FI62844C - NYTT FOERFARANDE FOER FRAMSTAELLNING AV BUFADIENOLID- OCH BUFATRIENODRAMNOSIDETRAR - Google Patents

Description

ΓβΊ m | ADVERTISEMENT | OLKAILU A 0 Q Δ A JgRf lBJ (11) UTLAGG NI NGSSKRI FT Ö 4 4 (45) Potent ceddelat ^ ^ (51) IC ».» K? /1nc.a.3 C 07 J 19 / 00 FINLAND — FINLAND (M) N «^« iM ~ hMi «weMA | 781823 (22) HakwnlspMv · —Amttnlniadae 07-06. 78 (23) AlkupUvt — CIKI | h «cadac 07-06.78 (41) Tullut HilkMal - MMt affmcll | 09-12.78 PMMl · j. r * kl * t * riK »llltu *,. kU Hutau "

Pkteno · och riglfUritynliin AnaMan wtltfd och utl ^ krKNn pubtkmd 30.11.82 (32) (33) (31) fyy4 «t * r« mIIum - »« | Μ prlerk · * 08.06.77

Austria-Austria (AT) A 1 + 056/77 (71) Laevosan-Gesellschaft mbH & Co KG, Estermannstrasse 17 »Linz, Austria-Austria (AT) (72) Wilhelmine Windhager, Linz, Austria-Austria (AT) (7) **) Berggren Oy Ab (5 * +) A new process for the preparation of bufadienolide and bufatrienolyramnoside ethers R '_J (I)

e OH

HO X

ψΐ,

I OH

och2r 2 62844 wherein when X is a double bond and R 'is a methyl group, R is an alkenyl or ethynyl residue having two carbon atoms, a branched alkyl residue containing six carbon atoms, a phenylmethyl or 2-phenylethyl residue, a dimethylaminoalkyl residue, wherein a carbon atom, a morpholinoethyl or terahydro-2-furfuryl or chloromethyl or bromoethyl group; when X is a double bond and R 'is a methylol group, R is a hydrogen atom or methyl; when X is an epoxide group and R 'is a methyl group, R is a hydrogen atom, a straight or branched alkyl group having 1 to 6 carbon atoms, a vinyl or ethynyl group, an alkoxy group having 2 to 4 carbon atoms, a phenylethyl group, a diethylamino group, an N-morpholinoethyl group or chlorine; a bromine-substituted alkyl group having 1 to 2 carbon atoms.

Finnish patent publication 55669 discloses a process for the preparation of such compounds, which process is based on the fact that bufadienolide or bufatrienol diglycoside of the general formula Λ R (II)

5 0H

0 \! X *

HO

$

I OH

OH

wherein X and R 'have the above meaning, are reacted with a diazoalkane of the general formula r.ch.n2 (III) wherein R has the above meaning, in a neutral solvent in the presence of a weakly acidic catalyst.

3,62844

Mildly acidic catalysts include: ferric chloride in ether, boron trifluoride dietherate, boronic acid ester, aluminum chloride, aluminum isopropylate, p-toluenesulfonic acid, polyphosphoric acid in tetrachloride, arsenic triacidide, arsenic trioxide, titanium tetrachloride, titanium tetrachloride, titanium tetrachloride (II) chloride, but mainly boric acid or m-boric acid.

It has now surprisingly been found that the yield of 3'-alkyl ether can be substantially improved, i.e. on average about 5%, if a mixture of titanium tetrachloride and boric acid or a mixture of titanium acid ester and titanium tetrachloride or titanium acid ester alone in absolute dioxane is used as catalyst according to the invention. Suitable titanium acid esters are: ethyl titanate, n-propyl, isopropyl, n-butyl, isobutyl, cresyl, 2-ethylhexyl titanate and diisopropoxy-bis- (2,4-pentanedione) titanium (IV ) (= titanium acetylacetonate).

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

The reaction is carried out in a neutral absolute solvent, mainly absolute dioxane. The reaction takes place more slowly than with boric acid alone, and is therefore more selective and quantitative.

In addition, it was found that when titanium tetrachloride alone or titanium ester alone was used as the catalyst at the same concentration, the same effect as the mixture of both was not obtained. The mixture of titanium tetrachloride and boric acid also has a more selective effect on the alkylation with diazoalkanes than titanium tetrachloride or boric acid alone. The reaction rate decreases in the following order: titanium tetrachloride, boric acid, titanium tetrachloride and boric acid.

The following examples are intended to further illustrate this invention.

62844 4

Example 1; 2 g of 3- (3-O- (α, L-rhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved in 100 ml of absolute dioxane and 16 ml of ethereal diazomethane solution (0 Finally, 4 ml of a catalyst solution containing 0.1 mmol of boric acid and 0.005 mmol of titanium tetrachloride / ml in absolute dioxane are added, the solution is left to stand for 4-5 hours at room temperature, the excess diazomethane is decolorized with a few drops of glacial acetic acid, The solution is then shaken once with 2% sodium hydrogen carbonate solution and twice with water, dried over anhydrous sodium sulphate, filtered off and evaporated to dryness in vacuo. % pure 3β-O- (α, L-3'-methylramnosido) -14-hydroxy-4,5-epoxy-bufa-20.22-dienolide, mp 220-232 ° C.

The catalyst solution is prepared as follows: Dissolve 0.62 g (10 mmol) of boric acid in a 100 ml graduated flask in about 50-60 ml of abs. dioxane. To this solution is added 10 ml of a solution of titanium tetrachloride abs. in dioxane (0.05 mmol / ml; i.e. 0.55 ml titanium tetrachloride / 100 ml abs. dioxane) and make up to the mark with abs. dioxane. The solution contains 0.1 mmol boric acid and 0.005 mmol titanium tetrachloride / ml. The solution, which initially turns yellow, turns colorless after some time. The solution can be stored for several days at room temperature.

Example 2: 2 g of 3- (3-O- (α, L-rhamnosido) -14-hydroxy-bufa-4,20,22-trienolide are dissolved in 80 ml of absolute dioxane and 10 ml of a solution of 2- ethyl diazohexane (0.8 mmol / ml) in ether, a further 4 ml of a catalyst mixture of 0.05 mmol of n-propyl titanate and 0.005 mmol of titanium tetrachloride / ml in dioxane are added to the solution, the reaction mixture is allowed to stand for 16 hours at room temperature and the solution is worked up as in the example. 1. Recrystallization from methanol / water gives 90% pure 3E-O- [α, L-3 '- (2 "-ethylhexyl) -ramnosido-7-hydroxy-bufa-4.20.22-trienolide, m.p. 235-241 ° C.

The catalyst solution is prepared by dissolving 0.35 ml of n-propylthi-62844 5 tananate in a 25 ml volumetric flask abs. to dioxane in a flask of about half its volume and then 2.5 ml of titanium tetrachloride dioxane solution (0.05 mmol / ml, see Example 1) is added and the flask is made up to the 25 ml mark.

Example 3; 2 g of 30-O- (α, L-rhamnosido) -14-hydroxy-bufa-4,20,22-trienolide are dissolved in 80 ml of abs. dioxane and 11 ml of 2-chlorodiazoethane solution (0.7 mmol / ml) are added. To the solution is added 4 ml of the boronic acid / titanium tetrachloride mixture catalyst described in Example 1, and the mixture is allowed to stand for 4-6 hours at room temperature. The work-up is then continued as described in Example 1, and after recrystallization from ethyl acetate, 36-yield of 95-O- [α], L-31- (2 "-chloroethyl) -ramnosido / -14-hydroxy-bufa-4.20% is obtained. , 22-trienolidia, mp 168-175 ° C.

Example 4: 1 g of 38-O-, L-rhamnosido-7-14-hydroxy-4,5-epoxy-bufa-20,22-dienolide is dissolved in 50 ml of abs. dioxane and add 20 ml of ethinyl diazomethane (0.2 mmol / ml). To the solution is added 2 ml of a n-butyl titanate dioxane solution (0.05 mmol / ml; 0.85 ml of n-butyl titanate in 50 ml of absolute dioxane) and the mixture is left to stand for 4-6 hours at room temperature. Further work-up is carried out as described in Example 1, and after recrystallization from ethyl acetate, 1 g (93%) of pure 36-O- (α, L-3'-propargylramnosido) -14-hydroxy-4,5-epoxy-bufa-20.22 is obtained. -dienolidia, so. 228-237 ° C.

Example 5: 1 g of 36-O- (α, L-rhamnosido) -14-hydroxy-bufa-4,20,22-trienolide is dissolved in 40 abs. dioxane and a solution of 3- (2-ethyl) -hexyloxydiazopropane (1) (0.6 mmol / ml) in ether is added. 2 ml of a solution of n-propyl titanate (0.05 mmol) and titanium tetrachloride (0.005 mmol / ml) are added to the reaction mixture as described in Example 2, and the mixture is allowed to stand at room temperature for 16 hours. The solution is then further treated as described in Example 1, and after recrystallization from ethyl acetate, 1.1 g (85%) of pure 36-O- (O, 3 '- (2', - ethyl) -hexyloxypropyl) -ramnoside are obtained. / -14-hydroxy-bufa-4,20,22-trienolidine, m.p. 225-230 ° C.

62844 6

Example 6; 3 g of 3β-O- (α, L-rhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved in 160 ml of abs. dioxane and add 50 ml of ethereal diazoethane solution (0.6 mmol / ml). To this is added 1 ml of ethyl titanate-titanium tetrachloride solution abs. in dioxane (0.05 mmol ethyl titanate and 0.005 mmol titanium tetrachloride / ml) and the mixture is allowed to stand at room temperature for 4-6 hours. After further work-up as described in Example 1 and recrystallization from methanol-water, 3.5 g (93%) of pure 3β-O- (ot, L-3'-ethylramnosido) -14-hydroxy-4,5-epoxy 20,22-bufa-dienolidia, m.p. 136-143 ° C.

Example 7: 2 g of 3β-O- (α, L-rhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved in 50 ml of abs. dioxane and 13 ml of an ethereal solution of diazopropane (0.4 mmol / ml) are added. 4 ml of a solution of i-propyl titanate (0.05 mmol / ml) and titanium tetrachloride (0.005 mmol / ml) in dioxane are then added. The solution is allowed to stand at room temperature for 3-4 hours. After further work-up as described in Example 1 and recrystallization from methanol-water, 2.1 g (96%) of pure 3β-O- (α, L-3'-propylramnosido) -14-hydroxy-4,5-epoxy-bufa are obtained. -20.22-dienolidia, m.p. 230-235 ° C.

The catalyst solution is prepared by dissolving 0.35 ml of i-propyl titanate in a 25 ml volumetric flask in a small amount of abs. dioxane and 2.5 ml of titanium tetrachloride solution (0.05 mmol / ml, see Example 1) are added abs. in dioxane and the bottle is filled to the mark with abs. dioxane.

Example 8: 2 g of 3β-O- (α, L-rhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved in 50 ml of abs. dioxane and 63 ml of an ether solution of 3-methoxydiazopropane (0.8 mmol / ml) are added. To the solution is added 4 ml of a catalyst solution of i-butyl titanate (0.05 mmol / ml) and titanium tetrachloride (0.005 mmol / ml) in dioxane. After standing at room temperature for 12 hours, the mixture is further treated as described in Example 1 and, after recrystallization from ethanol-water, 2.16 g (95%) of pure 3β-O- (α, L-3'-methoxypropylramnosido) -14 are obtained. -hydroxy-62844 7 4,5-epoxy-bufa-20,22-dienolide, m.p. 225-240 C.

The catalyst solution is prepared by dissolving 0.43 ml of i-butyl titanate in a 25 ml volumetric flask in a small amount of abs. dioxane and 2.5 ml of titanium tetrachloride solution (0.05 mmol / ml as in Example 1) are added and the flask is made up to volume with dioxane.

Example 9: 2 g of 38-O- (α, L-rhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved in 50 ml of abs. dioxane and add 25 ml of a solution of 2-methoxydiazoethane (0.3 mmol / ml) in ether. To the solution is added 4 ml of a mixture of cresyl titanate and titanium tetrachloride (0.4% cresyl titanate and 0.005 ml titanium tetrachloride / ml) in dioxane. The solution is allowed to stand for 16 hours at room temperature. After further work-up as described in Example 1 and refluxing of the methanol-water mixture, 2.15 g (95%) of pure 38-O- (et, L-3'-methoxyethylramnosido) -14-hydroxy-4,5- epoxy-bufa-20,22-dienolide, m.p. 215-221 ° C.

Catalyst solution, prepared by dissolving 0,1 g of cresyl titanate in a 25 ml graduated flask in a small quantity of abs. dioxane and add 2.5 ml of titanium tetrachloride dioxane solution, 0.05 mol / ml, and make up to the mark with dioxane.

Example 10: 2 g of 38-O- (α, L-rhamnosido) -14-hydroxy-bufa-4,20,22-trienolide are dissolved in 50 ml of abs. dioxane and a solution of 20 ml of 3-dimethylaminodiazopropane (0.4 mmol / ml) in ether is added. To the solution is added 4 ml of a solution of 2-ethylhexyl titanate and titanium tetrachloride (0.05 mmol 2-ethylhexyl titanate and 0.005 mmol / ml titanium tetrachloride / ml) abs. dioxane. After standing for 17 hours at room temperature, the solution is further treated as described in Example 1. After recrystallization from ethyl acetate, 2.1 g (94%) of pure 3,8-O - [[L, 3 '- (3 "-dimethylaminopropyl) -ramnosido] -114-hydroxy-bufa-4,20,22 are obtained. -trienolide, mp 135-146 ° C.

The catalyst solution is prepared by dissolving 0,78 ml of 2-ethylhexyl titanate in a 25 ml graduated flask in a small quantity of abs.

8 62844 dioxane and 2.5 ml of a titanium tetrachloride solution, 0.05 nunol / ml, (see Example 1) in dioxane are added and the flask is made up to the mark with abs. dioxane.

Example 11: 2 g of 3β-O- (α, L-rhamnosido) -14-hydroxy-bufa-4,20,22-trienolide are dissolved in 50 ml of abs. dioxane and add 20 ml of a solution of 2-phenyldiazoethane (0.4 mmol / ml) in ether. 4 ml of a mixture of ethyl titanate (0.05 mmol / ml) and titanium tetrachloride (0.005 mmol / ml) are then added abs. in dioxane and the solution is allowed to stand at room temperature for 16 hours. After further work-up as described in Example 1 and recrystallization from ethyl acetate, 2.2 g (94%) of pure 36-O '-, L-3' - (2 "-phenylethyl) -ramnosido / -14-hydroxy- bufa-4,20,22-trienolidine, mp 180-195 ° C.

The catalyst solution is prepared by dissolving 0,28 ml of ethyl titanate in a 25 ml graduated flask in a small quantity of abs. dioxane and add 2.5 ml (0.05 mmol / ml) of titanium tetrachloride dioxane solution and make up to the mark with abs. dioxane.

Example 12: 2 g of 3β-O- (α, L-rhamnosido) -14-hydroxy-bufa-4,20,22-trienolide are dissolved in 50 ml of abs. dioxane and 25 ml of a solution of diazopropine (0.3 mmol / ml) in ether are added, followed by 4 ml of a mixture of titanium acetylacetonate (0.4%) and titanium tetrachloride (0.005 mmol / ml) in dioxane. After standing at room temperature for 14 hours, after further work-up as described in Example 1 and recrystallization from ethyl acetate, 2.1 g (93%) of pure 38-O- (α, L-3 '- (propin-3 ") - are obtained. rhamnosido-7'-14-hydroxy-bufa-4,20,22-trienolidine, mp 170-175 ° C.

The catalyst solution is prepared by dissolving 0,1 ml of titanium acetylacetonate in a 25 ml graduated flask with abs. dioxane and add 2.5 ml of titanium tetrachloride solution (0.05 mmol / ml) abs. in dioxane (see Example 1) and the flask is filled to the mark with abs. dioxane.

Claims (5)

9 Claims 62 8 4 4 A new process for the preparation of bufadienolide and bufatrienol diramnoside ethers having a cardiac function and having the general formula O HO x ψ} \ OH OCH2R wherein when X is a double bond and R 'is a methyl group, R is an alkenyl or ethynyl residue containing two carbon atoms , a branched alkyl residue containing six carbon atoms, a phenylmethyl or 2-phenylethyl residue, a dimethylaminoalkyl residue in which the alkyl has 1 to 2 carbon atoms, a morpholinoethyl or tetrahydro-2-furfuryl or chloromethyl or bromoethyl group; when X is a double bond and R 'is a methylol group, R is a hydrogen atom or methyl; when X is an epoxide group and R 'is a methyl group, R is a hydrogen atom, a straight or branched alkyl residue having 1 to 6 carbon atoms, a vinyl or ethynyl residue, an alkoxy group having 2 to 4 carbon atoms, a phenylethyl group, a diethylamino group, an N-morpholinoethyl group or chlorine; a bromine-substituted alkyl group having 1 to 2 carbon atoms, in which process bufadienolide or bufatrienoliglycoside having the general formula 10 O 62844 Jk Jr Η'Γ 5. OH 0 '' X! HO X © I ^ OH OH in which X and R 'have the above meanings is reacted with a diazoalkane of the general formula R.CH.N2 (III) in which R has the above meanings in a neutral solvent of a catalyst in the presence of, characterized in that a mixture of titanium tetrachloride and boric acid or a titanium acid ester and titanium tetrachloride or a titanium acid ester alone in absolute dioxane is used as catalyst. Process according to Claim 1, characterized in that the titanium acid ester used is ethyl titanate, n-propyl, isopropyl, n-butyl, isobutyl, cresyl, 2-ethylhexyl titanate or diisopropoxy-bis- (2 , 4-pentanedionate) titanium (IV). 11 o,, ν 62844 A new formulation of high-performance bufadieno-lid- and bufatrienolidramnoside-etrar with the formula 0 ö (I) r 'I λ, OH «Ay 0' X HO x I / r ° 9 I OH OCH2R i vilken, dä X is a double bond and R 'is a methyl group, R is an alkenyl or ethynyl group having 2 cholatomers, a substituted alkyl group having 6 cholatomers, a phenylmethyl or 2-phenylethyl group, a dimethylaminoalkyl group, an alkyl group having 1-2 cholaters, en morpholinoethyl or tetrahydro-2-furfuryl or chloromethyl or bromethyl; and X is a double bond and R 'is methyl group, and R is a hydrogen atom or methyl; da X is a starch group with an epoxide group and R 'is a methyl group, and R is a hydrogen atom, and is preferably an alkyl group having 1 to 6 cholatomers, a vinyl or an ethynyl group, and an alkoxy group with 2 to 4 cholatomers, a phenylethyl group, a diethylamino group, an N- morpholinoethyl group or chlorine or bromine substituted alkyl group 1 to 2 carbon atoms in the form of bufadienolide or bufatrienol glycosides in the formulation