Process for the manufacture of 1-sulpho-2-oxoazetidine carboxylic acid intermediates via catalytic ester cleavage

The manufacture of 1-sulpho-2-oxazetidine derivatives of the formula ##STR1## in which Het is an optionally amino-substituted, 5- or 6-membered, aromatic heterocycle containing 1 or 2 nitrogen atoms and optionally also an oxygen or sulphur atom, R.sup.1 is hydrogen, lower alkyl, phenyl-lower alkyl, lower alkanoyl, lower alkoxycarbonyl, lower alkenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, phenyl-lower-alkoxycarbonyl-lower alkyl, nitrophenyl-lower-alkoxycarbonyl-lower alkyl or carboxy-lower alkyl and R.sup.2 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxycarbonyl, lower alkanoyloxy-lower alkyl, lower alkoxycarbonyl-lower alkenyl, hydroxyiminomethyl, lower alkoxyiminomethyl, carbamoyl, carbamoyl-lower alkenyl or carbamoyloxy-lower alkyl, the group .dbd.NOR.sup.1 being present at least partially in the syn-form, in racemic form or in the form of the 3S-enantiomer, and of readily hydrolyzable esters and pharmaceutically compatible salts of these compounds, by acylating a compound of the formula ##STR2## in which R.sup.20 equals R.sup.2 or can also represent a 2,2-dimethyl-1,3-dioxolan-4-yl group and R.sup.3 is hydrogen or sulpho, or a salt thereof with a thioester of the formula ##STR3## in which Het is as above and R.sup.10 has any of the values of R.sup.1 except carboxy-lower alkyl, and can also represent a tri-lower alkyl-silyl-lower-alkoxycarbonyl-lower alkyl group or a carboxy-lower alkyl group converted into a readily hydrolyzable ester group, and the group .dbd.NOR.sup.10 is present at least partially in the syn-form, and carrying out subsequent steps (N-sulphonation, conversion of R.sup.20 into R.sup.2, R.sup.10 into R.sup.1), some of which are optional. The invention also provides certain novel products of formula I and benzthiazolyl thioesters of formula III per se and the preparation of the benzthiazolyl thioesters by esterifying corresponding carboxylic acids. Finally, the invention provides a process for the preparation of carboxylic acids in which R.sup.1 is t-alkoxycarbonylmethyl. The compounds of formula I have antimicrobial activity.

The present invention is concerned with a process for the manufacture of 
1-sulpho-2-oxoazetidine derivatives of the formula 
##STR4## 
In which Het is an optionally amino-substituted, 5- or 6-membered, 
aromatic heterocycle containing 1 or 2 nitrogen atoms and optionally also 
an oxygen or sulphur atom, R.sup.1 is hydrogen, lower alkyl, phenyl-lower 
alkyl, lower alkanoyl, lower alkoxycarbonyl, lower alkenyl-lower alkyl, 
lower alkoxycarbonyl-lower alkyl, phenyl-lower-alkoxycarbonyl-lower alkyl, 
nitrophenyl-lower-alkoxycarbonyl-lower alkyl or carboxy-lower alkyl and 
R.sup.2 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower 
alkoxycarbonyl, lower alkanoyloxy-lower alkyl, lower alkoxycarbonyl-lower 
alkenyl, hydroxyiminomethyl, lower alkoxyiminomethyl, carbamoyl, 
carbamoyl-lower alkenyl or carbamoyloxy-lower alkyl, the group 
.dbd.NOR.sup.1 being present at least partially in the syn-form, 
in racemic form or in the form of the 3S-enantiomer, and of readily 
hydrolyzable esters and pharmaceutically compatible salts of these 
compounds. 
The heterocycle denoted by "Het" includes all 5- or 6-membered aromatic 
ring structures which contain 1 or 2 nitrogen atoms and which are 
optionally substituted by an amino group; for example, pyrazolyl groups 
such as 2-pyrazol-3-yl, amino-pyridyl groups such as 2-amino-6-pyridyl and 
amino-imidazolyl groups such as 2-amino-4-imidazolyl. They can optionally 
contain an oxygen atom such as, for example, in the case of amino-oxazolyl 
groups, for example 2-amino-4-oxazolyl, or a sulphur atom such as, for 
example, in the case of amino-thiadiazolyl groups such as 
5-amino-3-(1,2,4-thiadiazolyl) or, especially, in the case of 
amino-thiazolyl groups such as 2-amino-4-thiazolyl. 
The term "lower alkyl" alone or in combinations signifies an aliphatic 
hydrocarbon group which can be straight-chain or branched-chain and which 
preferably contains up to 7 carbon atoms such as, for example, methyl, 
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, 
n-pentyl, isopentyl, n-hexyl, n-heptyl etc. The term "lower alkoxy" has 
an analogous significance. The term "lower alkenyl" alone or in 
combinations signifies an olefinic hydrocarbon group which can be 
straight-chain or branched-chain and which preferably contains up to 7 
carbon atoms such as, for example, vinyl, allyl, isopropenyl, 2-methallyl, 
2-butenyl, 3-butenyl, 2-hexenyl, 2-heptenyl etc. The term "lower alkynyl" 
signifies an acetylenic hydrocarbon group which can be straight-chain or 
branched and which preferably contains up to 7 carbon atoms such as for, 
example, ethynyl, 1-propynyl, 2-propynyl, 2-hexynyl, 2-heptynyl etc. The 
term "lower alkanoyl" or "lower alkanoyloxy" signifies an aliphatic 
carboxylic acid residue which preferably contains up to 7 carbon atoms 
such as, for example, acetyl, propionyl, isobutyryl, acetoxy, propionyloxy 
and isobutyryloxy. 
Preferred goups denoted by R.sup.1 are hydrogen, methyl, ethyl, isopropyl, 
benzyl, 2-phenethyl, acetyl, propionyl, methoxycarbonyl, ethoxycarbonyl, 
methoxycarbonylmethyl, t-butoxycarbonylmethyl, carboxymethyl, 
1-methyl-1-t-butoxycarbonyl-ethyl, 1-methyl-1-benzhydryloxycarbonyl-ethyl, 
1-methyl-1-trityloxycarbonyl-ethyl, 
1-methyl-1-(p-nitrobenzyloxycarbonyl)-ethyl and 1-methyl-1-carboxyethyl; 
especially methyl, carboxymethyl and 1-methyl-1-carboxyethyl. 
Preferred groups denoted by R.sup.2 are methyl, ethyl, n-propyl, vinyl, 
allyl, ethynyl, 3-acetoxy-n-propyl, methoxycarbonyl, hydroxyiminomethyl, 
methoxyiminomethyl, 2-ethoxycarbonyl-1-methylvinyl, carbamoyl, 
carbamoylvinyl and carbamoyloxymethyl; especially carbamoyl and 
carbamoyloxymethyl. 
Preferred groups of the formula 
##STR5## 
are 2-pyrazol-3-yl-2-methoxyiminoacetyl, 
2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl, 
2-(2-amino-4-thiazolyl)-2-(carboxymethoxyimino)-acetyl, 
2-(2-amino-4-thiazolyl)-2-(1-methyl-1-carboxyethoxyimino)-acetyl, 
2-(2-amino-4-oxazolyl)-2-methoxyiminoacetyl, 
2-[5-amino-3-(1,3,4-thiadiazolyl)]-2-methoxyiminoacetyl, 
2-(2-amino-4-imidazolyl)-2-methoxyiminoacetyl and 
2-(2-amino-6-pyridyl)-2-methoxyiminoacetyl; especially 
2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl, 
2-(2-amino-4-thiazolyl)-2-(1-methyl-1-carboxyethoxyimino)-acetyl and 
2-(2-amino-4-thiazolyl)-2-(carboxymethoxyimino)-acetyl. 
The compounds of formula I can be present in various isomeric forms [e.g. 
cis, trans; syn(Z-form), anti(E-form); and as the 3S-enantiomer]. This 
also applies to the starting materials referred to hereinafter. 
The compounds of formula I can be present as free acids or as betains or 
also as pharmaceutically compatible salts which are obtained by salt 
formation with a basic salt former on the free 1-sulpho group or on a 
carboxy group which may be present in the substituent in the 3-position. 
Examples of basic salt formers are inorganic cations such as sodium and 
potassium ions, basic amino acids such as arginine, ornithine, lysine or 
histidine and polyhydroxyalkylamines such as N-methylglucamine, 
diethanolamine, triethanolamine etc. 
Carboxy groups present in a compound of formula I or salts thereof can be 
converted by appropriate esterification into readily hydrolyzable ester 
groups. Such readily hydrolyzable ester groups, which are cleaved in the 
body into the corresponding free carboxy groups, are, for example, 
.alpha.-(lower alkoxy)-lower-alkoxycarbonyl groups such as 
methoxymethoxycarbonyl and .alpha.-methoxyethoxycarbonyl, lower 
alkylthiomethoxycarbonyl groups such as methylthiomethoxycarbonyl, 
.alpha.-(lower alkanoyl)-lower-alkoxycarbonyl groups such as 
acetoxymethoxycarbonyl, pivaloyloxymethoxycarbonyl and 
.alpha.-pivaloyloxyethoxycarbonyl, .alpha.-(lower 
alkoxycarbonyl)-lower-alkoxycarbonyl groups such as 
ethoxycarbonyloxymethoxycarbonyl, t-butoxycarbonylmethoxycarbonyl and 
.alpha.-ethoxycarbonyloxyethoxycarbonyl, lactonyl groups such as 
phthalidyl and thiophthalidyl, or the group of the formula 
##STR6## 
Examples of compounds of formula I which can be manufactured in accordance 
with the present invention are the end products described in Examples 1-50 
hereinafter not only in the form in which they are present in the Examples 
(3S-enantiomer or racemates), but also in the form of readily hydrolyzable 
esters and pharmaceutically compatible salts of these compounds. 
Especially preferred compounds of formula I are the compounds of the 
formula 
##STR7## 
wherein R.sup.11 is methyl, carboxymethyl or 1-methyl-1-carboxyethyl and 
R.sup.21 is carbamoyl or carbamoyloxymethyl, 
in racemic form or in the form of the 3S-enantiomer and the corresponding 
readily hydrolyzable esters and pharmaceutically compatible salts of these 
compounds. 
Especially preferred among these compounds are 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(1-carboxy-1-methylethoxy]-imino 
]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid and 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxymethoxy)imino]acetamido] 
-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid and their 
pharmaceutically compatible salts. 
The following are further sub-groups of compounds of formula I: 
those in which Het, R.sup.1 and R.sup.2 are as above, with the proviso that 
when simultaneously Het is 2-amino-4-thiazolyl and R.sup.2 is lower alkyl, 
lower alkanoyloxy-lower alkyl, carbamoyloxy-lower alkyl, lower 
alkoxycarbonyl, lower alkoxyiminomethyl or carbamoyl, then R.sup.1 is 
hydrogen, lower alkyl, phenyl-lower alkyl, lower alkanoyl, lower 
alkoxycarbonyl or lower alkenyl-lower alkyl; 
those in which Het, R.sup.1 and R.sup.2 are as above, with the proviso that 
when simultaneously Het is 2-amino-4-thiazolyl and R.sup.2 is 
carbamoyloxy-lower alkyl, then R.sup.1 is hydrogen, lower alkyl, 
phenyl-lower alkyl, lower alkanoyl, lower alkoxycarbonyl or lower 
alkenyl-lower alkyl; 
in each case in racemic form or in the form of the 3S-enantiomer, and the 
corresponding readily hydrolyzable esters and pharmaceutically compatible 
salts of these compounds. 
The compounds of formula I and their readily hydrolyzable esters and 
pharmaceutically compatible salts are manufactured in accordance with the 
invention by acylating a compound of the formula which is present in 
racemic form or in the form of the 3S-enantiomer 
##STR8## 
in which R.sup.20 is equal to R.sup.2 or can also represent a 
2,2-dimethyl-1,3-dioxolan-4-yl group and R.sup.3 is hydrogen or sulpho, 
or a salt thereof with a thioester of the formula 
##STR9## 
in which Het is as above and R.sup.10 is equal to R.sup.1 except 
carboxy-lower alkyl and can also represent a tri-lower 
alkyl-silyl-lower-alkoxycarbonyl-lower alkyl group or a carboxy-lower 
alkyl group converted into a readily hydrolyzable ester group, and the 
group .dbd.NOR.sup.10 is present at least partially in the syn-form, 
to give a compound of the formula which is present in racemic form or in 
the form of the 3S-enantiomer 
##STR10## 
in which R.sup.10, R.sup.20, R.sup.3 and Het are as above and the group 
.dbd.NOR.sup.10 is present at least partially in the syn-form, 
subsequently sulphonating a resulting product in which R.sup.3 is hydrogen, 
converting a 2,2-dimethyl-1,3-dioxolan-4-yl group R.sup.20 which may be 
present into the hydroxyiminomethyl group, a lower alkoxyiminomethyl group 
or the carbamoylvinyl group, converting a tri-lower 
alkyl-silyl-lower-alkoxycarbonyl-lower alkyl group R.sup.10 into 
carboxy-lower alkyl, if desired converting a lower alkoxycarbonyl-lower 
alkyl, phenyl-lower-alkoxycarbonyl-lower alkyl or nitrophenyl-lower 
alkoxycarbonyl-lower alkyl group denoted by R.sup.10 or R.sup.1 into 
carboxy-lower alkyl and, if desired, converting a resulting product into a 
pharmaceutically compatible salt. 
The reaction of a compound of formula II with a compound of formula III is 
conveniently carried out in an inert organic solvent, for example in a 
chlorinated hydrocarbon such as methylene chloride or chloroform, in an 
ether such as tetrahydrofuran or dioxan, in an ester such as ethyl 
acetate, in a ketone such as acetone, in an aprotic solvent such as 
acetonitrile, dimethylformamide or dimethylacetamide or in a mixture of 
one of these solvents with water. The reaction is conveniently carried out 
at a temperature between about -40.degree. C. and +60.degree. C., 
advantageously between -15.degree. C. and +25.degree. C., especially 
between 0.degree. C. and 20.degree. C. The reaction is conveniently 
carried out using about stoichiometric amounts of the reactants or a 
slight excess of the thioester of formula III. The reaction is 
advantageously carried out in the presence of a base such as, for example, 
an organic amine such as triethylamine or N-methylmorpholine or an alkali 
metal bicarbonate such as sodium bicarbonate. 
Products obtained in which R.sup.3 is hydrogen are subsequently 
sulphonated. The sulphonation can be carried out in a manner known per se 
by reaction with sulphur trioxide or a reactive derivative thereof, for 
example with complexes of sulphur trioxide and an organic base such as 
pyridine, dimethylformamide, picoline etc. The reaction is carried out, 
for example, at about -10.degree. C. to +80.degree. C. in an inert organic 
solvent, for example in an ether such as dioxan, in an ester such as ethyl 
acetate, in a chlorinated hydrocarbon such as methylene chloride, in 
acetonitrile, in dimethylformamide or in pyridine. 
Where R.sup.20 in the reaction product of formula Ib is the 
2,2-dimethyl-1,3-dioxolan-4-yl group, this is converted into the 
hydroxyiminomethyl group or into a lower alkoxyiminomethyl group in 
accordance with the following Scheme: 
##STR11## 
The reactions are preferably carried out as follows: 
V.fwdarw.VI: In a lower alkanol such as methanol or in an aqueous ether 
such as aqueous dioxan or tetrahydrofuran in the presence of an acid 
catalyst such as a sulphonated ion exchanger, p-toluenesulphonic acid and 
the like, preferably at room temperature to about 60.degree. C. 
VI.fwdarw.VII: In aqueous alkali metal metaperiodate (e.g. sodium 
metaperiodate) at about room temperature. 
VII.fwdarw.VIII: With hydroxylamine in an inert organic solvent such as 
methylene chloride, preferably in the presence of an organic base such as 
pyridine and at about room temperature. 
VII.fwdarw.IX: With a O-lower-alkylhydroxylamine in analogy to 
VII.fwdarw.VIII. 
VII.fwdarw.XIII: With carbomoylmethylenetriphenylphosphorane in an inert 
solvent (e.g. methylene chloride) and at about room temperature. 
VII.fwdarw.IX: With a lower alkyl iodide in an inert organic solvent such 
as methylene chloride, preferably in the presence of an organic base such 
as pyridine or N-ethyldiisopropylamine and at about room temperature. 
Where R.sup.10 in the reaction product of formula Ib is a tri-lower 
alkyl-silyl-lower-alkoxycarbonyl-lower alkyl group, for example the 
[[2-(trimethylsilyl)ethoxy]carbonyl]methyl group or the 
1-methyl-1-[[2-(trimethylsilyl)ethoxy]carbonyl]ethyl group, this is 
converted into the corresponding carboxy-lower alkyl group, conveniently 
by treatment with a quaternary organic fluoride such as tetrabutylammonium 
fluoride. The temperature preferably lies in the proximity of room 
temperature and the reaction is conveniently carried out in an inert 
organic solvent such as tetrahydrofuran or methanol. 
Where R.sup.10 or R.sup.1 in the reaction product of formula Ib or I is a 
lower alkoxycarbonyl-lower alkyl group, for example the 
t-butoxycarbonylmethyl group or the 1-methyl-1-(t-butoxycarbonyl)-ethyl 
group, this can be converted, if desired, into the corresponding 
carboxy-lower alkyl group by treatment with a strong acid such as 
trifluoroacetic acid (optionally in the presence of anisole), hydrochloric 
acid or p-toluenesulphonic acid at a low temperature such as -10.degree. 
C. to room temperature. 
Where R.sup.10 or R.sup.1 in the reaction product of formula Ib or I is a 
phenyl-lower alkoxycarbonyl-lower alkyl group, for example the 
benzyloxycarbonylmethyl group or the 1-methyl-1-(benzyloxycarbonyl)-ethyl 
group, or a nitrophenyl-lower-alkoxycarbonyl-lower alkyl group, for 
example the p-nitrobenzyloxycarbonylmethyl group or the 
1-methyl-1-(p-nitrobenzyloxycarbonyl)-ethyl group, this can be converted, 
if desired, into the corresponding carboxy-lower alkyl group by catalytic 
hydrogenation with, for example, palladium/carbon or 
palladium/diatomaceous earth as the catalyst, for example in a lower 
alkanol such as ethanol at about 0.degree.-80.degree. C. 
The manufacture of the salts of the compounds of formula I can be carried 
out in a manner known per se; for example, by reacting an acid of formula 
I with an equivalent amount of the desired base, optionally in the form of 
an ion exchanger. The reaction is conveniently carried out in a solvent 
such as water or an organic solvent such as ethanol, methanol, acetaone, 
ethyl acetate and the like. The temperature at which the salt formation is 
carried out is not critical, but it generally lies in the range of about 
0.degree.-50.degree. C., preferably at room temperature. 
The thioesters of formula III can be prepared by reacting a carboxylic acid 
of the formula 
##STR12## 
in which R.sup.10 and Het are as above, with dithio-bis-benzthiazole in 
the presence of a tri-(lower-alkyl)-phosphite and a base or in the 
presence of triphenylphosphine. The reaction is conveniently carried out 
at a temperature between about -30.degree. C. and +50.degree. C., 
advantageously between about -20.degree. C. and +25.degree. C. The 
esterification is advantageously carried out in an organic solvent, for 
example in acetonitrile or in methylene chloride. The preferred embodiment 
comprises carrying out the reaction in the presence of a tri-(lower 
alkyl)-phosphite and a base. Triethyl phosphite is preferably used as the 
tri-(lower alkyl)-phosphate and an organic base, especially a tertiary 
organic base such as triethylamine, N-ethyl-diisopropylamine or, 
preferably, N-methylmorpholine, is preferably used as the base. 
The preparation of readily hydrolyzable esters of the thioesters of formula 
III can be carried out in a manner known per se by esterifying the 
carboxy-lower alkyl group R.sup.10 (as previously described in the 
products of formula Ib or I) and subsequently reacting the product with an 
esterifying agent yielding the readily hydrolyzable ester group, for 
example with the corresponding halide (e.g. the iodide), conveniently in 
the presence of a base, for example in the presence of an alkali metal 
hydroxide or alkali metal carbonate or in the presence of an organic amine 
such as triethylamine. The esterification is preferably carried out in an 
inert organic solvent such as dimethylacetamide, hexamethylphosphoric acid 
triamide, dimethyl sulphoxide or dimethylformamide. The esterification is 
preferably carried out at a temperature in the range of about 
0.degree.-40.degree. C. 
Referred thioesters of formula III are those of the formula 
##STR13## 
in which R.sup.12 is lower alkoxy-carbonyl-lower alkyl, 
phenyl-lower-alkoxycarbonyl-lower alkyl, nitrophenyl-lower 
alkoxycarbonyl-lower alkyl or tri-lower 
alkyl-silyl-lower-alkoxycarbonyl-lower alkyl. 
Especially preferred thioesters of formula IIIb are those in which R.sup.12 
is lower alkoxycarbonylmethyl, phenyl-lower-alkoxycarbonylmethyl, 
nitrophenyl-lower-alkoxycarbonylmethyl or tri-lower 
alkyl-silyl-lower-alkoxycarbonylmethyl, especially 
2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(t-butoxycarbonyl)methoxy]imino]-acetic 
acid 2-benzthiazolyl thioester and 
2-(2-amino-4-thiazolyl)-2-[[(Z)-(p-nitrobenzyloxycarbonyl)methoxy]imino]-a 
cetic acid 2-benzthiazolyl thioester; and also those thioesters of formula 
IIIb in which R.sup.12 is lower alkoxycarbonyl-1-methylethyl, 
1-(phenyl-lower-alkoxycarbonyl)-1-methylethyl, 
1-(nitrophenyl-lower-alkoxycarbonyl)-1-methylethyl or 1-(tri-lower 
alkyl-silyl-lower-alkoxycarbonyl)-1-methylethyl, especially 
2-(2-amino-4-thiazolyl)-2-[[(Z)-1-[2-(trimethylsilyl)ethoxycarbonyl]-1-met 
hylethoxy]imino]-acetic acid 2-benzthiazolyl thioester, 
2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(p-nitrobenzyloxycarbonyl)-1-methylethox 
y]imino]-acetic acid 2-benzthiazolyl thioester and 
2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(t-butoxycarbonyl)-1-methylethoxy]imino] 
-acetic acid 2-benzthiazolyl thioester. 
A particular problem arises in the preparation of the acids of formula IV 
in which R.sup.10 is t-alkoxycarbonyl-lower alkyl, for example the group 
--CH.sub.2 --COOC(R).sub.3 in which R represents C.sub.1-3 -alkyl. The 
conventional manner for the preparation of these compounds, namely the 
reaction of the methyl or ethyl ester of the corresponding hydroxyimino 
compound with a halo-acetic acid C(R).sub.3 -ester and subsequent 
saponification, does not yield the desired acid of formula IV in which 
R.sup.10 is --CH.sub.2 --COOC(R).sub.3, because the group --COOC(R).sub.3 
is saponified. It is therefore necessary to adopt a different procedure. 
The aforementioned acid of formula IV in which R.sup.10 is --CH.sub.2 
--COOC(R).sub.3 can, however, be prepared in good yield when in place of 
the aforementioned methyl or ethyl ester there is used the allyl or 
p-nitrobenzyl ester, i.e. by cleaving off the group R.sup.5 in an ester of 
the formula 
##STR14## 
in which Het is as above, R is C.sub.1-3 -alkyl and R.sup.5 is allyl or 
p-nitrobenzyl. 
The term "C.sub.1-3 -alkyl" embraces methyl, ethyl, n-propyl and isopropyl. 
The preferred group of the formula --COOC(R).sub.3 is that in which R is 
methyl, i.e. t-butoxycarbonyl. 
According to one embodiment of the process provided by the invention, an 
ester of formula X in which R.sup.5 is p-nitrobenzyl is cleaved 
hydrogenolytically. This cleavage is preferably carried out with the aid 
of hydrogen and a metal catalyst, preferably Raney-nickel, whereby the 
reaction can be accelerated by the addition of an organic base such as 
triethylamine. A lower alkanol such as methanol or ethanol is preferably 
used as the solvent. The reaction is preferably carried out at a 
temperature between about 0.degree. C. and 80.degree. C., especially at 
room temperature. 
According to a further embodiment of the process provided by the invention, 
an ester of formula X in which R.sup.5 is allyl is cleaved catalytically. 
This cleavage can be carried out by the action of a palladium compound in 
the presence of triphenylphosphine or a tri-(lower-alkyl)-phosphite (e.g. 
triethyl phosphite). As palladium compounds there come into consideration 
palladium/carbon and palladium salts, especially salts with hydrohalic 
acids such as hydrochloric acid or hydrobromic acid or with lower 
alkanecarboxylic acids such as acetic acid or propionic acid. 
Palladium-organic complexes with triphenylphosphine or a 
tri-(lower-alkyl)-phosphite such as triethyl phosphite, also come into 
consideration, whereby the reaction can also be carried out without the 
further addition of triphenylphosphine or a tri-(lower-alkyl)-phosphite. A 
further reaction partner is an alkali metal alkanoate, (e.g. sodium 
acetate) or, preferably, sodium-2-ethylcaproate, or also an organic base 
such as triethylamine or N-methylmorpholine. The reaction can be carried 
out at a temperature between about 0.degree. C. and 100.degree. C., but 
preferably at room temperature (when palladium/carbon is used the reaction 
is carried out at a somewhat higher temperature; about 
50.degree.-80.degree. C.). The reaction is preferably carried out in an 
inert organic solvent (e.g. in ethyl acetate or methylene chloride). 
The above p-nitrobenzyl esters of formula X can be prepared from a 
Het-2-(Z)-hydroxyimino-acetic acid by the addition of p-nitrobenzyl 
bromide or p-nitrobenzyl chloride and an alkali metal iodide and 
subsequently of a compound of the general formula 
EQU Hal--CH.sub.2 --COO--C(R).sub.3 XI 
in which R has the above significance and Hal represents chlorine, bromine 
or iodine, 
in the presence of a base such as an alkali carbonate, triethylamine or 
N-ethyldiisopropylamine and an alkali metal iodide. The allyl esters of 
formula X can be prepared starting from diketene, chlorine gas and allyl 
alcohol, which are converted into allyl 4-chloroacetoacetate. The latter 
is nitrosated with nitrous acid and subsequently converted with thiourea 
into an allyl Het-2-(Z)-hydroxyimino-acetate which is thereupon converted 
into the allyl ester of formula X by reaction with the above compound of 
formula XI in the presence of a base such as an alkali carbonate, 
triethylamine or N-ethyldiisopropylamine. 
The starting materials of formula II can be prepared according to various 
methods. For the preparation of optically uniform compounds of formula II 
having the 3S-cis configuration, one can start from 
isopropylidene-L-glyceraldehyde in accordance with the following Formulae 
Schemes (Schemes I-VII). The preparation of optically uniform compounds of 
formula II having the 3S-trans configuration is illustrated in Schemes V 
and VI: 
##STR15## 
______________________________________ 
Abbreviations used in Schemes I-VII 
______________________________________ 
DMB = 2,4-dimethoxybenzyl 
Ft = phthalimido 
Et = ethyl 
Me = methyl 
TSOH = p-toluenesulphonic acid 
THF = tetrahydrofuran 
PrOH = n-propanol 
DMSO = dimethyl sulphoxide 
Py = pyridine 
Py.SO.sub.3 = 
sulphur trioxide-pyridine complex 
Z = benzyloxycarbonyl 
Trt = trityl 
Ac = lower alkanoyl (e.g. acetyl). 
______________________________________ 
A sub-group of novel compounds of formula I comprises those of the formula 
##STR16## 
in which R.sup.1 is as in formula I, R.sup.4 is the same as Het in formula 
I and R.sup.21 is the same of R.sup.2 given in formula I, the group 
.dbd.NOR.sup.1 being present at least partially in the syn-form, with the 
proviso that at least one of the following two conditions is fulfilled: 
(a) R.sup.4 =2-amino-4-oxazolyl, 2-amino-6-pyridyl, 2-amino-4-imidazolyl, 
5-amino-3-(1,2,4-thiadiazolyl) or 2-pyrazol-3-yl, 
(b) R.sup.21 =hydroxyiminomethyl, lower alkoxyiminomethyl, lower 
alkoxycarbonyl-lower alkenyl or carbamoyl-lower alkenyl, 
in racemic form or in the form of the 3S-enantiomer, and readily 
hydrolyzable esters and pharmaceutically compatible salts of these 
compounds. 
Sub-groups of compounds of formula Ic comprise those of the formula 
##STR17## 
in which R.sup.1 and R.sup.2 are as in formula I above and R.sup.4 is 
2-amino-4-oxazolyl, 2-amino-6-pyridyl, 2-amino-4-imidazolyl, 
5-amino-3-(1,2,4-thiadiazolyl) or 2-pyrazol-3-yl, the group .dbd.NOR.sup.1 
being present at least partially in the syn-form, 
in racemic form or in the form of the 3S-enantiomer, and readily 
hydrolyzable esters and pharmaceutically compatible salts of these 
compounds; and those of the formula 
##STR18## 
in which R.sup.1 and Het are as in formula I and R.sup.21 is 
hydroxyiminomethyl, lower alkoxyiminomethyl, lower alkoxycarbonyl-lower 
alkenyl or carbamoyl-lower alkenyl, the group .dbd.NOR.sup.1 being present 
at least partially in the syn-form, 
in racemic form or in the form of the 3S-enantiomer, and readily 
hydrolyzable esters and pharmaceutically compatible salts of these 
compounds. 
The novel 1-sulpho-2-oxoazetidine derivatives of formula Ic and their 
readily hydrolyzable esters and pharmaceutically compatible salts can be 
manufactured in accordance with the invention by 
(a) reacting a carboxylic acid of the formula 
##STR19## 
in which R.sup.10 is as in formula III above and R.sup.40 is the same as 
R.sup.4 in formula Ic above, whereby, however, an amino group present can 
be protected, and the group .dbd.NOR.sup.10 is present at least partially 
in the syn-form, 
or a functional derivative thereof with a compound of the formula which is 
present in racemic form or in the form of the 3S-enantiomer 
##STR20## 
in which R.sup.21 is as in formula Ic above, or with a salt thereof and 
subsequently cleaving off an amino protecting group which may be present, 
or 
(b) sulphonating a compound of the formula which is present in racemic form 
or in the form of the 3S-enantiomer 
##STR21## 
in which R.sup.1 and R.sup.21 are as in formula I or formula Ic above and 
R.sup.41 is the same as R.sup.4 in formula Ic above, whereby, however, an 
amino group present is protected, and the group .dbd.NOR.sup.1 is present 
at least partially in the syn-form, 
or a salt thereof and subsequently cleaving off the amino protecting group, 
or 
(c) for the manufacture of a compound of formula Ic in which R.sup.21 is 
hydroxyiminomethyl, lower alkoxyiminomethyl or carbamoylvinyl, reacting a 
compound of the formula which is present in racemic form or in the form of 
the 3S-enantiomer 
##STR22## 
in which R.sup.4 is as in formula Ic above and R.sup.10 is as in formula 
Ib above, and the group .dbd.NOR.sup.10 is present at least partially in 
the syn-form, 
with hydroxylamine, with a O-lower-alkylhydroxylamine or with 
carbamoylmethylenetriphenylphosphorane and, if desired, lower alkylating a 
product obtained in which R.sup.21 is hydroxyiminomethyl, or 
(d) for the manufacture of a compound of formula Ic in which R.sup.1 is 
carboxy-lower alkyl, converting the group R.sup.13 in a compound of the 
formula which is present in racemic form or in the form of the 
3S-enantiomer 
##STR23## 
in which R.sup.21 and R.sup.40 are as above and R.sup.13 is tri-lower 
alkyl-silyl-lower-alkoxycarbonyl-lower alkyl, lower alkoxycarbonyl-lower 
alkyl, phenyl-lower-alkoxycarbonyl-lower alkyl or 
nitrophenyl-lower-alkoxycarbonyl-lower alkyl, the group .dbd.NOR.sup.13 
being present at least partially in the syn-form, into carboxy-lower 
alkyl, or 
(e) converting a compound of formula Ic or a readily hydrolyzable ester 
thereof into a pharmaceutically compatible salt. 
The reaction of a carboxylic acid of formula IVb or a functional derivative 
thereof with a compound of formula IIa can be carried out in a manner 
known per se. Where the free carboxylic acid of formula IVb is used, the 
reaction is preferably carried out in the presence of a condensation agent 
which can be, for example, a substituted carbodiimide such as 
N,N-dicyclohexylcarbodiimide, a quaternary 2-halopyridinium salt such as 
2-chloro-1-methylpyridinium iodide or 
1-chloro-N,N,2-trimethyl-1-propenamine. As functional derivatives of the 
carboxylic acids of formula IVb there come into consideration acid halides 
(e.g. acid chlorides), acid anhydrides (e.g. mixed anhydrides with 
C.sub.1-7 -alkanecarboxylic acids such as acetic acid), acid azides, 
active amides (e.g. amides with pyrazole, imidazole, benztriazole), active 
esters (e.g. a C.sub.1-7 -alkyl, methoxymethyl, 2-propynyl, 4-nitrophenyl 
or hydroxysuccinimide ester) or active thioesters (e.g. esters with 
2-pyridinethiol or 2-benzthiazolylthiol). The 2-benzthiazolyl thioesters 
are described above. 
The reaction of a compound of formula IVb or a functional derivative 
thereof with a compound of formula IIa is conveniently carried out in an 
inert organic solvent, for example in a chlorinated hydrocarbon such as 
methylene chloride or chloroform, in an ether such as tetrahydrofuran or 
dioxan, in an ester such as ethyl acetate, in a ketone such as acetone, in 
an aprotic solvent such as acetonitrile, dimethylformamide or 
dimethylacetamide or in a mixture of one of these solvents with water. The 
reaction is conveniently carried out at a temperature between about 
-40.degree. C. and +60.degree. C., advantageously between -15.degree. C. 
and +25.degree. C., especially between 0.degree. and 20.degree. C. The 
reaction is conveniently carried out using about stoichiometric amounts of 
the reactants or using a slight excess of the carboxylic acid of formula 
IVb or of the functional derivative thereof. The reaction is 
advantageously carried out in the presence of a base such as, for example, 
in the presence of an organic amine such as triethylamine or 
N-methylmorpholine or in the presence of an alkali metal bicarbonate such 
as sodium bicarbonate. 
Where the group R.sup.40 in the starting material of formula IVa or 
functional derivative thereof contains an amino substituent, then this can 
preferably remain unprotected (since thereby one reaction step, namely the 
subsequent cleavage of the amino protecting group, can be dispensed with). 
However, R.sup.40 can also contain a protected amino group. The amino 
protecting group can be a conventional amino protecting group; for 
example, a protecting group which is cleavable by acid hydrolysis such as 
t-butoxycarbonyl, benzhydryl, trityl or formyl, a protecting group which 
is cleavable by basic hydrolysis such as trifluoroacetyl or a 
chloroacetyl, bromoacetyl or iodoacetyl group which can be cleaved off 
using thiourea. The amino group can also be protected by salt formation 
with a mineral acid (e.g. hydrochloric acid). After the reaction of a 
carboxylic acid of formula IVb with a compound of formula IIa or of a 
functional derivative of a carboxylic acid of formula IVb with a compound 
of formula IIa, an amino protecting group which may be present is cleaved 
off. Protecting groups which are cleavable by acid hydrolysis are 
preferably removed with the aid of a lower alkanecarboxylic acid which, if 
desired, can be halogenated. In particular, there is used hydrochloric 
acid, formic acid or trifluoroacetic acid (the latter optionally in the 
presence of anisole) or also pyridinium hydrochloride. This cleavage is 
usually carried out at room temperature, although it can also be carried 
out at a slightly higher or slightly lower temperature (e.g. a temperature 
in the range of about 0.degree. C. to +40.degree. C.). Protecting groups 
which are cleavable using alkali are generally hydrolyzed using dilute 
aqueous caustic alkali at 0.degree. C. to 30.degree. C. The chloroacetyl, 
bromoacetyl and iodoacetyl protecting groups can be cleaved off using 
thiourea in an acidic, neutral or alkaline medium at about 
0.degree.-30.degree. C. 
In accordance with variant (b) of the process in accordance with the 
invention, a compound of formula XII is sulphonated. This sulphonation can 
be carried out in a manner known per se by reaction with sulphur trioxide 
or a reactive derivative thereof, for example complexes of sulphur 
trioxide with an organic base such as pyridine, dimethylformamide, 
picoline etc. The reaction is carried out, for example, at about 
-10.degree. C. to +80.degree. C. in an inert organic solvent, for example 
in an ether such as dioxan, in an ester such as ethyl acetate, in a 
chlorinated hydrocarbon such as methylene chloride or in acetonitrile, 
dimethylformamide or pyridine. 
In variant (b) of the process in accordance with the invention, the amino 
group present in R.sup.41 is protected. The amino protecting groups are of 
the same kind as the amino protecting groups in the starting materials of 
formula IVb and they are also cleaved off in the same manner as described 
earlier. 
The reaction of a compound of formula VIIa with hydroxylamine yields a 
compound of formula Ic in which R.sup.21 is hydroxyiminomethyl. This 
reaction is preferably carried out in an inert organic solvent (e.g. 
methylene chloride), preferably in the presence of an organic base such as 
pyridine. The reaction is preferably carried out at about 
0.degree.-60.degree. C., especially at about room temperature. If an 
O-lower-alkylhydroxylamine is used in place of hydroxylamine, there is 
obtained a compound of formula Ic in which R.sup.21 represents lower 
alkoxyiminomethyl. 
If the starting material of formula VIIa is reacted with 
carbamoylmethylenetriphenylphosphorane there is obtained a compound of 
formula Ic in which R.sup.21 is carbamoylvinyl. This reaction is 
preferably carried out in an inert solvent such as methylene chloride, 
tetrahydrofuran or dioxan and at a temperature between about room 
temperature and the boiling point of the mixture. 
If desired, a thus-obtained compound of formula Ic in which R.sup.21 is 
hydroxyiminomethyl can be lower alkylated. This lower alkylation is 
preferably carried out using a C.sub.1-7 -alkyl iodide, advantageously in 
an inert organic solvent such as methylene chloride, preferably in the 
presence of an organic base such as pyridine. The lower alkylation is 
preferably carried out at a temperature of about 0.degree.-60.degree. C., 
especially at room temperature. 
The conversion of the group R.sup.13 in a compound of formulae If into 
carboxy-lower alkyl is carried out in the same manner as described above 
in connection with the compounds of formulae Ib and I. This also applies 
for the manufacture in accordance with the invention of pharmaceutically 
compatible salts of the compounds of formula Ic. 
The compounds of formula I and their readily hydrolyzable esters and 
pharmaceutically compatible salts have a broad antimicrobial spectrum of 
activity, especially against gram-negative microorganisms such as, for 
example, pathogens of the family Enterobacteriacae, for example 
Escherichia coli, Proteus spp., Serratia spp. and Psuedomonas aeruginosa. 
These products can accordingly be used for the treatment and prophylaxis of 
infectious diseases. A daily dosage of about 10-600 mg/kg body weight 
comes into consideration for adults. 
The minimum inhibitory concentration (MIC, .mu.g/ml) in vitro of some 
representative products is given in the Tables hereinafter in which 
specific compounds obtained in the Examples hereinafter are referred to. 
TABLE 
__________________________________________________________________________ 
Organism Example 7 
Example 11a 
Example 13 
Example 27 
Example 29 
Example 31 
Example 
Example 
__________________________________________________________________________ 
35d 
E. cloacae 15M 
0.4 3.1 1.6 0.5 0.12 0.25 0.4 0.2 
S. marcescens 80315 
0.4 3.1 3.1 0.5 0.12 0.25 0.4 0.2 
Pr. mirabilis 2117 
.ltoreq.0.05 
0.8 0.8 0.06 .ltoreq.0.03 
0.06 0.2 0.1 
Pr. vulgaris 1028 
.ltoreq.0.05 
0.8 0.4 .ltoreq.0.06 
.ltoreq.0.03 
0.12 0.2 0.1 
Ps. aeruginosa 799/61 
0.8 1.6 0.2 0.12 0.12 0.06 0.1 .ltoreq.0.1 
E. coli UB 1005 
0.2 1.6 0.8 0.5 0.12 0.12 0.4 0.2 
K. pneumoniae 418 
0.1 0.8 0.8 1 0.12 0.12 0.8 .ltoreq.0.1 
K. oxytoca 22812 
-- 1.6 0.8 1 0.12 0.5 0.2 0.4 
__________________________________________________________________________ 
Organism Example 36a 
Example 44 
Example 45 
Example 46 
Example 47 
Example 48 
Example 
Example 
__________________________________________________________________________ 
50 
E. cloacae 15M 
0.5 4 0.5 0.25 16 0.5 4 16 
S. marcescens 80315 
2 8 1 0.25 32 0.5 8 32 
Pr. mirabilis 2217 
0.12 4 0.5 0.12 4 0.5 2 16 
Pr. vulgaris 1028 
0.25 2 0.25 0.12 2 0.5 16 64 
Ps. aeruginosa 799/61 
0.25 1 0.12 0.5 4 0.12 0.5 8 
E. coli UB 1005 
0.5 4 0.25 0.25 4 0.25 2 8 
K. pneumoniae 418 
0.25 4 0.5 0.06 8 0.25 4 8 
K. oxytoca 22812 
2 4 0.5 4 4 0.5 64 &gt;128 
__________________________________________________________________________ 
TABLE 
______________________________________ 
Organism Example 27 
Example 29 
______________________________________ 
Ent. cloaceae 4W-142 
2 4 
C. freundii 4f52 4 8 
P. vulgaris 10610 
.ltoreq.0.25 
0.25 
Ps. aeruginosa 5F 81-1 
8 4 
S. marcescens 1 .times. 172 
2 0.5 
______________________________________ 
The products provided by the present invention can be used as medicaments; 
for example, in the form of pharmaceutical preparations which contain them 
in admixture with a pharmaceutical, organic or inorganic inert carrier 
material which is suitable for parenteral administration. 
The following Examples illustrate the present invention:

EXAMPLE 1 
(a) 18 mg (0.087 mmol) of (3S,4S)-amino-2-oxo-4-propyl-1-azetidinesulphonic 
acid, 32 mg (0.095 mmol) of 
2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino-acetic acid 2-benzthiazolyl 
thioester and 14.5 mg (0.143 mmol) of triethylamine are stirred in 1 ml of 
dichloromethane for 2 hours. After evaporation of the solvent, the residue 
is taken up in 5 ml of water, washed five times with 5 ml of ether each 
time and lyophilized. There are obtained 35 mg of 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-2-oxo-4- 
propyl-1-azetidinesulphonic acid triethylamine salt as a colourless 
amorphous product. 
IR (KBr, cm.sup.-1): 3384, 3312, 3207, 1763, 1670, 1621, 1537, 1266, 1230, 
1044. 
NMR (DMSO, ppm): 9.24 (d, J=8.5 Hz, 1H) 7.17 (s, 2H); 6.64 (s, 1H); 4.50 
(dd, J=2.5/8.5 Hz; 1H), 3.79 (s, 3H), 3.59 (m, 2H); 3.07 (q, J=7.5 Hz, 
6H), ca. 2 (m, br, 1H); 1.4 (m, br, 1H); 1.17 (t, J=7.5 Hz, 9H); 0.88 (m, 
3H). 
The 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino-acetic acid 2-benzthiazolyl 
thioester used as the starting material can be prepared as follows: 
(b) 3.93 g of triphenylphosphine and 5 g of dithio-bis-benzthiazole are 
suspended in 50 ml of dichloromethane and the suspension is stirred at 
room temperature for about 30 minutes. After cooling to 0.degree. C., 
2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino-acetic acid are added and the 
mixture is stirred at 0.degree. C. for 3 to 4 hours. For the working-up, 
the insoluble material is filtered off under suction and washed with a 
small amount of cold methylene chloride. The solid is suspended in 25 ml 
of ethyl acetate, the suspension is stirred at 0.degree. C. for 30 
minutes, the solid material is filtered off under suction and washed with 
ethyl acetate. After recrystallization from 
tetrahydrofuran/dichloromethane, there is obtained 
2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino-acetic acid 2-benzthiazolyl 
thioester of melting point 128.degree.-130.degree. C. 
The (3S,4S)-3-amino-2-oxo-4-propyl-1-azetidinesulphonic acid used as the 
starting material can be prepared as follows: 
(c) 84 ml of a 1.0N solution of ethylmagnesium bromide in tetrahydrofuran 
are added dropwise to 10.8 g (84 mmol) of 3-(2-methoxy-2-propoxy)-propyne 
dissolved in 80 ml of dry tetrahydrofuran. The solution is held at room 
temperature by cooling with an ice-bath and, after the addition of the 
ethylmagnesium bromide, the mixture stirred at room temperature for 30 
minutes. The mixture is added dropwise at -70.degree. C. to -40.degree. C. 
to 8.5 g (20.9 mmol) of 
(3R,4R)-4-methylsulphonyl-3-tritylamino-2-azetidinone dissolved in 50 ml 
of dry tetrahydrofuran and the resulting mixture is stirred at -30.degree. 
C. for 30 minutes and at room temperature for 1.75 hours. The brown 
solution obtained is diluted with 1 l of ether and the ether phase is 
washed with 300 ml of saturated aqueous ammonium chloride solution and 
subsequently three times with 300 ml of water each time, dried and 
evaporated. The residue is chromatographed over 500 g of silica gel with 
t-butyl methyl ether/n-hexane (1:1). After a forerun of 1.8 l, there are 
obtained 0.9 l of eluate containing 1.2 g (13%) of substance A, 0.9 l of 
eluate containing 3.0 g (32%) of a mixture of substance A and substance B 
and finally 1.8 l of eluate containing 3.2 g (34%) of substance B. 
Substance A: Acetone methyl 
3-[(3S,4R)-2-oxo-3-tritylamino-4-azetidinyl]-2-propynyl acetal. 
NMR (CDCL.sub.3, ppm): 1.23 (s, 6H), 3.03 (s, 3H), 3.08 (d, J=10.5 Hz, 1H), 
3.57 (d, tr, J=2 Hz or 5 Hz, 1H) 3.94 (d, J=2 Hz, 1H), 4.39 (dd, J=5 or 
10.5 Hz, 1H), 5.76 (s, 1H), 7.15-7.6 (m, 15H). 
IR (KBr, cm.sup.-1 :) 706, 748, 1034, 1070, 1490, 1956, 1766, 3318, 
cm.sup.-1. 
Substance B: Acetone methyl 
3-[(3S,4S)-2-oxo-3-tritylamino-4-azetidinyl]-2-propynyl acetal. 
NMR (CDCl.sub.3, ppm): 1.30 (s, 6H), 2.87 (d, J=9 Hz, 1H), 3.14 (s, 3H), 
3.39 (q, J=2 Hz, 1H), 4.26 (dd, J=2 or 9 Hz, 1H), 5.82 (s, 1H), 7.15-7.55 
(m, 15H). 
(d) 2.4 g (5.3 mmol) of acetone methyl 
3-[(3S,4S)-2-oxo-3-tritylamino-4-azetidinyl]-2-propynyl acetal are stirred 
at room temperature for 15 minutes in 50 ml of ether and 50 ml of 1% 
aqueous picric acid. The aqueous phase is separated and the ether phase is 
washed with saturated aqueous sodium bicarbonate solution and with water, 
dried and evaporated. The residue corresponds to 1.8 g (89%) of 
3-[(3S,4S)-2-oxo-3-tritylamino-4-azetidinyl]-2-propynol. 
NMR (CDCl.sub.3, ppm): 2.3 (s, br, 1H), 2.8 (s, br, 1H), 3.35 (1H), 4.0 
(2H), 4.2 (1H), 6.45 (s, 1H), 7.0-7.8 (m, 15H). 
0.88 g (1.9 mmol) of acetone methyl 
3-[(3S,4R)-2-oxo-3-tritylamino-4-azetidinyl]-2-propynyl acetal are 
converted in the above manner with picric acid into 0.67 g (90%) of 
3-[(3S,4R)-2-oxo-3-tritylamino-4-azetidinyl]-2-propynol. 
NMR (CDCl.sub.3, ppm): 1.56 (1H), 3.0 (d, J=11 Hz, 1H), 3.72 (d, tr, J=1.5 
or 5 Hz, 1H), 4.07 (d, J=4.5 Hz, 2H), 4.46 (dd, J=5 and 11 Hz, 1H), 5.84 
(s, 1H), 7.2-7.6 (m, 15H). 
(e) 2.03 g (5.31 mmol) of 
3-[(3S,4R)-2-oxo-3-tritylamino-4-azetidinyl]-2-propynol, 0.65 g (6.37 
mmol) of acetic anhydride and 504 mg (6.38 mmol) of pyridine are stirred 
at room temperature for 3.5 hours in 10 ml of methylene chloride. The 
solution is subsequently diluted with 100 ml of methylene chloride, poured 
into 50 ml of ice-water, the aqeuous phase is separated, the methylene 
chloride phase is washed twice with 50 ml of water each time, dried and 
evaporated. The residue consists of 1.15 g (51%) of 
3-[(3S,4R)-2-oxo-3-tritylamino-4-acetidinyl]-2-propynyl acetate. 
NMR (CDCl.sub.3, ppm): 1.91 (s,3H), 3.01 (d, J=11 Hz, H), 3.64 (d, br, J=2 
Hz and 5 Hz, 1H), 4.46 (dd, J=5 and 11 Hz, 1H), 4.53 (d, J=2 Hz, 2H), 5.68 
(s, 1H), 7.2-7.6 (m, 15H). 
IR (KBr, cm.sup.-1): 705, 744, 1236, 1488, 1595, 1732, 1757, 2239, 2336, 
3336. 
From 3-(3S,4S)-2-oxo-3-tritylamino-4-azetidinyl]-2-propynol there is 
obtained in the same manner 
3-[(3S,4S)-2-oxo-3-tritylamino-4-azetidinyl]-2-propynyl acetate. 
NMR (CDCl.sub.3, ppm): 2.07 (s, 3H), 2.84 (d, J=9 Hz, 1H), 3.39 (q, J=2 Hz, 
1H), 4.29 (dd, J=2 and 9 Hz, 1H), 4.50 (d, J=2 Hz, 2H), 5.81 (s, 1H), 
7.2-7.6 (m, 15H). 
IR (KBr, cm.sup.-1): Identical with 
3-(3S,4R)-2-oxo-3-tritylamino-4-azetidinyl]-2-propynyl acetate. 
(f) 410 mg (0.97 mmol) of 
3-[(3S,4R)-2-oxo-3-tritylamino-4-azetidinyl]-2-propynyl acetate dissolved 
in 40 ml of methanol are hydrogenated over 100 mg of platinum oxide for 10 
minutes. The catalyst is filtered off under suction and the filtrate is 
evaporated. The residue is chromatographed over 70 g of silica gel with 
t-butyl methyl ether/n-hexane (2:1). After a forerun of 200 ml, there are 
obtained 120 ml of eluate containing 180 mg (50%) of 
(3S,4R)-4-propyl-3-tritylamino-2-azetidinone. After a further 500 ml, 
there are obtained 420 ml of eluate containing 67 mg (16%) of 
3-[(3S,4R)-2-oxo-3-tritylamino-4-azetidinyl]-propyl acetate. 
3-[(3S,4R)-2-Oxo-3-tritylamino-4-azetidinyl]-propyl acetate: 
NMR (CDCl.sub.3, ppm): 0.9-1.6 (m, 4H), 2.0 (s, 3H), 2.6 (1H), 3.2 (1H), 
3.85 (2H), 4.4 (1H), 6.2 (1H), 7.2-7.6 (15H). 
(3S,4R)-4-Propyl-3-tritylamino-2-azetidinone: 
NMR (CDCl.sub.3, ppm): 0.5-1.3 (7H), 2.7 (1H), 3.1 (1H), 4.35 (1H), 6.1 
(1H), 7.1-7.7 (15H). 
420 mg (1 mmol) of 3-[(3S,4S)-2-oxo-3-tritylamino-4-azetidinyl]-2-propynyl 
acetate are hydrogenated in the same manner with platinum oxide and the 
product is chromatographed over 70 g of silica gel with t-butyl methyl 
ether/n-hexane (1:1). After 125 ml, there are obtained 300 mg of 
(3S,4S)-4-propyl-3-tritylamino-2-azetidinone and, after 275 ml, there are 
obtained 87 mg of 3-[(3S,4S)-2-oxo-3-tritylamino-4-azetidinyl]-propyl 
acetate. 
3-[(3S,4S)-2-Oxo-3-tritylamino-4-azetidinyl]-propyl acetate: 
NMR (CDCl.sub.3, ppm) 0.5-1.4 (4H), 2.0 (s, 3H), 2.7 (1H), 3.0 (1H), 6.15 
(1H), 7.0-7.7 (15H). 
(3S,4S)-4-Propyl-3-tritylamino-2-azetidinone: 
NMR (CDCl.sub.3, ppm): 0.4-1.3 (7H), 3.0 (2H, 3.7 (1H), 6.3 (1H), 7.2-7.7 
(15H). 
(g) 180 mg (0.49 mmol) of (3S,4S)-4-propyl-3-tritylamino-2-azetidinone and 
239 mg (1.5 mmol) of sulphur trioxide-pyridinium complex are stirred at 
room temperature for 21 hours in 2 ml of dry dioxan. The residue is 
separated by centrifugation, dissolved in 10 ml of water, neutralized with 
sodium bicarbonate and the aqueous solution is extracted with methylene 
chloride. The methylene chloride phase is evaporated, the residue is 
dissolved in 1 ml of methylene chloride and treated with 40 .mu.l of 
formic acid (98%-100%). The product precipitates and is filtered off under 
suction. There are obtained 18 mg (18%) of 
(3S,4S)-3-amino-2-oxo-4-propyl-1-azetidinesulphonic acid which can be used 
directly for the reaction in accordance with the first paragraph of this 
Example. 
In an analogous manner, from (3S,4R)-4-propyl-3-tritylamino-2-azetidinone 
there is obtained crude 
(3S,4R)-3-amino-2-oxo-4-propyl-1-azetidinesulphonic acid which is likewise 
used directly. 
EXAMPLE 2 
(a) In the same manner as described in Example 1(a), from 20 mg of 
(3S,4R)-3-amino-4-(3-acetoxypropyl)-2-oxo-1-azetidine sulphonic acid there 
are obtained 20 mg of 
(3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-(3-ace 
toxypropyl)-2-oxo-1-azetidinesulphonic acid triethylamine salt. For 
purification, this salt is chromatographed on reverse-phase silica gel 
using water/methanol (4:1) for the elution. 6 mg of pure product are 
obtained as a lyophilizate. 
IR (KBr, cm.sup.-1): 3410, 3328, 3240, 1772, 1741, 1681 1545, 1247, 1045. 
NMR (DMSO, ppm): 9.27 (d, J=9 Hz), 7.1 (s, br. 2H); 6.69 (s, 1H), 5.10 (dd, 
J=5 and 9 Hz, 1H); ca. 3.9 (m, 3H); 3.80 (s, 3H); 3.03 (q, J=7 Hz, 6H); 
2.00 (s, 3H), 1.3-1.8 (m, 4H); 1.17 (t, J=7 Hz, 9H). 
The (3S,4R)-3-amino-4-(3-acetoxypropyl)-2-oxo-1-acetidinesulphonic acid 
used as the starting material can be prepared as follows: 
(b) 67 mg (0.16 mmol) of 
3-[(3S,4R)-2-oxo-3-tritylamino-4-azetidinyl]-propyl acetate are converted 
in an analogous manner to that described in Example 4(d) with sulphur 
trioxide-pyridinium complex into 
(3S,4R)-3-amino-4-(3-acetoxypropyl)-2-oxo-1-azetidinesulphonic acid which 
is acylated directly in the above reaction. 
EXAMPLE 3 
(a) In the same manner as described in Example 1(a), from 36 mg of 
(3S,4S)-3-amino-4-(3-acetoxypropyl)-2-oxo-1-azetidinesulphonic acid there 
are obtained 37 mg of 
(3S,4S)-3-[(Z)-(2-amino-4-thiazolyl-2-(methoxyimino)acetamido]-4-(3-acetox 
ypropyl)-2-oxo-1-azetidinesulphonic acid triethylamine salt as an amorphous 
lyophilizate. 
IR (KBr, cm.sup.-1): 3404, 3321, 1766, 1735, 1671, 1621, 1538, 1242, 1043. 
NMR (DMSO, ppm): 9.29 (J=8.5 Hz, 1H), 7.20 (s, br, 1H); 6.68 (s, 1H); 4.51 
(dd, J=2.5 and 8.5 Hz, 1H); ca. 4.0 (m, 2H), 3.82 (s, 3H), 3.07 (q, J=ca. 
7.5 Hz, 6H); 2.0 (s, 3H); ca. 1.5 (m, 3H); 1.17 (t, J=7.5 Hz, 9H). 
(3S,4S)-3-amino-4-(3-acetoxypropyl)-2-oxo-1-azetidinesulphonic acid used as 
the starting material can be prepared as follows: 
(b) 87 mg (0.20 mmol) of 
3-[(3S,4S)-2-oxo-3-tritylamino-4-azetidinyl]-propyl acetate are converted 
in a manner analogous to that described in Example 1(g) or 4(d) into 
(3S,4S)-3-amino-4-(3-acetoxypropyl)-2-oxo-1-azetidinesulphonic acid which 
is used directly as the crude product. 
EXAMPLE 4 
38 mg (0.2 mmol) of (3S,4R)-3-amino-4-ethynyl-2-oxo-1-azetidinesulphonic 
acid, 77 mg (0.22 mmol) of 
2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino-acetic acid 2-benzthiazolyl 
thioester and 56 .mu.l (0.4 mmol) of triethylamine are stirred at room 
temperature for 2 hours in 1 ml of acetone/water (4:1). The mixture is 
then filtered and evaporated. The residue is chromatographed over 
reverse-phase silica gel with water/methanol (2:1). After lyophilization, 
there are obtained 66 mg of amorphous 
(3S,4R)-3-[(Z)-2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-ethynyl-2 
-oxo-1-azetidinesulphonic acid triethylamine salt. 
IR (KBr, cm.sup.-1): 3440, 1771, 1672, 1601, 1531, 1282, 1253, 1055. 
NMR (CDCl.sub.3, ppm): 9.50 (d, J: 8 Hz; 1H); 7.18 (s, 2H); 6.80 (s, 1H); 
5.22 (dd, J=5.5 and 8 Hz; 1H), 4.61 (dd, J=2 and 5.5 Hz, 1H) 3.82 (s, 3H) 
3.45 (d, J=2 Hz, 1H). 
The (3S,4R)-3-amino-4-ethynyl-2-oxo-1-azetidine-sulphonic acid used as the 
starting material can be prepared as follows: 
(b) 30.1 g (0.306 mol) of trimethylsilylacetylene are dissolved in 300 ml 
of dry tetrahydrofuran. 290 ml of 1.05N ethylmagnesium bromide solution in 
tetrahydrofuran are added dropwise at 20.degree. C. within 30 minutes 
while cooling with ice. The solution is stirred at 20.degree. C. for 2 
hours and subsequently added dropwise at -70.degree. C. to -40.degree. C. 
to 31.3 g (0.077 mol) of 
(3R,4R)-4-methylsulphonyl-3-tritylamino-2-azetidinone in 200 ml of dry 
tetrahydrofuran. The solution is stirred at -30.degree. C. 30 minutes and 
subsequently at 20.degree. C. for 60 minutes and then diluted with ether. 
The ether phase is washed with saturated aqueous ammonium chloride 
solution and subsequently with water, dried and evaporated. The residue is 
chromatographed on 1.5 kg of silica gel with t-butyl methyl ether/n-hexane 
(2:3). After a forerun of 4 l, there are obtained 1 l of eluate containing 
substance A and subsequently 4 l of eluate containing substance B. The 
fractions are evaporated. 
Substance A: 10.3 g (32%) of 
(3S,4R)-3-tritylamino-4-[2-(trimethylsilyl)ethynyl]2-azetidinone. 
NMR (CDCl.sub.3, ppm): 0.08 (s, 9H), 3.23 (d, J=10 Hz, 1H), 3.59 (d, J=5 
Hz, 1H), 4.30 (dd, J=5 and 10 Hz, 1H), 5.88 (1H), 7.2-7.6 (15H). 
Substance B: 15.3 g (47%) of 
(3S,4S)-3-tritylamino-4-[2-(trimethylsilyl)ethynyl]2-azetidinone. 
NMR (CDCl.sub.3, ppm): 0.10 (s, 9H), 2.8 (1H), 3.40 (d, J=2 Hz, 1H), 4.23 
(1H), 5.86 (1H), 7.1-7.5 (15H). 
(c) 10.0 g (0.024 mol) of 
(3S,4S)-3-tritylamino-4-[2-(trimethylsilyl)ethynyl]-2-azetidinone and 1.5 
g (0.026 mol) of potassium fluoride are stirred at 20.degree. C. for 1.5 
hours in 100 ml of ethanol and 100 ml of dimethyl sulphoxide. The solution 
is diluted with ether, the ether phase is washed with water, dried and 
evaporated. 8.1 g (85%) of crude 
(3S,4S)-4-ethynyl-3-tritylamino-2-azetidinone are obtained. 
NMR (CDCl.sub.3, ppm): 1.8 (1H), 2.16 (d, J=2 Hz, 1H), 3.33 (tr, J=2 Hz, 
1H), 4.30 (1H), 5.87 (1H), 7.2-7.5 (15H). 
IR (KBr, cm.sup.-1): 706, 751, 1490, 1599, 1625, 1769, 2.24, 3306. 
In an analogous manner, from 9.4 g of 
(3S,4R)-3-tritylamino-4-[2-(trimethylsilyl)ethynyl]-2-azetidinone there 
are obtained 8.8 g (91%) of (3S,4R)-4-ethynyl-3-tritylamino-2-azetidinone. 
NMR (CDCl.sub.3, ppm): 2.35 (d, J=2 Hz, 1H), 3.09 (d, J=10.5 Hz, 1H), 3.58 
(dd, J=2 and 5 Hz, 1H), 4.38 (dd, J=5 and 10.5 Hz, 1H), 5.88 (1H), 7.1-7.6 
(15H). 
IR (KBr, cm.sup.-1): 705, 732, 1490, 1728, 1770, 2122, 3298. 
(d) 3.5 g (10 mmol) of (3S,4R)-4-ethynyl-3-tritylamino-2-azetidinone and 
4.0 g (25 mmol) of sulphur trioxide pyridinium complex are stirred at 
80.degree. C. for 15 minutes in 40 ml of pyridine. The solution is treated 
with 200 ml of ether and the resulting precipitate is dissolved in 100 ml 
of methylene chloride. After the addition of 5 ml of concentrated formic 
acid, there is obtained an oily precipitate which, after decanting off the 
solvent and adding ether, changes into white crystals. 1.19 g (58%) of 
(3S,4R)-3-amino-4-ethynyl-2-oxo-1-azetidinesulphonic acid are isolated. 
NMR (DMSO, ppm): 3.75 (d, J=1.5 Hz, 1H), 4.7 (2H, 7-8 (3H). 
IR (KBr, cm.sup.-1): 1197, 1255, 1504, 1525, 1607, 1788, 2130, 3268, 3514. 
Elemental analysis: Calculated: C 31.58, H 3.18, N 14.73, S 16.86%. Found: 
C 32.33, H 3.40, N 13.42, S 16.24 H.sub.2 O 1.46%. 
(e) 530 mg (1.5 mmol) of (3S,4S)-4-ethynyl-3-tritylamino-2-azetidinone and 
600 mg (3.75 mmol) of sulphur trioxide-pyridinium complex are stirred at 
room temperature for 21 hours in 6 ml of dry dioxan. The insoluble residue 
is filtered off under suction and the filtrate is treated with 30 ml of 
ether. The product is obtained as a gum-like precipitate which, after 
decanting off the solvent and scratching in the presence of a small amount 
of ether, changes into crystals. These crystals are filtered off under 
suction and correspond to 481 mg of 
(3S,4S)-4-ethynyl-2-oxo-3-tritylamino-1-azetidinesulphonic acid pyridinium 
salt. This product is dissolved in 20 ml of methanol, the solution is held 
at room temperature for 4 days, subsequently evaporated and the residue is 
filtered off under suction with a small amount of methanol. 180 mg (63%) 
of (3S,4S)-3-amino-4-ethynyl-2-oxo-1-azetidinesulphonic acid are obtained. 
NMR (DMSO, ppm): 3.63 (d, J=2 Hz, 1H), 4.38 (tr, J=2 Hz, 1H), 4.46 (d, J=2 
Hz, 1H). 
IR (KBr, cm.sup.-1): 1256, 1621, 2125, 2654, 3217. 
EXAMPLE 5 
(a) 60 mg (0.31 mmol) of 
(3S,4R)-3-amino-2-oxo-4-vinyl-1-azetidinesulfphonic acid, 120 mg (0.34 
mmol) of 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino-acetic acid 
2-benzthiazolyl thioester and 63 mg (0.62 mmol) of triethylamine are 
stirred at room temperature for 3 hours in 1.5 ml of acetone/water (4:1). 
The mixture is evaporated and the residue is chromatographed over 
reverse-phase silica gel using acetonitrile as the eluting agent. After 
evaporation, there are obtained 63 mg of 
(3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-2-oxo-4- 
vinyl-1-azetidinesulphonic acid triethylamine salt as an amorphous 
colourless powder. 
IR (KBr, cm.sup.-1): 3400, 1765, 1671, 1536, 1275, 1044. 
NMR (DMSO, ppm): 9.2 (d, J=9 Hz, 1H), 7.18 (s, br, 2H); 6.64 (s, 1H), ca. 
5.75 (m, 1H); ca. 5.2 (m, 3H) 4.4 (dd, J=6 and 8 Hz, 1H), 3.80 (s, 3H), 
3.08 (q, J= Hz, 6H), 1.17 (t, J=7 Hz, 9H). 
The foregoing triethylamine salt is dissolved in 6 ml of water and stirred 
for 3 hours with 5 ml of Amberlite CG 120 (Na.sup.+ form). After 
filtration, the product is lyophilized to give 26 mg of 
(3S,4R)-3-[2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-2-oxo-4-viny 
l-1-azetidinesulphonic acid sodium salt. 
NMR (DMSO, ppm): 9.22 (d, J=9 Hz, 1H); 7.21 (s, 2H); 6.64 (s, 1H); 5.84 (m, 
1H), 5.38 (m, 1H), 5.18 (m, 2H) 4.40 (m, 1H, 3.80 (s, 3H). 
The (3S,4R)-3-amino-2-oxo-4-vinyl-1-azetidinesulphonic acid used as the 
starting material can be prepared as follows: 
(b) 1.55 g (4.4 mmol) of (3S,4R)-4-ethynyl-3-tritylamino-2-azetidinone are 
dissolved in 200 ml of methanol and the solution is hydrogenated for 2 
minutes over 5% palladium/calcium carbonate catalyst (deactivated with 
lead). The catalyst is filtered off under suction, the filtrate is 
evaporated and the residue is chromatographed over 200 g of silica gel 
with ether/petroleum ether (2:1). After a forerun of 1.5 l, there are 
obtained 210 ml of eluate containing 0.50 g of 
(3S,4R)-3-tritylamino-4-vinyl-2-azetidinone. The next 1.4 l of eluate 
contain 0.80 g of a mixture of (3S,4R)-3-tritylamino-4-vinyl-2-azetidinone 
and (3S,4R)-4-ethyl-3-tritylamino-2-azetidinone. This mixture is 
chromatographed on silica gel impregnated with 30 g of silver nitrate. 
0.10 g of (3S,4R)-4-ethyl-3-tritylamino-2-azetidinone is eluted with 400 
ml of ether and 0.53 g of (3S,4R)-3-tritylamino-4-vinyl-2-azetidinone is 
eluted with 700 ml of ethyl acetate and 500 ml of acetone. The total yield 
is 66% of (3S,4R)-3-tritylamino-4-vinyl-2-acetidinone. 
NMR (CDCl.sub.3, ppm): 2.58 (d, J=ca. 10 Hz, 1H), 3.71 (d, tr, J=5 Hz and 1 
Hz, 1H), 4.35-4.83 (2H), 4.95-5.25 (2H), 5.75 (1H), 7.2-7.6 (15H). 
IR (KBr, cm.sup.-1): 705, 747, 272, 900, 923, 1000, 1489, 1595, 1638, 1764, 
3261. 
(c) 470 mg (1.33 mmol) of (3S,4R)-3-tritylamino-4-vinyl-2-azetidinone are 
sulphonated with sulphur trioxide-pyridinium complex and subsequently 
detritylated with formic acid in a manner analagous to that described in 
Example 4(d). 63 mg (25%) of 
(3S,4R)-3-amino-2-oxo-4-vinyl-1-azetidinesulphonic acid are obtained. 
NMR (DMSO, ppm): 4.44 (tr, H=6.5 Hz, 1H), 4.57 (d, J=6.5 Hz, 1H), 5.39 
(dd, J=2 and 10 Hz, 1H), 5.54 (dd, J=2 and 17 Hz, 1H), 5.74-6.13 (m, 1H), 
8.51-9 (m, 3H). 
IR (KBr, cm.sup.-1): 951, 994, 1200, 1229, 1254, 1529, 1770, 2640. 
EXAMPLE 6 
In the same manner as described in Example 5, from 110 mg of 
(3S,4S)-3-amino-4-ethynyl-2-oxo-1-azetidinesulphonic acid there are 
obtained 58 mg of 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-ethyny 
l-2-oxo-1-azetidinesulphonic acid triethylamine salt. 
Elemental analysis for C.sub.17 H.sub.26 N.sub.6 O.sub.6 S.sub.2 (474.55): 
Calculated: C 43.03, H 5.52, N 17.71%. Found: C 42.54, H 5.47, N 17.48%. 
IR (KBr, cm.sup.-1): 3265, 2125, 1776, 1672, 1619, 1535, 1275, 1245, 1046. 
NMR (DMSO, ppm): 9.41 (d, J=8 Hz, 1H); 7.21 (s, 2H); 6.73 (s, 1H), 4.72 
(dd, J=3 and 8 Hz 1H), 4.21 (dd, J=2 and 3 Hz, 1H), 3.82 (s, 3H), 3.52 (d, 
J=2 Hz, 1H); 3.09 (q, 7.5 Hz, 6H); 1.17 (t, 7.5 Hz, 9H). 
EXAMPLE 7 
(a) In the same manner as described in Example 5, from 
(3S,4R)-3-amino-4-ethyl-2-oxo-1-azetidinesulphonic acid there is obtained 
sodium 
(3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-ethyl- 
2-oxo-1-azetidinesulphonate. 
NMR (DMSO, ppm): 9.27 (d, J=9 Hz, 1H), 7.20 (s, 2H), 6.70 (s, 1H), 5.08 
(dd, J=6 and 9 Hz, 1H), 3.80 (s, 3H), 3.74 (m, 1H), 1.87 (m, 1H), 1.54 (m, 
1H), 0.83 (t, J=6.5 Hz, 3H). 
The (3S,4R)-3-amino-4-ethyl-2-oxo-1-azetidinesulphonic acid used as the 
starting material can be prepared as follows: 
(b) 2.0 g (5.7 mmol) of (3S,4R)-4-ethynyl-3-tritylamino-2-azetidinone are 
dissolved in 250 ml of methanol and the solution is hydrogenated for 15 
minutes over 2.0 g of 5% palladium/carbon. The catalyst is filtered off 
and the filtrate is evaporated. The residue corresponds to 1.4 g (69%) of 
(3S,4R)-4-ethyl-3-tritylamino-2-acetidinone. 
NMR (CDCl.sub.3, ppm): 0.65-1.25 (5H), 2.61 (d, J=8 Hz, 1H), 3.08 (1H), 
4.38 (dd, J=5 and 8 Hz, 1H), 5.89 (1H), 7.1-7.6 (15H). 
IR (KBr, cm.sup.-1): 703, 755, 1491, 1596, 1752, 3266. 
(c) (3S,4R)-4-Ethyl-3-tritylamino-2-azetidinone is converted in a manner 
analogous to that described in Example 4 into 
(3S,4R)-3-amino-4-ethyl-2-oxo-1-azetidinesulphonic acid which is reacted 
directly as the crude product. 
EXAMPLE 8 
(a) In the same manner as described in Example 5, from 80 mg of 
(3S,4S)-3-amino-2-oxo-4-vinyl-1-azetidinesulphonic acid there are obtained 
88 mg of 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-2-oxo-4- 
vinyl-1-azetidinesulphonic acid triethylamine salt as an amorphous 
lyophilizate. 
Elemental analysis for C.sub.17 H.sub.28 N.sub.6 O.sub.6 S.sub.2 (476.57): 
Calculated: C 42.85, H 5.92, N 17.63%. Found: C 42.38, H 5.82, N 17.41%. 
IR (KBr, cm.sup.-1): 3406, 3318, 3211, 1767, 1670, 1621, 1536, 1271, 1237, 
1044. 
NMR (DMSO, ppm): 10.33 (d, H=8 Hz, 1H), 7.19 (s, br, 2H), 6.70 (s, 1H), 
6.03 (ddd, J=17,10 and 7 Hz 1H), 5.37 (dd, J=1.5 and 17 Hz, 1H), 5.17 (dd, 
J=1.5 and 10 Hz, 1H), 4.56 (dd, J=3 and 8 Hz, 1H), 4.11 (dd, J=3 and 7 Hz, 
1H), 3.82 (s, 3H), 3.10 (m, 6H), 1.18 (t, J=7 Hz, 9H). 
The (3S,4S)-3-amino-2-oxo-4-vinyl-1-azetidinesulphonic acid used as the 
starting material can be prepared as follows: 
(b) 2.5 g (7.1 mmol) of (3S,4S)-4-ethynyl-3-tritylamino-2-azetidinone are 
dissolved in 250 ml of methanol and the mixture is hydrogenated for 10 
minutes over 1.5 g of 5% palladium/calcium carbonate catalyst (deactivated 
with lead). The catalyst is filtered off, the filtrate is evaporated and 
the residue is chromatographed over 200 g of silica gel with 
N-hexane/t-butyl methyl ether (1:2). 1.86 g (74%) of 
(3S,4S)-3-tritylamino-4-vinyl-2-acetidinone are obtained from the fraction 
600 ml to 900 ml of eluate. 
NMR (CDCl.sub.3, ppm): 2.8 (1H), 3.40 (1H), 3.76 (1H), 4.78 (d, J=2 Hz, 
3H), 5.78 (s, 1H), 7.2-7.6 (15H). 
IR (KBr, cm.sup.-1): 704, 748, 922, 1489, 1595, 1638, 1756, 3316. 
(c) 1.0 g (2.82 mmol) of (3S,4S)-3-tritylamino-4-vinyl-2-azetidinone is 
sulphonated with sulphur trioxide pyridinium complex and detritylated with 
methanol in a manner analogous to that described in Example 4(d). 87 mg 
(16%) of (3S,4S)-3-amino-2-oxo-4-vinyl-1-azetidinesulphonic acid are 
isolated. 
NMR (DMSO, ppm): 4.14-4.29 (2H), 5.27 (dd, J=2 and 10 Hz, 1H), 5.44 (dd, 
J=2 and 17 Hz, 1H), 5.79-6.20 (1H), 8-9 (br, 3H). 
IR (KBr, cm.sup.-1): 924, 981, 1272, 1307, 1513, 1596, 1763, 2604, 2679, 
3092. 
EXAMPLE 9 
In the same manner as described in Example 5, from 70 mg of 
(3S,4S)-3-amino-4-ethyl-2-oxo-1-azetidinesulphonic acid there are obtained 
152 mg of 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-ethyl- 
2-oxo-1-azetidinesulfphonic acid triethylamine salt as an amorphous 
lyophilizate. 
IR (KBr, cm.sup.-1): 3403, 3316, 3206, 1763, 1667, 1621, 1537, 1243, 1044. 
NMR (DMSO, ppm): 9.27 (d, J=8.5 Hz, 1H), 7.18 (s, br 2H), 6.66 (s, 1H), 
4.52 (dd, J=2.5 and 8.5 Hz, 1H), ca. 3.5 (m, 1H), 3.82 (s, 3H), 3.09 (q, 
J=7.5 Hz, 6H), ca. 1.8 br, 2H), 1.17 (t, J=7.5 Hz, 9H), 0.89 (tr, J=8 Hz, 
3H). 
The (3S,4S)-3-amino-4-ethyl-2-oxo-1-azetidinesulphonic acid used as the 
starting material can be prepared as follows: 
(b) 2.5 g (7.1 mmol) of (3S,4S)-4-ethynyl-3-tritylamino-2-azetidinone are 
hydrogenated for 10 minutes over 2.5 g of 5% palladium/carbon, the 
catalyst is filtered off, the filtrate is evaporated and the residue is 
chromatographed over 200 g of silica gel with t-butyl methyl 
ether/n-hexane (1:1). After a forerun of 750 ml, there are isolated with 1 
l of eluant 1.63 g (65%) of (3S,4S)-4-ethyl-3-tritylamino-2-azetidinone. 
NMR (CDCl.sub.3, ppm): 0.53-0.58 (5H), 2.7 (1H), 2.9 (1H), 3.75 (1H), 6.0 
(1H), 7.2-7.6 (15H). 
IR (KBr, cm.sup.-1): 705, 747, 1490, 1596, 1753, 3260. 
0.94 g (2.64 mmol) of (3S,4S)-4-ethyl-3-tritylamino-2-azetidinone are 
reacted in a manner analogous to that described in Example 4(d). 176 mg 
(34%) of (3S,4S)-3-amino-4-ethyl-2-oxo-1-azetidinesulphonic acid are 
obtained. 
NMR (DMSO, ppm): 0.91 (tr, J=7.5 Hz, 3H), 1.44-2.1 (2H), 3.60-3.78 (1H), 
4.07 (d, J=2.5 Hz, 1H), 8.69 (3H). 
IR (KBr, cm.sup.-1): 1206, 1268, 1512, 1599, 1760, 3092. 
EXAMPLE 10 
In a manner analogous to that described in Example 5 there can also be 
obtained 
(3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-2-oxo-4- 
propyl-1-azetidinesulphonic acid sodium salt. 
Elemental analysis for C.sub.12 H.sub.16 N.sub.5 O.sub.6 S.sub.2 Na: 
Calculated: C 34.87, H 3.90, N 16.94%. Found: C 34.54, H 3.91, N 16.43%. 
IR (KBr, cm.sup.-1): 3423, 3281, 3219, 1762, 1656, 1236. 
NMR (DMSO), ppm): 0.9 (3H, t, CH.sub.3), 1.10-1.95 (4H, m, --CH.sub.2 
--CH.sub.2 --), 3.85 (3H, s, OCH.sub.3), 3.85 (1H, dt, --CH--CH.sub.2 
--CH.sub.2 C.sub.3), 5.05 (1H, dd, 6 and 9 Hz, NH--CH) 6.73 (1H, s, 
S--CH.dbd.), 7.15 (2H, s, NH.sub.2), 9.25 (1H, d, 9 Hz, CONH)--. 
EXAMPLE 11 
(a) In the same manner as described in Example 1, from 224 mg of 
rac,cis-3-amino-4-methoxycarbonyl-2-oxo-1-azetidinesulphonic acid and 367 
mg of 2-(2-amino-4-oxazolyl)-2-methoxyimino-acetic acid 2-benzthiazolyl 
thioester (7:2 mixture of the Z:E isomers) there are obtained 259 mg of 
rac,cis-3-[2-(2-amino-4-isoxazolyl)-2-(methoxyimino)acetamido]-4-(methoxyc 
arbonyl)-2-oxo-1-azetidinesulphonic acid triethylamine salt as an amorphous 
lyophilizate (7:2 mixture of the Z:E isomers). 
IR (KBr, cm.sup.-1): 3410, 3333, 3288, 3223, 1758, 1658, 1559, 1539, 1285, 
1237, 1048. 
NMR (DMSO, ppm): 9.41 (d, J=8 Hz, 1H), 7.37 (s, 1H), 6.83 (s, br, 2H), 5.34 
(dd, J=5.5 and 8 Hz, 1H), 4.44 (d, J=5.5 Hz, 1H), 3.77 (s, 3H), 3.58 (s, 
3H), 3.06 (q, J=7.3 Hz, 6H), 1.16 (t, J=7.3 Hz, 9H). 
The 2-(2-amino-4-oxazolyl)-2-methoxyimino-acetic acid 2-benzthiazolyl 
thioester used as the starting material can be prepared as follows: 
(b) A solution of 50.4 g (0.2 mol) of ethyl 
2-methoxyimino-4-bromoacetoacetate [M. Ochiai et al., Chem. Pharm. Bull. 
25, 3115 (1977)] and 60.1 g (1 mol) of urea in 200 ml of dimethylformamide 
is heated to 100.degree. C. for 30 minutes. Thereafter, the mixture is 
evaporated, the residue is taken up in 800 ml of water, neutralized with 
sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate 
extract is chromatographed on silica gel with acetonitrile/methylene 
chloride (1:1). There is obtained ethyl 
2-(2-amino-4-oxazolyl)-2-methoxyimino-acetate in a yield of 26%; melting 
point 120.degree. C. (decomposition). 
NMR (DMSO, ppm): 7.77 (s, 1H), 6.93 (s, 2H), 4.15 (q, J=7 Hz, 2H), 3.90 (s, 
3H), 1.28 (tr, J=7 Hz, 3H). 
(c) 2.13 g (10 mmol) of ethyl 2-(2-amino-4-oxazolyl)-2-methoxyimino-acetate 
are treated at -20.degree. C. in 20 ml of methanol with 10 ml of 1N 
aqueous sodium hydroxide solution. After the addition of 10ml of 1N 
aqueous hydrochloric acid, 2-(2-amino-4-oxazolyl)-2-methoxyimino-acetic 
acid precipitates in a yield of 54%; melting point 190.degree. C. 
(decomposition). 
Elemental analysis for C.sub.6 H.sub.7 N.sub.3 O.sub.4 : Calculated: C 
38.93, H 3.81, N 22.70%. Found: C 38.40, H 4.01, N 22.33%. 
(d) 670 mg (4.05 mmol) of triethyl phosphite are added while cooling with 
ice to a solution of 560 mg (3 mmol) of 
2-(2-amino-4-oxazolyl)-2-methoxyimino-acetic acid, 1.2 g (3.6 mmol) of 
2,2-dithio-bis-benzthiazole and 360 mg (3.6 mmol) of N-methylmorpholine in 
20 ml of absolute acetonitrile. The mixture is stirred at room temperature 
for 3 hours. The precipitated product is then filtered off under suction, 
washed with water and dried. There is obtained 
2-(2-amino-4-oxazolyl)-2-methoxyimino-acetic acid 2-benzthiazolyl 
thioester (7:2 mixture of the Z:E isomers) in a yield of 55%; melting 
point 139.degree. C. (decomposition). 
NMR (DMSO, ppm): 4.0 and 4.22 (s, 3H; Z+E-isomer); 6.90 and 7.08 (s, br, 
2H; (E+Z); 7.5-8.5 (m, 5H). 
EXAMPLE 12 
In a manner analogous to that described in Example 1, from 95 mg of 
(3S,4R)-3-amino-4-ethynyl-2-oxo-1-azetidinesulphonic acid there are 
obtained 192 mg of 
(3S,4R)-3-[2-(2-amino-4-oxazolyl)-2-(methoxyimino)acetamido]-4-ethynyl-2-o 
xo-1-azetidinesulphonic acid triethylamine salt. The product is a 5:1 
mixture of the Z:E-isomers. 
IR (KBr, cm.sup.-1): 3339, 3263, 2683, 1773, 1659, 1541; 1277, 1254, 1045. 
NMR (DMSO, ppm): 9.48+9.67 (d, J=8.5, 1H; Z+E); 8.07+7.49 (s, 1H; E+Z); 
6.97+6.82 (s, br, 2H; E+Z); 5.2 (dd, J=6 and 8.5 Hz, 1H); 4.60 (dd, J=2 
and 6 Hz, 1H); 4.01.div.3.82 (s, 3H; E+Z); 3.47 (d, J=2 Hz, 1H); 3.06 (q, 
J=7.5 Hz, 6H); 1.17 (t, J=7.5 Hz, 9H). 
EXAMPLE 13 
291 mg (1.3 mmol) of 
rac-cis-3-amino-4-methoxycarbonyl-2-oxo-1-azetidinesulphonic acid, 640 mg 
(1.8 mmol) of 
2-[(5-amino-3-(1,2,4-thiadiazolyl)]-2-(Z)-methoxyimino-acetic acid 
1-benzthiazolyl thioester and 263 mg of triethylamine are stirred at room 
temperature for 30 hours in 6 ml of dichloromethane. After evaporation of 
the solvent, the residue is taken up in 20 ml of water, washed five times 
with 10 ml of ether each time and lyophilized. 610 mg of 
rac-cis-3-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetamido 
]-4-(methoxycarbonyl)-2-oxo-1-azetidinesulphonic acid triethylamine salt 
are obtained. 
IR (KBr, cm.sup.-1): 3397, 3305, 3204, 1755, 1688, 1622, 1530, 1281, 1235, 
1207, 1047. 
NMR (DMSO, ppm): 9.37 (d, J=8.5 Hz, 1H), 8.10 (s, br, 2H), 5.37 (dd, J=5.5 
and 8.5 Hz, 1H), 4.41 (d, J=5.5 Hz, 1H) 3.86 (s, 3H), 3.61 (s, 3H), 3.04 
(q, J=7.2 (Hz, 6H), 1.16 (t, J=7.2 Hz, 9H). 
EXAMPLE 14 
(a) 190 mg (1 mmol) of (3S,4R)-3-amino-4-ethynyl-2-oxo-1-azetidinesulphonic 
acid, 526 mg (1.1 mmol) of 
2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(t-butoxycarbonyl)-1-methylethoxy]-imino 
]-acetic acid 2-benzthiazolyl thioester and 0.280 ml (2 mmol) of 
triethylamine are stirred at room temperature for 20 hours in 5 ml of 
acetone/water (4:1). Thereupon, the mixture is concentrated, the residue 
is taken up in 4 ml of methanol and filtered. The filtrate is 
chromatographed over reverse-phase silica gel using water/methanol (10:1). 
After lyophilization there are obtained 213 mg of 
(3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-tert-butoxycarbonyl)-1-methyl 
ethoxy]imino]acetamido]-4-ethynyl-2-oxo-1-azetidinesulphonic acid as an 
amorphous powder. 
IR (KBr, cm.sup.-1): 3315, 1773, 1725, 1679, 1621, 1531, 1285, 1257, 1146, 
1055. 
NMR (DMSO, ppm): 9.17 (d, J=9 Hz, 1H), 7.22 (s, br, 2H), 6.77 (s, 1H), 5.26 
(dd, J=6 and 9 Hz, 1H), 4.63 (dd, J=2 and 6 Hz, 1H), 3.40 (d, J=2 Hz, 1H), 
1.38 (s, 15H). 
The 
2-(2-amino-4-thiazolyl-2-[[(Z)-1-(t-butoxycarbonyl)-1-methylethoxy]imino]- 
acetic acid 2-benzthiazolyl thioester used as the starting material can be 
prepared as follows: 
(b) 43 g (200 mmol) of ethyl 
2-(2-amino-4-thiazolyl)-2-(Z)-hydroxyimino-acetate are dissolved in 1.2 l 
of dimethylformamide. In a nitrogen atmosphere there are gradually added 
thereto 89.2 g (400 mmol) of t-butyl 2-bromo-2-methyl-propionate, followed 
by 110.6 g (800 mmol) of finely powdered potassium carbonate. The mixture 
is stirred at 45.degree. C. for 12 hours. After cooling to room 
temperature, there are added thereto 4 l of water and the mixture is 
extracted with 3.5 l of ethyl acetate. The organic phase is washed three 
times with 2 l of water. The aqueous phase extracted with 1.5 l of ethyl 
acetate. The combined ethyl acetate solutions are dried over magnesium 
sulphate and evaporated to dryness. After recrystallization from ether, 
there are obtained 61.4 g (85.9%) of ethyl 
2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(t-butoxycarbonyl)-1-methylethoxy]imino] 
-acetate of melting point 172.degree. C. 
(c) 240 g (671.5 mmol) of ethyl 
2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(t-butoxycarbonyl)-1-methyl-ethoxy]imino 
]-acetate are stirred at 50.degree. C. for 12 hours in 1.3 l of methanol 
and 1.34 l of 1N aqueous sodium hydroxide solution. The methanol is 
removed by evaporation and the aqueous phase is washed twice with 1 l of 
ethyl acetate. The product crystallizes out after the addition of 1.34 l 
of 1N aqueous hydrochloric acid. After cooling to 0.degree. C., the 
crystals are filtered off, washed successively with water, acetonitrile 
and ether and dried at 40.degree. C. under reduced pressure. The 
thus-obtained product crystallizes with 12% water and is stirred in 
acetonitrile for 2 hours in order to remove the water. After filtration 
and drying under reduced pressure at 40.degree. C., there are obtained 
177.7 g (80.3%) of 
2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(t-butoxycarbonyl)-1-methylethoxy]imino] 
-acetic acid of melting point 178.degree.-179.degree. C. The water content 
is 0.4%. 
(d) 28.8 g (86.4 mmol) of 
2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(t-butoxycarbonyl)-1-methylethoxy]imino] 
-acetic acid are dispersed in 360 ml of acetonitrile. 14.4 ml (130.5 mmol) 
of N-methylmorpholine are added thereto while stirring. After 10 minutes, 
34.6 g (103.5 mmol) of 2,2-dithio-bis-benzthiazole are added thereto and 
the suspension obtained is cooled to 0.degree. C. After the addition of 
20.2 ml (117 mmol) of triethyl phosphite (slow addition within 2 hours), 
the suspension is stirred at 0.degree. C. for 12 hours. The product is 
filtered off, washed successively with cold acetonitrile, isopropyl ether 
and petroleum ether and dried at room temperature under reduced pressure. 
There are obtained 33.7 g (81.5%) of 
2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(t-butoxycarbonyl)-1-methylethoxy]imino- 
acetic acid 2-benzthiazolyl thioester of melting point 
139.degree.-140.degree. C. 
EXAMPLE 15 
66 mg of 
(3S,4R)-3-[2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(tert-butoxycarbonyl)-1-methy 
lethoxy]imino]acetamido]-4-ethynyl-2-oxo-1-azetidinesulphonic acid are 
added at -10.degree. C. to 4 ml of trifluoroacetic acid. After 4 hours, 
the mixture is evaporated, the residue is taken up with a small amount of 
water and chromatographed over MCI gel using water. After lyophilization, 
there are obtained 10 mg of amorphous 
(3S,4R)-3-[2-(2-amino-4-thiazolyl)-2-[(Z)-(1-carboxy-1-methylethoxy)imino] 
acetamido]-4-ethynyl-2-oxo-1-azetidinesulphonic acid. 
IR (KBr, cm.sup.-1): 3292, 1771, 1679, 1638, 1531, 1276, 1047. 
NMR (DMSO, ppm): 9.38 (d, J=8.5 Hz, 1H,), 6.90 (s, 1H), 5.28 (dd, J=5.5 and 
8.5 Hz, 1H), 4.67 (dd, J=2 and 5.5 Hz, 1H), 3.44 (d, J=2 Hz, 1H), 1.36 (s, 
br, 6H). 
EXAMPLE 16 
In a manner analogous to that described in Example 14, there is obtained 
sodium 
(3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(1-carboxy-1-methylethoxy)imino] 
acetamido]-4-methyl-2-oxo-1-azetidinesulphonate. 
IR (KBr, cm.sup.-1): 3297, 2984, 2683, 1763, 1675, 1631, 1535, 1276. 
NMR (DMSO, ppm): 1.1 and 1.20 (6H, 2s, 2.times.CH.sub.3) 1.45 (3H, d, 3.5 
Hz, CH--CH.sub.3), 4.0 (1H, m, CH--CH.sub.3), 5.05 (1H, dd, 6 and 9 Hz, 
NH--CH), 6.75 (1H, s, S--CH.dbd.), 7.20 (3H, broad NH.sub.3), 9.15 (1H, d, 
9 Hz, CONH). 
EXAMPLE 17 
106 mg (0.55 mmol) of (3S,4S)-3-amino-4-ethyl-2-oxo-1-azetidinesulphonic 
acid, 288 mg (0.6 mmol) of 
2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(t-butoxycarbonyl)-1-methylethoxy]imino] 
-acetic acid 2-benzthiazolyl thioester and 0.153 ml of triethylamine (1.1 
mmol) are stirred at room temperature for 3 hours in 3 ml of acetone/water 
(4:1). The mixture is evaporated, the residue is taken up in 10 ml of 
water, washed three times with 20 ml of ether each time and lyophilized. 
270 mg of 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-(t-butoxycarbonyl)-1-methylet 
hoxy]imino]acetamido]-4-ethyl-2-oxo-1-azetidinesulphonic acid triethylamine 
salt are obtained. 
Elemental analysis for C.sub.24 H.sub.42 N.sub.6 O.sub.8 S.sub.2 (606.75): 
Calculated: C 47.51, H 6.98, N 13.85%. Found: C 47.29, H 6.96, N 13.68%. 
EXAMPLE 18 
250 mg of 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-(t-butoxycarbonyl)-1-methylet 
hoxy]imino]acetamido]-4-ethyl-2-oxo-1-azetidinesulphonic acid triethylamine 
salt are added at -10.degree. C. to 3 ml of trifluoroacetic acid. After 20 
hours at -10.degree. C., the mixture is evaporated and the residue is 
purified by DCCC [droplet counter current chromatography; rising droplets 
in the mixture chloroform/methanol/water (7:13:8)]. 58 mg of amorphous 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(1-carboxy-1-methylethoxy)imino] 
acetamido]-4-ethyl-2-oxo-1-azetidinesulphonic acid triethylamine salt are 
obtained. 
IR (KBr, cm.sup.-1): 1766, 1673, 1539, 1201, 1042. 
NMR (DMSO, ppm): 9.13 (d, J=9 Hz, 1H); 6.66 (s, 1H); 4.58 (dd, J=2.5 and 9 
Hz); 3.58 (m, 1H); 3.10 (, J=7 Hz, 6H); 1.42 (s, br, 6H); 1.19 (t, J=7 Hz, 
9H); 0.89 (tr, J=7 Hz, 3H). 
EXAMPLE 19 
224 mg (1 mmol) of 
rac-cis-3-amino-4-methoxycarbonyl-2-oxo-1-azetidinesulphonic acid, 526 mg 
(1.1 mmol) of 
(Z)-2-(2-amino-4-thiazolyl)-2-[[1-(t-butoxycarbonyl)-1-methylethoxy]imino] 
-acetic acid 2-benzthiazolyl thioester and 281 mg of triethylamine are 
stirred at room temperature for 4 hours in 5 ml of dichloromethane. After 
evaporation of the solvent, the residue is taken up in 20 ml of water, 
washed five times with 20 ml of ether each time and lyophilized. 569 mg of 
rac-cis-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-(t-butoxycarbonyl)-1-methylet 
hoxy]imino]acetamido]-4-methoxycarbonyl-2-oxo-1-azetidinesulphonic acid are 
obtained. 
EXAMPLE 20 
550 mg of 
rac-cis-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-)t-butoxycarbonyl)-1-methylet 
hoxy]imino]acetamido]-4-methoxycarbonyl-2-oxo-1-azetidinesulphonic acid are 
added at room temperature to 5.5 ml of trifluoroacetic acid. After 45 
minutes, the mixture is evaporated and the residue is purified by 
chromatography on reverse-phase silica gel using water/methanol (4:1). 
There are obtained 27 mg of pure 
rac-cis-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(1-carboxy-1-methylethoxy)imino] 
acetamido]-4-methoxycarbonyl-2-oxo-1-azetidinesulphonic acid as an 
amorphous lyophilizate. 
NMR (DMSO, ppm): 9.13 (d, J=8.5 Hz, 1H); 6.67 (s, 1H); 5.44 (dd, J=6 and 
8.5 Hz, 1H); 4.48 (d, J=6 Hz, 1H); 3.60 (s, 3H); 1.42 (s, br, 6H). 
EXAMPLE 21 
(a) 522 mg (1.0 mmol) of 
2-(2-amino-4-thiazolyl)-2-[[(Z)-1-[2-(trimethylsilyl)ethoxycarbonyl]-1-met 
hylethoxy]imino]-acetic acid 2-benzthiazolyl thioester and 224 mg (1.0 
mmol) of rac-cis-3-amino-4-methoxycarbonyl-2-oxo-1-azetidinesulphonic acid 
are suspended in 5.0 ml of absolute acetone and the suspension is treated 
with 0.278 ml (2.0 mmol) of triethylamine. The clear yellow solution 
obtained is stirred at room temperature for 24 hours and subsequently 
evaporated. The residue is subjected to DCCC chromatography [droplet 
counter current chromatography; rising droplets in the mixture 
chloroform/methanol/water (7:13:8)]. The interesting fractions are 
combined, concentrated and lyophilized. There are obtained 211 mg (31%) of 
rac-cis-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[[2-(trimethylsilyl)ethoxy]ca 
rbonyl]-1-methylethoxy]imino]acetamido-4-methoxycarbonyl-2-oxo-1-azetidines 
ulphonic acid triethylamine salt (1:1). 
NMR (D.sub.2 O, ppm): 0.03 (s, 9H), 0.96 (m, 2H), 1.24 (t, J=7.3 Hz, 9H), 
1.50 (s, 6H), 3.16 (q, J=7.3 Hz, 6H), 3.74 (s, 3H), 4.23 (m, 2H), 4.92 (d, 
J=6.0 Hz, 1H), 5.66 (d, J=6.0 Hz, 1H), 6.81 (s, 1H). 
IR (KBr, cm.sup.-1): 3434 (53%), 1783 (30%), 1740 (35%), 1685 (44%), 1624 
(56%), 1537 (39%), 1283 (21%), 1250 (27%), 1153 (33%), 1047 (23%) 840 
(47%). 
(b) 170 mg (0.25 mmol) of 
rac-cis-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[[2-(trimethylsilyl)ethoxy]ca 
rbonyl]-1-methylethoxy]imino]acetamido]-4-methoxycarbonyl-2-oxo-1-azetidine 
sulphonic acid triethylamine salt are dissolved in 10 ml of dry 
tetrahydrofuran and the solution is treated with 130 mg (0.50 mmol) of dry 
tetrabutylammonium fluoride. The mixture is stirred at room temperature 
overnight and subsequently evaporated. The residue is dissolved in a small 
amount of saturated aqueous sodium bicarbonate solution and 
chromatographed on Amberlite XAD-2 using water and subsequently 30% 
ethanol in water for the elution. After lyophilization, there are obtained 
40 mg (32%) of 
rac-cis-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(1-carboxy-1-methylethoxy)imino] 
acetamido]-4-methoxycarbonyl-2-oxo-1-azetidinesulphonic acid sodium salt. 
IR (KBr, cm.sup.-1): 1771, 1730. 
The 
2-(2-amino-4-thiazolyl)-2-[[(Z)-1-[2-(trimethylsilyl)ethoxycarbonyl]-1-met 
hylethoxy]imino]-acetic acid 2-benzthiazolyl thioester used as the starting 
material can be prepared as follows: 
(c) 24.9 g (102 mmol) of t-butyl 
2-(2-amino-4-thiazolyl)-2-(Z)-hydroxyimino-acetate are dissolved in 400 ml 
of dimethylformamide. After the addition of 54.7 g (205 mmol) of 
2-(trimethylsilyl)ethyl 2-bromo-2-methylpropionate, followed by 56.6 g 
(410 mmol) of finely ground potassium carbonate, the mixture is stirred at 
25.degree. C. for 4 hours in a nitrogen atmosphere. After the addition of 
3 l of water, the mixture is extracted with 1.5 l of ethyl acetate. The 
organic phase is washed twice with 1.5 l of water. The aqueous phase is 
extracted with 1.5 l of ethyl acetate. The combined ethyl acetate 
solutions are dried over sodium sulphate and evaporated to dryness. The 
product is purified by flash chromatography on silica gel [hexane/ethyl 
acetate (2:1)] and crystallized from methanol/water. There are obtained 
28.6 g (65.3%) of t-butyl 
2-(2-amino-4-thiazolyl)-2-[(1-(2-(trimethylsilyl)ethoxycarbonyl)-1-methyle 
thoxy]imino]-acetate of melting point 83.degree. C. 
(d) 13.4 g (31.2 mmol) of t-butyl 
2-(2-amino-4-thiazolyl)-2-[(Z)-(1-(2-(trimethylsilyl)ethoxycarbonyl)-1-met 
hylethoxy]imino]-acetate are stirred at room temperature for 1.5 hours in 
210 ml of acetic acid and 13.4 ml (104.5 mmol) of boron trifluoride 
etherate. The solution is poured into 650 ml of water and the pH is 
adjusted to 3.0 with sodium bicarbonate. The precipitated crystals are 
filtered off and dried at room temperature under reduced pressure. There 
are obtained 7.6 g (65.5%) of 
2-(2-amino-4-thiazolyl)-2-[[(Z)-1-[2-trimethylsilyl)ethoxycarbonyl]-1-meth 
ylethoxy]imino]-acetic acid of melting point 155.degree. C. 
(decomposition). (The compound contains 3.3% of water). After digesting 
the compound twice in 50 ml of dry acetonitrile and evaporation of the 
solvent, the water content after drying at room temperature (16 hours 
under reduced pressure-0.1 mm Torr) drops to 0.22%. 
(e) 10.9 g (29.2 mmol) of 
2-(2-amino-4-thiazolyl)-2-[[(Z)-1-[2-(trimethylsilyl)ethoxycarbonyl]-1-met 
hylethoxy]imino]-acetic acid are dispersed in 195 ml of acetonitrile (dried 
with molecular sieve 3 .ANG.) and the dispersion is treated while stirring 
with 4.09 ml (37.1 mmol) of N-methylmorpholine, followed by 11.7 g (35 
mmol) of 2,2-dithio-bis-benzothiazole and 6.7 ml (39.7 mmol) of triethyl 
phosphite. After stirring at room temperature for 1 hour, the clear yellow 
solution obtained is evaporated to dryness. The amorphous residue is 
purified by flash chromatography on silica gel [hexane/ethyl acetate 4:1)] 
and the pure fractions are crystallized from acetonitrile. There are 
obtained 4.6 g (30%) of 
2-(2-amino-4-thiaxolyl)-2-[[(Z)-1-[2-(trimethylsilyl)ethoxycarbonyl]-1-met 
hylethoxy]imino]-acetic acid 2-benzthiazolyl thioester of melting point 
92.degree. C. (decomposition). 
EXAMPLE 22 
(a) 201 mg (0.38 mmol) of 
2-(2-amino-4-thiazolyl)-2-[[(Z)-(p-nitrobenzyloxycarbonyl)methoxy]imino]-a 
cetic acid 2-benzthiazolyl thioester and 85 mg (0.38 mmol) of 
rac-cis-3-amino-4-methoxycarbonyl-2-oxo-1-azetidinesulphonic acid are 
suspended in 1.9 ml of absolute acetone and the suspension is treated with 
0.11 ml (0.79 mmol) of triethylamine. The mixture is stirred at room 
temperature for 3 hours and then evaporated. The residue is subjected to 
DCCC chromatography [droplet counter current chromatography; rising 
droplets in the mixture chloroform/methanol/water (7:13:8)]. The 
interesting fractions are combined, concentrated and lyophilized. There 
are obtained 56 mg (21%) of 
rac-cis-3-[2-(2-amino-4-thiazolyl)-2-[[(Z)-(p-nitrobenzyloxycarbonyl)metho 
xyimino]acetamido]-4-methoxycarbonyl-2-oxo-1-azetidinesulphonic acid 
triethylamine salt. 
NMR (D.sub.2 O, ppm): 1.26 (t, J=7.0 Hz, 9H), 3.18 (q, J=7.0 Hz, 6H), 3.71 
(s, 3H), 4.88 (s, 2H), 4.96 (d, J=6.0 Hz, 1H), 5.31 (s, 2H), 5.64 (d, 
J=6.0 Hz, 1H), 6.89 (s, 1H), 7.50 (d, J=8.5 Hz, 2H), 8.07 (d, J=8.5 Hz, 
2H). 
IR (KBr, cm.sup.-1): 3340 (56%), 1756 (26%), 1683 (43%), 1609 (46%), 1348 
(28%), 1281 (22%), 1213 (25%), 1046 (23%). 
Elemental analysis for C.sub.19 H.sub.18 N.sub.6 O.sub.12 S.sub.2 +C.sub.6 
H.sub.15 N (687.696): Calculated: C 43.66, H 4.84, N 14.26, S 9.32%. 
Found: C 43.70, H 4.80, N 14.24, S 9.30%. 
The 
2-(2-amino-4-thiazolyl)-2-[[(Z)-(p-nitrobenzyloxycarbonyl)methoxy]imino]-a 
cetic acid 2-benzthiazolyl thioester used as the starting material can be 
prepared as follows: 
(b) 6.1 g (25 mmol) of t-butyl 
2-(2-amino-4-thiazolyl)-2-(Z)-hydroxyimino-acetate are dispersed in 250 ml 
of dry acetonitrile. 13.7 g (50 mmol) of p-nitrobenzyl bromoacetate and 
12.9 ml (75 mmol) of N-ethyldiisopropylamine are now added thereto at room 
temperature while stirring. 7.5 g (50 mmol) of sodium iodide are added 
thereto 5 minutes later. The mixture is stirred at room temperature for 
3.5 hours in an argon atmosphere. The solvent is subsequently removed by 
evaporation and the residue is diluted with 500 ml of ethyl acetate. The 
solution obtained is washed four times with a total of 2 l of water. The 
aqueous phase is extracted with 300 ml of ethyl acetate and the combined 
ethyl acetate solutions are dried over sodium sulphate and evaporated to 
dryness. After crystallization from ethyl acetate/hexane, there are 
obtained 8.2 g (75%) of t-butyl 
2-(2-amino-4-thiazolyl)-2-[[(p-nitrobenzyloxycarbonyl)methoxy]imino]-aceta 
te of melting point 146.8.degree. C. (decomposition). 
(c) 5.0 g (11.4 mmol) of t-butyl 
2-(2-amino-4-thiazolyl)-2-[[(Z)-(p-nitrobenzyloxycarbonyl)methoxy]imino]-a 
cetate are stirred in 86 ml of acetic acid and treated with 5.2 ml (38.4 
mmol) of boron trifluoride etherate. The solution obtained is stirred at 
room temperature for 5 hours and subsequently poured into 260 ml of water. 
The precipitate obtained is filtered off and dried at 40.degree. C. under 
reduced pressure. There are obtained 3.5 g (80%) of 
2-(2-amino-4-thiazolyl)-2-[[(p-nitrobenzyloxycarbonyl)methoxy]imino]-aceti 
c acid of melting point about 175.degree. C. (decomposition). 
(d) 1.9 g (0.5 mmol) of 
2-(2-amino-4-thiazolyl)-2-[[(Z)-(p-nitrobenzyloxycarbonyl)methoxy]imino]-a 
cetic acid are dispersed in 30 ml of acetonitrile (dried with a 3 .ANG. 
molecular sieve). This suspension is treated while stirring with 1.4 ml 
(12.7 mmol) of N-methylmorpholine, followed by 2.0 g (6.0 mmol) of 
2,2-dithio-bis-benzthiazole and 1.14 ml (6.7 mmol) of triethyl phosphite. 
After stirring at room temperature for 1 hour, the mixture is cooled to 
0.degree. C. and filtered. The filtrate is evaporated and the residue is 
crystallized from methylene chloride. There are obtained 1.03 g (39%) of 
2-(2-amino-4-thiazolyl)-2-[[(Z)-(p-nitrobenzyloxycarbonyl)methoxy]imino]-a 
cetic acid 2-benzthiazolyl thioester of melting point 
124.degree.-126.degree. C. 
EXAMPLE 23 
343 mg (0.5 mmol) of 
rac-cis-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(p-nitrobenzyloxycarbonyl)metho 
xy]imino]aacetamido]-4-methoxycarbonyl-2-oxo-1-azetidinesulphonic acid 
triethylamine salt are dissolved in 20 ml of methanol and the solution is 
hydrogenated at room temperature with 230 mg of 5% palladium/siliceous 
earth in an atmosphere of hydrogen for 3 hours. The catalyst is removed by 
filtration and the solution is evaporated. The residue is taken up in a 
small amount of saturated aqueous sodium carbonate solution and 
chromatographed on Amberlite XAD-2 using water and subsequently 30% 
ethanol in water for the elution. After lyophilization, there are obtained 
120 mg (51%) of 
rac-cis-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxymethoxy)imino]acetamido] 
-4-methoxycarbonyl-2-oxo-1-azetidinesulphonic acid sodium salt. 
IR (KBr, cm.sup.-1): 1775, 1730. 
EXAMPLE 24 
265 mg (0.5 mmol) of 
(Z)-2-(2-amino-4-thiazolyl)-2-[[(p-nitrobenzyloxycarbonyl)methoxy]imino]-a 
cetic acid 2-benzthiazolyl thioester and 104 mg (0.5 mmol) of 
(3S,4S)-3-amino-4-carbamoyl-2-oxo-1-azetidinesulphonic acid are suspended 
in 2.5 ml of absolute acetone and the suspension is treated with 0.15 ml 
(1.1 mmol) of triethylamine. After 30 minutes, the suspension dissolves to 
give a yellow solution. After 24 hours at room temerature, the mixture is 
evaporated and the residue is subjected to DCCC chromatography [droplet 
counter current chromatography; rising droplets in the mixture 
chloroform/methanol/water (7:13:8)]. The interesting fractions are 
evaporated and lyophilized. There is obtained 0.139 g (41%) of 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(p-nitrobenzyloxycarbonyl)metho 
xy]imino]acetamido]-4-carbamoyl-2-oxo-1-azetidinesulphonic acid 
triethylamine salt. 
NMR (D.sub.2 O, ppm): 1.31 (t, J=7.5 Hz, 9H) 3.24 (q, J=7.5 Hz, 6H), 4.95 
(d, J=6.0 Hz, 1H) 4.95 (s, 2H), 5.34 (s, 2H), 5.69 (d, J=6.0 Hz, 1H), 6.98 
(s, 1H), 7.49 (d, J=9.0 Hz, 2H), 8.16 (d, J=9.0 Hz, 2H). 
IR (KBr, cm.sup.-1): 3333 (42%), 1773 (26%), 1687 (20%), 1608 (42%), 1348 
(27%), 1277 (22%), 1248 (26%), 1046 (19%). 
Elemental analysis for C.sub.18 H.sub.17 N.sub.7 O.sub.11 S.sub.2 +C.sub.6 
H.sub.15 N (672.698): Calculated: C 42.85, H 4.80, N 16.66, S 9.53, 
H.sub.2 O %. Found: C 41.22, H 4.81, N 16.13, S 9.45, H.sub.2 O 1.84%. 
EXAMPLE 25 
336 mg (0.5 mmol) of 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(p-nitrobenzyloxycarbonyl)metho 
xy]imino]actamido]-4-carbamoyl-2-oxo-1-azetidinesulphonic acid 
triethylamine salt are dissolved in 20 ml of methanol and the solution is 
hydrogenated at room temperature for 3-4 hours with 150 mg of 5% 
palladium-on-siliceous earth. The catalyst is removed by filtration and 
the solution is evaporated. The residue is dissolved in a small amount of 
saturated aqueous sodium bicarbonate solution and chromatographed on 
Amberlite XAD-2 using water and subsequently 40% ethanol in water for the 
elution. After lyophilization, there are obtained 150 mg (65%) of 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxymethoxy)imino]acetamido] 
-4-carbamoyl-2-oxo-1-azetidinesulphonic acid sodium salt. 
IR (KBr, cm.sup.-1): 3421, 1769, 1731, 1690 
EXAMPLE 26 
(a) 1.62 g (6.20 mmol) of 
(3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid 
sodium salt are dissolved in 180 ml of acetone/water (2:1) and the 
solution is treated with 3.27 g (6.83 mmol) of 
(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[t-butoxycarbonyl]-1-methylethoxy]imino] 
-acetic acid 2-benzthiazolyl thioester. The mixture is stirred at room 
temperature for 12 hours. A further 60 mg (0.12 mmol) of the 
aforementioned thioester are added thereto and the stirring is continued 
for a further 3 hours. Acetone is removed under reduced pressure and 50 ml 
of water are added thereto. The crystals obtained are filtered off and 
washed with water. The mother liquor is partially evaporated (37.degree. 
C., 15 mmHg) and chromatographed (MCI gel, water). After lyophilization, 
there are obtained 2.28 g (77%) of 
(3S,4S)-3-[2-amino-4-thiazolyl)-2-(Z)-[[1-(t-butoxycarbonyl)-1-methylethox 
y]imino] acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid 
sodium salt. 
IR (KBr, cm.sup.-1): 1766, 1723, 1683, 1617, 1531, 1458, 1369. 
NMR (DMSO, ppm): 1.35 (15H, s), 4.0-4.15 (3H, H.sub.4 and CH.sub.2 
--OCONH.sub.2), 5.25 (1H, dd, H.sub.3), 6.5 (2H, broad, CONH.sub.2), 6.7 
(1H, s, H--thiazole), 7.25 (2H, s, NH.sub.2), 8.9 (1H, d, CO--NH). 
The (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid 
sodium salt used as the starting material can be prepared as follows: 
(b) To a solution, stirred at room temperature, of 0.9 g (5.4 mmol) of 
2,4-dimethoxybenzylamine in 100 ml of methylene chloride are added 3 g of 
molecular sieve 4 .ANG. and, after 20 minutes, 0.7 g (5.4 mmol) of 
isopropylidene-L-glyceraldehyde and 5 g of anhydrous magnesium sulphate. 
The mixture is subsequently stirred at room temperature for 1 hour. The 
organic solution of isopropylidene-L-glyceraldehyde 
(2,4-dimethoxybenzyl)imine obtained is cooled to -20.degree. C. under 
argon and treated while stirring with 0.88 ml (5.4 mmol) of triethylamine. 
A solution of 1.25 g (5.6 mmol) of phthaloylglycyl chloride in 20 ml of 
dry methylene chloride is then added dropwise within 1 hour and the 
mixture is subsequently stirred at room temperature overnight. The mixture 
is washed three times with 100 ml of water each time and with 100 ml of 
sodium chloride solution and then dried ovr sodium sulphate. The organic 
solution is evaporated and the residue is chromatographed on silica gel 
(230-400 mesh) while eluting with hexane/ethyl acetate (1:1). There are 
obtained 1.77 g (70%) of 
N-[(3S,4S)-cis-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4- 
yl]-2-oxo-3-azetidinyl]phthalimide as a foam; [.alpha.].sub.D =+41.degree. 
(c=0.8 in chloroform); MS: 466 (M.sup.+). 
(c) A solution of 149.3 g (0.32 mol) of 
N-[(3S,4S)-cis-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4- 
yl]-2-oxo-3-azetidinyl]phthalimide in 2.5 l of methylene chloride is 
treated with 34 ml (0.64 mol) of methylhydrazine. The mixture is stirred 
at 20.degree. C. overnight, precipitated material is filtered off and the 
filtrate is evaporated under reduced pressure. The residue is taken up in 
1.2 l of ethyl acetate and the suspension obtained is filtered. The 
filtrate is washed three times with 500 l of water each time and with 500 
ml of sodium chloride solution and then dried over sodium sulphate. After 
evaporation of the solvent, there are obtained 104.3 g (86.8%) of crude 
(3S,4S)-cis-3-amino-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxol 
an-4-yl]-2-azetidinone which is used in the next step without further 
purification. 
(d) A stirred solution of 104 g (3.0 mol) of 
(3S,4S)-cis-3-amino-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxol 
an-4-yl]-2-azetidinone and 104 ml (1.2 mol) of butylene oxide in 1.5 l of 
methylene chloride is treated dropwise with 57.6 ml (0.4 mol) of 
carbobenzoxy chloride, the mixture is stirred for 1 hour and subsequently 
evaporated under reduced pressure. The crude material obtained is treated 
with 2 l of dry ether, a crystalline material being obtained. There are 
obtained 122.6 g (84%) of benzyl 
(3S,4S)-cis-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4yl]- 
2-oxo-3-azetidinecarbamate of melting point 115.degree.-116.degree. C.; 
[.alpha.].sub.D =+48.degree. (c=0.3 in methanol). 
(e) A solution of 160 g (0.34 mol) of benzyl 
(3S,4S)-cis-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl] 
-2-oxo-2-azetidinecarbamate in 1000 ml of tetrahydrofuran and 400 ml of 
water is stirred at about 60.degree. C. overnight in the presence of 8 g 
of p-toluenesulphonic acid. The mixture was neutralized with saturated 
sodium bicarbonate solution and the tetrahydrofuran is removed by 
evaporation. The aqueous solution is then extracted with 2 of ethyl 
acetate. After drying over sodium sulphate and evaporation, there are 
obtained 142 g (97.2%) of pure benzyl 
(3S,4S)-cis-4-[(R)-1,2-dihydroxyethyl]-1-(2,4-dimethoxybenzyl)-2-oxo-3-ace 
tidinecarbamate of melting point 177.degree.-178.degree. C. (from 
methanol). 
(f) A solution of 142 g (0.33 mol) of benzyl 
(3S,4S)-cis-4-[(R)-1,2-dihydroxyethyl]-1-(2,4-dimethoxybenzyl)-2-oxo-3-aze 
tidinecarbamate in 1000 ml of tetrahydrofuran is treated dropwise while 
stirring with a solution of 76.8 g (0.359 mol) of sodium metaperiodate in 
600 ml of water. The mixture is stirred for 1 hour, filtered and the 
filtrate is evaporated under reduced pressure. The residue is taken up in 
400 ml of ethyl acetate and washed twice with 100 ml of water each time 
and with 50 ml of sodium chloride solution. After drying and evaporation, 
there are obtained 105 g (87.8%) of pure benzyl 
(3S,4S)-cis-1-(2,4-dimethoxybenzyl)-4-formyl-2-oxo-3-azetidinecarbamate of 
melting point 145.degree.-147.degree. C. (from ethyl acetate/hexane): 
[.alpha.].sub.D =+13.7.degree. (c=1 in chloroform). 
(g) 4.27 g (113 mmol) of sodium borohydride are dissolved in 1.6 l of 
absolute ethanol and the solution is cooled to 0.degree. C. This solution 
is treated dropwise with a solution of 90 g (226 mmol) of benzyl 
(3S,4S)-cis-1-(2,4-dimethoxybenzyl)-4-formyl-2-oxo-3-azetidinecarbamate in 
720 ml of ethanol/tetrahdrofuran (1:1). The mixture is stirred at 
0.degree. C. for 2 hours, subsequently treated with 350 ml of saturated 
aqueous sodium sulphate solution and then stirred for 45 minutes. After 
filtration and evaporation of the solvent, the residue is taken up in 1.5 
l of ethyl acetate and washed until neutral. After drying over sodium 
sulphate and partial evaporation, there are obtained 72.2 g (79.6%) of 
(3S,4S)-cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-hydroxymethyl 
-2-azetidinone in the form of colourless crystals of melting point 
138.degree. C.; [.alpha.].sub.D =+41.6.degree. (c=1 in methanol). 
Elemental analysis for C.sub.21 H.sub.24 N.sub.2 O.sub.6 : Calculated: C 
62.99, H 6.04, 7.00%. Found: C 62.76, H 6.09, N 6.96%. 
IR (KBr, cm.sup.-1): 1718, 1698, 1615, 1589. 
NMR (CDCl.sub.3, ppm): 2.45 (1H, dd, OH), 3.55-3.75 (3H, broad, 
CH--CH.sub.2 --), 3.79 (6H, s, 2.times.OCH.sub.3), 4.35 (2H, s, 
N--CH.sub.2), 5.05 (2H, s, .phi.--CH.sub.2), 5.11 (1H, dd, 5 and 9 Hz, 
H.sub.3), 6.06 (1H, d, 9 Hz NH), 6.43 (2H, m, Ar), 7.15 (1H, m, Ar), 7.31 
(5H, m, C.sub.6 H.sub.5). 
MS: 292 (M-BzOH). 
(h) A solution of 30 g (74.9 mmol) of 
(3S,4S)-cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-hydroxymethyl 
-2-azetidinone in 600 ml of methylene chloride is treated at 
0.degree.-5.degree. C. with 21.22 g (1 equivalents) of 
chlorosulphonyl-isocyanate. After 15 minutes, the mixture is added 
dropwise to an aqueous solution, cooled to 5.degree. C., of 20.9 g (2.7 
equivalents) of sodium sulphite. The mixture is stirred for 2 hours, 
subsequently diluted with methylene chloride and the organic phase is 
separated, washed with aqueous sodium chloride solution and dried over 
sodium sulphate for 12 hours. The organic phase is subsequently treated 
with magnesium sulphate and stirred for a further 2 hours. After 
filtration and evaporation of the solvent, the residue is treated with 
ether, the crystals obtained are filtered off and washed with ether. There 
are obtained 32.6 g (97%) of 
(3S,4S)-cis-3-benzyloxycarboxamido-4-carbamoyloxymethyl-1-(2,4-dimethoxybe 
nzyl)-2-azetidinone of melting point 178.degree.-179.degree. C.; 
[.alpha.].sub.D =+84.7.degree. (c=0.8 in chloroform). 
Elemental analysis for C.sub.22 H.sub.25 N.sub.3 O.sub.7 : Calculated: C 
59.59, H 5.68, N 9.48%. Found: C 59.17, H 5.69, N 9.37%. 
IR (KBr, cm.sup.-1): 1761, 1708, 1618, 1587. 
(i) A suspension of 11.9 g (26.8 mmol) of 
(3S,4S)-cis-3-benzyloxycarboxamido-4-carbamoyloxymethyl-1-(2,4-dimethoxybe 
nzyl)-2-azetidinone, 14.5 g (53.5 mmol) of potassium peroxydisulphate, 
13.98 g (80.3 mmol) of dipotassium hydrogen phosphate and 1.33 g (5.36 
mmol) of copper sulphate pentahydrate in 270 ml of acetonitrile and 130 ml 
of water is heated to 95.degree. C. for 3.5 hours in an argon atmosphere 
at a pH between 6.5 and 7.0 (occasional addition of 10 g of dipotassium 
hydrogen sulphate). After cooling and filtration, the aqueous phase is 
discarded and the organic phase is evaporated. The residue is taken up in 
ethyl acetate and washed with water and sodium chloride solution. After 
drying over sodium sulphate, filtration and evaporation of the solvent, 
the residue is taken up in ether and filtered. The crude crystals (8.9 g) 
are chromatographed on silica gel [300 g, 40-63 .mu.m, 
chloroform/methanol/ethyl acetate 85:10:5]. There are obtained 5.5 g (70%) 
of (3S,4S)-cis-3-benzyloxycarboxamido-4-carbamoyloxymethyl-2-azetidinone 
as colourless crystals, [.alpha.].sub.D =+61.2.degree. (c=1 in methanol). 
Melting point 193.degree.-195.degree. C. 
Elemental analysis for C.sub.13 H.sub.15 N.sub.3 O.sub.5 : Calculated: C 
53.24, H 5.16, N 14.33%. Found: C 53.40, H 5.24, N 14.35%. 
IR (KBr, cm.sup.-1): 3414, 3315, 1757, 1701, 1610, 1540, 1498. 
NMR (DMSO, ppm): 3.31-4.06 (3H, m, CH--CH.sub.2 --), 4.95 (1H, dd, 4.5 and 
9 Hz, H.sub.3), 5.06 (2H, s, .phi.--CH.sub.2), 6.53 (2H, broad, NH.sub.2), 
7.35 (5H, s, C.sub.6 H.sub.5), 7.95 (1H, d, 9 Hz, CH.sub.3 --NH--CO), 8.35 
(1H, s, NH--CO). 
MS (CI with NH.sub.3): 251 (M+H).sup.+ --CONH. 
(k) 5.4 g (18.4 mmol) of 
(3S,4S)-cis-3-benzyloxycarboxamido-4-carbamoyloxymethyl-2-acetidinone in 
200 ml of absolute dioxan are treated at room temperature with 4.3 g (1.3 
equivalents) of pyridine/sulphur trioxide complex. The suspension obtained 
is stirred for 3 hours, subsequently treated with a further 0.99 g (0.3 
equivalents) of pyridinesulphur trioxide complex and the mixture is 
stirred for a further hour. After the addition of a further 1.37 g (0.4 
equivalents) of pyridine-sulphur trioxide complex and stirring for a 
further 2 hours, the solvent is partially removed under reduced pressure 
and the residue is treated with 110 ml of saturated aqueous sodium 
bicarbonate solution. The brown solution obtained is left to stand in a 
refrigerator for 12 hours and the crystals obtained are filtered off. The 
mother liquor is chromatographed [MCI gel, water/ethanol (1:1 to 9:1)]. 
After lyophilization, there are obtained 3.5 g (49%) of 
(3S,4S)-cis-3-benzyloxycarboxamido-4-carbamoyloxymethyl-2-azetidinone-1-su 
lphonic acid sodium salt as a colourless powder; [.alpha.].sub.D 
=+29.6.degree. (c=0.5 in water). 
Elemental analysis for C.sub.13 H.sub.14 N.sub.3 O.sub.8 SNa: Calculated: C 
39.50, H 3.57, N 10.63%. Found: C 39.41, H 3.45, N 10.36%. 
IR (KBr, cm.sup.-1): 1798, 1758, 1739, 1693, 1584, 1547. 
NMR (DMSO, ppm): 3.9-4.4 (3H, CH--CH.sub.2), 4.9 (dd, 1H, NH--CH), 5.1 (s, 
2H, .phi.--CH.sub.2), 6.4 (2H, broad, NH.sub.2), 7.4 (5H, S, C.sub.6 
H.sub.5), 8.0 (1H, d, NH). 
(1) 3.065 g (7.75 mmol) of 
(3R,4S)-cis-benzyloxycarboxamido-4-carbamoyloxymethyl-2-azetidinone-1-sulp 
honic acid sodium salt are dissolved in 180 ml of absolute methanol and the 
solution is hydrogenated for 1 hour in the presence of 1.5 g of 10% 
palladium/carbon. The catalyst is removed by filtration and the solution 
obtained is evaporated. 2.02 g (100%) of 
(3S,4S)-cis-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid 
sodium salt are obtained. 
IR (KBr, cm.sup.-1): 3444, 3207, 1754, 1725, 1611, 1249. 
EXAMPLE 27 
2.28 g (3.98 mmol) of 
(3S,4S)-3-[2-amino-4-thiazolyl)-2-(Z)-[[1-(t-butoxycarbonyl)-1-methylethox 
y]imino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid 
sodium salt are treated with 5 ml of trifluoroacetic acid while cooling 
with ice. The ice-bath is removed and the mixture is stirred at room 
temperature for 30 minutes. Excess trifluoroacetic acid is removed under 
reduced pressure (20.degree. C., 15 mmHg) and the oil obtained is treated 
with 100 ml of ether. The crystals obtained are filtered off, washed with 
ether and dried under greatly reduced pressure. After aqueous 
reverse-phase chromatography, there are obtained, after lyophilization, 
1.51 g (76.6%) of 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-carboxy-1-methylethoxy]imino] 
acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid; 
[.alpha.].sub.D =+35.7.degree. (c=0.3 in water). 
Elemental analysis for C.sub.14 H.sub.18 N.sub.6 O.sub.10 S.sub.2 : 
Calculated: C 34.01, H 3.67, N 17.00%. Found: C 34.52, H 3.72, N 16.63%. 
IR (KBr, cm.sup.-1): 1764, 1722, 1680, 1637. 
NMR (DMSO, ppm): 1.50 (6H, s, 2.times.CH.sub.3), 4.00-4.20 (3H, 
CH--CH.sub.2), 5.35 (1H, dd, 4.5 and 9 Hz, Hz), 6.50 (3H, broad, 
NH.sub.3.sup.+ or COOH, COHN.sub.2), 6.90 (1H, s, thiazole--5H), 9.15 (1H, 
d, 9 Hz, CONH). 
EXAMPLE 28 
In a manner analogous to that described in Example 26, from 
2-(2-amino-4-thiazolyl)-2-[[(Z)-(p-nitrobenzyloxycarbonyl)methoxy]imino]-a 
cetic acid 2-benzthiazolyl thioester and 
(3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid there 
is obtained 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(p-nitrobenzyloxycarbonyl)metho 
xyimino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-acetidinesulphonic acid 
sodium salt. 
Elemental analysis for C.sub.19 H.sub.18 N.sub.7 O.sub.12 S.sub.2 Na: 
Calculated: C 36.60, H 2.91, N 15.73, S 10.28%. Found: C 37.00, H, 2.88, N 
15.74, S 10.45%. 
IR (KBr, cm.sup.-1): 3353, 1761, 1729, 1524, 1348. 
NMR (DMSO, ppm): 4.0-4.2 (3H, m, CH--CH.sub.2), 4.3 (2H, s, 
.phi.--CH.sub.2), 5.30 (1H, dd, NH--CH--), 5.32 (2H, s, O--CH.sub.2), 6.70 
(2H, broad, NH.sub.2), 6.9 (1H, s, S--CH.dbd.), 7.10 (2H, broad, 
NH.sub.2), 7.70 and 8.2 (2.times.2H, 2d, 2.times.3 Hz, Ar), 9.5 (1H, d, 9 
Hz, NHCO). 
EXAMPLE 29 
270 mg (0.43 mmol) of 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(p-nitrobenzyloxycarbonyl)metho 
xy]imino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid 
sodium salt are dissolved in 30 ml of methanaol and the solution is 
hydrogenated over 150 mg of 5% palladium-on-silica gel. The catalyst is 
filtered off and the solvent is evaporated. The residue is taken up in 2.5 
ml of water and washed twice with ethyl acetate. The aqueous phase is 
chromatographed (reverse-phase using water as the eluting agent). There 
are obtained 115 mg (54%) of 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxymethoxy)imino]acetamido] 
-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid sodium salt. 
Elemental analysis for C.sub.12 H.sub.13 N.sub.6 O.sub.10 S.sub.2 Na: 
Calculated: C 29.51, H 2.68, N 17.21%. Found: C 27.09, H 2.35, N 15.33%. 
IR (KBr, cm.sup.-1): 3434, 1766, 1718, 1669, 1613, 1533, 1278, 1251. 
NMR (DMSO, ppm): 3.90-4.15 (3H, m, CH--CH.sub.2), 4.30 (2H, S, CH.sub.2 
--COOH), 5.20 (1H, dd, 5 and 9 Hz, NH--CH), 6.6 (2H, broad, NH.sub.2), 
6.78 (1H, s, S--CH.dbd.), 7.13 (2H, s, NH.sub.2), 10.90 (1H, d, 9 Hz, 
CONH). 
EXAMPLE 30 
In a manner analogous to that described in Example 26 there is likewise 
obtained: 
(a) 
(3S,4S)-3-[(5-amino-3-(1,2,4-thiadiazolyl)]-2-(Z)-methoxyimino)acetamido]- 
4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid sodium salt. 
Elemental analysis for C.sub.10 H.sub.12 N.sub.7 O.sub.8 S.sub.2 Na: 
Calculated: C 26.97, H 2.72, N 22.02, S 14.40%. Found: C 27.06, H 2.62, N 
21.60, S 14.28%. 
IR (KBr, cm.sup.-1), 3330, 1767, 1720, 1675, 1617, 1524, 1276, 1252. 
NMR (DMSO, ppm): 3.90 (3H, s, OCH.sub.3), 3.90-4.30 (3H, m, CH--CH.sub.2), 
5.20 (1H, dd, 6 and 9 Hz, NH--CH), 6.35, (2H, s, NH.sub.2), 8.10 (2H, s, 
NH.sub.2), 9.04 (1H, d, 9 Hz, CONH). 
[.alpha.].sub.589.sup.20 =+32.5.degree. (c=0.4 in water). 
The 2-[(5-amino-3-(1,2,4-thiadiazolyl)]-2-(Z)-methoxyimino-acetic acid 
2-benzthiazolyl thioester used as the starting material can be prepared as 
follows: 
(b) 2.0 g of 2-[5-amino-3-(1,2,4thiadiazol-yl)]-2-(Z)-methoxyimino-acetic 
acid in 60 ml of acetonitrile are treated at room temperature with 1.3 ml 
of N-methylmorpholine. After 5 minutes, 3.6 g of dithio-bis-benzthiazol 
are added thereto, followed by dropwise addition of 2.2 ml of 
triethyl-phosphite in 10 ml of acetonitrile within 1 hour. The mixture is 
stirred at room temperature for 12 hours and subsequently filtered, washed 
with acetonitrile and low-boiling petroleum ether, dried and crystallized 
from tetrahydrofuran/low-boiling petroleum ether. There are obtained 1.4 g 
(40%) of 2-[5-amino-3-(1,2,4-thiadiazolyl)]-2-(Z)-methoxyimino-acetic acid 
2-benzthiazolyl thioester of melting point above 160.degree. C. 
(decomposition). 
EXAMPLE 31 
In a manner analogous to that described in Example 26 there is obtained 
(3S,4S)-3-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino]acetamido]-4-carbamoylo 
xymethyl-2-oxo-1-azetidinesulphonic acid sodium salt. 
Elemental analysis for C.sub.11 H.sub.13 N.sub.6 O.sub.8 S.sub.2 Na: 
Calculated: C 29.73, H, 2.95, N 18.91%. Found: C 29.91, H 3.30, N 19.00%. 
IR (KBr, cm.sup.-1): 3364, 1775, 1739, 1680, 1625, 1537, 1284, 1256. 
NMR (DMSO, ppm): 3.90 (3H, s, OCH.sub.3), 4.10 (3H, m, CH--CH.sub.2), 5.25 
(1H, dd, 4.5 and 9 Hz, CH--NH), 6.45 (2H, s, NH.sub.2), 6.70 (1H, s, 
S--CH.dbd.), 7.10 (2H, s, NH.sub.2), 9.10 (1H, d, 9 Hz, CONH). 
EXAMPLE 32 
(a) In a manner analogous to that described in Example 26 there is obtained 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-carbam 
oyl-2-oxo-1-azetidinesulphonic acid sodium salt. 
Elemental analysis for C.sub.10 H.sub.11 N.sub.6 O.sub.7 S.sub.2 Na: 
Calculated: C 28.99, H 2.68, N 20.68%. Found: C 31.20, H 3.26, N 16.41%. 
IR (KBr, cm.sup.-1): 3282, 1790, 1640, 1612, 1527, 1260, 1230. 
NMR (DMSO, ppm): 3.85 (3H, s, OCH.sub.3), 4.3 (1H, d, 6 Hz, 
CH--CONH.sub.2), 5.30 (1H, dd, 6 and 9 Hz, NH--CH) 6.95 (1H, s, 
S--CH.dbd.), 7.40 (2H, d, 18 Hz, CONH.sub.2) 9.25 (1H, d, 9 Hz, NH--CO). 
The (3S,4S)-cis-3-amino-4-carbamoyl-2-azetidinone-1-sulphonic acid sodium 
salt used as the starting material can be prepared as follows: 
(b) 17 g (42.7 mmol) of benzyl 
(3S,4S)-cis-1-(2,4-dimethoxybenzyl)-4-formyl-2-oxo-3-azetidinecarbamate 
are dissolved in 100 ml of methylene chloride and 100 ml of n-propanol. 
This solution is treated with 3.5 g (50.3 mmol) of hydroxylamine 
hydrochloride, followed by 4.2 ml (52 mmol) of pyridine. The mixture is 
heated under reflux for 2 hours. The methylene chloride is subsequently 
distilled off and a solution of 6.3 g (57 mmol) of selenium dioxide in 100 
ml of n-propanol is added dropwise. The mixture is heated under reflux for 
2 hours and then cooled to room temperature and filtered. The solution 
obtained is evaporated under reduced pressure. The oil obtained is 
dissolved in 100 ml of n-propanol and evaporated. This procedure is 
repeated twice. The partially crystalline residue obtained is taken up in 
250 ml of methylene chloride and washed successively twice with in each 
case 200 ml of water and sodium chloride solution. Ater drying over sodium 
sulphate, filtration and evaporation of the solvent, the residue is taken 
up in 70 ml of n-propanol. The solution is left to stand in a refrigerator 
for 12 hours. There are obtained 16.4 g (97%) of benzyl 
(3S,4S)-cis-1-(2,4-dimethoxybenzyl)-4-cyano-2-oxo-3-acetidinecarbamate of 
melting point 152.degree.-153.degree. C.; [.alpha.].sub.D =+10.6.degree. 
(c=1 in chloroform). 
MS: 395 (M.sup.+). 
(c) 15.72 g (58.2 mmol) of potassium peroxydisulphate and 9.5 g (54.8 mmol) 
of potassium hydrogen sulphate are dissolved in 480 ml of water. The 
solution is heated to 80.degree. C. and treated with a solution of 1.2 g 
of copper sulphate in 10 ml of water. The suspension obtained is diluted 
with 180 ml of acetonitrile and treated dropwise with a solution of 14.4 g 
of benzyl 
(3S,4S)-cis-1-(2,4-dimethoxybenzyl)-4-cyano-2-oxo-3-azetidinecarbamate in 
300 ml of acetonitrile. The mixture is heated under reflux for 2.5 hours, 
subsequently cooled, filtered and partially evaporated. The oily aqueous 
solution obtained is extracted with ethyl acetate and the organic phase is 
washed successively three times with aqueous saturated sodium bicarbonate 
solution, water and sodium chloride solution. After drying and evaporation 
of the solvent, the oil obtained is chromatographed on silica gel [230-400 
mesh, eluting agent ethyl acetate/n-hexane (1:1)]. There are obtained 6.1 
g (68.3%) of benzyl (3S,4S)-cis-4-cyano-2-oxo-3-azetidinecarbamate of 
melting point 163.degree.-165.degree. C. 
MS: 245 (M.sup.+). 
(d) 6.16 g (25 mmol) of benzyl 
(3S,4S)-cis-4-cyano-2-oxo-3-azetidinecarbamate are dissolved in 45 ml of 
dimethyl sulphoxide and the solution is treated with 5.58 ml of 30% 
aqueous hydrogen peroxide. After the temperature has returned to 
25.degree. C., the mixture is treated with 5 ml of aqueous 1N sodium 
hydroxide solution. The temperature rises to 55.degree. C. A precipitate 
results after stirring for 45 minutes. 20 ml of ethyl acetate are added 
thereto and the crystals obtained are filtered off. The crystals are 
washed with aqueous ethanol and absolute ether. There are obtained 2.48 g 
(37.5%) of benzyl (3S,4S)-4-carbamoyl-2-oxo-3-azetidinecarbamate of 
melting point 248.degree.-249.degree. C.; [.alpha.].sub.D =+13.degree. 
(c=1 in dimethyl sulphoxide). 
The mother liquor is partially evaporated, a further 0.33 g of product 
being isolated. The thus-obtained mother liquor is diluted with water and 
chromatographed on MCI gel using ethanol/water (3:7) for the elution. The 
total yield of product amounts to 3.0 g (45.4%). 
(e) 7.9 g (30 mmol) of benzyl (3S,4S)-carbamoyl-2-oxo-3-azetidinecarbamate 
are dispersed in 470 ml of absolute dioxan and treated with 6.2 g (39 
mmol) of pyridine-sulphur trioxide complex. The suspension obtained is 
stirred at room temperature for 2 hours, subsequently treated with 1.41 g 
(8.8 mmol) of pyridine-sulphur trioxide complex and stirred for a further 
hour. After the addition of 1.90 g (12 mmol) of pyridine-sulphur trioxide 
complex and stirring for a further 2 hours, the solvent is removed by 
evaporation under reduced pressure and the residue is taken up in 200 ml 
of water. The aqueous solution obtained is treated with 15 g (44.24 mmol) 
of tetrabutylammonium hydrogen sulphate. The aqueous solution is extracted 
twice with 250 ml of methylene chloride each time and the methylene 
chloride extract is dried over sodium sulphate. After evaporation of the 
solvent, the oily residue obtained is dissolved in 150 ml of absolute 
methanol and the solution is hydrogenated over 2.5 g of 10% 
palladium/carbon. The catalyst is filtered off, the solution is evaporated 
and the residue is dissolved in a solution of 70 ml of formic acid in 100 
ml of methylene chloride. After 2 hours, the solvent is removed by 
evaporation and the residue is treated with 25 ml of water 2.3 g (36%) of 
(3S,4S)-3-amino-4-carbamoyl-2-oxo-1-azetidinesulphonic acid are obtained. 
The mother liquor is chromatographed on MCI gel using water/ethanol (1:0 
to 9:1) for the elution, a further 420 mg of product being obtained. The 
total yield is 2.7 g (43.3%). 
IR (KBr, cm.sup.-1): 1779, 1696, 1633, 1485, 1288, 1250. 
NMR (DMSO, ppm): 4.43 and 4.72 (2.times.1H, 2d, 6 Hz, CH--CH), 7.88 (2H, d, 
br, NH.sub.2), 8.59 (3H, br, NH.sub.3.sup.+). 
EXAMPLE 33 
In a manner analogous to that described in Example 32 or Example 26 there 
is obtained 
(3S,4S)-3-[(Z)-2-[5-amino-3-(1,2,4-thiadiazolyl)]-2-methoxyimino)acetamido 
]-4-carbamoyl-2-oxo-1-azetidinesulphonic acid sodium salt. 
Elemental analysis for C.sub.9 H.sub.10 N.sub.7 O.sub.7 S.sub.2 Na: 
Calculated: C 26.03, H 2.43, N 23.61%. Found: C 26.02, H 2.59, N 23.32%. 
IR (KBr, cm.sup.-1): 3424, 3334, 1776, 1688, 1618, 1524, 1278. 
NMR (DMSO, ppm): 3.90 (3H, s, OCH.sub.3), 4.45 (1H, d, 6 Hz, 
CH--CONH.sub.2), 5.40 (1H, dd, 6 and 9 Hz, NH--CH, 7.30 (2H, br, 
NH.sub.2), 8.10 (2H, br, NH.sub.2), 8.8 (1H, d, 9 Hz, NH--CO). 
EXAMPLE 34 
In an manner analogous to that described in Example 32 or Examples 26 and 
27 there is obtained 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-carboxy-1-methylethoxy]imino] 
acetamido]-4-carbamoyl-2-oxo-1-azetidinesulphonic acid. 
Elemental analysis for C.sub.13 H.sub.16 N.sub.6 O.sub.9 S.sub.2 : 
Calculated: C 33.62, H 3.47, N 18.10%. Found: C 33.24, H 3.18, N 17.94%. 
IR (KBr, cm.sup.-1): 3332, 3208, 2552, 1780, 1684, 1638, 1279, 1188. 
NMR (DMSO, ppm): 1.44 (6H, s, 2.times.CH.sub.3), 4.34 (1H, d, 6 Hz, 
CH--CONH.sub.2), 5.33 (1H, dd, 6 and 9 Hz, NH--CH--), 6.96 (1H, s, 
SA--CH.dbd.), 7.40 (2H, br, d, 7 Hz, CONH.sub.2), 8.95 (1H, d, 9 Hz, 
CONH). 
UV (EtOH): 292 nm (6846), 240 nm (12232). 
EXAMPLE 35 
(a) In a manner analogous to that described in Example 32, from 
(3S,4S)-3-amino-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-1-azetidinesu 
lphonic acid and 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino-acetic acid 
2-benzthiazolyl thioester there is obtained 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-(2,2-d 
imethyl-1,3-dioxolan-4-yl)-2-oxo-1-azetidinesulphonic acid sodium salt. 
IR (KBr, cm.sup.-1): 3429, 3345, 1770, 1673, 1620, 1531, 1253. 
NMR (DMSO, ppm): 1.23 and 1.33 (2.times.3H, 2s, 2.times.CH.sub.3), 3.83 
(3H, s, OCH.sub.3), 3.8-4.15 (4H, m, CH--CH--CH.sub.2 --), 5.22 (1H, dd, 
5.5 and 9 Hz, NH--CH), 6.75 (1H, s, S--CH.dbd.), 7.19 (2H, br, NH.sub.2), 
8.68 (1H, d, 9 Hz, NH--CO). 
(b) 740 mg (1.57 mmol) of 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-[(Z)-2 
,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-1-azetidinesulphonic acid sodium salt 
are dissolved in 40 ml of methanol/water (1:1) and the solution is stirred 
for 12 hours in the presence of 15 g of Amberlite IR 120 (previously 
washed in methanol). The catalyst is filtered off and the solvent is 
removed by evaporation. There are obtained 300 mg (0.7 mmol), 44%) of 
(3S,4S)-2-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-[(R)-1 
,2-dihydroxyethyl]-2-oxo-1-azetidinesulphonic acid sodium salt. 
Elemental analysis for C.sub.11 H.sub.14 N.sub.5 O.sub.8 S.sub.2 Na: 
Calculated: C 30.63, H 3.27, N 16.24%. Found: C 32.03, H 3.98, N 15,89%. 
IR (KBr, cm.sup.-1): 3290, 1772, 1742, 1678, 1638, 1270, 1227, 1045. 
NMR (DMSO, ppm): 3.2-4.15 (4H, m, CH--CH--CH.sub.2), 3.52 (3H, s, 
OCH.sub.3), 5.19 (1H, dd, 6 and 9 Hz, NH--CH), 6.98 (1H, s, S--CH.dbd.), 
7.1 (4H, br, NH.sub.2, 2.times.OH), 9.23 (1H, d, 9 Hz, CONH). 
(c) From 
(3S,4S)-2-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-[(R)-1 
,2-dihydroxyethyl]-2-oxo-1-azetidinesulphonic acid sodium salt there is 
obtained in a manner analogous to that described in Example 26 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-formyl 
-2-oxo-1-azetidinesulphonic acid sodium salt. 
Elemental analysis for C.sub.10 H.sub.10 N.sub.5 O.sub.7 S.sub.2 Na: 
Calculated: C 30.08, H 2.52, N 17.54%. Found: C 31.27, H 3.02, N 17.67%. 
IR (KBr, cm.sup.-1): 3177, 1771, 1636, 1524, 1271. 
NMR (DMSO, ppm): 3.93 (3H, s, OCH.sub.3), 4.30 (1H, dd, 4.0 and 6 Hz, 
CH--CHO), 5.14 (1H, dd, 6.0 and 8.0 Hz, NH--CH), 5.5 (2H, br, NH.sub.2), 
6.77 (1H, s, S--CH.dbd.), 9.61 (1H, d, 8 Hz, NH--CO), 9.65 (1H, d, 4.0 Hz, 
CHO). 
(d) 400 ml (1 mmol) of 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-formyl 
-2-oxo-1-azetidinesulphonic acid sodium salt are dissolved in 400 ml of 
methanol and the solution is treated with 100 mg (1.4 mmol) of 
hydroxylamine hydrochloride and 0.1 ml (1.24 mmol) of pyridine. After 
stirring for 2 hours, the mixture is evaporated and the product is 
chromatographed on silica gel [230-400 mesh, eluting agent methanol/ethyl 
acetate (3:7)]. The partially purified product is subsequently 
chromatographed on MCI gel using water as the eluting agent. There are 
obtained 45 mg (10%) of 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-[(E/Z) 
-(hydroxyimino)methyl]-2-oxo-1-azetidinesulphonic acid. 
Elemental analysis for C.sub.10 H.sub.11 N.sub.6 O.sub.7 S.sub.2 Na: 
Calculated: C 28.99, H 2.68, N 20.28%. Found: C 30.06, H 3.34, N 18.68%. 
IR (KBr, cm.sup.-1): 3430, 1775, 1655, 1622, 1531, 1286, 1216. 
NMR (DMSO, ppm): 3.82 (3H, s, OCH.sub.3), 4.46 (1H, dd, 5.5 and 8.0 Hz, 
CH--CH.dbd.), 5.22 (1H, dd, 6 and 9 Hz, NH--CH), 6.57 (1H, s, S--CH.dbd.), 
7.18 (2H, br, NH.sub.2), 7.32 (1H, d, 8.0 Hz, CH.dbd.N), 9.29 (1H, 9 Hz, 
NH--CO), 11.0 (1H, s, CH). 
The 
(3S,4S)-3-amino-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-1-azetidinesu 
lphonic acid used as the starting material can be prepared as follows: 
(e) 0.25 g (0.78 mmol) of benzyl 
(3S,4S)-cis-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-3-azetidinecarbam 
ate are dispersed in 4 ml of pyridine and treated with 0.5 g (3.1 mmol) of 
sulphur trioxide pyridinium complex. The mixture is heated for 1 hour. The 
solution is cooled and subsequently treated with 50 ml of ether. The ether 
is decanted off and the residue is treated with 300 ml of water. The 
solution is stirred at room temperature for 12 hours in the presence of 
ion exchanger Dowex 50 W (sodium form). The ion exchanger is filtered off 
and the solution is evaporated under reduced pressure. There are obtained 
325 mg (100%) of crude 
(3S,4S)-cis-3-benzyloxyformamido-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2- 
oxo-1-azetidinesulphonic acid sodium salt. 
IR (KBr, cm.sup.-1): 3329, 1775, 1724, 1698, 1526, 1257. 
NMR (DMSO, ppm): 1.28 and 1.35 (2.times.3H, 2s, 2 CH.sub.3), 3.8-4.4 (4H, 
m, CH--CH--CH.sub.2), 4.99 (1H, dd, 6 and 10 Hz, NH--CH), 5.15 (2H, s, 
N--CH.sub.2), 7.45 (5H, s, C.sub.6 H.sub.5), 7.5 (1H, d, 10 Hz, CONH). 
(f) The 
(3S,4S)-cis-3-benzyloxyformamido-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2- 
oxo-1-azetidinesulphonic acid sodium salt is hydrogenated with 
palladium/carbon in a manner analogous to that described in Example 33, 
there being obtained 
(3S,4S)-3-amino-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-1-azetidinesu 
lphonic acid. 
EXAMPLE 36 
(a) From (3S,4S)-3-amino-4-methoxyiminomethyl-2-oxo-1-azetidinesulphonic 
acid and 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino-acetic acid 
2-benzthiazolyl thioester there is obtained in a manner analogous to that 
described in Example 1 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-methox 
yiminomethyl-2-oxo-1-azetidinesulphonic acid sodium salt. 
Elemental analysis for C.sub.11 H.sub.13 N.sub.6 O.sub.7 S.sub.2 Na: 
Calculated: C 30.84, H 3.06, N 19.62%. Found: C 30.88, H 3.19, N 19.52%. 
IR (KBr, cm.sup.-1): 3424, 3336, 1772, 1671, 1622, 1532, 1274. 
The (3S,4S)-3-amino-4-methoxyiminomethyl-2-oxo-1-azetidinesulphonic acid 
used as the starting material can be prepared as follows: 
(b) 3.0 g (7.5 mmol) of benzyl 
(3S,4S)-[1-(2,4-dimethoxybenzyl)-4-formyl-2-oxo-3-azetidinyl]carbamate are 
dissolved in 40 ml of methylene chloride and the solution is treated with 
0.7 g (8.5 mmol) of O-methylhydroxylamine hydrochloride and 0.73 ml (9.0 
mmol) of pyridine. The mixture is stirred at room temperature for 2 days 
and subsequently washed with water and sodium chloride solution. After 
drying over sodium sulphate and evaporation of the solvent, the material 
is chromatographed [230-400 mesh, ethyl acetate/n-hexane (6:4)]. There are 
obtained 2.6 g (82%) of benzyl 
(2S,4S)-1-(2,4-dimethoxybenzyl)-4-[(methoxyimino)methyl]-2-oxo-3-azetidine 
carbamate (mixture of the E and Z isomers). 
IR (KBr, cm.sup.-1): 3290, 1772, 1686, 1210. 
MS: 319 (M--.phi.--CH.sub.2 OH). 
(c) 11.9 g (44 mmol) of potassium peroxydisulphate and 9.6 g of dipotassium 
hydrogen phosphate are dispersed in 110 ml of acetonitrile and 350 ml of 
water. The mixture is heated to 78.degree. C. and a solution of 11.8 g 
(27.6 mmol) of benzyl 
(3S,4S)-1-(2,4-dimethoxybenzyl)-4-[(methoxyimino)methyl]-2-oxo-3-azetidine 
carbamate (mixture of the E and Z isomers) in 300 ml of acetonitrile is 
added dropwise thereto. The pH of the solution is held at 7 by the 
addition of dipotassium hydrogen phosphate. After boiling for 6 hours, the 
mixture is cooled, the aqueous phase is discarded, the organic phase is 
diluted with ethyl acetate and washed successively with water, aqueous 
sodium bicarbonate solution and sodium chloride solution. After drying 
over sodium sulphate, the solvent is removed by evaporation and the crude 
mixture is chromatographed [230-400 mesh, ethyl acetate/n-hexane (8:2)], 
there being obtained 1.7 g (27%) of benzyl 
(3S,4S)-4-[(methoxyimino)methyl]-2-oxo-3-azetidinecarbamate (mixture of 
the E and Z isomers); melting point 170.degree.-171.degree. C. 
IR (KBr, cm.sup.-1): 3310, 3210, 1790, 1732, 1533, 1258. 
(d) 1.7 g (6.13 mmol) of benzyl 
(3S,4S)-4-[(methoxyimino)methyl]-2-oxo-3-azetidinecarbamate (mixture of 
the E and Z isomers) are dissolved in 100 ml of absolute dioxan, the 
solution is treated with 1.26 g (7.9 mmol) of sulphur dioxide pyridinium 
complex and the mixture is stirred at room temperature for 1.5 hours. 
After the addition of a further 0.29 g (1.8 mmol) of sulphur trioxide 
pyridinium complex, the suspension is stirred for a further 1.5 hours. 
After the addition of 0.39 g (2.45 mmol) of sulphur trioxide pyridinium 
complex and stirring for a further 1 hour, the solvent is removed by 
evaporation under reduced pressure and the residue is treated with 30 ml 
of saturated aqueous sodium bicarbonate solution. The aqueous solution 
obtained is extracted twice with ethyl acetate and the organic phase is 
discarded. The aqueous phase is evaporated to 10 ml and chromatographed 
[(MCI gel; water/ethanol (1:0 to 9:1 to 7:3)]. There are obtained 1.36 g 
(58.5%) of 
(3S,4S)-3-[(benzyloxy)formamido]-4-[(methoxyimino)methyl]-2-oxo-1-azetidin 
esulphonic acid (mixture of the E and Z isomers). 
Elemental analysis for C.sub.13 H.sub.14 N.sub.3 O.sub.7 SNa: Calculated: C 
41.16, H 3.72, N 11.08%. Found: C 40.21, H 3.81, N 10.72%. 
IR (KBr, cm.sup.-1): 3396, 3347, 1774, 1708, 1256. 
(e) The thus-obtained 
(3S,4S)-3-[(benzyloxy)formamido]-4-[(methoxyimino)methyl]-2-oxo-1-azetidin 
esulphonic acid is hydrogenated in a manner analogous to that described in 
the last paragraph of Example 26. In this manner there is obtained 
(3S,4S)-3-amino-4-methoxyiminomethyl-2-oxo-1-azetidinesulphonic acid. 
EXAMPLE 37 
In a manner analogous to that described in Example 1, from 
(3S,4S)-3-amino-4-methoxyiminomethyl-2-oxo-1-azetidinesulphonic acid 
(mixture of the E and Z isomers) and 
2-[(5-amino-(1,2,4-thiadiazolyl)]-2-(Z)-methoxyiminoacetic acid 
2-benzthiazolyl thioester there is obtained as the end product 
(3S,4S)-3-(1,2,4-thiadiazolyl)]-2-[(Z)-(methoxyimino)acetamido]-4-methoxyi 
minomethyl-2-oxo-1-azetidinesulphonic acid sodium salt. 
Elemental analysis for C.sub.10 H.sub.12 N.sub.7 O.sub.7 S.sub.2 Na: 
Calculated C 27.97, H 2.82, N 22.84, S 14.93%. Found C 28.50, H 3.37, N 
24.07, S 14.79%. 
IR (KBr, cm.sup.-1): 3419, 1771, 1671, 1622, 1523, 1278. 
EXAMPLE 38 
(a) 378 mg (2.1 mmol) of 
(3S,4R)-3-amino-4-methyl-2-oxo-1-azetidinesulphonic acid are dissolved in 
60 ml of acetone/water (1:1) and the solution is treated with 1.3 g (2.3 
mmol) of 
2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(p-nitrobenzyloxycarbonyl)-1-methylethox 
y]imino]-acetic acid 2-benzthiazolyl thioester and 176 mg (2.1 mmol) of 
sodium bicarbonate. The mixture is stirred at room temperature for 12 
hours. The acetone is removed by evaporation under reduced pressure and 
the residue is filtered. The aqueous solution obtained is evaporated. 
There are obtained 115 mg (10% of 
(3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-(p-nitro-benzyloxycarbonyl)-1 
-methylethoxy]imino]acetamido]-4-methyl-2-oxo-1-azetidinesulphonic acid 
sodium salt as an amorphous material. 
IR (KBr, cm.sup.-1): 3380, 1753, 1678, 1620, 1523, 1286, 1236. 
NMR (DMSO, ppm): 1.24 (3H, d, J=6 Hz, CH--CH.sub.3), 1.46 and 1.50 
(2.times.3H, 2s, (CH.sub.3).sub.2 C), 3.99 (1H, m, CH--CH.sub.3), 5.10 
(1H, dd, J=6 and 9 Hz, NH--CH), 5.33 (2H, s, O--CH.sub.2), 6.69 (1H, s, 
S--CH.dbd.), 7.30 (2H, br, NH.sub.2), 7.59-8.18 (4H, m, Ar), 9.26 (1H, d, 
9 Hz, NHCO). 
The 
2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(p-nitrobenzyloxycarbonyl)-1-methylethox 
y]imino]-acetic acid 2-benzthiazolyl thioester used as the starting 
material can be prepared as follows: 
(b) 33.0 g (136 mmol) of t-butyl 
2-(2-amino-4-thiazolyl)-2-(Z)-hydroxyimino-acetate are dissolved in 500 ml 
of dimethylformamide. After the addition of 84.5 g (272 mmol) of 
p-nitrobenzyl 2-bromo-2-methylpropionate and 75.2 g (544 mmol) of finely 
powdered potassium carbonate, the mixture is stirred at 45.degree. C. for 
5 hours in a nitrogen atmosphere. The mixture is cooled to room 
temperature and poured into a mixture of 5 l of water and 2.5 l of ethyl 
acetate. The organic phase is washed three times with a total of 2.5 l of 
water. The aqueous phase is extracted with 2.5 l of ethyl acetate. The 
combined ethyl acetate solutions are dried over sodium sulphate and 
evaporated to dryness. There are obtained 42 g (66.4%) of 
t-butyl-2-(2-amino-4-thiazolyl)-2-[[(Z)-(p-nitrobenzyloxycarbonyl)-1-methy 
lethoxy]imino]-acetate of melting point 150.3.degree. C. 
(c) 23.4 g (50.4 mmol) of t-butyl 
2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(p-nitrobenzyloxycarbonyl)-1-methylethox 
y]imino]acetate are dispersed in 60 ml of trifluoroacetic acid and stirred 
at room temperature for 30 minutes. The solution obtained is evaporated, 
the residue is dissolved in 200 ml of toluene and the solution is 
evaporated. After the addition of 700 ml (280 mmol) of a 0.4M aqueous 
sodium bicarbonate solution, the pH is adjusted to 3.8 with acetic acid. 
The precipitated crystals are filtered off and dried at 50.degree. C. 
under reduced pressure (0.05 mm). There are obtained 17.3 g (84%) of 
2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(p-nitrobenzyloxycarbonyl)-1-methylethox 
y]imino]acetic acid of melting point 194.degree. C. (decomposition). 
The water content of the product is reduced to 0.26%, which is advantageous 
for the following reaction, by two-fold suspension in 100 ml of dry 
acetonitrile each time and evaporation of the solvent, followed by drying 
for 20 hours at room temperature under reduced pressure (0.1 mm). 
(d) 16.4 g (40.2 mmol) of 
2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(p-nitrobenzyloxycarbonyl)-1-methylethox 
y]imino]-acetic acid are dispersed in 250 ml of acetonitrile (dried with 
molecular sieve 3 .ANG.. After the addition of 5.6 ml (50.8 mmol) of 
N-methylmorpholine while stirring, there are added thereto, likewise while 
stirring, 16.0 g (48 mmol) of 2,2-dithio-bis-benzthiazole and 9.2 ml (44.4 
mmol) of triethyphosphite. The suspension obtained has an intense yellow 
colour. After stirring at room temperature for 1 hour, the mixture is 
cooled to 0.degree. C., the crystals obtained are filtered off after 1 
hour and dried at 50.degree. C. under reduced pressure (0.1 mm). There are 
obtained 16.1 g (72.2%) of 
2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(p-nitrobenzyloxycarbonyl)-1-methylethox 
y]imino]-acetic acid 2-benzthiazolyl thioester of melting point 
162.degree.-164.degree. C. 
EXAMPLE 39 
115 mg (0.19 mmol) of 
(3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-(p-nitro-benzyloxycarbonyl)-1 
-methylethoxy]imino]acetamido]-4-methyl-2-oxo-1-azetidinesulphonic acid 
sodium salt are dissolved in 40 ml of water/tetrahydrofuran (1:1) and the 
solution is hydrogenated for 12 hours over 300 ml of 10% palladium/carbon. 
The catalyst is filtered off and the solvent is evaporated under reduced 
pressure. The oil obtained is chromatographed (230-400 mesh, 
chloroform/methanol/n-propanol/water (4:6:1:4) as the solvent]. There are 
obtained 28.6 mg (33%) of 
(3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(1-carboxy-1-methylethoxy]imino] 
acetamido]-4-methyl-2-oxo-1-azetidinesulphonic acid sodium salt. 
IR (KBr, cm.sup.-1): 3297, 2984, 2683, 1763, 1675, 1631, 1535, 1276. 
NMR (DMSO, ppm): 1.1 and 1.20 (6H, 2s, 2.times.CH.sub.3), 1.45 (3H, d, 3.5 
Hz, CH--CH.sub.3, 4.0 (1H, m, CH--CH.sub.3), 5.05 (1H, dd, 6 and 9 Hz, 
NH--CH), 6.75 (1H, s, S--CH.dbd.), 7.20 (3H, br, NH.sub.3.sup.+, 9.15 (1H, 
d, 9 Hz, CONH). 
EXAMPLE 40 
In the same manner as described in Example 1, from 
(3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid and 
2-(2-amino-4-thiazolyl)-2-[[(Z(-(t-butoxycarbonyl)methoxy]imino]-acetic 
acid 2-benzthiazolyl thioester there is obtained as the end product 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(t-butoxycarbonyl)methoxy]imino 
]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid 
triethylamine salt. This salt is brought into solution in ethanol (about 
4%). The product is precipitated as the sodium salt by adding an 
equivalent amount of a 2N solution of sodium 2-ethyl caproate in ethyl 
acetate, 2 volumes of acetone and 4 volumes of diethyl ether. 
.sup.1 H-NMR (DMSO, ppm): 9.15 (d, J=9.5 Hz, 1H); 7.20 (s, br, 2H); 6.75 
(s, 1H); 6.46 (s, br, 2H); 5.28 (dd, J=4 Hz, J=9 Hz, 1H); 4.53 (s, 2H); 
4.0-4.3 (m, 3H); 1.43 (s, 9H). 
The 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxy]imino]-acetic 
acid 2-benzthiazolyl thioester used as the starting material can be 
prepared as follows: 
(A) 245 g (1.0 mol) of 2-(2-amino-4-thiazolyl)-2-(Z)-(hydroxyimino)-acetic 
acid are dispersed at room temperature in 2.2 l of dimethylformamide and 
treated with 245 g (1.13 mol) of p-nitrobenzyl bromide and 170 g (1.13 
mol) of sodium iodide. The mixture is stirred in a nitrogen or argon 
atmosphere for 12 hours. The brown solution obtained is treated with 190 
ml (1.29 mol) of t-butyl bromoacetate and 386 ml (2.25 mol) of 
N-ethyl-diisopropylamine. After stirring at room temperature for 1 hour, 
the mixture is poured into 8 l of water and the resulting mixture is 
extracted with 4 l of ethyl acetate. The ethyl acetate phase is washed 
with 3 l of water. The aqueous phases are extracted in two portions with 5 
l of ethyl acetate. The combined ethyl acetate phases are concentrated to 
1 l and cooled in an ice-bath. The crystals which thereby result are 
filtered off, washed with cold ethyl acetate and ether and dried at 
50.degree. C. under reduced pressure. There are obtained 248 g (57%) of 
p-nitrobenzyl 
2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxy]imino]-acetate. 
Elemental analysis for C.sub.18 H.sub.20 N.sub.4 O.sub.7 S (436.447): 
Calculated: C 49.54, H 4.62, N 12.84, S 7.35%. Found: C 49.57, H 4.69, N 
12.73, S 7.30%. 
109 g (0.25 mol) of p-nitrobenzyl 
2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxy]imino]-acetate 
are dispersed in 2 l of methanol. After the addition of 42 ml (0.30 mol) 
of triethylamine and 55 g of Raney-nickel, the mixture is shaken in a 
hydrogen atmosphere for 2.5 hours. 20.5 l of hydrogen are consumed. The 
catalyst is removed by filtration over siliceous earth and the filtrate is 
evaporated. The residue is dissolved in 600 ml of water and extracted with 
two 1000 ml portions of ethyl acetate. The ethyl acetate phase is washed 
with two 200 ml portions of water. The aqueous phases are combined and 
filtered,, the filtrate then being adjusted to pH 3 by treatment with 
about 250 ml of 1N aqueous hydrochloric acid while stirring. The crystals 
obtained are filtered off, washed with acetonitrile and water and dried 
under reduced pressure at 45.degree. C. for 16 hours. The thus-obtained 
crystalline material contains about 5% of water. Treatment with 
isopropanol reduces the water content 0.9%. Therefore, the crystals 
containing the 5% of water are dispersed in 100 ml of dry isopropanol, 
stirred at room temperature for 12 hours and dried at 45.degree. C. for 16 
hours under reduced pressure. 67 g (89%) of 
2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxy]imino]-acetic 
acid are obtained. 
Elemental analysis for C.sub.11 H.sub.15 N.sub.3 O.sub.5 S (301.324): 
Calculated: C 43.85, H 5.02, N 13.95, S 10.64%. Found: C 43.73, H 5.06, N 
13.73, S 10.42, H.sub.2 O 0.89%. 
The starting material can also be prepared as follows: 
(B) 84 g of diketene are dissolved in 250 ml of carbon tetrachloride and 
the solution is cooled to -27.degree. C. The solution is turbid. 71 g of 
chlorine gas are introduced slowly within 5 hours while stirring, the 
temperature being held at -20.degree. C. to -30.degree. C. by cooling. The 
clear solution obtained is added slowly within 1 hour while stirring at 
0.degree. C. to -5.degree. C. to a solution of 58 g of allyl alcohol in 
250 ml of carbon tetrachloride and 80.5 ml of pyridine. After stirring for 
a further 15 minutes without cooling, the precipitated pyridine 
hydrochloride is filtered off and washed with 100 ml of carbon 
tetrachloride. The carbon tetrachloride solution is washed with two 300 ml 
portions of water, dried over sodium sulphate and evaporated under reduced 
pressure. The residue is distilled, there being obtained 136 g (77%) of 
allyl 4-chloro-acetoacetate as a colourless liquid of boiling point 
61.degree.-69.degree. C./0.1 mmHg. 
A solution of 35.2 g of allyl 4-chloro-acetoacetate in 34 ml of acetic acid 
is treated dropwise within 45 minutes while stirring and cooling with a 
solution of 14.6 g of sodium nitrite in 21 ml of water. During the 
addition the temperature falls gradually from 0.degree. C. to -15.degree. 
C. The mixture is subsequently stirred at -15.degree. C. for 2 hours. A 
solution of 15.2 g of thiourea in 120 ml of water, pre-warmed to 
30.degree. C., is treated with the resulting solution at such a rate that 
the temperature remains at about 30.degree.-35.degree. C. After stirring 
for an additional 7 hours, the crystalline precipitate obtained is 
filtered off, washed successively with water, acetonitrile and ether and 
crystallized from acetonitrile. There are obtained 21.8 g (48%) of allyl 
2-(2-amino-4-thiazolyl)-2-(Z)-hydroxyimino-acetate of melting point 
184.degree.-185.degree. C. 
A solution of 20.4 g of allyl 
2-(2-amino-4-thiazolyl)-2-(Z)-hydroxyimino-acetate in 100 ml of dimethyl 
sulphoxide and 100 ml of acetone is stirred at room temperature for 5 
hours together with 30 g of potassium carbonate and 19.5 ml of t-butyl 
bromoacetate. After removal of the acetone by evaporation under reduced 
pressure (bath temperature 50.degree. C.), 600 ml of ethyl acetate are 
added thereto and the solution is washed with ice-water until neutral, 
dried and evaporated under reduced pressure. There is obtained a yellowish 
crystalline residue which is dispersed in diisopropyl ether, filtered and 
dried under reduced pressure. There are obtained 20.1 g (65.5%) of allyl 
2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxy]imino]-acetate 
of melting point 135.degree.-136.degree. C. 
19 g of allyl 
2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxy]imino]-acetate 
in 500 ml of ethyl acetate are treated successively while stirring with 
0.9 g of palladium chloride, 0.46 ml of triethyl phosphite and 30 ml of 
sodium 2-ethyl caproate solution (2N solution of ethyl acetate). After 
stirring at room temperature for 4 hours, 500 ml of water and 100 ml of 
saturated aqueous sodium bicarbonate solution are added thereto. The 
aqueous solution is separated, washed with 100 ml of ethyl acetate and 
acidified to pH 2 with 2N aqueous hydrochloric acid. The crystalline 
precipitate is filtered off, washed successively with water, acetonitrile 
and ether and dried under reduced pressure. There are obtained 14.6 g 
(87%) of 
2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxy]imino]-acetic 
acid of melting point 175.degree.-176.degree. C. (decomposition). 
The following are further methods for the preparation of the starting 
material: 
(C) The allyl 
2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxy]imino]-acetate 
is reacted in the same manner as described in section (B), but using 0.12 
g of palladium acetate in place of palladium chloride. After identical 
working-up, there are obtained 14.5 g (86.3%) of 
2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxy]imino]-acetic 
acid of melting point 171.degree.-172.degree. C. 
(D) The allyl 
2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxy]imino]-acetate 
is reacted in a manner analogous to that described in section (C), but 
using 0.695 g of triphenylphosphine in place of triethyl phosphite. There 
are obtained 13.4 g (79.7%) of 
2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxy]imino]-acetic 
acid of melting point 167.degree.-169.degree. C. 
(E) A suspension of 1.4 g of allyl 
2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxy]imino]-acetate, 
86 mg of 5% palladium/carbon, 0.033 ml of triethyl phosphite and 2.25 ml 
of sodium 2-ethylcaproate solution (2N solution in ethyl acetate) in 50 ml 
of ethyl acetate is stirred at 60.degree. C. for 12 hours. After cooling 
to room temperature, the mixture is worked-up as described in section (B) 
above. There is obtained 0.81 g (65.5%) of 
2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxy]imino]-acetic 
acid of melting point 174.degree.-175.degree. C. 
(F) 3.41 g of allyl 
2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxy]imino]-acetate 
are dispersed in 100 ml of ethyl acetate and treated with 250 mg of 
triphenylphosphine and 250 mg of tetrakis-(triphenylphosphine)-palladium. 
The solution obtained is treated with 5.5 ml of sodium 2-ethylcaproate 
solution (2N solution in ethyl acetate). A thick pulp-like mass which can 
not be stirred results within a short time. After standing at room 
temperature for 15 minutes, this mass is shaken once with 100 ml of water 
and once with 30 ml of saturated aqueous sodium carbonate solution. The 
aqueous solutions are combined and washed once with 50 ml of ethyl 
acetate. The combined aqueous solutions are adjusted to pH 2 with 2N 
aqueous hydrochloric acid. The crystalline precipitate is filtered off and 
washed successively with water, acetonitrile and ether. There are obtained 
2.4 g of 
2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxy]imino]-acetic 
acid of melting point 167.degree.-169.degree. C. (decomposition). 
(G) 3.41 g of allyl 
2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxy]imino]-acetate 
are dispersed in 100 ml of ethyl acetate and treated with 18 mg of 
palladium chloride and 0.084 ml of triethyl phosphite. After the addition 
of 1.2 ml of N-methylmorpholine, the mixture is stirred at room 
temperature for 48 hours, crystallization occurring slowly. The mixture is 
left to stand for 4 days, the precipitate is filtered off under suction, 
washed with ethyl acetate and dried in vacuo. There are obtained 3.52 g of 
the N-methylmorpholine salt of 
2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxy]imino]-acetic 
acid. 
The crude salt is suspended in 100 ml of dry acetonitrile. 0.49 ml of 
N-methylmorpholine and 3.32 g of 2,2-dithio-bis-benzthiazole are 
successively added thereto while stirring and the suspension obtained is 
cooled to 5.degree. C. A solution of 2.5 ml of triethyl phosphite in 30 ml 
of dry acetonitrile is now added dropwise within 4 hours. After stirring 
for a further 30 minutes, the yellow suspension obtained is cooled to 
-10.degree. C. The crystals are filtered off under suction and washed with 
cold acetonitrile and ether. There are obtained 1.9 g of 
2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxy]imino]-acetic 
acid 2-benzthiazolyl thioester of melting point 142.degree.-143.degree. C. 
(decomposition). 
54.2 g (180 mmol) of 
2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxy]imino]-acetic 
acid are dispersed in 1.4 l of dry acetonitrile. There are added thereto 
29.6 ml (270 mmol) of N-methylmorpholine, followed by 72.1 g (216 mmol) of 
2,2-dithio-bis-benzthiazole. The suspension obtained is cooled to 
0.degree. C. Within 4.5 hours there is now added thereto a solution of 
53.8 ml (314 mmol) of triethyl phosphite in 350 ml of dry acetonitrile. 
After stirring for a further 30 minutes, the yellow suspension obtained is 
cooled to -10.degree. C. The crystals are filtered off and washed with 
cold acetonitrile and ether. There are obtained 59.7 g (73.6%) of 
2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxy]imino]-acetic 
acid 2-benzthiazolyl thioester. 
Elemental analysis for C.sub.18 H.sub.18 N.sub.4 O.sub.4 S.sub.3 (450.561): 
Calculated: C 47.99, H 4.03, N 12.44, S 21.35%. Found: C 47.88, H 4.34, N 
12.34, S 21.02%. 
EXAMPLE 41 
71.8 g (0.3 mol) of 
(3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid are 
dispersed in 1.5 l of methylene chloride and treated while stirring with 
45.6 g (0.45 mol) of triethylamine and 148.6 g (0.33 mol) of 
3-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxy]imino]-acetic 
acid 2-benzthiazolyl thioester. The mixture is stirred at room temperature 
for 5 hours. 1.5 l of water are subsequently added thereto, the aqueous 
phase is separated, extracted twice with 250 ml of methylene chloride and 
acidified by the addition of 850 ml of 37% aqueous hydrochloric acid. 
After stirring at room temperature for 2 hours, the suspension obtained is 
cooled to 0.degree. C. and stirred for a further 0.5 hour. The precipitate 
is filtered off, washed successively with 1000 ml of cold water, 1000 ml 
of methanol and 1000 ml of ether and dried at 40.degree. C./10 mmHg for 12 
hours. There are obtained 111 g (79.3%) of crude 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxymethoxy)imino]acetamido] 
-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid of melting point 
207.degree. C.; [.alpha.].sub.D.sup.20 =-46.2.degree. (c=1 in dimethyl 
sulphoxide). 
Elemental analysis for C.sub.12 N.sub.14 N.sub.6 O.sub.10 S.sub.2 : 
Calculated: C 30.90; H 3.03, N 18.02, S 13.75%. Found: C 28.23, H 3.81, N 
16.18, S 12.26, H.sub.2 O 3.61%. 
Corrected for anhydrous substance C 29.29, H 3.53, N 16.79, S 12.72%. 
An analytical sample gives the following data: 
[.alpha.].sub.D.sup.20 =+39.degree. (c=1 in water); corrected for anhydrous 
substance +42.5.degree. (c=0.9 in water). 
[.alpha.].sub.D.sup.20 =-43.5.degree. (c=1 in dimethyl sulphoxide); 
corrected for anhydrous substance -47.4.degree. (c=0.9 in water). 
IR (KBr, cm.sup.-1): 3458, 3428, 3354, 3291, 1777, 1712, 1648, 1617, 1557, 
1531. 
.sup.1 H-NMR (DMSO, ppm): 3.9-4.4 (3H, m, CH--CH.sub.2 --O) 4.79 (2H, s, 
O--CH.sub.2 --COOH), 5.30 (1H, dd, 5 and 9 Hz, NH--CH--CH); 6.5 (6H, br, 
NH.sub.3.sup.+, NH.sub.2, COOH), 6.90 (1H, s, H--thiazole), 9.45 (1H, d, 9 
Hz, CO--NH). 
Elemental analysis for C.sub.12 H.sub.14 N.sub.6 O.sub.10 S.sub.2 : 
Calculated: C 30.90, H 3.03, N 18.02, S 13.75%. Found: C 28.39, H 3.43, N 
16.44, S 12.47, H.sub.2 O 8.14%. 
Corrected for anhydrous substance C 30.91, H 2.74, N 17.90, S 13.58%. 
EXAMPLE 42 
110 g (0.235 mol) of crude 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxymethoxy)imino]acetamido] 
-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid (obtained according 
to Example 41) are dispersed in 4.7 l of methanol and treated with 72.3 ml 
(0.518 mol) of triethylamine and 282.9 ml (0.566 mol) of a 2N solution of 
sodium 2-ethylcaproate in ethyl acetate. The solution obtained is stirred 
for 10 minutes, diluted with 9 l of acetone and concentrated to 3 l. The 
residual suspension is diluted with 3 l of acetone, filtered and the 
crystalline salt is washed with ether and dried. 108.59 g (90.5%) of 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxymethoxy)imino]acetamido] 
-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid disodium salt are 
obtained. This crude salt is dissolved in 420 ml of water. 1050 ml of 
ethanol are added thereto and subsequently (after a few minutes) a further 
210 ml of ethanol are added. The solution is turbid and is stirred for 1 
hour. 1770 ml of ethanol are now added dropwise thereto within 2 hours. 
After stirring for a further 1 hour and cooling to 0.degree. C., the 
precipitate is filtered off and washed with ethanol. The crystals obtained 
are dispersed in 170 ml of ethanol and 680 ml of ether, filtered off and 
washed with ether. After drying under greatly reduced pressure at 
40.degree. C., there obtained 102.9 g (85.5%) of 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxymethoxy)imino]acetamido] 
-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid disodium salt. 
Elemental analysis for C.sub.12 H.sub.12 N.sub.6 O.sub.10 S.sub.2 Na.sub.2 
: Calculated: C 28.24, H 2.37, N 16.47, S 12.56%. Found: C 28.18, H 2.63, 
N 16.34, S 12.21, H.sub.2 O 1.02%. 
Corrected for anhydrous substance C 28.48, H 2.65, N 16.50, S 12.33%. 
[.alpha.].sub.D.sup.20 =+19.degree. (c=1 in water) 
IR (KBR, cm.sup.-1): 1777, 1712, 1648, 1617, 1557, 1417. 
UV [H.sub.2 O; .lambda. max (.epsilon.)]: 295 nm (6850), 233 nm (12330). 
.sup.1 H-NMR (D.sub.2 O, ppm): 4.2-4.8 (5H, m, CH--CH.sub.2 --O--CO, 
O--CH.sub.2 --COONa), 5.6 (1H, d, 5.5 Hz, O.dbd.C--CH), 7.05 (1H, s, 
H-thiazole). 
EXAMPLE 43 
In the same manner as described in Example 1, from 191 mg of 
(3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid and 
2-[5-(1-t-butoxyformamido)-3-(1,2,4-thiadiazolyl)]-2-[[(Z)-(t-butoxycarbon 
yl)methoxy]imino]-acetic acid 2-benzthiazolyl thioester there are obtained 
as the end product 355 mg of 
(3S,4S)-3-[(Z)-2-[[(t-butoxycarbonyl)methoxy]imino]-2-[5-(1-t-butoxyformam 
ido)-1,2,4-thiadiazol-3-yl]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidin 
esulphonic acid triethylamine salt. 
.sup.1 H-NMR (DMSO, ppm): 9.1 (d, J=9 Hz, 1H), 6.30 (s, br, 2H); 5.24 (dd, 
J=4 Hz, J=9 Hz, 1H); 4.63 (s, 2H); 4.0-4.3 (m, 3H); 3.04 (q, J=7.3 Hz, 
6H); 1.53 (s, 9H); 1.44 (s, 9H); 1.16 (t, J=7.3 Hz, 9H). 
The 
2-[5-(1-t-butoxyformamido)-3-(1,2,4-thiadiazolyl)]-2-[[(Z)-(t-butoxycarbon 
yl)methoxy]imino]-acetic acid 2-benzthiazolyl thioester used as the 
starting material can be prepared as follows: 
2 g of 
2-[5-(1-t-butoxyformamido)-3-(1,2,4-thiadiazolyl)]-2-[[(Z)-(t-butoxycarbon 
yl)methoxy]imino]-acetic acid and 2 g of 2,2-dithio-bis-benzthiazole are 
suspended in 50 ml of acetonitrile and 0.7 ml of N-methylmorpholine and 
treated while stirring within 1 hour with 1.1 ml of triethyl phosphite in 
10 ml of acetonitrile. The product is taken up in ethyl acetate, washed 
with water, dried and concentrated. The residual yellow oil is 
chromatographed on silica gel. The thioester crystallizes from hexane (0.8 
g). There is obtained 
2-[5-(1-t-butoxyformamido)-3-(1,2,4-thiadiazolyl)]-2-[[(Z)-(t-butoxycarbon 
yl)methoxy]imino]-acetic acid 2-benzthiazolyl thioester of melting point 
115.degree.-120.degree. C. 
Elemental analysis: Calculated C 47.96, H, 4.57, N 12.70, S 17.43%. Found: 
C 48.06, H 4.83, N 12.46, S 17.77%. 
EXAMPLE 44 
804 mg (2 mmol) of 
2-[5-(1-t-butoxyformamido)-3-(1,2,4-thiadiazolyl)]-2-[[(Z)-(t-butoxycarbon 
yl)methoxy]imino]-acetic acid 2-benzthiazolyl thioester are dissolved in 30 
ml of methylene chloride and the solution is treated with 0.25 ml (2.05 
mmol) of 1-chloro-N,N,2-trimethyl-1-propenamine, followed by 0.57 ml (2.05 
mmol) of triethylamine and 478 mg (2 mmol) of 
(3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid. The 
mixture is stirred for 12 hours and subsequently evaporated. The residue 
is treated with a solution of 370 mg of sodium bicarbonate in 30 ml of 
water. The crude mixture is chromatographed on MCI gel using 25% aqueous 
methanol for the elution, there being obtained 406 mg (34%) of 
(3S,4S)-3-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[[(t-butoxycarbonyl)met 
hoxy]imino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid 
triethylamine salt. 
Elemental analysis for C.sub.21 H.sub.36 N.sub.8 O.sub.10 S.sub.2 : 
Calculated: C 40.38, H 5.81, N 17.94%. Found: C 40.31, H 5.70, N 17.99%. 
.sup.1 H--NMR (DMSO, ppm): 1.17 (9H, t, 7.5 Hz, 3.times.CH.sub.2 CH.sub.3, 
1.42 (9H, s, 3.times.CH.sub.3), 3.09 (6H, q, J=7.5 Hz, 3.times.CH.sub.2), 
4.10 (3H, m, CH--CH.sub.2), 4.60 (2H, s, N--O--CH.sub.2), 5.25 (1H, dd, 
J=5 and 9 Hz, NH--CH), 6.30 (2H, s, NH.sub.2), 8.10 (2H, s, NH.sub.2), 9.0 
(1H, d, J=9 Hz NH--CH). 
EXAMPLE 45 
314 mg (0.502 mmol) of 
(3S,4S)-3-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[[(t-butoxycarbonyl)met 
hoxy]imino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid 
triethylamine salt are dissolved at 0.degree. C. in 5 ml of 3.5N aqueous 
hydrochloric acid. The mixture is stirred at 0.degree. C. for 2 days. The 
solvent is removed by evaporation under reduced pressure, the residue is 
taken up in 15 ml of ethanol/water (2:1) and treated with 2 ml of 2N 
sodium 2-ethylcaproate in ethyl acetate. The mixture is concentrated and 
the residue is chromatographed on MCI gel using water for the elution. 
There are obtained 135 mg (53%) of 
(3S,4S)-3-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(carboxymethoxy)imino] 
acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid disodium 
salt. 
Elemental analysis for C.sub.11 H.sub.11 N.sub.7 O.sub.10 S.sub.2 
Na.sub.2.NaCl: Calculated: C 23.41, H 1.81, N 17.20, S 11.03, Cl 6.52%. 
Found: C 23.19, H 1.95, N 17.21, S 11.15 Cl 6.22%. 
IR (KBr, cm.sup.-1): 1767, 1664, 1614. 
.sup.1 H-NMR (DMSO, ppm): 4-4.20 (3H, m, CH--CH.sub.2), 4.30 (2H, s, 
N--O--CH.sub.2), 5.26 (1H, dd, J=5 and 10 Hz, NH--CH), 6.50 (2H, br 
NH.sub.2), 8.11 (2H, s, NH.sub.2), 10.90 (1H, d, J=10 Hz, NH--CH). 
EXAMPLE 46 
In the same manner as described in Example 1, from 352 mg (1.5 mmol) 
(3S,4S)-3-amino-4-[(E)-2-carbamoylvinyl]-2-oxo-1-azetidinesulphonic acid 
and 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino-acetic acid 2-benzthiazolyl 
thioester there are obtained 180 mg (27%) of 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-[(E)-c 
arbamoylvinyl]-2-oxo-1-azetidinesulphonic acid sodium salt. 
Elemental analysis for C.sub.12 H.sub.13 N.sub.6 O.sub.7 S.sub.2 Na: 
Calculated: C 32.72, H 2.98, N 19.08%. Found: C 32.68, H 2.91, N 18.93%. 
IR (KBr, cm.sup.-1): 1769, 1675, 1648, 1613. 
.sup.1 H-NMR (DMSO, ppm): 3.80 (3H, s, OMe), 4.55 (1H, dd, J=6 and 7.5 Hz, 
NH--CH--CH), 5.30 (1H, dd, J=6 and 9 Hz, NH--CH--CH), 6.20 (1H, d, J=16 
Hz, .dbd.CH--CONH.sub.2), 6.70 (1H, dd, J=7.5 and 16 Hz, 
CH.dbd.CH--CONH.sub.2) 6.80 (1H, s, H--thiazole), 7.0-7.5 (4H, br, 
2.times.NH.sub.2), 9.40 (1H, d, J=9 Hz, NH--CH). 
The (3S,4S)-3-amino-4-[(E)-2-carbamoylvinyl]-2-oxo-1-azetidinesulphonic 
acid used as the starting material can be prepared as follows: 
59.08 g (0.175 mmol) of 
(3S,4S)-3-amino-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4 
-yl]-2-azetidinone in 1 l of dioxan are treated with 46.9 g (0.215 mol) of 
di-t-butyl dicarbonate in the presence of 16.4 g of potassium carbonate. 
After stirring at room temperature for 4 hours, the precipitate obtained 
is filtered off and the filtrate is evaporated under reduced pressure. The 
residual oily residue is recrystallized from methylene chloride/n-hexane. 
64.5 g (84.4%) of 
t-butyl(3S,4S)-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4- 
yl]-3-azetidinecarbamate are obtained. 
76.8 g (0.176 mol) of 
t-butyl(3S,4S)-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4- 
yl]-3-azetidinecarbamate are dissolved in 500 ml of tetrahydrofuran and 350 
ml of water and the solution is heated to 60.degree. C. for 24 hours with 
13.0 g of p-toluenesulphonic acid. The mixture is cooled, neutralized with 
10% aqueous potassium bicarbonate solution and evaporated. The residue is 
taken up in 300 ml of dioxan and treated with 21.8 g (0.1 mol) of 
di-t-butyl dicarbonate and 7.63 g of potassium carbonte. The mixture is 
stirred at room temperature for 24 hours and filtered. The solvent is then 
removed by evaporation. The crude product is recrystallized from 
acetonitrile. 61.3 g (88%) of 
t-butyl(3S,4S)-1-(2,4-dimethoxybenzyl)-4-[(R)-1,2-dihydroxyethyl]-2-oxo-3- 
azetidinecarbamate are obtained. 
5.0 g (12.6 mmol) of 
t-butyl(3S,4S)-1-(2,4-dimethoxybenzyl)-4-[(R)-1,2-dihydroxyethyl]-2-oxo-3- 
azetidinecarbamate are dissolved in 50 ml of methanol and the solution is 
treated with a solution of 2.95 g (13.8 mmol) of sodium metaperiodate in 
30 ml of water. The pH of the solution is held at 6.0 by the addition of 
aqueous saturated sodium bicarbonate solution. After stirring at room 
temperature for 30 minutes, the sodium iodate formed is filtered off and 
the filtrate is evaporated. The residue is taken up in ethyl acetate and 
washed with aqueous sodium chloride solution, dried over magnesium 
sulphate and evaporated. The oily residue is crystallized from ether, 
there being obtained 2.70 g (58.8%) of 
t-butyl(3S,4S)-1-(2,4-dimethoxybenzyl)-4-formyl-2-oxo-3-azetidinecarbamate 
Elemental analysis for C.sub.18 H.sub.24 N.sub.2 O.sub.6 : Calculated: C 
59.33, H 6,64, N 7.69%. Found: C 59.08, H 6.91, N 7.38%. 
4.0 g (11 mmol) of 
t-butyl(3S,4S)-1-(2,4-dimethoxybenzyl)-4-formyl-2-oxo-3-azetidinecarbamate 
are dissolved in 300 ml of methylene chloride and the solution obtained is 
treated dropwise with a solution of 3.9 g (12 mmol) of 
carbamoylmethylene-triphenylphosphorane in 100 ml of methylene chloride. 
After 1 hour, the mixture is filtered and the crystals obtained are washed 
with methylene chloride. There are obtained 3.6 g (81%) of 
t-butyl(3R,4S)-1-(2,4-dimethoxybenzyl)-4-[(E)-2-carbamoylvinyl]-2-oxo-3-az 
etidinecarbamate of melting point 270.degree. C. 
IR (KBr, cm.sup.-1): 1767, 1719, 1684, 1644. 
3.6 g (8.9 mmol) of 
t-butyl(3R,4S)-1-(2,4-dimethoxybenzyl)-4-[(E)-2-carbamoylvinyl]-2-oxo-3-az 
etidinecarbamate are dissolved in 80 ml of acetonitrile and 150 ml of water 
and the solution is treated dropwise under reflux with a solution of 4.9 g 
(17.8 mmol) of potassium peroxydisulphate in 50 ml of water. The pH is 
held at 6.5 by the addition of saturated aqueous sodium bicarbonate 
solution. After 4 hours 40 ml of acetonitrile are distilled off. The crude 
mixture is subsequently partially evaporated and cooled to +5.degree. C. 
The crystals obtained are filtered off. The filtrate is washed twice with 
100 ml of ether each time. The aqueous phase is saturated with sodium 
chloride and extracted three times with 300 ml of ethyl acetate each time. 
The combined organic phases are dried over sodium sulphate and evaporated. 
There is obtained a brown residue which yields 920 mg (41%) of 
t-butyl(3R,4S)-4-[(E)-2 -carbamoylvinyl]-2-oxo-3-azetidinecarbamate after 
recrystallization from methanol. 
IR (KBr, cm.sup.-1): 1784, 1732, 1689, 1673. 
Elemental analysis for C.sub.11 H.sub.17 N.sub.3 O.sub.4 : Calculated: C 
51.76, H 6.71, N 16.46%. Found: C 51.88, H 6.81, N 16.41%. 
1.45 g (5.68 mmol) of 
t-butyl(3R,4S)-4-[(E)-2-carbamoylvinyl]-2-oxo-3-azetidinecarbamate are 
dissolved in 80 ml of acetonitrile and the solution is treated with 1.86 g 
(11.6 mmol) of pyridine-sulphur trioxide complex. The mixture is stirred 
at 40.degree. C. for 20 hours. The solvent is subsequently removed by 
evaporation and the residue is taken up in 100 ml of water. The pH is 
adjusted to 7-8 by the addition of saturated aqueous sodium bicarbonate 
solution. The volume is reduced to 30 ml by evaporation and the solution 
obtained is chromatographed on MCI gel using water for the elution. 1.61 g 
(67.5%) of 
(3R,4R)-3-(1-t-butoxyformamido)-4-[(E)-2-carbamoylvinyl]-2-oxo-1-azetidine 
sulphonic acid sodium salt are obtained. 
Elemental analysis for C.sub.11 H.sub.16 N.sub.3 O.sub.7 SNa: Calculated: C 
36.98, H 4.51, N 11.76%. Found: C 37.31, H 4.89, N 11.19%. 
IR (KBr, cm.sup.-1): 1768, 1692, 1645. 
1.55 g (4.34 mmol) of 
(3R,4R)-3-(1-t-butoxyformamido)-4-[(E)-2-carbamoylvinyl]-2-oxo-1-azetidine 
sulphonic acid sodium salt are dissolved in 5 ml of anisole, the solution 
is cooled to 0.degree. C. and then treated with 5 ml of trifluoroacetic 
acid. The suspension obtained is stirred at 0.degree. C. for 1 hour and 
subsequently at room temperature for 2 hours. The mixture is diluted with 
100 ml of ether and 20 ml of n-hexane. The crystals obtained are filtered 
off and dried. The thus-obtained crude material is dissolved in 10 ml of 
water and chromatographed on MCI gel using water for the elution. 1.04 g 
(100%) of 
(3S,4S)-3-amino-4-[(E)-2-carbamoylvinyl]-2-oxo-1-azetidinesulphonic acid 
are obtained. 
IR (KBr, cm.sup.-1): 1779, 1683, 1648, 1608. 
EXAMPLE 47 
278 mg (1 mmol) of 
rac-cis-3-amino-4-[(Z)-2-(ethoxycarbonyl)-1-methylvinyl]-2-oxo-1-azetidine 
sulphonic acid are dissolved in 10 ml of water and 10 ml of acetone and the 
solution is treated with 290 mg (1.1 mmol) of sodium bicarbonate and 386 
mg (1.1 mmol) of 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino-acetic acid 
2-benzthiazolyl thioester. The mixture is stirred at room temperature for 
48 hours. The organic solvent is removed under reduced pressure and the 
resulting crystals are filtered off. The filtrate is chromatographed on 
MCI gel using water for the elution. 161 mg (43%) of 
rac-cis-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-[(Z)-2 
-(ethoxycarbonyl)-1-methylvinyl]-2-oxo-1-azetidinesulphonic acid sodium 
salt are obtained. 
Elemental analysis for C.sub.15 H.sub.18 N.sub.5 O.sub.8 S.sub.2 Na: 
Calculated: C 37.27, H 3.75, N 14.49%. Found: C 37.52, H 3.84, N 14.51%. 
IR (KBr, cm.sup.-1): 1771, 1688, 1620, 1533. 
.sup.1 H-NMR (DMSO, ppm): 1.21 (3H, t, J=7 Hz, CH.sub.3 CH.sub.2), 2.03 
(3H, d, J=1 Hz, CH.sub.3 --C.dbd.), 3.76 (3H, s, OCH.sub.3), 4.08 (2H, q 
J=7 Hz, CH.sub.3 --CH.sub.2), 4.54 (1H, dd, J=6 and 1 Hz, NH--CH--CH), 
5.28 (1H, dd, J=6 and 9 Hz, NH--CH), 6.05 (1H, t, J=1 Hz, .dbd.CH), 6.57 
(1H, s, H--thiazole), 7.17 (2H, br, NH.sub.2), 9.28 (1H, d, J=9 Hz, 
NH--CH). 
The 
rac-cis-3-amino-4-[(Z)-2-(ethoxycarbonyl)-1-methylvinyl]-2-oxo-1-azetidine 
sulphonic acid used as the starting material can be prepared as follows: 
6.68 (0.042 mol) of 2,4-dimethoxybenzylamine in 150 ml of methylene 
chloride are treated with 5.97 g (0.04 mol) of ethyl 3-formylcrotonate in 
the presence of magnesium sulphate. After stirring for 30 minutes, the 
precipitate obtained is filtered off. The imine solution obtained is 
cooled to 0.degree. C., treated with 6.7 ml of triethylamine and then 
dropwise with a solution of 10.2 g (0.046 mmol) of phthalimidoacetyl 
chloride in 50 ml of methylene chloride. The mixture is stirred at 
0.degree. C. for 1 hour, then warmed to room temperature and subsequently 
washed successively with dilute aqueous hydrochloric acid, water and 
aqueous sodium chloride solution. After drying and evaporation, the crude 
mixture is recrystallized from methylene chloride/n-hexane. There are 
obtained 15.6 g (81.6%) of pure ethyl 
rac-cis-1-(2,4-dimethoxybenzyl)-.beta.-methyl-4-oxo-3-phthalimido-2-azetid 
ineacrylate of melting point 159.degree.-160.degree. C. 
IR (KBr, cm.sup.-1): 1766, 1723, 1656. 
37.0 g (77.3 mmol) of ethyl 
rac-cis-1-(2,4-dimethoxybenzyl)-.beta.-methyl-4-oxo-3-phthalimido-2-azetid 
ineacrylate are dissolved in 500 ml of methylene chloride and the solution 
is treated with 8.2 ml (B 0.15 mmol) of N-methylhydrazine at 30.degree. C. 
for 48 hours. The mixture is filtered and the filtrate is evaporated. The 
residue is taken up in ethyl acetate and filtered. The filtrate is 
extracted with 200 ml of aqueous hydrochloric acid and the aqueous phase 
is separated, neutralized with saturated aqueous sodium bicarbonate 
solution and extracted twice with 200 ml of methylene chloride each time. 
After drying and evaporation, the crude colourless product is isolated. 
There are obtained 25.1 g (93%) of ethyl 
rac-cis-3-amino-3-(2,4-dimethoxybenzyl)-.beta.-methyl-2-oxo-4-azetidineacr 
ylate of melting point 89.degree.-93.degree. C. 
IR (KBr, cm.sup.-1): 1741, 1708, 1651, 1616. 
18.4 g (0.053 mol) of ethyl 
rac-cis-3-amino-1-(2,4-dimethoxybenzyl)-.beta.-methyl-2-oxo-4-azetidineacr 
ylate are dissolved in 350 ml of dioxan and the solution is treated with 15 
ml (0.068 mol) of di-t-butyl dicarbonate in the presence of 5 g of 
potassium carbonate. The mixture is stirred at room temperature for 12 
hours, subsequently filtered and the filtrate is evaporated. The residue 
is taken up in methylene chloride and washed with water and sodium 
chloride solution. After drying and evaporation, the crude material is 
recrystallized from methylene chloride/n-hexane. There are obtained 18.4 g 
(77.5%) of colourless ethyl 
rac-cis-3-(1-t-butoxyformamido)-1-(2,4-dimethoxybenzyl)-.beta.-methyl-2-ox 
o-4-acetidineacrylate of melting point 150.degree.-152.degree. C. 
4.0 g (8.9 mmol) of ethyl 
rac-cis-3-(1-t-butoxyformamido)-1-(2,4-dimethoxybenzyl)-.beta.-methyl-2-ox 
o-4-azetidineacrylate are dissolved in 300 ml of acetonitrile and the 
solution is treated at 90.degree.-95.degree. C. with 3.86 g (14.3 mmol) of 
potassium peroxydisulphate and 2.31 g (13.3 mmol) of potassium hydrogen 
sulphate for 2 hours. The organic solvent is removed by evaporation and 
the aqueous phase is extracted with chloroform. The combined organic 
phases are washed with aqueous sodium chloride solution and dried over 
sodium sulphate. The solution is evaporated and the residue is 
chromatographed on silica gel using ethyl acetate for the elution. 990 mg 
(37%) of t-butyl 
4-[2-(ethoxycarbonyl)-1-methylvinyl]-2-oxo-3-azetidinecarbamate are 
obtained. 
IR (KBr, cm.sup.-1): 1783, 1758, 1712, 1703, 1690. 
2.25 g (7.5 mmol) of 
t-butyl-4-[2-(ethoxycarbonyl)-1-methylvinyl]-2-oxo-3-azetidinecarbamate 
are dissolved in 20 ml of acetonitrile and the solution is treated at room 
temperature with 3.0 g (18.8 mmol) of sulphur trioxide-pyridine complex. 
The mixture is stirred at room temperature for 12 hours. The acetonitrile 
is removed by evaporation and the residue is treated with 3.16 g (36 mmol) 
of sodium bicarbonate in 60 ml of water. The solution is concentrated to 
30 ml by evaporation and cooled to 6.degree. C. 1.92 g (63%) of 
crystalline rac-cis-3-(1-t-butoxyformamido)-4-[(Z)-2-(ethoxycarbonyl)-1-me 
thylvinyl]-2-oxo-1-azetidinesulphonic acid sodium salt are obtained. 
Elemental analysis for C.sub.14 H.sub.21 N.sub.2 O.sub.8 SNa: Calculated: C 
42.00, H 5.29, N 7.00%. Found: C 42.07, H 5.27, N 7.23%. 
IR (KBr, cm.sup.-1): 1774, 1715, 1692, 1668. 
1.755 g (4.38 mmol) of 
rac-cis-3-(1-t-butoxyformamido)-4-[(Z)-2-(ethoxycarbonyl)-1-methylvinyl]-2 
-oxo-1-azetidinesulphonic acid sodium salt are dissolved in 7.5 ml of 
anisole and the solution is treated at -20.degree. C. with 10 ml of 
trifluoroacetic acid. After stirring at -20.degree. C. for 30 minutes and 
then at room temperature for a further 3 hours, the solution is diluted 
with 300 ml of ether/n-hexane (1:1). The crystals obtained are filtered 
off, dissolved in 10 ml of water and chromatographed on MCI gel. 808 mg 
(60%) of 
rac-cis-3-amino-4-[(Z)-2-(ethoxycarbonyl)-1-methylvinyl]-2-oxo-1-azetidine 
sulphonic acid are obtained. 
EXAMPLE 48 
717 mg (3 mmol) of 
(3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid are 
dispersed in 75 ml of methylene chloride and treated at room temperature 
while stirring with 0.46 ml (3.3 mmol) of triethylamine and 2.70 g (3.3 
mmol) of 2-(tritylamino-4-thiazolyl)-2-(Z)-trityloxyimino-acetic acid 
2-benzthiazolyl thioester. The solvent is removed by evaporation and the 
residue is chromatographed on silica gel using methylene chloride/methanol 
(92:8) for the elution. 1.58 g (53%) of 
(3S,4S)-3-[(Z)-2-(2-tritylamino-4-thiazolyl)-2-(trityloxyimino)acetamido]- 
4-carbamoyloxymethyl-3-oxo-1-azetidinesulphonic acid are obtained. 
1.42 g (1.43 mmol) of 
(3S,4S)-3-[(Z)-2-(2-tritylamino-4-thiazolyl)-2-(trityloxyimino)acetamido]- 
4-carbamoyloxymethyl-3-oxo-1-azetidinesulphonic acid in 15 ml of formic 
acid are stirred at room temperature for 4 hours with 0.01 ml of water. 
The solvent is removed by evaporation, the residue is taken up in water 
and azeotropically distilled with toluene. The residue is recrystallized 
from water/ethanol (4:1). 296 mg (51%) of 
(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-4-carbam 
oyloxymethyl-2-oxo-1-azetidinesulphonic acid are obtained. 
The 2-(2-tritylamino-4-thiazolyl)-2-(Z)-trityloxyiminoacetic acid 
2-benzthiazolyl thioester used as the starting material can be prepared as 
follows: 
67.2 g of 2-(2-tritylamino-4-thiazolyl)-2-(Z)-trityloxyimino-acetic acid 
and 40 g of 2,2-dithio-bis-benzthiazole are suspended in 1.6 l of 
acetonitrile and 16.5 ml of N-methylmopholine and the suspension is 
treated at 0.degree. C. while stirring with 30 ml of triethyl phosphite in 
200 ml of acetonitrile. A small amount of insoluble material is removed by 
filtration. The solution is concentrated to a small volume and treated 
with isopropanol. The mixture is again concentrated to a small volume. The 
thioester which crystallizes out is filtered off and dried. There are 
obtained 75.0 g of 
2-(2-tritylamino-4-thiazolyl)-2-(Z)-trityloxyimino-acetic acid 
2-benzthiazolyl thioester of melting point 111.degree.-112.degree. C. 
EXAMPLE 49 
478 mg of (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic 
acid, 338 mg of 2-(pyrazol-3-yl)-2-(Z)-methoxyimino-acetic acid and 0.892 
ml of triethylamine are dissolved in 5 ml of dimethylformamide and the 
solution is reacted for 1 hour with 613 mg of 2-chloro-1-methylpyridinium 
iodide. The mixture is evaporated at 25.degree. C. under reduced pressure. 
The residue is taken up in water and chromatographed over reverse-phase 
silica gel with water. After lyophilization, there are obtained 645 mg of 
(3S,4S)-4-carbamoyloxymethyl-3-[[2-(methoxyimino)-2-pyrazol-3-yl]acetamido 
]-2-oxo-1-azetidinesulphonic acid triethylamine salt. 
Elemental analysis for C.sub.17 H.sub.29 N.sub.7 O.sub.8 S (491.52): 
Calculated: C 41.54, H 5.95, N 19.95, S 6.52%. Found: C 41.47, H 5.57, N 
19.11, S 6.71%. 
EXAMPLE 50 
In the same manner as described in Example 49, from 360 mg of 
(3S,4S)-trans-3-amino-4-methyl-2-oxo-1-azetidinesulphonic acid and 
2-(pyrazol-3-yl)-2-(Z)-methoxyimino-acetic acid there are obtained 423 mg 
of 
(3S,4S)-trans-3-[[2-(methoxyimino)-2-(pyrazol-3-yl)]acetamido]-4-methyl-2- 
oxo-1-azetidinesulphonic acid triethylamine salt. 
.sup.1 H-NMR (DMSO, ppm): 9.25 (d, J=8 Hz, 1H), 7.77 (m, 1H), 6.45 (m, 1H), 
4.41 (dd, J=2, 5 Hz and 8 Hz, 1H), 3.85 (s, 3H), 3.64 (dd, J=2.5 Hz and 6 
Hz, 1H), 3.69 (q, J=7 Hz, 6H), 1.40 (d, J=6 Hz, 3H), 1.16 (t, J=7 Hz, 9H). 
EXAMPLE 51 
Manufacture of dry ampoules for intramuscular administration: 
A lyophilizate of 1 g of 
(3S,4S)-3-[(5-amino-3-(1,2,4-thiadiazolyl)]-2-(Z)-(methoxyimino)acetamido] 
-4-methoxyiminomethyl-2-oxo-1-azetidinesulphonic acid sodium salt is 
prepared in the usual manner and filled into an ampoule. Prior to the 
administration the lyophilizate is treated with 2.5 ml of a 2% lidocaine 
hydrochloride solution.