DE2754763A1 - PROCESS FOR MANUFACTURING CLAVULAN ACID ETHERS - Google Patents

Description

Process for the preparation of clavulanic acid ethers

Claimed December 11, 1976 - Great Britain - No. 5I808 / 76 Priorities: _{March 16} ^ ₇₇ _ _{Great Britain} _ _No. 11116/77

September 16, 1977 - Great Britain - No. 38753/77

The invention relates to a process for the production of clavulanic acid ethers .

In BE-PS 8 ^ 7 045 ethers of clavulanic acid and their salts and esters are described, which are able to increase the effectiveness of penicillins and cephalosporins. One method of making such compounds involves reacting a diazo compound with an ester of clavulanic acid. A process has now been found which is more advantageous, safer and often with higher yields.

The present invention accordingly provides a process for the preparation of clavulanic acid ethers of the general type Formula (I)

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-V- "O PH ₂ OR _(Ι)

CO ₂ H

in which R is the methyl or ethyl group, or their salts or esters, which is characterized in that one contains clavulanic acid or their salts or esters with an oxonium salt of the general formula (II)

R ₃ 0® χ ^θ (H)

in which R is the methyl or ethyl group and X® is an anion means, and optionally then converts the ester formed into the free acid or its salt and / or the formed converts free acid or its salts into another ester or another salt.

When the etherification is carried out with an ester of clavulanic acid is usually used at least one equivalent - for example 1 to 5 equivalents - of a compound of the general Formula (II) per equivalent ester of clavulanic acid. When the etherification is based on a salt of clavulanic acid or on the Free acid is used, one usually uses at least 2 equivalents - for example 2 to 5 equivalents - of a compound of the general formula (II) per equivalent of clavulanic acid salt. The most suitable is X® the tetrafluoroborate anion or its Equivalent to the hexafluorophosphate anion, 2,4,6-trinitrobenzenesulfonate or 2,4,6-trifluorobenzenesulfonate anion.

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In the aforementioned reaction, a salt or an ester of clavulanic acid of the formula (III) is usually used

When clavulanic acid or its salts are used, both etherification and esterification take place, so that either the 9-0-methylclavulanic acid methyl ester or the 9-0-ethyl clavulanic 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 sees the present Invention a process for the preparation of clavulanic acid ethers of the general formula (I) or their salts or Esters with the characteristic feature that the reaction of a clavulanic acid ester with trimethyloxonium tetrafluoroborate or with triethyloxonium tetrafluoroborate and that optionally then the free acid or its salts are formed from the ester.

As clavulanic acid esters, those are preferred which are in the free

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Acid or salts thereof hydrolyzable or hydrogenolyzable are.

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

CO ₂ A

(IV)

CH ₂ OH

CH ₂ OH

(V)

in which A is an alkyl radical having 1 to 8 carbon atoms which can be substituted by halogen atoms or a radical of the general formulas -OA, -OCOA, -SA or -SO ₂ A, the radical A being a hydrocarbon radical having up to 6 carbon atoms

2
A denotes a V / water off atom, an alkyl radical with up to 4 carbon atoms or the phenyl group, which can be substituted by halogen atoms or radicals k ^J or -OA ^, where A ^ is an alkyl radical with up to 6 carbon atoms, and A ^ represents the phenyl group formed by halogen atoms or radicals

cc c

A- ^ or -OA · ^ may be substituted, where k ^{J is} an alkyl radical. Furthermore, the radical A can stand for alkenyl or alkynyl radicals with up to 4 carbon atoms.

The radical k ^J also includes the nitrophenyl group

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Most expediently, the radical A is an alkyl radical with up to 4 carbon atoms, for example the methyl, ethyl, n-propyl or the n-butyl group, or such a radical which is represented by a The radical of the general formula is -OA or -OCOA, where A is an alkyl radical having up to 4 carbon atoms.

The radical A is preferably either the methyl group or the Ethyl group.

2 "5

In particular, the radical -CHA kr 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 that can be used include in vivo hydrolyzable esters as described in BE-PS 827 926 as in Vivo hydrolyzable esters are described when they are bound to clavulanic acid. Examples of such esters are the acetoxymethyl, ctf-acetoxyethyl, trimethylacetoxymethyl, phthalidyl, Ethoxycarbonyloxymethyl and the 06-Ä'thoxycarbonyloxyethyl ester.

When using a salt of clavulanic acid in the method of the present invention is used as the starting compound, the process offers the advantages of a good overall yield of pure compounds and a low number of reaction stages.

Suitable salts of clavulanic acid used in the process of the present invention Invention used are customary salts of clavulanic acid, such as the alkali metal or alkaline earth metal salts or a

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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 _t Tetramethylguariidiniumsalze.

The reaction of a compound of the general formula (II) with a salt or an ester of clavulanic acid takes place in one anhydrous inert organic solvent instead, as in

others

Dichloromethane or chloroform or a / haloalkane, or 3n others, hydroxyl group-free solvents such as nitromethane. At the most advantageously the solvent system is completely free of hydroxyl groups.

The etherification preferably takes place in the presence of a base. Most advantageously, the base is insoluble in the reaction medium. Examples of such bases are alkali metal carbonates or bicarbonates or alkaline earth metal oxides or hydroxides. Separate 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 present in excess. For example, you can have 1 to 5 equivalents of the base per equivalent of the oxonium salt.

It has also been found that the presence of crown ethers can increase the yield of the desired compound from a clavulanic acid salt in the reaction mixture. Examples of such Crown ethers are "l8-crown-6", "l5-crown-5"> "Dicyclo-

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hexo-l8-crovvn-6 "or their equivalents.

Another preferred embodiment of the present invention consists in a process for the preparation of 9-0-methylclavulanic acid methyl ester, which is characterized in that a salt of clavulanic acid is reacted with trimethyloxonium fluoroborate. Another preferred embodiment of the present invention consists in a process for the preparation of the 9-0-ethylclavulanic acid ethyl ester, which is characterized in that a salt of clavulanic acid with triethyloxonium tetrafluoroborate implements.

If the etherification is practically complete, what can be determined for example by means of thin layer chromatography by spraying with permanganate, the desired Compound from the reaction mixture by washing the organic phase with water to remove ionic compounds, Drying of the organic phase and evaporation of the solvent can be obtained. Then you can, if necessary, the ester ether Further purify by chromatography. Stationary phases such as silica gel, cellulose are used as suitable chromatography systems or the like, and solvents such as mixtures of esters and hydrocarbons such as mixtures of ethyl acetate and cyclohexane.

The esters of the compounds of the general formula (I) can be converted into the free by the processes described in BE-PS 84γ 045 Acid or its salts are transferred. Such processes include the hydrogenation of hydrogenolyzable esters such as the benzyl or p-methoxybenzyl ester or equivalents

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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 bicarbonate; t or the like, and in the presence of a transition 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 controlled addition of lithium hydroxide, sodium hydroxide or the like at a rate such as to adjust the pH of the solution - as indicated on a pH meter - to be kept in the range from 7.5 to 10, such as 7.5 to 9 or 8 to 10 or preferably 9 to 9.5. This can conveniently be accomplished by using a pH meter so that the base is used in a conventional 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, the present one Invention provides the process for the preparation of a salt of a compound of the general formula (I) that one the methyl ester of the methyl ether of clavulanic acid or the ethyl ester of the ethyl ether of clavulanic acid, as described above was, and then hydrolyzed the ester group, so that a salt of the methyl ether of clavulanic acid or of ethyl ether which receives clavulanic acid.

In general, the hydrolysis is carried out in an aqueous solvent system carried out, as in aqueous tetrahydrofuran or the

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to

same, using a base as described above.

The preferred salt of clavulanic acid in the process of the present invention is the sodium salt. Another preferred salt the clavulanic acid is the potassium salt. Another preferred salt in practicing the method 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 carried out at a temperature of -80 ° C (or more suitably from -60 ° C) to + 60 ° C (or up to the boiling point of the solvent system, although temperatures not above +40 C are more appropriate) and even more suitably from about -40 to +30 ⁰ C carried out. It is often advisable to start the reaction at a low temperature, such as - ^ O to O ⁰ C, and then allow the temperature of the reaction mixture to rise gradually until it is room temperature or a temperature slightly below, such as about 10 to 20 ⁰ C.

The hydrolysis is conveniently effected at about room temperature, for example at temperatures of about 10 to about 30 ⁰ C, such as at 15 to 25 ° C.

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When the reaction has ended, what can be achieved by no further uptake of base without degradation or by thin layer chromatography can determine, the pH of the reaction mixture can be adjusted to pH 7, e.g. by adding a small amount Amount of an acid, such as acetic acid.

In order to obtain the desired salt, the solvent can be removed, for example by evaporation, and the dried Salt 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 on iron, but one should use large amounts of Avoid water 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 obtain the lithium salt, since this salt is in a very pure and good form Yield is obtained.

If other 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 is applied to 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 eluted therefrom.

Examples of suitable cation exchange resins are crosslinked polystyrene-divinylbenzene copolymers with sulfonic acid groups

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pen, as they are under the trademarks "Amberlite", "Dowex", "Zerolit", "BioRad" and "Ionac" are on the market.

Usually the eluent is water or water im Mixture with an organic solvent such as methanol, ethanol or acetone. The most convenient eluant is water. The cation exchange resin is preferably present in a large excess, for example at least three times Excess, most expediently in at least an eight-fold excess and advantageously in at least one ten times the excess. In the simplest and most expedient embodiment of the method, a solution of the lithium salt is used simply allowed to seep through a bed of the resin from which it emerges again in the form of the other salt. The wished Salt can then be removed from the solution by conventional methods such as freeze-drying, evaporation, precipitation using a organic solvent or the like.

The free acids of the general formula (I) can be obtained from the lithium salt or another salt by acidification, for example using an acid such as a mineral acid or a strongly acidic cation exchange resin, as usual insoluble acid acts to be produced.

The examples illustrate the invention.

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example 1
ft-Q-ethylclavulanic acid ethyl ester

To a rapidly stirred suspension of 1.52 of Kfliumsalzes of clavulanic acid and 4 g of anhydrous sodium carbonate in 70 g ml to -20 ⁰ C cooled, anhydrous dichloromethane is added dropwise a solution of 4.86 g of triethyloxonium tetrafluoroborate added in 40 rnl of anhydrous dichloromethane. The reaction mixture is (very slow. Reaction), and then for 1 hour at about 5 ° C (ice bath) stirred for 3 hours at about -20 ⁰ C. The thin-layer chromatogram then 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 allowed to separate and the organic phase is dried over anhydrous sodium sulfate. After the drying agent has been filtered off, the filtrate is evaporated. An orange-colored oil is obtained. .

This "oil is subjected to chromatography on silica gel Use of 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 in the corresponding Way united and evaporated. 44 mg of crude ethyl clavulanate and 520 mg of the ester ether are obtained. These Compounds are chromatographed again separately. While the ester is chromatographed using the original solvent system and yields 15 mg of pure ester, the Xtherester chromatographed again using mixtures of ethyl acetate and cyclohexane in a ratio of J5: 2 up to 2: 3, and 375 mg of the pure 9-0-ethylclavulan are obtained

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df -

acid ethyl ester as a pale yellow oil.

IR spectrum: "V> (film) 18O2, 1744 and 1699 cm" ¹ .

NMR spectrum in CDCl3,: 5 = 1.14 (3H, t, J = 7 Hz, ether-CH,);

1.26 OE, t, J = 7 Hz, ester-CH,);

2.97 (IH, d, j = 17 Hs, 6-β-CH);

3.46 (IH, da, J = 17 and 3 Hz, 6-oi-CH);

3.39 (2H, q, J = 7 Hz, 9-0-CH _2);

4.01 (2H, d, J = 7 Hz, 9-CH _2);

4.17 (2H, q, J = 7 Hz, CO ₂ .CH ₂ );

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

4.99 (IH, s, 3-CH);

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

You can replace the potassium salt of clavulanic acid in this reaction by the tetramethylguanidinium salt of clavulanic acid, however, despite the solubility of the salt in dichloromethane, this is of no particular advantage.

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Example 2

9-0-ethylclavulanic acid ethyl ester

Kan is the effect to improve the method of Example 1 in that a catalytic amount of adding to the dichloromethane solution of the reactants prior to addition of the oxonium salt - in this case 0.17 g. - adding a crown ether ^f 'l8-erown-6 "In this case receives 1.1 g (= 75 % of theory) of practically pure 9-0-ethylclavulanic acid ethyl ester after the first column chromatography, based on 89 percent pure potassium salt as the starting compound.

Example 3 Lithium salt of 9-0-ethylclavulanic acid

A solution of 1.1 g of ethyl 9-0-ethylclavulanate 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 ⁰ C with stirring 4.0 ml have been used. A small drop of acetic acid is then added to lower the pH to 7.0. The solution is then evaporated at room temperature on a rotary evaporator to an orange gum, dissolved in about 20 ml of the acetone and 60 minutes, is cooled to 2 to 3 ⁰ C, wherein the lithium salt crystallized 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 9-0-ethylclavulanic acid is obtained as pale yellow crystals. The total yield, based on the potassium salt of clavulanic acid via Example 2, is $ 55

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2 θ when using copper Kbt 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 9-0-ethylclavulanic acid

Part 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 conventional Moisture content directed. 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 9-0-ethylclavulanic acid is obtained.

Example 5
9-O-ethylclavulanic acid ethyl ester

Crystalline sodium clavulanate hydrate is dehydrated under reduced pressure over phosphorus pentoxide to constant weight. A suspension of 1.11 g of the dried salt and 2.65 g of anhydrous sodium carbonate in 50 ml of water 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 cooled to -20 ° C with stirring and with exclusion of moisture. Then a solution of 3.8 g is added within 20 minutes Triethyloxonium tetrafluoroborate in 50 ml of anhydrous methylene chloride admitted. The mixture is stirred vigorously at -20 ° C. for 3 hours. Samples are taken at intervals and removed using thin

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Layer chromatography investigated with regard to the course of the reaction. 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 value, which is concluded from thin-layer chromatography compared to a standard sample. Then 50 ml of water are added to the reaction mixture, the phases are stirred thoroughly and they can be separated. The methylene chloride solution is washed several times with 50 ml of water each time, dried over anhydrous sodium sulfate and then filtered. After evaporation of the solvent under reduced pressure at temperatures above 2O ⁰ C g is obtained the crude compound mentioned in the title as a light orange oil in a yield of 1.10. 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 applied to a column which is charged with 50 g of silica gel which has been drawn 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 which contain the compound named in the heading are combined and evaporated ^{under reduced pressure and at a temperature above 20 ° C.} 640 mg (= 50 % of theory) of ethyl 9-0-ethylclavulanate are obtained as a colorless oil. The compound shows the same spectrographic properties as that obtained in Example 1. Those fractions which, compared to a standard sample, contain ethyl clavulanate by thin-layer chromatography are combined and evaporated. 35O mg (= 31 % of theory) of the ester are obtained as a colorless oil.

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Example 6

9-O-ethylclavulanic acid-η thy! 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.degree. C. with stirring and with the exclusion of moisture. Then over 20 minutes a solution of 3 8 g * Triäthyloxoniumtetrafluorborat is added in 50 ml of nitromethane and the mixture stirred for 3 hours at -20 ⁰ C agile.

The stirred reaction mixture is left on an ice / water bath for 5 hours kept at a temperature of about 5 C. After that shows the analysis of the reaction mixture by means of thin layer chromatography the presence of a broad zone typical of the ethyl 9-ö-ethylclavulanate, as compared with a standard sample shows.

Example 7

9-0-A * thylclavulanic acid r ^: thyl 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 with stirring and exclusion of moisture to -20 ⁰ C. Is then added over 20 minutes a solution of 3 * 8 g of triethyloxonium tetrafluoroborate in 50 ml of anhydrous methylene chloride are added and the mixture is stirred 1 hour at -20 ⁰ C. agile

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-Jf.

ι ¹

The stirred reaction mixture is kept at a temperature of about 5 ° C. in an ice / water bath for 5 hours. It is then treated with 50 ml of water and, according to the method given in Example 5, 250 mg of the crude ester ether, which is purified on a column with silica gel, is isolated. 130 mg (= 10 % of theory) of the compound mentioned in the heading and 50 mg (= 5 % of theory) of ethyl clavulanate are obtained.

Examples

9-0-ethylclavulanic acid ethyl ester

0.60 g of the magnesium salt of clavulanic acid, 1.5 g of anhydrous 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 with stirring and exclusion of moisture to -20 ⁰ C. A solution of 2.15 g of triethyloxonium tetrafluoroborate in 30 ml of anhydrous methylene chloride is then added over the course of 15 minutes, and the reaction mixture is vigorously stirred at -20 ° C. for 1 hour.

The stirred reaction mixture is then placed in an ice / water bath for 2 hours kept at a temperature of 5 ° C. Thereafter, the analysis of the reaction mixture by means of thin layer chromatography shows the presence of a broad zone typical of the ethyl 9-0-ethylclavulanate and only a narrow zone for the ethyl clavulanate.

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ΊΟ

Example 9

9-0-methylclavulanic acid methyl ester

1.52 g of the potassium salt of clavulanic acid with 95 percent purity and 4.0 g of anhydrous sodium carbonate 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. 0.17 g of a crown ether is then dissolved "18-crown-6" in methylene chloride. The suspension is cooled with stirring to a temperature of about -20 ⁰ C and slowly a suspension of 4.22 g with trimethyloxonium tetrafluoroborate in 90 ml of anhydrous methylene chloride. The reaction mixture is stirred for 3 hours at -20 C and then 1 hour at etv / a 0 ⁰ C. 90 ml of water are then added and the reaction mixture is allowed to separate 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 means of column chromatography on silica gel and eluting with a mixture of cyclohexane and ethyl acetate in a ratio of 1: 1.

After evaporation of the relevant elution fractions, 0.54 g (= 41 % of theory) of methyl 9-0-methylclavulanate and a further 0.37 g (= 29 % of theory) of methyl clavulanate are obtained.

A sample of the 9-0-> methylclavulanic acid methyl ester is in aqueous tetrahydrofuran solution with a content of 1 m lithium hydroxide hydrolyzed at a pH value of 9.5 adjusted by means of a pH meter.

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S / l

275A763

After evaporation and after addition of acetone, 0.43 g of crystalline lithium salt of 9-0-methylclavulanic acid is obtained.

In the X-ray diffraction diagram, the powdery substance shows the following diffraction angles.

2 θ (copper Kbt 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

methyl g-O-methylclavulanate

4.56 g of the potassium salt of clavulanic acid of 95prozentiger purity, 12 g of anhydrous sodium carbonate, 0.5 g of a crown ether "l8-crown-6", and 12.7 g trimethyloxonium tetrafluoroborate were cooled to -70 ⁰ C and stirred while slowly 200 ml of anhydrous methylene chloride are added. After the addition of the solvent, the temperature is allowed to rise slowly to 20 ⁰ C. After stirring for 3 hours at room temperature, thin layer chromatography shows 2 zones with running values R ^. = 0.35 and 0.12 with an area ratio of approximately 10: 1. 250 ml of water are then 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 as in Example 9 by means of column chromatography. The elution fractions containing the desired compound are evaporated and give 2.6 g (= 62 % of theory) of methyl 9-0-methylclavulanate, which is pure according to thin-layer chromatography.

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.J *

1.13 g of the aforementioned ether ester are dissolved in aqueous tetrahydrofuran dissolved with a content of potassium hydroxide and hydrolyzed at a pH value of 9.5 adjusted by means of a pH meter. The potassium salt of 9-0-methylclavulanic acid is obtained.

Example 11

9-0-methylclavulanic acid methyl ester

1.6 g of the sodium salt of clavulanic acid, which has been obtained by dehydration under reduced pressure from a tetrahydrate 92prozentiger purity, 4.0 g water-free sodium carbonate and 4.9 g of trimethyloxonium tetrafluoroborate are cooled to -70 ⁰ C 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 methyl 9-0-methylclavulanate are obtained. 0.22 g of methyl clavulanate is obtained as a by-product.

Nuclear Magnetic Resonance Spectrum in CDCU: S ^ 2.99 (1H, d, J = 16 Hz, 6-βCH); 3.24 (3H, s, ether-CH,); 3.44 (IH, dd, J = 16 Hz. And 3 Hz, 6- <XCH); 3.72 (3H, d, ester-CH4); 3.96 (2H, d, J = 7 Hz, 9-CH ₂ O);

4.79 (IH, t, J = 7 Hz, 8-CH); 5.00 (IH, broad singlet, 3-CH); 5.63 (IH, d, J = 3Hz, 5-CH).

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Qy-O-Me thy lclavulanic acid methyl ester

110 ml of anhydrous methylene chloride at a level of about 50 mg of a crown ether are "15-crown-5" slowly to a stirred, cooled to -70 ⁰ 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 are added. The temperature of the reaction mixture is then 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 methyl 9-0-methylclavulanate is obtained. The NMR spectrum is identical to that of the compound of Example 11.

Example 13

9-0-methylclavulanic acid methyl ester

80 ml of anhydrous methylene chloride containing 50 mg of a crown ether "l8-crown-6" are tetrafluoroborate Tetramethyloxonium-slowly to a stirred, cooled to -70 ⁰ C mixture of 0.6 g of magnesium salt of clavulanic acid, 3.0 g of magnesium oxide and given. The temperature of the reaction mixture is then allowed to rise to room temperature and the course of the reaction is followed by 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 9-0-methylclavulanate.

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Example 14

9-0-methylclavulanic acid methyl ester

110 ml of anhydrous nitromethane containing about 20 mg of a crown ether "15-crown-5" are slowly added to a stirred and cooled mixture of 1.52 g of the potassium salt of clavulanic acid, 4.0 g of anhydrous sodium carbonate and 4.5 g of trimethyloxonium tetrafluoroborate . The temperature of the reaction mixture is then 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 methyl 9-0-methylclavulanate, the NMR spectrum of which is identical to that of the compound of Example 11, is obtained.

Example 15

9-0-methylclavulanic acid benzyl ester

100 g of trimethyloxonium tetrafluoroborate are suspended in 2 liters of anhydrous dichloromethane at -30 ° C., while 110 g of anhydrous sodium carbonate are added all at once. Then quite rapidly 70 g clavulanic acid benzyl ester in 1 liter of anhydrous dichloromethane is added while the temperature is maintained at -30 ⁰ 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 9-0-methylclavulanate are obtained.

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-j *

Example 16 275A763

9-0-Äthylclavulansäure-p-methoxybenzyl ester pmethoxybenzylester clavulanic acid To a stirred at -30 ⁰ C solution of 9.6 g in 500 ml of dichloromethane successively 15 g of anhydrous sodium carbonate (excess) and a solution of 17.6 g are Triethyloxonium tetrafluoroborate added to 100 ml of dichloromethane.

Then the mixture is stirred for 6 hours at about -10 ⁰ C and then allowing the temperature of the reaction mixture for 30 minutes to rise to room temperature. 100 ml of water are then carefully added with stirring, the organic phase is separated off, dried over anhydrous sodium sulfate and evaporated to a syrup, which is based on column chromatography on silica gel and eluting with mixtures of ethyl acetate and cyclohexane first in a ratio of 1: 1 and then subjected to a ratio of 2: 1. The product eluted first is ethyl ether in a yield of 4.9 g after evaporation of the solvents. Then 4 g of p-methoxybenzyl clavulanate are recovered. The title compound is a pale yellow oil with the following properties.

IR spectrum (liquid film): v> 1805 (ß-lactam-C = O),

uicUw

1750 (Ester-C = 0), 1700 cm " ¹ (C = C).

NMR spectrum in CDCIy S = 1.17 (3H, t, J * 7 Hz, CH ₃ CH ₂ );

2.96 (IH, d, J = 17 Hz, 6-β-CH); 3.4l (2H, q, J = 7 Hz, CH ₃ CH ₂ -); 3.47 (IH, dd, j = 17 and 3 Hz, 6-oi-CH); 3 * 79 (3H, s, OCH ₃ );

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

5.04 (IH, s, 3-CH); 5.11 (2H, s, PhCH ₂ );

809824/0832

5.65, ( ^1Η » ^ά > J = 3 Hs, 5-CH); 6.9, 7.3 (^ H, A ₂ B ₂ quartet, J = IO Hz, C ₆ H ₂ ^).

Example YJ

Lithium and sodium salt of 9-0-ethylclavulanic acid 2.5 g of 9-0-fithylclavulanic acid p-methoxybenzyl ester in 25 ml of tetrahydrofuran containing 0.1 ml of water are added in the presence of 0.8 g of 10 percent palladium containing carbon catalyst hydrogenated. 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 an equal volume of water in order to obtain a solution of 9-0-ethylclavulanic acid. This solution is titrated to pH 7j0 using a 1-M lithium hydroxide solution. After evaporation of the solvent and trituration of the residue with acetone, 1.05 g of the lithium salt is obtained as pale cream-colored crystals.

The sodium salt is made in the same way but using of 1-m sodium hydroxide solution. Yield: 0.85 g.

IR spectrum (Nujol): VJL I785 (ß-lactam-C = O), Ι685 (C = C), I615 (-COp-) cm ". These values apply to both salts.

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

809824/0832

9-0-ethylclavulanic 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 "18-crown-6" are suspended in 50 ml of methylene chloride, which is free from water and methanol. The mixture is stirred and cooled to -20 ⁰ 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 V / 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 9-0-ethylclavulanate is obtained.

Example I9

9-0-methylclavulanic acid

A solution of 0.9 g of the lithium salt of O-methylclavulanic acid in 40 ml of water is covered with 150 ml of ethyl acetate. Then stir the two layers! brisk at room temperature. Then add 10 ml of a strongly acidic ion exchange resin in the moist state ("Amberlite IR 120") in the hydrogen orm. After 5 minutes, decant from the resin and allow the layers to separate. The aqueous layer becomes extracted again with 100 ml of ethyl acetate. The solvent layers are combined, washed with 5 ml of water, over anhydrous Calcium sulfate dried and filtered, ^ after the one

809824/0832

evaporate the solution under reduced pressure up to manure and then under greatly reduced pressure to remove residual solvent, 0.85 g of the free one is obtained G-methylclavulanic acid as colorless crystals.

Example 20

9-0-Methylclavulansäure-p-nitrobenzy! Ester J5i51 tetrafluoroborate Clavulansäüre g p-nitrobenzyl, 3> 15 S trimethyloxonium and 4.0 g of anhydrous sodium carbonate are stirred together and cooled to -70 ⁰ 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 9-0-methylclavulanic acid p-nitrobenzyl ester are obtained as white crystals.

809824/0832

Claims (1)

Claims (} y. Process for the preparation of clavulanic acid ethers of the general formula (I) / " ² - ⁰ - ⁸ (D CO ₂ H in which R is the methyl or ethyl group * or their salts or Esters, characterized in that one clavulanic acid or their salts or esters with an oxonium salt of the general formula (II) R η® γ © ^R 3 ° ^x (II) in which R is the methyl or ethyl group and Xr is an anion means, and optionally then converts the ester formed into the free acid or its salt and / or the formed converts free acid or its salts into another ester or another salt. 2. The method according to claim 1, characterized in that one as the anion of the oxonium salt of the general formula (II) is a tetrafluoroborate, hexafluorophosphate, 2, ^, 6-trinitrobenzenesulfonate or a 2,4,6-trifluorobenzenesulfonate anion is used. 'j>. Process according to claim 1, characterized in that trimethyloxonium tetrafluoroborate or triathyloxonium tetrafluoroborate is used as the oxonium salt of the general formula (II). 809824/0832 ORIGINAL INSPECTED 4. The method according to claims 1 to ~ j>, characterized in that a hydrolyzable ester of clavulanic acid or a hydrogenolysable ester of clavulanic acid is used. 5. The method according to any one of claims 1 to 4, characterized in that that one uses an ester of clavulanic acid of the general formula (III) ^ ₀ CII ₂ OII y = / you) ν ^ y CO ₂ A in which A is an alkyl radical having 1 to 8 carbon atoms, which is through Halogen atoms or a radical of the general formula -OA, 4 4 * '- 4 -OCOA, -SA or -SO ₀ A 'can be substituted, where A is a hydrocarbon radical with up to 6 carbon atoms, or an ALkenyl or alkynyl radical with up to 4 carbon atoms. 6. The method according to claim 5, characterized in that gokenrize is worthwhile a compound of the general formula (IEE) is used, in the A is an alkyl radical with up to 4 carbon atoms, eier substituted by an Ftest of the general formulas -OA or -OCOA can be, where A is an alkyl radical with up to 4 carbon atoms is. 7. The method according to claim 5, characterized in that d: if.i man a prebinding of the general formula (EEE) is used, i: i eier A dl ·: methyl odor · ethyl group. B 0 f) 8 2 A / 0 Π 3 2 8. The method according to at least one of claims 1 to 5 * characterized in that an ester of clavulanic acid of the general formula (III) is used, in which A is the icetoxymethyl, o (-Acetoxyäthyl-, Trimethylacetoxymethyl-, Phthalidyl-, Ethoxycarbonyloxymethyl or the ttf-Äthoxycarbonyloxyäthylgruppe is. 9. The method according to any one of claims 1 to 3, characterized characterized in that an ester of clavulanic acid of the general formula (V) CH ₂ OH CHA ² A ³ ρ
used, in which A is a hydrogen atom, an alkyl radical with up to k carbon atoms or the phenyl group, which can be substituted by halogen atoms or a radical -k ^ or -OA ^, where the radical A is an alkyl radical with up to 6 carbon atoms, and br represents a phenyl group formed by halogen atoms CE C or a radical -A ^ or -OA ^ may be substituted, where A ^ is an alkyl radical with up to 6 carbon atoms. 10. The method according to claims 1 to 9, characterized in that an ester of the general formula (V) is used p
det, in which A the in claim 5 and A- ^{5 is} the nitrophenyl group. p
det, in which A has the meanings given in claim 5 11. The method according to claims 9 or 10, characterized in that that a compound of the general formula (V) 809824/0832 ρ
used, in which Λ is a hydrogen atom. 12. The method according to claim 9, characterized in that a compound of the general formula (V) is used in which 2 "5 the group -CHA A ^ the benzyl, p-methoxybenzyl, p-bromine benzyl or the p-nitrobenzyl group. 13. The method according to claims 1 to 3> characterized in that a salt of clavulanic acid is used. 14. The method according to claim 13, characterized in that an alkali metal salt, an alkaline earth metal salt or a nitrogenous base is used as the salt of clavulanic acid. 15. The method according to claim 14, characterized in that the salt of clavulanic acid is its lithium salt, sodium salt, Potassium salt or its salt with tetramethylguanidine is used. 16. The method according to claims I3 to 15, characterized in that the salt is used in finely divided form. 17. ancestors according to claims I3 to 16, characterized in that as Ga] ζ used a freeze-dried salt. 18. The method according to claim I5, characterized in that mn η η]:. · KaIi ¹ J υπ ::;, ^0. ] :: a by dehydrating the tetrahydrate of NiJtri 1 ::: ": =«] ze :; rl · ·! 'C];ivu];; ^r.:-. Iure prepared GaIz used. 19. Procedure according to mj v.-lc: -.1 er.:; one (3 claims 1 to IB, «09824/0837 characterized in that the reaction is carried out at a temperature of -60 to + 6O ⁰ C. 20. The method of claim I9, characterized in that one carries out the reaction at a temperature of -40 to +30 ⁰ C. 21. The method according to claim 19 # characterized in that the reaction is carried out at a temperature of -30 to +20 ⁰ C. 22. The method of claim I9, characterized in that begins the reaction at a temperature of -30 to 0 ⁰ C. 23. The method according to claim I9 »characterized in that the reaction is ended at a temperature of +10 to +20 ⁰ C. 24. The method according to at least one of claims 1 to 23, characterized in that the solvent used is ilitromethane or a haloalkane is used. 25. The method according to claim 2h, characterized in that there is used as the haloalkane dichloromethane or chloroform. 26. The method according to at least one of claims 1 to 25, characterized in that the reaction Ln the presence of a Base performs. BfHJf) 24/03 1? 27547G3 27 · The method according to claim 26, characterized in that the base used is an insoluble base which is present in a large excess. 28. The method according to claims 26 or 27, characterized in that that the base is an alkali metal carbonate or bicarbonate, an alkaline earth metal carbonate or bicarbonate or an alkaline earth metal oxide or hydroxide is used. Process according to Claim 28, 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 is used. 30. Procedure according to at least one of the items 1 to 29> characterized in that the one obtained in the reaction framework Wash the ester ether with water to remove ionic compounds and then evaporate the organic phase. ~ j> l . Process according to at least one of claims 1 to 30, characterized in that the initially prepared ester of a compound of the general formula (E) is surrounded by hydrolysis Ln a salt wall Lt. 32. The method according to claim Jl , characterized in that the hydrolysis is effected by adding an AlkaLimetal Lbar.e. yj>. Procedure according to Jen. '.: t ::; pruohori ~' j \ or ')?., Dad :; ¹ T-Gh relyp.nzei :::.: U: I, dall man al; ·, lkt. - Ln Hyciroxi ei ν .:: "■. ·:> .: ritio '■' ■. · ^; ί ' ^: ι π -η ι ; ι η τ? 3 ^. Process according to one of Claims J> \ to 33 », characterized in that a lithium base, a sodium base or a potassium base is used as the base. 35 · The method according to claim 33 »characterized in that the base is lithium hydroxide, sodium hydroxide or potassium hydroxide used. 36. The method according to claim 31 »characterized in that the hydrolysis is effected by adding an alkaline earth metal base. 37. Process according to claims J> k or 35 *, characterized in that an initially produced lithium salt is converted into the sodium, potassium, calcium or magnesium salt. 38. The method according to at least one of claims 1 to 30 » characterized in that the initially prepared compound of the general formula (I) is prepared by hydrogenolysis converts a hydrogenolysable ester into the free acid. 39. The method according to at least one of claims 1 to 30, characterized in that the initially prepared hydrogenolysable ester by hydrogenolysis in the presence of a Ι3η: ·, (? Converts into a salt. ^; l0. Process according to Claim 38, characterized in that: n converts the:; acid into a Sa] ζ by reacting it with a base. 809824/083? 41. The method according to claims 3> 9 or 40, characterized in that that a carbonate, bicarbonate or hydroxide of lithium, sodium, potassium, calcium or magnesium is used as the base. 42. The method according to claim 41, characterized in that a carbonate of lithium, sodium or potassium is used as the base or sodium bicarbonate, or lithium hydroxide is used. 4; j. Method according to at least one of Claims 1 to 12, characterized in that the ester of clavulanic acid is prepared in situ. 44. The method according to claim 7> characterized in that the ester of clavulanic acid by reacting a salt of clavulanic acid with an oxonium salt of the general formula (II) manufactures. 45. The method according to claim 44, characterized in that trimethyloxonium tetrafluoroborate or triethyloxonium tetrafluoroborate is used as the compound of the general formula (II). 46. The method according to claims 44 or 45, characterized in that that the lithium salt, sodium salt or potassium salt thereof is used as the salt of clavulanic acid. 47. Process for the preparation of the 9-0-methylclavulanic acid methyl ester according to at least one of the preceding claims, characterized in that a salt of clavulanic acid is used with a trimethyloxonium salt. 809824/0832 48. Process for the preparation of ethyl 9-0-ethylclavulanate according to at least one of the preceding claims, characterized in that a salt of clavulanic acid is used with a triethyloxonium salt. 49. The method according to claims 47 or 48, characterized in that that a tetrafluoroborate is used as the oxonium salt. 50. The method according to any one of claims 47 to 49 * thereby characterized in that the reaction is carried out at a temperature as specified in claims I9 to 23. 51. The method according to claims 47 to 49, characterized in that one carries out the reaction at a temperature of -50 to +20 ⁰ C. 52. The method according to claims 47 to 5I »characterized in that that a solvent according to claims 24 or 25 is also used in the reaction. 53. Process for the preparation of a salt of 9-0-methylclavulanic acid according to at least one of the preceding claims, characterized in that 9-0-methylclavulanic acid methyl ester, according to at least one of claims 47 or 49 to is hydrolyzed in the presence of a base. 54. Process for the preparation of a salt of 9-0-ethylclavulanic acid according to at least one of the preceding claims, characterized in that 9-0-ethylclavulanic acid ethyl ester, the 809824/0832 ΊΟ has been produced according to one of claims 48 to 52, hydrolyzed in the presence of a base. 55 · Process according to claims 53 or 5 ^> characterized in that a base according to claims 3 ² to 37 is used in the hydrolysis. 56. The method according to claims 53 or 5 ^ -, characterized in that that the hydrolysis is carried out using lithium hydroxide . 57 · The method according to claim 56, characterized in that the initially produced lithium salt is converted into the sodium, potassium, calcium or magnesium salt. 58. The method according to claim 56, characterized in that the conversion is carried out in such a way that a solution of the lithium salt with a cation exchanger in the form of Bringing sodium, potassium, calcium or magnesium salt into contact and then eluting the corresponding salt from the resin. 59. Process for the preparation of the sodium, potassium, calcium or magnesium salt of 9-0-methylclavulanic acid or of 9-0-ethylclavulanic acid according to claim 58, characterized in that that a solution of the lithium salt of 9-0-methylclavulanic acid or 9-0-ethylclavulanic acid with a cation exchange resin in the form of the sodium, potassium, calcium or magnesium salt and then the corresponding salt eluted from the resin. 809824/0832 60. The method according to claim 59 »characterized in that one uses as eluant V / water or a Geraisch of water a miscible organic solvent is used. 61. The method according to claim 60, characterized in that the solvent used is water. 62. A salt of .9-0-ethylclavulanic acid, which is derived from ethyl 9-0-ethylclavulanate has been made. 63. An alkali metal salt or an alkaline earth metal salt of 9-0-ethylclavulanic acid. 64. The lithium salt, the sodium salt and the potassium salt of 9-0-ethylclavulanic acid. 65. Ethyl 9-0-ethylclavulanate. 66. Process for the preparation of 9-0-methylclavulanic acid or 9-0-ethylclavulanic acid according to at least one of the preceding claims, characterized in that a salt of 9-0-methylclavulanic acid is used or the 9-0-ethylclavulanic acid acidifies. 809824/0832