Preparation of 3-substituted cephalosporins

There is described a process for preparing an enamine of formula (IX): ##STR1## where R.sup.2 is a carboxylic acid protecting group and R.sup.3 is the residue of a carboxylic acid derived acyl group and where R.sup.5 and R.sup.6 are the same or different C.sub.1-4 alkyl or C.sub.7-10 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): ##STR2## with an amine of formula HNR.sup.5 R.sup.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.

This invention relates to an improved process for preparing 3-substituted 
cephalosporin derivatives and embraces within its ambit novel 
intermediates useful in that process. 
It has recently been discovered that 3-hydroxycephalosporins can be 
converted to their corresponding 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. Pat. 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-III of U.S. Pat. No. 
4,079,181 which process can be schematically illustrated by the following 
reaction schedule: 
##STR3## 
where R represents a para-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 (II) obtained in the 
functionalization of the enol (I) is considerably reduced (of the order of 
10%) by formation of the C-mesylated product (VI): 
##STR4## 
Thus, the maximum realizable yield of (V) is reduced by 10% and, of course, 
production of the unwanted C-mesylated product will result in purification 
problems during subsequent processing of the intermediate mixture ((II) 
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, functionalisation of the enol 
(I) occurs exclusively at the oxygen atom if the methanesulphonyl chloride 
is replaced by a phosphorus reagent of formula (VII): 
##STR5## 
where R.sup.a and R.sup.b are the same or different and can each represent 
phenyl or phenoxy optionally substituted by one to three groups selected 
from C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halogen and nitro; or are 
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.3-8 cycloalkyl, C.sub.3-8 
cycloalkoxy, chlorine or bromine; 
X is chlorine, bromine, nitrile or azide; provided that: 
(i) R.sup.a and R.sup.b cannot both be halogen; and 
(ii) when X is nitrile or azide, R.sup.a and R.sup.b are the same or 
different phenoxy; C.sub.3-8 cycloalkoxy or C.sub.1-4 alkoxy groups. 
Preferably, the reagent of formula (VII) is that in which R.sup.a and 
R.sup.b are phenoxy optionally substituted by one to three groups selected 
from C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halogen and nitro; C.sub.1-4 
alkoxy or C.sub.3-8 cycloalkoxy and X is bromine or chlorine. 
We have now discovered that, the product thus 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-hydroxycephem of formula (V) using the reaction conditions described in 
U.S. Pat. No. 4,079,181. 
Those skilled in the art will appreciate that in view of the extremely high 
cost involved in the preparation of 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 (VIII): 
##STR6## 
where R.sup.2 is a carboxylic acid protecting group and R.sup.3, together 
with the associated carbonyl group, is a carboxylic acid derived acyl 
group, which process comprises: 
(a) halogenating a compound of formula (IX): 
##STR7## 
where R.sup.5 and R.sup.6 are the same or different C.sub.1-4 alkyl or 
C.sub.7-10 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; 
(b) cyclising the halo product (X): 
##STR8## 
where X.sup.1 is chlorine, bromine or iodine, of (a) into the 3-hydroxy 
cephalosporin of formula (VIII) wherein the compound of formula (IX) is 
prepared by 
(c) reacting an enol of formula (XI): 
##STR9## 
with a phosphorus reagent of formula (VII): 
##STR10## 
where R.sup.a, R.sup.b and X are as previously defined, to form a product 
of formula (XII): 
##STR11## 
followed by reaction of this product with an amine of formula HNR.sup.5 
R.sup.6 to form the amine starting material of formula (IX) utilized in 
step (a). 
The reaction of the enol of formula (XI) with the phosphorus reagent of 
formula (VII) and the reaction of the product of formula (XII) with the 
amine of formula HNR.sup.5 R.sup.6 are both novel and inventive and are 
therefore 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 
the invention. 
The carboxylic acid derived acyl group R.sup.3 CO can be any of those 
groups conventionally utilized in the .beta.-lactam art, the nature of 
which groups will be readily apparent to those skilled in this field. 
Thus, for instance the R.sup.3 residue may be: 
(a) hydrogen, C.sub.1-3 alkyl, halomethyl, cyanomethyl or 
3(2-chlorophenyl)-5-methylisoxazol-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, C.sub.1-3 alkyl, and 
C.sub.1-4 alkoxy; 
(d) an arylalkyl group of the formula 
EQU R.degree.--(Q).sub.m --CH.sub.2 -- 
wherein R.degree. is R" as defined above, 2-thienyl, 3-thienyl, or 
1,4-cyclohexyldienyl, m is 0 or 1, and Q is O or S subject to the 
limitation that when m is 1 R.degree. is R"; 
(e) a substituted arylalkyl group of the formula 
##STR12## 
wherein R.degree. is as defined above and W is hydroxy, protected 
hydroxy, amino, protected amino, or protected carboxy; or 
(f) a heteroarylmethyl group of the formula R.sup.4 CH.sub.2 - wherein 
R.sup.4 is 2-furyl, 3-furyl, 2-thiazolyl, 5-isoxazolyl, or 5-tetrazolyl. 
In the foregoing description the term "C.sub.1-3 alkyl" refers to methyl, 
ethyl, n-propyl or isopropyl. Representative "C.sub.1-4 alkoxy" groups are 
methoxy, ethoxy, n-propoxy, and tert-butoxy. "Halomethyl" represents 
chloromethyl, bromomethyl, fluoromethyl and iodomethyl. 
When in the above definition R" represents a substituted phenyl group, R" 
can be a mono or disubstituted halophenyl group such as 4-chlorophenyl, 
2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 
3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dibromophenyl, 
3-chloro-4-fluorophenyl, 2-fluorophenyl and the like; a protected hydroxy 
phenyl group such as 4-benzyloxyphenyl, 3-benzyloxyphenyl, 
4-tert-butoxyphenyl, 4-tetrahydropyranyloxyphenyl, 
4-(4-nitrobenzyloxy)phenyl, 2-phenacyloxyphenyl, 4-benzhydroxyphenyl, 
4-trityloxyphenyl and like groups; a nitrophenyl group such as 
3-nitrophenyl or 4-nitrophenyl; a cyanophenyl group, for example, 
4-cyanophenyl; a mono or dialkyl substituted phenyl group such as 
4-methylphenyl, 2,4-dimethylphenyl, 2-ethylphenyl, 4-isopropylphenyl, 
4-ethylphenyl, 3-n-propylphenyl and the like; a mono or dialkoxyphenyl 
group, for example, 2,6-dimethoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 
4-isopropoxyphenyl, 4-tert-butoxyphenyl, 3-ethoxy-4-methoxyphenyl and the 
like. Also, R" represents disubstituted phenyl groups wherein the 
substituents are different for example, 3-methyl-4-methoxyphenyl, 
3-chloro-4-benzyloxyphenyl, 2-methoxy-4-bromophenyl, 
4-ethyl-2-methoxyphenyl, 3-chloro-4-nitrophenyl, 2-methyl-4-chlorophenyl 
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-methoxybenzyloxycarbonyl 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 hydroxyl group such as the formyloxy group, the 
chloroacetoxy group, the benzyloxy group, the benzhydryloxy group, the 
trityloxy group, the 4-nitrobenzyloxy group, the trimethylsilyloxy group, 
the phenacyloxy group, the tert-butoxy group, the methoxymethoxy group, 
the tetrahydropyranyloxy 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.sup.3 is preferably benzyl or phenoxymethyl (PhOCH.sub.2 --). 
The group R.sup.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 
other functional 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, tert-butyl, 
benzyl, 4-methoxybenzyl, C.sub.2-6 alkanoyloxymethyl, 2-iodoethyl, 
p-nitrobenzyl, diphenylmethyl (benzhydryl), phenacyl, 4-halophenacyl, 
dimethylallyl, 2,2,2-trichloroethyl, tri(C.sub.1-3 alkyl)silyl, 
succinimidomethyl and like ester forming moieties. Other known carboxy 
protecting groups such as those described by E. Haslam 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 function 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 of the molecule. Many such protective 
groups are 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 no novelty or inventiveness 
asserted with regard to the "protecting groups" referred to in this 
specification. 
Representative of the acylamino group R.sup.3 CONH- in the compound of 
formula (VIII) are formamido, acetamido, propionamide, butyramido, 
2-pentenoylamino, cyanoacetamido, chloroacetamido, bromoacetamido, 
5-tert-butoxycarbonylamino, and 5-tert-butoxycarbonylvaleramido. 
Illustrative of the particular acylamino group, 
##STR13## 
are benzamido, 2,6-dimethoxybenzamido, 4-chlorobenzamido, 
4-methylbenzamido, 3,4-dichlorobenzamido, 4-cyanobenzamido, 
3-bromobenzamido, and 3-nitrobenzamido. 
Exemplary of the acylamino group 
##STR14## 
when R.sup.3 is a group of the formula R.degree.(Q).sub.m CH.sub.2 -- and 
m is O, are cyclohexa-1,4-dienylacetamido, phenylacetamido, 
4-chlorophenylacetamido, 3-methoxyphenylacetamido, 3-cyanophenylacetamido, 
3-methylphenylacetamido, 4-bromophenylacetamido, 4-ethoxyphenylacetamido, 
4-nitrophenylacetamido, 3,4-dimethoxyphenylacetamido, 2-thienylacetamido, 
3-thienylacetamido and the like; and when m is 1 and Q is O, 
representative acylamino groups are phenoxyacetamido, 
4-cyanophenoxyacetamido, 4-chlorophenoxyacetamido, 
3,4-dichlorophenoxyacetamido, 2-chlorophenoxyacetamido, 
4-methoxyphenoxyacetamido, 2-ethoxyphenoxyacetamido, 
3,4-dimethylphenoxyacetamido, 4-isopropylphenoxyacetamido, 
3-cyanophenoxyacetamido, 3-nitrophenoxyacetamido and like substituted 
phenoxyacetamido groups; and when m is 1 and Q is S, representative groups 
are phenylthioacetamido, 2,5-dichlorophenylthioacetamido, 
4-bromophenylthioacetamido, 4-methoxyphenylthioacetamido, 
4-tolylthioacetamido and like substituted phenylthioacetamido groups. 
Illustrative of the acylamino groups when R.sup.3 is a substituted 
arylalkyl group of the formula 
##STR15## 
and when W is protected hydroxy are 2-formyloxy-2-phenylacetamido, 
2-benzyloxy-2-(4-methoxyphenyl)acetamido, 
2-(4-nitrobenzyloxy)-2-(3-chlorophenyl)acetamido, 
2-chloroacetoxy-2-(4-methoxyphenyl)acetamido, 
2-benzyloxy-2-phenylacetamido, 
2-trimethylsilyoxyl-2-(4-chlorophenyl)acetamido, and 
2-benzhydryloxy-2-phenylacetamido. Representative of such groups when W is 
protected amino are 2-(4-nitrobenzyloxycarbonylamino)-2-phenylacetamido, 
2-(2,2,2-trichloroethoxycarbonylamino)-2-phenylacetamido, 
2-chloroacetamido-2-(1,4-cyclohexadien-1-yl)acetamido, 
2-(4-methoxybenzyloxycarbonylamino)-2-(4-methoxyphenyl)acetamido, 
2-benzhydryloxycarbonylamino-2-phenylacetamido, 
2-(1-carbomethoxy-2-propenyl)amino-2-phenylacetamido and 
2-(4-nitrobenzyloxycarbonylamino)-2-(2-thienyl)acetamido. 
Exemplary of the acylamino group 
##STR16## 
when R.sup.3 is a heteroarylmethyl group of the formula R.sup.4 --CH.sub.2 
-- are 2-furylacetamido, 3-furylacetamido, a 2-thiazolylacetamido group of 
the formula 
##STR17## 
or a 5-isoxazolylacetamido group of the formula 
##STR18## 
The compound of formula (IX) may be halogenated using the reagents and 
conditions specified in U.S. Pat. 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.sub.2.sup.1, BrCl, IBr, C.sub.6 H.sub.5 I.X.sup.1.sub.2, C.sub.5 
H.sub.5 N.HX.sup.1.X.sub.2.sup.1, C.sub.6 H.sub.5 
N(CH.sub.3).sub.2.HX.sup.1.X.sup.1.sub.2, (alkyl).sub.2 SO.sub.4.HX', 
CuX.sub.2 '. 
2. --OX.sup.1, (alkyl)OX.sup.1, HOX.sup.1, (acyl)OX.sup.1. 
3. .dbd.NX.sup.1 (alkyl).sub.4 NX.sup.1.X.sup.1.sub.2, NO.sub.2 X.sup.1, 
(acyl)NHX.sup.1, (acyl).sub.2 NX.sup.1. 
4. --SX.sup.1, SX.sup.1.sub.2, S+X.sup.1.sub.2. 
5. --CX.sup.1, X.sup.1.sub.2, CHOCH.sub.3, CX.sup.1.sub.4, 
.alpha.-haloketones, .alpha.-halosulfones, or like reagents, where alkyl 
and acyl contain up to 4 carbon atoms; and X.sup.1 is chlorine, bromine or 
iodine. X.sup.1 is preferably bromine. 
When these halogenating reagents act via a halogen radical, the reaction 
can be initiated by heat, light, 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, 
lutidine, morpholine, diethylamine, triethylamine 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, 
tetrahydropyran, 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 (dimethylformamide, dimethylacetamide, 
hexamethylphosphorotriamide, etc.), organic nitriles (acetonitrile, 
benzonitrile, etc.), nitrohydrocarbons and alkyl sulfoxides (dimethyl 
sulfoxide, etc.). 
Representative examples of suitable --NR.sup.5 R.sup.6 groups are 
dimethylamino, diethylamino, methylethylamino, dipropylamino, 
dibutylamino, dibenzylamino and, when R.sup.5 and R.sup.6 represent a 
cyclic entity, morpholino, piperidino and piperazino. The preferred 
--NR.sup.5 R.sup.6 group for use in the invention is morpholino. 
The cyclisation reaction (b) can be effected by acid catalyzed hydrolysis. 
Suitable solvents for the cyclization are ethereal solvents e.g. 
tetrahydrofuran, tetrahydropyran and dioxan, amide solvents e.g. 
dimethylformamide, 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, perchloric acid, sulphurous acid), aqueous aryl 
sulphonic acids such as p-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.degree. to 50.degree. C., more preferably from 0.degree. to 25.degree. 
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, tetrahydropyran, 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, 
N-methylmorpholine 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 
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)phosphoryl chloride, 
bis-(3,4-dichlorophenyl)phosphoryl bromide, 
bis-(4-methylphenyl)phosphoryl chloride, 
bis-(4-butylphenyl)phosphoryl bromide, 
bis-(3,4-dimethylphenyl)phosphoryl chloride, 
bis-(3-chloro-4-methylphenyl)phosphoryl 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)phosphoryl chloride, 
bis-(3,4,5-trimethoxyphenyl)phosphoryl bromide, 
bis-(2-methoxy-3-methyl-4-fluorophenyl)phosphoryl 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, 
methyl phosphorodichloridate, 
methyl phosphorodibromidate, 
ethyl phosphorodichloridate, 
ethyl phosphorodibromidate, 
propyl phosphorodichloridate, 
isopropyl phosphorodichloridate, 
butyl phosphorodichloridate, 
phenyl phosphorodichloridate, 
phenyl phosphorodibromidate, 
2-chlorophenyl phosphorodichloridate, 
2-chlorophenyl phosphorodibromidate, 
3-chlorophenyl phosphorodichloridate, 
3-fluorophenyl phosphorodichloridate, 
2,4-dichlorophenyl phosphorodichloridate, 
2,4-dichlorophenyl phosphorodibromidate, 
3,4-dichlorophenyl phosphorodichloridate, 
4-methylphenyl phosphorodichloridate, 
3-chloro-4-methylphenyl phosphorodichloridate, 
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 methylphosphonochloridate, 
methyl methylphosphonobromidate, 
methyl phenylphosphonochloridate, 
ethyl methylphosphonochloridate, 
ethyl ethylphosphonochloridate, 
ethyl ethylphosphonobromidate, 
ethyl phenylphosphonochloridate, 
ethyl 3-chlorophenylphosphonochloridate, 
ethyl 2,4-dichlorophenylphosphonochloridate, 
ethyl 4-methylphenylphosphonochloridate, 
ethyl 4-methoxyphenylphosphonochloridate, 
ethyl 4-nitrophenylphosphonochloridate, 
ethyl cyclopentylphosphonochloridate, 
phenyl methylphosphonochloridate, 
phenyl phenylphosphonochloridate, 
phenyl phenylphosphonobromidate, 
phenyl 4-methylphenylphosphonochloridate, 
phenyl cyclohexylphosphonochloridate, 
2,4-dichlorophenyl ethylphosphonochloridate, 
2,4-dichlorophenyl phenylphosphonochloridate, 
2,4-dichlorophenyl cyclohexylphosphonochloridate, 
4-nitrophenyl ethylphosphonochloridate, 
4-nitrophenyl phenylphosphonochloridate, 
4-nitrophenyl cyclohexylphosphonochloridate, 
3,4,5-trimethoxyphenyl ethylphosphonochloridate, 
3,4,5-trimethoxyphenyl phenylphosphonochloridate, 
cyclopentyl ethylphosphonochloridate, 
cyclopentyl phenylphosphonochloridate, 
cyclohexyl phenylphosphonochloridate, 
dimethylphosphinyl chloride, 
dimethylphosphinyl bromide, 
diethylphosphinyl chloride, 
diethylphosphinyl bromide, 
dipropylphosphinyl chloride, 
di-isopropylphosphinyl chloride, 
dibutylphosphinyl chloride, 
diphenylphosphinyl chloride, 
diphenylphosphinyl bromide, 
bis-(2-chlorophenyl)phosphinyl chloride, 
bis-(2-chlorophenyl)phosphinyl bromide, 
bis-(3-chlorophenyl)phosphinyl chloride, 
bis-(3-fluorophenyl)phosphinyl chloride, 
bis-(2,4-dichlorophenyl)phosphinyl chloride, 
bis-(3,4-dichlorophenyl)phosphinyl chloride, 
bis-(4-methylphenyl)phosphinyl chloride, 
bis-(3-chloro-4-methylphenyl)phosphinyl chloride, 
bis-(3-methoxyphenyl)phosphinyl chloride, 
bis-(4-methoxyphenyl)phosphinyl chloride, 
bis-(3-butoxyphenyl)phosphinyl chloride, 
bis-(4-nitrophenyl)phosphinyl chloride, 
bis-(3,4,5-trimethoxyphenyl)phosphinyl chloride, 
dicyclopropylphosphinyl chloride, 
dicyclopentylphosphinyl chloride, 
dicyclohexylphosphinyl chloride, 
dicyclohexylphosphinyl bromide, and 
dicyclooctylphosphinyl chloride. 
Use of diphenylphosphoryl chloride as the phosphorus reagent is preferred. 
The product of the condensation reaction is a compound of formula (XII). 
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-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphate, 
diethyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphate, 
diisopropyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2-0]hept-2-en-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphate, 
dicyclopentyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphate, 
dicyclohexyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphate, 
diphenyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphate, 
bis-2-chlorophenyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphate, 
bis-3,4-dichlorophenyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphate, 
bis-4-methylphenyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphate, 
bis-3-methoxyphenyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphate, 
bis-3,4,5-trimethoxyphenyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphate, 
bis-4-nitrophenyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphate, 
dimethyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p-nitro 
benzyloxycarbonyl)-prop-1-en-2-yl phosphate, 
diethyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p-nitro 
benzyloxycarbonyl)-prop-1-en-2-yl phosphate, 
dicyclopentyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p-nitro 
benzyloxycarbonyl)-prop-1-en-2-yl phosphate, 
diphenyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p-nitro 
benzyloxycarbonyl)-prop-1-en-2-yl phosphate, 
bis-4-methoxyphenyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p-nitro 
benzyloxycarbonyl)-prop-1-en-2-yl phosphate, 
diethyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
2,2,2-trichloroethoxycarbonyl)-prop-1-en-2-yl phosphate, 
diphenyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
2,2,2-trichloroethoxycarbonyl)-prop-1-en-2-yl phosphate, 
diethyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(2,2,2-t 
richloroethoxycarbonyl)-prop-1-en-2-yl phosphate, 
diphenyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(2,2,2-t 
richloroethoxycarbonyl)-prop-1-en-2-yl phosphate, 
diethyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
diphenylmethoxycarbonyl)-prop-1-en-2-yl phosphate, 
diphenyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
diphenylmethoxycarbonyl)-prop-1-en-2-yl phosphate, 
diethyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(dipheny 
lmethoxycarbonyl)-prop-1-en-2-yl phosphate, 
diphenyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(dipheny 
lmethoxycarbonyl)-prop-1-en-2-yl phosphate, 
diethyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
benzyloxycarbonyl)-prop-1-en-2-yl phosphate, 
diphenyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
benzyloxycarbonyl)-prop-1-en-2-yl phosphate, 
diethyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(benzylo 
xycarbonyl)-prop-1-en-2-yl phosphate, 
diphenyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(benzylo 
xycarbonyl)-prop-1-en-2-yl phosphate, 
diethyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
t-butoxycarbonyl)-prop-1-en-2yl phosphate, 
diphenyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
t-butoxycarbonyl)-prop-1-en-2-yl phosphate, 
diethyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(t-butox 
ycarbonyl)-prop-1-en-2-yl phosphate, 
diphenyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(t-butox 
ycarbonyl)-prop-1-en-2-yl phosphate, 
diethyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
p-methoxyoxycarbonyl)-prop-1-en-2-yl phosphate, 
diphenyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
p-methoxybenzyloxycarbonyl)-prop-1-en-2-yl phosphate, 
diethyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p-metho 
xybenzyloxycarbonyl)-prop-1-en-2-yl phosphate, 
diphenyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p-metho 
xybenzyloxycarbonyl)-prop-1-en-2-yl phosphate, 
methyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphorochloridate, 
methyl-1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-y 
l)-1-(p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphorobromidate, 
ethyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphorochloridate, 
isopropyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphorochloridate, 
cyclopentyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphorochloridate, 
cyclohexyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphorochloridate, 
phenyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphorochloridate, 
phenyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphorobromidate, 
2-chlorophenyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphorochloridate, 
4-methylphenyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphorochloridate, 
4-methoxyphenyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphorochloridate, 
ethyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p-nitro 
benzyloxycarbonyl)-prop-1-en-2-yl phosphorochloridate, 
phenyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p-nitro 
benzyloxycarbonyl)-prop-1-en-2-yl phosphorochloridate, 
4-methoxyphenyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p-nitro 
benzyloxycarbonyl)-prop-1-en-2-yl phosphorochloridate, 
ethyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
2,2,2-trichloroethoxycarbonyl)-prop-1-en-2-yl phosphorochloridate, 
phenyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(2,2,2-t 
richloroethoxycarbonyl)-prop-1-en-2-yl phosphorochloridate, 
ethyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(dipheny 
lmethoxycarbonyl)-prop-1-en-2-yl phosphorochloridate, 
phenyl 
1-(phenoxymethyl-7-oxo-4thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(dip 
henylmethoxycarbonyl)-prop-1-en-2-yl phosphorochloridate, 
ethyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
benzyloxycarbonyl)-prop-1-en-2-yl phosphorochloridate, 
phenyl 1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]L 
hept-2-en-6-yl)-1-(benzyloxycarbonyl)-prop-1-en-2-yl phosphorochloridate, 
ethyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(t-butox 
ycarbonyl)-prop-1-en-2-yl phosphorochloridate, 
phenyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
t-butoxycarbonyl)-prop-1-en-2-yl phosphorochloridate, 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p 
-nitrobenzyloxycarbonyl)-prop-1-en-2-yl dimethylphosphinate, 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p 
-nitrobenzyloxycarbonyl)-prop-1-en-2-yl diethylphosphinate, 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6)-1-(p-ni 
trobenzyloxycarbonyl)-prop-1-en-2-yl dicyclohexylphosphinate, 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p 
-nitrobenzyloxycarbonyl)-prop-1-en-2-yl diphenylphosphinate, 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p 
-nitrobenzyloxycarbonyl)-prop-1-en-2-yl bis-2-chlorophenylphosphinate, 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p 
-nitrobenzyloxycarbonyl)-prop-1-en-2-yl bis-2,4-dichlorophenylphosphinate, 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p 
-nitrobenzyloxycarbonyl)-prop-1-en-2-yl bis-4-methylphenylphosphinate, 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p 
-nitrobenzyloxycarbonyl)-prop-1-en-2-yl bis-3-methoxyphenylphosphinate, 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p 
-nitrobenzyloxycarbonyl)-prop-1-en-2-yl bis-4-nitrophenylphosphinate, 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p-nitrob 
enzyloxycarbonyl)prop-1-en-2-yl dimethylphosphinate, 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p-nitrob 
enzyloxycarbonyl)prop-1-en-2yl bis-4-methoxyphenylphosphinate, 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(2 
,2,2-trichloroethoxycarbonyl)-prop-1-en-2-yl diethylphosphinate, 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(2,2,2-tr 
ichloroethoxycarbonyl)-prop-1-en-2-yl diethylphosphinate, 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(2 
,2,2-trichloroethoxycarbonyl)-prop-1-en-2-yl diphenylphosphinate, 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]-hept-2-en-6-yl)-1-(2,2,2-t 
richloroethoxycarbonyl)-prop-1-en-2-yl diphenylphosphinate, 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(b 
enzyloxycarbonyl)-prop-1-en-2-yl diethylphosphinate, 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]-hept-2-en-6-yl)-1-(benzylo 
xycarbonyl) prop-1-en-2-yl diphenylphosphinate, 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-di 
phenylmethoxycarbonyl)-prop-1-en-2-yl diethylphosphinate, 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p-nitrob 
enzyloxycarbonyl)-prop-1-en-2yl bis-4-methoxyphenylphosphinate, 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(2 
,2,2-trichloroethoxycarbonyl)-prop-1-en-2-yl diethylphosphinate, 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl) 
1-(2,2,2-trichloroethoxycarbonyl)-prop-1-en-2-yl diethylphosphinate, 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(2 
,2,2-trichloroethoxycarbonyl)-prop-1-en-2-yl diphenylphosphinate, 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(2,2,2-tr 
ichloroethoxycarbonyl)-prop-1-en-2-yl diphenylphosphinate, 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(b 
enzyloxycarbonyl)-prop-1-en-2-yl diethylphosphinate, 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(benzylox 
ycarbonyl) prop-1-en-2-yl diphenylphosphinate, 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-di 
phenylmethoxycarbonyl)-prop-1-en-2-yl diethylphosphinate, 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(diphenyl 
methoxycarbonyl)-prop-1-en-2-yl diphenylphosphinate, 
methyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p-nitro 
benzyloxycarbonyl)-prop-1-en-2-yl phenylphosphonate, 
ethyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p-nitro 
benzyloxycarbonyl)-prop-1-en-2-yl ethylphosphonate, 
phenyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p-nitro 
benzyloxycarbonyl)-prop-1-en-2-yl phenylphosphonate, 
ethyl 
1-(3-phenoxymethoxy-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1- 
(2,2,2-trichloroethoxycarbonyl)-prop-1-en-2-yl ethylphosphonate, 
phenyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(2,2,2-t 
richloroethoxycarbonyl)-prop-1-en-2-yl phenylphosphonate, 
ethyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(2,2,2-t 
richloroethoxycarbonyl)-prop-1-en-2-yl ethylphosphonate, 
phenyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
2,2,2-trichloroethoxycarbonyl)-prop-1-en-2-yl phenylphosphonate, 
ethyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
benzyloxycarbonyl)-prop-1-en-2-yl ethylphosphonate, 
phenyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-benzylox 
ycarbonyl)-prop-1-en-2-yl phenylphosphonate, 
ethyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
diphenylmethoxycarbonyl)-prop-1-en-2-yl ethylphosphonate, and 
phenyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(dipheny 
lmethoxycarbonyl)-prop-1-en-2-yl phenylphosphonate. 
Conversion of the intermediate of formula (XII) to the amine starting 
material of formula (IX) is preferably effected at a temperature in the 
range of from -10.degree. to 50.degree. C., most preferably from 0.degree. 
to 5.degree. C. Any suitable organic solvent may be utilized for the 
conversion, especially those mentioned previously in connection with the 
reaction of the enol of formula (XI) and the phosphorus reagent of formula 
(VII). The amine HNR.sup.5 R.sup.6, where R.sup.5 and R.sup.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 non-limitative 
Examples.

EXAMPLE 1 
p-Nitrobenzyl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate 
To a stirred suspension of p-nitrobenzyl 
.alpha.-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]-hept-2-en-6-yl]-.al 
pha.-(1-hydroxyethylidene)acetate (9.06 g) in tetrahydrofuran (120 ml) 
under a nitrogen atmosphere at 20.degree. C. was added triethylamine (3.21 
ml) and diphenylphosphoryl chloride (4.77 ml). The reaction was stirred 
for 2 hours and then cooled to 0.degree. C. Morpholine (4.01 ml) was added 
and the reaction stirred for 2 hours at 0.degree.-5.degree. C. The 
reaction was then cooled to -30.degree. to -35.degree. C. and pyridine 
(1.62 ml) added, followed by bromine (1.00 ml) dropwise over a period of 
10 minutes. 
The reaction was stirred for 20 minutes at -30.degree. to -35.degree. C., 
and then 5% hydrochloric acid (144 ml), methanol (120 ml) and 
tetrahydrofuran (20 ml) added. The reaction was then stirred at room 
temperature for 3 hours and stood at 0.degree. C. overnight. The product 
was isolated by filtration, and washed with methanol (30 ml), water (30 
ml) and methanol (30 ml) and then dried in vacuo at 40.degree. C. for 5 
hours. The total yield of title 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 
.alpha.-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo 
[3,2,0]hept-2-en-6-yl]-.alpha.-(1-hydroxyethylidene)acetate (9.38 g) in 
tetrahydrofuran (120 ml) under a nitrogen atmosphere at 20.degree. C. was 
added triethylamine (3.21 ml) followed by diphenylphosphoryl chloride 
(4.77 ml). The reaction mixture was then stirred for 2 hours and cooled to 
0.degree. C. Morpholine (4.01 ml) was added and the reaction mixture 
stirred for 2 hours at 0.degree.-5.degree. C. The reaction mixture was 
next cooled to -30.degree. to -35.degree. C. and pyridine (1.62 ml) added 
followed by the dropwise addition of bromine (1.00 ml) over a period of 10 
minutes. The reaction mixture was stirred at -30.degree. to -35.degree. C. 
for 20 minutes and 5% hydrochloric acid (144 ml) added, followed by 
further stirring at room temperature for 3 hours. The reaction mixture was 
then stood at 0.degree. 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 
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 40.degree. C. for 5 hours. The yield of 
p-nitrobenzyl 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate acetic 
acid solvate was 9.16 g (84%). 
EXAMPLE 3 
Diethyl 1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo 
[3,2,0]hept-2-en-6-yl)-1-(p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl 
phosphate 
To a solution of p-nitrobenzyl 
.alpha.-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-.alp 
ha.-(1-hydroxyethylidene)acetate (4.53 g) containing 
4-dimethylaminopyridine (0.1 g) in ethyl acetate (50 ml) under a nitrogen 
atmosphere at 20.degree. C. was added triethylamine (1.53 ml) followed by 
diethylphosphoryl chloride (1.59 ml) dropwise. The reaction mixture was 
stirred at 20.degree. C. for 3 hours. Water (40 ml) was added and the 
organic layer was separated, washed with water (20 ml) and saturated 
sodium chloride solution (20 ml), 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) R.sub.f 0.17 
(dichloromethane/ethyl acetate 15:2). The product was a mixture of 
geometric isomers (ca. 2:1) about the enol phosphate double bond. NMR 
.delta.CDCl.sub.3 1.11-1.60 (m, 6H), 1.98+2.60 (d, 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). 
EXAMPLE 4 
Diphenyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p-nitro 
benzyloxycarbonyl)-prop-1-en-2-yl phosphate 
To a suspension of p-nitrobenzyl 
.alpha.-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]-hept-2-en-6-yl)-.al 
pha.-(1-hydroxyethylidene) acetate (4.53 g) in tetrahydrofuran (60 ml) 
under a nitrogen atmosphere at 20.degree. C. was added triethylamine (1.53 
ml) followed by diphenylphosphoryl chloride (2.28 ml) dropwise. The 
reaction mixture was stirred at 20.degree. C. for 2 hours. Water (50 ml) 
was then added and the mixture was extracted with dichloromethane (60 ml). 
The organic layer was separated, washed with water (30 ml) and saturated 
sodium chloride solution (30 ml), dried with magnesium sulphate, filtered 
and evaporated to give the title compound as a yellow viscous oil in 
essentially quantitative yield. TLC (silica) R.sub.f 0.68 
(dichloromethane/ethyl acetate 15:2). The product was a mixture of 
geometric isomers (ca. 4:1) about the enol phosphate double bond. 
NMR.delta.CDCl.sub.3 1.93 (d, J=2 Hz)+2.58 (d, J=2 Hz) (3H), 3.48-3.90 (m, 
2H), 5.05 (s, 2H), 5.5-6.0 (m, 2H) and 7.0-8.2 (m. 19 H). 
EXAMPLE 5 
Diphenyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphate 
To a solution of p-nitrobenzyl 
.alpha.-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]-hept-2-en-6- 
yl)-.alpha.-(1-hydroxyethylidene) acetate (9.38 g) in dichloromethane (100 
ml) under a nitrogen atmosphere at 20.degree. C. was added triethylamine 
followed by diphenylphosphoryl chloride (4.35 ml). The reaction mixture 
was stirred at 20.degree. C. for 2 hours. Water (50 ml) was added and the 
organic layer was separated, washed with water (40 ml) and saturated 
sodium chloride solution (40 ml), dried with magnesium sulphate, filtered 
and evaporated to give the title compound as a yellow viscous oil in 
essentially quantitative yield. TLC (silica) R.sub.f 0.060 (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; R.sub.f 0.52 and 0.45 (toluene/ethyl acetate, 1/1). 
NMR.delta.CDCl.sub.3 2.10 (d, J=2 Hz)+2.63 (d, J=2 Hz) (3H), 4.22 and 4.67 
(ABq, J=14 Hz, 2H), 5.11 (s, 2H), 5.50-5.77 (m, 2H) and 6.50-8.13 (m, 
19H). 
EXAMPLE 6 
p-Nitrobenzyl 
.alpha.-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-.alp 
ha.-(1-morpholinoethylidene) acetate 
To a solution of diethyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p-nitro 
benzyloxycarbonyl)-prop-1-en-2-yl phosphate (5.90 g) in dichloromethane (70 
ml) at 0.degree.-5.degree. C. was added morpholine (1.83 ml) dropwise and 
the reaction mixture stirred at this temperature for 2 hours. Water (40 
ml) was added and the organic layer was separated, washed with water (30 
ml) 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) R.sub.f 0.60 (ethyl 
acetate). The product was a mixture of geometric isomers (ca. 1:1.4) about 
the enamine double bond. NMR.delta.CDCl.sub.3 1.72+2.40 (s, 3H), 3.01-4.07 
(m, 10H), 5.22 (s, 2H), 5.60-6.13 (m, 2H), 7.28-7.77 and 8.10-8.40 (m, 
9H). 
EXAMPLE 7 
p-Nitrobenzyl 
.alpha.-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-.alp 
ha.-(1-morpholinoethylidene)acetate 
To a solution of diphenyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p-nitro 
benzyloxycarbonyl)-prop-1-en-2-yl phosphate (6.86 g) in acetonitrile (50 
ml) at 0.degree.-5.degree. C. was added morpholine (1.83 ml) dropwise and 
the reaction mixture stirred at this temperature for 2 hours. Water (50 
ml) was added and the mixture was extracted with ethyl acetate (40 ml). 
The organic layer was separated, washed with water (30 ml) 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. 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. 
EXAMPLE 8 
p-Nitrobenzyl 
.alpha.-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-y 
l)-.alpha.-(1-morpholinoethylidene)acetate 
To a solution of diphenyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphate (7.02 g) in ethyl 
acetate (70 ml) at 0.degree.-5.degree. C. was added morpholine (1.83 ml) 
dropwise and the reaction mixture stirred at this temperature for 2 hours. 
Water (30 ml) was added and the organic layer was separated, washed with 
water (30 ml) 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) R.sub.f 0.57 
(ethyl acetate). The product was a mixture of geometric isomers (ca. 
1:1.4) about the enamine double bond. NMR.delta.CDCl.sub.3 1.93 (s), +2.43 
(s) (3H), 3.17-3.93 (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-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl)-1-(p 
-nitrobenzyloxycarbonyl)-prop-1-en-2-yl diphenylphosphinate 
To a stirred solution of p-nitrobenzyl 
.alpha.-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-y 
l)-.alpha.-(1-hydroxyethylidene)acetate (4.69 g) in tetrahydrofuran (60 ml) 
under a nitrogen atmosphere at 0.degree.-5.degree. C. was added 
triethylamine (1.6 ml.) followed by diphenylphosphinyl chloride (2.73 g.) 
dropwise over 5 minutes. After stirring for 3 hours at 20.degree. 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 (silica) R.sub.F 0.54 (ethyl acetate). 
NMR.delta.CDCl.sub.3 2.5 (s, 3H), 3.63 and 4.40 (ABq, 2H, J=14 Hz), 5.13 
(s, 2H), 5.68 (d, 1H, J=4 Hz), 5.85 (d, 1H, J=4 Hz) 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-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phenylphosphonate 
To a stirred solution of p-nitrobenzyl 
.alpha.-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-y 
l)-.alpha.-(1-hydroxyethylidene)acetate (4.69 g) in tetrahydrofuran (60 
ml.) under a nitrogen atmosphere at 0.degree. C. was added triethylamine 
(1.6 ml.) followed by phenyl phenylphosphonochloridate (2.91 g). After 
stirring for 3 hours at 20.degree. 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 evapoated to give the title compound as a pale yellow friable 
foam in essentially quantitative yield. TLC (silica)R.sub.f 0.64 (ethyl 
acetate). NMR .delta.CDCl.sub.3 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). 
EXAMPLE 11 
Diphenyl 
1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl)-1-(dipheny 
lmethoxycarbonyl)-prop-1-en-2-yl phosphate 
To a stirred solution of benzhydryl 
.alpha.-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl)-.alp 
ha.-(1-hydroxyethylidene)acetate (2.42 g.). in tetrahydrofuran (30 ml.) 
under a nitrogen atmosphere at 20.degree. C. was added triethylamine (0.74 
ml.) followed by diphenylphosphoryl chloride (1.09 ml.). After stirring 
for 2 hours at 20.degree. 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) R.sub.f 0.58 (ethyl acetate). NMR .delta. 
CDCl.sub.3 2.57 (d, 3H, J=ca. 1 Hz), 2.64 and 3.63 (ABq, 2H, J=16 Hz), 
5.43-5.9 (m, 2H), 6.77 (s, 1H) and 6.85-7.5 (m, 25H). 
EXAMPLE 12 
Diphenyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl)-1-( 
2,2,2-trichloroethoxycarbonyl)-prop-1-en- 2-yl phosphate 
To a stirred solution of 2,2,2-trichloroethyl 
.alpha.-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-y 
l)-.alpha.-(1-hydroxyethylidene)acetate (2.33 g.) in tetrahydrofuran (30 
ml.) under a nitrogen atmosphere at 20.degree. C. was added triethylamine 
(0.74 ml.) followed by diphenylphosphoryl chloride (1.09 ml.). After 
stirring for 1.75 hours at 20.degree. 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) R.sub.f 0.63 (ethyl acetate). The product 
was a mixture of geometric isomers (ca. 3:1) about the enol phosphate 
double bond. NMR .delta. CDCl.sub.3 2.08 (d)+2.68 (d) (3H), 4.4-5.0 (m, 
4H), 5.67-6.07 (m, 2H) and 6.63-7.43 (m, 15H). 
EXAMPLE 13 
p-Nitrobenzyl 
.alpha.-(3phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl 
)-.alpha.-(1-morpholinoethylidene)acetate 
To a stirred solution of 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl diphenylphosphinate (1.34 g.) in 
tetrahydrofuran (20 ml.) at 0.degree.-5.degree. C. was added morpholine 
(0.38 ml.). After stirring for 6 hours at 0.degree.-5.degree. 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 geometric isomers (ca. 1:1.4) 
about the enamine double bond and was identical to that produced in 
example 8. 
EXAMPLE 14 
p-Nitrobenzyl 
.alpha.-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-y 
l)-.alpha.-(1-morpholinoethylidene)acetate 
To a stirred solution of phenyl 
1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl)-1-( 
p-nitrobenzyloxycarbonyl)-prop-1-en2-yl phenylphosphonate (1.37 g.) in 
tetrahydrofuran (20 ml.) at 0.degree.-5.degree. C. was added morpholine 
(0.383 ml.). After stirring for 3 hours at 0.degree.-5.degree. 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 geometric isomers (ca. 1:1.4) 
about the enamine double bond and was identical to that produced in 
example 8. 
EXAMPLE 15 
p-Nitrobenzyl 
.alpha.-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl)-.alp 
ha.-(1-piperidinoethylidine)acetate 
To a stirred solution of p-nitrobenzyl 
.alpha.-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl)-.alp 
ha.-(1-hydroxyethylidene)acetate (3.02 g.) in tetrahydrofuran (40 ml.) 
under a nitrogen atmosphere at 20.degree. C. was added triethylamine (0.98 
ml.) followed by diphenylphosphoryl chloride (1.45 ml.). After stirring 
for 2 hours, the reaction mixture was cooled to 0.degree. C. and 
piperidine (0.76 ml.) was added. After stirring for 3 hours at 
0.degree.-5.degree. C., 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) R.sub.f 0.48 
(dichloromethane-ethyl acetate 15:2). The product was a mixture of 
geometric isomers about the enol phosphate double bond. NMR .delta. 
CDCl.sub.3 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, 5H) and 7.48 and 
8.23 (ABq, 4H, J=9 Hz). 
EXAMPLE 16 
2,2,2-Trichloroethyl 
.alpha.-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-y 
l)-.alpha.-(1-morpholinoethylidene)acetate 
To a stirred solution of 2,2,2-trichloroethyl 
.alpha.-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-y 
l)-.alpha.-(1-hydroxyethylidene) acetate (2.33 g.) in tetrahydrofuran (30 
ml.) under a nitrogen atmosphere at 20.degree. C. was added triethylamine 
(0.74 ml.) followed by diphenylphosphoryl chloride (1.09 (ml.) After 
stirring for 2 hours, the reaction mixture was cooled to 0.degree. C. and 
morpholine (0.92 ml.) was added. After stirring for 2 hours at 
0.degree.-5.degree. C., 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) R.sub.f 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 
.delta. CDCl.sub.3 1.83 (s)+2.37 (s) (3H), 3.0-3.9 (m, 8H), 4.48 and 4.92 
(ABq, 2H, J=13 Hz), 4.93 (s, 2H), 5.75-6.10 (m, 2H) and 6.8-7.5 (m, 5H). 
EXAMPLE 17 
p-Nitrobenzyl 
.alpha.-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-y 
l)-.alpha.-(1-morpholinoethylidene)acetate 
To a stirred solution of p-nitrobenzyl 
.alpha.-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-y 
l)-.alpha.-(1-hydroxyethylidene)acetate (4.69 g.) in tetrahydrofuran (60 
ml.) under a nitrogen atmosphere at 0.degree.-5.degree. C. was added 
triethylamine (1.6 ml.) followed by dropwise addition of ethyl 
dichlorophosphate (1.36 ml.) over 5 minutes. After stirring for 3 hours at 
20.degree. C., the reaction mixture was cooled to 0.degree. C. and 
morpholine (4.0 ml.) was added dropwise over 10 minutes with the reaction 
temperature maintained at 0.degree.-5.degree. C. 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) about the enamine double bond and 
was identical to that produced in example 8. 
EXAMPLE 18 
p-Nitrobenzyl 
.alpha.-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-y 
l)-.alpha.-(1-morpholinoethylidene)acetate 
To a stirred solution of p-nitrobenzyl 
.alpha.-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-y 
l)-.alpha.-(1-hydroxyethylidene)acetate (4.69 g.) in tetrahydrofuran (60 
ml.) under a nitrogen atmosphere at 0.degree.-5.degree. C. was added 
triethylamine (1.6 ml.) followed by dropwise addition of phenylphosphonic 
dichloride (1.63 ml.) over 5 minutes. After stirring for 3 hours at 
20.degree. C., the reaction mixture was cooled to 0.degree. C. and 
morpholine (4.0 ml.) was added dropwise over 10 minutes with the reaction 
temperature maintained at 0.degree.-5.degree. C. 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-Nitrobenzyl 
.alpha.-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-y 
l)-.alpha.-(1-morpholinoethylidene)acetate 
To a stirred solution of p-nitrobenzyl 
.alpha.-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-y 
l)-.alpha.-(1-hydroxyethylidene)acetate (4.69 g.) in tetrahydrofuran (60 
ml.) under a nitrogen atmosphere at 0.degree.-5.degree. C. was added 
triethylamine (1.6 ml.) followed by dropwise addition of phenyl 
dichlorophosphate (1.72 ml.) over 5 minutes. After stirring for 3 hours at 
20.degree. C., the reaction mixture was cooled to 0.degree. C. and 
morpholine (4.0 ml.) was added dropwise over 10 minutes with the reaction 
temperature maintained at 0.degree.-5.degree. C. 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 yellow 
foam 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 8. 
EXAMPLE 20 
Benzhydryl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate 
To a stirred solution of benzhydryl 
.alpha.-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl)-.alp 
ha.-(1-hydroxyethylidene)acetate (9.68 g.) in tetrahydrofuran (120 ml.) 
under a nitrogen atmosphere at 20.degree. C. was added triethylamine (2.93 
ml.) followed by diphenylphosphoryl chloride (4.35 ml.) After stirring for 
3 hours, the reaction mixture was cooled to 5.degree.-10.degree. C., 
morpholine (3.75 ml.) was added and the mixture stirred for 2 hours at 
5.degree.-10.degree. C. After cooling to -30.degree. to -35.degree. C., 
pyridine (1.62 ml.) was added followed by dropwise addition of bromine 
(1.00 ml.) over 10 minutes. The reaction mixture was stirred at 
-30.degree. to -35.degree. C. for 20 minutes and 5% hydrochloric acid (144 
ml.) was added. After stirring at 20.degree. C. 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 
(600 g.) with dichloromethane-acetone (20:1) as eluent to give 7.04 g. 
(78%) of the title compound as a foam. TLC (silica) R.sub.f 0.55 (ethyl 
acetate). NMR .delta. CDCl.sub.3 3.13 (s, 2H), 3.57 (s, 2H), 4.88 (d, 1H, 
J=4 Hz), 3.57 (dd, 1H, J=4 and 9 Hz) and 6.66-7.5 (m, 17H). 
EXAMPLE 21 
p-Nitrobenzyl 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate 
To a stirred solution of p-nitrobenzyl 
.alpha.-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-y 
l)-.alpha.-(1-hydroxyethylidene)acetate (9.38 g.) in tetrahydrofuran (120 
ml.) under a nitrogen atmosphere at 20.degree. C. was added triethylamine 
(3.21 ml.) followed by phenyl phenylphosphonochloridate (5.82 g.) After 
stirring for 2 hours at 20.degree. C., the reaction mixture was cooled to 
0.degree. C. and morpholine (4.01 ml.) added. After stirring for 2.5 hours 
at 0.degree.-5.degree. C., the mixture was cooled to -30.degree. to 
-35.degree. C. and pyridine (1.62 ml.) added followed by dropwise addition 
of bromine (1.00 ml.) over a period of 10 minutes. The reaction mixture 
was stirred at -30.degree. to -35.degree. C. for 20 minutes and 5% 
hydrochloric acid (144 ml.) added. After stirring at 20.degree. C. 
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 ml.) and the resulting solution stirred for 
approximately 10 minutes to crystallise the product. The crystallisation 
was completed by addition of isopropanol (120 ml.) over 0.5 hour. The 
crystals were isolated by filtration, washed with isopropanol and dried in 
vacuo at 40.degree. C. overnight. The yield of p-nitrobenzyl 
7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate 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 
.alpha.-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-y 
l)-.alpha.-(1-hydroxyethylidene)acetate (4.54 g.) in tetrahydrofuran (60 
ml.) under a nitrogen atmosphere at 0.degree. C. was added triethylamine 
(1.6 ml.) followed by diphenylphosphoryl chloride (2.39 ml.) After 
stirring for 3 hours at 0.degree.-5.degree. C., morpholine (2.0 ml.) was 
added and the reaction mixture stirred for a further 3 hours at 
0.degree.-5.degree. C. The mixture was cooled to -30.degree. to 
-35.degree. C. and pyridine (0.81 ml.) added followed by dropwise addition 
of bromine (0.5 ml.) over a period of 5 minutes. The reaction mixture was 
stirred at -30.degree. to -35.degree. C. for 20 minutes and 5% 
hydrochloric acid (72 ml.) added, followed by methanol (60 ml.) 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 dichloromethane-acetone (9:1) as eluent to give 3.6 g. 
(76.6%) 4-methoxybenzyl 
7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate as a foam. TLC 
(silica) R.sub.f 0.5 (toluene-ethyl acetate 1:1). NMR .delta. CDCl.sub.3 
2.53 (s, 2H), 3.73 (s, 3H), 4.47 (s, 2H), 4.93 (d, 1H, J=4 Hz), 5.13 (s, 
2H), 5.50 (dd. 1H, J=4 and 9 Hz), 6.67-7.37 (m, 9H) and 7.53 (d, 1H, J=9 
Hz). 
EXAMPLE 23 
2,2,2-Trichloroethyl 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate 
To a stirred solution of 2,2,2-trichloroethyl 
.alpha.-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-y 
l)-.alpha.-(1-hydroxyethylidene)acetate (2.33 g.) in tetrahydrofuran (30 
ml.) under a nitrogen atmosphere at 20.degree. C. was added triethylamine 
(0.74 ml.) followed by diphenylphosphoryl chloride (1.09 ml.) After 
stirring for 2 hours, the reaction mixture was cooled to 0.degree. C., 
morpholine (0.92 ml.) was added and the reaction mixture stirred for 2 
hours at 0.degree.-5.degree. C. The mixture was cooled to -30.degree. to 
-35.degree. C. and pyridine (0.42 ml.) added followed by the dropwise 
addition of bromine (0.25 ml.) over a period of 5 minutes. The reaction 
mixture was stirred at -30.degree. to -35.degree. for 20 minutes and 5% 
hydrochloric acid (60 ml.) 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 eluent to give 1.8 g. 
(74.7%) 2,2,2-trichloroethyl 
7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate as a foam. TLC 
(silica) R.sub.f 0.2 (toluene-ethyl acetate 1:1). NMR .delta. CDCl.sub.3 
3.22 and 3.53 (ABq, 2H, J=18 Hz), 4.5 (s, 2H), 4.82 (s, 2H), 5.03 (d, 1H, 
J=4 Hz), 5.53 (dd, 1H, J=4 and 9 Hz), 6.7-7.37 (m, 5H) and 7.63 (d, 1H, 
J=9 Hz).