GB2050380A - Phosphorus containing compounds used in the preparation of cephalosporins - Google Patents

Abstract

There is described a process for preparing an enamine of formula (IX): <IMAGE> where R<2> is a carboxylic acid protecting group and R<3> is the residue of a carboxylic acid derived acyl group and where R<5> and R<6> are the same or different C1-4 alkyl or C1-10 aralkyl groups; or taken together with the adjacent nitrogen atom form a heterocyclic ring containing from 4 to 8 carbon atoms and optionally a further heteroatom selected from oxygen and nitrogen; by reacting a compound of formula (XII): <IMAGE> with an amine of formula HNR<5>R<6>, the reactant of formula (XII) being prepared by reaction of an appropriate enol derivative with a phosphorus reagent. The enamines of formula (IX) are useful in the preparation of 3- hydroxycephalosporins. The compounds of formula (XII) are novel.

Description

1 i 5

SPECIFICATION

Improvements in or relating to the preparation of 3-substituted cephalosporins GB 2 050 380 A 1 This invention relates to an improved process for preparing 3-substituted cephalosporin derivatives and 5 embraces within its ambit novel intermediates useful in that process.

It has recently been discovered that 3-hydroxycephalosporins can be converted to their curresponding 3-alkoxy and 3-chloro derivatives and that those chloro and alkoxy derivatives are extremely efficacious antibacterial agents (see U.K. Patent Specifications Nos. 1,454,399 and 1, 456,221 and U.S. Patent No.

4,064,343).

Accordingly, a very great amount of research effort has been put into developing economically viable methods of preparing 3-hydroxycephalosporins. Perhaps, the best process heretofore described in the literature is that which appears in Example 17-111 of U.S. Patent No. 4, 079,181 which process can be schematically illustrated by the following reaction schedule:

1,Ph /,Ph 15 cHaso2cl THF 4 5 EtaN 20 -i 3 OH OS02CH3 C02R C02R 25 morphollne //Ph /_Ph 30 pyridine 26r 35 (IV) 1 111) 1 \110-6> C02R C02R 0-6 aqueous HCl PhCH a C0-NK, 1/3\ (111 // 1 \CH 45 i (V) 002R where R represents apara-nitrobenzyl ester protecting group.

It cannot be denied that this procedure constitutes an extremely valuable way of obtaining the 3-hydroxycephalosporin derivative (V). However, the Applicants have found that the yield of product (11) obtained in the functionalization of the enol (1) is considerably reduced (of the order of 10%) by formation of the C-mesylated product (Vi):

Ph 0 CH350a aR (V1) Thus, the maximum realizable yield of (V) is reduced by 10% and, of course, production of the unwanted 65 2 GB 2 050 380 A 2 C-mesylated productwill result in purification problems during subsequent processing of the intermediate mixture (01) and (VI)), as well as adversely affecting the stoichiometry of later reaction steps in the synthesis of the 3-hydroxycephem molecule (V).

The Applicants have found that, surprisingly, functional isation of the enol (1) occurs exclusively at the ox en atom if the methanesul hon 1 chloride is replaced by a phosphorus reagent of formula (Vil):

yg p y R a R bp = 0 (Vil) wherein R a and R b are the same or different and can each represent phenyl or phenoxy optionally substituted by one to three groups selected from C1-4 alkyl, C1-4 alkoxy, halogen and nitro; or are C1-4 alkyl, C1-4 alkoxy, C3-8 cycloalkyl, C3-8 cycloalkoxy, chlorine or bromine; X is chlorine, bromine, nitrile or azide; provided that:

(i) R a and R b cannot both be halogen; and (ii) when X is nitrile or azide, R' and R b are the same or different phenoxy; C3-8 cycloalkoxy or C1-4 alkoxy groups.

Preferably, the reagent of formula (VII) is that in which Ra and R b are phenoxy optionally substituted by one to three groups selected from CI-4 alkyl, CI-4 alkoxy, halogen and nitro; C1-4 alkoxy or C3-8 cycloalkoxy and X 20 is bromine or chlorine.

We have now discovered that, the productthus formed can be converted to the corresponding enamine derivative in high yield and under mild conditions. The enamine derivative can be converted to the corresponding 3-hydroxycephern of formula (V) using the reaction conditions described in U.S. Patent No. 4,079,181.

Those skilled in the art will appreciate that in view of the extremely high cost involved in the preparation Of 25 cephalosporins, increases in yield of even a few percent can have a dramatic influence on the economics of production, and therefore commercial viability, of this kind of antibiotic.

The present invention provides a process for preparing a 3-hydroxy cephalosporin of formula (Vill):

R3CONK\ T (Vill) //\CH C02e where R 2 is a carboxylic acid protecting group and R', together with the associated carbonyl group, is a carboxylic acid derived acyl group, which process comprises: (a) halogenating a compound of formula ((X):

d CO2R2 (1x) where R5 and R 6 are the same or different C1-4 alkYl Or C7-E) aralkyl groups; or taken together with the adjacent nitrogen atom form a heterocyclic ring containing from 4to 8 carbon atoms and optionally a further 50 heteroatom selected from oxygen and nitrogen; (b) cyclising the halo product (X):

R 3 CH2X C020 (X) where X' is chlorine, bromine or iodine, of (a) into the 3-hydroxy cephalosporin of formula (Vill) wherein the compound of formula OX) is prepared by 65 (c) reacting an enol of formula (Xi):

1 z 3 GB 2 050 380 A 3 e P with a phosphorus reagent of formula (V[[):

J 0 C020 R a b \p = 0 R 7 (V11) (xl) where 13% R b and X are as previously defined, to form a product of formula (Xli): R 3 1 20 0 a 11/R '-,op \Rb (X11) CO2R2 25 followed by reaction ofthis productwith an amineofformula HIMRWto form the amine starting material of formula (]X) utilized in step (a).

The reaction of the enol of formula (M) with the phosphorus reagent of formula (VII) and the reaction of the product of formula (Xli) with the amine of formula HNR 5 R 6 are both novel and inventive and are therefore 30 provided singly and in combination as further aspects of the invention.

For ease of representation, and to facilitate comprehension of the invention, structures possessing a side-chain double bond have been shown only in one of their stereoisomeric forms. However, those skilled in the art will immediately appreciate that these structures may exist in the alternative form and where this possibility exists, it is to be clearly understood that such alternative forms are embraced within the scope of 35 the invention.

The carboxyiic acid derived acyl group R'CO can be any of those groups conventionally utilized in the P-lactam art, the nature of which groups will be readily apparent to those skilled in this field. Thus, for instance the R 3 residue may be:

(a) hydrogen, C1-3 alkyl, halomethyl, cyanomethyl or 3(2-ch 1 oro p henyl)-5-m ethyl isoxazo 1 -4-yl; (b) benzyloxy, 4-nitrobenzyloxy, 2,2,2-trichloroethoxy, tert-butoxy, or 4- methoxybenzyloxy; (c) the group R" wherein R" is phenyl or phenyl substituted with 1 or 2 substituents independently selected from the group consisting of halo, protected hydroxy, nitro, cyano, trifluoromethyl, C1-3 alkyl, and C1-4 a I koxy; (d) an arylalkyl group of the formula W-(Q),-CH2- wherein RO is C as defined above, 2-thienyl, 3-thienyl, or 1,4- cyclohexyidienyi, m is 0 or 1, and Q is 0 or S 50 subject to the limitation that when m is 1 RO is C; (e) a substituted arylalkyl group of the formula WCH1 W wherein R' is as defined above and W is hydroxy, protected hydroxy, amino, protected amino or protected carboxy; or (f) a heteroaryl methyl group of the formula R 4 CH2- wherein R 4 is 2- furyl, 3-furyl, 2-thiazolyl, 5-isoxazolyl, 60 or5-tetrazolyl.

In the foregoing description the term "Cl-3 alkyi" refers to methyl, ethyl, n-propyl or isopropyl. Representative "Cl-4 alkoxy" groups are methoxy, ethoxy, n-propoxy, and tert-butoxy. "Halornethyl" represents chloromethyl, bromomethyl, fluoromethyl and iodomethy].

When in the above definition R" represents a substituted phenyl group, C can be a mono or disubstituted halophenyl group such as 4-chloropheny], 2,6-dichlorophenyi, 2,5- dichlorophenyi, 3,4-dichloropheny], 65 4 GB 2 050 380 A 3-chloropheny], 3-bromophenyl, 4-bromopheny], 3,4-dibromophenyi, 3-ch lo ro-441 uoro phenyl, 2fluorophenyl and the like; a protected hydroxy phenyl group such as 4-benzyloxyphenyl, 3-benzyloxyphenyl, 4-tertbutoxypheny], 4-tetra hydro pyranyloxypheny], 4-(4-nitrobenzy[oxy)-phenyi, 2-phenacyloxyphenyl, 4benzhydroxyphenyi, 4-trityloxyphenyl and like groups; a nitrophenyl group such as 3-nitrophenyl or 4-nitrophenVI; a cyanophenyl group, for example, 4-cyanophenyl; a mono or dialkyl substituted phenyl group such as 4-methylphenyl, 2,4-d imethyl phenyl, 2-ethylphenyl, 44sopropyl phenyl, 4-ethylphenyl, 3-n-propyl phenyl and the like; a mono or dialkoxyphenyl group, for example, 2,6- dimethoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyi, 4-isopropoxypheny], 4- tert-butoxyphenyi, 3-ethoxy-4-methoxyphenyl and the like. Also, W' represents disubstituted phenyl groups wherein the substituents are different for example, 3-methyi-4-methoxyphenyi, 3-chloro-4-benzyioxyphenyi, 2-methoxy4-bromopheny], 4-ethyl-2methoxyphenyi, 3-chloro-4-nitrophenyl, 2-methyl-4ch lo ro phenyl and like disubstituted phenyl groups bearing different substituents.

The term "protected amino" as employed in the foregoing definition has reference to an amino group substituted with one of the commonly employed amino blocking groups such as the tert-butoxycarbonyl group; the benzyloxycarbonyl group, the 4-methoxybenzyioxycarbonyl group, the 4-nitrobenzyloxycarbonyl group, the 2,2,2-trichloroethoxycarbonyl group, or the 1 -carbomethoxy-2-propenyl group formed with methyl acetoacetate. Like amino protecting groups such as those described by J. W. Barton in "Protective Groups in Organic Chemistry- J. F. W. McOmie, Ed. , Plenum Press, New York, N.Y., 1973, Chapter 2 shall be recognized as suitable.

The term -protected hydroxy- has reference to the readily cleavable groups formed with a hydroxy group 20 such as the formy[oxy group, the chloroacetoxy group, the benzyloxy group, the benzhydryloxy group, the trityloxy group, the 4-nitrobenzyioxy group, the trimethylsilyloxy group, the phenacyloxy group, the tert-butoxy group, the methoxymethoxy group, the tetra hydropyranyloxy group, and the like. Other hydroxy protecting groups, including those described by C. B. Reese in - Protective Groups in Organic Chemistry% supra, Chapter 3 shall be considered as within the term "protected hydroxy" as used herein.

R' is preferably benzyl or phenoxymethyl (PhOCH2_).

The group R 2 is a carboxylic acid protecting group. This term refers to the commonly used carboxylic acid protecting groups employed to block or protect the carboxylic acid functionality while reactions involving otherfunctional sites of the compound are carried out. Such carboxy protecting groups are noted for their ease of cleavage by hydrolytic or by hydrogenolytic methods to the corresponding carboxylic acid.

Examples of carboxylic acid ester protecting groups include methyl, tertbuty], benzyi, 4-methoxybenzyi, C2-6 a] kanoyloxym ethyl, 2-iodoethyl,p-nitrobenzyi, diphenyimethyl (benzhydryl), phenacyl, 4-halophenacyl, climethylallyl, 2,2,2-trichloroethyi, tri(C1-3 alkyl)silyl, succin i mido methyl and like ester forming moieties.

Other known carboxy protecting groups such as those described by E. Haslarn in "Protective Groups in Organic Chemistry-, supra, Chapter 5, shall be recognized as suitable. The nature of such ester forming groups is not critical although the Applicants have found that use of the para-nitrobenzyl protecting group is particularly desirable.

In the foregoing definitions, hydroxy, amino, and carboxy protecting groups are not exhaustively defined.

The fuction of such groups is to protect the reactive functional groups, for example, during the preparation of the starting materials, and to then be removed at some later point in time without disrupting the remainder 40 of the molecule. Many such protective groups as well known in the art and the use of other groups equally applicable to the process and compounds of the present invention shall be recognized as suitable. Thus, there is a no novelty or inventiveness asserted with regard to the - protecting groups" referred to in this specification.

Representative of the acylamino group R'CONI-1- in the compound of formula (V111) are formamido, 45 acetamido, propionamide, butyramido, 2-pentenoylamino, cyanoacetamido, chloroacetamido, bromoaceta mido, 5-tert-butoxycarbonylamino, and 5-tert-butoxycarbonylvaleramido.

Illustrative of the particular acylamino group, 4 0 50 11 R"CNH-, are benzamido, 2,6-dimethoxybenzamido, 4-chlorobenzamido, 4- methylbenzamido, 3,4-dichlorobenzamido, 4-cyanobenzamido,3-bromobenzamido, and 3-nitrobenzamido.

Exemplary of the acylamino group 0 H R3CNI-11, 60 when R 3 is a group of the formula RO(Q)mCl-12- and m is 0, are cyclohexa- 1,4-dienylacetamido, phenyl aceta m ido, 4-ch loro phenyl acetam ido, 3-methoxyphenylacetamido, 3-cyanophenylacetamido, 3 methyl phenylaceta m ido, 4-bromophenylacetamido, 4-ethoxyphenylacetamido. 4-nitrophenylacetamiclo, 3,4-dimethoxyphenylacetamido, 2-thienylacetamido, 3-thienylacetamido and the like; and when m is land65 4 GB 2 050 380 A 5 Q is 0, representative acylamino groups are phenoxyacetamido, 4- eyanophenoxyacetamido, 4chlorophenoxyacetamido, 3,4- dichlorophenoxyacetamido, 2-chlorophenoxyacetamido, 4methoxyphenoxyacetamido, 2-ethoxyphenoxyacetamido, 3,4-di methyl phenoxyaceta m ido, 4isopropylphenoxyacetamido, 3-eyanophenoxyacetamido, 3-nitrophenoxyacetamido and like substituted 5 phenoxyacetamido groups; and when m is 1 and Q is S, representative groups are phenylthioacetamido, 2,5-dichlorophenyithioacetamido, 4-bromopheny[thioacetamido, 4methoxypheny[thioacetamido, 4tolylthioacetamiclo and like substituted phenylthioacetamido groups.

Illustrative of the acylamino groups when R' is a substituted arylalkyl group of the formula R-CH 1 W and when W is protected hydroxy are 2-formyioxy-2-phenylacetamido, 2- benzyioxy-2-(4- methoxyphenyi)acetamido, 2-(4-nitrobenzyioxy)-2-(3-chlorophenyi)acetamido, 2-chloroacetoxy-2-(4methoxyphenyi)acetamido, 2-benzyioxy-2-phenylacetamido, 2-tri methyl si lyoxyl-2-W chlorophenyi)acetamido, and 2-benzhydryloxy-2-phenylacetamido. Representative of such groups when W is protected amino are 2-(4nitrobenzyioxycarbonylamino)-2-phenylacetamido, 2-(2,2, 2trichloroethoxycarbonylamino)-2-phenylacetamido, 2-chloroacetamido-2-(1, 4-cyclohexadien-l20 yi)acetamido, 2-(4-methoxy-benzyioxycarbonylamino)-2(4-methoxyphenyi)acetamido, 2benzhydryloxycarbonylamino-2-phenylacetamido, 2-(1-carbomethoxy-2-propenyi)amino-2phenylacetamido and 2-(4nitrobenzyioxycarbonylamino)-2-(2-thienyi)acetamido. Exemplary of the acylamino group 0 11 R3M1-1- when R' is a heteroaryl methyl group of the formula R 4_ CH2- are 2- furylacetamido, 3-furylacetamido, a 30 2-thiazolylacetamido group of the formula or a 5-isoxazoylacetamido group of the formula 0 0 11 "/"H2CNH- 11 0 / 0 \,CHj o MH- The compound of formula (IX) may be halogenated using the reagents and conditions specified in U.S. 40 Patent No. 4,079,181. Suitable halogenating reagents include those which halogenate through the halogen cation or halogen radical or its equivalent. Representative halogenating reagents belong to the categories listed below:

1. X',BrCl,lBr,C6H5l,Xl2,C5H5N.HX'.X',C6H5N(CH3)2.HXl,Xl2,(alkyl)2SO4.HX', CuX' 2 2 2 2. -OX1, (alkyl)OX', HOX1, (acyl)OX1.

3. =NX1 (alkyl)4NX'-Xl2, N02X1, (acyl)- NHX1, (acyl)2NX'.

4. _SX1, SX12, S+X12, 5. _CX1, X12, CHOCH3, CX14, a-haloketones, a-halosulfones, or like reagents, where alkyl and acyl contain up to 4 carbon atoms; and X1 is chlorine, bromine or iodine. X1 is preferably bromine.

When these halogenating reagents act via a halogen radical, the reaction can be initiated by heat, light, 50 peroxide (peracid, peroxide, hydroperoxide, etc.), azo compound (azobisisobutyronitrile, etc.) or other radical initiator.

When these halogenating reagents act via a halogen cation, the reaction is preferably carried out in the presence of an acid-trapping reagent (organic or inorganic base, e.g. sodium carbonate, pyridine, quinoline, 1 utidine, morphol ine, diethylami ne, triethyla mine etc.).

The reaction of the starting materials with the halogenating reagent is preferably carried out in an inert solvent. Suitable solvents include hydrocarbons (pentane, hexane, benzene, toluene, etc.), halogenated hydrocarbons (methylene chloride, chloroform, carbon tetrachloride, dichlorobenzene, etc.), esters (ethyl acetate, butyl acetate, methyl benzoate, etc.), ketones (acetone, cyclohexanone, benzophenone, etc.), ethers (diethyl ether, ethyleneglycol dimethyl ether, tetrahydrofuran, tetra hyd ropyra n, dioxan, anisole, etc.), alcohols (methanol, ethanol, ethyleneglycol, benzylalcohol, etc.), carboxylic acids (acetic acid, propionic acid, etc.), organic bases (butylamine, triethylamine, pyridine, picoline, etc.), organic amides (dimethylfor mamide, dim ethyl aceta m ide, hexamethylphosphorotriamide, etc.), organic nitriles (acetonitrile, benzonit rile, etc.), nitrohydrocarbons and alkyl sulfoxides (dimethyl sulfoxide, etc.).

Representative examples of suitable -NR'R 6 groups are dimethylamino, diethylamino, methylethylami- 65 6 GB 2 050 380 A 6 no, dipropylamino, dibutylamino, dibenzylamino and, when R5 and R 6 represent a cyclic entity, morpholino, piperidino and piperazino. The preferred -NR5R 6 group for use in the invention is morpholino. The cyclisation reaction (b) can be effected by acid catalyzed hydrolysis. Suitable solvents forthe cyclization are ethereal solvents e.g.. tetrahydrofuran, tetrahydropyran and dioxan, amide solvents e.g.

dimethy1formamide, dimethylacetamide and hexamethylphosphorotriamide, halohydrocarbon solvents e.g.

chloroform, methylene chloride and dichloroethane, aliphatic and aromatic esters such as ethyl acetate, aliphatic ketones such as acetone, aliphatic and aromatic nitriles such as acetonitrile and alkyl sulphoxides such as dimethyl sulphoxide.

Suitable acids used to acidify the reaction medium include aqueous mineral acids (e.g. hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, perchloriGacid, sulphurous acid), aqueous aryl 10 sulphonic acids such asp-toluene sulphonic acid and aqueous alkyl sulphonic acids such as methane.

sulphonic acid.

The reaction between the enol of formula (XI) and the phosphorus reagent of formula (VII) is preferably effected at a temperature in the range of from -30 to 500C., more preferably from O'to 25'C. At these temperatures, reaction is substantially complete in from 1/2 to 6 hours.

Any suitable inert organic solvent may be utilized. However, good results have been obtained using ethereal solvents such as diethyl ether, ethylene glycol dimethylether, tetrahydrofuran, tetra hyd ropyra n, dioxan and anisole. The use of tetrahydrofuran as the ethereal solvent is preferred. In addition, excellent results have been obtained using as solvent haloalkanes such as methylene chloride, alkyl nitriles such as acetonitrile and aliphatic esters such as ethyl acetate.

The condensation reaction between the enol and the phosphorus compound proceeds with elimination of HX The reaction is preferably effected in the presence of a base strong enough to generate the enolate anion such as a tertiary organic amine for example pyridine, triethylamine, Nmethylmorpholine or quinoline.

In certain circumstances, it may be desirable to effect the condensation reaction in the presence of an acylation catalyst and in such a circumstance the catalyst utilized may be a 4-dialkylaminopyridine of the 25 type described in Angew. Chem. Int. Ed. EngL 17 569-583 (1978).

Use of an inert gas atmosphere, such as nitrogen, is preferred.

Examples of suitable phosphorus compounds for use in the process of the invention are:

diphenylphosphoryl chloride, diphenylphosphoryl bromide, diethylphosphoryl chloride, diethylphosphoryl bromide, dibutylphosphoryl chloride, dibutylphosphoryl bromide, bis-(2-chlorophenyl)phosphoryl chloride, bis-(3-chlorophenyl)phosphoryl bromide, bis-(3-fluorophenyl)phosphoryl chloride, bis-(4-iodophenyl)phosphoryl bromide, bis-(2,3-dichlorophenyl)phosphoryI chloride, bis-(3,4-dichlorophenyl)phosphoryI bromide, bis-(4-methyl phenyl)phosphoryl chloride, bis-(4-butylphenyl)phosphoryl bromide, bis-(3,4-dimethylphenyl)phosphoryI chloride, bis-(3-ch I oro-4-m ethyl phenyl) phosph o ryl chloride, bis-(3-methoxyphenyl)phosphoryl chloride, bis-(4-methoxyphenyl)phosphoryl chloride, bis-(3-butoxyphenyl)phosphoryl chloride, bis-(4-nitrophenyl)phosphoryl chloride, bis-(3,4,5-trimethoxyphenyl)phosphoryI chloride, bis-(3,4,5-trimethoxyphenyl)phosphoryI bromide, bis-(2-methoxy-3-methyl-4-fluorophenyl)-phosphoryI chloride, dicyclopropylphosphoryl chloride, dicyclopropylphosphoryl bromide, dicyclohexylphosphoryl chloride, dicyclohexylphosphoryl bromide, dicyclooctylphosphoryl chloride, dicyclooctylphosphoryl bromide, dimethylphosphoryl azide, dimethylphosphoryl cyanide, diethylphosphoryl azide, diethylphosphoryl cyanide, diphenylphosphoryl azide, diphenylphosphoryl cyanide, dicyclohexylphosphoryl azide, dicyclohexylphosphoryl cyanide, k 7 methyl phosphorodichloridate, methyl phosphorodi bromidate, ethyl phosphorodichloridate, ethyl phosphorodibromidate, propyl phosphorodichloridate, isopropyl phosphorodichloridate, butyl phosphorodichloridate, phenyl phosphorodichloridate, phenyl phosphorodibromidate, 2-chlorophenyl phosphorodichloridate, 2-chlorophenyl phosph o rod ibrom i date, 3-chlorophenyl phosphorodichloridate, 3-fluorophenyl p hospho rodich lo ri date, 2,4-di ch lo ro phenyl phosphorodichloridate, 2,4-clichlorophenyl phosphorodibromidate, 3,4-dichlorophenyl phosphorodichloridate, 4-methylphenyl phosphorodichloridate, 3-ch loro-4- methyl phenyl phosp ho rodich lo ri date, 3-methoxyphenyl phosphorodichloridate, 4-methoxyphenyl phosphorodichloridate, 3-butoxyphenyl phosphorodichloridate, 4-nitrophenyl phosphorodichloridate, 3,4,5- trimethoxyphenyl phosphorodichloridate, cyclopropyl phosphorodichloridate, cyclopentyl phosphorodichloridate, cyclohexyl phosphorodichloridate, cyclohexyl phosphorodibromidate, cyclooctyl phosphorodichloridate, methyl methyl phosphonochl oridate, methyl methyl phosphonobro midate, methyl phenyl phosphonochloridate, ethyl methylphosphonochloridate, ethyl ethylphosphonochloridate, ethyl ethyl phosphonobrom idate, ethyl phenyl phosphonoch loridate, ethyl 3chlorophenyiphosphonochloridate, ethyl 2,4dichlorophenylphosphonochloridate, ethyl 4-methyl phenyl phosphonochloridate, ethyl 4-methoxyphenylphosphonochforidate, ethyl 4-nitrophenylphosphonochloridate, ethyl cyclopentylphosphonochloridate, phenyl methyl phosphonoch loridate, phenyl phenyl phosphonoch loridate, phenyl phenyl phosphonobromidate, phenyl 4-methyl phenyl phosphonochlo ridate, phenyl cyclohexylphosphonochloridate, 2,4-dichiorophenyl ethyl phosphonochloridate, 2,4,-dichlorophenyl phenyl phosphonoch loridate, 2,4dichlorophenyl cyclohexylphosphonochloridate.

4-nitrophenyl ethylphosphonochloridate, 4nitrophenyl phenyl phosphonochloridate, 4-nitrophenyl cyclohexylphosphonochloridate, 3,4,5trimethoxyphenyl ethyl phosphonoch loridate, 3,4,5-trimethoxyphenyl phenyl phosphonoch loridate, cyclopentyl ethyl phosphonochlo ridate, cyclopentyl phenyl phosphonoch loridate, cyclohexyl phenyl phosphonoch loridate, dimethylphosphinyl chloride, dimethylphosphinyl bromide, diethylphosphinyl chloride, diethylphosphinyl bromide, dipropylphosphinyl chloride, di-isopropylphosphinyl chloride, dibutylphosphinyl chloride, cliphenylphosphinyl chloride, GB 2 050 380 A 7 8 GB 2 050 380 A di phenyl phosph inyl bromide, bis-(2-chlorophenyi)phosphinyl chloride, bis-(2-chlorophenyi)phosphinyl bromide, bis-(3-chlorophenyi)phosphinyl chloride, 5 bis-(3-fi u oro phenyl) p hosph inyl chloride, bis-(2,4-dichlorophenyi)phosphinyl chloride, bis-(3,4-dichlorophenyi)phosphinyl chloride, bis-(4-methyl phenyl) phosph inyl chloride, bis-3-chloro-4-methylphenyi)phosphinyl chloride, bis-(3-methoxyphenyi)phophinyl chloride, bis-(4-methoxyphenyi)phosphinyl chloride, bis-(3-butoxyphenyi)phosphinyl chloride, bis-(4-nitrophenyi)phosphinyl chloride, bis-(3,4,5-trimethoxyphenyl)phosphinyl chloride, dicyclopropyiphosphinyl chloride, dicyclopentyiphosphinyl chloride, dicyclohexylphosphinyl chloride, dicyclohexylphosphinyl bromide, and dicyclooctylphosphinyl chloride.

Use of diphenylphosphory] chloride as the phosphorus reagent is preferred.

The product of the condensation reaction is a compound of formula (M). Such compounds are novel and are provided in a further aspect of the invention. Representative examples of these novel intermediates are listed below:

dimethyl 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en6-yi)-1-(p- nitrobenzyioxycarbonyi)-prop-l-en-2-yl phosphate, diethyl 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en6-yl)-1-(p-n itro- benzyioxycarbonyi)-prop-l-en-2-yl phosphate.

diisopropyl 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2-01hept-2en-6-yi)-1-(p- nitrobenzyioxycarbonyi(-prop-l-en-2-yl phosphate, dicyclopentyl 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept2-en-6-yi)-1-(p- nitrobenzyioxycarbonyi)-prop-l-en-2-yl phosphate, dicyclohexyl 1-(3-phenoxymethy]-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept2-en-6-yi)-1-(p- nitrobenzyioxycarbonyi)-prop-l-en-2-yl phosphate, diphenyl 1-(3-phenoxymethyi-7-oxo-4-thia-2,6,diazabicyclo[3,2,0]hept-2-en6-yi)-1-(p-n itro- benzy[oxycarbonyi)-prop-l-en-2-yl phosphate, bis-2-chlorophenyl 1-(3-phenoxymethy]-7-oxo-4-thia-2,6-diazabicyclo[3,2, Olhept-2-en-6-yi)-1-(p- nitrobenzyioxycarbonyi)-prop-l-en-2-yl phosphate, bis-3,4-dichlorophenyl 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3, 2,01hept-2-en-6-yl)1-(p- nitrobenzyioxycarbonyi)-prop-l-en-2-yl phosphate, bis-4-methylphenyl 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2, 0]hept-2-en-6-yi)-1-(p- nitrobenzyioxycarbonyi)-prop-l-en-2-yl phosphate, bis-3-methoxyphenyl 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyciO[3,2, Ojhept-2-en-6-yl)-1-(p- nitrobenzyloxycarbonyi)-prop-l-en-2-yl phosphate, bis-3,4,5-trimethoxyphenyl 1-(3-phenoxymethy]-7-oxo-4-thia-2,6diazabicyclo[3,2,Olhept-2-en-6-yi)-1-(pnitrobenzyioxycarbonyi)-prop-l-en-2-yl phosphate, bis-4-nitrophenyl 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2, Olhept-2-en-6-yi)-1-(p- nitrobenzyioxycarbonyi)-prop-l-en-2-yl phosphate, dimethyl 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yi)1-(p-nitrobe nzyloxycarbonyi)- prop-l-en-2-yl phosphate, diethyl 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)-1(p-nitrobe nzyloxycarbonyi)-prop- 50 1-en-2-yl phosphate, dicyclopentyl 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6yi)-1-(p-nitrobe nzyloxycarbonyi)- prop-l-en-2-yl phosphate, diphenyl 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)1-(p-nitrobe nzyioxycarbonyi)- prop-l-en-2-yl phosphate, bis-4-methoxyphenyl 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept2-en-6-yl)-1-(p- nitrobenzyioxycarbonyi)-prop-l-en-2-yl phosphate, diethyl 1-(3-phenoxymethy]-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en6-yi)-1-(2, 2,2- trichloroethoxycarbonyi)-prop-l-en-2-yl phosphate, diphenyl 1-(3-phenoxymethy]-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en6-Vi)-1-(2, 2,2- trichloroethoxycarbonyi)-prop-l-en-2-yl phosphate, diethyl 1-(3-benzy]-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)-1(2,2,2-tri chloroethoxycarbonyi)- prop-l-en-2-yl phosphate, diphenyl 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)1-(2,2,-tric hioroethoxycarbonyi)- prop-l-en-2-yl phosphate, 8 W z 9 G 13 2 050 380 A 9 diethyl 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en6-yi)-1- (di phenyl methoxyca rbonyl)-prop-1 -en-2-yl phosphate, diphenyl 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en- 6-yi)-1(d i phenyl methoxyca rbo nyi)-prop-1 -en-2-yl phosphate, diethyl 1-(3-benzy]-7-oxo-4-th-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)-1(diphenyime thoxycarbonyl)-prop- 5 1-en-2-yl phosphate, diphenyl 1-(3-benzy]-7-oxo-4-th ia-2,6-d iaza bicyclo [3,2,01 hept-2-en-6- yl)-1 -(di phenyl methoxyca rbonyi) prop-l-en-2-yl phosphate, diethyl 1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en6-yl)-1-(be nzyloxycarbonyl)- prop-l-en-2-yl phosphate, diphenyl 1-(3-phenoxymethy]-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en6-yi)-1-(be nzyloxycarbonyl)- prop-l-en-2-yl phosphate, diethyl 1-(3-benzy]-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)-1(benzyioxy carbonyi)-prop-l-en-2- yl phosphate, diphenyl 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yi)1-(benzyioxy carbonyi)-prop-l-en- 15 2-yl phosphate, diethyl 1-(3-phenoxymethy]-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en6-yi)-1-(t-b utoxycarbonyi)-prop- 1-en-2yl phosphate, diphenyl 1-(3-phenoxymethy]-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en6-yi)-1-(t-b utoxycarbonyi)- prop-l-en-2-yl phosphate, diethyl 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)-1-(t-butoxyc arbonyi)-prop-l-en-2-yl phosphate, diphenyl 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yl)1-(t-butoxyc arbonyi)-prop-l-en-2- yl phosphate, diethyl 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en6-yi)-1-(p- methoxyoxycarbonyi)-prop-l-en-2-yl phosphate, diphenyl 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3.2,Olhept-2-en6-yi)-1-(p- methoxybenzyioxycarbonyi)-prop-l-en-2-yl phosphate, diethyl 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yl)-1(p-methoxy benzyioxycarbonyi)- pro.p-l-en-2-yi phosphate, diphenyl 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)1-(p-methoxy benzyloxycarbonyi)- prop-l-en-2-yl phosphate, methyl 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6yi)-l-(p- nitrobenzyioxycarbonyl)-prop-l-en-2-yl phosphorochloridate, methyl-l-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6yi)-l-(p- nitrobenzyioxycarbonyi)-prop-l-en-2-yJ phosphorobromidate, ethyl 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6yi)-1-(p- nitrobenzyioxycarbonyi)-prop-l-en-2-yl phosphorochloridate, isopropyl l-Q-ph enoxym ethyl -7-oxo-4-th ia-2,6-d iaza bicyclo [3,2,01 hept-2-en-6-yl)-1 -(p- nitrobenzyioxycarbonyi)-prop-l-en-2-yl phosphorochloridate, cyclopentyl l-Q-p hen oxym ethyl-7-oxo-4-th ia-2,6-d iaza bicycl o [3,2, 01 h ept-2-en-6-yl)-1 -(p nitrobenzyioxycarbonyi)-prop-l-en-2-yl phosphorochloridate, cyclohexyl 1-(3-phenoxymethy]-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2en-6-yi)-1-(p- nitrobenzyioxycarbonyi)-prop-l-en-2-yl phosphorochloridate, phenyl 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6yl)-1-(p- nitrobenzyioxycarbonyi)-prop-l-en-2-yl phosphorochloridate, phenyl 1-(3-phenoxymethy]-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6yi)-l-(p- nitrobenzyioxycarbonyi)-prop-l-en-2-yl phosphorobromidate, 2-chlorophenyl 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2, Olhept-2-en-6-yi)-1-(p- nitrobenzyioxycarbonyi)-prop-l-en-2-yl phosphorochloridate, 4-methylphenyl 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2, Olhept-2-en-6-yl)-1-(p- nitrobenzyloxycarbonyl)-prop-l-en-2-yl phosphorochloridate, 4-methoxyphenyl 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2, 0]hept-2-en-6-yi)-1-(p- nitrobenzyioxycarbonyl)-prop-l-en-2-yl phosphorochloridatc, ethyl 1-(3-benzy]-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yi)-1(p-nitrobe nzyloxycarbonyi)-prop-l- 55 en-2-yl phosphorochioridate, phenyl 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)-1(p-nitrobe nzyloxycarbonyi)-prop- ll-en-2-yl phosphorochloridate, 4-methoxyphenyl 1-(3-benzy]-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en6-yi)-1-(p- nitrobenzyioxycarbonyi)-prop-l-en-2-yl phosphorochloridate, ethyl 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6yi)-1-(2, 2,2- trichloroethoxycarbonyl)-prop-l-en-2-yl phosphorochloridate, phenyl 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)-1(2,2,2-tri chloroethoxycarbonyi)- prop-l-en-2-yl phosphorochloridate, ethyl 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)-1(diphenyim ethoxycarbonyi)-prop-l-65 so GB 2 050 380 A 10 en-2-yl phosphorochloridate, phenyl 1-(phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6- y])-1(diphenyimethoxycarbonyi)-prop-l-en-2-yf phosphorochloridate, ethyl 1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6yl)-1-(be nzyloxycarbanyi)-prop- 1-en-2-yl phosphorochloridate, A 1 phenyl 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)-1(benzyloxy carbonyl)-prop- phosphorochloridate, ethyl 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)-1(t-butoxyc arbonyl)prop-l-en-2-yl phosphorochloridate, phenyl 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6yl)-1-(t-b utoxycarbonyi)-prop--10 1-en-2-y] phosphorochloridate, 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)-1(p-n itrobenzyioxycarbonyi)- prop-l-en-2-yl di methyl phosphi nate, 1-(3-phenoxymethy]-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en6-yi)-1(p-n itrobenzyioxycarbonyi)-prop- 1-en-2-yl diethylphosphinate, 1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)-1(p-n itrobenzyioxycarbonyi)- prop-l-en-2-yl dicyclohexylphosphinate, 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yl)-1 (p-nitrobenzyloxycarbonyi) prop-l-en-2-yl diphenylphosphinate, 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)-1(p-n itrobenzyioxycarbonyi)- prop-l-en-2-yl bis-2-chlorophenylphosphinate, 1-(3-phenoxymethy]-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi-l(p-n itrobenzyioxycarbonyi)-prop- 1-en-2-yl bis-2,4-dichlorophenylphosphinate.

1-(3-phenoxymethy]-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yl)-1(p-n itrobenzyioxycarbonyi)- prop-l-en-2-yl bis-4-methylphenylphosphinate, 1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)-1(p-n itrobenzyioxycarbonyl)- prop-l-en-2-yl bis-3-methoxyphenylphosphinate, 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicycio[3,2,Olhept-2-en-6-yi)-1(p-n itrobenzyioxycarbonyi)- prop-l-en-2-yl bis-4-nitro phenyl p h osphinate, 1-(3-benzyi-7oxo-4-thia-2,6-diazabicyclo-[3,2,Olhept-2-en-6-yl)-1-(pnitrob enzy[oxycarbonyi)-prop-l-en-2- yl dimethylphosphinate, 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo-[3,2,Olhept-2-en-6-y])-1-(pnitrob enzyloxycarbonyi)-prop-l-en- 2y] bis-4-methoxyphenylphosphinate, 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicycio[3,2,Olhept-2-en-6-y])-1(2, 2,2-trichloroethoxycarbonyi)- prop-l-en-2-yl diethylphosphinate, 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yt)-1-(2,2,2tri chloroethoxycarbonyi)-prop-l- en-2-yl diethylphosphinate, 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)-1(2, 2,2-trichloroethoxycarbonyi)- prop-l-en-2-yl diphenylphosphinate, 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)-1-(2,2,2tri chloroethoxycarbonyi-prop-l- 40 en-2-yl di phenyl phosph i nate, 1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)-1(be nzyloxycarbonyl)-prop-l-en- 2-y] diethylphosphinate, 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)-1(benzyloxy carbonyl)-prop-l-en-2-yl diphenylphosphinate, 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,0lhept-2-en-6-yi)-1dip henyimethoxycarbonyi)- prop-l-en-2-yl diethylphosphinate, 1-(3-benzy]-7-oxo-4-thia-2,6-diazabicyclo-[3,2,Olhept-2-en-6-yi)-1-(pnitrob enzyioxycarbonyi)-prop-l-en- 2yl bis-4-methoxyphenylphosphinate, 1-(3-phenoxymethy]-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1(2, 2,2-trichloroethoxycarbonyi)- 50 prop-l-en-2-yl diethylphosphinate, 1-(3-benzy]-7-oxo-4-thia-2,6-diazabicyclo-[3,2,Olhept-2-en-6-yl)l-(2,2,2tri chloroethoxycarbonyl)-prop-l- en-2-yl diethylphosphinate, 1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)-1(2, 2,2-trichloroethoxycarbonyi)- prop-l-en-2-yl diphenylphosphinate, 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)-1-(2,2,2tri chloroethoxycarbonyi)-prop-l- en-2-yl diphenylphosphinate, 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,01hept-2-en-6-yi)-1(be nzyloxycarbonyi)-prop-l-en- 2-yl diethylphosphinate, 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)-1(benzyioxy carbonyi)-prop-l-en-2-yl diphenylphosphinate, 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diaza bicyclo [3,2,01 hept-2-en-6-yl)1 -di phenyl meth oxyca rbonyi) prop-l-en-2-yl diethylphosphinate, 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo-[3,2,Olhept-2-en-6-yi)-1(diphenyi methoxycarbonyi)-prop-l-en-2- yl diphenylphosphinate, 1 55.

11 GB 2 050 380 A 11 methyl 1-(3-ben'zyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)-1(p-nitrob enzyioxycarbonyi)-prop- 1-en-2-yll phenyl phosphonate, ethyl 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)-1(p-nitrobe nzyloxycarbonyi)-prop-l- en-2-yl ethyl phosphonate, phenyl 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)-1(p-nitrobe nzyloxycarbonyi)-prop- 5 1-en-2-yl phenyl phosphonate, ethyl 1-(3-phenoxymethoxy-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6yi)-1-(2,2,2- trichloroethoxycarbonyi)-prop-l-en-2-yl ethyl ph osph onate, phenyl 1-(3-benzy]-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yi)-1(2,2,2-tri chloroethoxycarbonyi)- prop-l-en-2-yl phenyl ph osph on ate, ethyl 1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0].hept-2-en-6-yi)-1(2,2,2-tr ichloroethoxycarbonyi)- prop-l-en-2-yl ethyl phospho n ate, phenyl 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6yi)-l-(2, 2,2- trichloroethoxycarbonyi)-prop-l-en-2-yl phenylphosphonate, ethyl 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6yi-1-(ben zyl-oxycarbonyi)-prop- 15 1-en-2-yl ethyl phospho n ate, phenyl 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yi-l(benzyioxyc arbonyi)-prop-l-en-2-yl phenyl ph ospho nate, ethyl 1-(3-phenoxymethyi-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6yi)-1- (diphenyimethoxycarbonyi)-prop-l-en-2-yl ethyl phosphonate, and phenyl 1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yi)-1(diphenyim ethoxycarbonyi)-prop1-en-2-yl phenylphosphonate.

Conversion of the intermediate of formula (X11) to the amine starting material of formula (IX) is preferably effected at a temperature in the range of from - 10'to WC., most preferably from Wto 5'C. Any suitable organic solvent may be utilized for the conversion, especially those mentioned previously in connection with 25 the reaction of the enol of formula (X]) and the phosphorus reagent of formula (V11). The amine HNR'R, where R5 and R 6 are as previously defined, should be used in the form of the free base.

A very great advantage of the process of the invention is that since reaction conditions, temperature, solvent, etc., are very similar for each of the reaction stages, the whole procedure can be carried out in "one Pot".

To further illustrate the invention and to show how the same may be carried into effect reference will now be made to the following nonlimitative Examples.

EXAMPLE 1 p-Nitrobenzyl 7phenylacetamido-3-hydroxy-3-cephem-4-carboxylate To a stirred suspension of p-nitrobenzyl ct-[3-benzyi-7-oxo-4-thia-2,6diazabicyclo[3,2,01-hept-2-en-6-yil-a- (1-hydroxyethylidene)acetate (9.06 g) in tetrahydrofuran (120 m]) under a nitrogen atmosphere at 2WC. was added triethylamine (3.21 mi) and diphenylphosphoryl chloride (4.77 mi). The reaction was stirred for 2 hours and then cooled to O'C. Morpholine (4.01 mi) was added and the reaction stirred for 2 hours at O-WC.

The reaction was then cooled to -30'to -WC. and pyridine (1.62 ml) added, followed by bromine (1.00 mi) 40 dropwise over a period of 10 minutes.

The reaction was stirred for 20 minutes at -30'to -WC., and then 5% hydrochloric acid (144 mi), methanol (120 mi) and tetrahydrofuran (20 mi) added. The reaction was then stirred at room temperature for 3 hours and stood at O'C. overnight. The productwas isolated by filtration, and washed with methanol (30 mO, water (30 mi) and methanol (30 mi) and then dried in vacuo at 4WC. for 5 hours. The total yield of title 45 compound was 8.05 g (86%).

EXAMPLE 2 p-Nitrobenzyl 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate.

To a stirred solution of p-nitrobenzyl ot-[3-phenoxymethyl-7-oxo-4-thia-2, 6-diazabicyclo[3,2,Olhept-2-en-6- 50 yil-ct-(1 -hyd roxyethyl i den e) acetate (9.38 g) in tetrahydrofuran (120 mi) under a nitrogen atmosphere at WC.

was added triethylamine (3.21 mi) followed by diphenylphosphoryl chloride (4.77 ml). The reaction mixture was then stirred for 2 hours and cooled to O'C. Morpholine (4.01 mi) was added and the reaction mixture stirred for 2 hours at 0-5t. The reaction mixture was next cooled to - 30'to -WC. and pyridine (1.62 m]) added followed by the dropwise addition of bromine (1.00 mi) over a period of 10 minutes. The reaction mixture was stirred at -30'to -WC. for 20 minutes and 5% hydrochloric acid (144 mi) added, followed by further stirring at room temperature for 3 hours. The reaction mixture was then stood at O'C. overnight. The reaction mixture was extracted with dichloromethane and the organic extracts washed with water then saturated sodium chloride solution, dried with magnesium sulphate and evaporated to dryness. The product thus obtained was dissolved in dichloromethane and acetic acid added, the dichloromethane removed under 60 reduced pressure and then ether was added with stirring to complete crystallization. The product was isolated by filtration, washed with ether then dried in vacuo at WC. for 5 hours. The yield of p-nitrobenzyl 7-phen oxyaceta m ido-3-hyd roxy-3-cephem-4-ca rboxyl ate acetic acid solvate was 9.16 g (84%).

12 GB 2 050 380 A 12 EXAMPLE 3

Diethyl 1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo-[3,2,Olhept-2-en-6-yl)1-(p-nitrob enzyloxycarbonyl)-prop-l- en-2-ylphosphate.

Toa solution ofp-nitrobenzy] a-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo[3, 2,Olhept-2-en-6-yi)-a-(1- hydroxyethylidene)acetate (4.53 9) containing 4-dimethylaminopyridine (0. 1 g) in ethyl acetate (50 mi) under 5 A a nitrogen atmosphere at 20'C. was added triethylamine (1.53 m[) followed by diethylphosphoryl chloride (1.59 m]) dropwise. The reaction mixture was stirred at 20'C. for 3 hours. Water (40 mi) was added and the organic layerwas separated, washed with water (20 m]) and saturated sodium chloride solution (20 m]), dried with magnesium sulphate and carbon treated, filtered and evaporated to give the title compound as a yellow viscous oil in essentially quantitative yield. TLC (silica) Rf 0. 17 (dichloromethanelethyl acetate 15:2). 10 The product was a mixture of geometric isomers (ca. 2.:1) about the enol phosphate double bond. NMR 6 CDC131.11-1.60 (m, 6H), 1.98 + 2.60 (cl, 3H), 3.73- 4.65 (m, 6H), 5.22-5. 42 (m, 2H), 5.88-6.28 (m, 2H) and 7.25-7.80 and 8.18-8.58 (m, 9H).

EXAMPLE4

Diphenyl 1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6-yl)1-(p-nitrob enzyloxycarbonyl)-prop- 1-en-2-ylphosphate.

To a suspension of p-nitrobenzy] (x-(3-benzyi-7-oxo-4-thia-2,6diazabicyclo[3,2,Olhept-2-en-6-yi)-ct-(1 - hydroxyethylidene)acetate (4.53 g) in tetrahydrofuran (60 m[) under a nitrogen atmosphere at 20'C, was added triethylamine (1.53 m]) followed by d i phenyl phosph oryl chloride (2.28 mi) dropwise. The reaction mixture was stirred at 200C. for 2 hours. Water (50 mi) was then added and the mixture was extracted with dichloromethane (60 m]). The organic layer was separated, washed with water (30 mi) and saturated sodium chloride solution (30 m[), dried with magnesium sulphate, filtered and evaporated to give the title compound as a yellow viscous oil in essentially quantitative yield. TLC (silica) Rf 0.68 (dichloromethanelethyl acetate 15:2). The product was a mixture of geometric isomers (ca. 4:1) about the enol phosphate double bond.

NMR6CIDC131.93 (d,J =2Hz) + 2.58(d,J = 2Hz) (3H),3.48-3.90 (m,2H),5.05 (s, 2H), 5.5-6.0 (m,2H) and 7.0-8.2 (m. 191-1).

EXAMPLE 5

Diphenyl 1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicYclo[3,2,Olhept-2-en6-yl)-1-(p-n itro- benzyloxycarbonyl)-prop- 1-en-2-yl phosphate.

To a solution of p-nitrobenzyl a-(3-phenoxymethyi-7-oxo-4-thia-2,6diazabicyclo[3,2,01-hept-2-en-6-yi)-ot- (1-hydroxyethylidene)acetate (9.38 9) in dichloromethane (100 mi) under a nitrogen atmosphere at 20'C was added triethylamine followed by diphenylphosphory] chloride (4.35 mi). The reaction mixture was stirred at 20'C. for 2 hours. Water (50 mi) was added and the organic layer was separated, washed with water (40 mi) 35 and saturated sodium chloride solution (40 mi), dried with magnesium sulphate, filtered and evaporated to give the title compound as a yellow viscous oil in essentially quantitative yield. TLC (silica) Rf 0.60 (ethyl acetate). The product was a mixture of geometric isomers (ca. 3: 1) about the enol phosphate double bond.

TLC separation of these isomers could be achieved; Rf 0.52 and 0.45 (toluene/ethyl acetate, 1/1). NMR6 CDC13 2.10 (d, J = 2H4 + 2.63 (d, J = 2Hz) QH), 4.22 and 4.67 (ABq, J = 14Hz, 2H), 5.11 (s, 2H), 5.50-5.77 (m, 2H) and 40 6.50-8.13 (m, 19H).

EXAMPLE 6 p-Nitrobenzyla-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6yl) -(x-(1-morpholinoethylidene) acetate.

To a solution of diethyl 1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2, Olhept-2-en-6-yi)-1 -(p nitrobenzyioxycarbonyi)-prop-l-en-2-yl phosphate (5.90 g) in dichloromethane (70 mi) at 0-5'C. was added morpholine (1.83 m]) dropwise and the reaction mixture stirred at this temperature for 2 hours. Water (40 mi) was added and the organic layer was separated, washed with water (30 mi) and saturated sodium chloride solution (30 mi), dried with magnesium sulphate, filtered and evaporated to give the title compound as a 50 yellow foam in almost quantitative yield. TLC (silica) Rf 0.60 (ethyl acetate). The product was a mixture of geometric isomers (ca. 1: 1.4) about the enamine double bond. NMR 6 CDC13 1.72 + 2.40 (s, 3H), 3.01-4.07 (m, l OH), 5.22 (s, 2H), 5.60-6.13 (m, 2H), 7.28-7.77 and 8.10-8.40 (m, 9 H).

EXAMPLE 7 p-Nitrobenzyl a-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept-2-en-6yl)-a(l-morpholi noethylidene) ace tate To a solution of diphenyl 1-(3-benzyi-7-oxo-4-thia-2,6-diazabicyclo[3,2, Olhept-2-en-6-yl)-1-(pnitrobenzyioxycarbonyl)-prop-l-en-2-yl phosphate (6.86 9) in acetonitrile (50 mi) at O-YC. was added morpholine (1.83 mi) dropwise and the reaction mixture stirred at this temperature for 2 hours. Water (50 M1) 60 was added and the mixture was extracted with ethyl acetate (40 mi). The organic layer was separated, washed with water (30 mi) and saturated sodium chloride solution (30 mi), dried with magnesium sulphate, filtered and evaporated to give the title compound as a yellow foam in almost quantitative yield. The product obtained was a mixture of geometric isomers (ca. 1: 1.4) about the enamine double bond and was identical to that produced in Example 6. 65 x 1 Q 1 It L 13 GB 2 050 380 A 13 EXAMPLE 8 p-Nitrobenzyl a-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,Olhept2-en-6-yl)-U-(1- morpholinoethylidene) acetate To a solution of diphenyl 1-(3-p hen oxym ethyl -7-oxo-4-th ia-2,6-diaza bicycl o [3,2,Olhept-2-en-6-yl)-1-(p nitrobenzyloxycarbonyi)-prop-1 -en-2-yl phosphate (7.02 g) in ethyl acetate (70 mi) at 0-5'C. was added morpholine (1.83 m]) dropwise and the reaction mixture stirred at this temperature for 2 hours. Water (30 mi) was added and the organic layer was separated, washed with wafer (30 mi) and saturated sodium chloride solution (30 ml), dried with magnesium sulphate, filtered and evaporated to give the title compound as a yellow foam in almost quantitative yield. TLC (silica) Rf 0.57 (ethyl acetate). The product was a mixture of geometric isomers (ca. 1:11.4) aboutthe enamine double bond. NMR6 CDC13 1. 93 (s) + 2.43 (s) (3H), 3.17-3.93 10 (m, 8H), 4.90 (s, 2H), 5.25 (s, 2H), 5.68-6.13 (m, 2H) and 6.87-7.7 + 8.1- 8.4 (m, 9H).

EXAMPLE 9

1-(3-Phenoxymethyl-7-oxo-thia-2,6-diaza-bicyclo(3,2,0)hept-2-en-6-yl)1(p-nitrobenzyloxycarbonyl)-prop- 1 en-2-yldiphenylphosphinate To a stirred solution of p-nitrobenzy] a-(3-phenoxyrnethy]-7-oxo-4-thia-2, 6-diazobicyclo(3,2,0)hept-2-en-6- yl)-a-(1 -hydroxyethylidene)acetate (4.69 g) in tetrahydrofuran (60 mi.) under a nitrogen atmosphere at 0-50C was added triethylamine (1.6 mi.) followed by diphenylphosphinyl chloride (2.73 g) dropwise over 5 minutes.

After stirring for 3 hours at 20'C, the tetrahydrofuran was evaporated and the residue dissolved in dichloromethane. The resulting solution was washed with 1% hydrochloric acid and then water, dried with 20 magnesium sulphate and evaporated to give the title compound as a pale yellow friable foam in essentially quantitative yield. TLC (silica) Rf 0.54 (ethyl acetate). NMR 6 CDC13 2,5 (s, 3H), 3.63 and 4.40 (ABq, 2H, J = MHz),-5.13 (s, 2H), 5.68 (cl, 1 H, J = 4Hz), 5.85 (cl, 1 H, J = 4Hz) and 6.5 - 8.03 (m, 20H).

EXAMPLE 10

Phenyl 1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6yl)-l-(p- nitrobenzyloxycarbonyl)-propl-en-2-ylphenylphosphonate To a stirred solution of p-nitrobenzyl a-(3-phenoxymethyl-7-oxo-4-thia-2, 6-diazabicyclo(3,2,0)hept-2-en-6- yi)-a-(1 -hydroxyethylidene)acetate (4.69 9) in tetrahydrofuran (60 mi.) under a nitrogen atmosphere at O'C was added triethylamine (1.6 m[.) followed by phenyl phenyl phosphonochloridate (2.91 g). After stirring for 30 3 hours at 20'C, the tetrahydrofuran was evaporated and the residue dissolved in dichloromethane. The resulting solution was washed with 1 % hydrochloric acid and then water, dried with magnesium sulphate and evaporated to give the title compound as a pale yellow friable foam in essentially quantitative yield. TLC (silicaffif 0.64 (ethyl acetate). NIVIR 6 CDC13 2.60 (m, 3H), 3.70 - 4.67 (m, 2H), 5.15 (s, 2H), 5.57 - 5.87 (m, 2H) and 6.6 - 8.17 (m, 19H). 35 EXAMPLE 11

Diphenyl 1(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl)-1(diphenylm ethoxycarbonyl)-prop- 1-en-2-yl phosphate To a stirred solution of benzhydryl ct-(3-benzyl-7-oxo-4-thia-2,6diazabicyclo(3,2,0)hept-2-en-6-yl)-ct-(1- 40 hydroxyethylidene)acetate (2.42 g.). in tetrahydrofuran (30 mi.) under a nitrogen atmosphere at 20'C was added trithylamine (0.74 mi.) followed by cliphenylphosphoryi chloride (1. 09 mi.). After stirring for 2 hours at 20'C, the reaction mixture was diluted with dichloromethane, washed with brine, dried with magnesium sulphate and evaporated to give the title compound as a pale yellow foam is essentially quantitative yield.

TLC (silica) Rf 0.58 (ethyl acetate). NMR 6 CDC13 2.57 (cl, 3H, J = ca. 1 Hz), 2.64 and 3.63 (ABq, 2H, J = 16Hz), 45 5.43-5.9 (m, 2H), 6.77 (s, 1 H) and 6.85-7.5 (m, 25H).

EXAMPLE 12

Diphenyl 1-(3-phenoxymethyl-7oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en6-yl)-1-(2, 2,2- trichloroethoxycarbonyl)-prop- 1-en-2-yl phosphate To a stirred solution of 2,2,2-trichloroethyl (x-(3-phenoxymethyl-7-oxo-4thia-2,6-diazabicyclo(3,2,0)hept-2- en-6-yl)-a-(1 -hydroxyethylidene)-acetate (2.33 g.) in tetrahydrofuran (30 mi.) under a nitrogen atmosphere at 20'C was added triethylamine (0.74 mi.) followed by diphenylphosphoryl chloride (1.09) mi.). After stirring for 1.75 hours at 20'C, the reaction mixture was diluted with dichloromethane, washed with brine, dried with magnesium sulphate and evaporated to give the title compound as a pale yellow foam in essentially quantitative yield. TLC (silica) Rf 0.63 (ethyl acetate). The product was a mixture of geometric isomers (ca.

3:1) about the enol phosphate double bond. NMR 6 CDC13 2.08 (d) + 2.68 (d) QH), 4.4-5.0 (m, 4H), 5.67-6,07 (m, 2H) and 6.63-7.43 (m, 151-1).

EXAMPLE 13 p-Nitrobenzyl (x-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl)-(X-( l- morpholinoethylidene)acetate To a stirred solution of 1-(3-phenoxymethyl-7-oxo-4-thia-2,6diazabicyclo(3,2,O)hept-2-en-6-yl)-l-(p- nitro benzyl oxyca rbo nyl)-pro p-1 -e n-2-yl cliphenylphosphinate (1.34 g.) in tetrahydrofuran (20 ml.) at 0-5'C.

was added morpholine (0.38 ml.). After stirring for 6 hours at 0-5'C, the solvent was evaporated and the 65 14 GB 2 050 380 A residue dissolved in dichloromethane. The resulting solution was washed with water and then with saturated sodium chloride solution, dried with magnesium sulphate and evaporated to give the title compound as a pale yellowfoam in essentially quantitative yield. The product obtained was a mixture of geometric isomers (ca. 1: 1.4) about the enamine double bond and was identical to that produced in example 5 8.

14 EXAMPLE 14 p-Nitrobenzyla-(3-phenoxymethyl-7-oxo-4-thia-2,6diazabicyclo(3,2,0)-hept-2-e n-6-yl)-a-(1morpholinoethylidene)acetate To a stirred solution of phenyl 1-(3-phenoxymethyi-7-oxo-4-thia-2,6diazabicyclo(3,2,0)hept-2-en-6-yl)-1(p-nitrobenzy[oxycarbonyi)-prop-l-en-2-yl phenyl phospho nate (1.37 g.) in tetrahydrofuran (20 mi.) at O-YC was added morpholine (0.383 mi.). After stirring for 3 hours at 0-5'C, the solvent was evaporated and the residue dissolved in dichloromethane. The resulting solution was washed with water and then with saturated sodium chloride solution, dried with magnesium sulphate and evaporated to give the title compound as a pale yellow foam in essentially quantitative yield. The product obtained was a mixture of 15 geometric isomers (ca. 1:11.4) about the enamine double bond and was identical to that produced in example 8.

EXAMPLE 15 p-Nitrobenzyl a-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6- yl)-a-(1piperidinoethylidine)acetate To a stirred solution of p-nitrobenzyl a-(3-benzyi-7-oxo-4-thia-2,6- diazabicyclo(3,2,0)hept-2-en-6-yl)-a-(1hydroxyethylidene)acetate (3.02 g.) in tetrahydrofuran (40 mi.) under a nitrogen atmosphere at 2WC was added triethylamine (0.98 mi.) followed by diphenylphosphoryl chloride (1. 45 mi.). After stirring for 2 hours, the reaction mixture was cooled to O'C and piperidine (0.76 mi.) was added. After stirring for 3 hours at 0-5'C, 25 the tetrahydrofuran was evaporated and the residue dissolved in dichloromethane. The resulting solution was washed with water and then with saturated sodium chloride solution, dried with magnesium sulphate and evaporated to give the title compound as a pale yellow foam in essentially quantitative yield. TLC (silica) Rf 0.48 dichloromethane-ethyl acetate 15:2). The product was a mixture of geometric isomers about the enol phosphate double bond. NMR 6 CDC13 1.13-1.77 (m, 6H), 1.67 (s) + 2.33 (s) (3H),2.9-3.4(m,4H),3.83 (s,2H), 5.15 (s, 2H), 5.55-5.93 (m, 2H), 7.25 (s, 51-1) and 7.48 and 8.23 (ABq, 4H, J = 9Hz).

EXAMPLE 17 p-Nitrobenzyla-(3-phenoxymethyl-7-oxo-4-thia-2,6diazabicyclo(3,2,0)-hept-2-e n-6-yl)-a-(1morpholinoethylidene)acetate To a stirred solution of p-nitrobenzy] a-(3-phenoxymethyi-7-oxo-4-thia-2, 6-diazabicyclo(3,2,0)hept-2-en-6- V])-a-(1 -hyd roxyethyl idene) acetate (4.69 g.) in tetrahydrofuran (60 mi.) under a nitrogen atmosphere at 0-50C was added triethylamine (1.6 mi.) followed by dropwise addition of ethyl dichforophosphate (1.36 mi.) over 5 minutes. After stirring for 3 hours at 20'C, the reaction mixture was cooled to O'C and morpholine (4.0 mi.) was added dropwise over 10 minutes with the reaction temperature maintained at 0-50C. After stirring for 3 hours at this temperature, the tetrahydrofuran was evaporated and the residue dissolved in dichloromethane. The resulting solution was washed with water and then with saturated sodium chloride solution, dried with magnesium sulphate and evaporated to give the title compound as a pale yellow foam in essentially quantitative yield. The product obtained was a mixture of geometric isomers (ca. 1: 1.4) aboutthe enamine double bond and was identical to that produced in example 8.

EXAMPLE 18 p-Nitrobenzyla-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)-hept2-e n-6-yl)-a-(1- morpholinoethylidenejacetate To a stirred solution of p-nitrobenzyl a-(3-phenoxymethy]-7-oxo-4-thia-2, 6-diazabicyclo(3,2,0)hept-2-en-6- yi)-a-(1-hydroxyethylidene)acetate (4.69 g.) intetrahydrofuran (60 mi.) under a nitrogen atmosphere atO-50C65 5.

w 11 EXAMPLE 16

2,2,2-Trichloroethyla-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2, 0)h ept-2-en-6-yl)-ct-(1- morpholinoethylidene)acetate p To a stirred solution of 2,2,2-trichloroethyl a-(3-phenoxymethyi-7-oxo-4thia-2,6-diazabicyclo(3,2,0)hept-2- en-6-y])-a-(1 -hydroxyethylidene) acetate (2.33 g.) in tetrahydrofuran (30 mi.) under a nitrogen atmosphere at 2WC was added triethylamine (0.74 m].) followed by di phenyl phospho ryl chloride (1.09 (mi.) After stirring for 2 hours, the reaction mixture was cooled to OOC and morpholine (0.92 mi.) was added. After stirring for 2 hours at O-YC, the tetrahydrofuran was evaporated and the residue dissolved in dichloromethane. The resulting solution was washed with water and then with saturated sodium chloride solution, dried with magnesium sulphate and evaporated to give the title compound as a pale yellow foam in essentially quantitative yield. TLC (silica) Rf 0.20 (dichloromethane-ethyl acetate 15:2). The product was a mixture of geometric isomers (ca. 1.5: 1) about the enol phosphate double bond. NMR 6 CDC13 1.83 (s) + 2.37 (s) (31-1), 3.0-3.9 (m, 8H), 4.48 and 4.92 (ABq, 2H, J = 13Hz),4.93 (s, 2H), 5.75-6. 10 (m, 21-1) and 6.8-7.5 (m, 5H). 45 _z n z Z_ GB 2 050 380 A 15 was added triethylamine (1.6 m].) followed bydropwise addition of phenyl phosphonic dichloride (1.63 mi.) over 5 minutes. After stirring for 3 hours at 200C, the reaction mixture was cooled to O'C and morphoHne (4.0 mi.) was added dropwise over 10 minutes with the reaction temperature maintained at 0-50C. After stirring for 3 hours at this temperature, the tetrahydrofuran was evaporated and the residue dissolved in dichloromethane. The resulting solution was washed with water and then with saturated sodium chloride solution, dried with magnesium sulphate and evaporated to give the title compound as a pale yellow foam in quantitative yield. The product obtained was a mixture of geometric isomers (ca. 1: 1.4) about the enamine double bond and was identical to that produced in example 8.

EXAMPLE 19 p-Nitrobenzyla-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept2e n-6-yl)-a-(1- morpholinoethylidene)acetate To a stirred solution of p-nitrobenzy] ct-(3-phenoxymethyi-7-oxo-4-thia-2, 6-diazabicyclo(3,2,0)hept-2-en-6- yl)-a-(1-hydroxyethylidene)acetate (4.69 g.) in tetrahydrofuran (60 mi.) under a nitrogen atmosphere at O-WC was added triethylamine (1.6 mO followed by dropwise addition of phenyl dichlorophosphate (1.72 mi.) over 15 minutes. After stirring for 3 hours at 2TC, the reaction mixture was cooled to OT and morpholine (4.0 mi.) was added dropwise over 10 minutes with the reaction temperature maintained at O-WC. After stirring for 3 hours at this temperature, the tetrahydrofuran was evaporated and the residue dissolved in dichlor omethane. The resulting solution was washed with water and then with saturated sodium chloride solution, dried with magnesium sulphate and evaporated to give the title compound as a yellow foam in essentially 20 quantitative yield. The product obtained was a mixture of geometric isomers (ca. 1.1.4) about the enamine double bond and was identical to that produced in example 8.

EXAMPLE 20

Benzhydryl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate To a stirred solution of benzhydryl a-(3-benzyi-7-oxo-4-thia-2,6diazabicyclo(3,2,0)hept-2-en-6-yi(-a-(1- hydroxyethylidene)acetate (9.68 g.) in tetrahydrofuran (120 mi.) under a nitrogen atmosphere at WC was added triethylamine (2.93 mi.) followed by di phenyl phospho ry] chloride (4.35 mi.) After stirring for 3 hours, the reaction mixture was cooled to 5-10'C, morpholine (3.75 mi.) was added and the mixture stirred for 2 hours at 5-10'C. After cooling to -30 to -350C, pyridine (1.62 mi.) was added followed by dropwise addition 30 of bromine (1.00 mi.) over 10 minutes. The reaction mixture was stirred at -30 to -WC for 20 minutes and 5% hydrochloric acid (144 mi.) was added. After stirring at 200C for 1.5 hours the reaction mixture was extracted with ethyl acetate and the extract washed with water, dried with magnesium sulphate and evaporated to give a foam (10.3 g.) The foam (9.3 g.) was purified by column chromatography on silica gel 35 (600 g.) with dichloromethane-acetone (201) as eluentto give 7.04 g. (78%) of the title compound as a foam. 35 TLC (silica) Rf 0.55 (ethyl acetate). NIVIR 6 CIDD33.13 (s,2H),157 (s,2H), 4.88 (cl, 1H,J = 4Hz), 3.57 (dd, 1H,J = 4 and 9Hz) and 6.66-7.5 (m, 17H).

EXAMPLE 21 p-Nitrobenzyl 7-phenoxyacetamido-3-hydroxy-3cephem-4-carboxylate To a stirred solution of p-nitrobenzyl a-(3-phenoxymethyi-7-oxo-4-thia-2, 6-diazabicyclo(3,2,0)hept-2-en-6- -hyd roxyethyl i den e) acetate (9.38 g.) in tetrahydrofuran (120 mi.) under a nitrogen atmosphere at 20oC was added triethylamine (3.21 mi.) followed by phenyl phenylphosphonochloridate (5.82 g.) After stirring for 2 hours at 2TC, the reaction mixture was cooled to O'C and morpholine (4. 01 mi.) added. After stirring for 2.5 hours at O-WC, the mixture was cooled to -30oto -WC and pyridine (1.62 mi. ) added followed by dropwise 45 addition of bromine (1.00 mi.) over a period of 10 minutes. The reaction mixture was stirred at -30 to -350C for 20 minutes and 5% hydrochloric acid (144 mi.) added. After stirring at WC overnight the mixture was extracted with dichloromethane and the extracts washed with water and saturated sodium chloride solution, dried with magnesium sulphate and evaporated to dryness. The residue was dissolved in glacial acetic acid (10 mi.) and the resulting solution stirred for approximately 10 minutes to crystallise the product. The crystallisation was completed by addition of isopropanol (120 mi.) over 0.5 hour. The crystals were isolated by filtration, washed with isopropanol and dried in vacuo at 4WC overnight. The yield of p-nitrobenzyl 7-ph en oxyaceta mid o-3-hyd roxy-3-ce ph e m- 4-ca rboxyl ate acetic acid solvate was 8.29 g. (76%).

EXAMPLE 22

4-Methoxybenzyl 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate To a stirred solution of 4-methoxybenzyl a-(3-phenoxymethyl-7-oxo-4-thia2,6-diazabicyclo(3,2,O)hept-2- en-6-yl)-a-(l-hydroxyethylidene)-acetate (4.54 g.) in tetrahydrofuran (60 mi.) under a nitrogen atmosphere at O'C was added triethylamine (1.6 ml.) followed by diphenylphosphoryl choride (2.39 ml.) After stirring for 3 hours at 0-5'C, morpholine (2.0 ml.) was added and the reaction mixture stirred for a further 3 hours at 0-50C. 60 The mixture was cooled to -30 to -35'C and pyridine (0.81 ml.) added followed by dropwise addition of bromine (0.5 mi.) over a period of 5 minutes. The reaction mixture was stirred at -30 to -350C for 20 minutes and 5% hydrochloric acid (72 ml.) added, followed by methanol (60 mi.) After stirring overnight at room temperature, the mixture was extracted with dichloromethane and the extract washed with water, dried with magnesium sulphate and evaporated. The residual gum was chromatographed on silica gel (300 g.) with 65 16 GB 2 050 380 A 16 dichloromethane-acetone (9:1) as eluent to give 3.6 g. (76.6%) 4- methoxybenzyl 7-phenoxyacetamido-3hyd roxy-3-cephem-4-carboxyl ate as a foam. TLC (silica) Rf 0.5 (toluene-ethyl acetate 1:1). NIVIR 6 CDC13 2.53 (s, 2H), 3.73 (s, 3H), 4.47 (s, 2H), 4.93 (d, 1 H, J = 4Hz), 5.13 (s, 2H), 5.50 (dd. 1 H, J = 4 and 9Hz), 6.67-7.37 (m, 91-1) and 7.53 (cl, 1 H, J = 9Hz).

EXAMPLE 23 2,2,2-Trichforoethyl 7-phenoxyacetamido-3-hydroxy-3-cephem-4carboxylate To a stirred solution of 2,2,2-trichloroethyl a-(3phenoxymethy]-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2en-6-yi)-a-(1hydroxyethylidene)-acetate (2.33 g.) in tetrahydrofuran (30 m].) under a nitrogen atmosphere at 200C was added triethylamine (0.74 m[.) followed by diphenylphosphory] chloride (1.09 mi.) After stirring for 2 hours, the reaction mixture was cooled to OOC, morpholine (0.92 mi.) was added and the reaction mixture stirred for 2 hours at 0-50C. The mixture was cooled to -30 to -WC and pyridine (0.42 ml.) added followed by the dropwise addition of bromine (0. 25 mi.) over a period of 5 minutes. The reaction mixture was stirred at - 30 to -WC for 20 minutes and 5% hydrochloric acid (60 mi.) added. After stirring for 2 hours at room temperature, the mixture was extracted with ethyl acetate and the extract washed with water, dried with magnesium sulphate and evaporated to give a yellow foam. The foam was purified by column chromatography on silica gel (100 g.) with dichloromethane-acetone (25:1) as eluentto give 1.8 g. (74. 7%) 2,2,2-trichloroethyl 7-p henoxyacetamido-3-hydroxy-3-cephem-4-ca rboxyl ate as a foam. TLC (silica) Rf 0.2 (toluene-ethyl acetate 1: 1). NMR 6 CDC13 3.22 and 3.53 (ABq, 2H, J = 18Hz), 4.5 (s, 2H), 4.82 (s, 2H), 5.03 (cl, 1H,J=4Hz),5.53(dd,1H,J=4and9Hz),6.7-7.37(m,5H)and7.63(d,1H,J=9Hz).

Claims (14)

1- 1. A process for preparing an enamine of formula (IX):

R3 T-T 3 ce CO2FZ2 (1x) where R

2 is a carboxylic acid protecting group and R 3 is the residue of a carboxylic acid derived acyl group and where R' and R' are the same or different C1_4 alkyl or C7-1o aralkyl groups; or taken together with the 35 adjacent nitrogen atom form a heterocyclic ring containing from 4to 8 carbon atoms and optionally a further heteroatom selected from oxygen and nitrogen; by reacting an enol of formula (XI):

RO P J 0 40 ( H3 (xl) Oil," \OH 45 C020 with a phosphorus reagent of formula MW Ra 50 Rt) \, = 0 (V11) where R' and R b are the same or different and can each represent phenyl or phenoxy optionally substituted by one to three groups selected from C1-4 alky], C1-4 alkoxy, halogen and nitro; or is C1-4 alkyl, C1-4 alkoxy, C3-8 55 cycloalkyl, C3-8 cycioalkoxy, chlorine or bromine; X is chlorine, bromine, nitrile or azide; provided that:

(i) Wand R b cannot both be halogen; and (H) when X is nitrUe or azide, Ra and R b are the same or different phenoxy; C3-8 cycloalkoxy or C1-4 alkoxy groups, to form a product of formula (Xli):

4 Q R 3 1 0 1 PRb COzRR (X11) GB 2 050 380 A 17 followed by reaction of this product with an amine of formula HNRIR'to form the enamine of formula (IX). 10 2. A process according to claim 1, where a reagent of formula (VII) is utilized in which Re and R b are phenoxy optionally substituted by one to three groups selected from C1-4 alkyl, C1-4 alkoxy, halogen and nitro; CI- 4 alkoxy or C3-8 cycloalkyloxy and X is bromine or chlorine.

3. A process according to claim 2, where R a and R b are phenoxy, R 2 is para-nitrobenzyl, R 3 is benzyl or phenoxymethyl, R5 and R 6 taken together with the adjacent nitrogen atom represent a morpholino group and X is chlorine.

4. An enamine of formula (IX) whenever produced by a method according to anyone of claims 1 to 3.

5. A process for preparing a 3-hydroxyceDhalosporin of formula (Vlll):

is R 3 CONK, M. /-\ T 20 V// \ OH 1 CDzR2 25 where R 2 and R 3 are as defined in any one of claims 1 to 3 which process comprises:

(a) halogenating a compound of formula (R) as defined in claim 4, and (b) cyclising the halo product W:

R 3 CH2X COzR' (X) where X' is chlorine, bromine or iodine, into the 3-hydroxycephalospgrin of formula (V111).

6. A process according to claim 5, wherein the halogenation instep (a) is effected with molecular 40 bromine.

7. A3-hydroxycephaiosporin whenever prepared by a process according to claim 5 or 6.

8. A process for preparing an enamine of formula OX) as defined in claim 1 which comprises reacting a compound of formula (X11) as defined in claim 1 with an amine of formula HW R 6

9. A compound of formula (Xii):

R 3.

0 T- 0 11 a 0,1 op b CO2R2 (X11) where R', R 3, Wand R b are as defined in any one of claims 1 to 3, in either (E)- or (Z)- form.

10. A compound of formula (X11) as claimed in claim 9, wherein R' and R b are phenoxy, R 2 isp-nitrobenzyl and R' is benzyl or phenoxymethyl.

11. A process according to claim 1 substantially as described herein with reference to the Examples.

12. A process according to claim 5 substantially as described herein with reference to the Examples. 60

13. A process according to claim 8 substantially as described herein with reference to the Examples.

14. A compound according to claim 9 substantially as described herein with reference to the Examples.

Printed for Her Majesty's Stationery Office, by Croydon Printing Company limited, Croydon Surrey, 1980. Published by the Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.