DK165505B - PROCEDURE FOR THE PREPARATION OF CRYSTALLINIC CEFUROXIMAXETIL AND THIS CONNECTION IN A HIGH FORM - Google Patents

Description

DK 165505 B

The present invention relates to a particular process for the preparation of crystalline cefuroxime-1-acetoxyethyl ethyl ester (cefuroxime axetil) having a purity of at least 95% mass / mass crystallized in an R-5 to S isomer ratio of 0.9-1. 1: 1, and such a crystalline compound.

The compound (6R, 7R) -3-carbamoyloxymethyl-7 - [{2) -2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid has the adopted name "cefuroxime". This compound is a valuable antibiotic which is distinguished by its high and broad spectrum action against gram-positive and Gram-negative microorganisms, a property enhanced by the very high stability of the compound against B-lactamases formed by a variety of Gram-negative microorganisms. The compound is well tolerated by the mammalian body and is widely used as an antibiotic in clinical practice. Cefuroxime and its salts are primarily valuable as injectable antibiotics as they are poorly absorbed from the gastrointestinal tract and are therefore present in sera and urine at only low concentrations after oral administration.

Therefore, there has been a need for a form of cefuroxime which is capable of being absorbed from the gastrointestinal tract after oral administration.

It has been found that appropriate esterification of the carboxyl group in cefuroxime improves efficacy after oral administration.

The presence of such an appropriate esterifying group results in substantial absorption of the compound from the gastrointestinal tract, after which the esterifying group is hydrolyzed by enzymes present in, for example, serum and body tissues to produce the antibiotically active parent acid.

To be effective after oral administration, the ester must be stable enough to reach the site of absorption without significant degradation, but must be sufficiently absorbed after reaching that site in the body and must be sufficiently sensitive to hydrolysis under the influence of systemic esterases. -so that the parent acid is released shortly after the ester has been absorbed. British patent no.

1,571,683 lists a number of esters of cefuroxime as having properties that render them of significant potential value as orally administered antibiotics.

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2

Among the esters disclosed in British Patent Specification No. 1,571,683 it has been found that cefuroxime maxetil is of particular interest. This product has an asymmetric carbon atom at the 1-position of the 1-acetoxyethyl group and can therefore exist in the form of R and S isomers or mixtures thereof. The processes for making this ester exemplified in British Patent Specification No. 1,571,683 lead to the formation of the material either in a relatively impure amorphous form or in the form of a crystalline material. In addition, the crystalline material produced by the methods described in said patent generally contains either the R or S isomer, while a ratio of approximately 1: 1 is advantageous for the administration. Therefore, the crystalline product is not ideally suited for administration.

It has now succeeded in developing a method by which cefuroxime maxetil can be obtained in the right crystalline form and in high yield. Such a product is not only useful in that it is a right-handed form of the active compound and therefore better suited for biological administration, but in particular, such a form is also very useful as a starting material for preparing a right , essentially an amorphous form of cefuroxime maxetil, a form which has surprisingly been found to have high bioavailability after oral administration and a better balance of commercial utilization properties than the crystalline material. The amorphous cefuroxime maxetil having these properties desirably contains an approx. 1: 1 ratio of the R to S isomer since this has proved valuable in maximizing the solubility in aqueous media of the amorphous product, and the presently developed process can lead to crystalline cefuroxime maxetil with approximately this amount ratio of the isomers. .

The present process for producing high-purity crystalline cefuroxime maxetil according to the invention is characterized by crystallizing 35 cefuroxime maxetil from a solution thereof in an organic or aqueous solvent or a mixture thereof, isolating and drying the product. The crystalline product is characterized by the characterizing parts of claim 8 and / or claim 10.

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The choice of crystallization solvent has been found to be important if the yield is to be maximized and if the ratio of R and S isomer in the product is to be desirably approximately 1: 1, for example in the range of 0.9: 1 to 5 1.1: first It has been found that the various isomers of cefuroxime axetil have different solubilities, one of the isomers being consistently more soluble than the other. The solubility ratios vary according to solvent, and a solvent system is therefore conveniently chosen to allow a practically quantitative recovery of the cefuroxime axetil present before crystallization, thereby ensuring an approximately 1: 1 ratio of the isomers.

The solvent system from which the product is crystallized is conveniently selected from esters, for example methyl-15 or ethyl acetate, and halogenated hydrocarbons such as methylene chloride, optionally but preferably in admixture with an ether, e.g. diisopropyl ether, or an aliphatic or aromatic hydrocarbon such as petroleum; or an alcohol such as ethanol or isopropanol, optionally, but preferably in admixture with water such as in aqueous industrial methylated ethanol; or an amide such as dimethylformamide or dimethylacetamide or a ketone such as acetone in admixture with water.

The crystallization step is conveniently carried out at ambient temperature, for example at 10-30 ° C, and the concentration of cefuroxime maxetil in the solution from which crystallization will occur will generally be controlled, e.g., by evaporation of the solvent or by dilution so that the solution does not become too thin. or too concentrated. The crystallization may comprise the last 30 step or steps of a reaction in which the cefuroxime maxetile is formed.

In such a case, the initial steps of crystallization may be at a very high temperature, e.g. 65 ° C, but in order to maximize the yield and obtain an appropriate amount ratio of the isomers in the product, a temperature range of 10-30 ° C is preferred at the final insulation.

The reaction by which the cefuroxime axetil is formed will preferably be an esterification reaction carried out in the manner described in British Patent Specification No. 1,571,683 using a high purity sodium cephuroxim starting material.

DK 165505B

4 rials. A preferred reagent for the esterification is 1-acetoxy-ethyl bromide and to ensure an approximately 1: 1 ratio of the R to S isomer prior to recrystallization, it is preferred for obvious reasons that such a reagent be racemic.

The preferred sodium cephuroxim starting material will generally in itself be high-purity. Such a material can be obtained, inter alia, by the reaction of (6R, 7R) -3-hydroxymethyl-7- [Z-2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxyΙ- ΙΟ acid with chlorosulfonyl isocyanate in an alkyl acetate as a solvent at a temperature of -25 ° C to + 10 ° C, followed by in situ hydrolysis at a temperature of + 10 ° C to + 30 ° C and crystallization after addition of sodium-2 -ethyl hexanoate in acetone or methyl acetate as solvent. Such a material will generally have a degree of purity of 90% mass / mass (m / m) or greater.

The cefuroxime axetil produced by the process of the present invention has a molar ratio of the R and S isomer of about 1: 1 and is generally not less than 20 95% m / m pure (uncorrected for residual solvents).

In its right, crystalline form, the cefuroxime maxetil which can be prepared by the process of the invention is a novel material which is a particular feature of the present invention. A sample of this material has the nujol IR spectrum shown in the drawing.

The process according to the invention will now be illustrated in more detail by some examples, with an example of the preparation of the starting material prior to the examples.

The individual R and S isomers of cefuroxime-1-acetoxy-30 ethyl ester are for practical reasons marked with the letters A and B, these letters being used to designate the respective isomers in the same manner as in British Patent Specification no.

1571683. The identities of isomers A and B are not listed.

The isomer ratios shown in the examples are expressed as the ratio A: B.

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5

starting Material

Sodium Cephuroxim 226 ml of chlorosulfonyl isocyanate was added to a solution of 10 ml of triethylamine in 3.8 liters of methyl acetate. The resulting clear solution is cooled to -15 ° C and added over 10 minutes. a pre-cooled suspension of 763 g (6R, 7R) -3-hydroxymethyl-7- [Z-2- (fur-2-yl) -2-methoxyimino-acetamido] -ceph-3-em ~ 4-Carboxylic Acid in 2.3 L Methyl Acetate. The residual solid was rinsed with 700 ml of methyl acetate.

The mixture was stirred at -5 ° C for 30 minutes to obtain a clear solution after 10 minutes. 1.2 liters of water at a temperature of 18 ° were quickly added to the reaction mixture and the temperature rose rapidly to 10 ° C and then slowly to 17 ° C. The mixture was stirred for 60 minutes at 15 ° C to form a thick white suspension. 3.6 L of methyl acetate was added followed by the gentle addition of a solution of 288 g of sodium hydroxide in 5.2 L of water. This gave a clear biphasic mixture at 26 ° C with a pH of 2.35. The layers were separated and the upper organic layer was washed with a solution of 600 g of sodium chloride in 2 liters of water. The two aqueous layers were washed sequentially with 2 L of methyl acetate. The aqueous layers were combined, stirred with 76 g of "Norit" ® SX Plus charcoal for 30 minutes and filtered (S) through a bed of "Hyflo" Supercel, washing the bed with 1.5 L of methyl acetate. The filtrate and wash were combined and stirred at 20 ° C while adding a solution of 338 g of sodium 2-ethyl hexanoate in a mixture of 2 L of methyl acetate and 40 ml of water over 20 minutes to form a white suspension with a pH value of 5.5. The suspension was stirred for 10 minutes and filtered and the filter cake washed with 5x1 30 liters of methyl acetate, suction dried and dried at 30 ° C in vacuo for 24 hours to give 851.9 g of sodium cephuroxim.

- + 60 ° (c = 0.5 in 0.1M pH 4.5 buffer); xmax (^O) 273 nm 1% (W387); impurities according to HPLC 2.0%. Purity rating by HPLC 92% m / m; water content (Karl Fischer) 2.8% m / m; solvents (g.l.c.) 0.5% m / m.

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Example 1 Cefuroxime maxetil 12.5 g (RS) -1-acetoxyethyl bromide was added to a stirred mixture of 20 g sodium cephuroxim (prepared in a similar manner as described above for starting material preparation) in 110 ml of dimethylacetamide at 0 ° C. The mixture is stirred at + 1 ° C for 90 minutes and 0.5 g of potassium carbonate is added. Stirring was continued for an additional 2 hours at 1-3 ° C, then the reaction mixture was added to a 10-speed mixture of 200 ml of ethyl acetate and 200 ml of aqueous 3% sodium bicarbonate to destroy any excess 1-acetoxyethyl bromide. After 1 hour, the organic layer (1.5% 2 Δ isomer assessed by HPLC) was separated, washed with 100 ml of M hydrochloric acid and 30 ml of 20% sodium chloride containing 2% sodium bicarbonate.

All three aqueous phases were washed sequentially with 100 ml of ethyl acetate. The combined organic extracts are stirred for 30 minutes with charcoal ("Norit" SX Plus 2 g) and filtered through a bed of diatomaceous earth which is washed with 2 x 25 ml of ethyl acetate.

The combined filtrates and washings are evaporated in vacuo to 150 g and stirred at ambient temperature for 1 hour until crystallization is well underway. Over 45 minutes, 250 ml of diisopropyl ether was added to complete crystallization and stirring was continued for an additional 1 hour. The product was collected by filtration, washed with 150 ml of diisopropyl ether / ethyl acetate 2: 1 and dried over a weekend in vacuo at 50 ° C to give 19.3 g of crystalline cefuroxime maxetil in infrared spectrum as shown in the drawing, a spectrum which is typical of a mixture of crystalline isomers.

Solvent content (g.l.c.) 0.2% m / m. Impurities 2 rated by HPLC 1.8% including Δ-isomer, 0.3% m / m; E-isomer 0.6% m / m. Isomer ratio (HPLC) 1.09: 1. [α] = + 37 ° (c = 1% in 1% υ dioxane); E = cni = 389 (278 mm, MeOH). Assessment by HPLC 99% m / m (uncorrected).

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Example 2 Cefuroxime maxetil

A stirred suspension of 20 g of sodium cephuroxim in 110 ml of dimethylacetamide was cooled to 15 ° C and 12.5 g of (RS) -1-acetoxyethyl bromide was added. Stirring at the above temperature was continued for 45 minutes and 0.5 g of potassium carbonate was added.

After stirring the mixture for an additional 45 minutes at 15 ° C, the mixture was poured into a mixture of 200 ml of ethyl acetate and 200 ml of aqueous 3% sodium bicarbonate in rapid stirring.

After 1 hour, the layers were separated and the organic phase (where 2 HPLC showed 1.6% Δ isomer) was washed with 100 ml of 1M hydrochloric acid and 30 ml of aqueous 20% s sodium chloride containing 2% sodium bicarbonate. All the aqueous phases were washed sequentially with 100 ml of ethyl acetate. The combined organic extracts were stirred for 30 minutes with 2 g of charcoal ("Norit" ® SX Plus) and filtered through a bed of diatomaceous earth which was washed with 2 x 25 ml of ethyl acetate. After evaporating the combination of filtrate of washing liquids to 120 g, the concentrate was stirred for 20 minutes to initiate crystallization. 20 120 ml of industrial methylated ethanol was rapidly added followed by 15 minutes with 240 ml of distilled water. The resulting slurry was concentrated in vacuo to 310 g and stirred at ambient temperature for 45 minutes. The product was collected, washed with 200 ml of distilled water and dried for 67 hours in vacuo at 50 ° C to give 20.01 g of crystalline cefuroxime axetil. Solvent content (g.l.c.) 0.2% m / m? impurities (HPLC) 1.5% m / m including 0.5% 2 m / m Δ isomer and 0.6% m / m E isomer; isomer ratio 1.01: 1? [α] = + 40 ° (c = 1.0 in dioxane); E m = 388 (278 nm, methanol); 30 rating by HPLC 98% m / m (uncorrected).

Example 3 Cefuroxime maxetil 20 g of sodium cephuroxim was stirred with 100 ml of dimethylacetamide at ca. 25 ° C for 15 minutes, the mixture was cooled to 15 ° C and 9.8 ml of (RS) -1-acetoxyethyl bromide was added. Bian-

DK 165505B

The mixture was stirred for an additional 90 minutes at 14-16 ° C with 0.5 g of 60 mesh potassium carbonate added halfway through this period. Then, the red-brown mixture was diluted with 200 ml of ethyl acetate and 200 ml of 3% aqueous sodium bicarbonate 5 and stirred for 1 hour at room temperature (about 25 ° C). The layers were then separated and the aqueous layer re-extracted with 200 ml of ethyl acetate and discarded (ot, 0.21 ° / dm). The organic solutions were washed sequentially with 100 ml of 1M hydrochloric acid, then 30 ml of 20% sodium chloride containing 2% sodium hydrogen-10 carbonate and then combined and treated with 2 g of "Norit" ® SX Plus charcoal for 25 minutes. The charcoal was filtered through a pad of "Standard Supercel" ®, the filter washed with 50 ml of ethyl acetate and the combined filtrates evaporated in vacuo to 120 g. The remaining solution was seeded and stirred at 22 ° C for 1 hour then 250 ml of toluene was introduced into the slurry was stirred for 30 minutes and the mixture was stirred for a further 30 minutes. The suspension was evaporated in vacuo to 182 g, cooled to ca. 25 ° C and stirred for 30 minutes. The product was collected, washed with 20 100 ml of toluene, suction dried for 15 minutes and then dried in vacuo at 45 ° C overnight to give 19.8 g of crystalline cefuroxime maxetil. Solvent content according to g.l.c. 0.9% (ethyl acetate 0.7%, toluene 0.15%); impurities rated by HPLC 0.9%, HPLC determination 100%, isomer ratio 1.03: 1, 2.25 δ <0.1% m / m. Water (according to Karl Fischer) 0.4% m / m.

Example 4 Cefuroxime maxetil 30 The washed and to ca. 125 g of evaporated ethyl acetate solution of cefuroxime axetil, obtained by a similar reaction as described in Example 1, was stirred at room temperature until crystallization was well underway. A drop of 188 ml of petroleum ether (b.p. 100-120 ° C) was added dropwise over a period of 35 hours, then the suspension was stirred at room temperature for a further 2 hours. The crystalline precipitate was collected by filtration, washed with 75 ml of petroleum ether (bp 100-120 ° C) / ethyl acetate 2: 1 and dried overnight at

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9

In vacuo to give 19/2 g of the title compound. Water content (Karl Fischer) 0.4% m / m, solvent content (g.l.c.) 0.4% m / m. Assessment by HPLC

100% m / m. Impurities, likewise assessed by HPLC, 1.1% m / m (wherein of 0.1% and 0.6% m / m were the Δ isomer and anti-isomer, respectively); the isomer ratio was 0.98: 1.

Example 5 Cefuroxime maxetil

One washed and for approx. 125 g of concentrated solution of the required cefuroxime axetil in ethyl acetate prepared as described in Example 1 was stirred for 1 hour at 33 ° C until crystallization was well underway. After storage of the suspension overnight at room temperature, 62.5 ml of industrial methylated ethanol was added over 5 hours with stirring, followed by the next hour of 250 ml of petroleum ether with b.p. 100-120 ° C. After stirring the crystalline suspension for a further 1.5 hours, it was collected, 20 was washed with 75 ml of a mixture of petroleum ether (bp 100-120 ° C) / ethyl acetate 2: 1 and dried overnight in vacuo at 45 ° C to give 19.2 g of the title compound. Water content (Karl Fischer) 0.2% m / m; solvent content (g.l.c.) 0.8% m / m. Impurities judged by HPLC 0.8% m / m (of which 0.1% m / m and 0.7% m / m respectively Δ-isomer and anti-isomer); isomer ratio 1.05: 1. Assessment by HPLC 96% m / m.

Example 6

Cefuroximaxetil

A washed and charcoal-treated concentrate (about 100 g) of cefuroxime maxetil in ethyl acetate, containing ca. 2% Δ isomer, and obtained in a similar manner as described in Example 1, was seeded and stirred for 30 minutes until crystallization was well underway. 100 ml of isopropanol was added dropwise over 30 minutes, followed by 50 minutes of 170 ml of distilled water. The resulting slurry was concentrated

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10 in vacuo to 250 g and cooled to 12 ° C over 1 hour.

The crystalline product was collected by filtration, washed with an ice-cold solution of 100 ml of 20% isopropanol in distilled water and dried over a weekend in vacuum 5 at 40 ° C. The title compound was watered in an amount of 20.1 g. Water content according to Karl Fischer 0.4% m / m, solvent content (g.l.c.) 0.03% m / m. Impurities rated by HPLC 1.5% (of which 0.4% m / m and about 0.6% m / m respectively, 2 Δ isomer and anti-isomer). Isomer ratio 1.05: 1.

Claims (10)

A process for the preparation of crystalline cefuroxime-1-acetoxyethyl ester having a purity of at least 95% mass / mass crystallized in an R Process according to claim 1, characterized in that the cefuroxime-1-acetoxyethyl ester is crystallized in an R to S isomer ratio of approx. 1: 1. Process according to claim 1 or 2, characterized in that the solvent used includes an ester. Process according to claim 3, characterized in that the solvent comprises an ester or halogenated hydrocarbon, optionally in admixture with an ether, or an aliphatic or aromatic hydrocarbon; or a ketone or an amide in admixture with water. Process according to claim 1 or claim 2, characterized in that the solvent comprises an alcohol in admixture with water. S-isomer ratio of 0.9-1.1: 1, characterized by crystallizing cefuroxime-1-acetoxyethyl ester from a solution thereof in an organic or aqueous solvent or a mixture thereof, isolates and dries the product. Process according to claim 4, characterized in that the solvent is methyl or ethyl acetate, optionally 25. admixture with diisopropyl ether, petroleum ether or toluene. Process according to any one of the preceding claims, characterized in that at least a relatively late portion of the crystallization step is carried out at 10-30 ° C. Crystalline cefuroxime-1-acetoxyethyl ester, characterized in that it has a purity of at least 95% mass / mass and wherein the R to S isomer ratio is 0.9-1.1: 1. Crystalline cefuroxime-1-acetoxyethyl ester according to claim 8, characterized in that the R to S isomer ratio 35 is approx. 1: 1. Crystalline cefuroxime-1-acetoxyethyl ester, characterized in that it has an infrared spectrum in nujol as shown in the drawing.