NZ209046A

NZ209046A - Crystalline cefuroxime 1-acetoxyethyl ester of at least 95 percent mass/mass purity

Info

Publication number: NZ209046A
Application number: NZ209046A
Authority: NZ
Inventors: H A Crisp; M Wright; J P Turbull; J F Oughton
Original assignee: Glaxo Group Ltd
Priority date: 1983-07-29
Filing date: 1984-07-30
Publication date: 1988-02-29
Also published as: KR910008377B1; GB2145409A; FI76808C; NO843055L; PT78985B; DK165505C; ES8601869A1; NO167292C; JPS6075484A; AU634965B2; JPH0613526B2; BE900241A; DK366684A; KR850001221A; DK165505B; PT78985A; CA1265511A; GB2145409B; DE3427828A1; AU3125684A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £09046 o RECEIV- Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "IMPROVEMENTS IN OR RELATING TO CEPHALOSPORINS n 5, WE GLAXO GROUP LIMITED, a British company of Clarges House, 6-12 Clarges Street, London W1Y 8DH, England, hereby declare the invention, for which~t/we pray that a patent may be granted to-me/us, and the method by which it is to be performed, to be particularly described in and by the following statement -1- (folfowed by page I A.) 2090 46 - l&r 3U141-280 Improvements in or relating to cephalosporins This invention relates to improvements in or relating to cephalosporins. More particularly 5 it 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-methoxyirainoacetamido]ceph-3-em-4-carboxylie acid has the approved name "cefuroxime", 10 This compound is a valuable antibiotic characterised by high broad spectrum activity against 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 15 gram-negative microorganisms. It is well tolerated in the mammalian body and is used widely as an antibiotic in clinical practice. Cefuroxime and ita salts are principally of value as injectable antibiotics since they are poorly absorbed from 20 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 25 following oral administration. We have found that appropriate ester ification of the carboxyl group of cefuroxime improves the effectiveness on oral administration. The presence of such an appropriate esterifying group results 30 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 35 upon oral administration the ester must be stable enough to reach the site of absorption without significant degradation, must be sufficiently absorbed : • - / 0 209046 - 2 - 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. New Zealand 5 Patent Specification No. 183345 discloses and claims a number of esters of cefuroxime as having properties rendering them of significant potential value as orally administrable antibiotics. Of the esters described in New Zealand Patent 10 Specification No. 183345 we have found cefuroxime axetil to be of particular interest. This product possesses an asymmetric carbon atom at .the 1-position of the 1-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 New Zealand Patent Specification No. 183345 produce the material either in relatively impure amorphous form or in the form of a crystalline 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 administratis E ^ ? and a better balance of properties for commercial use than the crystalline material. The amorphous -8 DECI987mi h 5 - 3 - cefuroxime axetil which has these properties is desirably an approximately 1:1 ratio of R to S isomers since this has been found to be of value in maximising the solubility in aqueous media of 5 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 10 axetil in high yield which comprises crystallising cefuroxime axetil from a solution thereof in an organic or aqueous solvent or a mixture thereof, isolating and drying the product. The choice of crystallisation solvent has 15 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 1:1, for example in the range 0.9:1 to 1.1:1. We have found the different isomers of cefuroxime axetil to have 20 different solubilities, one of them being consistently more soluble than the other. The levels of solubility vary according to the solvent, and so a solvent system will desirably be chosen which allows a practically quantitative recovery of the cefuroxime 25 axetil that is present prior to crystallisation, thereby assuring an approximately 1:1 ratio of isomers. The solvent system from which the product may be crystallised will desirably be selected 30 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 hydrocarbon, for example 35 petroleum ether or toluene; or an alcohol, for example ethanol or isopropanol, optionally but preferably in admixture with water, such as in aqueous industrial methylated spirit; or an amide, 209046 - 4 - such as dimethylformamide or dimethylacetamide, or ketone, such as acetone, in admixture with water. The crystallisation step will desirably be 5 carried out at ambient temperature, for example at from about 10 to 30°C and the concentration of the cefuroxime axetil in the solution from which crystallisation will occur will generally be adjusted —i > e.g. by evaporation of solvent or by dilution so 10 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 15 at quite a high temperature, e.g. up to about 65°C, but in order to maximise the yield and obtain a suitable ratio of isomers in the product, a temperature range of from 10 to 30° is preferred for the. final isolation. 20 The reaction in which the cefuroxime axetil is formed will preferably be an esterification reaction carried out in the manner described in New Zealand Patent Specification No. 183345 and using a highly pure sodium cefuroxime starting 25 material. A preferred reagent for the ester ification is 1-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. 30 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-methoxy iminoacetamido]ceph-3-em-4-carbo*ylic 35 acid with chlorosulphonyl isocyanate in an alkyl acetate as solvent at a temperature of from -25° to +10°C, followed by hydrolysis i_n situ at a temj^V- ature of +10 to +30°C and crystallisation following "8 DEC 1987mjj X *> ' s*.: *;•/- -•■<'-••-.."'15 209046 - 5 - addition of sodium 2-ethylhexanoate in acetone or methyl acetate as solvent- Such a material will generally have a purity level of 90% mass/mass (m/m) or greater . 5 The cefuroxime axetil produced by the process of this invention 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 10 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 w Nujol shown in the accompanying drawing. 15 The invention will now be illustrated by the following non-limiting Preparation and Examples. The individual R and S isomers of cefuroxime 1-acetoxyethyl ester are denoted for convenience by-the letters A and B, these letters being used 20 to denote the respective isomers as in New Zealand Patent No. 183345. 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. 25 Preparation 1 Sodium Cefuroxime vS/ Chlorosulphonyl isocyanate (226 ml) was added to a solution of triethylamine (10 ml) in methyl 30 acetate (3.8 1). The resulting clear solution was cooled to -15° 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 --35 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) "8DEC1987' - ' __ ' ^ --flptf ' ">90 i<& - 6 - 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. 5 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 pH of 2.35. The layers were separated and the upper, organic layer was 10 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 SX Plus charcoal (76 g) for 30 minutes and filtered 15 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 20 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 (5x11), sucked dry, and dried at 30° i_n vacuo for 24 hours to give sodium 25 cefuroxime (851.9 g) ; [ot]p°+ 60°, (c0.5; O.lMpH 4.5 buffer); Xmax (f^O) 273 nra (E2*m ^87); 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. 30 Example 1 Cefuroxime Axetil (RS)-1—Acetoxyethylbromide (12.5 g) was added to a stirred mixture of sodium cefuroxime (20 g) (prepared by a method similar to that in Preparation 35 1) in dimethyl acetamide (110 ml) at 0°C. 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 i n c=y ^ ^ i - 7 - 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-acetoxy-ethylbromide. After 1 hour the organic layer (1.5% 5 A isomer by HPLC) was separated, washed with M hydrochloric 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 10 were stirred for 30 minutes with charcoal (Norit SX Plus; 2g), filtered through a kieselgOhr bed which was washed with ethyl acetate (2 x 25 nal) . The combined filtrate and washes were evaporated in vacuo to 150 g and stirred at ambient temperature for 1 hour until 15 the crystallisation was well established. Di-isopropyl ether (250 ml) was added over 45 minutes to complete the crystallisation and stirring was continued for an additional 1 hour. The product was collected by -filtration, washed with 2:1 di-isopropyl ether/ethyl 20 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. 25 Solvent content (GLC) 0.2% m/m. Impurities 2 by HPLC 1.8% including A isomer 0.3% m/m; E-isomer 0.6% m/m. Isomer ratio (HPLC) 1.09:1 t<*lD (1% in w dioxan) +37°; (278 mm, MeOH) 389. Assay by 30 HPLC 99% m/m (uncorrected). Example 2 Cefuroxime Axetil o A stirred suspension of sodium cefuroxime (20 g) in dimethylacetamide (110 ml) was cooled to 15° and 35 (RS)-1-acetoxyethyl 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 - 8 - 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 2 5 1.6% A isomer) 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 10 for 30 minutes with charcoal (Norit SX Plus; 2 g), filtered through a bed of kiesielgOhr which was washed with ethyl acetate (2 x 25 ml). After evaporating the combined filtrate and washes to 120 g the concentrate was stirred for 20 minutes to enable crytallisation 15 to become established. Industrial 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 20 was harvested, 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) 2 0.2% m/m; impurities (HPLC) 1.5% m/m including A isomer 0.5% m/m and E-isomer 0.6% m/m; isomer ratio 25 1.01:1; [a]D(l% in dioxan) +40°; (278 nm, methanol) 388; Assay by HPLC 98% m/m (uncorrected). Example 3 Cefuroxime Axetil 30 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 35 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 209046 - 9 - temperature (ca 25°). The layers were then separated and the aqueous layer was re-extracted with ethyl acetate (200 ml) and discarded (a, 0.21°/dm). The organic solutions were washed sequentially with M 5 hydrochloric acid (100 ml), then 20% sodium chloride (30 ml) containing 2% sodium hydrogen carbonate and were then combined and treated with Nor it SX Plus charcoal (2 g) for 25 minutes. The charcoal was filtered off through a Standard Supercel pad, the 10 filter was washed with ethyl acetate (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 15 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-dried for 15 minutes, then dried jLn vacuo at 45° 20 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 1.03:1, A <0.1% m/m. Water (by Karl Fischer) 0.4% m/m. 25 Example 4 Cefuroxime Axetil The washed and evaporated (ca 125 g) ethyl acetate solution of cefuroxime axetil obtained from a similar 30 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 35 for a further 2 hours. The crystalline precipitate was collected by filtration, displacement washed with 2:1 light petroleum ether (b.p. 100-120°) -ethyl acetate mixture (75 ml) and dried overnight 209 A - 10 - at 40° in 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 and anti isomer 5 respectively); the isomer ratio was 0.98:1. Example 5 Cefuroxime Axetil A washed and concentrated (ca 125 g) solution 10 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 15 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 harvested, displacement washed with 2:1 light petroleum ether (b.p. 100-120° - ethyl acetate mixture 20 (75 ml) and dried overnight iri 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 arid 0.7% m/m were 2 A and anti isomers respectively); isomer ratio was 25 1.05:1. Assay by HPLC 96% m/m. Example 6 Cefuroxime Axetil O' A washed and charcoaled concentrate (ca 100 g) of cefuroxime axetil in ethyl acetate, containing 2 30 ca 2% A isomer, obtained similarly to that in Example 1 was seeded and stirred for 30 minutes until crystallisation was well established. Isopropanol (100 ml) was added dropwise over 30 minutes followed over 50 minutes by distilled water (170 ml). The resultant 35 slurry was concentrated iji 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 </div>

Claims

- 11 - in distilled water (100 ml) and dried for a weekend iji 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 A and anti isomers respectively); isomer ratio 1.05:1. -^""'■>1 ■ 12 OWrtMfr WHAT>tfYVE CLA'M IS:- at least 15 20 25 1. A process for the Preparation of/95% m/m purity, crystalline cefuroxime 1-acetoxyethyl ester which crystallises in a ratio of R to S isomer of 0.9:1 to 1.1:1, comprising the steps of crystallising cefuroxime 1—acetoxyethyl ester from a solution thereof in an organic or aqueous solvent or a mixture thereof, isolating and drying the product. 2. A process as claimed in claim 1 or olaiw 2 wherein the solvent includes an ester. 3. A process as claimed in claim, 1 °r olain>,3| wherein the solvent comprises an ester or halogenated hydrocarbon optionally in admixture with an ether or an aliphatic or aromatic hydrocarbon; or a ketone or amide in admixture with water. 4. A process as claimed in claim 1 or claim 2 wherein the solvent includes an alcohol in admixture, with water. 5. A process as claimed in claim 3 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 one of the preceding claims wherein at least a later portion of the crystallisation step is carried out at from 10 to 30°C. 7. A process as claimed in claim 1, substantially as hereinbefore described with reference to the Examples. 8. Crystalline cefuroxime 1-acetoxyethyl ester having a purity level of at least 95% mass/mass in which the ratio of R to S isomer is from 0.9:1 to 1.1:1. 9. Crystalline cefuroxime

1. -acetoxythyl ester having the [R spectrum in Nujol as shown in the accompanying drawing.