DE2808116A1 - PROCESS FOR THE MANUFACTURING OF ETHERS FROM CLAVULAN ACID ESTERS - Google Patents

Description

Brentford, Middlesex, UK

Process for the production of ethers of clavulan acid esters

claimed March 10, 1977 - Great Britain - No. IOO82 / 77 Priorities: _{1Q March} ^ ₇₇ _ _Gr . _{ossbrifcannien} _ _No. loil6 / 77

The invention relates to a process for the production of sters from clavulanic acid esters.

In DE-OS 26 46 004, among other things, ethers of clavulanic acid esters are of the general formula I.

~ Χ ~ \ / ^CH 2- ° - ^R 2 (D

described, in which the group -CO ₂ R _{1 is} an esterified carboxylic acid group and R _{2 is} an inert organic radical with up to 18 carbon atoms.

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28Ό8116

The present invention now relates to a process for the preparation of ethers of clavulanic acid esters of the general types Formula II

CH ₂ -OC

(II)

in which the group -COoRi is an esterified carboxylic acid group, R ^ ₅ and R ^, are identical or different and denote hydrogen atoms or alkyl radicals having 1 to 4 carbon atoms and Rc- is such a radical that the group -CR ^ RhRj- is an inert one is an organic radical with up to 18 carbon atoms, which is characterized in that a clavulanic acid ester of the general formula (III)

N-

CH ₂ OH

(III)

in which R _{1 has} the above meaning with a halide of the general formula IV

^R 3

X-C

• R /

(IV)

in which X is an iodine, bromine or chlorine atom and R ^, R ₁ , and Rp- have the above meanings, is reacted in the presence of a compound which provides silver ions.

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~ ir -

Optionally, an alkaline earth metal oxide, preferably Calcium oxide, can also be used. The oxide is preferably in powder form.

Silver oxide is preferably used as the compound which provides silver ions. Generally about 1 to 2 equivalents used per equivalent of the clavulanic acid ester of the general formula III.

If calcium oxide is also used, it is generally present in a proportion of about 1 to 2 equivalents per equivalent of clavulanic acid ester of the general formula III.

Conveniently, the radicals R, and R ^ represent hydrogen atoms, Methyl, ethyl, n-propyl or n-butyl groups.

The radicals R ^ and R ₁ are preferably hydrogen atoms, so that it can be seen that certain preferred processes according to the invention are suitable for the preparation of ethers of clavulanic esters of the general formula II in which the group -CR ₅ R ^ Rj- is the group -CHg -R is, where the group -CHpR is an inert organic radical with up to 18 carbon atoms.

Suitable radicals for Rc- are the hydrogen atom, the methyl, Ethyl, n-propyl, η-butyl, n-pentyl, isopropyl, vinyl, benzyl, p-methoxy-benzyl or the phenyl group and the like.

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"" Jf "

Particularly suitable radicals for R ₁ - are the hydrogen atom and ■ the methyl, ethyl, benzyl, phenyl and vinyl groups.

The radical Rj- is preferably a hydrogen atom or the methyl or ethyl group. _{R 4} particularly preferably denotes a hydrogen atom or the methyl group.

The most preferred processes of the present invention are based on the preparation of ethers of clavulanic acid esters of the general formula II directed, in which the group -CR-zR ^ Rjdie Is methyl or the ethyl group.

.Suitable esters of the general formula II are those at

1 ? "= 5 1

where R _{1 is} the radical A or -CHA kr , where A is a. Is an alkyl radical with 1 to .8 carbon atoms, which is replaced by halogen atoms or radicals of the general formulas -OA, -OCOA, -SA or -SOpA

4th
may be substituted, where A is a hydrocarbon radical with

is up to 6 carbon atoms, A is a hydrogen atom, an alkyl radical with up to 4 carbon atoms or the phenyl group, which can be substituted by halogen atoms or radicals -k ^ or -OA- ^, the radical -k ^{J being} an alkyl radical with up to Is 6 carbon atoms, and Ar represents the phenyl group,

substituted by halogen atoms or the radicals -k ^J or -OA- ^
can be iert, where the radical -A ^ is an alkylres-t.

In the case of other suitable esters of the general formula II, the radical R ^ is an alkenyl radical having up to 8 carbon atoms. Examples of such esters are allyl esters.

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ΛΑ

The esters of the present invention are preferably hydrolyzable in vivo. Such ester groups are disclosed in BE-PS 827 described. Particularly suitable in vivo hydrolyzable esters are the Äcetoxymethyl-, C ^ -AeetQxyäthyl-, Trimethylaeetoxymethyl-j, Phthalidyl, ethoxycarbonyloxymethyl and ethoxycarbonyloxyethyl esters and the same.

Most expediently is an ester residue , which can be converted in a simple way by mild hydrolysis or hydrogenolysis into a salt corresponding to a compound of the general formula II, as disclosed in the patent mentioned.

Particularly suitable esters are benzyl, p-methoxy-benzyl, Methyl and methoxymethyl esters. Nitrobenzyl esters, for example p-nitrobenzyl esters are also useful.

The etherification is generally carried out in an inert medium carried out at not extreme temperatures.

Suitable solvents for the reaction are hydrocarbons, such as benzene, toluene and the like, and other common solvents such as ethyl acetate, tetrahydrofuran, acetone and like that.

The reaction is most conveniently at a temperature of about 10 to about 100 ⁰ C, for example at ^ O to 8o ° C.

It is desirable to keep the reaction mixture under exclusion

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to keep from water »

After completion of the reaction, what by thin layer chromatography can be determined, the reaction mixture is allowed to cool and filtered to remove suspended solids and steam it up. If appropriate, the substance obtained can be used by customary methods, such as by means of column chromatography, clean..

In those cases in which the reaction product is a compound of the general formula II in which R _{1 is} the group -CIUR ^ Rj-, the starting compound can be a salt of clavulanic acid. which leads to the formation of an ester of clavulanic acid with subsequent etherification. Such a reaction is usually carried out in the presence of a crown ether in order to solubilize the salt of clavulanic acid. However, this method is a less preferred embodiment.

The examples illustrate the invention.

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Example 1 ·

0-. ^y th7l ~ clavulanic acid p-methoxybenzyl ester

H.

rry

A mixture of 3.19 g of C-p-methoxybenzyl ctavulanate., 4.0 g powdered. Calcium oxide, 4.0 g of silver oxide and 6 ml of ethyl iodide in 50 ml of benzene is refluxed for 2 hours. After cooling, the reaction mixture is filtered and the filtrate is evaporated. An oil is obtained which on 30 g of silica gel is chromatographed. After eluting the column with a mixture of 1 part of ethyl acetate and 4 parts of cyclohexane gives 0.74 g of the compound named in the title in pure form, which is identical to an authentic sample, as a comparison of the IR and NMR spectra shows.

The same result can be obtained by using ethyl iodide replaced by ethyl bromide and the implementation for a longer period Time at 40 ° C. The corresponding methyl ether can be replaced by methyl iodide in an analogous way VJust be made.

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Example 2

0- ^c ? E ^v ?? 7A-cl3.vulanic acid p-methoxybenzyl ester

A mixture of 5 * 19 S clavulanic acid p-methoxybenzyl ester, 4.0 g powdered calcium oxide, 4.0 g silver oxide and 5 ml Benzyl bromide in 50 ml of benzene is refluxed for 2 hours heated. After cooling, the reaction mixture is filtered and evaporate the hasty council. An oil is obtained which is 30 g Silica gel is chromatographed. After eluting the column with a mixture of 1 part of ethyl acetate and 4 parts of cyclohexane 1.0 g of the compound named in the title is obtained.

IR spectrum (liquid film): Y * = 1810, 1750, IJ10, I250, II80 and 1040 cm "^.

Nuclear Magnetic Resonance Spectrum (CDCl3,): S = 7.22 (5H, s, ArH); 7.19 (2H, d, J = 9 Hz,

ArH); 6.76 (2H, d, J = 9 Hz, ArH); 5.58 (IH, d, J = 2.5 Hz, '5-CH); 5.08 (2H, s, -CH ₂ Ar); 5.00 (IH, broad singlet, 3-CH); 4.8θ (IH, broad triplet, J = 8 Hz, 8-CH); 4, ^ 8 (2H, s, -CH ₂ Ar); 4.05 (2H, broad doublet, J-8 Hz, 9-CH ₂ ); 3.70 (3H, s, OCH ₃ );

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3.4θ (IH, ddt, J = 17 Hz, J '= 2.5 Hz, βοί-CH), · and 2.96 (IH, cJ, J = 17 Hz, 6β-CH).

Example 3
O-allyl-clavulanic acid-p-methoxybenzyl ester

^m 2 ^m \ ^ 0. .CH ₀ OCH ₀ CHiI

A geroich of 3.19 S p-methoxybenzyl clavulanate, 4.0 g of powdered calcium oxide, 4.0 g of silver oxide and 4 ml of allyl bromide in 30 ml of benzene is stirred for 66 hours at room temperature. The mixture is then filtered and the piltrate is evaporated. An oil is obtained which is chromatographed on 20 g of silica gel. After eluting the column with a mixture of 1 part of ethyl acetate and 4 parts of cyclohexane, 0.65 g of the compound named in the title is obtained.

IR spectrum (liquid film): V ^ _x = 3020, 1810, 1750, 1700, 1310, 1255, 1080 and 1040 cm " ¹ .

Nuclear Magnetic Resonance Spectrum (CDCl ₅ ): S = 7.30 (2H, d, J = 9 Hz, ArH); 6.86 (2H, d,

J = 9 Hz, ArH); 5.95 (1H, m, C = CH); 5.67 (IH, d, J = 2.5 Hz, 5-CH); 5.32 (2H, m, C = CH); 5.13 (2H, s, -CHgAr 5.06 (IH, s, 3-CH); 4.83 (IH, broad Triplet, J = 8 Hz, 8-CH);

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Mon

4.06 (2PI, broad doublet, J = 8 Hz,
5.92 (2H, m, -GCH ₂ -CH = CK ₂ );
5.80 (3Η, s, OCH ₃ ) J 3.50 (IH, dd,
J = 17 Hz, J '= 2.5 Hz, 6oi-CH); and
3.00 (IH, d, J = 17 Hz, 6P-CH).

Example · ¹ +
Q-methyl clavulanic acid benzyl ester

CH OH

A mixture of 8.67 g of benzyl clavulanate, 12 g of calcium oxide, 12 g of silver oxide and 15 ml of methyl iodide in 50 ml of benzene
is refluxed for 2 hours. The mixture is allowed to cool, filtered and the filtrate is evaporated. The oil obtained is chroniatographed on 50 g of silica gel. After eluting with a mixture of 1 part of ethyl acetate and 4 parts of cyclohexane, 2.81 g of the compound mentioned in the title are obtained.

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-M example 5

O -! Rcnyl-clavulanic acid benzyl ester

CH OH

^CO 2 ^CH 2 ^C 6 ^H 5

280Ö116

2.89 g of benzyl clavulanate in 10 ml of ethyl acetate and 12.7% of iodononane are refluxed for 5 hours with stirring in the presence of 4 g of silver oxide and 4 g of calcium oxide. The thin-layer chromatogram shows a rapidly moving zone and a very weakened zone. the source compound relates. The mixture is filtered and insoluble matter is washed with 50 ml of ethyl acetate washed "the FiItrat is evaporated under reduced pressure to a dark colored oil, is the chrornatographiert on silica gel = To elute using mixtures of ethyl acetate and cyclohexane ι in proportions of 1 10 to 1% 2ο The fractions. Which are eluted after the nonyl iodide ^ contain the desired compound, which is isolated as a pale yellow oil in a yield of 0.64 g after evaporation of the solvent.

IR spectrum (liquid film); ν '= 1805, 1750, 1695 cm

NMR Spectrum (CDCl ^): & = 0 _s 86

t _? J = 7 Hz,

1.25

m, 0-ClI ₂ (CK ₂ ) "GIL •) ', 2.98" (IH, d, J = 17 Hz, 6-β-CH) j 3.51 (2H ₅ J = 7 Hz, 0CH ₂ (CK ₂ ) ₇ ) | 3A3 (IH, dd, J = 17 Hz

and 5 Hz, 6-oi-CH); 3.98 (2H, d, J = 7 Hz, CH ₂ CH =); 4.78 (IH, t, J = 7 Hz, CH =); 5.02 (IH, s, 3-CH); 5.12 (2H, s, PhCH ₂ ); 5.61 (IH, d, J = 3Hz, 5-CH); and 7.27 (5H, s, C ₆ H ₅ ).

Example6

(DL) -Q-2-butylclavulanic acid benzyl ester

CHJ) H

CH "

CH ₂ -O-CH-C ₃ H

CO ₂ CH ₂ C ₆ H ₅

2.89 g of benzyl clavulanate in 7 ml of ethyl acetate and 9 g of 2-joa-butane are heated under reflux for 150 minutes with stirring in the presence of 4 g of silver oxide and 4 g of calcium oxide. Insolubles are filtered off. The filtrate is evaporated under reduced pressure to give a yellow oil which is chromatographed on silica gel * For elution, mixtures of ethyl acetate and cyclohexane in ratios of 1:10 to 1: 2 are used. The desired ether is eluted after the 2-iodo-butane. Fractions with a content of the ether, which are determined by thin-layer chromatography, are evaporated under reduced pressure. O ₃ 57 g of the compound are obtained as a pale yellow oil.

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IR spectrum (liquid film): V * = I808, 1753, I698 cm " ¹ .

Nuclear Magnetic Resonance Spectrum (CDCl3,): S = 0.84 (3H, t, J = 7 Hz, CH

1.07 (3H, d, J = 7.Hz, CH ₃

1.26 to 1.6 ^ (2H, m, CH ₂ CH ₃₎ J

2.96 (IH, d, J = 17 Hz, 6-β-CH);

3 * 26 (IH, qt, J = 7 Hz, OCH) J.

3.41 (OH, dd, J = 17 Hz and 3 Hz, 6-cX-CH);

3.8 to 4.25 (IH, m, 9-CH ₂₎ J

4.77 (IH, t, J = 8 Hz, '8-CH) j

5.20 (IH, s, 3-CH) j 5.12 (2H, s,

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

7.28 (5H, s, C ₆ H _5).

ν B e i s pi e 1 7

0-tert-amylclavulanic acid benzyl esters

° \ ^CH 2 ^0H

-0. ' CH ₀ -OC-CH ₀ CH ₀

² I ²³

CO ₂ CH ₂ C ₆ H ₅

2.89 g of benzyl clavulanate in 20 ml of ethyl acetate and 6.5 ml (9.9 g) of 2-iodo-2-methyl-butane are at room temperature in the presence of 4 g of silver oxide and 4 g of calcium oxide for 35 hours touched. The insolubles are filtered off and washed with 50 ml of ethyl acetate washed. The filtrate becomes one under reduced pressure

80983.8 / 0613

evaporated dark colored oil, which is chromatographed on silica gel will. Obtained after eluting with mixtures of cyclohexane and styl acetate in ratios of 10: 1 to 3: 1 one 0.43 g of the compound named in the title as a pale yellow oil.

IR spectrum (liquid film): Y * _v = 18O5, 1755 * 1698 cm " ¹ .

NMR spectrum (CDCl,):

= 0.83 (3H, t, J = 7 Kz, CH ₂ CH ₃ );

1.11 (6h, s, (CH ^) ₂ ); 1.46 (2H, q, J = 7 Hz, CH ₂ CH ₃ ); 2.96 (IH, d, J = 17 Hz, 6-β-CH); 3.40 (IH, dd, J = 17 and 3 Hz, 6-c ^ CH); 3.6-4.3 (2H, m, = CHCH _2); 4.74 (IH, dt, J = 7 and ^ 2 Hz, CH =); 5.0 (IH, d, J ~ 2 Hz, 3-CH);

5.12 (2H, s, PhCH ₂ ); 5.59 (IH, d, J = 3Hz, 5-CH); 7.27 (5H, s,

Example 8 9-0- (2-Propyl) -clayulanic acid benzyl ester

r ^

CO ₂ CH ₂ C ₆ H ₅

CH ₂ - 0 - CH _(CH3 J ₂

CO ₂ CH ₂ C ₆ H ₅

According to the method described in Example 6, by replacing the iodobutane with 5 ml of 2-iodo-propane, 0.47 g of the in the

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Connection mentioned in the heading.

IR spectrum: v>"= I805, 1750, I698 cm" ¹ .

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): S = 1.10 (βΗ, d, J = 7 Hz); 2.96 (IH, d,

J = 17 Hz); 3.40 (IH, dd, J = 17 and 3 Hz);

5.51 (IH, dq, J = 7 Hz); 3.80-4.50 '. (2H, m);

4.77 (IH, t, J = 7 Hz); 5.02 (IH, s);

5.59 (IH, d, J = 3 Hz); 7.26 (5H, s).

Example 9

9-0-n-Butylclavulanic acid benzyl ester

-0. CH ₃ OH

H N

-N

CO CH C H 2 2 6 5

CH.-O-CH-CH.CH-CH,

^{0> bO} 2 ^CH 2 ^C 6 ^H 5

A mixture of 2.89 g of benzyl clavulanate, 4 g of silver oxide, 4 g calcium oxide and 5.7 ml 1-iodo-butane in 7 ml ethyl acetate is refluxed for 150 minutes with stirring. to this time shows the thin-layer chromatogram with a solvent mixture of cyclopentane and methyl acetate in the ratio 2: 1 a mixture of the starting compound and the desired one The ether ester insolubles are filtered off and washed with 10 ml of ethyl acetate. The filtrate is added under reduced pressure evaporated to an orange oil, which chromatographed on silica gel will. Mixtures of

- each & -

Cyelohexane and ethyl acetate in ratios of 10: 1 to 1: 1. The fractions containing the ether ester what determined by thin layer chromatography are collected, combined and evaporated under reduced pressure to a pale yellow oil. 0.34 S of the pure ether ester is obtained and 0.4 g of a somewhat less pure ether ester.

IR spectrum: v * _mev = 1805, 1750 ', 1695 cm " ¹

Nuclear Magnetic Resonance Spectrum (CDCl3,): S = 0.90 (3H, t, J = 6.5 Hz, CH ₂ CH ₅ );

1.12 to 1.70 (4H, m, (CHg) ₂ CH _5); 2.99 (IH, d, J = 17 Hz, 6-β-CH); 3.3: 3 (2H, t, J = 6.5 Hz, OCH ₂ CH ₂ ); 3.44 (IH, dd, J = 17 Hz and 3 Hz, 6-oi-CH); 3.83 to 4.19 (2H, m, 9-CH _2); 4.66-4.91 (IH, m, 8-CH); 5.05 (IH, s, 3-CH); 5.15 (2H, s, CH 1 Ph); 5.63 (IH, d, J = 3Hz, 5-CH); and 7.29 (5H, s, CH ₂ C ₆ H ₅ ).

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- Vf- example 10

^ n-Hexylclavulanic acid benzy! ester

^ XJ

CO ₂ CH ₂ C ₆ H ₅

Following the procedure described in Example 9, Ver use of 10.6 g of 1-iodo-hexane instead of 1-iodo-butane 0.4 g obtained the compound mentioned in the heading as an oil.

IR spectrum: γ> _ν 1805, 1757 * 1698 cm " ¹

ΙΠσ, Χ

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 5 = 0.88 (3H, t, J = 6 Hz); 1.12-1.50 (8H ₅

broad multiplet); 2.99 (IH, -d, . J = 17 Hz) j 3.32 (2H, t, J = 6 Hz)]

3 _S 43 (IH, dd, J = 17 and 3 Hz); 4.02 (2H, broad doublet, J = 7 Hz); 4.79 (IH, t, J = 7 Hz); 5.05 (IH, s); 5.15 (2H, s); 5.64 (IH, broad singlet); and 7.29 (5H, s).

Examples 11 through IJ

The reactions described in Examples 1 to 3 are repeated, but without using calcium oxide. In each case the desired compounds are obtained, but in a somewhat lower yield. · .

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Claims (30)

Claims '■ ■ 1 J A process for preparing Kthern Clavulansäureestern of the general formula II 0 ' in which the group -COpR _{1 is} an esterified carboxylic acid group, R ^ ₅ and R ₂ , are identical or different and denote hydrogen atoms or alkylr & ste with 1 to 4 carbon atoms and Rf- represents a radical such that -CR ^ RhRp- is an inert organic radical with up to 18 carbon atoms, characterized in that a clavulanic acid ester of the general formula III CH ₂ OH in which R _{1 has} the above meaning with a halide of the general formula IV X-C R, (IV) in which X is an iodine, bromine or chlorine atom and R ^, Rj, and Rpdie Have the above meanings, in the presence of a compound which yields silver ions. 809838/0613 ORIGINAL INSPECTED 2. The method according to claim 1, characterized in that an alkaline earth metal oxide is also used in the implementation . J5. Method according to claim 2, characterized in that calcium oxide is used as the alkaline earth metal oxide. 4. The method according to one of the claims 1 to J5, thereby characterized in that silver oxide is used as the compound which provides silver ions. 5- The method according to any one of claims 1 to 4, characterized characterized in that 1 to 2 equivalents of a silver ion-donating compound per equivalent of clavulanic acid ester of the general Formula III used. 6. The method according to any one of claims 3 to 5. » through this characterized in that 1 to 2 equivalents of calcium oxide j « Equivalent of a clavulanic acid ester of the general formula III used. 7. The method according to any one of claims 1 to 6, characterized in that a halide of the general formula IV used in the R, a hydrogen atom or the methyl, Is ethyl, n-propyl or the n-butyl group. 8. The method according to at least one of claims 1 to J, characterized in that a halide of the general formula IV is used in which R ^ is a hydrogen atom or the 609838/0613 Is methyl, ethyl, h-propyl or n-butyl group. 9. The method according to any one of claims 1 to 8, characterized characterized in that a halide of the general formula IV is used in which PU is a hydrogen atom. 10. The method according to any one of claims 1 to 9, characterized in that a halide of the general formula IV is used in which R _{2 is} a hydrogen atom. 11. The method according to any one of claims 1 to 6, characterized in that a halide of the general formula IV is used in which the group -CIUR ^ R, - is the group -CH ₂ R, which is an inert organic radical with up to Represents 18 carbon atoms. 12. The method according to any one of claims 1 to 11, characterized in that a halide of the general formula IV used, in which R, - a hydrogen atom or the methyl, Ethyl, n-propyl, η-butyl, n-pentyl, isopropyl, vinyl, Is benzyl or the p-methoxybenzyl group. 13. The method according to any one of claims 1 to 11, characterized in that a halide of the general formula IV is used in which R _{r is} a V / water atom or the methyl, ethyl, benzyl or vinyl group. 14> Process according to one of Claims 1 to 11, characterized in that a halide of the general formula IV , 8 0 9838/0613 used in the R ^. a hydrogen atom, or the methyl, or is the ethyl group. 15. The method according to any one of claims 1 to 11, characterized characterized in that a halide of the general formula IV is used in which Rj- is a hydrogen atom. 16. The method according to any one of "claims 1 to 11, characterized characterized in that a halide of the general formula IV is used in which R ^. is the methyl group. 17 · The method according to any one of claims 1 to 6, characterized characterized in that a methyl halide is used as the halide of the general formula IV. l8. Process according to one of Claims 1 to 6, characterized in that the halide of the general formula IV a ftthy! halide used. 19. The method according to one of claims 1 to l8, characterized in that a clavulanic acid ester of the general 1 2 ^ nen formula III used in which R-, the radical -A or -CHA A ^ is, where the radical-Α is an alkyl radical with 1 to 8 carbon atoms, which is replaced by halogen atoms or a radical of the general K h. H. H. my formulas -OA, -OCOA, -SA or -SOpA may be substituted Yy. can, where the radical -A is a hydrocarbon radical with up to 6 carbon atoms, A is a hydrogen atom, an alkyl radical with up to 4 carbon atoms or the phenyl group means C tet, which by halogen atoms or a radical -A ^ or -OA ^ sub- , 809838/0613 may be substituted, where the radical -k ^{J is} an alkyl radical with up to 6 carbon atoms, and hr represents the phenyl group, which can be substituted by halogen atoms or a radical -A ^ or -OA ^, the radical - ^? is an alkyl radical. 20.. Process according to one of Claims 1 to 18, characterized in that a clavulanic acid ester of the general Formula III used in which R ^ is an alkenyl radical with up to 8 Is carbon atoms. 21. The method according to claim 20, characterized in that a clavulanic acid ester of the general formula III is used, in which R ^ is the Ally! group. 22. The method according to any one of claims 1 to 19. » through this characterized in that such a clavulanic acid ester general formula III used, which provides a compound of the formula JI which is an in vivo hydrolyzable ester radical having, 23. The method according to claim 22, characterized in that a clavulanic acid ester of the general formula III is used the compound of formula II can be introduced, det, the as / in vivo hydrolyzable ester group the acetoxymethyl-jC ^ -Acetoxyäthyl-, Trimethylacetoxymethyl, phthalidyl, A'thoxycarbonyloxymethyl- or the A'thoxycarbonyloxyäthylgruppe contains. 24. The method according to any one of claims 1 to 19 * thereby characterized in that a clavulanic acid ester of the general formula III is used, the ester group of which is the benzyl, p-methoxy 809838/0613 - 23 - has benzyl, methyl or the methoxymethyl group. 25. The method according to any one of claims 1 to 18, characterized characterized in that the clavulanic acid p-nitrobenzyl ester used. 26. The method according to any one of claims 1 to 25, characterized in that the reaction is carried out in an inert medium Performs at temperatures that are not extreme. 27. The method according to claim 26, characterized in that the solvent used is benzene, toluene, stylacetate, tetrahydrofuran or acetone is used. 28. The method according to any one of claims 1 to 27 _, characterized in that one carries out the reaction at a temperature of 10 to 100 ⁰ C. 29. The method according to claim 28, characterized in that the reaction is carried out at temperatures of 30 to 80 ° C. 30. The method according to any one of claims 1 to 29, characterized in that the clavulanic acid ester of the general Formula III in situ by esterifying a salt that produces clavulanic acid. 809838/0613