SE442015B - SET TO MAKE BUFADIENOLID AND BUFATRIENOLIDETERS - Google Patents

Description

7806364-1 10 15 20 25A 2 The characteristic of this process is that a bufadienolide or bufatrienolide of the general formula e (II) OH ¶ „O Cda \ OH where X and R 'have the indicated meaning, is reacted with a diazoalkane with the general formula '(111) R.CH.N2 in an inert solvent and in the presence of a weakly acid catalyst.

Slightly acidic catalysts include ferrous chloride in ether, boron trifluoride diethylate, boric acid esters, aluminum chloride, aluminum isopropylate, p-toluenesulfonic acid, polyphosphoric acid in ether, arsenic trioxide, titanium tetrachloride, molybdenum (VI) tenene sulphonyl chloride, (II) chloride but preferably boric acid or boric acid.

It has now surprisingly been found that the yield of 3 'alkyl ether can be substantially improved if, according to the present invention, a mixture of titanium tetrachloride and boric acid or of titanium tetrachloride and an ester of titanium acid with an aliphatic or aromatic alcohol in absolute dioxane is used as catalyst. and if the radical R represents alkenyl or ethynyl having two carbon atoms, branched alkyl having 6 carbon atoms, phenylmethyl or 2-phenylethyl, dimethylaminoalkyl having 1 or 2 carbon atoms in the alkyl moiety, morpholinoethyl, tetrahydro-2-furfuryl, chloromethyl or bromomethyl, then the radical X represents a double bond and the radical R 'represents methyl, R represents hydrogen or methyl, when X represents a double bond and R' represents methylol or R represents hydrogen, straight or branched alkyl having 1-6 carbon atoms, vinyl, 7806364-1 ethynyl, alkoxy having 2-4 carbon atoms, 2-phenylethyl, diethylamino, N-morpholinoethylcellular or chloro-substituted alkyl having 1 or 2 carbon atoms, when X represents an ep oxy group and R 'represents methyl.

Examples of titanium acid esters are ethyl titanate, n-propyl, isopropyl, n-butyl, isobutyl, cresyl, 2-ethylhexyl titanate and diisopropoxy-bis- (2,4-pentanedionate) -titanium (IV) (= titanium I-acetylacetone ).

The advantage of these catalysts is that the alkylation in the 3 'position takes place selectively and that, in contrast to boric acid, only smaller amounts of non-polar products (dimethyl ether) are formed. Sales are slower than with boric acid and are therefore more selective and quantitative.

It has further been found that the same effect is not obtained with the same concentration of titanium tetrachloride alone as catalyst or with the same concentration of titanium ester alone as with a mixture of both. Also a mixture of titanium tetrachloride and boric acid acts more selectively 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 invention is further illustrated by reference to the following examples.

Example gel 1. 2 g of 3β (u, L-frame nosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved in 100 ml of absolute dioxane and added with a solution of diazomethane in ether (0.5 mmol / ml). Then 4 ml of a catalyst solution of 0.1 mmol of boric acid and 0.005 mmol of titanium tetrachloride / ml in absolute dioxane are added. The solution is allowed to stand for 4 to 5 hours at room temperature, the excess diazomethane is decolorized with a few drops of glacial acetic acid, carefully evaporated in vacuo and the residue is taken up in chloroform. The solution is shaken once with a 2% sodium bicarbonate solution and twice with water, dried over anhydrous sodium sulphate, filtered off and evaporated in vacuo. The residue is recrystallized several times from the methanol-water, 95-98% pure 38-O- (α, L-3'-methylramnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide with melting point 220-232 ° C is obtained.

The catalyst solution is prepared as follows: In a 100 ml volumetric flask, 0.62 g (10 mmol) of boric acid are dissolved in about 50-60 ml of absolute dioxane. To this solution is added 10 ml of a solution of titanium tetrachloride in absolute dioxane (0.05 mmol / ml); ie 0.55 ml titanium tetrachloride / 100 ml absolute dioxane) and make up to the grade with absolute dioxane. The solution contains 0.1 mmol boric acid and 0.005 mmol titanium tetrachloride / ml. The initially yellow solution becomes colorless after some time. The solution is stable for several days at room temperature. Example 2. 2 g of 35-O- (u, L-ramnosido) -14-hydroxy-bufa-4,20,22-tri-enolide are dissolved in 80 ml of absolute dioxane and added with a solution of 2-ethyldiazohexane (0 .8 mmol / ml) in ether. To the solution is added an additional 4 ml of a catalyst mixture of 0.05 mmol of n-propyl titanate and 0.005 mmol of titanium tetrachloride / ml in dioxane. The reaction mixture is allowed to stand for 16 hours at room temperature and further treated according to Example 1. Recrystallization from methanol-water gives 90% pure 3B-O- [a, L-3 '- (2 "-ethylhexyl) -ram nosido] -14-hydroxy-bufa-4,20,22-trienolide, m.p. 235-241 ° C.

The catalyst solution is prepared by dissolving 0.35 ml of n-propyl titanate in a 25 ml volumetric flask in about half the volume of absolute dioxane and then adding 2.5 ml of a titanium tetrachloride solution in dioxane (0.05 mmol / ml , see Example 1) and make up to 25 ml.

Example 3. 2 g of 33-O- (α, L-ramnosido) -24-hydroxy-bufa-4,20,22-trienolide are dissolved in 80 ml of absolute dioxane and added to 11 ml of a solution of 2-chlorodiazoethane (0.7 mmol / ml). To the solution was added 4 ml of the mixed catalyst boric acid / titanium tetrachloride according to Example 1 and left to stand for 4-6 hours. It was then further treated according to Example 1 and after recrystallization from acetic acid ethyl ester obtained with a 95% yield. [u, L-3 '- (2 "-chloroethyl) -ramnosido] -14-hydroxy-bufa-4,20,22-trienolide, m.p. 168-17 ° C.

Example 4. 1 g of 36-O- (α, L-rhamnosido) -14-hydroxy-bufa-4,20,22-trienolide is dissolved in 40 ml of absolute dioxane and added to 15 ml of a solution of 3- (2- ethyl) -hexyloxidiazopropane- (1) (0.6 mmol / 9 ml) in ether. To the reaction solution is added Z ml of an n-propyl titanate (0.0S mmol / ml) and titanium tetrachloride (0.005 mmol / ml) solution according to Example 2 and left to stand for 16 hours at room temperature. Then the solution according to Example 1 is further carried out and after recrystallization from acetic acid ethyl ester, 1.1 g (85%) of pure 330- [0,1-L '3' - (3 "- (T" -ethyl) are obtained. ) -hexyloxypropyl-ramnosido] -14-hydroxy-bufa-4,20,22-trienolide, m.p.

Example 5. '3 g of 3β-O- (α, L-ramnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved in 160 ml of absolute dioxane and added to 50 ml of an ether solution of diazomethane (0.6 mmol / ml). Add 1 ml of an ethyl titanate-titanium tetrachloride solution in absolute dioxane (0.05 mmol ethyl titanate and 0.005 mmol titanium tetrachloride / ml) and leave for 4-6 hours at room temperature. After further treatment according to Example 1, after recrystallization from methanol-water, 3.5 g (93%) of pure 36-O- (o, L-3'-ethylramnosido) -14-hydroxy-4,5-epoxy-zo are obtained. zz «bufad1en01id med smä1rpunkren 136-14s ° c.

Example 6. 2 g of 36-O- (0,1-L-ramnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved in 50 ml of absolute dioxane and added to 13 ml of a solution of diazopropane (0.4 mmol / ml) in ether. Then 4 ml of a solution of i-propyl titanate (0.05 mmol / ml) in titanium tetrachloride (0.005 mmol / ml) in dioxane are added. The solution is allowed to stand for 3-4 hours at room temperature. After further treatment according to Example 1, after recrystallization from methanol-water, 2.1 g (96%) of pure 36-O- (0,1'-3'-propylramnosido) -14-hydroxy-4,5-epoxy-bufa- 20,22-dienolide with a melting point of 230 ° C.

The catalyst solution is prepared by dissolving 0.35 ml of i-propyl titanate in a 25 ml graduated flask in some absolute dioxane and 2.5 ml of a titanium tetrachloride solution (0.05 mmol / ml), see Example 1) in dioxane (absolute) is added, after which it is made up to the grade with absolute dioxane.

Example 7. 2 g of 36-O- (O, L-ramnosido) -14-hydroxy-4,5-epoxy-bufadienolide are dissolved in 50 ml of absolute an dioxane and added to 63 ml of a solution of 3-methoxydiazopropane (0 .8 mmol / ml) in ether To the solution is added a catalyst solution of i-butyl titanate (0.05 mmol / ml) and titanium tetrachloride (0.005 mmol / ml) in dioxane.

After 12 hours at room temperature further treated according to Example 1 and after recrystallization from ethanol-water, 2.16 g (95%] of pure 36-O- (d, L-3'-methoxypropylramnosido) -14-hydroxy-4,5- epoxy-bufa-20,2Z-dienolide with melting point 225-Z40 ° C.

The catalyst solution is prepared by dissolving 0.43 ml of i-butyl titanate in a 25 ml volumetric flask in some absolute dioxane and adding 2.5 ml of a titanium tetrachloride solution (0.05 mmol / ml according to Example 1) and adding dioxane up to the gradient. 7806364-1 10 15 20 25, g 25 ml dissolve 0.78 ml of 2-ethylhexyl titanate in some absolute dioxane Example 35 2 g 36-O- (u, L-ramnosido) -14-hydroxy-4,5 -epoxy-bufa-20,22-dienolide is dissolved in 50 ml of absolute dioxane and added with 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 treatment according to Example 1, after recrystallization from methanol-water, 2.15 g (95%) of pure 5β-O- (α, L-3'-methoxy-ethylramnosido) -14-hydroxy-4,5-epoxy are obtained. bufa-20,22-dienolide with melting points 215-zz1 ° c.

The catalyst solution is prepared by dissolving 0.1 g of cresyl titanate in a 25 ml graduated flask in some absolute dioxane and 2.5 ml of a 0,05 mol / ml titanium tetrachloride solution in dioxane and making up to the grade with dioxane.

Example 9. 2 g of 3β-O- (α, L-ramnosido-14-hydroxy-bufa-4,20,2Z-trienolide are dissolved in 50 ml of absolute dioxane and added with a solution of 20 ml of 3-dimethylaminodiazopropane (0.4 mmol / ml) in ether.

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 titanium tetrachloride / ml) in absolute dioxane. After 17 hours at room temperature, the solution of Example 1 is further treated.

After recrystallization from acetic acid ethyl ester 2.1 g (94%) of pure SB-O {u, L-3 '- (3 "-dimethylaminopropyl) -ramnosido] -14-hydroxy-bufa-4,20, Z2-trienolide with melting point 135 DEG-146 DEG.

The catalyst solution is prepared by adding 2.5 ml of a titanium tetrachloride solution (0.05 mmol / ml, see Example 1) to dioxane in a volumetric flask and making up to the grade with dioxane.

Example 10.2 g of 36-O- (α, L-Ramnosido) -14-hydroxy-bufa-2,20,22-trienolide are dissolved in 50 ml of absolute dioxane and added to 20 ml of a solution of 2-phenyldiazoethane (0 , 4 mmol / ml) in ether. Then 4 ml of a mixture of ethyl titanate (0.05 mmol / ml] and titanium tetrachloride (0.005 mmol / ml) in absolute dioxane are added and the solution is allowed to stand for 16 hours at room temperature. After further treatment according to Example 1, after recrystallization from acetic acid ethyl ester 2.2 g (94%) of pure 36-O-EnL-3 '- (2 "-phenylethyl) -ramino-side] -14-hydroxy-bufa-4,20,22-trienolide, m.p. The catalyst solution is prepared by dissolving 0.28 ml of ethyl titanate in a 25 ml graduated flask in some absolute dioxane and adding 2.5 ml of a titanium tetrachloride solution consisting of 0.05 mmol / ml. in dioxane and replenishes to the grade with absolute dioxane.

Example Gel 11. Dissolve 2 g of 36-O- (α, L-ramnosido] -14-hydroxy-bufa-4,20,22-trienolide in 50 ml of absolute dioxane and add 25 ml of a solution of diazopropyne (0.3 mmol / ml) in ether and then with 4 ml of a mixture of titanium acetylacetonate (0.4%) and titanium tetrachloride (0.005 mmol / ml] in dioxane After 14 hours at room temperature and further treatment according to Example 1, after recrystallization from acetic acid ethyl ester 2.1 g (93%) of pure 35-O- [α, L-3 '- (propyn-3 ") -ramnosido] -14-hydroxy-bufa-4,20, Z2-trienoid with melting point 180 DEG-177 DEG C. The catalyst mixture is prepared by dissolving 0.1 ml of titanium acetylacetonate in absolute dioxane in a 25 ml graduated flask and adding 2.5 ml of a titanium tetrachloride solution consisting of 0.05 mmol / ml of absolute oxane (see example 1) and add to the gradation with absolute) doxan.

Claims (2)

7 8 0 6 3 6 4 - 'å 8 PATENT CLAIMS A process for preparing new bufadienolide and bufatrienolide ethers of the general formula (I), OH AND R wherein X represents a double bond between carbon atoms 4 and 5 or an epoxide group and R represents hydrogen, a straight or branched alkyl radical having 1 to 7 carbon atoms , an ethinyl radical, a straight or branched alkoxyalkyl group having 2 to 11 carbon atoms, a phenylmethyl radical, a dialkylaminoalkyl radical having 4 carbon atoms or a chloromethyl radical, with the exception of the following compounds X = double bond, R = H; X = double bond, R = alkyl of 4 or S carbon atoms; wherein a bufadienolide or bufatrienolide glycoside of the general formula (II), wherein X is as defined, is reacted with a diazoalkane of the general formula R.CH.N (III) 2 wherein R is as defined, in an inert solvent in the presence of a catalyst, characterized as indelated as catalyst, a mixture of titanium tetrachloride and boric acid or of titanium acid ester and titanium tetrachloride in absolute dioxane was used. Process according to Claim 1, characterized in that ethyl titanate, n-propyl, isopropyl, n-butyl, isobutyl, cresyl, 2-ethylhexyl titanate or diisopropoxy-bis- (Z, 4 ~ pentanedione) -titanium (IV).