Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
11~77Z~
,
The present invention relates to a process for pre-
paring ethers of bufadienolide and bufatrienolide.
A process for preparing ethers of bufadienolide and
bufatrienolide of the general formula
0
C~
~ , I (I)
R' I
\ ~ )H
0/~
HO O ¦
l/~H3 y
I - OH
~CH2R
is described and claimed in applicants Austrian patent No. 349,159
from the above formula, X is a double bond between the carbon
atoms 4 and 5 or an epoxide group, R' is a methyl, formyl or
methylol group, and R is hydrogen, a straight or branched alkyl
radical having 1 to 16 carbon atoms, a straight or branched
alkenyl radical having 2 to 6 carbon atoms, an ethyinyl radical,
a straight or branched alkoxy radical having 2 to 11 carbon atoms,
a cycloaliphatic radical, the group CH2 attached on R forming
together with R a nucleus having 6 to 12 carhon atoms, an arornatic
or aliphatic-aromatic radical, e.g. a phenyl, phenylmethyl, 2-
phenylethyl or 3-phenylpropyl radical, a straight or branched
dialkylaminoalkyl radical having 1 to 7 carbon atoms, the nitrogen
atom of which is tertiary and may carry two alkyl radicals ha~ing
1 to 4 carbon atoms, in which substituents the straight or
branched
772V
aliphatic chains may be substituted by nitrogen or oxygen-
con'ainin~ heterocycles, e.g. pyridine, piperazine, pyrrolidine,
furyl, tetrahydrofur~l or morpholino groups or by halogen, e.g.
chlorine or bromine, except for compounds in which X is a double
bond, R' is methyl and R is H, R' is methyl, X is a double bond
and R is alkyl having 4 or 5 carbon atoms, and R' is formy], X
is a double bond and R is hydrogen or an alkyl group having 1 to
5 carbon atoms.
This process comprises reacting a glycoside of bufadieno-
lide or bufatrienolide of the ~eneral formula
~3
~~ `~"~
~ 1 ~H
O ~ (II)
`X
H ~ o
OH
OH
in which X and R' are as defined above, with a diazolkane of the
general formula
R.CH.N2 (II~)
in which R is as defined above, in an inert solvent in the
presence of a weakly acid catalyst.
Examples of such weakly acid catalysts are iron (III~
chloride in ether, borotrifluoride dietherate, boric acid ester,
aluminium chloride, aluminium isoprop~late, p-toluene ~ulfonic
acid, polyphosphoric acid in ether, arsenic trioxide titanium-
2~
tetrachloride, molybdenum(VI)~oxychloride, tin dichlorid~, tintetrachloride, tin sulfate, copper(II)-chloride, preferably ~oric
acid or m-boric acid.
It has been found, that the yield of the 3'-alkylether
can be improved substantially, if a mixture of titaniumtetrachlor-
ide and boric acid or of titanic acid ester and titaniumtetrachlor-
ide or titanic acid ester alone in absolute dioxane is used as
catalyst. As titanic acid esters may be used ethyl titanate,
n-propyl-, isopropyl-, n-butyl-, isobutyl-, cresyl-, 2-ethylhexyl-
titanate and diisopropoxy-bis-(2,4-pentan-dionato)-titanium(IV)
(=titanium acetylacetonate).
These catalysts are advantageous inasmuch as the
alkylation in position 3' of the rhamnose occurs more selectively
and less non-polar products (dimethylethers) are obtained in
comparison with boric acid.
According to the present invention therefore there is
provided a process for preparing an ether of bufadienolide and
bufatrienolide of the general formula O
oJI~
CH3
HO ¦ X
OH
OCH2R
in which formula X is a double bond between the car~on atoms
j7~z~
and 5 or an epoxide group, R' is a methyl, formyl or methylol
group, and R is hydrogen, a straight or branched alkyl radical
having 1 to 16 carbon atoms, a straight or branched alkenyl
radical having 2 to 6 carbon atoms, an ethyinyl radical, a straight
or branched alkoxy radical having 2 to 11 carbon atoms, a
cycloaliphatic radical, the group CH2 attached on R forming
together with R a nu_leus h.~ving 6 to 12 carbon atoms, an aromatic
or aliphatic-aromatic radical, a straight or branched dialkylamino-
alkyl radical havin~ l to 7 carbon atoms, the nitrogen atom of
which is tertiary and may carry two alkyl radicals having 1 to 4
carbon atoms, in which substitucnts the straight or branched
aliphatic chains may be substituted by nitrogen or oxygen-
containing heterocycles, or by halogen, except for compounds in
which X is a double bond, R' is methyl and R is H, R is methyl,
X is a double bond and R is alkyl having 4 ot 5 carbon atoms, and
Rl is formyl, X is a double bond and R is hydrogen or an alkyl
group having 1 to 5 carbon atoms, which process comprises reacting
a glycoside of bufadienolide or bufatrienolide of the general
formula O
l~ ~
CH
R~ ~ 1
OH (II)
OH
OH
- 4 -
1~77~ ~
in which X and R~ are as defined above, with a diazoalkane of
the general formula
R.CH.N2 (III)
in which R is as defined above, in an inert solvent and in the
presence of a catalyst selected from a mixture of titanium tetra-
chloride and boric acid a mixture of a titanic acid ester and
titanium tetrachloride and a titanic acid ester alone in absolute
dioxane.
The reaction is carried out in an inert absolute
solvent, preferably in absolute dioxane. The reaction proceeds
more slowly than with boric acid alone, ho~ever it is more
selective and more quantitative.
Furthermore, it has been found that the same concen-
tration of titanium tetrachloride alone as catalyst or the same
concentration of titanic acid ester alone do not provide the
same effect as the use of a mixture thereof. Also the mixture
of titanium tetrachloride and boric acid has a more selective
effect on the alkylation with diazoalkanes than titanium tetra-
chloride or boric acid alone. The reaction rate decreases in the
following order: titanium tetrachloride, boric acid and titanium
tetrachloride and boric acid.
The compounds of the present invention show an increased
activity on the hcart, in which connection the oral resorption is
especially improved_ .It should be particularly noted, that the
acti~ity firstly increased with increasing chain length of the
alkyl ether and then remains constant although the toxicity
becomes lower. The compounds also have an especially good
tolerance in the stomach and a slightly sedative action, which
latter may be a desired side action in case of cardiac diseases.
The new compounds can be administered in a form usual for heart
glycosides, e.g. in form of ta~lets, capsules or solutions con-
taining the active substance in pure form or in mixture with
11~772iD - -
xanthine derivatives.
The present invention will be further illustrated by
way of the following Examples.
Example 1
2 g of 3~-O-(~,L-rhamnosido)-14-hydroxy-4,5-epoxy-~ufa-
20,22-dienolide are dissolv~d in 100 ml of ahsolute dioxane and
16 ml of a solution of diazomethane in ether (O.5 mmoles/ml) are
added thereto. Finally 4 ml of a solution of 0.1 mmole of boric
acid and 0.005 mmoles of titanium tetrachloride/ml ;n absolute
dioxane are added ~s catalyst solution. The solution is allowed
to stand for 4 to 5 hours at room temperature, the excess of
diazomethane is decolored with a few drops of gl~cial acetic
acid, evaporated carefully in vacuo and the residue is taken up
into chloroform. ~he s~lution is shaken once with a 2~ solution
of sodium bicarbonate and twise with water, dried over anhydrous
sodium sulfate, r~moved hy filtration and evaporated in vacuo.
The residue is recrystallized several times from methanol-water
and 95 to 98~ of pure 3~-O-(~,L-3'-methyl-rhamnosido)-14-hydroXy-
4,5-epoxy-bufa-20,22-dienolide is obtained, mp. 220 to 232C.
The solution of the catalyst is prepared as follows:
In a 100 ml graduated flask 0~62 ~ boric acid (J0 mmoles)
~re dissolved in about 50 to 60 ml of absolute dioxane. 10 ml of
a solution of titanium tetrachloride in absolute dioxane (0.05
mmoles/ml; i.e. 0.55 ml of titanium tetrachloride/100 ml of
absolute dioxane) are added to the above solution and the flask
is fillPd up to the marking with absolute dioxane. The solution
contalns 0.1 mmole boric acid and 0.005 mmoles titanium tetra-
chloride/ml. The initially yellow colored soLution becomes
colorless ~fter a period of time. The solution is durable several
days at room temperature.
Example 2
.
2 ~ of 3~ ,L-rhamnosido~-14-hydroxy-bufa-4 t 20,22-
- 6 -
77~
trien~lide are dissolved in 80 ml of absolute dioxane and 10 ml
of a solution of 2-ethyl-diazohexane (0.8 mmoles/ml) in ether
are added thereto. Then 4 ml of a catalyst mixture of 0.05
mmoles n-propyltitanate and 0.005 mmoles titanium tetrachloride/
ml in dioxane are added. The reaction mixture is allowed to stand
for 16 hours at room temperature. Then the solution is worked
up, as descxibed in Ex~mple 1. By recrystallization from methanol-
water 90% of pure 3~-O-[~,L-3'-(2"-ethylhexyl)-rhamnosido]-14-
hydroxy-bufa-4,20,22-trienolide is obtained, mp. 235 to 241C.
The catalyst solution is prepared by dissolving 0.35 ml
of n-propyltitanate in a 25 ml-gradua~ed flask in about the half
of the volume of a~solute dioxane and adding 2.5 ml of a solution
of titanium tetrachloride in dioxane (0.05 mmoles/ml, see Example
1~ and completing to 25 ml.
Example 3
2 g of 3~-O-(~,L-rhamnosido)-14-hydroxy-bufa-4,20,22-
trienolide are dissolved in 80 ml of absolute dioxane and 11 ml
of a solution of 2-chlorodiazoethane (0.7 mmoles/ml) are added.
Then 4 ml of the mixed c~talyst boric acid/titanium tetrachloride,
as described in Example 1, are added and allowed to stand for 4
to 6 hours at room ~mperature. Then it is worked up as descri~ed
in Example 1. After recrystallization from acetic acid ethylester
3~-O-[a,L-3'-(2"-chloroethyl)-rhamnosido~-14-hydroxy-bufa-4,20,
22-trienolide is obtained in a yield of 95~, mp. 168 to 175C.
Example 4
_
1 g of 3~-O-I~,L-rhamnosido]-14-h~droxy-4,5-epox~.~-bufa-
20,22-dienolide is dissol~ed in 50 ml of absolute dioxane and
20 ml of ethynyldiazome~hane tO.2 mmoles/ml) are added. Then 2 ml
of a solution of n-butylti~anate in dioxane (0.05 mmoles/ml; 0.85
~0 ml of n-butyltitanate in 50 ml of ab~ol~lte dioxane) are added
and it is allowed to stand for 4 to 6 hours at room temperature.
Then it is worked up as described in ~xample 1. After recrystal-
11~772~ -
lization from acetic acid ethyl ester 1 g (93%) of pure 3~-O-
(~,L-3'-propargylrhamnosido)-1~-hydroxy-4,5-epoxy-bufa-20,22-
dienolide is obtained, mp. 228 to 237C.
Example 5
. _
1 g of 3~-O-(~,L-rhamno~sido)-14-hydroxy-bufa-4,20,22-
trienolide is dissolved in 40 ml of absolute dioxane and 15 ml of
a solution of 3-(2-ethyl)-hexyloxydiazopropane-(1) (0.6 mmoles/
ml) in ether are added. Then 2 ml of a solution of n-propyl-
titanate (0.05 mmoles/ml) and titan um tetrachloride (0.005 mmoles/
ml) are added, as described in Example 2, and allowed to stand
for 16 hours at room temperature. Then the solution is worked
up, as described in Example 1. After recrystallization from
acetic acid ethylester 1.1 g (85%) of pure 3~-O-[~,L-3'-(3"-(2"-
ethyl)-hexyloxypropyl)-rhamnosido]-14-hydroxy-bufa-4,20,22-
trienolide are obtained, mp. 225 to 230C.
Example 6
. .
3 g of 3~-O-(a,I,-rhamnosido)-14-hydroxy-4,5-epoxy-bufa-
20,22-dienolide are dissolved in 160 ml of absolute diox~ne and
~QLm1 of an etherica~lution of diazoeth~ Q.6 mmoles/ml)
are added thereto. 1 ml of a solution of ethyltitanate and
titanium tetrachloride in absolute dioxane (0.05 mmoles ethyl-
titanate and 0.005 mmoles titanium tetrachloride/ml are added
.
thereto and it is allcwed to stand for 4 to 6 hours at room
temperature~ After working up as described in Example 1 3.5 g
(93%) of pure 3~-O-(a,L-3'-ethylrhamnosido)-14-hydroxy-4,5-epoxy-
20,22-kufa-dienolide are obtained after recrystallization from
methanol-water, mp. 136 to 143C.
Example 7-
2 g of 3~-O-(~,L-rhamnosido)-14-hydroxy-4,5-epoxy-bufa-
20,22-dienolide are dissolved in 50 ml of absolute dioxane and
13 ml of a solution of diazopropane (0.4 mmoles/ml) in ether are
added thereto. Then 4 ml of a solution of iso-propyltitanate
~772~
(0.00~ mmoles/ml) and titanium tetrachlcride (0.005 mmoles/ml)
in dioxane are added. ~he solution is allGwed to stand for 3 to
4 hours at room temperature. After working up as described in
Example 1 2.1 g (96%) of pure 3~-O-(~,L-3'-propylrhamnosido)-14-
hydroxy-4,5-epoxy-bufa-20,22-dienolide are obtained after
recrystallization from methanol-water, mp. 2~0 to 235~C.
The catalyst solution is prepared by dissolving in a
graduated flask 0.35 ml of iso-propyltitanate in absolute dioxane
and adding 2.5 ml of a solution of titanium tetrachloride (0.05
mmoles/ml, see Example 1) in absolute dioxane and filling up to
the marking with absolute dioxane.
Example 8
2 g of 3~-O-(~,L-rhamnosido)-14-hydroxy-4,5-epoxy-bufa-
20,22-dienolide are dissolved in 50 ml of absolute dioxane and
63 ml of a solution of 3-methoxydiazopropane in ether (0.8 mmoles/
ml) are added thereto. To the solution 4 ml of a catalyst solution
of iso-butyltitanate and titaniu.~ tetrachloride ( n . 05 mmoles
iso-butyltitanate and 0.005 mmole.s titanium tetrachloride/ml) in
dioxane are a~de~. After standing for 12 hours at room temperature
it is worked up as described in Examp~e 1. After recrystalliz~tion
from eth~nol-water 2.16 g (95%) of pure 3~-O-(~,L-~'-methoxy-
propylrhamnos~do)-14-hydroxy-4,5-epox~-buffa-20,22-dienolide are
obtained, mp. 225 to 240C.
The catalyst solution is prepared by dissolving 0.43 ml
of iso-butyltitanate in a 25 ml-graduated flask in ab~olute dio-
xane and adding 2.5 ml of a solution of titanium tetrachloride
(0.05 mmoles/ml, as de~cribed in Example 1) and fillin~ up to the
marking with dioxane.
Example _
2 g of 3~ ,L-rhamnosido)-14-hydroxy-4,5-epcxy-bufa-
20,22-dienolide are dissolved in 50 ml of absolute dioxane and
25 ml of a solution of 2-methoxydiazoethane (O.3 mmoles/ml) in
xi 9
7~Y2~
ether are added. 4 ml of a mixture of cresyltitanate and titanium
tetrachloride in dioxan~ (0.~% ~resyltitanate and 0.005 ml of
titanium tetrachloride/ml) are added to the above solution. The
.solution is allowed to stand for 16 hours at room temperature.
After working up as described in Example 1 2.15 g (~5%) of pure
3~-O-t~,L-3'-methoxyethylrhamnosido)-14-hydroxy-4,5-epoxy-bufa-
20,22-dienolide are obtained after recrystallization from methanol-
water, mp. 21~ to 221C. -- ~
The catalyst solution is prepared by dissolving 0.1 g
of cresyltitanate in some absolute dioxane in a 25 ml-graduated
flask, adding 2.5 ml of a solution of titanium tetrachLoride
(0.05 mmoles/ml) in dioxane and filling up to the marking with
dioxane.
Example 10
2 g of 3~-O-(~,L-rhamnosido)-14-hydroxy-bufa-4,20,22-
trienolide are disso~ved in 50 ml of absolute d;oxane ~nd 20 ml
- of a solution of 3-dimethylaminodiazopropane (0.4 mmoles/ml) in
ether are added thereto. To the solution 4 ml of a solution of
2-ethylhexyltitanate and titanium tetrachloride (0.05 mmoles
2-ethylhexyltitanate and 0.005 mmoles titanium tetrachloride/ml)
in absolute dioxane are added. After standing for 17 hours at
room temperature the solution is worked up as described in Example
1. After recrystallization from acetic acid ethyl ester 2.1 g
(94%~ of pure 3~-0-[~ 3'-(3"-dimethylaminopropyl)-rhamnosido]-
14-hydroxy-bufa-4,20t22-trienolide are obtained, mp. 13~ to 146C.
The catalyst solution is prepared by dissolving 0.73
ml of 2-ethylh~xyltitanate in ~bsolute dioxane in a 25 ml-
graduated flask, adding 2.5 ml of a solution of titanium tetra-
chloride (0.05 mmoles/ml, see Example 1) in dioxane and filling
up to the marking with absolutc dicxanc.
Example 11
_ . _
2 g of 3~-O-~,L-rhamnosido)-l~-hydroxy-bufa-4,20,22-
- 10 -
~1~77Z~
trienolide are dissolved in 50 ml of absolu~e dioxane and ~0 ml
of a solution of 2-phenyldiazoethane (0.4 mmoles/ml) in ether
are added. Then 4 ml of a mixture of e~hyltitanate (0.05 mm~les/
ml) and titanium tetrachloride (0.005 mmoles/ml) in absolute
dioxane are added and the solution is allowed to stand 16 hours
at room temperature. After working up as described in Example 1
2.2 g (94%! of pure 3~-O-[~,L-3'-(2"-phenylethyl)-rhamnosido]-
14-hydroxy-bufa-4,20,22-trienolide are obtained after recrystal-
lization from acetic acid ethyl ester, mp. 180 to 195C.
The catalyst solution is prepared b dissolving 0.28 ml
of ethyl tit~nate in some absolute dioxane in a 2~ ml-graduated
flask, adding 2.5 ml--of a solution of titanium tetrachloride
(0.05 mmoles/ml) in dioxane and filljng up to the marking with
absolute dioxane.
Ex~mple 12
2 g of 3~-O-(~,L-rhamnosido)-14-hydroxy-bufa-4,20,22-
trienolide a~e dissolved in 50 ml of absolute dioxane and 25 ml
of a solution of diazopropyne (0.3 mmoles) in ether are added.
Then 4 ml of a mixture of titanium acetylacetonate (0.4%) and
titanil~m tetrachloride (0.005 mmoles/ml) in dioxane are added.
After standing for 14 hours at room temperature and working up
as described in Example 1 2.1 g (93%) of pure 3~-O-[~,L-3'-
(propyne-3")-rhamnosido]-14-hydroxy-bufa-4,20,22-trienolide are
obtained after ~ecrystallization from acetic acid ethyl ester,
mp. 170 to 175~C.
The catalyst so]ution is prepared by dissolving 0.1 ml
of titanium acetylacetonate in absolute dioxane in a 25 ml-
graduated flask, adding 2.5 ml of a solution of titanium tetra-
chloride (0.05 mmol~sjml) in absolute dioxane (see Example 1) and
filling up to the marking with absolute dioxane.
- 11 -
