GB1601539A

GB1601539A - Preparation of ethers of bufapolyenolides

Info

Publication number: GB1601539A
Application number: GB22676/78A
Authority: GB
Original assignee: Laevosan GmbH and Co KG
Current assignee: Laevosan GmbH and Co KG
Priority date: 1977-06-08
Filing date: 1978-05-26
Publication date: 1981-10-28
Also published as: FI62844C; JPS5416463A; EG13431A; CA1107720A; IL54850A0; IT7824056A0; AT368523B; FR2393813B2; IT1109164B; BE867944A; YU127978A; FI62844B; NL7805797A; SE7806364L; ATA405677A; LU79783A1; ES470578A2; DE2824318A1; CH637145A5; YU40194B

Abstract

Bufadienolide or bufatrienolide ethers of the formula I <IMAGE> are prepared by reaction of the corresponding bufadienolide glycoside or bufatrienolide glycoside with a diazoalkane. The reaction is carried out in an inert solvent in the presence of a mixture, which serves as a catalyst, of titanium tetrachloride and boric acid or of titanic acid ester and titanium tetrachloride or titanic acid ester on its own in absolute dioxane. The symbols in formula I have the meaning given in Claim 1. The compounds of the formula I are employed in the therapy of heart disorders.

Description

(54) PREPARATION OF ETHERS OF BUFAPOLYENOLIDES (71) We, LAEVOSAN-GESELL SCHAFT mbH & CO. KG., an Austrian Company, of Estermannstrasse 17, Linz, O.b, Austria, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement::- A process for preparing new ethers of bufadienolide and bufatrienolide of the general formula

has previously been disclosed in which formula X is a doube bond between the cabon atoms 4 and 5 or an epoxide group, R' is a methyl, formyl or methylol group, and R is hydrogen, a straight or branched alkyl radical having 1 to 16 carbon atoms, a straight or branched alkenyl radical having 2 to 6 carbon atoms, an ethynyl radical, a straight or branched alkoxy radical having 2 to 11 carbon atoms, a cycloaliphatic radical, an aromatic or aliphatic-aromatic radical, e.g. a phenyl, phenylmethyl, 2-phenylethyl or 3-phenylpropyl radical, a straight or branched dimethyl- or diethyl-aminoalkyl radical having in total 3 to 6 carbon atoms, in which values of R the straight or branched aliphatic chains may be substituted by nitrogen or oxygencontaining heterocycles, e.g. pyridine, piperazine, pyrrolidine, furyl, tetrahydrofuryl or morpholino groups or by halogen, e.g. chlorine or bromine, with exclusion of the compounds wherein (i) X is a double bond, R' is methyl, R is H; (ii) R' is methyl, X is a double bond, R is alkyl having 4 or 5 carbon atoms; and iii) R' is formyl, X is a double bond, R is hydrogen or an alkyl group having 1 to 5 carbon atoms.

This previous process comprises reacting a glycoside of bufadienolide or bufatrienolide of the general formula

in which X and R' are as defined above, with a diazoalkane of the general formula R.CH.N2 (III) in which R is as defined above, in an inert solvent in the presence of a weakly acid catalyst.

Examples of such weakly acid catalysts are iron(III)-chloride in ether, borotrifluoride dietherate, boric acid ester, aluminium chloride, aluminium isopropylate, p-toluene sulfonic acid, polyphosphoric acid in ether, arsenic trioxide, titanium tetrachloride, molybdenum(VI)-oxychloride, tin dichloride, tin tetrachloride, tin sulfate, copper(II)-chloride, preferably boric acid or m-boric acid.

According to the present invention it has been found that the yield of the 3'alkylether can be improved substantially, if a mixture of titanium tetrachloride and boric acid or of a titanic acid ester and titanium tetrachloride or a titanic acid ester alone in an inert solvent such as absolute dioxane is used as catalyst. As titanic acid esters may be used ethyl titanate, n-propyl-, isopropyl-, n-butyl-, isobutyl-, cresyl-, 2ethylhexyl titanate and diisopropoxy - bis (2,4 - pentane - dionato)- titanium(IV) (=titaniumacetylacetonate).

Thus the present invention provides a method of preparing ethers of formula I by reacting a glycoside of formula II with a diazoalkane of formula III in an inert solvent and in the presence as catalyst of (a) a mixture of titanium tetrachloride and boric acid or (b) a mixture of titanium tetrachloride and a titanic acid ester or (c) a titanic acid ester.

These catalysts are advantageous inasmuch as the alkylation in position 3' of the rhamnose occurs more selectively and less non-polar products (dimethylethers) are obtained in comparison with boric acid.

The reaction is carried out in an inert solvent, preferably in absolute dioxane. The reaction proceeds slower than with boric acid alone, but more selective and with better yield.

Furthermore, it has been found that the same concentration of titanium tetrachloride alone as cataylst or the same concentration of titanic acid ester alone do not provide the same effect as the use of a mixture of both. Also the mixture of titanium tetrachloride and boric acid 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 illustrate the improved process in detail.

EXAMPLE 1 2 g of 3p - 3p - L - rhamnosido) - 14 hydroxy - 4z,5 - epoxy - 5a bufa - 20,22 dienolide are dissolved in 100 ml of absolute dioxane and 16 ml of a solution of diazomethane in ether (0.5 mmoles/ml) are added thereto. Finally 4 ml of a solution of 0.1 mmole of boric acid and 0.005 mmoles of titanium tetrachloride/ml in absolute dioxane are added as catalyst solution. The solution is allowed to stand for 4 to 5 hours at room temperature, the excess of diazomethane is decolored with a few drops of glacial acid, evaporated carefully in vacuo and the residue is taken up into chloroform. The solution is shaken once with a 2% solution of sodium bicarbonate and twice with water, dried over anhydrous sodium sulfate, removed by filtration and evaporated in vacuo.The residue is recrystallized several times from methanolwater and 95 to 98% of pure 3P - (3' - 0 methyl - a - L - rhamnosido) - 14 hydroxy - 4,Sa - epoxy - bufa - 20,22 - dienolide is obtained, m.p. 220 to 232"C.

The solution of the catalyst is prepared as follows: In a 100 ml graduated flask 0.62 g boric acid (10 mmoles) are dissolved in about 50 to 60 ml of absolute dioxane. 10 ml of a solution of titanium tetrachloride in absolute dioxane (0.05 mmoles/ml; i.e. 0.55 ml of titanium tetrachloride/100 ml of absolute dioxane) are added to the above solution and the flask is filled up to the marking with absolute dioxane. The solution contains 0.1 mmole boric acid and 0.005 mmoles titanium tetrachloride/ml.

The initially yellow colored solution becomes colorless after a period of time.

The solution is durable several days at room temperature.

EXAMPLE 2 2 g. of 3P - (cg - 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 mmoles/ml) in ether are added thereto. Then 4 ml of a catalyst mixture of 0.05 mmoles n-propyl titanate and 0.005 mmoles titanium tetrachloride/ml in dioxane are added. The reaction mixture is allowed to stand for 16 hours at room temperature. Then the solution is worked up as described in Example 1. By recrystallization from methanol-water 90% of pure 3p - [3' - 0 - (2" - ethylhexyl) - a L - rhamnosido] - 14 - hydroxy - bufa 4,20,22 - trienolide is obtained, m.p. 235 to 241"C.

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

EXAMPLE 3 2 g of 3P - 3A - L - rhamnosido) - 14 hydroxy - bufa - 4,20,22 - trienolide are dissolved in 80 ml of absolute dioxane and 11 ml of a solution of 2 - chlorodiazoethane (0.7 mmoles/ml) are added. Then 4 ml of the mixed catalyst boric acid/titanium tetrachloride, as described in Example 1, are added and allowed to stand for 4 to 6 hours at room temperature. Then it is worked up as described in Example 1. After recrystallization from acetic acid ethylester 3h - [3' - O - (2" - chloroethyl) - a - L - rhamnosido] - 14 - hydoxy - bufa 4,20,22 - trienolide is obtained in a yield of 95%, m.p. 168 to 1750C.

EXAMPLE 4 1 g of 3ss - [a - L - rhamnosido] - 14 hydroxy - 4α,5 - epoxy - Sa - bufa 20,22 - dienolide is dissolved in 50 ml of absolute dioxane and 20 ml of ethynyldiazomethane (0.2 mmoles/ml) are added. Then 2 ml of a solution of n-butyl titanate in dioxane (0.05 mmoles/ml; 0.85 ml of n-butyl titanate in 50 ml of absolute dioxane) are added and it is allowed to stand for 4 to 6 hours at room temperature. Then it is worked up as described in Example 1.

After recrystallization from acetic acid ethyl ester I g (93%) of pure 3k - (3' - 0 propargyl- a - L - rhamnosido) - 14 hydroxy - 4a,5 - epoxy - Sa - bufa 20,22 - dienolide is obtained, m.p. 228 to 237 C.

EXAMPLE 5 1 g of 3k - (a - L - rhamnosido) - 14 hydroxy - bufa- 4,20,22 - trienolide is dissolved in 40 ml of absolute dioxane and 15 ml of a solution of 3 - (2 - ethylhexyloxy) diazopropane - (1) (0.6 mmoles/ml) in ether are added. Then 2 ml of a solution of npropyl titanate (0.05 mmoles/ml) and titanium tetrachloride (0.005 mmoles/ml) are added, as described in Example 2, and allowed to stand for 16 hours at room temperature. Then the solution is worked up, as described in Example 1. After recrystallization from acetic acid ethyl ester 1.1 g (85; ó) of pure -[3' -o -(3" (2"' - ethylhexyloxy)propyl) - a - L rhamnosido] - 14 - hydroxy - bufa 4,20,22 - trienolide are obtained, m.p. 225 to 2300C.

EXAMPLE 6 3 g of 3,5 - (a - L - rhamnosido) - 14 hydroxy - 4a,5 - epoxy - Sa - bufa 20,22 - dienolide are dissolved in 160 ml of absolute dioxane and 50 ml of an etherical solution of diazoethane (0.6 mmoles/ml) are added thereto. I ml of a solution of ethyl titanate and titanium - tetrachloride in absolute dioxane (0.05 mmoles ethyl titanate and 0.005 mmoles titanium tetrachloride/ml) are added thereto and it is allowed to stand for 4 to 6 hours at room temperature.After working up as described in Example 1 3.5 g (93%) of pure 3 - (3' 0 - ethyl - a - L - rhamnosido - 14 hydroxy - 4a,5 - epoxy - Sa - bufa 20,22 - dienolide are obtained after recrystallization from methanol - water, m.p. 136 to 1430C.

EXAMPLE 7 2 g of k - 3p - L - rhamnosido) - 14 - hydroxy - 4a,5 - epoxy - Sa - bufa 20,22 - dienolide are dissolved in 50 ml of absolute dioxane and 13 ml of a solution of diazopropane (0.4 mmole/ml) in ether are added thereto. Then 4 ml of a solution of ipropyl titanate (0.05 mmoles/ml) and titanium tetrachloride (0.005 mmoles/ml) in dioxane are added. The solution is allowed to stand for 3 to 4 hours at room temperature. After working up as described in Example 1 2.1 g (96%) of pure 3k - (3' - O- propyl- a - L - rhamnosido) - 14 hydroxy - 4a,5 - epoxy - 5a - bufa 20,22 - dienolide are obtained after recrystallization from methanol-water, m.p.

230 bis 235 C.

The catalyst solution is prepared by dissolving in a graduated flask 0.35 ml of ipropyl titanate in absolute dioxane and adding 2.5 ml of a solution of titanium tetrachloride (0.05 mmoles/ml, see Example 1) in absolute dioxane and filling up to the marking with absolute dioxane.

EXAMPLE 8 2 g of 3ss - ( - L - rhamnosido) - 14 hydroxy - 4a,5 - epoxy - 5a - bufa - 20,22-, dienolide are dissolved in 50 ml of absolute dioxane and 63 ml of a solution of 3 methoxydiazopropane in ether (0.8 mmoles/ml) are added thereto. To the solution 4 ml of a catalyst solution of i-butyl titanate and titanium tetrachloride (0.05 mmoles i-butyl titanate and 0.005 mmoles titanium tetrachloride/ml) in dioxane are added. After standing for 12 hours at room temperature it is worked up as described in Example 1.After recrystallization from ethanol-water 2.16 g (95%) of pure 3p - [3' o - (3" - methoxypropyl) - a - L - rhamnosidol - 14 - hydroxy - 4α,5 epoxy - 5a - bufa - 20,22 - dienolide are obtained, m.p. 225 to 2400C.

The catalyst solution is prepared by dissolving 0.43 ml of i-butyl titanate in a 25 ml-graduated flask in some absolute dioxane and adding 2.5 ml of a solution of titanium tetrachloride (0.05 mmmoles/ml, as described in Example 1) and filling up to the marking with dioxane.

EXAMPLE 9 2 g of 3k - (a - L - rhamnosido) - 14 hydroxy - 4a,5 - epoxy - Sa - bufa 20,22 - dienolide are dissolved in 50 ml of absolute dioxane and 25 ml of a solution of 2-methoxydiazoethane (0.3 mmoles/ml) in ether are added. 4 ml of a mixture of cresyl titanate and titanium tetrachloride in di6xane (0.4% cresyl titanate and 0.005 ml of titanium tetrachloride/ml) are added to the above solution. The solution is allowed to stand for 16 hours at room temperature.

After working up as described in Example 1 2.15 g (95%) of pure 3p - [3' - 0 - (2" methoxyethyl)a - L - rhamnosido] - 14 hydroxy - 4cog,5 - epoxy - 5a - bufa - 20,22-- dienolide are obtained after recrystallization from methanol-water, m.p.

215 to 2210C.

The catalyst solution is prepared by dissolving 0.1 g of cresyl titanate in some absolute dioxane in a 25 ml-graduated flask, adding 2.5 ml of a solution of titanium tetrachloride (0.05 mmoles/ml) in dioxane and filling up to the marking with dioxane.

EXAMPLE 10 2 g of 3P - 3p - L - rhamnosido) - 14 hydroxy - bufa - 4,20,22- trienolide are dissolved in 50 ml of absolute dioxane and 20 ml of a solution of 3 dimethylaminodiazopropane (0.4 mmoles/ml) in ether are added thereto. To the solution 4 ml of a solution of 2ethylhexyl titan ate and titanium tetrachloride (0.05 mmoles 2-ethylhexyl titan ate and 0.005 mmoles titanium tetrachloride/ml) in absolute dioxane are added. After standing for 17 hours at room temperature the solution is worked up as described in Example 1. After recrystallization from acetic acid ethylester 2.1 g (94%) of pure 3p - [3' - 0 - (3off - dimethylaminopropyl) - a - L - rhamnosidol - 14 - hydroxy - bufa 4,20,22 - trienolide are obtained, m.p. 135 to 146 C.

The catalyst solution is prepared by dissolving 0.78 ml of 2-ethylhexyl titanate in some absolute dioxane in a 25 ml-graduated flask, adding 2.5 ml of a solution of titanium tetrachloride (0.05 mmoles/ml, see Example 1) in dioxane and filling up to the marking with absolute dioxane.

EXAMPLE 11 2 g of 3p - (a - L - rhamnosido) - 14 hydroxy - bufa - 4,20,22 - trienolide are dissolved in 50 ml of absolute dioxane and 20 ml of a solution of 2 - phenyldiazoethane (0.4 mmoles/ml) in ether are added. Then 4 ml of a mixture of ethyl titanate (0.05 mmoles/ml) and titanium tetrachloride (0.005 mmoles/ml) in absolute dioxane are added and the solution is aallowed to stand 16 hours at room temperature. After working up as described in Example 1 2.2 g (94%) of pure 3A - [3' - 0 - (2" phenylethyl) - a - L - rhamnosido] - 14 hydroxy - bufa - 4,20,22 - trienolide are obtained after recrystallization from acetic acid ethyl ester, m.p. 180 to 1950C.

The catalyst solution is prepared by dissolving 0.28 ml of ethyl titanate in some absolute dioxane in a 25 ml-graduated flask, adding 2.5 ml of a solution of titanium tetrachloride (0.05 mmoles/ml) in dioxane and filling up to the marking with absolute dioxane.

EXAMPLE 12 2 g of 3A - (eg - L - rhamnosido) - 14 hydroxy - bufa - 4,20,22 - trienolide are dissolved in 50 ml of absolute dioxane and 25 ml of a solution of diazopropyne (0.3 mmoles) in ether are added. Then 4 ml of a mixture of titanium acetyl acetonate (0.4%) and titanium tetrachloride (0.005 mmoles/ml) in dioxane are added. After standing for 14 hours at room temperature and working up as described in Example 1 2.1 g (93%) of pure 3p - [3' - 0 - (propargyl - 3") - L- rhamnosido] - 14 - hydroxy - bufa - 4,20,22 - trienolide are obtained after recrystallization from acetic acid ethyl ester, m.p. 170 to 1750C.

The catalyst solution is prepared by dissolving 0.1 ml of titanium acetylacetonate in absolute dioxane in a 25 ml-graduated flask, adding 2.5 ml of a solution of titanium tetrachloride (0.05 mmoles/ml) in absolute dioxane (see Example 1) and filling up to the marking with absolute dioxane.

Compounds of formula I in which R' is other than methyl can be prepared in similar manner from starting materials of formula II having the appropriate substituent in 10-position. For example, a compound in which R' is formyl is scilliglaucosidin - alpha - L - rhamnoside, contained in squill (scilla maritima). This compound may be reduced with sodium boro - hydride to the compound in which R' is methylol.

The compounds made by the process of this invention are cardiotonics. They show an increased activity on the heart, in which connection especially the oral resorption is improved. Especially it should be noted --that the activity firstly increases with increasing chain length of the alkyl ether and remains then constantly, although the toxicity becomes lower.

The compounds obtained are characterized also by an especially good tolerance in the stomach and by a slightly sedative action, which latter may be a desired side action in case of cardiac diseases.

The new compounds can be administered in a form usual for heart glycosides e.g. in the form of tablets, capsules or solutions containing the active substance in pure form or in mixture with xanthine derivatives.

WHAT WE CLAIM IS: 1. A process for preparing ethers of bufadienolide and bufatrienolide of the general formula

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **.

After working up as described in Example 1 2.15 g (95%) of pure 3p - [3' - 0 - (2" methoxyethyl)a - L - rhamnosido] - 14 hydroxy - 4cog,5 - epoxy - 5a - bufa - 20,22-- dienolide are obtained after recrystallization from methanol-water, m.p.

215 to 2210C.

The catalyst solution is prepared by dissolving 0.1 g of cresyl titanate in some absolute dioxane in a 25 ml-graduated flask, adding 2.5 ml of a solution of titanium tetrachloride (0.05 mmoles/ml) in dioxane and filling up to the marking with dioxane.

EXAMPLE 10

2 g of 3P - 3p - L - rhamnosido) - 14 hydroxy - bufa - 4,20,22- trienolide are dissolved in 50 ml of absolute dioxane and 20 ml of a solution of 3 dimethylaminodiazopropane (0.4 mmoles/ml) in ether are added thereto. To the solution 4 ml of a solution of 2ethylhexyl titan ate and titanium tetrachloride (0.05 mmoles 2-ethylhexyl titan ate and 0.005 mmoles titanium tetrachloride/ml) in absolute dioxane are added. After standing for 17 hours at room temperature the solution is worked up as described in Example 1. After recrystallization from acetic acid ethylester 2.1 g (94%) of pure 3p - [3' - 0 - (3off - dimethylaminopropyl) - a - L - rhamnosidol - 14 - hydroxy - bufa 4,20,22 - trienolide are obtained, m.p. 135 to 146 C.

The catalyst solution is prepared by dissolving 0.78 ml of 2-ethylhexyl titanate in some absolute dioxane in a 25 ml-graduated flask, adding 2.5 ml of a solution of titanium tetrachloride (0.05 mmoles/ml, see Example 1) in dioxane and filling up to the marking with absolute dioxane.

EXAMPLE 11

2 g of 3p - (a - L - rhamnosido) - 14 hydroxy - bufa - 4,20,22 - trienolide are dissolved in 50 ml of absolute dioxane and 20 ml of a solution of 2 - phenyldiazoethane (0.4 mmoles/ml) in ether are added. Then 4 ml of a mixture of ethyl titanate (0.05 mmoles/ml) and titanium tetrachloride (0.005 mmoles/ml) in absolute dioxane are added and the solution is aallowed to stand 16 hours at room temperature. After working up as described in Example 1 2.2 g (94%) of pure 3A - [3' - 0 - (2" phenylethyl) - a - L - rhamnosido] - 14 hydroxy - bufa - 4,20,22 - trienolide are obtained after recrystallization from acetic acid ethyl ester, m.p. 180 to 1950C.

The catalyst solution is prepared by dissolving 0.28 ml of ethyl titanate in some absolute dioxane in a 25 ml-graduated flask, adding 2.5 ml of a solution of titanium tetrachloride (0.05 mmoles/ml) in dioxane and filling up to the marking with absolute dioxane.

EXAMPLE 12

2 g of 3A - (eg - L - rhamnosido) - 14 hydroxy - bufa - 4,20,22 - trienolide are dissolved in 50 ml of absolute dioxane and

25 ml of a solution of diazopropyne (0.3 mmoles) in ether are added. Then 4 ml of a mixture of titanium acetyl acetonate (0.4%) and titanium tetrachloride (0.005 mmoles/ml) in dioxane are added. After standing for 14 hours at room temperature and working up as described in Example 1 2.1 g (93%) of pure 3p - [3' - 0 - (propargyl - 3") - L- rhamnosido] - 14 - hydroxy - bufa - 4,20,22 - trienolide are obtained after recrystallization from acetic acid ethyl ester, m.p. 170 to 1750C.

The catalyst solution is prepared by dissolving 0.1 ml of titanium acetylacetonate in absolute dioxane in a 25 ml-graduated flask, adding 2.5 ml of a solution of titanium tetrachloride (0.05 mmoles/ml) in absolute dioxane (see Example 1) and filling up to the marking with absolute dioxane.

Compounds of formula I in which R' is other than methyl can be prepared in similar manner from starting materials of formula II having the appropriate substituent in 10-position. For example, a compound in which R' is formyl is scilliglaucosidin - alpha - L - rhamnoside, contained in squill (scilla maritima). This compound may be reduced with sodium boro - hydride to the compound in which R' is methylol.

The compounds made by the process of this invention are cardiotonics. They show an increased activity on the heart, in which connection especially the oral resorption is improved. Especially it should be noted --that the activity firstly increases with increasing chain length of the alkyl ether and remains then constantly, although the toxicity becomes lower.

The compounds obtained are characterized also by an especially good tolerance in the stomach and by a slightly sedative action, which latter may be a desired side action in case of cardiac diseases.

The new compounds can be administered in a form usual for heart glycosides e.g. in the form of tablets, capsules or solutions containing the active substance in pure form or in mixture with xanthine derivatives.

WHAT WE CLAIM IS: 1. A process for preparing ethers of bufadienolide and bufatrienolide of the general formula

in which formula X is a double bond between the carbon atoms 4 and 5 or an epoxide group, R' is a methyl, formyl or hydroxymethyl group, and R is hydrogen, a straight or branched alkyl radical having 1 to 16 carbon atoms, a straight or branched alkenyl radical having 2 to 6 carbon atoms, an ethynyl radical, a straight or branched alkoxy radical having 2 to 11 carbon atoms, a cycloaliphatic radical, an aromatic or araliphatic radical, a straight or branched dimethyl- or diethylaminoalkyl radical having in total 3 to 6 carbon atoms, in which values of R the straight or branched aliphatic chains may be substituted by nitrogen or oxygencontaining heterocycles or by halogen, with exclusion of the compounds wherein (i) X is a double bond, R' is methyl, R is H; (ii) R' is methyl, X is a double bond, R is alkyl having 4 or 5 carbon atoms; and (iii) R' is formyl, X is a double bond, R is hydrogen or an alkyl group having 1 to 5 carbon atoms; by reacting a glycoside of bufadienolide or bufatrienolide of the general formula

in which X and R' are as defined above, with a diazoalkane of the general formula R.CH.N2 (III) in which R is as defined above, in an inert solvent, in which process there is used as catalyst a titanium-containing catalyst selected from (a) a mixture of titanium tetrachloride and boric acid, or (b) a mixture of titanium tetrachloride and an ester of titanic acid; and (c) an ester of titanic acid.
2. A process according to claim 1 in which ethyl titanate, n-propyl-, isopropyl-, n-butyl-, isobutyl-, cresyl-, or 2-ethylhexyl titanate or diisopropoxy-bis - (2,4 pentanedionato)- titanium (IV) is the titanic acid ester of catalyst (b) or (c).
3. A process according to claim 1, substantially as hereinbefore described.
4. Bufadienolide and bufatrienolide glycoside ethers when prepared by a process according to claim 1. 2 or 3.