FI76808C - FOERFARANDE FOER FRAMSTAELLNING AV CEFUROXIM-1-ACETOXIETYLESTER. - Google Patents

Description

1 76308

This invention relates to improvements in or related to cephalosporins. More specifically, it relates to improvements in the preparation of cefuroxime 1-acetoxyethyl ester (cefuroxime axetil).

"Cefuroxime" is the approved name for the compound (6R, 7R) -3-carbamoyloxymethyl-7 '- [2- (fur-2-yl) -2-methoxyiminoacetamide] cef-3-em-4-carboxylic acid. This co-10 diste is a valuable antibiotic characterized by high broad-spectrum activity against gram-positive and gram-negative microorganisms, which is enhanced by the very high stability of the compound produced by some gram-negative microorganisms. J-lactamase and against.

15 It is well tolerated by the mammalian body and is widely used as an antibiotic in clinical use. Cefuroxime and its salts are valuable mainly as injectable antibiotics, as they are poorly absorbed from the stomach and intestines and therefore occur only at low concentrations in serum and urine after oral administration. For this reason, there has been a need to provide cefuroxime that is capable of being absorbed from the stomach and intestine after oral administration.

We have found that esterification of the carboxyl group of cefuroxime in a suitable manner improves efficacy when administered orally. As a result of the presence of such a suitable esterifying group, the compound is absorbed to a significant extent from the stomach and intestines, after which, for example, enzymes contained in serum and body tissues hydrolyze the blocking group to form an antibiotically active parent acid. To be effective when administered orally, the ester must be stable enough to reach the site of absorption without significant degradation, be sufficiently absorbed when it reaches the appropriate site, and hydrolysed easily enough by systemic esterases to release the parent acid within the short absorption time of the ester • _ r ______ 2 76 GB 1 571 683 discloses a few esters of cefuroxime esters and their compounds as having properties which give them considerable potential value as oral antibiotics.

Of the esters disclosed in GB 1,571,683, we have found cefuroxime axetil to be of particular interest. This product contains an asymmetric carbon atom at the 1-position of the 1-acetoxyethyl group and can therefore exist as 10 R and S isomers or mixtures thereof. The methods illustrated by the examples of GB 1 1,571,683 for the preparation of the above-mentioned ester give the product in either a relatively impure amorphous form or a crystalline form. In addition, in the crystalline material produced by the methods disclosed in this patent publication, either the R or S isomer predominates, while a ratio of approximately 1: 1 is preferred for administration. Therefore, this crystalline product is not the best to be administered.

We have now been able to develop a process by which 20 cefuroxime axetil can be obtained in a very pure crystalline form and in a high yield. Such a product is useful not only because it is a very pure form of the active compound and thus more suitable for biological administration, but also and most importantly, it is very useful as a starting material for the preparation of a very pure, largely amorphous form of cefuroxime axetil. found high for oral administration and a better balance of properties for commercial use than the crystalline substance. Such amorphous cefuroxime axetil preferably contains the R and S isomers in a ratio of about 1: 1, as we have found this important in order to maximize the solubility of the amorphous product in the aqueous medium and the methods we have developed can provide crystalline cefuroxime acetyl. the ratio of isomers is approximately this.

3 76308

Thus, we provide a process for preparing high purity crystalline cefuroxime axetil in good yield, which process comprises crystallizing cefuroxime axetil from a solution containing it in an organic solvent or water or a mixture thereof and 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 ratio of R and S isomer in the product is to be, as desired, about 1: 1, for example in the range 0.9: 1 to 1.1: 1. We have found that the solubilities of the different isomers of cefuroxime axetil vary; one of them is consistently more soluble than the other. Solubility levels vary with solvent, and thus it is desirable to select a solvent-15 system that allows for the recovery of cefuroxime axetil in solution prior to crystallization in a substantially quantitative manner, ensuring that the isomer ratio is about 1: 1.

The desired solvent system from which the product can be crystallized is an ester, for example methyl or ethyl acetate, or a halogenated hydrocarbon, such as methylene chloride, optionally and preferably mixed with an ether, for example diisopropyl ether, or an aliphatic or aromatic hydrocarbon, for example petroleum ether or toluene. 25 nia; or an alcohol, for example ethanol or isopropanol, optionally and preferably mixed with water, for example a water-containing technical alcohol denatured with methanol; or an amide such as dimethylformamide or dimethylacetamide, or a ketone such as acetone to which water has been added.

The crystallization step is preferably carried out at ambient temperature, for example about 10-30 ° C, and the concentration of cefuroxime axetil in the solution from which the crystallization takes place is generally adjusted, for example by evaporation of the solvent or dilution, so that the solution is neither too dilute nor too concentrated. Crystallization can form the last step or steps of the reaction, ___ .. TT- --------- 4 76808 in which cefuroxime axetil is formed. In such a case, the first step of crystallization can be carried out at a fairly high temperature, for example up to about 65 ° C, but in order to maximize the yield and obtain a suitable ratio of isomers to the product, a temperature range of 10-30 ° C is preferred for final isolation.

The reaction in which cefuroxime axetil is formed is preferably an esterification reaction carried out as described in GB Patent 10,571,683 and starting from highly pure cefuroxime sodium. The preferred reagent for esterification is 1-acetoxyethyl bromide, and in order to obtain a ratio of R to S isomer prior to recrystallization of about 1: 1, it is clearly preferred that said reagent be racemic.

The preferred cefuroxime sodium starting material is generally very pure itself. Such a substance can be obtained e.g. by reacting (6R, 7R) -3-hydroxymethyl-7- [trans-2- (fur-2-yl) -2-methoxyiminoacetamide] ceph-3-em-4-carboxylic acid with chlorosulfonyl isocyanate in an alkyl acetate solvent -25 to + 10 ° C, followed by in situ hydrolysis at 10-30 ° C and, after addition of sodium 2-ethylhexanoate dissolved in acetone or methyl acetate, crystallization. The purity of such a substance is generally at least 90% by weight.

In the cefuroxime axetil produced by the process of this invention, the molar ratio of the R to S isomer is about 1: 1 and its purity is generally at least 95% by weight (uncorrected for solvent residues).

30 Cefuroxime axetil is a method provides the initial form of the, in highly pure crystalline material of this invention, the new shape and form another aspect of the present invention. One experimental batch of this substance, run on a Nujol, has an IR spectrum shown in the attached 35 drawings.

5 76308

The invention will now be illustrated by the following preparation and the following examples, which are not intended to limit the invention.

The various isomers of the T-acetoxyethyl ester of cefuroxime, the 5 R and S isomers, are denoted for convenience by the letters A and B, which are used to denote isomers similar to those in GB 1,571,683. Isomers A and B are not disclosed. The isomer ratios given in the following examples are given as A: B. All 10 temperatures are given in degrees Celsius.

Preparation 1

Natriumkefuroksiimi

To a solution of triethylamine (10 mL) in methyl acetate (3.8 L) was added chlorosulfonyl iso-cyanate (226 mL). The resulting clear solution was cooled to -15 ° C and a suspension pre-cooled to -15 ° C containing (6R, 7R) -3-hydroxymethyl-7- [Z-2- (fur-2- yl) -2-methoxyiminoacetamide-3-ceph-3-em-4-carboxylic acid (763 g) in methyl acetate (2.3 L). Residual solids were rinsed with methyl acetate (700 mL). The mixture was stirred at -5 ° C for 30 minutes; a clear solution was obtained after 30 minutes. Water (1.2 L) from 18 ° C was added rapidly to the reaction mixture, causing the temperature to rise rapidly to 10 ° C and then slowly to 17 ° C. The mixture was stirred at 15 ° C for 60 minutes to give a thick white suspension. Methyl acetate (3.6 L) was added followed by a constant rate of a solution of sodium hydroxide (288 g) in water (5.2 L). This gave a clear, biphasic mixture with a temperature of 26 ° C and 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). Each aqueous layer was washed separately with methyl acetate (2 L). The organic layers were combined, mixed with Norit SX 35 Plus activated carbon (76 g) for 30 minutes, the mixture was filtered through a pad of Hyflo Supercel and the pad was washed with 6 76308 methyl ethyl acetate (1.5 L). The filtrate and the washing solution were combined and stirred at 20 ° C while a solution of sodium 2-ethylhexanoate (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, then filtered and the cake was washed with methyl acetate (5x11) and dried under suction and then at 30 ° C under reduced pressure for 24 hours to give cefuroxime sodium (851.9 g); Λ max = + 60 ° 10 (c = 0.5; 0.1 M buffer pH 4.5); % v (H_0) = 273 nm (e! * = max δ I cm 387); impurities by HPLC 2.0% by weight. HPLC analysis result 92% by weight; water content (Karl Fisher) 2.8% by weight; solvents (GLC) 0.5% by weight.

Example 1 15 Cefuroxime axetil

To a mixture of cefuroxime sodium (20 g; prepared by a similar method to Example 1) in dimethylacetamide (110 ml) at 0 ° C was added (RS) -1-acetoxyethyl bromide 20 (12.5 g) with stirring. The mixture was stirred at + 1 ° C for 90 minutes, after which potassium carbonate (0.5 g) was added. Stirring was continued at 1-3 ° C for an additional two hours, at which time the reaction mixture was added to destroy any excess 1-acetoxyethyl bromide in a mixture of ethyl acetate (200 mL) and 3% aqueous sodium bicarbonate (200 mL) and stirred. was stirred rapidly. After 1 h, the organic layer (1.5% α-isomer by HPLC) was separated and washed with 1 M hydrochloric acid (100 mL) and 20% aqueous sodium chloride containing 2% sodium bicarbonate (30 mL). mL). All three aqueous phases were washed separately with ethyl acetate (100 mL). The combined organic extracts were stirred with activated carbon (Norit SX Plus; 2 g) for 30 minutes and the mixture was filtered through a pad of silica, which was washed with ethyl acetate (2 x 25 mL). The filtrate and washings were combined and concentrated under reduced pressure to a weight of 150 g, and the concentrate was stirred at ambient temperature for 7 hours to initiate crystallization well. Diisopropyl ether was added to complete the crystallization. (250 ml) over 45 minutes and stirring was continued for another hour. The product was collected by filtration and washed with a mixture of diisopropyl ether and ethyl acetate (2: 1; 150 ml) and dried over the weekend under reduced pressure at 50 ° C to give crystalline cefuroxime axetil (19.3 g) with IR in Nujol. spectrum shown in the accompanying drawing and typical of a mixture of crystalline isomers.

Solvent content (GLC) 0.2% by weight. Impurities by HPLC 1.8% by weight, including 0.3% by weight of the Δ isomer and 0.6% by weight of the E isomer. Isomer ratio (HPLC) 1.09: 1; {α] D = + 37 ° (1% in dioxane), λmax (278 nm, 15 MeOH) = 389. HPLC analysis 99% by weight (uncorrected).

Example 2

Cefuroxime axetil

A mixture of cefuroxime sodium (20 g) in dimethylacetamide (110 ml) and stirred was cooled to 15 ° C and (RS) -1-acetoxyethyl bromide (12.5 g) was added. Stirring was continued at the above temperature for 45 minutes, after which potassium carbonate (0.5 g) was added. After stirring at 15 ° C for an additional 45 minutes, the mixture was poured into a mixture of ethyl acetate (200 mL) and 3% aqueous sodium bicarbonate (200 mL) and stirred rapidly. After 1 h, the layers were separated and the organic layer (1.6% Δ-isomer by HPLC) was washed with 1 M hydrochloric acid (100 mL) and 20% sodium chloride in water containing 2% sodium bicarbonate ( 30 ml). All aqueous phases were washed separately with ethyl acetate (100 mL). The combined organic extracts were stirred with activated carbon (Norit SX Plus; 2 g) for 30 minutes and the mixture was filtered through a pad of diatomaceous earth, which was washed with ethyl acetate (2 x 25 mL). The filtrate and washings were combined and concentrated to a weight of 120 g, after which the concentrate was stirred for 20 minutes to initiate crystallization well. Methanol-denatured technical alcohol (IMS) (120 ml) was added rapidly, followed by distilled water (240 ml) over 15 minutes. The resulting suspension was concentrated to 310 g under reduced pressure and stirred at ambient temperature for 45 minutes. The product was collected and washed with distilled water (200 ml) and dried for 67 hours under reduced pressure at 50 ° C to give crystalline cefuroxime axetil (20.01 g). Solvent content (GLC) 0.2% by weight; impurities (HPLC) 1.5% by weight, 2 containing the Δ isomer and 0.5% by weight and the E isomer 0.6% by weight; isomer ratio 1.01: 1; [α] D = + 40 ° (1% in di-1% in oxane); Elcm (278 nm, methanol) = 388; HPLC analysis result 98% by weight (uncorrected).

15 Example 3

Cefuroxime axetil

Cefuroxime sodium (20 g) was stirred with dimethylacetamide (100 ml) at about 25 ° C for 15 minutes, the mixture was cooled to 15 ° C and (RS) -1-acetoxy-20-diethyl bromide (9.8 ml) was added. The mixture was stirred at 14-16 ° C for an additional 90 minutes, at which point sodium carbonate (60 mesh; 0.5 g) was added halfway through. The red-brown mixture was then diluted with ethyl acetate (200 mL) and 3% aqueous sodium bicarbonate 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 (OC, 0.21 ° / dm). The organic solutions were washed separately with 1 M hydrochloric acid (100 ml) followed by 20% sodium chloride (30 ml) containing 2% sodium hydrogen carbonate and then combined and treated with Norit SX Plus activated carbon (2 g) for 25 minutes. The activated carbon was removed by filtering the mixture through a pad of Standard Supercel, which was washed with ethyl acetate (50 mL), and the combined filtrates were concentrated under reduced pressure to a weight of 120 g. Crystallization centers were added to the residual solution, and it was stirred at 22 ° C for one hour, to which was added toluene (250 ml) over 30 minutes, and the mixture was stirred for another 30 minutes. The suspension was then reconcentrated under reduced pressure to a weight of 182 g and cooled to about 25 ° C and stirred for 30 minutes. * The product was collected and washed with toluene (100 ml) and suction dried for 15 minutes and then under reduced pressure at 45 ° C: overnight to give crystalline cefuroxime axetil (19.8 g). Solvent content according to GLC 0.9% by weight (EtAc 0.7% by weight and toluene 0.15% by weight); impurities by HPLC 0.9% by weight; HPLC analysis result 100% by weight; isomer ratio 2 1/03: 1; Λ isomer less than 0.1% by weight. Water content (Karls Fischer) 0.4% by weight.

Example 4 15 Cefuroxime axetil

The washed and concentrated (to about 125 g) ethyl acetate solution of the cefuroxime axetil obtained by the reaction of Example 1 was stirred at ambient temperature until crystallization began well. Petroleum ether (b.p. 100-120 ° C; 188 ml) was added dropwise over one hour, after which the suspension was stirred at ambient temperature for a further two hours. The crystalline precipitate was collected by filtration and washed several times with a mixture of petroleum ether (b.p. 100-120 ° C) and ethyl acetate (2: 1; 75 ml) and the precipitate was dried overnight at 40 ° C under reduced pressure to give the title compound (19, 2 g). Water (Karl

Fischer) 0.4% by weight; solvents (GLC) 0.4% by weight. HPLC analysis result 100% by weight. Impurities according to HPLC 2 1.1% by weight (of which 0.1% by weight of the Δ isomer and 0.6% by weight of the 30 opposite isomers), isomer ratio 0.98: 1.

Example 5

Cefuroxime axetil

A washed and concentrated (about 125 g to 35 weight) ethyl acetate solution of the required cefuroxime axetil prepared according to Example 1 was stirred for one hour at 33 ° C to initiate crystallization well. After the suspension was kept at ambient temperature overnight, IMS (62.5 ml) was added with stirring over 5 minutes, followed by petroleum ether (b.p. 100-120 ° C; 250 ml) over the next hour. After stirring the crystalline suspension for an additional 1.5 hours, the product was collected and washed several times with a mixture of petroleum ether (b.p. 100-120 ° C) and ethyl acetate (2: 1; 75 ml) and dried under reduced pressure at 45 ° C. overnight to give the title compound (19.2 g). Water (Karl Fischer) 10 0.2% by weight; solvents (GLC) 0.8% by weight. Impurities 2 by HPLC 0.8% by weight (of which 0.1% by weight of the Λ-isomer and 0.7% by weight of the anti-isomer); isomer ratio 1.05: 1. HPLC analysis result 96% by weight.

Example 6 15 Cefuroxime axetil

To the washed and activated carbon-treated concentrate of cefuroxime axetil in ethyl acetate (about 100 g) containing about 2% / S isomer obtained according to Example 1, crystallization centers were added and stirred for 30 minutes to allow crystallization to proceed well. to the top. Isopropanol (100 ml) was added dropwise over 30 minutes, followed by distilled water (170 ml) over 50 minutes. The resulting suspension was concentrated under reduced pressure to a weight of 250 g and cooled to 12 ° C over one hour. The crystalline product was collected by filtration and washed several times with an ice-cold solution (100 ml) containing 20% isopropanol in distilled water, and the product was dried over the weekend under reduced pressure at 40 ° C. The amount of the title compound was 20.1 g. Water (Karl Fischer) 0.4 0.4% by weight; solvents (GLC) 0.03% by weight. Impurities 2 by HPLC 1.5 wt% (of which 0.4 wt% Δ isomer and about 0.6 wt% anti-isomer); isomer ratio 1.05: 1.

Il

Claims (3)

11 76808 A process for the preparation of highly pure crystalline cefuroxime-1-acetoxyethyl ester in a ratio of about 1: 1 to the R and S isomers, characterized in that the cefuroxime-1-acetoxyethyl ester is crystallized from its solution, wherein the solvent is an ester or a halogenated hydrocarbon. optionally mixed with an ether, aliphatic or aromatic hydrocarbon or alcohol, optionally mixed with water or an aliphatic or aromatic hydrocarbon; or an amide or ketone to which water has been added; after which the product is isolated and dried. Process according to Claim 1, characterized in that the solvent is methyl or ethyl acetate, optionally mixed with diisopropyl ether, petroleum ether or toluene. Process according to Claim 1 or 2, characterized in that at least part of the crystallization step is carried out at 10 to 30 ° C.