GB2145408A

GB2145408A - Improvements in or relating to preparing sodium cefuroxime

Info

Publication number: GB2145408A
Application number: GB08419201A
Authority: GB
Inventors: Herbert James White; David Thomas Eastlick; John Francis Oughton
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 1983-07-29
Filing date: 1984-07-27
Publication date: 1985-03-27
Also published as: ATA244384A; CH660594A5; AT386205B; DK164508B; DE3427859A1; JPS6075485A; IT8448655A0; US4775750A; ZA845831B; FI843010A; SE463262B; FI80042B; FI843010A0; GB2145408B; FR2549836B1; KR910004301B1; ES8601868A1; FR2549836A1; JPH07107068B2; SE8403896D0

Description

1 GB 2 145 408 A 1

SPECIFICATION

Improvements in or relating to antibiotics This invention relates to improvements in or relat- 70 ing to antibiotics. More particularly it relates to im provements in a process for the preparation of sodium cefuroxime.

Cefuroxime, (6R,7R)-7-[Z-2-(fur-2-yi)-2-methoxy imino-acetamidol-3-carbamoyloxymethyi-ceph-3- em-4-carboxylic acid as described and claimed in British Patent Specification No..11,453,049 is a valuable broad spectrum antibiotic characterised by high activity against a wide range of gram- positive and gram-negative microorganisms, this property being enhanced by the very high stability of the compound to p-lactamases produced by a range of gram-negative microorganisms.

Cefuroxime may be administered, in human or veterinary medicine, as a non-toxic derivative, i.e. one which is physiologically acceptable at the dosage at which it is administered. Such non-toxic derivatives conveniently include those salts, e.g. alkali metal, alkaline earth metal and organic base salts which on admixture with sterile, pyrogen-free water form aqueous solutions or suspensions for injection. In British Patent Specification No. 1,453,049 the sodium salt of cefuroxime is described as being a substance well suited to admin- istration on injection and it is now recognised as being an antibiotic of outstanding value. For convenience this sodium salt will hereinafter be referred to as sodium cefuroxime.

In our British Patent Specification No. 2043070, we have described a process for the preparation of 100 sodium cefuroxime, starting from (6R,7R)-7-(Z-2(fur-2-yi)-2-methoxyiminoacetamidol-3hydroxymethylceph-3-em-4-carboxylic acid, which involves reacting this compound with trichloroacetyl isocyanate, followed by treatment of the product with an alcohol and a solution of sodium 2-ethylhexanoate. Whilst this reaction does have a number of advantages over processes proposed earlier, in view of the small number of steps involved and its general simplicity, there is still a need to be able to prepare a purer product and for an even simpler or more economical process capable of providing it.

In particular, the process of British Patent Speci- fication No. 2043070 requires as a specific step the addition to the product of an alcohol in the presence of a base to alcoholyse the protecting group. This creates a multicomponent organic solvent system from which the sodium cefuroxime crystal- lises as a soivate, usually the tetrahydrofuran solvate, and this solvate has to be dried to produce the sodium cefuroxime.

We have now been able to devise a process for preparing sodium cefuroxime in a higher degree of purity and which avoids much of the complication of this earlier process. Our new process is in fact capable of providing sodium cefuroxime in a degree of purity sufficiently high as to enable it to be used directly as a starting material either in the preparation of sodium cefuroxime in a purity highly suitable as input material for making highly pure sterile commercial product, or it may be used as a starting material from which other valuable pharmaceutical products may be made in high yield and high purity. Other particularly valuable pharmaceutical products which may be prepared from the sodium cefuroxime prepared according to the invention are cefuroxime esters such as the 1acetoxyethyi ester of cefuroxime (cefuroxime axe- til). This cannot easily be achieved using the product of our British Patent Specification No. 2043070.

Accordingly, we provide a process for the preparation of sodium cefuroxime in high purity which comprises reacting (6R,7R)-7-[Z-2-[fur-2- yl)-2-methoxyimino-acetamidol-3-hydroxymethylceph-3-em-4carboxylic acid with a halosulphonyl isocyanate in an alkyl acetate solvent, conveniently at a temperature of from -25' to +25'C, hydrolysing the resulting intermediate product, preferably in situ at a temperature conveniently of from +10' to +30'C, forming sodium cefuroxime product by the addition of the sodium salt of a weak acid and isolating sodium cefuroxime in high purity.

The alky) acetate solvent in which the reaction with the halosulphonyl isocyanate occurs is desira- bly a lower (e.g. Q-4) alkyl acetate e.g. methyl or ethyl acetate. The halosulphonyl isocyanate is de sirably chlorosulphonyl isocyanate.

The reaction is preferably effected at from about -15' to -5d9C.

The hydrolysis which forms part of the overall process will preferably be effected by adding an aqueous medium to the reaction mixture. The aqueous medium is preferably water though a mixture of water and an appropriate organic sol vent, e.g. a ketone such as acetone may be em ployed. The aqueous medium will desirably be added rapidly to the reaction mixture. The hydroly sis will desirably be carried out at from 10 to 25'C.

The salt of a weak acid which may be used to form the sodium cefuroxime salt in the above process is desirably the sodium salt of an acid hav ing a pKa value of more than 3.5. The salt is pref erably a salt of a carboxylic acid, particularly a C,-, alkanoic acid, examples of such salts including sodium acetate, sodium propionate, sodium lactate and sodium 2-ethylhexanoate, the latter being especially preferred. The salt may be added to a solution of the product of hydrolysis either as a solid or as a solution in an organic solvent e.g. lower a]kyl ester, alcohol or ketone, for example, methyl or ethyl acetate, ethanol or acetone; or water.

The sodium cefuroxime produced by the process of this invention is highly pure, frequently exceed- ing a purity level of 90% mass/mass (m/m) (uncorrected for residual solvents). Such material is extremely suitable for further processing, for example for the preparation of highly pure sterile cefuroxime or an ester of cefuroxime such as cefuroxime 1 acetoxyethyl ester (cefuroxime axetil) in a high degree of purity.

The invention will now be more particularly described in the following non-limiting Examples. All temperatures are in 'C.

2 GB 2 145 408 A 2 EXAMPLE 1

Sodium Cefuroxime Chlorosulphonylisocyanate (226 m]) was added to a solution of triethylamine (10 m]) in methyl acetate (3.7 1). The resulting clear solution was cooled to -15' and a suspension of (6R,7R) 3-hy droxymethyi-7-[Z-2-(fur-2-yi)-2-methoxyimino-acetamidolceph-3-em-4-carboxylic acid (763 g) 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 m[). The mixture was stirred at -Y for 30 minutes, a clear solution being obtained after 10 minutes. Water (1.2 1) at 18' was added rapidly to the reaction mixture, the 80 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 ace tate (3.6 1) was added followed by a steady addi tion of a solution of sodium hydroxide (288 g) in 85 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 washed with a so lution of sodium chloride (600 9) in water (2 1). The two aqueous layers were washed sequentially with 90 methyl acetate (2 1). The organic layers were bulked, stirred with Norit SX Plus charcoal (76 g) for 30 minutes and filtered through a bed of Hyflo Supercel, the bed being washed with methyl ace tate (1.5 1). The filtrate and wash were combined 95 and stirred at 20' whilst a solution of sodium 2 ethy[hexanoate (388 g) in a mixture of methyl ace tate (2 1) and water (40 mi) was added over 20 min utes to give a white suspension with a pH of 5.5.

The suspension was stirred for 10 minutes and fil- 100 tered, and the cake was washed with methyl ace tate (5 x 1 1), sucked dry, and dried at 30' in vacuo for 24 hours to give sodium cefuroxime (851.9 g); [UJ20 + 600 (cO.5; 0.1 M pH 4.5 buffer); D Xmax (H,O) 273 rim (E,1l, 387); impurities by hplc 105 2.0% mlm. Assay (hplo 92% mlm; Water content (Karl Fischer) 2.8% mlm; Solvents (g.i.c.) 0.5% m/ M.

EXAMPLE 2

Sodium Cefuroxime Chlorosulphonyl isocyanate (39.0 ml) was added to a stirred solution of triethylamine (1.5 ml) in ethyl acetate (280 ml) pre-cooled to -10', the tem- 115 perature of the mixture rising to 0'. This mixture was recooled to -10', and a suspension of (6R,7R) 3-hydroxymethyl-7-[Z-2-(fur-2-yi)-2-methoxyiminoacetamidolceph-3-em-4-carboxylic acid (114.4 g) in ethyl acetate (350 ml), pre-cooled to -12', was 120 blown in by nitrogen pressure. Ethyl acetate (60 ml) was used to wash through the residual solid.

The temperature of the reaction mixture rose to 0'.

The mixture was stirred at 0 to 30 for 40 minutes to give a clear solution which was blown under nitro- 125 gen pressure over 221 minutes into a stirred mixture of water (180 ml) and acetone (300 ml) pre-cooled to 80. Ethyl acetate (60 ml) was used as a line wash. The temperature of the mixture rose graclu ally to 25o and a granular off-white precipitate 130 formed after ca 10 minutes. Stirring was continued for a total of 60 minutes before acetone (450 mi) was added followed by, over 5 minutes, a solution, pre-cooled to 5', of sodium hydroxide (48 g) in water (300 m]). This gave a clear two-phase mixture at 29' with a pH of 2. 2. The layers were separated and the upper, organic layer was washed with a solution of sodium chloride (90 g) in water (300 m[). The two aqueous layers were sequentially back extracted with the same portion of ethyl acetate (150 mi). The organic layers were combined and stirred with SS 110 charcoal (11.59) for 1 hour. The charcoal was removed by filtration on a bed of Hyflo Supercei which was washed with a mixture of acetone (150 mi) and ethyl acetate (150 mi) applied in two parts, the filtrate and wash being cornbined. Sodium 2-ethylhexanoate (54.9 g) was dissolved in a mixture of acetone (300 m[) and water (3 mi) and the solution was clarified by ffitration through a bed of Hyflo Supercel which was washed with acetone (150 mi). The combined wash and filtrate was added over 25 minutes to the stirred cefuroxime solution to give a suspension with a pH of 6.3. The suspension was stirred for 10 minutes and filtered, and the cake was washed by displacement with acetone (4 x 150 mi), sucked dry for 10 minutes and dried in vacuo at 200 to give sodium cefuroxime (130.25 g); [0j20 + 60' (c 0.5; 0. 1 M D pH 4.5 buffer); Xmax (H20) 273 nm, (E,,,, 382); impurities by hplc 1.8% m/m. Assay (hplc) 92% m/ m; water (Karl Fischer) 2.6% mlm; solvents (g.i. c) 0.75% m/m.

Claims

1. A process for the preparation of sodium cefuroxime which comprises reacting (6R,7R)-7-[Z-2(fur-2-yi)-2-methoxyimino-acetamidol-3hydroxymethylceph-3-em-4-carboxylic acid with a halosulphonyl isocyanate in an alkyl acetate solvent, hydrolysing the resulting intermediate product, forming sodium cefuroxime by the addition of the sodium salt of a weak acid and isolating the sodium cefuroxime in high purity.

2. A process as claimed in claim 1 wherein the hydrolysis is carried out in situ.

3. A process as claimed in claim 1 or claim 2 wherein the alkyl acetate solvent is methyl acetate or ethyl acetate.

4. A process as claimed in any one of claims 1 to 3 wherein the halosulphonyl isocyanate is chicrosulphonyl isocyanate.

5. A process as claimed in any of the preceding claims wherein the reaction of (6R,7R)-7-[Z-2-(fur-2yi)-2-methoxyimino-acetamido]-3hydroxymethyiceph-3-em-4-carboxylic acid with the halosulphonysocyanate is carried out at a temperature of from -25'C to 25'C.

6. A process as claimed in claim 5 wherein the reaction of (6R,7R)-7-[Z-2(fur-2-yi)-2-methoxyiminoacetamidol-3-hydroxymethylceph-3-em-4-carboxylic acid with the halosulphonyl isocyanate is carried out at a temperature of from -115'C to -5'C.

7. A process as claimed in any of the preceding 3 GB 2 145 408 A 3 claims wherein the hydrolysis of the intermediate product is carried out at a temperature of from + 10' to + 30T.

8. A process as claimed in claim 7 wherein the hydrolysis of the intermediate product is carried out at a temperature of from +10T to 25T.

9. A process as claimed in any of the preceding claims wherein the hydrolysis of the intermediate product is carried out in an aqueous medium.

10. A process as claimed in any of the preceding claims wherein the hydrolysis of the intermediate product is carried out in water or a mixture of water and a ketone.

11. A process as claimed in any of the preced- ing claims wherein the salt of a weak acid that is used to form the sodium cefuroxime salt is the sodium salt of an acid having a pKa value greater than 3.5.

12. A process as claimed in claim 11 wherein the salt of the weak acid used to form the sodium cefuroxime salt is the salt of an alkanoic acid having from 2 to 10 carbon atoms.

13. A process as claimed in any of the preceding claims wherein the salt used to form the so- dium cefuroxime is sodium 2-ethylhexanoate.

14. A process as claimed in any of the preceding claims substantially as hereinbefore described with reference to the Examples.

15. Sodium cefuroxime having a purity in ex- cess of 90% mass/mass whenever prepared by a process as claimed in any of claims 1 to 14.

Printed in the UK for HMSO, D8818935, 1185, 7102. Published by The Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.