CH637145A5 - Process for the preparation of bufadienolide ethers and bufatrienolide ethers - Google Patents

Description

637 145

2nd

PATENT CLAIMS 1. Process for the preparation of bufadienolide and bufa-trienol ether of the formula I

O

CH

OH

HO

OH

OCIUR

in which X represents a double bond between the C atoms 4 and 5 or an epoxy group, R 'is a methyl, formyl or methylol group and R is hydrogen, a straight or branched alkyl radical having 1 to 16 C atoms, a straight or branched alkenyl radical with 2 to 6 C atoms, an ethynyl radical, a straight or branched alkoxy group with 2 to 11 C atoms, a methoxymethyl or methoxyethyl radical, a cycloaliphatic radical, the CH 2 group attached to R with R being a ring with 6 forms up to 12 carbon atoms, an aromatic or araliphatic radical, a dialkylaminoalkyl radical with 1 to 7 carbon atoms in the alkylene chain, the nitrogen atom carrying two straight or branched alkyl radicals with 1 to 4 carbon atoms, the straight or branched aliphatic chains can be substituted by nitrogen- or oxygen-containing heterocycles or by halogen, with the exception of the compounds in which R 'is methyl or formyl, X is a double bond and R is mean hydrogen or alkyl having 1 to 5 carbon atoms, with a bufadienolide or bufatrienolide glycoside of the formula II

O

CH

011

HO

OH

OH

wherein X and R 'have the above meaning, with a diazo-alkane of the formula III

R-CH-N2 (IE),

wherein R has the meaning given above, in an inert solvent in the presence of a catalyst, characterized in that a mixture of titanium tetrachloride and boric acid or of titanium acid ester and titanium tetrachloride or titanium acid ester is used alone in absolute dioxane as the catalyst.

2. The method according to claim 1, characterized in that as titanium ester ethyl titanate, n-propyl, isopropyl, n-butyl, isobutyl, cresyl, 2-ethylhexyl titanate or diisopropoxy-bis- (2,4-pentanedionato) - titanium (IV) is used.

CH-PS 615 200 describes a process for the preparation of bufadienolide and bufatrienol ether of the formula I.

O

CH

OH

HO

CH

OH

in which X represents a double bond between the C atoms 4 and 5 or an epoxy group, R 'is a methyl, formyl or methylol group and R is hydrogen, a straight or branched alkyl radical having 1 to 16 C atoms, a straight or branched alkenyl radical with 2 to 6 C atoms, an ethynyl radical, a straight or branched alkoxy group with 2 to 11 C atoms, a methoxymethyl or methoxyethyl radical, a cycloaliphatic radical, the CH 2 group attached to R with R being a ring with 6 to 12 C -Atoms forms an aromatic or araliphatic radical, such as a phenyl, phenylmethyl, 2-phenylethyl or 3-phenylpropyl radical, a dialkylaminoalkyl radical with 1 to 7 carbon atoms in the alkyl chain, the nitrogen atom carrying two straight or branched alkyl radicals with 1 to 4 carbon atoms, the straight ones in each case or branched aliphatic chains by nitrogen- or oxygen-containing heterocycles, such as Pyridine, piperazine, pyrrolidine, furyl, tetrahydrofuryl or morpholino groups or may be substituted by halogen, such as chlorine or bromine, with the exception of the compounds in which R 'is methyl or formyl, X is a double bond and R is hydrogen or

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

3rd

637 145

Alkyl with 1 to 5 carbon atoms mean, described and claimed, which consists in that a bufadienolide or bufatrienolide glycoside of the formula II

O

in the following order: titanium tetrachloride, boric acid, titanium tetrachloride and boric acid.

The compounds of the formula I are used in the therapy of heart diseases, whereby they are distinguished by a good oral absorption as well as by a high enteral effectiveness and a high decay rate. They also have the advantage of not having any side effects.

The following examples are intended to explain the present invention in more detail.

(II),

wherein X and R 'have the meaning given above, with a diazoal-kyn of the formula III 30

R-CH-N,

(HI),

where R has the meaning given above, in an inert solvent in the presence of a weakly acidic catalyst. 35 The compounds excluded by the disclaimer are the subject of AT-PS 299 456.

The following are mentioned as weakly acidic catalysts: iron (III) chloride in ether, boron trifluoride diethylate, boric acid ester, aluminum chloride, aluminum isopropylate, p-toluenesulfonic acid 40 re, polyphosphoric acid in ether, arsenic trioxide, titanium tetrachloride, molybdenum (VI) oxychloride, tin tetrachloride, tin , Copper (II) chloride, but preferably boric acid or m-boric acid.

It has now surprisingly been found that the yield of the 3'-alkyl ether can be substantially improved if a mixture of titanium tetrachloride and boric acid or of titanium acid ester and titanium tetrachloride or titanium acid ester alone in absolute dioxane is used as the catalyst. Suitable titanium acid esters are: ethyl titanate, n-propyl, iso-50 propyl, n-butyl, isobutyl, cresyl, 2-ethyl hexyl titanate and diisopropoxy-bis- (2,4-pentanedionato) titanium (IV) ( = Titanium acetylacetonate).

The advantage of these catalysts is that the alkylation takes place more selectively in the 3 'position of the rhamnose and, in contrast to boric acid, 55 less non-polar products (dimethyl ether) are formed.

The reaction is carried out in an inert, suitably absolute solvent, preferably in absolute dioxane. The conversion is slower than with boric acid alone, but 60 more selective and quantitative.

It was also found that with the same concentration of titanium tetrachloride alone as a catalyst or with the same concentration of titanium ester alone, the same effect was not achieved as with the mixture of the two. The mixture of titanium tetrachloride and boric acid also has a more selective effect with respect to alkylation with diazoalkanes than titanium tetrachloride or boric acid alone. The reaction speed increases

example 1

2 g of 3ß-0- (aL-rhamnosido) -14-hydroxy-4,5-epoxy-bu-fa-20,22-dienolide are dissolved in 100 ml of absolute dioxane 15 and with 16 ml of a solution of diazomethane in ether ( 0.5 mM / ml) was added. Finally, 4 ml of a catalyst solution of 0.1 mM boric acid and 0.005 mM titanium tetrachloride / ml in absolute dioxane are added. The solution is left to stand for 4 to 5 hours at room temperature, the excess 20 of diazomethane is decolorized with a few drops of glacial acetic acid, then evaporated carefully in vacuo and the residue is taken up in chloroform. The solution is now shaken once with a 2% sodium bicarbonate solution and twice with water, dried over anhydrous sodium sulfate, filtered off and evaporated in vacuo. The residue is recrystallized several times from methanol-water and 95 to 98% pure 3ß-0- (a, L-3 '-methylrhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide is obtained, Mp 220-232 ° C.

The catalyst solution is prepared as follows: 0.62 g (10 mM) boric acid in about 50 to 60 ml abs. Dioxane dissolved. 10 ml of a solution of titanium tetrachloride in abs are added to this solution. Dioxane (0.05 mM / ml; i.e. 0.55 ml titanium tetrachloride / 100 ml absolute dioxane) and fills to the mark with abs. Dioxane. The solution contains 0.1 mM boric acid and 0.005 mM titanium tetrachloride / ml. The initially colored yellow solution becomes colorless after some time. The solution is stable for several days at room temperature.

Example 2

2 g of 3ß-0- (a, L-rhamnosido) -14-hydroxy-bufa-4,20,22-trienolide are dissolved in 80 ml of abs. Dissolved dioxane and mixed with 10 ml of a solution of 2-ethyldiazohexane (0.8 mM / ml) in ether. 4 ml of a catalyst mixture of 0.05 mM n-propyl titanate and 0.005 mM titanium tetrachloride / ml in dioxane are added to the solution. The reaction mixture is left to stand at room temperature for 16 hours and the solution is worked up as described in Example 1. 90% of pure 3β-0- [a, L-3 '- (2 "-ethylhexyl) rhamnosido] -14-hydroxy-bufa-4,20,22-trienolide, mp 235, is obtained by recrystallization from methanol-water up to 241 ° C.

The catalyst solution is prepared by placing 0.35 ml n-propyl titanate in a 25 ml volumetric flask in approximately half the volume in abs. Dioxane dissolves and then mixed with 2.5 ml of a titanium tetrachloride solution in dioxane (0.05 mM / ml, see Example 1) and made up to 25 ml.

Example 3

1 g of 3β-0- [a, L-rhamnosido] -14-hydroxy-4,5-epoxy-bu-fa-20,22-dienolide are dissolved in 50 ml of abs. Dissolved dioxane and mixed with 20 ml of ethynyldiazomethane (0.2 mM / ml). 2 ml of a solution of n-butyl titanate in dioxane (0.05 mM / ml; 0.85 ml of n-butyl titanate in 50 ml of absolute dioxane) are added to the solution and the mixture is left to stand for 4 to 6 hours at room temperature. It is worked up as described in Example 1 and, after recrystallization from ethyl acetate, 1 g (93%) of pure 3β-0- (a, L-3'-propargylrhamnosido) -14-hydroxy-4,5-epoxy-bufa- 20,22-dienolide, mp 228-237 ° C.

637145

4th

Example 4 The catalyst solution is prepared by 0.1 g

3 g 3ß-0- (a, L-rhamnosido) -14-hydroxy ~ 4,5-epoxy-bu-cresyl titanate in a 25 ml volumetric flask in a little abs. Dioxane fa-20,22-dienolide are abs. In 160 ml. Dissolve dioxane and dissolve and add 2.5 ml of a 0.05 M / ml titanium tetrachloride solution in di-50 ml of an ethereal diazoethane solution (0.6 mM / ml) and add to the mark with dioxane.

puts. 1 ml of an ethyl titanate titanium tetrachloride solution 5 is added

in abs. Dioxane (0.05mM ethyl titanate and 0.005mM titante example 8

trachloride / ml) and leaves for 4 to 6 hours at room temperature - 2 g 3ß-0- (a, L-rhamnosido) -14-hydroxy-bufa-4,20,22-

stand temperature. After working up as described in Example 1, 50 ml abs. Dissolved dioxane and with a solder, obtained after recrystallization from methanol-water solution of 20 ml of 3-dimethylaminodioazopropane (0.4 mM / ml) in 3.5 g (93%) of pure 3ß-0- (a, L-3 '-Äthylrhamnosido) -14- 10 ether added. 4 ml of a solution of hydroxy-4,5-epoxy-20,22-bufa-dienolide, mp. 136 to 143 ° C., are added to the solution. 2-ethylhexyl titanate and titanium tetrachloride (0.05 mM 2-ethyl

hexyl titanate and 0.005 mM titanium tetrachloride in abs. Dioxane Example 5 added. After standing at room temperature for 17 hours, the

2 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-4,5-epoxy-bu solution, as described in Example 1, worked up. Fa-20,22-dienolide is obtained in 50 ml abs. Dioxane dissolved and with 15 after recrystallization from ethyl acetate 2.1 g (94%) 13 ml of a solution of diazopropane (0.4 mM / ml) in ether pure 3ß-0- [a, L-3 '- (3 "-dimethylaminopropyl ) Then add 4 ml of a solution of i-propyl titanate do] -14-hydroxy-bufa-4,20,22-trienolide, mp 135 to 146 ° C. (0.05 mM / ml) in titanium tetrachloride (0.005 mM / ml) in dioxane The catalyst solution is prepared by adding one in. The solution is left to stand for 3 to 4 hours at room temperature in a 25 ml volumetric flask with 0.78 ml of 2-ethylhexyl titanate in slightly abs. After working up, as described in Example 1, 20 dioxane dissolves and 2.5 ml of a 0.05 mM / ml titanium tetrachloride solution is obtained after recrystallization from methanol-water, 2.1 g solution (see Example 1) in dioxane and added until Make up (96%) pure 3ß-0- (a, L-3 '-propylrhamnosido) -14-hydroxy- with absolute dioxane.

4,5-epoxy-bufa-20,22-dienolide, mp 230-235 ° C.

The catalyst solution is prepared by 0.35 ml of i-propyl titanate in a 25 ml volumetric flask in a little abs. Dioxane 25 Example 9

dissolves and 2.5 ml of a titanium tetrachloride solution (0.05 mM / ml, sie- 2 g 3ß-0- (a, L-rhamnosido) -14-hydroxy-bufa-4,20,22-he example 1) in abs . Add dioxane and to the mark with trienolide in 50 ml abs. Dissolved dioxane and with 20 ml abs. Replenishes dioxane. a solution of 2-phenyldiazoethane (0.4 mM / ml) in ether. Then 4 ml of a mixture of ethyl titanate Example 6 30 (0.05 mM / ml) and titanium tetrachloride (0.005 mM / ml) in abs.

Add 2 g of 3ß-0- (a, L-rhamnosido) -14-hydroxy-4,5-epoxy-bu-dioxane and leave the solution for 16 hours at room temperature-fa-20,22-dienolide in 50 ml abs. Dissolve dioxane and stand with temperature. After working up, as described in Example 1, 63 ml of a solution of 3-methoxydiazopropane (0.8 mM / ml) are obtained in ether after recrystallization from ethyl acetate. 4 ml of a catalyst - 2.2 g (94%) of pure 3β-0- [a, L-3 '- (2 "-phenylethyl) rhamno solution of i-butyl titanate (0.05 mM / ml) and titanium tetrachloride 35 sido] -14-hydroxy-bufa-4,20,22-trienolide, mp 180 to 195 ° C. (0.005 mM / ml) in dioxane. After standing for 12 hours at The catalyst solution is prepared, by preparing 0.28 ml of room temperature, as described in Example 1, ethyl titanate in a 25 ml volumetric flask in a little absolute dioxane and, after recrystallization from ethanol, and 2.5 ml of 0.05 mM / ml titanium tetrachloride solution in 2.16 g (95%) of pure 3β-0- (a, L-3'-methoxypropylrham-dioxane and added to the mark with absolute dioxane. nosido) -14-hydroxy-4, 5-epoxy-bufa-20,22-dienolide, mp 225 40 to 240 ° C.

The catalyst solution is prepared by placing 0.43 ml of i-butyl titanate in a 25 ml volumetric flask in a little abs. Dioxane example 10

dissolves and 2.5 ml of a titanium tetrachloride solution (0.05 mM / ml, such as 2 g 3ß-0- (a, L-rhamnosido) -14-hydroxy-bufa-4,20,22-in Example 1) and with Fill up dioxane to the mark. 45 trienolids are abs in 50 ml. Dissolved dioxane and mixed with 25 ml of a solution of diazopropine (0.3 mM / ml) in ether Example 7 and then 4 ml of a mixture of titanium acetylacetonate

2 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-4,5-epoxy-bu- (0.4%) and titanium tetrachloride (0.005 mM / ml) added in dioxane-fa-20.22- dienolid are abs in 50 ml. Dissolved dioxane and sets. After standing for 14 hours at room temperature and on 25 ml of a solution of 2-methoxydiazoethane (0.3 mM / ml) in the manner described in Example 1, Umkri ether is added. 4 ml of a mixture of ethyl acetate are added to the solution, 2.1 g (93%) of pure 3β-0-cresyl titanate and titanium tetrachloride (0.4% cresyl titanate and [a, L-3 '- (propyne-3 "- yl) -rhamnosido] -14-hydroxy-bufa-0.005 ml titanium tetrachloride / ml) in dioxane, the solution 4, 20, 22-trienolide, mp 170 to 175 ° C.

allowed to stand at room temperature for 16 hours. The catalyst solution is prepared by working in a process as described in Example 1, and after recirculation, 25 ml volumetric flasks 0.1 ml titanium acetylacetonate in abs. Dioxane stall from methanol-water 2.15 g (95%) of pure 3ß-0 dissolves and 2.5 ml of a 0.05 mM / ml titanium tetrachloride solution in (a, L-3'-methoxyethylrhamnosido) -14-hydroxy-4 , 5-epoxy bu abs. Add dioxane (see Example 1) and to the mark with fa-20,22-dienolide, mp. 215 to 221 ° C. Section. Replenishes dioxane.

C.