SI8510745A8 - Process for preparing salt-hydrates of cephalosporine derivates - Google Patents

Description

CEPHALOSPORINA

1. The technical field of the invention

This invention is within the chemistry of cephalosporins used for the treatment and prophylaxis of infectious diseases, designated by the international patent classification C 07D 50L / 00, A 61K 31/545.

2. Technical problem

The technical problem to be solved by the present invention is to obtain new cephalosporin derivatives, which are more active than previously known derivatives and which can remain in the bloodstream for a long period of time, thus providing longer application intervals, an obvious preference for both patients and treatment staff.

3. State of the art

Cephalosporins having a 2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido group in position 7 are known e.g. of DOS 25 56 736 and DOS 27 15 385. The cephalosporins of the present invention have such a substituent in position 7, and additionally have a specific substituent in position 3, which is not published in the above-mentioned publications, namely 2,5- dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl-thiomethyl group (or its tautomeric form 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-astriazine -3-yl-) thiomethyl group. Qualifying selection with respect to disclosure of the aforementioned disclosures provides unexpectedly novel cephalosporins with superior pharmacological properties such as increased antimicrobial activity and longer half-life, i.e. the new cephalosporins provided by the present invention remain in the bloodstream for an extended period of time.

4. Description of the solution to a technical problem with implementation examples

According to the foregoing, the present invention relates to a process for the preparation of solihydrates of eephalosporin derivatives of the general formula

COOH in which X denotes a 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl group or its corresponding tautomeric form, 2,5-dihydro-6-hydroxy-2methyl A -5-oxo-as-triazin-3-yl group comprising reacting the compounds of Formula I above with a base and isolating the resulting salt in the form of salt hydrates.

Examples of salts of the compounds of formula I are alkali metal salts such as sodium and potassium salts, ammonium salts, alkaline earth metal salts such as calcium salts, salts with organic bases such as salts with amines (e.g., salts with N-ethyl- piperidine, procaine, dibenzyl-amine, N, N-dibenzylethylethylenediamine, alkylamines or dialkylamines) and salts with amino acids (eg salts with arginine or lysine). These salts may be monosols or di-salts. The second salt formation can be carried out in hydroxy-type compounds of the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-sa-triazin-3-yl group.

The compound of formula I also forms acid addition salts with organic or inorganic acids. Examples of such salts are hydrohalides (eg hydrochlorides, hydrobromides and hydroiodides), salts of other mineral acids such as sulfates, nitrates, phosphates, etc., alkyl sulfonates and monoarylsulfonates such as ethanesulfonates, toluenesulfonates, benzenesulfonates, etc., as well as salts of other organic acids such as acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.

Salts of the compounds of formula I can be hydrated to form salt hydrates. Hydration can be accomplished during the preparation process, or it may be gradual as a result of the hygroscopic properties of the product, which was initially anhydrous.

The cephalosporin derivatives of the present invention may exist in syn-isomic form

ch ₃ o or as mixtures of these two forms. The syn-isomeric form has advantages as well as mixtures in which the syn-isomeric form predominates.

A suitable form of the product of this invention is:

Disodium salt trihydrate (6R, 7R) -7- [2- (2-amino-4-thiazyl) -2- (Z-methoxyimino) acetamido] -3 - [[(2,5-dihydro-6-hydroxy-2 -methyl-5-oxo-as-triazin-3-yl) thio] methyl] -8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

The starting carboxylic acid of the formula I as defined above can be obtained by a process comprising cleaving a protecting group R (or optionally a carboxy protecting group and optionally present) in the compound with the general formula

in which X has the meaning given above, R denotes a cleavable protecting group and the carboxy group may be present in protected form.

If desired, the carboxy group present in the compounds of formula II may be protected; e.g. by esterification to form a cleavable ester such as a silyl ester (e.g. trimethyl silyl ester). The carboxy group can also be protected in the form of an ester that can be easily hydrolyzed. Examples of such esters, which may be of the conventional type, are lower alkanoyloxyalkyl esters (e.g., acetoxymethyl, pivaloyloxymethyl-, 1-acetoxyethyl- and 1-pvaloyloxyethyl-ester), lower alkoxycarbonylalkoxyalkyl-esters (e.g. methoxycarbonyloxymethyl, 1-ethoxyloxy-ethyl and 1-ethoxyloxymethyl, 1-ethoxyloxy) -isopropoxycarbonyloxyethyl ester), lactonyl esters (eg phthalidyl and thiophthalidyl ester), lower alkoxymethyl esters (eg methoxymethyl ester) and lower alkanoylaminomethyl esters (eg acetamidomethyl ester). Further, the carboxy group may be protected by the formation of salts with an inorganic or tertiary organic base such as triethylamine. Possible protecting groups denoted by R are e.g. protecting groups which can be cleaved by acid hydrolysis (eg tert-butoxycarbonyl or trityl groups) or by basic hydrolysis (eg trifluoroacetyl group). Suitable protecting groups designated by R are the chloroacetyl, bromoacetyl and iodoacetyl groups, in particular the chloroacetyl group. The aforementioned protecting groups can be cleaved by thiourea treatment.

Compounds of the above formula II can be obtained e.g. by N-acylation of the corresponding 7 amino compound, namely by reacting a compound of the general formula

Η Η

CH g —— S · - · X III

COOH in which X has the above meaning and the carboxy group and / or amino group may be present in protected form with an acid of the general formula

CH ₃ 0N = C-COOH

RHN '

IV in which R has the above meaning, or by a reactive functional derivative of this acid and optionally, by cleavage of a protecting group protecting the carboxy group and optionally present.

If desired, the carboxy group present in the 7-amino compounds of formula III can be protected in the same manner as mentioned above with respect to the starting materials of formula II. The amino group in the compounds of formula III may be protected e.g. with a protecting silyl group such as trimethylsilyl group.

Examples of reactive functional acid derivatives of formula IV are halides (i.e., chlorides, bromides and fluorides), azides, anhydrides, especially mixed strong acid anhydrides, reactive esters (e.g. N-hydroxysuccinimide esters) and amides (e.g. imidazolides).

The reaction of the 7-amino-compounds of formula III with an acid of formula IV or a functional reactive derivative thereof can be carried out in a manner known per se. So e.g. the free acid of formula IV may be reacted with the aforementioned ester of a compound of formula III in the presence of a carbodiimide, such as dicyclohexylcarbodiimide, in an inert organic solvent such as ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide, and then methylpyrimidine, then group. Oxazolium salts (eg N-ethyl-5-phenyl-isoxazolium 3′-sulfonate) may be used instead of carbodiimide in the above reaction.

According to another embodiment of the process of the present invention, an acid salt of formula III (e.g., a trialkylammonium salt such as triethylammonium salt) is reacted with a reactive functional acid acid of formula IV, as mentioned above, in an inert solvent (e.g., in one of the solvents mentioned above).

In another embodiment of the process of this invention, an acid halide, preferably chloride, of an acid of formula IV is reacted with an amine of formula III. The reaction is conveniently carried out in the presence of an acid-binding agent, e.g. in the presence of an aqueous solution of alkali, in particular sodium hydroxide, or in the presence of an alkali metal carbonate such as potassium carbonate, or in the presence of a lower alkylamine such as triethylamine. Water is used primarily as a solvent, optionally in admixture with an inert organic solvent such as tetrahydrofuran or dioxane. The reaction can also be carried out in an aprotic organic solvent such as dimethylformamide, dimethylsulfoxide or hexamethylphosphoric acid triamide. When using a silylated compound of formula III, the reaction is carried out in anhydrous medium.

The reaction of a 7-amino-compound of Formula III with an acid of Formula IV or its reactive functional derivative is typically carried out at a temperature between about -40 ° C and room temperature, e.g. at a temperature of about 0 to 10 ° C.

As previously stated, the parent carboxylic acid of formula I can be obtained by cleaving an amino protecting group protected by R in the compound of formula II. The acid-hydrolysis cleavable protecting groups are removed primarily by lower alkanecarboxylic acid, which may be halogenated. We mainly use formic acid or trifluoroacetic acid. Generally, acidic hydrolysis is carried out at room temperature, although it can be performed at slightly elevated or slightly reduced temperature with respect to room temperature, e.g. at a temperature in the range of 0 to + 40 ° C. The alkali-cleavable protecting groups are generally hydrolyzed with a dilute alkali metal hydroxide solution at a temperature of 0 to + 30 ° C. The chloracetyl, bromoacetyl and iodoacetyl protecting groups may be cleaved by means of thiourea in acidic, neutral or alkaline medium at a temperature of from about 0 to + 30 ° C. In this case, the use of hydrogenolytic cleavage (eg, cleavage of the benzyl group) is not appropriate, since during the hydrogenolysis the oxime group is reduced to the amino group.

After cleavage of an amino group protecting group (indicated by R) in a compound of formula II, a carboxy protecting group may be optionally cleaved which may be present in the product obtained. If the protecting group is a silyl-ester group, this group can be separated in particular by treatment with water. The lower alkanoyloxy alkyl-, alkoxycarbonyloxyalkyl-, lactonyl-, alkoxymethyl- and alkanoylaminomethyl-esters are cleaved mainly by the enzymatic route by suitable esterase at a temperature of about 20 to 40 ° C. If the carboxy group is protected by salt formation (e.g. triethylamine), cleavage of this protecting group bound by salt formation can be carried out by acid treatment. For example, we can use e.g. hydrochloric, sulfuric, phosphoric or citric acid.

The carboxy protecting group may be cleaved in the same manner as previously described for the cleavage of the R protected group.

The preparation of the hydrates of the salts of the compounds of formula I by the method of this invention can be carried out in a manner known per se; e.g. by reacting a carboxylic acid of formula I with an equivalent amount of the desired base, conveniently in a solvent such as water or an organic solvent (eg ethanol, methanol, acetone, etc.). If a second base equivalent is used, salt formation is also carried out on a tautomeric enol form, which may also be present (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group, designated with X in Formula I) to form a di-sol. The temperature at which salt formation takes place is not critical. Salt formation usually takes place at room temperature, but can also take place at a temperature slightly higher or lower than room temperature, e.g. in the range from 0 to + 50 ° C.

The preparation of the hydrate is usually carried out automatically during the preparation process, or as a result of the hygroscopic properties of the product, which was initially anhydrous. For the controlled preparation of the hydrate, fully or partially anhydrous carboxylic acid of formula I or its ester, ether or salt may be exposed to the action of moisture (or humid atmosphere) (eg at a temperature of from about + 10 to + 40 ° C).

The 7-amino-compounds of formula III above can be obtained by reacting compounds of general formula

H H

COOH

VII in which Y denotes a cleavable atom or group of atoms and the carboxy group may be present in a protected form, with a thiol of the general formula

HS-X VI in which X has the above meaning, in the presence of water.

Examples of cleavable atoms and cleavable groups denoted by Y in the compound of formula VII are halogen atoms (e.g., chlorine, bromine or iodine atom), acyloxy groups (e.g., lower alkanoyloxy groups such as an acetoxy group), lower alkylsulfonyloxy or arylsulfonyloxy- ^ blackberries (e.g., mesyloxy or tosyloxy groups) and an azido group. The compound of formula VII may be protected on the carboxy group in the same manner as previously described with respect to the starting materials of formula III.

The reaction of the compounds of formula VII with the thiol of formula VI may be carried out in a manner known per se, e.g. at a temperature between about 40 and 80 ° C, suitable at about 60 ° C, in a polar solvent, e.g. in an alcohol such as lower alkanol (eg ethanol, propanol, etc.), dimethylformamide or dimethylsulfoxide, in water or in a buffer solution having a pH of about 6 to 7, preferably 6.5.

<-)

The syn-anti-mixture of isomers which may be obtained can be separated into the corresponding syn- and antioforms in the usual way, e.g. by recrystallization or by chromatographic methods, using a suitable solvent or mixture of solvents.

The hydrates of the salts obtained by the process of the present invention have antibiotic, in particular bactericidal activity. They have a wide range of activities against gram-positive and gram-negative microorganisms, including β-lactamase-forming Staphylococce and various 0-lactamase-forming Gram-negative bacteria, such as e.g. Pseudomonas aeruginosa, Haemophilus influenzae, Escherichia coli, Serratia marcescens, and Proteus and Klebsiella species.

The hydrates of the salts of the present invention can be used for the treatment and prophylaxis of infectious diseases. The daily dose for adults is from about 0.1 g to about 2 g. Particularly preferred is the parenteral administration of the compounds of this invention.

To demonstrate the antimicrobial activity of the compounds of this invention, the following representative compound was tested:

Compound A: Disodium salt of (6R, 7R) -7- [2- (2 amino-4-thiazolyl) -2- (Z-methoxyimino) acetamido] -3 - [[(2,5-dihydro-6-hydroxy-methyl) -5-Oxo-as-triazin-3-yl) -thio] methyl] -8-oxo-5-thia-lazabicyclo [4.2.0] oct-2-en-2-carboxylic acid. 3.5 H2O.

In vitro activity: minimal inhibitory concentration

Og / ml)

A Haemophilus influenzae strain 1 strain 2 strain 3 strain 4 strain 5 strain 6 strain 7 0.08 0.005 0.005 0.005 0.0025 0.0025 0.0025 Klebsiela pneumoniae 1.2 Escherichia coli strain 1 0.02 strain 2 0.6 Proteus mirabilis strain 1 <0.01 strain 2 <0.01 Proteus vulgaris <0.01 Proteus rettjeri <0.01 Staphylococcus strain ATCC 6538 2.5 aureus strain resistant to penicillin 2.5 Pseudomonas aeruginosa strain 1 0.3 strain 2 10 strain 3 2.5 strain 4 5 strain 5 5 strain 6 10 strain 7 5

Serratia marcescens

0.08

In vivo activity

We intraperitoneally infected groups of 5 mice with an aqueous suspension of Escherichia coli. The test substance was administered subcutaneously in sodium chloride saline three times, i.e. 1 hour, 2.5 hours and 4 hours after infection. On the fourth day, we determined the number of surviving animals. Different doses were administered and the dose at which 50% of the test animals (CD50, mg / kg) survived was determined by interpolation.

Test substance A CD ₅₀ , mg / kg <0.005 Toxicity Test substance A LD50, mg / kg i.v. 250-500 s.c. > 4000 p.o. > 5000

The cephalosporin derivatives of the present invention can be used as medicaments, e.g. in the form of pharmaceutical preparations containing them in association with carriers compatible with them. This carrier material may be organic or inorganic inert carrier material suitable for enteral or parenteral administration, such as e.g. water, gelatin, arabic gum, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petrolatum gel, etc. The pharmaceutical preparations may be formulated in solid form (eg as tablets, dragees, suppositories or capsules) or in liquid form (eg as solutions, suspensions or emulsions). The pharmaceutical preparations may be sterilized and / or may contain additives such as preserving, stabilizing, moisturizing or emulsifying agents, osmotic pressure-varying salts, anesthetics or buffers. Pharmaceutical preparations may also contain other therapeutically valuable substances. They are particularly suitable for parenteral administration and are preferably made in the form of lyophilisates or dry powders, which are diluted with conventional agents such as water or isotonic sodium chloride solution.

The following Example illustrates the process of the present invention:

Example

Preparation of disodium salt trihydrate of (6R, 7R) -7- [2- (2-amino-4-thiazolyl) 2- (Z-methoxyimino) -acetamido] -3 - [[(2,5-dihydro-6-hydroxy- 2-Methyl-5-oxo-astriazin-3-yl) -thio] -methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid

15.3 g (6R, 7R) -7- [2- [2- (2-chloroacetamido) -4-thiazolyl] -2- (Z-methoxyimino) acetamido] -3 - [[(2,5-dihydro-6- hydroxy-2-methyl-5-oxo-as-triazin-3-yl) -thio] -methyl] -8xo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid ( fraction I, see below) is suspended in 150 ml of water along with 5 g of thiourea. With vigorous nitrogen purging and gentle stirring, the pH is adjusted to 6.8-7.0 with a saturated solution of sodium hydrogen carbonate to form an orange-colored solution. The pH of this solution was maintained constant at 6.8 for 6 hours by the addition of sodium hydrogen carbonate solution using an autotitrator. A further 2.5 g of thiourea is then added and the solution is stirred for a further 3 hours while maintaining the pH to 6.8 by addition of a saturated solution of sodium hydrogen carbonate. After that, keep the red solution overnight in the refrigerator, turning dark. Adjust the pH of this solution to 2.0 to 2.5 by adding 100% formic acid, eliminating the substance. The precipitate was filtered off under vacuum in vacuo and washed with 100 ml of 10% formic acid. The mother liquor is discarded. The brown colored filter material was suspended in 200 ml of water and the pH was adjusted to 7 with triethylamine to give a brown colored solution. This solution was mixed with 2 g of activated carbon for 30 minutes, then the activated carbon was filtered off and the brown filtrate was still adjusted to pH 3.5 with 100% formic acid with vigorous stirring. The precipitated substance is filtered off under vacuum in a vacuum, washed with 50 ml of 10% formic acid and then discarded. The dark yellow colored filtrate was adjusted to pH 2 - 2.5 with 100% formic acid, precipitating the substance. This precipitate was filtered off under vacuum in vacuo, washed with ice water and dried. To convert the disodium salt, the resulting cephalosporanic acid was suspended in a mixture of 40 ml of acetone and 40 ml of water and treated with 20 ml of a 2N solution of 2-ethylcaproic acid sodium salt in ethyl acetate. 50 ml of acetone were added to the resulting orange-colored solution, eliminating the brown colored resin, which was decided by filtration. The yellow filtrate was stirred for 30 minutes, crystallizing the disodium salt. The mixture was treated in portions with 50 ml of acetone and maintained overnight in the refrigerator. The crystallizate was filtered off under vacuum in vacuo, washed successively with a mixture of acetone / water (85: 15), pure acetone and light petroleum at low boiling point and dried overnight at 40 ° C in vacuo.

The title compound is obtained in the form of crystals of beige color;

[α] _D ²⁰ = -144 ° (c = 0.5 in water). Nuclear magnetic resonance spectrum and microanalysis correspond to the structure ascribed. The disodium salt thus obtained contains 3.5 hydrates of water per mole of substance and is therefore called trihydrate.

(6R, 7R) -7- [2- [2- (2-chloroacetamido) -4-thiazolyl] -2- (methoxyimino) -acetamido] -3 - [[(2,5-dihydro-6-hydroxy-2 -methyl-5-oxo-as-triazin-3yl) -thio] -methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid used can be obtained as starting material as follows:

22.24 g of 2- (2-chloroacetamido-thiazol-4-yl) -2- (Z-methoxyimino) -acetic acid was suspended in 240 ml of methylene chloride. 13.39 ml of triethylamine were added to this suspension to give a light-brown solution. This solution was cooled to 0 to 5 ° C and treated with 16.72 g of phosphorus pentachloride. This mixture was stirred for 5 minutes at 0 to 5 ° C and then without cooling for 20 minutes. The resulting yellow solution was evaporated at 35 ° C in vacuo. Shake the evaporation residue twice with nheptane and decant the latter. The resinous substance was treated with 240 ml of tetrahydrofuran and then the insoluble triethylamine hydrochloride was filtered off. The yellow filtrate contains acid chloride.

g (7R) -7-amino-3-desacetoxy-3 - [(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-astriazin-3-yl) -thio] -cephalosporic acid was suspended in a mixture 300 ml of water and 150 ml of tetrahydrofuran. A solution of 2N sodium hydroxide was added dropwise to this suspension by vigorous nitrogen purging until a brownish solution having a pH value of 8. This solution was cooled to 0 to 5 ° C and treated for 15 minutes by dropwise addition of acid chloride in tetrahydrofuran obtained as described in the previous paragraph. The mixture was then stirred at 25 ° C for 2.5 hours. The pH of this mixture was maintained constant at 8 by the addition of 2N sodium hydroxide solution. Tetrahydrofuran was removed from the almost black-colored solution at 40 ° C in vacuo. Then add 100 ml of 2N sulfuric acid. The precipitated material is filtered off under vacuum in vacuo, washed with water and filtered off well under vacuum in vacuo. The wet brown filter material was dissolved in 1.5 l of acetone. The dark colored solution was filtered through Hyflo made from a small amount of dark colored insoluble material, then treated with activated charcoal, stirred for 30 minutes and filtered again through Hyflo. The orange-colored filtrate was dried over sodium sulfate, concentrated in vacuo and evaporated with ethyl acetate. Black resin precipitates. This resin is filtered and discarded. The two-phase filtrate containing water is azeotropically distilled three times with benzene at 40 ° C in vacuo. The precipitated material is filtered off under vacuum in a vacuum and then dried at 40 ° C under vacuum. This substance was mixed twice with 1 L of acetone (each time) leaving a brown resin which was then discarded. The combined, orange-colored acetone extracts were concentrated to about 150 ml at 40 ° C in vacuo, and the brown resin was filtered off and discarded. The filtrate was treated with 1 L of ethyl acetate and concentrated at 40 ° C in vacuo. The precipitated material is filtered off under vacuum in vacuo, washed with ethyl acetate and then with ether [to obtain (6R, 7R) -7- [2- [2- (2chloroacetamido) -4-thiazolyl] -2- (Z-methoxy- imino) -acetamido] -3 - [[(2,5-dihydro-6-hydroxy-2-methyl] -5-oxo-as-triazin-3-yl) -thio] -methyl] -8-oxo-5-thia -1-Azabicyclo [4.2.0] oct-2-en-2-carboxylic acid, fraction I; beige colored amorphous acid.]. This fraction can be used directly to prepare the desired cephalosporin derivative.

The ethyl acetate mother liquor was concentrated extensively in vacuo at 40 ° C, diluted with ether and the precipitated material filtered off under vacuum in vacuo [(6R, 7R) -7- [2- [2- (2-chloroacetamido) -4-thiazolyl] - 2- (Z-methoxyimino) -acetamido] -3 - [[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) -thio] -methyl] -8-oxo -5-thia-lazabicyclo [4.2.0] oct-2-en-2-carboxylic acid, fraction II; light beige colored, amorphous acid, slightly purer than fraction I, by thin layer chromatography].

To prepare the disodium salt, dissolve 3.5 g of acid (fraction II) in a mixture of 20 ml of acetone and 11 ml of water. The solution was treated with 7 ml of a 2N solution of the sodium salt of 2-ethylcarboxylic acid in ethyl acetate, crystallizing the disodium salt. Now a further 25 ml of acetone is added portionwise and the mixture is maintained in the freezer for 2 hours. The crystallizate was then filtered off under vacuum in vacuo, washed successively with 25 ml of ice-cold acetone / water (80: 20), pure acetone and petroleum ether at low boiling point and dried overnight at 40 ° C in high vacuum. Disodium salt of (6R, 7R) -7- [2- [2- (2-chloroacetamido) 4-thiazolyl] -2- (Z-methoxyimino) -acetamido] -3 - [[(2,5- dihydro-6-hydroxy-2-methyl-5oxo-as-triazin-3-yl) -thio] -methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] -oct-2-en- 2 carboxylic acids in the form of light yellow crystals;

[a] _D ²⁰ = —142.7 ⁰ (c = 1 in water). Nuclear magnetic resonance spectrum and microanalysis correspond to the structure mentioned above.

F. Hoffmann-La Roche AG:

AUGUST J A O Left

For

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STATEMENT Ο THE BEST WAY FOR ECONOMIC APPLICATION OF THE INVENTION

The best way to make economic use of this invention is by preparing the disodium salt of (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2- (Z-methoxyimino) acetamido] -3 - [[(2 , 5-Dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) -thio] -methyl] -8oxo-5-thia-1-azabicyclo- [4.2.0] oct-2 -en-2-carboxylic acid, which has a very high antibacterial activity and remains in the bloodstream for a long period of time. The preferred method of preparing this compound is apparent from a given embodiment and comprises reacting a starting carboxylic acid of formula I in an aqueous diluent such as acetone / water with at least two equivalents of 2-ethylcaproic acid in a diluent such as ethyl acetate at room temperature. Using an aqueous diluent, the resulting salt after treatment is automatically hydrated with 3.5 moles of hydrated water per mole of substance (trihydrate).

For

F. HOFFMANN-LA ROCHE AG

AURELY O

J. / 9 /

-OORlUr ι +

Claims (3)

A process for the preparation of a salt-hydrate of the cephalosporin derivative of the general formula ^h 2 -S- in which M cation is a pharmaceutically acceptable base, both hydrated and in the form of a syn-isomer, characterized in that it comprises reacting a compound of general formula v which X represents a 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl group or its corresponding tautomeric form of 2,5-dihydro-6-hydroxy-2methyl-5- oxo-as-triazin-3-yl group, 35 in the form of a sin isomer with at least two base equivalents, in a solvent selected from water and organic solvents such as ethanol, methanol and acetone, at a temperature between room temperature and about + 50 ° C, and isolating the resulting salt in the presence of water, or humid atmospheres as hydrates of salts. Iz A process according to claim 1 for the preparation of (6R, 7R) -7- / 2 (2-amino-4-thiazolyl) -2- (Z-methoxyimino) -acetamino / -3 - [(2,5) disodium salt trihydrate -Dihydro-6-hydroxy-2methyl-5-oxo-as-triazin-3-yl) thio / methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en- 2 carboxylic acids, characterized in that a sodium-giving base is used 5 ions and the product is isolated as (almost) trihydrate. 3. The process of claim 2, wherein the sodium salt of 2-ethylcaproic acid is used as the base to give the sodium ions. For F. HOFFMANN-LA ROCHE AG: (9 ABSTRACT PROCEDURE FOR THE PREPARATION OF CEFALOSPORINE DERIVATIVES SOLID HYDRATES The invention relates to a process for the preparation of salt hydrates of cephalosporin derivatives in which X denotes a 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl group or a corresponding tautomeric form of this group , which comprises reacting a compound of Formula I above with a base and isolating the resulting salt in the form of a hydrate of that salt. The products have antibiotic activity and can be used to treat and