NL8402372A - PROCESS FOR THE PREPARATION OF CEFUROXIM-AXETIL. - Google Patents

Description

«R -Process for the preparation of exercise uroxime-axetil -

This invention concerns improvements in the field of cephalosporins. More specifically, it concerns the preparation of the 1-acetoxyethyl-ester of cefuroxime (cefuroxime-axetill.

The compound (6R, 7ll-3-carbamoyloxymethyl-7- (Zi-5 2-furyl-2I-2-methoxyiminoacetamido] cef-3-em-4-carboxylic acid has the accepted trivial name "cefuroxime". This compound is a valuable antibiotic characterized by a broad spectrum against gram-positive and gram-negative microorganisms, which property is enhanced by the very high stability of IQ this compound against ft-lactamases that form many gram-negative microorganisms. tolerated and extensively used as an antibiotic in clinical practice Cefuroxime and its salts are especially valuable as injectable antibiotics as they are poorly absorbed from the gastrointestinal tract and after oral administration only in low concentrations in blood serum and urine There was therefore a need for a form of cefuroxime which is resorbable from the gastrointestinal tract after oral administration.

It has been found that proper esterification of the 2Q carbaxyl group of cefuroxime improves its efficacy after oral administration. The presence of such a suitable ester group leads to an important resorption of the compound from the gastrointestinal tract, after which that ester group is hydrolysed by the enzymes that are present eg in serum and body fluids 25 8402372> Λ _ o _ A # and the antibiotic active parent substance is released again. To be effective after oral administration, the ester must be stable enough to reach the resorption site without significant degradation, must be sufficiently reabsorbed upon reaching the appropriate site, and must be susceptible enough to hydrolysis by the systemic esterases, so that the mother substance is released shortly after absorption. British Patent 1571683 has cited a number of cefuroxime esters and is said to have properties that make them of potential interest as antibiotics to be administered orally.

Among the esters described in British Patent No. 1571683, cefuroxime axetil has proven to be of particular interest.

This product has an acyrametric carbon atom in the 1-position of the 1-acetoxyethyl group, and therefore may exist in R and S forms and as a mixture thereof. The process for the preparation of this ester described in British Patent No. 1571683 leads either to relatively impure, amorphous material or to crystalline material. Furthermore, the crystalline material formed by the method described consists essentially of either 20 R or S isomer, while a ratio of about 1: 1 is advantageous for administration. The crystalline product is therefore not quite ideal for oral administration.

A process has now been found by which cefuroxime axetil can be obtained in very pure crystalline form and in high yield. Such a product is useful not only from the standpoint of having a pure form of the active substance which is better suited for biological administration, but also as a starting material for the preparation of very pure, mainly amorphous cefuroxime axetil, which form surprisingly high bioavailability after oral administration matches a better balance of properties for commercial use than the crystalline material. The amorphous cefuroxime axetil with these properties is preferably an approximately 1: 1 mixture of R and S isomers, 8402372 iv-3, as it has been found to be valuable in maximizing the solubility of the amorphous product in aqueous media. However, by the method to be described below, one can also obtain crystalline cefuroxime axetil with approximately that ratio of isomers.

According to the invention, therefore, very pure, crystalline 1-acetoxyethyl ester of cefuroxime is prepared by crystallizing 1-acetoxyethyl ester of cefuroxime from a solution thereof in an organic or aqueous solvent or a mixture thereof, and the product is isolates and dries.

The choice of the crystallizable solvent has proved important if the yield is to be maximal, and it is desirable that the ratio between R and S isomers in the product is about 1: 1, for example, between 0.9: 1® . 1.1: 1. It has been found that the different isomers of cefuroxime axetil have different solubilities, one is clearly more soluble than the other. How much those solubilities differ depending on the solvent, and so it is best to choose a solvent that has a practically quantitative recovery of cefuroxime— axetil, thus assuring an approximately 1: 1 ratio between the isomers.

The solvent system from which the product can be crystallized is preferably selected from the esters such as methyl or ethyl acetate, the halohydrocarbons such as methylene chloride (optionally and preferably in combination with an ether such as diisopropyl ether or with aliphatic or aromatic hydrocarbons such as petroleum ether or toluene. the alcohols, such as ethanol and isopropanol (optionally and preferably in combination with water, such as in denatured spirit, the amides: such as dimethylformamide and dimethylacetamide, and the ketones such as acetone in combination with water.

Crystallization preferably takes place at ambient temperature, e.g. between 10 ° and 30 ° C, and the concentration at 3402372 4 Ί.

- 4 - cefuroxime-axetil The solution from which crystallization will take place will generally be adjusted, eg by evaporation or by dilution, so that it is neither too weak nor too strong. Crystallization can be the last step of the synthesis to form the cefuroxime axetil. In that case, the first crystallization can be done at a rather high temperature e.g. up to about 65 ° C, but to obtain a maximum yield and a a good ratio of isomers in the product is preferred in the final isolation, so a temperature between 10 ° and 30 ° C is preferred.

The reaction with which the cefuroxime axetil is formed is preferably an esterification carried out as described in British Patent No. 1571683, starting from relatively pure sodium cefuroxime. A preferred esterification reagent is 1-acetoxyethyl bromide, and to achieve an approximately 1: 1 ratio between R and S isomers for recrystallization, it is highly preferred that the reagent be racemic.

The preferred starting material sodium cefuroxime u will generally be relatively pure itself. Such material is obtained, for example, by reaction of (6R, 7R) -3-hydroxy-methyl-7- / Z-2- (furyl-2l-2-methoxyiminoacetamid <27-cef-3-em-4- carboxylic acid with chlorophenyl isocyanate in an alkyl acetate as a solvent at a temperature between -25 ° and + 10 ° C, followed by OC oo hydrolysis in situ at a temperature between +10 and +30 G, and finally crystallization after the addition of sodium-2- ethyl hexanoate in acetone or methyl acetate as a solvent Such material will generally have a purity of 90% or better.

The cefuroxime axetil by the process of the invention has a ratio between R and S isomers of about 1: 1, and will generally be at least 95% pure (excluding solvent residues!).

8402372

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In its highly pure, crystalline form, the cefuroxime axetil to be prepared by the process of the invention is a novel substance, and that is therefore an aspect of the invention.

An example of this material is the IJt spectrum in Nujol which is shown in the accompanying drawing.

The invention is now illustrated by the following non-limiting examples.

The individual isamers of the 1-acetoxyethy 1 ester of cefuroxime are herein conveniently referred to by the letters A and B, which have the same meaning here as in British

10. Patent 1571683. The identities of isomers A and B

is not fixed. The isomer ratios in the combing examples are all given as A: E.

Preparation of the starting material sodium cefuroxime

226 ml of chlorosulfinyl isocyanate were added to a solution of 10 ml of triethylamine in 3.7 l of methyl acetate.

0

The clear solution obtained was cooled to -15 ° C and a suspension of 763 g (6R, 7R1-3-hyiroxymethyl-7-Z-2- (fury 1-21 -2-maths yeminoacetamidg7-cef-3-em- 4-carboxylic acid in 2.3 L of methyl acetate, which had previously cooled to -15 ° C, was added over 10 2 minutes The last bit of solid was rinsed with 700 ml of methyl acetate The mixture was stirred at -5 for 30 minutes Stirred at 0 ° C, and after 10 minutes a clear solution was already present.

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After those 30 minutes, 1.2 L of water at 18 ° C was added rapidly, the temperature rising rapidly to 10 ° C and then slowly to 17 ° C. The mixture was stirred at 15 ° C for an additional 60 minutes to give a thick white suspension. 3.6 L of methyl acetate was then added, followed by the gradual addition of a solution of 288 NaOH and 5.2 L of water. This gave a clear two-phase system of 26 ° C and a pH of 2.35. The two phases were separated and the top organic layer was treated with a 600 g solution

Nad. washed in 2 l of water. The two portions of water were washed successively with 2 L of methyl acetate. The organic layers were put together, stirred for 30 minutes with 76 g Norit SX Plus, and filtered through a bed of Hyflo Supercel, which was rinsed with 1.5 L of methyl acetate. Filtrate and washings were combined at Stirred at 20 ° C while adding a solution of 5 388 g of sodium 2-ethylhexanoate in a mixture of 2 l of methyl acetate and 40 ml of water over 20 minutes to give a white suspension with a pH of 5.5. was stirred for 10 minutes and filtered, and the filter cake was washed with 5x11 "methyl acetate, sucked dry under vacuum at 30 ° C for 24 hours.

This gave 851.9 g of sodium cefuroxime 1 & l ^ = + 60 ° (C = 0.5 in Ο, ΙΜ buffer with pK = 4.51 V max (H_öl 273 nm (e |% - 3871, according to hplc 2.0% 5 . Ί- X cm impurities-Strength (hplcl 92% m / m; water (Karl Fischer1 2.8% $ solvents (gas chromatography 0.5% -

2Q Example I

To a mixture of 20 g of sodium cefuroxime (prepared on the wafer indicated above and 110 ml of 0-dimethyl acetamide

0 C was added with stirring 12.5 g of (RS1-1-acetoxyethyl bromide. The mixture was stirred at + 1 ° C for an additional 90 minutes, after which time 25.5 g of K 2 CO 2 was added. -3 ° C

stirred and then the whole was added to a rapidly stirred mixture of 200 ml ethyl acetate and 200 ml aqueous 3% NaHCO 2 solution to destroy any excess 1-acetoxyethyl bromide. After 1 hour, the organic layer (with 2 3Q HPLC 1.5% Δ-isomer 5 was separated and successively with 100 ml of tlECI, 30 ml of aqueous 20% NaCL solution and 30 ml of aqueous 2% NaECO solution. All three aqueous phases were then back-extracted with 100 ml of ethyl acetate The combined organic 8402372-7 extracts were stirred with 2 g of charcoal (Norit SX Plus) for 30 minutes and filtered through a bed of kieselguhr, which was washed with 2 x 25 ml of ethyl acetate. were evaporated together under vacuum to 150 g and this was stirred at room temperature for 1 hour until crystallization had taken place, 250 ml of diisopropyl ether were now added over 45 minutes and stirred for an additional hour to complete the crystallization. filtered, washed with 150 ml of diisopropyl ether / ethyl acetate 2: 1 and dried under vacuum at 50 ° 5 for a weekend to give 19.3 g of cefuroxime axetil. ol is shown in the accompanying drawing; this spectrum is representative of mixtures of crystalline isomers.

Solvents (from gas chromatography 0.2%. Impurities 2 15 (according to HPICl 1.8%, including 0.3% Δ isomer and 0.6% E isomer. Ratio A: B 1.09: 1; + 37 ° (1% in dioxane}; 1% uE, 389 (at 278 nm, in MeOHl. Strength (according to HPLCl 99% (not 1cm corrected for solvents).

Example 2 2Q To a suspension of 20 g of sodium cefuroxime in 110 ml of dimethylacetamide cooled to 15 ° C was added 12.5 g of (BS) -1-acetoxyethyl bromide with stirring. After stirring for another 45 minutes o

0.5 g of K2CO3 was added. After stirring for another 45 minutes at 15 ° C

the reaction mixture was poured into a rapidly stirred mixture of 200 ml ethyl acetate and 200 ml aqueous 3% NaHCl 3 solution.

After 1 hour the phases were separated and the organic phase 2 (with HPLC 1.6% Δ-isomer with 100 ml and hydrochloric acid and 30 ml 20% Na-CL containing 2% Na 2 CO 2) was washed. All washings were then back extracted with 100 ml of ethyl acetate.

The organic exacts were stirred together with 2 g of charcoal (Norit SX Plus) for 30 minutes and filtered through a bed of kieselguhr, which was then washed with 2 x 25 ml ethyl acetate. Filtrate and washings were evaporated together to 120 g, and after 3402372 was stirred for 20 minutes so that crystallization was well started, first 120 ml of industrial spirit was added, and then 240 ml of distilled over 15 minutes. water. This suspension was evaporated to 310 g under vacuum and stirred at room temperature for 45 minutes. The product was harvested, washed with 200 ml of distilled water and dried under vacuum at 50 ° C for 67 hours to give 20.01 g of cefuroxime axetil.

Gas chromatography shows 0.2% residual solvent .2% and HPLC shows 1.5% impurities, including 0.5% Δ -

10 isomer and 0.6% E isomer; ratio A: B 1.01: 1; Z "<> 67_ + 40 ° C

1% (1% in dioxane); E. 388 (at 278 nm in methanol}. Strength 1 cm 98% (from HPLC, not corrected !.

Example 3

A mixture of 20 g of sodium cefuroxime and 100 ml of dimethyl acetamide was stirred at about 25 ° C for 15 minutes and then cooled to 15 ° C, then 9.8 ml (RS1-1-acetoxyethyl bromide was added. The mixture was added Stirred at 14-16 ° C for 90 minutes, and at the middle of that time, 0.5 g of K 2 CO 2 that had passed through a 0.25 mm sieve was added At the end of those 60 minutes, the reddish brown mixture was ml of ethyl acetate and 200 ml of aqueous 3% NaHCO2 solution diluted After stirring for an additional hour at room temperature (approx. 25 ° 1, the phases were separated and the aqueous phase was extracted with 200 ml of ethyl acetate and then discarded («0, 0.21 ° / dml The organic solutions were successively treated with 100 ml of M hydrochloric acid and 30 ml of 20% NaHCL solution containing 2% NaHCO 2 and then treated with 2 g Norit SX Plus for 25 minutes The charcoal was filtered through a layer of Standard Super cell which was rinsed with 50 ml ethyl acetate The filtrate and washing liquid were combined under vacuum to 120 g in vaporized.

This concentrate was seeded with crystals and stirred at 22 ° C for 1 hour, then 250 ml of 34 02 37 2 - 9 - toluene was added dropwise over 30 minutes with stirring. The suspension was again evaporated to 132 g under vacuum, cooled to about 25 ° C and stirred for 30 minutes. The product was then harvested, washed with 100 ml of toluene, vacuumed for 15 minutes and then dried under vacuum at 45 ° C overnight to give 19.8 g of crystalline cefuroxime-axeti.

Solvents (from 0.9% gas chromatograph (0.7% EtAc and 0.15% toluene); impurities (by HPLC) 0.9%; strength 2 100%, A: B 1.03: 1, Δ A 0, 1% Water (according to Karl Fischer) 0.4% Example 4 jq In accordance with Example 1, cefuroxime-axetil was prepared until crystallization was well underway, about 125 g of which was then obtained over an hour. underwear

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stirring 188 ml of petroleum ether (kP 100-120 Cl) were added, after which the suspension was stirred for an additional 2 hours at room temperature.

A set of crystalline precipitate was filtered off and washed with petroleum ether / ethyl acetate 2: 1 by displacement and dried overnight under vacuum at 40 ° C to give 19.2 g of the title compound.

Water (according to Karl Fischer1 0.4%, residual solvent 2Q (according to gas chromatography 0.4%. Strength (from HPLC1 100%.

2

Impurities (from HPLC) 1.1% (of which 0.1% Δ-isomer and 0.6% anti-isomer; A: B ratio was 0.98: 1.

Example 5

In accordance with Example 1, cefuroxime axetil was prepared to the point that crystallization was well initiated.

The approx. 125 g of suspension which was then allowed to stand at room temperature overnight, then 63.5 ml of industrial spirit was added over 5 minutes with stirring, and then over 250 ml of petroleum ether (kP 100-120 ° C) over 1 hour. Stirring for 1½ hours, the crystals were harvested and washed out with displacement with 75 ml of petroleum ether / ethyl acetate 2: 1, and dried overnight at 45 ° C to give 19.2 of the title compound.

§402372 Λ - 10 -

Water (according to Karl Fischer1 0.2%; solvent residues (according to gas chromatography 0.8%. Impurities (from HPLC) 0.8% 2 (of which 0.1% & isomer and 0.7% anti-isomer; A: B was 1.05: 1. Strength (by HPLC1 was 96%.

^ Example 6

In accordance with Example 1, cefuroxime axetil was prepared to the point of having an eluted and charcoal-treated concentrate in ethyl acetate. This solution (2 of which contained the product about 2% L-isomer) was seeded and stirred 1 Ω for 30 minutes, after which the crystallization was well underway. Now 100 ml of isopropanol was added dropwise over 30 minutes, then 170 ml distilled over 50 minutes. water The suspension obtained was concentrated in vacuo to 250 g and cooled to 12 ° C in 1 hour.

1C

filtered, washed with displacement with 100 ml of ice-cold isopropanol / water 1: 5, and dried under vacuum at 40 ° C for a weekend. This gave 20.1 g of cefuroxime axetil.

Water (0.4% according to Karl Fischerl; solvent residues (0.03% according to gas chromatography. Impurities (from HPLCl 1.5% 2Q 2 (of which 0.4% is isomer and about 0.6% anti-isomer). Ratio 'A: B was 1.05: 1.

8402372

Claims (10)

1. Process for the preparation of a high purity crystalline 1-acetoxyethyl ester of cefuroxime, characterized in that 1-acetoxyethyl ester vein cefuroxime is used. crystallizes from a mixture thereof in an organic or aqueous solvent or mixture thereof, and the product is isolated and dried. The process according to claim 1, wherein the 1-acetaxyethyl ester of cefuroxime is crystallized at a ratio of ft to S isomer of about 1: 1. 3. A method according to claim 1 or 2, wherein the solvent is or contains an ester. The method of claim 3, wherein the solvent is an ester or a halohydrocarbon optionally in combination with an ether or an aliphatic or aromatic hydrocarbon, or a ketone or an amide in combination with water. 15 The method of claim 4, wherein the solvent is methyl or ethyl acetate, optionally in combination with diisopropyl ether, petroleum ether or toluene. The method of claim 1 or 2, wherein the solvent is an alcohol in combination with the water. 2Ü A method according to any one of the preceding claims, wherein at least the later part of the crystallization takes place at a temperature between 10 and 3 ° C. 8. Method mainly according to description and / or examples. 25 9. Crystalline 1-acetoxyethyl ester of cefuroxime with a purity of at least 95%. 10. Crystalline i-acetoxyethyl ester of cefuroxime with segoIR spectrum. in Nu jol as healed in the accompanying 8402372