GB2218092A - Process introducing an O-methyl oxime group into a cephalosporin - Google Patents

Description

r) f 11 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 exetil, the 1-acetoxyethyl ester of (6R,7R)3carbemoyloxymethyl-7-1(Z)-2-(fur-2-yl)-2-methoxyiminoacetamidoleeph -3em4-carboxylic acid (cefuroxime) is described in British Patent Specification No. 1571683. Cefuroxime exetil 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 gboup 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 exetil and protected derivatives thereof in which the 0-methyl oxime group is introduced as the last major chemical step in the synthesis, by a oximation reaction.

According to one aspect of the invention, therefore, we provide a process for the preparation of compounds of general formula (I) H H Z C CONH 0 N N CH20CONHR OCH3 0 CO0r0COCH3 CH3 (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 2 ceph-2-em or ceph-3-em compound) which compr-Lses reacting a compound of formula (II) 0 @_ C - CONH 11 0 0 H H Z ---N CH20CONHR 0 UUUt'UUUU['3 CH3 k-'I I) (wherein R, Z and the dotted line are as defined above) with an 0-methyl- oximating agent, for example, methoxylamine, or a salt thereof.

The oximation reaction may be effected in aqueous or non-aqueous media, conveniently at a temperature in the range -200 to +1000C, for example 00 to + 750C.

Examples of reaction media which may be employed include water; alcohols such as methanol or ethanol; ethers, e.g. cyclic ethers such as tetrahydrofuran or dioxan or acylic ethers such as diethyl ether or diglyme; amides such as N,N-dimethylformamide, N, N-d imeth ylacet amid e or hexamethylphosphoramide; nitriles such as acetonitrile; nitroalkanes such as nitromethane; sulphoxides such as dimethylsulphoxide; sulphones such as sulpholane; halogenated hydrocarbons. such as dichloromethane; and esters such as ethyl acetate, as well as mixtures of two or more such solvents.

If the oximation is carried out. in an anhydrous reaction medium a Lewis acid, such as BF3 conveniently in the form of a solvate e.g. an etherate; magnesium chloride or zinc chloride, is desirably present.

When aqueous conditions are employed the reaction may conveniently be effected at a pH in the range from 2.0 to 9.0, preferably from 3 to 8. The pH may conveniently be maintained in this range by the addition of an appropriate acid or base., for example a mineral acid such as hydrochloric or sulphuric acid or an alkali metal carbonate, or bicarbonate e.g. sodium bicarbonate.

J.

The oximation re artion may be followed where 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:reduction of a compound wherein Z is S->. 0 to a compound wherein Z is S; k-'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 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 A3derivative 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 1-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 sit by -,r U 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, diaxan, dimethylformamide or dimethylacetamide. The reaction may be effected at a temperature in the range -200 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 alkenoyl group such as is 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 292,2trichloroethoxycarbonyl.

Any carbamoyl protecting group present in the compound offormula (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 2,2,2-trichloroethoxycarbonyl 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 mixture, 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.

Where a compound of formula (I) is obtained as a mixture of isomers, the syn isomer may be obtained by conventional methods, such as crystallisation or chromatography. Also, 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 5, and the dotted line represents a ceph-3em compound, followed if desired by removal of the protecting group, optionally in situ.

A compound of formula (II) may be prepared, for example, by esterification of a compound of formula (III) h r 1 2 51 C - CONH 0 0 is H H Z ---N CH20CONHR # 0 COOH (III) (wherein R, Z and the dotted line are as defined above) or a salt thereof, e.g. an alkali metal salt (such as the sodium or potassium salt) or an onium salt. e.g. an ammonium salt (such as a quaternary ammonium salt) with an appropriate haloester, for example, 1-acetoxyethyl bromide.

The reaction is conveniently effected in an inert solvent, for example, an N,N-disubstituted amide such as N,N-dimethylformamide, N,Ndimethylacetamide; a ketone such as acetone; a sulphoxide such as dimethylsulphoxide; a halogenated hydrocarbon such as dichloromethane; or a nitrile such as acetonitrile. The reaction may be carried out at a temperature in the range -500 to +1500, e.g. -100 to +500C, conveniently between -100 and room temperature.

Whe"re the free acid is employed as starting material the esterification is generally carried out in the presence of a base serving to generate an anion from the 4-carboxyl function. Suitable bases include for example, inorganic bases such as alkali metal carbonates e.g. sodium or potassium carbonate.

A compound of formula (III) may be prepared, for example, by conventional acylation methods as described in British Patent Specification No. 1453049.

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.

1 is Intermediate 1 Diphenylmethyl (6R,7R)-3-carbamoyloxymethyl-7-r(fur-2yl)glyoxemidolceph-3-em-4-carboxylate Diphenylmethyl (6R,7R)-7-amino-3carbamoyloxymethyleeph-3-em-4carboxylate toluene-27sulphonic acid salt (4. 28g) was dissolved in_ ethyl acetate (200m1) and sodium bicarbonate solution (200m1). The ethyl acetate layer was separated, washed with water, dried and cooled to 00. To this solution were added ethyl acetate solutions of dicyclohexylcarbodiimide (1.46g) and 2-fury1glyoxylic acid (991mg). The reaction mixture was stirred at 00 for 20 minutes, filtered and the filtrate was evaporated in vacuo. Trituration of the residue with ethanol gave the title Compound (3.53g), m.p. 169-1710.

Intermediate 2 (6R,7R)-3-Carbamoyloxymethyl-7-[(fur-2-yl)glyoxamidolceph3-em-4carboxylic acid Trifluaroacetic acid (5.5m1) was added to a cold (00) stirred mixture of anisole (5.5m1) and the product of Intermediate 1 (1.84g). After 10 minutes, the reaction mixture was poured into aqueous sodium bicarbonate (100m1) and ethyl acetate (100m1). The aqueous layer was separated, washed with ethyl acetate (100m1) and acidified to pH 2 under ethyl acetate. Insoluble material was filtered off and combined with the solid obtained after washing, drying and evaporating the ethyl acetate layer. The product was crystallised from methanol to give the title compound (678mg); [a] 22 + 640 (c 0.988 in aqueous sodium bicarbonate).

D - Intermediate 3 (R and S)-1-Acetoxyethyl (6R,7R)-3-Carbamoyloxymethyl-7- [(fur-2-yl) glyoxamidoiceph-3-em-4-carboxylete A solution of the product of Intermediate 2 (3.00g) in dimethylformamide (30m1) was stirred with potassium carbonate (0.5349) at 220 under nitrogen for 1 hour. The mixture was cooled to about 00 and stirred with M,S)-1-acetoxyethyl bromide (1.3949) for 3 hours.

v f Z.b 11 The mixture was partitioned between 2M-hydrochloric acid and ethyl acetate. The aqueous layer was extracted with ethyl acetate (2x) and the organic layers were combined and washed with water, saturated sodium bicarbonate solution (2x), and brine. This solution was dried, concentrated to about 15m1 and added to petrol to give the_title com. pound as a solid (2.42g); v (CHBr3) 1788 and 1736cm max 6 (MC13) 8.07 (1H,d J 4Hz), 8.01 (1H9d J 8Hz), 7.75 (1H,s), 7.09 and 6.97 (1H, q), 6.61 (1H,m), 5.80 (1H,m), 5.03 (1H,d J 8Hz), 4.93 (2H, s),, 4.81 and 5.08 (2H,m), 3.6 and 3.44 (2H,m), 2.02 (3% s) and 1.52 OH,d J 4Hz).

Example (R and 5)-l-Acetoxyethyl (6Rl7R)-3-Carbamoyloxymethyl-7-[(Z)-2(fur-2-, _vl)-2-methoxyiminoacetamidoleeph-3-em-4-carboxylate A suspension of the product of Intermediate 3 (500mg) and methoxylamine hydrochloride (178mg) in ethanol (10ml) was stirred with dimethy1formamide (3ml) at about 00 to give a solution. Pyridine (0.36ml) was added so that an aliquot had pH 4.2 when shaken with water, and the solution was stirred at 0 to 40 for 50 hours. The solution was partitioned between ethyl acetate and 2M-hydrochloric acid and the aqueous layer was separated and extracted with ethyl acetate. The organic layers were combined and washed with water, saturated sodium bicarbonate solution, and brine. The solution was dried, concentrated to about 5ml, and added to petrol to give the title compound as a solid (258mg) which was identified by comparison with a reference sample of cefuroxime axetil by HPLC.

OT 52-870

Claims (7)

1. CLAIMS:

   A process for the preparation of compounds of general formula (I) H H Z C CONH N ----N CH20CONHR! OCH3 0 (I) (wherein R repredents 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 reacting a compound of formula (II) C 0 _. 0 H H z fl A E/ \ 0 C - CONH -CH20CONHR UUUhuLOCH3 CH3 0 (II) (wherein R, Z and the dotted line are as defined above) with an 0-methyl- oximating agent followed where desired by conversion of the compound of formula (I) initially obtained into a different i> I; compound of formula (1) by means of one or more of the following reactions:- I 1 (i) reduction of a compoundwherein Z is -SO- to a compound wherein Z is S; 2 - (ii) conversion of a A -isomer into a 3.

   !2 -isomer; (iii) removal of any carbamoyl substituents.
2. 2. A process as claimed in claim 1 oximation reaction is effected at a temperature in the range -20' to 100'C.

   wherein the
3. 3. A process as claimed in any of the preceding claims wherein the oximating agent comprises methoxylamine or a salt thereof.
4. 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-3em compound) is reacted with the said 0-methyl-oximating agent.
5. 5. A process for the preparation of compounds of general formula (I) as defined in claim 1, substantiallv as herein defined in the Example.
6. 6. Compounds of general formula (1) as defined ir claim 1, when prepared by a process as claimed in any of the preceding claims.
7. 7. Cefuroxime axetil, when prepared by a process as claimed in claim 4.

   DLed 1989 EitThe Patent OMOe, State House. 66"71 High Hollborn, London WC1R 4TP. Further copies maybe obtained from The Patent Office. Wes Brazcb. St Maxy Cray. Orpington. Kent BR5 3RD. Printed by Multiplex techniques ltd, St Mary Cray, Kent, Gon. 1/87