CH636880A5 - Process for preparing clavulanic acid ethers - Google Patents

Description

The present invention accordingly relates to a process for the preparation of carboxylic acid esters of cla-vulcanic acid ethers of the general formula (I)

H

° /

: h2or

(I)

O

/ r co2h in which R is the methyl or ethyl group, which is characterized in that clavulanic acid or its carboxylic acid salts or carboxylic acid esters with an oxonium salt of the general formula (II)

RsO X

chgoh

(iii)

co2h

If clavulanic acid or its carboxylic acid salts are used, both etherification and esterification take place, so that either the 9-O-methylclavulanic acid methyl ester or the 9-O-ethylclavulanic acid ethyl ester are produced. This reaction usually proceeds via the methyl or ethyl ester intermediates formed in situ.

The most suitable compound of the general formula (II) is either trimethyloxonium tetrafluoroborate or triethyloxonium tetrafluoroborate.

Accordingly, a particularly preferred embodiment of the present invention provides a process for the preparation of clavulanic acid ethers of the general formula (I) or their carboxylic acid salts or carboxylic acid esters with the characteristic feature that the reaction of a clavulanic acid ester with trimethyloxonium tetrafluoroborate or with triethyloxonium tetrafluoroborate takes place. The free carboxylic acid or its salts s can be formed from the ester obtained.

The clavulanic acid esters used are those which can be hydrolyzed or hydrogenolyzed into the free carboxylic acid or its salts.

Advantageous esters of clavulanic acid for use as starting materials in the process of the present invention are those of the general formulas (IV) and (V)

chgoh

(iv)

(II)

h in which R is the methyl or ethyl group and Xe is an anion. The carboxylic acid esters formed are converted into the free carboxylic acid or its salt by hydrolysis or hydrogenolysis. The free carboxylic acid or its salts obtained can be converted into another ester or another salt.

If the etherification is carried out with an ester of clavulanic acid, at least one equivalent - for example 1 to 5 equivalents - of a compound of the general formula (II) is usually used per equivalent of ester of clavulanic acid. If the etherification is applied to a salt of clavulanic acid or also to the free acid, usually at least 2 equivalents - for example 2 to 5 equivalents - of a compound of the general formula (II) per equivalent of clavulanic acid salt are used. The most suitable is X • 'the tetrafluoroboratanion or its equivalent, such as the hexafluorophosphate anion, 2,4,6-trinotrobenzenesulfonate or 2,4,6-trifluorobenzenesulfonate anion. In the above reaction, a carboxylic acid salt or a carboxylic acid ester of clavulanic acid of the formula (III) is used

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chgoh

% CCL-CH-A '

2 i

(v)

in which A1 is an alkyl radical having 1 to 8 carbon atoms, which can be substituted by halogen atoms or a radical of the general 35 formulas -OA4, -OCOA4, -SA4 or -SO2A4, the A4 radical being a hydrocarbon radical having up to 6 hydrocarbon atoms, A2 represents a hydrogen atom, an alkyl radical having up to 4 carbon atoms or the phenyl group, which may be substituted by halogen atoms or 40 radicals A5 or -OA5, where A5 is an alkyl radical having up to 6 carbon atoms, and A3 represents the phenyl group by halogen atoms or residues A5 or -OA5 can be substituted, where A5 is an alkyl residue. The radical A1 can furthermore be alkenyl or alkynyl radicals 45 with up to 4 carbon atoms.

The rest A3 also includes the nitrophenyl group.

The most suitable radical A1 is an alkyl radical having up to 4 carbon atoms, for example the methyl, ethyl, n-propyl or n-butyl group, or such a radical which is represented by a radical of the general formulas -OA4 or -OCOA4 is substituted, wherein A4 is an alkyl radical having up to 4 carbon atoms.

The radical A1 is preferably either the methyl group or the ethyl group.

55 In particular, the radical -CHA2A3 denotes the benzyl group or a monosubstituted benzyl group, such as the bromobenzyl, nitrobenzyl or methoxybenzyl group, in which the substituent is preferably in the p-position.

Other esters which can be used include 60 in vivo hydrolysable esters, as described in BE-PS 827 926 as in vivo hydrolysable esters when bound to clavulanic acid. Examples of such esters are the acetoxymethyl, a-acetoxyethyl, trimethyla-cetoxymethyl, phthalidyl, ethoxycarbonyloxymethyl and 65 the a-ethoxycarbonyloxyethyl ester.

When a carboxylic acid salt of clavulanic acid is used as a starting compound in the process of the present invention, the process offers the advantages of a good one

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Total yield of pure compounds and a low number of reaction stages.

Suitable salts of clavulanic acid which are used in the process of the present invention are customary salts of clavulanic acid, such as the alkali metal or alkaline earth metal salts or a salt of a nitrogenous base. Examples of such suitable salts of clavulanic acid for use in the present process are lithium, sodium, potassium, calcium, magnesium, barium or tetramethylguanidinium salts.

The reaction of a compound of general formula (II) with a carboxylic acid salt or a carboxylic acid ester of clavulanic acid normally takes place in an anhydrous, inert organic solvent, such as in dichloromethane or chloroform or another haloalkane, or in other hydroxyl-free solvents, such as nitromethane. Most advantageously, the solvent system is completely free of hydroxyl groups.

The etherification preferably takes place in the presence of a base. The base is most advantageously insoluble in the reaction medium. Examples of such bases are alkali metal carbonates or bicarbonates or alkaline earth metal oxides or hydroxides. Individual such suitable bases are sodium carbonate, sodium bicarbonate, lithium carbonate, calcium carbonate or magnesium carbonate. The base used must be anhydrous.

Such insoluble bases are preferably in excess. For example, 1 to 5 equivalents of the base can be used per equivalent of the oxonium salt.

It has also been found that the presence of crown ethers in the reaction mixture can increase the yield of the desired compound from a clavulanic acid salt. Examples of such crown ethers are “18-crown-6”, “15-crown-5”, “Dicyclohexo-18-crown-6” or their equivalents.

A further preferred embodiment of the present invention consists in a process for the preparation of 9-O-methylclavulanic acid methyl ester, which is characterized in that a carboxylic acid salt of clavulanic acid is reacted with trimethyloxonium fluoroborate. A further preferred embodiment of the present invention consists in a process for the preparation of the 9-O-ethylclavulanic acid ethyl ester, which is characterized in that a salt of clavulanic acid is reacted with triethyloxonium tetrafluoroborate.

When the etherification is practically complete, which can be determined, for example, by thin layer chromatography by spraying with permanganate, the desired compound can be obtained from the reaction mixture by washing the organic phase with water to remove ionic compounds, drying the organic phase and evaporating off the solvent will. Thereafter, the ester ether can optionally be further purified by chromatography. Suitable chromatography systems are stationary phases, such as silica gel, cellulose or the like, and solvents, such as mixtures of esters and hydrocarbons, such as mixtures of ethyl acetate and cyclohexane.

The carboxylic acid esters of the compounds of the general formula (I) can be converted into the free carboxylic acid or its salts by the processes described in BE-PS 847 045. Such processes include the hydrogenation of hydrogenolyzable esters, such as the benzyl or p-methoxybenzyl ester or equivalent esters, such as the p-nitrobenzyl or p-bromobenzyl ester, optionally in the presence of a base such as lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicar- bonat or the like, and in the presence of a transitional

metal catalyst, such as 10% palladium on charcoal. Such methods also include hydrolysis under mild conditions with a base, e.g. hydrolysis of the methyl ester by means of a controlled addition of lithium hydroxide, sodium hydroxide or the like at a rate such that the pH of the solution, as indicated on a pH meter, is in the range of 7.5 to 10, such as 7.5 to hold 9 or 8 to 10 or preferably 9 to 9.5. This can expediently be brought about by using a pH meter, so that the base is used in a customary manner in an aqueous medium. Examples of bases that can be used are lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, magnesium hydroxide or calcium hydroxide.

In a particularly preferred embodiment of the present invention, the process for the preparation of a salt of a compound of the general formula (I) provides that the methyl ester of the methyl ether of clavulanic acid or the ethyl ester of the ethyl ether of clavulanic acid is formed as described above, and then that Hydrolysed ester group, so that a salt of the methyl ether of clavulanic acid or the ethyl ether of clavulanic acid is obtained.

In general, the hydrolysis is carried out in an aqueous solvent system, such as in aqueous tetra-hydrofuran or the like, using a base as described above.

The preferred carboxylic acid salt of clavulanic acid in the process of the present invention is the sodium salt. Another preferred salt of clavulanic acid is the potassium salt. Another preferred salt in carrying out the process of the present invention is the lithium salt.

It has been shown that the use of a finely divided form of the salt leads to improved yields. Such finely divided forms can be produced, for example, by freeze-drying a solution or by dehydrating a salt hydrate such as the tetrahydrate of the sodium salt of clavulanic acid.

The etherification is usually at a temperature of -80 ° C (or more appropriately from -60 ° C) to + 60 ° C (or up to the boiling point of the solvent system, although temperatures of not more than + 40 ° C are more appropriate) and more suitable from about -40 to + 30 ° C. It is often appropriate to start the reaction at a low temperature, such as -30 to 0 ° C, and then to gradually raise the temperature of the reaction mixture until it reaches room temperature or a slightly lower temperature, such as 10 to 20 ° C.

The hydrolysis is conveniently carried out at about room temperature, e.g. at temperatures from about 10 to about 30 ° C, such as at 15 to 25 ° C.

When the reaction is complete, which can be determined by no further uptake of base without degradation or by thin layer chromatography, the pH of the reaction mixture can be adjusted to pH 7, e.g. by adding a small amount of an acid such as acetic acid.

J In order to obtain the desired carboxylic acid salt, the solvent can be removed, for example, by evaporation and the dried salt can be obtained in crystalline form by adding a suitable solvent, such as acetone, acetonitrile or tetrahydrofuran. It can be advantageous if such solvents have a moisture content, but large amounts of water should be avoided because of the solubility of the ether.

A particularly suitable embodiment of this part of the invention consists in the hydrolysis of the ester in order to avoid the s

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To obtain lithium salt, since this salt is obtained in a very pure form and in good yield.

If other carboxylic acid salts of methyl or ethyl ether are desired, these can be conveniently prepared from the lithium salt, for example by dissolving the lithium salt in water, this solution onto a polymeric cation exchange resin in the form of the desired salt, e.g. in the form of the sodium, potassium, calcium or magnesium salt, and then the desired salt is eluted therefrom.

Examples of suitable cation exchange resins are crosslinked polystyrene-divinylbenzene copolymers with sulfonic acid groups, as are commercially available under the trademarks “Amber-lite”, “Dowex”, “Zerolit”, “BioRad” and “Ionac”.

Typically the eluent is water or water mixed with an organic solvent such as methanol, ethanol or acetone. The most suitable is water as the eluent. The cation exchange resin is preferably in a large excess, for example at least a three-fold excess, most suitably in an at least eight-fold excess and advantageously in an at least ten-fold excess. In the simplest and most practical embodiment of the method, a solution of the lithium salt is simply let through a bed of the resin from which it emerges in the form of the other salt. The desired salt can then be obtained from the solution by conventional methods such as freeze-drying, evaporation, precipitation using an organic solvent or the like.

The free carboxylic acids of general formula (I) can be prepared from the lithium salt or other carboxylic acid salt by acidification, for example using an acid such as a mineral acid or a strongly acidic cation exchange resin which acts as a common insoluble acid.

The examples illustrate the invention.

example 1

9-O-ethylculavulanic acid ethyl ester

A solution of 4.86 g of triethyloxonium tetrafluoroborate in 40 ml of anhydrous solution is added dropwise to a vigorously stirred suspension of 1.52 g of the potassium salt of clavulanic acid and 4 g of anhydrous sodium carbonate in 70 ml of anhydrous di-chloromethane cooled to -20 ° C. Dichloromethane added. The reaction mixture is stirred for 3 hours at about -20 ° C (very slow reaction) and then for 1 hour at about 5 ° C (ice bath). Then the thin layer chromatogram shows a moderately strong ester zone and a strong ester ether zone. Then 90 ml of water are added to the reaction mixture, the phases are separated and the organic phase is dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate is evaporated. An orange oil is obtained.

This oil is subjected to chromatography on silica gel using ethyl acetate and cyclohexane, starting with a ratio of 1: 1 to pure ethyl acetate. The ether ester is eluted before the ester. Fractions which contain this compound on the basis of the thin-layer chromatogram are combined in a corresponding manner and evaporated. 44 mg of raw clavulanic acid ethyl ester and 520 mg of the ester ether are obtained. These compounds are separated again by chromatography. While the ester is chromatographed using the original solvent system and provides 15 mg of pure ester, the ether ester is made using 3: 2 to 2: 3 mixtures of ethyl acetate and cyclohexane

Chromatographs again, and 375 mg of the pure 9-O-ethylclavulanic acid ethyl ester are obtained as a pale yellow oil.

IR spectrum: Vmax (film) 1802, 1744 and 1699 cm-1.

NMR spectrum in CDCb: 5 =

1.14 (3H, t, J = 7 Hz, ether CHs);

1.26 (3H, t, J = 7 Hz, ester CHj);

2.97 (1H, d, J = 17 Hz, 6-β-CH);

3.46 (1H, dd, J = 17 and 3 Hz, 6-cc-CH);

3.39 (2H, q, J = 7 Hz, 9-O-CH2);

4.0Î (2H, d, 3 = 7 Hz, 9-CHz);

4.17 (2H, q, J = 7 Hz, CO2.CH2);

4.78 (1H, t, J = 7 Hz, 8-CH);

4.99 (1H, s, 3-CH);

5.63 (1H, d, J = 3 Hz, 5-CH).

The potassium salt of clavulanic acid can be replaced by the tetramethylguanidinium salt of clavulanic acid in this reaction, but this does not bring any particular advantage despite the solubility of the salt in dichloromethane.

Example 2

9-O-ethyl clavulanic acid ethyl ester

The process of Example 1 can be improved by adding a catalytic amount — in this case 0.17 g — of an “18-crown-6” crown ether to the dichloromethane solution of the reactants before adding the oxonium salt. In this case, 1.1 g (= 75% of theory) of practically pure 9-O-ethyl ciavulanic acid ethyl ester is obtained after the first column chromatography, based on 89 percent pure potassium salt as the starting compound.

Example 3

Lithium salt of 9-O-EthylIclavulanic acid

A solution of 1.1 g of ethyl 9-O-ethyl clavulanate in 60 ml of a mixture of one part of tetrahydrofuran and two parts of water is kept at pH 9.4 by adding a 1 m lithium hydroxide solution using a pH meter until after about 90 Minutes at 22 ° C with stirring 4.0 ml have been used. Then add a small drop of acetic acid to lower the pH to 7.0. The solution is then evaporated at room temperature on a rotary evaporator to give an orange-colored gummy substance, which is dissolved in about 20 ml of acetone and cooled to 2-3 ° C. for 60 minutes, during which the lithium salt crystallizes out. After filtering off the salt, washing with 20 ml of acetone and then with 20 ml of ether and drying under reduced pressure, 0.73 g of very pure lithium salt of 9-O-ethylclavulanic acid is obtained as pale yellow crystals. The overall yield, starting from the potassium salt of clavulanic acid in Example 2, is 55%. 2e when using copper Ka rays = 12.6, 13.3, 14.7, 17.2, 17.8, 18.7, 19.9, 20.8, 21.6, 22.8, 24.6, 26.8, 27.4, 28.2 and 28.7 °.

Example 4

Sodium salt of 9-O-ethylclavulanic acid

A portion of the substance obtained according to Example 3 (0.25 g) in 2 ml of water is passed through 8 ml of a bed of a commercially available polystyrene-divinylbenzene copolymer of the "Amberlite IR 120" type in the Na + form and with a customary moisture content headed. The eluate is collected and evaporated under reduced pressure at room temperature. The residue is triturated with a mixture of acetone and ether, filtered, washed with ether and dried. 0.2 g of the sodium salt of 9-O-ethylclavulanic acid is obtained.

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Example 5 Ethyl 9-O-ethylclavulanate

Crystalline sodium clavulanate hydrate is dewatered to constant weight under reduced pressure over phosphorus pentoxide. A suspension of 1.11 g of the dried salt and 2.65 g of anhydrous sodium carbonate in 50 ml of anhydrous and methanol-free methylene chloride (which has been treated with 3A molecular sieves) is treated with 20 mg of a crown ether "18-crown-6" and under Stir and cool to -20 ° C with exclusion of moisture. A solution of 3.8 g of triethyloxonium tetrafluoroborate in 50 ml of anhydrous methylene chloride is then added within 20 minutes. The mixture is stirred vigorously at -20 ° C. for 3 hours. Samples are taken at intervals and examined for the course of the reaction by means of thin layer chromatography. The reaction mixture is kept in an ice / water bath with stirring at a temperature of about 5 ° C until the amount of the desired compound has reached a maximum, which is concluded from the thin layer chromatography compared to a standard sample. Then 50 ml of water are added to the reaction mixture, the phases are stirred well and can be separated. The methylene chloride solution is washed several times with 50 ml of water, dried over anhydrous sodium sulfate and then filtered. After evaporation of the solvent under reduced pressure at temperatures above 20 ° C., the crude compound mentioned in the heading is obtained as a light orange oil in a yield of 1.10 g. The crude ether ester is dissolved in 25 ml of a mixture of cyclohexane and ethyl acetate in a ratio of 1: 1 and then placed on a column which is loaded with 30 g of silica gel which has been taken up with the same solvent mixture. The column is eluted with a mixture of cyclohexane and ethyl acetate in a ratio of 1: 1. In each case 10 ml of eluate are examined by thin layer chromatography. Those fractions containing the compounds mentioned in the heading are combined and evaporated under reduced pressure and at a temperature above 20 ° C. 640 mg (= 50% of theory) of ethyl 9-O-ethylclavulanate are obtained as a colorless oil. The compound shows the same spectrographic properties as that obtained in Example 1. Those fractions which contain ethyl clavulanate by thin layer chromatography compared to a standard sample are combined and evaporated. 350 mg (= 31% of theory) of the ester are obtained as a colorless oil.

Example 6 9-O-ethylclavulanic acid ethyl ester 1.19 g of the potassium salt of clavulanic acid, 2.65 g of anhydrous sodium carbonate and 1 drop of a crown ether “15-crown-5” are suspended in 50 ml of nitromethane. The mixture is cooled to -20 ° C. with stirring and with the exclusion of moisture. A solution of 3.8 g of triethyloxonium tetrafluoroborate in 50 ml of nitromethane is then added over the course of 20 minutes and the mixture is stirred vigorously at -20 ° C. for 3 hours.

The stirred reaction mixture is kept on an ice / water bath at a temperature of about 5 ° C for 5 hours. Then the analysis of the reaction mixture by means of thin layer chromatography shows the presence of a wide zone, which is typical of the 9-O-ethyl clavulanic acid ethyl ester, as the comparison with a standard sample shows.

Example 7 9-O-ethylclavulanic acid ethyl ester 1.03 g of the lithium salt of clavulanic acid, 2.65 g of anhydrous sodium carbonate and 1 drop of a crown ether

"15-crown-5" are suspended in 50 ml of anhydrous methylene chloride. The reaction mixture is cooled to -20 ° C. with stirring and with the exclusion of moisture. Then, in the course of 20 minutes, a solution of 3.8 g of triethyloxonium tetrafluoroborate in 50 ml of anhydrous methylene chloride is added and the mixture is stirred vigorously at -20 ° C. for 1 hour.

The stirred reaction mixture is kept in an ice / water bath at a temperature of about 5 ° C. for 5 hours, after which it is treated with 50 ml of water and 250 mg of the crude ester ether isolated on the column using the method described in Example 5 Silica gel is cleaned. This gives 130 mg (= 10% of theory) of the compound mentioned in the heading and 50 mg (= 5% of theory) of ethyl clavu-lsanoate.

Example 8

9-O-ethyl clavulanic acid ethyl ester

0.60 g of the magnesium salt of clavulanic acid, 1.5 g of water-20 free sodium carbonate and 10 mg of a crown ether "18-crown-6" are suspended in 30 ml of anhydrous methylene chloride. The reaction mixture is cooled to -20CC with stirring and with the exclusion of moisture. A solution of 2.15 g of 25 triethyloxonium tetrafluoroborate in 30 ml of anhydrous methylene chloride is then added over the course of 15 minutes and the reaction mixture is stirred vigorously at -20 ° C. for 1 hour.

The stirred reaction mixture is then kept in an ice / water bath at a temperature of 5 ° C. for 2 hours. Thereafter, analysis of the reaction mixture by means of thin-layer chromatography shows the presence of a wide zone, which is typical of the 9-O-ethylclavulanic acid ethyl ester, and only a narrow zone for the clavulanic acid, ethyl ester.

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Example 9

9-O-methylclavulanic acid methyl ester

1.52 g of the potassium salt of clavulanic acid with 95% purity and 4.0 g of anhydrous sodium carbonate 40 are suspended in 70 ml of anhydrous methylene chloride in a reaction vessel which is protected against the ingress of moisture by means of a calcium chloride tube. Then 0.17 g of a crown ether "18-crown-6" is dissolved in methylene chloride. The suspension is cooled to a temperature of about -20 ° C. with stirring and a suspension of 4.22 g of trimethyloxonium tetrafluoroborate in 90 ml of anhydrous methylene chloride is slowly added. The reaction mixture is stirred at -20 ° C for 3 hours and then at about 0 ° C for 1 hour. Then you add 90 ml of water and so the reaction mixture can be separated into phases. The organic phase is dried over anhydrous sodium sulfate. After the solvent has been evaporated off under reduced pressure, the product obtained is purified by column chromatography on silica gel and eluting with a 55: 1 mixture of cyclohexane and ethyl acetate.

After evaporation of the elution fractions in question, 0.54 g (= 41% of theory) of methyl 9-O-methylcla-vulcanate and a further 0.37 g (= 29% of 60 theory) of methyl clavulanate are obtained.

A sample of the 9-O-methylclavulanic acid methyl ester is hydrolyzed in aqueous tetrahydrofuran solution containing 1-M lithium hydroxide at a pH value of 9.5 adjusted by means of the pH meter.

65 After evaporation and after the addition of acetone, 0.43 g of crystalline lithium salt of 9-O-methylclavulanic acid is obtained.

In the X-ray diffraction pattern shows the powder

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Substance the following diffraction angles

2 & (copper Ka-rays) = 11.5 12.9 14.2, 15.3, 17.9, 19.1, 21.0, 21.3, 22.1, 23.5, 24.1, 24.6, 25.4, 28.6, 29.4.

Example 10 9-O-methylclavulanic acid methyl ester 4.56 g of the potassium salt of clavulanic acid of 95% purity, 12 g of anhydrous sodium carbonate, 0.5 g of a crown ether "18-crown-6" and 12.7 g of trimethyloxonium tetrafluoroborate Chilled to -70 ° C and stirred while slowly adding 200 ml of anhydrous methylene chloride. After adding the solvent, the temperature is allowed to rise slowly to 20 ° C. After stirring for 3 hours at room temperature, thin layer chromatography shows 2 zones with run values Rr = 0.35 and 0.12 with an area ratio of approximately 10: 1. Then 250 ml of water are added to the reaction mixture with stirring and the phases are allowed to separate. The organic phase is dried with anhydrous sodium sulfate, evaporated and purified by means of column chromatography as in Example 9. The elution fractions containing the desired compound are evaporated to give 2.6 g (= 62% of theory) of methyl 9-O-methylclavulanate, which is pure by thin layer chromatography.

1.13 g of the aforementioned ether ester are dissolved in aqueous tetrahydrofuran containing potassium hydroxide and hydrolyzed at a pH value of 9.5 adjusted by means of a pH meter. The potassium salt of 9-O-methylclavulanic acid is obtained.

Example 11 Methyl 9-O-methylclavulanate 1.6 g of the sodium salt of clavulanic acid, which was obtained by dewatering under reduced pressure from a tetrahydrate of 92% purity, 4.0 g of anhydrous sodium carbonate and 4.9 g of trimethyloxonium tetrafluoroborate -70 ° C cooled and stirred, during which 100 ml of anhydrous methylene chloride containing about 50 mg of a crown ether "15-crown-5" are slowly added. Stirring is continued while the temperature is allowed to rise to room temperature. The progress of the reaction is followed by thin layer chromatography. After 3 hours at room temperature, the reaction mixture is worked up as in Example 10. 1.03 g (= 70% of theory) of 9-O-methylclavulanic acid methyl ester are obtained. As a by-product, 0.22 g of methyl clavulanate is obtained.

NMR spectrum in CDCb: 5 = 2.99 (1 H, d, J = 16 Hz, 6-ßCH);

3.24 (3H, s, ether CHs); 3.44 (1H, dd, J = 16 Hz and 3 Hz, 6-aCH);

3.72 (3H, d, ester CHs); 3.96 (2H, d, J = 7 Hz, 9-CH2O); 4.79 (1H, t, J = 7 Hz, 8-CH); 5.00 (1H, broad singlet, 3-CH);

5.63 (1H, d, J = 3 Hz, 5-CH).

Example 12 Methyl 9-O-methylclavulanate 110 ml of anhydrous methylene chloride containing about 50 mg of a crown ether "15-crown-5" slowly become a stirred, cooled to -70 ° C. mixture of 1.0 g of crystalline lithium salt of Clavulanic acid, 4.0 g of anhydrous sodium carbonate and 4.4 g of trimethyloxonium tetrafluoroborate. Then the temperature of the reaction mixture is allowed to rise to room temperature and the mixture is stirred for a further 4 hours. After working up and after chromatography as in Example 10, 0.65 g (= 57% of theory) of pure 9-O-methylclavulanic acid methyl ester is obtained. The NMR spectrum is identical to that of the compound of Example 11.

EXAMPLE 13 Methyl 9-O-methylclavulanate 80 ml of anhydrous methylene chloride containing 50 mg of a crown ether “18-crown-6” slowly become a stirred, cooled to -70 ° C. mixture of 0.6 g of magnesium salt of clavulanic acid, 3.0 g of magnesium oxide and tetramethyloxonium tetrafluoroborate were added. Then the temperature of the reaction mixture is allowed to rise to room temperature and the course of the reaction is monitored by means of thin layer chromatography. After several hours at room temperature, zones can be seen on the developed thin-layer chromatography plates which belong to the methyl clavulanate and the methyl 9-O-methylelavulanate.

Example 14 Methyl 9-O-methylclavulanate 110 ml of anhydrous nitromethane containing about 20 mg of a crown ether “15-crown-5” slowly become a stirred and cooled mixture of 1.52 g of potassium salt of clavulanic acid, 4.0 g anhydrous sodium carbonate and 4.5 g of trimethyloxonium tetrafluoroborate. Then the temperature of the reaction mixture is allowed to rise to room temperature and the mixture is stirred at this temperature for a further 3 hours. After working up and cleaning as in Example 10, 0.72 g (= 51% of theory) of 9-O-methylclavulanic acid methyl ester is obtained, the NMR spectrum of which is identical to that of the compound of Example 11.

Example 15 Benzyl 9-O-methylclavulanate 100 g of trimethyloxonium tetrafluoroborate are slurried in 2 liters of anhydrous dichloromethane at -30 ° C., while 110 g of anhydrous sodium carbonate are added all at once. Then 70 g clavulanic acid benzyl ester in 1 liter anhydrous dichloromethane is added quite quickly while the temperature is kept at -30 ° C. The reaction is then carried out and the reaction mixture obtained is worked up in the same manner as described in Example 10. 39.2 g of benzyl 9-O-methylclavulanate are obtained.

Example 16

9-O-ethylclavulanate p-methoxybenzyl ester 15 g of anhydrous sodium carbonate (excess) and a solution are added to a solution of 9.6 g of 9-O-clavulanic acid p-methoxybenzyl ester in 500 ml of dichloromethane, stirred at -30 ° C of 17.6 g of triethyloxonium tetrafluoroborate in 100 ml of dichloromethane.

The mixture is then stirred at about -10 ° C. for 6 hours and the temperature of the reaction mixture is then allowed to rise to room temperature over 30 minutes. Then 100 ml of water are carefully added with stirring, the organic phase is separated off, dried over anhydrous sodium sulfate and evaporated to a syrup which is subjected to column chromatography on silica gel and eluting with mixtures of ethyl acetate and cyclohexane first in the ratio 1 : 1 and then subjected to a ratio of 2: 1. The product eluted first is the ethyl ether in a yield of 4.9 g after evaporating off the solvent. Then 4 g of p-methoxy-benzyl clavulanate are recovered. The verbin5 mentioned in the heading

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Manure is a pale yellow oil with the following properties.

IR spectrum (liquid film): Vmax 1805 (β-lactam-C = 0), 1750 (ester-C = 0), 1700 cm- '(C = C).

Nuclear Magnetic Resonance Spectrum in CDCk 5 = 1.17 (3H, t, J = 7 Hz, CH3CH2);

2.96 (1H, d, J = 17 Hz, 6-β-CH); 3.41 (2H, q, J = 7 Hz, CH3CH2-);

3.47 (1 H, dd, J = 17 and 3 Hz, 6-a-CH); 3.79 (3H, s,

OCH3);

4.03 (2H, d, J = 7 Hz, -CH2O); 4.82 (1H, t, J = 7 Hz, CH =);

5.04 (1H, s, 3-CH); 5.11 (2H, s, PhCHz);

5.65 (1H, d, J = 3 Hz, 5-CH); 6.9 7.3 (4H, AîBî quartet, J = 10 Hz, CöH4).

Example 17

Lithium and sodium salt of 9-O-ethyl clavulanic acid

2.5 g of 9-O-ethyiclavulanoic acid p-methoxybenzyl ester in 25 ml of tetrahydrofuran containing 0.1 ml of water are hydrogenated in the presence of 0.8 g of a carbon catalyst containing 10 percent palladium. After 2 hours, thin layer chromatography no longer shows any starting compound. After filtering off the catalyst through a bed of finely divided silica, the filtrate is diluted with the same volume of water to obtain a solution of 9-0-ethylavavanic acid. This solution is titrated to pH 7.0 using a 1m lithium hydroxide solution. After evaporation of the solvents and trituration of the residue with acetone, 1.05 g of the lithium salt is obtained as pale cream crystals.

The sodium salt is prepared in the same manner but using 1M sodium hydroxide solution. Yield: 0.85 g.

IR spectrum (Nujol): Vmax 1785 (β-lactam-C = 0), 1685 (C = C), 1615 (-C02-) cnr '. These values apply to both salts.

The starting compound for this example is made according to the procedure described in Example 16.

Example 18

9-O-ethyl clavulanic acid ethyl ester

1.1 g of anhydrous sodium salt of clavulanic acid, 2.65 g of anhydrous sodium carbonate and 10 mg of a crown ether

636880

"18-crown-6" are suspended in 50 ml of methylene chloride, which is free of water and methanol. The mixture is stirred and cooled to -20 ° C. A solution of 5.0 g of triethyloxonium hexafluorophosphate in 50 ml of anhydrous methylene chloride is then added dropwise over the course of 20 minutes and the reaction mixture is stirred vigorously at -20 ° C. for 3 hours. The stirred reaction mixture is then kept at a temperature of about 5 ° C. for 7 hours, then treated with 50 ml of water, the reaction mixture is worked up as in Example 5 and 250 mg of the ester ether are obtained. The compound is purified on a column with silica gel, and the desired ethyl 9-O-ethylclavulanate is obtained.

Example 19 9-O-methylclavulanic acid

A solution of 0.9 g of the lithium salt of O-methylcla-vulanoic acid in 40 ml of water is overlaid with 150 ml of ethyl acetate. The two layers are then stirred vigorously at room temperature. Then add 10 ml of a strongly acidic ion exchange resin in the wet state («Amberlite IR 120») in the hydrogen form. After 5 minutes, decant from the resin and let the layers separate. The aqueous layer is extracted again with 100 ml of ethyl acetate. The solvent layers are combined, washed with 5 ml of water, dried over anhydrous calcium sulfate and filtered. After evaporating the solution under reduced pressure until the crystals form and then under greatly reduced pressure to remove solvent residues, 0.85 g of the free O-methylclavulanic acid is obtained as colorless crystals.

Example 20

9-O-methylclavulanic acid p-nitrobenzyl ester 3.51 g clavulanic acid p-nitrobenzyl ester, 3.15 g trimethyloxonium tetrafluoroborate and 4.0 g anhydrous sodium carbonate are stirred together and cooled to -70 ° C. 150 ml of methylene chloride containing about 100 mg of a crown ether “18-crown-6” are slowly added to the stirred mixture. After the addition, the temperature of the reaction mixture is allowed to rise to room temperature and the reaction mixture is stirred for a further 3 hours. After working up as in Example 10, 2.91 g of 9-O-methylclavulanic acid p-nitrobenzyl ester are obtained as white crystals.

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Claims (4)

636880 2. The method according to claim 1, characterized in that a tetrafluoroborate, hexafluorophosphate, 2,4,6-trinitrobenzenesulfonate or a 2,4,6-trifluorobenzenesulfonate anion is used as the anion of the oxonium salt of the general formula (II). 2nd PATENT CLAIMS 1. Process for the preparation of carboxylic acid esters of • clavulanic acid ethers of the general formula (I) in which R is the methyl or ethyl group, characterized in that clavulanic acid or its carboxylic acid salts or carboxylic acid esters with an oxonium salt of the general formula RÎO; X J (II) in which R is the methyl or ethyl group and X® is an anion. 3rd 636880 records that you start the reaction at a temperature of -30 to 0 ° C. 22. The method according to claim 18, characterized in that the reaction is ended at a temperature of +10 to + 20 ° C. 23. The method according to any one of claims 1-22, characterized in "that nitromethane or a haloalkane is used as the solvent. 24. The method according to claim 23, characterized in that dichloromethane or chloroform is used as the haloalkane. 25. The method according to any one of claims 1-24, characterized in that one carries out the reaction in the presence of a base. 26. The method according to claim 25, characterized in that the base used is an insoluble base which is present in an excess based on the oxonium salt. 27. The method according to claim 25 or 26, characterized in that an alkali metal carbonate or bicarbonate, an alkaline earth metal carbonate or bicarbonate or an alkaline earth metal oxide or hydroxide is used as the base. 28. The method according to claim 27, characterized in that the base used is sodium carbonate, sodium bicarbonate, lithium carbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, calcium bicarbonate, magnesium carbonate or magnesium bicarbonate. 29. The method according to any one of claims 1-28, characterized in that the ester ether obtained in the reaction mixture is washed with water to remove ionic compounds and then the organic phase is evaporated. 30. The method according to claim 1 for the preparation of the 9-O-methylclavulanic acid methyl ester, characterized in that reacting a carboxylic acid salt of clavulanic acid with a trimethyloxonium salt. 31. The method according to claim 1 for the preparation of 9-O-ethyl clavulanic acid ethyl ester, characterized in that reacting a carboxylic acid salt of clavulanic acid with a triethyloxonium salt. 32. The method according to claim 30 or 31, characterized in that a tetrafluoroborate is used as the oxonium salt. 33. The method according to any one of claims 30 to 32, characterized in that one carries out the reaction at a temperature as specified in claims 19 to 22. 34. The method according to any one of claims 30 to 32, characterized in that one carries out the reaction at a temperature of -50 to + 20 ° C. 35. The method according to any one of claims 30 to 34, characterized in that a solvent according to claim 23 or 24 is used in the reaction. 36. Process for the preparation of clavulanic acid ethers of the formula I and their carboxylic acid salts, characterized in that a carboxylic acid ester of the compound of the formula I is prepared by the process of claim 1 and this is subsequently converted into the free carboxylic acid or its salt by hydrolysis or hydrogenolysis. 37. The method according to claim 36, characterized in that the initially prepared carboxylic acid ester of a compound of general formula (I) is converted into a salt by hydrolysis in the presence of a base. 38. The method according to claim 37, characterized in that one carries out the hydrolysis by adding an alialimetal base. 39. The method according to claim 37 or 38, characterized in that a hydroxide is used as the base. 40. The method according to any one of claims 37 to 39, characterized in that a lithium base, a sodium base or a potassium base is used as the base. 41. The method according to claim 39, characterized in that the base used is lithium hydroxide, sodium hydroxide or potassium hydroxide. 42. The method according to claim 37, characterized in that the hydrolysis is effected by adding an alkaline earth metal base. 43. The method according to claim 40 or 41, characterized in that one converts an initially prepared lithium salt into the sodium, potassium, calcium or magnesium salt. 44. The method according to claim 36, characterized in that the initially prepared carboxylic acid ester of a compound of general formula (I) is converted into the free acid by hydrogenolysis of a hydrogenolyzable ester. 45. The method according to claim 36, characterized in that the hydrogenolyzable carboxylic acid ester initially prepared is converted into a salt by hydrogenolysis in the presence of a base. 46. The method according to claim 44, characterized in that the acid obtained is converted into a salt by reaction with a base. 47. The method according to claim 45 or 46, characterized in that a carbonate, bicarbonate or hydroxide of lithium, sodium, potassium, calcium or magnesium is used as the base. 48. The method according to claim 47, characterized in that a carbonate of lithium, sodium or potassium or sodium bicarbonate or lithium hydroxide is used as the base. 49. The method according to claim 36 for the preparation of a salt of 9-O-methylclavulanic acid, characterized in that 9-O-methylclavulanic acid methyl ester, which has been prepared according to one of claims 30 or 32 to 35, is hydrolyzed in the presence of a base. 50. The method according to claim 36 for the preparation of a salt of 9-O-ethylclavulanic acid, characterized in that 9-O-ethylclavulanic acid ethyl ester, which has been prepared according to any one of claims 31 to 35, is hydrolyzed in the presence of a base. 51. Process according to claims 49 or 50, characterized in that a base according to one of claims 38 to 42 is used in the hydrolysis. 52. Process according to claims 49 or 50, characterized in that the hydrolysis is carried out by means of lithium hydroxide. 53. The method according to claim 52, characterized in that converting the lithium salt initially prepared into the sodium, potassium, calcium or magnesium salt. 54. The method according to claim 53, characterized in that one carries out the conversion in such a way that a solution of the lithium salt with a cation exchanger in the form of the sodium, potassium, calcium or magnesium salt is brought into contact and then the corresponding salt the resin eluted. In BE-PS 847 045 ether of clavulanic acid and its salts and esters are described, which are able to increase the effectiveness of penicillins and cephalosporins. A process for the preparation of such compounds includes the reaction of a diazo compound to an ester of Cla- 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 636880 3. The method according to claim 1, characterized in that tri-methyloxonium tetrafluoroborate or triethyloxonium tetra-fluoroborate is used as the oxonium salt of the general formula (II). 4. Process according to claims 1 and 2, characterized in that a hydrolyzable carboxylic acid ester of clavulanic acid or a hydrogenolyzable carboxylic acid ester of clavulanic acid is used as the starting material. 5. The method according to any one of claims 1-3, characterized in that an ester of clavulanic acid of the general formula (III) is used as the starting material A1 is an alkyl radical having 1 to 8 carbon atoms, which can be substituted by halogen atoms or a radical of the general formulas -OA4, -OCOA4, -SA4 or -SO2A4, A4 being a hydrocarbon radical having up to 6 carbon atoms, or an alkenyl or is alkynyl radical having up to 4 carbon atoms, or represents a phthalidyl, ethoxycarbonyloxymethyl or a-ethoxycarbonyloxyethyl radical. 6. The method according to claim 5, characterized in that one uses a compound of the general formula (III) in which A1 is an alkyl radical having up to 4 carbon atoms, which can be substituted by a radical of the general formulas -OA4 or -OCOA4, where A4 is an alkyl radical with up to 4 carbon atoms. 7. The method according to claim 5, characterized in that one uses a compound of general formula (III) in which A 'is the methyl or ethyl group. 8. The method according to any one of claims 1 -5, characterized in that an ester of clavulanic acid of the general formula (III) is used, in which A1 the acetoxy-methyl, a-acetoxyethyl, trimethylacetoxymethyl, phthalidyl, ethoxycarbonyloxymethyl or the a-ethoxycarbonyloxyethyl group. 9. The method according to any one of claims 1 and 2, characterized in that an ester of clavulanic acid of the general formula (V) used as the starting material in which A2 is a hydrogen atom, an alkyl radical having up to 4 carbon atoms or the phenyl group, which can be substituted by halogen atoms or a radical -A5 or -OA5, the radical A5 being an alkyl radical having up to 6 carbon atoms and A3 represents a phenyl group which may be substituted by halogen atoms, the nitro group or a radical -A5 or -O A5, where A5 is an alkyl radical having up to 6 carbon atoms. 10. The method according to claim 9, characterized in that one uses an ester of the general formula (V) in which A2 has the meanings given in claim 9 and A3 is the nitrophenyl group. 11. The method according to claim 10, characterized in that one uses a compound of general formula (V) in which A2 is a hydrogen atom. 12. The method according to claim 9, characterized in that one uses a compound of general formula (V) in which the group -CHA2A3 is the benzyl, p-methoxybenzyl, p-bromobenzyl or the p-nitrobenzyl group. 13. The method according to claims 1 and 2, characterized in that one uses a carboxylic acid salt of clavulanic acid as a starting material. 14. The method according to claim 13, characterized in that an alkali metal salt, an alkaline earth metal salt or a salt of a nitrogenous base is used as the carboxylic acid salt of clavulanic acid. 15. The method according to claim 14, characterized in that the lithium salt, sodium salt, potassium salt or salt thereof with tetramethylguanidine is used as the carboxylic acid salt of clavulanic acid. 16. The method according to claims 13 to 15, characterized in that the carboxylic acid salt is used in finely divided form. 17. The method according to claims 13 to 16, characterized in that a freeze-dried salt is used as the carboxylic acid salt. 18. The method according to any one of claims 1-17, characterized in that one carries out the reaction at a temperature of -60 to + 60 ° C. 19. The method according to claim 18, characterized in that one carries out the reaction at a temperature of -40 to + 30 ° C. 20. The method according to claim 18, characterized in that one carries out the reaction at a temperature of -30 to + 20 ° C. 21. The method according to claim 18, thereby gelcenn- 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 4th vulcanic acid. A process has now been found which is more advantageous, safer and often with higher yields.