GB2218094A - Cephalosporin S-oxide reduction - Google Patents

Abstract

Compounds of general formula (I> <IMAGE> (wherein R represents a hydrogen atom or a carbamoyl protecting group) are prepared by reacting a compound of formula (II> <IMAGE> (wherein R is as defined above) or an acyloxysulphonium salt thereof with a reducing agent capable of converting the suphoxide or acyloxysulphonium salt thereof into a sulphide in the presence of other sensitive functional groups, and, where the compound of formula (I) initially obtained is a compound in which R is a carbamoyl protecting group, conversion, where desired, into a different compound of formula (I) wherein R is a hydrogen atom by removal of said carbamoyl protecting 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 is the l-acetoxyethyl ester of (6R,7R)-3 carbamoyloxymethyl-7-t(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph -3-em-4-carboxylic acid (cefuroxime) and 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 sulphoxide group in the cephalosporin nucleus is converted to the sulphide as the last major chemical step in the synthesis, by a reduction 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) which comprises reacting a compound of formula (II)

(wherein R is as defined above) with a reducing agent capable of converting the sulphoxide (or the corresponding acyloxysulphonium salt thereof) into a sulphide in the presence of other sensitive functional groups. Examples of such reducing agents suitable for use in the invention include, for example, iodide ion, or a dithionite such as sodium dithionite, or a dihaloborane such as dichloroborane, or a benzodioxaphosphole such as 2-chloro-1,3,2-benzodioxaphosphole.

The reduction may be effected in an organic medium, conveniently at a temperature in the range -500 to +1000, preferably between -200 and +100.

Examples of reaction media which may be employed include ethers such as tetrahydrofuran or dioxan; amides such as N,Ndimethyl formamide or N,N-dimethylacetamide; lower ketones such as acetone; halogenated hydrocarbons such as dichloromethane; hydrocarbons such as toluene or hexane; and esters such as ethyl acetate, as well as mixtures of two or more such solvents.

For example, reduction may be effected by initially preparing the corresponding acyloxysulphonium salt in situ by reaction of the compound of formula (II) with e.g. acetyl chloride. Reduction of the acetoxysulphonium salt may be effected by, for example, reaction with sodium dithionite or, more preferably, with iodide ion, for example using a solution of potassium iodide in a solvent such as acetic acid, acetone, tetrahydrofuran, dioxan, dimethylformamide or dimethylacetamide. A preferred solvent for this reaction is acetone.

The reaction may be effected at a temperature from -200 'to +5O0C, preferably from about OOC to 250C.

The reduction 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 removal of any carbamoyl protecting group.

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 2,2,2-trichloroethoxycarbonyl may also be cleaved reductively, which process if desired, may be combined with the reduction of a sulphoxide group. A chloroacetyl group 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 compound of formula (II) may be prepared , for example, by oxidation of a compound of formula (III)

(wherein R is as defined above) with an oxidising agent.

The oxidising agent (which also induces isomerisation of the double bond of the cephalosprin nucleus) may be, for example, a peracid such as a percarboxylic acid (e.g. m-chloroperbenzoic acid, trifluoroperbenzoic acid, peracetic acid or performic acid).

The oxidation may be effected in a non-aqueous medium conveniently at a temperature in the range of -500 to +700, preferably between -200 and +150C.

Examples of reaction media which may be employed include an N,N-disubstituted amide such as N,N-dimethylformamide; a ketone such as acetone; a halogenated hydrocarbon such as dichloromethane; an ether such as tetrahydrofuran; a hydrocarbon such as benzene or toluene, or a mixture of two or more such solvents.

The products of the oxidation reaction are generally obtained as a mixture of epimeric R and S sulphoxides in which the S isomer normally greatly predominates. Separation of the epimers may be performed in conventional manner, if desired. However, in general, separation of epimers is not necessary, since the desired sulphide cephalosporin, prepared by the reduction of the sulphoxide, does not retain the asymmetric sulphur centre. It will be appreciated that the oxides of formula (II) may be employed either in the S or R form or as a mixture of isomers.

Alternatively, a compound of formula (II) may be prepared , for example, by esterification of a compound of formula (IV)

(wherein R is 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 acetonitrile. The reaction may be carried out at a temperature in the range -50 to +1500, e.g. -100 to +500C, conveniently between -100 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 esterification of a compound of formula (V)

(wherein R is 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) according to the method described above for esterification of compounds of formula (IV).

The compounds of formulae (II), (III), (IV) and (V) may also be prepared, for example, by conventional acylation methods on the appropriate 7-aminocephalosporin as described in British Patent Specification No. 1399086.

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

Intermediate 1 (4R,6R,7R)-3-Acetoxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyimino acetamido iceph-2-em-4-carboxylic acid A solution of (6R,7R)-3-acetoxymethyl-7-[(Z)-2-(fur-2-yl)-2 methoxyiminoacetamido ]ceph-3-em-4-carboxylic acid (8.83 g) in pyridine (40 ml) was stirred at 220 with acetic anhydride (2.56 ml) for 45 minutes. The mixture was concentrated to give an oil and 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, then brine and dried.The solution was concentrated to about 40 ml and cooled to give the title compound as crystals (3.72 g), m.p. 166.10; Xmax(ethanol) 284.5nm (E1 350); 6 (DMSO-d6) 9.77 (lH,d J 8Hz), 7.83 (1H, s), 6.73 (2H, m) 6.64 (lH,m), 5.60 (1H, dd J 8 and 5Hz), 5.26 (lH,d J 5Hz), 4.91 (1H, s), 4.72 and 4.62 (2H, m), 3.91 (3H, s) and 2.04 (3H, s).

Intermediate 2 (4R,6R,7R)-7-[(Z)-2-(Fur-2-yl)-2-methoxyiminoacetamido]-3-(Z)-2-(Fur-2-yl)-2-methoxyiminoacetamido]-3- hydroxymethylceph-2-em-4-carboxylic acid.

A mixture of the product of Intermediate 1 (3.60 g) and potassium carbonate (3.5 g) in water (50 ml) was stirred with methanol (5 ml) at 380 under nitrogen for 6 hours. The pH of the mixture was lowered to 7.2 with ortho phosphoric acid. The mixture was added to ethyl acetate and stirred and acidified to pH 2.5. The organic layer was separated and the aqueous layer was extracted with ethyl acetate.

The organic layers were combined, washed with water then brine, and were dried. This solution was evaporated to give the title compound as a foam (3.04 g); max (ethanol) 285 nm (E1 393); 6-(DMS0-d6) 9.78 (lH,d J 8Hz), 7.85 (lH,m), 6.75 (lH,m),6.66 (lH,s), 6.46 (1H, s) 5.58 (1H, dd J 8 and 5Hz), 5.27 (1H, d J 5Hz), 4.93 (1H, s), 4.05 (2H,m) and 3.93 (3H,s).

Intermediate 3 Potassium (4R,6R,7R)-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamidol- 3-hydroxymethylceph-2-em-4-carboxylate.

A solution of the product of Intermediate 2 (2.84 g) in ethanol (75 ml) was stirred with potassium acetate (0.80 g) in ethanol (10 ml), added dropwise, at 220. After 2 hours the crystalline solid was filtered off, washed and dried to give the title compound (1.99 g); Xmax (ethanol) 285 nm (E1382).

Intermediate 4 (R and S)-l-Acetoxyethyl (4R,6R,7R)-7-[(Z)-2-(fur-2-yl)-2- methoxyiminoacetamidol-3-(trichloroacetylcarbamoyloxymethyl)ceph- 2-em-4-carboxylate.

A solution of the product of Intermediate 3 (1.90 g) in dimethylformamide (50 ml) was stirred under nitrogen at about 00 with (R,S)-l-acetoxyethyl bromide (0.98 g) for 1.5 hours. Trichloroacetyl isocyanate (0.67 ml) was added at between -30 and 00 and the mixture was stirred at 30 for 15 minutes then at about 100 for 1 hour. The mixture was diluted with ethyl acetate and washed with 2M hydrochloric acid. The acidic layer was extracted with ethyl acetate (2x) and the organic layers were combined, washed with 2M hydrochloric acid, water, saturated sodium bicarbonate solution, and brine.The solution was dried, concentrated to about 15 ml and added to petrol (400 ml) to give the title compound as a solid (1.93 g); Xmax (ethanol) 278 nm (E1 277); 6 (CDCl3) 8.94 (1H,s), 7.70 (lH,s), 7.32 (1H, d J 8 Hz), 6.90 (2H,m), 6.48 (1H, m), 5.79 (1H,m), 5.32 (1H, d J 3Hz), 4.5 to 5.2 (2H,m), 4.08 (3H,s), 2.10 (3H,s), 2.08 (3H,s) and 1.50 (3H,m).

Intermediate 5 (R and S)-l-Acetoxyethyl (4R ,6R ,7R )-3-carbamoyloxymethyl-7- r (z )-2-(fur-2-yl-2-methoxyiminoacetamidoiceph-2-em-4-carboxylate.

A solution of the product of Intermediate 4 (0.80 g) in dioxan (10 ml) was stirred with a solution of sodium formate (0.28 g) in water (3 ml) at 220 for 2 days, then left at 40 for 5 days. The solution was concentrated to about 5 ml and partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate and the organic layers were combined and washed with water and brine (2x). The solution was dried, concentrated to about 10 ml and added to petrol (100 ml) to give the title compound as a solid (0.51 g). Part (0.49 g) of this solid was adsorbed on silica (5 g) and was chromatographed on a column of Kieselgel 60 (70-230 mesh, 25 g) in dichloromethane-ethyl acetate (3:1).Appropriate fractions were combined, concentrated, and added to petrol to give the title compound as a solid (357 mg); Xmax (ethanol) 279.5 nm (E1 310); (CDCl3) 7.48 (1H,s), 7.45 (1H, d J 8Hz), 6.84 (2H,m), 6.46 (2H,m), 5.76 (1H,m), 5.32 and 5.28 (1H,m), 4.83 (2H, s), 4.61 (1H,s) 4.68 and 4.47 (2H,m), 2.08 (3H,s), 2.07 (3H,s) and 1.50 (3H,m).

Intermediate 6 (R and S)-l-Acetoxyethyl (15,6R,7R)-3-carbamoyloxymethyl-7-r(Z)-2-(fur -2-yl)-2-methoximinoacetamidoiceph-3-em-4-carboxylate l-oxide.

A solution of the product of Intermediate 5 (300 mg) in dichloromethane (25 ml) was stirred at 00 to-5 with a solution of m-chloroperbenzoic acid (119 mg) in dichloromethane (5 ml) for 2 hours. The mixture was evaporated and the solid triturated with ether then methanol to give the title compound as a solid (198 mg); Xmax (ethanol) 275.5 nm (E1337); 6 (DMSO-d6) 9.28 (1H, d J 8Hz), 7.85 (1H,s) 7.06 and 6.98 (lH,m), 6.78 (lH,m), 6.65 (3H,m), 5.97 (lH,m), 5.05 (lH,m), 5.02 and 4.60 (2H,m) 3.98 and 3.65 (2H,m), 3.94 (3H,s), 2.12 (3H,s), 2.10 (3H,s) and 1.54 (3H,d J 6Hz).

Example (R and S)-l-Acetoxyethyl (6R ,7R )-3-Carbamoyloxymethyl-7- I(Z)-2-(fur-2-yl)-2-methoxyiminoecetamid iceph-3-em-4-carboxylate A mixture of the product of Intermediate 6 (100 mg) and potassium iodide (252 mg) in dimethylformamide (5 ml) was stirred at 00 under nitrogen for 15 minutes. The mixture was cooled to -150 and acetyl chloride (0.05 ml) was added. The mixture was stirred at -120 for 35 minutes and then added to a mixture of a 10S solution of sodium thiosulphate (25 ml) and ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and brine (2x). The solution was dried, concentrated to about 3 ml and added to petrol to give the title compound as a solid (63 mg) which was identical to a reference sample of cefuroxime axetil by HPLC.

Claims (6)

CLAIMS:

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

(wherein R represents a hydrogen atom or a carbamoyl protecting group) which comprises reacting a compound of formula (II)

(wherein R is as defined above) or an acyloxysulphonium salt thereof with a reducing agent capable of converting the sulphide or acyloxysulphonium salt thereof into a sulphide in the presence of other sensitive functional groups and, where the compound of formula (I) initially obtained is a compound in which R is a carbamoyl protecting group, conversion, where desired, into a different compound of formula (I) wherein R is a hydrogen atom by removal of said carbamoyl protecting group.

2. A process as claimed in claim 1 wherein the reduction is effected at a temperature in the range -50 to 1O00C.

3. A process as claimed in claim 1 or claim 2 wherein the reducing agent comprises iodide ion, a dithionite, a dihaloborane or a benzodioxaphosphole.

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

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

6. Cefuroxime axetil when prepared by a process as claimed in any of the preceding claims.