NO167292B - PROCEDURE FOR THE PREPARATION OF CEFUROXIM 1 ACETOXYLYL ESTE. - Google Patents

Description

The present invention relates to a method for the production of cefuroxime 1-acetoxyethyl ester (cefuroxime axetil) as stated in claim 1's preamble.

The compound (6R,7R)-3-carbamoyloxymethyl-7-(Z)-2-(fur-2-yl)-2-methoxy iminoacetamido/cef-3-em-4-carboxylic acid has the trivial name "cefuroxime". This compound is a valuable antibiotic characterized by a very broad-spectrum activity against gram-positive and gram-negative microorganisms, and this property is reinforced by the very high stability of the compound against 3-lactamases produced by a number of gram-negative organisms . It is well tolerated by mammals and is widely used as an antibiotic in clinical practice. Cefuroxime and its salts are mainly valuable as injectable antibiotics since they are poorly absorbed from the digestive tract and are therefore only present in low concentrations in sera and urine after oral administration. There has therefore been a need for a form of cefuroxime that can be absorbed from the digestive tract after oral administration.

Proper esterification of the carboxyl group of cefuroxime has been found to improve efficacy after oral administration. The presence of such an esterification group leads to significant absorption of the compound from the digestive tract, after which the esterification group is hydrolysed by enzymes present in e.g. serum and body tissue and gives the antibiotic active mother acid. To be effective after oral administration, the ester must be sufficiently stable to reach the point of absorption without significant degradation, must be sufficiently absorbed after reaching the appropriate point, and must be sufficiently hydrolytically sensitive to systemic esterases that the parent acid is released within a short time from the ester is absorbed. British Patent No. 1571683 describes and claims that a number of esters of cefuroxime have properties which make them particularly potentially valuable orally administrable antibiotics.

Of the ester described in British patent no. 1571683, it has now been found that cefuroxime axetil is of particular interest. This product has an asymmetric carbon atom in the 1-position in the 1-acetoxyethyl group and can therefore exist in the form of R and S isomers or mixtures thereof. The method for producing the above-mentioned ester exemplified in British patent no. 1571683 gives the material either in a relatively impure amorphous form or in the form of a crystalline material. Furthermore, the crystalline material produced by the methods described in this patent contains a preponderance of either the R or S isomer, while an approximate 1:1 ratio is advantageous for administration. The crystalline product is therefore not ideally suited for administration.

It has now been possible to develop a method by which cefuroxime axetil can be obtained in very pure crystalline form and in high yield. Such a product is not only useful because it exists in a very pure form of the active compound and is consequently more suitable for biological administration, but even more so it is also particularly useful as a starting material for the production of a very pure, mainly amorphous form of cefuroxime axetil, which form has surprisingly been found to be highly biologically utilizable after oral administration, and which has better balanced properties for commercial use than the crystalline material. The amorphous cefuroxime axetil having these properties exists as desired in an approximately 1:1 ratio of R to S isomers, as this has been found to be valuable in maximizing the solubility in aqueous media of the amorphous product, and the method now developed can provide crystalline cefuroxime axetil with this approximate ratio of isomers.

Accordingly, a method is provided for the production of very pure crystalline cefuroximaxetil in high yield in which one crystallizes cefuroximaxetil from a solution thereof in an organic or aqueous solvent or a mixture thereof, and isolates and dries the product as

stated in claim 1<1>'s characterizing part.

The choice of crystallization solvent has been found to be important if the yield is to be maximized and the R to S isomer ratio in the product is to be, as desired, approximately 1:1,

e.g. in the range 0.9:1 to 1.1:1. It has been found that different isomers of cefuroxime axetil have different solubilities and consequently one of them is more soluble than the other. The degrees of solubility vary depending on the solvent, and thus it is desirable to choose a solvent system which allows practically quantitative recovery of cefuroxime axetil that is present before crystallization, thereby ensuring an approximately 1:1 ratio of the isomers.

The solvent system from which the product can be crystallized will preferably be chosen from methyl or ethyl acetate, optionally, in a mixture with diisopropyl ether, petroleum ether or toluene; or ethanol or isopropanol, optionally in mixture with water, such as in aqueous methanol denatured alcohol; or dimethylformamide or dimethylacetamide, or acetone, in mixture with water.

The crystallization step will preferably be carried out at ambient temperature, e.g. from approx. 10 to 30°C and the concentration of cefuroxime axetil in the solution from which the crystallization will occur will generally be adjusted, e.g. by evaporation of the solvent or by such dilution that the solution is neither too dilute nor too concentrated. The crystallization may comprise the last step or steps in a reaction in which cefuroxime axetil is formed. In such a case, the initial step of crystallization can take place at a rather high temperature, e.g. up to approx. 65°C, but in order to maximize the yield and achieve an appropriate ratio of the isomers in the product, a temperature range of 10 to 30°C is preferred for the final isolation. The reaction in which cefuroxime axetil is formed will preferably be an esterification reaction carried out in the manner described in British Patent No. 1,571,683, and using a very pure sodium cefuroxime starting material. A preferred reagent for the esterification is 1-acetoxyethyl bromide, and in order to produce an approximately 1:1 ratio of R and S isomers prior to the recrystallization, it is certainly preferred that such a reagent is racemic.

The preferred sodium cefuroxime starting material will generally itself be very pure. Such a material can be obtained, inter alia, by reaction of (6R,7R)-3-hydroxymethyl-7-/Z-2-(fur-2-yl)-2-methoxyiminoacetamido/cef-3-em-4-carboxylic acid with chlorosulfonyl isocyanate in an alkyl acetate as solvent at a temperature from 25° to +10°C, followed by hydrolysis in situ at a temperature of +10° to +30°C and crystallization after addition of sodium 2-ethylhexanoate 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 ethylate produced by the method of this invention has an R to S isomer ratio of approximately 1:1, and is generally not less than 95% m/m pure (uncorrected for solvent residues).

In its very pure crystalline form, cefuroxime axetil, which can be produced by the method of the present invention, is a new form of the substance. A sample of this material has the IR spectrum in Nujol shown in the accompanying drawing.

The invention will now be illustrated by the following starting materials and examples.

The individual R and S isomers of cefuroxime 1-acetoxyethyl ester are given the letters A and B for convenience, these letters being used to denote the respective isomers as in British Patent No. 1571683. The identities of the isomers A and B have not been determined. The isomer ratios in the following examples are expressed as A:B. All temperatures are given in °C.

Output material 1

Sodium cefuroxime

Chlorosulfonyl isocyanate (22 6 mL) was added to a solution of triethylamine (10 mL) in methyl acetate (3.8 L). The resulting clear solution was cooled to -15°C and a suspension of (6R,7R)-3-hydroxymethyl-7-/Z-2-(fur-2-yl)-2methoxyiminoacetamido/cef-3-em-4 -carboxylic acid (763 g) in methyl acetate (2.3 L) precooled to -15°C was added over 10 minutes. The remaining solid was flushed with methyl acetate (700 mL). The mixture was stirred at -5°C for 30 minutes, and a clear solution was obtained after 10 minutes. Water (1.2 L) at 18°C was quickly added to the reaction mixture, the temperature rose rapidly to 10°C and then slowly to 17°C. The mixture was stirred for 60 minutes at 15°C and gave a thick white suspension. Methyl acetate (3.6 L) was added followed by a steady addition of a solution of sodium hydroxide (288 g) in water (5.2 L). 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 sodium chloride (600 g) in water (2 L). The two aqueous layers were washed gradually with methyl acetate (2 1). The organic layers were combined, stirred with Norit SX Plus carbon (76 g) for 30 minutes and filtered through a pad of Hyflo Supercel, washing the pad with methyl acetate (1.5 L). The filtrate and washings were combined and stirred while a solution of sodium 2-ethyl hexanoate (338 g) in a mixture of methyl acetate (2 L) and water (40 mL) was added over 20 minutes to give a white suspension with a pH of 5.5. The suspension was stirred for 10 minutes and filtered and the cake was washed with methyl acetate (5 x 1 L), sucked dry, and dried at 30°C in vacuo for 24 hours to give sodium cefuroxime (851.9 g); /cx/<2>0D+ 60°, (c0.5; 0.1M pH 4.5 buffer); Xmax (H 2 O) 273 nm (E<1>%1cm 387); impurities by HPLC 2.0%. Measurement (HPLC) 92% m/m; Water content (Karl Fisher) 2.8% m/m; Solvents (gas chromatographic) 0.5% m/m.

Example 1

Cefuroxime axetil

(RS)-1-acetoxyethyl bromide (12.5 g) was added to a stirred mixture of cefuroxime sodium (20 g) (prepared by a similar method to starting material 1) in dimethyl acetate

(110 ml) at 0°C. The mixture was stirred at +1°C for 90 minutes and sodium carbonate (0.5 g) was added. Stirring was continued for an additional 2 hours at 1-3°C, after which the reaction mixture was added to a rapidly stirred mixture of ethyl acetate (200 mL) and aqueous 3% sodium bicarbonate (200 mL) to destroy any excess 1-acetoxyethyl bromide. After 1 hour, the organic layer (1.5% A<2> isomer by HPLC) was separated, washed with M hydrochloric acid (100 mL) and aqueous 20% sodium chloride containing 2% sodium bicarbonate (30 mL). All three aqueous phases were gradually washed with ethyl acetate (100 mL). The combined organic extracts were stirred for 30 minutes with activated carbon (Norit SX Plus; 2g), filtered through a pad of silica washed with ethyl acetate (2 x 25 ml). The combined filtrates and washings were concentrated in vacuo to 150 g and stirred at ambient temperature for 1 hour until crystallization was well under way. Di-isopropyl ether (250 mL) was added over 45 minutes to complete crystallization and stirring was continued for a further hour. The product was collected by filtration, washed with 2:1 di-isopropyl ether/ethyl acetate (150 mL) and dried over a weekend in vacuo at 50°C to give crystalline cefuroxime axetil (19.3 g) with an infrared spectrum in Nujol as shown in the figure in the attached drawing which is typical of a mixture of crystalline isomers.

Solvent content (gas chromatography) 0.2% m/m. Impurities by HPLC 1.8% include A<2> isomer 0.3% w/w; E-isomer 0.6% w/w. Isomer ratio (HPLC) 1.09:1 /cx/D (1% in dioxane) +37°C; E<1>%1cm (278 mm, MeOH) 389. Measurement by HPLC 99% m/m (uncorrected).

Example 2

Cefuroxime axetil

A stirred slurry of sodium cefuroxime (20 g) in dimethylacetamide (110 ml) was cooled to 15°C and (RS)-1-acetoxyethyl bromide (12.5 g) was added. Stirring at the initial temperature was continued for 45 minutes and potassium carbonate (0.5 g) was added. After stirring the mixture for an additional 45 minutes at 15°C, it was poured into a rapidly stirred mixture of ethyl acetate (200 mL) and aqueous 3% sodium bicarbonate (200 mL). After 1 hour the layers were separated and the organic phase (HPLC showed 1.6% A<2> isomer) was washed with M hydrochloric acid (100 ml) and aqueous 20% sodium chloride containing 2% sodium bicarbonate (30 ml). All the aqueous phases were gradually washed with ethyl acetate (100 ml). The combined organic extracts were stirred for 30 minutes with activated charcoal (Norit SX Plus; 2 g), filtered through a pad of silica which was washed with ethyl acetate (2 x 25 mL). After evaporating the combined filtrates and wash water to 120 g, the concentrate was stirred for 20 minutes to initiate crystallization. Methanol denatured alcohol (120 mL) was added rapidly followed by 240 mL of distilled water over 15 minutes. The resulting slurry was concentrated in vacuo to 310 g and stirred at ambient temperature for 45 minutes. The product was harvested, washed with distilled water (200 mL) and dried for 67 hours in vacuo at 50°C to give crystalline cefuroxime axetil. (20.01 g). Solvent content (GLC) 0.2% m/m; impurities (HPLC) 1.5% w/w containing A<2> isomer 0.5% w/w and E-isomer 0.6% w/w; isomer ratio 1.01:1; /a/D(1% in dioxane) +40°; E<1>%^cm (278 nm, methanol) 388; Measured by HPLC 98% m/m (uncorrected).

Example 3

Cefuroxime axetil

Sodium cefuroxime (20 g) was stirred with dimethylacetamide (100 ml) at approx. 25°C for 15 minutes, the mixture was cooled to 15°C and (RS)-1-acetoxyethyl bromide (9.8 mL) was added. The mixture was stirred for a further 90 minutes at 14-16°C, and 60-mesh potassium carbonate (0.5 g) was added after half of this time. The reddish-brown mixture was then diluted with ethyl acetate (200 mL) and 3% aqueous sodium bicarbonate (200 mL) and stirred for one hour at ambient temperature (about 25°C). The layers were then separated and the aqueous layer was re-extracted with ethyl acetate (200 mL) and discarded (eo, 0.21°/dm). The organic solutions were washed sequentially with M hydrochloric acid (100 mL), then 20% sodium chloride (30 mL) containing 2% sodium hydrogencarbonate and were then combined and treated with Norit SX Plus activated carbon (2 g) for 25 minutes. The activated carbon was filtered off through Standard Supercel, the filter was washed with ethyl acetate (50 mL), and the combined filtrates were evaporated in vacuo to 120 g. The residual solution was seeded, stirred at 22°C for 1 hour, then toluene (250 mL ) was added to the stirred slurry over 30 minutes, and the mixture stirred for another 30 minutes. The suspension was then re-evaporated in vacuo to 182 g, cooled to approx. 25°C and stirred for 30 minutes. The product was harvested, washed with toluene (100 mL), suctioned dry for 15 min, then dried in vacuo at 45°C overnight to give crystalline cefuroxime axetil (19.8 g). Solvents by GLC, 0.9% (EtAc 0.7%; toluene 0.15%); impurities by HPLC, 0.9%, HPLC measured 100%, isomer ratio 1.03:1, A<2><0.1% m/m. Water (by Karl Fischer) 0.4% m/m.

Example 4

Cefuroxime max i1

The washed and evaporated (about 125 g) ethyl acetate solution of cefuroxime axetil obtained from a similar reaction to that described in Example 1 was stirred at ambient temperature until crystallization was well underway. Low-boiling petroleum ether (b.p. 300-320°C, 188 ml) was added dropwise over 1 hour, after which the suspension was stirred at ambient temperature for a further 2 hours. The crystalline precipitate was isolated by filtration, washed by displacement with 2:1 low boiling petroleum ether (b.p. 100-120°C) ethyl acetate mixture (75 ml) and dried overnight at 40°C in vacuo to give the title compound, (19.2 g) . Water (Karl Fischer) 0.4% m/m, solvents (gle) 0.4% m/m. Test by HPLC 100% m/m. Impurities by HPLC 1.1% m/m (of which 0.1% and 0.6% m/m were A<2> and antiisomer respectively); the isomer ratio was 0.98:1.

Example 5

Cefuroxime axetil

A washed and concentrated (approx. 125 g) solution of the correct cefuroxime axetil in ethyl acetate as prepared in Example 1 was stirred for 1 hour at 33°C until crystallization was well under way. After storing the suspension overnight at ambient temperature, IMS (62.5 mL) was added over 5 minutes with stirring, followed over the next hour by low-boiling petroleum ether (b.p. 100-120°C; 250 mL). After stirring the crystalline slurry for an additional 1.5 hours, it was harvested, displacement washed with 2:1 petroleum ether (b.p. 100-120°C - ethyl acetate mixture (75 mL) and dried overnight in vacuo at 45°C to give the title compound, 19.2 g. Water (Karl Fischer) 0.2% m/m: solvents (gle) 0.8% m/m. Impurities by HPLC 0.8% m/m (of which 0.1% m/m and 0.7% m/m were A<2> and antiisomers respectively); isomer ratio was 1.05:1. Experiment by HPLC 96% m/m.

Example 6

Cefuroxime axetil

A washed and actively treated concentrate (approx. 100 g) of cefuroxime axetil in ethyl acetate, containing approx. 2% A<2 >isomer, obtained in a similar manner to Example 1, was seeded and stirred for 30 minutes until crystallization was well underway. Isopropanol (100 mL) was added dropwise over 30 minutes followed by distilled water (170 mL) over 50 minutes. The resulting slurry was concentrated in vacuo to 250 g and cooled to 12°C over a period of 1 hour. The crystalline product was collected by filtration, washed by displacement with an ice-cold solution of 20% isopropanol in distilled water (100 ml) and dried over a weekend in vacuum at 40°C. The title compound reached 20.1 g. Water (Karl Fischer) 0.4% w/w, solvents (gle) 0.03% w/w. Impurities by HPLC 1.5% (of which 0.4% m/m and approx. 0.6% m/m were A<2> and antiisomers respectively); isomer ratio 1.05:1.

Claims (3)

1. Process for the production of purer than 95% crystalline cefuroxime 1-acetoxyethyl ester, characterized in that cefuroxime 1-acetoxyethyl ester in a ratio of R- to S-isomer of 0.9:1 to 1.1:1 is crystallized from a solution thereof in methyl or ethyl acetate, possibly in mixture with diisopropyl ether, petroleum ether, toluene, ethanol or isopropanol, where the ethanol or isopropanol is possibly in mixture with water; or dimethylformamide or dimethylacetamide in a mixture with water, after which the product is isolated and dried in a manner known per se. 2. Method according to claim 1, characterized in that the solvent is selected from methyl or ethyl acetate, possibly in a mixture with diisopropyl ether, petroleum ether or toluene. 3. Method according to each of the preceding claims, characterized in that at least part of the crystallization steps are carried out at from 10 to 30°C.