-dien-
3-one is re~luxed with 1 ml of normal aqueous ~12SO4 in 90 ml of acetone,
with stirring, for 45 minutes. The mixture is then cooled to 0C, and with
~tirring, 7 ml of 8 normal Cr03 in 8 normal a~ueous H2SO4 are added dropwise
- 17 -
;- " : , , ~ , ,. . : .
s~g
in the course of 15 minutes. The batch is kept for a further 10 minutes
at 0C, then lO m] of methanol are added. The batch is diluted with ethyl
acetate and washed ~ times with saturated aqueous solutions of sodium
acetate and sodium chloride respectively. The organic phase is dried over
Na2S04 and evaporated to dryness. The crude product is filtered in CH2C12
over Al203 (activity II), in the course of which 840 mg of 3-oxo-17~-pregna-
4,6-diene-21,17-carbolactone are eluted; m.p. 152-153C after crystallisa-
tion from acetone/petroleum ether. Yield: 720 mg ~81.8% of theory).
IR.: 1770, 1658, 1620, 1585 cm 1 (CH2C12). - UV.: 283 (24000) in C2H50H. -
NMR.: 1.00, s, CH3(18); 1.11, s, CH3(19); 5.67, s, CH(4); 6.08, s (2H),
CH~6) ~ CH~7) ~CDC13).
Example 5
1 g of 3-oxo-17~-pregna-4,6-diene-21,17-carbolactone are dissolved
at room temperature in 6 ml of methanol and to the solution are added in
succession 1.5 ml of water and 0.5 ml of thioacetic acid. '~he mixture is
stirred for 3 hours at room temperature and extracted with ethyl acetate.
The extract is washed in succession with 2 normal aqueous Na}lC03 solution
and with saturated aqueous sodium chloride solution until the neutral point
is reached. The organic phase is dried over Na2S04 and evaporated in vacuo,
to yield 1,1 g of crude product from which 550 mg of spironolactone are
obtained after crystallisation from methanol at -10C, ~ direct comparison
reveals thls compound to be identical in every respect with tho preparation
obta:lned in Example 3.
Example 6
3.4 g of 3-oxo-17~-pregna-4,6-diene-21,17-carbolactone are dis-
solved in 10.2 ml Oe boiling methanol. Then 2 ml o thioacetic acid are
added dropwise to the boiling solution in the course o 5 minutes and the
mixture is boiled subsequently for a further 30 minutes, and then cooled to
~-~ 1 - 18
~,,,.1
.
'
0C, whereupon the reaction product crystallises out, The batch is allowed
to stand for 15 minutes at -10C and the crystals are collected by suction
filtration, washed with lO ml of cold methanol and dried in vacuo at 40C.
Yield: 3.~1 g of pure spironolactone with a double melting point of 135 and
202C and which a direct comparison reveals to be identical in every respect
with the material described in Example 3.
Example 7
1.80 g of 17~-hydroxy-17~-~3'-ethylenedioxy-propyl)-androsta-4,6-
dien-3-one are dissolved in 5.1 ml of boiling methanol. Then 1 ml of thio-
acetic acid are added dropwise to the boiling solution in the course of 5minutes and boiling is continued for a further 3~ minutes. The batch is
; thereafter cooled, diluted with ethyl acetate and the ethyl acetate extract
is washed in succession ~ith aqueous solutions of N~lC03 and NaCl until the
neutral point is reached. The organic phase is then dried over Na2S~ and
evaporated to dryness in vacuo, to yield 2.09 g of crude product, ~hich is
treated in 80 ml of acetone at 0C, with stirring, with ~ ml af a 8 normal
CrO3 solution in 8 normal aqueous H2S0~. The mixture is subsequently
stirred for 1 hour at room temperature, treated once more with 2 ml of the
above CrO3 solution and stirred for 1 hour. Extraction is effected with
ethyl acetate, the extract is washed 3 times wi~h saturated aqueous solu-
tions of sodium acetate and NaCl respectively, dried over Na2S0~, and
evaporated in vacuo to dryness. Yield: 1.87 g of crude spironolactone from
which 1.25 g o~ pure compound are obtainecl after one crystall:isation from
Ctl2C12-methanol. ~Physical data as in ~xamplc 3~.
Example 8
20 g of dehydro-epi-androsterone are dissolved in 500 ml of abs.
tetrahydrofuran. Then 5.2 g of clean lithium wire cut into small pieces
are added. The mixture is cooled to 0C with an ice bath and 38 g of ~-
chloropropionaldehyde ethylene acetal in 50 ml of abs. tetrahydrofuran are
-~.! - 19
;,5~
added drop~ise, ~ith ~tirring, in the course of 15 minutes in a nitrogen
atmosphere. The reaction mixture is so intensively cooled that the tempera-
ture does not rise above 10C. The mixture is then stirred for a further
2 1/2 hours at 0C and overnight at room temperature ~in both cases under
nitrogen). Excess lithiu~ is then separated off and the mixture poured into
; ice water. Excess reagent and its degradation products are separated off by
steam distillation The residue which is non-volatile in steam is finally
~ extracted with methylene chloride. The methylene chloride phase is washed
neutral with saturated aqueous NaCl solutionl dried o~er Na2S0~ and
evaporated to dryness in vaGuo. The crude product is filtered through
600 g of A1203 (activity II~ and in doing so 4 fractions are eluted with 1
litre of methylene chloride on each occasion. The column is then washed
out with 6 fractions of meth~lene chloride/eth~l acetate mixture 4:1 (using
1 litre on each occasion). ~vaporation of the third frackion ~ield 3.2 g o~
unreacted crude dehydro-epi-androsterone from which 2 65 g o pure substance
are recoverecl ~y crystallisation from acetone petroleum ekher. Fractions ~
to 10 yield 2~.1 g of 17~-(3-0th~1enedioxy-propyl)-androst-5-en-3~,17~-diol,
which me}ts ak 181-182C~C ater crystallisation from methylene chloride/
petroleum. (Yield 17 g = 7~% of theory, taking into account the starting
material recovered).
; ~ - 20 _
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