SE463263B - PROCEDURES FOR THE PREPARATION OF CRYSTALLINE CEFUROXIM-1 ACETOXYTHYLESTER - Google Patents

Description

463,263 enzymes present in, for example, serum and body tissues to provide the antibiotically active parent acid. To be effective in oral administration, the ester must be sufficiently stable to reach the site of absorption without significant degradation, it must be sufficiently absorbed when reached. the site in question and it must be sufficiently sensitive to hydrolysis by systemic esterases for the parent acid to be released shortly after the ester is absorbed. British Patent Specification No. 1,571,683 states that a number of esters of cefuroxime have properties which give them a significant potential value as orally administrable antibiotics.

Of the esters described in British Patent Specification No. 1,571,683, we have found cefuroxime axetil to be of particular interest. This product has an asymmetric carbon atom in the 1-position of the 1-acetoxyethyl group and may therefore be in the form of R and S isomers or mixtures thereof. The processes for the preparation of the above ester exemplified in British Patent Specification No. 1,571-683 give the material either in a relatively crude amorphous form or in the form of a crystalline material. In addition, the crystalline material prepared according to the methods described in this patent generally contains a predominance of either the R or S isomer, while an approximate 1: 1 ratio is advantageous for administration. Thus, the crystalline product is not ideally suited for administration.

We have now succeeded in developing a process according to which cefuroxime axetil can be obtained in very pure crystalline form and in high yield. Such a product is not only useful from the point of view that it constitutes a highly pure form of the active compound and thus is more suitable for biological administration, but it is above all also very useful as a starting material for the preparation of a very pure , mainly amorphous form of cefuroxime axetil, which form has surprisingly been found to have high bioavailability in oral administration and a better property balance for commercial use than the crystalline material. The amorphous cefuroxime axetil having these properties preferably has a 1: 1 ratio of R to S isomers, as this has been found to be valuable in maximizing the solubility of the amorphous product in aqueous media, and the process we have developed can give crystalline cefuroxime axetil. with this approximate isomer ratio.

Accordingly, there is provided a process for producing highly pure crystalline cefuroximaxetil in high yield, which comprises crystallizing cefuroximaxetil from a solution thereof in an organic or aqueous solvent or a mixture thereof, isolating 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, should be in the range 0.9: 1 to 1.1: 1. We have found that the different isomers of cefuroxime axetil have different solubilities, one of which is consistently more soluble than the other.

The solubility levels vary depending on the solvent and therefore a solvent system should preferably be selected which allows a practically quantitative recovery of the cefuroxime axetil present before crystallization to thereby ensure the above isomer ratio.

The solvent system from which the product can be crystallized is preferably selected from an ester, for example methyl or ethyl acetate, or a halogenated hydrocarbon, such as methylene chloride, optionally but preferably in admixture with an ether, e.g. diisopropyl ether, or an aliphatic or aromatic hydrocarbon, e.g. petroleum ether or toluene; or an alcohol, e.g. ethanol or isopropanol, optionally but preferably in admixture with water, such as in aqueous industrial denatured spirits; or an amide such as dimethylformamide or dimethylacetamide, or ketone such as acetone, in admixture with 463,263 water.

The crystallization step is preferably carried out at room temperature, fl) for example at from approx. 10 ° to 30 ° C, and the concentration of the cefuroxime axetil in the solution from which crystallization takes place is generally adjusted, e.g. by evaporation of solvent or by dilution, so as not to become too dilute or too concentrated. The crystallization may comprise the last step or steps of a reaction in which the cefuroxime axillary is formed. In that case, the initial crystallization step can take place at a relatively high temperature, eg up to approx. 65 ° C, but in order to maximize the yield and obtain a suitable isomer ratio in the product, a temperature range of from 10 ° to 30 ° C is preferred for the final insulation.

The reaction in which the cefuroxime axetil is formed is preferably an esterification reaction which is carried out in the manner described in British Patent Specification No. 1,571,683 and using a highly pure sodium cefuroxime starting material. A preferred reagent for the esterification is 1-acetoxyethyl bromide and to provide an approximate 1: 1 ratio of the R and S isomers before the recrystallization, it is clearly preferred that this reagent be racemic.

The preferred sodium cefuroxime starting material is generally very pure in itself. Such a material can e.g. obtained by reacting (6R, 7R) -3-hydroxymethyl-7-1Z-2- (fur-2-yl) -2-methoxyiminoacetamidolcef-3-em-4-carboxylic acid and chlorosulfonyl isocyanate in an alkyl acetate as solvent at a temperature of from -25 ° C to + 10 ° C, followed by in situ hydrolysis 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 generally has a purity level of 90% mass / mass (m / m) or higher.

The cefuroxime axetile prepared by the process of the present invention exhibits an R to S isomer molar ratio U1 C * LN in of about 1: 1 and generally has a purity of not less than 95% m / m (uncorrected for residual solvent).

In its very pure crystalline form, the cefuroxime axetile which can be prepared by the process of the present invention is a new product form and constitutes a further aspect of the present invention. A sample of this material has the IR spectrum of Nujol shown in the accompanying drawing.

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

The individual R and S isomers of cefuroxime 1-acetoxyethyl ester are named for convenience of the letters A and B, which letters are used to denote respective isomers as in British Patent No. 1,571,683. The identity of the isomers A and B has not determined. The isomer ratios given in the following examples are expressed as A: B. All temperatures are given in ° C.

Preparation Example 1 Sodium cefuroxime Chlorosulfonyl isocyanate (226 ml) was added to a solution of triethylamine (10 ml) in methyl acetate (3.8 l). The resulting clear solution was cooled to -15 ° and a suspension of (6R, 7R) -3-hydroxymethyl-7β-2- (fur-2-yl) -2-methoxyiminoacetamido | cef-3-em-4-carboxylic acid (763 g) in methyl acetate (2.3 L), precooled to -15 °, was added over 15 minutes. The residual solid was rinsed with methyl acetate (700 ml). The mixture was stirred at -5 ° for 30 minutes, a clear solution was obtained after 10 minutes. Water (1.2 l) at 18 ° was added quickly to the reaction mixture, the temperature rising rapidly to 10 ° and then slowly to 17 °. The mixture was stirred for 60 minutes at 15 ° to give a thick, white suspension. Methyl acetate (3.6 L) was added, followed by even addition of a solution of sodium L 2 C 4 (JJ ND CD).

U-1 hydroxide (288 g) in water (5.2 l). This gave a clear two-phase mixture at 26 ° 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 successively with methyl acetate (2 L). The organic layers (R) sx Plus charcoal (76 g) in (R) were bulked, stirred with Norit for minutes and filtered through a bed of Hyflo washed with methyl acetate (1.5 L). Filtrate and washings were combined and stirred at 20 ° while a solution of Supercel as sodium 2-ethylhexanoate (338 g) in a mixture of methyl acetate (2 l) and water (40 ml) was added for 20 minutes to give a white suspension with a pH of 5.5. The suspension was stirred for 10 minutes and filtered, the cake was washed with methyl acetate (5 x 1 l), vacuum dried and dried at 30 ° in vacuo for 24 hours to give sodium cefuroxime (85l, 9 g); | dJš0 + 60 °, (c 0.5; 0.1M pH 4.5 buffer), λmax (H 2 O) 273 nm (nâcâ 387); impurities according to HPLC 2.0%. Analysis (HPLC) 92% m / m; water content (Karl Fischer) 2.8%; solvent (g.l.c.) 0.5% m / m.

. Example 1 Cefuroxime axetil (RS) -1-acetoxyethyl bromide (1.2 g) was added to a stirred solution of sodium cefuroxime (20 g) (prepared according to a method similar to that of Example 1) in dimethylacetamide (110 ml) at 0 °. The mixture was stirred at + 1 ° for 90 minutes and potassium carbonate (0.5 g) was added. Stirring was continued for a further 2 hours at 1-3 °, when 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 was separated (1.5% β-isomer by HPLC), washed with 1M hydrochloric acid (100 ml) and aqueous 20% sodium chloride containing 2% sodium bicarbonate (30 ml). All three aqueous phases were washed successively with ethyl acetate (100 ml). The combined organic extracts were stirred for 30 minutes with »Ps C '\ i, \ l FJ Ch CN (R) SX Plus; 2g), filtered through a kieselguhr charcoal (Norit bed washed with ethyl acetate (2 x 25 ml). The combined filtrate and washings were evaporated in vacuo to 150 g and stirred at room temperature for 1 hour until crystallization started. Diisopropyl ether (250 ml) was added over 45 minutes to complete the crystallization and stirring was continued for a further 1 hour.

The product was collected by filtration, washed with 2: 1 diisopropyl ether / ethyl acetate (150 ml) and dried for one weekend in vacuo at 50 ° to give crystalline cefuroxime axetil (19.3 g) with an infrared spectrum in Nujol shown in the figure in the accompanying drawing, which is typical of a mixture of crystalline isomers.

Solvent content (GLC) 0.2% m / m. Pollutants according to HPLC 1.8% including A + isomer 0.3% m / m; E-isomer 0.6% m / m.

Isomer Ratio (HPLC) 1.09: 1.0 μD (1% in dioxane) + 37 °; Ecce (278 mm, MeOH) 389. Analysis according to HPLC 99% m / m (uncorrected).

Example 2 Cefuroxime axetil A stirred suspension of sodium cefuroxime (20 g) in dimethylacetamide (110 ml) was cooled to 15 ° and (RS) -1-acetoxyethyl bromide (1.2 g) was added. Stirring at the previous temperature was continued for 45 minutes and potassium carbonate (0.5 g) was added.

After stirring the mixture for a further 45 minutes at 15 °, 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% Å2 isomer) was washed with 1M hydrochloric acid (100 ml) and aqueous 20% sodium chloride containing 2% sodium bicarbonate (30 ml). All aqueous phases were washed successively with ethyl acetate (100 ml). The combined organic extracts were stirred for 30 minutes with charcoal (Norit (R) SX Plus; 2 g), filtered through a bed of kieselguhr washed with ethyl acetate (2 x, inter alia, Od TO C \ LN 25 ml). After evaporating the combined filtrate and washings to 120 g, the concentrate was stirred for 20 minutes to allow crystallization to begin. Industrial denatured spirit (120 ml) was added rapidly, followed for 15 minutes by distilled water (240 ml). The resulting slurry was concentrated in vacuo to 310 g and stirred at room temperature for 45 minutes. The product was harvested, washed with distilled water (200 ml) and dried for 67 hours in vacuo at 50 ° to give crystalline cefuroxime maxetil (20.0l 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; | dJD (1% in dioxane) + 40 °; El% (278 lcm nm, methanol) 388; analysis by HPLC 98% _m / m (uncorrected).

Example 3 Cefuroxime axetil Sodium cefuroxime (20 g) was stirred with dimethylacetamide (100 ml) at ca. 25 ° for 15 minutes, the mixture was cooled to 15 ° and (RS) -1-acetoxyethyl bromide (9.8 ml) was added. The mixture was stirred for an additional 90 minutes at 14-16 °, with 60-mesh potassium carbonate (0.5 g) being added after half the time. The red-brown mixture was then diluted with ethyl acetate (200 mL) and 3% aqueous sodium carbonate (200 mL) and stirred for 1 hour at room temperature (ca. 25 °). The layers were then separated and the aqueous layer was re-extracted with ethyl acetate (200 ml) and discarded (.mu.l, 0.2l / dm). The organic solutions were washed successively with 1M hydrochloric acid (100 ml) and then with 20% sodium chloride (30 ml) containing 2% sodium bicarbonate and then combined and treated with Norit (R) SX Plus charcoal (2 g) for 25 minutes. . The charcoal was filtered off through a standard Supercel pad, the filter was washed with ethyl acetate (50 ml) and the combined filtrates were evaporated in vacuo to 120 g. The remaining solution was inoculated, stirred at 22 ° for 1 hour, then toluene (250 ml) stirred the slurry for 30 minutes, and the mixture was stirred for a further 30 minutes. The suspension was then evaporated again in vacuo to 182 g, cooled to about 25 ° and stirred for 30 minutes. The product was harvested, washed with toluene (100 ml), vacuum dried for 15 minutes and then dried in vacuo at 45 ° overnight to give crystalline cefuroxime axetil (19.8 g).

GLC solvent, 0.9 ° (EtAc 0.7%; toluene 0.15%); impurities according to HPLC, 0.9%, HPLC analysis 100%, isomer ratio 1.03 = 1.1, A2 Fischer) 0.4% m / m. Example 4 Cefuroximaxetil The washed and evaporated (about 125 g) ethyl acetate solution of cefuroximaxetil obtained from a reaction similar to that described in Example 1 was stirred at room temperature until crystallization started. Light petroleum ether (b.p. 10 DEG-120 DEG C.; 188 ml) was added dropwise over 1 hour, after which the suspension was stirred at room temperature for a further 2 hours. The crystalline precipitate was collected by filtration, displaced washed with 2: 1 light petroleum ether (b.p. 100-120 °) -ethyl acetate mixture (75 ml) and dried overnight at 40 ° in vacuo to give the title compound (19 , 2 g). Water (Karl Fischer) 0.4 m / m, solvent (GLC) 0.4% m / m. Analysis by HPLC 100% m / m. Pollutants according to HPLC% 1.1 m / m (of which 0.1% and 0.6 m / m were Åa and anti-isomer, respectively); the isomer ratio was 0.88: 1.

Example 5 Cefuroxime axetil A washed and concentrated (ca. 125 g) solution of the necessary cefuroxime axetile in ethyl acetate prepared in Example 1 was stirred for 1 hour at 33 ° until crystallization started. After storage of the suspension overnight at.

-W CN.

PO O \ C fl 10 room temperature was added with stirring IMS (62.5 ml) for 5 minutes, followed by the addition of light petroleum ether (b.p. 100-120 °; 250 ml) for the next hour. After stirring the crystalline suspension for a further 1.5 hours, it was harvested, displacement washed with a 2: 1 light petroleum ether (b.p. 100-120 °) ethyl acetate mixture (75 ml) and dried overnight in vacuo at 45 ° to give the title compound, 19.2 g. Water (Karl Fischer) 0.2% m / m; solvent (GLC) 0.8% m / m. Pollutants according to HPLC 0.8% m / m (of which 0.1% m / m and 0.7% m / m were A 2 and anti-isomers, respectively); the isomer ratio was 1.05: 1. Analysis by HPLC 96% m / m.

Example 6 Cefuroxime axetil A washed and charcoal-treated concentrate (ca. 100 g) of cefuroxime axetil in ethyl acetate, containing ca. 2% A 2 isomer, obtained in a similar manner to Example 1, was seeded and stirred for 30 minutes until crystallization started. Isopropanol (100 ml) was added dropwise over 30 minutes, followed by the addition of distilled water (170 ml) over 50 minutes. The resulting slurry was concentrated in vacuo to 250 g and cooled to 12 ° over a period of 1 hour.

The crystalline product was collected by filtration, displaced washed with an ice-cold solution of 20% isopropanol in distilled water (100 ml) and dried for one weekend in vacuo at 40 °. The title compound was 20.1 g. Water (Karl Fischer) 0.4% m / m, solvent (GLC) 0.03% m / m. Impurities according to HPLC 1.5% (of which 0.4% m / m and about 0.6% m / m were Ag- and anti-isomers, respectively); isomer ratio 1.05: 1.

Claims (10)

N -Ffæ CÄ LJ FO G \ Od PATENTKRAV A process for the preparation of crystalline cefuroxime 1-acetoxyethyl ester having a purity of at least 95% mass / mass, which crystallizes in an R to S isomer ratio of 0,9: 1 to 1,1: 1, comprising crystallization of cefuroxime 1-acetoxyethyl ester from a solution thereof in an organic or aqueous solvent or a mixture thereof, isolating and drying the product. A process according to claim 1, wherein the cefuroxime 1-acetoxyethyl ester crystallizes in an R to S isomer ratio of about 1: 1. A process according to claim 1 or 2, wherein the solvent comprises an ester. A process according to claim 3, wherein the solvent comprises an ester or a halogenated hydrocarbon, optionally in admixture with an ether, or an aliphatic or aromatic hydrocarbon; or a ketone or amide in admixture with water. A process according to claim 1 or 2, wherein the solvent comprises an alcohol in admixture with water. A process according to claim 4, wherein the solvent is selected from methyl or ethyl acetate, optionally in admixture with diisopropyl ether, petroleum ether or toluene. A process according to any one of the preceding claims, wherein at least a later part of the crystallization step is carried out at from 10 to 30 ° C. Crystalline cefuroxime-1-acetoxyethyl ester having a purity of at least 95% mass / mass, wherein the R to S isomer ratio is from 0,9: 1 to 1,1: 1. 46 265 12 CN Crystalline cefuroxime-1-acetoxyethyl ester having an R to S isomer ratio of about 1: 1. 10. Crystalline cefuroxime-1-acetoxyethyl ester with an IR spectrum in Nujol as shown in the accompanying drawing.