EP0785937A1 - 2-(imidazol-4-yl)carbapeneme derivatives, intermediates thereof and use as antibacterials - Google Patents

Abstract

Compounds of general formula (I), in which Ra or Rb alone is hydrogen, optionally substituted (C¿1-6?)alkyl or together form a 5 or 6 membered heterocyclic ring which may contain at least one additional heteroatom selected from oxygen, nitrogen or sulphur; R?1¿ is (C¿1-6?)alkyl which is unsubstituted or substituted by fluoro, a hydroxy group which is optionally protected by a readily removable hydroxy protecting group, or by an amino group which is optionally protected by a readily removable amino protecting group; R?2¿ is hydrogen or methyl and -CO¿2R?3 is carboxy or a carboxylate anion or the group R3 is a readily removable carboxy protecting group, are useful in the treatment and prophylaxis of bacterial infections in animals and humans.

Description

2- ( IMIDAZ0L-4-YL) CARBAPENEME DERIVATIVES , INTERMEDIATES THEREOF AND USE AS ANTIBACTERIALS

This invention relates to a class of antibacterial compounds, in particular a class of carbapenems, processes for their preparation, pharmaceutical and veterinary compositions comprising such compounds, intermediates thereof, and their use in antibacterial therapy.

Carbapenems such as imipenem, the compound of formula (A):

(A) have a potent, broad spectrum of antibacterial activity (see US 3 950 357 and US 4 194 047; Merck and Co). Such carbapenems however tend to be vulnerable to hydrolysis by the enzyme renal dehydropeptidase-l (DHP-1) and this limits their use in chemotherapy. In the case of imipenem, this problem may be overcome by the co- administration of an inhibitor of DHP- 1.

Stability towards DHP-1 may also be imparted by chemical modification of the carbapenem nucleus, for instance by incorporating a 1 β-methyl substitutent, as in the compound meropenem, the compound of formula (B):

(B) (see Shih D.H. et al, Heterocycles, 1984, 21, 29 and Sunagawa M. et al, J. Antibiotics, 1990, 43, 519). More recently, this has been extended to a lβ- aminoalkyl substituent (see EP 0433 759, Bristol-Meyers Squibb). An alternative approach to imparting improved stability to DHP- 1 utilises 2- carbon substituted carbapenems, for instance, 2-aryl, 2-heteroaryl and 2- heteroaromatic carbapenems (US 4 543 257, US 4 260 627, US 4 962 101, US 4 978 659, EP 0 14 493, EP 0 414489, EP 0 010 316 and EP 0 030 032 Merck & Co) and 2-(substituted)methyl carbapenems (Schmidt et al, J.Amibiotics, 41, 1988, 780).

UK Patent 1 593 524, Merck & Co. discloses a number of C-2 substituted 5- me bered heteroaromatic carbapenem derivatives, including diazolyl and tetrazolyl compounds. However, in the case of the imidazolyl derivatives, the heterocyclic ring is attached to the carbapenem nucleus through the C-2 position of the imidazole ring.

Other structural modifications introduced at the carbapenem C-2 position include a substituted vinyl group -C(R_a)=CHRι₀ in which, for instance, R_a is hydrogen or methyl and RK. is hydrogen or lower alkyl (EP 0 330 108; Fujisawa) or R_a and R_D arc selected from hydrogen, lower alkyl, aminocarbanyl, lower alkoxy, cyano, nitro and lower alkoxycarbonyl (EP 0 430037, Banyu Pharmaceutical Co.). In the absence of a 1 β-methyl substituent, such a modification does not however appear to impart DHP- 1 stability. We have surprisingly found that other types of structural modification at position-2 are advantageous.

Accordingly the present invention provides a compound of the general formula (I):

(I) in which:

R^a or R*³ alone is hydrogen, optionally substituted (Cι_6)alkyl or together form a 5 or

6 membered heterocyclic ring which may contain at least one additional heteroatom selected from oxygen, nitrogen or sulphur;

R! is (Cι_6)alkyl which is unsubstituted or substituted by fluoro, a hydroxy group which is optionally protected by a readily removable hydroxy protecting group, or by an amino group which is optionally protected by a readily removable amino protecting group; R is hydrogen or methyl and

-CO2R^ is carboxy or a carboxylate anion or the group R3 is a readily removable carboxy protecting group.

Compounds of formula (I) have a broad spectrum of anti-bacterial activity and show good stability towards DHP- 1. Suitable (C_j.g) alkyl groups for the substituent R^a or R& include straight and branched chain alkyl groups having from 1 to 6 carbon atoms, for instance methyl, ethyl, n-propyl and wo-propyl, preferably methyl.

Suitable optional substituents for the (Cj_6) alkyl group in R^a or R^D include, for example, halogen, hydroxy, (C^alkoxy, carboxy and salt thereof, (Cι-6)alkoxycarbonyl, carbamoyl, mono- or di(Cι-6)alkylcarbamoyl, sulphamoyl, mono- and di(Cι-6)alkylsulphamoyl, amino, mono- and di(Cι-6)alkylamino, (Cι-6)acylamino, ureido, (Cι-6)alkoxycarbonylamino, 2,2,2-trichloroethoxycarbonylamino, aryl, heterocyclyl, oxo, acyl, 2-thienyl, (C j -6)alkylthio, arylthio, (C i -6)alkane-sulphinyl, arylsulphinyl, (C i -^Jalkanesulphonyl, arylsulphonyl, (Ci-gjalkoxyimino, hydroxyimino, hydrazono, benzohydroxyimoyl, and 2-thiophenecarbohydroxyimoyl. Preferred substituents include carbamoyl, aryl, especially phenyl, and heteroaryl.

A representative example of when R^a and/or R^D is substituted with a (C_j.6) alkyl, is when the substituent is methyl.

Suitable (Cj.g) alkyl groups for R* include straight and branched chain alkyl groups having from 1 to 6 carbon atoms. Preferred alkyl groups include methyl, ethyl and isø-prσpyl, of which ethyl is especially preferred.

Preferably the (Cj.g) alkyl group of R^ has a hydroxy, fluoro or amino substituent which is suitably at position- 1 of the alkyl group. Advantageously R* is (R)- 1 -hydroxyethyl.

Suitably R^ is hydrogen.

When used herein, the term "aryl" includes phenyl and naphthyl. Suitably an aryl group, including phenyl and naphthyl, may be optionally substituted by up to five, preferably up to three substituents. Suitable substituents include halogen, (Ci.gjalkyl, aryl(Cι_4)alkyl (C_j.6)alkoxy, (Cμ6)alkoxy(Cι_6)alkyl, halo(Cι_6)alkyl, hydroxy, amino, mono- and di-/V-(Cι_6)alkylamino, acylamino, carboxy, carboxy salts, carboxy esters, carbamoyl, mono- and di-N-(Cμ6)alkylcarbamoyl, (Cι_6)alkoxycarbonyl, (Cι-6)alkoxycarboxylate, aryloxycarbonyl, (Cι_6)alkoxycarbonyl-(Cι_6)alkyl aryl, oxy groups, ureido, guanidino, sulphonylamino, aminosulphonyl, (Cι_6)alkylthio, (C\. 6)alkyl sulphinyl (Cι_6)alkylsulphonyl, heterocyclyl and heterocyclyl (Cι_4)alkyl. In addition, two adjacent ring carbon atoms may be linked by a (C3_5)alkyl or alkylene chain, to form a carbocyclic ring.

When used herein, the term "heteroaryl" includes aromatic single and fused rings containing up to four heteroatoms in each ring, each of which is selected from oxygen, nitrogen and sulphur, which rings may be unsubstituted or substituted by, for example, up to three substituents. Each heteroaryl ring suitably has 5 or 6 ring atoms. A fused heteroaryl ring may include carbocyclic rings and need include only one heteroaryl ring. When used herein the terms "heterocyclyl" and "heterocyclic" suitably include, unless otherwise defined, aromatic and non-aromatic, single and fused, rings suitably containing up to four heteroatoms in each ring, each of which is selected from oxygen, nitrogen and sulphur, which rings ,may be unsubstituted or substituted by, for example, up to three substituents. Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ring atoms. A fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring.

Preferably a substituent for a heteroaryl or a heterocyclyl group is selected from halogen, (Cι_6)alkyl, aryl(Cι_4)alkyl(Cι_6)alkoxy, (Cμ6)alkoxy(Cι_6)alkyl, halo(Ci_6)alkyl, hydroxy, amino, mono- and di-N-(C^6)alkyl-amino, acylamino,carboxy salts.carboxy esters, carbamoyl, mono- and di-N- (Cι.6)alkylcarbonyl, (Cι-6)alkoxycarboxylate, aryloxycarbonyl, (C\. 6)alkoxycarbonyl(Cι.6)alkyl, aryl, oxy groups, ureido, guanidino, sulphonylamino, aminosulphonyl, (Cι_6)alkylthio, (Cμ^alkylsulphinyl, (Cμ6)alkylsulphonyl, heterocyclyl and heterocyclyl(C \ _4)alkyl.

Suitable hydroxy and amino protecting groups for use in R* are those well known in the art and which may be removed under conventional conditions and without disrupting the remainder of the molecule. A comprehensive discussion of the ways in which hydroxy and amino groups may be protected and methods for cleaving the resulting protected derivatives is given in for example "Protective Groups in

Organic Chemistry" (T.W. Greene, Wiley-Interscience, New York, 2nd edition, 1991). Particularly suitable hydroxy protecting groups include, for example, triorganosilyl groups such as, for instance, trialkylsilyl and also organooxycarbonyl groups such, as for instance, allyloxycarbonyl, trichloroethyloxycarbonyl, 4-methoxybenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl. Particularly suitable amino protecting groups include alkoxycarbonyl, 4-methoxybenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl.

Since the carbapenem compounds of the present invention are intended for use in pharmaceutical compositions, it will be readily appreciated that preferred compounds within formula (I) are pharmaceutically acceptable i.e. are compounds of formula (la):

(la) in which R^a, R^D, R* and R^ are as hereinbefore defined or pharmaceutically acceptable salts or pharmaceutically acceptable in vivo hydrolysable esters thereof. Non-pharmaceutically acceptable salts of the compound of formula (I) in which

R^ is hydrogen are primarily of use as intermediates in the preparation of compounds of formula (I) in which R^ is hydrogen or a pharmaceutically acceptable salt thereof. Salts within compounds of formula (I) may be prepared by salt exchange in a conventional manner. Similarly, carboxy-protected derivatives of formula (I) i.e. those compounds of formula (I) in which R^ is a readily removable carboxy protecting group, may be used in the preparation of a compound of formula (I) in which R^ is hydrogen or a pharmaceutically acceptable salt thereof. Included within the scope of readily removable carboxy protecting groups for R^ are ester groups including pharmaceutically acceptable in vivo hydrolysable ester groups.

Suitable readily removable carboxy protecting groups for the group -CO2R^ include groups forming ester derivatives of the carboxylic acid, including in vivo hydrolysable esters. The derivative is preferably one which may readily be cleaved. Suitable ester-forming carboxy-protecting groups are those which may be removed under conventional conditions. Such groups for R^ include benzyl, 4-methoxybenzyl, benzoylmethyl, 4-nitrobenzyl, 4-pyridylmethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, t-butyl, t-amyl, allyl, diphenylmethyl, triphenylmethyl, adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofuran-2-yl, tetrahydropyran-2-yl, pentachlorophenyl, acetonyl, p-toluenesulphonylethyl, methoxymethyl, a silyl, stannyl or phosphorus- containing group, an oxime radical of the formula -N=CHR^X where R^x is aryl or heterocyclic, or an in vivo hydrolysable ester radical such as defined below.

A carboxy group may be regenerated from any of the above esters by the usual methods appropriate to the particular R3 group, for example, acid- and base-catalysed hydrolysis, enzymically-catalysed hydrolysis or photochemical methods, under conditions wherein the remainder of the molecule is substantially unaffected.

Preferably the ester-forming carboxy-protecting group is 4-methoxybenzyl, which may be suitably be removed using aluminium chloride and anisole, 4-nitrobenzyl which may be suitably removed using iron powder and ammonium chloride (1M soln) or by hydrogenation using palladium on a carbon catalyst; or allyl which may be suitably removed using rerrα£w(triphenylphosphine)-palladium and triphenylphosphine.

Advantageously, the hydroxy, amino and carboxy-protecting groups, when used, are selected so that they can be removed under the same conditions, in a single reaction step; for example allyloxycarbonyl (for hydroxy) and allyl (for carboxy) which may be both removed using tetrα&.s(triphenylphosphine)palladium and triphenylphosphine. Another suitable combination is trialkylsilyl (for hydroxy) and 4- methoxybenzyl (for carboxy) which may both be removed using aluminium chloride and anisole.

Examples of suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which break down readily in the human body to leave the parent acid or its salt. Suitable ester groups of this type include those of part formula (a), (b),

(c) and (d):

-CO2CH(R^a)O.CO.R^b (a) -CO₂R^cNR^dR^e (b)

-CO₂CH₂OR^f (c)

-CO₂CH(R )O.CO.C₆H₄YCOCH(Rg)NH2 (d)

in which:

R^a is hydrogen, (Cj-6)alkyl, (C3-7)cycloalkyl, methyl, or phenyl;

R^D is (Cj-^alkyl, (Cι-6)alkoxy, phenyl, benzyl, (C3-7)cycloalkyl, (Cι-6)alkyl(C3-7)cycloalkyl, l-amino(Cι-6)alkyl, or 1 -(Chalky l)amino(Cι-6)alkyl; or

R^a and R^D together form a 1,2-phenylene group optionally substituted by one or two methoxy groups;

R^c is (Cι-6)alkylene optionally substituted with a methyl or ethyl group; R and R^e which may be the same or different is each (C \ -6)alkyl;

R^fis (Cι-6)alkyl;

R§ is hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (Cι-6)-alkyl, or (Cj-6)alkoxy; and

Y is oxygen or NH. Examples of suitable pharmaceutically acceptable in vivo hydrolysable ester groups include, for example, acyloxyalkyl groups such as acetoxymethyl, pivaloyloxy ethyl, α-acetoxyethyl, α-pivaloyloxyethyl,

1 -(cyclohexyloxycarbonyloxy)ethyl, and ( 1 -aminoethy l)-carbonyloxymethyl; alkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl and α -ethoxycarbonyloxyethyl; dialkylaminoalkyl especially di-loweralkylamino alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl; lactone groups such as phthalidyl and dimethoxyphthalidyl; and esters linked to a second β-lactam antibiotic or to a β-lactamase inhibitor.

A further suitable pharmaceutically acceptable in vivo hydrolysable ester group is that of the formula:

-C0₂CH_{2 R} ^h

in which Rⁿ is hydrogen, (C^alkyl or phenyl.

Suitable pharmaceutically acceptable salts of the carboxy group of the compound of formula (I) include metal salts, for example aluminium, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium; and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy-lower alkylamines such as 2- hydroxyethylamine, bw-(2-hydroxyethyl)-amine or tm-(2-hydroxyethyl)-amine, cycloalkylamines such as dicyclohexylamine, or with procaine, dibenzylamine, Nj - dibenzylethylenediamine, 1-ephenamine, N-methylmorpholine, N-ethylpiperidine, N- benzyl-b-phenethylamine, dehydroabietylamine, N^V-bw-dehydro-abietylamine, ethylenediamine or N-methylglucosamine; or basic amino acids such as lysine, arginine, or bases of the pyridine type such as pyridine, collidine or quinoline; or other amines which have been used to form salts with known penicillins and cephalosporins. Other useful salts include the lithium salt and silver salt.

Since the carbapenem compounds of the present invention are intended for use in pharmaceutical compositions, it will be further understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions. Although the purity of intermediate compounds of the present invention is less critical, it will readily be understood that the substantially pure form is preferred as for the carbapenem compounds. Preferably, whenever possible, the compounds of the present invention are obtained in crystalline form.

When some of the compounds of this invention are allowed to crystallise or are recrystallised from organic solvents, solvent of crystallisation may be present in the crystalline product. This invention includes within its scope such solvates. Similarly, some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be present in the crystalline product. This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.

Specific compounds within this invention include the compounds described hereinbelow in the Examples.

The carbapenem antibiotic compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, according to techniques and procedures per se known in the an with reference to other antibiotics, and the invention therefore includes within its scope a pharmaceutical composition comprising an antibiotic compound according to the present invention such as, for example, a compound of formula (la) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, together with a pharmaceutically acceptable carrier or excipient. The compositions may be formulated for administration by any suitable route, such as oral, parenteral or topical application. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dose presentation form and may contain conventional excipients such as binding agents, for example, syrup acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters, glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and, if desired conventional flavouring or colouring agents. Suppositories will contain conventional suppository base, eg cocoa-butter or other glyceride.

For parenteral administration, fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, agents such as local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99.5% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 50-500 mg of the active ingredient. The dosage as employed for adult human treatment will preferably range from 100 mg to 12 g per day for an average adult patient (body weight 70 kg), for instance 1500 mg per day, depending on the route and frequency of administration. Such dosages correspond to approximately 1.5 to 170 mg/kg per day. Suitably the dosage is from 1 to 6g per day.

The daily dosage is suitably given by administering a compound of the invention several times in a 24-hour period. Typically, 250 mg is administered 4 times a day although, in practice, the dosage and frequency of administration which will be most suitable for an individual patient will vary with the age, weight and response of the patients, and there will be occasions when the physician will choose a higher or lower dosage and a different frequency of administration. Such dosage regimens are within the scope of this invention. No toxicological effects are indicated when a compound of the invention of formula (la) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof is administered in the above mentioned dosage range.

The present invention also includes a method of treating bacterial infections in humans and animals which method comprises administering a therapeutically effective amount of an antibiotic compound of the present invention of the formula (la) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.

In a further aspect, the present invention also provides for the use of a compound of formula (la) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof for the manufacture of a medicament for treating bacterial infection.

The compounds of the present invention of formula (la) or pharmaceutically acceptable salts or in vivo hydrolysable esters thereof are active against a broad range of Gram-positive and Gram-negative bacteria, and may be used to treat a wide range of bacterial infections including those in immunocompromised patients. Amongst many other uses, the compounds of the invention of formula (la) or salts or pharmaceutically acceptable in vivo hydrolysable esters thereof are of value in the treatment of skin, soft tissue, respiratory tract and urinary tract infections in humans and may also be used to treat mastitis in cattle.

A particular advantage of the antibacterially active compounds of this invention is their stability to β-lactamase enzymes and they are therefore effective against β-lactamase producing organisms.

The present invention further provides a process for the preparation of a compound of formula (I) which process comprises treating a compound of formula (II):

(ID in which R , R^, R , and R^D are as hereinbefore defined,

R3 is a readily removable carboxy protecting group, X is oxygen or a group PR^R5R6

R , R5 and R^ which may be the same or different and is each an optionally substituted (Cι.g)alkyl or an optionally substifuted aryl group, preferably an n-butyl or a phenyl group; under carbapenem ring forming conditions; and thereafter, and if necessary, carrying out any or all of the following steps: removing any protecting group(s); converting a first group R^ comprising a hydroxyl substituent into a further group R* comprising an amino or fluoro group; and/or converting the product into a salt. Suitable carbapenem ring forming conditions are well known in the art.

When X is oxygen, suitable ring forming conditions include treating the compound of formula (II) with a trivalent organic phosphorus compound of formula

(III):

PR7(0R⁸)(0R⁹) (III)

in which:

R is (Cι_4)alkyl, (Cι_3)alkoxy or phenyl optionally substitued by (Cι_3)alkyl; and

R8 and R⁹ which may be the same or different is each (Cι_4)alkyl, allyl, benzyl or phenyl optionally substitued by (C]_3)alkyl or (Cj.3)alkoxy; by analogy with the process described in EP 0476649-A (Hoechst AG). Suitable reagents of formula (III) include trimethyl phosphite, triethyl phosphite, dimethyl methylphosphonite and diethyl methylphosphonite. Suitably, the reaction is effected in an organic solvent such as tetrahydrofuran, ethyl acetate, an aromatic solvent such as benzene, toluene, xylene or mesitylene or a halogenated hydrocarbon solvent such as dichloromethane, trichloromethane or 1,1,2-trichloroethane, and at a temperature between 50 and 180° C, preferably between 70 and 165°C.

When X is a group PR4R5R6₍ compounds of formula (I) may be obtained by the well known Wittig cyclisation route to carbapenems (Guthikonda et al, J. Med. Chem., 1987, 30, 871). For instance, when R^, R5 and R^ is each phenyl, the process comprises the ring closing with elimination of the elements of triphenylphosphine oxide. The ring closure may be suitably effected by heating the compound of formula (II, X = PR⁴R⁵R⁶) at a temperature which is preferably in the range 80 to 140°C, more preferably 90 to 120°C, in an inert solvent such as toluene or xylene, preferably under dry conditions and under an inert atmosphere and optionally in the presence of a radical scavanger such as hydroquinone. When R⁴, R and R > is each w-butyl, cyclisation may be effected at a lower temperature, for instance 50°C - 80°C, by analogy with the process described in WO 92/01695 (Beecham Group, for analogous penems).

In the substituent R , a hydroxyl or an amino group, if present, may optionally be protected. Suitable hydroxy protecting groups include organosilyl, for instance a trialkylsilyl group such as trimethylsilyl or t-butyl dimethylsilyl, or trichloroethyloxycarbonyl, 4-nitrobenzyloxy-carbonyl, 4-methoxybenzyloxy carbonyl and allyloxycarbonyl. Suitable amino protecting groups include alloxycarbonyl, 4-methoxybenzyloxy carbonyl and 4-nitrobenzyloxycarbonyl.

Suitable values for the protecting group R^ include allyl, 4-methoxybenzyl and 4-nitrobenzyl. The conditions necessary for removing the protecting group will, of course, depend upon the precise nature of the protecting group. For instance, when of R is 4-methoxybenzyl, aluminium trichloride at -30 to -70°C may be used and when R is allyl (prop-2-en-l-yl), a combination of triphenylphosphine, sodium-2- ethylhexanoate in ethyl acetate/MDC and tetr^w-(triphenylphosphine)palladium (0) may be used and when R^ is p-nitrobenzyl, hydrogenation in the presence of palladium on carbon catalyst in aqueous solvent eg, aqueous l,4,dioxan THF ethanol may be used.

Compounds of formula (II) are novel compounds and useful as intermediates in the preparation of compounds of formula (I).

Accordingly, in a further aspect, the present invention provides a compound of formula (II), as hereinbefore defined. Compounds of formula (II) in which X is oxygen may be obtained by a process which comprises reacting a compound of formula (IV):

(IV) in which R^a,RD, R! and R^ are as hereinbefore defined, with a compound of formula (V):

ClCOCO₂R³ (V)

in which R³ is a readily removable carboxy protecting group; under acylating conditions, by analogy with the process described in Tetrahedron Letters, 25, 1984, 2395.

Compounds of formula (IV) are novel compounds and useful as intermediates in the preparation of compounds of formula (II). Accordingly, in a further aspect, the present invention provides a compound of formula (IV), as hereinbefore defined.

Compounds of formula (II) in which X is a group PR⁴R5R6 _mav ^ obtained from a compound of formula (IV) as hereinbefore defined by the following sequence of steps: (a) reacting with a suitably protected glyoxylic acid derivative of formula (VI) or a functional equivalent thereof such as the hydrate;

OHC CO₂R³ (VI)

in which R³ is a readily removable carboxy protecting group; or a functional equivalent thereof; under dehydrating conditions, for instance azeotropic removal of water;

(b) treating the intermediate formed in step (a) with a halogenating agent, for instance thionyl chloride, in the presence of a suitable base such as 2,6-lutidine; and (c) treating the intermediate formed in step (b) with a phosphorus reagent of the formula (VII):

PR⁴R⁵R⁶ (VII)

in which R⁴, R^ and R^ are as hereinbefore defined, in the presence of a suitable base such as 2,6-lutidine.

Compounds of formula (IV) may be prepared by treating a compound of formula (VIII):

(VIII) in which R^a, R^b and R² are hereinbefore defined; with a compound of formula (IX)

(IX) in which R s as hereinbefore defined; R! * is an acyl group, for instance acetyl; in the presence of a base, such as, for instance, lithium hexamethyldisilazide (LHMDS); according to the procedures described in Tetrahedron Lett., 1987, 28, 507, Can. J. Chem, 1988, 66, 1537

Compounds of formula (IV) may also be prepared by treating a compound of formula (Villa) :

₅α

(Villa)

in which R^a, R^D and R² are as hereinbefore defined and SiR3^⁴ is a trialkylsilyl such as trimethylsilyl or t-butyldimethylsilyl, with a compound of formula (IXa):

(IXa) in which R^ and R^ are as hereinbefore defined and

R ³ is either hydrogen or an aminoprotecting group, for instance, a trialkylsilyl group such as trimethylsilyl; in the presence of a Lewis acid, such as, for instance, zinc chloride or trimethylsilyl trifluoromethane sulphonate, in an inert organic solvent such a halogenated hydrocarbon solvent, for instance dichloromethane at ambient temperature:

Compounds of formula (Villa) may be prepared by treating compounds of formula (VIII) with trialkylsilyl chloride or trialkylsilyl triflate, and triethylamine in

MDC. If the aminoprotecting group R*³ in (IXa) requires subsequent removal, this may be achieved by conventional means, such as mild acid treatment eg, methanol and hydrochloric acid or pyridinium p-toluenesulphonate, where R*³ is trimethylsilyl.

Compounds of formula (VIII) are well known to those skilled in the art and may be obtained by standard synthetic methodology from the corresponding aldehyde described in WO 95/11905.

Compounds of formula (IX) are well known to those skilled in the an and may be obtained by standard synthetic procedures such as described in, for example, Het., 1982, 17, 201 (IX, R¹ is 1-hydroxyethyl) and EP 0 234 484 (IX, R¹ is 1-fluoroethyl). Compounds of formula (I) in which Rl is an amino-substituted alkyl or cycloalkyl may be conveniently prepared from a corresponding compound of formula (I) in which R^ includes a hydroxy group by a Mitsunobu-type azide displacement of the hydroxy group thereof, followed by catalytic reduction, according to the procedure described in J Chem Soc, Perkin I, 1982, 3011. Compounds of formula (I) may also be prepared by a process which comprises reacting a compound of formula (X):

(X)

in which R* and R² are as hereinbefore defined, R³ is a readily removable carboxy protecting group and X* is a leaving group, with a compound of formula (XI):

(XI) in which M is a metallo group and R^a and R^b is as hereinbefore defined; in a cross-coupling reaction in the presence of a cross-coupling reaction catalyst selected according to the identity of M and thereafter and if necessary removing any protecting group and/or converting the product into a salt. The hydroxy or amino group in substituent R * , may be optionally protected.

Suitable hydroxy protecting groups include organosilyl, for instance a trialkylsilyl, group such as trimethylsilyl; 4-nitrobenzyloxycarbonyl and 4-methoxybenzyloxy carbonyl. Suitable amino protecting groups include 4-methoxybenzyloxy carbonyl and 4-nitrobenzyloxycarbonyl.

Suitable values for the protecting group R³ include 4-methoxybenzyl and 4-nitrobenzyl. Examples of suitable leaving groups X * include for instance trifluoromethanesulphonyloxy, methanesulphonyloxy, 4-toluene sulphonyloxy, fluorosulphonyloxy, chloro, bromo, iodo and diphenoxyphosphoryloxy.

Suitable metals for use in the metallo group M are well known in the art and include tin, aluminium, zinc, boron, mercury and zirconium. Preferred examples of the metallo group M include for instance

R¹⁴R¹⁵R¹⁶Sn, B(OR)₂ and Cl Zn in which R¹⁴, R*5 and R¹⁶ which may the same or different are each (Cj.g) alkyl. Preferably, the metallo group M is an organostannane R14R15R16SΠ, and R₁₄=R₁₅=R₁₆= methyl or n-butyl.

Suitable cross-coupling catalysts are well known in the art and include palladium compounds, in particular palladium (0) and palladium (II) compounds, such as those described in "Palladium Reagents in Organic Synthesis", RF Heck, Academic Press Ltd, 1985. Examples thereof include trø(dibenzylideneacetone)dipalladium (0), tetrα£w(triphenylphosphine)palladium (0), trans dimethyl bw(triphenylphosphine)palladium (II), and palladium (II) acetate, benzyl bw(triphenylphosphine)palladium (II) chloride, b/.s(triphenylphosphine)palladium (II) dichloride. Such palladium reagents are preferably used in combination with a halide source such as zinc chloride or lithum chloride and optionally in the presence of a phosphine ligand of palladium, for instance a compound such as a triarylphosphine, for example, rrw(4-methoxyphenyl)phosphine or trw(2,4,6-trimethoxyphenyl) phosphine; a tri-heteroarylphosphine, for example, trifurylphosphine, or a triarylarsine, for example triphenylarsine.

When M is an organostannane R^⁴ R^ R^ Sn-, a prefened catalyst system is trw(dibenzylideneacetone)dipalladium (0), in the presence of zinc chloride and a phosphine compound. When M is ClZn, a preferred catalyst is t (dibenzylideneacetone dipalladium (0), in the presence of a phosphine compound.

Suitably the reaction is effected in an inen aprotic polar coordinating solvent such as tetrahydrofuran, diethylether, dioxane, 2-dimethoxyethane, acetonitrile, dimethyl formamide, dimethyl sulphoxide and the like, and under a dry, inert atmosphere such as argon. Suitably, the reaction is effected initially at a low temperature, for instance about -78°C, with the final phase of the reaction then being effected at ambient temperature.

Analogous procedures in which M is organostannane are described in EP 0444 889 (Merck & Co.) and EP 0430037 (Banyu Pharmaceutical Co.). Compounds of formula (X) are well known in the art and may be obtained according to the procedures described in EP 0444 889 (Merck & Co.), EP 0 430037 (Banyu Pharmaceutical Co.) and by Rano et al, Tet. Letters, 1990, 31, 2853.

The following examples illustrate the invention but are not intended to limit the scope in any way.

General Instructions - Solutions were dried using anhydrous magnesium sulphate and solvents were removed by evaporation under reduced pressure using a rotary evaporator. Column chromatography on silica gel used Merck silica gel 60, particle size <0.063mm.

Preparation 1

(3S.4R)-3-rf/?Vl-t-Butyldimethylsilyloxyethvn-4-l(^'2.3-dihydroimidazor2.1-blthiazol- 6-ylcarbonyl methyl]azetidin-2-one

O

6-Acetylimidazo[2,l-b]thiazoline (0.504g; 3mM) was dissolved in dry THF (50ml) and cooled to -78°C under an atmosphere of argon. A solution of lithium hexamethyldisilazide (IM solution in hexane; 3.0ml; 3.0mM) was added and stirring was continued at -78°C for 30min. A solution of 4-acetoxy-3-[(/?)-l-t- butyldimethylsilyloxyethyl]azetidin-2-one (0.43 lg; 1.5mM) in dry THF (5ml) was added and stirring was continued at -78°C for 2h. Saturated ammonium chloride solution was then added followed by ethyl acetate. After warming to room temperature the organic layer was washed with water, brine, dried (MgSU4) and evaporated at reduced pressure. The residual oil was chromatographed over silica gel (20g), eluting with a gradient of 0 to 5% ethanol/dichloromethane to yield the title compound as a white foam (0.199g); v^ (MDC) 3420, 1762, 1670cm^{" 1}; δ_H (CDC1 ) 0.10 (6H, s), 0.88 (9H, s), 1.20 (3H, d, J 6.14Hz), 2.89 (1H, dd, J 2.4, 4.9Hz), 3.10 (1H, dd, 7 10.0, 17.4Hz) and 3.47 (1H, dd, 73.25, 17.4Hz) (ABX), 3.86 (2H, t), 4.10 (1H, dt), 4.12-4.30 (3H, m), 6.18 (1H, s), 7.69 (1H, s); m/e 338.0993 (Ci4H₂øN3θ3SSi requires 338.0995).

Preparation 2

AIM f (3S.4R)-3-r(r? l-t-butyldimethylsilyloxyethyll-4-l(2.3-dihvdroimidazor2.1- blthiazol-6-ylcarbonyl)methyl1-2-oxoazetidin- 1 -yl 1 triphenylphosphoranylideneacetate

(3S,4R)-3-[(R)-l-t-butyldimethylsilyloxyethyl]-4-[(2,3-dihydroimidazo[2,l-b]thiazol-6- ylcarbonyl)methyl]azetidin-2-one (0.366g; 0.927mM) and allyl glyoxylate monohydrate (0.172g; 1.30mM) were dissolved in toluene (50ml) and heated to reflux, with the provision for the removal of water, for 16 hours. After cooling, the solvent was evaporated and the residue was chromatographed over silica gel. Elution with a gradient of 50 to 100% ethyl acetate-hexane gave the diastercoisomeric mixture of hemiaminals as a white foam ; v_max (CH₂C1₂) 3500 (broad), 1765, 1670cm^{- 1}.

The diastercoisomeric mixture of hemiaminals was dissolved in dry THF (25ml) and cooled to -20°C under an atmosphere of argon. To the stined solution was added 2,6- lutidine (0.163ml), followed by thionyl chloride (0.151ml). Stirring was continued at - 20°C for 15min. The resulting suspension was then filtered, washing the precipitate with THF. The filtrate was evaporated to yield the diastereoisomeric chlorides as a pale yellow oil, v^^ (CH₂C1₂) 1760, 1680cm^" 1. The above product was dissolved in dry NN-dimethylformamide and stined at room temperature for 2 hours with 2,6-lutidine (0.119ml), triphenylphosphine (0.97 lg) and sodium iodide (0.278g). The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) ^ancl evaporated at reduced pressure. The residue was chromatographed over silica gel (50g), eluting with a gradient of 25 to 100% ethyl acetate-hexane. The title phosphorane was obtained as a colourless gum (0.20g), v,^ (CH₂C1₂) 1740, 1680, 1618cm-¹; m/e (thioglycerol FAB) 754 (MH+).

Preparation 3

Allyl (5R.6SV6-r(/?Vl-t-Butyldimethylsilyloxyethvn-2-r(^'2.3-dihvdroimidazol2.1- blthiazol-6-yl)carbapen-2-em-3-carboxylate

The phosphorane from Preparation 2 (0.20g) was dissolved in dry toluene (25ml) and heated at 100°C for 6 hours under an atmosphere of argon. After cooling, the solvent was evaporated and the product chromatographed over silica gel (lOg). Elution with a gradient of 25 to 100% ethyl acetate-hexane gave the title compound as a pale yellow oil (0.084g), Vmax (CH₂C1₂) 1775, 1710, 1595cm^{" 1}; δ_H (CDC1₃) 0.1 1 (6H, s), 0.89 (9H, s), 1.29 (3H, d, J 6.2Hz), 3.01 (1H, dd, J 2.6, 6.9Hz), 3.26 (1H, dd, J 9.0, 18.8Hz) and 3.69 (1H, dd, J 9.9, 18.8Hz) (ABX), 3.82 (2H, t), 4.1-4.3 (4H, m), 4.6- 4.9 (2H, m), 5.2-5.5 (1H, m), 5.9-6.1 (1H, m), 8.42 (1H, s); m/e 475.1968 (C₂ H33N₃O₄SSi requires: 475.1961). Preparation 4

AUyl (5R.6SV2-f2.3-Dihvdroimidazor2.1-blthiazol-6-ylV6-rf/?Vl- hydroxyethyncarbapen-2-em-3-carboxylate

The t-butyldimethylsilyl ether from Preparation 3 (0.082g) was dissolved in dry THF (10ml) and stirred at room temperature for 64 hours with acetic acid (0.104g) and tetra-n-butyl ammonium fluoride (0.518ml of a IM solution in THF). The reaction solution was then diluted with ethyl acetate and washed with sat. sodium hydrogen carbonate solution and brine. The organic layer was dried (MgSO4) and evaporated at reduced pressure. The residue was chromatographed over silica gel, eluting with a gradient of 25 to 100% ethyl acetate-hexane, to yield the title compound as a pale yellow solid (0.018g), \_mzx (CHC1₂) 3600, 1775, 1710, 1595cm"¹; λ_max (EtOH) 349nm; δ_H (CDC1₃) 1.38 (3H, d, J 6.3Hz), 3.19 (1H, dd, / 2.7, 6.8Hz), 3.29 (1H, dd, J 9.0, 18.8Hz), 3.7 (1H, dd, J 9.8, 18.8Hz), 3.83 (2H, t), 4.1-4.3 (4H, m), 4.65-4.9 (2H, m), 5.25-5.50 (2H, m), 5.9-6.18 (1H, m), 8.42 (1H, s); m/e 361.1098 (Ci7H₁₉N3O₄S requires: 361.1096).

Example 1

Sodium f5/?.6SV2-(2.3-Dihvdroimidazor2.1-blthiazol-6-ylV6-r(RVl- hydroxyethyllcarbapen-2-em-3-carboxylate

A solution of the allyl ester from Preparation 4 (0.017g; 0.047mM), triphenylphosphine (0.0013g, sodium 2-ethylhexanoate (0.0942ml of a 0.5M solution in ethyl acetate) and tetrakis(triphenylphosphine)palladium (0) (0.0019g) in dichloromethane-ethyl acetate (1:1, 3ml) was stined at room temperature under an atmosphere of argon for 1.5 hours, during which time a white precipitate formed. The reaction suspension was then evaporated to low volume at reduced pressure and room temperature, and triturated with diethyl ether. The precipitate was collected by centrifuging and decanting off the solvent. After drying in vacuo the solid was dissovled in water and chromatographed over HP20SS. Elution with a gradient of 0 to 5% ethanol-water provided the title compound as a white fluffy solid after lyophilisation (O.Ollg); λ^^ (H₂O) 321.5nm (ε 5515); v^ (KBr) 3414 (broad), 1745, 1604cm"¹; δ_H (D₂O) 1.37 (3H, d, J 6.4Hz), 3.27 (IH, dd, / 8.6, 17.3Hz), 3.35 (IH, dd, J 9.8, 17.4 Hz), 3.49 (IH, dd, J 2.8, 6.2Hz), 3.96 (2H, t), 4.22-4.35 (4H, m), 7.86 (IH, s).

Example 2

Sodium (5R. βS) 2-ri.2-Dimethvlimidazol-4-vl1-6 f/?Vl-hvdroxyethyl1- carbapen-2- em-3-carboxylate

Preparation 1

(3S. 4/?V3-r(/?Vl-t-Butyldimethylsilyloxyethyll-4-rπ.2-dimethylimidazol- 4- ylcarbonyl^')methyllazetidin-2-one

4-Acetoxy-3-[(R)-l-t-butyldimethylsilyloxyethyl]azetidin-2-one was reacted with 4- acetyl-l,2-dimethylimidazole by the procedure of Example 1, Preparation 1 to yield the title compound as a gum (43% yield); u_max (CH₂C1₂) 3410, 1761, 1669, 1548cm"¹; m/z (NH₃ DCI) 366 (MH+).

Preparation 2

Allylf r3S. 4/?V3-r(RVl-t-Bntyldimethylsilyloxyethyll-4-rπ .2-dimethyl- imidazol-4- ylcarbonyDmethyll-2-oxoazetidin-l -yπtriphenylphosphoranyl- ideneacetate

The product from Preparation 1 was elaborated to the title compound by the procedure described in Example 1., Preparation 2 (49% yield); u_max (CH₂C1₂) 1734, 1673, 1610 and 1546cm^{" 1} Preparation 3

Allylff3S. 4RV3-rfRVl-hvdroxyethyll-4-rπ.2-dimethylimidazol-4-yl- carbonvDmethyπ-2-oxoazetidin- 1 -yl 1 triphenylphosphoranylideneacetate

The product from Preparation 2 (0.400gm) was dissolved in methanol (5ml) - water (3ml) and stirred at 5°C for lhr with 5M hydrochloric acid solution (1.6ml). The reaction solution was partitioned between ethyl acetate and sat. NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4) and evaporated, to yield the title compound as a white foam in quantitative yield (0.340g); u_max (CH₂C1₂) 3436, 1741, 1654, 1613 and 1550cm"¹.

Preparation

Allylf f3S. 4/?V3-rr/?Vl-trimethylsilyloxyethyll-4-rfl .2-dimethylimidazol-4- ylcarbonyl')methvn-2-oxoazetidin-l-ylltriphenylphosphoranylideneacetate

The product from Preparation 3 (0.400g) was dissolved in dichloro- methane (20ml) and stirred at 5°C for lhr with trimethylsilyl chloride (166μl) and triethylamine (183 μl). The reaction solution was then diluted with ethyl acetate and washed with sat. NaHCC>3 solution, brine, dried (MgSO4) and evaporated. The crude product was purified by silica gel column chromatography, eluting with acetone-toluene mixtures to yield the title compound in 90% yield (0.380g) as a pale yellow foam, u_max (CH₂C1₂) 1735, 1673, 1610, 1546cm^{" 1}.

Preparation 5

Allyl (5R. 6SV2-f1.2-dimethylimidazol-4-vn-6-rf/?Vl-hvdroxyethvll carbapen-2-em- 3-carboxylate

The product from Preparation 4 (0.380g) and quinol (0.005g) were dissolved in toluene (50ml) and heated to 110°C under argon for 9h. After cooling, the solvent was evaparated and the crude product was chromato- graphed over silica gel, eluting with a gradient of 0 to 50% acetone-toluene. The resulting trimethylsilylether was dissolved in THF (15ml)-H₂O (5ml) and stirred at room temperature for 15 min with IM hydrochloric acid (1ml). The reaction solution was then partitioned between ethyl acetate and sat. NaHCO3 solution. The organic solution was washed with brine, dried (MgSO4) and evaporated. The crude product was chormatographed over silica gel eluting with 0 to 75% acetone-toluene to yield the title compound as a white solid (71%); v_max (CH₂C1₂) 3606, 1771, 1708, 1591cm^{" 1}; mlz 331.1531 (Cι₇H₂1N3O4 requires 331.1532).

Ex mple 2

Sodium <5R. 6S 2-π.2- imethvlimidazol-4-vn-6-rfRVl-hvdroxvethyn carbapen-2-em-3-carboxvlate

The product from Preparation 5 was convened to the title compound by the procedure of Example 1. The white fluffy solid obtained after HP 20SS column chromatography was re-chromatographed over Biogel P-2, eluting with water, followed by further chromatography over HP 20SS eluting with a gradient of 0 to 10% ethanol-water. The pure product was obtained as a white fluffy solid, v_max (KBr), 3415 (broad), 1750, 1602 (shoulder) 1558cm"¹; λ_max (H₂O) 31 lnm (e_m 15,585).

Example 3

Preparation 1

(35. 4RV3-rfR)-l-r-Butyldimethylsiloxyethyl1-4-r(5.6.7.8-tetrahvdroimidazori.2- alpyridin-2-ylcarbonyl)methyllazetidin-2-one

2-Acetyl-5,6,7,8-tetrahydroimidazo[l-2-a]pyridine (2.61g, 15.95mmol) was dissolved in dry THF (260ml) and cooled to -78°C whilst under an atmosphere of argon. A solution of lithium hexamethyldisilazide (IM in hexane; 15.95ml; 15.95mmol) was added and the reaction stirred at -78°C for 0.3h. A solution of 4-acetoxy-3-[(R)-l-t- butyldimethylsiloxyethyl]azeιidin-2-one (2.29g, δ.OOm ol) was added and the reaction stirred at -78°C for lh. The crude material was isolated according to the methods described in Example 1, Preparation 1. Attempted purification by chromatography on silica gel gave an inseparation mixture of the title compound and the starting ketone (1.88g) (ca. 2:1 ketone:title compound). Preparation 2

Allyl ((3S. 4RV3-rf/?)-l-t-B_Utvldimethvlsiloxvethvn-4-rr5.ή.7.8- tetrahvdroimidazori.2-a1pvridin-2-vlcarbonvnmethvn-2-oxoazetidin-l- vl 1 triphenvlphosphoran vlideneacetate

The mixture from Preparation 1 (1.88g) and allyl glyoxylate monohydrate (0.61g, 4.6mmol) in benzene (45ml) were reacted in the manner described in Example 1, Preparation 3. Purification was accomplished by chromatography on silica gel loading and eluting with 10% acetone in toluene. The product, a mixture of hemiaminals, was isolated as a white foam (0.75g); υ_max (CH₂C1₂) 3446, 2959, 1661, and 1546cm^"1.

The diastereomeric mixture of hemiaminals (l.lg, 2.1mmol) was dissolved in dry THF (18ml) and treated with 2,6-lutidine (0.37ml, 3.2mmol) followed by thionyl chloride (0.23ml, 3.2mmol) whilst at -20°C. The reaction and purification were carried out as in Example 1, Preparation 2 to give a diastereomeric mixture of chlorides as a yellow oil (1.12g); υ_max (CH₂C1₂) 2958, 1769, 1670, 1544, and 1376cm"-

The above product was dissolved in dioxan (5ml) and treated with triphenylphosphine (2.25g, 8.6mmol) and 2,6-lutidine (0.27ml, 2.4mmol) in the manner described in Example 1, Preparation 2. The title compound was isolated as a clear oil (0.36g) which was used immediately in the next reaction.

Preparation 3

Allyl (5R. 6SV6-r(RVl-t-Bntyldimethylsiloxyethyll-2-(5.6.7.8- tetrahvdroimidazori.2-a1pyridin-2-yl1carbapen-2-em-3-carboxylate

The phosphorane from Preparation 3 (0.36g) was dissilved in toluene (10ml) and the reaction warmed to reflux for 5.5h. After cooling and removal of solvent the crude material was purified by chromatography on silica gel, loading and eluting with 20% acetone in toluene.The title compound was isolated as a yellow gum (0.15g); υ_max (CH₂C1₂) 1771 and 1712cm"¹; MS (El) m/z 471 (M+), NH3DCI) m/z 472 (MH+). Preparation 4

Allyl (5R. 6SV2-(5.6.7.8-Tetrahvdrimidazoπ.2-alpyridin-2-vn-6-rf/? 1- hvdroxvethvllcarbapen-2-em-3-carboxvlate

The t-butyldimethylsilyl ether from Preparation 3 (0.15g) was dissolved in THF (22ml) and treated with acetic acid (0.19mg) and tetra-n-butylammonium fluoride (0.95ml of a l.OM solution in THF). The mixture was purified in the same manner as Example 1, Preparation 4, to give the title compound as a yellow oil (0.036g); υ_max (CH₂C1₂) 2960, 1765, 1732, 1672 and 1588cm^{" 1}; MS (El) m/z 357 (M+), (NH3DCI) m/z 358 (MH+).

Example 3

Sodium (5R. 6SV2-(5.6.7.8-Tetrahvdroimidazor 1.2-alpyridin-2-vn-6-r(r?)- 1 - hvdroxyethyllcarbapen-2-ern-3-carboxylate

A solution of allyl ester from Preparation 4 (35mg), triphenyl- phosphine (2.6mg), sodium ethylhexanoate (0.2ml of 0.5M solution in ethyl acetate) and tetrakis(triphenylphosphine)palladium (0) (3.8mg) were reacted in the manner described in Example 1. The title compound was isolated as a solid after freeze drying (3mg); l_max (H₂O) 31 lnm; d_H (400mHz) (D₂O) 1.36 (3H, d, J 6.4Hz), 2.02- 2.14 (4H, m), 2.99-3.02 (2H, m), 3.31 and 3.33 (2H, s + s), 3.50 (IH, dd, J 6.1, 2.7Hz), 4.12-6.65 (2H, m), 4.27-4.32 (2H, m), 7.51 (IH, s).

Example 4

Sodium (5 ?.65)-6-[( ?)-l-hydroxyethyll-2-(2-methanesulfonyl-l-methylimidazol-4- yl)carbapen-2-em-3-carboxylate

Preparation 1

Ethyl 2-methylthioimidazole-4-carboxylate

Ethyl imidazole-2-thiol-4-carboxylate (30 g, 174.2 mM) was dissolved in DMF (100 ml) and iodomethane (11.93 ml, 27.2 g, 191.6 mM) was added. Triethylamine (26.7 ml, 19.4 g, 191.6 mM) was then added dropwise over 15 min. After stirring for 1 hour, the DMF was removed in vacuo and the residue diluted with EtOAc. The solid was removed by filtration and the filtrate evaporated to an oil, which solidified on standing to give crude ethyl 2-methylthioimidazole-4-carboxylate, suitable for further use.

Preparation 2

Ethyl 1 -methyl-2-methylthioimidazole-4-carboxylate

Crude ethyl 2-methylthioimidazole-4-carboxylate (174.2 mM theoretical) from Preparation 1 was dissolved in dry THF (500 ml) and the solution stirred and cooled in an ice bath. Sodium hydride (60% oil dispersion) (8.34 g, 208.5 mM) was added portionwise over 40 minutes. Methyl iodide (9.72 ml, 22.2 g, 156 mM) was then added. After 2 hours, sodium hydride (0.83 g, 20.9 mM) and methyl iodide (0.97 ml, 2.2 g, 15.6 mM) were added. After a further 1 hour, the mixture was evaporated to dryness and the residue taken up in EtOAc. A white solid was removed by filtration and the filtrate washed 3 times with water and once with brine, dried (MgSO4) and evaporated in vacua. The residue was chromatographed over silica gel using 5% CH₂C1₂ in EtOAc as eluent to give ethyl l-methyl-2-methylthioimidazole-4- carboxylate (9.5 g); δ _H (CDC1₃) 1.36 (3H, t,), 2.67 (3H, s), 3.60 (3H, s), 4.35 (2H, q,) and 7.57 (IH, s).

Preparation 3

Sodium 1 -methyl-2-methylthioimidazole-4-carboxylate

Ethyl l-methyl-2-methylthioimidazole-4-carboxylate (7.0 g, 35 mM) was dissolved in EtOH (400 ml) and aqueous 2M NaOH (18.4 ml, 36.7 mM) was added. The mixture was heated to reflux for 2.5 h. The solvent was then removed by evaporation in vacua to give a white solid which was dried overnight at 40°C / 1 mmHg to give crude sodium l-methyl-2-methylthioimidazole-4-carboxylate suitable for further use.

Preparation 4

N- Methoxy- 1.N-dimethyl-2-methylthioimidazole-4-carboxamide

Crude sodium 1 -methyl- 2-methylthioimidazole-4-carboxylate (35 mM theoretical) from Preparation 3 was suspended in dry CH₂C1 (250 ml) and DMF (10 drops) was added. Oxalyl chloride (9.15 ml, 13.3 g, 105 M) was added and the heterogeneous mixture stirred for 3.5 h . Evaporation in vacuo gave a solid residue which was re- suspended in dry CH C1 and again evaporated. The resulting solid was suspended in CHCI3 (300 ml) and N,O-dimethylhydroxylamine hydrochloride (6.8 g, 70 mM) was added. The stirred mixture was cooled in an ice bath and E13N (19.5 ml, 14.2 g, 140 mM) was added dropwise over 10 min. The cooling bath was removed and stirring continued for 1. The mixture was evaporated in vacuo and the residue taken up in EtOAc. Saturated aqueous NaHCO3 was then added. The aqueous phase was separated, adjusted to pH9 by addition of 2M aqueous NaOH and extracted 4 times with EtOAc. The extracts were combined with the original organic solution, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed over silica gel, eluting with EtOAc, to give N-methoxy-l,N-dimethyl-2-methylthioimidazole-4- carboxamide (5.4 g) as a white solid; v_max (KBr) 1628 and 1597 cm"¹; δ H (CDCL3) 2.66 (3H, s), 3.43 (3H, s), 3.59 (3H, s), 3.77 (3H, s), 7.54 (IH, s); m/e 215.0734 (C8H₁₃N₃O S requires 215.0729).

Preparation 5

4- Acety 1- 1 -methyl-2-methylthioimidazole

N-Methoxy-l,N-dimethyl-2-methylthioimidazole-4-carboxamide (5.6 g, 26 mM) was dissolved in dry THF (90 ml) and the solution cooled in an ice bath under an atmosphere of argon. A solution of MeMgBr (3M in Et O) (10.4 ml, 31.2 mM) was added over 10 min. The cooling bath was then removed and the mixture stirred for 1.75 h. A mixture of EtOH (14 ml) and 5M hydrochloric acid (2.6 ml) was added and stirring continued for 30 min. The solvents were then removed by evaporation in vacuo and the residue partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous phase was separated, adjusted to pH9 with 2M aqueous NaOH and extracted twice with EtOAc. The combined organic solution was dried (MgSO4) and evaporated in vacuo to give 4-acetyl-l-methyl-2-methylthioimidazole (4.2 g). v π^ (KBr) 1689 cm"¹; δ _H (CDCL3) 2.51 (3H, s), 2.59 (3H, s), 3.62 (3H, s), 7.56 (IH, s); m e 170.0514 (C₇H₁₀N₃O₂S requires 170.0514).

Preparation 6

(3S.4R)-3-\(R)- 1 -tgrt-butyldimethylsilyloxyethyll-4- f(l-methyl-2-methylthioimidazol-4-ylcarbonyl)methyll-2-oxoazetidine

4-Acetyl-l-methyl-4-methylthioimidazole (1.7 g, 10 mM) in dry THF (50 ml) and the resulting solution cooled to -70°C under an atmosphere of argon. Lithium hexamethyldisilazide (IM solution in hexane) (10 ml, 10 mM) was added and the resulting mixture stined for 30 min. A solution of 4-acetoxy-3-[(lR)-l-tert- butyldimethylsilyloxyethyl]-2-oxoazetidine (1.44 g, 5 mM) in dry THF (15 ml) was added and stirring continued for 30 min. Saturated aqueous NH4CI (10 ml) was then added, the cooling bath removed and the reaction mixture allowed to warm to ambient temperature. After partitioning between EtOAc and water the phases were separated and the organic phase washed with brine and dried (MgSO4). Following evaporation in vacuo, the gummy residue was chromatographed on silica gel eluting with EtOAc in hexane (30-100% EtOAc gradient), to give (3S,4R)-3-[(lR)-l-t - butyldimethylsilyloxyethyl]-4-

[(l-methyl-2-methylthioimidazol-4-ylcarbonyl)methyl]-2-oxoazetidine (0.811 g). v max (^KBr) ¹⁷⁵² and ¹⁶⁶⁹ cm^{" 1}; δ_H (CDCL3) 0.07 (6H, s), 0.86 (9H, s), 1.22 (3H, d), 2.64 (3H, s), 2.90 (IH, dd), 3.11 (IH, dd), 3.46 (IH, dd), 3.63 (3H, s), 4.08 (IH, dt), 4.20 (IH, m), 6.14 (IH, s), 7.59 (IH, s); m/e 397.1856 ( C₁₈H3iN₃O3SSi requires 397.1855

Preparation 7

(3S.4 ?)-3-r(R)-l-t-Butyldimethylsilyloxyl-4-r(2-methanesulphonyl-l-methylimidazol-

4-ylcarbonyl)methyn-2-oxoazetidine.

The product from Preparation 6 (0.998 g; 2.51 mM) in DCM (50 ml) was treated with 3-chloroperoxybenzoic acid (1.65 g; 55% pure) and the mixture heated at 40-50°C for 3h. More 3-chloroperoxybenzoic acid (0.82 g) was added and heating continued for a further lh. The reaction mixture was diluted with EtOAc (100 ml) and washed with sat'd.,aq. sodium bisulphite, sat'd. brine, dried (MgSO4) and evaporated to dryness under reduced pressure, Chromatography over silica gel, eluting with EtOAc, gave the title compound (0.941 g; 87 %) ; υ^^ (DCM) 1762cm^{" 1}; δjι (CDCL3) 0.07 (6H, s), 0.87 (9H, s), 1.22 (3H, d J 6Hz), 2.89-2.92 (IH, m), 3.11 and 3.18 (lH, dd /10 and 18Hz), 3.43 (3H, s), 3.46 and 3.53 (IH, dd 73 and 18Hz), 3.97-4.33 (5H, m), 6.25 (IH, br s, exchangeable), 7.68 (IH, s); m/e (ES/MS) 430 (MH+), 452 (MNa⁺).

Preparation 8.

Allyl (r?.SVrf3S.4/?V3rfRVl-t-hutyldimethylsilyloxyethvn-4-rr2-methanesulphonyl- 1 -methv1imidazol-4-ylcarbonvttmethvll-2-oxoazetiriin- 1 -vllhvdroxvacetate. The product from Preparation 7 (0.941 g; 2.19 mM) and allyl glyoxylate (0.579 g; 4.38 mM) were heated under reflux for 5h then evaporated to dryness under reduced pressure. The residue was purified by chromatography over silica gel, eluting with mixtures of EtOAc in hexane (50-100% EtOAc gradient), to give the title compound (0.8 g; 69 %) as a mixture of diastereoisomers; v_max(DCM) 1762 and 1683 cm^{" 1}; m/e (NH3 DCI) 544 (MH⁺), 561 (MNH₄+) Preparation 9.

Allyl r(35.4 ?1-3-rr/?Vt-hutyldimethylsilyloxyethyll-4-rr2-methanesulphonyl- methvlimidazol-4-vlcarhonvnmethvll-2-oxoazetidin- 1 - vntriphenvlphosphoranvlideneacetate.

The product from Preparation 8 (0.721 g; 1.37 mM) was dissolved in dry, redistilled THF (50 ml) under argon and the solution cooled to -20°C. 2,6-Lutidine (0.22 g; 2.05 mM) then thionyl chloride (0.244 g; 2.05 mM) were added and the mixture stirred at -20°C for lh. The insolubles were removed by filtration and the filtrate evaporated to dryness under reduced pressure. The residue was dissolved in DMF (15 ml) and the solution treated sequentially with 2,6-lutidine (0.22 g; 2.05 mM), triphenylphosphine (1.43 g; 5.47 mM) and sodium iodide (0.41 g; 2.73 mM). After lh, the reaction mixture was diluted with DCM and washed with water (5x), sat'd. brine, dried (MgSO4) and evaporated to dryness under reduced pressure.

Chromatography over silica gel, eluting with EtOAc in hexane (50-100% EtOAc gradient), gave the title compound (1.03 g; 96%); v_max 1737 and 1684 cm"¹; m/e (NH₃ DCI) 788 (MH+).

Preparation 10.

Allyl r(3S.4RV4-rf2-methanesulphonyl-l-methylimidazol-4-ylcarbonyl methyll-3- l(/?Vtrimethylsilyloxyethyll-2-oxoazetidin-l-ylltriphenylphosphoranylideneacetate. The product from Preparation 9 (l.Olg; 1.28mM) was dissolved in MeOH (20 ml) and treated at ambient temperatures with.2.5M.hydrochloric acid (20 ml; 50 mM). After 0.5h, sat'd, aq. sodium hydrogencarbonate was added to pH 8.0 and the mixture extracted with EtOAc. The extracts were combined, washed with water, sat'd. brine, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography over silica gel, eluting with EtOAc then 10% EtOH/EtOAc, gave the intermediate hydroxyethyl derivative as a white foam (0.854 g; 99%). This was dissolved in DCM (20 ml) and treated with triethylamine (0.384 g; 3.80 mM) then chlorotrimethylsilane (0,413 g; 3.80 mM) at ambient temperatures and the mixture stirred for lh. The reaction mixture was evaporated to dryness under reduced pressure and the residue purified by chromatography over silica gel, eluting with mixtures of EtOAc in hexane (50-100% EtOAc gradient), to give the title compound (0.846g ; 90%); v_max (DCM) 1738 and 1684 cm"¹; m/e (NH₃ DCI) 746 (MH+). Preparation 11.

Allvl f5/?.6.yi-2-f2-methanesulphonvl-l-methvlimidazol-4-vn-6-rCgV1- tτimethvlsilvloxvethvllcarbape-2-em-3-carboxvlate. The product from Preparation 10 (0.84 g; 1.13 mM) was dissolved in toluene (50 ml) and the mixture heated under reflux for 4h. The solvent was removed under reduced pressure and the residue subjected to chromatography over silica gel. The product was obtained by elution with EtOAc (0.398 g; 75%); v_max (DCM) 1775 and 1711 cm^{" 1}; δ_H (CDC1₃) 0.15 (9H, s), 3.23 (3H, d 76Hz), 3.14-3.18 (IH, m), 3.19-3.30 and 3.61-3.72 (2H, 2m), 3.36 (3H, s), 4.00 (3H, s), 4.10-4.26 (2H, m), 4.68-4.89 (2H, m), 5.26-5.53 (2H, m), 5.92-6.07 (IH, m), 8.33 (IH, s); m/e (NH3 DCI) 468 (MH+).

Preparation 12.

Allyl f5R.6SV6-rfRVl-hvdroxyethyll-2-<^"2-methanesulphonyl-l-met ylimidazol-4- vncarbapenen-2-em-3-carboxvlate.

The product from Preparation 11 (0.395 g; 0.84 mM) was dissolved in THF (20 ml) and treated with 0.05M hydrochloric acid (10 ml; 0.50 ml). After 5 min, sat'd., aq. sodium hydrogencarbonate was added to pH 8.0 and the mixture extracted with EtOAc. The extracts were combined, washed with sat'd. brine, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography over silica gel, eluting with EtOAc, gave the product (0.282 g; 84%); v_max (DCM) 1775 and 1711 cm"¹; δ_H (CDCI3) 1.37 (3H, d J 6Hz), 1.83 (IH, d J 1.83, exchangeable),. 3.19-3.33 and 3.63-3.75 (3H, s), 4.00 (3H, s), 4.19-4.31 (2H, m), 4.68-4.90 (2H, m), 5.27-5.52 (2H, m), 5.93-6.08 (IH, m), 8.34 (IH, s); m/e 295.1159. C₁₇H₂₁N₃O₆S requires 295.1151.

Preparation 1 .

Sodium (5r?.6SV6-r(RVl -hvdroxyethyll-2-(2-methanesulphonyl-l-methylimidazol-4- vncarbapen-2-em-3-carboxvlate.

The product from Preparation 12 (0.147 g; 0.4 mM) was dissolved in dry, redistilled THF (10 ml) under argon and treated sequentially with triphenylphosphine (0.01 g), tetrakis(triphenylphosphine)palladium(0) (0.01 g) and a solution of sodium 2- ethylhexanoate in EtOAc (0.5M; 0.94 ml; 0.47 mM). After lh., the volatiles were removed under reduced pressure and the residue partitioned between EtOAc and water. The aqueous phase was washed with EtOAc and lyophilised. Chromatography over Diaion HP20SS resin, eluting with mixtures of THF in water (0-20% THF gradient), followed by concentration under reduced pressure then lyophilisation, gave the title compound (0.112 g; 80%); v_max (KBr) 1752 and 1614 cm"¹; δ_H (D₂O) 1/26 (3H, d J 6Hz), 3.25 and 3.64 (2H, 2m), 3.32 (3H, s), 3.93 (3H,s), 4.18-4.26 (2H,m), 7.81 (IH, s); m/e (ES/MS) 378 (MH+), 400 (MNa+).

Example 5

Preparation 1.

6.7-Dihvdro-5H-imidazor2.1-blf l.31thiazine-2-caboxvlic acid. Ethyl 6,7-dihydro-5H-imidazo[2,l-b][l,3]thiazine-2-carboxylate (8.45 g; 39.9 M) was dissolved in EtOΗ (150 ml) and treated with 2.5M, aq. sodium hydroxide solution (32 ml; 40 mM) and the mixture heated at 50°C for lh. The reactin mixture was concentrated to low volume under reduced pressure and the residue diluted with water (50 ml). The pΗ of the resulting solution was adjusted to 4.0 by addition of cone, hydrochloric acid. The volatiles were removed under reduced pressure and the residue extracted with hot MeOΗ (2 x 50 ml), the extracts combined, filtered hot and the filtrate evaporated to dryness under reduced pressure to give the title compound (7.33 g; 100%); δ_Η (CD3OD) 2.23-2.39 (2H, m), 3.27 (2H, t J 6Hz), 4.19 (2H, t J 6Hz), 7.72 (IH, s); m/e 184.0307. C₇H₈N₂O₂S requires 184.0307.

Preparation 2.

N.O-Dimethyl-6.7-dihydro-5H-imidazor2.1-blfl.31thiazine-2-hydroxamic acid. 6,7-Dihydro-5H-imidazo[2,l-b][l,3]thiazine-2-carboxylic acid (6.23 g; 33.86 mM) was suspended in dry DCM (250 ml) under argon and treated with oxalyl chloride (4 ml) then dry DMF (3 drops). The mixture was stirred vigorously at ambient temperatures for 1.5h. then evaporated to dryness under reduced pressure. The residue was suspended in dry DCM (250 ml) and treated with N.O- dimethylhydroxylamine hydrochloride (6.61 g; 135 mM) followed by triethylamine (13.69 g; 135 mM) and the resulting mixture stined at ambient temperatures for lh. The insolubles were removed by filtration and the filtrate eavaporated to dryness under reduced pressure to give a brown, gummy solid, which was dissolved in water. The pΗ was adjusted to 9 with 10% aq, NaOΗ and the volatiles removed under reduced pressure. Chromatography over silica gel, eluting with 2% MeOΗ/DCM gave the title compound (4.17 g; 54%), which was crystallised from TΗF, mp 164-165°C; v_max (DCM) 1639 cm"¹; δ_Η (CDCI3) 2.29-2.39 (2H, m), 3.15 (2H, J 6Hz), 3.43 (3H, s), 3.74 (3H, s), 4.09 (2H, t / 6Hz), 7.50 (IH, s); Found: C, 47.25; H, 5.67; N, 18.42; S, 13.89 %. CoHi3N3O₂S requires; C, 47.56; H, 5.77; N, 18.49; S, 14.11 %; m/e 227.0732. C9H₁₃N3O₂S requires 227.0729. Preparation 3.

2-Acetyl-6.7-dihvdro-5H-imidazor2.1-bin.31thiazine. N_i -Dimethyl-6,7-dihydro-5H-imidazo[2, 1-b] [ 1 ,3]thiazine-2-hydroxamic acid (4.17 g; 18.4 mM) in hot TΗF (500 ml) under argon was cooled to 0-5 °C and treated with MeMgBr (3.0M in Et O; 7.4 ml; 22.2 mM). Cooling was removed and the mixture stirred at ambinet temperatures for lh. More methyl magnesium bromide (3.7 ml; 11.1 mmol) was added and the mixture stirred for a further lh. at ambient temperatures then neutralised by additon of sat'd. aq. ammonium chloride. The volatiles were removed under reduced pressure and the residue extracted with hot MeOΗ, filtered hot and the filtrate adsorbed onto silica gel 60 and thoroughly dried under high vacuum. Chromatography, eluting with mixtures of MeOΗ in DCM (0-10% MeOΗ gradient) gave the title compound (2.64 g; 79 %). Recrystallisation from EtOAc-hexane gave a white, microcrystalline solid, mp 119°C; v_max (DCM) 1671 cm^{" 1}; δjj (CDCI3) 2.30- 2.40 (2Η, m), 2.48 (3H, s), 3.17 (2H,t / 6Hz), 4.10 (2H, t J 6Hz), 7.50 (IH, s); Found: C52.36; H, 5.51; N, 15.35; S, 17.46 %. C8H₁₀N₂OS requires: C, 52.73; H, 5.33; N, 15.37; S, 17.59 % ; m/e 182.0514. C₈H₁₀N₂OS requires 182.0514.

Preparation 4.

(3S.4/?V3-r(/?Vl-t-Butyldimethylsilyloxyethyll-4-rr6.7-dihvdro-5H-imidazor2.1- bl f 1.3]thiazin-2ylcarbonyl)methyll -2-oxoazetidine. 2-Acetyl-6,7-dihydro-5H-imidazo[2,l-b][l,3]thiazine (1.04 g; 5.6 mM) in dry, redistilled TΗF (100 ml) under argon was cooled to -70°C and treated dropwise with a solution of lithium hexamethyldisilazide in hexane (l.OM; 5.6 ml; 5.6 mM). The mixture was stirred at -70C for 20 min. then treated with a solution of 4-acetoxy-3- [(R)-l-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (0.816 g; 2.8 mM). After lh. at - 70°C, the mixture was neutralised by addition of sat'd., aq. ammonium chloride and the mixture filtered through Celite. The filter bed was washed with a little acetone and the filtrate evaporated to dryness under reduced pressure. This residue was dissolved in DCM, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography over silica gel, eluting with mixtures of EtOAc in DCM (25-100% EtOAc gradient), gave the title compound (0.69 g; 62%); Vπ^ (DCM) 1760 and 1671 cm"¹; δ_Η (CDCI3) 0.04 (6H, s), 0.84 (9H, s), 1.18 (3H, d J 8Hz), 2.30-2.41 (2H, m), 2.83-2.85 (IH, m), 3.03-3.47 (4H,m), 3.96-4.22 (4H, m), 6.35 (IH, br s, exchangeable), 7.60 (IH, s); m e (NH3 DCI) 410 (MNH₄+). Preparation 5.

Allyl fR.SVrf3S.4RV3-r(/?Vl-t-butyldimethylsilyloxyethvn-4-rf6.7-dihvdro-5H- imidazor2.1-b] 1.31thiazin-2-ylcarbonyl⁾methyll-2-oxoazetidin-l-ynhvdroxyacetate. The product from Preparation 4 (0.69 g; 1.76 mM) was dissolved in toluene (100 ml) and treated with allyl glyoxylate (0.464 g; 3.52 mM) and the mixture heated under reflux for 18h. The volatiles were removed under reduced pressure and the residue chromatographed over silica gel, eluting with mixtures of EtOAc in hexane (50-100 % EtOAc gradient), to give the product (0.777 g; 84 %); Vmax (DCM) 1759 cm"¹; m/e (NH₃ DCI) 524 (MH+).

Preparation 6.

Allvi rf3S.4RV3-f(/?Vl-t-butyldimethylsilyloxyethyll-4-rf6.7-dihvdro-5H-imidazor2.1- bl 1.31thiazin-2-ylcarbonyl)methyll-2-oxoazetidin-l- ylltriphenylphosphoranylideneacetate.

The product from Preparation 5 (0.735 g; 1.4 mM) was dissolved in dry, redistilled TΗF (50 ml) under argon and the solution cooled to -20°C. 2,6-Lutidine (0.226 g; 2.1 mM) was added followed by thionyl chloride (0.25 g; 2.1 mM). After 0.5h., the mixture was filtered and the filtrate evaporated to dryness under reduced pressure. The residue was dissolved in DMF (15 ml) and treated sequentially with 2,6-lutidine (0.226 g; 2.1 mM), triphenylphosphine (1.47 g; 5.6 mM) and sodium iodide (0.421 g;2.8 mM). After 1.5h., the reaction mixture was diluted with DCM and washed with water (5x), sat'd. brine, dried ( gSO4) and evaporated to dryness under reduced pressure. The reidue was purified by chromatography over silica gel, eluting with mixtures of EtOAc in hexane (50-100% EtOAc gradient), to give the title compound (0.73 g; 68%); v^ (DCM) 1736 and 1670 cm^{" 1}; m/e 767.2979. C4₂Η₅₀N₃θ5PSSi requires 767.2978.

Preparation 7.

Allvi r(3S.4R)-3-r(/?Vl-hvdroxyethvn-4-rf6.7-dihvdro-5H-imidazol2.1-bin.31thiazin- 2-ylcarbonyl)methylltriphenylphosphoranylideneacetate.

The product from Preparation 6 (0.61 g; 0.79 mM)was dissolved in MeOΗ (15 ml) and treated with 2.5M hydrochloric acid (12.5 ml; 31.25 mM). After 0.5h., the reaction mixture was neutralised by the addition of sat'd. aq. sodium hydrogen carbonate and extracted with EtOAc. The extracts were combined, washed with sat'd. brine, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography over silica gel, eluting with mixtures of EtOΗ in EtOAc (0-40% EtOH gradient), gave the title compound (0.501 g; 97%);v_max (DCM) 1741 and 1712 cm"¹.

Preparation 8.

Allyl f5R.6S 2-f6.7-dihvdro-5H-imidazor2.1-biπ.31thiazin-2-vn-6-rfR l- trimethylsilyloxyethyllcarbapen-2-em-3-carboxylate.

The product from Preparation 7 (0.481 g; 0.74 M) was dissolved in DCM (10 ml) under argon and treated with chlorotrimethylsilane (0.16 g; 1.48 mM) and triethylamine (0.149 g; 1.48 mM). After lh., the mixture was evaporated to dryness under reduced pressure and the residue partitioned between EtOAc and water. The phase were separated and the organic phase washed with sat'd. brine, dried (MgSO4) and evaporated to dryness under reduced pressure to give the trimethylsilyl-protected phosphorane (0.415 g; 78%). The trimethylsilyl-protected phosphorane (0.315 g; 0.43 mM) was dissolved in toluene (20 ml) and the mixture heated under reflux for 1.5h. before the volatiles were removed under reduced pressure. Chromatography over silica gel, eluting with 70% EtOAC in hexane, gave the title compound (0.176 g; 94%); v_max (DCM) 1771, 1709 and 1191 cm"¹; δ_Η (CDCI3) 0.13 (9H, s), 1.28 (3H, d 76Hz), 2.29-2.38 (2H, m), 3.10-3.29 and 3.63-3.75 (5H, 2m), 4.05-4.22(4H, m), 4.65-4.89 (2H, m), 5.23-5.52 (2H, m), 5.92-6.05 (IH, m), 8.28 (IH, s).

Preparation 9.

AUvπ5R.6SV2-f6.7-dihvdro-5H-imidazor2.1-biπ.31thiazin-2-vn-6-f(RVl- hydroxyethyπcarbapen-2-em-3-carboxylate.

The product from Preparation 8 (0.182 g; 0.42 mM) was dissolved in THF (10 ml) and treated with 0.05M hydrochloric acid (5 ml; 0.25 mM). The reaction mixture was stirred at ambient temperatures for 15 min. then neutralised by the addition of sat'd. aq. sodium hydrogen carbonate. The mixture was extracted with EtOAc, the extracts combined, washed with sat'd. brine, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography over silica gel, eluting with EtOAc, gave the title compound (0.15 g; 95%); v_max (DCM) 3464 and 1772 cm^{" 1}; δ_H (CDCI3) 1.35 (3H, d J 6Hz), 2.25-2.37 (2H, m), 3.13-3.30 and 3.61-3.72 (5H, m), 4.05-4.27 (4H, m), 4.64-4.87 (2H, m), 5.23-5.49 (2H, m), 55.91-6.06 (IH, m), 8.27 (IH, s); m e 375.1258. Ci8H₂₁N₃O₄S requires 375.1253. Preparation 10.

Sodium r5R.6SV2-(6.7-dihvdro-5H-imidazor2.1-hiπ .31thiazin-2-ylV6-rr/?Vl - hvdroxyethyllcarbapen-2-em-3-carboxvlate. The product from Preparation 9 (0.14 g; 0.4 mM) was dissolved in DCM (4 ml) and EtOAc (4 ml) under argon and treated sequentially with triphenylphosphine (0.01 g), tetrakis(triphenylphosphine)palladium(0) (0.01 g) and a solution of sodium 2- ethylhexanoate in EtOAc (0.5M; 0.94 ml; 0.47 mM). The mixture became cloudy immediately and was stirred at ambient temperatures for 1.5h. Et₂O was added and the crude product (0.129 g; 97%) collected by fitration, washed with Et₂O and dried under reduced pressure. The crude product was purified by chromatography over Diaion ΗP20SS resin, eluting with mixtures of THF in water (0-10% THF gradient). The appropriate fractions were combined, concentrated under reduced pressure and lyophilised to give the title compound (0.094 g; 71%); v_max (KBr) 1748 and 1608 cm"¹; δ_H (D₂O) 1.26 (3H,d J 6Hz), 2.23-2.25 (2H, ), 3.06-3.27 and 3.36-3.39 (5H, 2m), 4.00-4.04 (2H, m), 4.12-4.25 (2H, m), 7.67 (IH, s); m/e (ES/MS) 336 (MH+).

Claims

1. A compound of the general formula (I):

(I) in which:

R^a or R^D alone is hydrogen, optionally substituted (Cι_6)alkyl or together form a 5 or 6 membered heterocyclic ring which may contain at least one additional heteroatom selected from oxygen, nitrogen or sulphur;

R is (Cι_g)alkyl which is unsubstituted or substituted by fluoro, a hydroxy group which is optionally protected by a readily removable hydroxy protecting group, or by an amino group which is optionally protected by a readily removable amino protecting group; R2 is hydrogen or methyl and

-CO₂R³ is carboxy or a carboxylate anion or the group R³ is a readily removable carboxy protecting group.

2. A compound according to claim 1, for use as an active, therapeutic substance.

3. A compound according to claim 1 , for use in the treatment or prophylaxis of bacterial infections in animals or humans.

4. Use of a compound according to claim 1 in the manufacture of a medicament for use in the treatment or prophylaxis of bacterial infections in animals or humans.

5. A method of treating a bacterial infection in an animal or human which comprises administering to a patient in need thereof an antibacterially effective amount of a compound according to claim 1.

6. A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable carrier.

7. A process for the preparation of a compound of formula (I) as defined in claim

1, which process comprises treating a compound of formula (II):

(ID in which R , R², R^a, and R^D are as hereinbefore defined,

R³ is a readily removable carboxy protecting group,

X is oxygen or a group PR⁴R^R6,

R⁴, R5 and R^ which may be the same or different and is each an optionally substituted (Cχ.6)alkyl or an optionally substituted aryl group, preferably an n-butyl or a phenyl group; under carbapenem ring forming conditions; and thereafter, and if necessary, carrying out any or all of the following steps: removing any protecting group(s); converting a first group R¹ comprising a hydroxyl substituent into a further group R¹ comprising an amino or fluoro group; and/or converting the product into a salt.

8. A compound of formula (II) as defined in claim 7.

9. A compound of formula (la) :

(la) in which R^a, R^D, R¹ and R² are as defined in claim l.or a pharmaceutically acceptable salt or pharmaceutically acceptable in vivo hydrolysable ester thereof.

10. A compound of formula (IV) :

(IV) in which R^a,R^D, R¹ and R² are as defined in claim 1.