ESTERS DE LA BUFATRIENOLIDE RHAMNOSIDE ET LEURS PROCEDES DE PREPARATION

BUFATRIENOLIDE RHAMNOSIDE ETHERS AND A PROCESS FOR THEIR PREPARATION

Abrégé anglais

A B S T R A C T
Proscillaridin-2',3'-orthoester-4'-methylether or proscillaridin
2',3'-orthocarbonate-4'-methylether derivatives of formula I
<IMG> I
in which R1 represents an alkyl group containing from 1 to 4 carbon atoms and
R2 represents a hydrogen atom,
or an alkoxy group containing from 1 to 4 carbon atoms. These compounds find
application in the treatment of cardiac insufficiency.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the production of a proscillaridin-2',3'-orthoester-4'-
methylether or proscillaridin-2',3'-orthocarbonate-4'-methylether, conforming
to the general formula:
<IMG> I
in which R1 represents an alkyl group containing from 1 to 4 carbon atoms
and R2 represents a hydrogen atom, or an alkoxy group containing from 1 to
4 carbon atoms, which comprises methylating a corresponding 4'-hydroxy com-
pound of the formula:
<IMG> II

in which R1 and R2 are as previously defined.
2. Process according to claim 1 in which the starting material of
formula II is prepared by reacting proscillaridin with a compound of the
formula (R1O)3 CR2 wherein R1 and R2 are as defined in claim 1.
3. Process according to claim 1 for production of a proscillaridin-2',-
3'-orthoester-4'-methylether or a proscillaridin-2',3'-orthocarbonate-4'-
methylether conforming to the general formula I
<IMG> I
wherein R1 represents an alkyl group containing one to four carbon atoms and
R2 represents hydrogen,
or an alkoxy group containing one to four carbon atoms, which comprises
reacting proscillaridin with a compound of formula (R1O)3 CR2, in which R1
and R2 have the above meanings, and thereafter methylating the product in
the 4'-position.
4. Proscillaridin-2',3'-orthoester-4'-methylethers and proscillaridin-
2',3'-orthocarbonate-4'-methylethers whenever prepared by the process of
claim 1, 2 or 3 or by an obvious chemical equivalent thereof.

5. Process according to claim 1, 2 or 3 in which the methylation in
the 4'-position is effected by reaction with methyl iodide in the presence
of sodium hydride or barium hydroxide.
6. Process according to claim 1, 2 or 3 in which the methylation in
the 4'-position is effected by reaction with methyl iodide in the presence
of sodium hydride using dimethylformamide as solvent.
7. Process according to claim 2 in which the reaction of proscillari-
din with a compound of the formula (R1O)3 CR2 is effected in a polar aprotic
organic solvent and in the presence of catalytic amount of an inorganic or
organic acid.
8. A process according to claim 7 in which the solvent is dioxan,
tetrahydrofuran, ethylene glycol dimethylether or diethylene glycol dimethyl-
ether.
9. A process according to claim 7 in which the inorganic or organic
acid is hydrochloric or p-toluene-sulphonic acid.
10. A process according to claim 7, 8 or 9 in which the reactant of
formula (R1O)3 CR2 is trimethyl orthoformate, triethyl orthoformate,
tetramethyl orthocarbonate or tetraethyl orthocarbonate.
11. A process according to claim 1, 2 or 3 in which R1 is methyl and
R2 is hydrogen.
12. A process according to claim 1 in which proscillaridin 2',3'-methyl-
orthoformate 4'-methylether is prepared by methylating proscillaridin 2',3'-
methylorthoformate.
13. A process according to claim 12 in which the methylation is effect-
ed by reaction with methyl iodide in the presence of sodium hydride.

14. A process according to claim 12 in which the proscillaridin 2',
3'-methylorthoformate is prepared by reacting proscillaridin with trimethyl
orthoformate.
15. Proscillaridin 2',3'-methylorthoformate 4'-methylether whenever
prepared by the process of claim 12, 13 or 14 or by an obvious chemical
equivalent thereof.
16. A process according to claim 1, 2 or 3 in which R1 is ethyl and
R2 is hydrogen.
17. A process according to claim 1 in which proscillaridin 2',3'-
ethylorthoformate 4'-methylether is prepared by methylating proscillaridin
2',3'-ethylorthoformate.
18. A process according to claim 17 in which the methylation is
effected by reaction with methyl iodide in the presence of sodium hydride.
19. A process according to claim 17 in which the proscillaridin 2'-3'-
ethylorthoformate is prepared by reacting proscillaridin with triethylortho-
formate.
20. Proscillaridin 2',3'-ethylorthoformate 4'-methylether whenever
prepared by the process of claim 17, 18 or 19 or by an obvious chemical
equivalent thereof.
21. A process according to claim 1, 2 or 3 in which R1 is methyl and
R2 is methoxy.
22. A process according to claim 1 in which proscillaridin 2',3'-
dimethylorthocarbonate 4'-methylether is prepared by methylating proscill-
aridin 2'-3'-dimethoxyorthocarbonate.

23. A process according to claim 22 in which the methylation is
affected by reaction with methyl iodide in the presence of sodium hydride.
24. A process according to claim 22 in which the proscillaridin 2',
3'-dimethylorthocarbonate is prepared by reacting proscillaridin with
tetramethyl orthocarbonate.
25. Proscillaridin 2',3'-dimethylorthocarbonate 4'-methylether, when-
ever prepared by the process of claim 22, 23 or 24 or by an obvious
chemical equivalent thereof.

Description

-` 1054593
The present invention relates to bufatrienolide rhamnoside ethers
and to a process for their preparation.
Proscillaridin 4'-methylether is ~nown, and, has good pharmacologi-
cal properties which make it very suitable for the treatment of cardiac in-
sufficiency. However, known processes for preparing this compound produce
comparatively low yields. Thus, it is known that proscillaridin can be methy-
lated and from the mixture of ethers thus obtained, a small yield of the 4'-
methylether is isolated. Alternatively, proscillaridin can be converted into
its 2',3'-acetonide, which can then be methylated. The isopropylidene
residue is then separated. The yield obtained by using this process is
about 25 %.
; It has now been found that certain bufatrienolide rhamnoside
ethers can be produced more readily and in greater yields. Moreover, on
~; account of their enteral resorption characteristics, they are very suitable
for the treatment of cardiac diseases.
According to the present invention, there is provided compounds
of the general formula I
o~3 '
¦ I
~/; )H
CH30 0 / ~J
X
R10 R2
in which Rl represents an alkyl group containing from 1 to 4 carbon atoms
and R2 represents a hydrogen atom or an alkoxy group containing from 1 to 4
carbon atoms.
According to the present invention there is also provided a
- 1 -
`:
: '

1054593 `: :
process for the production of a proscillaridin-2',3'-orthoester-4'- :
methylether or proscillaridin-2',3'-orthocarbonate-4'-methylether, conform- ~ :
ing to the general formula
O~
CH30 o
~Y ~
'
O O ~ '
1 2
in which Rl represents an ethyl group containing from 1 to 4 carbon atoms
and R2 represents a hydrogen atom or an alkoxy group containing from 1 to 4
carbon atoms, which comprises methylating a corresponding 4'-hydroxy com-
pound of the formula:-
O
0~
~ II
~\ /~/~ ''- '
l ¦ OH -: :~
OH O ~ ~ . . . .
1~
.
\~/
'. : :
O ,:
.
R10 R2

lOS4593
in whLch Rl and R2 are as previously defined.
The starting of formula II is itself prepared by the reacting
proscillaridin with a compound of the formula: CR10)3 CR2J wherein Rl and R2
have the same significance as stated above.
The reaction of proscillaridin with (R10)3 CR2 is effected in a
suitable polar aprotic organic solvent, such as dioxan, tetrahydrofuran,
ethylene glycol dimethylether or diethylene glycol dimethylether, with a tri-
-- alkylorthoester~ which is preferably trimethyl or triethyl orthoformate ~
~ i orthoa~ or with a tetraalkyl orthocarbonate, preferably tetramethyl or
tetraethyl orthocarbonate, and traces of an inorganic or organic acid, such
as, for example, hydrochloric acid or p-toluene-sulphonic acid. The crude
product thus obtained, after conventional working up in an identical manner
to that described in the literature for proscillaridin 2',3'-acetonide, is
methylated in dimethylformamide utilising methyl iodide and an inorganic
or organic base, preferably sodium hydride or barium hydroxide.
The invention will be further described, with reference to the ~-~
following non-limitative Examples.
EXAMPLE 1
Proscillaridin 2',3'-ethylorthoformate 4'-methylether.
To a solution of proscillaridin (5.3 g. 10 mMol) in an hydrous
tetrahydrofuran ~25 ml) is added triethylorthoformate (5 ml) and p-toluene-
sulphonic acid ~5 mg). The reaction mixture is stirred for 15 minutes at room
temperature~ and is then treated with ethyl acetate (100 ml) and is shaken out
with a saturated aqueous sodium bicarbonate solution ~30 ml). The organic
phase is washed with water, dried over sodium sulphate and evaporated in
vacuo. There is thus obtained 6.5 g of crude proscillaridin 2',3'-ethylortho-
formate. The crude product is dissolved in dimethylformamide (50 ml), treated
with methyl iodide (10 ml) and a substantially 55% suspension of sodium hydride
in oil (4 g) and stirred for one hour at room temperature. Ethyl acetate is
used for working-up the mixture, the organic phase then being repeatedly shaken

1054593
out with water, dried over sodium sulphate and concentrated in vacuo. The
residue is subjected to chromatography on kiesel gel using a 2 : 1 mixture
of methylene chloride and ethyl acetate as eluant.
There is thus obtained 3.5 g of pure proscillaridin 2', 3'-ethyl-
orthoformate 4'-methylether, which represents 58% of the theoretical yield.
The product, in amorphous form, has a melting point of 120 to 125C and an
[alD of - 74. (c = 0.5 chloroform). The compound has an Rf-value of 0.37
(thin layer chromatography on kiesel gel completed plates 60 R254 made by the
firm E. Merck, Darmstadt; the eluant being a 2 : 1 mixture of methylene chlor-
; 10 ide and ethyl acetate chamber saturation, flow path lS cm). The compound has
an empirical formula of C34H4809 and a molecular weight of 600.7.
Elementary Analysis
Calculated C 67.98% H 8.05%
Found C 68.0% H 8.3 %
Example 2
:~, Proscillaridin 2',3'-methYlorthoformate 4'-methvlether. ~ -
., ~
In a manner analogous to that described in Example 1, starting
! .`.
`~ from proscillaridin (1.0 g) and the methyl ester of orthoformic acid (1.0 ml),
there is obtained 0.45 g. of pure proscillaridin 2',3i-methylorthoformate
4'-methylether (41 % of the theoretical yield). Melting point: 108 to
113C (in amorphous form) [~]20 : _ 78 (c = 0.5 chloroform) f-value : 0.32
(conditions as in Example 1)
Empirical Formula: C33
Molecular Weight: 586.7
Elementary Analysis:
; Calculated C 67.55% H 7.90%
Found C 67.6 % H 8.1 %
- Example 3
Proscillaridin 2',3'-dimethylorthocarbonate 4'-methylether ;
In a manner analogous to that described in Example 1, by utilizing
1.0 g proscillaridin and 1.5 ml of the methyl ester of orthocarbonic acid,
_ 4 _
,.
, .

lOS4S93
0.41 g of pure proscillaridin 2',3'-dimethylorthocarbonate 4'-methylether
(36% of the theoretical yield) is obtained. Rf-value 0.36 (conditions as in
Example l)