AT404251B - NEW CRYSTALLINE SALT FROM CEFIXIM - Google Patents

Description

AT 404 251 B

The invention relates to a new crystalline salt of cefixime of the formula

»COOH

, 0 ~ CH_ N

x2HN

Process for its preparation and its use for the purification of cefixime of the formula

, COOH N / 0-CH2

II and its hydrates.

Cefixime as trihydrate is a modern, orally available cephalosporin with excellent antibacterial properties and high 0-lactamase stability (see, for example, H. Yamamanaka et al., J. Antibiotics (1985), 38 (12), p 1738-1751).

Cefixime can be prepared in various ways, the last stage of the synthesis often being the active ingredient by acidic cleavage of the protective groups from compounds of the formula COOR,

wherein Ri is a protecting group and R2 is a protecting group or hydrogen. The choice of Ri as a protective group which can be split off under acidic conditions is economically advantageous because, in the structure of the side chain, 2- (2-aminothiazoly-4-yl) -2-carboxymethoximinoacetic acid, there must be discrimination between the two carboxylic acids, and because of the accessibility the choice for Ri as an acidic protective group, for example a tert-butyl protective group, brings considerable advantages.

However, in the case of cefixime, the removal of protective groups under acidic conditions is difficult. For example, in the above article, among other things, cefixime from 2- (2-amino-4-thiazolyl) -2- (tert.butoxycarbonylmethoximino) acetamido) -3-vinyl-3-cephem-4-carboxylic acid benzyl ester is eliminated by splitting off the protective groups with trifluoroacetic acid / Anisole produced in a yield of 34.1%. A chromatography step is also activated to purify the fission product. In EP 30.630, the cleavage of the same compound in Example 160 also includes mixtures 2 which are more ecologically compatible

AT 404 251 B from concentrated HCl / acetic acid, p-toluenesulfonic acid / formic acid or acetic acid or methanesulfonic acid in a mixture with acetic acid or formic acid and the cleavage products isolated in various yields as addition salts and crude products by entries in diisopropyl ether. Since the acidic cleavage does not take place without considerable by-product formation, these raw products cannot be converted into a high-quality active ingredient without an additional cleaning operation.

In WO 95/33753 the protective groups are cleaved with aluminum trichloride and anisole. The hydrochloride of the cefixime is isolated as an intermediate, which is then released further to a crude cefixime. The crude product is then purified using a chromatography step. In addition to the cumbersome cleaning of the raw products using cost-intensive chromatography, the disposal of the aluminum in the cleavage solutions and the isolation of cefixime hydrochloride from a strongly hydrochloric acid solution are also a serious problem due to the corrosion properties.

Accordingly, there is a need for an efficient cleaning method for cefixime, in particular for cefixime, which is produced by acidic cleavage of protective groups. This object is achieved by using the salt of the formula I.

The salt of formula I is characterized by a high cleaning power with regard to by-products of cefixime and therefore provides a high-quality active ingredient after their release. The salt of formula I is very easy to produce.

To prepare the compound of formula I, cefixime or cefixime in the form of its hydrates is optionally suspended in an organic solvent in the presence of water. After addition of dicyclohexylamine, the compound of the formula I then crystallizes out, the impurities predominantly remaining in solution. The crystalline salt of the compound of formula I is then isolated, optionally dried and then the active substance is released as a trihydrate. If appropriate, the isolated compound of the formula I can be resuspended again in a solvent or solvent mixture suitable for salt formation in order to bring about a further depletion of the by-products before the active substance is released.

Suitable organic solvents are ketones, e.g. Acetone, diethyl ketone or methyl isobutyl ketone, alcohols, for example methanol, ethanol or one of the isomeric propanols, nitriles, for example acetonitrile, esters, for example alkyl (Ci to Ca) alkyl esters, or also amides, e.g. Dimethylformamide. If necessary, water can be added to an organic solvent in order to ensure better solubility of the unclean cefixime to be dissolved. If, on the other hand, the compound of the formula I is too readily soluble in the organic solvent, an anti-solvent, for example an ether or a hydrocarbon, can be added to the system. However, the preferred solvent system is acetone in combination with water. To form the salt of the compound of formula I, however, an acid addition salt of cefixime can also be used. The choice of the acid addition salt is free; it is possible to use acid addition salts such as are used, for example, to cleave acid-labile protective groups. Examples include the hydrochloride, the formate, the acetate, the toluenesulfonate and the mesylate. However, cefixime can also be present as a mixed salt with the acids mentioned above.

If, for the preparation of the compound of the formula I, an acid addition salt of cefixime is used, the amount of dicyclohexylamine to be used must have been correspondingly increased. If normally 2.2 to 3 equivalents of dicyclohexylamine are used, based on the cefixime used, 3.2 to approx. 4 equivalents of dicyclohexylamine are used when using an acid addition salt of cefixime. A further excess of dicyclohexylamine can, however, be regarded as not critical.

The cefixime is released from the compound of the formula I as follows:

The compound of the formula I is dissolved in water or a mixture of water and an organic solvent, for example acetone or an alcohol, the solution is filtered, optionally over carbon or a filter aid or over a small adsorber resin cartridge, and the active ingredient of the formula II then falls through Addition of an acid at a pH of approx. 2 to 3. Inorganic acids such as phosphoric acid or sulfuric acid are particularly suitable as acids. If one wants to remove most of the dicyclohexylamine before the crystallization of the active ingredient, this is conveniently done by extraction. The pH of an aqueous solution of the compound of the formula I is adjusted to pH 8 to 9 using one of the bases mentioned above, and the mixture is extracted with an organic solvent such as dichloromethane, an ester or a ketone, for example methyl isobutyl ketone. The pH of the aqueous solution is then optionally adjusted to pH 2 to 3 in the presence of an organic solvent such as acetone or an alcohol, with the product precipitating. To remove dicyclohexylamine, there are also ion exchangers or adsorber resins or ion retardation resins, for example AG 11 A8 from Biorad or Dianion Snake cage resin from Mitsubishi or adsorber resins such as 3

Claims (6)

AT 404 251 B, for example, styrene-divinylbenzene copolymers (e.g. Dianion HP 20, Dianion HP 21, Dianion SP 207, Amberlite XAD 1180, XAD 1600, XAD 16 or adsorber resins CG 161) are suitable. In the following example, which explains the invention without, however, restricting its scope, all the temperatures are given in degrees Celsius. Example: 7- [2- (aminothiazol-4-yl-2-carboxymethoximino) acetamido-3-vinyl-3-cephem-4-carboxylic acid. Bisdicyclohexylammonium salt. To a suspension of 15 g of 7- [2- (aminothiazol-4-yl ) -2- (carboxymethoximino) acetamido-3-vinyl-3-cephem-4-carboxylic acid. Trihydrate (content of unknown by-products (HPLC): 5.76 area%) in a mixture of 60 ml acetone and 15 ml water, 15 g dicyclohexylamine dripped. 540 ml of acetone are added dropwise to the resulting solution at 20 * in the course of 30 minutes, during which the dicylohexylamine salt crystallizes. The crystal suspension is stirred for 1 hour at room temperature, then cooled to 0 * and stirred at this temperature for 2 hours. Then the crystalline precipitate is filtered off, the crystal cake is washed with acetone and dried in vacuo. 21.7 g of the title compound are obtained in the form of a white powder. Unknown by-product content (HPLC): 2.59 area% Melting point: 175 * (dec.) 1 H-NMR spectrum (DMSO-de): 0.90-2.30 (m, 40H, cyclohexyl-H); 3.03 (m, 4H, cyclohexyl-H); 3.46 (s (broad), 2H, S-CH2); 4.33 (s, 2H, O-CHa-); 4.96 (d, J = 8.0Hz, 1H, vinyl-H); 5.12 (d, J = 5.4Hz, 1H, β-lactam-H); 5.16 (d, J = 18.0Hz, 1H, vinyl-H): 5.68 (m, 1H; β-lactam-H); 6.83 (s, 1H, thiazolyl-H); 6.93 (dd, J = 12.0 and 18.0Hz, 1H, vinyl-H). The cefixime of formula II can be obtained as follows: A) 7- [2- (aminothiazol-4-yl) -2- (carboxymethoximino) acetamido-3-vinyl-3-cephem-4-carboxylic acid. Trihydrate A solution of 5 g of 7- [2- (aminothiazol-4-yl) -2- (carboxymethoximino) acetamido-3-vinyl-3-cephem-4-carboxylic acid.Bisdicyclohexylammoniumsaiz (content of unknown by-products (HPLC): 2.59 area%) in 50 1 g of activated carbon is added to ml of water, the mixture is stirred at room temperature for 10 minutes and filtered. The almost colorless filtrate is diluted with 20 ml of ethanol and the pH is adjusted to 2.5 by dropwise addition of 2 ml of sulfuric acid within about 45 minutes, the title compound crystallizing. To complete the crystallization, stirring is continued for 1 hour at room temperature and then for 1 hour at 0 *. Then the precipitate is filtered off, washed with water and dried in vacuo. 2.78 g of the title compound are obtained in the form of a white, crystalline powder. Unknown by-product content (HPLC): 0.62 area% B) 7- [2- (Aminothiazol-4-yl) -2- (carboxymethoximino) acetamido-3-vinyl-3-cephem-4-carboxylic acid-right trihydrate A solution of 5 g of 7- [2- (aminothiazol-4-yl) -2- (carboxymethoximino) acetamido-3-vinyl-3-cephem-4-carboxylic acid. Bicyclohexylammonium salt (content of unknown by-products (HPLC): 2.59 area%) in 50 ml of water is mixed with 25 ml of methylene chloride and cooled to 0 *. 6.1 ml of 2 M NaOH are added dropwise with stirring. After phase separation, the dicylohexylamine-containing methylene chloride phase is discarded. The aqueous phase is washed with methylene chloride. After the methylene chloride phase has been separated off, 1 g of activated carbon is added, the mixture is stirred in an ice bath for 10 minutes and filtered. The title compound is isolated from the filtrate as described in A). Yield: 2.78 g content of unknown by-products (HPLC): 1.13 area% of claims 1. New crystalline salt of cefixime of the formula 4 AT 404 251 B ^ COOH COOH 2. Process for the preparation of the new crystalline salt of the formula ^ .COOH COOH, characterized in that dicyclohexylamine in an organic solvent, optionally in the presence of water, is added to cefixime in anhydrous form, in the form of its hydrates or in the form of a protected derivative, and the product which crystallizes out is separated off, if appropriate after adding an anti-solvent. 3. The method according to claim 2, characterized in that 2 to 4 equivalents of dicyclohexylamine are used per mole of cefixime. 4. Process according to claims 2 and 3, characterized in that the solvent used is ketones, such as acetone, diethyl ketone or methyl isobutyl ketone, alcohols, such as methanol, ethanol or one of the isomeric propanols, nitriles, such as acetonitrile, esters, such as acetic acid (Ci to COalkyl esters, or amides, such as dimethylformamide, are used. 5. Process according to claims 2 and 3, characterized in that an ether or hydrocarbon is added as the anti-solvent. 6. Use of the crystalline salt of the formula COOH COOH for the purification of cefixime, characterized in that a crude product containing 5 cefixime 5 AT 404 251 B or contaminated product is converted into the salt of formula I, this salt is isolated, optionally dried and then converted into the free cefixime. 6