BG61948B1 - Diaminosalts of clavulanic acid - Google Patents

Abstract

The invention relates to the preparation of new diaminosaltsof the clavulanic acid and of pharmaceutical compositionscontaining them. The invention also relates to a method for theapplication of the diaminosalts for the production of clavulanicacid and its salts and esters.

Description

The invention relates to new diamino salts of clavulanic acid, to pharmaceutical compositions with them, and to the use of these salts for the preparation of clavulanic acid and its salts and esters.

BACKGROUND OF THE INVENTION

GB 1508977 describes clavulanic acid of formula

and its pharmaceutically acceptable salts and esters are antibacterial agents capable of enhancing the efficacy of penicillin and cephalosporins against many L-lactamase producing bacteria.

US 4 650 795 describes a group of primary aminosols of clavulanic acid that give stable pharmaceutical compositions.

EP 26044 describes the use of tert-butylaminosol, useful as an intermediate for the preparation of clavulanic acid.

EP 562583 describes the use of di N, N-diisopropylethylenediammonium salt of clavulanic acid and di N, N-diethylethylenediammonium salt of clavulanic acid, both secondary types, for the preparation of clavulanic acid.

SUMMARY OF THE INVENTION

Unexpectedly, it has now been found that tertiary, tertiary diamino salts of clavulanic acid have improved properties compared to the tert-butylamino salts of clavulanic acid mentioned above. For example, large crystals of mono, Ν, Ν, Ν ′, N′-tetramethyl 1,2,2-diaminoethane salt of clavulanic acid can be easily precipitated in pure form. Therefore, the salt is a very useful intermediate for the preparation of clavulanic acid.

Accordingly, the invention relates to tertiary, tertiary diaminosomals of formula

and tertiary tertiary diaminodisols of formula n

(IIb) wherein Rj and R ₂ each represent (1-8C) alkyl, (3-8C) cycloalkyl or (3-8C) cycloalkyl (1-8C) alkyl group, optionally with one or more inert substituents or are interconnected to form a ring of 4-7 ring atoms, R ₃ and R 1 each represent a (1-8) alkyl, (3-8C) cycloalkyl or (3-8C) cycloalkyl (1-8C) alkyl group, optionally with one or more inert substituents or interconnected to form a ring of 4-7 ring atoms, X means hydrogen or a group forming a hydrogen bridge and n and 1, independently of one another, are the numbers 0-5.

The alkyl group may be straight or branched.

The C 1 to C ₈ alkyl group is preferably a C to C ₄ alkyl group, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl, more particularly a methyl group C ₃ to C _g cycloalkyl group preferably is a C _s to C ₇ cycloalkyl group, for example a cyclopentyl, cyclohexyl or cycloheptyl group.

Preferably X is hydrogen, hydroxy or halogen, for example bromine or chlorine. Most preferred is X as hydrogen or hydroxy.

Preferably η stands for the numbers 0 to 3 and m - 0 to 3, especially when X represents hydrogen or a hydroxy group. It is particularly preferred that n = 1 or = 0 and 1X be hydrogen or ne 1, 1 and 1 is hydroxy.

Suitable inert substituents are halogen, hydroxy, C ₁ to C ₄ alkyl, C ₍ to C ₄ alkoxyl, C ₁ to C ₄ acyloxyl and C, to C ₄ esterified carboxyl.

The halogen atom is, for example, bromine, chlorine or fluorine, preferably bromine or chlorine.

C 1 to C ₄ alkyl is preferably methyl or ethyl. C 1 to C ₄ alkoxyl is preferably methoxy or ethoxyl. to C ₄ acyloxyl is preferably C to C ₂ acyloxyl. C 1 to C ₄ esterified carboxyl is preferably C 1 or C ₂ esterified carboxyl.

In total, R _p R ₂ R ₃ and R ₄ have three substituents or less, preferably two substituents or less. It is particularly preferred that R _p R ₂ , R ₃ and R ₄ fla have one substituent or are unsubstituted.

When R _p R ₂ or R ₃ and R ₄ are interconnected to form a ring of 4 to 7 atoms, the ring preferably consists of carbon atoms and is particularly preferably saturated. Methyl is especially preferred as R _p R ₂ , R ₃ and R ₄ .

Normally, the amine of formula ^R, \ 7 L '

Ν - (CH ₂₎ n -C - (CH ₂₎ ni-R ^ (ill) from which obtain the salts of formula IIa and IIb is a pharmaceutically acceptable amine.

Preferably the salts of the formula Pa and Pb are derived from Ν, Ν, Ν ', N'-tetramethyl-1,2-diaminoethane, 1, 3-bis (dimethylamino) 2-propanol, Ν, Ν, Ν', tetramethyl-1,4diaminobutane, Ν, Ν, Ν ', H'-tetramethyl-1,6diaminohexane, 1,2-dipiperidinoethane and dipiperidinomethane.

The invention also relates to a process for the preparation of a salt of formula 11a and IIb, which consists of reacting clavulanic acid with a diamine of formula

✓ * 2

N - (CH ₂ ) n -C - (CHpm-N 2)

X (111) in which Rp R ₂ , R ₃ , R ₄ , X, m and n are defined above. The clavulanic acid diaminosol is formed when the amount of diamine is relatively high compared to that of clavulanic acid, and the diaminosisol of clavulanic acid is formed when the amount of diamine is relatively low compared to clavulanic acid or a mixture of the same at intermediate concentration.

The conditions under which the clavulanic acid mono- or diamino salts will be formed or mixed will not be studied for each amine, but it will be understood by one skilled in the art that they will vary depending on the diamine used.

The concentration of diamine in the reaction mixture will vary, for example, depending on the change in pH. At a relatively high pH of 30 (depending on the amine and solvent used), more monoprotonated diamine of the formula ^R1 ₊ H1 will be obtained »

Η - N - (CH ₂ ) n -C - (CH ₂ ) pGF1, µ;

(ill.) and therefore more monosol will precipitate and more diprotonated diamine of formula ^R \ ₊ 7 ₊ will be obtained at relatively low pH.

HN- (CH ₂ ) n -C - (CH ₂ ) m-N -H

Rj ^Z * 4 (IIIb) and therefore more diesel will precipitate. The invention also relates to the use of clavulanic acid diamino salts 50 as defined above as intermediates for the preparation of clavulanic acid and its pharmaceutically acceptable salt or ester.

The invention further relates to a process for the preparation of clavulanic acid or a pharmaceutically acceptable salt or ester thereof, which consists in converting the diaminosol of clavulanic acid as defined above into clavulanic acid, mainly by acidification or its pharmaceutically acceptable salt or ester, mainly by the addition of a source forming the corresponding salt or ester.

The invention also relates to a method of purifying clavulanic acid or a pharmaceutically acceptable salt or ester thereof, which consists of the following:

1. Interaction of the impure clavulanic acid in a restricted solvent with diamine to form a salt.

2. Isolation of the salt obtained in step 1.

3. Conversion of the isolated salt to clavulanic acid mainly by acidification or its pharmaceutically acceptable salt or ester, mainly by the addition of a source forming the corresponding salt or ester. For example, the potassium salt of clavulanic acid is formed by the addition of potassium acetate or potassium ethyl hexanoate.

It is particularly appropriate to prepare the diaminosols of clavulanic acid in an organic solvent. Suitable solvents are non-hydroxyl solvents such as tetrahydrofuran, dioxane, ethyl acetate, methyl acetate, acetone, methyl ethyl ketone and the like or mixtures thereof.

The reaction may be carried out at from about - 50 to 40 ° C and preferably from about 0 to 15 ° C.

The invention also relates to pharmaceutical compositions comprising a salt of formula IIa and / or IIb and a pharmaceutically acceptable carrier.

Suitable formulations of the compositions of the invention are tablets, capsules, complex powders and sterile forms suitable for injection or infusion. Such compositions may contain conventional pharmaceutically acceptable materials such as diluents, binders, colorants, flavors, preservatives and disintegrants.

The injection or infusion compositions of the salts of formulas Pa and IIb are particularly suitable for high levels of clavulanic acid in the tissues, which is detected after injection or infusion. Thus a preferred composition according to the invention contains salts of formulas Pa and IIb in sterile form.

Another preferred formulation according to the invention is a dosage unit containing a salt of formula II adapted for oral administration.

The following examples illustrate the invention. These pH values were measured with an Ingold electrode, type U402-S7 / 120, in the solvent used.

Examples of carrying out the invention

Example 1. Comparison of crystallization of different diamino salts.

A solution of the clavulanic acid potassium salt in ice-cooled water was stirred with ethyl acetate under ice-water cooling. With a solution of about 10% by weight. the sulfuric acid was adjusted to pH 2, the aqueous layer was separated and extracted twice with ethyl acetate. The combined extracts were dried with magnesium sulfate, filtered and washed with ethyl acetate to give a clavulanic acid solution of about 2% by weight. Clavulanic acid was diluted with an equal volume of acetone and diamine was added.

The results are summarized in Table 1.

The molar diamine / mol ratio of clavulanic acid is indicated in the last column. The tertiary, tertiary type diamino salts of clavulanic acid are obtained only in crystalline form and not in the form of oil.

Table 1

Diamine Type ¹ Crystals Laelo Diamine Ν, Ν, Ν ', Ν'-tetramethyl- !, 2-aminoamino n t, t + 1.90 Ν, Ν, N ', N' -tetramethyl-1,2-diaminoethane t, t + 0.68 Ν, Ν, Ν ', Ν'-tetramethyl-1,3-diaminopropane t, t + 1.89 1, 3-bis (dimethyl-amino) - 2-propanol t, t + 1.74 Ν, Ν, N ', N' -tetramethyl-1,4-diaminobutane t, t + 1.34 Ν, Ν, N ′, N ′ -tetramethyl-1,6-diaminohexane t, t + 1.84 1,2-dipiperidinoethane t, t + 2.70 1,2-diaminoethane n, n + + 3.98 1,3-diaminopropane n, n + + 1.69 1,6-diaminohexane n, n + 1.69 1,10-diaminodecane n, n + 1.46 N-methyl-! , 3-diaminopropane n, d + 1.69 N, N-dimethyl-1,3-diaminopropane n, t + 1.86 Ν, N-dimethyl-1,2-diaminoethane n, t + 1.69 piperazine in, in + 1,20 N-methylpiperazine in, t + 1,20 Ν, N-diethyl-1,2-diaminoethane n, t - - 0.81 N-2-aminoethyl-morpholine n, t - - 1,20 dipiperidinomethane t, t + - 14.92

¹ n: primary, in: secondary, t: tertiary

Example 2. Preparation of the mono-Ν, Ν, Ν ′, M′-tetramethyl-1,2-diaminoethane salt of clavulanic acid from ethyl acetate / acetone solution.

Clavulanic acid extract in dry ethyl acetate (828 g containing 18 g of clavulanic acid / kg obtained according to Example 1) was added over 1 min to 1 L of acetone under cooling (8 ° C) and maintaining the pH at 9 s Ν. N, N ', N'-tetramethyl-1,2diaminoethane (19.18 g, molar ratio 2.2 to clavulanic acid). Stirring was continued at 100C for 1 hour. The precipitate was filtered off, washed with 100 ml of acetone and dried in vacuo at 35 ° C to give 20.09 g of the clavano-45 acid acid mono-Ν, Ν, Ν ', ('-tetramethyl-1,2-diaminoethane salt ( large crystals). The stock solution (1642 g) contains about 1.12 g of clavulanic acid.

NMR spectrum (DMSO-d ₆₎ 2,37 ppm, NSN ₃ (s, 12H), 2,70 ppm, N-CH ₂ (s, 4H), 2,95 ppm , Ce-βΗ (d, 1H), 3.49 ppm, Cb-αΗ (dd, 1H), 3.99 ppm, CH2OH (m, 2H), 4.60 ppm,

C3-H (s, 1H), 4.66 ppm, = C-H (tr, 1H), 5.58 ppm, C5-H (d, 1H).

To 1 g of mono-Ν, Ν, Ν ′, N'-tetramethyl-1,2-diaminoethane salt of clavulanic acid was added 200 ml of ethyl acetate / acetone (1/1 v / v) mixture containing 1ml Ν, N, Ν ', Ν'-tetramethyl - !, 2-diaminoethane After stirring for 1 h at room temperature and filtering the solution, the filtrate was evaporated slowly to give large crystals.

All parameters were obtained from the least squares of 2 0 reflectance values measured on a diffractometer under the following test conditions:

- CAD 4Rf Nonius

- θ = 30ο

- Mo - Ka radiation

- λ = 0.70145 E

- The salt (C ^ H ^ NjOj, group 1 C _g H ₉ NO _S and group C ₆ H ₁₆ N ₂ , Mw = 315,37) crystallizes in the orthorhombic species group P2 _J 2 _I 2 ₎ with a = 8,268 ( 1), b = 9.929 (7) and c = 20.221 (2) A. α, β and γ = 90 °.

are 1.20 (1) and 1.275 (9) A, respectively, showing the nature of a non-perfect simple bond between C (6) - O (3).

The atomic coordinates are shown in Table 2.

- R = 0,206 reflections

- Z = 4

- The molecules are bonded through a strong hydrogen bond (2.65 (1) A) between N (2) and O (3). C (6) - O (2) and C (6) - O (3) distances $

Table 2

x / a y / b z / c sigx sigy sigz Cl 0,73451 0,61143 0,51083 0,00109 0,00094 0,00039 C2 0,72822 0,73554 0,46864 0,00099 0,00085 0,00037 C3 0,77712 0,80814 0,53160 0,00099 0,00091 0,00038 C4 0,62466 0,80092 0,62729 0,00091 0,00081 0,00035 C5 0,74057 0,68316 0,63023 0,00092 0,00079 0,00033 C6 0,87476 0,71031 0,68279 0,00092 0,00083 0,00034 C7 0,51426 0,83929 0,67005 0,00099 0,00089 0,00039 C8 0,40390 0,95903 0,66482 0,00104 0,00092 0,00040 C9 0,94385 0,09742 0,62131 0,00161 0,00119 0,00049 C10 0,77651 209810 0,70628 0,00115 0,00169 0,00053 Cll 1,36988 0,31842 0,57368 0,00165 0,00182 0,00077 C12 1,28231 0,42860 0,66215 0,00211 0,00137 0,00068 C13 1,07802 0,36142 0,57942 0,00185 0,00171 0,00077 C14 0,92742 0,34721 0,63555 0,00146 0,00127 0,00064 N2 0,92914 0,21251 0,66938 0,00078 0,00080 0,00031 N3 1,22359 0,33641 0,61693 0,00091 0,00091 0,00037 OI 0,69320 0,49552 0,50870 0,00079 0,00072 0,00030 02 0,98843 0,77785 0,66617 0,00065 0,00064 0,00027 03 0,84583 0,65805 0,73917 0,00070 0,00070 0,00025 04 0,64046 0,86534 0,56720 0,00068 0,00060 0,00026 05 0,42783 1,04139 0,72369 0,00074 0,00075 0,00031 N1 0,80549 0,68028 0,56442 0,00069 0,00067 0,00028 H21 0,82775 0,76503 0,43642 0,00679 0,00618 0,00278 H22 0,60667 0,74308 0,44395 0,00696 0,00637 0,00278 H31 0,87967 0,86532 0,53289 0,00739 0,00655 0,00279 H51 0,69414 0,59219 0,64269 0,00759 0,00616 0,00283 H71 0,51235 0,78215 0,69945 0,00721 0,00654 0,00273

Example 3.

Preparation of the mono-Ν, Ν, Ν ′, N′-tetramethyl-1,2-diaminoethane salt of clavulanic acid from ethyl acetate solution.

A solution of clavulanic acid in ethyl acetate (75 g containing about 20 g of clavulanic acid / kg) was added over 10 minutes to 75 ml of ethyl acetate at 8 ° C while stirring and maintaining the pH between 8 and 9 with Ν, Ν, Ν ' , N-tetramethyl-1,2diaminoethane (5.11 g, molar ratio 8 to clavulanic acid). Stirring was continued for 0.5 h and the precipitate was filtered off, washed with ethyl acetate and dried in vacuo at 35 ° C to give 2.62 g of mono N. Ν, Ν ', N'-tetramethyl-1,2-diaminoethane salt. clavulanic acid (large crystals'. The mother liquor (155 g) contains 0.03 g of clavulanic acid.

NMR spectrum (DMSO-d ₄ ): 2.38 ppm, Ν -CH ₃ (s, 12H), 2.70 ppm, Ν -CH ₂ (s, 4H). 2.93 ppm, Cb-βΗ (d, 1H), 3.48 ppm, C6-aH (dd, 1H), 3.98 ppm, HF (m, 2H), 4.58, C3

- H (s, 1H), 4.65 ppm, = C-H (tr, 1H), 5.58 ppm, C5 - H (d, 1H).

Example 4. Getting di Ν, Ν, Ν ', N'-tetramethyl-! , 2-diaminoethane salt of clavulanic acid from ethyl acetate / acetone solution.

A solution of clavulanic acid in ethyl acetate (200 ml containing 1.1 g of clavulanic acid) was added over 10 minutes to 200 ml of cold acetone (100 C) while stirring and maintaining the pH between

7.5 and 8 with Ν, Ν, Ν ', N'-tetramethyl-1,2-diaminoethane (0.64 g, molar ratio of 1.45 to clavulanic acid). Stirring was continued for 0.5 h and the precipitate was filtered off, washed with acetone and dried in vacuo at 35 ° C to give 1.24 g of the di-Ν, Ν, Ν ′, те ′ tetramethyl-1,2-diaminoethane salt of clavulan acid (needle shaped crystals). The stock solution (337 g) contained 0.11 g of clavulanic acid.

NMR spectrum (DMSO-d ₆ ): 2.45 ppm, Н CH ₃ (s, 12H), 2.80 ppm, Ν - CH ₂ (s, 4H), 2.99 ppm, C 6 -βΗ (d, 2H) ), 3.53 ppm, C6-aH (dd, 2H), 3.99 ppm, CH ₂ OH (m, 4H), 4.69 ppm, = CH (tr, 2H), 4.76 NW - H ( s, 2H), 5.61 ppm, ppm, C5 H (d, 2H).

Example 5. Preparation of Clavulanic Acid Mono 1,3bis (dimethylamino) -2-propanol salt.

A solution of clavulanic acid in ethyl acetate (100 g) containing 20 g of clavulanic acid / kg) was added over a period of 10 min to 100 ml of acetone with stirring at 8 ° C and maintaining the pH between 8.5 and 8.7 with 1, 3-bis (dimethylamino) -2-propanol (2.54 g, molar ratio 1.74 to clavulanic acid). Stirring was continued for 0.25 h and the precipitate was filtered off and washed with 50 ml of a 1/1 mixture of acetone and ethyl acetate and acetone. Vacuum drying at room temperature afforded 1.82 g of mono 1, 3-bis (dimethylamino) 2-propanol salt of clavulanic acid with a purity of 25.6% as free acid.

NMR (DMSO-d ₆ ) M 2.41 ppm, N

- CH ₃ (s, 12H), 2.50 ppm, N - CH ₂ (dABq, 4H, J 12.6 Hz, J 4.8 Hz), 2.61 ppm, Ν - CH ₂ (dABq, 4H, J 12.6 Hz, J 4.8 Hz), 2.94 ppm, Cb-βΗ (d, 1H, J 16.5 Hz), 3.49 ppm, Cb-αΗ (dd, 1H, J

16.5 Hz. J 2.7 Hz), 3.96 ppm, CH ₂ OH, CHOH (m, 3Hi, 4.58 ppm, C 3 - H (s, 1H), 4.64 ppm, = CH (tr, 1H, J 6 , 8 Hz), 5.57 ppm, C5 - H (dd, 1H, J 2.6 Hz).

Example 6. Conversion of the mono-Ν, Ν, Ν ', \' - tetramethyl-1,2-diaminoethane salt of clavulanic acid into the potassium salt of clavulanic acid.

ml of 0.35 M solution of potassium acetate (solvent isopropyl alcohol and 1% (w / v) water) is added dropwise to a suspension of 2 g mono Ν. Ву, Ν ', #-tetramethyl-1,2-diaminoethane fat of clavulanic acid (content

68.6 ° ₀ ) in 50 ml of isopropanol. After 0.75 hours of stirring at room temperature, the precipitate was filtered off, washed with 10 ml of isopropanol and dried in vacuo at 35 ° C to give 1.44 g of clavulanic acid crystalline potassium content of 87% (clavulanic acid) and ca. 1.5% potassium acetate (HPLC analysis). The mother liquor contains about 0.06 g of clavulanic acid.

Example 7. Conversion of the di Ν, Ν, Ν ′, #-tetramethyl-1,2-diaminoethane salt of clavulanic acid into the potassium salt of clavulanic acid.

4.5 ml of a 2 M solution of potassium salt of 2-ethyl-hexanoic acid in isopropanol was added to a stirred solution of 2 g of di Ν, Ν. N ”, N′-tetramethyl-1,2-diaminoethane salt of clavulanic acid (75.8% purity calculated as free acid) in 20 ml of isopropanol and 2 ml of water at room temperature. After stirring for 0.25 h, the precipitate was filtered off and washed with 5 ml of isopropanol. Vacuum drying at room temperature yields 0.30 g of clavulanic acid potassium salt in purity

83.6 ° ₀ . calculated as free acid.

Another 2.5 mJ 2 M solution of 2-ethylhexanoic acid potassium salt in isopropanol was added to the mother liquor and stirring continued. The precipitate was filtered off, washed with 5 ml of isopropanol and dried to give 0.68 g of the clavulanic acid potassium salt, 82.3% pure, calculated as the free acid.

Example 8. Conversion of clavulanic acid mono 1,3bis (dimethylamino) -2-propanol salt to clavulanic acid potassium salt.

1.6 ml of a 2 M solution of potassium salt of 2-ethyl-hexanoic acid in isopropanol is added to a stirred solution of 1 g of mono 1, 3-bis (dimethylamino) -2-propanol salt of $ clavulanic acid in 19 ml of isopropanol and 1 ml water at room temperature. After stirring for 0.25 h, the precipitate was filtered off and washed with 15 ml of isopropanol. Drying in vacuo at room temperature gave 0.38 g of the clavulanic acid potassium salt with a purity of 80% as free acid.

Claims (13)

15 Claims A salt of clavulanic acid of formula Ia or IIb H I-C - (CHJar-N I H X ^{(1, b)} 35 in which Rj and R ₂ each represent a (18C) alkyl, (3-8C) cycloalkyl or (38C) cycloalkyl (1-8C) alkyl group, optionally with one or more inert substituents or are interconnected to form a 40 ring having 4-7 ring atoms, R ₃ and R ₄ each represent a (1-8) alkyl, (3-8C) cycloalkyl or (3-8C) cycloalkyl (1-8C) alkyl group in a given in the case of one or more inert substituents or interconnected to form a ring of 4-7 ring atoms, X means hydrogen or a group forming a hydrogen bridge and η and m, independently of one another, are the numbers 0-5. The clavulanic acid salt of claim 1, wherein R _p R _r R ₃ and R ₄ represent a methyl group. A clavulanic acid salt according to claim 1 or 2, characterized in that X is hydrogen, n is 1 and m is 0. 4. The clavulanic acid salt according to claim 1 or 2, characterized in that X is hydrogen, η is 1 and m is 1. 5. The clavulanic acid monosol of formula Pa according to claim 1, characterized in that R _p R ₂ , R ₃ and R ₄ denote a methyl group, X represents hydrogen, η is 1 and m is 0. 6. A process for the preparation of a salt according to claim 1, 2, 3 or 4, characterized in that clavulanic acid is reacted with a diamine of the formula Ν - (CHjJn -C - (CH ^ nr-N ^ R ₂ χ in which R _p Rj, R ₃ and R ₄ , X, m and n have the meanings defined in claim 1, 3 or 4, in a limited solvent. 7. The method of claim 6, wherein the molar amount of diamine is greater than that of clavulanic acid. A method according to claim 6, characterized in that the molar amount of diamine is less than that of clavulanic acid. 9. A process for the preparation of a salt according to claim 5, wherein clavulanic acid is reacted with N, N, Ν ', N-tetramethyl-1,2-diaminoethane, such as the molar amount of Ν, Ν, Ν', N '-tetramethyl-1,2-diaminoethane is greater than that of clavulanic acid. 10. A process for the preparation of clavulanic acid or a pharmaceutically acceptable salt or ester thereof, wherein the mono- or diaminosol according to claims 1, 2, 3, 4 and 5 is converted to clavulanic acid or a pharmaceutically acceptable salt or ester thereof. A method of purifying clavulanic acid or a pharmaceutically acceptable salt or ester thereof, characterized in that 1. impure clavulanic acid is reacted in an organic solvent with diamine to form a salt; 2. the salt obtained in step 1 is isolated; and 3. the isolated salt in clavulanic acid is converted into a pharmaceutically acceptable salt or ester thereof. A pharmaceutical composition comprising a clavulanic acid salt according to claim 1, 2, 3, 4 and 5 and a pharmaceutically acceptable carrier or diluent. Use of a salt according to claim 1, 2, 3, 4 or 5 as an intermediate for the preparation of clavulanic acid or a pharmaceutically acceptable salt or ester thereof.