BG99212A - Diaminosalts of clavulanic acid - Google Patents

Abstract

The invention relates to the preparation of novel diamino salts of clavulanic acid and to pharmaceutical compositions containing them. The invention also relates to a process for the use of diaminosols for the preparation of clavulanic acid and its salts and esters.

Description

Clavulanic acid diaminosols

The present invention relates to novel diamino salts of clavulanic acid, to pharmaceutical compositions thereof, and to the use of these salts for the preparation of clavulanic acid and its salts and esters.

GB patent No. 1508977 discloses that clavulanic acid is of formula (I)

and its pharmaceutically acceptable salts and esters are antibacterial agents capable of enhancing the effectiveness of penicillins and cephalosporins against many β-lactamase-producing bacteria.

U.S. Patent No. 4,657,795 describes a group of primary aminosols of clavulanic acid that give stable.

pharmaceutical compositions.

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

European Patent Application No. 562583 describes the use of di-Ν-diisopropylethylenediammonium salt of clavulanic clavulanic acid and di-, Ν-diethylethylenediammonium salt of both secondary types for the preparation of clavulanic acid.

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 the mono-Ν, Ν, Ν ′, Ν ′ -tetramethyl-1,2-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 present invention relates to tertiary, tertiary diaminosomals of formula (IIa)

-r ₄ (Na) and tertiary, tertiary diaminodisols of formula (IIb)

X

(IIb) wherein R1 and R2 each represent a (1-8C) alkyl, (3-8C) cycloalkyl or (3-8C) cycloalkyl (1-8C) alkyl group, optionally with one or more inert substituents or are internally linked forming a ring of 4-7 ring atoms, R3 and R4 each represent a (1-8C) alkyl, (3-8C) cycloalkyl or (38C) cycloalkyl (1-8C) alkyl group, optionally with one or more inert substituents or are interconnected to form a ring of 4-7 ring atoms, X is hydrogen or a group forming a hydrogen bridge and η and m are independently 0-5.

The alkyl group may be straight or branched.

C | to the C 1 alkyl group is preferably C 1-3 to a C 1-6 alkyl group, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or t-butyl, in particular a methyl group C 3 to C 3 cycloalkyl group is preferably a C 5 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 means the numbers 0 to 3 means the numbers 0 to 3, especially when X is hydrogen or a hydroxy group.

It is particularly preferred that η be hydrogen or η is 1, m is 1 and X is hydroxy.

Suitable inert substituents include halogen, hydroxy, Cf to C4 alkyl, Cj to C ₄ alkoxy, Cj to

With ₄ acyloxyl and C to C ₄ esterified carboxyl.

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

TO

C ₄ alkyl is preferably methyl or ethyl.

Up to ₄ alkoxyl is preferably methoxy or ethoxyl.

It is preferably acyloxyl

C] to with ₂ acyloxyl.

TO with ₄ esterified carboxyl is preferably C or C2 esterified carboxyl.

Total

R 1, R ₂ , 3, and R ₄ have three substituents or less, preferably two substituents or less.

Particularly preferred are R1, R2, R3 and

R ₄ have one substituent or are unsubstituted.

When R1, R2 or

R ₃ and

R ₄ are interconnected to form a ring of 4 to 7 atoms, the ring consists preferably o ^f carbon atoms and particularly preferably saturated. Methyl is especially preferred as Rj,

R ₂ , R 3 and R ₄

Normally, the amine of formula (III) • · · · · · ·

N - (CH ₂ ) n -C - (CH ₂ ) m N ^ _{R 4}

X (III) from which the salts of formula (IIa) and (IIb) are obtained is a pharmaceutically acceptable amine.

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

1,2-dipiperidinoethane and dipiperidinomethane.

The present invention also relates to a process for the preparation of a salt of formula (IIa) or (IIb) which consists of reacting clavulanic acid with a diamine of formula (III)

/ Ν - (CH ₂ ) n -C - (CH 2 nr-N ^ ^r ₂ χ (III) in which R 1, R ₂ , R 3, R 4, X, m and η are defined above.

Clavulanic acid diaminosol is formed when the amount of diamine is relatively high compared to clavulanic acid, and 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 tested for each amine, but it will be understood by one of skill 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 relatively high pH (depending on the amine and solvent used), more monoprotonated diamine of formula (IIa) will be obtained

R1H ¹ \ ₊ I

N-N (CH ₂ ) n -C- (CH ₂ ) m-N / I ^Rz X

Lz

-r ₄ (1Pa) and therefore more monosol will precipitate and more diprotonated diamine of formula (IIIb) ^R 4 ₊ will be obtained at relatively low pH.

HN- (CH ₂ ) n

R ₂

Η ₊ Lz

-C- (CH ₂ ) mNH ¹ ^ 4

X and because of (IIIb) this will precipitate more disol.

The present invention also relates to the use of the diamino salts of clavulanic acid as defined above as intermediates for the preparation of clavulanic acid and its pharmaceutically acceptable salt or ester.

• · · ·

The present 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 in its pharmaceutically acceptable salt or ester , mainly by adding a source forming the corresponding salt or ester.

The present invention also relates to a method of purifying clavulanic acid or a pharmaceutically acceptable salt or ester thereof, comprising:

1) reacting the impure clavulanic acid in an organic solvent with diamine to form a salt,

2) isolating the salt obtained in step a) and

3) converting 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, clavulanic acid potassium salt 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, for example, tetrahydrofuran, dioxane.

ethyl acetate, methyl acetate, acetone, methyl methylethyl ketone and the like or mixtures thereof.

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

The present invention also relates to pharmaceutical compositions containing a salt of formula (IIa) and / or (IIb) and a pharmaceutically acceptable carrier

Suitable forms of the compositions of the present 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 injectable or infusion compositions of the salts of formulas (IIa) and (IIb) are particularly suitable for high levels of clavulanic acid in the tissues, which are detected after administration by injection or infusion. Thus a preferred composition of the present invention contains salts of formulas (IIa) and (IIb) in sterile form.

Another preferred composition of the present invention is a unit 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

Crystallization comparison 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 sulfuric acid,

- 9 The pH was adjusted to about 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 solution of clavulanic acid 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 I.

The mole diamine / mole 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.

Diamine Type 1 TABLE Chris- I Butter Diamine Ν, Ν, Ν ', Ν'-tetramethyl- t, t hoists + 1.90 1,2-diaminoethane Ν, Ν, Ν ', Ν'-tetramethyl- t, t + 0.68 1,2-diaminoethane Ν, Ν, Ν ', Ν'-tetramethyl- t, t + - 1.89 1.3- diaminopropane 1.3 bis (my ethyl smoke but) - t, t + - 1.74 2-propanol Ν, Ν, Ν ', Ν'-tetramethyl- t, t + - 1.34 1,4-diaminobenzane Ν, Ν, Ν ', Ν'-tetramethyl- t, t + - 1.84 1,6-diaminohexane 1,2-dipiperidinoethane t, t + - 2.70 1,2-diaminoethane n, n + 4- 3.98

• ·

TABLE I (continued) Diamine Type 1 Chris- Butter Diamine hoists 1,3-diaminopropane n, n + + 1.69 1,6-diaminohexane n, n - + 1.69 1,10-diaminodecane n, n - + 1.46 N-methyl-1,3-diamine- n, d - + 1.69 nopropane Ν, Ν-dimethyl-1,3- n, t - + 1.86 diaminopropane Ν, Ν-dimethyl-1,2- n, t - 4- 1.69 diaminoethane piperazine in, in - 4- 1,20 N-methylpiperazine in, t - + 1,20 N, N-diethyl-1,2- n, t - - 0.81 diaminoethane Ν- 2-aminoethyl) - n, t - - 1,20 morpholine dipiperidinomethane t, t + - 14.92

n: primary, secondary: t: tertiary

EXAMPLE 2

Preparation of the mono-Ν, Ν, Ν ', Ν'-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 20 minutes to a liter of acetone under cooling (8 ° C) and maintaining the pH at 9 with Ν, Ν, N ′, Ν ^1- tetramethyl-1,2-diaminoethane (19.18 g, molar ratio 2.2 to clavulanic acid). Stirring was continued at 10 ° C for 1 hour. The precipitate was filtered off and washed with 100 ml of acetone and dried in vacuo at 35 ° C to give 20.09 g of mono-Ν, Ν Ν, Ν Ν tetramethyl-! , 2-diaminoethane salt of clavulanic acid (large crystals). The stock solution (1642 g) contained about 1.12 g of clavulanic acid.

NMR spectrum (DMSO-d ₆ ): 2.37 ppm, N-CH ₃ (s, 12H),

2.70 ppm, N-CH ₂ (s, 4H), 2.95 ppm, Cb-βΗ (d, 1H), 3.49 ppm, C6aH (dd, 1H), 3.99 ppm, CH ₂ OH ( m, 2H), 4.60 ppm, C3-H (s, 1H), 4.66 ppm, = CH (tr, 1H), 5.58 ppm, C5-H (d, 1H).

To 1 g of clavulanic acid mono N, N, N ', N'-tetramethyl-1,2-diaminoethane salt of clavulanic acid was added 200 ml of ethyl acetate / acetone (1/1 v / v) containing 1 ml Ν, Ν , Ν ', Ν'-tetramethyl - !, 2-diaminoethane. After stirring for one hour at room temperature and filtering the solution, the filtrate was evaporated slowly to give w-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 4 Rf Nonius

- Θ = 30 °

- Μο-Κα radiation

- λ = 0.70145 A

- The salt (C14H ₂ 5N ₃ O5, group 1 CgHgNOs and group CgH] gN ₂ , Mw = 315,37) crystallizes in an orthorhombic species.

- 12 group P2 ₁ 2 ₁ 2 ₁ with a = 8.268 (1), b = 9.929 (7) and c = 20.221 (2) A. axis, β and γ = 90 °.

- R = 0,206 reflections

- Ζ = 4

- The molecules are linked by a strong hydrogen bond (2.65 (1) A) between N (2) and 0 (3). C (6) -O (2) and C (6) -O (3) distances are 1.20 (1) and 1.275 (9) A, respectively, showing the nature of an incomplete simple relationship between C (6) -O ( 3).

The atomic coordinates are shown in Table II

TABLE II

x / a y / b z / c sigx sigy sigz C1 0,73451 0.61 143 0,51083 0,00109 0,00094 0,00039 C2 0,72822 0,73554 0,46864 0,00099 0,00085 0,00037 Sun. 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 0.001 19 0,00049 C10 0,77651 209810 0,70628 0.001 15 0,00169 0,00053 SI 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

• · · · · · ·

- 13 · · · · · · ·

TABLE II (continued)

x / a y / b z / c sighx sighy sighz 01 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 ', Ν'-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 , N ', N'-tetramethyl-1,2-diaminoethane (5.11 g, molar ratio 8 to clavulanic acid). Stirring was continued for 0.5 hour and the precipitate was filtered off, washed with ethyl acetate and dried under vacuum at 35 ° C to give 2.62 g of mono-Ν, Ν, Ν ', Ν'-tetramethyl-1,2-diaminoethane salt of clavulanic acid (large crystals). The stock solution (155 g) contained 0.03 g of clavulanic acid.

NMR (DMSO-dg): 2.38 ppm, N-CH3 (s, 12H), · · · · · ·

2.70 ppm, N-CH ₂ (s, 4H), 2.93 ppm, Cb-βΗ (d, 1H), 3.48 ppm, C6-ocH (dd, 1H), 3.98 ppm, CH ₂ OH (m, 2H), 4.58, C3-H (s, 1H),

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

EXAMPLE 4

Preparation of the di Ν, Ν, Ν ', Ν'-tetramethyl-1,2-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 (10 ° C) while stirring and maintaining the pH between 7.5 and 8 s. , Ν, Ν ', Ν'-tetramethyl-1,2-diaminoethane (0.64 g, molar ratio of 1.45 to clavulanic acid) Stirring is continued for 0.5 hour and the precipitate is filtered off, washed with acetone and dried under vacuum at 35 ° C to give 1.24 g of di Ν, Ν, Ν ′, Ν'-tetramethyl-1,2-diaminoethane salt of clavulanic acid (needle-shaped crystals). The stock solution (337 g) contained 0.11 g of clavulanic acid.

w NMR spectrum ((DMSO-dg): 2.45 ρ, ρτη, N-CH3 (s, 12H),

2.80 ppm, N-CH ₂ (s, 4H), 2.99 ppm, Cb-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 C3-H (s, 2H), 5.61 ppm, C5-H (d, 2H).

EXAMPLE 5

Received? of mono 1,3-bis (dimethylamino) -2-propanol salt of clavulanic acid

Clavulanic acid solution in ethyl acetate (100

e) containing 20 g of clavulanic acid / kg) was added over a period of 10 minutes to 100 ml of acetone, with stirring at. .....

. ·· · · · e ····· ”. · · · · · · · · · · · ·

- 15 8 ° C and maintaining the pH between 8.5 and 8.7 with 1.3bis (dimethylamino) -2-pr opanol (2.54 g, molar ratio of 1.74 to clavulanic acid). Stirring was continued for 0.25 hours and the precipitate was filtered off and washed with 50 ml of a 1/1 mixture of acetone and ethyl acetate and acetone. Drying under vacuum at room temperature afforded 1.82 g of mono 1,3bis (dimethylamino) -2-propanol salt of clavulanic acid, with a purity of 25.6% as free acid.

NMR (DMSO-dg) M 2.41 ppm, N-CH3 (s, 12H), 2.50 ppm, N-CH ₂ (dABq, 4H, J 12.6 Hz, J 4.8 Hz), 2 , 61 ppm, NCH 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, 3H), 4.58 ppm, C3-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 mono N, N, N ', Ν'-tetramethyl-1,2diaminoethane salt of clavulanic acid into potassium salt of clavulanic acid ml of 0.35 M potassium acetate solution (solvent' isopropyl alcohol and 1% iw / v) water ) is added dropwise to a suspension of 2 g of mono-Ν, Ν, Ν ′, Ν'-tetramethyl-1,2-diaminoethane salt of clavulanic acid (68.6% content) 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 under vacuum at 35 ° C to give 1.44 g of the clavulanic acid crystalline potassium salt containing 87% (clavulanic acid) and about 1.5% potassium acetate (HPLC analysis). The mother liquor contains about 0.06 g of clavulanic acid.

• ·

EXAMPLE 7

Conversion of di Ν, Ν, Ν ', Ν'-tetramethyl-1,2-diaminoethane salt of clavulanic acid into potassium salt of clavulanic acid

4.5 ml of a 2M solution of 2-ethyl-hexanoic acid potassium salt in isopropanol was added to a stirred solution of 2 g of di Ν, Ν, Ν ', Ν'-tetramethyl-1,2-diaminoethane salt of clavulanic acid (purity 75, 8% calculated as free acid) in 20 ml of isopropanol and 2 ml of water at room temperature. After stirring for 0.25 hours, the precipitate was filtered off and washed with 5 ml of isopropanol. Drying in vacuo at room temperature gave 0.30 g of the clavulanic acid potassium salt with a purity of 83.6% calculated as the free acid.

An additional 2.5 ml of a 2M solution of 2-ethyl-hexanoic 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 potassium salt of clavulanic acid at a purity of 82.3% calculated as free acid.

EXAMPLE 8

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

1.6 ml 2 M solution of the potassium salt of? - ^d tilheksanoena acid in isopropanol was added to a stirred solution of 1 g of mono-1,3-bis (dimethylamino) -2-propionic salt of clavulanic acid in 19 ml isopropanol and 1 ml water at room temperature. After stirring for 0.25

-4 ··········

I f ··· »* ······· · * ···· ······ · · · ··· ·· *

- For 17 hours the precipitate is filtered off and washed with 15 ml of isopropanol.

Vacuum drying at room temperature is obtained

0.38 g of clavulanic acid potassium salt with a purity of 80% as free acid.

Claims (16)

1) contaminated clavulanic acid is reacted in an organic solvent with diamine to form a salt, 1 or 2, characterized in that X is hydrogen, η is the number 1 and m is 1. 1, characterized in that R1, R2, R3 and R4 represent a methyl group. 1, A clavulanic acid salt of formula (IIa) or (IIb) H ₂ OH ^R \ ₊ HN- (CH ₂ ) n R ₂ I -C - (CH ₂ ) mN L 3 N 4 (Pa) wherein T 1 and R 2 each represent a (1-8C) 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, R3 and R4 each represents a (1-8C) alkyl, (3-8C) cycloalkyl or (38C) cycloalkyl (1-8C) alkyl group, optionally with one or more inert substituents or interconnected to form a 4-7 ring ring atoms, X represents hydrogen or a hydrogen bonding group and η and m independently of one another are the numbers 0-5. 2) the salt obtained in step a) is isolated and 2, 3 or 4, characterized in that clavulanic acid is reacted with a diamine of formula (III) N - (CH 2) n - C - (CH ₂ ) n-N 2 _r I 1X4 i X in which R 1, R 2, R 3, R 4, X, m and η are as defined in claim A clavulanic acid salt according to claim 3) the isolated salt in clavulanic acid is converted into its pharmaceutically acceptable salt or ester. - 3 1, 3 or 4 values, in an organic solvent. A clavulanic acid salt according to claim 1 or 2, characterized in that X is hydrogen, η is the number 1 and m is 0. A clavulanic acid salt according to claim 5. A clavulanic acid monosol of formula Pa according to claim 1, characterized in that R1, R2, R3 and R4 represent a methyl group, X represents hydrogen, η is the number 1 and m is 0. A method for preparing a salt according to claim 1, 7. The method of claim 6, wherein the molar amount of diammonium is greater than that of clavulanic acid. The method of claim 6, wherein the molar amount of diammonium 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 Ν, Ν, Ν ′, Ν'-tetramethyl-1,2-diaminoethane as the molar amount of N, N, N ′. N'-Tetramethyl-1,2diaminoethane is greater than that of clavulanic acid. A process for the preparation of clavulanic acid or a pharmaceutically acceptable salt or ester thereof, wherein the mono- or diamino salt according to claims 1,2,3,4 and 5 is converted to clavulanic acid or its pharmaceutically acceptable salt or ester. 11. A method for the purification of clavulanic acid or a pharmaceutically acceptable salt or ester thereof. characterized in that A pharmaceutical composition comprising the clavulanic acid salt of claim 1,2,3,4 or 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. 14. Clavulanic acid as described in any of Examples 2 to 8. 15. A process for the preparation of diaminosol of clavulanic acid as described in any of Examples 2,3,4, and 5. 16. A process for the preparation of clavulanic acid from diaminosol as described in any of Examples 6,7 and 8.