GB2218091A - Cephalosporin methylation - Google Patents

Abstract

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 reacting a compound of formula (II> <IMAGE> (wherein R, Z and the dotted line are as defined above) with a methylating agent serving to introduce an etherifying methyl group.

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 methyl group in the 7-oxime substituent is introduced as the last major chemical step in the synthesis by a methylation reaction.

According to one aspect of the invention, therefore, we provide a process for the preparation of 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 reacting a compound of formula (II)

(wherein R, Z and the dotted line are as defined above) with a methylating agent serving to introduce the etherifying methyl group.

Examples of such methylating agents suitable for use in the invention are well known in the literature.

The methylating agent may be, for example, an organic halide or sulphate, or a sulphonate such as tosylate, and may thus be a methyl halide (e.g. methyl iodide) or dimethylsulphate. Other methylating agents include diazomethane, methyl fluorosulphonate, and methyloxonium tetrafluoroborates (e.g trimethyloxonium tetrafluoroborate). Methylations using diazomethane, methyl fluorosulphonate or a tetrafluoroborate may require assistance e.g.

with a Lewis acid such as BF3.

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

Examples of reaction media which may be employed include 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-dimethylacetamide or hexamethylphosphoramide; lower ketones such as acetone; nitriles such as acetonitrile; nitroalkanes such as nitromethane; sulphoxides such as dimethylsulphoxide; sulphones such as sulpholane; hydrocarbons such as toluene or hexane; and esters such as ethyl acetate, as well as mixtures of two or more such solvents.The reaction medium may contain some water, but is preferably anhydrous. The methylation may be carried out in the presence of an agent serving to generate an anion from the hydroxime function, and/or as an acid binding agent, for example, a base such as an alkali metal carbonate (e.g. sodium, potassium or lithium carbonate), hydride (e.g.

sodium, potassium or lithium hydride), alkoxide (e.g. sodium, potassium or lithium t-butoxide), dialkylamide (e.g. lithium diisopropylamide) or disilylamide.

The methylation reaction may be effected in a single liquid-phase or a two phase reaction medium such as a solid-liquid or two liquid phase reaction medium. When a two-phase system is used the reaction is generally carried out in the presence of a base together with a phase transfer reagent, such as a crown ether (i.e. a macrocyclic polyether), or TDA-1. The crown ether may contain for example a number of ethyleneoxy units, which may be substituted, e.g.

by phenyl or cyclohexyl groups joined to form a ring. Examples of such a reagent include 18crown6 (containing 6 ethyleneoxy units) e.g. dibenzo or dicyclohexyl 18-crown-6, and 15-crown-5 (containing 5-ethyleneoxy units). A preferred two-phase medium is water/dichloromethane.

The methylation reaction 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: (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 ceph2-em reaction product may also be pxidised 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 therefor 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 2,2,2trichloroethoxycarbonyl.

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 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 as a mixture with an approximately 1:1 mole ratio of R and 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 esterification of a compound of formula (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, l-acetoxyethyl bromide.

The reaction is conveniently effected in an inert solvent, for example, an N,N-disubstituted amide such as N,N-dimethylformamide or N,N-dimethylacetamide; a ketone such as acetone; a sulphoxide such as dimethyl sulphoxide; a halogenated hydrocarbon such as dichloromethane; or a nitrile such as acetontrile. The reaction may be carried out at a temperature in the range -50 to +1500, e.g. -100 to +500C, conveniently between -10 and room temperature.

Where 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. 1389194.

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.

Intermediate 1 (6R ,7R )-3-Carbamoyloxymethyl-7- ( (Z )-2- (fur-2-yl )-2-hydroxyimino- acetamido] ceph-3-em-4-carboxylic Acid A suspension of (Z)-2-(fur-2-yl)-2-hydroxyiminoacetic acid (3.009) in dichloromethane (100 ml) at 100 was stirred with 2-methoxypropene (10 ml). The solution formed was then stirred at about 220 for 15 minutes and evaporated to an oil. This oil was redissolved in dichloromethane (100 ml) and stirred at 220 with methoxypropene (5 ml) for 15 minutes. The solution was evaporated and the oil was dissolved in dichloromethane (50 ml) to give a solution of the protected acid.

Oxalyl chloride (1.85 ml) was added to a solution of dimethylformamide (1.9 ml) in dichloromethane (40 ml) with stirring under nitrogen at -20 . The mixture was stirred at ca 00 for 10 minutes, then cooled to -200 and stirred with the solution of the protected acid from above. This mixture was stirred at about 00 for 10 minutes, cooled to -200 and added to a solution of (6R , 7R )-7-amino-3-carbamoyloxymethylceph-3-em-4-carboxylic acid (5.465g) and triethylamine (8 ml) in industrial methylated spirits (40 ml) and water (12 ml) at about 00. The mixture was stirred, warming to 220 over 25 minutes. It was poured into dichloromethane (300 ml) and water (50 ml) and the aqueous layer was separated and washed with dichloromethane (2 x 100 ml).The aqueous layer was allowed to stand at 220 and pH 8 for about 2 hours. The pH was adjusted to 1.5 with 2M hydrochloric acid, and the mixture was extracted with ethyl acetate (4 x 200 ml). The organic layers were combined and washed with 2M hydrochloric acid (100 ml), water (100 ml) and brine. The solution was dried and evaporated to give a foam, which was triturated with ether to give the title compound as a solid (4.115 g); Xmax(ethanol)270.5 nm (E1 420).

Intermediate 2 (R and S)-l-Acetoxyethyl (6R,7R)-3-Carbamoyloxymethyl-7-0(Z)-2- (fur-2-yl)-2-hydroxyiminoacetamidoiceph-3-em-4 carboxylic Acid.

A solution of the product of Intermediate 1 (2.00 g) in dimethylformamide (20 ml) was stirred with potassium carbonate under nitrogen at 200 for 1 hour. The mixture was cooled and stirred with (R,S)-l-acetoxyethyl bromide at O to 40 for 90 minutes. The reaction mixture was partitioned between ethyl acetate and 2M hydrochloric acid and the aqueous layer was extracted with ethyl acetate (2x). The organic layers were combined and washed with 2M hydrochloric acid, water, saturated sodium bicarbonate solution (3x) and brine.The solution was dried, concentrated to about 15 ml and added to petrol to give the title compound as a solid (0.409 g); -1 vmax(CHBr3) 1789 and 1733 cm; 6(CDC13) 8.07 (1H,s), 7.90 (lH,d J 8Hz), 7.50 (1H,m), 7.10 and 6.90 (lH,q), 6.50 (1H,m), 5.95 (1H,dd 3 8 and 5Hz) 5.05 (1H,d J 5Hz), 5.08 and 4.84 (2H,m), 3.60 and 3.44 (2H,m) 2.09 (3H,s) and 1.55 (3H,d J 4Hz).

Example (R and S)-l-Acetoxyethyl (6R ,7R )-3-Carbamoyloxymethyl-7- \L (Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate A solution of the product of Intermediate 2 (300 mg) in ethyl acetate (10 ml) was stirred with a solution of diazomethane (prepared from 2 9 N-nitrosomethylurea in 20 ml ether) at 220 for 4 hours. The mixture was cooled to about 00, treated with excess acetic acid, and then diluted with ethyl acetate. This solution was washed with water, saturated sodium bicarbonate solution, water and brine. After drying, the solution was concentrated to about 5 ml, and added to petrol to give a solid (327 mg) which was purified by preparative layer chromatography on silica (Whatman PK 6F), developing with dichloromethane - ethyl acetate (1:1). The product was eluted with ethyl acetate, the solution concentrated and added to petroleum ether to give the title compound as a solid (37 mg) which was identical to a reference sample of cefuroxime axetil by HPLC.

Claims (9)

CLAIMS:

1. A process for the preparation of 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 reacting a compound of formula (11)

(wherein R, Z and the dotted line are as defined above) with a methylating agent serving to introduce an etherifying methyl group 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; (ii) conversion of a iN2-isomer into a A3-isomer; (iii) removal of any carbamoyl substituents.

2. A process as claimed in claim 1 wherein the etherification reaction is effected at a temperature in the range -50 to 100 cm.

3. A process as claimed in claim 1 or claim 2 wherein the methylating agent comprises an organic halide, sulphate or sulphonate,a methyloxonium tetrafluoroborate or methyl fluorosulphonate.

4. A process as claimed in claim 1 or claim 2 wherein the methylating agent comprises diazomethane.

5. A process as claimed in any preceding claim wherein the reaction medium is anhydrous.

6. 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 reacted with the said methylating agent.

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

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

9. Cefuroxime axetil, when prepared by a process as claimed in claim 6.