GB2045235A - Cyclisation of sulphides - Google Patents

Abstract

Many pharmaceutically useful compounds contain ring structures and the present invention relates to a process for producing ???-lactam- containing ring structures by cyclising azetidinone derivatives. The present invention provides a process for the desulphurization of an organic sulphide with accompanying ring formation, which comprises treating a ???-lactam having a nucleophilic group linked to the nitrogen atom via an unsubstituted or substituted divalent organic radical, and a dithio or polythio group linked to the adjacent carbon atom, with a tervalent organophosphorus compound. The sulphide is preferably also treated, simultaneously or subsequently, with a thiophilic agent. The invention also provides a process for desulphurizing an organic sulphide with accompanying ring formation, which comprises treating a monosulphide corresponding to a disulphide or polysulphide defined above, with a thiophilic agent. A thiophilic agent is preferably a thiophilic metal salt or a thiophilic metal salt plus a base.

Description

SPECIFICATION Cyclisation of sulphides This invention relates to a process for the cyclisation of organic compounds.

Many pharmaceutically useful compounds contain ring structures. The process described here is useful for the production of,3-lactam-containing ring structures. The present invention is based on a surprising observation that certain mono, di-, or poly-thio azetidinone derivatives can be cyclised, providing a convenient and relatively simple process for the synthesis of pharmaceutically useful P-lactam containing ring structures.

The present invention provides a process for the desulphurzation of an organic sulphide with accompanying ring formation, which comprises treating a p-lactam having a nucleophilic group linked to the nitrogen atom via an unsubstituted or substituted divalent organic radical, and a dithio or polythio group linked to the adjacent carbon atom, with a tervalent organophosphorus compound. The sulphide is preferably also treated, simultaneously or subsequently, with a thiophilic agent (as hereinafter defined).

The starting material preferably has the general formula I

in which Nuc represents a nucleophilic group, Z represents an unsubstituted or substituted aroma tic heterocyclic radical having up to 15 and prefer ably up to 9 carbon atoms and at least one ring nit rogen atom, and optionally a further ring hetero atom, which radical is bonded to the thio group iS],- by one of its ring carbon atoms, which carbon atom is bonded to a ring nitrogen atom by a double bond, or Z represents an acyl radical derived from an organic carboxylic orthiocarboxylic acid, Y represents an unsubstituted or substituted divalent organic radical, and n represents an integer of from 2 to 4, the p-lactam ring being unsubstituted 0': further sub- stituted.

Examples of nucleophilic groups Nuc are -OH, -SH, -NH2, -00, -SOand -NHOgroups; -SR' groups in which R' represents a protecting group, for example,

SiR"3 and SnR"3, R" representing a straight or branched chain unsubstituted or substituted alkyl group having up to 8 carbon atoms, for example, a methyl or n-butyl group; and -NHR" and NCR-" in which R" represents an organic group, for example, an unsubstituted or substituted alkyl or aryl group, for example, a lower alkyl group, a phenyl group or an aralkyl group, for example, a benzyl group.

It will be appreciated that a requirement for ring formation on desulphurization is that the divalent organic radical Y is able to attain a configuration or conformation such that the nucleophilic group can approach within chemical bonding distance of the carbon atom to which the [S]nZ group is bonded.

The nucleophilic group is preferably linked to the ss-lactam nitrogen atom via a vinylidene, alkylene or aromatic radical, which is preferably substituted.

A starting material preferably has the following partial structure of formula Ill or IV

in which Nuc is as defined above, R4 represents a hydrogen atom or a carboxyl protecting group. The group -COOR4 is, for example, an ester formed with an unsubstituted or substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or aryl or araliphatic alcohol having up to 18 carbon atoms and R5 represents a hydrogen atom or organic radical. An organic radical may be an unsubstituted or substituted cycloaliphatic radical, especially having from 5 to 7 ring carbon atoms, or an unsubstituted or substituted aryl, especially phenyl, radical, or an unsubstituted or substituted, straight or branched chain aliphatic group.

An aliphatic group R5 is, for example, an alkyl, alkenyl or alkynyl group having up to 8 carbon atoms, and especially up to 4 carbon atoms.

A group R5 may be substituted by one or more substituents, as appropriate. Examples of substituents are halogen atoms; oxo groups; hydroxyl and mercapto groups, alkoxy and alkylthio groups; alkylcarbonyl groups; carboxy, alkoxycarbonyl and alkylthiocarbonyl groups; alkanoyloxy and alkanoythio groups; carbamoyl and carbomoyloxy groups and carbamoyl and carbonoyloxy groups substituted by one or two groups selected from alkyl and aryl groups, and the corresponding unsubstituted and substituted groups in which the, each or either oxygen atom is replaced by a sulphur atom; nitro, cyano and azido groups; amido and imido groups; imino, amino, mono- and di- alkylamino, mono- and di-arylamino groups, and N,Nalkylarylamino groups; acylamino groups; sulphinyl, sulphonyl and sulphonamido groups; cycloalkyl groups, aryl, aryloxy, arylthio, aryloxycarbonyl, arylthiocarbonyl, arylcarbonyloxyl, arylcarbonylthio, arylkoxycarbonyl, aralkylthiocarbonyl, aralkylcarbonyloxy, aralkylcarbonylthio, aralkoxy, and aralkylthio groups; aromatic and non-aromatic heterocyclic groups, aromatic and non-aromatic heterocyclicoxy groups and aromatic and nonaromatic heterocyclicthio groups.

Examples of aromatic heterocyclic groups are 1 -methylimidazol-2-yl, 1,3 - thiazol - 2 - yl, 1,3,4 thiadiazol - 2 - yl, 1,3,4,5 - thiatriazol - 2 - yl, 1,3 oxazol - 2 - yl, 1,3,4,5 - oxatriazol - 2 - yl, 1,3,4,5 tetrazol - 2 - yl, 2 - quinolyl, 1 - methyl - benzimidazol - 2 - yl, benzoxazol - 2 - yl and benzthiazol - 2 - yl groups, and the corresponding 2 - yl - oxy and 2 - yl thio groups.

Any substituent of R1 that is itself capable of substitution may be substituted, for example, by any one or more of the substituents described above.

Alkyl groups are preferably alkyl groups having up to 8 and especially up to 4 carbon atoms.

R' preferably represents a methyl group our a sub stituted methyl group, preferably substituted by one of the groups described above, for example, a methyl group having one or more substituents, for example, bromoethyl; a methoxymethyl group; an etherified or esterified methyl group, for example, a lower alkoxymethyl group, for example, a methox ymethyl group, our a loweralkanoyloxymethyl group, for example, a methylcarbonyloxymethyl group; a methyl group substituted by an azide nitrile or thiocyanate group; a methyl group substituted by a -SHet group in which Het represents an aromatic or non-aromatic heterocyclic group especially an aromatic heterocyclic group as mentioned above; or a methyl group substituted by an amino group or by a mono or di lower alkylamino, mono or diarylamino or lower alkyl-arylamino group; or a methyl group substituted by an acylamino group.

An aromatic heterocyclic radical Z may be monocyclic or bicyclic and may be substituted, for exam ple, by a lower alkyl group, for example, a methyl or ethyl group, a lower alkoxy group, for example, a methoxy or ethoxy group, a halogen- atom, for example, fluorine or chlorine atom or an aryl group, for example, a phenyl group.

Such a radical is, for example, a monocyclic five membered thiadiazacyclic, thiatriazacyclic, oxadiazacyclic or oxatriazacyclic radical of aromatic character, especially a monocyclic five-membered diazacyclic, oxazacyclic orthiazacyclic radical of aromatic character, and above all, the corresponding benzdiazacyclic, benzoxazacyclic or benzthiazacyclic radicals, wherein the heterocyclic part is five membered and is of aromatic character In radicals Z a substitutable ring nitrogen atom can be substi tuted, for example, by a lower alkyl group.Examples of such groups Z, are 1 - methyl - imidazol - 2 - yl, 1,3 - thiazol - 2 - yl, 1,3,4 - thiadiazol - 2 - yl, 1,3,4,5 thiatriazol - 2 - yl, 1,3 - oxazol - 2 - yl, 1,3,4 - oxadiazol - 2 - yl, 1,3,4,5 - oxatriazol - 2 - yl, 2 - quinolyl, 1 methyl - benzimidazol - 2 - yl, benzoxazol - 2 - yl and especially benzthiazol - 2 - yl groups.Z may also represent an acyl radical of organic carboxylic or thiocarboxylic acid, for example, an unsubstituted or substituted aliphatic, cycloaliphatic, araliphatic or aromatic acyl orthioacyl group having upto 18, preferably up to 10, carbon atoms, for example, lower alkanoyl groups, for example acetyl and propionyl groups, lowerthioalkanoyl groups, for example thioacetyl and thiopropionyl groups, cycloal kanecarbonyl groups, for example a cyclohex anecarbonyl group, cycloalkanethiocarbonyl group, for example, a cyclohexanethiocarbonyl group, benzoyl, thiobenzoyl, naphthylcarbonyl, and naphthylthiocarbonyl groups, heterocyclic carbonyl and thiocarbonyl groups, for example, 2-, 3- or 4-pyridylcarbonyl, 2- or3-thenyl, 2- or3-furoyl, 2-, 3-, or4-pyrodylthiocarbonyl, 2- or3-thiothenoyl, and 2 or3-thiofuroyl groups, and corresponding substituted acyl and thioacyl groups, for example acyl and thioacyl groups monosubstituted or polysubstituted by lower alkyl groups, for example methyl groups, halogen atoms for example fluorine and chlorine atoms, lower alkoxy groups, for example, methoxygroups, aryl groups for example phenyl groups, aryloxy groups, for example phenyloxy groups.

Z preferably represents a

The tervalent organophosphorous compound is especially one of the general formula Ill PR1R2R3 (111) wherein R', R2 or R3, which may be the same or d,ffer- ent, each represents an unsubstituted or substituted hydrocarbon group, for example, a straight or branched chain aliphatic group, an unsubstituted or substituted cycloaliphatic group or an unsubstituted or substituted aryl group or an unsubstituted or substituted hydrocarbon group in which one or more carbon atoms are replaced by hetero atoms, especially nitrogen, oxygen and sulphur atoms, for example, alkyl and alkoxy groups, amine groups, aromatic hydrocarbon groups, aromatic and nonaromatic heterocyclic groups. Preferred tervalent organophosphorus compounds aretriphenylphosphine, tributylphosphine, trimethylphosphite and triethylphosphite.

A further preferred group of tervalent organophosphorus compounds are those in which, in formula Ill, one or more of the groups Rt, R2 and R3 comprises an insoluble polymer, which aids removal afterthe reaction. Generally, one polymeric substituent is adequate.

Another preferred group oftervalent organophosphorus compounds are those in which, in formula Ill, one or more of the groups R', R2 and R3 comprise a cationic or anionic centre, for example, a quaternary ammonium group or a carboxylate or sulphate group. The presence of a charged group assists removal of the resulting organophosphorus sulphide, for example, by partition or by absorption on an insoluble ion exchange resin or by extraction into an aqueous solution at an appropriate pH, when the organophosphorus sulphide is water soluble.

The thiophilic agent is especially a thiophilic metal salt, for example, a thiophilic salt of an element from Group Ib, llb orVIII ofthe Periodic Table of the Elements (cf. Advanced Inorganic Chemistry, F.A. Cotton and G. Wilkinson, Interscience), for example, a silver, copper, zinc, nickel, iron, cadmium, mercury or cobal; thiophilic salt, silver and copper salts being preferred.Examples of preferred thiophilic salts are (i) Ago3, AgOSO2CF3, AgOSO2Me,AgBF4 O, AgPF6 Q CuCI, CuBr, Curl2, CuBr2, CuOSO2Me, CuOSO2CF3, CoS04, Cu(NO3)2 and the corresponding nickel, zinc, iron and cobalt salts; and (ii) Ag2CO3, AgO, Cu(acac)2, Cu(CO3)2, Cu2CO3, CuOR in which R represents an alkyl group or cycloalkyl group for example, comprising up to 8 carbon atoms, preferably CH3, C2Hs, t-butyl.

If the metal salt is itself sufficiently basic, for example, the salts of group (ii) above, it is not necessary to incorporate a base in the reaction mixture. If, however, the metal salt is only weakly basic, for example, the salts of group (i) above, then it is necessary to use a base. The term "thiophilic agent" is used herein to mean a thiophilic metal salt alone, or a thiophilic metal salt plus base, as appropriate.

The base may be inorganic or organic, and preferred organic bases are pyridine, alkyl substituted pyridines, alkylamine substituted pyridines, piperidine and alkyl substituted piperidine e.g.

2,2,6,6 - tetramethylpiperidine, and trisubstituted amines, for example, trialkylamines, for example triethylamine and ethyldi - iso - propyl - amine, and alkyl - arylamines, for example, 1,8 - bis (dimethylamine) naphthalene, or N,N - dimethylphenylamine. Examples of preferred inorganic bases are metal hydrides, e.g. sodium hydride, and metal carbonates e.g. sodium carbonate.

According to the preferred method of carrying out the process, the starting material is reacted with the phosphine and simultaneously, a thiophilic agent, especially a metal salt, and where appropriate, a base.

A monosulphide corresponding to a disulphide starting material, may be formed as an intermediate, and when a disulphide starting material is reacted with a phosphine alone, there is generally formed a mixture of the monosulphide and the cyclic product.

Such a mixture, or the isolated monosulphide, may be treated with a thiophilic agent and, where necessary, a base for conversion to the desired cyclic product.

The present invention accordingly also provides a process for desulphurizing an organic sulphide with accompanying ring formation, which comprises treating a p-lactam comprising a nucleophilic group linked to the nitrogen atom and a monothio group linked to the adjacent carbon atom, with a thiophilic agent.

The monosulphide starting material preferably has the general formula II

in which Nuc and Z are as defined above and the p-lactam ring may be unsubstituted or substituted at the 3-position, and the preferred reagents are as described above.

The process of the invention is preferably carried out in the presence of an appropriate, inert, anhydrous solvent or diluent. Any solvent or diluent can be used which is inert to the sulphide, the tervalent phosphorus compound and the final product. Examples of solvents and diluents are benzene, toluene, acetonitrile, ethylacetate, dichloromethane, chloroform, and dioxane. Mixtures of two or more solvents and diluents may also be employed. The process may be carried out at a temperature of from 40 to +80 , preferably from 0 to +200.

In the case of di- and polythio starting materials, taking x as the total number of sulphur atoms in the di- or polythio moiety, it is preferable to use x-1 equivalents of the tervalent organophosphorus compound. There is preferably used 1 to 2 equivalents of thiophilic agent per equivalent of mono, dior polysulphide starting material.

It is preferable to incorporate both the tervalent organophosphorus compound and the thiophilic agent in the reaction mixture when a di- or poly-thio starting material is treated.

The process of the invention is particularly useful for converting a substituted azetidinone into an oxapenem or oxacephem ring system or an analogue thereof. Oxapenem and oxacephem compounds generally have antibacterial properties.

In this case, the starting material has the general formula V

in which Z, n and Nuc are defined as above, R6 and R7, which may be the same or different, each represents a hydrogen or halogen atom or an unsubstituted or substituted aliphatic group and Y represents a divalent organic group, for example,

in which R4 and R5 are as defined above. In general, the nucleophilic group must be cis to the azetidinone ring to enable ring formation to occur.

The following examples illustrate the invention.

Temperatures are given in degrees Celsius, and ratios of solvents for chromatography are by volume.

Example 1 2- Methyl - 3- (4- nitrobenzyloxycarbonyl) oxapenem.

To a stirred solution of 0.338 g of silver carbonate and 0.428 g of triphenylphosphine in 4 ml dry chloroform was added dropwise a solution of 0.80 g of 4 - nitrobenzyl - 2 - [4R - benzthiazolyldithio - 2 oxo - 1 - azetidinyl] - 3 - hydroxy - crotonate in dry chloroform. The resulting mixture was stirred at room temperature for half an hour and then chromatographed directly (short path rapid chromatography, silica gel H, methylene chloride/hexane) to give 0.195 g (41% of the theoretical yield) of 2 - methyl - 3 - (4 - nitrobenzyloxycar bonyl) - oxapenem as a colourless, crystalline solid.

8 (CDCl3) 2.32 (3H, s, CH3) 3.42 (1 H, dd J 17Hz Jtrans 1 he, 6-H) 3.86 (1H, dd J 17HzJ,, 2.5 Hz, 6-H) 5.22 (1 H, dd J 14 Hz, -CH2-) 5.50(1 H, d J 14Hz, -CH2-) 5.93 Jtrans 1 Hz Jcjs 2.5Hz, 5-H) Vmax = 1810,1710,1640cm-1. mp 128.5 - 129'C.

Example 2 2- Methyl -3- (4- nitrobenzyloxycarbonyl) oxapenem.

To a suspension of 0.024 g of silver oxide and 0.028 g of triphenylphosphine in 0.2 ml deuterochloroform was added dropwise a solution of 0.050 g of 4 - nitrobenzyl - 2 - [4R - benzthiazolyldithio - 2 oxo - 1 - azetidinyl] - 3 - hydroxy - crotonate in 0.4 ml deuterochloroform. After 10 minutes the reaction mixture was centrifuged, and NMR specroscopic examination of the supernatant confirmed the presence of 2 - methyl - 3 - (4 - nitrobenzyloxycarbonyl) oxapenem as the main product.

Example 3 To a stirred solution of 0.05 of 4 - nitrobenzyl - 2 [4R - benzthiazolyldithio - 2- oxo - 1 - azetidinyl] - 3- hydroxy - crotonate and 0.0134 g of copper acetylacetonate in 0.4 ml deuterochloroform was added 0.0267 g oftriphenylphosphine in 0.1 ml deuterochloroform. After 5 min the solution was centrifuged. NMR spectroscopy of the solution showed 2 - methyl - 3 - (4- nitrobenzyloxycarbonyl) oxapenem as the major product. TLC analysis confirmed this result.

Example 4 A solution of 0.05 g of 4 - nitrobenzyl - 2 - [4R benzthiazolyldithio -2 - oxo - 1 - azetidinyl] - 3 - hydroxy - crotonate and 10,ul deuteriopyridine in 0.5 ml deuteriochloroform was added to a stirred solution of 0.028 g of triphenylphosphine and 0.0201 g of silver methanesulphonate in 0.3 ml deuteriochloroform. After 5 min the reaction mixture was cen trifugedto remove the precipitated solid, and NMR spectroscopy of the supernatant showed that 2 methyl - 3- (4 - nitrobenzyloxycarbonyl) - oxapenem was the major product. Tlc analysis confirmed this result.

Example 5 To a solution of 0.05 g of 4 - nitrobenzyl - 2 -[4R benzthiazolyldithio - 2- oxo - 1 - azetidinyl] - 3- hydroxy - crotonate in 0.5 ml deuteriochloroform was added 0.028 g of triphenylphosphine in 0.1 ml deuteriochloroform. The solution was shaken at room temperature. NMR indicated the formation of 2 - methyl - 3- (4 - nitrobenzyloxycarbonyl) oxapenem and 4 - nitrobenzyl - 2 - [45- benzthiazolylthio - 2 - oxo - 1 - azetidinyl] - 3 - hydroxy crotonate in the ratio 1:4.

Example 6 To a solution of 0.075 g of 4 - nitrobenzyl - 2 [4 pyridinedithio - 2 - oxo - 1 - azetidinyl] - 3 - hydroxy crotonate in 4 ml dry methylene chloride was added 0.045 g of triphenylphosphine in 1 ml dry methylene chloride. The solution was stirred for 1.5 hr, evapo rated in vacuo, and NMR analysis of the residue showed the formation of 2 - methyl - 3 - (4 - nitrobenzylcarbonyl) - oxapenem and 4 -p - nitrobenzyl - 2 [4 - pyridinethio - 2- oxo - 1 - azetidinyl] - 3 - hydroxy crotonate in the ratio 1:1.

The residue was chromatographed on silica gel (2 g) eluting with ethyl acetate - hexane mixtures to afford triphenyl phosphine sulphide then 10 mg of 2 - methyl - 3- (4 - nitrobenzyloxycarbonyl) oxapenem as a colourless oil which crystallised on standing.

y max 1810cm-1. mp 128.5 - 129"C.

Example 7 2- Methyl - 3-p - nitrobenzyloxycarbonyl oxapenem.

To 0.035 g of 4 -p - nitrobenzyl - 2 - [45 - benz thiazolylthio - 2 - oxo - 1 - azetidinyl] - 3 - hydroxyc rotonate in 0.7 ml CDCI3 was added 6.4,ul pyridine followed by 0.025 g of silver methylsulphonate, and the mixture was stirred for 20 minutes at room temperature. The reaction mixture was centrifuged and the supernatant examined by NMR spectros copy and byTLO. Both analyses clearly indicated, by comparison with a known sample, the presence of 2 - methyl - 3 - (4 - nitrobenzyloxycarbonyl) oxapenem.

Example 8 2- Methyl - 3-p - nitrobenzyloxycarbonyl oxapenem.

To 0.035 g of 4 - nitrobenzyl - 2 - [45- - benz- thiazolylthio - 2 - oxo - 1 - azetidinyl] - 3 - hydroxyc rotonate in 0.5 ml CDCI3 was added 6.5 yl of pyridine followed by 0.038 g of silvertrifluoromethylsulpho-~ nate, with shaking and at room temperature. The reaction mixture was centrifuged and the supernat ant examined by NMR spectroscopy and thin layer chromatography shown to be 2 - methyl - 3 - nit robenzyloxycarbonyl - oxapenem.

Example 9 2-Methyl - 3- (4- nitrobenzyloxycarbonyl) oxapenem.

To 33 mg of 4 - nitrobenzyl - 2 - [4S - benzthiazolyl thio - 2 - oxo - 1 - azetidinyl] .3 - hydroxycrotonate in 0.5 ml of chloroform was added, at room tempera ture, excess sodium hydride, followed by 25 mg of silvertrifluoromethylsulphate, and the mixture was stirred for 6 < hours. The solid by-products were fil tered off and the solvent was evaporated to give a crystalline solid, shown by TLC and NMR analysis to be 2 - methyl - 3 - (4 - nitrobenzyloxycar bonyl)oxapenem.

Example 10 2-Methyl - 3- (4- nitrobenzyloxycarbonyl) oxapenem.

To 200 mg of 4 - nitrobenzyl - 2 - 4S - benz thiazolylthio - 2 - oxo - 1 - azetidinyl - 3- hydroxy crotonate in 5 ml of dry chloroform was added, with stirring, 47 mg of triethylene. After 1 minute, 220 mg of freshly ground silvertrifluoromethylsulphonate was added at room temperature, and the mixture was stirred for 15 minutes. The precipitate was removed by centrifugation and the solution applied to a short-path silica-gel column. Rapid elution with dichloromethane-hexane gave fractions containing 2 - methyl - 3 - (4 - nitrobenzyloxycarbonyl) oxapenem. These fractions were combined and evaporated under reduced pressure to give 27 mg of the product as a white solid.

Example 11 Sodium salt of2 - methyloxapenem.

To a solution of0.10gof2- methyl -3-(4- nit robenzyloxycarbonyl) - oxapenem in 7 ml ethyl ace tate was added 0.10 g of palladium on charcoal (10% by weight) and a solution of 0.027 g of sodium bicar'-- bonate in 7 ml of water. The reaction mixture was hydrogenated until the reaction was judged com plete (TLC), then the aqueous solution washed withi ethyl acetate then lyophilized to afford the sodium salt of 2 - methyloxapenem.

Claims (29)

1. A processforthehesulphurization of an organic sulphide with accompanying ring formation, which comprises treating a ss-lactam having a nuc leophilic group linked to the nitrogen atom via an unsubstituted or substituted diva lent organic radical, and a dithio or polythio group linked to the adjacent carbon atom, with a tervalent organophosphorus compound.

2. A process as claimed in claim 1, wherein the starting material has the general formula I

in which Nuc represents a nucleophilic group, Z represents an unsubstituted or substituted aromatic heterocyclic radical having up to 15 carbon atoms and at least one ring nitrogen atom, and optionally a further ring hetero-atom, which radical is bonded to the thio group iS],- by one of its ring carbon atoms, which carbon atom is bonded to a ring nitrogen atom by a double bond, or Z represents an acyl radical derived from an organic carboxylic or thiocarboxylic acid, Y represents an unsubstituted or substituted divalent organic radical, and n represents an integer of from 2 to 4, the p-lactam ring being unsubstituted or further substituted.

3. A process as claimed in claim 1, wherein a nucleophilic group Nuc is an -OH, -SH, -NH2, -O9, -S) or-NHOgroup; an -SR' group in which R' represents a protecting group, or an -NHR"' or -N O R"' groups, in which R"' represents an organic group.

4. A process as claimed in claim 3, wherein R"' represents an unsubstituted or substituted alkyl or aryl group.

5. A process as claimed in any one of claims 1 to 4, wherein the nucleophilic group is linked to the p-lactam nitrogen atom via an unsubstituted or substituted vinylene or allylene group.

6. A process as claimed in claim 5, wherein the starting material has the partial structural formula Ill orlV

in which Nuc is as in claim 1 or claim 3, R4 represents a hydrogen atom or a protecting group and R5 represents an organic radical.

7. A process as claimed in claim 6, wherein R5 represents un unsubstituted or substituted alkyl, alkenyl, or alkynyl group having up to 8 carbon atoms.

8. A process as claimed in claim 7, wherein R5 represents an unsubstituted or substituted alkyl, alkenyl, or alkynyl group having up to 4 carbon atoms.

9. A process as claimed in claim 9, wherein R5 represents an unsubstituted or substituted methyl group.

10. A process as claimed in claim 7, wherein an aliphatic group R5 is substituted by one or more substituents selected from halogen atoms; oxo groups; hydroxyl and mercapto groups, alkoxy and alkylthio groups; alkylcarbonyl groups; carboxy, alkoxycarbonyl and alkylthiocarbonyl groups; alkanoyloxy and alkanoythio groups; carbamoyl and, carbomoyloxy groups and carbamoyl and carbamoyloxy groups substituted by one or two groups selected from alkyl and aryl groups and the corresponding unsubstituted and substituted groups in which the, each or either oxygen atom is replaced by a sulphur atom; nitro, cyano and azido groups; amido and imido groups; imino, amino, mono- and di- alkylamino, mono- and di-arylamino groups, and N,N - alkylarylamino groups; acylamino groups; sulphinyl, sulphonyl and sulphonamido groups; cycloalkyl groups; aryl, aryloxy, arylthio, aryloxycarbonyl, aryithiocarbonyl, arylcarbonyloxyl, arylcar bonylthio, a ralkoxycarbonyl, a ral kyithiocarbonyl, aralkylcarbonyloxy, aralkyica rbonylthio, aralkoxy, and aralkylthio groups; aromatic and non-aromatic heterocyclic groups, aromatic and non-aromatic heterocyclicoxy groups, and aromatic and nonaromatic heterocyclicthio groups.

11. A process as claimed in claim 10, wherein R' represents a methyl group substituted by one or more halogen atoms, an esterified or etherified methyl group, a methyl group substituted by a -SHet group in which Het represents an aromatic or nonaromatic heterocyclic group, a methyl group substituted by an amino, mono- or di-lower alkylamino group, mono- or di-arylamino group or lower alkylarylamino group, or a methyl group substituted by an acylamino group.

12. A process as claimed in claim 11,whereinR4 represents a carboxylic acid esterified with an aliphatic, cycloaliphatic, cycloaliphaticaliphatic aryl or araliphatic alcohol having upto 18 carbon atoms.

13. A process as claimed in any one of claims 1 to 12, wherein Z represents a monocyclic five membered thiadiazacycjic, thiatriazacyclic, oxadiazacyclic, oxatriazacyclic, diazacyclic, oxazacyclic or thiazacyclic radical of aromatic character, or a benzdiazacyclic, benzoxazacyclic or benzthiacyclic radical, wherein the heterocyclic moiety is five membered and of aromatic character, a substitutable ring nitrogen atom being optionally substituted.

14. A process as claimed in claim 13, wherein Z represents a 1 - methyl - imidazol - 2 - yl, 1,3 -thiazol 2 - yl, 1,3,4 - thiadiazol - 2 - yl, 1,3,4,5 - thiatriazol - 2 yl, 1,3 - oxazol - 2 - yl, 1,3,4 - oxadiazol - 2 - yl, 1,3,4,5 - oxatriazol - 2 - yl, 2 - quinolyl, 1 - methyl - ben- zimidazol - 2 - yl, benzoxazol - 2 - yl or benzthiazol - 2 -yl group.

15. A process as claimed in any one of claims 1 to 12, wherein Z represents an acyl radical derived from an unsubstituted or substituted aliphatic, cycloaliphatic, araliphatic or aromatic acyl orthioacyl group having upto 18 carbon atoms.

16. A process as claimed in any one of claims 1 to 15, wherein the starting material is treated simultaneously with a tervalent organophosphorus compound and a thiophilic agent, or is treated first with a tervalent organophosphorus compound and then with a thiophilic agent either in situ or optionally after isolating any desulphurised compound formed.

17. A process as claimed in any one of claims 1 to 16, wherein the tervalent organophosphorus compound has the general formula Ill PR'R2R3 (111) in which R', R2 or R3, which may be the same or different, each represents an unsubstituted or substi tuted hydrocarbon group, or an unsubstituted or substituted hydrocarbon group in which one or more carbon atoms are replaced by hetero atoms.

18. A process as claimed in claim 17, wherein the tervalent organo phosphorus compound is triphenylphosphine, tributylphosphine, trimethylphosphite and triethylphosphite.

19. A process as claimed in claim 17, wherein, in formula Ill, one or more of the groups R1, R2 and R3 comprises an insoluble polymer.

20. A process as claimed in claim 17, wherein, in formula Ill, one or more of the groups R', R2 and R3 comprises an anionic or cationic centre.

21. A process for desulphurizing an organic sulphide with accompanying ring formation, which comprises treating a p-lactam comprising a nucleophilic group linked to the nitrogen atom via an unsubstituted or substituted divalent organic radical and a monothio group linked to the adjacent carbon atom, with a thiophilic agent.

22. A process as claimed in claim 21, wherein the P-lactam has the general formula la

in which Z, Y and Nuc are as defined in any one of claims 2 to 15 and the ss-lactam ring may be unsubstituted or substituted at the 3-position.

23. A process as claimed in any one of claims 6 to 22, wherein the thiophilic agent is a thiophilic silver, copper, zinc, nickel, iron, cadmium, mercury or cobalt salt.

24. A process as claimed in claim 23, wherein the thiophilic agent is Ag2CO3, AgO, Cu(acac)2, Cu(CO3)2, Cu2CO3, CuOR in which R represents an alkyl group orcycloalkyl group.

25. A process as claimed in claim 23, wherein the thiophilic agent is (i) Ago3, AgO5O2CF3, AgOSO2Me, AgBF4, AgPF6, CuCl, CuBr, CuCi2, CuBr2, CuOSO2Me, CuOSO2CF3, CuSO4, Cu(NO3)2 or a corresponding nickel, zinc, iron or cobalt salt, and (ii) a base.

26. A process as claimed in claim 25, wherein the base is pyridine, an alkyl-substituted pyridine, an alkylamino-substituted pyridine, piperidine, an alkyl-substituted piperidine, a trisubstituted amine, sodium hydride or sodium carbonate.

27. A process as claimed in claim 1, carried out substantially as described in any one of Examples 1 to6.

28. A process as claimed in claim 21, carried out substantially as described in any one of Examples 7 to 10.

29. Ap-lactam having a fused ring, whenever produced by a process as claimed in any one of claims 1 to 28.