GB2195627A - Penem derivatives - Google Patents

Description

1 GB2195627A 1

SPECIFICATION

Antibacterial 7-oxo-4-thia-l-azabicyclo[3.2.0]hept-2-ene derivatives This invention relates to a process for the production of penem derivatives having antibacterial activity and/or 8-lactamase inhibitory and/or inactivating activity.

7-Oxo-4-thia-l-azabicyclo[3.2.0]hept-2-ene has the following formula A, and derivatives thereof having an aliphatic side chain at position 6 are numbered as shown in formula B:

1 n 6 5 4 B5 5 4 10 1 1 1- S S - (A) 7 3 N _5/ 3 N N (B) P D1 - 0 1 2 0 1 2 15 By an alternative system of nomenclature, the above nucleus A may be described as a "penem", in which case the ring numbering is as shown in formula C, with derivatives having an aliphatic side chain at position 6 being numbered as shown in formula D:

6 5 1 8 6 1 20 S ', 5 S ?j / 2 2 x) 0 (C) 7 "'^ 7N (D) N N D1 0 4 3 4 3 25 The present invention relates to 5R,3-(4-aminocarbonylphenoxy)-6S-(1 Rhydroxyethyl)-7-oxo-4thia-l-azabicyclo-[3.2.0]hept-2-ene-2-carboxylic acid and to 5R,3-(4-lower alkylaminocarbonylphenoxy)-6S-(lR-hydroxy)-7oxo-4-thia-l-azabicyclo[3.2.0]-h ept-2-ene-2-carboxylic acid, to esters thereof at the 2-carboxylic acid group and/or at the 8-hydroxy group, and to salts thereof, 30 especially physiologically tolerable salts. The free acids have the formula I given below:

HO - 1 CH3CH S -CCONHR1 35 E, 0 0 COOH in which R' represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms. R, most preferably represents a hydrogen atom or a methyl group.

The compounds of formula 1, and salts and esters thereof, are described and claimed in our Application GB 2 161 161 A. These compounds have particularly good activity against a variety of microorganisms, particularly against fl-lactamase-producing organisms, including gram positive, gram negative and anaerobic organisms. Moreover, they are more effective than other penems against methicillin-resistant organisms.

Application GB 2 161 161 A discloses certain processes for the production of a compound of formula 1 and of salts and esters thereof. The present invention relates to further processes for the production of a compound of formula 1 and of salts and esters thereof. These processes have certain advantages over those disclosed previously. The particular advantages will be given in each case.

Accordingly, the present invention provides a process for the production of a compound of formula [a R20 55 CH3CH, (Ia) 0-// '\ CONHR1.N 0 COOR 60 in which R represents a hydrogen atom or a carboxy protecting group, or an esterifying group that is removable under physiological conditions; R' is as defined above, and 2 GB2195627A 2 R2 represents a hydrogen atom a hydroxy protecting group, or an esterifying group that is removable under physiological conditions, or a salt thereof, which comprises (1) producing a compound of formula lb R20 L h Y_ H.

co-z C10- N COOR (1b) in which R and R2 are as defined above, and Z represents an -NHRI, -NHR3, -NW 3, -NR'R3 -R4 or -OH group in which R3 represents a nitrogen protecting group (in the case of -NW3 the two groups R3 may be 15 the same or different), and R4 represents a carboxylic acid activating group, or -COZ represents -CN, by (A) heating a compound of formula 11 R20 CH3CH.

1 0 5 0- C0z 0 COOR (li) in which R, R2 and Z are as defined above, or (B) reacting, a compound of formula IV H00C0z (IV) in which Z is as defined above, with a compound of formula Ill R2 0 S -Y (III) 0';Eq COOR in which R and R2 are defined as above, and Y represents a leaving group selected from phenoxy and phenylthio groups which may be unsubstituted or substituted by one or more substituents, which may be the same or different, 45 selected from halogen atoms and nitro, cyano, trifluoromethyl and trifluoroacetyl groups; groups of formula 0 11 50 -XP (OR a) 2 0 11 or -XP (R a) 2 in which X represents an oxygen or sulphur atom and the two groups 11, which may be the same or different, each represents a straight or branched chain alkyl group having from 1 to 6 carbon atoms, or a phenyl group which may be unsubstituted or substituted, for example, by 55 one or more substituents selected from halogen atoms, cyano, nitro and methyl groups, espe cia;ly by a methyl group in the para-position; groups -OSO2Rb in which R, represents a straight or branched chain alkyl group having from 1 to 4 carbon atoms, which may be substituted by one or more fluorine atoms, for example, may be fully fluorinated, for example, a -CF, or -C4F, _group, or Rb represents a phenyl group that is unsubstituted or is substituted by a p-nitro, pbromo- or p-methyl group; 0 T groups -SRa and -SO,R. in which R,, is defined as above; and 11t, 1 T' -Y 3 GB2195627A 3 groups 0 Q -OCCF31 and, if the resulting compound has the formula 11 R20 S 0 N-o \--i COZ COOR (11) in which R, R2 and Z are defined as above, converting compound 11 to compound lb and/or isolating compound lb from compound 11; (C) cyclising a compound of formula Va, Vb or Vc R 20 R 20 20 (Va) CM3( H, S OC/ \COZ 1"3kH,,, -- S O/ \COZ (Vb) -T.4 \--i NH j: N1'H ^ 0 it 0 0 0 1 COOR H:COOR 25 R20 CH3-",,, S OFcoz (v.) 30 oH Y^ \.:-/ N2 COOR 0 in which R, R2 and Z are as defined above, and 35 L' represents a chlorine or bromine atom, (i) in the case of compound Va eliminating HIL1 (a) by treatment with a base and/or a metal, (b) by electrolysis, (c) by photolysis, or (d) by reaction with a free radical-producing compound optionally in the presence of an 40 initiator; (ii) in the case of compound Vb by treatment with a Lewis acid or a base, and (iii) (D) M in the case of compound Vc by treatment with a rhodium- or copper- containing compound; cyclising a compound of formula Via, Vib, Vic or Vid 45 R20 X R2() X SCO //;xcoz CHP4 sco--l \coz 50 COOR COOR (Via) (VIb) - 55 R20 X 11 C0z 0)-N, H-RS COOR (VIC) R20 ''3t-M INIA, S_ 0 YPIQ13 COOR (VId? in which formulae R, R 2 and Z are as defined above, R6 GB2195627A 4 X represents an oxygen or sulphur atom, the group -PPh represents a group derived from a trivalent organophosphorus reagent, R 5 represents a bromine or chlorine atom, R 6 represents Cuffi), Pb(11) or Hg(H), in which case n represents 2, or represents Ag(l), in which case n represents 1, (i) in the case of compound Via, by heating compound Via or allowing compound Via to stand at room temperature; (ii) in the case of compound Vib, by treatment with a trivalent organophosphorus reagent and heating the resulting compound or allowing the resulting compound to stand at room temperature; (iii) in the case of compound Vic, by treatment with a phlosphine and a base, and they heating the resulting compound or allowing the resulting compound to stand at room temperature, (iv) in the case of compound Vid by reaction with a compound of formula V11 X 15 I F?C 00C0z (VII) in which X and Z are as defined above and R' represents an activating group, for example, an activating ester group or a halogen atom, and 20 heating the resulting compound or allowing the resulting compound to stand at room temperature; (E) cyclising a compound of formula Villa or Villb R20 (VII1a) CH3L, S - 0 iN L L ROOC<OOCOZ R20 -R6 CH3L SRO (VIIIb) 0 rNl; L r R0(3C 0/ \Coz in which formulae R, R2, R6, n, and Z are defined as above, L represents a leaving group, for example, that can be replaced in a nucleophilic displacement reaction, for example, a halogen atom, preferably a bromine or iodine atom; hydroxy group (in which case keto-enol tautomerism can occur); a modified hydroxy group, especially a sulphonate 35 ester group, for example, a sulphonyloxy group of the formula -OSO213b in which Rb represents a straight or branched chain alkyl group having from 1 to 4 carbon atoms, which may be substituted by one or more fluorine atoms, for example, may be fully fluorinated, for example, a -CF3 or -CJ, group, or Rb represents a phenyl group that is unsubstituted or is substituted by a p-nitro, p-bromo- or p-methyl group; or L represents a phosphoruscontaining group for example 40 0 (d) (3) 0 fl 0 -OP (R a) 2 -SP (R a) 2 -OP (OR a) 2 45 in which the two groups R,,, which may be the same or different, are as defined above, and RO represents a hydrogen atom or a sulphur protecting group, (i) in the case of compound Villa, effecting cyclisation, and (5) in the case of compound Villb, removing the sulphur protecting group, if present, and either reacting the resulting thiol compound with a reagent capable of converting the compound into compound Villa, and cyclising compound Villa, or cyclising the thiol compound by treatment with a base; 55 and as desired, and as required carrying out any of one or more of the reactions set out in 55 the further steps (2) to (4) in any appropriate order: (2) in a compound in which -COZ represents other than a -CONHRI group carrying out one of the following reactions, (a) when -COZ is -CONHR3 or -CONR3R3, removing the protecting group(s) R 3; (b) when -COZ is COR4, reacting the compound with ammonia, a lower alkylamine or a 60 chemical equivalent thereof; (c) when -COZ is -COOH, activating the -COOH group, and then reacting the resulting corn pound with amrlionia or methylamine; when -COZ represents -CN, converting M to -CONHRI in a resulting compound of formula la, lb or 11 in which the free or protected 8-hydroxy 65 -4 .1 R; GB2195627A 5 group has S-stereochemistry carrying out a stereochemical inversion to give the corresponding 8R compound; (4) if desired or required, carrying out any one or more of the following steps in any desired order; (a) hydrolysing a 2-carboxylic ester group in a compound to give the corresponding free acid, 5 (b) treating a free acid compound or a salt thereof with an agent capable of forming a 2 carboxylic acid ester, for example, with an alcohol, a phenol or a reactive derivative thereof, to give a 2-carboxylic acid ester thereof, (c) carrying out an acid- or base-catalysed ester interchange on a 2carboxylic acid ester to give a different ester of that compound, (d) treating a free acid compound with a base to give a salt at the carboxy group at positions 2, (e) treating a free acid compound or 2-carboxylic acid ester having a basic group present with an acid to give an acid addition salt thereof, (f) treating a salt of a compound with an acid to give a free acid of that compound, (9) removing a hydroxy protecting group from a compound having a protecting 8-hydroxy group to give the corresponding compound having a free 8-hydroxy group, (h) treating a compound having a free hydroxy group at the 8-position with an organic acid derivative to form an ester at the 8-position.

It will be appreciated that when Z represents an -NHRI, group, then a compound of formula la 20 is obtained directly by processes (A) to (E). It is generaly preferable to protect a free aminocar bonyl group -CONHR' during various reactions involved in the production of a compound of formula la. A methylaminocarbonyl group is less reactive, however, and may be carried as such throughout a reaction sequence. Nitrogen protecting groups, their introduction and their removal are well known and are described, for example, by McOmie, Protecting Groups in Organic Chemistry, Plenum Press, London and New York, 1981 and T.M Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1981.

References herein to---acompound of formula lb- accordingly include compounds of formula ]a.

The term -pro-drug- group' is used to denote a group that can be removed under physiolog- 30 ical conditions.

The term -lower alkyl- is used herein to denote an alkyl group having from 1 to 4 carbon atoms. A lower alkyl group is especially a methyl group.

As indicated in (B) above, a compound of formula lb may be isolated from compound 11 which may be in the form of an isomeric mixture comprising compound lb and the corresponding 5S- 35 isomer. Chromatographic or other techniques known for isolating isomers may be used.

A compound of formula 11, which may be obtained by process (B) or by any other method, is preferably converted into a compound of formula lb by heating, that is to say, a 5R,5S-mixture (compound 11) can be converted to predominantly the desired 5R-isomer (compound lb), or a substantially pure 5S-isomer can be converted into substantially pure 5R- isomer. In the thermal 40 interconversion, 5R5S the position of the solution equilibrium lies more towards formation of the desired 513-isomer.

The stereochemical inversion is carried out simply by heating compound 11, for example, to a temperature within the range of from 30 to 20WC, preferably from 60 to 15WC.

This reaction is generally carried out in a solvent or diluent, or a mixture of two more solvents 45 and/or diluents. It is not generally necessary to ensure that compound 11 is completely dissolved at the reaction temperature.

The solvent or diluent should be inert under the reaction conditions and may be an ether, for example, diethyl ether, dioxane, tetrahydrofuran, diisopropyl ether or di- n-butyl ether; an aromatic hydrocarbon, for example, toluene or xylene; an ester, for example, ethyl acetate; an aprotic solvent, for example dimethylformamide or dimethylacetamide, a halogenated hydrocarbon, for example, carbon tetrchloride or chloroform; a ketone, for example, acetone or methyl ethyl ketone; acetonitrile; or a mixture of two or more of such substances. The solvent is chosen with regard to the nature of the groups -COZ and R20- and the solubility and stability characteristics conferred by them.

As indicated above, the hydroxy group at position 8 in compound 11 may be free or protected.

It is generally preferable to use a free hydroxy compound 11 and to introduce any desired ester group, for example, a -pro-drug- group after formation of compound lb or, preferably, la.

The substituent at the 4-position of the phenoxy group in compound 11 may be a cyano group, a carboxylic acid group, an activated carboxylic acid group or a free or protected aminocarbonyl 60 group. In the case of a protected aminocarbonyl group, conversion to the free aminocarbonyl group or a methylaminocarbonyl group may be carried out before or after the stereochemistry inversion at position 5. If a compound of formula 1 having a free a methylaminocarbonyl group -CONHRI is desired, it is preferable to use a compound of formula 11 having the corresponding aminocarbonyl group as starting material. Conversions of groups at the 4- position are disclosed 65 6 GB2195627A 6 in more detail below.

The stereochemistry at position 8 in compound 11 may be R or S, but is preferably R, as this configuration is maintained during the inversion at position 5, resulting in a compound of formula 1 having the desired 5R,6S,817t stereochemistry without the need for a further inversion.

Accordingly, a particularly preferred compound of formula 11 has the following structure lla 5 HO v oS / \ 0-nCONHR1 0 N COOR in which R represents a carboxy protecting group, preferably a p- nitrobenzyl group, and RI is defined as above. For compound Ila, a preferred solvent is acetonitrile. The use of a compound 15 Ila as starting material gives a compound of formula Ic HO Y 20 CH3CH S 0-n\ C0z (IC) 0:

COOR A general advantage of the process described above for the production of compound lb from a compound 11 over the processes described previously is that the stereochemistry at position 5 25 in compound 11 is not important. As indicated above, the equilibrium 5R5S is in favour of the 5R-isomer. Accordingly, it is not necessary to separate the 5-isomers, for example, chromatogra phically at preceding stages of the reaction sequence. This is a considerable advantage.

Moreover, depending on the nature of the groups R, W, R2 and Z, we have found that, to varying degrees, the resulting compound lb is relatively insoluble in liquids that are, to varying 30 degrees, solvents for compound 11. This effect is particularly marked when a compound lla in which R2 is hydrogen is used as the starting material, as the resulting compound lc is substan tially insoluble in solvents in which the compound lla is more soluble. Accordingly, the equilib rium between compounds lc and lla is driven even more towards compound lc. Moreover, the relative insolubility of compound lc means that it can be removed from the reaction mixture very easily, for example, merely by filtration, in very good field and in substantially pure form, thus also obviating the need for further purification, for example, chromatography.

As indicated above, a compound of formula 11 may result from process B described briefly above and in more detail below. In some cases depending, for example, on the starting material, reagents and reaction conditions used, the product of process B may already be predominantly 40 the 5R-isomer i.e. a compound of formula lb. In other cases, the product may be a mixture of 5R,5S-isomers in which the 5S-isomer may predominate. In the case of a mixture, the desired 5R-isomer may be separated from any 5S-isomer, for example, chromatographically, but this is not necessary because of the preferred final thermal inversion, A compound of formula 11 may also be produced as described in Reaction Scheme 1 below. 45 0 7 GB2195627A 7 REACTION SCHEME 1 10 14 5R10 5 CH3CH SR CH3C 0 0 SCOR9 COOR RO0r, C0z 10 (xl) (X) i Feo 0 15 CH3CH S C0z 4 j COOR (xl? CH 3 CH N, CL 5C00 0 RO0C OF --\coz ( TX) In Reaction Scheme 1, Z, R, and R2 are as defined above, and R9 and R10 each independently represents a phenyl group or an alkyl group having from 1 to 4 carbon atoms. It is preferable 25 that R2 in compounds IX, X and XI represents a hydroxy protecting group to prevent the hydroxy group from reacting with the various reagents used, and the carboxy group is preferably protected in compounds Xl, X, IX and 11 to prevent it from taking part in any undesired reactions. (in compound 11, as indicated above, R2 preferably represents a hydrogen atom, if this is the desired R2 in the final product.) Certain compounds of formula XI have been described previously see, for example, GB 2 102 798A, GB 2 087 880A, and T. Tanaka et A J.C.S. Chem. Comm. 1982, (13), 713. Other compounds of formula XI may may be prepared analogously. Compound XI is reacted, in the presence of a base, with a compound of formula X11 S 11 FC-0 U,,/ COZ (Xii) in which Z is as defined above, and R" represents a halogen atom, preferably a chlorine atom 40 or an imidazolide group, followed by reaction with an activated carboxylic acid derivative which comprises the group R9 as defined above, for example, with an acyl halide of formula X111 0 1k 45 R9 C -- R12 (Xiii) in which R9 is as defined above and R12 represents a chlorine or bromine atom.

Many phenyl chlorothionoformates are known, see, for example, Rivier & Schalch, HeIv. Chem. 50 Acta., Vol 6, 1923, p605, and Reich & Martin, Chem. Berichte, Vol 98, 1965, p2063. Other compounds of formula X11 may be prepared by methods analogous to those described for the preparation of known compounds.

The reaction between compound XI and compound XII is carried out in the presence of a base, preferably having a pK,>--20, preferably a metallated amine, and examples of preferred bases are lithium diisopropylamide, lithium hexamethyldisilazide, lithium 2,2,6,6-tetramethylpiperi dide, lithium cyclohexylisopropylamide, and sodamide.

The reaction is generally carried out in an aprotic solvent, for example, an oxygenated hydro carbon preferably an ether, for example, diethyl ether, tetrahydrofuran, dioxane, glyme or di glyme. The reaction temperature is, for example, from - 120 to + 300C, preferably from - 78 to 60 - 20"C.

The amount of base used is, for example, from 1 to 3 moles, calculated per mole of compound XI, preferably from 1.5 to 2.5 moles of base. The compound of formula X11 is preferably used in an amount of from 1 to 1.5 moles per mole of compound X1, preferably form 1 to 1. 1 moles of compound XII per mole of compound X1.

8 GB2195627A 8 The reaction may be carried out as follows: The base may be added to a stirred solution of compounds XI and XII. Alternatively, to a stirred solution of compound X1 under an inert atmosphere is added the base and subsequently a solution of compound XII in the same or a different solvent.

The activated acid derivative, preferably of formula XIII, is preferably added to the mixture resulting from the reaction of compounds XI and XII, especially in an amount of from 1 to 2 moles calculated on compound XI. The reaction is preferably carried out at a temperature of from -70 to + 40C, adding the compound of formula XIII to the reaction mixture at the temperature at which the reaction between compounds XI and XII took place, and then warming, or working-up at this temperature.

Then -SCOR9 group in the resulting compound of formula X may be E or Z to the -COOR group. (The terms E and Z are as defined on page 142 of Allinger et al, "Organic Chemistry" 1971, Worth, New York.) The isomers may be separated for the subsequent reaction, but this is not generally necessary, and the isomeric mixture is generally used as both isomers give a compound of formula 11.

The resulting compound X is then chlorinated using an agent capable of splitting a carbon sulphur bond and of introducing a chlorine atom. Such agents are well known in the art and include, for example, molecular chlorine, sulphuryl chloride, t-butyl hypochlorite and cyanogen chloride.

The reaction is generally carried out at a temperature within the range of from -60 to +20'C. 20 The reaction is generally carried out in a solvent or diluent that is non- protic, and is inert under the reaction conditions, for example, an ether, a hydrocarbon or a halogenated hydrocarbon, for example, dioxane, benzene, chloroform or methylene chloride. A mixture of two or more sol vents may be used. Examples of halogenating systems are: chlorine in chloroform, chloride in benzene and t-butyl hypochlorite in benzene. In the latter two cases, the temperature is prefera- 25 bly form 5 to 20"C, and normally from 5 to 10'C. Generally, 1 to 2 moles of chlorine are used per mole of compound X, cf. S. Kukolja, J. Amer. Chem. Soc. (1971), 93, 6267 and P.C.

Cherry, C.E. Newall and N.S. Watson, J.C.S. Chem. Comm. 1979, p.663.

The resulting compound of formula IX may be converted into a compound of formula 11 in the presence of a base. The base may be inorganic or organic, and may be chosen, for example, 30 from ammonia, or an alkali metal, especially a sodium or potassium, carbonate, bicarbonate, alkoxide or hydroxide; a primary amine, for example, having a pK,, within the range of from 5 to 9, for example, methylamine, ethylamine, aniline or benzylamine; or imidazole, pyridine or a substituted pyridine, for example, an alkyl, amino or alkylamino- substituted pyridine or 4-dimethy laminopyridine. Imidazole, pyridine, ammonia and methylamine are particularly preferred. It will be 35 appreciated that if Z in compound IX represents an activated carboxylic acid group and the base used is ammonia or methylamine, then the activated group can be converted simultaneously into a group -CONHRI.

The reaction is generally carried out in a solvent or diluent, the choice of which is wide, provided that it is inert under the reaction conditions. Examples of solvents and diluents are 40 oxygenated hydrocarbons, for example, alcohols, for example, having up to 4 carbon atoms, for example, ethanol; ethers, for example, having up to 8 carbon atoms, for example, diethyl ether, also tetrahydrofuran and dioxane; ketones, for example, having up to 4 carbon atoms, for example, acetone and methyl ethyl ketone; esters, for example, methyl acetate and ethyl acetate; and amides, for example, dimethy1formamide and dimethylacetamide; also chlorinated hydrocar- 45 bons, for example, chloroform, methylene chloride and carbon tetrachloride; aromatic hydrocar bons, for example, benzene and toluene; and other solvents for example, acetonitrile and nitro methane. A mixture of two or more solvents may be used, and solvents are preferably used in admixture with water, preferably a water-miscible solvent is used in admixture with 5 to 20% (v/v) water.

The reaction is generaly carried out at a temperature within the range of from -20 to 40C, preferably from 0 to, 200C.

A resulting compound 11 is then converted into a compound lb, preferably by heating as described above to produce the desired 511 stereoisomer of formula lb. If present a hydroxy protecting group may be removed, if desired, or converted into a "pro- drug" group.

A group -COZ other than a group -CONHR1 is converted into the desired group -CONHR1 at an appropriate point. This and other interconversions may be carried out as described briefly about and in more detail below.

As indicated above, the present invention provides a process for the production of a com pound of formula la Q1 d 9 GB2195627A 9 R20 N0- C1 CONHR' COOR (1a) in which R, R' and R2 are as defined above which comprises producing a compound of formula lb R20 S 0 0 - C0z (ib) COOR in which R, R 2 and Z are defined as above by reacting a compound of formula IV H00C0Z (IV) in which Z is defined as above with a compound of formula (111) R20 CH3CH,, - S C;N Y COOR ( I I I) in which R, R2 and Y are as defined above and, if the resulting compound has the formula 11 R20 e CH..C H 1 C.

rm COOR (II) in which R, R2 and Z are as defined above, converting compound 11 to compound lb and/or isolating compound lb from compound 11; and as appropriate and as desired, carrying out any one or more of the reactions described in steps (2) to (4) above, in any appropriate order.

The reaction between compounds III and IV is preferably carried out in the presence of a base, for example, a non-nucleophilic base, for example, a tertiary amine, for example, triethy lamine, pyridine or lutidine or an alkali metal hydroxide or alkoxide having from 1 to 4 carbon atoms. A solvent is generally used, for example, a polar solvent, for example, acetonitrile, dimethylformamide, dimethylsulphoxide or dimethylacetamide. The reaction temperature is, for example, within the range of from 0 to 100'C, preferably from 20 to 80'C. A molar excess of 50 the phenol of formula IV may be used, for example, the molar ratio compound lll:compound IV is 1:5 to 1:2.

If compound III is a mixture of 511 and 5S isomers the resulting mixture of isomers of formula 11 may be separated chromatographically or, preferably, may be subjected to a thermal stereo- chemical inversion as described above. If a substantially pure 513-isomer of formula III is used, the resulting compound lb is the corresponding 513-isomer, also in substantially pure form.

If Z in the resulting compound is other than a free amino or lower alkylamino group, then the group Z is converted into such a aminocarbonyl group, for example, as described below. This reaction may be carried out at any appropriate point in the series of reactions involved in the production of compound Ia. A protecting group R or R2 present may be removed, or converted 60 into a different, for example, "pro-drug", group. These and other interconversions may be carried out as outlined above and described in more detail below.

Many compounds of formula III are known and may be produced by reacting a compound of formula XlVa or XIVb C113CH,,' r--rrs\-S (XlVa) COOR GB2195627A 10 CHPt, S 00O (XIVb) COOR in which R and R2 are defined as above or a tautomer thereof having an endocyclic double bond with the appropriate reagent to produce the desired compound of formula 111. Such reactions are either known per se or may be carried out analogously to known reactions for the production of similar compounds. (The term "known" is used herein to mean in actual use in the art or described in the literature of the art.) A compound of formula XIVa. may be produced by a process as described in our Specification

No. 2 087 880A or Specification No. 2 118 546A, and a compound of formula XIVIJ may be produced as described in DE 2 950 898 or J 56 115 788.

Examples of methods for producing various compounds of formula III from a compound of formula XIVa, from a compound of formula XIVb, or from another starting material are as follows:

(i) Where Y represents certain phenoxy groups, a compound of formula IIImay be produced as 20 described in our UK Specification No. 2 102 798A, and where Y represents certain phenylthio groups, as described in EP 0 002 2 1 OA. Other compounds of formula III may be prepared analogously. (ii) Where Y represents a group

0 (1 -XP (ORa)) 0 or -X5 (Ra) 2 in which X and R,, are defined as above, a compound of formula III may be produced by reacting 30 compound XlVa or compound XIVb with a phosphorus halide of formula XVIa or XVIb 0 (XVIa R -P (ORa) 2 0 11 t R - P(Ra) M1b) 2 in which R" represents a halogen atom and Ra is as defined above. The reaction is preferably carried out in the presence of a base, for example, a base having a pK>7, for example, a tertiary amine base, for example, triethylamine, diisopropylethylamine, or pyridine. The reaction is preferably carried out in a solvent or diluent that is inert under the reaction conditions, for example, a halogenated aliphatic or aromatic hydrocarbon, for example, chloroform or dichloromethane; a hydrocarbon, for example, toluene or xylene; an ether, for example, diethyl ether, tetrahydrofuran or dioxane; or acetonitrile. The reaction temperature is, for example, within the range of form -40 to +50C. The resulting phosphorylated compound of formula III is not generally isolated but is preferably reacted in situ with the compound of formula IV. (iii) Where Y represents a group - OSO,Rb in which R, is defined above, a compound of formula III may be produced by reacting a compound of formula XIVb with a compound of formula Cl-SO^ in which R, is as defind as above, this reaction generally being carried out in the presence of a base, for example, a base as described in section (ii) immediately above, and at a temperature generally within the range of from-78' to +50'C, preferably from -30 to OC, the product generally not being isolated but reacted subsequently in situ.. (iv) Where Y represents a group 0 1 -SR. or -SO,R,, in which R,, is as defined above, by oxidising the corresponding group SRa The oxidation may be carried out by means of a chemical oxidising agent, for example, a peracid, for example, peracetic acid or m-chloroperbenzoic acid; hydrogen peroxide; an alkylhy droperoxide, for example, t-butyl hydroperoxide; a permanganate, for example, potassium per- 65 4 4 n IS 11 GB2195627A 11 manganate; a perborate, for example, sodium perborate; or a persulphate, for example, potas sium persulphate.

The oxidation is carried out in a solvent or diluent that is inert under the reaction conditions, for example, a chlorinated hydrocarbon, for example, dichloromethane or chloroform or an oxygenated hydrocarbon, for example, diethyl ether, tetrahydrofuran or ethyl acetate. Particularly 5 preferred solvents are dichforomethane and ethyl acetate.

The oxidation is generally carried out at a temperature within the range of from -70 to +20'C, preferably from -40 to O'C.

The starting penem material having an -SR. group may be produced by as described in our UK Specification No. 2 102 798A or by a process analogous thereto. (v) Where Y represents a group

0 11 -U 1-CF31 a compound of formula Ill may be produced by reacting compound Mb with trifluoroacetic anhydride in the presence of a base.

An advantage of the process described above for the production of a compound of formula fa is that compounds of formula Ill, in which the group Y does not represent a -CONHR, group, 20 may be produced under conditions in which the desired group -CONHR, is unstable. The group can be converted into the desired -CONHIR1 group subsequently. This leads to higher yield and ease of handling the intermediate compounds.

As indicated above, the present invention provides a process for the production of a corn pound of formula fa Ia FO 1A13L C)-n\ CONHR1 COOR in which R, R' and R2 are defined as above, which comprises 35 producing a compound of formula lb RZO i-N 0; COOR (jb) in which R, R 2 and Z are defined as above by cyclising a compound of formula Va, Vb or Vc CH3CH, OC C0z NH CH3CH, 5 OOCOZ CH3CH,,, 5 OOCOZ )COOR 0 t 0 2 CZ0R Y COOR CX4 M 0 (Va) R70 (V))) (VC) in which R, R2 and Z are as defined above, and L' represents a chlorine or bromine atom; (i) in the case of compound Va eliminating HU (a) by treatment with a base a metal or a metal-containing reagent, a base and a metal or a base and a metal-containing reagent, (b) by electrolysis, (C) by photolysis, or (d) by reaction with a free radical-producing compound optionally in the presence of an initiator; (ii) in the case of compound V1a by treatment with a Lewis acid or a base, and (iii) in the case of compound Ve by treatment with a rhodium- or copper- containing compound 60 and, if desired or required, (B) carrying out step (2) as defined above and, as desired and as required, carrying out any one or more of the reactions defined in steps (2) to (4) above, in any appropriate order.

In process (i) (a) or (ii) the base used to cyclise compound Va or Vb preferably has a pK>9 and is, for example, a proton sponge, a tertiary amine, for example, triethylamine, an alkali metal 12 GB2195627A 12 alkoxide, for example, sodium or potassium methoxide or sodium or potassium athoxide, or lithium hexamethyidisilazide or lithium diisopropylamide.

A metal used to bring about cyclisation of compound Va is, for example, copper, palladium or nickel and a metal-containing reagent is, for example, CuCI, CuBr, Cut, NiCI2, Pc1C12 or a metal containing complex, for example, cuprous iodide-dimethyl sulphide complex, cuprous bromide dimethyl sulphide complex, cuprous iodide-tri-n-butylphosphine complex, tetrakis(triphenylphos phine) Pd(O), tetrakis(triphenylphosphine) Ni(O), bis)cyclooctadienyl) nickel and bis[1,2-di-(diphenyi phosphino)ethane]nickel dichloride. Palladium (0) metal is particularly prefered.

The reaction is preferably carried out in a solvent or diluent, inert, non hydroxylic solvents being prefered. Examples of such solvents are tetra hydrofuran, hexamethylphosphoramide, and dimethoxyethane. The reaction temperature is, for example, in the range of from -78'C to room temperature.

When compound Va is caused to cyclise by electrolysis, the electrodes are, for example, graphite, or a metal, for example, copper or platinum, In wire, plate or gauze form. The electrolysis cell used is generally divided by a semi-permeable membrane, for example, by a frit 15 covered with a gel comprising 0.1 M lithium perchloride in dimethyl formamide and methylcellu lose, or by a perfluorinated exchange membrane.

The supporting electrolyte may be selected from those in conventional use in electrolysis of organic compounds, for example, lithium perchlorate, tetraethylammonium perchlorate, tetraethy lammonium p-toluenesulphonate or tetra butylammon ium tetrafluoroborate. The solvent may also 20 be one in conventional use, for example, acetonitrile or aqueous acetonitrile, or an alcohol, for example, methanol. The temperature may be, for example, within the range of from -10 to +30'C, for example, from 0 to 20'C.

A photolytically induced cyclisation of a compound of formula Va is preferably carried out using a medium or high pressure mercury lamp, and in a solvent, for example, an aliphatic 25 hydrocarbon, for example, pentane or hexane, an ether, for example, diethyl ether, or an alcohol, for example, ethanol.

A free radical-producing reagent may be used to effect cyclisation of compound Va, for example, an alkyitinhydride, for example, tri-n-butyltin hydride preferably in the presence of an initiator, for example, azabisisobutyronitrile or a peroxide. The reaction is preferably carried out the presence of a solvent, for example, an aliphatic or aromatic hydrocarbon, for example, hexane, xylene or toluene, a halogenated hydrocarbon, for example, dichloromethane or chloro form, or an ether, for example, diethyl ether, dioxane or tetra hydrofuran. The reaction tempera ture is generally within the range of from 30 to 100'C, preferably from 60 to 800C.

According to reaction (ii), the epoxide Vb is cyclised by treatment with either a Lewis acid, for 35 example, trimethylaluminium trifluoroacetic acid, borontrifluoride- etherate, aluminium trichloride, tin (N) chloride or p-toluenesulphonic acid, or with a base generally having a pK>9, for example, as described above. The reaction is generally carried out in a solvent, for example, a hydrocarbon, for example, benzene or toluene, an ether, for example, diethyl ether, tetrahydrofuran or dioxane, a halogenated hydrocarbon, for example, dichloromethane or chloroform, an aprotic solvent, for 40 example, dimethylformamide, or dimethylacetamide, or acetonitrile.

According to reaction (iii), the diazo compound Vc is cyclised in the presence of a copper- or rhodium-containing compound. A rhodium-containing compound is, for example, rhodium acetate, and a copper-containing compound is, for example, copper- bis(acetylacetonate) cf, for example, D.M. Brunwin et al J. Chem. Soc. 1971, 3756. The reaction is generally carried out in a solvent, 45 for example, an aromatic hydrocarbon, for example, toluene, xylene or, especially benzene, a chlorinated hydrocarbon, for example, dichloromethane or carbon tetrachloride, or an ether for example, tetrahydrofuran or dioxane. The reaction temperature is generally within the range of from 30 to 100'C, preferably from 40 to 80'C.

Any one or more of the reactions described in steps (2) to (4) above may be carried out on a 50 resulting compound, if desired or required.

Compounds of formula Va, Vb and Vc may be produced as shown in the Reaction Scheme 11 below.

Q in 30 13 GB2195627A 13 REACTION SCHEME 11 R20 -"3t-" VL NH 0 NH lx) R70 15 IS on\ Coz ]H _J 0:1H V] COOR (XX) 20 R 20 25 25 CH3CH NfAH S ' OF5,0Z ti \ 0 COOR R2C) CH3CH, S 0C C07 0 N2'_'C,00R (D (va) (VC) 30 R20 'S o 0 C0z 35 0j- NIAH M Ll - (V b) COOR in which R, R2, L and Z are defined as above.

Certain compounds of formula XIX are known, for example, when R2 represents a dimethyl-t- 40 butylsily] group (Belgian Patent Specification No. 882 764), and when R2 represents a p-nitroben zyloxycarbonyl group (EP 0 002 2 1 OA). Other compounds of formula XIX may be prepared analo gously.

When compound X1X is reacted with a compound of formula XX1a S 45 ROOC CH 2 - c 0-&COZ XXIa 50 in whichR and Z are defined as above, compound XX is obtained. This reaction is generally carried out in the presence of a base, for example, an alkali metal alkoxide, sodium hydride or a tertiary amine base, for example, sodium methoxide, or triethylamine. The reaction is generally 55 carried out in a solvent or diluent, for example, acetonitrile or hexamethylphosphoramide, an alcohol, for example, methanol, an ether, for example, tetrahydrofuran or a chlorinated hydrocar bon, for example, dichloromethane. A mixture of two or more solvents may be used, for example, a mixture of hexamethylphosphoramide and tetrahydrofuran. The reaction temperature is for example, in the range of from O'C to room temperature.

Compound XX may then be reacted with the appropriate reagent to give a compound of formula Va, Vb or Vc:

Compound Va may be produced by reacting compound XX with a halogenating agent, for example, bromine, N-chlorosuccinimide, N-bromosuccimide, N-bromoacetamide, or pyridine hydro bromide perbromide. The reaction may be carried out in the presence of a base, for example, an 65 14 GB2195627A 14 amine base, for example, triethyLamine or pyridine. The reaction is generally carried out in a solvent or diluent, for example, Afi ether, for example, tetrahydrofuran or diethyl ether, an aromatic hydrocarbon, for example, benzene, or a chlorinated hydrocarbon, for example, dichloromethane, at a reaction temperature, for example, within the range of from -70 to 6WC.

Compound XX may be converted into the epoxide Vb by reaction with a peracid, for example, peracetic, m-chloroperbenzoic, mono-perphthalic or trifluoroperacetic acid, t-butyl hydroperoxide, or hydrogen peroxide optionally in the presence of a base. In the case of t-butyl hydroperoxide a metal agent is also often used, for example, vanadyl acetoacetonate, or a salt of vanadium (V) or of molybdenum (V1). The reaction is generally carried out in a solvent or diluent, for example, an ester, for example, ethyl acetate, a chlorinated hydrocarbon, for example, dichloromethane or 10 chloroform, or an aromatic hydrocarbon, for example, toluene, and at a temperature, for example, within the range of from -70 to +40'C, preferably from -20 to +20'C.

Compound Vc may be produced from compound XX by diazo transfer, for example, using pdodecylbenzenesulphonyl azide or p-toluenesulphonyl azide which may be polymer-bound. This reaction is generally carried out in the presence of a base, preferably an organic base, for 15 example, a tertiary amine, for example, triethylamine or diisopropylethylamine or DBU. The reaction is preferably carried out in a solvent that is inert under the reaction conditions used, for example, acetonitrile or a chlorinated hydrocarbon, for example, dichloromethane. The reaction temperature is generally within the range of from -20 to +20C.

Compound Va may be obtained directly from compound XIX by treating a compound of 20 formula XXlb t L S 1 11 ROOC-CH-C-0 0\/ COZ in which L, R and Z are defined as above, with a base, preferably having a pK>-9, for example, as described above and preferably triethylamine and then incorporating compound XX A solvent is generally used, for example, an ether, for example, diethyl ether, dioxane or tetrahydrofuran, a hydrocarbon, for example, benzene or toluene, a chlorinated hydrocarbon, for example, dichloro methane, or a mixture of two or more solvents. The reaction temperature is generally within the 30 range of from -20 to +WC.

The conversion of a resulting compound lb into a compound la, and any of the further various optional interconversions desired may be carried out at an appropriate point as described briefly above and in more detail below.

One advantage of the processes described above for the production of a compound of formula 35 la using a compound of formula Va, Vb or Vc is that a strong base is not used, so the possibility of undesired side reactions is reduced. A further advantage is that the number of steps from the initial compound of formula XIX is small, indeed, compound]a can be produced from compound XIX via compound Va in only,two steps. For the other routes only three steps are involved.

As indicated above, the present invention provides a process for the production of a compound of formula la R20 45 CHP4,, --T" S 0-n\ CONIAR1 1N Ia COOR 50 in which R, R' and R2 are defined as above, which comprises producing a compound of formula lb R20 CH3CH,, ' -",S 0-0_%, C0Z 0J1 N COOR 60 in which R, R2 and Z are defined as above by cyclising a compound of formula Vla, Vlb, VIc or VId GB2195627A 15 ' R70 X CH3CH 11 SCO COZ 3 0 N p(O) COOR R20 LH31 l SC110- n/coz 0 COOR X (VIa) (VIb) 10 R20 X R20 k-"3CH, osco-n\ COZ S R6 15 0) H-RS 0):, f P(O13 COOR CO3OR n 20 (Vic) (Vid? in which formulae R, R2, Rs, R6, X, Z, n and P03 are as defined above, 2 5 (i) in the case of compound Via, by heating compound Via or allowing compound Via to stand 25 at room temperature, (ii) in the case of compound Vib, by treatment with a trivalent organophosphorus reagent and the heating the resulting compound or allowing the resulting compound to stand at room temperature; (iii) in the case of compound Vie, by treatment with a phosphine followed by treatment with a 30 base, and then heating the resulting compound or allowing the resulting compound to stand at room temperature; (iv) in the case of compound Vid by reaction with a compound of formula V11 X 35 7 1 R - c - 0 -00 -COZ (Vii in which R7, X and Z are as defined above, and heating the resulting compound or allowing the resulting compound to stand at room temperature; and as required and as desired, carrying out any one or more of the reactions described in steps (2) to (4) above, in any appropriate order.

The procedures described in (i) to (iv) above are each generaly carried out in a solvent, for example, an aromatic hydrocarbon, for example, benzene, toluene or xylene, a chlorinated hydro carbon, for example, dichloromethane, chloroform or 1,2-dichloroethane, an ether, for example, 45 dioxane, tetrahydrofuran or di-n-butyl ether. The reaction in each case is generally carried out at a temperature within the range of from 20T to 14WC, preferably from 800 to 1 100C. In each case the reaction is generally carried out under an inert atmosphere, for example of nitrogen and, if desired in the presence of hydroquinone, for example, in an amount 0.01 to 0.1%, % mole ratio calculated on compound Via, Vib or Vic. Each reaction may be carried out under high 50 dilution. In those cases where X in a compound of formula Vib used in sulphur, the organophos phorus compound is preferably added slowly to the reaction mixture comprising the compound of formula V1 used.

Further details of the organophorus reagents used are given below.

Compounds of formulae Via, Vib, VIc and Vid may be produced as described in Reaction 55 Scheme Ill below:

16 GB2195627A 16 REACTION SCHEME N R20 CH3CH L 0 NH IX) R20 R20 X X Cli,CH C9 0 -FCOZ CHjCH, 0 C07 0 _JINN1H (XXII) 1 R20 1 X SCO-OCOZ 0 IZN COOR (VIb) RIO 5---7 N 01'41?P(O13 GOOR (VId) ,n 11 R6 R20 0 COOR N H-OH COUTI (Xxvi RIO X I N coz - CH3C", '4SC0-<_\) - I J N, CH-R5 I COOR (VIC) R20 X CH 11 3( S 0 0CO2 0,5,1-A,?P[0)3 COOR (VIa) In Reaction Scheme Ill, R, R2, R, Z, L and P(Q), are defined as above.

Certain compounds of fomula XIX are known, for example, when R2 represents a dimethyl-t butylsilyl group (Belgian Patent Specification No. 882 764), and when R2 represents a p-nitroben- 40 zyloxycarbonyl group (EP 0 002 2 1 OA). Other compounds of formula XIX may be prepared analo gously.

The compound of formula XXII may be prepared by reacting a compound of formula XIX with a compound of formula XXIII X ^ 11 c 00C0Z (XXIII) in which X and Z are defined as above, and M represents an alkali metal or alkaline earth metal atom, or an ammonium group that is unsubstituted or substituted by, for example, one to four 50 groups selected from alkyl groups having from 1 to 4 carbon atoms.

in this process, the reaction is generally carried out in a solvent that is inert under the reaction conditions, for example, in an ether, for example, diethyl ether, dioxane or tetra hydrofuran, an aromatic hydrocarbon, for example, benzene, toluene or xylene, or a halogenated hydrocarbon, for example, chloroform, carbon tetrachloride or dichlorom ethane.

Compounds of formula XXIII in which M represents an alkali metal or alkaline earth metal atom may be prepared by reacting a compound of formula XXIV HOOCOZ WIV) in which Z is defined as above in the presence of a base comprising the radical M, for example, an alkali metal hydroxide or ammonium hydroxide with carbon disulphide or carbon oxysulphide.

A compound of formula XX11 may then be acylated using a compound of formula XXV 17 GB2195627A 17 COR14 COOR 1Z (XXV) in which R is as defined above and R14 represents a group that can be displaced by the azetidinone nitrogen in the compound of formula XXII to give a compound of formula VIb.

A group R14 is, for example, a halogen atom, an imidazolide group, or a mixed anhydride group, for example, a group -OCORc or -OC(O)01Rc in which Rc represents a straight or branched chain alkyl group having from 1 to 4 carbon atoms. R14 preferably represents a halogen atom, especially a chlorine atom.

The reaction between compound XX11 and the acylating agent of formula XXV is carried out in the presence of a base, for example, a tertiary amine, preferably a trialkylamine (each alkyl moiety having from 1 to 4 carbon atoms and having a straight or branched chain, the three alkyl moieties being the same or different), and especially triethylamine or ethyidiisopropylamine; or pyridine or a substituted pyridine, for example, 4-dimethylaminopyridine. Particularly preferred bases are triethylamine and ethyidiisopropylamine. A mixture of two or more bases may be used, and a base may be polymer-bound.

In addition to an organic base as described above, it is preferable to include an acid binding agent in the reaction mixture. Examples of acid binding agents are alkali metal and alkaline earth metal carbonates and bicarbonates, and organic epoxides, for example, propylene oxide. Calcium carbonate is a commonly-used binding agent.

In general, for each mole of compound XXII there is used from 1 to 2 moles of the acylating 25 agent XXV, from 1 to 4 moles of an amine base (or a total of from 1 to 4 moles of a mixture of amine bases), and from 0 to 10 moles of the acid binding agent, if present.

The compound of formula XXII and the acylating agent of formula XXV are generally reacted in a solvent or diluent that is inert to the reaction, for example, in a halogenated hydrocarbon, for example, dichloromethane or chloroform, in an oxygenated hydrocarbon, for example, an ether, for example, tetrahydrofuran, dioxane or diethyl ether, or in an aromatic hydrocarbon, for example, benzene or toluene. The reaction is generally carried out at a temperature within the range of from -20 to +WC, preferably from 0 to 2WC.

Compound Vib, the product of the acylation reaction, may be isolated if desired, but is generally reacted without further purification with a trivalent organophosphorus reagent to give a 35 compound of formula Via or to give a compound of formula lb directly.

Examples of trivalent organophosphorus reagents which may be used to convert compound VIb to compound Via or compound lb are phosphites and phosphoramides, for example, of the following formulae XXVia and XXVib, and phosphines of formula XXVIc in combination with phosphites of formula XXVia OR 16 OR 16 R 16 15 11 _ 17 16 11 17 18 16_)_ 17 45 R 0-P OR R 0-P-NR R R P R MVI a) (XXVI b) (XXVI c) in which formula R15, R16, R17, and RIO, which may be the same or different, each represents a 50 straight or branched chain alkyl group having from 1 to 6 carbon atoms or a phenyl group whicK may be unsubstituted or substituted, for example, by a methyl group, especially a para-methyl group; also cyclic trialkyl phosphites, each alkyl moiety having from 1 to 4 c&bon atoms, for example, of formula XXVId / A-0 \ CH 3 -C-A-0- P \ A-0 / (XXVI d) in which each group A denotes an alkylene group having from 1 to 4 carbon atoms; and also catechol phosphites and catechol dimer phosphites, for example, of the following formulae XXVie and XXV]f, respectively:

18 GB2195627A 18 1 o', P-00 '-'-,0-, P-A- lo"r:5 U, 0/ p\0AJ (XXVIe) ('XXVTf) in which R's and A are defined as above. A trivalent organophosphorus compound may be bound to an inert polymer.

A preferred trivalent organophosphorus reagent is a phosphite or phosphoramide of formula XXV[a or XXVIb respectively, or a combination of a phosphine of formula XXVic with a phosphite of formula XXVia. Particularly preferred are the trialkyl phosphites, and especially trimethyl phosphite and triethyl phosphite.

When the organophosphorus reagent used is a phosphite or phosphoramide, generally from 2 to 3 moles thereof are used per mole of compound Vib. When a phosphine is chosen, from 1 to 3 moles are generally used per mole of compound Vib, in combination with a phosphite, generally 1 mole thereof. The phosphite is preferably added slowly to a mixture of the phos phine and the compound Vib.

As described above, a resulting compound of formula Via may be isolated and then cyclised to a compound of formula lb, or a compound of formula Vib may be reacted with the organo phosphorus reagent and cyclised in situ to give a compound lb. In the latter case, the reaction 20 may proceed via compound Via or via another intermediate.

The cyclisation reaction is generally carried out in a refluxing solvent. When X in compound Vib or compound Via represents a sulphur atom, preferred solvents are aromatic hydrocarbons, for example, benzene, toluene and xylene, and halogenated hydrocarbons, for example, dichloro methane, chloroform and 1,2-dichloroethane. When X in compound Via or Vib represents an oxygen atom, preferred solvents are benzene, toluene and xylene. An ether, for example, di-n butyl ether, may be used as solvent when X is a sulphur atom or an oxygen atom.

In a compound of formula Via, it can be seen that the group P(Q)3 is derived from the trivalent organo-phosphorus reagent or mixture of reagents used in its production, which reagent or mixture of reagents is preferably selected from the reagents of formula XXV]a to XXVif 30 described above. As mentioned above, the organophosphorus reagent may be polymer-bound, in which case a resulting compound of formula Via will also be polyer-bound.

Compound lb may be produced from compound XXII by an alternative route via compounds XXVII, Vic and optionally Via as shown in Reaction Scheme Ill.

By this route, a compound of formula XXII is reacted with a glyoxylic ester of formula XXVIII 35 0 0 11 H FIC - C - OR (XY.VI I I) in which R is as defined above, or with a reactive derivative thereof, for example, a hydrate or hemiacetal, a herniacetal preferably being formed with an alcohol having from 1 to 4 carbon atoms, for example, ethanol.

When a hydrate of a compound of formula XXVIII is used, the water formed during the 45 reaction is preferably removed, for example, azeotropically or by use of a dehydrating agent, for example, a molecular sieve.

The reaction is generally carried out in a solvent or diluent that is inert under the reaction conditions, for example, an ether, for example, tetra hydrofuran, dioxane or diethyl ether, an aprotic solvent, for example, dimethylacetamide or dimethylformamide, or an aromatic hydrocar50 bon, for example, benzene or toluene. A mixture of two or more solvents may be used. The reaction is generally carried out at a temperature within the range of from 0 to 100'C. Preferably from 1 to 2 moles of the glyoxylate derivative are used per mole of compound XXII.

The resulting compound of formula XXVII is obtained as a mixture of the Rand S-isomers at the >CH-OH group. These isomers may be separated, if desired, but the R,S- mixture is gener- 55 ally used for the next reaction.

In the next step, the alcohol of formula XXVII is converted into a halide of formula Vic. The halogenation may be carried out in a conventional manner using an appropriate agent, for example, thionyl chloride or bromide, phosphorus oxychloride or oxybromide, or a phosphorus halide, for example, phosphorus pentachloride or pentabromide, or a mixture of two or more 60 thereof.

The reaction is preferably carried out in the presence of a base, for example, a heterocyclic base, for example, pyridine, 4-dimethylaminopyridine, or lutidine, or a trialkylamine, for example, triethylamine or diisopropylethylamine. The base may be polymer-bound.

The reaction is generally carried out in a solvent, for example, an ether, for example, diethyl 65 19 GB2195627A 19 ether or dioxane. The reaction temperature is generally within the range of from -40 to +400C, preferably room temperature and, if desired, the reaction may be carried out under an inert atmosphere.

The resulting compound of formula Vic is obtained as a mixture of the Rand S-isomers at the >CH-Cl or >CH-Br group. As in the case of compound XXVII, the isomeric mixture may be 5 separated into the individual isomers, but generally the R,S-mixture is used.

A compound of formula VIc may be converted into a compound of formula lb. This reaction may proceed via a compound of formula Via or via another intermediate. If desired, a compound of formula Vic may be treated with a phosphine and a mild base to give a compound of formula Via, which may then be isolated and cyclised to give a compound of formula lb.

A compound of formula VIc may be converted into a compound of formula lb or of formula Via by reaction at an appropriate temperature as described above with a phosphine of formula XXVIc, for example, triphenylphosphine.

The reaction is preferably carried out in the presence of a base, for example, an alkali metal carbonate or bicarbonate, or an organic amine,for example, a tertiary amine, for example, pyridine or a pyridine derivative, or a trialkylamine, for example, triethylamine or diisopropylethy lamine. The reaction is generally carried out in a solvent that is inert under the reaction conditions, for example, an aromatic hydrocarbon, for example, benzene or toluene, or an ether, for example, diethyl ether, tetrahydrofuran or dioxane.

The reaction temperature is generally within the range of form - 10 to 150C. As mentioned 20 above, the use of lower temperatures, for example, room temperature or below, generally enables a compound Via to be isolated, whereas higher temperatures, for example, above room temperature, generally lead to compound lb directly.

A compound of formula lb may be produced by a third method, which is also shown in Reaction Scheme 111. This method comprises reacting a heavy metal mercaptide of formula VId 25 R20 -R6 N 0 1?P"3 COOR A (VId) in which P(Q)3, R2 and R6 and are defined as above, with a compound of formula Xlia X nil C-OCCOZ (XIIa) in which R", Z and X are defined as above.

A compound analogous to formula Vid but in which Q represents a phenyl group is described in GB 2 042 515A, which also describes a process for the production thereof. The present compound of formula Vid may be produced analogously, using the appropriate trivalent organophosphorus reagent.

Compound Vid and Xlia are generally reacted in a solvent, for example, an ether, for example, 45 diethyl ether or dioxane, an aromatic hydrocarbon, for example, benzene, toluene or xylene, an ester, for example, ethyl acetate, a halogenated hydrocarbon, for example, dichloromethane or chloroform, or an aprotic solvent, for example, dimethylformamide or dimethylacetamide. The reaction temperature is generally within the range of from -40 to 1OWC, preferably from 0 to 50 4WC.

Compound Vid may be converted to compound lb either via compound Via or via another intermediate, compound Via optionally being isolated and then converted to compound lb. Lower temperatures, for example, from -40'C to room temperature, generally enable compound Via to be isolated, whereas higher temperatures, for example, from room temperature to 15WC, gener55 ally lead to compound lb.

In all the various intermediates involved in the production of a compound of formula lb by the procedures described in Reaction Schemes Ill the 8hydroxy group and the 2-carboxy group, when present, are preferably protected, with removal of the protecting groups preferably being delayed until after compound lb has been formed and, if appropriate, until any conversions of 60 groups R and/or R2, have been carried out.

Compound Vib may be produced by a different route, as shown in Reaction Scheme IV below:

GB2195627A 20 REACTION SCHEME IV R2C) R20 CH3CH, 5 CH SA9 N 3 h 1,H 0 CDOR ROOC CH3 10 MIX) (M) 15 R20 X R20 X J!0-n\ C0z SC o(/--\coz 20 0 0 XH3 C0OR ROOC CH3 (Vlb) (XXXI) 25 FO 30 X CH3CH 11 1, SCO-// \\coz -V 0 PN H (XXI I) in which R, R2, X and Z are as defined above.

The optionally protected penicillin derivative X= is reacted with a silver salt, for example, as described by M. Alpegiani et al, J. Am. Chem. Soc. 107, 6398 (1985). The reaction is carried 40 out for example, using silver nitrate generally in the presence of a base, for example, DBN or DBU. The reaction is generally carried out in a solvent that is inert under the reaction conditions, for example, acetonitrile, and at a temperature within the range of from - 30,C to +40'C, preferably from 0' to 2WC.

The resulting silver compound XXX may be isolated but generally the reaction mixture is 45 treated with a compound of formula Xlia X 1111 R C-OGCW (XIIa) in which W', X and Z are defined as above, optionally in the presence of a base, to give a compound of formula XXXl. The base, if present, is generally an organic base, especially triethylamine or pyridine. The reaction is generally carried out in a solvent, for example, an ether, for example, diethyl ether; a chlorinated hydrocarbon, for example, dichloromethane or chloro- 55 form; acetonitrile, dimethyifgrmamide or ethyl acetate. The reaction is generally carried out at a temperature within the range of from-20' to +45'C, preferably from 0, to 2WC.

Compound XXX1 may be converted directly into compound Vib by ozonolysis, or by using a chemical oxidising agent, for example, a permanganate, for example, potassium permanganate; or a persulphate, for example, potassium persulphate.

The oxidation is carried out in a solvent or diluent that is inert under the reaction conditions, for example, a chlorinated hydrocarbon, for example, dichloromethane or chloroform or an oxygenated hydrocarbon, for example, diethyl ether, tetrahydrofuran or ethyl acetate, methanol or acetone. Particularly preferred solvents are dichloromethane, ethyl acetate and acetone.

The oxidation is generally carried out at a temperature within the range of from -78 to 65 21 GB2195627A 21 a ;i +20"C, preferably from -50 to O'C.

Alternatively, compound XXXI may be converted into compound Vib via compound XXII. In this case, ozonolysis or chemical oxidation is carried out in the same manner and under the same conditions as described above for the production of compound Vlb. The product from this reaction is then treated with methanol at room temperature, optionally in the presence of silica 5 gel to give compound XXII. Compound Vib may then be obtained from compound XXII as described in Reaction Scheme III above.

In compound XXXI, when X represents a sulphur atom, the oxidation can be controlled to give a compound of formula Vib in which X represents either a sulphur or an oxygen atom. Those compounds of formula Vib in which X represents a sulphur atom, are preferred and such compounds may be obtained by using an appropriate predetermined amount of ozone or chemi cal oxidant.

A carboxy protecting group R in compound XXXI in this Reaction Scheme is that present in the starting penam XXIX. If this carboxy protecting group is a group desired for the final penem of formula 1, for example, a p-nitrobenzyl group, then the direct route from compound XXXI to 15 compound Vlb is preferred. If, however, it is desired to change the carboxy protecting group R, then the indirect route via compound XXII enables this to be done.

Any interconversion preferred or required, to produce a desired compound la may be carried out at an appropriate point, for example, as described briefly above and in more detail below.

The routes to compound I described in Reaction Scheme IV have the advantage of being 20 shorter than would be described in UK Specification No. 2 161 161A, especially if the route chosen is from compound XXIX via compounds XXX, XXXI and Vib. Moreover, the starting material of formula XXIX is readily available and relatively cheap (the silver salt can be recovered for further use). Furthermore, the stereochemistry at position 5 of the starting material of formula XXIX is retained throughout the reaction sequence. The naturally occurring penicIlin generally 25 used has the desired 5R-stereochemistry, and so ultimately does the end product of formula Ia.

As indicated above, the present invention provides a process for the production of a com pound of formula Ia R20 CH3CH - 5 0 CONHR1 0. Nr (1a) COOR in which R, R' and R2 are defined as above, which comprises producing a compound of formula lb R20 '3UH,, COZ (1b) 0-(/ oN \_ COOR in which R, R2 and Z are defined as above by cyclising a compound of formula Villa or Villb 45 (viiia L ROOCKOO\ C0Z 1 1 ill p20 (V111b) 0 L ROO',Koi ",' , =2 1 0 7 in which formulae R, R2, R 6, and W, n, L and Z are defined as above and 5 5 (i) in the case of compound Villa, effecting cyclisation, and (ii) in the case of compound Villb, removing the sulphur protecting group, if present, and either reacting the resulting thiol compound with a reagent capable of converting that compound into a compound of formula Villa, and cyclising compound VIIIA or cyclising the thiol compound by treatment with a base; and as required and as desired, carrying out any one or more of the reactions described in steps (2) 60 to (4) above, in any appropriate order.

In some cases, on removing the sulphur protecting group R11 and reacting compound VIllb with a metal salt, compound lb generally in protected form may be produced directly. In some cases, a compound of formula Villa is produced as an intermediate and may be isolated, if desired, or reacted further in situ.

22 GB2195627A 22 Compound Villa can be cyciised spontaneously to give a compound of formula]b. This reaction is preferably carried out in a solvent or diluent, that is inert under the reaction conditions, for example, acetonitrfle, an aromatic hydrocarbon, for example, benzene or toluene, a halogenated hydrocarbon, for example, chloroform or dichloromethane, or an ether, for example, diethyl ether, dioxane or tetrahydrofuran. Acetonitrile is particularly preferred. The reaction mixture may be cooled, in which case the cyclisation takes place more slowly, or may be heated, in which case the reaction takes place more quickly. An example of a temperature range for carrying out this process is 0' to 100'C.

As indicated above compound Villa may be produced from compound V111b and may be isolated before cyclisation, or compound Villa may be produced from compound Vilib and cyclised in situ. In some cases, compound Villa may not be formed as an intermediate, but compound V1111b may be converted directly to compound lb.

Methods of removing sulphur protecting groups are well known, for example, McOmie, Protecting Groups in Organic Chemistry Plenum Press, London and New York, 1981, and T.W.

Greene, Protective Groups in Organic Synthesis, Wiley, New York 1981.

In some cases, it is not necessary to react compound Vilib with a suitable metal salt as cyclisation occurs spontaneously on removal of the sulphur-protecting group or upon treatment with a base. This is the case, for example, when R' in compound Vilib represents a pnitrobenzy] group. This compound Vilib may be reduced, for example, electrochemicaily or by catalytic hydrogenation. The use of, for example, hydrogen over a palladium-on-charcoal catalyst, 20 followed by treatment with a base, for example, an organic base, for example, triethylamine yields compound lb directly. A wide variety of bases may be used, providing the pK is greater than 9.

In some cases, R' must be removed first, and the resulting sulphurdeprotected compound reacted with a suitable metal salt, and in yet other cases the protected compound Vilib need not 25 be deprotected at the sulphur atom, but, can be reacted directly with a suitable metal salt.

A suitable metal salt is a salt capable of yielding Ag(i), Hg(il), Pb(11) or Cuffi), for example, silver nitrate, mercury diacetate, lead dinitrate, or copper (11) chloride.

When M' in compound Villb represents a triphenyimethyl group, then compound Villb may be reacted with a suitable metal salt, for example, with mercury diacetate or silver nitrate, especially 30 silver nitrate. This reaction which is generally carried out in a solvent or diluent, for exmaple, acetonitrile, a halogenated hydrocarbon, for example, chloroform or dichloromethane or an ether, for example, diethyl ether, tetrahydrofuran or dioxane, may be conducted in the presence of a protic or Lewis acid, for example, trifluoroacetic acid, anisole or hydrogen bromide in acetic acid.

The reaction temperature is, for example, within the range of from -20 to +100'C, preferably 35 from 0 to +50'C. Compound Villa may be isolated if desired by carrying out the reaction at a lower temperature, but it is generally satisfactory to use a temperature within the range of from 0 to 80'C, whereupon the cyclisation occurs in situ.

When R8 in compound Vilib represents a propen-2-yl group, compound Vilib may be con- verted into compound Villa by oxidation, for example, using ozone or a permanganate or periodate followed by hydrolytic cleavage using, for example, an organic base, for example, imidazole or pyridine in the presence of a metal salt capable of yielding Ag(I), Hg(I1), Pb(11) or Cuffi), for example, as described above. The ozonolysis reaction is, for example, carried out at a temperature within the range of from -80 to O'C, preferably from -60 to -20'C.

The hydrolytic cleavage may be carried out using. for example, silver nitrate or CdC03 in acetonitrile and in the presence of an acid binder. This reaction is preferably carried out at a temperature within the range of from -40 to +40'C. The reaction is generally carried out in a solvent or diluent.

When R' in compound Villa represents a t-butyl group this compound may be reacted with, for example, hydrogen fluoride, in a solvent, for example, anisole.

The reaction product from any of the above reactions has the desired 5Rstereochemistry and, if desired or required, may be subjected to any of the further processes described above, for example, the product may be deprotected to give a compound of formula 1, or may be converted into another ester, for example, a pro-drug form, and/or salt form, for example, as described briefly above, and in more detail below.

A compound of formula Vilib may be produced from a compound of formula XXXII A RIO H, SR 8 CH3C' "'F-T' (XXXII) 60 N XH 0 ROOC Orl -\coz in which R, R2, R8, X and Z are as defined above, by reaction with a reagent capable of 65 A 23 GB2195627A 23 introducing a group as defined above, for example, an acylating agent, for example, acetic anhydride or a trimethylcarbonyl halide, or another activating group for example, CH3S02CI1 (CF3SO2)20, (CF3CO)2O or p-toluenesulphonyl chloride.

The reaction is generally carried out in the presence of a base, for example, an organic base 5- having a pK>5, for example, a trialkylamine, for example, triethylamine, or pyridine. The reaction 5 is generally carried out in a solvent, for example, a hydrocarbon, for example, benzene or toluene; an ether, for example, diethyl ether, tetrahydrofuran or dioxane; a halogenated hydrocar bon, for example, dichloromethane, or an ester, for example, ethyl acetate.

A compound of formula XXXII may be produced by reacting a compound of formula XXXIII R20 CH3C SR8 0 N COOR MXIII) with a compound of formula VII X 20 Fc 0 0C0Z (VII) in which Z and X are as defined above, R7 represents a halogen atom, especially a chlorine atom, in the presence of a base.

While many phenyl chlorothionoformates are known, other chlorothionoformats of formula VII have not been described before; they may be prepared by methods analogous to those described for the preparation of known compounds, see for example, Rivier & Schalch, HeIv. Chem. Acta., Vol. 6, 1923, p 605 and Reich and Martin, Chem. Berichte, Vol. 98, 1965, p 2063. Chloroformates of formula VII may be produced by reacting the appropriate phenol of formula IV H00C0Z (IV) in which Z is as defined above, with phosgene. The reaction is generally carried out in a solvent or diluent, for example, an aliphatic or aromatic hydrocarbon or an aliphatic or aromatic chlori nated hydrocarbon, for example, hexane, benzene, toluene carbon tetrachloride, methylene chlo ride. The reaction temperature is, for example, within the range of from - 20 to +20T. For reactions of this type see for example, RJ. Cotter, M. Mauner and R.P. Kurkjy, Chem. in 40 Industry 1965, 791 or D.R. Patent Specification No. 287805.

The reaction between compound XXXIII and compound VII is carried out in the presence of a base, preferably having a pK,,-20, preferably a metallated amine, and examples of preferred bases are lithium diisopropylamide, lithium hexamethyidisiazide, lithium 2,2,6,6-tetramethylpiperi dide, lithium cyclohexyl isopropylamide, and sodamide.

The reaction is generally carried out in an aprotic solvent, for example, an oxygenated hydro carbon, preferably an ether, for example, diethyl ether, tetra hyd rofuran, dioxane, glyme or di glyme. The reaction temperature is, for example, from -120 to +30'C, preferably -78 to - 20'C.

The amount of base used is, for example, from 1 to 3 moles, calculated per mole of compound VII, preferably from 1.5 to 2.5 moles of base. The compound of formula XXX111 is preferably used in an amount of from 1 to 1. 5 moles per mole of compound VII, preferably from 1 to 1. 1 moles of compound V11 per mole of compound XXXIII.

The reaction may be carried out as follows: The base may be added to a stirred solution of compounds XXXIII and VII. Alternatively, to a stirred solution of compound XXXIII under an inert 55 atmosphere is added the base and subsequently a solution of compound V11 in the same or different solvent.

Some compounds of formula XXXIII are known, see, for example, GB 2 102 798A. Others may be prepared analogously.

An advantage of this process for the production of a compound of formula 1 is that the 60 stereochemistry at position 5 can be established in the initial starting material and maintained throughout the reactions involved. In particular, the initial starting material is conveniently com pound XXXIII, which can be obtained from commercially available materials and which, being derived from naturally occuring pencillin, has the desired R- stereochemistry at position 4. As no high temperature need be used in the various reactions involved, for example, the cyclisation of 24 GB2195627A 24 Villa or Vilib to compound lb can occur spontaneously, there is no substantial thermal interconversion at position 5. Accordingly, by starting with a substantially pure 4R-azetidinone derivative, a substantially pure 5R-compound of formula 1 can be obtained.

In each of the processes described above for the production of a compound of formula la FPO S 0--nCONHRS 0; (Ia) COOR 10 in which R, R' and R2 are defined as above, the initial product has the formula lb R20 15 U13LH (1b) 0 N o--/,/ \coz =j COOR in which R, R2 and Z are defined as above.

It will be appreciated that as mentioned above the group -COZ in formula lb can represent the ultimately desired -CONHRI group. In this case, compound la is produced directly. If -COZ in compound lb represents a protected aminocarbonyl group -CONHR3, -CONRIR3 or -CONR3R3, R3 representing a protecting group, the protecting group(s) R3 may be removed after formation of 25 compound lb or at any earlier stage of the reaction sequence. Similarly, if -COZ represents a -COR 4 group, for example, a -COXR5 group (x, R4 and R5 being defined as above), then this group may be converted to the desired aminocarbonyl group at any stage in the reaction sequence, either before formation of compound lb or after the otherwise desired compound is obtained.

Furthermore, and analogously, a -COOH group represented by -COZ may be converted into a free aminocarbonyl or lower alkylaminocarbonyl group at any stage before or after formation of compound lb, for example, at any appropriate point in any of the reaction sequences involved in the production of compound lb, for example, in compound 11. It is generally necessary to activate this carboxy group before reaction with ammonia or a lower alkylamine, respectively, or with an 35 equivalent reagent known in the art. The activating group may be introduced at any stage of the reaction sequence and, independently or concommitantly, the activated carboxyl group converted into a free aminocarbonyl or lower alkylaminocarbonyl group at any stage, that is to say, the intermediate activated compound may be produced in a separate reaction step and isolated, if desired, or it may be converted in situ into an aminocarbonyl compound, 4 The conversion of a carboxylic acid group into a free aminocarbonyl or lower alkylaminocarbo nyl group is well known in chemistry, and there is available to those versed in the art a wide range of reagents and methods. In general, as indicated above, the reagents function by convert ing a carboxylic acid group into an activated derivative thereof, which derivative is then reacted with ammonia or a lower alkylamine. Examples of the activation of a carboxylic acid group are 45 by conversions as follows:

(i) to an activated ester, for example, to a phenyl ester using, for example, a bisphenyl carbonate; (ii) to a phosphorous or phosphoric ester, or a phosphoric acid anhydride, using for example, a phosphinyl halide or a phosphoryl halide; (iii) to a carboxylic acid anhydride, especially a mixed anhydride, using for example, an acid chloride or bromide, for example, pivaloyl bromide, a carbodiimide, for example, dicyclohexylcar bodiimide or 1-(3-dimethylaminopropyl)-3-ethy[carbodiimide, or a chloroformate; (iv) to an imidazolide using, for example, N,N'-carbonyldiimidazole; (v) to an acid chloride using, for example, thionyl chloride; or (vi) to an O-acylurea using, for example, a carbodiimide, for example, as described above, and if desired, converting the 0-acylurea into an active ester, for example, an ester with 1-hydroxy benzotriazole or with N-hydroxysuccinimide.

Examples, of activated acid groups -COR4 that can be converted into groups of formula -CONHRI under reaction conditions that do not affect other parts of the compounds in question 60 (other than groups -COXR-1 as defined above) are, for example, groups of the formula -COOR9 in which R9 represents one of the following groups z 0 GB2195627A 25 0 0 0 0 11 11 R g 11 OR - C - R e - c - OR f R h - p OR h 5 0 N 10 N 0 1 in which R. represents an alkyl group having up to 4 carbon atoms, especially a t-butyl group; R, 15 represents an alkyl group having up to 4 carbon atoms, especially an iso- butyl group; R. and Rh, which may be the same or different, each represents an alkyl group having up to 4 carbon atoms or a phenyl group.

The above methods are examples of the techniques available to the art, and do not constitute an exhaustive list. For further information see, for example, M. Bodanszky, Y.S. Klausner and 20 M.A. Ondetti,---PeptideSynthesis-, J. Wiley and Sons, New York, 1976, and N.F. Norton, Organic Reactions, Vol. 12, 157 (1962).

Some of the methods for converting a carboxylic acid group into an aminocarbonyl or lower alkylaminocarbonyl group are extremely mild and therefore well suited to the conversion of a penem containing a carboxylic acid group into a penem containing an aminocarbonyl or lower alkylaminocarbonyl group without damage to any other part of the molecule. Thus, for example, a solution of a carboxylic acid of formula lb (Z=OH) in an inert solvent for example, dichloro methane, acetonitrile or tetra hyd rofura n, may be treated with a carbodiimide, for example, dicy clohexylcarbodiimide and 1-hydroxybenzotriazole at a temperature within the range of from -40 to +40'C, preferably from 0 to 20'C, to form the benzotriazol-l-yl ester.

In the case of a compound in which -COZ represents the group -COXRS, R5 preferably represents a phenyl group substituted by one or more chlorine and/or fluorine atoms. When X represents a sulphur or oxygen atom, R5 especially represents a pentafluorophenyl group, and when X represents a sulphur atom, 4-chlorophenyl, 4-cyanopheny], 4-methoxyphenyl and 2,4,5trichlorophenyl groups are also particlarly preferred as R5.

Reaction of a compound having an activated acid group -COR4 with ammonia or a lower alkylamine is preferably carried out at a temperature within the range of from -40 to +40,C, preferably from 0 to 20'C. The choice of solvent is wide, provided that the solvent does not itself react with any of the reagents or intermediates. For this reason it is often preferable to use a solvent mixture that is substantially free of water. Example of suitable solvents are dimethylfor- 40 mamide and, acetonitrile.

The reaction between ammonia or a lower alkylamine and the appropriate compound may be carried out in the presence of a metal salt, especially a salt of a metal selected from Groups IB, IIB and Vill of the Periodic Classification of the Elements (cf E. Cartmell & G.W.A. Fowles, Valency and Molecular Structure, Butterworths, 1966), for example, a salt or copper, rhodium, 45 mercury, zinc, cadmium, or especially, silver. The salt is, for example, a salt with an organic or inorganic acid, for example, with perchloric tetrafluoroboric, acetic, trifluoromethanesulphonic, or trifluoroacetic acid, or with imidazole. Examples of preferred salts are silver acetate, silver trifluoroacetate, silver trif luoromethanesul phonate, and silver imidazolide.

The degree of advantage resulting from the presence of a metal salt during the reaction 50 between ammonia or a lower alkylamine and the appropriate compound depends on the reacti vity of the -COR4 group in the compound in question, and may be determined empirically, for example, there is not generally a substantial advantage when -COR4 represents a group -COXR5 in which X represents an oxygen atom. In the case of a compound having a pentafluorophenyl- thio ester group, a metal salt may be used if desired, but the resulting advantage is not large, whereas for other compounds in which X represents a sulphur atom, the presence of a metal salt during the reaction may greatly increase the yield. A cyano group COZ can be converted into a group -NHRI by methods as described in J. March, Advanced Organic Chemistry, 3rd Edition, J. Wiley. (1984), 788-789. 60 A further reaction which may be carried out at any suitable point in a reaction sequence before or after formation of a compound lb or la is the conversion of an 8S-hydroxy group, which may be free or protected, into the desired 813-configuration. Methods for carrying out a stereochemical inversion at the 8-position of a penem are known, see, for example, 1. Shinkai et al, Tetrahedron Letters, 1982, 4899. 65 In one example of such a technique a free 8-hydroxy group is oxidised to give an oxo group, 65 26 GB2195627A 26 which is then reduced to a hydroxy group. The oxidation may be carried out using, for example, a dimethylsulphoxide-trifluoroacetic anhydride- triethylamine reagent, cf A.K. Sharma and D. Swern, Tetrahedron Letters, 1974, 1508, and S.L. Huang et al, Synthesis 1983, 279. The reducing agent used may be an alkali metal tri-sec-butylborohydride in which the alkali metal component is, for example, lithium, sodium or potassium, c.f. F.A., Bouffard et al, J. Org. Chem. 1981, 46, 2210, or may be a di- isopropylamine-borane complex in the presence of magnesium trifluoroacetate cf P.J. Reider et A Tetrahedron Letters 23 2293 (1982). The reduction may give one substantially pure diastereoisomer, or a mixture of isomers which can be separated.

In another method, a di-lower alkyl azodicarboxylate-triphenylphosphine complex reagent is used. This type of reaction is described by 0. Mitsonobu in Synthesis, 1981 page 1. It involves, 10 for example, reacting the free hydroxy compound with a mixture of triphenylphosphine and the di-lower alkyl azodicarboxylate in the presence of a nucleophilic agent, for example, an acid, for example, a carboxylic acid, for example, formic or benzoic acid, or a carboxylate and in solution in a solvent that is inert to the reaction conditions followed by hydrolysis of the modified hydroxy group to give the free hydroxy group again, for example, as shown below in the case 15 of a hydroxy group converted into a benzoyloxy group:

OH OCOC 6 H 5 OH v T S ': R, F, -., 20 p", 0 J - N 1. 0 AI - N \ 0 25 The term -known- is used herein to mean in actual use in the art or described in the literature of the art. The term ---lower-denotes a group, radical or moiety having from 1 to 4 carbon atoms.

The various 2-ester, 8-ester and salt interconversions can also be carried out at any appropri ate point in a reaction scheme, after formation of compound lb or la or before their formation, 30 that is to say, at any appropriate point in the various reaction sequences described above for each of the process variants.

In general, when manipulations are to be carried out on a compound then conventional protecting groups at positions 2 and 8 may be advisable to prevent those groups from taking part in undesired reactions.

Preferred hydroxy-protecting groups R' are those that may be removed under conditions that do not otherwise affect the compound in which they are present. One type of preferred hydroxy protecting group R2 can be removed under

acidic conditions.

Such groups are well known in the art and are, for example, tetrahydropyranyl and tetrahydrofu ranyl groups; acetal and ketal groups, for example, of formula - C. - OR k R. R.

1 3 in which R, and R, which may be the same or different, each represents a hydrogen atom or a lower alkyl group, preferably a methyl group or Ri and R, together with the carbon atoms to which they are attached, represent a cycioalkyl ring having from 4 to 7 carbon atoms, and R, 50 represents a lower alkyl group, preferably a methyl or ethyl group, or Ri and R,, together with the carbon atom and the oxygen atom to which they are attached, respectively, represent a tetrahydropyranyl ring and, in this case, R, is hydrogen; also sily] ethers, for example, having three substituents on the silicon atom, and preferably up to 24 carbon atoms in total, the three substituents being the same or different, and selected from alky], alkenyl and cycloalkyl groups, 55 and phenyl and phenalkyl groups which may be unsubstituted or substituted as defined above, for example, -SiRR.R,, groups, in which R,, Rm and R,, may be the same or different, and each represents a lower alkyl group or a phenyl group, for example, giving trimethylsilyi, triethylsilyl, diphenyi-t-butylsilyi, t-butyidimethyisiiyi, and methyldiphenyisilyl groups; and stannyl groups, for example, having up to 24 carbon atoms and three substituents, which may be the same or different, selected from alkyl, alkenVI, cycloalkyl, alkoxy and phenoxy groups, and phenyl and phenalkyl groups which may be unsubstituted or substituted, for example, groups of the formu ]as SnR.RpR., in which R., RP and Rq, which may be the same or different, each represents a lower alkyl group, for example, a tri-n-butylstannyl group. (The term--- lower-is used in the present specification to denote groups having up to 4 carbon atoms.)

1; p j 27 GB2195627A 27 A further type of preferred hydroxy protecting groups R2 are carbonates, for example, unsubstituted or substituted alkyl or phenylalkyl carbonates, for example, p-nitrobenzyl carbonate and trichloroethyl carbonate.

Preferred hydroxy protecting groups R2 are p-nitrobenzyl carbonate, trichloroethyl carbonate, tetrahydropyranyl, 2-methoxyprop-2-yi, trimethylsilyl and, especially, triethylsilyl and t-butyidimethylsilyl groups.

Such groups may be removed, when required, by acid hydrolysis, for example, using 0.1 to 2M, preferably 0.5M hydrochloric acid, for example, 6M HCI in, for example, tetra hydrofuran, cf. Belgian patent specification No. 882 764; or aqueous hydrogen fluoride, for example, in the presence of acetonitrile, cf. J. Chem. Soc. Perkin 1, 1981, 2055.

In a compound of formula fa, the 8-hydroxy group, if esterified, is preferably in -pro-drug form that is to say, is esterified with a group that can be removed in vivo to give the free hydroxy group, that is to say, an ester group that can be removed under physiological condi tions. Examples of suitable esterifying groups are carboxylic acid acyl groups of the formula R 20CO- in which R20 represents a hydrogen atom or a straight or branched chain alkyl group having from 1 to 6 carbon atoms, especially a methyl, ethyl or t-butyl group, or represents a phenyl group or a phenoxyalkyl group in which the alkyl moiety is straight-chained or branched and has from 1 to 4 carbon atoms, and is especially a methylene group.

A non-physiologically removable protecting group R2 is generally removed from a resulting compound of formula fa, and may be replaced by a physiologically removable group, if desired. 20 In some cases, a carboxylic acid acyl group R2 may fulfil a protective role during the synthesis of compound fa. Such a dual function protective group may be removed, retained or replaced in formula fa, as desired.

An ester group at the 8-position may be the only ester group present, or it may be present in addition to an ester group at the 2-carboxyl group. As mentioned above, a physiologically removable group may be present as a protecting group R2 during the formation of a compound of formula fa, or it may be introduced at the free 8-hydroxy group of a compound of formula fa, after removal of a non-physiologically removable hydroxy protecting group, if present. An ester ifying group may be introduced at the 8-hydroxy group by a reaction with an organic acid derivative in known manner. A particularly convenient method is to react a compound of formula 30 fa with an activated acid derivative, for example, an acid anhydride in the presence of an organic base, for example, 4-dimethylaminopyridine.

As indicated above, various compounds may be in the form of an ester COOR at the carboxy group (R representing a carboxy esterifying group). Such an ester is particularly one that can be converted into the free acid by hydrolysis, photolysis, or reduction. Examples of such esters are 35 those formed with unsubstituted or substituted aliphatic alcohols or phenols having up to 20 carbon atoms in total. In an esterified carboxy group of formula -COOR,, the group R,, may be, for example, a straight or branched chain substituted or unsubstituted alkyl, alkenyl or alkynyl group having up to 18 carbon atoms, preferably up to 8 carbon atoms, and especially up to 6 carbon atoms, for example, a methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-penty], n-hexyi, allyl or vinyl group. An aliphatic group R. , especially a methyl or ethyl group, may be substituted, for example, by an acyloxy example (further details of such groups are given below) or by an aminoalkanoyloxy group, or an ethyl group R., may be substituted by an optionally substituted amino group at the 2-position, or a methyl group R., may be substituted by phenyl groups. A phenyl group, either per se or as a substituent of an aliphatic group, may 45 be substituted, for example, by one or more substituents, selected especially from nitro groups and halogen atoms. Examples of phenyl substituted-aliphatic groups are benzyi, p-nitro-benzy], benzhydryl and trityl groups.

As indicated above, for pharmaceutical use, an ester group is especially one that can be removed by hydrolysis, photolysis or reduction, or two or more of these methods may be used, 50 for example, reduction followed by hydrolysis. A group R. that can be removed readily without substantial degradation of the rest of the molecule is particularly useful as a carboxy protecting group. Examples of esters that are readily split by reduction are phenyl substituted-methyl esters, which may be unsubstituted or substituted, for example, benzyi, p- nitrobenzyl, benzhydry] and trityl esters.

Reduction of an ester, for example, a phenyl substituted-methyl ester, for example, a p nitrobenzyl ester, may be carried out using hydrogen and a metal catalyst, for example, a noble metal catalyst, for example, platinum, palladium or rhodium, which catalyst may be supported, for example, on charcoal or kieselguhr.

Alternatively, a p-nitrobenzyi ester may be converted into the corresponding free acid by a two-step method, with an initial reduction of the nitro group followed by hydrolysis. The nitro group may be reduced by noble method catalysed hydrogenation, for example, using platinum, or palladium on carbon, or by a metal reducing agent, for example, zinc in acetic acid. Other metal reducing agents are, for example, aluminium amalgam, and iron and ammonium chloride, see for example, British Patent Specification No. 1,582,960. Reduction of the nitro group is

28 GB2195627A 28 followed by hydrolysis which may occur in situ during reduction of the nitro group or which may be carried out subsequently by treatment with an acid or a base.

An o-nitrobenzyi ester may be split off by photolysis, or a group may be used which is capable of removal by base hydrolysis, for example, acetyimethyl and acetoxymethyl ester groups.

There may be used an esterifying group that is removable under physiological conditions, that is to say, the esterifying group is split off in vivo to give the free acid or the carboxylate, for example, an acyloxymethyl or acyloxyethyl ester, for example, an acetoxymethyl, Y(acetoxy)ethy] or pivaloyloxymethyl ester, a 5-methyidioxalen-2-on-4-yimethyI ester, an aminoalkanoyloxy- methyl ester, for example, a glycyloxymethyl, L-valyloxymethyl or Lleucyloxymethyl ester or a 10 phthalidyl ester, or a V-(alkoxycarbonyloxy)ethyl ester, for example, a 1'-(methoxycarbonyloxy)ethy] or 1'-(ethoxycarbonyloxy)ethyl ester, or an optionally substituted 2-aminoethyl ester, for example, a 2diethylaminoethyl or 2-(1-morpholino)-ethyl ester (acyl and alkanoyl groups having 1 to 12 carbon atoms).

Preferred esterifying groups are p-nitrobenzyl groups for protection, and phthaiidyl, pivaloyloxy- 15 methyl, ethoxycarbonyioxymethyi, and 5-methyidioxalen-2-on-4-yi-methyl groups as -pro-drug groups.

For pharmaceutical use, it is preferable that the 8-hydroxy group in compound fa should either be free or in---prodrug- form, that is to say, in the form of an ester that can be hydrolysed in vivo to give the free hydroxy group. Similarly, the 2-carboxy group may be free, in -pro-drug20 form, or in physiologically tolerable salt form.

The present invention also provides salts of those compounds of formula fa that have salt forming groups, especially the salts of a free acid of formula 1 and acid addition salts of compounds of formula fa having a basic group. The salts are especially physiologically tolerable salts, for example, alkali metal and alkaline earth metal salts, for example, sodium, potassium, 25 lithium, calcium, and magnesium salts, ammonium salts, and salts with organic amines; also physiologically tolerable acid addition salts.

These may be formed with a suitable inorganic or organic acid, for example, hydrochloric acid, sulphuric acid, or an organic carboxylic or organic sulphonic acid, for example, p-toluenesulphonic acid.

A salt of a free acid of formula fa may be produced by reacting the free acid with the appropriate base in a solvent, preferably under those conditions under which the salt precipi tates. A preferred base is potassium 2-ethylhexanoate.

A salt may be produced directly from an ester by splitting off the ester group under suitable reaction conditions, for example, catalytic reduction of an ester, for example, a p-nitrobenZY1 ester, in an aqueous/organic solvent, for example, comprising water and ethyl acetate, dioxane or tetrahydrofuran, in the presence of a metal salt, especially a metal bicarbonate, for example, in an equivalent amount or in a slight excess, yields the salt directly.

When an acidic centre and a basic centre are both present in a compound of formula fa, the compound may exist in zwitterionic form.

Protecting groups may be introduced or removed at any appropriate point in the reactions involved in the production of a compound of formula fa.

At any stage in the production of a compound of formula fa, a compound produced may be isolated from the reaction mixture in which it was prepared and, if desired, purified by the appropriate techniques used for the purification of organic compounds, for example, chromato- 45 graphy and crystallisation.

As indicated above, various intermediates may be produced in the form of mixtures of isomers of various kinds. Such mixtures may be separated or resolved at any stage, or an isomeric mixture may be used per se for subsequent reactions.

Compounds of formula fa possess excellent activity against gram positive bacteria and gram 50 negative bacteria. Moreover, the compounds of formula fa and salts of show activity against these organisms in the presence of P-lactamase enzymes produced by both gram positive organisms, for example, Staphylococcus aureus and gram negative organisism, for example, Enterobacter cloacae, thus indicating resistance to these enzymes.

Compounds of formula fa are also inhibitors of Pactamase enzymes.

The compounds of formula fa and physiologically tolerable salts there of may be used in humans and other animals to treat, for example, bacterial infections caused by both gram positive and gram negative bacteria, for example, Staphylococcus aureus, Streptococus pyo genes, Escherichia coli, Bacillus subtills and Proteus morganfi, some strains of which are resistant to conventional penicillin therapy.

Compounds of formula fa are also particularly useful in combination with other fl-lactam antibotics, in particular cephalosporins. in such a combination, very broad spectrum antibiotic activity is produced and synergystic effects are observed.

The present invention accordingly provides a pharmaceutical preparation which comprises a compound of formula fa, or a physiologically tolerable salt thereof, or a mixture of two or more 65 29 GB2195627A 29 such substances as active ingredient, as produced according to the invention, in admixture or conjunction with a pharmaceutically suitable carrier. The preparation may also advantageously comprise one or more other pharmaceutically active substances, for example, another antibacterial substance, preferably one having a P-lactam ring and especially a cephaloporin antibiotic. The preparations may be in a form suitable for enteral or parenteral administration, for example, for oral, intravenous or intramuscular administration, for example, as tablets, capsules, syrups, or sterile injectable or infusion solutions. The preparations are advantageously in unit dosage form and preferably comprise from 10 to 2000 mg of the active ingredient per unit dose. The daily dosage of the active ingredient is generally from 20 to 8000 mg, in divided doses, generally up to 4 doses.

The invention also provides the use of a compound of formula la or a physiologically tolerable ester or salt thereof as produced according to the present invention, for the manufacture of a medicament for the treatment of bacteria[ infections.

The invention further provides a method of treating mammals, especially humans, to combat a bacterial infection, which comprises administering to the mammal a compound of formula la or a 15 physiologically tolerable ester or salt thereof, as produced according to the present invention. A fl-lactam antibiotic, especially a cephalosporin antibiotic, is preferably also administered simultaneously or substantially simultaneously, by the same route or by a different route.

The invention further provides a pharmaceutical preparation which comprises an active ingredi- ent as defined above, in unit dosage form.

The invention also provides a pharmaceutical preparation which comprises an active ingredient as defined above, or a physiologically tolerable salt thereof or a mixture of two or more such substances, in unit dosage form. Unit dosages are preferably as described above.

Compounds of formula la are also useful in the production of the antibacterially active com- pounds.

The present invention further provides compounds of formula la, Va, Vb, Vc, Via, Vlb, Vic, Vid, Vllla and Villb.

In the following Examples, which illustrate the invention, temperatures are expressed in degrees Celsius. Hyflo and Nujol are Registered Trade Marks, and t.l.c. denotes thin layer chro- matography.

Example 1

4-Nitrobenzyl 2-13(S)-[1(R)-(tert-butyldimethyisilyloxy)-ethyll-4-(R)ethylthio azetidin-2-on-l-yll-3-[4 (pentafluorophenoxycarbonyl)phenoxy]-3-trimethylacetylthio-propenoate To a stirred mixture of 4-nitrobenzyi 13(S)-[1-(R)-(tertbutyidimethyisilyloxy)-ethyll-4-(R)-ethyithio 35 azetidin2-on-l-yilacetate (73.8 g), pentafluorophenyl 4-(chloro- thiocarbonyloxy)benzoate (64.1 9) and dry tetrahydrofuran (400 mi) was added at -78 a mixture of hexamethyidisilazane (75.5 m]) and tetrahydrofuran (200 mi) of which had been added at -20' a 1.55M solution of N butyllithium in hexane (221 mi). After the resultant mixture had been stirred an additional 5 min.

trimethylacetyl bromide (40.5 mi) was added; the temperature of the mixture was adjusted to -20' and the mixture was then partitioned between diethyl ether (2 1) and 0.33M hydrochloric acid (1 1). The aqueous layer was washed with diethyl ether, and the combined organic layers were washed with water, with saturated aqueous potassium bicarbonate, with brine, were dried over anhydrous magnesium sulphate and then evaporated in vacuo to afford the title compound as a viscous brown/red oil (150 g) as a mixture of E- and Z-isomers.

* vm (CDOJ 1760 cm-1 J (CD03) 8.23, 8.16, 7.58 and 7.17 (8H, 2xAA'BB', J=81-1z); 5.44-5.24 (3H, m); 4.23 (1H, m); 3.23 (1H, -t, J=31-1z); 2.81-2.58 (2H, m); 1.24 and 1.30 (3H, 2d, J=61- 1z); 1.22 (3H, t, 50 J=71-1z); 1.14 and 1.07 (9H, 2s); 0.87 and 0.79 (9H, 2s); 0.05 and 0.01 (6H, 2s) p.p.m.

Example 2 4-Nitrobenzyl 2-[3(S)-[1(R)-(tert-butyidimethyisilyloxy)-ethyll4-(R)-chforo-azetidin-2-on -l-yll-3-[4(pentafluorophenoxycarbonyl)phenoxy]-3-trimethylacetylthlopropenoate To a stirred solution of the unpurified product (150 9) from the preceding Example in dry chloroform (450 m[) at -45' was added a solution of chlorine (15.1 g) in carbon tetrachloride (226 mi); over a 45 min. period the mixture is warmed to 20', and then evaporated in vacuo to afford the title compound (150 9) as a brown foam as a mixture of E and Z isomers.

v,,,,, (CDCI,) 1790, 1771 and 1750 cm-l; 8(CDC]3) 8.24, 8.17, 7.58 and 7.16 (8H, 2xAA'BB', J=8.71-1z); 6.11, 6.03 (1H,2D, J=1.51-1z); 5.33 (2H,AB, J14 Hz); 4.22 (1H, m); 3.48, 3.47 (1H, 2xdd, J=3.4 and 1. 5Hz); 1.30, 1.24 (3H, 2xd, J=61-1z); 1.15, 1.08 (9H, 2xs); 0.86, 0.81 (9H, 2xs); 0.05, 0. 02 (6H, 2xs) p.p.m.65 GB2195627A 30 Example 3

4-Nitrobenzyl 5(S),6(S)-[1(R)-(tert-butYIdimethyisityloxy)ethyll-7-oxo-3[4-(pentafluoroph enoxy-1-4- thia- 1 -azabicyclo[3.2, Olhept-2-ene-2-carboxylate To a stirred mixture of the unpurified product from Example 2 (150 g), tetrahydrofuran (270 5 mi) and water (30 mi) was added at 0' pyridine (32 m]); the reaction mixture was warmed to room temperature, was stirred for up to five hours, and then partitioned between diethyl ether and 0.5M-hydrochloric acid. The aqueous layer was washed with diethyl ether; the combined organic layers were washed with water, with saturated aqueous potassium bicarbonate and with brine, were dried over anhydrous magnesium sulphate, and evaporated in vacuo to afford the title compound as a brown foam (120 g). (This material was not purified before further reaction).

v.,, (MCIJ 1790, 1761 and 1720 em'; (5 (CDCI,); 8.22, 8A8, 7.51, 7.26 (8H, 2xAA'BB', J=8.7Hz); 5.80 (1H, cl, J=4.2Hz); 5.39, 5.20 15 (2H, AB, J=14Hz); 4.43 (1H,m); 3.99 (1H, dd, J=4. 2 and 9.8Hz); 1.46 (3H, cl, J=6Hz); 0.82 (9H,s) 0.06, 0.01 (6H, 2s). p.p. m.

Small (typically <10%) amounts of the corresponding 5(R),6(S) penem carboxylate are also formed with physical data essentially as above except (5 5.70 (1H, cl, J=1.6Hz) and 1.24 (3H, cl, 20 J=61-1z).

Example 4 4-Nitrobenzyl 5(S),6(S)-[1(R)-hydroxyethyll-7-oxo-3-[4(pentafluorophenoxycarbonyl)phenoxy]-4thia-l-azabicyclo[3.2.Olhept-2-ene-2-carboxylate To a stirred solution of unpurified 4-nitrobenzyl 5(S), 6(S)-[1R-(tertbutyidimethyisiloxy)ethyll-7oxo-3-[4-(pentafluorophenoxycarbonyi)phenoxy]4-thia- 1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylate (7.35 g) in acetonitrile (250 H) was added 40% aqueous hydrofluoric acid (80 H). After 40 min., dichloromethane was added; the pH was adjusted to 5 with potassium bicarbonate and the mixture partitioned. The aqueous layer was washed with dichloromethane, and the combined organic extracts were washed with water and dried over anhydrous magnesium sulphate. Evaporation in vacuo afforded the title compound (6.06 g).

8 (CDCI,) 8.23, 8.20, 7.53 and 7.29 (8H, 2xAA'1313', J=8.8 Hz); 5.84 (1H, cl, J4.1Hz); 5.41, 5.22 (2H, AB, J=13.7Hz); 4.44 (1H,m); 396 (1H, dd, J=4.1 and 10.3Hz); 1. 53 (3H, cl, 35 J6.1Hz) p.p.m.

Together with this compound there was also obtained a minor quantity (typically <10%) of the corresponding 5(R),6(S) penem compound whose physical properties are essentially as above except (5 5.74 (1 H, d, J = MHz; 3.85 (1 H, dd, J = 1.4 and 6.5Hz); 1.39 (3H, d, J =6.3Hz) p.p.m.

Example 5

4-Nitrobenzyl 5(S), 3-(4-aminocarbonylphenoxy)-6-(S)-[I(R)-(tertbutyldimethylsilyloxy)ethyl]-7-o xo- 45 4-thia- 1 -azabicyclo[3.2. 0)]hept-2-ene-2-carboxylate Diisopropylethylamine (52 ml) and a solution of ammonia (5.13 g) in ethanol (114 ml) were added sequentially to a stirred solution of unpurified 4-nitrobenzyl 5(S), 6(S)-[1(R)-(tert-butyldime thylsilyloxy)ethylj-7-oxo-3-[4-(pentafluorophenoxycarbonyl)phenoxyj-4thia- 1 -azabicyclo-[3.2.0]hept 2-ene-2-carboxylate (120 g) in acetonitrile (600 ml). When t.l.c. (Si02, ethyl acetate) showed the 50 reaction to be complete, ethyl acetate was added, and then the pH was adjusted to 2 with M hydrochloric acid. After addition of water the mixture was partitioned; the aqueous layer was extracted with ethyl acetate, and the combined organic phases were washed with water, with 20% aqueous potassium carbonate, and with water, were dried and evaporated in vacuo to afford the crude title compound as a brown oil (- 120 g). Non-penem byproducts could be removed by chromatography over silica gel of a portion of the residue; elution with ethyl acetate-hexane mixtures afforded a sample of a mixture of the pure title compound.

a v,, (nujol) 1784, 1700, 1656 em-'; J (CDC13) 8.14, 7.48 (4H, AX1313% J=8.8Hz); 7.83, 7.17 (4H, AA'BB', J=8. 91-1z); 6.35 (2H, broad); 5.73 (1H, d, J=4.0Hz); 5.37, 5.18 (2H, AB, J=13. 8Hz); 4.39 (1H, dq, J=9.8 and 6.0Hz); 3.93 (1H, dd, J9.8 and 4.0Hz); 1.42 (3H, d, J=6.0Hz); 0.78 (9H,s); 0.06, 0.00 (6H,2s) p.p.m.

31 GB2195627A 31 together with some of the corresponding 5(R),6(S) penern whose physical properties were essentially as above except for J 5.65 (1 H, d, J = 1. 4Hz); 4.25 (1 H, m), 3.75 (1 H, dd, J = 1.4 and 4.8 Hz) and 1.25 (3H, d, J=6Hz) p.p.m.

Example 6 4-Nitrobenzyl 5(S),3-(4-aminocarbonylphenoxy)-6(S)-[1(R)hydroxyethyll-7-oxo-4-thia-l-azab icyclo[3.2.01hept-2-ene-2-carboxylate Method A To a stirred mixture of unpurified 4-nitrobenzyl 5(R),3-(4aminocarbonylphenoxy)-6(S)-[1(R)-(tertbutyidimethyisilyloxy)ethyll-7-oxo-4-thia-l-azabicyclo[3.2.0]hept-2-ene-2ca rboxylate (136 g) in dry tetrahydrofuran (1500 mi) at 10' was added glacial acetic acid (86 mi), followed by a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (450 mi). The mixture was stirred at 20' for 16 hours, and was then worked up by partitioning between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the combined organic phases were washed 15 with water, with aqueous sodium bicarbonate solution, with water and with brine and were evaporated in vacuo to afford a dark brown gum (ca 75 g). Diethyl ether (300 mi) was added; the mixture was stirred at room temperature for 2 hours and filtered to afford the crude title compound (44 9) as a buff solid, which was chromatographed on silica gel. Elution with.

hexane-ethyl acetate-acetonitrile mixtures afforded the title compound (23 g) as a fawn solid. 20 m.p. 170-172' (dec) vm,,. (Nujol) 3500, 3400, 3300, 1768, 1688, 1656, 1614 and 1606 cm-l; 3 (DMSO-d,) 8.19, 7.94, 7.60, 7.3718H, 2xAA'BB', J=8.8Hz); 8.03 (1H, broad); 7.44 (1H, broad); 5.90 (1H, d, J=3.91-1z) 5.40, 5.28 (2H, AB, J=14.21-1z); 5.20 (1H, d, J=5.11-1z); 4.11 (1H, m); 4.01 (1H, dd, J=10.3 and 3.9Hz); 1.29 (3H, d, J=5.8Hz) p.p.m.

Method B To a solution of pure 4-nitrobenzyl 5(S),3-(4-aminocarbonylphenoxy)-6(S)- [1(R)-(tert-butyidime-thyisilyloxy)ethyll-7-oxo-4-thia-l-azabicyclo[3.2.Olhept-2-ene-2carboxylate (37 9) in tetrahydrofu ran (400 mi) at room temperature was added glacial acetic acid (35.5 mi) followed by a 1M solution of tetrabutylammonfum fluoride in tetrahydrofuran (186 m]). The mixture was stirred for 16 hours and then diluted with ethyl acetate, and worked up as in Method A to afford the title 35 compound (18 9) with physical properties identical to those given in Method A.

Method C To a stirred mixture of the unpUrified 4-nitrobenzyl 5(S),6(S)-[1(R)- hydroxyethyll-7-oxo-3-[4(pentafluorophenoxycarbonyl)phenoxy]-4-thia-l-azabicyclo-[3.2.Olhept-2ene-2 -carboxylate (5 9) 40 obtained in Example 4 and acetonitrile (50 mi) at 0' was added diisopropylethylamine (2.24 mi) followed by a solution of ammonia (219 mg) in ethanol (6.7 m]). The mixture was warmed to 10' and stirred for one hour, and then partitioned between cold ethyl acetate and 0.25M hydrochloric acid. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water, were dried over anhydrous magnesium sulphate and 45 evaporated in vacuo. Chromatography of the residue over silica gel and elution with ethyl acetate-hexane mixtures afforded the title compound (1.2 9) with physical properties identical to those described in Method A.

Example 7 4-Nitrobenzyl 5(R), 3-(4-aminocarbonylphenoxy)-6(S)-[l(R)hydroxyethyll-7-oxo-4-thia-l-azabicycl o[3.2.0]hept-2-ene-2-carboxylate A stirred suspension of 4-nitrobenzyl 5(S), 3-[4-(aminocarbonyl)phenoxyl6(S)-[l(R)-hydroxyethyl]-7-oxo-4-thia-l-azabicyclo[3.2.0]-hept-2-ene-2carboxylate (18 g, but including ca 10% of the diastereoisomeric 5(R) compound) in acetonitrile (360 ml) was rapidly heated to 80 and then maintained at this temperature for 2 hours. The mixture was cooled to 20 over a 15 minute period and then allowed to stand at 0' for 30 minutes. Filtration, and washing of the residue with ethyl acetate-dichloromethane mixtures, and drying in. vacuo afforded pure title compound (14.5 g) as an off-white microcrysta I line solid.

m.p. 196-200 Vmax (Nujol) 3450(m), 3200, 1748(s), 1706(s) 1658, 1624 cm-1.

5 (DIVISO-dj 8.18, 7.58 (4H, AA'BB', J=8.7Hz); 7.92, 7.35 (4H, AASW, J8. 8Hz); 8.02 (1H, 65 32 GB2195627A 32 broad); 5.78 (1H, d, J=MHz); 5.40, 5.27(2H, AB, J=14.31-1z); 5.25 (1H, broad; 4.04 (1H, m); 3.90 (1H, dd, J=6.6 and MHz); 1.71 (3H, d, J=MHz) p. p.m.

Example 8

Potassium 5(R),3-(4-aminocarbonylphenoxy)-6(S)-[1(R-hydroxyethyll-7-oxo-4thia-l-azac yclo[3.2.0- 5 lhept-2-ene-2-carboxylate A mixture of 4-nitrobenxyl 5(R),3-(4-aminocarbonylphenoxy)-6S-[1(R)hydroxyethyll-7-oxo-4-thia- 1-azabicyclo[3.2.Olhept-2-ene-2-carboxylate (5 g), dioxane (50 mi), potassium bicarbonate (1.03 g), water (50 m[) and 10% palladium on charcoal (5 9) was hydrogenolysed at 345 KPa (50 psi) for 60 minutes, was filtered through Hyflo and evaporated to half volume. The mixture was then 10 washed with diethyl ether, and lyophilised to afford the title compound (4.0 g).

6 (D20) 7.33 and 7.87 (4H, AA'BB', J=8.8Hz); 5.74 (1H, cl, J=1.3Hz); 4.28 (1H, m); 3.98 (1H, dd, J=1.3 and 6Hz); 1.32 (3H, d, J=6Hz) p.p.m.

Example 9

4-Nitrobenzyl 3-methyl-2-(4(R)-[4-(pentafluorophenoxycarbonyl)phenoxythiocarbonylthiol-3( S)-[1(R)(tert-butyldimethyisilyloxy)ethyll-2-oxoazetidin- l -y11-2-butenoate A solution of 4-(pentafluorophenoxycarbonyi) phenyl chlorothionoformate (1.08 g) in dry aceton itrile (3 mi) was added to a stirred solution of silver (1) 3 (S)-[ 1 (R)- (tert-butyidimethyisilyloxy) ethyll1-[1'-isopropylidene-l'-(4-nitrobenzyioxycarbonyi)methyll-2oxoazetidinone-4 -thiolate (1.55 g) in acetonitrile (25 mi) and the mixture stirred as pyridine (0.103 mi) was added. When the reaction was complete as judged by fl.c., the mixture was filtered to remove precipitated silver salts and the filtrate evaporated to leave a brown gum. Chromatography of the gum on silica gel using hexane/ethyl acetate mixtures as eluant gave the product as a pale yellow oil (1.73 g).

v,n,,,, (CH03) 1775 (sh), 1762 (s), 1724 (m), 1522 (s), 1252 (s), 1050 (S), 910 (S) CM-1 (CDCI,) 8.40-8.15 (4H, m); 7.60-7.15 (4H, m); 5.97 (1H, d, J=2.7H4; 5.25 (2H, s); 4.26 (1H, m); 3.36 (1H, dd, J=2.71-1z and 6.3Hz); 2.32 (31-1, s); 2.26 (31-1, s); 1.33 (3H, d, J=6.2Hz); 30 0.87 (9H, s); 0.22, 0.18 (61-1, 2x5) p.p.m.

Example 10 4-Nitrobenzy,l 2-[4(R)-[4aminocarbonylphenoxythiocarbonylthiol-3(S)-fl(R)-(tert-butyldimet hylsilylc y)ethyl]-2-oxoazetidin-1-yll-3-methyl-2-butenoate A solution of 4- nitrobenzyl 3-methyl-2-14(R)-[4(pentafluorophenoxycarbonyl)phenoxythiocarbonylthiol-3(S)-[l(R)-(tert-butyldimethylsilyloxy)ethyll-2-oxoazetidin-1-yll-2 -butenoate (1.73 g) in acetonitrile (20 ml) was stirred at room temperature and a solution of ammonia (0.042 g) in ethanol (1. 11 mi) a - dded. Stirring was continued for 1 hr. when solvents were removed by evaporation in vacuo and the residue chromatographed on 10% deactivated silica gel using hexane/ethyl acetate 40 mixtures as eluant to afford the title compound as a yellow gum (0.84 g).

3 (CDC13) 8.17, 7.50 (4H, AA'BB', J=8.7Hz); 7.87, 7.05 (4H, AA'BB', J=8. 71-1z); 6.10, 5.80 (2H, 2xbr.s); 5.97 (1H cl, J=2.7Hz); 5.22 (2H,s); 4.354.20 (1H,m) 3.33 (1H, dd, J=2.5 and MHz); 2.25 (3H,s); 2.4 (3H,s); 1.33 (3H, cl, J=6.2Hz); 0.86 (9H,s); 0.07, 0.01 (6H,2xs) P.P.M.

Example 11 4-Nitrobenzyl 2-14(R)-[4-aminocarbonylphenoxythiocarbonylthiol3(S)-[1-(R)-(tert-butyldime thylsily- foxy)ethyll2oxoazetidinl-yl)-2-oxoacetate A solution of 4-nitrobenzyl 2-14(R)-[4-aminocarbonylphenoxythiocarbonyithiol-3(S)-[1(R)-(tert-butyidimethyisilyloxy)ethyll-2oxazetidin-l-yl)-3-methyi-2-butenoate (0.84 g) in acetone (15 ml) was cooled to -70'C and added to a stirred solution of ozone (1.5 equivs) in acetone (62 mi) also at -70'C. The pale blue solution was stirred at 70'C for 30 mins. and dimethyl sulphide (1 m]) added and the mixture stirred whilst being allowed to warm up to room temperature. Volatile 55 solvents were removed by evaporation in vacuo and the residue taken up in ethyl acetate (50 m]), washed with water (2x30 mi) and brine (20 mi). Evaporation of the dried (MgSO, anhyd.) solution gave the title compound as a colourless foam (0.68 9) contaminated with ca. 25% of the 4-aminocarbonylphenoxy-carbonyithio- isomer.

J (CDC[,) 8.23, 7.58 (4H, AA'BB', J=8.8Hz); 7.90, 7.25 (4H, AA'BB', J=8. 6Hz); 6.30, (11-1, d' J=3.7Hz); 6.06, 5.75 (2H, 2xbr.s); 5.42 (21-1,s); 4. 47-4.32 (1H,m); 3.62 (11-1, dd, J=3.7Hz and 6-2Hz); 1.29 (3H, d, J=6.3 Hz); 0.87 (91-1,s); 0.08, 0.01 (61-1, 2xs) p.p.m.

Example 12 t w.

33 GB2195627A 33 4-Nitrobenzyl 5(R),3(4-aminocarbonylphenoxy)-6-(S)-[1(R)-tertbutyidimethyisilyfoxyethyll -7-oxo-4thia- 1-azabicyclo[3.2. Olhept-2-ene2-carboxylate A solution of 4-nitrobenzyl 2-{4(R)-[4-aminocarbonylphenoxythiocarbonylthio]-3(S)-[1(R)-(tertbutyidimethyisilyloxy)ethyll-2oxoazetidin-l-yil-2-oxoacetate (0.68 9) in dry chloroform (40 mi) was gently refluxed under an atmosphere of nitrogen and protected from atmospheric moisture. A solution of triethyl phosphite (0.36 mi) in chloroform (10 mi) was added dropwise via a syringe pump over 75 min. to the gently refluxing solution. The mixture was heated for a further 30 mins. when it was cooled and solvent removed by evaporation in vacuo. The crude product was chromatographed on silica gel using hexane/ether mixtures as eluant to give the title compound 10 as a pale yellow foam (0. 26 g).

3 (CDC'3) 8.17, 7.55 (4H, AAM13% J=8.7Hz); 7.83, 7.21 (4H, AA'BB', J=8. 8Hz); 6.05, 5.73 (2H, 2xbr.s); 5.65 (1H, d, J=MHz); 5.38 5.21 (2H, AB, J=13.8Hz); 4.34-4.14 (1H,m) 3.76 (1H, dd, J1.4Hz and 4.8Hz); 1.25 (3H, cl, J=-6.2Hz); 0.88 (9H, s); 0.09, 0.05, (6H, 2xs) 15 p.p.m.

Example 13

4Nitrobenzy] 5(R),3-(4-aminocarbonylphenoxy)-6(S)-[1(R)-hydroxyethyll-7oxo-4-thia-l-azab icy- clo[3.2.Olhept-2-ene-2-carboxylat6 To a stirred solution of 4-nitrobenzy] 5(R),3-(4-aminocarbonylphenoxy)6(S)-[1(R)-(tert-butyidime- 20 thylsilyloxy)ethyll-7-oxo-4-thia-l-azabicyclo[3.2.Olhept-2-ene-2carboxylate (0.26 9) in tetrahydro furan (3 m]) was added acetic acid (0.25 mi) followed by a 1 molar solution of tetra-n butylammonium fluoride in tetrahydrofuran (1.31 mi). The solution was stirred at room tempera ture for 20 hr., diluted with ethyl acetate and the organic solution washed successively with saturated sodium bicarbonate solution, water and brine. Evaporation of the dried (anhyd. magnesium sulphate) solution left a residue which was chromatographed on 10% deactivated silica gel using hexane/ethyl acetate mixtures as eluant to give the title compound as a pale yellow solid (0. 112 g).

v (Nujol) 3450(m), 3200(br.m), 1748(s), 1706(s), 1658(s), 1624(m) cml 3 (DMSO-d6) 8.18, 7.58 (4H, AA'BB', J=8.71-1z); 7.92, 7.35 (4H, AA'BB', J=8.8Hz); 8.02 (1H, br.s.); 7.43 (1H, br.s); 5.78 (1H, d, J1.4Hz); 5.40, 5.27 (2H, AB, J=14.3 Hz); 5.25 (1H, br.s); 4.04 (1H, br.m); 3.90 (1H, dd, J=6.6Hz and 1.4 Hz); 1.17 (3H, cl, J=6.1Hz) p.p.m.

Example 14

4-Nitrobenzyl 5(R),3-(4-aminocarbonylphenoxy)-6(S)-[1(R)-hydroxyethyll-7oxo-4-thia-1-azab icy- clo[3.2.Olhept-2-ene-2-carboxylate Di-isopropylethylamine (0.101 mi) was added to a solution of diphenyl chlorophosphate (0.121 mi) and 4-nitrobenzyl 5(R),6(S)-[1(R)-hydroxyethyl]-7-oxo-4-thia-3-thioxol-azabicyclo[3.2.0]hep- 40 tane-2-carboxylate (0.201 9) in dry acetonitrile (6 mi) and the solution stirred at WC for 11. hr.

2 Following this a solution of 4-a mi nocarbonyl phenol (0.08 g) in acetonitrile (1 m]) and di-isopropy lethylamine (0.101 ml) were added and the mixture continued to be stirred during the time it took to reach room temperature and then at 4WC until the reaction was complete. The mixture was partitioned between ethyl acetate and water and the organic layer washed with water, dried 45 over anhydrous magnesium sulphate and evaporated in vacuo. Chromatography of the residue on 10% deactivated silica gel using hexane/ethyl acetate mixtures as eluant gave the title compound (0.026 g).

The spectral data of this product was identical to that of the compound prepared in Example so 13.

Example 15

0-(4-Aminocarbonylphenyl) carbonochloridothioate To a vigorously stirred mixture of thiophosgene (5 mi) and water (10 mi) at 0' was added dropwise a mixture of 4-hydroxybenzamide (3 9) water (30 mi) and 2M sodium hydroxide (14.2 55 mi). The precipitate was filtered and washed with water, with dichloromethane, and then dried in vacuo to afford the title compound (4.08 g).

3 (acetone-d6) 8.10 and 7.42 (4H, AA'BB', J=7.9Hz); 7.62 (1H, broad) and 6.85 (1H, broad) p.p.m.

Exampib 16 4-Nitrobenzyl 3-(4-aminocarbonylphenoxy)-2-[3(S)-[1(R)-(tertbutyidimethylsilyloxy)ethyll-4 (R)-propy- thio-azetidin-2-onl-yll-3-trimethylacetylthiopropenoate To a stirred mixture of 4-nitrobenzy] 2-13(S)-[1(R)-(tertbutyldimethyisilyloxy)ethyll-4(R)-propyi- 65 34 GB2195627A 34 thioazetidin-2-on-l-yilacetate (2 9) in dry tetrahydrofuran (12 mi) was added at -40' a preformed mixture of hexamethyidisilazane (2 mi), dry tetrahydrofuran (6 mi) and 1.55M-n-butyllithium in hexane (5.8 mi). After 15 minutes a solution of 0-(4-amino carbonylphenyl) carbonchloridothioate (0.955 9) in dry tetrahydrofuran (6 m]) was added, followed by trimethylacetyl bromide (1,07 mi). After 15 minutes the mixture was poured onto a mixture of diethyl ether and 2M-hydrochloric acid. The organic layer was separated; the aqueous layer was washed with ethyl acetate, and the combined organic layers were washed with water, with saturated potassium bicarbonate, with water and with brine, and were evaporated in vacuo. Chromatography of the residue on silica gel afforded the title compound (1.04 9) as a yellow solid as a mixture of 10 the E- and Zisomers.

(5 (CIDC13) 8.23 and 8.07 (2H, 2xd, J=8.7Hz); 7.76 (3H,m); 7.58 and 7.35 (2H, 2xcl, J=8.71-1z); 7.09 (3H,m); 5.30 (3H,m); 4.23 (1H,m) 3.20 (1H,dd, J=2.9 and 3.9Hz); 2.61 (2H,m); 1,34 (3H, cl, J=61-1z); 1.3 (2H, m); 1.10 and 1.03 (9H, 2xs); 0.96-0.79 (12H,m); 0.09 and 15 0.06 (3H, 2Xs); 0.01 (3H,s) p.p.m.

Example 17

4-Nitrobenzyl 3-(4-aminocarbonylphenoxy)-2-13(S)-[1(R)-(tertbutyldimethylsityloxy)ethyll-4 (R)-chio- roazetidin-2-onl-yll-3-trimethylacetylthiopropenoate A solution of chlorine (43 mg) in carbon tetrachloride (0.51 mi) was added to a stirred mixture 20 of 4-nitrobenzyl 3-(4-aminocarbonylphenoxy)-2-3(S)-[1(R)-(tertbutyidimethylsilyloxy)ethyi-4 (R)-propyithio-azetidin-2-on-lyil-3-trimethylacetyithiopropenoate (0.33 g), propylene oxide (0.0015 m]) and chloroform (5 m]) at -45'. The mixture was evaporated to dryness to afford the crude title compound (0.33 g). Chromatography of a portion over silica gel and evaporation in vacuo afforded a sample of the pure title compound as a mixture of E- and Zisomers.

3 (CDCI:,) 8.23 and 8.10 (2H, 2xd, J=8.81-1z); 7.79 (3H,m); 7.56, 7.37 (2H, 2xd, J=8.13Hz); 7.08 (2H,m); 6.08 and 6.05 (1H, cl, J=1.51-1z); 5.30 (2H,m); 4.24 (1H,m); 3.47 (1H, dd, J=1.5 and 3.4 Hz); 1.24 (3H, d, J=711z); 1.10 and 1.03 (9H, 2xs); 0.86, 0.79 (9H, 2xs); 0.08, 0.04, 0,01 (6H, 3 x s).

Example 18

4-Nitrobenzyl 5(S),3-(4-aminocarbonylphenoxy)-6(S)-[I-(R)-(tertbutyldimethylsilyloxy)ethy ll-7-oxo-4- thia- 1 -azabicyclo[3.2. Olhept-2-ene-2-carboxylate Pyridine (0.038 ml) was added to a stirred mixture of 4-nitrobenzyl 3-(4- aminocarbonylphonoxy)-2-13(S)-[l(R)-(tert-butyldimethylsilyloxy)ethyl]-4(R)chloroazetidin-2 -on-1-yll-3-trimethylacetyl- thiopropenoate (132 mg), tetrahydrofuran (2 ml) and water (0.2 ml). After two hours the mixture was evaporated in vacuo and chromatographed on silica gel. Elution with hexane-ethyl acetate mixtures afforded the title compound (66 mg) with physical properties identical to those de- scribed in Example 5.

Claims (49)

1. CLAIMS 1. A process for the production of a compound of formula fa

   R20 LH3CH 11 -.a S 1 _C)-.WCONHR' 0 J7N COOR (Ia,' in which R represents a hydrogen atom or a carboxy protecting group, R' represents a hydrogen atom or an alkyl group, having from 1 to 4 carbon atoms, especially hydrogen or a methyl group, and R2 represents a hydrogen. atom or a hydroxy protecting group, or a salt thereof, which comprises (1) producing a compound of formula lb 9 GB2195627A 35 p20 CU-Z o:7N COOR in which R and R2 are as defined above, and (Ib) Z represents an -NHR', -NHR3, -NR3R3, -NR'R 3, -R 4 or -OH group in which R3 represents a nitrogen protecting group (in the case of NW3 the two groups R3 may be the same or different), and R4 represents a carboxylic acid activating group, or 15 -COZ represents -CN, by (A) heating a compound of formula 11 Fo S 0 N O-WC0z COOR (II) in which R, R2 and Z are as defined above, or (B) reacting a compound of formula IV HO -& C0z (IV) in which Z is as defined above, optionally in the presence of a base with a compound of formula Ill R2 0 C I-IH3CH S _Y COOR (III) in which R and R2 are defined as above, and Y represents a leaving group selected from phenoxy and phenylthio groups which may be unsubstituted or substituted by one or more substituents, which may be the same or different, 45 selected from halogen atoms and nitro, cyano, trifluoromethyl and trifluoroacetyl groups; groups of formula 0 _ 11 XP (OR a) 2 or 0 st -XP (R a) 2 in which X represents an oxygen or sulphur atom and the two groups R,,, which may be the same or different, each represents a straight or branched chain alkyl group having from 1 to 6 carbon atoms, or a phenyl group which may be unsubstituted or substituted, for example, by 55 one or more substituents selected from halogen atoms, cyano, nitro and methyl groups, espe cially by a methyl group in a para-position; groups -OSO2Rb in which Rb represents a straight or branched chain alkyl group having from 1 to 4 carbon atoms, which may be substituted by one or more fluorine atoms, for example, may be fully fluorinated, for example, a -CF, or _C4F.

   group, or Rb represents a phenyl group that is unsubstituted or is substituted by a p-nitro, p- 60 bromo- or p-methyl group; 36 GB2195627A 36 0 1 groups -SR. and -S02R. in which R. is defined as above; and; groups 0 - OCW 3 and if the resulting compound has the formula 11 Rt S 0-n\ C0z 0 ' COOR (11) in which R, R2 and Z are defined as above, converting compound 11 to compound lb and/or isolating compound lb from compound 11, (C) cyclising a compound of formula Va, Vb or Vc R20 L,h3CH,,, S 0 (F\ coz NH Q 0 L COOR R 20 -M3,H NT'AH S 00C0z (Vb) 0 0 0 H:COOR (Va) R20 LA131 M' S 00C0z - 'd ' ', :ú N H (VC) 0 N 02 COOR in which R, R2 and Z are as defined above, and L' represents a chlorine or bromine atom, (i) in the case of compound Va eliminating HU (a) by treatment with a base and/or a metal or a metal-containing reagent, (b) by electrolysis, (c) by photolysis, or (d) by reaction with a free radical-producing compound optionally in the presence of an initiator; (ii) in the case of compound Vb by treatment with a Lewis acid or a base, and (iii) in the case of compound Vc by treatment with a rhodium- or copper- containing compound; (D) cyclising a compound of formula Via, Vib, Vic or Vid, 37 GB2195627A 37 RIO X c,, C)-coz o):NrA;p(O)3 COOR (V1a) RIO X sco-OrOZ 0 l, ?0 COOR (Vlb) R20 R20 X LM3LM,,' Asco-ncoz O,PN, CH-RS O-N,?P(0)3 oc)R COOR RS -in (Vic) (VId) in which formulae R, R2 and Z are defined above, X represents an oxygen or sulphur atom, the group p(Q)3 represents a group derived from a trivalent organophosphorus reagent, 20 R5 represents a bromine or chlorine atom, R6 represents Cu(11), Pb(11) or Hg(H), in which case n represents 2, or represents Ag(l), in which case n represents 1, in the case of compound Via, by heating compound Via or allowing compound Via to stand at room temperature; in the case of compound Vib, by treatment with a trivalent organophosphorus reagent and heating the resulting compound or allowing the resulting compound to stand at room temperature; in the case of compound Vic, by treatment with a phosphine and a base, and then heating the resulting compound or allowing the resulting compound to stand at room temperature, 30 (iv) in the case of compound Vid by reaction with a compound of formula V11 X 1 Fc 0GC0z (Vii) in which X and Z are as defined above and R7 represents an activating group, for example, an activating ester group or a halogen atom, and heating the resulting compound or allowing the resulting compound to stand at room temperature or below; (E) cyclising a compound of formula Villa or Villb 1 RIO CH3CH, --r 's- 4, fN L 0 0 F-5CO'Z ROOC) (VIIIa) R20 CH3',,, SR' 0,F,] 1 1 1 ROOCK0Q C0z -RG 1 n (VII1b) in which formulae A, R2, R6, n, and Z are defined as above and L represents a leaving group, for example, that can be replaced in a nucleophilic displacement reaction, for example, a halogen atom, preferably a bromine or iodine atom; a hydroxy group (in which case ketoenol tautomerism can occur); a modified hydroxy group, especially a sulphonate ester group, for example, a sulphonyloxy group of the formula -OSO2Rb in which Rb represents a 55 straight or branched chain alkyl group having from 1 to 4 carbon atoms, which may be substituted by one or more fluorine atoms, for example, may be fully fluorinated, for example, a -CF, or -C,F, group, or Rb represents a phenyl group that is unsubstituted or is substituted by a p-nitro, p-bromo- or p-methyl group; or L represents a phosphorus-containing group for example 0 0 0 11 H P - OP (R a) 2 -SP (R a) 2 -OP (ORa) 2 65 38 GB2195627A 38 in which the two groups IR,, which may be the same or different, are as defined above and R8 represents a hydrogen atom or a sulphur protecting group, in the case of compound Villa, effecting cyclisation, and in the case of compound Vilib, removing the sulphur protecting group, if present, and either reacting the resulting thiol compound with a reagent capable of converting the compound 5 into compound Villa, and cyclising compound Villa, or cyclising the thiol compound by treatment with a base, and as described and as required, carrying out any of one or more of the reactions set out in the further steps (2) to (4) in any appropriate order; (2) in a resulting compound in which -COZ represents other than a -CONHR' group carrying out one of the following reactions, (a) when -COZ is CONHR3, CONR1R3 or CONR3R3, removing the protecting group(s) R3; (b) when -COZ is COR4, reacting the compound with ammonia or methylamine, or a chemical equivalent thereof; (c) when -COZ is -COOH; activating the -COOH group, and then reacting the resulting corn pound with ammonia or a lower alkylamine; (d) when -COZ represents -CN, converting the group -M into the group - CONHR'; (3) in a resulting compound of formula la, lb, or 11 in which the free or protected 8-hydroxy group has S-stereochemistry carrying out a stereochemical inversion to give the correspond- 20 ing 8R compound; (4) if desired or required, carrying out any one or more of the following steps in any desired order:

   (a) hydrolysing a 2-carboxylic ester group in a compound to give the corresponding free acid, (b) treating a free acid compound or a salt thereof with an agent capable of forming a 2 carboxylic acid ester, for example, with an alcohol, a phenol or a reactive derivative thereof, to give a 2-carboxylic acid ester thereof, (c) carrying out an acid- or a base-catalysed ester interchange on a 2- carboxylic acid ester to give a different ester of that compound, (d) treating a free acid compound with a base to give a salt at the carboxy group at position 2, 30 (e) treating a 2-carboxylic acid ester having a basic group present with an acid to give an acid addition salt thereof.

   (f) treating a salt of a compound with an acid to give a free acid of that compound, (g) removing a hydroxy protecting group from a compound having a protected 8-hydroxy group to give the corresponding compound having a free 8-hydroxy group, (h) treating a compound having a free hydroxy group at the 8-position with an organic acid derivative to form an ester at the 8-position.
2. 2. A process as claimed in claim l(A), wherein the compound of formula 11 has the following structure lia HO T LC13LH % 0-1//;corHR, 0 \-/ COOR (Ila) in which R represents a carboxy protecting group, especially a pnitrobenzyi group, and R, is as defined in claim 1.
3. 3. A process as claimed in claim 1, wherein compound 11 is produced by treating a corn50 pound of formula IX R20 CH3CH 'F_ZfJC1 1 0 FN, SCOR9 ROOC 00C0z (IX) in which Z, R, and R2 are as defined in claim 1, and R9 represents a phenyl group or an alkyl group having from 1 to - 4 carbon atoms, with a base.
4. 4. A process as claimed in, claim 3, wherein a compound of formula IX is produced by 60 reacting a compound of formula X r.

   1 39 GB2195627A 39 R20 CH3CH r-010 (X) 5:N, "" SCOR9 ROOC 0 c\ )C0z in which R, R2 and Z are defined as in claim 1, R9 is defined as in claim 3, and RIO indepen- dently represents a phenyl group or an alkyl group having from 1 to 4 carbon atoms, with a 10 chlorinating agent.
5. 5. A process as claimed in claim 4, wherein a compound of formula X is produced by reacting a compound of formula XI R20 CH 10 3CH SR 1 0 COOR (xl) in which R and R2 are as defined in claim 1 and RIO is as defined in claim 4, in the presence of a base, with a compound of formula M S 25 11 FC-0 0C0z in which Z is as defined above, and 1111 represents a halogen atom, or an imidazolide group, followed by reaction with an activated carboxylic acid derivative which comprises the group R9 30 as defined above, for example, with an acyl halide of formula XIII 0 9 It 12 (M1I R c R 35 in which R9 is as defined above and R12 represents a chlorine or bromine atom.
6. 6. A process as claimed in claim l(B), wherein a compound of formula Ill is produced by introducing the group Y into a compound of formula XIVa or X^ R 20 R2o 40 L'M3Url,', r-Tr's I_ S LtV H,, S 0 45 COOR COOR (X1Va) MIVb) in which R and R2 are defined as above or a tautomer thereof having an endocyclic double bond 50 in a manner known per se or in an analogous manner.
7. 7. A process as claimed in claim l(C), wherein a compound of formula Va is produced (a) by reacting a compound of formula XIX R20 3CH r,-L (M) 0 I-Nf H in which R2 and L are as defined in claim 1, with a compound of formula XXib GB2195627A 40 L S 1 H (XXlb) ROOC-CH-C-0 0\/ COZ in which R, L and Z are as defined in claim 1, that has been treated with a base, or (b) by reacting a compound of formula XX R20 10 CH3CH, As OF \coz (xx) 0::ENH H 'LLtn COOR in which R, R2 and Z are defined as in claim 1, with a halogenating agent.
8. 8. A process as claimed in claim l(C), wherein a compound of formula Vb is produced by reacting a compound of formula XX as defined in claim 7, with hydrogen peroxide optionally in the presence of a base, or with a peracid.
9. 9. A process as claimed in claim 1 (C), wherein a compound of formula Ve is produced by 20 carrying out a diazo transfer on a compound of formula XX as defined in claim 7.
10. 10. A process as claimed in any one of claims 7 to 9, wherein a compound of formula XX is produced by reacting a compound of formula AX as defined in claim 7 with a compound of formula XXfa S ROOC - CH 2 - C \ 0-&COZ (XXIa) 30 in which R and Z are defined as in claim 1.
11. 11. A process as claimed in claim 1 (D), wherein a compound of formula Vib is produced by 35 reacting a compound of formula XXII R?() X cHcH 11 SC0-n\ CC)z M11) 0 j:; X=/ in which R, R 2, X and Z are as defined in claim 1, with a compound of formula XXV COR14 (XXv) 50 COOR in which R is as defined in claim 1, and R14 represents a group that can be displaced by the azetidinone nitrogen in the compound of formula XXII, for example, a halogen atom, an imidazo55 lide group, or a mixed anhydride group.
12. 12. A process as claimed in claim l(D), wherein a compound of formula Via is produced by halogenating a compound of formula XXVII R20 60 CH CH SCO C0z 0)IC-OH OOR (XXVII) R z i 41 GB2195627A 41 in which R, R2, X and Z are as defined in claim 1.
13. 13. A process as claimed in claim 12, wherein a compound of formula XXVII is produced by reacting a compound of formula XXII as defined in claim 11 with a compound of formula XWII 0 0 11 U M - C - OR (XXVI 11) in which R is as defined above, or with a reactive derivative thereof.
14. 14. A process as claimed in claim 11 or claim 13, wherein a compound of formula M1 is produced by reacting a compound of formula XIX F20 LI-13CH 1 0 1 NH (XIX) in which R2 and L are defined as in claim 1 with a compound of formula Mill X 11 25 bMC 00C0Z in which X and Z are defined as in claim 1, and M represents an alkali metal or alkaline earth metal atom, or an ammonium group that is unsubstituted or substituted by, for example, one to four groups selected from alkyl groups having from 1 to 4 carbon atoms.
15. 15. A process as claimed in claim l(D), wherein a compound of formula Vib is produced (i) by subjecting a compound of formula XXXI R20 X CH3CH,, 11 SC 0 COZ H 3 ROOC CHI (XXXI) in which R, R2, X and Z are defined as above, to ozonolysis or to oxidation using a chemical oxidising agent or (ii) by subjecting compound XXXI to ozonolysis or chemical oxidation, treating the reaction product with methanol, and acylating that reaction product with a compound of formula XXV COR 14 1 MY'V) COOR
16. 16. A process as claimed in claim 15, wherein a compound of formula XXXI is produced by 50 reacting a compound of formula XXX R20 CH3CH, SAn Et CH3 0 J- ROOC CH3 (M) in which R and R2 are as defined in claim 1 and Aq denotes Ag(I) with a compound of formula X11a 42 GB2195627A 42 X I FM 00C0Z (XIIa) - in which X and Z are as defined in claim 1 and W' is as defined in claim 5. '
17. 17. A process as claimed in claim 16, wherein a compound of formula XXX is produced by reacting a compound of formula MIX R20 10 CH3CH,, -Z'S CH3 O,;J N j< MIX) = CH3 EOOR in which R and R2 are as defined in claim 1 with a silver salt.
18. 18. A process as claimed in claim l(D), wherein a compound of formula Via is produced by reacting a compound of formula Vib as defined in claim 1 with a trivalent organophosphorus reagent.
19. 19. A process as claimed in claim l(D), wherein a compound of formula Via is produced 20 (a) by reacting a compound of formula Vib as defined in claim 1 with a trivalent organophos phorus reagent or, (b) by reacting a compound of formula Vie as defined in claim 1 with a phosphine in the presence of a base.
20. 20. A process as claimed in claim l(E), wherein a compound of formula Villb is produced by 25 reacting a compound of formula XXXII R20 H, 8 CH3C SR K XH 0 RC)0C on\ C0z \--i (XXXII) in which R, R2, R8, X and Z are as defined in claim 1, with a reagent capable of converting the 35 group XH to the group L as defined in (;]aim 1.
21. 21. A process as claimed in claim 20, wherein a compound of formula XXXII is produced by reacting a compound of formula XXX111 R20 ' CH3CH SR8 0)1 MXIII) COOR 45 in which R, R2 and W are as defined in claim 1, with a compound of formula V11 X 50 711 C- 0 G= (Vil) 50 in which R7, X and Z are as defined in claim 1.
22. 22. A process as claimed in any one of claims 1 to 21, wherein a group at the 8-position having S-stereochemistry in a resulting compound is converted into a 8R-group by (i) oxidising a free 8-hydroxy group to give an oxo group, which is then reduced to a hydroxy group, (ii) reacting a compound having a free 8S-hydroxy group with a mixture of triphenylphosphine and a di-lower alkyl azodicarboxylate in the presence of a nucleophilic agent then hydrolysing the modified 8R-hydroxy group to give a free 813-hydroxy group.
23. 23. A process as claimed in any one of claims 1 to 22, wherein a protected group -OR2 is a group from which the protecting group R2 can be removed under acidic conditions.
24. 24. A process as claimed in claim 23, wherin a protected hydroxy group is a tetrahydropyranyloxy or tetra hydrofu ranyloxy group; an acetal or ketal group; or a sily] ether.
25. 25. A process as claimed in claim 24, wherein an acetal or ketal group has the formula 43 GB2195627A 43 OR k 1 0 - C - R j 1 in which R, and R,, which may be the same or different, each represents a hydrogen atom or an 10 alkyl group having from 1 to 4 carbon atoms, or R, and R, together with the carbon atoms to which they are attached, represent a cycloalkyl ring having from 4 to 7 carbon atoms, and Rk represents an alkyl group having from 1 to 4 carbon atoms, or Ri and Rk, together with the carbon atom and the oxygen atom to which they are attached, respectively, represent a tetrahy- dropyranyl ring; and a sily] ether has three substituents on the silicon atom and up to 24 carbon atoms in total, the three substituents being the same or different, and selected from alkyl, alkenyl and cycloalkyl groups, and phenyl and phenalkyl groups which may be unsubstituted or substituted.
26. 26. A process as claimed in claim 25, wherein a protected hydroxy group is an -0SiR,R,,Rn group in which R,, R,,, and R, which may be the same or different, each represents a lower alkyl 20 group or a phenyl group.
27. 27. A process as claimed in claim 26, wherein a hydroxy protecting group R2 is a tetrahydropyranyl, 2-methoxyprop-2-yl, trimethyisily], triethylsilyl or t-butyldimethyisilyl group.
28. 28. A process as claimed in claim 1 carried out substantially as described in any one of Examples 7, 8, 12, 13 and 14.
29. 29. A compound of formula la as defined in claim 1, whenever produced by a process as claimed in any one of claims 1 to 28.
30. 30. A compound as claimed in claim 29, wherein a hydroxy protecting group R2 can be removed under physiological conditions.
31. 31. A compound as claimed in claim 30, wherein a group R2 is a carboxylic acid acyl group 30 of the formula R20CO- in which R20 represents a hydrogen atom or a straight or branched chain alkyl group having from 1 to 6 carbon atoms, or represents a phenyl group or a phenoxyalkyl group in which the alkyl moiety is straight-chained or branched and has from 1 to 4 carbon atoms.
32. 32. A compound as claimed in claim 31, wherein R20 represents a methyl, ethyl or t-butyl 35 group, or a phenoxymethyl group.
33. 33. A compound as claimed in any one of claims 29 to 32 wherein an ester at the 2 carboxy group is formed with an unsubstituted or substituted aliphatic alcohol or phenol having up to 20 carbon atoms in total.
34. 34. A compound as claimed in claim 33, wherein in an esterified carboxy group -COOR, the 40 group R is a phenyl group or is a methyl or ethyl group optionally substituted, by an acyloxy group; by an arninoalkanoyloxy group; by an optionally substituted amino group; or, in the case of a methyl group, by one or more unsubstituted or substituted phenyl groups; and wherein a phenyl group, either as R or as a substituted of a methyl group, is optionally substituted by one or more substituents selected from methoxy and nitro groups and halogen atoms; or R repre- sents a phenoxyethyl or trichloroethyl group; or R represents a trialkylsilyl or trialkylsilylalkyl ester in which alkyl moieties have from 1 to 4 carbon atoms.
35. 35. A compound as claimed in claim 34, wherein R represents a benzy], nitrobenzyl, methox ybenzyi, dimethoxybenzy], benzhydry], trity], trimethylsilyl or trimethylsilylethyl group.
36. 36. A compound as claimed in claim 29, wherein the esterifying group can be removed 50 under physiological conditions to give the free acid or a carboxylate.
37. 37. A compound as claimed in claim 36, in the form of an acyloxymethyl or acyloxyethyl ester having from 2 to 12 carbon atoms in the acyl moiety, an aminoalkanoyloxymethyl ester having from 2 to 12 carbon atoms in the alkanoyl moiety, a 1'(alkoxycarbonyloxy)ethyl ester, an optionally substituted 2-aminoethyl ester or a phthalidyl ester.
38. 38. A compound as claimed in claim 37, in the form of a glycyloxymethyl, L-valinyloxymethyl or L-leucyloxymethyl ester, a Y-(methoxyca rbonyloxy) ethyl ester, a 2-diethylarninoethyl or 2-(lmorpholino)-ethyl ester.
39. 39. A compound as claimed in claim 36, in the form of a pivaloyloxymethyl ethoxycarbony- loxymethyl, 5-methyidioxalen-2-on-4-yl-methyl, acetyimethyl, acetoxymethyl, 1'-(acetoxy)ethy], Y- 60 (acetyl)ethyl or 1'-(ethoxycarbonyloxy) ethyl ester.
40. 40. A compound as claimed in any one of claims 29 to 39, wherein R' represents a hydroflin atom or a methyl group.
41. 41. A pharmaceutical preparation which comprises a compound of formula 1 as claimed in any one of claims 29 to 40 or a physiologically tolerable salt thereof, or a mixture of two or 65 44 GB2195627A 44 more such substances as active ingredient, in admixture or conjunction with a pharmaceutically suitable carrier..
42. 42. A pharmaceutical preparation as claimed in claim 41, which also comprises one or more other fl-lactam antibiotics.
43. 43. A pharmaceutical preparation as claimed in claim 42, wherein a fllactarn antibiotic is a cephalosporin antibiotic.
44. 44. A method of treating mammals to combat a bacterial infection, which comprises administering to the mammal a compound of formula I as claimed in any one of claims 29 to 40, or a physiologically tolerable ester or salt thereof.
45. 45. - A method as claimed in claim 43, wherin a cephalosporin antibiotic is also administered. 10
46. 46. A compound of formula Ila HO 1 1"S 15 Z 0, N O-OcOwRl COOR in which R' is as defined in claim 1 and R represents a carboxy protecting group, especially a p- 20 nitrobenzy] group.
47. 47. A compound of formula Va, Via or Vc RIO FOO ",0 CH3CH, 5 O0C0z C0z CH3CM,:

    X H 0 t".

    CH3CH5 00 0 COOR 0 COOR (va) (Vb) (VC) in which R, R2, Z and L are as defined in claim 1.
48. 48. A compound. of formula Via, Vib, Vic or Vid R20 X RIO cH,c H. 5, D-OC0z CH,CH SCOI17--\coz 35 0 '?P1013 1 -1 - 'N, o,-N COOR COOR (V1a (Vlb) 40 RIO R20 X CHjCH 11 CH,CH 5-0 C0z R6 , 1 r 0)3]r.

    0- ICH-RS P( 1 01 45 OOR COOR V.1c 1 Vid) in which R, R2, Z, X, R5, R6, n and. the group = P(Q). are as defined in claim 1 50
49. 49. A compound of formula Villa or Vilib R20 CH3CH, 5 0) NI', 1 ROOCOF-COZ -R6 _n VIlla P20 CHjCH SR8 0 L ROO' <F\COZ V111b in which R, R2, R6, n, L and Z are as defined in claim 1.

    Published 1988 at The Patent Office, State House, 66/71 High Holborn, London WC 1 R 4TP. Further copies may be obtained from The Patent Office, Sales Branch, St Mary Cray, Orpington, Kent BR5 3RD. Printed by Burgess & Son (Abingdon) Ltd. Con. 1/87.