CH637395A5 - Process for preparing ether compounds of clavulanic acid - Google Patents

Description

The invention relates to processes for the production of ethers of clavulanic acid and its salts and esters. The new compounds increase the antibacterial effect of penicillins and cephalosporins. They can be used in medicinal products.

In BE-PS 847 045 it is disclosed that clavulanic acid ether can be prepared by reacting a corresponding clavulanic acid ester with an etherifying agent, such as a diazo compound.

It has now been found that some clavulanic acid ethers can be produced in good yield by a simple reaction.

The invention relates to processes for the preparation of compounds of formula I, their salts and esters cho-0-cr r -xr

\

in which X represents an oxygen or sulfur atom, R1 and R2 are hydrogen atoms or lower alkyl radicals which are optionally linked to one another, R3 is an optionally inertly substituted lower alkyl radical or forms an optionally inertly substituted 5- or membered heterocyclic ring with the radical R2.

The term "lower" means that the remainder does not have more than 6 carbon atoms, especially not more than 4 carbon atoms.

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3rd

637395

“Inert substituted” here means that the radical is substituted by one or more radicals of the formulas CH2OR4 or OR4, in which R4 is a hydrogen atom, a lower alkyl or acyl radical or a benzyl radical.

The oxygen atom is preferred for X in formula I.

The hydrogen atom, the methyl and ethyl radical is suitable for R ". The hydrogen atom is preferred for R1.

Compounds of the formula II, their salts and esters are preferably available according to the invention

Sodium and potassium salts.

Suitable esters of the compounds of the formula I are compounds of the formulas III and IV

ch2 - o - crV-xr3

(iii)

(ii)

in which R2 and R3 are as defined in formula I.

In compounds of the formulas I and II in which R2 is not bound to R1 or R3, the hydrogen atom, the methyl and ethyl radical are suitable for R2. The hydrogen atom and the methyl radical, in particular the hydrogen atom, are preferred.

For compounds of the formulas I and II in which R2 and 25 R 'are not connected, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, and tert-butyl radical are suitable. The methyl, ethyl or propyl radical, in particular the methyl and ethyl radical, preferably the methyl radical, is particularly suitable for R3. 30th

In compounds of the formulas I and II in which R2 and R3 are connected, the radical -CR'R2-XR3, particularly advantageously a radical of the formulas a or b cho - o - cr1r2-xr3

R

* V

r-

(a)

(b)

>> co- - ch - a I

i3

(iv)

35

in which R1, R2, X and R3 are as defined in formula I and A1 is an alkyl radical having 1 to 8 carbon atoms, which is optionally substituted by halogen atoms or a radical of the formulas OA4, OCOA4, SA4 or SO2A4, in which A4 is a hydrocarbon radical having up to 6 carbon atoms, A2 is a hydrogen atom, an alkyl radical having up to 4 carbon atoms or a phenyl radical which is optionally substituted by halogen atoms or an alkyl or alkoxy radical having up to 6 carbon atoms, and A3 is a phenyl radical which is optionally substituted by Halogen atoms or an alkyl or alkoxy radical is substituted. For the radical 0-CR'R2-XR3 in formula I, radicals of the formulas a to f are particularly suitable

-CH2OCH3 -CH (CH3) OCH3 -CH2OC2H5 40 -CH (CH3) OC2H5 -CH (C2H5) OC2H5 -CH2-O-R3

(a)

(b)

(c)

(d)

(e)

(f)

in which Ra, Rb, Rc, Rd, Re and Rf are each a radical R4 or OR4 and Ra is a radical R4 or CH2R4, where R4 is a hydrogen atom, a lower alkyl or acyl radical or a benzyl radical, preferably an alkyl or acyl radical with up to 4 carbon atoms. The hydrogen atom, the lower alkyl radical or a radical of the formula OR5 in which R5 is a hydrogen atom, an acetyl, benzoyl or benzyl radical is particularly suitable for R'1 to Rf. The hydrogen atom, a lower alkyl radical or a radical of the formula CHzOR5 is particularly suitable for Rs. For R'1 to Rf, hydrogen atoms or lower alkyl radicals, such as the methyl radical, are preferred. The hydrogen atom is particularly preferred.

In compounds of the formula I in which R1 and R2 are linked, the radical -CR'R2 means, for example, a cyclopentyl or cyclohexyl radical which is optionally substituted by a radical R4 or OR4.

Suitable salts of the compounds of the formula I according to the invention are lithium, sodium, potassium, calcium and magnesium salts and also ammonium and substituted ammonium salts, such as methylamine, dimethylamine, trimethylamine, pyrrolidine salts and other lower alkylamine salts such as di-alkyl, tri-alkylamine and heterocyclic amine salts. Lithium, sodium, potassium and calcium salts are particularly suitable, preference is given to lithium,

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In formula f, R3 is as defined in formulas I and II and in particular means a lower alkyl radical, such as the methyl or ethyl radical. The remainder is preferably a.

Particularly interesting compounds according to the invention are 9-O-methoxymethylclavulanic acid and its lithium, sodium, potassium, calcium and magnesium salt, and also their salts with ammonia and pharmacologically acceptable amines.

The invention relates to a process for the preparation of esters of the compounds of the formula I, which is characterized in that a clavulanic acid ester is reacted with a compound of the formula V.

Y-CR'R2-XR3

(V)

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65

in which X, R1, R2 and R3 are as defined in formula I and Y is an easily displaceable radical. To produce the free acids or their salts, the ester obtained is cleaved by hydrolysis or hydrogenolysis. Suitable for Y in formula V is the iodine, bromine or chlorine atom, the methanesulfonyl or toluenesulfonyl group and other radicals which are easily displaceable by a nucleophilic radical. The bromine or chlorine atom is particularly suitable for Y.

The reaction according to the invention generally takes place in the presence of a base with low nucleophilicity, such as 2,4,6-

637395

4th

Colliditi, potassium carbonate, sodium bicarbonate or 2,6-lutidine, at non-extreme temperatures such as -20 to + 30 ° C, e.g. about 0 to 20 ° C.

Dichloromethane, chloroform, dimethylformamide and tetrahydrofuran are suitable as solvents for this reaction.

Another process according to the invention for the preparation of esters of compounds of the formula I in which X is an oxygen atom, R1 is a hydrogen atom and R2 is a radical -CHRhR 'and R \ R' and R3 have the meanings given in Claim 10, is characterized in that reacting an ester of clavulanic acid of the formula X with a compound of the formula VI

RhR'C = CH-O-R3 (VI)

in which Rh, R 'and R3 are as defined above. To produce the free acid or its salt, the ester obtained is cleaved by hydrolysis or hydrogenolysis.

The hydrogen atom is particularly suitable for Rh.

Particularly suitable for R 'in formula VI is the hydrogen atom or a radical linked to R3.

Particularly suitable compounds of the formula VI are

Compounds of formulas VII and VIII.

(vii) (viii)

in which Rb, Rc, Rd, Rf and Rs are as defined in formulas a and b.

In general, this reaction takes place in the presence of an acid or an acid precursor as a catalyst, e.g. Hydrochloric acid, phosphorus oxychloride, p-toluenesulfonic acid or boron trifluoride.

In one embodiment of the process according to the invention, esters of compounds of the formula I can also be prepared by reacting a clavulanic acid ester with a compound of the formula IX

R5-0-CHR2-0R3 (IX)

in which R2 and R3 are as defined in formula I and R5 is a tertiary alkyl radical having 4 to 6 carbon atoms. The resulting ester is optionally converted into the free acid or its salt by hydrolysis or hydrogenolysis.

The tert-butyl radical is particularly suitable for R5 in formula IX.

R2 and R3 in formula IX are preferably connected to one another so that the radical -CHR2OR3 forms a heterocyclic ring.

If R2 and R3 are not connected, the radicals R2 and R3 expediently have the same meaning, e.g. both mean the methyl or ethyl radical.

An excess of the compound of the formula IX, generally at least 1 mol, preferably 2 to 5 mol, of excess is advantageously used for this reaction. If the compound of formula IX is a volatile liquid, it can be used as a solvent.

The free carboxylic acids of the formula I or their salts are obtained by converting a corresponding ester of a compound of the formula I into the free carboxylic acid or its salt by hydrolysis or hydrogenolysis.

This hydrolysis can be carried out by subjecting an ester to mild basic hydrolysis, a salt of a compound of the formula I is then obtained. Alternatively, an ester can be catalytically hydrogenated, using the free acid or, in the presence of a base, the salt receives. In particular, one can hydrolyze a lower alkyl ester, such as the methyl ester, at a pH of 7 to 10 by slowly adding an appropriate base. The benzyl, methoxybenzyl or nitrobenzyl ester can be hydrogenated in the presence of a transition metal catalyst, such as palladium on carbon, optionally in the presence of a base, such as sodium, potassium or lithium carbonate or sodium or potassium bicarbonate.

However, compounds of the formula I according to the invention can also be reacted with a diazo compound or a salt of a compound of the formula I according to the invention can be reacted with a reactive halogen compound.

Compounds of the formula I, their salt or ester can be used in combination with conventional pharmacologically acceptable carriers and / or diluents in medicinal products.

The compounds of the formula I are preferably present in the pharmaceutical preparations according to the invention in the form of a pharmacologically acceptable salt or an ester which can be saponified in vivo.

The medicinal products can be administered orally or parenterally and are suitable for the treatment of humans and animals.

In general, the medicinal products are in the form of single doses with about 20 to 250 mg, in particular about 50 to 100 mg, of active ingredient. These preparations are used two to six times a day, e.g. three to four times a day, so that a daily dose is about 60 to 1000 mg, in particular about 200 to about 1000 mg.

The medicinal products expediently also contain a penicillin or cephalosphorin, preferably in a weight ratio of compound of the formula I, their salt or ester to penicillin or cephalosporin of 1:10 to 10: 1, in particular 2: 1 to 1: 5, e.g. 1: 1 to 1: 3.

Penicillins and cephalosporins suitable for these synergistic preparations are described in BE-PS 827 926. Particularly suitable penicillins are ampicillin, amoxycillin and their precursors, such as their in vivo saponifiable esters, ampicillin trihydrate and amoxycillin trihydrate, and the pharmacologically acceptable salts of amoxycillin.

Suitable for such medicinal products which can be administered orally are benzylpenicillin, phenoxymethylpenicillin, propicillin, amoxycillin, ampicillin, epicillin, cyclacillin and other orally active penicillins, their salts and in vivo hydrolysable esters, and aldehyde and ketone adducts of a-penicillins with penicillins 6 acylamido side chains and their salts. Suitable in vivo hydrolysable esters of penicillins are the acetoxymethyl, pivaloyloxymethyl, a-ethoxycarbonyloxyethyl and phthalidyl esters of ampicillin or amoxycillin and the phenyl, tolyl and indanyl a-esters of carbenicillin and ticarcillin and their salts. Suitable aldehyde and ketone adducts of penicillins with a 6-a-aminoacylamido side chain are the formaldehyde and acetone adducts of metampicillin and hetacillin and their salts.

Suitable esters for infusions and injections are the salts of benzylpenicillin, phenoxymethylpenicillin, carbenicillin, propicillin, ampicillin, amoxycillin, epicillin, ticarcillin, cyclacillin and other known penicillins.

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Suitable cephalosporins for orally administrable medicinal products according to the invention are cephalexin, cephradine, cephaloglycine and their salts, as well as other known cephalosporins, their salts and esters saponifiable in vivo, and also aldehyde and ketone adducts of cephalosporins with a 7-a-aminoacylamido their saline.

Suitable cephalosporins for infusions and injections are the salts of cephaloridine, cephalothin, cefazolin,

ch2oh c02ch2c6h5

(e 1)

2.89 g (0.01 mol) of benzyl clavulanate (el), 1.6 ml (1.7 g) of chlorodimethyl ether and 1.3 ml of 2,4,6-collidine are added at 5 ° C. with stirring in 20 ml Dichloromethane dissolved. After 1 hour at 10 ° C, thin layer chromatography shows that the benzyl clavulanate has almost completely disappeared. The mixture is mixed with 50 ml of water and shaken, then separated (the aqueous solution is very acidic). The dichloromethane phase is mixed with 50 ml of 3 percent sodium bicarbonate solution. The organic phase is separated off, dried over sodium sulfate, filtered, concentrated and chromatographed on a silica gel column using ethyl acetate and cyclohexane as the eluent. You get

Cephalexin, cephacetril, cephamandol, cephapirin, cephradin, cephaloglycin and other known cephalosporins.

The examples illustrate the invention.

example 1

Benzyl 9-O-methoxymethylclavulanate tH

ch2och2och3

x co2ch2c6h5

(e 2)

20 1 g of a pale yellow oil.

Vmax (film): 1803.1753.1700 cm-1 (C = C).

5 (CDCb): 3.01 (1H, broad, J = 17Hz, 6-ß-CH), 3.33 (3H, s, OCH3), 3.50 (1H, double doublet, J = 3 and 17Hz, 6a-CH), 4.14 (2H, broad doublet, J = 7Hz, CHCH2O), 4.57 (3H, Sin-2s gulet, CH3O), 4.86 (1H, broad triplet, J = 7 and 1, 5Hz, CH =), 5.10 (1H, doublet, J = 1.5Hz), 5.69 (1H, broad doublet, J = 3Hz, 5-CH), 7.36 (5H, singlet, C6H5.) .

30 Example 2

9-O-methoxymethylclavulanic acid lithium salt

(e 2)

| -KUV / CH2OCH2OCH3

d ^ -N— /

\ c02h

(e3)

ch2och2och3

X c02Li (e4)

0.7 g of O-methoxymethylclavulanic acid benzyl ester (e2) in 7 ml of tetrahydrofuran containing 0.5 ml of water are hydrogenated over 0.2 g of 10% palladium on carbon for 1 hour. The catalyst is filtered off from the solution of e3, the filtrate is mixed with 10 ml of water, neutralized to pH 7.0 with lithium hydroxide solution and evaporated to dryness. Colorless crystals are obtained, which are treated with acetone, filtered, washed with ether and dried in air. Yield: 0.45 g of compound e4.

(el)

Vmax (Nujol muli): 1785.1705.1617 cm "1.

8 (D2O): 2.98 (1H, doublet, J = 17Hz, 6ß-CH), 3.43 (1H, double doublet, J = 17 and 3 Hz, 6a-CH), 4.07 (2H, doublet , «J = 8Hz, 9-CH2), -4.5 (under HOD, OCH2O), 4.79 (1H, triplet, J = 8Hz, 8-CH =), 4.83 (1H, singlet, 3- CH), 5.61 (1H, d, J = 3Hz, 5-CH).

50

Example 3

9-O-ethoxymethylclavulanic acid benzyl ester

, ch2och2oc2h5

\ co2ch2c6h5 (e5)

A mixture of 5.78 g of benzyl clavulanate (el), 5.8 ml of 2,4,6-collidine and 3.7 ml of chloromethyl ethyl ether in 100 ml of dichloromethane is stirred at room temperature for 2 hours. The mixture is washed with 100 ml of 2M hydrochloric acid, dried over anhydrous sodium carbonate / magnesium sulfate and evaporated to dryness. An oil is obtained which is chromatographed over 50 g of silica gel with cyclohexane / ethyl acetate as the eluent. 6.15 g of 65 of the desired compound e5 are obtained as an oil.

[o] 2d ° + 45.2 ° (c, 1.0; CHCb).

Vmax (CHCb): 1810.1755.1705, 1310.1190 and 1030 cm-1. 5 (CDCb): 7.28 (5H, ArH), 5.61 (1H, doublet, J = 2.5Hz,

637395

5-CH), 5.13 (2H, singlet, -CH2AR), 5.03 (IH, broad singlet, 3-CH) 4.78 (IH, broad triplet, J = 8Hz, 8-CH), 4, 56 (2H, singlet, -OCH2O-), 4.09 (2H, broad doublet, J = 8Hz, 9-CH2), 3.52 (2H, q, J = 7.5Hz, -OCH2CH3), 3.41 (1H, double doublet, J = 17Hz, J = 2.5Hz, 6cc ~ CH), 2.99 (1H, doublet, J = 17Hz, 6ß-CH) and 1.18 (3H, triplet, J = 7, 5Hz, OCH2CH3).

CisH2iN06

%: C Found%: C

62.25; 62.2;

H 6.1; H 6.15;

N 4.05 N 3.8

Example 4

9-O-Ethoxymethylclavulanic acid lithium salt

(e5)

4th

ch2och2oc2h5

(e6)

^ C02Li

A solution of 5.95 g of 9-O-ethoxymethylclavulanic acid benzyl ester (e5) in 80 ml of tetrahidrofuran, which contains 2 drops of water, is hydrogenated at room temperature and atmospheric pressure in the presence of 3.35 g of 1% palladium on carbon for 30 minutes . The mixture is filtered, the filtrate is diluted with 250 ml of water and neutralized to pH 7.2 with an aqueous lithium hydroxide solution. The mixture is evaporated to dryness. After treatment with ether, 4.4 g of the desired compound e6 are obtained from the residue.

[a] 2D ° + 34.8 ° (c, 1.0; H2O).

Vmax (KBr): 1780, 1700, 1620, 1320 and 1030 cm "1st S (D2O): 5.70 (1H, doublet, J = 2.5Hz, 5-CH), 4.90 (1H, singlet, 3-CH), 4.88 (1H, broad triplet, J = 8Hz, 8-CH), 4.68 (2H, singlet, -OCH2O-), 4.17 (2H, doublet, J = 8Hz, 9- CH2), 3.58 (2H, q, J = 8Hz, -OCH2CH3), 3.52 (1H, double doublet, J = 17Hz, J '= 2.5Hz, 6a-CH), 3.04 (1H, Doublet, J = 17Hz, 6ß-CH) and 1.13 (3H, triplet, J = 8Hz, -OCH2CH3).

Example 5

9-O-methylthiomethylclavulanic acid benzyl ester

Vmax (liquid film): 1805.1750, 1695.1300.1180 and 20 1035 cm-1.

8 (CDCb): 7.28 (5H, singlet, ArH), 5.61 (1H, doublet, J = 2.5Hz, 5-CH), 5.12 (2H, singlet, -CHsAr), 5.03 (1H, singlet, 3-CH), 4.75 (1H, broad triplet, J = 8Hz, 8-CH), 4.49 (2H, singlet, -OCHîSMe), 4.10 (2H, doublet, J = 8Hz, 2s 9-CH2), 3.42 (1H, double doublet, J = 17Hz, J '= 2.5Hz, 6a-CH), 2.99 (1H, doublet, J = 17Hz, 6ß-CH) and 2.09 (3H, singlet, -SCH3).

m / e (relative intensity): 301.0968 (25, M + -MeSH), 288.0849 (10, M + -C2HsS), 272.0903 (5, M + -C2HsOS), 230 (30, M + 30 -C2H5OS- C2H5OS-C2H2O) and 91 (100).

Example 6

9-O-methylthiomethylclavulanic acid lithium salt

35

40

och2sch3

(el)

o%

co-ll te9)

och2sch3

(e8)

A solution of 2.89 g (0.1 mol) of benzyl clavulanate (el) and 2 ml (0.015 mol) of 2,4,6-collidine in 10 ml of dimethoxyamine is mixed with a mixture of 1.5 g of sodium iodide and 0.97 g (0.01 mol) of chloromethyl methyl sulfide in 20 ml of dimethoxyethane at 0 ° C. under argon protection. The mixture is stirred for 3 hours at 50 ° C., then for 66 hours at room temperature, then poured into 40 ml of ice water and extracted three times with 40 ml of ethyl acetate. The organic extract is washed with 100 ml of 5M hydrochloric acid and 100 ml of saturated sodium chloride solution, dried and evaporated. An oil is obtained which is chromatographed on 30 g of silica gel with cyclohexane / ethyl acetate as the eluent. 0.4 g of compound e8 is obtained as a colorless oil.

[a] o + 38.3 ° (c, 2.0; CHCb).

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A mixture of 0.35 g of 9-O-methylthiomethylclavulan-50 acid benzyl ester, 15 ml of tetrahydrofuran and 15 ml of water is titrated in a pH stat at 24 ° C. with a lithium hydroxide solution to a constant pH of 10. After 2 hours, the addition of lithium hydroxide is interrupted. The solution is concentrated to 10 ml under reduced pressure, then diluted with 10 ml of water. This aqueous mixture is extracted twice with 20 ml of ethyl acetate and evaporated to dryness. The residue is chromatographed on a column with 10 g cellulose with butanol / water / ethanol in a ratio of 5: 5: 1 (upper phase). «# 0.04 g of the desired compound e9 is obtained.

Vmax (Nujol): 1780,1695,1620,1300 and 1020 cm-1. 8 (D2O): 5.80 (1H, doublet, J = 2.5Hz, 5-CH), 5.05 (1H, singlet, 3-CH), 4.97 (1H, broad triplet, J = 8Hz, 8-CH), 4.73 "s (2H, singlet, -OCmSMe), 4.27 (2H, doublet, J = 8Hz, 9-CH2), 3.63 (1H, double doublet, J = 18Hz, J '= 2.5Hz, 6a-CH), 3.14 (1H, doublet, J = 18Hz, 6ß-CH) and 2.19 (3H, singlet, -SCH3).

7

637 395

Example 7

9-0- (1-Butoxy) ethyl 4-methoxybenzyl ester ery ~

c02

(elO)

A solution of 1 g of clavulanic acid p-methoxybenzyl ester (e 10) and 1 ml of vinyl n-butyl ether in 10 ml of ethyl acetate is mixed with 50 mg of p-toluenesulfonic acid and stirred for 30 minutes at room temperature. The mixture is then chromatographed through a short silica gel column using ethyl acetate as the eluent. The solvent is evaporated off and the product is isolated by column chromatography on silica gel with ethyl acetate / cyclohexane in a ratio of 1: 1. 0.848 g of the desired compound e 11 are obtained.

Cf02-CH2

(hurry)

° -C4H9

O-CH-CH.

-O-

OMe

Vmax (film): 1805, 1750, 1700 cm-1.

ô (CDCb): 8.0 to 9.0 (3H, triplet, J = 7Hz), 1.26 (3H, doublet, J = 6Hz), 1.10 to 1.70 (4H, multiplet), 2, 97 (1H, doublet, J = 17Hz), 3.20 to 2.55 (3H, multiplet), 3.74 (3H, 20 singlet), 4.0 to 4.2 (2H, multiplet), 4.45 to4, 75 (1H, multiplet), 4.75 (1H, triplet), 4.99 (1H, singlet), 5.07 (2H, singlet), 5.59 (1H, doublet, J = 3Hz), 6.80 (2H, doublet, J = 8Hz), 7.20 (2H, doublet, J = 8Hz).

Example 8

9-0-Tetrahydropyran-2'-yl-clavulanic acid benzyl ester

(el)

- ° \ ch2o j-kr

-O

> C02CH2C6H5

(el2)

1.0 g of benzyl ester of clavulanate (e 1) in 5 ml of benzene and 4 ml of dihydropyran is mixed with 1 drop of boron trifluoride etherate complex and stirred overnight. The solvents are evaporated off under reduced pressure and the residue is chromatographed on a silica gel column using ethyl acetate and cyclohexane as the eluent. After evaporation of the solvents, 1.63 g of the desired compound el2 are obtained as an oil. This oil has a purity of around 80%, the impurities are presumably polymers that are derived from the pyran.

Vmax (liquid film): 1805.1755.1700 cm "1.

8 (CDCb): 1.0 to 2.1 (excess H, broad multiplet, 3 ', 4', 5'-CH2), 2.97 (1H, doublet, J = 17Hz, 6ß-CH), 3, 41 45 (1H, double doublet, J = 2.5 and 17Hz, 6a-CH), 3.6 to 3.95 (excess H, multiplet, 6'-CH2), 3.95 to 4.4 (2H, Multiplet, 9-CH2), 4.52 (1H, broad singlet, 2'-CH), 4.79 (1H, broad triplet, J = 7.5Hz, 8-CH), 5.03 (1H, singlet, 3-CH), 5.12 (2H, singlet, PhCH2), 5.60 (1H, doublet, so J = 2.5Hz, 5-CH) and 7.27 (5H, singlet, CeHs).

Example 9

9-0-tetrahydropyran-2'-yl-clavulanic acid lithium salt

(el2) -)

(el3)

co2H

(el'4)

637 395

8th

1.0 g of benzyl 9-0-tetrahydropyran-2-yl-clavulanate (e 12) is dissolved in 1 ml of tetrahydrofuran and 0.05 ml of water and hydrogenated over 0.3 g of 1% palladium on carbon for 45 minutes. A solution of the corresponding acid el3 is obtained, from which the catalyst is removed. The filtrate is diluted with an appropriate volume of water and titrated to pH 7.0 with lithium hydroxide solution. The solution is evaporated to a syrup, mixed with 50 ml of acetone, evaporated again, treated with 30 ml of acetone, filtered off, washed with acetone and ether and air-dried. Yield: 0.46 g of the desired compound el4.

H

(elO)

rf

Vmax (Nujol muli): 1783, 1790, 1700, 1620, 1625 cm- '. 8 (D20): 1.16 to 1.6 (6H, broad multiplet, 3 ', 4', 5'-CH2), 2.89 (1H, doublet, J = 17Hz, 6ß-CH), 3.39 (1H, double doublet, J = 17 and 3Hz, 6a-CH), 3.55 to 3.91 (2H, multiplet, 6'-CH2,4,6 (2H, doublet, J = 8Hz, 9-CH2) , 4.5 to 4.9 (3H, multiplet, 2'-CH, 8-CH, 3-CH), 5.55 (1H, doublet, J = 3Hz, 5-CH).

i Example 10

4-methoxybenzyl 9-0-tetrahydrofuran-2'-yl-clavulanate

CH.

% C02CH2C6H40CH3

(el5)

A solution of 3.19 g (0.1 mol) of clavulanic acid 4-methoxy-8 (CDCb): 7.20 (2H, doublet, J = 9Hz, ArH), 6.80 (2H, benzyl ester (elO) and 4.32 g (0.3 mol) 2-tert-butoxytetrahy- 25 J = 9Hz, ArH), 5.59 (1H, doublet, J = 2.5Hz, 5-CH), 5.08 (2H, drofuran in 30 ml dry dichloromethane is mixed with 1 kri singlet, CH2Ar), 5.00 (1H, singlet, 3-CH), 5.10 to 5.00 p-toluenesulfonic acid and 15 minutes at room (1H, m, 2-CH), 4.65 (1H, triplet, J = 7Hz, 8-CH), 3.75 (3H, temperature stirred. The mixture is stirred with 50 ml aqueous singlet, OCH3), 3.40 (2H , double doublet, J = 17Hz, sodium bicarbonate solution, washed and dried After J '= 2.5Hz, 6a-CH), 2.99 (1H, doublet, J = 17Hz, 6ß-CH) and evaporation, 3.8 is obtained g of the desired compound 30 l, 6 to 2.0 (4H, multiplet, 3 'and 4'-CH2).

fertilize 15.

Vmax (liquid film): 1805, 1750, 1700, 1250, 1180 and Example 11

1025 cm-1. 9-0-tetrahydrofuran-2-yl clavulanic acid sodium salt

1.46 g of 9-0-tetrahydrofuran-2-yl-clavulanic acid p-methoxy-benzyl ester (el 5) and 0.315 g of sodium bicarbonate in 30 ml of tetrahydrofuran / water in a ratio of 5: 1 at room temperature and atmospheric pressure are equivalent to 0. 5 g of 1% palladium on carbon hydrogenated for 30 minutes. The mixture is filtered, the solid is washed with a little water. The combined solutions are evaporated to remove the tetrahydrofuran. The aqueous solution is extracted with 20 ml of ethyl acetate and freeze-dried. 0.9 g of the desired compound el 6 are obtained.

Vmax (Nujol muli): 1785, 1695, 1615 (broad) cm-1.

Vmax (KBr): 1785.1693.1615 (very wide) cm "1.

8 (D2O): 1.86 (4H, multiplet, 3 'and 4'-CH2), 3.02 (1H, doublet, J = 17Hz, 6ß-CH), 3.51 (1H, double doublet, so J = 17 and 2.5Hz, 6ct-CH), 3.83 (2H, multiplet, 5'-CH2), 4.11 (2H, doublet, J = 8Hz, 9-CHz), 4.82 (1H, triplet , J = 8Hz, 8-CH), 4.90 (1H, singlet, 3-CH), 5.20 (1H, multiplet, 2'-CH) and 5.66 (1H, doublet, J = 2.5Hz , 5-CH).

55

(e 1)

Example 12

9-0- (1-ethoxy) prop-1-yl-clavulanic acid benzyl ester

0-CH - CH,

1 2 3

0-CH-CH2-CH3

C00CHoCcHc (e 17) 2 2 6 5

637395

5 mg of p-toluenesulfonic acid are added to a stirred solution of 578 mg of benzyl clavulanate (el) and 0.3 ml of ethyl propenyl ether in 10 ml of ethyl acetate, the mixture is stirred at room temperature for 75 minutes and then chromatographed on a short silica gel column using ethyl acetate as the eluent. After evaporation of the solvent, the product is eluted by column chromatography on silica gel with a gradient of cyclohexane / ethyl acetate in a ratio of 3: 1 to 1: 1. 601 mg of the desired compound e 17 are obtained.

Vmax (film): 1805, 1750 and 1700 cm-1.

8 (CDCb): 0.88 (3H, triplet, J = 7Hz), 1.17 (3H, triplet, J = 7Hz), 1.60 (2H, broad quintet, J = 7Hz), 2.99 (1H , Doublet, J = 17Hz), 3.44 (1H, double doublet, J = 3 and s 17Hz), 3.54 (2H, q, J = 7Hz), 4.0 to 4.2 (2H, multiplet) , 4.36 (1H, triplet, J = 6Hz), 4.79 (1H, broad triplet, J = 7Hz), 5.05 (1H, singlet), 5.15 (2H, singlet), 5.63 ( 1H, doublet, J = 3Hz), 7.29 (5H, singlet).

Example 13

10 9-0- (1-ethoxy) prop-1-yl-clavulanic acid sodium salt

(e 17)

o — ch ~ -ch,

I 2 3

-0 ~ CH-CH2-CH3

A solution of 572 mg of 9-0- (1-ethoxy) prop-1-yl-clavulanic acid benzyl ester (e 17) and 128 mg of sodium bicarbonate in 22.5 ml of tetrahydrofuran and 7.5 ml of water is stirred for 1 hour 250 mg of 1% palladium hydrogenated on carbon. The solution is filtered through diatomaceous earth and diluted with water. The tetrahydrofuran is removed in a rotary evaporator. The aqueous solution is extracted with ethyl acetate and freeze-dried. 370 mg of the desired compound el8 are obtained.

(e 1)

(• 18) C02Na

Vmax (KBr): 1785 and 1615 cm-1.

25 8 (D2O): 0.85 (3H, triplet, J = 7Hz), 1.16 (3H, triplet, J = 7Hz), 1.59 (2H, broad quintet, J = 7Hz), 3.05 ( 1H, doublet, J = 17Hz), 3.4 to 3.85 (4H, multiplet), 4.19 (2H, doublet, J = 7Hz), 4.90 (1H, broad triplet, J = 7Hz), 4, 93 (1H, singlet), 5.71 (1H, doublet, J = 3Hz).

30th

Example 14

9-0- (2-ethoxy) prop-2-yl clavulanic acid benzyl ester

OC2H5

(e 19)

C02CH2C6H5

5 mg of p-toluenesulfonic acid are added to a stirred solution of 1 g of benzyl clavulanate (el) and 0.5 ml of ethyl isopropenyl ether in 10 ml of ethyl acetate, and the mixture is stirred at room temperature for 20 minutes. The mixture is chromatographed through a short silica gel column using ethyl acetate as the eluent. The solvent is evaporated off and the product is chromatographed on a silica gel column using cyclohexane / ethyl acetate in a ratio of 3: 1. 743 mg of the desired compound e 19 are obtained.

Vmax (film): 1805, 1750 and 1700 cm "1.

8 (CDCb): 1.12 (3H, triplet, J = 7Hz), 1.31 (6H, singlet), 2.96 (1H, doublet, J = 17Hz), 3.37 (2H, q, J = 7Hz), 3.39 (1H, double doublet J = 3 and 17Hz), 3.9 to 4.1 (2H, multi-so plett), 4.73 (1H, broad triplet, J = 7Hz), 5, 01 (1H, broad singlet), 5.13 (2H, singlet), 5.60 (1H, doublet, J = 3Hz), 7.26 (5H, singlet).

Example 15

9-0- (l-ethoxy) cyclohexylclavulanic acid benzyl ester

(e 1)

oc2h5

(e20)

C02CH2C6H5

637 395

10th

A stirred mixture of 578 mg of benzyl ester of clavulanate (el) and 2 ml of ethylcyclohexenyl ether is mixed with 20 mg of mercury trifluoroacetate. The mixture is stirred for 90 minutes at room temperature. The majority of the solvent is removed in a rotary evaporator, the product is isolated by chromatography on silica gel with cyclohexane / ethyl acetate in a ratio of 4: 1. 767 mg of the desired compound e20 are obtained.

Vmax (film): 1805.1750.1700 cm- '.

8 (CDCb): 1.14 (3H, triplet, J = 7Hz), 1.2 to 1.8 (10H, multiplet), 2.96 (1H, doublet, J = 17Hz), 3.37 (2H, q, J = 7Hz), 3.43 (1H, double doublet, J = 3 and 17Hz), 3.9 to 4.15 (2H, multiplet), 4.76 (1H, broad triplet, J = 7Hz), 5.04 (1H, Sin-5 gulet), 5.14 (2H, singlet), 560 (1H, doublet, J = 3Hz), 7.27 (5H, singlet).

Example 16

9-O-methoxymethylclavulanic acid sodium salt

CH2OCH2OCH3

C02CH2C6H40CH3

(e7)

H2OCH2OCH3

C02Na

(e21)

6.0 g of 9-O-methoxymethylclavulanoic acid p-methoxybenzyl ester (e7) are dissolved in 60 ml of ethanol in a pressure bottle and 1.39 g of sodium bicarbonate in 8 ml of water are added. The bottle is purged with nitrogen, then 0.75 g of 10% palladium on carbon is added. The mixture is hydrogenated at a pressure of 1.75 kg / cm21 hours. Thin layer chromatography on silica gel with ethyl acetate / chloroform in a ratio of 50:50 shows that the hydrogenation is complete. The mixture is filtered through diatomaceous earth, the diatomaceous earth is washed with 10 ml of water. The filtrate is evaporated to a rubber-like product in a rotary evaporator. This product is dissolved in 10 ml of acetone and 25 900 ml of dry diethyl ether are added with vigorous shaking. A fine white precipitate is obtained. The suspension is cooled to 4 ° C. for 2 hours and then filtered. The solid is washed twice with 100 ml of ether and immediately dried in a desiccator at low pressure. 2.1 g 30 of the desired compound e21 are obtained as a hydroscopic pale yellow powder.

Example 17

9-0- (2,3,4,6-Tetra-0-acetyI-a-D-glucopyranosyl) -clavu-35 p-methoxybenzyl lanoate

(elO)

*

CH2OCOCH3

(e22)

A solution of 6.38 g of clavulanic acid p-methoxybenzyl ester (elO) in 10 ml of dry dimethylformamide is added dropwise over the course of a few minutes to a stirred solution of 16.78 g of a-acetobromoglucose and 5.3 ml of collidine in 50 ml given dry dimethylformamide at 0 ° C under nitrogen protection. The mixture is stirred at room temperature overnight, then poured into 100 ml of ice water. The ice water is extracted three times with 100 ml of methyl acetate each. The organic extract is washed with 200 ml of 5m hydrochloric acid, dried over anhydrous sodium carbonate / magnesium sulfate and evaporated. An oil is obtained which is chromatographed on a column with 100 g of silica gel using cyclohexane / ethyl acetate as the eluent. 5.7 g of the desired compound e22 are obtained as an oil,

55

60

65

then 7.8 g of a mixture of the desired compound e22 and a small amount of starting material.

Properties of the oil:

[<x] d 45.8 ° (c 1.7, CHCb).

vmax (CHCb): 1805, 1745, 1700, 1230, 1175, 1040 and 980 cm-1.

8 (CDCb): 7.22 (2H, doublet, J = 9Hz, ArH), 6.83 (2H, doublet, J = 9Hz, ArH), 5.64 (1H, doublet, J = 4Hz, l'- CH), 5.61 (1H, doublet, J = 2.5Hz, 5-CH), 5.08 (2H, s, -CH2Ar), 3.76 (3H, singlet, -OCH3), 2.06 ( 9H, singlet, CH3CO2-) and 1.68 (3H, singlet, CH3CO2-).

m / e: 649 (M +), 621,607,594,549,403,331,289,288,271, 259,200 and 169.

11

637 395

C30H35NO15

Ber. %: C 55.45; Found%: C 55.1;

H 5.45; N 2.15 H 5.4; N 1.95

Example 18

9-0- (2,3,4,6-tetra-0-acetyl-cc-D-glucopyranosyl) -clavu-lanoic acid sodium salt ococh

H

(e22)

CH3C

ch2-o

3rd

ococh.

0- - ^ h2ococh3

C02Na

(e23)

A mixture of 1.3 g9-0- (2,3,4,6-tetra-0-acetyl-aD-glu-copyranosyl) -clavulanoic acid p-methoxybenzyl ester (e22) and 0.168 g of sodium bicarbonate in 24 ml of tetrahydrofuran / water in a 5: 1 ratio, the mixture is hydrogenated for 15 minutes at room temperature and atmospheric pressure in the presence of 0.4 g of 10% palladium on carbon. The mixture is filtered, the filtrate is evaporated. 0.96 g of the desired compound e23 is obtained.

[a] D + 27.7 ° (c, 2.3, H2O).

Vmax (KBR): 1785, 1740, 1690, 1615 cm "1.

ô (D2O): 5.83 (1H, doublet, J = 5Hz, l'-CH), 5.75 (1H, 30 doublet, J = 2.5Hz, 5-CH), 3.60 (1H, double Doublet, J = 18Hz, J '= 2.5Hz, 6ci-CH), 3.07 (1H, doublet, J = 18Hz, 6ß-CH), 2.15 (9H, singlet, CH3CO2-) and 1.79 (3H, singlet, CH3CO2-).

35 Example 19

9-0- (2,3,5-Tri-0-benzyl-D-arabinofuranosyl) clavulanic acid p-methoxybenzyl ester

(elO)

C6H5CH2 °

qch0cch ,, / 2 6 3

O ^ o ^ CH2óch2C6H3

c02ch2cgh40ch3

(e24)

A solution of 1.68 g of 2,3,5-tri-O-benzyl-β-D-arabinofura-nose, 1.06 ml of collidine and 1.29 g of tetrabutylammonium bromide in 5 ml of dry dichloromethane is mixed with 1.13 g of trifluoromethanesulfonic acid anhydride at -70 ° C. The mixture is stirred at room temperature for 1 hour, then a solution of 0.96 g of p-methoxy-benzyl clavulanate (elO) in 5 ml of dichloromethane is added. The mixture is stirred at room temperature overnight, then washed at 0 ° C. with 10 ml of 5M hydrochloric acid, dried over anhydrous sodium carbonate / magnesium sulfate and evaporated. An oil is obtained which is chromatographed on a column with 20 g of silica gel and cyclohexane-ethyl acetate as the eluent. 0.7 g of the desired compound e24 are obtained.

60 Vmax (CHCb): 1805, 1745 and 1700 cm- '.

5 (CDCb): 7.20 (17H, singlet, ArH), 6.80 (2H, doublet, J = 9Hz, ArH), 5.51 (1H, doublet, J = 2.5Hz, 5-CH), 5.30 (1H, multiplet, l'-CH), 5.05 (2H, singlet, CH2Ar), 4.98 (1H, multiplet, 3-CH), 4.48 (6H, singlet, CH2Ar), 3 , 70 (3H, 65 singlet, OCH3) and 2.90 (1H, doublet, J = 17Hz, 6ß-CH).

Example 20

9-0- (l-butoxy) ethyl clavulanic acid sodium salt

637395

12

(hurry)>

H

I.

/ CH3

^ 0

(e25)

CH - 0-CH

■ \

OCH2CH2CH2CH3

C02Na

A solution of 800 mg of 9-0- (l-butoxy) ethylclavulanic acid 15 vmax (KBr disc): 1780.1690.1610 cm- '.

4-methoxybenzyl ester (el 1) and 160 mg sodium bicarbonate 0 (020): 0.84 (3H, triplet, J = 8Hz), 1.20 (3H, doublet,

in a solution of 5 ml water and 25 ml tetrahydrofuran J = 5Hz), 1.15 to 1.65 (4H, multiplet), 3.01 (1H, doublet,

is 20 minutes over 400 mg 10% palladium on J = 18 Hz), 3.45 to 3.7 (3H, multiplet), 4.15 (2H, doublet,

Coal hydrogenated. The solution is filtered, the main amount J = 8Hz), 4.65 to 4.95 (3H, multiplet), 5.68 (1H, doublet,

of tetrahydrofuran is removed under reduced pressure (20 J = 3 Hz).

distant. The aqueous solution is extracted twice with ethyl acetate and freeze-dried. 447 mg of Example 21 are obtained

desired connection e25. 9-0- (1-ethoxy) ethylclavulanoic acid 4-methoxybenzyl ester

(elO)

*

H

CH.

3rd

A solution of 1.5 g clavulanic acid p-methoxybenzyl ester Vmax (film): 1805, 1750.1700 cm "'.

(elO) and 1 ml of vinyl ethyl ether in 15 ml of ethyl acetate is with '40 5 (CDCb): 1.16 (3H, triplet, J = 8Hz), 1.27 (3H, doublet,

25 mg of p-toluenesulfonic acid are added and the mixture is stirred for 15 minutes. J = 5Hz), 2.97 (1H, doublet, J = 17Hz), 3.25 to 3.7 (3H, multi-

The mixture is passed through a short column with silica gel plett), 3.75 (3H, singlet), 4.0 to 4.15 (2H, multiplet), 4.5

chromatographed with ethyl acetate as the eluent. That up to 4.85 (2H, multiplet), 5.0 (1H, singlet), 5.07 (2H, singlet)

Solvent is removed under reduced pressure, the lett), 5.60 (1H, doublet, J = 3Hz), 6.80 (2H, doublet, J = 9Hz),

Product is on a silica gel column with cyclohexane / ethyl 45 7.21 (2H, doublet, J = 9Hz).

Chromatograph 3: 1 acetate as eluent. Example 22

1.26 g of the desired compound e26 are obtained. 9-0- (1-ethoxy) ethyl clavulanic acid sodium salt

(e26)

R

I.

CH.

CH2-0-CH-0-CH2CH3

(e27)

C02Na

A solution of 1,185 g9-0- (l-ethoxy) ethyl clavulanic acid 4-methoxybenzyl ester (e26) and 254 mg sodium bicarbonate in a mixture of 5 ml water and 25 ml tetrahydrofuran is hydrogenated over 400 mg 10% palladium on carbon for 25 minutes. The solution is filtered through diatomaceous earth and then evaporated under reduced pressure,

until most of the tetrahydrofuran is removed. The aqueous solution is extracted three times with ethyl acetate and freeze-dried. The product is purified by chromatography on a silica gel column with n-butanol / ethanol / water in a ratio of 4: 1: 1. After evaporation of the solvents, 5.89 mg of the desired compound e27 are obtained.

13

637395

Vmax (KBr): 1795.1695.1615 cm- '.

S (DzO): 1.23 (3H, triplet, J = 8Hz), 1.34 (3H, doublet, J = 6Hz), 3.11 (1H, doublet, J = 18Hz), 3.45 to 4 , 0 (3H, multiplet), 4.25 (2H, doublet, J = 8Hz), 4.75 to 5.1 (3H, multili,

(e4)

plett), 5.77 (1H, doublet, J = 3Hz).

Example 23

9-O-methoxymethylclavulanic acid h20ch20ch3

iy

ß— N-—

c02h

A solution of 0.43 g of 9-O-methoxymethylclavulanic acid a) tablets mg of lithium salt in 25 ml of water is mixed with 50 ml of ethyl acetate over sodium methoxymethylclavulanic acid 150

layered, stirred and with a strongly acidic ion exchange 20 water-free Ampicillin 300

H-form shear resin added until the pH of the water-microcrystalline cellulose 600

phase below 2.0 (about 20 ml of wet resin). The magnesium stearate 15 mixture is filtered, the filtrate is separated off. The aqueous phase is extracted three times with 30 ml of ethyl acetate.

The ethyl acetate extracts are combined, quickly dried over 30 g of 25 b) capsules mg of a molecular sieve (type 3A), filtered and in methoxymethylclavulanic acid sodium salt 250

a rotary evaporator under reduced pressure to a magnesium stearate 2.5

Evaporated oil. 0.3 g of the desired compound starch glycollate sodium salt 5.0 dung are obtained.

30th

Vmax (film): 2500 to 3600 (very wide), 1805.1750, c) ampoules for resumption in sterile water

1695 cm-1. for immediate mg injection

8 (CDCb): 3.00 (1H, doublet, J = 17Hz, 6ß-CH), 3.33 (3H, methoxymethylclavulanic acid sodium salt 50

Singlet, OCH3), 3.45 (1H, double doublet, J = 2.5 and sodium ampicillin 250

17Hz, 6a-CH), 4.13 (2H, doublet, J = 7Hz, 9-CH2), 4.58 (2H, 35 singlet, OCH2O), 4.88 (1H, triplet, J = 7Hz, 8- CH), 5.01

(1H, singlet, 3-CH), 5.63 (1H, doublet, J = 2.5Hz, 5-CH). pharmacology

Example 24 Using conventional methods

Using dry constituents, the minimum inhibitory concentration of ampicillin when added in a conventional manner in a dry atmosphere is produced by the compounds according to the invention as inhibitor preparations: determined.

a) Connection of example 16

Minimum inhibitory concentration of ampicillin (| xg / ml) Inhibitor concentration (| ig / ml) Staph. Proboscis prot. C 889 adhesive E 70 E. coli JT 39

20-1.0

5 - 2.0 1.6 4

1 0.3 - 1.6 125

0 125> 2000 1000> 2000

b) Connection of example 7

Minimum inhibitory concentration of ampicillin (jig / ml) Inhibitor concentration (jig / ml) Staph. Proboscis adhesive E 70 Proteus C 889 E. coli JT 39 E. coliJT410

20 - - 15.6> 500 62.5

5 0.15 12.5 125 500

1 1.25 25

0 500 1000> 2000 2000 62.5

637395

c) Connection of example 20

14

Minimum inhibitory concentration of ampicillin (ng / ml)

Inhibitor concentration (jig / ml)

Staph. Proboscis

Adhesive E 70

Proteus C 889 E. coli JT 410

20th

2000

5

(0.04)

1.6-3.1

15> 2000

1

0.08

6 -12

62.5.

0

> 500

2000

> 2000 62.5

d) Connection of example 4

Minimum inhibitory concentration of ampicillin (µg / ml)

Inhibitor concentration ((ig / ml)

Staph. Proboscis

Adhesive E 70

ProteusC889 E.coIiJT39 E.coliJT410

20th

_

5

0.04

3.12

1.0 2.0 125

I.

0.6

3.12

15.6 4.0

0

250

500

> 2000 1000 250

e) blood levels

After subcutaneous administration of sodium methoxymethyl-clavulanic acid in a dose of 10 mg / kg to mice, the following blood level values are obtained. The values for clavulanic acid sodium salt are given for comparison:

Time (minutes) 20 30 45 60 (ig / ml methoxymethyl

clavulanic acid sodium salt 3.1 3.4 1.3 0.8

[ig / ml clavulanic acid sodium salt 4.2 2.2 0.8 0.5

Following oral administration to sodium methoxy-methylclavulanic acid at a dose of 20 mg / kg, the following blood level values are obtained. The values for clavulanic acid sodium salt are given for comparison:

Time (minutes)

p.g / ml methoxymethyl-clavulanic acid sodium salt | Xg / ml clavulanic acid sodium salt

15 30 45 60

10.8 3.5

7.4 2.6

2.1 1.5

1.4 0.6

25 of the infection or administered orally 1, 3 and 5 hours after the infection:

Test compounds CDSo (mg / kg) amoxycillin

(subcutaneous)

so 2.5 mg / kg

Methoxymethylclavulanic acid sodium salt + amoxycillin 6.8 2.5 mg / kg

Clavulanic acid sodium salt +

35 amoxycillin 14

1 mg / kg

Methoxymethylclavulanic acid sodium salt + amoxycillin 23.4 1 mg / kg 4ft clavulanic acid sodium salt +

Amoxycillin 40

CD5o (3 x mg / kg) amoxycillin (oral)

45

0 Healing effects of sodium methoxymethylclavulanic acid and amoxycillin

The following CDSO values are obtained for intraperitoneal infections with Escherichia coli JT 39. The test compounds are either subcutaneously 1 and 5 hours after

20 mg / kg

Methoxymethylclavulanic acid sodium salt + amoxycillin 11 20 mg / kg s # clavulanic acid sodium salt + amoxycillin 9

B

Claims (13)

637395 2. The method according to claim 1, characterized in that one uses a compound of formula V, in which Y is the iodine, bromine or chlorine atom, the methanesulfonyloxy or toluenesulfonyloxy group. 2nd PATENT CLAIMS 1. Process for the preparation of esters of a compound of formula I. ch -o-cr r -xr \ \ co2h in which X represents an oxygen or sulfur atom, R1 and R2 are hydrogen atoms or lower alkyl radicals which are optionally linked to one another, R3 is an optionally inertly substituted lower alkyl radical or forms an optionally inertly substituted 5- or o-membered heterocyclic ring with the radical R2 , characterized in that an ester of a compound of formula X cooh with a compound of formula V reacts Y-CR'R2-X-R3 (V) in which Y is an easily displaceable residue. 3. The method according to claim 1 or 2, characterized in that one uses a compound of formula V, in which Y is the bromine or chlorine atom. 4. The method according to any one of claims 1 to 3, characterized in that one carries out the reaction in the presence of a base with low nucleophilicity. 5. The method according to any one of claims 1 to 4, characterized in that one carries out the reaction at a temperature of -20 to + 30 ° C. 6. The method according to claim 1, characterized in that one uses a compound of formula V, in which Y is a radical of formula -OR5, wherein R5 is a tertiary alkyl radical having 4 to 6 carbon atoms and X is oxygen. 7. The method according to claim 6, characterized in that R5 is a tertiary butyl radical. 8. A process for the preparation of a free carboxylic acid of the formula I, in which X and R1 to R3 have the meanings given in claim 1, or their salts, characterized in that an ester of a compound of the formula I is prepared according to claim 1, and by Hydrolysis or hydrogenolysis cleaves, and the free carboxylic acid obtained optionally converted into a salt thereof. 9. The method according to claim 8, characterized in that an ester of a compound of formula I is prepared according to claim 6, and this is converted into the free carboxylic acid or into a salt thereof. 10. A process for the preparation of an ester of a compound of the formula I in which X is an oxygen atom, R1 is a hydrogen atom and R2 is a lower alkyl radical of the formula -CHRhRi, in which Rh and R 'are hydrogen or an alkyl such that R2 does not have a total of 6 C atoms, R3 is an optionally inertly substituted lower alkyl radical or is linked to the radical R1 to form an optionally inertly substituted tetrahydrofuran or tetrahyropyran ring, characterized in that an ester of the compound of the formula X with a compound of Formula VI RhR'C = CH-O-R3 (VI) implemented in which Rh, R1 and R3 have the meanings given above. 11. The method according to claim 10, characterized in that one carries out the reaction in the presence of an acid as a catalyst. 12. The method according to claim 10 or 11, characterized in that acid hydrochloric acid, phosphorus oxychloride, p-toluenesulfonic acid or boron trifluoride is used. 13. A process for the preparation of a free carboxylic acid of formula I, wherein X and R1 to R3 have the meanings given in claim 10, and their carboxylic acid salts, characterized in that an ester of a compound of formula I is prepared according to claim 10 and this by hydrolysis or hydrogenolysis cleaves and the free carboxylic acid obtained is optionally converted into a salt thereof.