GB2218095A - Cepholosporin isomerisation - Google Patents

Abstract

Syn compounds of general formula (I> <IMAGE> (wherein R represents a hydrogen atom or a carbamoyl protecting group, Z is S or -SO- and the dotted line indicates that the compound is a ceph-2-em or ceph-3-em compound) are prepared by isomerising an anti compound of formula (II> <IMAGE> (wherein R, Z and the dotted line are as defined above).

Description

CHEMICAL PROCESS This invention relates to improvements in or relating to cephalosporins. More particularly it relates to processes for the preparation of the oral antibiotic cefuroxime axetil.

Cefuroxime axetil, the l-acetoxyethyl ester of (6R,7R)-3 carbamoyloxymethyl-7-[ (Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph -3-em-4-carboxylic acid (cefuroxime) is described in British Patent Specification No. 1571683. Cefuroxime axetil is a particularly valuable cephalosporin since it may be administered orally. The compound has been shown to possess good antibiotic activity, following oral administration, against a broad spectrum of gram-positive and gram-negative bacteria and has high stability to p-lactamases.

Cephalosporin esters may conventionally be prepared by the acylation of an appropriate 7-aminocephalosporin with a compound serving to introduce a preformed 7-substituent, or by esterification of the 4-carboxyl group of the corresponding cephalosporin 4-carboxylic acid, for example by reaction with a haloester to introduce the desired esterifying group. These general processes are described in British Patent Specification No. 1571683 for the preparation of cefuroxime axetil.

We have now devised a process for the preparation of cefuroxime axetil and derivatives thereof in which the oxime group in the 7substituent is converted from the anti into the syn configuration as the last significant chemical step in the synthesis, by an isomerisation reaction.

According to one aspect of the invention, therefore, we provide a process for the preparation of syn compounds of general formula (I)

(wherein R represents a hydrogen atom or a carbamoyl protecting group, Z is S or S + 0 and the dotted line indicates that the compound is a ceph-2-em or ceph-3-em compound) which comprises isomerising a compound of formula (II)

(wherein R, Z and the dotted line are as defined above).

The isomerisation may be conveniently carried out, for example by irradiating the anti isomer at a wavelength or wavelengths in the range 200 to BOOnm, preferably between 290 and 400nm. Suitable ultra violet and visible light sources include, for example, mercury arcs or tungsten lamps.

The isomerisation reaction may be effected in an organic medium, conveniently at a temperature in the range Oo to +1000C, preferably between 100 and 500C.

Examples of reaction media which may be employed include ethers, e.g. cyclic ethers such as tetrahydrofuran; nitriles such as acetonitrile; and alcohols such as t-butanol, as well as mixtures of two or more such solvents.

The reaction is carried out such that a compound of formula (I) is obtained as the syn isomer or as a mixture containing at least 75 of the syn isomer. Preferably, a mixture should contain at least 90S of the syn isomer and not more than 10S of the anti isomer.

The isomerisation may be followed where necessary and/or desired by conversion of the compound of formula (I) initially obtained into a different compound of formula (I), for example by means of one or more of the following reactions: (i) reduction of a compound wherein Z is S + O to a compound wherein Z is S; (ii) conversion of a A2-isomer into a a3 - isomer; (iii) removal of any carbamoyl protecting group.

The reactions may be effected by conventional methods, and in any convenient order.

Thus, if desired, a A2-cephalosporin obtained in accordance with the process of the invention may be converted into the corresponding A3-derivative by, for example, treatment of the A2- ester with a base, such as pyridine or triethylamine.

A ceph-2-em reaction product may also be oxidised to yield the corresponding ceph-3-em l-oxide, for example by reaction with a peracid, e.g. peracetic or m-chloroperbenzoic acid; the resulting sulphoxide may subsequently be reduced as described hereinafter to yield the corresponding ceph-3-em sulphide.

Where a compound of formula (I) is obtained in which Z is S + 0 this may, if desired, be converted into the corresponding sulphide by, for example, reduction of the corresponding acyloxysulphonium or alkoxysulphonium salt prepared in situ by reaction with e.g. acetyl chloride in the case of an acetoxysulphonium salt, reduction being effected by, for example, sodium dithionite or by iodide ion as in a solution of potassium iodide in a solvent e.g. acetic acid, acetone, tetrahydrofuran, dioxan, dimethylformamide or dimethylacetamide. The reaction may be effected at a temperature in the range -20 to +500C.

A carbamoyl protecting group present in the compounds of formula (I) or intermediates thereof is conveniently a group which may be readily removed at an appropriate stage in the reaction sequence, for example an acyl group, especially a lower alkanoyl group such as acetyl, a halo-substituted lower alkanoyl group such as mono-, di- or trichloroacetyl, a chlorosulphonyl or bromosulphonyl group, a dihalophosphonyl group such as a dichlorophosphonyl group, or a halogenated alkoxycarbonyl group such as 2,2,2-trichloroethoxy carbonyl.

Any carbamoyl protecting group present in the compound of formula (I) may be removed, if desired, by any appropriate methods known in the art. Labile groups such as chlorosulphonyl, dichlorophosphonyl and trichloroacetyl may generally be cleaved by acid or base catalysed hydrolysis (e.g. by base catalysed hydrolysis using sodium bicarbonate). Halogenated groups such as 2,2,2trichloroethoxycarbonyl may also be cleaved reductively, while groups such as chloroacetyl may also be cleaved by treatment with thioamides such as thiourea.

The reaction product may be separated from the reaction mixtures, which may contain, for example, unchanged cephalosporin starting material and other substances, by a variety of processes including solvent extraction, recrystallisation, ionophoresis, column chromatography, high pressure liquid chromatography, ion-exchange chromatography or chromatography on macroreticular resins.

The product may be recovered in a mixture with an approximately 1:1 mole ratio of R and S isomers of the esterifying group, for example, as described in UK Patent Specification No. 2145409.

A preferred embodiment of the invention relates to the preparation of cefuroxime axetil or a protected derivative thereof, i.e., the compound of formula (I) in which R represents a hydrogen atom or a carbamoyl protecting group, Z represents S, and the dotted line represents a ceph-3-em compound, followed if desired by removal of the protecting group, optionally in situ.

A compound of formula (II) may be prepared , for example, by acylation of a compound of formula (III)

(wherein R, Z and the dotted line are as defined above) or a salt thereof, e.g. an acid addition salt (for example a hydrochloride, hydrobromide, sulphate, nitrate, phosphate, methanesulphonate or toluene-p-sulphonate) or a 7-N-silyl derivative thereof with a compound of formula (IV)

or a salt thereof using methods well known in the art.

Suitable acylating derivatives of the acid (IV) include acid halides (e.g. acid chlorides); anhydrides (e.g. symmetrical anhydrides or mixed anhydrides formed, for example, with pivaloyl chloride); amides or nitriles. Conventional acylation methods involving derivatives of the acid of formula (IV) are described in British Patent Specification No. 1399086.

The configuration of the oxime group is assigned on the basis of the work of Ahmed and Spencer (Can. J. Chem., 1961, 39, 1340). The syn isomer is represented as shown in formula (I) and the anti isomer is shown in formula (II).

The invention is exemplified by the following. All temperatures are in degrees Celsius. The term "dried" refers to drying over sodium sulphate or magnesium sulphate. Petrol refers to petroleum ether b.p. 40-600C unless stated otherwise.

Preparation (R and S)-l-Acetoxyethyl (6R ,7R)-3-Carbamoyloxymethyl-7-[ (E)-2- (fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate (anti isomer) A solution of (R and S)-l-acetoxyethyl (6R,7R)-7-amino-3carbamoyloxymethylceph-3-em-4-carboxylate (400mg) and (E)-2-(fur-2-yl)-2-methoxyiminoacetic acid (198mug) in dichloromethane (15ml) was stirred at 220 and treated with dicyclohexylcarbodiimide (266 mg). The mixture was stirred for 75 minutes, treated with acetic acid (2 drops) filtered and evaporated to a foam. This foam was dissolved in ethyl acetate, which was washed with saturated sodium bicarbonate solution (2x), water and brine. The solution was dried and evaporated to a foam. This was dissolved in ethyl acetate, filtered and added to petrol to give the title compound as a solid (339mg).

Part (302mg) of this solid was purified by chromatography on a column of Kieselgel 60 (70-230 mesh, 209) eluting with dichloromethane-ethyl acetate (1:2) to give fractions which were combined and evaporated to a foam. This foam was dissolved in ethyl acetate and the solution added to petrol to give the title compound as a solid (207mg); ethanol 275 nm CE 359); max 1 6 (CDCl3) 7.58 (lH,s), 7.38 (1H,d), 7.36 (1H,m), 7.15 and 7.03 (lH,q), 6.52 (1H,m), 5.96 (lH,m), 5.06 (lH,m), 4.98-4.70 (3H,m), 4.12 (3H,s), 3.7-3.4 (2H,m), 2.10 (3H,s) and 1.55 (3H,m).

Example (R and S)-l-Acetoxyethyl (6R,7R)-3-Carbamoyloxymethyl-7-[(Z)-2- (fùr-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate (syn isomer) A solution of the anti isomer (100mg) in acetonitrile (120ml) was irradiated by a water-cooled Hanau high-pressure ZI 125 watt lamp through Pyrex under nitrogen for 45 minutes. The solution was evaporated to an oil. The oil was dissolved in ethyl acetate which was added to petrol to give the title compound as a solid (84mg) which was identified by comparison with a reference sample of cefuroxime axetil by HPLC.

Claims (7)

CLAIMS:

1. A process for the preparation of syn compounds of general formula (I)

(wherein R represents a hydrogen atom or a carbamoyl protecting group, Z is S or -SO- and the dotted line indicates a ceph-2-em or ceph-3-em compound) which comprises isomerising an anti compound of formula (11)

(wherein R, Z and the dotted line are as defined above) followed where desired by conversion of the compound of formula (I) initially obtained into a different compound of formula (I) by means of one or more of the following reactions: (i) reduction of a compound wherein Z is -SO- to a compound wherein Z is S; 2 (ii) conversion of a A2-isomer into a A3-isomer; (iii) removal of any carbamoyl substituents.

2. A process as claimed in claim 1 wherein the isomerisation is effected at a temperature in the range 0 to 1000C.

3. A process as claimed in claim 1 or claim 2 wherein the isomerisation is effected by irradiation of the anti-isomer at a wavelength or wavelengths in the range 200 to 800nm.

4. A process as claimed in any of the preceding claims wherein a compound of formula (II) (wherein R represents a hydrogen atom or a carbamoyl protecting group, Z represents S and the dotted line indicates a ceph-3-em compound) is isomerised.

5. A process for the preparation of compounds of general formula (I) as defined in claim 1, substantially as herein defined in the Example.

6. Compounds of general formula (I) as defined in claim 1, when prepared by a process as claimed in any of the preceding claims.

7. Cefuroxime axetil, when prepared by a process as claimed in claim 4.