CH615200A5 - Process for the preparation of bufadienolide or bufatrienolide ethers - Google Patents

Description

The present invention now relates to a process for the production of bufadienolide or bufatrienol ether of the general formula

, (I)

OCHRR "OH

615 200

4th

wherein X represents a double bond between the C atoms 4 and 5 or the epoxy group, R 'is a methyl, formyl or methylol group, R "represents a hydrogen atom and R represents hydrogen, a straight or branched alkyl radical having 1 to 16 C atoms , a straight or branched alkenyl radical having 2 to 6 carbon atoms, an ethynyl radical, an alkoxyalkyl group which has 1 or 2 carbon atoms in the alkoxy and alkyl moiety, an aromatic or araliphatic radical, such as, for example, phenyl, phenylmethyl, 2-phenylethyl - or 3-phenyl-propyl radical, which represents the dimethylaminomethyl, dimethylaminoethyl, diethylaminoethyl, morpholinoethyl, tetrahydrofuryl, bromoethyl or chloromethyl radical, or R and R "

R '

OH

wherein X and R 'have the above meaning, with a diazoalkane of the general formula

N2 = CRR ", (III)

wherein R and R "have the meaning given above, is reacted in an inert solvent and in the presence of a weakly acidic catalyst.

Compounds of the general formula (I) in which R 'is a methyl group, X is a double bond and R is an alkyl group with 4 or 5 C atoms or R' is a formyl group, X is a double bond and R is a hydrogen atom or an alkyl group with 1 to 5 C atoms are known from OE-PS 299 456; however, according to this disclosure, a method is proposed for its production in which a mixture of the various ethers is formed, which then only have to be separated by column chromatography. The maximum yield according to the examples is approx. 58% of theory In contrast, the process according to the invention provides the desired monoethers directly and selectively in a yield of about 90% of theory

together with the neighboring C atom can form a cycloaliphatic ring with 6 to 12 C atoms, where if X denotes an e double bond and R 'denotes a methyl group, R cannot be a hydrogen atom, which compounds are new with the following exceptions are: R '= methyl, X = double bond, R = alkyl with 4 or 5 carbon atoms; R '= formyl, X = double bond, R = H or alkyl with 1 to 5 carbon atoms.

Surprisingly, it has now been shown that the above 3'-ethers are obtained in a yield of more than 90% if a hi bufadienolide or bufatrienolide glycoside of the general formula

O

, (II)

In DT-OS 1 768 541, a process for the preparation of new Prozararidin-A derivatives is described, according to which all three hydroxyl groups of the rhamnose residue are protected by triethers, mixed ether esters, mixed cyclic acetal or ketal -Ester or mixed cyclic acetal or ketal ether produces. The process described therein consists in reacting Pro oscillaridin-A with suitable O-alkylating agents and / or O-acylating agents in a manner known per se until all three hydroxyl groups of the rhamnose residue have been alkylated or acylated. According to this laid-open specification, a suitable O-alkylating agent includes also mentioned diazoalkanes. The reaction with diazoalkanes takes place in the presence of a mild, acidifying catalyst. Depending on the amount of the alkylating agent used, partly or completely etherified derivatives can be obtained; the partially etherified derivatives obtained are reacted further 65 with an acylating agent in accordance with the aforementioned publication until all three hydroxyl groups of the rhamnose residue are protected.

CH.

OH

5

615 200

In contrast to this teaching, it is now important according to the present invention that only the hydroxyl group on the carbon atom 3 of the rhamnose residue is substituted. It has not previously been described that it is possible to produce derivatives substituted on the rhamnose residue 3 using diazoalkanes.

A solvent with a high dielectric constant, such as e.g. Acetonitrile, propionitrile, tetrahydrofuran, dimethylformamide, dioxane or a mixture of these solvents. As a weakly acid catalyst, e.g. Iron III chloride in ether, boron trifluoride dietate, boric acid ester, aluminum chloride in ether, aluminum isopropylate, p-toluenesulfonic acid, polyphosphoric acid in ether and arsenic trioxide, but preferably boric acid or meta-boric acid in dioxane. Acetonitrile as solvent and boric acid in dioxane as catalyst have proven to be particularly advantageous in this reaction. The dioxane should only be regarded as a solubilizer for boric acid. Mixtures of acetonitrile and tetrahydrofuran can also be used as solvents for the less soluble epoxybufadienolides. In terms of the amount of catalyst, it is convenient, e.g. in the case of boric acid, to use one tenth to one fifth of the molar amount of the glycoside used. When using smaller amounts of catalyst, the yield deteriorates, larger ones do not improve.

The conversion of the bufatrienolide to the epoxybufadienolide can be carried out in a known manner (OE-PS 280 487) either before or after the alkylation according to the invention by the glycoside in question in an inert solvent at room temperature with an organic peracid such as peres

Table 1

physico-chemical properties example substance

- 3 ß-0- (a, L-rhamnosido) - 14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

1 3 ß-0- (a, L-3 '-methylrhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

2 3ß-0- (a, L-3'-ethylrhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

3 3ß-0- (a, L-3'-propylrhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

4 3ß-0- (a, L-3'-butylrhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

5 3 β-0- (a, L-3 '-pentylrhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

- 3 ß-0- (a, L-rhamnosido) -14-hydroxy-bufa-4,20,22-trienolide

6 3 ß-0- (a, L-3 '-ethylrhamnosido) -14-hydroxy-bufa-4,20,22-trienolide

7 3β-0- (a, L-3 '-propylrhamnosido) -14-hydroxy-bufa-4,20,22-trienolide

8 3ß-0- (a, L-3'-butylrhamnosido) -14-hydroxy-bufa-4,20,22-trienolide acetic acid, perbenzoic acid, monoperphthalic acid or m-chloro-perbenzoic acid.

The reaction is expediently carried out at about 20 ° C. In the case of the less reactive diazoalkanes, it is advantageous to raise the temperature to about 30 ° C. Generally temperatures from 10 to 30 ° C can be used.

The alkylation with diazoalkanes is specific in two respects: firstly, rhamnosidic steroid glycosides are alkylated only in the 3'-position and secondly, the alkylation does not attack the epoxy ring, which is surprising since it is known that epoxides are caused by epoxides electro-phile reagents the ring is opened. On the other hand, it is also noteworthy that with 2 ', 3' blocking of rhamnose, as is the case with the ketals, the still free hydroxyl-15 grappe in the 4 'position is not attacked. This reaction is therefore specific for monoalkylation in the 3'-position of the rhamnose and cannot be achieved with this high selectivity by means of alkyl halides and basic catalysts. The aglycone is not etherified in this reaction. 2 (i Glycosides with a monosaccharide other than rhamnose give a variety of alkylation products in this reaction, which are very difficult to separate.

The constitution of the alkylated rhamnoside glycosides can be clearly determined chemically via the periodate reaction and the keta-25 lization and is supported by the NMR spectra.

On the other hand, the homologous alkyl ethers also show typical differences in the Rf value in thin layer chromatography, so that a certain Rf value can be assigned to a certain chain length of the alkyl radical.

Formula mp. ° C Rf value in the eluent

Ethyl methyl ketone ethyl acetate

Toluene water water

Methanol glacial acetic acid saturates 70/20/6/5/2

C30H42O "235-240 0.27 0.11

C31H440, 220-232 0.35 0.23

C32H4fi09 136-143 0.55 0.35

C33H48Oy 230-255 0.62 0.49

C34H50O9 245-260 0.65 0.54

C35H5209 250-256 0.70 0.60

C30H42O8 226-228 0.36 0.23

C32H4608 199-207 0.60 0.46

C33H4808 115-124 0.61 0.55

C34H5 (A 135-141 0.69 0.62

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Example substance

9 3β-0- (a, L-3'-pentylrhamnosido) -14-hydroxy-bufa-4,20,22-trienolide

14 3ß-0- [a, L-3 '- (2 "-methoxyethyl) rhamnosido] -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

12 3β-0- [a, L-3 '- (3 "-methoxypropyl) -rhamnosi-do] -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

30 3β-0- [a, L-3 '- (propyne-3 "rhamnosido) -14] -hydroxy-bufa-4,20,22-trienolide

31 3β-0- [a, L-3 '- (3 "-bromopropyl) rhamnosido] -14ß-hydroxy-bufa-4,20,22-trienolide

32 3β-0- [a, L-3 '- (2 "chloroethyl) rhamnosido] -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

33 3β-0- [a, L-3 '- (3 "-bromopropyl) rhamnosido] -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

34 3β-0- [a, L-3 '- (allylrhamnosido)] - 14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

35 3β-0- [3 '- (3 "-phenylpropyl) rhamnosido] -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

36 3β-0- [3 '- (3 "-phenylpropyl) rhamnosido] -14ß-hydroxy-bufa-4,20,22-trienolide

37 3β-0- [a, L-3 '- (1 ", 3" -dimethyl-n-pentyl) rhamnosido] -14-hydroxy-bufa-4,20,22-trienolide

38 3β-0- [a, L-3 '- (l ", 3" -dimethyl-n-pentyl) rhamnosido] -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

39 3β-0- [a, L- (3 '-methylrhamnosido)] - 14,19-dihydroxy-bufa-4,20,22-trienolide

40 3β-0- [a, L- (3'-ethylrhamnosido)] - 14,19-dihydroxy-bufa-4,20,22-trienolide

The preparation of the diazoalkanes is described in detail in the literature (Houben-Weyl Vol. X / 4, pages 482 to 610) and is explained in more detail in the practical part.

The new compounds show an increased cardiac activity compared to the starting substances, in particular the oral absorption being improved, and it is remarkable

6

Formula mp. ° C Rf value in the eluent

Ethyl methyl ketone ethyl acetate

Toluene water water

Methanol glacial acetic acid saturates 70/20/6/5/2

C, 6H5208 147-153 0.75 0.68

C ^ H ^ O ,,, 215-221 0.42 0.16

C34H5i) O10 225-240 0.52 0.23

C "H4408 170-175 0.70 0.65

C "H4708Br 180-185 0.60 0.55

C, 2H450 "C1 210-215 0.50 0.45

C "H4709Br 220-225 0.52 0.47

C "H4ftO" 192-197 0.72 0.63

C, "H5209 225-230 0.60 0.52

C "H52Ox 165-170 0.62 0.60

C "H, (1Ox 240-245 0.75 0.65

C "H46Oq 255-260 0.72 0.70

Cj.H ^ Oc, 168-172 0.55 0.42

C12H44Oy 170-176 0.61 0.58

that the activity initially increases with increasing chain length of the alkyl ether 55 and then remains constant, although the toxicity becomes lower.

The following table shows the cardiac activity in mg / kg in guinea pigs and enteral absorption in the cat.

7

615 200

Table 2

Pharmacological data example substance

12

14

13

15

3β-0- (a, L-rhamnosido) ~ 14-hydroxy-bufa-4,20,22-trienolide

3β-0- (a, L-3'-ethylrhamnosido) -14-hydroxy-bufa-4,20,22-trienolide

3β-0- (a, L-3'-propylrhamnosido) -14-hydroxy-bufa-4,20,22-trienolide

3β-0- (a, L-3'-butylrhamnosido) -14-hydroxy-bufa-4,20,22-trienolide

3β-0- (a, L-rhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

3β-0- (a, L-3 '-methylrhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

3β-0- (a, L-3 '-ethylrhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

3β-0- (ct-L-3 '-propylrhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

3β-0- (a, L-3'-butylrhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

3β-0- [a, L-3 '- (3 "-methoxypropyl) rhamnosido] -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

3β-0- [a, L-3 '- (2 "-methoxyethyl) rhamnosido] -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

3β-0- [a, L-3 '- (3 "-methoxypropyl) rhamnosido] -14-hydroxy-bufa-4,20,22-trienolide

3β-0- [a, L-3 '- (2 "-methoxyethyl) rhamnosido] -14-hydroxy-bufa-4,20,22-trienolide

Acute toxicity absorption

DL 100 mg / kg quotient%

Guinea pig (cat) (colorful)

0.53 0.37 0.36 0.38 0.41 0.53 0.55 0.74 0.77 0.57 0.36 0.40 0.37

14.8

47.0

10.6

31.4

31.5

Absorption half-life (minutes)

226

117

257

67

155

The increase in enteral absorbability with increasing chain length and thus a good lipoid solubility to overcome the barrier of the intestinal tract also stand? in accordance with the work of REPKE (Pharmazie 27, H. 11 (1972) p. 693).

The new compounds can be administered in the form customary for cardiac glycosides, e.g. Tablets, capsules or solutions containing the active substance in pure form or in a mixture 5 with xanthine derivatives.

The following examples are intended to explain the present invention in more detail, but without restricting it to them.

First, the production of the starting substances used in the process according to the invention is explained in more detail.

The homologous series from diazomethane to diazo-n-pentane and the branched aliphatic diazo compounds were prepared via the corresponding N-nitroso-N-alkylurea derivatives, according to the instructions of E.A. Werner, <Chem. Soc. 115, 1098 (1919) and Chem. Soc. (1952), 3701.

Diazomethane and diazoethane can also be prepared from dimethyl sulfate or diethyl sulfate via the nitrosourea derivatives according to F. Arnd, L. Loewe and S. Avan, Ber. 73, 606 (1940).

1-Diazopropane, -butane and -pentane can also be prepared by alkaline cleavage of N-nitroso-N "-nitro-N-alkyl-guanidines. (Houben-Weyl, Vol. X / 4,4th edition, S. 543) The aromatic-aliphatic diazo compounds can also be prepared according to this procedure.

The alkoxydiazoalkanes can be obtained either from the corresponding N-nitroso-N-alkoxyalkylurea derivatives or by alkaline cleavage from the corresponding N- (alkoxy-alkyl) -p-toluenesulfonamides according to C.Grot, E. Pfeil, E. Weinrich, Ann.Bd. 679 (1964), p. 42.

I.

The diazoalkenes and diazoalkynes are according to J.Marx and L.Marx-Moll, Ber. 87, 1499 (1954) from the urea derivatives.

The cycloaliphatic diazo compounds are prepared according to the instructions from Bruchhausen and Hoffmann, Ber. 74, 1588 (1941) or according to K-Heyns and A. Heins, Ann. Vol. 604 (1957) p. 133.

The diazoalkanes in which the aliphatic radical is

615 200

or substituted N-containing heterocycles are also produced via the urea derivatives.

The content of the diazo compounds is determined in all cases by allowing an aliquot of the diazo compound to flow out in ether to a precisely weighed amount of benzoic acid and, after the evolution of gas has ended, diluted with water and back titrating the excess of benzoic acid against phenolphthalein with 0.1N sodium hydroxide solution (Marshall and Aeree, Ber. 43, 2324 (1910).

The formation of the acetonide of the end products, which together with the periodate reaction can serve as proof of the constitution for the 3'-alkylation on the rhamnose, is carried out by adding 0.05 mM of the substance in 5 ml of 0.05% sulfuric acid in acetone for 2 hours Stirred at 20 ° C and followed the course of the reaction by thin layer chromatography.

The periodate oxidation is carried out by stirring 0.05 mM of the alkylated compound together with 15 mg of sodium periodate, 50 mg of sodium acetate trihydrate and 5 ml of 50% acetic acid at 20 ° C. for 2 hours and the reaction is monitored by thin layer chromatography.

All 3'-ethers of the rhamnosides give neither an acetonide nor a periodate reaction.

example 1

3β-O- (a, L-3 '-methylrhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

2 g of 3ß-0- (a, L-rhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved in 150 ml of acetonitrile with heating and in with 2 ml of a solution of 620 mg of boric acid 100 ml of dioxane (0.1 mM / ml) were added and a solution of 70 ml of diazomethane in ether (0.1 mM / ml) was added. The solution is left to stand at 20 to 25 ° C for 2 hours. The excess of diazomethane is then destroyed with a few drops of acetic acid, gently evaporated in vacuo and the residue is taken up in 100 ml of chloroform. The solution is shaken with 30 ml of a 2% sodium bicarbonate solution and then three times with 20 ml of water and dried over anhydrous sodium sulfate and evaporated in vacuo. After recrystallization from methanol-water, 1.9 g (93%) of analytically pure 3β-0- (a, L-3'-methylrhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dieno -lid, mp. 220 to 232 ° C.

Example 2

3β-0- (a, L-3'-ethylrhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

6 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved with heating in 540 ml of acetonitrile and 60 ml of tetrahydrofuran and with 10 ml of boric acid solution in dioxane (0.1 mM / ml) was added. 200 ml of an ethereal diazoethane solution (0.3 mM / ml) are then added. After standing at 20 to 25 ° C. for 2 hours, the mixture is worked up as described in Example 1. After recrystallization from methanol-water, 6 g (92%) of analytically pure 3β-0- (a, L-3'-ethylrhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide, mp. 136 to 143 ° C.

Example 3

3β-0- (a, L-3'-propylrhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

6 g of 3ß-0- (a, L-rhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved with heating in 540 ml of acetonitrile and 60 ml of tetrahydrofuran and with 10 ml of a solution of Boric acid in dioxane (0.1 mM / ml) added. After adding a solution of 200 ml of diazopropane in ether (0.1 mM / ml), the solution is left to stand at 25 ° C. for 2 hours. After working up as described in Example 1 and recrystallization from ethanol-water, 6.1 g (95%) of analytically pure 3β-0- (a, L-3'-propylrhamnosido) -14-hydroxy-4,5-epoxy are obtained -bufa-20,22-dienolide, mp. 230 to 255 ° C.

Example 4

3β-0- (a, L-3 '-butylrhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

2 g of 3ß-0- (a, L-rhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved in 150 ml of acetonitrile with heating and 2 ml of a solution of boric acid in dioxane (0 , 1 mM / ml) was added. A solution of 25 ml of diazo-n-butane (0.3 mM / ml) is then added and the mixture is left to stand at 20 to 25 ° C. for 2 hours. After working up, as described in Example 1, 2 g (91%) of analytically pure 3β-0- (a, L-3'-butylrhamnosido) -14-hydroxy-4,5-epoxy-bufa-20 are obtained after recrystallization from ethyl acetate , 22-dienoIid, mp. 245 to 260 ° C.

Example 5

3β-0- (a, L-3'-pentylrhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

2 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved in 140 ml of acetonitrile and 10 ml of tetrahydrofuran with heating and with 2 ml of a solution of Boric acid in dioxane (0.1 mM / ml) added. After adding 35 ml (0.2 mM / ml) of diazo-n-pentane in ether, the solution is left to stand at 20 to 25 ° C. for 2 hours. After working up as described in Example 1, after recrystallization from ethyl acetate, 2.02 g (91%) of analytically pure 3β-0- (a, L-3'-pentylrhamnosido) -14-hydroxy-4,5-epoxy-bufa is obtained -20,22-dienolide, mp. 250 to 256 ° C.

Example 6

3β-0- (a, L-3'-ethylrhamnosido) -14-hydroxy-bufa-4,20,22-trienolide

1 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-bufa-4,20,22-trienolide is dissolved in 50 ml of acetonitrile and with 1 ml of a solution of boric acid in dioxane (0.1 mM / ml ) and 20 ml of a solution of diazoethane in ether (0.2 mM / ml) were left to stand at 20 to 25 ° C. for 2 hours. After working up as described in Example 1, after recrystallization from ethyl acetate, 1.05 g (94%) of analytically pure 3β-0- (a, L-3'-ethylrhamnosido) -14-hydroxy-buf a-4.20 is obtained , 22-trienolide, mp 199 to 207 ° C.

Example 7

3β-0- (a, L-3 '-propylrhamnosido) -14-hydroxy-bufa-4,20,22-trienolide

4 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-bufa-4,20,22-trienolide are dissolved in 300 ml of acetonitrile with heating and with 5 ml of a solution of boric acid in dioxane (0.1 mM / ml). 50 ml of an ethereal diazopropane solution (0.3 mM / ml) are then added and the solution is left to stand at 20 to 25 ° C. for 2 hours. After working up as described in Example 1, after recrystallization from ethyl acetate, 4.1 g (95%) of analytically pure 3β-0- (a, L-3'-propyl-rhamnosido) -14-hydroxy-bufa-4.20 is obtained , 22-trienolide, mp 115 to 124 ° C.

Example 8

3β-0- (a, L-3'-butylrhamnosido) -14-hydroxy-bufa-4,20,22-trienolide

2 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-bufa-4,20,22-trienolide are dissolved in 150 ml of acetonitrile with heating and with 2 ml of a solution of boric acid in dioxane (0.1 mM / ml). After adding 35 ml of diazo-n-butane solution (0.2 mM / ml) and allowing the solution to stand for 2 hours at 20 to 25 ° C., the mixture is worked up as described in Example 1. After recrystallization from ethyl acetate, 2 g are obtained

8th

5

10th

15

20th

25th

30th

35

40

45

50

55

Ml

(> 5

(90%) analytically pure 3ß-0- (a, L-3'-butylrhamnosido) -14-hydroxy-bufa-4,20,22-trienolide, mp. 135 to 141 ° C.

Example 9

3 β-0- (a, L-3 '-pentylrhamnosido) - 14-hydroxy-bufa-4,20,22-trienolide

2 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-bufa-4,20,22-trienolide are dissolved in 150 ml of acetonitrile and with 2 ml of a solution of boric acid in dioxane (0.1 mM / ml ) offset. 35 ml of a diazo-n-pentane solution (0.2 mM / ml) are then added and the mixture is left to stand at 20 to 25 ° C. for 2 hours. After working up as described in Example 1, after recrystallization from ethyl acetate, 2.1 g (92%) of analytically pure 3β-0- (a, L-3'-pentylrhamnosido) -14-hydroxy-bufa-4.20.22 are obtained -trienolid. Mp 147-153 ° C.

Example 10

3β-0- (a, L-3 '-isobutylrhamnosido) - 14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

2 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved in 140 ml of acetonitrile and 10 ml of tetrahydrofuran with heating and with a solution of 2 ml Boric acid in dioxane (0.1 mM / ml) added. After adding 35 ml of diazoisobutane in ether (0.2 mM / ml), the solution is left to stand at 20 to 25 ° C. for 2 hours. After working up as described in Example 1, after recrystallization from ethyl acetate, 2.1 g (95%) of analytically pure 3β-0- (a, L-3'-isobutylrhamnosido) -14-hydroxy-4,5-epoxy-bufa is obtained -20.22-dienolide, mp 235 to 241 ° C.

Example 11

3β-0- (a, L-3'-isopentylrhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

1 g of 3ß-0 - (<x, L-rhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide is dissolved in 100 ml of acetonitrile with heating and with 0.2 ml of a solution of meta -Boric acid in dioxane (4.38 g of meta-boric acid are dissolved in 100 ml of dioxane, which corresponds to 0.1 mol in 100 ml. Modification III of meta-boric acid, mp. 176 ° C., was carried out according to the instructions from FC Kracet, GW Morey and HF Merwin Am. Journ. Of Science 35A, (1938), p. 143). 35 ml of a solution of diazoisopentane (0.1 mM / ml) are then added and the solution is left to stand at 20 to 25 ° C. for 2 hours. After working up as described in Example 1 and recrystallization from ethyl acetate, 1 g (89%) of analytically pure 3β-0- (a, L-3'-isopentylrhamnosido) -14-hydroxy-4,5-epoxy-bufa-20 is obtained , 22-dienolide, mp. 258 to 261 ° C.

Example 12

3β-0- [a, L-3 '- (3 "-methoxypropyl) rhamnosido] -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

4 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved in 270 ml of acetonitrile and 30 ml of tetrahydrofuran with heating and with 1 ml of a solution of meta-boric acid in dioxane (1 mM / ml) was added. A solution of 50 ml of 3-methoxydiazopropane in ether (0.2 mM / ml) is then added. After standing at 20 to 25 ° C. for 3 hours, the solution is worked up as described in Example 1 and, after recrystallization from ethanol-water, 4.1 g (91%) of pure 3β-0- [a, L-3 are obtained '- (3 "-methoxypropyl) rhamnosido] -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide, mp. 225 to 240 ° C.

Example 13

3β-0- [a, L-3 '- (3 "-methoxypropyl) rhamnosido] -14-hydroxy-bufa-4,20,22-trienolide

2 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-bufa-4,20,22-trienolide are dissolved in 150 ml of acetonitrile with heating

9 615 200

and 0.4 ml of a 0.1 M solution of aluminum isopropylate in dioxane (20.4 g of aluminum isopropylate are dissolved in 100 ml of dioxane; aluminum isopropylate is prepared according to Organicum 6th edition, p. 617. mp 118 ° C., bp 7130 to 140 ° C) and 35 ml 5 of a solution of 3-methoxydiazopropane in ether (0.2 mM / ml) added. After standing at 20 to 25 ° C. for 2 hours, the mixture is worked up as described in Example 1. After recrystallization from methanol-water, 2 g (88%) of pure 3β-0- [a, L-3 '- (3 "-methoxypropyl) -rhamnosido] -14-i (ihydroxy-bufa-4,20,22) are obtained -trienolide, mp. 145 to 152 ° C.

Example 14

3β-0- [a, L-3 '- (2 "-methoxyethyl) rhamnosido] -14-hydr-15 oxy-4,5-epoxy-bufa-20,22-dienolide

3 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved in 180 ml of acetonitrile and 20 ml of tetrahydrofuran. 5 ml of a solution of meta-boric acid in dioxane (1 mM / ml) are added and 50 ml of a solution: o of 2-methoxy-diazoethane in ether (0.2 mM / ml) are added. After standing at 20 to 25 ° C. for 3 hours, the solution is worked up as described in Example 1 and, after recrystallization from methanol-water, 3.1 g (91%) of analytically pure 3β-0- [a, L- 3 '- (2 "-methoxyethyl) -rhamnosido] -14-: 5 hydroxy-4,5-epoxy-bufa-20,22-dienolide, mp. 215 to 221 ° C.

Example 15

3β-O- [a, L-3 '- (2 "-methoxy-ethyl) -rhamnosido] -14-hydr-M oxy-bufa-4,20,22-trienolide

2 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-bufa-4,20,22-trienolide are dissolved in 150 ml of acetonitrile with heating and mixed with 2 ml of a 0.1 M solution of triethyl borate in acetonitrile . 40 ml of a solution of 2-methoxy-35 diazoethane (0.2 mM / ml) in ether are added and the solution is left to stand at 20 to 25 ° C. for 3 hours. After working up as described in Example 1 and recrystallization from ethanol-water, 2 g (90%) of analytically pure 3β-0- [a, L-3 '- (2 "-methoxyethyl) -rhamnosido] -14-hydroxy- bufa-4,20,22-trieno-40 lid, mp 138 to 145 ° C.

Example 16

3β-0- [a, L-3 '- (3 "-N-morpholinopropyl) rhamnosido] -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide 45 1 g 3ß-0- (a , L-3'-rhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide is dissolved in 80 ml of acetonitrile and 20 ml of tetrahydrofuran and mixed with 1 ml of a solution of boric acid in dioxane (0.1 A solution of 20 ml of 3-N-morpholinodiazopropane (0.2 mM / ml) is then added and the solution is left to stand for 2 hours at 20 to 25 ° C. After working up as described in Example 1 , and recrystallization from isopropanol gives 1.1 g (90%) of analytically pure 3β-0- [a, L-3 '- (3 "-N-morpholinopropyl) rhamnosido] -14-hydroxy-4,5-epoxy-bufa -20.22-dienolide, mp. 248 to 256 ° C.

55

Example 17

3β-0- [a, L-3 '- (3 "-N-morpholinopropyl) rhamnosido] -14-hydroxy-bufa-4,20,22-trienolide

2 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-bufa-4,20,22-60 trienolide are dissolved in 150 ml of acetonitrile with heating and 2 ml of a 0.1 M solution of trimethyl borate in acetonitrile are added . 70 ml of an ethereal 3-N-morpholinodiazopropane solution (0.1 mM / ml) are then added and the solution is left to stand at 20 to 25 ° C. for 2 hours. After 65 working up, as described in Example 1, and recrystallization from ethyl acetate, 2.15 g (85%) of pure 3β-0- [a, L-3 '- (3 "-N-morpholinopropyl) rhamnosido] -14 are obtained -hydroxy-bufa-4,20,22-trienolide, mp. 156 to 163 ° C.

615 200

10th

Example 18

3β-0- (a, L-3'-propargylrhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

1 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide is dissolved in 120 ml of acetonitrile with heating and with 0.2 ml of a solution of meta- Boric acid in dioxane (1 mM / ml) added. A solution of 20 ml of ethynyldiazomethane (0.2 mM / ml) is then added and the solution is left to stand at 20 to 25 ° C. for 3 hours. After working up as described in Example 1 and recrystallization from ethyl acetate, 0.95 g (90%) of analytically pure 3β-0- (a, L-3'-propargylrhamnosido) -14-hydroxy-4,5-epoxy-bufa is obtained -20,22-dienolide, mp 228 to 237 ° C.

Example 19

3β-0- [a, L-3 '- (2 "-dimethylaminoethyl) rhamnosido] -14-hydroxy-bufa-4,20,22-trienolide

3 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-bufa-4,20,22-trienolide are dissolved in 200 ml of acetonitrile and with 3 ml of a solution of triphenylborate in acetonitrile (0.1 mM / ml ) offset. After adding 60 ml of a solution of 2-dimethylaminodi-azoethane (0.2 mM / ml) in ether, the solution is left to stand at 20 to 25 ° C. for 3 hours. After working up as described in Example 1 and recrystallization from isopropanol, 3 g (88%) of analytically pure 3β-0- [a, L-3 '- (2 "-dimethylamino-ethyl) -rhamnosido] -14- hydroxy-bufa-4,20,22-trienolide, mp. 148 to 155 ° C.

Example 20

3β-0- [a, L-3 '- (3 "-dimethylaminopropyl) rhamnosido] -14-hydroxy-bufa-4,20,22-trienolide

3 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-bufa-4,20,22-trienolide are dissolved in 200 ml of acetonitrile and mixed with 3 ml of a 0.1 M solution of trimethyl borate in acetonitrile. After adding 60 ml of a solution of 3-dimethylaminodiazopropane (0.2 mM / ml), the solution is left to stand at 20 to 25 ° C. for 3 hours. After working up as described in Example 1 and recrystallization from isopropanol, 3 g (86%) of analytically pure 3β-0- [a, L-3 '- (3 "-dimethylaminopropyl) rhamnosido] -14-hydroxy- bufa-4,20,22-trienolide, mp. 135 to 146 ° C.

Example 21

3β-0- [a, L-3 '- (2 "chloroethyl) rhamnosido] -14-hydroxy-bufa-4,20,22-trienolide

2 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-bufa-4,20,22-trienolide are dissolved in 150 ml of acetonitrile with heating and in with 0.4 ml of a 0.1 M solution of aluminum isopropylate Dioxane added. 20 ml of a solution of 2-chlorodiazoethane (0.4 mM / ml) in ether are then added. After standing at 20 to 25 ° C. for 3 hours, the solution is worked up as described in Example 1 and, after recrystallization from ethyl acetate, 2 g (89%) of pure 3 .beta.-O are obtained. [a, L-3 '- (2 "-chloroethyl) rhamnosido] -14-hydroxy-bufa-4,20,22-trienolide, mp. 168 to 175 ° C.

Example 22

3β-0- [a, L-3 '- (3 "-diethylaminopropyl) rhamnosido] -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

1 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide is dissolved in 120 ml of acetonitrile with heating and with 1 ml of a 0.1 M solution of Boric acid added. Then 20 ml of a solution of 3-diethyl-aminodiazo-propane (0.2 mM / ml) in ether are added and the solution is left to stand at 20 to 25 ° C. for 3 hours. After working up as described in Example 1, after recrystallization from methanol-water, 1 g (83%) of analytically pure 3β-0- [a, L-3 '- (3 "-

Diethylaminopropyl) rhamnosido] -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide, mp. 138 to 145 ° C

Example 23

s 3β-0- [a, L-3 '- (tetrahydrofurfuryl) rhamnosido] -14-hydroxy-bufa-4,20,22-trienolide

2 g of 3ß-0- (a, L-rhamnosido) -14-hydroxy-bufa-4,20,22-trienolide are dissolved in 150 ml of acetonitrile with heating and mixed with 0.4 ml of a solution of trimethyl borate in acetonitrile m (0 , 1 mM / ml). 20 ml of a solution of tetrahydrofuryldiazomethane (0.4 mM / ml) are then added. After standing for 3 hours at 20 to 25 ° C. and working up as described in Example 1, 1 g (89%) of pure 3β-0- [a, L-3 '- (tetrahy-) is obtained after recrystallization from ethyl acetate. 15 drofurfuryl) rhamnosido] -14-hydroxy-bufa-4,20,22-trienolide, mp. 125 to 137 ° C.

Example 24

3β-0- (a, L-3'-allylrhamnosido) -14-hydroxy-bufa-4,20,22-2o trienolide

2 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-bufa-4,20,22-trienolide are dissolved in 150 ml of acetonitrile with heating and with 2 ml of a solution of boric acid in dioxane (0.1 mM / ml). 35 ml of a vinyl diazomethane solution 25 (0.4 mM / ml) are then added and the mixture is left to stand at 30 ° C. for 3 hours. After working up as described in Example 1 and recrystallization from ethyl acetate, 2 g (93%) of analytically pure 3β-0- (a, L-3'-allylrhamnosido) -14-hydroxy-bufa-4,20,22-trienolide are obtained , Mp 113 to 120 ° C.

-10

Example 25

3β-0- [a, L-3 '- (2 "-phenylethyl) rhamnosido] -14-hydroxy-bufa-4,20,22-trienolide

2 g of 3ß-0- (a, L-rhamnosido) -14-hydroxy-bufa-4,20,22-15 trienolide are dissolved in 150 ml of acetonitrile with heating and with 0.4 ml of a solution of meta-boric acid in dioxane (1 mM / ml) was added. 20 ml of a solution of 2-phenyldiazoethane (0.4 mM / ml) in ether are then added and the solution is left to stand at 30 ° C. for 3 hours. After working up, 40 as described in Example 1, and recrystallization from ethyl acetate, 2.1 g (90%) of pure 3β-0- [a, L-3 '- (2 "-phenyethyl) -rhamnosido] -14-hydroxy are obtained -bufa-4,20,22-trienolide, mp. 180 to 195 ° C.

45 Example 26

3β-0- [a, L-3 '- (2 "-ethoxyethyl) rhamnosido] -14-hydroxy-bufa-4,20,22-trienolide

2 g of 3ß-0- (a, L-rhamnosido) -14-hydroxy-bufa-4,20,22-trienolide are dissolved in 150 ml of acetonitrile and mixed with 2 ml of a solution of meta-boric acid in acetonitrile (0.1 mM / ml). 35 ml of a solution of 2-ethoxydiazoethane in ether (0.2 mM / ml) are then added and the solution is left to stand at 20 to 25 ° C. for 2 hours. After working up as described in Example 1 and recrystallization from ethanol-water 55 2.1 g (92%) of analytically pure 3β-0- [a, L-3 '- (2 "-ethoxy-ethyl) -rhamnosido] are obtained. -14-hydroxy-bufa-4,20,22-trienolide, mp. 150 to 156 ° C.

Example 27

so 3ß-0- [a, L-3 '- (3 "-ethoxypropyl) rhamnosido] -14-hydroxy-bufa-4,20,22-trienolide

2 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-bufa-4,20,22-trienolide are dissolved in 150 ml of acetonitrile and mixed with 2 ml of a solution of meta-boric acid in acetonitrile (0.1 mM / ml). 65 Then 35 ml of a solution of 3-ethoxydiazopropane in ether (0.2 mM / ml) are added and the solution is left to stand at 20 to 25 ° C. for 2 hours. After working up as described in Example 1 and recrystallization from ethanol

11

615 200

Water is obtained 2.15 g (92%) analytically pure 3β-0 - [<x, L-3 '- (3 "-ethoxypropyl) rhamnosido] -14-hydroxy-bufa-4,20,22-trienolide, mp . 160 to 168 ° C.

Example 28

3β-0- [a, L-3 '- (2 "-ethoxyethyl) rhamnosido] - 14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

2 g of 3ß-0- (a, L-rhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved in 200 ml of acetonitrile with heating and mixed with 2 ml of a solution of boric acid in dioxane ( 0.1 mM / ml) was added. 35 ml of a solution of 2-ethoxydiazoethane in ether (0.2 mM / ml) are then added and the solution is left to stand at 20 to 25 ° C. for 2 hours. After working up as described in Example 1 and recrystallization from ethyl acetate, 2.1 g (90%) of analytically pure 3β-0- [a, L-3 '- (2 "-ethoxyethyl) rhamnosido] -14-hydroxy- 4,5-epoxy-bufa-20,22-dienolide, mp. 232 to 240 ° C.

Example 29

3β-0- [a, L-3 '- (3 "-ethoxypropyl) rhamnosido] -l 4-hydroxy-4,5-epoxy-bufa-20,22-dienolide

2 g of 3ß-0- (a, L-rhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved in 200 ml of acetonitrile with heating and mixed with 2 ml of a solution of boric acid in dioxane ( 0.1 mM / ml) was added. 35 ml of a solution of 3-ethoxydiazopropane in ether (0.2 mM / ml) are then added and the solution is left to stand at 20 to 25 ° C. for 2 hours. After working up as described in Example 1 and recrystallization from ethyl acetate, 2.2 g (89%) of analytically pure 3β-0- [a, L-3 '- (3 "-ethoxypropyl) -rhamnosido] -14-hydroxy- 4,5-epoxy-bufa-20,22-dienolide, mp. 237 to 245 ° C.

described in Example 1, after three recrystallizations from ethyl acetate, 0.8 g (36%) of analytically pure 3β-0- [a, L-3 '- (2 "-chloroethyl) rhamnosido] -14-hydroxy-4,5 is obtained -epoxy-bufa-20,22-dienolide, mp. 210 to 215 ° C.

5

Example 33

3β-0- [a, L-3 '- (3' '-Broxnopropyl) rhamnosido] - 14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

1 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-4,5-epoxy-bufa-i (i 20,22-dienolide is heated in 80 ml of acetonitrile

Tetrahydrofuran (8: 2, v / v) dissolved, 1 ml of boric acid in dioxane (0.1 mM / ml) was added and, after the solution had cooled, 12 ml of a 3-bromodiazopropane solution (0.3 mM / ml) were added. After standing in the ice box for 17 hours, the mixture is worked up as described in Example 1 and, after recrystallization from ethyl acetate, 0.9 g (73%) of analytically pure 3β-0- [a, L-3 '- (3 "-bromopropyl) are obtained ) -rhamnosido] -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide, mp. 220 to 225 ° C.

in Example 34

3β-0- [a, L-3 '- (allylrhamnosido)] - 14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

2 g of 3ß-0- (a, L-rhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved in 140 ml of acetonitrile and 10 ml of tetrahy-

25 drofuran dissolved, mixed with 2 ml of a solution of boric acid in dioxane (0.1 mM / ml). After adding 35 ml (0.2 mM / ml) of vinyl diazomethane in ether, the mixture is left to stand at room temperature for 2 hours. After working up as described in Example 1, after recrystallization from ethyl acetate, 1.9 g (89%) of analytically pure 3β-0- [a, L-3 '- (allylrhamnosido)] - 14-hydroxy-4,5-epoxy are obtained -bufa-20,22-dienoIid, mp. 192 to 197 ° C.

Example 30

3β-O- [a, L-3 '- (propyne-3 "rhamnosido)] - l 4-hydroxy-buf a-4,20,22-trienolide 35

2 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-bufa-4,20,22-trienolide are dissolved in 150 ml of acetonitrile with heating, 2 ml of a boric acid solution in dioxane (0.1 mM / ml) added and then a solution of 70 ml of diazopropin in ether (0.1 mM / ml) added. After standing at room temperature for 3 hours, the mixture is worked up as described in Example 1 and, after recrystallization from methanol-water, 1.8 g (84%) of pure 3β-0- [a, L-3 '- ( Propin-3 "-rhamnosido)] - 14-hydroxy-bufa-4,20,22-trienolide, mp. 170 to 175 ° C.

45

Example 31

3β-0- [a, L-3 '- (3 "-bromopropyI) rhamnosido] -14ß-hydr-oxy-bufa-4,20,22-trienolide

6 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-bufa-4,20,22-trienolide are dissolved in 600 ml of acetonitrile-tetrahydrofuran (8: 2, v / v) while heating, 6 ml of boric acid in dioxane (0.1 mM / ml) were added and, after cooling, 100 ml of an ethereal diazo-3-bromopropane solution (0.6 mM / ml) were added. After standing overnight in the ice box, the mixture is worked up as described in Example 1 and, after recrystallization from ethyl acetate, 3 g (41%) of analytically pure 3β-0- [a, L-3 '- (3 "-bromopropyl) rhamnosido are obtained ] -14ß-hydroxy-bufa-4,20,22-trienolide, mp. 180 to 185 ° C.

Example 32 60

3β-O- [a, L-3 '- (2 "chloroethyl) rhamnosido] -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

2 g of 3ß-0- (a, L-rhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved in 150 ml of acetonitrile with heating and 2 ml of a solution of boric acid in dioxane (0 , 1 mM / 65 ml) was added. After the solution has cooled, 2.5 ml of a solution of 2-chlorodiazoethane (0.3 mM / ml) is added and left to stand in the ice box for 17 hours. After working up as

Example 35

3β-0- [3 '- (3 "-phenylpropyl) rhamnosido] -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

4 g of 3ß-0- (a, L-rhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved in 300 ml of acetonitrile-tetrahydrofuran (8: 2, v / v) and 4 ml of a boric acid solution in dioxane (0.1 mM / ml) was added. After cooling, 17 ml (0.6 mM / ml) of 3-phenyldiazopropane are added. After the reaction solution has been left to stand for 4 hours, the mixture is worked up as described in Example 1 and, after recrystallization from ethyl acetate, 2.8 g (57%) of analytically pure 3β-0- [3 '- (3 "-phenylpropyl) rhamnosido] - are obtained. 14-hydroxy-4,5-epoxy-bufa-20,22-dienolide, mp. 225 to 230 ° C.

Example 36

3β-0- [3 '- (3 "-phenylpropyl) rhamnosido] -14ß-hydroxy-bufa-4,20,22-trienolide

4 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-bufa-4,20,22-trienolide are dissolved in 300 ml of acetonitrile with heating and with 5 ml of a solution of boric acid in dioxane (0.1 mM / ml). 50 ml of an ethereal solution of 3-phenyldiazopropane (0.3 mM / ml) are then added and the solution is left to stand at 20 to 25 ° C. for 2 hours. After working up as described in Example 1, after recrystallization from ethyl acetate, 4 g (82%) of analytically pure 3β-0- [3 '- (3 "-phenylpropyl) -rhamnosido] -14ß-hydroxy-bufa-4.20 are obtained. 22-trieno-lid, mp 165 to 170 ° C.

Example 37

3β-0- [a, L-3 '- (l ", 3" -dimethyl-n-pentyl) rhamnosido] -14-hydroxy-bufa-4,20,22-trienolide

2 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-bufa-4,20,22-trienolide are dissolved in 150 ml of acetonitrile with heating and 0.4 ml of a 0.1 M solution of aluminum isopropylate in dioxane transferred. 20 ml of a solution of 1,3-dimethyldiazopentane (0.4 mM / ml) in ether are then added. To

615 200

12

Standing for 3 hours at 20 to 25 ° C., the solution is worked up as described in Example 1 and, after recrystallization from ethyl acetate, 2 g (89%) of analytically pure 3β-0- [a, L-3 '- (1' , 3 "-dimethyl-n-pentyl) rhamnosido] -14-hydroxy-bufa-4,20,22-trienolide, mp. 240 to 245 ° C.

Example 38

3β-0- [a, L-3 '- (l ", 3" -dimethyl I-n-pentyl) rhamnosido] -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide

3 g of 3β-0- (a, L-rhamnosido) -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved in 200 ml of acetonitrile and 23 ml of a 0.1 N solution of trimethyl borate in acetonitrile transferred. After adding 60 ml of a solution of 1,3-dimethyldiazo-pentane, the solution is allowed to stand at 20 to 25 ° C. After working up as described in Example 1 and recrystallization from isopropanol, 2.2 g (61.8%) of analytically pure 3β-0- [a, L-3 '- (1 ", 3" -dimethyl-n-pentyl) are obtained ) -rhamnosido] -14-hydroxy-4,5-epoxy-bufa-20,22-dienolide, mp. 255 to 260 ° C.

Example 39

3β-0- [a, L- (3'-methylrhamnosido)] - 14,19-dihydroxy-bufa-4,20,22-trienolide

2 g of 3β-0- (a, L-rhamnosido) -14,19-dihydroxy-bufa-4,20,22-trienolide are dissolved in 100 ml of acetonitrile and mixed with 2 ml of a solution of boric acid in dioxane (0.1 mM / ml). After cooling, a solution of 10 ml of diazomethane (0.7 s mM / ml) is added and the solution is left overnight in the ice box. After working up as described in Example 1 and recrystallization from isopropanol, 2 g (97%) of analytically pure 3β-0- [a, L- (3'-methylrhamnosido)] - 14,19-dihydroxy-bufa-4.20 are obtained , 22-trienolide, mp 168 to 172 ° C.

in

Example 40

3β-0- [a, L- (3'-ethylrhamnosido)] - 14,19-dihydroxy-bufa-4,20,22-trienolide

2 g of 3ß-0- (a, L-rhamnosido) -14,19-dihydroxy-bufa-15 4,20,22-trienolide are dissolved in 100 ml of acetonitrile and mixed with 2 ml of a boric acid solution in dioxane (0.1 mM / ml) are added. After the solution has cooled, 15 ml of a solution of diazoethane (0.4 mM / ml) in ether are added. After standing at 20 to 25 ° C. for 2 hours, work up as described in Example 1 and, after recrystallization from isopropanol, 1.5 g (71%) of pure 3β-0- [a, L- ( 3'-Ethylrhamnosido)] - 14,19-dihydroxy-bufa-4,20,22-trienolide, mp. 170 to 176 ° C.

C.

Claims (6)

615 200 2. The method according to claim 1, characterized in that the inert solvent is one with a high dielectric constant, such as. Acetonitrile, propionitrile, tetrahydrofuran, dimethylformamide, dioxane or a mixture of these solvents is used. 2 to 6 carbon atoms, an ethynyl radical, an alkoxyalkyl group can form atoms, characterized in that a bufa- each with 1 or 2 carbon atoms in the alkoxy and alkyl moiety, dienolide or bufatrienolide glycoside of the general formula O 2nd PATENT CLAIMS 0 where X is a double bond between the C atoms 4 and 5 an aromatic or araliphatic radical, the dimethyl or represents the epoxy group, R 'is methyl, formyl or aminomethyl, dimethylaminoethyl, diethylaminoethyl, Is methylol group, R "represents a hydrogen atom and R represents morpholinoethyl, tetrahydrofuryl, bromoethyl or chlorine hydrogen, a straight or branched alkyl radical having 1 to methyl radical, or R and R" together with the neighboring 16 carbon atoms, a straight or branched alkenyl radical with a beard carbon atom, a cycloaliphatic ring with 6 to 12 carbon atoms 3. The method according to claim 1 or 2, characterized in that the weakly acidic catalyst is ferric chloride in ether, boron trifluoride dietate, boric acid ester, aluminum chloride in ether, aluminum isopropylate, p-toluenesulfonic acid, polyphosphoric acid in ether and arsenic trioxide, but preferably Boric acid or meta-boric acid used in dioxane. 3rd 615 200 wherein X and R 'have the above meaning, with a diazoalkane of the general formula N, = CRR " (III) wherein R and R "have the meaning given above, is reacted in an inert solvent and in the presence of a weakly acidic catalyst. 4. The method according to claim 1, characterized in that acetonitrile is used as the solvent and boric acid in dioxane as the catalyst. 5. Process according to claims 1 to 4, characterized in that the catalyst is used in a molar amount, corresponding to 1/5 of the molar amount of the glycoside used. 6. The method according to claims 1 to 5, characterized in that one carries out the reaction at a temperature of 20 to 30 ° C. It is known that the oral absorption of cardiac glycosides is favorably influenced by blocking one or more hydroxyl groups by acylation, ketal formation or etherification. Of these types of reactions, etherification in both the cardenolide and bufadienolide series proved to be particularly favorable. Numerous examples of these latter cardiac glycoside derivatives are known in the literature in both classes of compounds. In the series of cardenolides, the 3 ', 4'-dimethyl ether was produced from both Helveti-cosid and Helveticosol (OE-PS 274 247, Boehringer Mannheim Ges.mbH), the m 3 "' - and 4" '- 0 -Methyldigoxin (OE-PS 302 544, CA-PS 909 207, US-PS 3 538 078), the Acovenosid-A-2'- and 4'-monoalkyl ethers (DT-OS 1 905 725, Boehringer Mannheim Ges.mbH) . In these cited patents, alkyl halides, dialkyl sulfates in the presence of weak bases or diazoalkane in the presence of weakly acidifying catalysts were used as alkylating agents. In the series of bufatrienolides the 4,20,22-bufa-trienolidrhamnosidäther were made (GB-PS 1 266 251) and the 3-methyl ether of 3-hydroxy-4,5-epoxy-14-hydroxy-bufa -; <i 20,22-dienolide (DT-OS 2 132 488) and 4,5-epoxy ether of cardenolide and bufadienolide glycones (Knoll AG, DT-OS 2 132 489). For the bufadienolides and bufatrienolides, only alkyl halides in the presence of a base in an inert solvent were used. A mixture of the various mono- and dialkyl ethers is always obtained, which can only be purified by the complex process of a Craig distribution or by column chromatography.