FR2549837A1 - PROCESS FOR THE PREPARATION OF 1-ACETOXYETHYL ESTER OF CEFUROXIME - Google Patents

Abstract

ACCORDING TO THE INVENTION, A PROCESS FOR OBTAINING VERY PURE CRYSTALLINE CEFUROXIME AXETIL IS DESCRIBED. THE PROCESS CONSISTS OF CRYSTALLIZING CEFUROXIME AXETIL FROM ONE OF ITS SOLUTIONS IN AN ORGANIC OR AQUEOUS SOLVENT OR IN A MIXTURE OF THESE TWO TYPES OF SOLVENTS, THEN DRYING AND INSULATING THE PRODUCT. THE PREFERRED SOLVENTS ARE ALKYL ACETATES MIXED WITH ETHERS OR ALIPHATIC OR AROMATIC HYDROCARBONS. THE HIGHER THE YIELD OF CRYSTALLIZATION, THE CLOSER TO 1: 1 THE STOECHIOMETRIC RATIO OF THE R: S ISOMERS THE PRODUCT CONTAINS, THIS RATIO BEING THE MOST DESIRABLE FOR A PRODUCT HAVING THE DESIRED PROPERTIES.

Description

1 2549837

  The invention relates to improvements in u x, or relating to / cephalosporins. More specifically, it relates to improvements relating to the manufacture of the ester.

  cefuroxime 1-acetoxyethyls (cefuroxime axetil).

  The compound (6 R, 7 R) -3-carbamoyloxymethyl-7L (Z) -2- (fur-2-yl) -2-methoxyiminoacetamido-ceph-3-mme-4-carboxylic acid is registered under the name "cefuroxime" This compound is an interesting antibiotic characterized by a very wide spectrum of activity against gram-positive and gram-negative microorganisms, this property being reinforced by the very high stability of the compound against lactamases produced by various gram-negative microorganisms. mammal tolerated and is widely used as an antibiotic in clinical practice Cefuroxime and its salts are especially useful as injectable antibiotics because they are poorly absorbed by the gastrointestinal tract and are therefore not present in serum and urine. in low concentrations after oral administration It was therefore necessary to have a form of cefur 6 xime which is capable of being absorbed by the gastrointestinal tract. s after a

oral administration.

  Applicant has found that an appropriate esterification of the carboxyl group of cefuroxime improves the effectiveness of oral administration. The presence of such an appropriate esterifying group results in a significant uptake of the compound by the gastrointestinal tract, after which the ester group is hydrolyzed by enzymes present in, for example, serum and body tissues to give the antibiotically active parent acid. To be effective by oral administration, the ester must be stable enough to reach the site of absorption. without significant degradation, but must be sufficiently absorbed when it reaches the appropriate site, and must be sufficiently hydrolyzable by systemic esterases -2 for release of the parent acid shortly after the ester is absorbed. GB 571,683 discloses and claims several cefuroxime esters having properties which give them a p value. significant otential as antibiotics administered orally. Of the esters described in GB 1 571 683, we have found that cefuroxime axetil is of particular interest. This product has an asymmetric carbon in the 1-position of the 1-acetoxyethyl group and can therefore exist in the form of R isomers. and S or mixtures thereof. The processes for the preparation of the above ester described in the examples of GB 1,571,683 produce the material either in a relatively impure amorphous form or in the form of a crystalline material. furthermore, the crystalline material produced by the processes described in this application generally contains a predominance of the R-isomer or the S-isomer, while a ratio of about 1: 1 is advantageous for administration. The crystalline product so is not the

  ideal product for administration.

  The applicant has now been able to develop a process which makes it possible to obtain cefuroxime axetil in a very pure crystalline form and with a high yield. This product is not only usable because it represents a very pure form of the compound. active and is therefore more suitable for biological administration, but, more particularly, it is also very useful as a starting material for the preparation of a substantially amorphous, very pure form of cefuroxime axetil, which form shows, surprisingly, very good bioavailability by oral administration and a better balance of properties for commercial use than the crystalline material Amorphous cefuroxime axetil which has these properties is advantageously an approximately 1: 1 mixture of R and S isomers, because this ratio is is interesting to maximize the solubility of the amorphous product in aqueous media, and the procedure developed by the Applicant can provide a crystalline cefuroxime axetil having

  this approximate ratio of isomers.

  Accordingly, the Applicant provides a process for the preparation of high purity, crystalline cefuroxime axetil in high yield, which process consists in crystallizing cefuroxime axetil from a solution of the material in an organic or aqueous solvent or in an aqueous solution. a mixture of these two types of solvents and then isolate

and to dry the product.

  The choice of the crystallization solvent has been found to be important if the yield is to be maximized and the ratio of the R and S isomers of the product should be, preferably, about 1: 1, for example in the range of 0 , 9: 1 to 1.1: 1 The applicant has found that the different isomers of cefuroxime axetil show different solubilities, one of them being significantly more soluble than the other The solubility rates vary depending on the solvent and c It is thus preferable to choose a solvent system which allows a practically quantitative recovery of the cefuroxime axetil present before crystallization.

  thus ensuring a ratio of about 1: 1 of the isomers.

  The solvent system from which the product can be crystallized is advantageously selected from an ester, for example methyl or ethyl acetate, or a halogenated hydrocarbon such as methylene chloride, optionally but preferably mixed, 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, optionally but preferably mixed with water; as in an aqueous industrial alcooldenate; or an amide such as dimethylformamide or dimethylacetamide or

  a ketone, such as acetone, mixed with water.

  The crystallization step is advantageously carried out at room temperature, for example about 10 to 30 ° C., and the concentration of cefuroxime axetil in the solution from which crystallization takes place must generally be adjusted, for example by evaporation of the solvent or by dilution, so as to be neither too dilute nor too concentrated The crystallization may comprise the last stage or the last stages of a reaction in which the cefuroxime axetil is formed In such a case, the initial stage The crystallization can take place at a fairly high temperature, that is to say up to about 65 ° C., but to maximize the yield and obtain an appropriate ratio of isomers in the product, a temperature in the range of 10 to 10 is preferred. 300 C for final isolation. The reaction in which the cefuroxime axetil is formed is preferably an esterification reaction carried out as described in GB 1 571 683 and using as a starting material a very pure sodium salt of cefuroxime. the esterification is 1-acetoxyethyl bromide and in order to produce a ratio of about 1: 1 of the R and 5 isomers before recrystallization, it is well

  preferably such a reagent is racemic.

  The starting material The sodium salt of cefuroxime will generally be very pure itself. Such a material can be obtained inter alia by reaction of (6R, TR) -3-hydroxy-methyl-7-Z-2- acid ( fur-2-yl) -2-methoxyiminoacetamido 7-ceph-3-yl-4-carboxylic acid with a chlorosulfonyl isocyanate in an alkyl acetate solvent, at a temperature between -25 and + 10 l C, followed in situ hydrolysis at a temperature between + 10 and + 301 ° C and crystallization after addition of sodium 2-ethyl hexanoate in acetone or methyl acetate

  Such a material generally has a purity level of 90% w / w (w / w) or higher.

  Cefuroxime axetil produced by the process of the invention

  It has a molar ratio of R and S isomers of about 1: 1, and is generally not less than 95% w / w of purity.

  (without correction for residual solvents).

  In its very pure crystalline form, cefuroxime axetil, which can be produced by the process of the invention, is a new form of material and constitutes another aspect of the invention. The attached drawing shows the spectrum

  IR of a sample of this material in the Nujol.

  The following preparation and non-limiting examples are given by way of illustration of the invention.

  For the sake of convenience, the individual isomers R and S of the acetoxyethyl ester of cefuroxime are designated by the letters A and B, these letters being used for

  designate the respective isomers in GB 1,571,683. The identities of the isomers A and B have not been assigned.

  The ratios of the isomers given in the following examples

are expressed in A: B.

  Preparation 1 Sodium salt of furoxime 226 ml of chlorosulfonyl isocyanate are added to a solution of 10 ml of triethylamine in 3.8 liters of methyl acetate. The resulting clear solution is cooled to -151 ° C. and over 10 minutes. add a suspension of 763 g of (6 R, 7 R) -3-hydroxymethyl-7-Z 2 -2 (fur-2-yl) -2-methoxyiminoacetamido 7-ceph-3-yl-4-carboxylic acid in 2 3 liters of methyl acetate, pre-cooled to -15 ° C. The residual solid is rinsed with 700 ml of methyl acetate. The mixture is stirred at -55 ° C. for 30 minutes, a clear solution being obtained in 10 minutes. 1.2 liter of water are rapidly added to the reaction mixture at 18 ° C., the temperature then rapidly rising to 100 ° C. and then slowly to 170 ° C. The reaction mixture is stirred for 15 minutes at 151 ° C. to obtain a slurry. 3.6 liters of methyl acetate are added, followed by a continuous solution of 288 g of sodium hydroxide. In this way, a clear, 2-phase mixture is obtained at 26 ° C. with a pH of 2.35. The layers are separated and the upper organic layer is washed with water.

  600 g solution of sodium chloride in 2 liters of water.

  The two aqueous layers are washed with each 2 liters of methyl acetate. The organic layers are combined, shaken with Norit SX Plus charcoal (76 g) for 30 minutes and filtered on a bed of Hyflo Supercel. washed with 1.5 liters of methyl acetate The filtrate and the washing solvent are combined and stirred at 10 ° C., while adding, over 20 minutes, a solution of 388 g of sodium 2-ethylhexanoate in a mixture of 2 liters of methyl acetate and 40 ml of water to obtain a white suspension with a pH of 5.5. The suspension is stirred for 10 minutes and filtered and the filter cake is washed with 5 ml of water. 1 liter of methyl acetate is added, the mixture is filtered off with suction and dried at 30 ° C. under vacuum for 2-4 hours to obtain 851.9 g of cefuroxime sodium salt; O = + 600, (c 0.5, 0.1 M buffer pH 4.5, ax (H 20) 1% Ma 2 = 273 nm (E 1% 387), impurities by liquid chromatography high pressure 2.0% Analysis (high pressure liquid chromatography) 92% w / w, water content (Karl Fischer) 2.8% w / w, solvents (liquid chromatography /

gas) 0.5% w / w.

Example 1

  Cefuroxime axetil 12.5 g of (RS) -1-acetoxyethyl bromide are added to a stirred mixture of 20 g of cefuroxime sodium salt (prepared by a process similar to that given in Preparation 1) in 110 ml of dimethylacetamide. The mixture is stirred at + 1 ° C. for 90 minutes and 0.5 g of potassium carbonate is added. The mixture is stirred for a further 2 hours at 1 ° to 30 ° C. and the reaction mixture is poured into a mixture rapidly. stirred with 200 ml of ethyl acetate and 200 ml of 3% aqueous sodium bicarbonate to destroy any excess of 1-acetoxyethyl bromide. After one hour, the organic layer (1.5% isomer 2 was separated by high pressure liquid chromatography), washed with 100 ml of 1 M hydrochloric acid and with 30 ml of a 20% aqueous solution of sodium chloride containing 2% of sodium bicarbonate. The 3 aqueous phases are washed successively with 100 ml of ethyl acetate are stirred organic extracts combined for 30 minutes with 2 g of charcoal (Norit SX Plus), filtered through a Kieiselguhr bed, washed with 2 times 25 ml of ethyl acetate. The filtrate and the precipitates were evaporated under vacuum. washing solvents combined up to 150 g and stirred at room temperature for 1 hour until crystallization is well established In 45 minutes, 250 ml of diisopropyl ether are added to complete the crystallization and stirring is continued The product was collected by filtration, washed with 150 ml of a 2: 1 mixture of diisopropyl ether and ethyl acetate and dried over a weekend at 500.degree. 19.3 g of crystalline cefuroxime axetil whose IR spectrum in Nujol, as represented in the accompanying drawing, is typical of a mixture

crystalline isomers.

  Solvent content (gas / liquid chromatography) 0.2% m / m Impurities by 1.8% high pressure liquid chromatography including 0.3% m / m isomer & 2 isomer E 25 0.6% m / m Isomer ratio (high pressure liquid chromatography) 1.09: 1; 7 D (1% in dioxane) 1% 37 (28 nm, MOH) 39 Analysis by chromatography = 70, 1 cm 78 nm, Me UH) 389 Analysis by chromatography

  in high pressure liquid phase 99% m / m (uncorrected).

Example 2

  Cefuroxime axetil A stirred suspension of 20 g of cefuroxime sodium salt in 110 ml of dimethylacetamide is cooled to 15 ° C.

  and 12.5 g of (RS) -1-acetoxyethyl bromide are added.

  Stirring was continued at the previous temperature for 45 minutes and 0.5 g of potassium carbonate was added.

  After stirring the mixture for a further 45 minutes at C, it is poured rapidly into a vigorously stirred mixture of 200 ml of ethyl acetate and 200 ml of 3% aqueous sodium bicarbonate. After 1 hour, the layers are separated and the organic phase (1.6% of Z 2 isomer is washed with chroma-to-weight in high-fluid phase) with 100 ml of acyl,

  1 M hydrochloric acid and 30 ml of a 20% aqueous solution of sodium chloride containing 2% sodium bicarbonate.

  The aqueous phases are washed successively with 100 ml of ethyl acetate. The combined organic extracts are stirred for 30 minutes with 2 g of charcoal (Norit SX Plus), filtered through a bed of kieselguhr which is washed With 2 times 25 ml of ethyl acetate. After evaporating the filtrate and the washing solvents combined at 120 g, the concentrate is stirred for 20 minutes to allow the crystallization to take place. 120 ml of dialcohol are rapidly added. denatured industrial, then in 15 minutes 240 ml of distilled water The resulting suspension is concentrated under vacuum to 310 g and stirred at room temperature for 45 minutes. The product is collected and washed with 200 ml of water. distilled and dried for 67 hours under vacuum at 50 ° C.

  to obtain crystalline cefuroxime axetil (20.01 g).

  Solvent content (gas / liquid chromatography) 0.2% w / w; impurities (high pressure liquid chromatography) 1.5% w / w including 0.5% w / w h 2 isomer and U, 6% w / w E isomer; ratio of 1, 01: 1 isomers; cD (1% in dioxane) = + 400; E 1% (278 nm, methanol) 388; analysis by 1 cm high pressure liquid chromatography 98% m / m (uncorrected),

Example 3

  Cefuroxime axetil 20 g of cefuroxime sodium salt are stirred with 100 ml of dimethylacetamide at 250 ° C. for 15 minutes, the mixture is cooled to 15 ° C. and 9.8 ml of (RS) -1-acetoxyethyl bromide are added. The mixture is stirred for a further 90 minutes at 14-160 ° C., 0.5 g of potassium carbonate having a particle size of 0.250 mm are added after half the time of this stirring period. The red mixture is then diluted. 200 ml of ethyl acetate and 20 ml of 3% aqueous sodium bicarbonate are added and the mixture is stirred for one hour at room temperature (approximately 25.degree. C.). The layers are then separated and the mixture is again extracted with water. aqueous layer with 200 ml of ethyl acetate before discarding (e, 0.21 / dm) The organic solutions are then washed with 100 ml of 1 M hydrochloric acid and then 30 ml of a chloride solution. of 20% sodium containing 2% of sodium bicarbonate and the organic extracts are combined before treated with 2 g of Norit SX Plus charcoal for 25 minutes. The charcoal is filtered on a pad of Supercel Standard, the filter is washed with 50 ml of ethyl acetate and the filtrates are collected under reduced pressure. vacuum to 120 g The remaining solution is inoculated, stirred at 22 ° C. for one hour, 250 ml of toluene are added to the suspension in 30 minutes.

  The mixture is stirred and the mixture is stirred for a further 30 minutes.

  The suspension is again evaporated to dryness to 182 g, cooled to 25 ° C. and stirred for 30 minutes. The product is collected, washed with 100 ml of toluene, dried by spinning for 15 minutes, and then dried. vacuum at 45 ° C. overnight to obtain 19.8 g of crystalline cefuroxime axetil Solvents by gas / liquid chromatography 25 μ, 9%; analysis by high liquid chromatography

  pressure 100%, isomer ratio 1.03: 1, A 2 <0.1% w / w.

  Water (by the Karl Fischer process) 0.48% w / w.

Example 4

  Cefuroxime axetil The washed and evaporated solution (about 125 g) of cefuroxime axetil in ethyl acetate was stirred at room temperature, obtained by a reaction similar to that described in Example 1, until crystallization is well established For 188 hours 188 ml of light petroleum ether (boiling point 100.degree.-100.degree. C.) are added dropwise, and the suspension is then stirred at ambient temperature for a further 2 hours. precipitated product by filtration, washed by displacement with a mixture (75 ml) 2: 1 light petroleum ether (boiling point 100-120 C) and ethyl acetate and dried overnight under vacuum at 40 ° C. to obtain 19.2 g of the title compound Water (Karl Fischer) 0.4% w / w, solvents (gas / liquid chromatography 0.4% w / w Analysis by high pressure liquid chromatography 100% m / m Impurities by high pressure liquid chromatography 1.1% m / m - of which 0.1% m / m isomer 2 and 0.6% w / w of anti isomer); the report

isomers is 0.98: 1.

Example 5

  Cefuroxime axetil A washed and concentrated solution (about 125 g) of the required cefuroxime axetil in acetate is prepared.

  of ethyl as in Example 1 and stirred for 1 hour at 330 C until crystallization is well established.

  After keeping the suspension overnight at the boiling temperature, 62.5 ml of industrial denatured alcohol are added over 5 minutes with stirring and then over 1 hour 250 ml light petroleum ether (boiling point 100.degree. (C) The crystalline suspension is stirred for a further 1.5 hours, the product is collected, washed by displacement with 75 ml of a 2: 1 mixture of light petroleum ether (boiling point 100-120 ° C.) and ethyl acetate and dried overnight under vacuum at 450 ° C to obtain 19.2 g of the title compound Water (Karl Fischer)

  0.2% w / w; solvents (gas / liquid chromatography) 0.8% m / m.

  Impurities by high pressure liquid chromatography

  0.8% w / w (including 0.1% w / w L-isomer and 0.7% w / w anti-isomer); 1.05: 1 isomer ratio Analysis by high pressure liquid chromatography 96% w / w.

Example 6

  Cefuroxime axetil A washed and carbon-treated concentrate of cefuroxime axetil wood is inoculated in ethyl acetate (approx. 100 g), containing about 2% of the 2-isomer, obtained in the same manner as in the example 1, and stir for a minute until a crystallization is well

  After 30 minutes, 100 ml of isopropanol are added dropwise, followed by 170 ml of distilled water in the course of 50 minutes.

  The resulting slurry is concentrated under vacuum to 250 g and cooled to 12 ° C over 1 hour. The crystalline product is collected by filtration, washed by displacement with 20% isopropanol in distilled water ( 100 ml) -refro-die in ice and dried over a weekend vacuum under 40 C is obtained, 1 g of title compound Water (Karl Fischer) 0.4% m / m, solvents (chromatography gas / liquid) 0.03% w / w Impurities by 1.5% high pressure liquid chromatography (d = 0.4% w / w isomer / about 0.6% w / w) isomer

  anti); 1.05: 1 isomer ratio.

Claims (8)

  A process for the preparation of a very pure crystalline 1-acetoxyethyl decafuroxime ester which comprises crystallizing the acetoxyethyl ester of cifuroxime from one of its solutions in an organic or aqueous solvent or a mixture thereof two types of solvents,   then isolate and dry the product.   Process according to Claim 1, characterized in   that the 1-acetoxyethyl ester of odefoxime crystallizes in a ratio of R to S isomers of about 1: 1.   3. Method according to one of claims 1 and 2,   characterized in that the solvent comprises an ester.   4. Process according to claim 3, characterized in that the solvent comprises an ester or a halogenated hydrocarbon optionally mixed with an ether, or an aliphatic or aromatic hydrocarbon; or a ketone or an amide mixed with water.   process according to one of claims 1 and 2,   characterized in that the solvent comprises an alcohol mixed with water.   Process according to Claim 4, characterized in   the solvent is selected from methyl or ethyl acetate, optionally mixed with diisopropyl ether, petroleum ether or toluene.   Process according to any one of the claims   preceding, characterized in that at least a last part of the crystallization operation is carried out between and 300 C.   A crystalline cefuroxime 1-acetoxyethyl ester having a purity level of at least 95% w / w.   A crystalline cefuroxime 1-acetoxyethyl ester having the IR spectrum in Nujol, as shown in FIG. attached drawing.