GB1598568A

GB1598568A - Esters of(6r,7r)-3-carbamoyloxymethyl-7-((z)-2-(fur-2-yl)-2-methoxyiminoacetamido)-ceph-3-em-4-carboxylic acid

Info

Publication number: GB1598568A
Application number: GB16202/77A
Authority: GB
Original assignee: Glaxo Laboratories Ltd
Current assignee: Glaxo Laboratories Ltd
Priority date: 1977-04-19
Filing date: 1977-04-19
Publication date: 1981-09-23
Also published as: IT7848941A0; YU90978A; DK147513B; IE46726B1; KR840000081B1; IT1104842B; ZA782211B; IE780760L; KR830000246A; SE433748B; NL7804097A; FR2387988A1; ATA274878A; AU521098B2; ES468895A1; DK168778A; BE866093A; AT363183B; FR2387988B1; IL54531A

Abstract

Cephalosporin derivatives of the formula: <IMAGE> in which R<1> denotes lower alkyl and R<2> denotes hydrogen or lower alkyl. In contrast to the free carboxylic acids, these novel esters are very well absorbed by the gastrointestinal tract and then hydrolyse rapidly to give corresponding carboxylic acids having a broad spectrum antibiotic action. They are prepared by esterification of the carboxyl group in the 4-position, by N-acylation of the 7-aminocephemcarboxylic acid ester or by carbamoylation of the hydroxymethyl group in the 3-position.

Description

(54) ESTERS OF (6R,7R)-3-CARBAMOYLOXYMETHYL-7 [(Z)-2-(FUR-2-YL)-2-METHOXYIMINOACETAMIDO]- CEPH-3-EM-4-CARBOXYLIC ACID (71) We, GLAXO LABORATORIES LIMITED, a British Company of Greenford, Middlesex, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention is concerned with improvements in or relating to cephalosporin antibiotics. More particularly the invention is concerned with esters of (6R,7R) 3 - carbamoyloxymethyl - 7 - [(Z) - 2 - (fur - 2 - yl) - 2 methoxyiminoacetamidoiceph - 3 - em - 4 - carboxylic acid (i.e. the syn isomer), which has the approved name "cefuroxime".

Cefuroxime, as disclosed in British Patent Specificattion No. 1,453,049 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. Additionally the compound is stable in the body owing to its resistance to the action of mammalian esterases, and gives high serum levels following parenteral administration (e.g. in the form of the sodium salt) to human and animal subjects, while exhibiting low serum binding.

Cefuroxime and its salts, for example alkali metal salts such as the sodium salts. are principally of value as injectable antibiotics since they are poorly absorbed from the gastro-intestinal tract and are therefore present in sera and urine only in low concentrations after oral administration. We have accordingly conducted extensive studies into the result of administering various derivatives of cefuroxime by the oral route, since the development of derivatives which are absorbed from the gastro-intestinal tract and are converted in the body sera to the parent antibiotic following oral administration would extend still further the valuable therapeutic potential of cefuroxime.

It is known from the literature pertaining to p-lactam antibiotics that the absorption from the gastro-intestinal tract following oral administration of certain penicillin and cephalosporin antibiotics can be improved (compared with the parent antibiotic) by converting the free 3-carboxy group in the case of penicillin compounds, or the free 4-carboxy group in the case of cephalosporin compounds, to particular esterified carboxy groups. Thus, for example, Penicillin G may be converted into its acetoxymethyl ester to provide a compound having improved absorption from the gastro-intestinal tract after oral administration compared with Penicillin G itself.

It is believed that the presence of an appropriate esterifying group enhances absorption of the parent antibiotic from the gastro-intestinal tract, the esterifying group being hydrolysed after absorbtion by enzymes present in, for example, serum and body tissues to yield the antibiotically-active parent acid. It will be appreciated that the precise nature of the esterifying group is critical since it is necessary that the ester should be sufficiently stable to allow the ester to reach the site of absorption without undergoing significant degradation, e.g. in the stomach, while on the other hand the ester must be sufficiently susceptible for conversion to the antibiotically active parent acid within a short time of the ester being absorbed.

Moreover, the extent to which the particular ester group enhances the oral absorption of the p-lactam antibiotic is random and unpredictable and depends upon the nature of the parent acid selected. For example, an esterifying group which has been found to be effective in improving the usefulness of a penicillin antibiotic does not necessarily convey similar advantages to an antibiotic of the cephalosporin series, and inconsistencies are noted within each of these particular series of p-lactam antibiotics.

We have now surprisingly found that cefuroxime may be esterified at the 4carboxy group with certain esterifying groups (as defined below) to provide compounds which have a high level of absorption from the gastro-intestinal tract and which break down readily after absorption to yield the parent antibiotic.

The new cefuroxime esters of our invention may be represented by the formula

(wherein R' is an alkyl group containing 1 to 6 carbon atoms, R2 is hydrogen or an alkyl group containing 1 to 6 carbon atoms, and the asterisk denotes an asymmetric carbon atom when R2 is other than hydrogen). These esters possess properties which render the compounds of significant potential value as orally administrable antibiotics. Individual diasteroisomers, as well as mixtures thereof, are embraced by the invention.

The esters (I) possess reasonable stability as evidenced by the fact that they exhibit low antibacterial activity in vitro compared to cefuroxime (this indicates that a high proportion of ester remains unchanged throughout the in vitro tests and so confirms the stability of the esters). The esters are, on the other hand, extremely susceptible to esterase hydrolysis leading to formation of cefuroxime, as evidenced for example by in vitro tests employing esterases derived from rat liver, human liver or human serum.

In vivo testing in rats confirms that oral administration of the esters (I) leads to significantly greater absorption of cefuroxime, as evidenced by higher serum levels and increased urinary recovery, than does oral administration of cefuroxime itself.

Compounds of formula (I) wherein R' represents a C13 alkyl group and R2 represents a hydrogen atom or a methyl group have been shown to provide particularly good absorption of cefuroxime, as evidenced by animal tests, examples of such compounds including: methoxycarbonyloxymethyl (6R,7R) - 3 - carbamyloxymethyl - 7 - [(Z) - 2 (fur - 2 - yl) - 2 - methoxyiminoacetamido]ceph - 3 - em - 4 - carboxylate; 1- - (ethoxycarbonyloxy) - ethyl (6R,7R)- 3 - carbamoyloxymethyl - 7 - [(Z)- 2 - (fur - 2- yl)- 2- methoxyiminoacetamido]ceph - 3 - em - 4 - carboxylate; and 1 - (methoxycarbonyloxy) - ethyl (6R,7R) - 3 - carbamoyloxymethyl - 7 [(Z)- 2 - (fur - 2 - yl) - 2- methoxyiminoacetamido]ceph - 3 - em - 4 - carboxylate.

The esters of formula (I) may be used for treating a variety of diseases caused by pathogenic bacteria in human beings and animals, such as respiratory tract and urinary tract infections.

The compounds (I) may be prepared in conventional manner, for example by reacting cefuroxime, a salt thereof (e.g. an alkali metal salt such as the sodium of potassium salt or an onium salt, e.g. an ammonium salt for example a quaternary ammonium salt) of a corresponding oxide, with a haloester of formula

(where R1, R2 and the asterisk have the above-defined meanings and X is halogen such as chlorine, bromine or iodine) and, where a oxide is formed, reducing the resulting product, e.g. by treatment with acetyl chloride and potassium iodide, to produce the desired compound of formula I. The reaction is conveniently effected in solution in an inert organic solvent (e.g. an N,N-disubstituted amide such as N,Ndimethylformamide or N,N-dimethylacetamide, a ketone such as acetone, a sulphoxide such as dimethylsulphoxide, a nitrile such as acetonitrile, or hexamethylphosphoric triamide) at a temperature in the range -50" to + 1500 C, e.g. 100 to +500C, conveniently between 0 C and room temperature. When a cefuroxime salt, for example, the potassium salt, is employed as starting material and the reaction is effected in a nitrile solvent, a crown ether such as 18-crown-6 may, if desired, be employed. When cefuroxime acid is employed as starting material it may be advantageous to effect the reaction in the presence of a base, e.g.

a weak inorganic base such as sodium carbonate or potassium carbonate; it is convenient to add the base to the cefuroxime-containing reaction system prior to addition of the haloester (II). The use of potassium carbonate as base in conjunction with a compound (II) in which X is bromine or iodine has been found advantageous in that under these conditions the formation of a ceph-2-em ester product is kept to a minimum. It is convenient to employ substantially equivalent amounts of cefuroxime and base, e.g. about 0.5 moles of diacidic base such as potassium carbonate per mole of cefuroxime. The haloester (II) is conveniently employed in slight excess, e.g. in an amount of 1--1.5 moles per mole of cefuroxime.

The course of the reaction may readily be monitored by t.l.c., since the process involves conversion of a polar acid or salt starting material to a neutral ester product.

The esters (I) may also be prepared by acylation of a compound of formula:

(wherein R' and R2 are as hereinbefore defined) or an acid addition salt or n-silyl derivative thereof, using an acylating agent corresponding to (Z) - 2 - (fur - 2 yl) - 2 - methoxyiminoacetic acid, for example, an acid halide, acid anhydride or carbodiimide, for example, in the manner disclosed in British Patent Specification No. 1,453,049.

The above-described starting materials of formula (III) may be prepared in conventional manner, for example, using the techniques described in U.S. Patent Specification No. 3,905.963 and British Patent Specifications Nos. 1,041,985 and 1,350,772.

Alternatively, the esters of formula (I) may be prepared by in situ carbamoylation of a compound of formula:

(wherein R' and R2 are as hereinbefore defined), by conventional means, for example, in the manner disclosed in British Patent Specification No. 1,453,049.

Carbamoylation may be effected for example using an appropriate isocyanate or cyanic acid.

The above-described starting materials of formula (IV) may be prepared in situ by the esterification of the corresponding 4-carboxylic acid, or a salt thereof (e.g.

an alkali metal salt such as the sodium or potassium salt) with a haloester of formula II, as described above except that a temperature in the range -1000C to +1500C, conveniently between -70"C to OOC, is preferably employed.

If the desired ester product is significantly contaminated by the corresponding ceph-2-em isomer the product may be oxidised (e.g. by treatment with a peracid such as metaperiodic acid, peracetic acid, monoperphthalic acid or mchloroperbenzoic acid or with t-butyl hypochlorite in the presence of a weak base such as pyridine) to give the ceph-3-em l-oxide ester, which may then be reduced (e.g. by treatment with acetyl chloride and potassium iodide) to yield substantially pure ceph-3-em ester.

The individual diastereoisomers may be isolated from the isomeric mixture by crystallisation.

The esters of formula I may be formulated as compositions for oral administration in conventional manner, with the aid of any necessary pharmaceutical carriers or excipients. The compositions are conveniently prepared as tablets, capsules or sachets, advantageously in unit dose form, and may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants and wetting agents. Tablets may be coated in conventional manner. Alternatively, the compositions may be formulated as liquid preparations e.g. suspensions or emulsions, which may contain edible oils, e.g. peanut oil. The active compounds may further be formulated in rectal compositions such as suppositories or retention enemas.

The compositions may contain from 0.1% upwards, e.g. 0.1--99";.

conveniently from 1060% of the active ingredient (I), depending on the method of administration. Compositions in dosage unit form conveniently contain 50--500 mg of the active ingredient (calculated as cefuroxime). Doses employed for adult human treatment will typically be in the range 5005000 mg per day, e.g. 1500 mg per day, (calculated as cefuroxime), although the precise dose will depend on, inter alia, the frequency of administration. The following Examples illustrate the invention. All temperatures are quoted in "C. Melting points were determined in a Mettler apparatus and take the form (mix) where x is the rate of heating (in "C per minute) and y is the insertion temperature. The N,N dimethylformamide employed was dried by passage through acidic alumina.

Organic solutions were dried over anhydrous magnesium sulphate.

T.l.c. plates were developed in chloroform:methanol:formic acid (45:8:1) and the compounds located under U.V. light at 254 nm and by exposure to iodine vapour, or by spraying with ninhydrin and heating to 1200.

Preparation 1 Iodomethyl methyl carbonate A solution of chloromethyl methyl carbonate (7.07 g, 56.75 mmole) in acetone (5 ml) was treated with a solution of sodium iodide (8.51 g, 56.75 mmole) in acetone (30 ml). The resultant suspension was stirred at 220 for 2- hours after which it was evaporated in vacuo to a solid. This solid was partitioned between ether (75 ml) and water (75 ml). The aqueous phase was extracted with more ether (2x75 ml) and the combined organic extracts were washed successively with water (3x75 ml), aqueous sodium metabisulphite (50 ml) and saturated brine (100 ml). The solution was dried and evaporated in vacuo to give the title ester (6.45 g).

Preparation 2 (R,S)-l-Chloroethyl chloroformate Ethyl chlordformate (100 ml) was treated with chlorine at room temperature for 5 hours and the reaction mixture was allowed to stand for 5 days. Distillation of the mixture at atmospheric pressure afforded the title ester (71.8 g) b.p. 120 to 1300.

Preparation 3 (R,S)-l -Chloroethyl methyl carbonate (R,S)-l-Chloroethyl chloroformate (10.0 g, 70 mmole) and methanol (25 ml) were stirred together for 1 hour; initially the reaction was exothermic but the reaction mixture cooled down to ca 200. The excess methanol was removed in vacuo to give the title compound (11.37 g).

Preparation 4 (R,S)-l-Chloroethyl isopropyl carbonate (R,S)-l-chloroethyl chloroformate (10.14 g, 71 mmole) was refluxed with propan-2-ol (35 mol) for 30 minutes and triethylamine (8 drops) was added, and refluxing was continued for 20 minutes. The solution rapidly darkened and it was distilled to give two fractions:- (i) Fraction 1: b.p. 80 to 90 /760 mm (30 ml) (ii) Fraction 2; b.p. 60 to 700/15 mm (5.93 g), which was the title ester.

Example 1 Methoxycarbonyloxymethyl (6R,7R) - 3 - carbamoyloxymethyl - 7 - [(Z) - 2 - (fur - 2 - yl) - 2 - methoxyiminoacetamido]ceph - 3 - em - 4 - carboxylate Iodomethyl methyl carbonate (0.93 g, 4.3 mmole) in N,N-dimethylformamide (3 ml) was added to a solution of potassium (6R,7R) - 3 - carbamoyloxymethyl 7 - [(Z) - 2 - (fur - 2 - yl) - 2 - methoxyiminoacetamido]ceph - 3 - em - 4 carboxylate (1.00 g, 2.2 mmole) in N,N-dimethylformamide (10 ml) and the solution was stirred at 220 for 45 minutes (t.l.c. indicated essentially complete reaction after 30 minutes).

The above solution was partitioned between ethyl acetate (80 ml) and 2-Nhydrochloric acid (80 ml) and the aqueous phase was re-extracted with ethyl acetate (2x 100 ml). The combined organic extracts were successively washed with water (100 ml), 3% aqueous sodium bicarbonate solution (2x75 ml), water (75 ml), aqueous sodium metabisulphite (50 ml), water (50 ml, 2-N-hydrochloric acid (4x50 ml), water (50 ml) and saturated brine (50 ml). The solution was dried and evaporated in vacuo to a foam (1.19 g). This foam was triturated with anhydrous ether (50 ml); the solid obtained was filtered off and washed with anhydrous ether (2x20 ml) and dried in vacuo to give the title ester (0.93 g), m.p. (M20) 100 , []2 +41 (c 0.71, DMSO).

Example 2 (R and S) - 1 - (Ethoxycarbonyloxy) - ethyl (6R,7R) - 3 - carbamoyloxymethyl 7 - [(Z) - 2 - (fur - 2 - yl) - 2 - methoxyiminoacetamido]ceph - 3 - em - 4 carboxylate (a) (R,S)-l-Iodoethyl ethyl carbonate A solution of (R,S)-I-chloroethyl ethyl carbonate (13.14 g, 86.4 mmole) and sodium iodide (14. 8 g, 99 mmole) in acetone (100 ml) was refluxed for 35 minutes.

The acetone was removed in vacuo and the residue was partitioned between ether (150 ml) and water (150 ml). The organic phase was separated and washed successively with water, aqueous sodium metabisulphite solution, water (3 times) and saturated brine and dried. The ether was removed in vacuo to give the title ester.

(b) (R and S) - 1 - (Ethoxycarbonyloxy) - ethyl (6R,7R) - 3 carbamoyloxymethyl - 7 - [(Z) - 2 - (fur - 2 - yl) - 2 methoxyiminoacetamido] - ceph - 3 - em - 4 - carboxylate and its A2 isomer The product from (a) was immediately dissolved in N,N-dimethylformamide (20 ml) and was added to a solution of potassium (6R,7R)- 3 carbamoyloxymethyl - 7 - [(Z) - 2 - (fur - 2 - yl) - 2 methoxyiminoacetamido]ceph - 3 - em - 4 - carboxylate (8.-58 g, 18.5 mmole) in N,N-dimethylformamide (50 ml). The reaction mixture was stirred at 250 for 1 hour and was then partitioned between ethyl acetate (150 ml) and 2-N-hydrochloric acid (200 ml). The aqueous layer was extracted with further ethyl acetate (3x 100 ml) and the combined organic extracts were washed successively with water (2x200 ml), 3% aqueous sodium bicarbonate solution (200 ml), water (3x200 ml) and saturated brine (200 ml) and dried and the solvent was removed in vacuo to give a glass (5.64 g). Trituration of this glass with ether gave the title compound (5.51 g) as a gel [this contained ca 20 of A2 isomer].

(c) (R and S)- 1 - (ethoxycarbonyloxy) - ethyl (lS,6R,7R) - 3 carbamoyloxymethyl - 7 - [(Z) - 2 - (fur - 2 - yl) - 2 methoxyiminoacetamidolceph - 3 - em - 4 - carboxylate, 1 - Oxide A solution of the product from (b) (1.985 g, 3.65 mmole) in dry dichloromethane (40 ml) was treated with a solution of m-chloroperbenzoic acid (0.8 g, 465 mmole) in dichloromethane (40 ml) to give an immediate gelatinous precipitate. The reaction mixture was stirred at 210 for 45 minutes and the solvent was removed in vacuo to give a solid. Trituration of this solid with ether (2x 100 ml) gave the title ester sulphoxide (1.47 g) which decomposed without melting at ca 200 : tmax (EtOH) 275.5 nm (Et9m 356).

(d) (R and S) - 1 - (Ethoxycarbonyloxy) - ethyl (6R,7R) - 3 carbamoyloxymethyl - 7 - [(Z)- 2 - (fur - 2 - yl) - 2 methoxyiminoacetamido]ceph - 3 - em - 4 - carboxylate A solution of the product from (c) (1.18 g, 2.12 mmole) in N,N dimethylformamide (20 ml) was cooled to -10" and treated with potassium iodide (1.38 g, 8.3 mmole) followed by acetyl chloride (0.31 ml, 0.34 g, 4.35 mmole). The reaction mixture was stirred at10 for 30 minutes and then allowed to warm up over the next 45 minutes by which time t.l.c. indicated disappearance of sulphoxide starting material.

The reaction mixture was partitioned between ethyl acetate (80 ml) and 2-Nhydrochloric acid (80 ml) and the aqueous solution was extracted with further ethyl acetate (80 ml). The combined organic extracts were successively washed with sodium metabisulphite solution, water and saturated brine and then dried and the solvent was removed in vacuo to give a froth (1.35 g) which, on trituration with ether (30 ml) afforded the title ester (1.00 g) m.p. (M80) 103 , [a]D+12.8 (c 1.09, DMSO).

Example 3 (R and S) - 1 - (Methoxycarbonyloxy) - ethyl (6R,7R) - carbamoyloxymethyl 7 - [(Z) - 2 - (fur - 2 - yl) - 2 - methoxyiminoacetamido]ceph - 3 - em - 4 carboxylate (A). (R and S)- 1 - (Methoxycarbonyloxy) - ethyl (1S,6R,7R)- 3 carbamoyloxymethyl - 7 - [(Z)- 2 - (fur - 2- yl) - 2 methoxyiminoacetamido]ceph - 3 - em - 4 - carboxylate, 1 - oxide Method (i) (a) (R and S) - 1 - (Methoxycarbonyloxy) - ethyl (6R,7R) - 3 carbamoyloxymethyl - 7 - [(Z) - 2- (fur - 2- yl) - 2 methoxyiminoacetamido]ceph - 3 - em - 4 - carboxylate and its A2 Isomer A solution of(R,S)-l-chloroethyl methyl carbonate (11.37 g) in acetone (10 ml) was treated with a solution of sodium iodide (17.0 g, 113 mmole) in acetone (50 ml).

A precipitate formed immediately and after stirring for 5 minutes the mixture was evaporated in vacuo to dryness. The residue was partitioned between ether (150 ml) and water (100 ml) and the aqueous phase was re-extracted with ether (3x50 ml).

The combined organic extracts were successively washed with water (100 ml), sodium metabisulphite solution (75 ml), water (75 ml) and saturated brine (70 ml) and were dried and evaporated in vacuo to dryness to give (R,S)-l-iodoethyl methyl carbonate (5.5 g) as a solid.

A solution of (R,S)-l-iodoethyl methyl carbonate (5.50 g, 24 mmol) in N,Ndimethylformamide (5 ml) was added to a solution of potassium (6R,7R) - 3 carbamoyloxymethyl - 7 - - [(Z) - 2 - (fur - 2 - yl) - 2 methoxyiminoacetamido]ceph - 3 - em - 4 - carboxylate (4.0 g, 8.6 mmole) in N,N-dimethylformamide (15 ml). The reaction mixture was stirred at 220 for 4 hours and was then allowed to stand overnight.

The mixture was then partitioned between ethyl acetate (75 ml) and 2-Nhydrochloric acid (75 ml).

The aqueous phase was extracted with further ethyl acetate (3x50 ml) and the combined organic extracts were successively washed with water (50 ml), aqueous sodium bicarbonate solution (3%, 2x50 ml), water (2x50 ml) and saturated brine (50 ml) and dried and evaporated in vacuo to dryness. Trituration of the residue (3.8 g) with di-isopropyl ether (100 ml) afforded a solid which was filtered off and dried in vacuo to give the title ester (2.7 g), m.p. (M30) < 70 (decomp), [a:]D2 +183" (e 0.84, DMSO), imax (EtOH) 281 nm (E1.m 278) with an inflection at 260 nm (E1%m 219).

(b) (R and S)- 1 - (Methoxycarbonyloxy) - ethyl (1S,6R,7R)- 3 carbamoyloxymethyl- 7 - [(Z)- 2- (fur - 2 - yl) - 2 methoxyiminoacetamido]ceph - 3 - em - 4 - carboxylate, 1 - Oxide A solution of the product from (a) (2.59 g, 4.92 mmol) in dichloromethane (20 ml) was treated with m-chloroperbenzoic acid (1.06 g, 6.14 mmole). The reaction mixture was stirred for 1 hour at 210 and then diluted with anhydrous ether (20 ml).

The resultant solid was filtered off and washed with ether and dried in vacuo to give the title ester sulphoxide.

The filtrate was evaporated to dryness and the residue was triturated with anhydrous ether (100 ml) and the resultant solid processed in a similar manner to that described above to give a further crop of title ester sulphoxide. The two batches of sulphoxide ester were combined to give 2.26 g of product, m.p. (M140) 1650, [a]22 +44.70 (c 0.91, DMSO).

Method (ii) (a) Potassium (a) Potassium (lS,6R,7R) - 3 - carbamoyloxymethyl - 7 - [(Z) - 2 (fur - 2 - yl) - 2 - methoxyiminoacetamido] ceph - 3 - em - 4 carboxylate, 1 - oxide A solution of potassium acetate (0.216 g, 2.2 mmole) in ethanol (15 ml) was added to a solution of (lS,6R,7R) - 3 - carbamoyloxymethyl - 7 - [(Z) - 2 - (fur 2 - yl) - 2 - methoxyiminoacetamido]ceph - 3 - em - 4 - carboxylic acid, oxide (0.88 g, 2 mmole) in dry N,N-dimethylformamide (15 ml) and more ethanol (10 ml) was added.

The resultant suspension was cooled and the solid filtered off and dried to give the title salt as a DMF solvate (0.946 g, 86%), may pH 6 buffer), 263 nm (E196m 312) with an inflection at 280 nm (E1%m 278).

(b) (R and S)- 1 - (Methoxycarbonyloxy) - ethyl(lS,6R,7R)- 3 carbamoyloxymethyl - 7 - [(Z) - 2 - (fur - 2 - yl) - 2 methoxyiminoacetamido]ceph - 3 - em - 4 - carboxylate, I-oxide (R,S)-l-Chloroethylmethyl carbonate (1.07 g, 7.7 mmole) in N,Ndimethylformamide (5 ml) was added to a heated (40 ) suspension of potassium (1S,6R,7R) - 3 - carbamoyloxymethyl - 7 - [(Z) - 2 - (fur - 2 - yl) - 2 methoxyiminoacetamido]ceph - 3 - em - 4 - - carboxylate, I-oxide, N,Ndimethylformamide solvate (2.76 g, 5 mmole) in dry N,N-dimethylformamide (45 ml). After 24 hours the reaction mixture was poured into 2N-hydrochloric acid (100 ml) and ethyl acetate (100 ml). The aqueous layer and solid were extracted with ethyl acetate (2x100 ml) and the organic solutions were combined and washed successively with 2N-hydrochloric acid (3x100 ml), water (100 ml), saturated aqueous sodium bicarbonate (2x 100 ml), water (100 ml) and saturated brine (2x 100 ml). The solution was treated with charcoal then dried (magnesium sulphate) and evaporated to a yellow solid (0.64 g). Trituration of this material with ether gave the title sulphoxide ester (0.06 g), [am21 +40 (c 0.58 in DMSO), Amax (CHCl3) 277.5 nm (E1icm 289).

(B) (R and S) - 1 - (Methoxycarbonyloxy) - ethyl (6R,7R) - 3 carbamoyloxymethyl - 7 - [(Z) - 2 - (fur - 2 - yl) - 2 methoxyiminoacetamido]ceph - 3 - em - 4 - carboxylate A cooled solution of (R and S)- 1 - (methoxycarbonyloxy) - ethyl (1S,6R,7R)- 3- carbamoyloxymethyl- 7 - [(Z) - 2 - (fur - 2 - yl) - 2methoxyiminoacetamido]ceph - 3 - em - 4 - carboxylate, 1 - oxide (2.12 g, 3.9 mmole) in N,N-dimethylformamide (10 ml) was treated successively with potassium iodide (2.59 g, 15.6 mmole) and acetyl chloride (0.55 ml) and the mixture was stirred at ca 40 for 1 hour and was then partitioned between ethyl acetate (60 ml) and 2-N-hydrochloric acid (60 ml). The aqueous phase was extracted with ethyl acetate (3x40 ml) and the combined organic extracts were successively washed with water (40 ml), aqueous sodium bicarbonate solution (3%, 40 ml), water (40 ml), aqueous sodium metabisulphite (50 ml), water (40 ml) and saturated brine (50 ml).

The organic solution was dried and evaporated to dryness in vacuo.

Trituration of the residue (2.1 g) with di-isopropyl ether (50 ml) afforded a solid which was filtered off, washed with further di-isopropyl ether and dried in vacuo.

This solid (1.99 g) was stirred with anhydrous ether (20 ml) for 2 hours and successively filtered, washed with more ether, filtered off and dried in vacuo to give the title ester (1.6 g) m.p. (M30) 121" (decomp), [a]+ll.80 (c 0.91, DMSO).

Example 4 (R and S) - 1 - (Isopropoxycarbonyloxy) - ethyl (6R,7R) - 3 Carbamoyloxymethyl - 7 - [(Z) - 2 - (fur - 2 - yl) - 2 methoxyiminoacetamido]ceph - 3 - em - 4 - carboxylate (a) (R and S) - 1 - (isopropoxycarbonyloxy) - ethyl - (6R,7R) - 3 carbamoyloxymethyl - 7 - [(Z) - 2 - (fur - 2 - yl) - 2 methoxyiminoacetamido]ceph - 3 - em - 4 - carboxylate and its A2 isomer A solution of (R,S)-l-chloroethyl isopropyl carbonate (1.0 g, 6 mmole) in acetone (5 ml) was stirred with a solution of sodium iodide (1.50 g, 10 mmole) in acetone (20 ml) for 4 hours.

The mixture was then evaporated to dryness in vacuo and the resi 2 - (fur - 2 - yl) - 2 - methoxyiminoacetamidoiceph - 3 - em - 4 - carboxylate (2.50 g, 5.4 mmole) in N,N-dimethylformamide (20 ml) which was stirred for 2 hours. Further portions of (R,S) - 1 chloroethyl isopropyl carbonate (1.0, g, 1.0 g and 1.5 g; 6, 6 and 9 mmole).were added after 0,16 and 22 hours and the reaction mixture. was stirred for a further 16 hours by which time reaction was essentially complete (by t.l.c.). The reaction mixture was partitioned between ethyl acetate (70 ml) and 2-N hydrochloric acid (80 mlY. The aqueous phase was extracted with ethyl acetate (3x40 ml) and the combined organic extracts were successively washed with water (2x50 ml), aqueous sodium bicarbonate solution (50 ml), water (50 ml) and saturated brine (50 ml) and dried and evaporated in vacuo to dryness.

Trituration of the residue with di-isopropyl ether (50 ml) afforded a mixture of the two title esters. This mixture possessed the following physical properties: Amax (EtOH) 277.5 nm (E1%m 303).

(b) (R and S) - 1 - (isopropoxycarbonyloxy) - ethyl (lS,6R,7R) - 3 - carbamoyloxymethyl - 7 - [(Z) - 2 - (fur - 2 - yl) - 2 methoxyiminoacetamidolceph - 3 - em - 4 - carboxylate, I - oxide A solution of the product from (a) (1.90 g, 3.43 mmole) in dichloromethane (20 ml) was treated with m-chloroperbenzoic acid (0.74 g, 4.3 mmole).

The mixture was stirred at 22 for 1 hour and was then evaporated in vacuo to dryness. Trituration of the residue with anhydrous ether (80 ml) afforded a solid which was filtered off, washed (with anhydrous ether) and dried in vacuo to give the title ester sulphoxide (1.50 g) m.p. (M140) 1760 (decomp), [a]022+55.40 (c 1.0, DMSO).

(c) (R and S)- 1 - (Isopropoxycarbonyloxy) - ethyl - (6R,7R)- 3 carbamoyloxymethyl- 7- [(Z)- 2- (fur - 2- yl)- 2 methoxyiminoacetamido]ceph - 3 - em - 4 - carboxylate A cooled (ca 4 ) solution of the product from (b) (1.37 g, 2.4 mmole) in N,Ndimethylformamide (20 ml) was treated with potassium iodide (1.60 g, 9.64 mmole) and acetyl chloride (0.34 ml) and the reaction mixture was stirred at 4" for I hour.

The mixture was the partitioned between ethyl acetate (70 ml) and 2-N hydrochloric acid (80 ml).

The aqueous phase was extracted with ethyl acetate (3x50 ml) and the combined organic extracts were successively washed with water (2x50 ml), aqueous sodium metabisulphite solution (50 ml), water (50 ml) and saturated brine (50 ml) and dried and evaporated to dryness in vacuo. The resultant residue was triturated with anhydrous ether (100 ml), filtered off and dried in vacuo to give the title ester (0.86 g), m.p. (Mgo) 1090 (decomp), []D+18.2 (c 1.0. DMSO).

Pharmaceutical Examples A. Powder for Oral Suspension (in sachet) Composition per sachet (R and S)- 1 -(Methoxycarbonyloxy)-ethyl(6R,7R)-3 carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2- equivalent to methoxyiminoacetamido] ceph-3-em-4- carboxylate 250 mg (milled) (product of Example 3) cefuroxime Sodium Carboxymethyl Cellulose (low Viscosity) 90 mg Sunset Yellow FCF 5 mg Spray-dried Orange Flavour 150 mg Caster Sugar 2.2 g The product of Example 3 is milled (using a fluid energy mill) and blended intimately with the Sodium Carboxymethyl Cellulose and the flavouring and colouring agents. This blend is then further blended with the Caster Sugar, adding the latter in two stages. The required weight is transferred to a paper/aluminium/polythene sachet and sealed by heat. The contents of each sachet are intended for constitution in about 15 mls of water, shortly before administration.

B. Product of Example 3, micronized (250 mg acid) 338.4 mg Sodium Starch Glycolate 8.0 mg Magnesium Stearate 2.0 mg Microcrystalline Cellulose 51.6 mg Total Weight 400.0 mg Method The ingredients are mixed in ascending order of weights and the mixture compressed on a F3 single punch machine using 13/32" normal concave punch to produce the required tablet.

WHAT WE CLAIM IS: 1. Compounds of the formula

(wherein R' is an alkyl group containing I to 6 carbon atoms, R2 is hydrogen or an alkyl group containing 1 to 6 carbon atoms and- the asterisk denotes an asymmetric carbon atom when R2 is other than hydrogen).

2. Compounds as claimed in claim I wherein R' represents an alkyl group containing 1 to 3 carbon atoms and R2 represents hydrogen or a methyl group.

3. Methoxycarbonyloxymethyl (6R,7R) -3 - carbamoyloxymethyl - 7 - [(Z) - 2 - (fur - 2 - yl) - 2 - methoxyiminoacetamido]ceph - 3 - em - 4 - carboxylate.

4. 1 - (Ethoxycarbonyloxy) - ethyl (6R,7R) - 3 - carbamoyloxymethyl - 8 [(Z)- 2 - (fur - 2 - yl) - 2 - methoxyiminoacetamido]ceph - 3 - em - 4 - carboxylate.

5. 1 - (Methoxycarbonyloxy) - ethyl (6R,7R) - 3 - carbamoyloxymethyl - 7 [(Z) - 2 (fur - 2 - yl) - 2 - methoxyiminoacetamido] ceph - 3 - em - 4 carboxylate.

6. A process for the preparation of a compound of formula I (as defined in claim 1) which comprises either (A) reacting (6R,7R) - 3 - carbamoyloxymethyl 7 - 1(Z) - 2 - (fur - 2 - yl) - 2 - methoxyiminoacetamido]ceph - 3 - em - 4 carboxylic acid (i.e. cefuroxime), a salt thereof or a corresponding oxide, with a haloester of formula

(where R' and R2 are as defined in claim 1 and X is halogen) and, where a oxide is formed, reducing the resulting product to produce the desired compound of formula I: (B) acylating a compound of formula

(where R' and R2 are as defined in claim 1) or an acid addition salt or N-silyl derivative therof, with an acylating agent corresponding to (Z)-2-(fur-2-yl)-2methoxyiminoacetic acid; or (C) carbamoylating the 3-hydroxymethyl group of a compound of formula:

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. Method The ingredients are mixed in ascending order of weights and the mixture compressed on a F3 single punch machine using 13/32" normal concave punch to produce the required tablet. WHAT WE CLAIM IS:

1. Compounds of the formula

(wherein R' and R2 are as hereinbefore defined).

7. A process as claimed in claim 6 wherein cefuroxime or a salt thereof is reacted with a haloester of formula (II) in which X is chlorine, bromine or iodine.

8. A process as claimed in claim 6 or claim 7 wherein an alkali metal or onium salt of cefuroxime is reacted with the said haloester of formula (II).

9. A process as claimed in claim 6 or claim 7 wherein cefuroxime is reacted with the said haloester of formula (II) in the presence of a base.

10. A pharmaceutical composition comprising a compound as claimed in any of claims I to 5 in association with at least one pharmaceutical carrier or excipient.