CH662121A5 - METHOD FOR PRODUCING HIGH PURITY CRYSTALLINE CEFUROXIM-1-ACETOXYETHYLESTER. - Google Patents

Description

The present invention relates to improvements in the manufacture of cefuroxime 1-acetoxyethyl ester (cefuroxime axetil).

The compound (6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyimonoacetamido] -ceph-3-em-4-car-bonic acid has the approved name « Cefuroxime ». This compound is a valuable antibiotic, which is characterized by a high broad-spectrum activity against gram-positive and gram-negative microorganisms, which property is also due to the very high stability of the compound for β-lactamases, which is produced by a number of gram-negative microorganisms be increased. It is very well tolerated by the mammalian body and is widely used as an antibiotic in clinical practice. Cefuroxime and its salts are primarily of value as injectable antibiotics because they are poorly absorbed by the gastrointestinal tract and are therefore only present in low concentrations in serum and urine after oral administration. There has therefore been a need for a form of cefuroxime that is capable of being absorbed by the gastrointestinal tract after oral administration.

It has now been found that suitable esterification of the carboxyl group of cefuroxime improves the effectiveness when administered orally. The presence of such a suitable esterifying group results in significant absorption of the compound from the gastrointestinal tract, after which the esterifying group is hydrolyzed by enzymes, for example in serum or in body tissue, and gives the antibiotic active parent acid. In order to be effective after oral administration, the ester must be stable enough to achieve the seat of absorption without substantial degradation, must be sufficiently absorbed after reaching the appropriate seat and must be capable of hydrolysis by systemic esterases so that the parent acid of the absorbed ester is released within a short time. A number of esters of cefuroxime are described in British Patent Specification 1,571,683 and in the claims that they have properties that make them of significant value as orally administrable antibiotics.

It has been found from the esters described in British Patent Specification 1,571,683 that the cefuroxime axetil is of particular interest. This product has an asymmetric carbon atom in the 1-position of the 151-acetoxyethyl group and can therefore exist in the form of R and S isomers or mixtures thereof. The methods of making the above ester, exemplified in British Patent Specification 1,571,683, produce the material either in a relatively non-pure amorphous form or in the form of a crystalline material. Furthermore, the crystalline material produced by the methods described in this patent specification generally contains predominantly either the R or the S isomer, while an approximate 1: 1 ratio is advantageous for administration. The crystalline product is therefore not ideal for administration.

'A process has now been developed whereby cefuroxime axetil can be obtained in highly pure crystalline form and in high yield. Such a product is not only useful from the point of view that it is in a highly pure form of the active compound and is therefore more suitable for biological administration, but it is also particularly useful as a starting material for the production of a highly pure, essentially amorphous form of cefu -35 roxim-Axetil, which has surprisingly been found to have high bioavailability after oral administration and a better balance of properties for commercial use than the crystalline material. The amorphous cefuroxime axetil, which has these properties 40, is desirably an approximately 1: 1 ratio of R and S isomers, as it has been found to be of value in maximizing solubility in aqueous medium of the amorphous product, and the method developed in accordance with the invention can provide crystalline cefuroxime axetil 45 which has this approximate ratio of isomers.

As a result, there is provided a process for preparing high purity crystalline cefuroxime axetil in high yields which consists in crystallizing cefuroxime axetil from a solution thereof in an organic or aqueous solvent or a mixture thereof, and drying the product.

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 of the product as desired is about 1: 1, for example in the range 0.9: 1 to 1, 1: 1. It has been found that the different isomers of the cefuroxime axetil have different solubilities, one of which is consistently more soluble than the other. The solubility levels vary depending on the solvent and so a solvent system is desirably chosen that allows practically quantitative recovery of the cefuroxime axetil that is present before crystallization, thereby ensuring an approximately 1 ^ ratio of the isomers. 65 The solvent system from which the product can be crystallized is desirably countered by an ester such as methyl or ethyl acetate or a halogenated hydrocarbon such as methylene chloride

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662 121

however, preferably selected in a mixture with an ether, for example diisopropyl ether, or an aliphatic or aromatic hydrocarbon, for example petroleum ether or toluene; or an alcohol, for example ethanol or isopropanol, but optionally preferably in a mixture with water, such as in aqueous industrial methylated spirit; or an amide, such as dimethylformamide or dimethylacetamide, or a ketone, such as acetone, in a mixture with water.

The crystallization step is desirably carried out at ambient temperature, e.g. from about 10 to 30 ° C, and the concentration of the cefuroxime axetil in the solution from which crystallization occurs is generally adjusted e.g. by evaporation of the solvent or by dilution so that it is neither too dilute nor too concentrated. Crystallization can include the final step or steps of a reaction in which the cefuroxime axetil is formed. In such a case, the initial stage of crystallization at a fairly high temperature, e.g. up to about 65 ° C, but to maximize yield and maintain a suitable ratio of isomers in the product, a temperature range of 10 to 30 ° C is preferred for final isolation.

The reaction in which the cefuroxime axetile is formed will preferably be an esterification reaction carried out in the manner described in British Patent Specification 1,571,683 and using a high purity sodium cefuroxime as a starting material. A preferred reagent for the esterification is 1-acetoxyethyl bromide, and in order to produce an approximately 1: 1 ratio of the R and S isomers prior to recrystallization, it is clearly preferred that such a reagent be race-mixed.

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

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

In its highly pure crystalline form, the cefuro-xim-axetil, which was produced by the method according to the invention, is a new form and represents a further aspect of the present invention.

A sample of this material has the IR spectrum in Nu-jol, shown in the attached

Drawing.

The present invention will now be explained in more detail with the aid of the following examples and production examples. The individual R and S isomers of cefuroxime-1-acetoxyethyl 1-ester are conveniently designated by the letters A and B, which letters are used to designate the relevant isomers as in British Patent 1,571,683. The identities the isomers A and B were not assigned. The isomer ratios reported in the following examples are expressed as A: B. All temperatures are given in C.

Her position example l

Sodium cefuroxime

226 ml of chlorosulfonyl isocyanate was added to a solution of 10 ml of triethylamine in 3.8 l of methyl acetate. The resulting clear solution was cooled to -15 C and a suspension of 763 g (6R, 7R) -3-hydroxymethyl-7- [Z-2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3- em-4-carboxylic acid in 2.3 liters of methyl acetate, which had been pre-cooled to -15 ° C, was added over 10 minutes. The remaining solid was rinsed in with 700 ml of methyl acetate. The mixture was stirred at -5 ° C for 30 minutes, a clear solution being obtained after 10 minutes. 1.2 l of water at 18 ° C was added rapidly to the reaction mixture, the temperature rising rapidly to 10 C and then slowly to 17 C. The mixture was stirred at 15 ° C for 60 minutes and gave a thick white suspension. 3.6 liters of methyl acetate were added and then a continuous addition of a solution of 288 g of sodium hydroxide in 5.2 liters of water followed. This resulted in a clear two-phase mixture at 26 C with a pH of 2.35. The layers were separated and the top organic layer was washed with a solution of 600 g sodium chloride in 2 liters of water. The two aqueous layers were washed successively with 2 1 methyl acetate. The organic layers were combined, stirred with 76 g of Norit SX Plus carbon for 30 minutes and filtered through a bed of Hyflo Supercel, washing the bed with 1.5 liters of methyl acetate. The filtrate and the washing liquids were combined and stirred at 20 ° C. while a solution of 338 g of sodium 2-ethylhexanoate in a mixture of 2 1 of methyl acetate and 40 ml of water was added over 20 minutes to make a white suspension with a pH of 5.5 The suspension was stirred for 10 minutes and filtered and the cake was washed with 5x11 methyl acetate, dried under suction and dried at 30 ° C. in vacuo for 24 hours, giving 851.9 g of sodium cefuroxime

[ci] n + 60 C <(c ° -5; 0.1 M pH 4.5 buffer); A.max (H20) 1%

273 nm (E j cm 387); Impurities due to HPLC

2.0%. Analysis (HPLC) 92% m / m; Water content (Karl Fisher) 2.8% m / m; Solvent (GLC) 0.5% m / m.

example 1

Cefuroxime Axetil

12.5 g of (RS) -l-acetoxyethyl bromide was added to a stirred mixture of 20 g of sodium cefuroxime (prepared by a method similar to that in Preparation Example 1) in 110 ml of dimethylacetamide at 0 ° C. The mixture was stirred at +1 C for 90 minutes and 0.5 g of potassium carbonate was added. Stirring was continued at 1 to 3 C for an additional two hours, then the reaction mixture was added to a rapidly stirred mixture of 200 ml of ethyl acetate and 200 ml of 3% sodium bicarbonate to destroy any excess of 1-acetoxyethyl bromide. After 1 hour the organic layer (1.5% A 2 isomer by HPLC) was separated, washed with 100 ml M hydrochloric acid and 30 ml aqueous 20% sodium chloride containing 2% sodium bicarbonate. All three aqueous phases were subsequently washed with 100 ml of ethyl acetate. The combined organic extracts were stirred for 30 minutes with 2 g of Norit SX Plus carbon, filtered through a bed of Kieselguhr which was washed with 2 x 25 ml of ethyl acetate. The combined filtrate and the washing liquids were in vacuo

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

The solvent content (GLC) was 0.2% m / m. Contamination by HPLC 1.8% including A2 isomer 0.3% m / m; E-isomer 0.6% m / m. Isomer ratio

(HPLC) 1.09: 1 aD (1% in dioxane) + 37 °; E

(278 mm, MeOH) 389. Analysis based on HPLC 99% m / m (uncorrected).

Example 2

Cefuroxime Axetil

A stirred suspension of 20 g sodium cefuroxime in 110 ml dimethylacetamide was cooled to 15 ° C and 12.5 g (RS) -1-acetoxyethyl bromide were added. Stirring at the previous temperature was continued for 45 minutes and 0.5 g of potassium carbonate was added. After stirring the mixture for a further 45 minutes at 15 ° C, it was poured into a rapidly stirred mixture of 200 ml of ethyl acetate and 200 ml of aqueous 3% sodium bicarbonate. After one hour the layers were separated and the organic phase (HPLC showed 1.6% A2 isomers) was washed with 100 ml of M hydrochloric acid and 30 ml of aqueous 20% sodium chloride containing 2% sodium bicarbonate. All aqueous phases were washed successively with 100 ml of ethyl acetate. The combined organic extracts were stirred with 2 g of Norit SX Plus charcoal for 30 minutes, filtered through a bed of Kieseiguhr which was washed with 2 x 25 ml of ethyl acetate. After evaporating the combined filtrate and washes to 120 g, the concentrate was stirred for 20 minutes to allow crystallization to begin. 120 ml of industrial methylated spirit were added quickly and then 240 ml of distilled water over 15 minutes. The resulting slurry was concentrated to 310 g in vacuo and stirred at ambient temperature for 45 minutes. The product was collected, washed with 200 ml of distilled water and dried in vacuo at 50 ° C for 67 hours to give crystalline cefuroxime axetil (20.01 g). Solvent content (GLC) 0.2% m / m; Impurities (HPLC) 1.5% m / m including A2 isomer 0.5% m / m and E isomer 0.6% m / m; Isomer ratio

1.01: 1; aD (1% in dioxane) + 40 °; E J ^ (278 nm, methanol) 388; Analysis based on HPLC 98% m / m (uncorrected).

Example 3

Cefuroxime Axetil

20 g of sodium cefuroxime was stirred with 100 ml of dimethylacetamide at about 25 ° C for 15 minutes, the mixture was cooled to 15 ° C and 9.8 ml of (RS) -1-acetoxyethyl bromide was added. The mixture was stirred for a further 90 minutes at 14-16 ° C, then 0.5 g of 60-mesh potassium carbonate was added in half the period. The red-brown mixture was then diluted with 200 ml of ethyl acetate and 200 ml of 3% aqueous sodium hydrogen carbonate and stirred for one hour at ambient temperature (approx. 25 ° C.). The layers were then separated and the aqueous layer was back extracted with 200 ml of ethyl acetate and discarded (a, 0.21 ° / dm). The organic solutions were washed successively with 100 ml of M-5 hydrochloric acid and then with 30 ml of 20% sodium chloride containing 2% sodium hydrogen carbonate and then combined and treated with 2 g of Norit SX Plus carbon for 25 minutes. The coal was filtered through a standard Supercel pad, the filter was washed with 50 ml of ethyl acetate and the combined filtrates were evaporated to 120 g in vacuo. The remaining solution was inoculated, stirred at 22 ° C for one hour, introducing 250 ml of toluene into the stirred slurry over 30 minutes and the mixture stirred for an additional 30 minutes. The suspension was then evaporated again to 182 g in vacuo, cooled to about 25 ° C. and stirred for 30 minutes. The product was collected, washed with 100 ml of toluene, sucked dry for 15 minutes, then dried in vacuo at 45 ° C. for 20 nights and gave 19.8 g of crystalline cefuroxime axetil. Solvent by GLC 0.9% (EtAc 0.7%; toluene 0.15%); Impurities due to HPLC, 0.9%, HPLC analysis 100%, isomer ratio 1.03: 1, A2 <0.1% m / m. Water (due to Karl Fischer) 0.4% m / m.

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Example 4

Cefuroxime Axetil

The washed and evaporated (approx. 125 g) ethyl acetate solution of Cefuroxime-Axetil, which was obtained from a similar reaction as described in Example 1, was stirred at ambient temperature until crystallization was well initiated. 188 ml of light petroleum ether (boiling point 100 to 120 ° C.) was added dropwise over 1 hour, after which the suspension was stirred at ambient temperature for a further 35 hours. The crystalline precipitate was collected by filtration, displacement washing with 2: 1 light petroether (bp. 100-120 C) ethyl acetate mixture (75 ml) and dried in vacuo at 40 C overnight to give 19.2 g of the title compound. Water 40 (Karl Fischer) 0.4% m / m, solvent (GLC) 0.4% m / m. Analysis based on HPLC 100% m / m. Impurities due to HPLC 1.1% m / m (of which 0.1% or 0.6% m / m were A2 or anti isomers); the isomer ratio was 0.98: 1.

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Example 5

Cefuroxime Axetil

A washed and concentrated (about 125 g) solution of the required cefuroxime axetil in ethyl acetate, prepared 50 as in Example 1, was stirred at 33 C for 1 hour until crystallization was well initiated. After standing the suspension overnight at ambient temperature, 62.5 ml of IMS were added with stirring for 5 minutes and then 250 ml of light petro-55 ether (bp. 100-120 ° C.) over the next hour. After the crystalline suspension had been stirred for a further 1.5 hours, it was collected, washed with 2: 1 light petroether (bp. 100-120 ° C.) / ethyl acetate mixture (75 ml) and dried overnight in vacuo at 45 ° C. to give 19 , 2 g title link. Water (Karl Fischer) 0.2% m / m; Solvent (GLC) 0.8% m / m. Impurities due to HPLC 0.8% m / m (of which 0.1% m / m or 0.7% m / m were A2 or anti isomers); Isomer ratio 1.05: 1. Analysis based on HPLC 96% m / m.

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Example 6

Cefuroxime Axetil

A washed and coal-treated concentrate

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(approx. 100 g) of cefuroxime axetil in ethyl acetate containing approx. 2% Ä2-isomer, obtained in a similar manner as in Example 1, was inoculated and stirred for 30 minutes until crystallization was well initiated. 100 ml of isopropanol was added dropwise over 30 minutes and then 170 ml of distilled water over 50 minutes. The resulting slurry was concentrated in vacuo to 250 g and cooled to 12 ° C over a 1 hour period. The crystalline product was collected by filtration, washed with displacement with 100 ml of an ice-cold solution of 20% isopropanol in distilled water and dried in vacuo at 40 ° C. over the weekend. The title compound was 20.1 g. Water (Karl 5 Fischer) 0.4% m / m, solvent (GLC) 0.03% m / m. Impurities due to HPLC 1.5% (of which 0.4% m / m or approx. 0.6% m / m were A2 or anti isomers); Isomer ratio 1.05: 1.

C.

1 sheet of drawings

Claims (9)

662 121 1. A process for the preparation of high-purity crystalline cefuroxime-1-acetoxyethyl ester, characterized in that cefuroxime-1-acetoxyethyl ester crystallizes from its solution in an organic or aqueous solvent or a mixture thereof, isolated and the product is dried. 2. The method according to claim 1, characterized in that the cefuroxime-1-acetoxyethyl ester crystallizes in a ratio of R to S isomers of about 1: 1. 2nd PATENT CLAIMS 3. The method according to claim 1 or 2, characterized in that the solvent comprises an ester. 4. The method according to claim 3, characterized in that the solvent is an ester or halogenated hydrocarbon, optionally in a mixture with an ether or an aliphatic or aromatic hydrocarbon; or comprises a ketone or amide mixed with water. 5. The method according to claim 1 or claim 2, characterized in that the solvent comprises an alcohol mixed with water. 6. The method according to claim 4, characterized in that the solvent is selected from methyl or ethyl acetate, optionally in a mixture with diisopropyl ether, petroleum ether or toluene. 7. The method according to any one of the preceding claims, characterized in that at least a later portion of the crystallization step is carried out at 10 to 30 ° C. 8. Crystalline cefuroxime-1-acetoxyethyl ester with a purity of at least 95% mass / mass. 9. Crystalline cefuroxime-1-acetoxyethyl ester according to claim 8 with the IR spectrum in nujol according to the attached drawing.