WO2005066175A2

WO2005066175A2 - Carbapenem intermediates and processes for their preparation

Info

Publication number: WO2005066175A2
Application number: PCT/GB2005/000034
Authority: WO
Inventors: Michael Anthony Harris; Simon Lancelot Howie
Original assignee: Glaxo Group Limited
Priority date: 2004-01-09
Filing date: 2005-01-07
Publication date: 2005-07-21
Also published as: GB0400405D0; WO2005066175A3

Abstract

The cyclization of compounds of formula (II) to carbapenem compounds of formula (III). wherein R1 is an oxygen protecting group, such as a silyl ether e.g. TBS and R is a readily removable carboxy protecting group, may be used in an improved process to prepare antibacterial compounds of formula (I).

Description

NOVEL PROCESSES

The present invention relates to novel synthetic routes to certain carbapenem compounds, useful as antibacterial agents.

A class of carbapenem compounds is disclosed in International Patent Application, Publication Number WO 95/11905 (SmithKline Beecham pic) as antibacterial agents. A general synthetic methodology for preparing such compounds is disclosed.

Included in this class are compounds of general formula (I):

(I) wherein -CO2R is carboxy or a carboxylate anion or the group R is a readily removable carboxy protecting group.

Compounds o f formula (I) have a broad spectrum of anti-bacterial activity and show good stability towards DHP-1.

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 c ompounds of formula ( I) may b e p repared b y s alt e xchange in a c onventional manner. Similarly, c arboxy-protected d erivatives o f 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, tert-butyl, tert-amyl, allyl, diphenylmethyl, triphenylmethyl, adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofuran-2-yl, tetrahydropyran-2-yl, pentachlorophenyl, acetonyl, jo-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 R 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 maybe suitably r emoved using iron powder and ammonium chloride ( 1M soln) or by hydrogenation u sing p alladium o n a c arbon c atalyst o r z inc d ust a nd p hosphate b uffer solution as described in Heterocycles, 1993, 36(2), 1727; or allyl which may be suitably removed using tetrαfo^'s(triphenylphosphine)palladium and triphenylphosphine. Advantageously, the protecting groups are hydroxy, amino and carboxy- protecting groups, which when used, are selected so that they can be removed under the same conditions, in a si ngle r eaction step; for example allyloxycarbonyl (for hydroxy) and allyl (for . carboxy) which may be both removed using tetr λώ(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)

-CO₂CH₂ORf (c) -CO₂CH(R^a)O.CO.C₆H₄YCOCH(Rg)NH₂ (d)

in which:

R^a is hydrogen, (Cj-6)alkyl, (C3-7)cycloalkyl, methyl, or phenyl; R^D is (Cι -6)alkyl, (Cι-6)al o y, (C3-?)cycloalkyloxy, phenyl, benzyl, (C3-7)cycloalkyl, (Cι-6)alkyl(C3-7)cycloalkyl, l-amino(Cι-6)alkyl, or l-(Cι-6alkyl)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 (Cj-6)alkylene optionally substituted with a methyl or ethyl group;

Rd and R^e, which may be the same or different, is each (Cι-6)alkyl; R^f is (Cι-6)alkyl;

RS is hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (Cι-g)-alkyl, or (Cι-g)alkoxy; and

Y is oxygen or NH. Examples of suitable pharmaceutically acceptable in vivo hydrolysable ester groups include, for example, acyloxy alkyl groups such as acetoxymethyl, pivaloyloxymethyl, α-acetoxyethyl, α-pivaloyloxyethyl and (1-aminoethyl)- carbonyloxymethyl; alkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl and α-ethoxycarbonyloxyethyl; cycloalkoxycarbonyloxyalkyl groups, such as cyclohexyloxycarbonyloxymethyl (hexmetil) and l-(cyclohexyloxycarbonyloxy)ethyl (hexetil); dialkylammoalkyl 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:

-CO H, h R O O II o in which R ¹ is hydrogen, (Cι-g)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, bis-(2- hydroxyethyl)-amine or trt.f-(2-hydroxyethyl)-amine, cycloalkylamines such as dicyclohexylamine, or with procaine, dibenzylamine, NJV-dibenzylethylenediamine, 1- ephenamine, N-methylmorpholine, N-ethylpiperidine, N-benzyl-t>-phenethylamine, dehydroabietylamine, N,N-/3w-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.

In 2002 and 2003, Mori et al, (Tetrahedron Letters, 2002, 43, 111 and J. Ofg. Chem., 2003, 68, 3064) disclosed the preparation of the carbapenem nucleus by a palladium catalyzed amidation of a vinyl halide. The chemistry described requires a specific catalyst, base and ligand combination and heating at 100°C in toluene. Cyclization to afford carboxylate esters, where the substrate is a vinyl bromide, required prolonged heating of 22 - 48 hours. In 1989, Joyeau et al. revealed attempts to form the carbapenem nucleus by cyclization of a vinyl bromide with copper in DMF at 110°C, (Tetrahedron Letters, 1989, 30, 337). No product was formed under these reaction conditions and they concluded that the reaction conditions were too harsh for the product.

The present invention provides a novel and efficient method of synthesis for preparing a compound of formula (I) .

In a first aspect the invention provides the cyclization of compounds of formula (II) to carbapenem compounds of Formula (III).

Scheme 1

Ri is an oxygen protecting group, such as a silyl ether e.g. TBS. R is as defined for compounds of formula (I).

The cyclization may be driven by high temperatures, the presence of copper iodide, sodium hydride and suitable solvents. Preferably the solvent is DMF and the temperature around 120°C.

As shown in Scheme 2, compounds of formula (I) may be prepared by deprotection of the silyl ether of compounds of formula (III) by conventional means, for example by using triethylamine trihydrogen fluoride. Compounds of formula (I) where R = an in vivo hydrolysable ester may be prepared by deprotection of R and subsequent alkylation by conventional means, e.g. as described in WO95/11905.

Deprotection

(I)

Scheme 2

As shown in Scheme 3, compounds of formula (II) are prepared by N-desilylation of compounds of formula (IN). Compounds of formula (IN) are prepared by treatment of compounds of formula (V) with reagent (Z) in the presence of a base, preferably lithiumdicyclohexylamine, in a suitable solvent, preferably THF at low temperature.

Compounds of formula (N) are prepared by dehydration of compound of formula (NI) and treatment with tert-butyldimethylsilyl chloride in the presence of a suitable base, preferably triethylamine, in a suitable solvent, preferably DMF.

Cul, NaH, DMF, 120°C

(III) (I) Scheme 3

Reagent (Z) is prepared by treatment of trimethylsilylketene with bromine in n-hexane followed sequentially by the addition of a suitable base, preferably triethylamine then a suitable alcohol, preferably allyl alcohol. Trimethylsilylketene is described in the literature and is commercially available.

Compounds of formula (VI) as the monohydrate may be prepared by reacting a compound of formula (A):

(A) with a compound of formula (B):

in the presence of a Lewis acid in a suitable solvent, wherein Ri is tert-butyldimethylsilyl and R" is a ligand such as C_1-6alkyl.

R" may be methyl or tert-butyl, for example R"₃ may be trimethyl or tert-butyldimethyl.

Preferably compounds (A) and (B) may be mixed and heated in the presence of copper(I) chloride in DME, cooled, washed with EDTA, tetrasodium salt followed by n-heptane. The organic phase i s isolated, w ashed with water and cooled. The resulting product i s then filtered, washed with heptane and air dried to produce compound (VI).

Compounds of formula (A) may be prepared from compound (C), according to scheme 4 wherein R"₃ is as defined above.

Scheme 4

Compound (C) may be prepared by conventional means but preferably by means of the process as shown in Scheme 5.

Scheme 5

Ethyl iodide is added to compound (D) in the presence of base and a solvent to produce compound (C). Preferably the base is sodium ethoxide and the solvent is THF.

One example of the preparation of compound (D) is described in scheme 4.

C0₂Et Acetone

EtO OEt NaOEt

N₂H₄.H₂0 EtOH

(D)

Scheme 4

Compound (B) may be prepared by conventional means and is also available commercially.

Compounds (II), (III), (IV), (V) and (VI) are novel and form further aspects of the invention.

Conventional methods of cooling and heating such as ice/salt baths and electric heating mantles may be employed. Conventional methods of purification such as flash chromatography, crystallisation or trituration may be employed.

As has previously been mentioned with reference to International Patent Application, Publication Number WO 95/11905, the contents of which are incorporated herein by reference, compounds of formula (I) are anti-bacterial agents.

Accordingly, another aspect of the present invention provides a method of treating bacterial infection in a human or animal patient in need thereof, which method comprises administering to the human or animal patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof as a diastereoisomer or entantiomer obtainable or obtained by the processes of this invention. - In a further aspect of the present invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable derivative thereof obtainable or obtained by the processes of this invention, in the manufacture of a medicament for treating bacterial infection in a human or animal patient.

Administration of a compound in accordance with the invention for treatment of the conditions mentioned above may be carried out as disclosed in the above mentioned International Patent Application, Publication Number WO 95/11905.

The processes and intermediates of the present invention are illustrated by the following Examples and Preparations. However, it should be understood that the invention is not limited to the specific details of these Examples and Preparations which are given for exemplification purposes only.

Abbreviations

DBU = l,8-Diazabicyclo[5.4.0]undec-7-ene

DCM = dichloromethane

DME = 1,2-dimethoxyethane

DMF = NN-dimethylformamide HC1 = hydrochloric acid

ΝMP = 4-methyl-2-pyrrolidinone

THF = tetrahydrofuran

Preparations

2-(TrimethylsilyI)ethenone preparation (E. Nalenti, M.A. Pericas and F. Serratosa. J. Org. Chem., 1990, 55, 395).

Preparation of 3-AcetyI-l-ethyl-5-methyI-lfT-pyrazoIe, Compound (C)

a) 3(5)-Acetyl-5(3)-methyI-lfl-pyrazole, Compound (D) Concentrated HC1 (54 mL) was added over 25 minutes to a mixture of ethyl pyruvate (120 g, 1.03 mol) and triethyl orthoformate (580 mL, 3.4 ol) in ethanol (240 mL), maintaining the temperature below 30°C. When the addition was complete, the mixture was stirred for 2.4 hours at ambient temperature, then the ethanol replaced with n-hexane by 'put and take' distillation at atmospheric pressure. The resulting solution of ethyl 2,2-diethoxypropionate in n-hexane (600 mL) was added to a suspension of sodium ethoxide (89.5 g @ 96%, 1.26 mol) in n-hexane (50 mL) followed by acetone (76 mL, 1.04 mol) over 45 minutes. The mixture was heated under reflux for 15 minutes then n-hexane (600 mL) added and heating continued. Solvent was removed by distillation at atmospheric pressure and replaced periodically with n-hexane (3 x 200 mL) to maintain constant volume. The mixture was cooled to 50°C after 4.1 hours and water (500 mL) added. The phases were separated and the aqueous -phase washed with n-hexane (300 mL). The aqueous phase was mixed with DCM (500 mL) and the pH of the mixture adjusted to 5 by the addition of 2M HC1 (480 mL). The phases were separated and the aqueous phase was washed with DCM (2 x 400 mL). The organic phases were combined and washed with a 10% aqueous sodium chloride (500 mL) and the solution concentrated by distillation at atmospheric pressure to 600 mL, ethanol (600 mL) was added and distillation continued to a base temperature of 60°C, removing an additional 300 mL distillate. Hydrazine hydrate (42 mL @ 55%, 0.74 mol) was added to the cooled solution over 40 minutes. The mixture was stirred at 40 - 50°C for 30 minutes then concentrated to 200 mL by distillation at atmospheric pressure and cooled to 25°C. The concentrate was added to a solution of HC1 (11 mL, 0.134 mol) in water (500 mL) (pH = 1.2) and the mixture stirred for 55 minutes. The mixture was extracted with ethyl acetate (1 x 300 & 2 x 500 mL) and the combined extracts washed with aqueous sodium chloride (500 mL), adjusting the pH to 6 by the addition of IM sodium hydroxide (50 mL). The organic phase was concentrated to 600 mL by distillation at atmospheric pressure, n-heptane (600 mL) was added and distillation continued to remove further solvent (800 mL) to a base temperature o f 85°C. T he mixture w s c ooled to O - 5 °C and s tirred for 1 h our then filtered. The cake was washed with cold n-heptane and dried under vacuum at 20 to 25°C to give the title product, compound (D), as a yellow solid (64.87 g).

b) S-Acetyl-l-ethyl-S-methyl-lff-pyrazoIe, Compound (C) A solution of compound (D) (30 g, 0.24 mol) in THF (300 mL) was added, under a nitrogen atmosphere, to a suspension of 96% sodium ethoxide (17.14 g, 0.24 mol) in THF (600 mL) over 7 minutes, maintaining the temperature at 15 to 20°C. The mixture was stirred at ambient temperature for 45 minutes then heated to reflux. Ethyl iodide (21.3 mL, 0.27 mol) was added to the boiling mixture over 1.5 hours and heating continued for a further 3.75 hours. Water (500 mL) was added and solvent removed by distillation at atmospheric pressure. The mixture was cooled to below 30°C, diluted with DCM (500 mL) and acidified to pH 2.9 with 2M HC1 (4 mL). The phases were separated and the aqueous phase extracted with DCM (2 x 250 mL). The combined extracts were washed with water (500 mL), aqueous sodium chloride (250 mL), filtered and distilled at atmospheric pressure to remove 1 L distillate. n-Heptane (500 mL) was added and distillation continued to remove further solvent (500 mL) to give a base temperature of 100°C. The mixture was cooled, seeded at 30°C, and further cooled to 5°C, stirred for 1.5 hours then filtered. The cake was washed with cold n-heptane and dried under vacuum at 20 to 25°C to give the title product, compound (C), as an off white solid (30 g).

Examples

Example 1

Preparation of (3S,4R)-3-{(lR)-l-[(tert-ButyldimethyIsilyloxy)ethyl]}-4-[2-(l-ethyI-5- methyl-l/7-pyrazol-3-yl)-2-oxoethyl]-2-azetidinone hydrate, Compound (VI).

a) l-Ethyl-5-methyl-3-[l-(trimethylsiIyϊoxy)ethenyl]-liϊ-pyrazole, Compound (A)

DBU (3.9 mL, 26.1 mmol) was added drop wise over 30 minutes to a mixture of trimethylsilyl chloride and compound (C) (2.4 g, 15.8 mmol) in DCM (21 mL). The mixture was stirred for 5 hours then quenched with 4% w/v sodium bicarbonate (21 mL) and the phases separated. The organic phase was washed with water (2 x 21 mL), dried (MgSO₄) and evaporated under reduced pressure to give the title product, compound (A), as an oil (3.51 g).

b) (3S,4R)-3-{(lR)-l-[(tβ^-ButyldimethyIsiIyIoxy)ethyI]}-4-[2-(l-ethyl-5-methyl-liy- pyrazol-3-yl)-2-oxoethyI]-2-azetidinone hydrate, Compound (VI) Compound (A) (92 g, 0.41 mol) was added to a mixture of copper(I) chloride (0.34 g 3.43 mmol) and compound (B) (98 g, 0.311 mol) in DME (0.5 L). The mixture was heated under reflux for 1.5 hours then cooled and poured into a mixture of 1% ethylenediaminetetraacetic acid, tetrasodium salt (1 L) and n-heptane (1 L). The mixture was stirred for 5 minutes and separated. The organic phase was washed with water (1 L) then stirred vigorously with water (96 mL) and cooled in an ice bath for 1 hour. The resulting product was filtered, washed with heptane and air dried to give the title product, compound (VI), as a white solid^r( 104.4 g) Example 2

Allyl 2-bromo-2-trimethylsilylacetate, Reagent (Z) A 10% solution of bromine in dichloromethane (360 mL, 36 g, 0.23 mol bromine) was added slowly to a solution of 2-(trimethylsilyl)ethenone (26.58 g, 0.11 mol) in n-hexane (1.5 L) maintaining the temperature at 20°C. When the addition was complete, the mixture was stirred for 5 minutes then treated with triethylamine (23.6 g, 0.23 mol), stirred for 30 minutes then allyl alcohol (14.9 g, 0.26 mol) added. The mixture was stirred for 30 minutes then washed with water (500 mL), 5% citric acid (500 mL), water (500 mL), dried (MgSO₄) and evaporated under reduced pressure. The residue was distilled at 80 - 82°C, 0.5 mmHg to give the title product, reagent (Z), as a pale yellow oil (36.3 g).

Example 3

[(3S,4R)-l-(tert-ButyldimethyIsilyl)]-3-[(lR)-l-(tert-butyldimethylsilyloxy)ethyI]-4- ^-(l-ethyl-S-methyl-lfl-pyrazol-S-y - -oxoethyll^-azetidinone, Compound (V)

A solution of tert-butyldimethylsilyl chloride (17.81 g, 0.118 mol) in NN-dimethylformamide (36 mL) was added to a mixture of anhydrous compound (NI) (17.84 g, 0.047 mol) and triethylamine (14.35 g, 0.14 mol) in NN-dimethylformamide (180 mL) maintaining the temperature at 0 - 5°C. When the addition was complete the cooling was removed, the mixture stirred for 2.17 hours then quenched with water (180 mL). The mixture was extracted with ethyl acetate (2 x 180 mL) and the combined extracts washed with water (180 mL), 5% aqueous citric acid (180 mL), water (180 mL), dried (MgSO₄) and evaporated under reduced pressure. Chromatography over silica gel eluting with ethyl acetate:hexane (2:8 - 4:6) afforded the title product, compound (V), as an off white solid (22.5 g).

Example 4 Allyl (2 )-2-bromo-4-{[(2R,3S)-l-(tert-butyldimethylsilyl)]-3-[(lR)-l-(tert-butyl- dimethylsilyloxy)ethyl]-4-oxo-2-azetidinyl}-3-(l-ethyl-5-methyl-l_JH-pyrazol-3-yl)-2- butenoate, Compound (IV) n-Butyllithium (10.74 mL of 1.6M in hexane, 0.017 mol) was added drop wise to a solution of dicyclohexylamine (3.11 g, 0.017 mol) in tetrahydrofuran (50 mL) at -70°C. The mixture was stirred for 10 minutes then treated with a solution of allyl 2-bromo-2- trimethylsilylacetate (4.314 g, 0.017 mol) in tetrahydrofuran (25 mL). When the addition was complete, the mixture was stirred at -70°C for 15 minutes then treated with a solution of compound (V) (4.24 g, 8.59 mmol) in tetrahydrofuran (25 mL) over 5 minutes, the mixture stirred for 15 minutes then allowed to warm to 0°C over 30 minutes. The mixture was stirred at 0°C for 1 hour then warmed to ambient temperature over 30 minutes. The mixture was poured into a mixture of 10% aqueous citric acid (100 mL) and ethyl acetate (100 mL) and the phases separatedf The aqueous phase was ^{^}extracted with ethyl acetate (100 mL) and the combined organics washed with water (2 x 100 mL) dried (MgSO₄) and evaporated under reduced pressure. Chromatography over silica gel eluting with 7:3 hexane:ethyl acetate afforded the title product, compound (TV), as a white solid (1.772 g).

Example 5

Allyl (2E)-2-bromo-4-{[(2R,3S)-3-[(lR)-l-(tert-butyldimethylsilyloxy)ethyl]-4-oxo-2- azetidinyl}-3-(l-ethyl-5-methyl-lH-pyrazol-3-yl)-2-butenoate, Compound (II)

A solution of tetrabutylammonium fluoride hydrate (0.679 g, 2.59 mmol) in dichloromethane (10 mL) was added drop wise to a solution of compound (IV) (1.7 g, 2.59 mmol) in dichloromethane (50 mL) at -20°C. The mixture was allowed to warm to 0°C over 15 minutes and stirred for 30 minutes then pH 7 buffer (100 mL) added, the mixture stirred and the phases separated. The organic phase was washed with water (50 mL), dried (MgSO ) and evaporated under reduced pressure. Chromatography over silica gel eluting with ethyl acetate:hexane 1:9 — 1:1 afforded the title product, compound (II), as a white solid (0.822 g).

Example 6

Allyl (5R,6S)-3-(l-ethyl-5-methyl-l_JH-pyrazol-3-yl)-7-oxo-6-[(lR)-l-(teri'-butyl- dimethylsilyloxy)ethyl]-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate, Compound

A solution of compound (II) (0.111 g, 0.2 mmol) in dry NN-dimethylformamide (5 mL) was treated with a 60% suspension of sodium hydride in oil (10.7 mg, equivalent to 6.4 mg, 1.3 eq.) and copper(I) iodide (40 mg, 1.03 eq.). The mixture was stirred and warmed to 125°C o ver 1 5 minutes, h eated for 45 minutes, then cooled and a mixture o f p H 4 buffer (10 mL) and ethyl acetate (10 mL) added. The resulting mixture was filtered through celite and the phases separated. The aqueous phase was extracted with ethyl acetate (10 mL) and the combined organic parts washed with water (2 x 10 mL), dried (MgSO₄) and evaporated under reduced pressure. Chromatography over silica gel eluting with ethyl acetate:hexane 1:9 — 1:1 afforded the title product, compound (III), as a white solid (0.053 g).

Claims

1. A compound of formula (II)

00 wherein i is an oxygen protecting group and CO₂R is carboxy or a carboxylate anion or R is a readily removable carboxy protecting group.

2. A compound of formula (III)

(III) wherem Ri is an oxygen protecting group and CO2 is carboxy or a carboxylate anion or R is a readily removable carboxy protecting group.

3. A compound of formula (IV)

(IV) wherein R] is an oxygen protecting. group and CO₂R is carboxy or a carboxylate anion or R is a readily removable carboxy protecting group.

4. A compound of formula (V)

(V) wherein Ri is an oxygen protecting group and CO2R is carboxy or a carboxylate anion or R is a readily removable carboxy protecting group.

5. A compound of formula (VI)

wherein R\ is an oxygen protecting group and CO2R is carboxy or a carboxylate anion or R is a readily removable carboxy protecting group.

6. A process for the preparation of a compound of formula (I) comprising the deprotection of a compound of formula (IH):

(III) (I)

wherein R\ and CO₂R are as defined as above.

7. A process for the preparation of a compound of formula (III) comprising cyclisation of a compound of formula (II):

cyclisation

(ID (III) wherein R_Ϊ and CO₂R are as defined as above.

8. A process for the preparation of a compound of formula (IN) comprising desilylation of a compound of formula (II):

Desilylation

(IV) (II)

wherein and CO₂R are as defined as above.

9. A process for the preparation of a compound of formula (IN) comprising reacting a compound of formula (V) with reagent (Z):

wherein Ri and CO₂R are as defined as above.

10. A process for the preparation of a compound of formula (N) comprising reaction of a compound of formula (VI) with TBSCl in the presence of a suitable base and a suitable solvent

<^VI) (V) wherein

and CO₂R are as defined as above.

11. Use of a compound according to any one of claims 1 to 5 in a process for the preparation of compounds of formula (I)

(I) wherein CO2R is carboxy or a carboxylate anion or R is a readily removable carboxy protecting group.

12. A compound of formula (I) or a pharmaceutically acceptable derivative thereof obtained by a process comprising any one of the processes described in claims 6 to 10.

13. The product according to claim 12 for use in the manufacture of a medicament for treating bacterial infection in a human or animal patient.

14. A pharmaceutical composition comprising the product according to claim 12.

15. A method of treating bacterial infection in a human or animal patient in need thereof, which method comprises administering to the human or animal patient an effective amount of the product according to claim 12.

16. Use of the product of claim 12 in the treatment of a bacterial infection in a human or an animal patient.