CA1265511A

CA1265511A - Cephalosporins

Info

Publication number: CA1265511A
Application number: CA000459929A
Authority: CA
Inventors: John Francis Oughton; Michael Wright; Harold Alfred Crisp; John Peter Turnbull
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 1983-07-29
Filing date: 1984-07-27
Publication date: 1990-02-06
Anticipated expiration: 2007-02-06
Also published as: DK165505C; GB2145409B; ES8601869A1; ATA244484A; DE3427828A1; GB8419202D0; SE8403897D0; IE57726B1; AU3125684A; IL72536A0; FI843011A0; FR2549837B1; JPS6075484A; NO167292C; ES534695A0; AU582121B2; AU634965B2; FI843011A; SE463263B; BE900241A

Abstract

ABSTRACT

There is described a process for obtaining highly pure crystalline cefuroxime axetil. The process comprises crystallising cefuroxime axetil from a solution thereof in an organic or aqueous solvent or a mixture thereof and then drying and isolating the product. Preferred solvents are alkyl acetates in admixture with ethers or aliphatic or aromatic hydrocarbons. The higher the yield from crystallisation, the closer to a 1:1 stoichiometric ratio of R:S isomers the product will contain, this being most desirable for a product having the desired properties.

Description

~2~S5~

3U1~1-280 Improvements in or relating to cephalosporins This invention relates to improvements in or relating to cephalosporins. More particularly it relates to improvements in the manufacture of cefuroxime l-acetoxyethyl ester (cefuroxime axetill.
The compound (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic acid has the approved name "cefuroxime".
10 This compound is a valuable antibiotic characterised by high broad spectrum activity agains~ gram-positive and gram-negative microorganisms, this property being enhanced by the very high stability of the compound to ~-lactamases produced by a range of gram-negative microorganisms. It is well tolerated in the mammalian body and is used widely as an antibiotic in clinical practice. Cefuroxime and its salts are principally of value as injectable antibiotics since they are poorly absorbed from the gastro-intestinal tract and are therefore present in sera and urine only in low concentrations after oral administration. There has therefore been a need for a form of cefuroxime which is capable of being absorbed from the gastro-intestinal tract following oral administration.
We have found that appropriate esterification of the carboxyl group of cefuroxime improves the effectiveness on oral administration. The presence of such an appropriate esterifying group results in significant absorption of the compound from the gastro-intestinal tract, whereupon the esterifying group is hydrolysed by enzymes present in, for example, serum and body tissues to yield the anti-biotically active parent acid. To be effective upon oral administration the ester must be stable enough to reach the site of absorption without significant degradation, must be sufficiently absorbed ~2~i5~

upon reaching the appropriate site, and must be sufficiently susceptible to hydrolysis by systemic esterases for the parent acid to be liberated within a short time of the ester being absorbed. British 5 Patent Specification No. 1571683 discloses and claims a number of esters of cefuroxime as ha~7ing properties rendering them of significant potential value as orally administrable antibiotics.
Of the esters described in ~3ritish Patent 10 Specification No. 1571683, we have found cefuroxime axetil to be of particular interest. This product possesses an asymmetric carbon atom at the l-position of the l-acetoxyethyl group and can therefore exist in the form of R and S isomers or mixtures thereof.
15 The processes for the preparation of the above ester exemplified in British Patent Specification No. 1571683 produce the material either in relatively impure amorphous form or in the form of a crystal-line material. Furthermore, the crystalline material 20 produced by the methods described in this specification generally contains a predominance of either the R or the S isomer whereas an approximately 1:1 ratio is advantageous for administration. The crystalline product is not therefore ideally suited 25 to administration.
We have now been able to develop a process whereby cefuroxime axetil may be obtained in highly pure crystalline form and in high yield. Such a product is not only useful from the point of 30 view of being a highly pure form of the active compound and hence more suitable for biological administration but, more particularly, is also highly useful as a starting material for the preparation of a highly pure, substantially amorphous form 35 of cefuroxime axetil, which form we have surprisingly found has high bioavailability upon oral administration and a better balance of properties for commercial use than the crystalline material. The amorphous ~265~

cefuroxime axeti] which has these properties is desirably and approximately l:l ratio of R to S isomers since this has been found to be of value in maximising the solubility in aqueous media of the amorphous product, and the process we have developed can provide crystalline cefuroxime axetil having this approximate ratio of isomers.
Accordingly, we provide a process for the preparation of highly pure crystalline cefuroxime l-acetoxyethyl ester which comprises crystallizing cefuroxime l-acetoxyethyl ester from a solution thereof wherein the solvent is an ester or a halogenated hydrocarbon, optionally in admixture with an ether, an aliphatic or aromatic hydrocarbon or an alcohol, said alcohol op-tionally in admixture with water or an aliphatic or aromatic hydrocarbon; or wherein the solvent is an amide or ketone in admixture with water, isolating and drying the product.
The choice of crystallisation solvent has been found important if the yield is to be maximised and the R to S isomer ratio of the product is to be, as is desirable, approximately l:l, for example i.n the range 0.9:1 to l.l:l. We have found the different isomers of cefuroxime axetil to have different solu-bilities, one of them being consistently more soluble than the other. The levels of solubi].ity vary according to the solvent, and so a solvent system will desirably be chosen which allows a practically quantitative recovery of the ceEuroxime axetil that is present prior to crystallization, thereby assuring an approxi-mately l:1 ratio of isomers.
The solvent system from which the product may be . .

~2~S~
-3a- 20208-l230 crystallized will be 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, for example diisopropyl ether or an aliphatic or aromatic hydro-carbon, for example petroleum ether or toluene; or an alcohol, for example ethanol or isopropanol, optionally but preferably in ad-mixture with water r such as in aqueous industrial methylated spirit; or an amide, ~2~ss~

such as dimethylformamide or dimethylacetamide, or ketone, such as acetone, in admixture with water.
The crystallisation step will desirably be carried out at ambient temperature, for example at from about 10 to 30C and the concentration of the cefuroxime axetil in the solution from which crystallisation will occur will generally be adjusted e.g. by evaporation of solvent or by dilution so as to be neither too dilute nor too concentrated respectively. The crystallisation may comprise the last stage or stages of a reaction in which the cefuroxime axetil is formed. In such a case, the initial stage of crystallisation may occur at quite a high temperature, e.g. up to about 65C, but in order to maximise the yield and obtain a suitable ratio of isomers in the product, a temper-ature range of from 10 to 30 is preferred for the final isolation.
The reaction in which the cefuroxime axetil is formed will preferably be an esterification reaction 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 l-acetoxyethyl bromide and in order to produce an approximately 1:1 ratio of R and S isomers prior to recrystallisation, it is clearly preferred that such a reagent be racemic.
The preferred sodium cefuroxime starting material will generally be itself highly pure.
Such a material may be obtained inter alia, by reaction of (6R,7R)-3-hydroxymethyl-7-[Z-2-(fur-

2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic acid with chlorosulphonyl isocyanate in an alkyl acetate as solvent at a temperature of from -25 to +10C, followed by hydrolysis in situ at a temper-ature of +10 to +30C an~ crysta1lisation eollowing ~2655~L~

addition of sodium 2-ethylhexanoate in acetone or methyl acetate as solvent. Such a material will generally have a purity ]evel of 90% mass/mass (m/m) or greater.
The cefuroxime axetil produced by the process of this inven~ion has an R to S isomer mole ratio of approximately 1.1, and is generally not less than 95% m/m pure (uncorrected for residual solvents).
In its highly pure, crystalline form the cefuroxime axetil which may be produced by the process of this invention is a novel form of matter and constitutes a further aspect of this invention.
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 non-limiting Preparation and Examples.
The individua] R and S isomers of cefuroxime l-acetoxyethyl ester are denoted for convenience by the letters A and B, these letters being used to denote the respective isomers as in British Patent No. 1571683. The identities of isomers A and B have not been assigned. The isomer ratios given in the following Examples are expressed as A:B. All temperatures are given in C.
PreParation 1 odium Cefuroxime Chlorosulphonyl isocyanate (226 ml) was added to a solution of triethylamine (10 ml) in methyl acetate (3.8 1). The resulting clear solution was cooled to -lS and a suspension of (6R,7R)-

3-hydroxymethyl-7-[Z-2-(fUr-2-yl)-2-methoxyiminoacet-amido]ceph-3-em-4-carboxylic acid (763g) in methyl acetate (2.3 1), pre-cooled to -15, was added over 10 minutes. The residual solid was rinsed in with methyl acetate (700 ml). The mixture was stirred at -5 for 30 minutes, a clear solution being obtained after 10 minutes~ Water (1.2 1) * Trade Mark ~6SS~l at 18 was added rapidly to the reaction mixture, the temperature rising quickly 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 1) was added followed by a steady addition of a solution of sodium hydroxide (288 g) in water (5.2 1). This gave a clear two-phase mixture at 26 with a p~ 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 1). The two aqueous layers were washed sequentially with methyl acetate--(2 1).
The organic layers were bulked, stirred with Norit S~ Plus charcoal (76 g) for 30 minutes and filtered through a bed of Hyflo*Supercel, the bed being washed with methyl acetate (1.5 1). The filtrate and wash were combined and stirred at 20 whilst a solution of sodium 2-ethylhexanoate (338 g) in a mixture of methyl acetate (2 1) 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 1), sucked dry, and dried at 30 in vacuo for 24 hours to give sodium ,.
cefuroxime (851.9 g); [~]DO+ 60, (c0.5; O.lM pH
~.5 buffer); ~max (H20) 273 nm (ElCm 387); impurities by HPLC 2.0%. Assay (HPLC) 92% m/m; Water content (Karl Fisher) 2.8~ m/m; Solvents (g.l.c.) 0.5% m/m.

Example 1 Cefuroxime Axetil _ (RS)-l-Acetoxyethylbromide (]2.5 g) was added to a stirred mixture of sodium cefuroxime (20 g) (prepared by a method similar to that in Preparation 1) in dimethyl acetamide (110 ml) at 0C. 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 * Trade Mark ".~

~;26S~
-7~ 20208-1230 mixture was added to a xapidly stirred mixture of ethyl acetate (200 ml) and aqueous 3% sodium bicarbonate (200 ml) to destroy any excess l-acetoxy-ethyl bromide. After l hour the organic layer (1.5% ~2 isomer by HPLC) was separated, washed with M hydro-chloric acid (100 ml) and aqueous 20% sodium chloride containing 2% sodium bicarbonate (30 ml). All three aqueous phases were sequentially washed with ethyl acetate (100 ml). The combined organic extracts were stirred for 30 minutes with charcoal (Norit SX Plus; 2g), filtered thxough a kieselgiihr bed which was washed with ethyl acetate (2 x 25 ml). The combined filtrate and washes were evaporated in _cuo to 150 g and stirred at ambient tempera-ture for 1 hour until the crystallisation was well established .
Di-isopropyl ether (250 ml) was added over 45 minutes to complete the crystallisation and stirring was continued for the additional 1 hour. The product was collected by flltration, washed with 2:1 di-isopropyl ether/ethyl acetate (150 ml) and dried for a weekend in vacuo at 50 to give crystalline cefuroxime axetil (19.3 g) with an infra-red spectrum in Nujol as shown in the Figure in the accompanying drawing which is typical of a mixture of crystalline isomers. The spectrum has the following absorption bands:
vrnax (Nujol) 3500, 3420, 3356, 3308, 3282, 3218, 1778, ]770 (shoulder), 1748, 1708, 1650, 1622, 16:L0, 1526, l332, :1300, 1220, 1102, 1074, 1054, 1040, 1010, 940, 884, 860, 818, 776 and 748 cml.
Solvent content (GLC) 0.2 m/m. Impurities by HPLC
1.8% including ~ isomer 0.3% m/m; E-isomer 0.6% m/m. Isomer ratio (HPLC) 1.09:1 [~]D (1% in dioxan) + 37; ElCm (278 mm, MeOH) 389. Assay by HPLC 99% m/m (uncorrected).

~2655~i -7a- 20208 1230 Example 2 Cefuroxime Axetil A stirred suspension of sodium cefuroxime (20 g) in dimethylacetamide (110 mL ) was cooled to 15 and (RS)-l-acetoxy-ethyl bromide (12.5 g) was added. Stirring at the foregoing temperature was continued for 45 minutes and potassium carbonate (0.5 g) was added. After stirring the mixture for an additional * Trade Mark 55~1 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 (EIPLC showed 1.6% ~2isomer) was washed with M hydrochloric acid (100 ml) and aqueous 20% sodium chloride containing 2~ sodium bicarbonate (30 ml). All the aqueous phases were sequentially washed with ethyl acetate (100 ml). The combined organic extracts were stirred for 30 minutes with charcoal (Norit SX Plus~ 2 g), filtered through a bed of kiesielgUhr which was washed with ethyl acetate (2 x 25 ml). After evàporating the combined filtrate and washes to 120 g the concentrate was stirred for 20 minutes to enable crytallisation to become established. Industri~al methylated spirit (120 ml) was added rapidly followed over 15 minutes by distilled water (240 ml). The resultant slurry was concentrated in vacuo to 310 g and stirred at ambient temperature for 45 minutes. The product was harveste~, washed with distilled water (200 ml) and dried for 67 hours in vacuo at 50 to give crystalline cefuroxime axetil. (20.01 g). Solvent content (GLC) 0.2~ m/m; impurities (HPLC) 1.5% m/m including ~
isomer 0.5% m/m and E-isomer 0.6% m/m; isomer ratio 25 1.01:1; [a]Dtl% in dioxan) +40; ElCm (278 nm, methanol) 388; Assay by HPLC 98% m/m (uncorrected).

Example 3 Cefuroxime Axetil Sodium cefuroxime (20 g) was stirred with dimethyl-acetamide (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 a further 90 minutes at 14-16, adding 60-mesh potassium carbonate (0.5 g) halfway through this period. The red-brown mixture was then diluted with ethyl acetate (200 ml) and 3% aqueous sodium hydrogen carbonate (200 ml) and stirred for an hour at ambient ~rade JnaJ~k ~2~5~

g temperature (ca 25)~ The layers were then separated and the aqueous layer was re-extracted with ethyl acetate (200 ml) and discarded (~, 0.21/dm). The organic solutions were washed sequentially with M
hydrochloric acid (100 ml), then 20% sodium chloride (30 ml) containing 2% sodium hydrogen carbonate and were then combined and treated with Norit SX Plus charcoal (2 g) for 25 minutes. The charcoal was filtered off through a Standard Supercel*pad, the filter was washed with ethyl ac~tate (50 ml), and the combined filtrates were evaporated in vacuo to 120 g. The residual solution was seeded, stirred at 22 for 1 hour when toluene (250 ml was run into the stirred slurry over 30 minutes, and the mixture stirred for a further 30 minutes. The suspension was then re-evaporated in vacuo to 182 g, cooled to ca 25 and stirred for 30 minutes. The product was harvested, washed with toluene (100 ml), suction- -dri-ed for 15 minutes, then dried in vacuo at 45 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 assay 100%, isomer ratio 1.03~ 0.1% m/m. Water (by Karl Fischer) 0.4% m/m.
Example 4 Cefuroxime Axetil The washed and evaporated (ca 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 crystallisation was well established. Light petroleum ether (b.p. 100-120; 188 ml) was added dropwise during 1 hour after which the suspension was stirred at ambient temperature for a further 2 hours. The crystalline precipitate was collected by filtration, displacement washed with 2:1 light petroleum ether tb.p. 100-120) -ethyl acetate mixture (75 ml) and dried overnight * Trade Mark at 40 ln vacuo to give the title compound, (19.2 g)~
Water (Karl Fischer) 0.4% m/m, solvents (glc) 0.4~ m/m.
Assay by HPLC 100% m/m. Impurities by HPLC 1.1% m/m (of which 0.1% and 0.6% m/m were ~2 and anti isomer respectively); the isomer ratio was 0.98:1.

Example 5 Cefuroxime Axetil A washed and concentrated (ca 125 g) solution of the required cefuroxime acetil in ethyl acetate as prepared in Example 1 was stirred for 1 hour at 33 until crystallisation was well established.
After storing the suspension overnight at ambient temperature IMS (62.5 ml) was added over 5 minutes with stirring followed, over the next 1 hour by light petroleum ether (b.p. 100-120; 250 ml). After stirring the crystalline suspension for a further 1.5 hours it was harvestea, displacement washed with 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; solvents (glc) 0.8% m/m. ImpuritieS by HPLC 0.8~ m/m (of which 0.1% m/m and 0.7% m/m were ~2 and anti isomers respectively); isomer ratio was 1.05: lo Assay by HPLC 96% m/m.
Example _ Cefuroxime Axetil A washed and charcoaled concentrate (ca 100 g) of cefuroxime axetil in ethyl acetate, containing ca 2~ ~2 isomer, obtained similarly to that in Example 1 was seeded and stirred for 30 minutes until crystal-lisation was well established. Isopropanol (100 ml) was added dropwise over 30 minutes followed over 50 minutes by distilled water (170 ml). The resultant slurry was concentrated _ vacuo to 250 g and cooled_ to 12 over a period of 1 hour. The crystalline product was collected by filtration, displacement washed with an ice-cold solution of 20% isopropanol ~2~55~L1 in distilled water (100 ml) and dried for a week-end in vacuo at 40. The title compound amounted to 20.1 g. Water (Karl Fischer) 0.4% m/m, solvents (glc) 0.03% m/m. Impurities by HPLC 1.5% (of which 0.4% m/m and ca 0.6% m/m were ~2 and anti isomers respectively~; isomer ratio 1~05:1.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of highly pure crystalline cefuroxime 1-acetoxyethyl ester which comprises crystallizing cefuroxime 1-acetoxyethyl ester from a solution thereof wherein the solvent is an ester or a halogenated hydrocarbon, optionally in admixture with an ether, an aliphatic or aromatic hydrocarbon or an alcohol, said alcohol optionally in admixture with water or an aliphatic or aromatic hydrocarbon; or wherein the solvent is an amide or ketone in admixture with water, isolating and drying the product.

2. A process as claimed in claim 1 wherein the cefuroxime 1-acetoxyethyl ester crystallizes in a ratio of R to S isomer of approximately 1:1.

3. A process as claimed in claim 1 wherein the solvent includes an ester.

4. A process as claimed in claim 1 or claim 2 wherein the solvent comprises an alcohol in admixture with water.

5. A process as claimed in claim 1 wherein the solvent is selected from methyl or ethyl acetate, optionally in admixture with diisopropyl ether, petroleum ether or toluene.

6. A process as claimed in any of claims 1, 2 and 3 wherein at least a latter portion of the crystallization step is carried out at from 10 to 30°C.

7. Crystalline cefuroxime 1-acetoxyethyl ester having a purity level of at least 95% mass/mass.

8. Crystalline cefuroxime 1-acetoxyethyl ester having the IR spectrum in Nujol (Trade Mark) having the following absorption bands: vmax (Nujol) 3500, 3420, 3356, 3308, 3282, 3218, 1778, 1770 (shoulder), 1748, 1708, 1650, 1622, 1610, 1526, 1332, 1300, 1220, 1102, 1074, 1054,1040, 1010, 940, 884, 860, 818, 776 and 748 cm-1.