KR100187333B1 - Diamine salts of clavulanic acid - Google Patents

Abstract

New diamine salts of clavulanic acid, pharmaceutical compositions containing it, and novel methods of using the diamine salts in the preparation of clavulanic acid and its salts and esters are provided.

Description

Diamine salt of clavulanic acid

The present invention relates to the use of these salts in the preparation of new diamine salts of clavulanic acid, pharmaceutical compositions thereof, clavulanic acid and its salts and esters.

British Patent 1508977 discloses a compound of formula (I)

Discloses that clavulanic acid and its pharmaceutically acceptable salts and esters are antibacterial agents capable of increasing the efficacy of penicillin and cephalosporin against many [beta] -lactamase-producing bacteria.

U.S. Patent 4,650,795 discloses a group of primary amine salts of clavulanic acid that provide a stable pharmaceutical composition.

European Patent 26044 discloses the use of t-butylamine salts as intermediates useful in the production of clavulanic acid.

Unpublished European patent application 562583 discloses the same use for both secondary and secondary types of N, N-diisopropylethylenediammonium dichloroborate and N, N-diethylethylenediammonium dichloroborate .

Surprisingly, it has been found that the tertiary and tertiary diamine salts of clavulanic acid have improved properties compared to the above-mentioned t-butylamine salts of clavulanic acid. For example, large crystals of a mono salt of N, N, N ', N'-tetramethyl-1,2-diaminoethane clavulanate can easily be precipitated in pure form. Therefore, this salt is an intermediate product which is very useful in the production of clavulanic acid.

The present invention therefore also relates to the use of a tertiary, tertiary diamine mono salt of formula (IIa)

And a tertiary, tertiary diamine di-salt of formula (IIb)

Wherein R ₁ and R ₂ are each (1-8C) alkyl, (3-8C) cycloalkyl or (3-8C) cycloalkyl (1-8C) alkyl, optionally having one or more inert substituents Or are linked to each other to form a ring of 4-7 ring atoms; R ₃ and R ₄ are each (1-8C) alkyl, (3-8C) cycloalkyl or (3-8C) cycloalkyl (1-8C) alkyl, optionally having one or more inert substituents, Form a ring of 4-7 ring atoms; X is hydrogen or a hydrogen bridge former; m and n are each independently 0-5. The alkyl group may be branched or straight-chain.

The C ₁ to C ₈ alkyl group is preferably a C ₁ to C ₄ alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, secondary butyl or tertiary butyl, more preferably methyl.

The C ₃ to C ₈ cycloalkyl group is preferably a C ₅ to C ₇ cycloalkyl group, such as cyclopentyl, cyclohexyl or cycloheptyl.

Preferably, X is hydrogen, hydroxy or halogen, such as bromine or chlorine. Most preferably, X is hydrogen or hydroxy.

Preferably, n is from 0 to 3 and m is from 0 to 3, more preferably wherein X is hydrogen or hydroxy. Most preferably n = 1, m = 0, X is hydrogen or n = 1, m = 1 and X is hydroxy.

Suitably the inert substituent comprises halogen, hydroxy, C ₁ to C ₄ alkyl, C ₁ to C ₄ alkoxyl, C ₁ to C ₄ acyloxyl and C ₁ 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 methoxyl or ethoxyl.

C ₁ to C ₄ acyloxyl is preferably C ₁ to C ₂ acyloxyl.

The C ₁ to C ₄ esterified carboxyl is preferably a C ₁ to C ₂ esterified carboxyl.

In general, R ₁ , R ₂ , R ₃ and R ₄ have three substituents or fewer substituents, preferably two substituents or fewer substituents. Most preferably R ₁ , R ₂ , R ₃ and R ₄ have one substituent or are not substituted.

When R ₁ and R ₂ or R ₃ and R ₄ are interconnected to form a ring of 4 to 7 atoms, the ring is preferably composed of carbon atoms and is most preferably saturated.

Most preferably R ₁ , R ₂ , R ₃ and R ₄ are methyl.

The amine of formula (III)

Is a pharmaceutically acceptable amine, from which salts of formulas (IIa) and (IIb) may be derived.

Preferably, the salt of formulas (IIa) and (IIb) is selected from the group consisting of N, N, N ', N'-tetramethyl-1,2-diaminoethane, 1,3-bis (dimethylamino) -2- propanol, N N, N ', N'-tetramethyl-1,6-diaminohexane, 1,2-dipiperidinoethane and 1,2,4- Can be derived from dipiperidinomethane.

The present invention also provides a process for the preparation of the salts of formulas (IIa) and (IIb), which comprises the reaction of diamin (III) with clavulanic acid,

Wherein R ₁ , R ₂ , R ₃ , R ₄ , X, m and n are as defined above. When the amount of diamine is relatively high compared to the amount of clavulanic acid, diamine monoclavulanate will form, and when the amount of diamine is relatively low compared to the amount of clavulanic acid, diamine dichloroburaniumate will be formed, A mixture of the same will be formed.

The conditions under which a mono or diamine salt of clavulanic acid or a mixture of the same can be formed have not been investigated for each diamine, but it will be apparent to those skilled in the art that these will vary depending on the diamine employed.

The concentration of the diamine present in the reaction mixture may vary, for example, by varying the pH. More mono-protonated diamines (IIIa) at relatively high pH (depending on the amine and solvent used):

Will be present and thus more mono salt will precipitate. More di-protonated diamines (IIIb) at relatively low pH:

Will be present and thus more di salt will precipitate.

The present invention further provides the use of the diamine salt of clavulanic acid as defined above as an intermediate in the preparation of clavulanic acid and its pharmaceutically acceptable salts or esters.

Another aspect of the present invention provides a process for the preparation of clavulanic acid or a pharmaceutically acceptable salt or ester thereof which comprises reacting a diaminic salt of clavulanic acid as defined above with clavulanic acid, Or generally by the addition of a source of the corresponding salt or ester forming compound to its pharmaceutically acceptable salts or esters.

Another aspect of the present invention provides a method of purifying clavulanic acid or a pharmaceutically acceptable salt or ester thereof, the method comprising the steps of:

i) contacting undesired clavulanic acid in an organic solvent with a diamine to form a salt;

ii) separating the salt produced in step i); And

iii) Converting the isolated salt to the clavulanic acid, generally by acidification, or generally by adding a source of the corresponding salt or ester forming compound, to its pharmaceutically acceptable salts or esters.

Potassium clavulanate is formed by adding potassium acetate or potassium ethylhexanoate, for example.

Most preferably, the formation of the diamine salt of clavulanic acid occurs in an organic solvent. Suitable solvents include non-hydroxylic solvents such as, for example, solvents such as tetrahydrofuran, dioxane, ethyl acetate, methyl acetate, acetone, methyl ethyl ketone and mixtures thereof.

The reaction can be carried out at about -50 캜 to 40 캜, most preferably at about 0 캜 to 15 캜.

The present invention also provides a pharmaceutical composition comprising a salt of formula (IIa) and / or (IIb) and a pharmaceutically acceptable carrier.

Suitable forms of the compositions of the present invention include tablets, capsules, reconstitutable powders, and sterile forms suitable for injection or infusion. Such compositions may include conventional pharmaceutically acceptable materials such as diluents, binders, pigments, seasonings, preservatives and disintegrants.

The injection function or injectable composition of the salts of the formulas (IIa) and (IIb) is particularly suitable as it may result in compounds of clavulanic acid with high tissue levels after administration by injection or infusion. Thus one preferred composition aspect of the present invention contains salts of formulas (IIa) and (IIb) in sterile form.

A unit dose composition containing a salt of formula (II) suitable for oral administration forms a further preferred composition aspect of the present invention.

The following examples will illustrate the invention. The pH value referred to herein refers to the value measured by the Ingold electrode type U402-S7 / 120 in the applied solvent.

[Example 1]

[Comparison of crystallization of various diamine salts]

The potassium clavulanate solution in ice-cooling water was stirred with ethyl acetate while cooling with ice-water. The pH was brought to about 2 with about 10% (w / w) sulfuric acid solution, the aqueous layer was separated and extracted twice with ethyl acetate. The extracts were collected, dried over magnesium sulfate, filtered and washed with ethyl acetate to give a solution of clavulanic acid in about 2% (w / w). The clavulanic acid was diluted with the same volume of acetone and the diamine added.

The results are shown in Table 1. The diamine molar ratio per clavulanic acid mole is shown in the last column. The tertiary, tertiary type diamine salts of clavulanic acid are present in only the preferred crystalline form. It does not exist in the form of oil.

[Example 2]

[Preparation of N, N, N ', N'-tetramethyl-1,2-diaminoethane monoclavulanate from ethyl acetate / acetone solution]

The clavulanic acid extract in dry ethyl acetate (828 g containing 18 g clavulanic acid / kg prepared according to Example 1) was cooled (8 ° C) and N, N, N ', N'-tetramethyl- , 2-diaminoethane (TMEDA, 19.18 g, i.e., 2.2 molar ratio with respect to clavulanic acid) was added to 1 liter acetone for 20 minutes while maintaining the pH at 9. Lt; RTI ID = 0.0 > 10 C < / RTI > The precipitate was filtered off, washed with 100 ml of acetone and dried in vacuo at 35 DEG C to give 20.09 g of TMEDA monoclavulanate (large crystals). The mother solution (1642 g) contained about 1.12 g of clavulanic acid.

To 1 g of this TMEDA monoclavulanate was added 200 ml of a mixture of ethyl acetate / acetone (1/1 v / v) containing 1 ml of TMEDA. After stirring at room temperature for 1 hour and filtering the solution, the filtrate was slowly evaporated to obtain a large crystal.

All parameters were obtained by least square method from the 2? Values for the reflected light measured with a diffractometer under the following experimental conditions:

-CAD 4 Rf Nonius

-θ = 30 °

-Mo-K? Radiation

-λ = 0.70145Å

- salt (C ₁₄ H ₂₅ N ₃ O ₅ , group 1 C ₈ H ₉ NO ₅ and group 2 C ₆ H ₁₆ N ₂ ; mW = 315.37) is a = 8.268 (1), b = 9.929 = 20.221 (2) A. ?,? and? = 90 °, respectively. The crystallization is carried out in the orthorhombic space group P2 ₁ 2 ₁ 2 ₁ .

-2747 R = 0.206 for reflected light

-Z = 4

These molecules are coupled through a strong hydrogen bond (2.65 (1) Å) between N (2) and O (3).

The distance between C (6) -O (2) and C (6) -O (3) is 1.20 (1) and 1.275 .

The atomic coordinates are shown in Table 2.

[Example 3]

[Preparation of N, N, N ', N'-tetramethyl-1,2-diaminoethane monoclavulanate from ethyl acetate solution]

N, N, N ', N'-tetramethyl-1, 2-diaminoethane (TMEDA, 5.11 g, 1 mmol) was added to a solution of clavulanic acid in ethyl acetate (about 75 g containing about 20 g clavulanic acid / kg) I.e., a molar ratio of 8 to clavulanic acid) was added to 75 ml of ethyl acetate at 8 占 폚 for 10 minutes while the pH was maintained between 8 and 9. Stirring was continued for 0.5 h and the precipitate was filtered off, washed with ethyl acetate and vacuum dried at 35 [deg.] C to give 2.62 g of TMEDA monoclavulanate (large crystals).

The parent solution (155 g) contained 0.03 g of clavulanic acid.

[Example 4]

[Preparation of N, N, N ', N'-tetramethyl-1,2-diaminoethane diclavulanate from ethyl acetate / acetone solution]

The clavulanic acid solution in ethyl acetate (200 ml containing 1.1 g of clavulanic acid) was stirred and N, N, N ', N'-tetramethyl-1,2-diaminoethane (TMEDA, 0.64 g, Clavulanic acid at a molar ratio of 1.45) to 200 ml of cold acetone (10 ° C) for 10 minutes while maintaining the pH between 7.5 and 8. Stirring was continued for 0.5 hours and the precipitate was filtered off, washed with acetone and vacuum dried at 35 [deg.] C to give 1.24 g of TMEDA dicloburanate (needle crystals). The parent solution (337 g) contained 0.11 g of clavulanic acid.

[Example 5]

Preparation of [1,3-bis (dimethylamino) -2-propanol monoclavulanate]

A solution of clavulanic acid in ethyl acetate (100 g containing 20 g clavulanic acid / kg) was stirred at 8 占 and 1,3-bis (dimethylamino) -2-propanol (2.54 g, ) In 100 ml of acetone for 10 minutes while maintaining the pH between 8.5 and 8.7. Stirring was continued for 0.25 hour and the precipitate was filtered off and washed with 50 ml of a 1/1 mixture of acetone and ethyl acetate and with acetone. And dried in vacuo at room temperature to obtain 1.82 g of 1,3-bis (dimethylamino) -2-propanol monoclavulanate with a purity of 25.6% by free acid.

[Example 6]

[Conversion of N, N, N ', N'-tetramethyl-1,2-diaminoethane monoclavulanate to potassium clavulanate]

30 ml of a 0.35 M potassium acetate solution (solvent isopropyl alcohol and 1% (w / v) water) was added to a solution of N, N, N ', N'-tetramethyl-1,2-diaminoethane monoclavulanate in 50 ml of isopropanol (Content: 68.6%). After stirring at room temperature for 0.75 hours, the precipitate was filtered, washed with 10 ml of isopropanol and vacuum dried at 35 [deg.] C to give the clavulanate in crystalline form with a content of 87% (clavulanic acid) and about 1.5% To obtain 1.44 g of potassium carbonate. The mother liquor contained about 0.06 g of clavulanic acid.

[Example 7]

[Conversion of N, N, N ', N'-tetramethyl-1,2-diaminoethane diclobulanate to potassium clavulanate]

4.5 ml of a 2M solution of potassium 2-ethyl-hexanoate in isopropanol were added to a solution of N, N, N ', N'-tetramethyl-1,2-diaminoethane diclavanate Gt; 75% < / RTI > purity). After stirring for 0.25 hours, the precipitate was filtered off and washed with 5 ml of isopropanol. And then vacuum-dried at room temperature to obtain 0.30 g of potassium clavulanate in a purity of 83.6% as calculated as free acid.

2.5 ml of a 2M solution of potassium 2-ethyl-hexanoate in isopropanol was further added to the mother liquor and stirring was continued. The precipitate was filtered off, washed with 5 ml of isopropanol and dried to obtain 0.68 g of potassium clavulanate in a purity of 82.3% calculated as free acid.

[Example 8]

[Conversion of 1,3-bis (dimethylamino) -2-propanol monoclavulanate to potassium clavulanate]

1.6 ml of a 2M solution of potassium 2-ethyl-hexanoate in isopropanol was added to a stirred solution of 1 g of 1,3-bis (dimethylamino) -2-propanol monoclavulanate in 19 ml isopropanol and 1 ml water at room temperature. After stirring for 0.25 hours, the precipitate was filtered off and washed with 15 ml of isopropanol. And vacuum-dried at room temperature to obtain 0.38 g of potassium clavulanate as a free acid in a purity of 80%.

Claims (12)

A salt of clavulanic acid of formula (IIa) or (IIb) Wherein R ₁ and R ₂ are each (1-8C) alkyl, (3-8C) cycloalkyl or (3-8C) inde cycloalkyl (1-8C) alkyl, optionally has one or more inert substituents, or interconnection To form a ring of 4-7 ring atoms; R ₃ and R ₄ are each (1-8C) alkyl, (3-8C) cycloalkyl or (3-8C) cycloalkyl (1-8C) alkyl, optionally having one or more inert substituents, Form a ring of 4-7 ring atoms; X is hydrogen or a hydrogen bridge former; m and n are each independently 0-5. The salt of clavulanic acid according to claim ₁ , wherein R ₁ , R ₂ , R ₃ and R ₄ are methyl. 3. The salt of clavulanic acid according to claim 1 or 2, wherein X is hydrogen, n is 1 and m is 0. 3. The salt of clavulanic acid according to claim 1 or 2, wherein X is hydroxy, n is 1 and m is 1. The mono salt of clavulanic acid of formula IIa according to claim 1, characterized in that R ₁ , R ₂ , R ₃ and R ₄ are methyl, X is hydrogen, n is 1 and m is 0. A process for producing a salt according to claim 1 or 2, Characterized in that the diamine and clavulanic acid of the formula (I) are reacted in an organic solvent, wherein the diamines of R ₁ , R ₂ , R ₃ , R ₄ , X, m and n are as defined in claim 1 or 2, . 7. The process of claim 6 wherein the molar amount of diamine is greater than the molar amount of clavulanic acid. 7. The process of claim 6 wherein the molar amount of diamine is less than the molar amount of clavulanic acid. A process for preparing a salt according to claim 5, wherein the clavulanic acid is reacted with N, N, N ', N'-tetramethyl-1,2-diaminoethane in the presence of N, N, N' -1,2-diaminoethane is greater than the molar amount of clavulanic acid. CLAIMS 1. A process for the preparation of clavulanic acid or a pharmaceutically acceptable salt or ester thereof, which process comprises reacting a mono or diamine salt according to any one of claims 1, 2 or 5 with clavulanic acid or its pharmaceutical ≪ / RTI > to an acceptable salt or ester. CLAIMS 1. A process for the purification of clavulanic acid or a pharmaceutically acceptable salt or ester thereof, characterized in that the process comprises the steps of: i) converting the undigested clavulanic acid in an organic solvent into a compound of formula III Of the diamine to form a salt; ii) separating the salt produced in step i); And iii) converting the isolated salt to clavulanic acid or a pharmaceutically acceptable salt or ester thereof. A pharmaceutical composition comprising a salt of clavulanic acid according to any one of claims 1, 2, 3, 4 or 5, and a pharmaceutically acceptable carrier or diluent.