NO832001L - PROCEDURE FOR PREPARING 1-SULFO-2-OXO-AZETIDIN DERIVATIVES - Google Patents

Abstract

l-sulfo-2-oxoazetidine derivatives with the general for—. where Het is an optionally amino-substituted, 5- or 6-membered, aromatic heterocyclic ring containing 1. or 2 nitrogen atoms, possibly also an oxygen or sulfur atom, R^" means hydrogen, lower-alkyl, phenyl-lower-alkyl, lower -alkanoyl, lower-alkoxycarbonyl, lower-,.vere-alkenyl-lower-alkyl, lower-alkoxycarbonyl-• lower-alkyl, phenyl-lower-alkoxycarbonyl-lower-alkyl , nitrophenyl-lower-alkoxycarbonyl-lower-al-2. alkyl or carboxy-lower-alkyl, and R means hydro-|_j gen, lower-alkyl, lower-alkenyl, lower-alkynyl,.lower-alkoxycarbonyl, lower-alkanoyloxy-lower-alkyl, lower-alkoxycarbonyl-lower-alkenyl, hydro-j_I xyiminomethyl, lower-alkoxyiminomethyl, carbamoyl,.carbaraoyl-lower-alkenyl or carbamoyloxy-lower-j!alkyl, the group =NORi being at least partially present in syn form,.i.jji racemic form or in the form of the 3S -enantiomers, as well as of easily hydrolyzable esters or pharmaceutically acceptable salts of these compounds. one is described. The compounds have anti-microbial action.

Description

I il I The present invention relates to a method by

J preparation of 1-sulfo-2-oxoazetidine derivatives with the ' i ' i i general formula ! In !i

i : i where Het is an optionally amino-substituted 5- or 6-membered, aromatic heterocycle containing 1 or 2 nitrogen atoms, optionally also

in an oxygen or sulfur atom,'

j R^" means hydrogen, lower alkyl, phenyl-lower alkyl, 1

j lower alkanoyl, lower alkoxycarbonyl, lower- : j alkenyl-lower alkyl, lower alkoxycarbonyl-lower-

! alkyl, phenyl-lower-alkoxycarbonyl-lower alkyl,

in nitrophenyl-lower-alkoxycarbonyl-lower alkyl or carboxy-lower alkyl, and

in R 2hydrogen, loweralkyl, loweralkenyl, loweralkynyl,.loweralkoxycarbonyl, loweralkanoyloxy-loweralkyl, loweralkoxycarbonyl-loweralkenyl,

hydroxyiminomethyl, lower alkoxyiminomethyl, carbamoyl, carbamoyl-lower alkenyl or carbamoyloxy-lower alkyl, the group =NOR"'' being at least partially present in syn-form,

1 racemic form or in the form of the 3S enantiomers, as well

as easily hydrolyzable esters or pharmaceutically acceptable salts of these compounds.

The heterocycle denoted by "Het" includes all 5- or 6-membered, aromatic ring structures, which have 1 or 2 nitrogen atoms and are optionally substituted by an amino group, e.g. pyrazolyl groups, such as 2-pyrazol-3-yl, amino-pyridyl groups, such as 2-amino-6-pyridyl, amino-imidazolyl groups, such as 2-amino-4-imidazolyl. Optionally, they may contain an oxygen atom, such as e.g. in amino-oxazolyl groups,<:>In e.g. 2-amino--4-oxazolyl or a sulfur atom, such as <:>i amino-thiadiazolyl groups, such as 5-amino-3-(1,2,4-thiadiazo^ lyl) or especially amino-thiazolyl groups, which 2-amino-4-| thiazolyl.

i The term "lower-alkyl" alone or in combinations means an aliphatic hydrocarbon group, which may be straight-chain

; or branched and preferably contains up to 7 carbon atoms, such as e.g. 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 meaning. The term "lower alkenyl" alone or in compounds means an olefinic hydrocarbon group, which may be straight-chain or branched and preferably contain up to 7 carbon atoms, such as eg vinyl, allyl, isopropenyl, 2-methallyl, 2-butenyl, 3-butenyl, 2-hexenyl, 2-heptenyl, etc. The term "lower alkynyl" means an ace-;

tylenic hydrocarbon group, which can be straight-chain or branched and preferably contain up to 7 carbon atoms, such as e.g. ethynyl, 1-propynyl, 2-propynyl, 2-hexynyl, 2-heptynyl, etc.. The term "lower alkanoyl" acc. "lower-alkanoyloxy" means an aliphatic carboxylic acid residue with up to 7 carbon atoms, such as, for example, acetyl, propionyl, isobutyryl, acetoxy, propionyloxy, isobutyryloxy.

Preferred R^ groups are: hydrogen, methyl, ethyl, isopropyl, benzyl, 2-phenethyl, acetyl, propionyl, methoxycarbonyl, ethoxycarbonyl, methoxycarbonylmethyl, t-butoxycarbonylmethyl, carboxymethyl, 1-methyl-l-t-butoxycarbonyl-ethyl, 1-methyl -1-benzhydryloxycarbonyl-ethyl, 1-methyl-1-trityl-oxycarbonyl-ethyl, 1-methyl-1-(p-nitrobenzyloxycarbonyl)-ethyl, 1-methyl-1-carboxyethyl; particularly preferred are methyl, carboxymethyl and 1-methyl-1-carboxyethyl.

Preferred R 2 groups 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 with the formula

j

is 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;

in particular 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 may exist in various isomeric forms [e.g. cis, trans; syn(Z-form), anti(E-form); as well as 3S enantiomers]. The same applies to the subsequently described output connections.

The compounds of formula I can be present as free acids, e.g. as betaines or also as pharmaceutically tolerable salts, which are obtained by salt formation of the free 1-sulfo group acc. of a random carboxy group in the substituent in the 3-position with a basic salt former. As basic salt formers, e.g. in consideration: inorganic cations, such as sodium and potassium ions, basic amino acids, such as arginine, ornithine, lysine or histidine, polyhydroxyalkyl amines, such as N-methylglucamine, diethanolamine, triethanolamine, etc.

Carboxy groups present in a compound of formula I acc. salts of these can, by corresponding esterification, be transferred into easily hydrolyzable ester groups. Such easy

hydrolyzable ester groups, which in the body are split into the corresponding free carboxy groups, are e.g. a-(lower-

alkoxy)-lower-alkoxycarbonyl groups, such as methoxymethoxy-carbonyl, a-methoxyethoxycarbonyl, lower-alkylthiomethoxy-carbonyl groups, such as methylthiomethoxycarbonyl, a-(lower-alkanoyl)-lower-alkoxycarbonyl, such as acetoxymethoxycar-j I bonyl, pivaloyloxymethoxycarbonyl, a-pivaloyloxyethoxy- > carbonyl; α-(lower oxycarbonyl)-lower alkoxycarbonyl, j such as ethoxycarbonyloxymethoxycarbonyl, t-butoxycarbonyl-I methoxycarbonyl or α-ethoxycarbonyloxycarbonyl; lacto-nyl groups, such as phthalidyl or thiophthalidyl; or the group.

In Examples of compounds of formula I, which can be prepared according to the invention, the end products described in the following examples 1-50 are both in the form in which they exist according to the examples (3S-enantiomers according to racemate) as well as also in the form of light hydrolyzable esters and f maceutically tolerable salts of these compounds. 1 Particularly preferred compounds under formula I are the compounds with the general formula

where R 1^" is methyl, carboxymethyl or 1-methyl-

21

1-carboxyethyl and R carbamoyl or carbamoyloxymethyl,

in racemic form or in the form of the 3S enantiomers as well as

IN

; the corresponding easily hydrolyzable esters and pharmaceutical '

in tolerable salts of these compounds. j i i i Particularly 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-azetidine sulfonic acid and (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-

in

[(carboxymethoxy)imino]acetamido]-4-carbamoyloxymethyl-

in 2-oxo-1-azetidine sulfonic acid as well as their pharmaceutical;

' tolerable salts.

Further subgroups of the process products of formula I are the following:

- where Het, R 1 and R 2 have the above meaning, with

the restriction that when at the same time Het means 2-amino-4-thiazolyl and R 2 means lower-alkyl, lower-alkanoyloxy-lower-alkyl, carbamoyloxy-lower-alkyl, lower-alkoxycarbonyl, lower-alkoxyiminomethyl or carbamoyl, R^" is hydrogen, lower-alkyl, phenyl-lower-alkyl, lower-alkanoyl, lower-alkoxycarbonyl or lower-alkenyl-lower-alkyl;

1 2

where Het, R and R have the above meaning, with

the limitation that when at the same time Het means 2-amino^4-thiazolyl, and R 2 means carbamoyloxy-lower-alkyl, R is hydrogen, lower-alkyl, phenyl-lower-alkyl, lower-^alkanoyl, lower-alkoxy-carbonyl or lower-alkenyl-lower-alkyl;

either in racemic form or in the form of the 3S enantiomers as well as the corresponding easily hydrolyzable esters and pharmaceutically acceptable salts of these compounds.

The compounds of formula I as well as their easily hydrolyzable esters and pharmaceutically acceptable salts are prepared according to the invention according to a method which is characterized by acylating a racemic form or

f

ler in the form of the 3S enantiomer present compound with the general formula 1

where R 20 has the same meaning as R 2, or can ! be a 2,2-dimethyl-1,3-dioxolan-4-yl group, and I R is hydrogen or sulfo,

in

or a salt thereof with a thioester of the general formula

where Het has the above-mentioned meaning, and R"*"0 has the same meaning as R"*", however, does not mean carboxy-lower-alkyl, but can also be a tri-lower alkyl-silyl-lower-alkoxycarbonyl-lower-alkyl group or a to an easily hydrolysable ester group converted to a carboxy-lower alkyl group, and the group =NOR"^ exists at least partially in syn-form, to a compound with the general formula present in racemic form or in the form of the 3S-enantiomer

10 20 3

where R , R , R and Het have the meanings indicated above, and the group =N0R"^ is at least partially present in syn form,

then sulphonates a product obtained, where R^ is hydro-

7

IN

gene, transfers a 2,2-di-jmethyl-1,3-dioxolan-4-yl group R present in all cases to hydroxyiminomethyl-i in the group, a lower-alkoxyiminomethyl group or the carbam■ oyl jiIVinyl group, transfers one in all cases the presence-l i.de tri-lower alkylsilyl-lower-alkoxycarbonyl-lower-alkyl-' jgroup R 10 in carboxy-lower-alkyl, converts if desired i;

In the substituents R"^ according to R"^" in the sense of lower- alkyl-. if desired, converts an er^i 1 kept product into a pharmaceutically acceptable salt.

The reaction according to the invention of the compounds with the I general formulas II and IH is suitably carried out in an inert organic solvent, e.g. in a chlorinated hydrocarbon, such as methylene chloride or chloroform, in an ether, I I e.g. tetrahydrofuran or dioxane, in an ester, e.g. ethyl acetate, in a ketone, e.g. acetone, in an aprotic form

solvent, such as acetonitrile, dimethylformamide or di-

t

methylacetamide, or in a mixture of one of these solvents with water. The reaction temperature is suitably between approx. -40° and +60°C, preferably between -15°C and +25°C, especially 0-20°C. The reaction participants are used appropriately in approx. stoichiometric ratio or with a small excess of thioether of the formula III. The reaction is advantageously carried out in the presence of a base, which e.g. an organic amine, such as triethylamine or N-methylmorpholine, or an alkali metal bicarbonate, such as sodium bicarbonate.

The products obtained are then sulphonated, where R<3> is hydrogen. The sulphonation can take place in a manner known per se by reaction with sulfur trioxide or a reactive derivative thereof, e.g. with complexes of sulfur trioxide and an organic base, such as pyridine, dimethylformamide, jpicoline, etc. The conversion takes place e.g. at approx. -10°C to ; +80°C in an inert organic solvent, e.g. in an ether, such as dioxane, in an ester, such as ethyl acetate, in a chlorinated hydrocarbon such as methylene chloride; in acetonitrile, dimethyl forma-

Oh I

mid or pyridine.

i jIf in the reaction product with formula Ib R is the 2,2-dimethyl-11,3-dioxolan-4-yl group, this must be transferred into hydroxy-; , the imino group or in a lower-alkoxyimino group according to

following form:

in

If in the reaction product of formula Ib R^ is a trilower-: alkylsilyl-lower-alkoxycarbonyl-lower-alkyl group (such as [[2-(trimethylIsilyl)ethoxy]-carbonyl]methyl- or 1-methyl-1-[ [2-(trimethylsilyl)ethoxy]carbo<n>Y<l>]ethyl group) this is converted into the corresponding carboxy-lower-alkyl group-:.pe, suitably by treatment with a quaternary organic fluoride, such as tetrabutylammonium fluoride. The temperature is preferably close to room temperature, and the reaction is conveniently carried out in an inert organic solvent, such as tetrahydrofuran or methanol.

;If in the reaction ion product with formula Ib acc. In R^ acc. R means a lower carboxycarbonyl-lower alkyl group (such as t-butoxycarbonylmethyl or 1-methyl-1-(t-butoxycarbonyl)-ethyl group), this can if desired be converted into the corresponding carboxy-lower alkyl group, and then by treatment with a strong acid, such as trifluoroacetic acid (possibly in the presence of anisole), hydrochloric acid or p-toluenesulfonic acid, at a lower temperature, such as -10°C to room temperature.

If in the reaction the ion product with formula Ib acc. I, R"*"^ acc. R<1>is a phenyl-lower-alkoxycarbonyl-lower-alkyl group (such as the benzyloxycarbonylmethyl- or 1-methyl-1-(benzyloxycarbonyl)-ethyl group) or a nitrophenyl-lower-alkoxycarbonyl-lower-alkyl group (such as p-nitrobenzyloxycarbonylmethyl or 1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyl group, this can, if desired, be converted into the corresponding carboxy-lower alkyl group, and then by catalytic "hydrogenation with e.g. palladium carbon or palladium diatomaceous earth as a catalyst, for example in a lower alkanol, such as ethanol, at about 0-80°C.

The preparation of salts of the process products with

.formula I can take place in a manner known per se, e.g. by reacting an acid of formula I with an equivalent amount of the desired base, possibly in the form of an ion exchanger. One works appropriately in a solvent, such as water, or in an organic solvent, such as ethanol, methanol, acetone, ethyl acetate and the like. The temperature during salt formation is not critical, however, it is usually within the range 0-50°C, preferably at room temperature. The thioesters of formula III can be prepared by reacting a carboxylic acid with the general formula

where R and Het have the above meanings,

with dithio-bis-benzthiazole in the presence of a tri-(lower alkyl)-phosphite and a base or in the presence of triphenyl-phosphine. The reaction temperature is conveniently between approx. -30°C and +50°C, advantageously between approx. -20° and +25°C. The esterification is advantageously carried out in an organic solvent, e.g. in acetonitrile or in methylene chloride. The preferred embodiment is the reaction in the presence of a tri-(lower alkyl) phosphite and a base. As tri-(lower-alkyl)-phosphite, triethyl phosphite is preferably used and as base preferably an organic base, especially a tertiary organic base, such as triethylamine, N-ethyl-diisopropylamine, or preferably, N-methylmorpholine.

The preparation of easily hydrolyzable esters of the thioesters

■ with formula III can take place in a manner known per se by releasing the carboxy 1-lower alkyl group R"^ (as described above - for the end products with formula Ib according to I)

11

and then reaction with an esterification agent which provides the easily hydrolyzable ester group, e.g. with the corresponding halide, e.g. iodide, suitably in the presence of a base, e.g. in the presence of an alkali metal hydroxide or carbonate or in the presence of an organic amine, 1 such as triethylamine. The esterification is preferably carried out in an inert organic solvent, such as dimethylacetamide, hexamethylphosphoric acid triamide, dimethylsulfoxide or dimethylformamide. The temperature is preferably within

.the area approx. 0-40°C.

Preferred thioesters of formula III are those of the formula

where R 12 is lower-alkylcarbonyl-lower-alkyl, phenyl-lower-alkylcarbonyl-lower-alkyl, nitrophenyl-lower-alkylcarbonyl-lower-alkyl or tri-lower-alkylsilyl-lower-alkylcarbonyl-lower-alkyl.

Particularly preferred thioesters of formula IIIb are those in which

12

R is lower-alkoxycarbonylmethyl, phenyl-lower-alkoxy-carbonylmethyl, nitrophenyl-lower-alkoxy-carbonylmethyl or tri-lower-alkylsilyl-lower-alkoxycarbonylmethyl, especially 2-(2-amino-4-thiazolyl)-2-[[(Z) The -1-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid 2-benzthiazolyl thioester and 2-(2-amino-4-thiazolyl)-2-[[(Z)-(p-nitrobenzyloxycarbonyl)-methoxy ]imino]-acetic acid 2-benzthiazolyl thioester; moreover also such thioesters of formula IIIb, where R 12 is lower-alkoxycarbonyl-1-methylethyl, 1-(phenyl-lower-alkoxycarbonyl)-1-methylethyl, 1-(nitrophenyl-lower- alkoxycarbonyl)-'1-methylethyl or 1 -(tri-lower alkylsilyl-lower oxycar-

X/L. • •

bonyl)-1-methylethyl, especially 2-(2-amino-4-thiazolyl)-2-[[(Z)-1- [2-(trimethylsilyl)-ethoxycarbonyl]-1-methylethoxy ]-imino]-acetic acid -2-benzthiazol1-thioester, 2-(2-amino-4-thiazolyl)- i i2 - [ [ (Z) -1-(p-nitrobenzyloxy carbony 1)-1-methylethoxy] -imino]-acetic acid -2-benzthiazolyl thioester and 2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(t-butoxycarbonyl)-1-methyl-ethoxy]-imino]-acetic acid- The 2-benzthiazolyl thioester.

A particular problem arises in the preparation of the acids of formula IV, where R"^"0 is the group -Cf^-COOC (R^), where R

is C1-2-alkyl. However, the traditional method for the recovery of such compounds, namely reaction of the methyl or ethyl ester of the corresponding hydroxyimino compound with a haloacetic acid C(R)3 ester and subsequent saponification, does not give the desired acid of formula IV with R<10 >= -CH0-COOC(R)3, as the group -COOC(R)3 is saponified. It is thus necessary to embark on a new path of synthesis.

The aforementioned acid with formula IV, where R<10>= -CH2-COOC(R)3, can however be recovered in good yield when, instead of the aforementioned methyl or ethyl ester, the allyl or p-nitrobenzyl ester is introduced, i.e. .that one in an ester with the general'formula

where Het has the above meaning, R is C 1-3 alkyl and R 5 allyl or p-nitrobenzyl,

gap- group R^ of.

"C 1-3 alkyl" includes: methyl, ethyl, n-propyl and isopropyl. The preferred residue of formula -COO-C(R)3 is that in which R is methyl, i.e. t-butoxycarbonyl.

1J

According to one embodiment of the method according to the invention, an ester with the formula X, where R 5 is <1>p-nitrobenzyl, is split hydrogenolytically. This cleavage is preferably carried out with the aid of hydrogen and a metal catalyst, preferably Raney nickel, whereby the reaction can

is accelerated by the addition of an organic base, such as tri-•ethylamine. A la-' is preferably used as a solvent. vere-alkanol, such as methanol or ethanol. The temperature is preferably between approx. 0 and 80°C, especially work : man at room temperature.

According to a further embodiment of the method according to the invention, an ester of formula X, where R 1 is allyl, is cleaved catalytically. This cleavage takes place 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 come into consideration: palladium-carbon, palladium salts, especially salts with halogen hydrogen acids, such as hydrochloric or hydrobromic acid, or with lower alkane carboxylic acids, such as acetic acid or propionic acid. Organic palladium complexes with triphenylphosphine or a tri-(lower alkyl) phosphite, such as triethyl phosphite, are also suitable, since it is also possible to work without additional triphenylphosphine or tri-(lower alkyl) phosphite. Furthermore, the reactant is an alkali metal alkanoate, e.g. sodium acetate or, preferably, sodium 2-ethyl caproate, or also an organic base, such as triethylamine or N-methyl-morpholine. The reaction temperature can vary between approx. 0 and 100°C, but is preferably at room temperature (when using palladium carbon, however, somewhat higher; approx. 50-80°C). Preferably work is done in an inert organic solvent, e.g. in ethyl acetate or methylene chloride.

The aforementioned p-nitrobenzyl esters of formula X can be prepared by starting from a Het-2-(Z)-hydroxyiminoacetic acid by adding p-nitrobenzyl bromide or chloride and an alkali metal iodide and then adding a compound of the general formula

in

14

Hal - CH2 - COO - C(R)3 XI

where R has the aforementioned meaning, and Hal is chlorine,

bromine or iodine, in the presence of a base, such as alkali carbonate, triethylamine or N-ethyl-diisopropylamine, and an alkali metal iodide. The allylic esters of formula X can be prepared by starting from the diketene, chlorine gas and allyl alcohol, which turns into allyl-4-chloroacetoacetate. The latter is nitrosated with nitric acid and then transferred with thiourea into the Het-2-(Z)-hydroxyimino-acetic acid allyl ester, which is then converted with the aforementioned compound of formula XI in the presence of a base, such as alkali carbonate, triethylamine or N-ethyl -diisopropylamine,

in the allyl ester of formula X.

The starting compounds of formula II can be obtained by various methods. For the production of optically uniform compounds of formula II with 3S-cis configuration, one can work by starting from isopropylidene-L-glyceraldehyde according to the formula scheme below (scheme I - VII). The preparation of optically uniform compounds of formula II with 3S-trans configuration is illustrated in Schemes V and VI.

Explanations to forms I- VII

in

DMB = 2,4-dimethoxybenzyl Ft = phthalimido

Et = ethyl

Me = methyl

TSOH = p-toluenesulfonic acid

THF = tetrahydrofuran

PrOH = n-propanol

DMSO = dimethyl sulfoxide

Py = pyridine

Py.SO^= sulfur trioxide-pyridine complex

Z = benzyloxycarbonyl

Trt = trityl

Ac = lower-alkanoyl, e.g. acetyl

A subset of novel compounds of formula I are those of the general formula

where R"^" has the meaning given under form I,

R 4 has the same meaning as Het in formula I, and

21 2

R has the meaning given for R in formula I, with the group =NOR"^ at least partially present in syn-form, with the proviso that at least one of the following two conditions is met: a) R^ = 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 21= hydroxyaminomethyl, lower- Alkoxyiminomethyl, Lower-Alkoxycarbonyl-Lower-Alkeny1

or carbamoyl-lower—alkenyl,

in racemic form or in the form of the 3S enantiomer, as well as easily hydrolyzable esters, henh, pharmaceutically acceptable

in I salts of these compounds. '

i A subgroup of the compounds of formula Ic are those of the general formula j

1 2

where R and R have the same meaning as in formula I above and R 4 is 2-amino-4-oxazoly1, 2-amino-6-pyridyl, 2-amino-4-imidazoly1, 5-amino-3-(1, 2,4-thiadiazolyl) or 2-pyrazol-3-yl, wherein the group

^NOR"<*>" is at least partially available in syn-form,

in racemic form or in the form of the 3S enantiomer, as well as easily hydrolyzable esters acc. pharmaceutically acceptable salts of these compounds; as well as those with the general formula

where R"<*>" and Het have the same meaning as in formula I, and R 21 is hydroxyiminomethyl, lower-alkoxyiminomethyl, lower-alkoxycarbonyl-lower-alkenyl or carbamoyl-lower-alkenyl, the group =NOR^

at least partially available in visual form,

in racemic form or in the form of the 3S enantiomer, as well as easily hydrolyzable esters acc. pharmaceutically acceptable salts of these compounds.

salts of these compounds.

The new 1-sulfo-2-oxo-azetidine derivatives with the general

formula Ic and their easily hydrolyzable esters acc. pharmaceutically tolerable salts can be prepared according to the invention by

a) reacts a carboxylic acid with the general formula

where R^ ® has the same meaning as in formula III 40 4 above, and R the same meaning as R in formula Ic above, although a present amino group may be protected, and the group =N0R"'" exists at least partially in syn- form, or a functional derivative thereof, with a compound present in racemic form or in the form of the 3S-enantiomer with the general formula 21 where R has the same meaning as in formula Ic above, or with a salt thereof and then cleaves off any amino protecting group, or that one b) sulfonates a compound present in racemic form or in the form of the 3S enantiomer with the general formula

1 1 21

in where R and R have it in the formulas I acc. Ic for-

j 41

in the meaning indicated, and R has the same meaning. in ; I as R 4 in formula Ic above, although an amino group present in I is protected, and the group =NOR<1>:

at least partially available in visual form,

in

or a salt thereof, and then cleaves the amino protecting group off, or that one

c) for the preparation of a compound of formula Ic, where 21

R is hydroxyiminomethyl, lower-alkoxyiminomethyl or carbamoylvinyl, reacts a compound present in racemic form or in the form of the 3S-enantiomer with the general formula

where R 4 has the meaning given in formula Ic above and R 10 has the meaning given in formula Ib above, and the group =N0R^^ at least partially exists in syn-form, with hydroxylamine, an O-lower alkylhydroxylamine or with carbamoylmethylenetriphenylphosphorane and in all cases a product obtained with R 21 = hydroxyiminomethyl is lower-alkylated, or that one d) for the preparation of a compound of formula Ic, where R is carboxy-lower-alkyl, in a compound present in racemic form or in the form of the 3S-enantiomer with the general formula

where R and R have the above meaning, and

in 13i I R is tri-lower-alkyl-silyl-lower-alkoxycarbo- j

nyl-lower-alkyl, lower-alkoxycarbonyl-lower-al-;

In kyl, phenyl-lower-alkoxycarbonyl-lower-alkyl or

in nitrophenyl-lower-alkoxycarbonyl-lower-alkyl, wherein:

In 1 the group =NOR is at least partially present in syn form, the group R 13 transfers into carboxyl-lower-alkyl, or that one

e) transfers a compound of formula Ic acc. a readily hydrolyzable ester thereof in a pharmaceutically acceptable form

salt.

The reaction according to the invention of the carboxylic acid of formula IVb (according to a functional derivative thereof) with the compound of formula Ila can be carried out in a manner known per se. If the free carboxylic acid of formula IVb is used, one preferably works in the presence of a condensing agent, as the condensing agent, e.g. a substituted carbodiimide, such as N,N-dicyclohexylcarbodiimide; a quaternary 2-halopyridinium salt, e.g. 2-chloro-1-methylpyridinium iodide; or also l-chloro-N,N,2-trimethyl-1-propenamine comes into question. As functional derivatives of the carboxylic acid of formula IVb come into consideration: acid halides, e.g. acid chlorides, acid anhydrides, e.g. mixed anhydrides with C 2 -, alkanecarboxylic acids, such as acetic acid; acid azides; active amides, e.g. amides with pyra^o] , imidazole, benz-triazole; active husbands, ~. p.Sk.a. C 3 -alkyl, methoxymethyl, 2-propynyl, 4-nitrophenyl or hydroxysuccinimide esters or also active thioesters, such as esters with 2-pyridinethiol or 2-benzthiazolylthiol. The 2-benzthiazolylthioesters are described above.

The reaction of the compound with the general formula IVb (or a functional derivative thereof) with the compound of formula Ila conveniently takes place in an inert organic solvent, e.g. in a chlorinated hydrocarbon, such as methylene chloride or chloroform in an ether, e.g. tetrahydrofuran

IN

in or dioxane, in an ester, e.g. ethyl acetate, in a ketone, e.g. acetone, in an aprotic solvent, such as acetonitrile, dimethylformamide or dimethylacetamide, or in a mixture of one of these solvents with water. The reaction temperature is suitably between approx. -40°C

and +60°C, advantageously between -15°C and +25°C, especially 0-20°C. The reaction participants are used appropriately in approx. stoichiometric ratio or with a small excess of carboxylic acid with the formula IVb acc. its functional derivative. The reaction is advantageously carried out in the presence of a base, such as e.g. in the presence of an organic amine, such as triethylamine or N-methyl-morpholine, or in the presence of an alkali metal bicarbonate, such as sodium bicarbonate.

40

If the group R in the initial expression with formula. IVa acc. its functional derivative contains an amino substituent, then this can preferably remain unprotected (because a reaction step, the subsequent cleavage of the amino protecting group, can thereby be saved). However, R 40 can also contain a protected amino group, in which case ordinary amino protecting groups come into play, e.g. acid-hydrolytically cleavable protecting groups, such as t-butoxycarbonyl, benzhydryl, trityl or formyl, basic-hydrolytically cleavable protecting groups, such as e.g. trifluoroacetyl or also chloro-, bromo- or iodoacetyl, which can be split off with thiourea. The amino group can also be protected by salt formation with a mineral acid, e.g. hydrochloric acid. After the turnover of the output connections IVb and Ila acc. the functional derivative of the compound IVb with the compound Ila, an occurring amino protecting group is cleaved. Protective groups that can be removed by acid hydrolysis are preferably removed by means of a lower alkane carboxylic acid, which can optionally be halogenated. In particular, hydrochloric acid, formic acid or trifluoroacetic acid (the latter possibly in the presence of anisole) or also pyridinium hydrochloride are used. The temperature is usually room temperature, although also slightly higher according to a slightly lower temperature can be used, e.g. in the area approx. 0°C to +40°C. Alkaline-cleavable protecting groups are generally hydrolysed with dilute aqueous lye at 0°C to 30°C. The chloroacetyl, bromoacetyl and iodoacetyl protecting groups can be cleaved off with the aid of thiourea in an acidic, neutral or alkaline environment at approx. 0- 30°C.

According to variant b) according to the method according to the invention, a compound of formula XII is sulphonated. This sulfonation can take place in a manner known per se by reaction with sulfur trioxide or a reactive derivative thereof, e.g. complexes of sulfur trioxide with an organic base, such as pyridine, dimethylformamide, picoline, etc. The conversion takes place e.g. at approx. -10°C to +80°C in an inert organic solvent, e.g. in an ether, such as dioxane; in an ester, such as ethyl acetate; in a chlorinated hydrocarbon, such as methylene chloride; or in acetonitrile, dimethylformamide or pyridine.

In variant b) according to the method according to the invention, the amino group in the residue R 41 is protected. The amino protecting groups are of the same type as in the starting compounds of formula IVb. They are also split off in the same way as described there.

The reaction according to the invention of the starting compound of formula VIIa with hydroxylamine gives a compound of formula Ic, where R 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 temperature is advantageously between approx. 0 and 60°C, especially work at approx. room temperature. If uranium is used instead of hydroxylamine, an O-lower alkylhydroxylamine results in a compound of formula Ic, where

21

R is lower alkoxyiminomethyl.

If you react the starting compound of formula VIIa with carbamoylmethylenetriphenylphosphorane, you get a compound with for-21

mel Ic, where R is carbamoylviny1. This reaction preferably takes place in an inert solvent, such as methylene chloride, tetrahydrofuran or dioxane, and at the solvent's approximate room temperature and up to the boiling point.

Such an obtained product of formula Ic, where R 21 is hydroxy-imino, can, if desired, be lower alkylated. For this purpose, it is preferably reacted with a C1__!-alkyl iodide, advantageous'

in an inert organic solvent, such as methylene chloride, preferably in the presence of an organic base, such as pyridine. The temperature is advantageous at approx. 0-60°C, especially work at approx. room temperature.

The transfer according to the invention of the group R 13 of the compounds of formula If is carried out in the same way as for the compounds of formula Ib acc. In described above. The same applies to the preparation according to the invention of pharmaceutically acceptable salts of the compounds of formula Ic.

The compounds of formula I as well as their easily hydrolyzable esters and pharmaceutically acceptable salts have a broad spectrum of antimicrobial activity, especially against gram-negative microorganisms, such as e.g. pathogens of the enterobacteria family, for example Eschirichia coli, Proteus spp., Serratia spp. and Pseudomonas aeruginosa.

In accordance with this, these products can be used for the treatment and prophylaxis of infectious diseases. For adults, a daily dose of approx. 10-600 mg/kg body weight in consideration.

The minimum inhibitory concentration MIC, jjg/ml) in vitro for some representative representatives is given in the following table (reference is made to some of the compounds obtained in the following examples).

The products according to the invention can be used as pharmaceuticals, e.g. in the form of pharmaceutical preparations, which contain them or their salts in mixture with a pharmaceutical, organic or inorganic inert carrier material suitable for parenteral application.

in

in EXAMPLE 1 I

In a) 18 mg (0.087 mmol) [3S,4S]-3-amino-4-propyl-2-oxo-

• 1-azetidine sulfonic acid, 32 mg (0.095 mmol) 2-(2-amino-4-;i thiazolyl)-2-(Z)-methoxyimino-acetic acid-2-benzthiazolyl-jthio-j ! ester and 14.5 mg (0.143 mmol) triethylamine are stirred for 2 hours!

In 1 ml of dichloromethane. After evaporation of the solvent: take , take up in 5 ml of water, wash 5 times, each time with 5 ml of ether and lyophilize. 35 mg of [3S,4S]-3-[(Z)-2-(2-j I amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-propyl-2- j are obtained

■ oxo-i-azetidine sulfonic acid triethylamine salt as colorless^

tamorphic product. !

in

IR: (KBr, cm"<1>): 3384, 3312, 3207, 1763, 1670, 1621,!

1537, 1266, 1230, 1044 j in NMR: (DMSO, ppm): 9.24 (d, J = 8.5 Hz, 1H), 7.17 (s, 2H);

j 6.64 (s, 1H); 4.50 (dd, J = 2.5/8.5 Hz; 1H), 3.79

j (s, 3H), 3.59 (m, 2H); 3.07 (q, J = 7.5 Hz, 6H) ,j approx. 2 (m, br, 1H) ; 1.4 (m, br, 1H) ;. 1.17 (t, J = 7.5 Hz, 9H); 0.88 (m, 3H) .

in

The 2-(2-amino-4-thiazolyl)-1 2-(Z)-methoxyimino-acetic acid-2-benzthiazolyl thioether used as starting compound can be prepared as follows: , b) 3.93 g of triphenylphosphine and 5 g of dithio-bis-benzthiazole is suspended in 50 ml of dichloromethane and stirred for approx. 30 minutes at room temperature. After cooling to 0°C, 2 g of 2-(2-amino-4-thiazolyl)-2-(Z)-methoxy-imino-acetic acid are added and further stirred at 0°C for 3 to 4 hours. During the work-up, undissolved components are filtered off and washed with a little cold methylene chloride. The solid is suspended in 25 ml of ethyl acetate, stirred for 30 minutes at 0°C, sucked off again and washed with ethyl acetate. After recrystallization from tetrahydrofuran/dichloromethane, 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino-acetic acid-2-benzthiazolyl-thioester with a melting point of 128-130°C is obtained.

The [3S,4S]-3-amino-4-propyl-2-oxo-"1-azetidine sulfonic acid used as starting compound can be prepared on ! '

the following way: j

! in

c) 84 ml of a 1.0N solution of ethylmagnesium bromide i'

, tetrahydrofuran is added dropwise to 10.8 g (84 mmol) of 3-(2-meth-

In oxy-2-propoxy)-propyne, dissolved in 80 ml of dry tetrahydro-

In furan. The reaction solution is kept by cooling with an ice bath j at room temperature and stirred after the addition of ethyl magnesium

sium bromide for 30 minutes at room temperature. reaction mixture

The mixture is added dropwise at -70°C to -40°C to 8.5 g (20.9 mmol)

(3R,4R)-4-methylsulfonyl-3-tritylamino-2-azetidinone, dissolved in 50 ml of dry tetrahydrofuran, 30 minutes at -30 o C and<1>

1 3/4 hours at room temperature. The obtained brown solution i

diluted with 1 liter of ether and the ether phase is washed with 300 ml of saturated aqueous ammonium chloride solution and then 3 times, each time with 300 ml of water, dried and evaporated. The rest

i is chromatographed with t-butyl methyl ether:n-hexane 1:1 over 500

in g silica gel. After 1.8 1 preeluate, 0.9 1 eluate with 1.2 q (13%) substance A follows, 0.9 1 eluate with 3.Og (32%) mixture of , substance A and substance B and finally 1.8 1 eluate with 3.2 g (34%) substance B.

l Substance A: acetone-methyl-3-[(3S,4R)-2-oxo-3-tritylamino-4-azetidinyl]-2-propynyl-acetal.

NMR (CDCl 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 resp.

5 Hz, 1H), 3.94 (d, J = 2 Hz, 2H), 4.39

(dd, J = 5 resp, 10.5 Hz, 1H), 5.76

(s, 1H), 7.15-7.6 (m, 15H).

IR (KBr, cm"1): 706, 748, 1034, 1070, 1490, 1596, 1766,

3318.

Substance B: acetone-methyl-3-[(3S,4S)-2-oxo-3-trityl-amino-4-azetidinyl]-2-propynyl-acetal.

NMR (CDCl 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-ytri-'tylamino-4-azetidinyl]-2-propynyl-acetal are stirred in 50 ml jets

and 50 ml of 1% aqueous picric acid for 15 minutes at room temperature. The aqueous phase is separated and the ether phase is washed with saturated aqueous sodium carbonate solution and with water, dried and evaporated. The residue corresponds to 1.8 g (89%) of 3-[(3S,4S)r1\2-oxo-3-tritylamino-4-azetidinyl]-2-propinol. i j i' NMR (CDCl 3 , ppm): 2.3 (s, br., 1H), 2.8 (s, br., 1H), 3.35

(1H), 4.0 (2H), 4.2 (1H), 6.4S (s, 1H), 7.0 - 7.8 (m, 15H). j

in

!!0.88 g (1.9 mmol) of acetone-methyl-3-[(3S,4R)-2-oxo-3-trityl-j amino-4-azetidinyl]-2-propynyl-acetal is transferred onto the front In the aforementioned manner with picric acid in 0.67 g (90%) of 3-[(3S,4R)-2-oxp-13-tritylamino-4-azetidinyl]-2-propinol.

IN

INMR (CDC13, ppm): 1.56 (1H>, 3.0 (d, J U Hz, 1H). 3.72 (d,tr,J= 1.5 resp. 5 Hz, 1H) , 4.07 (d, J = 4.5 Hz, 2H), 4.46 (dd,

J = 5 or 11 Hz, 1H), 5.84 (s, 1H), j 7 f 2 - 7.6 (m, 15H).

e) 2.03 g (5.31 mmol) 3-[(3S,4R)-2-oxo-3-tritylamino-4-azetidinyl]-2-propinol, 0.65 g (6.37 mmol) acetic anhydride and

1504 mg (6.38 mmol) of pyridine is stirred in 10 ml of methylene chloride for !3.5 hours at room temperature. The reaction solution is then diluted with 100 ml of methylene chloride, poured onto 50 ml of ice water, the aqueous phase is separated, the methylene chloride phase is washed 2 times each times with 50 ml of water, dried and evaporated The residue consists of 1.15 g (51%) of 3-[(3S,4R)-2-oxo-3-triethyl-amino-4-azetidinyl]-2-propynyl acetate .

NMR (CDCl 3 #ppm): 1.91 (s, 3H), 3.01 (d, J = 11 Hz, 1H),

3.64 (d, br, J = 2 Hz resp. 5 Hz, 1H), 4.46 (dd, J = 5 Hz resp. 11 Hz, 1H) , 4.53 (d, J = 2 Hz, 2H ), 5.68 (s, 1H),

7.2 - 7.6 (m, 15H).

in i

|IR (KBr, cm x): 705, 744, 1236, 1488, 1595, 1732, 1757,

I 2239, 2336, 3336. i

ijFrom 3-[(3S,4S)-2-oxo-3-tritylamino-4-azetidinyl]-2-propi-jnol one obtains in the same way 3-[(3S,4S)-2-oxo-3-tritylamino- 14-azetidinyl]-2-propynyl acetate.

NMR (CDCl 3 , ppm): 2.0 7 (s, 3H), 2.8 4 (d, J = 9 Hz, 1H),

3.39 (q, J = 2 Hz, 1H), 4.29 (dd,

J = 2 or 9 Hz, 1H), 4.50 (d, J = 2

Hz, 2H), 5.81 (s, 1H), 7.2 - 7.6 (m, 15H).

' 1 i

'■IR (KBr, cm"<1>): Identical to 3- [ 3S , 4R )-2-oxo-3-trityl-j-amino-4-azetidinyl]-2-propynyl acetate. |

i ' i ! ■ i if) 410 mg (0.97 mmol) 3-[(3S,4R)-2-oxo-3-tritylamino-4-I I ' 1

• iazetidinyl ]-2-propynyl acetate, dissolved in 40 ml of methanol, is hydrogenated for 10 minutes over 100 mg of platinum oxide. The catalyst is filtered off and the filtrate is evaporated. The rest inn- ! matographed with t-butyl methyl ether:n-hexane 2:1 over 70 g in silica gel. After 200 ml of preeluate, 120 ml of eluate with 180 mg (50%) of (3S,4R)-4-propyl-3-tritylamino-2-azetidinone follows. After a further 500 ml, you get 420 ml of eluate with 67 mg (16%)j 3-j ; [(3S,4R)-2-oxo-3-tritylamino-4-azetidinyl]-propyl acetate

i3-[(3S,4R)-2-oxo-3-tritylamino-4-azetidinyl]-propyl acetate: NMR (CDCl 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:

in

IN

NMR (CDCl 3 , ppm): 0.5 - 1.3 (7H), 2.7 (1H), 3.1 (1H), : : 4.35 (1H), 6.1 (1H), 7, 1 - 7.7 (15H). j

420 mg (1 mmol) of 3-[(3S,4S)-2-oxo-3-tritylamino-4-azetidinyl]-2-propynyl acetate is hydrogenated in the same way with IN

platinum oxide and the product mixture is chromatographed with t-bu-

: I

phthyl methyl ether :n-hexane 1:1 over 70 g silica gel. After 125 ml, you get 300 mg of (3S,4S)-4-propyl-3-tritylamino-2-azetidinone and after 275 ml, 87 mg of 3-[(3S,4S)-2-oxo-3-tritylamino-j [4 -azetidinyl ]-propyl acetate.<:>

in

in

>3-[(3S,4S)-2-oxo-3-trity1amino-4-azetidinyl]-propyl acetate:

I I

in NMR (CDC1,, ppm): 0.5 - 1.4 (4H), 2.0 (s, 3H), 2.7 (1H),

in 3.0 (1H), 3.8 (1H), 6.15 (1H), 7.0

7.7 (15H). I!

IN

i(3S,4S)-4-propyl-3-tritylamino-2-azetidinone:

in

NMR (CDG13, ppm): 0.4 - 1.3 (7H), 3.0 (2H), 3.7 (1H), |6.3 (1H), 7.2 - 7.7 (15H) .<]>

! 1 g) 180 mg (0.49 mmol) (3S,4S)-4-propyl-3-tritylamino-2-1 azetidinone and 239 mg (1.5 mmol) sulfur trioxide pyridine complex are stirred in 2 ml dry dioxane for 21 hours at room temperature. The residue is centrifuged off, dissolved in 10 ml of water, neutralized with sodium bicarbonate and the aqueous solution extracted with methylene chloride. The methylene chloride phase is evaporated, the residue is dissolved in 1 ml of methylene chloride and 40 ml of formic acid (98% - 100%) is added. The product precipitates and is filtered off. 18 mg (18%) of (3S,4S)-3-amino-2-oxo-4-propyl-1-azetidine sulfonic acid is obtained, which can be used directly for the reaction according to the first paragraph in this example.

In an analogous manner, crude (3S,4R)-3-amino-2-oxo-4-propyl-1-azetidinesulfonic acid is obtained from (3S,4R)-4-propyl-3-tritylamino-2-azetidinone, which can likewise is further used directly.

EXAMPLE 2

a) In the same way as in example la) one obtains from 20 mg of [3S,4R)-3-amino-4-(3-azetoxypropyl)-2-oxo-1-azetidine sulfonic acid 20 mg of (3S,4R)-3- [(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-(3-acetoxypropyl)-2-oxo-1-azetidine sulfonic acid triethylamine salt. For purification, chromatograph<1>using silica gel in reverse phase. (Eluent H.O-CH OH.4:1)'<.>You get 6 mg of pure product as a lyophilisate. j

in

IR: (KBr'cm<_1>) 3410, 3328, 3240, 1772, 1741, 1681,

1545, 1247, 1045.

NMR: (dm 50 , ppm ) : 9.27 (d, J = 9 Hz, 1H), 7.1 (s, br.

2H); 6.69 (s, 1H), 5.10 (dd, J = 5 and 9 Hz, 1H);

about. 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-azetidine sulfonic acid used as starting compound can be prepared read as follows: j j

b) 67 mg (0.16 mmol) of 3-[(3S,4R)-2-oxo-3-tritylamino-4-j azetidinyl]-propyl acetate is transferred in analogy with example

4d) with sulfur trioxide-pyridine complex in (3S,4R)-3-amino-| 4-(3-acetoxypropyl)-2-oxo-1-azetidine sulfonic acid, which is acylated directly as a crude product in the aforementioned reaction.

EXAMPLE 3

a) In the same way as in example la) one obtains from 36 mg of [3S,4S)-3-amino-4-(3-acetoxypropyl)-2-oxo-1-azetidine sulfonic acid 37 mg of (3S,4S)-3- [(Z)-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-(3-acetoxypropyl)-2-oxo-1-azetidinesulfonic acid triethylamine salt as amorphous lyophilisate: IR: ^ KBr, cm "<1>): 3404, 3321 , 1766, 1735, 1671, 1621,

1538, 1242, 1043.

NMR: (ppm, DMSO): 9.29 (d, J = 8.5 Hz, 1H), 7.20 (s,

br, 1H); 6.68 (s, 1H); 4.51 (dd, J = 2.5/8.5 Hz, 1H); about. 4.0 (m, 2H), 3.82 (s, 3H), 3.07 (q, J = ca. 7.5 Hz, 6H); 2.0 (s, 3H); about. 1.5 (m, 3H);

1.17 (t, J = 7.5 Hz, 9H).

The [3S,4S]-3-amino-4-(3-acetoxypropyl)-2-oxo-1-azetidine sulfonic acid used as starting compound can be prepared as follows: j J ,£>) 87 mg (0.20 mmol) 3- [(3S,4S)-2-oxo-3-tritylamino-4-azetidinyl]-propyl acetate is transferred in analogy to example 1g) or 4d) in (3S,4S)-3-amino-4-(3-acetoxypropyl)- 2-j(oxo-1-azetidine sulfonic acid, which is reacted further directly as: crude product. i I 1

EXAMPLE 4

138 mg (0.2 mmol) [ 3S , 4R ]-3-amino-4-ethynyl-2-oxo-1-azetidir-sulfonic acid, 77 mg (0.22 mmol) 2-(2-amino-4-thiazolyl )-2-: ; (Z)-Methoxyimino-acetic acid-2-benzthiazolyl thioester and 56 p. 1 ■ in (0.4 mmol) of triethylamine are stirred in 1 ml of acetone-water (4:1) for 2 hours at room temperature, then filtered and concentrated; per. The residue is chromatographed over silica gel in reverse phase with H20:CH3OH. After lyophilization, 66 mg of amorphous (3S|,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetamido]-4-ethynyl-2-oxo-1-azetidine sulfonic acid triethylamine salt. '

IR: (KBr, cm"<1>): 3440, 1771, 1672, 1601, 1531, 1282, 12.53 , 1055.

NMR: (ppm, CDCl 3 ): 9.50 (d, J = 8 Hz; 1H); 7.18 (p.

2H); 6.80 (s, 1H); 5.22 (dd, J = 5.5/8 Hz;

1H), 4.61 (dd, J = 2/5.5 Hz, 1H) 3.82 (s, 3H)

3-, 45 (d, J = 2 Hz, 1H).

The [3S,4R]-3-amino-4-ethynyl-2-oxo-1-azetidine sulfonic acid used as starting compound can be prepared as follows: b) 30.1 g (0.306 mol) of trimethysilylacetylene is dissolved in 300 ml of dry tetrahydrofuran. Drizzle while cooling with ice

during 30 minutes at 20°C 290 ml of 1.05 N ethylmagnesium bromide solution in tetrahydrofuran. The solution is stirred for 2 hours at 20°C and then at -70°C to -40°C 31.3 g (0.077 mol) (3R,4R)-4-methylsulfonyl-3-tritylamino-2-azetidinone are added dropwise in 200 ml dry tetrahydrofuran. The reaction solution is stirred for 30 minutes at -30°C and then for 60 minutes at 20°C and diluted with ether. The ether phase is washed with saturated aqueous ammonium chloride solution, then with water, dried and evaporated. The evaporation residue is chromatographed with t-butyl-j

; in

methyl ether:n-hexane 2:3 on 1.5 kg of silica gel. After 4 l of preeluate, you get 1 1 eluate with substance A and then 4 1 eluate with substance B. The fractions are evaporated.

Substance A: 10.3 g (32%) of (3S , 4R )-3-tritylamino-4-[2-(1,trimethylsilyl)ethynyl]-2-azetidinone. j

in i

;NMR (CDC1J -., ppm): 0.08 (s, 9H), 3.23 (d, J = 10 Hz, 1H)

I 3.59 (d, J = 5 Hz, 1H) , 4.30 (dd, oj =

in 5/10 Hz, 1H), 5.88 (1H) j17.2-7.6 ppm.

in

.Substance B: 15.3 g (47%) (3S,4S)-3-tritylamino-4-[2-

in (trimethylsilyl)ethynyl]-2-azetidinone.

NMR (CDCl 3 , ppm): 0.10 (s, 9H), 2.8 (1H), 3.40 (d, J =

In 2 Hz, 1H), 4.23 (1H), 5.86 (1H), 7.1 -

l in I 17.5(15H). I.i

c) 10.0 g (0.024 mol) (3S,4S)-3-tritylamino-4-[2-(trimethylsilyl)ethynyl]-2-azetidinone and 1.5 g (0.026 mol) potassium-<1 >

fluoride is stirred in 100 ml of ethanol and 100 ml of dimethylsulfoxide for 1.5 hours at 20°C. 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.

in !

NMR (CDCl 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"<1>): 706, 751, 1490, 1599, 1625, 1769, 2124,

3306 .

In an analogous manner, 8.8 g (91%) of (3S,4R)-4- ethynyl-3-tritylamino-2-azetidinone.

in

<1>i

!NMR (CDC13, ppm): 2.35 (d, J = 2 Hz, 1H), 3.09 (d, J = 10.5 Hz, 1H), 3.58 (dd, J = 2 resp. ^ 5 Hz, 1H), 4.38 (dd, J = 5 resp. 10.5

j Hz, ZH), 5.88 (1H), 7.1 - 7.6 (15H).

IR (KBr, cm"<1>): 705, 732, 1490, 1728, 1770, 2122, 3298.

d) 3.5 g (10 mmol) (3S,4R)-4-ethynyl)-3-tritylamino-2-! azetidinone and 4.0 g (25 mmol) of sulfur trioxide-pyridine complex are stirred in 40 ml of pyridine for 15 minutes at 80°C. Reac-

: 200 ml of ether are added to the ion solution and the resulting precipitate is dissolved in 100 ml of methylene chloride. After adding;

5 ml of concentrated formic acid produces an oily precipitate, which turns into white crystals after decanting the solvent and adding ether. 1.19 g (58%) is isolated

[3S,4R]-3-amino-4-ethynyl-2-oxo-1-azetidine sulfonic acid. in

NMR (DMSO, ppm): 3.75 (d, J = 1.5 Hz, 1H), 4.7 (2H)

7-8 ppm (3H.) .

IR (KBr, cm"<1>): 1197, 1255, 1504, 1525, 1607, 1788, 2130,

3268, 3514.

MA: Pray. C 31.58 H 3.18 N 14.73.S 16.86%

Gift C 32.33 H 3.40 N 13.42 S 16.24 H20 1.46% e) 530 mg (1.5 mmol) (3S,4S)-4-ethynyl-3-tritylamino-2-azetidinone and 600 mg (3.75 mmol) of sulfur trioxide-pyridine complex is stirred in 6 ml of dry dioxane for 21 hours at room temperature. The undissolved residue is filtered off, and 30 ml of ether is added to the filtrate. The product falls out as a gummy precipitate, which after pouring off the solvent and tearing, in the presence of a little ether turns into crystals. These are filtered from and correspond to 481 mg of (3S,4S)-4-ethynyl-2-oxo-3-tritylamino-1-azetidine sulfonic acid pyridinium salt. The product is dissolved in 20 ml of methanol, kept for 4 days at room temperature, the solution is then evaporated and the residue is filtered off with a little methanol. The result is 180 mg (63%) of (3S,4S)-3-amino-4-ethynyl-2-oxo-1-azetidine sulfonic acid.

in

in

<1>NMR (DMSO, ppm): 3.63 (d, J = 2 Hz, 1H) , 4.38 (tr,<j>j =

2 Hz, 1H), 4.46 (d, J = 2 Hz, 1H). IR (KBr, cm<_1>): 1256, 1621, 2125, 2654, 3217.

I i EXAMPLE 5 ! in !<!>!<!>

in i!a) 60 mg (0.31 mmol) [3S,4R]-3-amino-4-vinyl-2-oxo-1-i azetidine-1-sulfonic acid, 120 mg (0.34 mmol) 2-(2- amino-4-j

thiazolyl)-2-(Z)-methoxyimino-acetic acid-2-benzthiazolyl-thioester and 63 mg (0.62 mmol) of triethylamine are stirred in 1.5 ml;

I ' ■

acetone-water (4:1) for 3 hours at room temperature. One steams

in and chromatograph over silica gel in reverse phase with j

in

acetonitrile as eluent. After evaporation, 63 is obtained; mg (3S , 4R)-3-[ (Z )-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-acetamido]-2-oxo-4-vinyl-1-azetidinesulfonic acid-triethyl- j i amine salt as amorphous colorless powder. j j

IR (KBr, cm"1 ) :3400; 1765, 1671, 1536, 1275, 1044.

NMR (DMSO, ppm): 9.2 (d, J = 9 Hz, 1H), 7.18 (s, br, 2H);

6.6 4'(s, 1H) , approx. 5.75 (m, 1H); about. 5.2

(m, 3H) 4.4 (dd, J = 6/8 Hz, 1H), 3.80 (s, 3H), 3.08 (q, J = 7 Hz, 6H), 1.17 (t, J = 7 Hz, 9H).

The preceding triethylamine salt is dissolved in 6 ml of water and stirred

in 5 ml "Amberlite CG 120" (Na<+->form) for 3 hours. The product is filtered, filtered and lyophilized, thus obtaining 26 mg of (3S,4R)-3-[2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-2-oxo-4-vinyl- l-Azetidine sulfonic 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-i 4-vinyl-2-oxo-1-azetidine-1-sulfonic acid used above as starting compound can be prepared as follows: i i

in

i -i

b) 1.55 g (4.4 mmol) (3S,4R)-4-ethynyl-3-tritylamino-2-'azetidinone is dissolved in 200 ml MeOH and hydrogenated for 2 minutes over 5% palladium-calcium carbonate catalyst (for -j married with lead). The catalyst is filtered off, the filtrate is evaporated and chromatographed with ether petroleum ether 2:1 over 200 g of silica gel. After 1.5 1 of pre-eluate, 210 ml of eluate are included

i i 0.50 g of (3S,4R)-3-tritylamineb-4-vinyl-2-azetidinone. They he-,

<1>th 1.4 liters of eluate contains 0.80 g of mixture of (3S/4R)-

i 3-tritylamino-4-vinyl-2-azetidinone and (3S,4R)-4-ethyl-3- i!

tritylamino-2-azetidinone. This mixture is chromatographed

on with 30 g of silver nitrate impregnated silica gel. 0.10 g (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. Total yield 66% (3S,4R)-3-tritylamino-4-vinyl-2-azetidinone. '

, NMR (CDCl 3 , ppm): 2.58 (d, J = ca. 10 Hz, 1H) , 3.-71

(d, tr, J = 5 Hz resp. 1 Hz, 1H), 4.35-4.83 (2H), 4.95-5.25 (2H), 5.75 (1H),

7.2 - 7.6 (15H).

■ IR (KBr, cm<-1>): 705, 747, 272, 900, 923, 1000, 1489, 1595 1638, 1764, 3261. c) 4 70 mg (1.33 mmol) (3S,4R)- 3-Tritylamino-4-vinyl-2-azetidinone is sulphonated analogously to example 4d) with sulfur trioxide pyridine complex and then detritylated with formic acid. The result is 63 mg (25%) of (3S,4R)-3-amino-2-oxo-4-vinyl-1-azetidine sulfonic acid.

NMR (DMSO, ppm): 4.44 (tr, J = 6.5 Hz, 1H), 4.57

(d, J = 6.5 Hz, 1H), 5.39 (dd, J = 2

respectively 10 Hz, 1H), 5.54 (dd, J = 2 or 17 Hz, 1H), 5.74 - 6.13 (m, 1H), 8.51 -

9 ppm (m, 3H).

IR (KBr, cm<-1>): 951, 994, 1200, 1229, 1254, 1529, 1770,

2640.

in

EXAMPLE 6 j In the same way as in example 5, 58 mg of [3S,4S]-3-[(Z)-1-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-ethynyl is obtained '1-j 2-oxo-1-azetidinesulfonic acid triethylamine salt from 110 mg of [3S, 4S]-3-amino-4-ethynyl-2-oxo-1-azetidinesulfonic acid.

in

; (IN

j Elementary analysis: j |

IN

<C>17H26N6°6S2(474.55):calc.: C43.03%,

in H 5.52%, N 17.71%; gef.: C42.54%, H 5.47%,

N 17.48%.'

IR: (KBr, cm<-1>) 3265, 2125, 1776, 1672, 1619,

1535, 1275, 1245, 1046.

1 NMR (DMSO, ppm): 9.41 (d, J = 8 Hz, 1H); 7.21 (p, 2H); 6.73 (s, lH), 4.72 (dd, J = 3/8 Hz lH), 4.21

(dd, J = 2/3 Hz, 1H), 3.82 (s, 3H), 3.52

(d, J = 2H, 1H); 3.09 (q, 7.5 Hz, 6H); 1.17 (h, 7.5 Hz, 9H).

EXAMPLE 7

i a) In the same way as stated in example 5, sodium (3S,4R)-3-t(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acet-i amido]- The 4-ethyl-2-oxo-1-azetidine sulfonate from [3S,4R]-3-

! amino-4-ethyl-2-oxo-1-azetidine sulfonic acid.

in

<1>NMR (DMSO, ppm):9.27 (d, J = 9 Hz, lH), 7.20 (s, 2H), 6.70 (s, lH) , 5.08 .(dd, J = 6/9 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-azetidine sulfonic acid used as starting compound can be prepared as follows: b) 2.0 g (5.7 mmol) (3S,4R) -4-ethynyl-3-tritylamino-2-azetidinone is dissolved in 250 ml of MeOH and hydrogenated over 2.0

g 5% palladium-carbon for 15 minutes. The catalyst filters; is removed and the filtrate is evaporated. The remainder corresponds to 1.4 g in

(69%) (3S,4R)-4-ethyl-3-tritylamino-2-azetidinone. j'

J

! IN

NMR (CDCl 3 , ppm): 0.65 - 1.25 (5H), 2.61 (d, J = 8 Hz,

I 1H), 3.08 (1H), 4.38 (dd, J = acc. 8

In Hz, 1H), 5.89 (1H), 7.1 - 7.6 (15H).

in IR (KBr, cm"<1>): 703, 755, 1491, 1596, 1752, 3266.<1>

in c) (3S,4R)-4-ethyl-3-tritylamino-2-azetidinone is transferred analogously to example 4 in (3S,4R)-3-amino-4-ethyl-2-oxo-1-;

!azetidinesulfonic acid, which is converted further directly as a raw product. in

EXAMPLE 8 j

a) In the same way as in example 5, 88 mg of (3S,;4S)-

13-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-j

2-oxo-4-vinyl-1-azetidinesulfonic acid triethylamine salt as j amorphous lyophilisate from 80 mg of [3S,4S]-3-amino-4-vinyl-2-oc-i so-1-azetidinesulfonic acid.

<C>17<H>28<N>6°6<S>2(476.57): ber.: C 42.85%

H 5.92%, N 17.63%; gef.: C 42.38%,

H: 5.82%, N 17.41%.

IR: (KBr, cm<-1>): 3406, 3318, 3211, 1767, 1670,

1621, 1536, 1271, 1237, 1044.

NMR (DMSO, ppm): 10.33 (d, J = 8 Hz, 1H), 7.19 (s, br, 2H),

6.70 (s, 1H), 6.03 (ddd, J = 17/10/7 Hz lH), 5.37 (dd, J = 1.5/17 Hz, lH), 5.17 (dd, J = 1.5/10 Hz, 1H), 4.56 (dd, J = 3/8 Hz, lH) , 4.11 (dd, J = 3/7 Hz, 1H), 3.82 (s, 3H), 3.10 (m, 6H), 1.18 (t, J = 7 Hz, 9H).

The [3S,4S]-3-amino-4-vinyl-2-oxo-1-azetidine sulfonic acid used above as starting compound can be prepared as follows: b) 2.5 g (7.1 mmol) (3S,4S) -4-ethynyl-3-tritylamino-2-azetidinone is dissolved in 250 ml of methanol and hydrogenated for 10 minutes over 1.2 g of 5% palladium-calcium carbonate catalyst (poisoned with lead). The catalyst is filtered off, the filtrate is evaporated and chromatographed with n-hexane:t-bu-i , ethyl methyl ether 1:2 over 200 g of silica gel. From 600 to 900 ml, the result of the elution of 1.86 g (74%) of (3S,4S)-3-tri-tylamino-4-vinyl-2-azetidinone NMR (CDCl 3 , ppm): 2.8 ppm (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"<1>): 704, 748, 922, 1489, 1595, 1638, 1756, 3316. c) 1.0 g (2.82 mmol) (3S,4S)-3-tritylamino-4 -vinyl-2-azetidinone is sulfonated analogously to example 4d) with sulfur trioxide-pyridine complex and detritylated with methanol 87 mg (16%) of (3S,4S)-3-amino-4-vinyl-2-oxo-1-azetidinsul - ;

phonic acid is isolated.

NMR (DMSO, ppm): 4.14 - 4.29 (2H), 5.27 (dd, J = 2 resp. 10 Hz, 1H), 5.44 (dd, J = 2 resp. 17 Hz, 1H ), 5.79 - 6.20 (1H), 8-9 (br, 3H).

IR (KBr, cm<-1>): 924, 981, 1272, 1307, 1513, 1596, 1763,

2604, 2679, 3092.

EXAMPLE 9

In the same way as in example 5, from 70 mg of [3S,4S]-3-amir 4-ethyl-2-oxo-1-azetidine sulfonic acid, 152 mg (3S , 4SJ-3-[ (Z)-2-(2 -amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-ethyl-2-oxo-1-azetidine sulfonic acid triethylamine salt as amorphous lyophilisate.

IR: (KBr'cm<-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 =2.5/8.5

Hz, 1H), approx. 3.5 (m, lH), 3.82 (s, 3H),

3.09 (q, j = 7.5 Hz, 6H), approx. 1.8 (m, 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-azetidine sulfonic acid used as starting compound above can be prepared as follows: b) 2.5 g (7.1 mmol) (3S,4S )-4-ethynyl-3-tritylamino-2-azetidinone is hydrogenated in 250 ml of methanol over 2.5 g of 5% palladium carbon for 10 minutes, the catalyst is filtered off, the filtrate is evaporated and chromatographed with t-butylmethyl- : ether:n-hexane (1:1) over 200 g of silica gel. After 750 ml of pre-t eluate, 1.63 g (65%) of (3S,4S)- i i 4-ethyl-3-tritylamino-2-azetidinone.

NMR (CDCl , ppm): 0.53 - 0.58 (5H), 2.7 (1H), 2.9 (1H),

3.75 (1H), 6.0 (1H), 7.2 - 7.6 (15H). j IR (KBr, cm"<1>): 705, 747, 1490, 1596, 1753, 3260. !<!>

0.94 g (2.64 mmol of (3S,4S)-4-ethyl-3-tritylamino-2-azetidinone is reacted analogously to example 4d). 176 mg (34%) of (3S, 4S)-3-amino-4-ethyl-2-oxo-1-azetidine sulfonic acid is 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"<1>): 1206, 1268, 1512, 1599, 1760, 3092.

EXAMPLE 10

Likewise, analogously to example 5, one can obtain (3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-acetamido]-2-oxo-4-propyl- The 1-azetidine sulfonic acid sodium salt.'

Elemental analysis:

Calculated: C^H-^N^S^a C 34 .87, H 3.90, N 16.94% •Found: C 34.54, H 3.91, N 16.43%

in

i i i

IN

IR: (KBr, cm"1 ) 3423, 3281, 3219, 1762, 1656, 1236.' NMR: (dg-DMSO, ppm): 0.9 (3H, t, CH-j), 1.10 -

1.95 (4H, m, -CH2-CH2-), 3.85 (3H, s, OCH3), 3.85 (1H, dt, -CH-CH2-CH2CH3), 5.05 (1H, dd, 6 und 9 Hz, NH-CH) 6.73 (1H, s, S-CH=), 7.15 (2H, s, NH2), 9.25 (1H, d, 9 Hz, CONH).

in EXAMPLE 11

a) In the same way as in example 1, from 224 mg of rac, cis-3-amino-4-methoxycarbonyl-2-oxo-1-azetidine sulfonic acid is obtained

and 367 mg of 2-(2-amino-4-oxazolyl)-2-methoxyimino-acetic acid-2-benzthiazolyl thioester (7:2 mixture of Z:E isomers) 259

mg rac, cis-3-[2-(2-amino-4-isoxazolyl)-2-(methoxyimino)-acetamido]-4-(methoxycarbonyl)-2-oxo-1-azetidinesulfonic acid triethylamine salt as amorphous lyophilisate (7: 2 mixture of Z:E isomers).

in

IR: (KBr, cm"<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 = 5.5/8 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 starting compound can be prepared as follows: b) A solution of 50.4 g (0.2 mol) of 2-methoxyimino -4-Bromo-acetoacetic acid ethyl ester (M, Ochiai et al., Chem. Pharm. Bull.

25, 3115 (1977)) and 60.1 g (1 mol) of urea in 200 ml of dimethylformamide are heated for 30 minutes at 100°C. It is then evaporated, taken up in 800 ml of water, neutralized with sodium bicarbonate and extracted with vinegar. The acetic ester extract is chromatographed with acrylonitrile: methylene chloride 1:1 on silica gel. 2-(2-amino-4-oxazolyl)-2-methoxyimino-acetic acid is obtained

the acid ethyl ester in 26%<1>ig yield, freezing point 120 C (decomposition).

i i i

NMR (DMSO, ppm): 7.77 (s, 1H), 6.93 (s, 2H), 4.15 (q,'j=j

7 Hz, 2H), 3.90 (s, 3H), 1.28 (tr,'j;= j

7 Hz, 3H). in

c) 2.13 g (10 mmol) of 2-(2-amino-4-oxazolyl)-2-methoxyimi-! no-acetic acid ethyl ester is treated in 20 ml of methanol at -20°C

with 10 ml IN aqueous caustic soda. After addition of 10 ml IN aqueous hydrochloric acid, 2-(2-amino-4-oxazolyl)-2-methoxyimino-acetic acid precipitates in a yield of 54%, freezing point 190°C

(fission)..

: in Elementary analysis:

CgH7N304Calculated: 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 triethylphosphite is added under ice-cooling to a solution of 560 mg (3 mmol) 2-(2-amino-4-oxazolyl)-2-methoxyimino-acetic acid, 1.2 g (3.6 mmol) 2,2-dithio-bis-benzthiazole and 360 mg (3.6 mmol) of N-methyl-morpholine in 20 ml of absolute acetonitrile. Stir for 3 hours at room temperature. The precipitated product is then filtered off, washed with water and dried. 2-(2-amino-4-oxazolyl)-2-methoxyimino-acetic acid-2-benzthiazol1-thioester (7:2 mixture of the Z:E isomers) is obtained. Dividend 55%; freezing point 139°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 an analogous manner as indicated in example 1, 95 mg of [3S,4R]-3-amino-4-ethynyl-2-oxo-1-azetidinesulfonic acid yields 192 mg of (3S,4R)-3-[2-(2- amino-4-oxazolyl)-2-(methoxyimino)acetamido]-4-ethynyl-2-oxo-1-azetidine sulfonic acid triethylamine salt. The product is a "5:1 mixture of the Z:E isomers."

IN

IR: (cm<-1>, KBr): 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 = 6/8.5 Hz, 1H);

4.60 (dd, J =2/6 Hz, 1H); 4.01 + 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).

<1>EXAMPLE 13

j 291 mg (1.3 mmol) rac-cis-3-amino—4-methoxycarbonyl-2-oxo-

In 1-azetidine sulfonic acid, 640 mg (1.8 mmol) of 2-[(5-amino-3-j (1,j 2 ,4-thiadiazolyl)]-2-(Z)-methoxyimino-acetic acid-1-benzthia- zolyl thioester and 263 mg of triethylamine are stirred in 6 ml of dichloromethane for 30 hours at room temperature.

; the solvent is taken up in 20 ml of water, washed 5 times, each time with 10 ml of ether and lyophilized. 610 mg of rac-cis-3-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)-acetamido]-4-(methoxycarbonyl) are obtained -2-oxo-1-azetidine sulfonic acid triethylamine salt.

!IR: (KBr'cm<_1>): 3397, 3305, 3204, 1755, 1688,

in 1622, 1530, 1281, 1235, 1207, 1047.

iNMR (DMS0,ppm):9.37 (d, J = 8.5 Hz, lH), 8.10 (s, br, 2H), 5.37 (dd, J = 5.5/8.5 Hz , lH), 4.41 (d, J L

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) .

i EXAMPLE 14 i

a) 190 mg (1 mmol) [3S,4R]-3-amino-4-ethynyl-2-oxo-1-azetidinesulfonic acid, 526 mg (1.1 mmol) 2-(2-amino-4-thiazolyl)- Stir 2-[[(Z)-1-(t-butoxycarbonyl)-1-methyl-ethoxy]-imino]-acetic acid-2-benzthiazolyl thioester and 0.280 ml (2 mmol) of triethylamine in 5 ml of acetone-water 4: 1 for 20 hours at room temperature. It is then concentrated, taken up in 4 ml of methanol and filtered. The filtrate is chromatographed over silica gel in reverse phase using H20-methanol 10:1. After lyophilization j ! 213 mg of (3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2f[[1-j (tert-butoxycarbonyl)-1-methylethoxy]imino]acetamido]- 4-I ethynyl-2-oxo-1-azetidine sulfonic acid as amorphous powder, j

i i i ; I i!IR: (KBr'cm_1': 3315, 1773, 1725, 1679, 1621, 1531, 1285, _ 1257, 1146, 1055.

jMMR (DMS0,ppm):9.17 (d, J 9 Hz, lH), 7.22 (s, br, 2H), 6.77 (s, 1H), 5.26 (dd, J = 6/ 9 Hz, 1H), 4.63 (dd, J = 2/6 Hz, 1H), 3.40 (d, J = 2Hz,

1H), 1.38 (s, 15H).

The starting compound used 2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(t-butoxycarbonyl)-1-methyl-ethoxy]-imino]-acetic acid-2-benzthiazolyl -thioester can be prepared as follows: .!

. ; in b) 43 g (200 mmol) of 2-(2-amino-4-thiazolyl)-2-(Z)-hydroxy-imino-acetic acid ethyl ester are dissolved in 1.2 1 dimethylformamide. <:>In a nitrogen atmosphere add a little after a little 89.2 g (400 mmol) of 2-bromo-2-methyl-propionic acid t-butyl ester, followed by 110.6 g (800 mmol) of finely powdered potassium carbonate. The reaction mixture is stirred for 12 hours at 45°C. After cooling at room temperature, 4 1 of water are added, and everything is extracted with 3.5 1 of ethyl acetate. The organic phase is washed 3 times with 2 1 water. The water is further extracted with 1.5 1 ethyl acetate. The combined ethyl acetate solutions are dried with mag nesium sulfate and evaporated to dryness. After recrystallization from ether, 61.4 g (85.9%) of 2-(2-amino-4-thiazolyl)-2-[ [ (Z)-1-(t-butoxycarbonyl)-1-methylethoxy] are obtained imino-acetic acid ethyl ester with melting point 172°C. c) 240 g (671.5 mmol) of 2-(2-amino-4-thiazolyl-2-[[(Z)-1-(t-butoxycarbonyl)-1-methyl-ethoxy]imino]-acetic acid ethyl ester is stirred in 1.3 1 methanol and 1.34 1 IN aqueous sodium hydroxide solution for 12 hours at 50° C. The methanol is evaporated off and the aqueous phase is washed twice with 1 1 ethyl acetate. After addition of 1.34 1 IN aqueous hydrochloric acid, the product crystallizes out .;

j After cooling to 0 C, the crystals are filtered off, washed in

j 1 sequence with water, o acetonitrile and ether and dried under reduced pressure at 40 C. The product thus obtained crystallizes with 12% water and is stirred for 2 hours in acetonitrile to remove the water. After filtering and drying under ! reduced pressure at 40°C gives 177.7 g (80.3%) of 2-(2-amino-\no-4-thiazolyl)-2-[[(Z)-1-(t-butoxycarbonyl)-1 -methylethoxy]-imino]acetic acid with melting point 178-179°C. Water content, 0.4%. IN

; ,

d) 28.8 g (86.4 mmol) 2-(2-amino-4-thiazolyl)-2-[[(Z)-1- \ '•• (t-butoxycarbonyl)-1-methyl-ethoxy] imino]-acetic acid is dispersed in 360 ml of acetonitrile. 14.4 ml (130.5 mmol) of N-methyl-1-morpholine are added while stirring. After 10 minutes add-; 34.6 g (103.5 mmol) of 2,2-dithio-bis-benzthiazole are added and the resulting suspension is cooled to 0°C. After adding a<y>i , 20.2 ml (117 mmol) of triethyl phosphite (slow addition during 2 hours), the suspension is stirred for 12 hours at 0°C. The product is filtered off, washed successively with cold acetonitrile, isopropyl ether and petroleum ether and dried at room temperature under reduced pressure. 2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(t-butoxycarbonyl)-1-methylethoxy]imino]-acetic acid-2-benzthiazolyl-thioester (33.7 g• = 81.5%) with

melting point 139-140°C.

EXAMPLE 15

66 mg (3S,4R)-3-[2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(tert-butoxycarbonyl)-1-methylethoxy]imino]acetamido]-4- ethynyl-2-oxo-1-azetidine sulfonic acid is added at -10°C to 4 ml of trifluoroacetic acid. After 4 hours, evaporate, take up with a little water and chromatograph over MCI gel using water. After lyophilization, 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-azetidine sulfonic acid.

in l

' j i

in

;• I

:IR: (KBr-cm"<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 = 5.5/8.5 Hz, 1H), 4.67 (dd,

J = 2/5.5 Hz, 1H), 3.44 (d, J = 2 Hz, 1H), 1 . 36 (s, br, 6H).

! EXAMPLE 16 I

■ i Analogous to example 14, sodium (3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(1-carboxy-1-methylethoxy)imino]- <!>

in

acetamido]-4-methyl-2-oxo-1-azetidine sulfonate. !

i i IR: (KBr cm"<1>): 3297, 2984 , 2683, 1763 , 1675 ,;

1631, 1535, 1276. j

NMR (DMSO, ppm): 1.1 und 1.20 (6H, 2s, 2 x CH3) 1.45 (3H, d,

3.5 Hz, CH-CH3), 4.0 (lH, m, CH-CH3), 5.05 (lH, dd, 6 und 9 Hz, NH-CH) 6.75 (lH, s, S< -CH=>),<7>,20 (3H, breitNH3),9.15(1H,d,

9 Hz, CONH).

EXAMPLE 17 i

IN

106 mg (0.55 mmol) [3S,4S]-3-amino-4-ethyl-2-oxo-1-azetinesulfonic acid, 288 mg (0.6 mmol) 2-(2-amino-4- thiazolyl)-2-[[(Z)-1-(t-butoxycarbonyl)-1-methyl-ethoxy]-imino]-acetic acid-2-benzthiazolyl-thioester and 0.153 ml of triethylamine (1.1 mmol) are stirred in 3 ml acetone-water (4:1) for 3 hours at room temperature. Evaporate, take up in 10 ml of water, wash three times, each time with 20 ml of ether and lyophilize. 2 70 mg of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-(t-butoxycarbonyl)-1-methylethoxy]imino]acetamido] are obtained -4-ethyl-2-oxo-1-azetidine sulfonic acid triethylamine salt.

<C>24<H>42<N>6°8S <606'75>'

calculated: C 47.51; H 6.98; N 13.85%;

found: C 47.29; H 6.96; N 13.68% '

<1>

IN

EXAMPLE 18 ! 250 mg (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-(t-but

oxycarbonyl)-1-methylethoxy]imino]acetoamido]-4-ethyl-2-oxo-1-azetidinesulfonic acid triethylamine salt is added at !

-10°C to 3 ml trifluoroacetic acid. After 20 hours at -10° C, it is evaporated off and purified with DCCC (Droplet Counter Current Chromatographie: rising small 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-methyl- ■ i I 1 ethoxy)imino]acetamido]-4-ethyl-2-oxo-1-azetidine sulfon!sy- j' re-triethylamine salt.!

IR (KBr, cm"<1>) 1766, 1673, 1539, 1201, 1042

NMR (DMSO, ppm): 9.13 (d,J=9Hz,1H); 6.66 (s, 1H); 4.58 (dd,J=2.5/9Hz); 3.58 (m,1H); 3.10 ( ,J=7Hz, 6H); 1.42 (s,br,6H); 1.19 (t,J=7Hz,9H); 0.89 (tr,J=7Hz,3H).

EXAMPLE 19 '<!>

in 224 mg (1 mmol) rac,cis-3-amino-4-methoxycarbonyl-2-oxo-ji 1-azetidine sulfonic acid, 526 mg (1.1 mmol) (Z)-2-(2-amino-4-! thiazolyl)-2-[[1-(t-butoxycarbonyl)-1-methyl-ethoxy]imino]-acetic acid-2-benzthiazolyl-thioester and 261 mg of triethylamine

stirred in 5 ml of dichloromethane for 4 hours at room temperature. After evaporation of the solvent, 20 ml of water are taken up, washed five times, each time with 20 ml of ether and lyophilized. rer. 569 mg of rac-cis-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-(t-butoxycarbonyl)-1-methyl-ethoxy]-imino]-acetamido are obtained ]-4-methoxycarbonyl-2-oxo-1-azetidine sulfonic acid.

EXAMPLE 20

550 mg rac-cis-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-(t-butoxycarbonyl)-1-methyl-ethoxy]-imino]-acetamido]- 4-Methoxycarbonyl-2-oxo-1-azetidine sulfonic acid is added at room temperature to 5.5 ml of trifluoroacetic acid. After 45 minutes, it is evaporated and purified by chromatography on silica gel in reverse phase with water-methanol 4:1. 27 mg of pure rac-cis-3-t(Z)-2-(2-amino-4-thiazolyl)-2-[(1-carboxy-1-methyl-j'' ethoxy)imino]acetamido] are obtained -4-(Methoxycarbonyl)-2-oxo-1-aze- !

tidinesulfonic acid as amorphous lyophilisate.

1 in 1 NMR (DMSO, ppm): 9.13 (d, J = 8.5 Hz, 1H); 6.67 (p, lH),

i 5.44 (dd, J = 6/8, 5 Hz, 1H); 4.48 (d, j J = 6 Hz, 1 H); 3.60 (s, 3H); 1.42 (sbr, 6 h) . in 1

in

<1> EXAMPLE 2

ja) 522 mg (1.0 mmol) 2-(2-amino-4-thiazolyl)-2-[[(Z)-1-

i [2-(trimethylsilyl)-ethoxycarbonyl]-1-methylethoxy]-imino]- ! acetic acid 2-benzthiazolyl thioester and 224 mg (1.0 mmol) of rac

-cis-3-amino-4-methoxycarbonyl-2-oxo-1-azetidine sulfonic acid is suspended in 5.0 ml of absolute acetone and 0.278 ml of ! (2.0 mmol) of triethylamine. The clear yellow solution obtained is stirred at room temperature for 24 hours and then evaporated; in after . One chromatographs with DCCC (Droplet Counter Cur-; pure Chromatographie ascending small droplets in the mixture: CHCl3/MeOH/H20 7:13:8). The fractions of interest are combined, concentrated and lyophilized. 211 mg (31%) of rac-cis-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[[2-(trimethylsilyl)-'ethoxy]-carbonyl are obtained ]-1-methylethoxy]imino]acetamido]-4-methoxycarbonyl-2-oxo-1-azetidine sulfonic acid triethylamine salt (1:1) .

NMR (D 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 = 6,0,1H), 6.81 (s,lH)

IR (KBr, cm"<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) rac-cis-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[[2-(trimethylsilyl)ethoxy]carbonyl] -1-methyl-ethoxy ]imino]acetamido]-4-methoxycarbonyl-2-oxo-1-azetidinsulfonic acid triethylamine salt is dissolved in 10 ml of tetrahydrofuran and 130 mg (0.50 mmol) of tetrabutylammonium fluoride (dry) is added. The reaction mixture is stirred overnight at room temperature and then evaporated. The rest is dissolved in J

in

<;><+>/ (dry) 1

slightly saturated aqueous sodium bicarbonate solution and chromatographed on "Amberlite XAD-2" (eluent: water, then

30% ethanol in water). After lyophilization, 40 mg (32%) of rac-cis-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(1-carboxy-1-methylethoxy)imino]-acetamido] are obtained -4- (methoxycarbonyl);-2-

1 oxo-1-azetidine sulfonic acid sodium salt.

1

in IR (KBr, cm"<1>): 1771, 1730

IN

'The starting compound used 2-(2-amino-4-thiazolyl)-2-[[(Z)-1-[2-trimethylsilyl)-ethoxycarbonyl]-1-methylethoxy]-imino]acetic acid 2-benzthiazol1-thioester can be produced in as follows:

In j

IN

c) 24.9 g (102 mmol) of 2-(2-amino-4-thiazolyl)-2-(Z)-hydroxy-imino-acetic acid-t-butyl ester are dissolved in 400 ml of dimethyl ■ formamide. After addition of 54.7 g (205 mmol) of 2-bromo-2-| methylpropionic acid-(2-trimethylsilyl)-ethyl ester, followed by 56.6 g (410 mmol) of finely ground potassium carbonate: the reaction mixture is stirred for 4 hours at 25°C in a nitrogen atmosphere. After adding 3 1 of water, the whole is extracted with 1.5 1 of ethyl acetate. The organic phase is washed twice with 1.5 liters of water. The water is further extracted with 1.5 1 ethyl acetate. The combined ethyl acetate solutions are dried over sodium sulfate and evaporated to dryness. The product is purified by flash chromatography on silica gel (hexane-ethyl acetate 2:1) and crystallized from methanol/water. 28.6 g (65.3%) of 2-(2-amino-4-thiazolyl)-2-[(Z)-1-(2-trimethylsilyl)ethoxycarbonyl)-1-methylethoxy]imino]-acetic acid are obtained t-butyl ester with melting point 83°C.

d) 13.4 g (31.2 mmol) 2-(2-amino-4-thiazolyl)-2-[(Z)-(1-(2-(trimethylsilyl)ethoxycarbonyl)-1-methylethoxy]imino]- acetic acid t-butyl ester is stirred in 210 ml of acetic acid and 13.4 ml (104.5 mmol) of boron trifluoride etherate for 1.5 hours at room temperature. The solution is poured into 650 ml of water and the pH value is adjusted to 3.0 with sodium bicarbonate. The precipitated crystals are filtered off and dried at room temperature under reduced pressure. 7.6 g (65.5%) of 2-(2-amino-4-thiazolyl)-2-[[(Z)-!1-[2- (trimethylsilyl)ethoxycarbonyl]-1-methylethoxy]-imino]-;acetic acid with melting point 155°C (decomposition) .(Compound-;

in sen contains 3.3% water). After dispersing the compound (twice) in 50 ml of dry acetonitrile and evaporating

j ning of the solvent, the water content drops after drying \

in at room temperature (16 hours under reduced pressure - 0.1] ram ! torr) to 0.22%.

in

in i

e) 10.9 g (29.2 mmol) 2-(2-amino-4-thiazolyl)-2- [ [ (Z) r-1- ,

: i

[2-(trimethylsilyl)ethoxycarbonyl]-1-methylethoxy]imino]acetic acid is dispersed in 195 ml of acetonitrile (dried with a molecular sieve of 3 Å) and 4.09 ml° (37.1 mmol) of N-methyl-morpholine are added while stirring, followed by 11.7 g (35 mmol) of 2,2 -di- , ! thio-bis-benzothiazole and 6.7 ml (39.7 mmol) of triethyl phosphite. i After stirring for 1 hour at room temperature, 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 crystallize from acetonitrile. 4.6 g (30%) of 2-(2-amino-4-thiazolyl)-2-[[(Z)-1-[2-(trimethylsilyl)-ethoxycarbonyl]-1-methylethoxy]-imino]- Acetic acid 2-benzthiazolyl thioester with melting point 92°C;

■ (cleavage).

in EXAMPLE 2 2

a) 201 mg (0.38 mmol) 2-(2-amino-4-thiazolyl)-2-[[(Z)-(p-nitrobenzyloxycarbonyl)-methoxy]-imino]-acetic acid-2-benz-thiazolyl- thioester and 85 mg (0.38 mmol) of rac-cis-3-amino-4-(methoxycarbonyl)-2-oxo-1-azetidinesulfonic acid are suspended in 1.9 ml of absolute acetone and 0.11 ml (0.79 mmol ) triethylamine. Stir for 3 hours at room temperature and then evaporate. One chromatographs with DCCC: ascending small drops of the mixture CHCl^:MeOH:H20 = 7:13:8). The fractions of interest are combined, concentrated and lyophilized. 56 mg (21%) of rac-cis-3-[2-(2-amino-4-thiazolyl)-2-[[(Z)-(p-nitrobenzyloxycarbonyl)methoxyimino]acetamido]-4-methoxycarbonyl1-2 are obtained -oxo-1-azetidine sulfonic acid triethylamine salt.

In NMR (D20,ppm) i , 2 6 ( t, J= 7 , 0 , 9 H ) , 3.18 ( q , J= 7 , 0 , 6 H) , 3.71 (s,3H),

4.88 (s,2H), 4.96 (d,J=6.0, 1H), 5.31 (s,2H), j 5.64 (d,J=6.0, 1H), 6 .89 (s,lH), 7.50 (d,J=8.5, 2H), 8.07 (d,J=8.5, 2H)

in IR (KBr,an<-1>): 3 3 4 0 (56%), 1756 ( 26%), 1682 (43%), 1609 ( 46%), 1348 (28%), 1281 (22%) ,.1213 (25%), 1046 (23%)

<C>19<H>18<N>6°12<S>2<+><C>6<H>15<N>(687-696)

■ Praying. C 43.66 H 4.84 N 14.26 S 9.32%

Gift C 43.70 H 4.80 N 14.24 S 9.30%

The 2-(2-amino-4-thiazolyl)-2-[[(Z)-(p-nitrobenzyloxycarbonyl)-methoxy]-imino]-acetic acid-2-benzthiazolyl-thioester used as starting compound can be prepared as follows:

in

in

b) 6.1 g (25 mmol) of 2-(2-amino-4-thiazolyl)-2-(Z)-hydroxy-imino-acetic acid t-butyl ester are dispersed in 250 ml of dry acetonitrile. 13.7 g (50 mmol) of bromoacetic acid 4-nitrobenzyl ester and 12.9 ml (75 mmol) of N-ethyldiisopropylamine are now added while stirring at room temperature. 5 minutes later, 7.5 g (50 mmol) of sodium iodide is added. The reaction mixture is stirred for 3 1/2 hours in an argon atmosphere at room temperature. The solvent is then evaporated off and the residue is diluted with 500 ml of ethyl acetate. The solution obtained is washed 4 times with a total of 2 1 water. The water is extracted with 300 ml of ethyl acetate, and the combined ethyl acetate solutions are dried over sodium sulfate and evaporated to dryness. After crystallization from ethyl acetate-hexane, however, 8.2 g (75%) of 2-(2-amino-4-thiazolyl)-2- t t (p-nitrobenzyloxycarbonyl)-methoxy]-imino]-acetic acid t-butyl ester with m.p. 146.8°C (decomposition). c) 5.0 g (11.4 mmol) 2-(2-amino-4-thiazolyl)-2-[[(Z)-(p-nitrobenzyloxycarbony 1 )-methoxy]-imino]-acetic acid t-butyl ester stir in 86 ml of acetic acid and add 5.2 ml (38.4 mmol) of boron trifluoroetherate. The resulting solution is stirred for 5 hours at room temperature and then poured into 260 ml of water.

in I i

i The precipitate obtained is filtered off and dried at 40 C jun-

in there reduced pressure. 3.5 g (80%) of 2-(2-amino-4-thiazol-yl)-2-[t(p-nitrobenzyloxycarbonyl)-methoxy]-imino]-ed-!

; 'acetic acid. Melting point approx. 175°C (decomposition). j I

I I i ' i < i

d) 1.9 g (0.5 mmol) 2-(2-amino-4-thiazolyl)-2-[[(Z)-(p-'nitrobenzyloxycarbonyl)-methoxy]-imino]-acetic acid dispers

j is dried in 30 ml of acetonitrile (dried with a 3 Å molecular sieve). This suspension is mixed with 1.4 ml (12.7 mmol) of N-methylmor-

: folin with stirring, 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;

After stirring for 1 hour at room temperature, the reaction mixture is cooled and filtered. The filtrate is evaporated and the residue is crystallized from methylene chloride. 1.03 g (39%) of 2-(2-amino-4-i thiazolyl)-2-[[( Z)-(p-nitrobenzyloxycarbonyl)-methoxy]-imino]-acetic acid-2-benzthiazolyl thioester with melting point - , 124-126°C.

I >

EXAMPLE 2 3

343 mg (0.5 mmol) rac-cis-3-[(Z)-2-(2-amino-4-thiazolyl)-2-t[(p-nitrobenzyloxycarbonyl)-methoxyimino]acetamido]-4-methoxycarbonyl- 2-oxo-1-azetidine sulfonic acid triethylamine salt is dissolved in 20 ml of methanol and hydrogenated with 230 mg

5% palladium/kieselguhr in an atmosphere of hydrogen for 3 hours at room temperature. The catalyst is removed by filtration and the solution is evaporated. The residue is taken up in a slightly saturated aqueous sodium carbonate solution and chromatographed on "Amber-lige XAD-2" (eluent: water, then 30% ethanol in water). After the lyophilization, 120 mg (51%) of rac-cis-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxymethoxyimino)acetamido]-4-methoxycarbonyl-2-oxo are obtained -1-azetidine sulfonic acid sodium salt.

IR (KBr, cm"<1>): 1775, 1730.

IN

EXAMPLE 24

265 mg (0.5 mmol) (Z)-2-(2-amino-4-thiazolyl)-2-[[(p-nitro-

: benzyloxycarbonyl)-methoxy]-imino]-acetic acid-2-benzthia-I

in ! zolyl thioester and 104 mg (0.5 mmol) (3S,4S)-3-amino-4-1 ■<1>

carbamoyl-2-oxo--1-azetidine sulfonic acid is suspended in 2.5 ml of absolute acetone and 0.15 ml (1.1 mmol) of triethylamine is added. After 30 minutes, the suspension dissolves into a ! ,yellow solution. After 24 hours at room temperature, the mixture is evaporated and the residue is chromatographed with DCCC (Droplet Counter Current Chromatographie: ascending small droplets in the mixture, in 'CHCl^:Me0H:H20 = 7:13:8). The fractions of interest are evaporated and lyophilized. 0.139 g (41%) of (3S,4S)-3-' is obtained

[ (Z)-2-(2-amino-4-thiazolyl)-2-[[(p-nitrobenzyloxycarbonyl)-methoxyimino]acetamido]-4-carbamoyl-2-oxo-1-azetidine sulfonic acid triethylamine salt. !

NMR (<d>20, ppm): 1.31 (t, J=7.5, 9H), 3.24 (q, J=7.5, 6H),

4.95 (d,J=6.0, 1H), 4.95 (s,2H), 5.34 (s,2H), 5.69 (d,J=6.0, 1H), 6, 98 (s,lH), 7.49 (d,J=

9.0, 2H), 8.16 (d,J=9.0, 2H)

» IR (KBr, cm<-1>): 3333 (42%), 1773 (26%), 1687 (20%), 1608

(42%), 1348 (27%), 1277 (22%), 1248 (26%), 104 6 (19%)

<C>1<gH>17<N>7<0>11<S>2<+><C>6<H>15<N>(672,698)

Pray. C 42.85 H 4.80 N 16.66 S 9.53 H.,0% Gef. C 41.22 H 4.81 N 16.13 S 9.45 H20 1.84%

EXAMPLE 25

336 mg (0.5 mmol) (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(p-nitrobenzyloxycarbonyl)-methoxyimino]acetamido]-4- Carbamoyl 1-2-oxo-1-azetidine sulfonic acid triethylamine salt is dissolved in 20 ml of methanol and hydrogenated with 150 mg of 5% palladium on diatomaceous earth for 3-4 hours at room temperature. The catalyst is removed by filtration and the solution is evaporated. The residue is dissolved in slightly saturated aqueous sodium bicarbonate solution and chromatographed on "Amberlite XAD-2" (eluent: water, then 40% ethanol in water). After lyophilization, 150 mg (65%) of (3s,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxy-methoxy)imino]acetamido]-4-carbamoyl are obtained -2-oxo-1-azetidine sulfonic acid sodium salt.<1><!>

J IR (KBr, cm 3421, 1769, 1731, 1690.

EXAMPLE 26 (1 i ja) 1.62 g (6.20 mmol) (3S, 4S)-3-amino-4-carbamoyloxyme-;I ! tyl-2-oxo-1-azetidine sulfonic acid sodium salt is dissolved in 180 ml J acetone-water (2:1) and treated with 3.27 g (6.83 mmol) (Z)-2-(2-amino-4 -thiazolyl)-2-[[1-[t-butoxycarbonyl]-1-methyl-'ethoxy]imino]-acetic acid 2-benzthiazol1-thioester. The reaction I mixture is stirred for 12 hours at room temperature. Further, 60 mg (0.12 mmol) of the latter compound is added and stirring is continued for a further 3 hours. Acetone is removed in ; under reduced pressure and 50 ml of water are added. The crystals obtained are filtered off and washed with some water. The mother liquor

is partially evaporated (37°C, 15 mmHg) and chromatographed (MCI, gel, H20). After lyophilization, 2.28 g (77%) of (3S,; ; 4S)-3-[2-amino-4-thiazolyl)-2-(Z)-[[1-(t-butoxycarbonyl)-1- :, methylethoxy]imino]-acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidine sulfonic acid sodium salt.

IR (KBr, cm"<1>): 1766, 1723, 1683, 1617, 1531, 1458,

1369

NMR (DMSO, ppm): 1.35 (15H,s), 4.0-4.15 (3H,H4and CH2~

0C0NH2), 5.25 (1H,dd,H3), 6.5 (2H,broad, C0NH2), 6.7 (1H,s,H-Thiazole), 7.25 (2H,s,NH2), 8 .9 (1H,d,C0-NH).

The (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidine sulfonic acid sodium salt used as starting material can be prepared as follows: b) To a solution of 0.9 g (5.4 mmol) stirred at room temperature ) 2,4-dimethoxybenzylamine in 100 ml of methylene chloride, 3 g of molecular sieve 4Å are added and after 20 minutes 0.7 g (5.4 mmol) of isopropylidene-L-glyceraldehyde and 5 g of anhydrous magnesium sulfate. It is then stirred for a further 1 hour at room temperature. The obtained organic solution of iso-propylidene-L-glyceraldehyde-(2,4-dimethoxybenzyl)imine is cooled under argon to -20°C and 0.88 ml (5.4 mmol) of triethylamine is added with stirring. Then avi is added in the course

In hour a solution of 1.25 g (5.6 mmol) phthaloylglycyl chloride: ■ i ; in 20 ml of dry methylene chloride and then stir further overnight at room temperature. The reaction mixture is washed three times, each time with 100 ml of water and 100 ml of sodium chloride solution. in and dried over sodium sulfate. The residue is evaporated and chromatographed on silica gel (230-400 mesh) eluting with ; hexane/acetic acid (1:1). 1.77 g (70%) of N-[(3S,4S)- are obtained. cis-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxo-lan-4-yl]-2-oxo-3-azetidinyl]-phthalimide as foam ; ta]D' = +41°

(c = 0.8 in chloroform); MS: 466 (M<+>).

in ■

c) A solution of 149.3 g (0.32 mol) N-[(3S, 4S)-cis-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl -1,3-di-oxolan-4-yl]-2-oxo-3-azetidinyl]phthalimide in 2.5 L of methylene chloride with 34 ml (0.64 mol) of methylhydrazine. It is stirred overnight at 28°C, filtered off from precipitated material and in-; evaporate the filtrate under reduced pressure. The residue is taken up in 1.2 1 vinegar and the suspension obtained is filtered. ; The filtrate is washed three times, each time with 500 ml of water and 500 ml of sodium chloride solution and dried over sodium sulphate. After evaporation of the solvent, 104.3 g (86.8%) crude is obtained

(3S,4S)-cis-3-amino-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone which without further purification is used in the next step.

d) A stirred solution of >104 g (3.0 mol) is mixed

(3S,4S)-cis-3-amino-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone and 104 ml (1.2 mol) butylene oxide dropwise in 1.5 1 methylene chloride with 57.6 ml (0.4 mol) carbobenzoxychloride, stir for 1 hour and then evaporate under reduced pressure. The crude material obtained is treated with 2 1 of dry ether, whereby a crystalline material is obtained. 122.6 g (84%) of benzyl-(3S,4S)-cis-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolane-4 are obtained -yl]-2-oxo-3-azetidine carbamate with melting point 115-116°C; [ci]^= +48° (c = 0.3 in methanol).

e) A solution of 160 g (0.34 mol) benzyl-(3S,4S)-cis-1- i

i (2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolane-4- >

i yl]-2-oxo-2-azetidine carbamate in 1000 ml of tetrahydrofuran I and 400 ml of water is stirred in the presence of 8 g of p-toluenesulfonic acid at 60°C overnight. The reaction mixture is neutralized with saturated NaHCO 3 and the tetrahydrofuran is evaporated. The aqueous solution is then extracted with 2 1 acetic acid. After I drying over Na^SO^ and evaporation, 142 g (97.2%) are obtained! pure benzyl-(3S ,4S)-cis-4-[ (R)-1,2-dihydroxyethyl]-1-(2,4-1 dimethoxybenzyl)-2-oxo-3-azetidine carbamate, m.p. 177-<;>178°C (MeOH). in

f) A solution of 142 g (0.33 mol) of benzyl-(3S,4S)-cis-4-[(R)-1,2-dihydroxyethyl]-1-(2,4-dimethoxy-benz< y>1)-2-oxo-3-azetidine carbamate in 1000 ml of tetrahydrofuran while stirring dropwise with a solution of 76.8 g (0.359 mol) of sodium metaperiodate in 600 ml of water. Stir for 1 hour, filter and evaporate the filtrate under reduced pressure. The residue is taken up in 400 ml of vinegar and washed twice, each time with 100 ml of water and 50 ml of sodium chloride solution. After drying and evaporation, 105 g (87.8%) of pure benzyl-(3S,4S)-cis-1-(2,4-dimethoxybenzyl)-4-formyl-2-oxo-3-azetidine carbamate with a melting point of 145- 147°C (from acetic acid/hexane);

[α]D = +13.7° (c = 1, CHCl 3 ).

g) 4.27 g (113 mmol) of sodium borohydride are dissolved in 1.6 1 of absolute ethanol and cooled to 0°C. This solution is added dropwise to a solution of 90 g (226 mmol) of benzyl-(3S,4S)-cis-1-(2,4-dimethoxybenzyl)-4-formyl-2-oxo-3-azetidine carbamate in 720 ml of ethanol-tetrahydrofuran ( 1:1). The reaction mixture is stirred for 2 hours at 0°C and then treated with 350 ml of saturated aqueous sodium sulphate solution and stirred for 45 minutes. After filtering and evaporating the solvent, the residue is taken up in 1.5 1 ethyl acetate and washed until the reaction is neutral. After drying over sodium sulfate. and partial evaporation gives crystalline (3S,4S)-cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-hydroxymethyl-2-azetidinone in the form of 72.2 g of colorless crystals (79.6%) with melting point 138°C, [a]D= +41.6° (c = 1 in methanol). i i I Elemental analysis calculated for C2iH24<N>2°6: C 62.99, H 6.04, N 7.00% found: c62.76, H 6.09, N 6.96% j IR (KBr, cm'1): 1718, 1698, 1615, 1589

;NMR (CDC13 , ppm): 2.45 (1H,dd,OH), 3.55-3.75 (3H,broad, CH-CH2-) , 3.79 (6H,s,2xOCH3) , 4, 35 (2H,s,N-CH2), 5.08 (2H,s,O-CH2),

5.11 (lH,dd,5 und 9 Hz.Hj), 6.06 (lH,d, 9Hz,NH), 6.43 (2H,m,Ar), 7.15 (lH.m.Ar) , 7.31 (5H,m,CgH5)

MS: 292 (M-BzOH)

i h) A solution of 30 g (74.9 mmol) (3S,4S)-cis-3-benzyl-;

oxycarboxamido-1-(2,4-dimethoxybenzyl)-4-hydroxymethyl- j

2-azetidinone in 600 ml of methylene chloride is treated at 0-5°C with 21.22 g of chlorosulfonyl isocyanate (2 equivalents). After 15 minutes, an aqueous solution is added dropwise to the reaction mixture

5°C chilled solution of 20.9 g (2.7 equivalents) of sodium sulphite. The reaction mixture is stirred for 2 hours, then diluted with methylene chloride and the organic phase is separated, washed with aqueous sodium chloride solution and dried over sodium sulfate for 12 hours. The organic phase is then 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 and washed with ether. 32.6 g (97%) of (3S,4S)-cis-3-benzyloxycarboxamido-4-carbamoyloxymethyl-1-(2,4-dimethoxybenzyl)-2-azetidinone with melting point 178-179°C is obtained, [ a]D= +84.7° (c = 0.8

in chloroform).

Elemental analysis: calculated for C^H^N-jO.^:

C 59 .59 , H 5.68, N 9.48% found: C 59.17, H 5.69, N 9.37%

IR (KBr, cm"<1>): 1761, 1708, 1618, 1587

i) A suspension of 11.9 g (26.8 mmol) of 3S,4S)-cis-3-benzyl-oxycarboxamido-4-carbamoyloxymethyl-1-(2,4-dimethoxy-'benzyl)-2-azetidinone, 14 .5 g (53.5 mmol) of potassium peroxide

sulfate, 13.98 g (80.3 mmol) dipotassium hydrogen phosphate and 1.33

g (5.36 mmol) of copper sulphate (5H20) in 270 ml of acetonitrile and 130 ml of water is heated for 3 1/2 hours to 95°C in an argon atmosphere, at a pH value between 6.5 and 7, 0 (occasional addition of 10 g dipotassium hydrogen sulfate). After cooling and filtering, 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, filtering and evaporating the solvent, the residue is taken up in ether and filtered. The crude crystals (8.9 g) are chromatographed on

in SiO 2 (300 g, 40-63 pm, chloroform:methanol:ethyl acetate 85:10:5). 5.5 g (70%) of (3S,4S)-cis-3-benzyloxycarboxamido-4-carbamoyloxymethyl-2-azetidinone are obtained as colorless crystals, [a], U ^ = +61.2° (c = 1 in methanol). Melting point 1 in 93-in 195°C. in

IN

Elemental analysis: calculated:fqrC^H^t^O,.:

C 53.24, H 5.16, N 14.33% found: C 53.40, H 5.24, N 14.35% IR (KBr, cm"<1>): 3414, 3315, 1757, 1701, 1610,

1540, 1498

NMR (DMSO, ppm): 3.31-4.06 (3H,m,CH-CH2~), 4.95

' (lH,dd,4.5 und 9Hz,H3), 5.06 (2H,s,<!>0-CH2), 6.53 (2H,broad,NH2), 7.35

;(5H,s,C6H5), 7.95 (1H,d,9Hz,CH3-NH-C0), 8.35 (1H,s,NH-C0)

MS (CI with NH 3 ): 251 (M+H)<+>-CONH

k) 5.4 g (18.4 mmol) (3S,4S)-cis-3-benzyloxycarboxamido-4-carbamoyloxymethyl-2-azetidinone in 200 ml absolute dioxane is treated at room temperature with 4.3 g (1.3 equivalents) pyridine-sulfur trioxide complex. The resulting suspension is stirred for 3 hours, then treated with a further 0.99 g (0.3 equivalents) of pyridine-sulfur dioxide complex and the reaction mixture is stirred for a further 1 hour. After addition of a further 1.37 g (0.4 equivalents) of pyridine-sulfur trioxide complex and a further 2 hours of stirring, the solvent is partially removed under reduced pressure and the residue is treated with 110 ml of saturated aqueous sodium bicarbonate

In solution. The obtained brown solution is left for 12 hours in a refrigerator and the crystals obtained are filtered off. Moderi<->I the lye is chromatographed (MCI gel, water-ethanol 1:1 to 9:1). I After lyophilization, 3.5 g (49%) of (3S,4S)-cis-3-

i i j Benzyloxycarboxamido-4-carbamoyloxymethyl-2-azetidinone-1-sulfonic acid sodium salt as a colorless powder, [ a]^' = J +29.6° (c = 0.5 in water). j ;

' i 1 i Elementary analysis: calculated for:<C>^^<H>^^N^OgSNa: i C39.50, H3.57, N10.63« found: C 39.41, H 3.45, N 10 .36% 1 IR (KBr, cm"<1>): 1798, 1758, 1739, 1693, 1584, 1547 NMR (DMSO, ppm): 3.9-4.4 (3H,CH-CH2), 4, 9 (dd,lH,

NH-CH) , 5.1 (s ,2H,0-CH2) , 6.4 (2H,broad,NH2), 7.4 (5H,s,CgH5), 8.0 (1H,d,NH)

in

,1) 3.065 g (7.75 mmol) (3R,4S)-cis-benzyloxycarboxamido-4-carbamoyloxymethyl-2-azetidinone-1-sulfonic acid sodium salt are dissolved in 180 ml of absolute methanol and hydrogenated for 1 hour in the presence of 1.5 g of 10% palladium carbon. The catalyst is removed by filtration and the resulting solution is evaporated. 2.02 g (100%) of (3S,4S)-cis-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidine sulfonic acid sodium salt are obtained.

<:>IR (KBr, cm"<1>): 3444, 3207, 1754, 1725, 1611, 1249

EXAMPLE 2 7

2.28 g (3.98 mmol) (3S,4S)-3-[2-amino-4-thiazolyl)-2-(Z)-t[1-(t-butoxycarbonyl)-1-methylethoxy]imino] acetamido]-4-carbamoyloxynrethyl-2-oxo-1-azetidine sulfonic acid sodium salt is treated under ice-cooling with 5 ml of trifluoroacetic acid. The ice bath is removed and the reaction mixture is stirred for 30 minutes at room temperature. Excess trifluoroacetic acid is removed under reduced pressure (20°C, 15 mm Hg) 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 chromatography in reverse phase, one obtains

after the 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-azetidine-sulfone-

o 1 acid, [a]D= +35.7 (c = 0.3 in water).

i Elemental analysis: calculated for c14H18N6O10S2: C 34.01, H 3.67, N 17.00 %

found: c 34.52, H 3.72, N 16.63% IR (KBr, cm<-1>): 1764, 1722, 1680, 1637

NMR (DMSO, ppm): 1.50 (6H,s,2xCH3), 4.00-4.20 (3H,CH-CH2),

5.35 (lH.dd.4.5 und 9Hz,H3), 6.50 (3H, breit,NH<+>oderCOOH, CONH2), 6.90 (lH,s, Thiazol-5H), 9.15 (lH,d,9Hz,CONH)

EXAMPLE 2 8 Analogously to example 26, 2-(2-amino-4-thiazolyl)-, 2-[[(Z)-(p-nitrobenzyloxycarbonyl)-methoxy]-imino]-acetic acid-2-benzthiazolyl-thioester is obtained and (3S,4S)-3-amino-4-carbamoy 1-oxy-methyl-2-oxo-1-azetidine sulfonic acid sodium salt (3S,4S)-3-[(Z)-2-(2-amino-4 -thiazolyl)-2-[[(p-nitrobenzyloxycarbonyl)-methoxyimino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidine sulfonic acid sodium salt.

Calculated for ClgH^gN70^2S2Na

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"<1>):3353, 1761, 1729, 1524, 1348

NMR (DMSO, ppm): 4.0-4.2 (3H,m,CH-CH2), 4.3 (2H,s,0-CH2),

5.30 (1H,dd,NH-CH-), 5.32 (2H,s,0-CH2), 6.70 (2H,broad,NH2), 6.9 (1H,s,S-CH= ), 7.10 (2H,broad,NH2), 7.70 und 8.2 (2x2H, 2d,2x3Hz,Ar), 9.15 (1H,d,9Hz,NHCO)

EXAMPLE 2 9

2 70 mg (0.43 mmol) (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(p-nitrobenzyloxycarbonyl)methoxyimino]acetamido]-4- Carbamoyloxymethyl-2-oxo-1-azetidine sulfonic acid sodium salt is dissolved in 30 ml of methanol and hydrogenated over 5% palladium on silica (150 mg). The catalyst is filtered off and solution-! the agent evaporates. The residue is taken up in 2.5 ml of water and washed twice with ethyl acetate. The aqueous phase is chromatographed

i : (reverse phase, water as eluent). You get 115 mg

(54%) (3S,4S)-3-[ (Z)-2-(2-amino-4-thiazolyl)-2-[(carboxy- j

in ! methoxy)-imino]acetamido]-4-carbamoyloxymethyl-2-oxo-1- | azetidine sulfonic acid sodium salt. j ;

Elementary analysis: calculated for <~'l2^13^6<^10^2^a

C 29.51, H 2.68, N 17.21% found: c 27.09, H 2.35, N 15.33% IR (KBr em"<1>): 3434, 1766, 1718, 1669, 1613, 1533,

1278, 1251 ■

NMR (DMSO, ppm): 3.90-4.15 (3H,m,CH-CH2), 4.30 (2H,s,CH2-COOH), 5.20 (lH,dd,5 und 9Hz,NH -CH),

6.6 (2H,broad,NH2), 6.78 (1H,s,S-CH=), 7.13 (2H,s,NH2), 10.90 (1H,d,9Hz,CONH)

EXAMPLE 30 Analogously to example 26, the following is also obtained: j a) (3S,4S)-3-[(5-amino-3-(1,2,4-thiadiazolyl)]-2-(Z)-(meth-,oxyimino) acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidine sulfonic acid sodium salt.

Elementary analysis: calculated for^lo^l2^7^8^2^a

C 26.97, H 2.72, N 22.02, S 14.40% found: C 2 7.06, H 2.62, N 21.60, S 14.28%

IR (KBr, cm ): 3330, 1767, 1720, 1675, 1617, 1524,

1276, 1252

NMR (DMSO, ppm): 3.90 (3H,s,0CH3), 3.90-4.30 (3H,m,

CH-CH2), 5.20 (lH,dd,6 und 9Hz,NH-CH), 6.35 (2H,s,NH2), 8.10 (2H,s,NH ), 9.04

(1H,d,9Hz,C0NH)

IN

[a]589= +32.5° (c = 0.4 in water)

The 2-[(5-amino-3-(1,2,4-thiadiazolyl)]-2-(Z)-methoxyimino-acetic acid-2-benz-thiazolyl-thioester used for this as starting material can be prepared as follows: i I I! i b) 2.0 g 2-(5-amino-3-(1,2,4-thiadiazol-yl)]-2-(Z)-methoxy-i<1>

in imino-acetic acid in 60 ml of acetonitrile is mixed at room temperature in turn with 1.3 ml of N-methylmorpholine. After 5 minutes, 13.6 g of dithio-bis-benzthiazole are added, followed by the dropwise addition of 2.2 ml of triethyl phosphite in 10 ml of acetonitrile over 1! \

IN

[ hour. The reaction mixture is stirred for 12 hours at room temperature in ; and then filtered, washed with acetonitrile and low-boiling petroleum ether, dried and crystallized from tetrahydrofuran/low-boiling petroleum ether. 1.4 g (40%) of 2-[(5-amino-3-(1,2,4-thiadiazolyl)]-2-(Z)-methoxyimino-acetic acid-2-bene are obtained; Thiazolyl thioester with melting point >160°C (decomposition).

In EXAMPLE 31

Analogous to example 26, the following is also obtained: (3S, 4S)-3-[2-amino-4-thiazolyl)-2-(Z)-methoxyimino]acetami-! do]-4-carbamoyloxymethyl-2-oxo-1-azetidine sulfonic acid sodium salt.

Elemental analysis: calculated for C. -, H.. ,N^0oS_Na

Il lo D o 2

C 29.73, H 2.95, N 18.91% found: C 29.91, H 3.30, N 19.00%'IR (KBr, cm<-1>): 3364, 1775, 1739, 1680, 1625, 1537,

1284, 1256

NMR (DMSO, ppm): 3.90 (3H,s,0CH3), 4.10 (3H,m,CH-CH2),

5.25.(lH,dd, 4.5 und 9Hz,CH-NH), 6.45 (2H,s,NH2), 6.70 (1H,s,S-CH=) , 7.10

(2H,s,NH2), 9.10 (1H,d,9Hz,CONH)

EXAMPLE 32

a) Analogously to example 2G, the following is also obtained: (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-acetamido]-4-carbamoyl1-2-oxo -1-azetidine sulfonic acid sodium salt.

l

Elemental analysis: calculated for cioHHN6°7S2Na

C 28.99, H 2.68, N 20.68% found: c 3lf2o, H 3.26, N 16.41% IR (KBr, cm<-1>): 3282, 1790, 1640, 1612, 1527 , 1260,

1230

NMR (DMSO, ppm): 3.85 (3H,s,0CH3), 4.3 (1H,d,6Hz,

CH-CONH2), 5.30 (1H,dd,6 und 9 Hz,NH-CH), 6.95 (1H,s,S-CH=), 7.40 (2H,d,18Hz, CONH2), 9.25 (1H,d,9Hz,NH-CO)

The (3S,4S)-cis-3-amino-4-carba-,moyl-2-azetidinone-1-sulfonic acid sodium salt used for this purpose can be prepared as follows: ■ b) 17 g (42.7 mmol) benzyl -(3S,4S)-cis-1-(2,4-dimethoxybenzyl-4-formyl-2-oxo-3-azetidine-carbamate is dissolved in 100 ml of 1 methylene chloride and 100 ml of n-propanol. This solution is mixed with 3, 5 g of hydroxylamine hydrochloride (50.3 mmol), followed by 4.2 ml of pyridine (52 mmol). The reaction mixture is heated for 2 hours under reflux conditions. Then the methylene chloride is distilled off and a solution of 6.3 g of selenium dioxide (57 mmol) in 100 ml of n-propanol is added dropwise. The reaction mixture is heated for 2 hours under reflux conditions, the reaction mixture is cooled to room temperature and filtered and the resulting solution is evaporated under reduced pressure. The resulting oil 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, each time with 200 ml of ann and saline solution. After drying over sodium sulphate, filtering and evaporating the solvent, the residue is taken up in 70 ml of n-propanol. The solution is left for 12 hours in the refrigerator. 16.4 g (97%) of benzyl (3S,4S)-cis-1-(2,4-dimethoxybenzyl)-4-cyano-2-oxo-3-azetidine carbamate with a melting point of 152-153°C are obtained [a]D= +10.6° (c = 1 in chloroform).

MS: 395 (M<+>). j

in

!

in c) 15.72 g of potassium peroxide sulfate (58.2 mmol) and 9.5 g of potassium hydrogen sulfate (54.8 mmol) are dissolved in 480 ml of water. The solution is heated to 80° C. and treated with a solution of 1.2 g of copper sulphate in 10 ml of water. The obtained suspension J 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-dimethoxy-jbenzyl-4-cyano-2-oxo-3 -azetidine carbamate in 300 ml of acetonitrile. The reaction mixture is heated for 2 1/2 hours under reflux conditions, then 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 bicarbonate solution After drying and evaporation of the solvent, the obtained oil is chromatographed on silica gel I (230-400 mesh, eluent ethyl acetate:n-hexane 1:1).

6.1 g (68.3%) of benzyl-(3S,4S)-cis-4-cyano-2-oxo-3-

in ,azetidine carbamate with melting point 163-165°C.

MS: 245 (M<+>).

d) 6.16 g (25 mmol) of benzyl-(3S,4S)-cis-4-cyano-2-oxo-3-azetidine-carbamate are dissolved in 45 ml of dimethylsulfoxide and be-,

is traded with 5.58 ml of 30%<1>ig aqueous hydrogen peroxide. After the temperature has dropped to 25°C, the mixture is treated with 5 ml of aqueous IN sodium hydroxide solution. The temperature rises to 55°C. After 45 minutes of stirring, a precipitate forms.

20 ml of ethyl acetate are added and the crystals obtained are filtered off. The crystals are washed with aqueous ethanol and absolute ether. 2.48 g (37.5%) of benzyl-(3S,4S)-4-carbamoyl-2-oxo-3-azetidine carbamate is obtained with melting point 248-249°C [ct]D= +13° (c = 1 in dimethylsulfoxide) .

The mother liquor is partially evaporated, whereby a further 0.33 g of product is isolated. The mother liquor thus obtained is diluted with water and chromatographed on MCI gel (ethanol-water 3:7 as eluent). The total yield of final product amounts to 3.0 g (45.4%).

i i : i

in

e) 7.9 g (30 mmol) of benzyl-(3S,4S)-4-carbamoyl-2-oxor3-azetidine-carbamate are dispersed in 470 ml of absolute dioxane and

is treated with 6.2 g (39 mmol) of pyridine-sulfur dioxide complex. The resulting suspension is stirred for 2 hours at room temperature;

1 perature, then with 1.41 g (8.8 mmol) of pyridine-sulphur dioxide complex and stirred for a further hour. After addition of 1.90 g (12 mmol) pyridine-sulphur dioxide complex and stirring for a further 2 hours, the solvent is evaporated 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. This aqueous solution is extracted

twice, each time with 250 ml of methylene chloride, and then dried over sodium sulphate. After evaporation of the solvent, the obtained oily residue is dissolved in 150 ml of absolute methanol and hydrogenated over 2.5 g of 10% palladium carbon. The catalyst is filtered off and the solution is evaporated and dissolved again in a solution of 70 ml of formic acid in 100 ml of methylene chloride. After 2 hours, the solvent is evaporated and the residue is treated with 25 ml of water. 2.3 g (36%) of (3S,4S)-3-amino-4-carbamoyl-2-oxo-1-azetidine sulfonic acid are obtained. The mother liquor is chromatographed on MCI gel. (Eluent: water-ethanol 1:0

to 9:1), whereby a further 420 mg of product is obtained. Total yield 2.7 g (43.3%).

IR (KBr, cm"<1>): 1779, 1696, 1633, 1485, 1288, 1250

NMR (DMSO, ppm): 4.43 and 4.72 ( Z *1H,2d,6Hz,CH-CH), 7.88

(2H,d,br.,NH^, 8.59 (3H,br.,NH<*>).

EXAMPLE 3 3

Analogous to example 32 acc. example 26 also gives: (3S,4S)-3-[(Z)-2-[[5-amino-3-(1,2,4-thiadiazol1)]-2-[methoxyimino]-acetamido]-4 -carbamoyl-2-oxo-1-azetidine sulfonic acid sodium salt.

in

1 Analysis: calculated for CgH10N7O7S2Na

C 26.03, H 2.43, N 23.61% found: C 26.02, H 2.59, N 23.32 ^

IR (KBrcm"<1>):3424, 3334, 1776, 1688, 1618, 1524,

1278

NMR (DMSO, ppm): 3.90 (3H,s,OCH ), 4.45 (1H,d,6Hz,

CH-CONH2), 5.40 (lH,dd,6 und 9Hz,NH-CH), 7.30 (2H,br-,NH2), 8.10 (2H,br.,NH2), 8.8 ( 1H,d,9Hz,NH-CO).

EXAMPLE 34

Analogous to example 32 acc. examples 26 and 27 also give: (3S,4S)-3-[(Z)-2-[2-amino-4-thiazolyl)-2-[[1-carboxy-1-methylethoxy]imino]acetamido ]-4-carbamoyl-2-oxo-1-azetidine sulfonic acid.

Elemental analysis: calculated for ia>^ 9^ 2

C 33.62, H 3.47, N 18.10% found: C 33.24, H 3.18, N 17.94%

IR (KBr, cm"<1>): 3332, 3208, 2552, 1780, 1684, 1638,

1279, 1188

NMR (DMSO, ppm): 1.44 (6H,s,2xCH3), 4.34 (1H,d,6Hz,

CH-C0NH2), 5.33 (lH,dd,6 und 9Hz,NH-CH-), 6.96 (lH,s,S-CH=), 7.40 (2H,br., d, 7Hz, C0NH2), 8.95 (1H,d,9Hz,CONH)

UV (EtOH): 292 nm (6846), 240 nm (12232).

EXAMPLE 35

Analogous to example 32, one obtains from (3S,4S)-3-amino-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-1-azetidine sulfonic acid and 2 -(2-amino-4-thiazolyl)-2-(Z)-methoxyimino-acetic acid-2-benzthiazolyl-thioester (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl) -2-(Methoxyimino)-acetamido]-4-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-okeo-1-azetidine sulfonic acid sodium salt.

in

■ IR (KBr, cm"<1>): 3429, 3345, 1770, 1673, 1620, 1531,

1253

NMR (DMSO, ppm): 1.-23 und 1.33 ( 2x3H, 2s , 2xCH3 ), 3.83

(3H,s,OCH3), 3.8-4.15 (4H,m,CH-CH-CH2-),

5.22 (1H,dd,5.5 und 9Hz,NH-CH_), 6.75 (1H,s,S-CH=), 7.19 (2H,br-,NHj), 8.68

(1H,d,9Hz,NH-CO).

"! i i : b) 740 mg (1.57 mmol) (3S,4S)-3-[(Z)-2-(2-amino-4-thiazol-1yl)-2-(methoxyimino)acetamido]- 4-[(R)-2,2-dimethyl-1,3r

j ■ in dioxolan-4-yl]-2-oxo-1-azetidine-sulfonic acid sodium salt , dissolve in 40 ml methanol-water', (1:1) and stir for 12 hours in! near-

! i!I weather of 15 g "Amberl.ite IR 120" (pre-washed in meta- j I noi) . The catalyst is filtered off and the solvent1 off-j ; steamed. 300 mg (0.7 mmol, 44%) of (3S,4S)-2-[(Z)-2- j j j j (2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-[ (R)-1,2-dihydroxyethyl]-2-oxo-1-azetidine sulfonic acid sodium salt. ! in

!

■Elementary analysis: calculated for C-^H-^N,.0gS2Na |

C 30.63, H 3.27, N 16.24% found: C 32.03, H 3.98, N 15.89% in

! ;IR (KBr , cm 1 ): 3290, 1772, 1742, 1678, 1638, i<1>1270, 1227, 1045

INMR (DMSO ,_ppm): 3.2-4.15 (4H,m,CH-CH-CH2), 3.52

(3H,s,0CH3), 5.19 (1H,dd,6 und 9Hz, NH-CH), 6.98 (1H,s,S-CH=),

7.1 (4H,br.,NH2.2xOH), 9.23 (1H,d,!9Hz,CONH).

c) From (3S,4S)-2-t(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4- [ (R)-1,2-dihydroxyethyl]- 2-oxo-l-aze-, ; tidine sulphonic acid sodium salt is obtained analogously to example | 26 (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyimino)- acetamido]-4-formyl-2-oxo-1-azetidine sulfonic acid sodium I salt. j

; i Elementary analysis: calculated for ■ C^H^^O^Na

C 30.08, H 2.52, N 17.54% found: G 31.27, h 3.02, N 17.67%

IR (KBr, cm"<1>): 3177, 1771, 1636, 1524, 1271

NMR (DMSO, ppm): 3.93 (3H,s,0CH3), 4.30 (l.H,dd,4.0 und

j 6Hz,CH-CH0), 5.14 (lH,dd,6.0 und 8.0Hz, I NH-CH), 5.5 (2H,br., NH2), 6.77 (lH,s, S-CH=), 9.61 (1H,d,8Hz,NH-C0), 9.65

(1H,d,4.0Hz, CHO).

in

in ; • 'd) 400 ml (1 mmol) (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-formyl-2-oxo -1-azetidine-sulfonic acid sodium salt is dissolved in 400 ml of methanol and treated with 100 mg (1.4 mmol) of hydroxylamine hydrochloride and 0.1 ml of

(1.24 mmol) pyridine. After 2 hours of stirring, the reaction is evaporated! sion mixture and the product are chromatographed on silica gel !

(230-400 mesh, methanol:ethyl acetate 3:7 as eluent). The partially purified product is chromatographed on MCI gel in (water

as eluent). You get 45 mg (10%) of (3S,4S)-3-[ (Z)-

IN

2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-[(E/Z)i-(hydroxyimino)methyl]-2-oxo-1-azetidine sulfonic acid.. i li i Elementa<p>ranalysis: calculated for <-]_o^ll^6<^>7^2^a

C 28.99, H 2.68, N 20.28%

found: C30.06, H 3.34, N 18.68 IR (KBr, cm"<1>):3430, 1775, 1655, 1622, 1531, 1286,

1216

NMR (DMSO, ppm): 3.82 (3H,s,0CH3), 4.46 (1H,dd,5.5 und 8.0Hz,CH-CH=), 5.22 (1H,dd,6 und 9Hz, NH-CH), 6.57 (1H,s,S-CH=), 7.18 (2H, br., NH2), 7.32 (1H,d,8.0Hz,CH=N), 9.29 (1H.9Hz,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-azetidine sulfonic acid used as starting compound can be prepared as follows:

: e) 0.25 g (Q.78 mmol) benzyl-(3S,4S)-cis-4-[(R)-2,2-di-j

! IN

methyl 1,3-dioxolan-4-yl]-2-oxo-3-azetidine carbamate disper-I ' I

, is dissolved in 4 ml of pyridine and treated with 0.5 g (3.1 mmol) of sulfur trioxide-pyridine complex. The reaction mixture up-! heat for 1 hour. The solution is cooled and then treated with

50 ml of ether. The ether is decanted off and the residue is mixed with ! 300i

in i ml of water. The solution is stirred for 12 hours at room temperature in ! presence of ion exchange "Dowex 50 W" (Na form). The ion exchange is filtered off and the solution is evaporated under reduced ! ! Print. 325 mg (100%) of crude (3S,4S)-cis-3-benzyloxy- is obtained. j formamido-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxoyl-1-1' azetidine sulfonic acid sodium salt. '\

; IR: (KBr cm"<1>): 3329, I77S, 1724, 1698, 1526,

1257.

NMR (DMSO, ppm): 1.28 und 1.35 (2 x 3H, 2s, 2 CH ), 3.8 -

4.4 (4H, m, CH-CH-CH2), 4.99 (1H, dd, 6

und 10 Hz, NH-CH), 5.15 (2H, s, N-CH2),

7.45 (5H, s, C6H5), 7.5 (1H, d, 10Hz, CONH).

f) (3S,4S)-cis-3-benzyloxyformamido-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-1-azetidine sulfonic acid sodium salt

is hydrogenated analogously to example 33 with palladium carbon, whereby (3S,4S)-3-amino-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo- l-azetidine sulfonic acid.

EXAMPLE 36

a) From (3S,4S)-3-amino-4-methoxyiminomethyl-2-oxo-1-azeridinesulfonic acid and 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino-acetic acid-2 -benzthiazolyl thioester is obtained analogously to example 1 (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-acetamido]-4-methoxyiminomethyl-2- octo-1-azetidine sulfonic acid sodium salt.

Elemental analysis: C1 , H.. _N,0_,S_Na calculated: C 30.84, H 3.06, N 19.62 % 1113b12.

found: C 30.88, H 3.19, N 19.52% IR: (KBr cm"<1>): 3424, 3336, 1772, 1671, 1622,

1532, 1274 . 1 in

; The (3S,4S)-3-amino-4-meth-1oxyiminomethyl-2-oxo-1-azetidine sulfonic acid used as starting compound can be prepared as follows: i

!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 treated with 0.7 g (8.5 mmol) of 0-methylhydroxylamine hydrochloride and 0.73 ml (9.0 mmol) of pyridine. The re-■ 'aks ion mixture is stirred for 2 days at room temperature and! va-, ,is then done with water and sodium chloride solution. After drying over sodium sulfate and evaporating the solvent 1,i

. the material is chromatographed (230-400 mesh, ethyl acetate:n-hexane 6:4). 2.6 g (82%) of benzyl-(3S,4S)-1-(2,4-di-:methoxybenzyl)-4-[(methoxyimino)methyl]-2-oxo-3-azetidine-:carbamate are obtained 'I

■ (mixture of the E/Z isomers): i

j IR KBr, cm"<1>): 3290, 1772, 1686, 1210

MS: 319 (M-O-CH 2 OH).

c) 11.9 g of potassium peroxydisulfate (44 mmol) and 9.6 g of dipotassium hydrogen phosphate are dispersed in 110 ml of acetonitrile

and 350ml of water. The mixture is heated to 78°C and a solution

i of 11.8 g (27.6 mmol) benzyl-(3S,4S)-1-(2,4-dimethoxybenzyl)-4-[(methoxyimino)methyl]-2-oxo-3-azetidine carbamate (mixture of E The /Z isomers) are added dropwise into 300 ml of acetonitrile. After addition of dipotassium hydrogen phosphate, the solution's pH value is maintained at 7. After 6 hours of boiling, the reaction 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 bicarbonate solution. After drying over sodium sulfate, the solvent is evaporated and the crude mixture is chromatographed (230-400 mesh, ethyl acetate:n-hexane 8:2), whereby 1.7 g (27%) of benzyl-(3S, 4S)-4-[( methoxyimino)methyl]-2-oxo-3-azetidine carbamate [mixture of the E/Z isomers). Melting point 170-171°C.

IR (KBr, cm"<1>): 3310, 3210, 1790, 1732, 1533, 1258.

d) 1.7 g (6.13 mmol) of benzyl-(3S,4S)-4-[(methoxyimino)-methyl]-2-oxo-3-azetidine-carbamate (mixture of the E/Z isomers) is dissolved in 100 ml of absolute dioxane, treated with l|,26

in g (7.9 mmol) of sulfur dioxide-pyridine complex and stirred for 1.5 hours at room temperature. After addition of a further 0.29 g (1.8 mmol) of sulfur trioxide-pyridine complex, the suspension is stirred for a further 1.5 hours. After addition ay

in 0.39 g (2.45 mmol) of sulfur trioxide-pyridine complex and surface

After a further 1 hour of stirring, the solvent is evaporated under reduced pressure and the residue is treated with 30 ml saturated aqueous

sodium bicarbonate solution. The obtained aqueous solution; extracted twice with ethyl acetate and the organic phase ! thrown away. The aqueous phase is evaporated to 10 ml and chromato-

! graphed (MCI gel; H2O:ethanol 1:0 to 9:1 to 7:3). Mah obtains in 1.36 g (58.5%) of (3S,4S)-3-[(benzyloxy)formamido]-4-[(meth-'oxyimino)methyl]-2-oxo-1-azetidine-sulfonic acid ( mixture

i of the E/Z isomers). 'in

', Elementary analysis : i

i C13H14N3°7SNa calculated: C 41.16, H 3.72, N 11.08% i found: C 40.21, H 3.81, N 10.72% j IR (KBr, cm<-1>) : 3396, 3347, 1774, 1708, 1256.

le) The thus obtained (3S,4S)-3-[(benzyloxy)formamido]-4-[(methoxy<y>imino)meth<y>l]-2-oxo-1-azetidine-sulfone is hydrogenated analogously to the last section of example 26. In this way (3S,4S)-3-amino-4-methoxyiminomethyl-2-oxo-1-azetidine sulfonic acid is obtained.

EXAMPLE 37

Analogously to example 1, one obtains from (3S,4S)-3-amino-4-meth-oxyiminomethyl-2-oxo-1-azetidine sulfonic acid (mixture of the E/Z isomers) and 2-[(5-amino-3- (1,2,4-thiadiazolyl)]-2-(Z)-methoxyimino-acetic acid-2-benzthiazolyl thioester as 'final product (3S,4S)-3-[(5-amino-3-(1,2,4- thiadiazolyl)]-2-1 (Z)-(methoxyimino)acetamido]-4-methoxyiminomethyl-2-oxo-1-azetidine sulfonic acid sodium salt.

<!>

! Elemental analysis:<C>10H12N707S2Na calculated: C 27.97, H 2.82, N 22.84,

' S14.93 I

!found: C 28.50, H 3.37, N 24.07,

in ! S 14.79 I IR (KBr, cm"<1>).: 3419 , 1771, 1671, 1622 , 1523, 1278^ j ; i i j EXAMPLE 38 i j ! a) 378 mg (2.1 mmol) (3S,4R )-3-amino-4-methyl-2-oxo-1-j in azetidinesulfonic acid is dissolved in 60 ml of acetone/water 1:1 and, treated with 1.3 g (2.3 mmol) of 2-(2- amino-4-thiazolyl)- 2-' I [[(Z)-1-(p-nitro-benzyloxycarbonyl)-1-methylethoxy]imino]-acetic acid-2-benzthiazolyl-thioester and 176 mg (2.1 mmol) sodium bicarbonate. The reaction mixture is stirred for 12 hours at I: room temperature. The acetone is evaporated off under reduced pressure1 and the j residue is filtered. The aqueous solution obtained is evaporated.

[ 115 mg (10%) of (3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-(p-nitrobenzyloxycarbonyl)-1-methylethoxy] are obtained -imino]-acetamido]-4-methyl-2-oxo-1-azetidine sulfonic acid sodium salt as amorphous material.

; IR (KBr, cm"1): 3380, 1753, 1678, 1620, 1523, 1286,

in 1236

NMR (DMSO, ppm): 1.24 (3H,d,J=6Hz,CH-CH3), 1.46 und 1.50 ! (2x3H,2s,(CH3)2C), 3.99 (1H,m,CH-CH3),

15.10 (1H,dd,J=6 und 9Hz,NH-CH)/5.33 (2H,s,0-CH2), 6.69 (1H,s,S-CH=), 7.30

(2H,br.,NH2), 7.59-8.18 (4H,m,Ar), 9.26 (1H,d,9Hz,NHC0)

The 2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(p-nitrobenzyloxycarbonyl)-1-methylethoxy]imino]-acetic acid-2-benzthiazolyl-thioester used above can be prepared as follows: b) 33.0 g (136 mmol) of 2-(2-amino-4-thiazolyl)-2-(Z)-hydroxy-imino-acetic acid t-butyl ester are dissolved in 500 ml of dimethylformamide. After adding 85.4 g (272 mmol) of 2-bromo-2-, methyl propionic acid 4-nitrobenzyl ester and 75.2 g (544 mmol) of powdered potassium carbonate, the reaction mixture is stirred for .5 hours at 45 C in a nitrogen atmosphere. The reaction mixture is cooled to room temperature and poured into a mixture of 5 1 water and 2.5 1 ethyl acetate. The organic phase is washed with a total of 2.5 1 water 3 times. The water is extracted with 2.5 1 ethyl acetate. The combined ethyl acetate solutions are dried over sodium sulfate and evaporated to dryness. You get 42 g (66.4%)! 2- i i(2-amino-4-thiazolyl)-2-[[(Z)-(p-nitrobenzyloxycarbonyl)-1-methylethoxy]imino]-acetic acid t-butyl ester with melting point j 150.3°C.

IN

c) 23.4 g (50.4 mmol) 2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(p-nitrobenzyloxycarbonyl)-1-methylethoxy]imino]-acetic acid-t -butyl ester is dispersed in 60 ml of trifluoroacetic acid and stirred for 30 minutes at room temperature. The solution obtained is evaporated, the residue is dissolved in 200 ml of toluene and evaporated again. After addition of 700 ml (280 mmol) of a 0.4 molar aqueous sodium bicarbonate solution, the pH value is adjusted to 3.8 with acetic acid. The precipitated crystals are filtered off and dried under reduced pressure (0.05 mm) at 50°C. 17.3 g (84%) of 2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(p-nitrobenzyloxycarbonyl)-1-methylethoxy]imino)-acetic acid are obtained with melting point 194°C (decomposition).

The water content of the product is reduced to 0.26% by twice suspending each time in 100 ml of dry acetonitrile and evaporating the solvent, followed by drying for 20 hours at room temperature under reduced pressure (0.1 mm), which is beneficial for the subsequent reaction.

d) 16.4 g (40.2 mmol) 2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(p-nitrobenzyloxycarbonyl)-1-methylethoxy]imino]-acetic acid

dispersed in 250 ml of acetonitrile (dried with molecular sieve 3A). After adding 5.6 ml (50.8 mmol) of N-methylmorpholine while stirring, 16.0 g are likewise added while stirring

(48 mmol) of 2,2-dithio-bis-benzthiazole and 9.2 ml (44.4 mmol) of triethyl phosphite. The obtained suspension is colored intensively yellow. After stirring for 1 hour at room temperature, the reaction mixture is cooled to 0°C, the crystals obtained are filtered off after 1 hour and dried at 50°C under reduced pressure (0.1

etc.). 16.1 g (72.2%) of 2-(2-amino-4-thiazolyl)-2-[:[ (Z)-|1-(p-nitrobenzyloxycarbonyl)-1-methylethoxy]imino]-acetic acid are obtained -2-benzthiazolyl thioester with melting point 162-164°C.|

in EXAMPLE 39 li

IN

115 mg (0.19 mmol) (3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-'[ [1-(p-nitro-benzyloxycarbonyl)-1- Methylethoxy]imino]acetamino]-4-methyl-2-oxo-1-azetidine sulfonic acid sodium salt is dissolved in 40 ml of water/tetrahydrofuran 1:1 and 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 solvent). 28.6 mg (33%) of (3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[\carboxy-1-methylethoxy)imino]acetamido] are obtained -4-methyl-2-oxo-1-

in azetidine sulfonic acid sodium salt. j

IR (KBr,cm"<1>): 3297, 2984, 2683, 1763, 1675, 1631,

1535, 1276'

NMR (DMSO, ppm): 1.1 und 1.20 (6H,2s,2xCH3), 1.45 (3H,d,

3 .5Hz ,CH-CH_3 ) , 4.0 ( 1H , m , CH-CH 3 ) , 5.05

(lH,dd,6 und 9Hz,NH-CH) , 6.75 (lH,s, S-CH=), 7.20 (3H,br., m*) , 9.15 dH,d, 9Hz, C0NH).

EXAMPLE 40.

In the same way as in example 1, one obtains from (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidine sulfonic acid and 2-(2-amino-4-thiazolyl)-2-[[(Z )-(t-butoxycarbonyl)-methoxy]imino-acetic acid-2-benzthiazolyl-thioester as reaction product (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[ The (t-butoxycarbonyl)methoxy]-imino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidine sulfonic acid triethylamine salt. This is dissolved in ethanol (approx. 4%). By adding an equivalent amount of a 2N solution of sodium 2-ethyl caproate in ethyl acetate;2

Vol. acetone and 4 vol. diethyl ether, the product precipitates as the sodium salt.

<.>.<.>i

IN

1 H NMR (DMSO, ppm): 9.15 (d, J=9.5 Hz, 1H); 7.20 (s,br, 2H); 6.75 (p. 1H); 6.46 (s,br,2H); 5.28 (dd, J=4Hz, J=9Hz, 1H); 4.53 (s, 2H); 4.0-4.3 (m, 3H); 1.43

in (p,9H).

in

The 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxy]imino]-acetic acid 2-benz-;1thiazolyl thioester used as starting material can be prepared as follows: 1

in ;A. 245 g (1.0 mol) of 2-(2-amino-4-thiazolyl)-2-(Z)-(hydroxy-imino)-acetic acid are dispersed at room temperature in 2.2 1 of di-<;>methylformamide and 245 g (1.13 mol) p-nitrobenzyl bromide and 170 g (1.13 mol sodium iodide. The reaction mixture is stirred for 12 hours in a nitrogen or argon atmosphere): The brown solution obtained is mixed with 190 ml (1 .29 mol) t-butyl bromoacetate and 386 ml (2.25 mol) n-ethyldiisopropyl-amine. After stirring for 1 hour at room temperature, the reaction mixture is poured into 8 1 of water, and everything is extracted with 4 1 of ethyl acetate. The ethyl acetate phase is washed with 3 1 water. The water phase is extracted in two portions with 5 1 ethyl acetate. The combined ethyl acetate phases are concentrated to 1 1 and cooled in an ice bath. The crystals obtained in this way are filtered off, washed with cold ethyl acetate and ether and dried at 50°C under reduced pressure. Man 248 g (57%) of 2-(2-amino-4-thiazolyl)-2-[t(Z)-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid p-nitrobenzyl ester are obtained

Calculated for C,0H0_N.0_S (436,447):

loZU4 /

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 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxyJrimi.no]-acetic acid p-nitrobenzyl ester are dispersed in 2 1 of methanol. After adding 42 ml (0.30 mol) of triethylamine and 55 g of Raney nickel, the mixture is shaken for 2 1/2 hours in a hydrogen atmosphere. 20.5 1 hydrogen is consumed. The catalyst is removed by filtration with diatomaceous earth, and

, the filtrate is evaporated. The residue is dissolved in 600 ml of water and extracted with 2 x 1000 ml of ethyl acetate. The ethyl acetate phase is washed with 2 x 200 ml of water. The aqueous phases are combined, filtered and mixed while stirring with approx. 250 ml IN aqueous hydrochloric acid | (pH 3). The crystals obtained are filtered off, washed with acetonitrile and water and dried for 16 hours at 45°C under reduced pressure. The crystalline material thus obtained contains approx. 5% water. Treatment with isopropanol reduces the water content to 0.9%. In addition, the crystals containing 5% water are dispersed in 100 ml of dry isopropanol, stirred for 12 hours at room temperature and dried at 45°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.

i Calculated for C11H15<N>3°5<S>(301.324): 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 2 O 0.89%.

The starting material can be prepared as follows:

B. Dissolve 84 g of diketene in 250 ml of carbon tetrachloride and cool to -27°C. The resolution becomes unclear. 71 g of chlorine gas :■ introduced over 5 hours slowly with stirring, the temperature during cooling being kept at -20 to -30°C. The clear solution obtained is added slowly over the course of 1 hour to a solution of 58 g of allyl alcohol in 250 ml of carbon tetrachloride and 80.5 ml of pyridine with stirring at 0 - -5°C. After a further 15 minutes of stirring without cooling, the precipitated pyridine hydrochloride is filtered off and washed with 100 ml of carbon tetrachloride. The carbon tetrachloride solution is washed with 2 x 300 ml of water, dried over sodium sulphate and evaporated under reduced pressure. The remainder is distilled. 136 g (77%) of allyl-4-chloroacetoacetate is obtained as a colorless liquid with a boiling point of 61-69°C (0.1 mm Hg).

in

A solution of 35.2 g of allyl-4-chloroacetoacetate in 34 ml of acetic acid is mixed dropwise with a solution of 14.6 g of sodium nitrite in 21 ml of water during 45 minutes with stirring and cooling. During the addition, the temperature eventually drops! in fro a 0 to -15°C. Then stir for 2 hours at -15°C. Eri 1jtil I 30 C preheated solution of 15.2 g thiourea in 120 ml water

i is mixed with the resulting solution at such a rate that i ! the reaction temperature remains at approx. 30-35°C. After surface

for a further 7 hours of stirring, the resulting crystal is filtered

in

; linical precipitate from, washed successively with water, acetonitrile and ether and crystallized from acetonitrile. 21.8 g (48%) of 2-(2-amino-4-thiazolyl)-2-(Z)-hydroxyimino-acetic acid allyl ester with melting point 184-185°C is obtained.

in

A solution of 20.4 g of 2-(2-amino-4-thiazolyl)-2-(Z)-hydroxy-; Cyimino-acetic acid allyl ester in 100 ml dimethylsulfoxide and 100 ml acetone is stirred together with 30 g of potassium carbonate and

■ in 19.5 ml of t-butyl bromoacetate for 5 hours at room temperature.; After evaporation of the acetone under reduced pressure (bath temperature 50°C), 600 ml of ethyl acetate is added and the solution is washed with ice water until neutral reaction, dried and evaporated under reduced pressure. A crystalline, yellowish residue is obtained which is dispersed in diisopropyl ether, filtered and dried under reduced pressure. 20.1 g (65.5%) of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid allyl ester with a melting point of 135 -136°C.

19 g of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid allyl ester in 500 ml of ethyl acetate are mixed with stirring successively with 0.09 g palladium chloride, 0.46 ml of triethyl phosphite and 30 ml of sodium 2-ethyl caproate solution (2N solution in ethyl acetate). After stirring for 4 hours at room temperature, 500 ml of water and 100 ml of saturated, aqueous sodium bicarbonate solution are added. The aqueous solution is separated, washed with 100 ml of ethyl acetate and acidified with 2N aqueous hydrochloric acid to pH 2. The crystalline precipitate is filtered off, washed successively with water, acetonitrile and ether

, and dried under reduced pressure. 14.6 g (87%) of 2-(2-

, amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid with melting point 175-176°C (decomposition).

in

i Additional methods for producing the starting material1

y! are the following: !i i j C. 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-

In methoxy]-imino]-acetic acid allyl ester react according to B

\ in front, however using 0.12 g of palladium acetate instead of palladium chloride. After identical work-up j, 14.5 g (86.3%) of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-1) are obtained

I butoxycarbonyl)-methoxy]-imino]-acetic acid with m.p.

<1>171-172°C.<1>'

, in I 1 ! D. 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)- | Methoxy]-imino]-acetic acid allyl ester is reacted analogously to, C in front, however using 0.695 g of triphenylphosphine instead of triethylphosphite. 3.4 g (79.7%) of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid with a melting point of 167-169 are obtained °C. '

E. A suspension of 1.4 g of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid allyl ester,

86 mg palladium carbon (5%), 0.033 ml triethyl phosphite and 2.25 ml sodium 2-ethyl caproate solution (2N solution in ethyl acetate)

in 50 ml of ethyl acetate is stirred for 12 hours at 60°C. After cooling to room temperature, the reaction mixture is worked up according to B above. 0.81 g (65.5%) of 2-(2-amino-4-thiazolyl)-2-[[ (Z)-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid with melting point 174-175 is obtained °C.

F. 3.41 g of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid allyl ester is dispersed in 100 ml of ethyl acetate and mixed with 250 mg of triphenylphosphine and 250 mg of tetrakis-(triphenylphosphine)-palladium. The solution obtained is mixed with 5.5 ml of sodium 2-ethyl caproate solution (2N solution in ethyl acetate). Within a short time, a thick unstirring porridge is formed. After standing for 15 minutes at room temperature, this 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. 2.4 g of 2-(2-amino-4-thiazolyl)-2- [ [ (Z) - (t-but-f

I I

j oxycarbonyl)-methoxy]-imino]-acetic acid with melting point ! 167-169° (decomposition). in j

' ! G. 3.41 g of 2-■ (2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxyl arb'ol-nyl)methoxy]-imino]-acetic acid allyl ester is dispersed in! ■'i I 100 ml of ethyl acetate and mixed with 18 mg of palladium. ium chloride ' and 0.084 ml of triethyl phosphite. After addition of 1.2 ml of N-me-| in tylmorpholine is stirred for 48 hours at room temperature, whereby , crystallization begins slowly. The mixture is allowed to stand for 4 days, the precipitate is filtered off, washed with ethyl acetate

and dried in a vacuum. 3.52 g of N-methylmorpholine salt j of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)meth-!

! i!oxy]-imino]-acetic acid. i<i>' i

i The crude salt is suspended in 100 ml of dry acetonitrile. 0.49 ml of N-methylmorpholine and 3.32 g of 2,2'-dithiobenzothiazole are added

successively with stirring and the suspension obtained is cooled to 5°C. Over the course of 4 hours, a solution I of 2.5 ml of triethyl phosphite in 30 ml of dry acetonitrile is now added dropwise. After further stirring for 30 minutes, the resulting yellow suspension is cooled to -10°C. The crystals are removed and washed! with cold acetonitrile and ether. 1.9 g of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxy]-imino]-acetic acid-2-benzthiazolyl thioester with melting point 142-143°C is obtained

(fission).

54.2 g (180 mmol) of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid are dispersed in 1.4 1 of dry acetonitrile. 29.6 ml (270 mmol) of N-methylmorpholine are added with stirring, followed by 72.1 g (216 mmol) of 2,2'-dithio-bisbenzothiazole. The resulting suspension is cooled to 0°C. In the course of 4 1/2 hours, a solution of 53.8 ml (314 mmol) of triethyl phosphite in 350 ml of dry acetonitrile is now added. After 1 further stirring for 30 minutes, the obtained yellow suspension ■ is cooled to -10°C. The crystals are filtered from o[ g!j

wash with cold acetonitrile and ether. You get 59.7 g (73.6

1 i i %) 2-(2-Amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid 2-benzthiazolyl thioester. j

Elemental analysis calculated for<C>i8<H>i8<N>4°4<S>3 (450,561):

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 j% ECZEM PEL 4_1 71.8 g (0.3 mol (3S,4S)-3-amino-4-carbamoyloxymethyl-2-ox-so-1-azetidinesulfonic acid is dispersed in 1.5 1 methylene chloride and added with stirring 45.6 g (0.45 mol) 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 reaction mixture is stirred for 5 hours at room temperature. Then 1.5 1 of water is added, the aqueous phase is separated, extracted twice with 250 ml of methylene chloride and acidified by adding 850 ml of 37% aqueous hydrochloric acid. After 2 hours of stirring at room temperature, the resulting suspension is cooled to 0° C and stirred for a further 1/2 hour. The precipitate is filtered off, washed successively with 1000 ml cold water, 1000 ml methanol and 1000 ml ether and dried for 12 hours at 40° C/10 mm Hg. 111 g (79.3%) of crude (3S, 4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxylethoxy)-imino]-acetamido] are obtained -4-carbamoyloxymethyl-2-oc sol-1-azetidine sulfonic acid with melting point 207°C, [α]^<0>-46.2° (c = 1 in dimethyl sulfoxide).

Elemental analysis calculated for ci2N14<N>6°10<S>2

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 2 O 3.61%.

corrected for

anhydrous substance C 29.29, H 3.53, N, 16.79, S 12.72%

An analytical sample provides the following data:

[a]^ = +39° (c = 1 in water) . Corrected for anhydrous substance, '+42.5° (c = 0.9' in water) j iajD- -43.b (c = 1 x dxmethylsulfoxide). Corrected for anhydrous substance -47.4° (c = 0.9 in water). ! \ !!

<1>

IR (KBr, cm"<1>): 3458, 3428, 3354, 3291, 1777, 1712, 1648,

in 1617, 1557, 1531

1<1>H-NMR (DMSO, ppm): 3.9-4.4 (3H,m,CH-CH2-0), 4.79 (2H,

s, 0-CH2-COOH), 5.30 (1H,dd.5 und 9 Hz, NH-CH-CH); 6.5 ( 6H,br., NH3<+>, NH2, COOH), 6.90 (lH,s, H-Thiazole), 9.45 (lH,d,9 Hz,

CO-NH).

in

1 Elemental analysis calculated :for C.„H N„0 S„:

12 14 6 102

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? j H 2 O 8.14°/=

i Corrected for water

I' free subs.tans c 30.91, H 2.74, N 17.90, S 13.58°/

EXAMPLE 42

110 g (0.235 mol) crude (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxymethoxy)-imino]-acetamido]-4-carbamoyloxymethyl-2 -oxo-1-azetidine sulfonic acid, obtained according to example

41, is 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-ethyl caproate in ethyl acetate. The obtain-

te solution is stirred for 10 minutes, diluted with 9 1 acetone and concentrated to 3 1. The remaining suspension is diluted with 3 1 acetone, filtered and the crystalline salt is washed with ether and dried. 8.59 g (90.5%) of (3S, 4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxymethoxy)-imino]-acetamido]- 4-Carbamoyloxymethyl-2-oxo-1-azetidine-sulfonic acid disodium salt. This raw salt is dissolved in 420 ml of water. 1050 ml of ethanol is added and then (after a few minutes) another 210 ml of ethanol. The solution becomes cloudy and is stirred for 1 hour. 1770 ml of ethanol are added dropwise over the course of 2 hours. After a further 1 hour of stirring and cooling to 0°C, the precipitate is filtered off and washed with ethanol. The

crystals obtained are dispersed in 170 ml of ethanol and 680 ml:

in

<->in ether, filtered off and washed with ether. After drying

under strongly reduced pressure and 4U C obtain 102.3 g (8b.5%)

In (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxymethoxy'-

<i>j imino]-acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidine sulfonic acid disodium salt.

Elemental analysis calculated for c H m,0,nS_Na„:

! 1z1zfa 1-0z 2.

C 28.24, H 2.37, N 16.47, S 12.563found: c 28.18, H 2.63, N 16.34, S 12.21

in

H20 1.02%

corrected for water

free substance: c 28.46, H 2.65, N 16.50, S 12.333

2 0

[a]p = +19° (c = 1 in water)

; IR (KBr, cm"<1>): 1777, 1712, 1648, 1617, 1557, 1417

In UV (H90; \max (e)): 295 nm (6850), 233 nm (12330)

in 1,<i>H-NMR (D 2 O, ppm): 4.2-4.8 ( 5 H, m , CH-CH 2 -O-CO , 0-CH 2~

1 COONa), 5.6 (1H,d,5.5 Hz, 0=C-CH),

7.05 (1H/s, H-Thiazole).

EXAMPLE 43

In the same way as in example 1, one obtains from 191 mg of (3S;4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidine sulfonic acid and 2-[5-(1-t-butoxyformamido)-3-( 1,2,4-thiadiazolyl)]-2-[[(Z)-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid-2-benzthiazolyl thioester as reaction product 355 mg (3S,4S)-3-[ (Z )-2-[[ (t-butoxycarbonyl)-methoxy]-imino]-2- [5-(1-t-butoxyformamido )-1,2,4-thiadiazol-3-yl]acetamido]-4-carba- moyloxymethyl-2-oxo-1-azetidine sulfonic acid triethylamine salt.

<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=7.3Hz, 6H); 1.53 (p.9H).; 1.44

(s, 9H); 1.16 (t, J = 7.3 Hz, 9 H).

It used as starting compound 2-[5-(1-t-butoxyform-amido)-3-(1,2,4-thiadiazolyl)]-2-[[(Z)-(t-butoxycarbonyl)-methoxy]-imino ]-acetic acid-2-benzthiazolyl-thioester can- '

i is produced as follows: j

2 g 2-[5-(1-t-butoxyformamido)-3-(1,2,4-thiadiazolyl)]-

j 2-[[(Z)-(t-butoxycarbonyl)-methoxy]-imino]acetic acid and

2 g of 2,2-dithio-bis-benzothiazole are suspended in 50 ml of acetoni-

in tril and 0.7 ml of N-methylmorpholine and mixed while stirring<!>

In the course of 1 hour 1.1 ml of triethyl phosphite in 10 ml of acetoy i

In nitrile. It is then taken up in ethyl acetate, washed with water, dried and concentrated. The remaining yellow oil is micrographed on silica gel. The thioester crystallizes from ,

hexane (0.8 g). 2-[5-(1-t-butoxyformamide)-3-(1,j 2,4-thiadiazolyl)]-2-[[(Z)-(t-butoxycarbonyl)-methoxy]-<1>imino ]-acetic acid-2-benzthiazolyl thioester with melting point 115-120°C. in

in Analysis: Calculated for C 47.96, H 4.57, N 12.70, S 17.43%

Found: C 48.06, H, 4.83, N 12.46, S 17.7.7%

in

in EXAMPLE 4 4,804 mg (2 mmol) 2-[ [5-(1-t-butoxyformamido)-3-(1,2,4-thiadiazolyl)-2-[[(Z)-(t-butoxycarbonyl)- Methoxy]-imino]-acetic acid is dissolved in 30 ml of methylene chloride and 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) triethylamine and 478 mg (2 mmol) (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidine sulfonic acid. The reaction mixture is stirred for 12 hours and then evaporated. The remainder is treated with a solution of 370 mg of sodium bicarbonate in 30 ml of water. The crude mixture is chromatographed on MCI gel (25% aqueous methanol as eluent). 406 mg (34%) of (3S,4S)-3-[(Z)-2-[5-amino-1,2,-4-thiadiazol-3-yl]-2-[[(t-butoxycarbonyl )-methoxy]-imino]-acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidine sulfonic acid triethylamine salt.

Elemental analysis calculated for 02^H3gNg0^0S2

C 40.38, H 5.81, N 17.94%

found: C 40.31, H 5.70, N 17.99%

h 1

, I

IN

^H-NMR (DMSO, ppm): 1.17 (9H,t,7.5 Hz,3xCH2CH3), 1.42 (9H,s,3xCH3), 3.09 (6H,q,J=7.5 Hz,

I 3xCH2), 4.10 (3H,m,CH-CH2), 4.60 (2H,s,N-0-CH2), 5.25 (lH,dd,J=5

und 9 Hz, NH-CH), 6.30 (2H,s,NH2), 8.10 (2H,s,NH2), 9.0 (lH,d,J=9 Hz,

NH-CH).

i<!>EXAMPLE 4 5<!>

! 314 mg (0.502 mmol) (3S,4S)-3-[(Z)-2-[5-amino-1,2,4-thiadirazol-3-yl]-2-[[(t-butoxycarbonyl)- methoxy]-imino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidine sulfonic acid triethylamine salt is dissolved at 0°C in 5 ml of 3.5 N aqueous salt-

: acid. The reaction mixture is stirred for 2 days at 0°C. The solvent is evaporated off under reduced pressure and the residue is taken up in 15 ml of ethanol/water (2:1) and treated with 2 ml of 2N sodium: 2-ethyl caproate in ethyl acetate. The reaction mixture is concentrated and chromatographed on MCI gel (water as eluent). 135 mg (53%) of (3S,4S)-3-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(carboxymethoxy)-imino] are obtained -acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulfonic acid disodium salt.

Elemental analysis calculated for c^ ^^yO^S^a NaCl

C 23.41, H 1.81, N 17.20, S 11.03 Cl 6.5 2%

found: c 23.19, H, 1.95, N 17.21, S 11.1!

Cl 6.2 2%

IR (KBr, cm"<1>): 1767, 1664, 1614

<1>H-NMR (DMSO, ppm): 4-4.20 (3H,m,CH-CH2), 4.30 (2H,s,

N-0-CH2), 5.27 (lH,dd,J=5 und 10 Hz NH-CH), 6.50 (2H,br,NH2), 8.11 (2H,s,NH2), 10, 90 (1H,d,J=10 Hz,NH-CH).

EXAMPLE 4 6

In the same way as in example 1, one obtains from 352 mg (1.5 m-mol) (3S, 4S.)-3-amino-4-[(E)-2-carbamoylviny 1]-2-oxo-1- j:azetidmsultonic acid and 2-(2-amino-4-thiazolyl)-2-(Z)-methoxy-iminoacetic acid-2-benzthiazolyl-thioester 180 mg (27%) !

(3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)- i acetamido]-4-[(E)-carbamoylvinyl]-2-oxo-1 -azetidine sulfonic acid sodium salt. IN

; Elemental analysis calculated for C,-H--N..0-S Na

12 13 6 7 2

C 32.72, H 2.98, N 19.08%

found: C 32.68, H 2.91, N 18.93%

IR (KBr, cm ): 1769, 1675, 1648, 1613

: H-NMR (DMSO, ppm): 3.80 (3H,s,0Me), 4.55 (1H,dd,J=6

und 7.5 Hz, NH-CH-CH), 5.30 (lft, dd,J=6 und 9 Hz, NH-CH-CH), 6.20

I (1H,d,J=16 Hz, =CH-CONH2), 6.70

(l'H,dd, J=7, 5 und 16 Hz, CH=CH-C0NH2)

6.80 (1H,s,H-Thiazole), 7.0-7.5 (4H,br,2xNH2), 9.40 (1H,d,J=9Hz,

NH-CH)..

The (3S,4S)-3-amino-4-[(E)-2-carbamoylvinyl]-2-oxo-1-azetidine sulfonic acid used as starting compound can be prepared as follows: 59.08 g (0.175 mmol) (3S,4S )-3-amino-1-(2,4-dimethoxybenzyl)-4[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone in 1 1 dioxane is treated in the presence of 16.4 g potassium carb nat with 46.9 g (0.215 mol) of di-t-butyl dicarbonate. After stirring for 4 hours at room temperature, the precipitate obtained is filtered off and the filtrate is evaporated under reduced pressure. The remaining 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-dioxolane are obtained -4-yl]-3-azetidine carbamate. 76.8 g (0.176 mol) t-butyl-(3S,4S)-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl ]-3-azetidine carbamate is dissolved in 500 ml of tetrahydrofuran and 350 ml of water and : heated with 13.0 g of p-toluenesulfonic acid for 24 hours at 60°C. ! The reaction mixture is cooled and neutralized with 10% aqueous potassium bicarbonate solution and evaporated. The residue is taken up in 300 ml of dioxane and treated with 21.8 g (0.1 mol) of di-t-butyl dicarbonate and 7.6 3 g of potassium carbonate. The reaction mixture is stirred at room temperature for 24 hours and filtered. The solvent is then evaporated. The crude product is recrystallized from acetonitrile. 61.3 g (88%) of t-butyl-(3S, 4S) in 1-(2,4-dimethoxybenzyl)-4-[(R)-1,2-dihydroxyethyl]-2-oxo-in 3 are obtained -azetidine carbamate. li i i i 5.0 g (12.6 mmol) t-butyl-(3S,4S)-1-(2,4-dimethoxybenzyl)-: ■ 4-[(R)-1,2-dihydroxyethyl]-2-oxo-3-azetidine carbamate is dissolved in 50 ml of methanol and treated with a solution of 2.95 in

i g (13.8 mmol) of sodium metaperiodate in 30 ml of water. The pH value of the solution is kept at 6.0 by the addition of aqueous, saturated sodium bicarbonate solution. After stirring for 30 minutes at room temperature, 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. 2.70 g (58.8%) of t-butyl-(3S,4S)-1-(2,4-dimethoxy-''benzyl)-4-formyl-2-oxo-3-azetidine carbamate are obtained.

Elemental analysis calculated for C]_gH24<N>2°6

C 59.33, H 6.64, N 7.69%

C 59.08, H 6.91, N 7.38%

4.0 g (11 mmol) of t-butyl-(3S,4S9-1-(2,4-dimethoxybenzyl)-4-formyl-2-oxo-3-azetidine carbamate is dissolved in 300 ml of methylene chloride and treated dropwise with a solution of 3.9 g (12 mmol) of carbamoylmethylene-triphenylphosphorane in 100 ml of methylene chloride. After 1 hour, the reaction mixture is filtered, and the crystals obtained are washed with methylene chloride. 3.6 g (81%) of t-butyl-(3R,4S)- 1-(2,4-dimethoxybenzyl)-4-[(E)-2-carbamoylvinyl]-2-oxo-3-azetidine carbamate with melting point 270°C.

IR (KBr, cm"<1>): 1767, 1719, 1684, 1644.

in I

...li

3.6 g (8.9 mmol) t-butyl-(3R,4S)-1-(2,4-dimethoxybenzyl)-<!>4-[(E)-2-carbamoylvinyl]-2-oxo-3 -azetidine carbamate dissolves in! 80 ml of acetonitrile and 150 ml of water and treated dropwise under reflux conditions with a solution of 4.9 g (17.8 mmol) of potassium peroxodisulphate in 50 ml of water. The pH value is maintained at 6.5 by adding saturated, aqueous sodium bicarbonate

in iibonate solution. After 4 hours, 40 ml of acetonitrile is distilled: ; from. The crude reaction mixture is then partially evaporated ! and cooled to +5°C. The crystals obtained are filtered off. The filtrate is washed twice, each time with 100 ml of ether. The aqueous phase is saturated with sodium chloride and extracted three times, each time with 300 ml of ethyl acetate. The combined organic phases are dried over sodium sulfate and evaporated. A brown residue is obtained which, after recrystallization from methanol, gives 9 20 mg (41%) of t-butyl-(3R,4S)-V-[(E)-2-carbamoylvinyl]-2-oxo-3-azetidine carbamate. in i

IR (KBr, cm"<1>): 1784, 1732, 1689, 1673 Analysis calculated for O-^H^<N>^O^: 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-azetidine carbamate is dissolved in 80 ml of acetonitrile and treated with 1.86 g (11.6 mmol) pyridine-sulfur trioxide complex. The reaction mixture is stirred at 40°C for 20 hours. The solvent is then evaporated off and the residue is taken up in 100 ml of water. The pH value is adjusted to 7-8 by the addition of saturated, aqueous sodium bicarbonate solution. The volume is reduced by evaporation to 30 ml and the solution obtained is chromatographed on MCI gel (water as eluent). 1.61 g (67.5%) of (3R,4R)-3-(1-t-butoxyformamido)-4-[(E)-2-carbamoylvinyl]-2-oxo-1-azetidine sulfonic acid sodium salt are obtained.

Elemental analysis calculated for C^H^gN^O^SNa

C 36.98, H 4.51, N 11.76%

found: C 37.31, H 4.89, N 11.19% ! IR (KBr, cm_1)r 1768, 1692, 1645. I

in 1.55 g (4.34 mmol) (3R,4R)-3-(1-t-butoxyformamido)-4-[(E)-12-carbamoylvinyl]-2-oxo-1-azetidine sulfonic acid sodium salt

Dissolve in 5 ml of anisole, cool to 0°C and treat with 5 ml of trifluoroacetic acid. The resulting suspension is stirred for 1 hour at 0°C and then for 2 hours at room temperature. The reaction mixture is diluted with 100 ml of ether and 20 ml of n-hexane<1>. The crystals obtained are filtered off and dried. The raw material thus obtained is dissolved in 10 ml of water and chromatographed on MCI gel (water as eluent). 1.04 g are obtained: (100%) (3S,4S)-3-amino-4-[(E)-2-carbamoylvinyl]-2-oxo-yl-azetidine sulfonic acid.

!IN

; IR (KBr, cm -1 ) : 1779, 1683, 1648, 1608. in I

IN

! IN

EXAMPLE 4 7: 278 mg (1 mmol) of rac-cis-3-amino-4-[(Z)-2-ethoxycarbonyl]-,.1-methylvinyl]-2-oxo-1-azetidine sulfonic acid are dissolved in 10 ml of water and 10 ml of acetone and treated with 290 mg (1.1 mmol) in sodium bicarbonate and 386 mg (1.1 mmol) of 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyiminoacetic acid-2-benzthiazolyl thioester. The reaction mixture is stirred for 48 hours at room temperature. The organic solvent is removed under reduced pressure, and the crystals obtained are filtered off. The filtrate is chromatographed on MCI gel (water as eluent). You get 161

mg (43%) rac-cis-3-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxy-'imino)acetamido]-4-[(Z)-2-(ethoxycarbonyl) -1-methylvinyl]- i 2-oxo-1-azetidine sulfonic acid sodium salt.

Elemental analysis calculated for C^^H^gN^0gS2Na

C 37.27, H 3.75, N 14.49%

found: C 37.52, H 3.84, N 14.51%

IR (KBr, cm"<1>): 1771, 1688, 1620, 1533

<1>H-NMR (DMSO, ppm.): 1.21 (3H,r,J=7 Hz, CH_3CH2), 2.03

(3H,d,J=lHz, CH3-C=), 3.76 (3H,s, 0CH3), 4.08 (2H,q,J=7 Hz, CH3~CH2), 4.54 (lH, dd,J=6 and 1 Hz, NH-CH-CH), i 5.28 (lH,dd,J=6 and 9 Hz, NH-CH), , 6.05 (lH,t,J=l Hz , =CH), 6.57 (1H,

: s,H-thiazole), 7.17 (2H, br,NH 2 ), 9.28

(lH,d,J=9 Hz, NH-CH). |

IN

in i ; The rac-cis-3-amino-4-[(Z)-1 I 2-(ethoxycarbonyl)-1-methylvinyl]-2-oxo-1-azetidine sulfo1 n-!I I j acid used as starting compound can be prepared as follows: j i<!>: 6.68 g (0.042 mol) of 2,4-dimethoxybenzylamine in 150 ml of methylene chloride is treated in the presence of magnesium sulfate with 5.97 g j (0.04 mol) of 3-formylcrotonic acid ethyl ester. After 30 minutes of stirring, the precipitate obtained is filtered off. The resulting j!imine solution is cooled to 0°C with 6.7 ml of triethylamine and then treated dropwise with a solution of 10.2 g (0.046

mmol) phthalimidoacetyl chloride in 50 ml methylene chloride. The reaction mixture is stirred for 1 hour at 0°C, then warmed to room temperature and then washed successively with diluted

.aqueous hydrochloric acid, water and aqueous sodium chloride solution. After drying and evaporation, the crude mixture is recrystallized from methylene chloride/n-hexane. 15.6 g (81.6%) of pure ethyl: rac-cis-1-(2,4-dimethoxybenzyl)-3-methyl-4-oxo-3-phthalimido-2-azetidine acrylate with a melting point of 159-160 °C.

in

:IR (KBr, cm"<1>): 1766, 1723, 1656. 1 in

37.0 g (77.3 mmol) of ethyl rac-cis-1-(2,4-dimethoxybenzyl)~3~methyl-4-oxo-3-phthalimido-2-azetidine acrylate are dissolved in 500 ml of methylene chloride and treated with 8, 2 ml (0.15 mmol) of N-methylhydrazine at 30°C for 48 hours. The reaction mixture is filtered and 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, each time with 200 ml of methylene chloride. After drying and evaporation, the crude colorless product is isolated. 25.1 g (93%) of ethyl rac-cis-3-amino-1-(2,4-dimethoxybenzyl)-p-methyl-2-oxo-4-azetidine acrylate with a melting point of 89-93°C is obtained.

IR (KBr, cm"<1>): 1741, 1708, 1651, 1616. i i<:>

IN

18.4 g (0.053 mol) of ethyl rac-cis-3-amino-1-(2,4-dimethoxy-<1>benzyl)-|3-methyl-2-oxo-4-azetidinacrylate are dissolved in 350 ml dij -Ioxane and treated in the presence of 5 g of potassium carbonate in 15 ml (0.068 mol) of di-t-butyl dicarbonate. The reaction mixture is stirred at room temperature for 12 hours and then filtered and evaporated. The residue is taken up in methylene chloride and washed with water and sodium chloride solution. After drying and re-evaporation, the crude material is crystallized from methylene chloride/n-hexane. I One obtains 18.4 g (77.5%) of colorless ethyl-rac-cis-3-(1-t-but-, I oxyformamido)-1-(2,4-dimethoxybenzyl)-(3-methyl-2-oxo -4- j iazetidin acrylate with melting point 150-152°C.

4.0 g (8.9 mmol) ethyl-rac-cis-3-(-t-butoxyformamido)-1; - j ; (2,4-Dimethoxybenzyl)-3-methyl-2-oxo-4-azetidinacrylate is dissolved in 300 ml of acetonitrile and treated at 90-95°C with 3.86 g (14.3 mmol) of potassium peroxodisulphate and 2.31 g (13.3 µmol) of potassium hydrogen sulfate for 2 hours. The organic solvent is evaporated, and the aqueous phase is extracted with chloroform. The combined organic phases are washed with aqueous sodium chloride solution and dried over sodium sulfate. The solution is evaporated and chromatographed on silica gel (ethyl acetate as eluent). 990 mg (37%) of t-butyl-4-[2-(ethoxycarbonyl)-1-methylvinyl]-2-oxo-3-azetidine carbamate is obtained.

IR (KBr, cm"<1>): 1783, 1758, 1712, 1703, 1690.

2.25 g (7.5 mmol) of t-butyl-4-[2-(ethoxycarbonyl)-1-methyl-vinyl]-2-oxo-3-azetidine carbamate are dissolved in 20 ml of acetonitrile and treated at room temperature with 3.0 g (18.8 mmol) sulfur trioxide-pyridine complex. The reaction mixture is stirred for 12 hours at room temperature. The acetonitrile is evaporated off,

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°C. 1.92 g (63%) of crystalline rac-cis-3-(1-t-butoxyformamido)-4-[(Z)-2-(ethoxycarbonyl)-1-methylvinyl]-2-oxo-1-azetidine sulfonic acid are obtained - sodium salt.

in i

in I

Elemental analysis calculated for<C>,<.H>„nN„0oSNa

J. 4z ± Zo ! ,

C 42.00, H 5.29, N 7.00% found: C 42.07, H 5.27, N 7.23%

IN

IR (KBr, cm"<1>): 1774, 1715, 1692, 1668.

1.755 g (4.38 mmol) rac-cis-3-(1-t-butoxyformamido)-4r[(Z)-j-(ethoxycarbonyl)-1-methylvinyl]-2-oxo-1-azetidinesulfon-I acid- sodium salt is dissolved in 7.5 ml of anisole and treated at j j-20°C with 10 ml of trifluoroacetic acid. After stirring for 30 minutes at -20°C and then a further 3 hours at room temperature, the reaction solution is diluted with 300 ml of ether/n-hex-isane 1:1. The crystals obtained are filtered off, dissolved in ; 10 ml of water and chromatographed on MCI gel. 808 mg, in (60%) rac-cis-3-amino-4-[(Z)-2-(ethoxycarbonyl)-1-methyl-1;vinyl]-2-oxo-1-azetidine sulfonic acid are obtained. in 'i■

in i<1>i

EXAMPLE 4 8 in 717 mg (3 mmol) of (3S,4S)-3-amino-4-carbamoyloxymethyl-2-!oxo-1-azetidine sulfonic acid is dispersed in 75 ml of methylene chloride in

; and treated with stirring for 24 hours at room temperature with I 0.46 ml (3.3 mmol) triethylamine and 2.70 g (3.3 mmol) 2-(2-; i tritylamino-4-thiazolyl)-2- (Z)-Trityloxyiminoacetic acid 2-;benzthiazolyl thioester. The solvent is evaporated off and the residue '

in

<1> is chromatographed on silica gel (methylene chloride/methanol 92:8!I as eluent). 1.58 g (53%) of (3S, 4S)-3-[(Z)-1 2-(2-tritylamino-4-thiazolyl)-2-(trityloxyimino)acetamido]-4-carbamoyloxymethyl-3- oxo-1-azetidine sulfonic acid.

1.42 g (1.43 mmol) (3S,4S)-3-[(Z)-2-(2-tritylamino-4-thiazolyl)-2-(trityloxyimino)acetamido]-4-carbamoyloxy-methyl-3 -oxo-1-azetidine sulfonic acid in 15 ml of formic acid is stirred with 0.01 ml of water for 4 hours at room temperature. The solvent is evaporated off, resuspended in water and distilled azeotropically with toluene. The residue is recrystallized from water/ethanol 4:1. Man: 296 mg (51%) of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-4-carbamoyloxymethyl]- are obtained 2-oxo-1-azetidine sulfonic acid. in

in f

The 2-(2-tritylamino-4-thia-'ziolyl)-2-(Z)-trityloxyiminoacetic acid-2-benzthiazolylthio ester used as starting compound is 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 4-methylmorpholine and treated at 0 C while stirring with 30 ml of triethyl phosphite in 200 ml of acetonitrile. Some undissolved material is removed by filtration. ! The solution is concentrated to a small volume and isopropanol is added. You concentrate again to a small volume. It! re-crystallized thioesters are filtered off and dried. 75.0 g of 2-(2-tritylamino-4-thiazolyl)-2-(Z)-trityloxyimino-acetic acid-2-benzthiazolyl thioester with a melting point of lll-112°C are obtained.j

EXAMPLE 4_9 4 78 mg of (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidinesulfonic acid, 338 mg of 2-(pyrazol-3-yl)-2-(Z)-methoxyiminoacetic acid and 0 .89 2 ml of triethylamine are dissolved in 5 ml of dimethylformamide and reacted for 1 hour with 613 mg of 2-chloro-1-methylpyridinium iodide. The reaction mixture is evaporated at 25°C under reduced pressure. The residue is taken up in water and chromatographed with water over silica gel in reverse phase. After lyophilization, 645 mg of (3S,4S)-4-carbamoyloxymethyl-2-[2-(methoxyimino)-2-pyrazol-3-yl]acetamido]-2-oxo-1-azetidine sulfonic acid triethylamine salt is obtained.

Elemental analysis calculated for<C>17<H>29N70<gS>(491.52)

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 30

In the same way as in example 49, from 360 mg of (3S,4S)-trans-3-amino-4-methyl-2-oxo-1-azetidinesulfonic acid and 2-(pyrazol-3-yl)-2- (Z)-Methoxyimino-acetic acid 423 mg (3S,4S)-trans-3-[2-(Methoxyimino)-2-pyrazol-3-yl-acetamido]-4-methyl-2-oxo-1-azetidine sulfonic acid triethylamine salt .

in i

<1>H-NMR (DMSO, ppm). 9.25 (d,J=8 Hz,lH), 7.77 (m,l1 H), 6.45 (m,lH), 4.41 (dd,J=2.5 Hz und 8 Hz, 1H), 3.85 (s,3H), 3.64 (dd,J=2.5 Hz und 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 50 Preparation of dry ampoules for intramuscular administration: A lyophilisate of 1 g of (3S,4£j)-3-[(5-amino-3-(1,2,4-thiadiazolyl)]- is prepared in the usual way 2-(Z)-(Methoxyimino)-acetamido]-4-methoxyiminomethyl-2-oxo-1-azetidine sulfonic acid sodium salt and pour into an ampoule. Before administration, the lyophilisate is mixed with 2.5 ml of a 2% aqueous lidocaine hydrochloride solution.

Claims (28)

i 1. Process for the preparation of 1-sulfone-2-oxo- i azetidine derivatives with the general formula where Het is an optionally amino-substituted, 5- or 6-membered, aromatic heterocyclic ring containing 1 or 2 nitrogen atoms, optionally also an oxygen or sulfur atom. In R1 means hydrogen, lower alkyl, phenyl-lower alkyl, lower alkano1, lower-alkoxycarbonyl, lower-alkenyl-lower-alkyl, lower-alkoxycarbonyl1-lower-alkyl, phenyl-lower-alkoxycarbonyl-lower-alkyl, nitrophenyl-lower-alkoxycarbonyl-lower -alkyl or carboxy-lower alkyl, and 2 R hydrogen, lower-alkyl, lower-alkenyl, lower-alkynyl, lower-alkoxycarbonyl, lower-alkanoyloxy-lower-alkyl, lower-alkoxycarbonyl-lower-alkenyl, hydroxy-iminomethyl, lower-alkoxyiminomethyl, carbamoyl, carbamoyl-lower- alkenyl or carbamoyloxy-lower alkyl, with the group =NOR <1> at least partially present in vision form, in racemic form or in the form of 3S-enantiomers, as well as of easily hydrolyzable esters acc. pharmaceutically acceptable salts of these compounds, characterized by acylating a compound with the general formula present in racemic form or in the form of the 3S-enantiomer <1> where *^ 0 has the same meaning as R 2 or can also be a 2,2-dimethyl-1,3-dioxolan-4-yl group, and 3 in ' R is hydrogen or sulfo, ' or a salt thereof with a thioester having the general 'formula i i where Het has the aforementioned meaning, and R 1 ^ has the same meaning as R 1 , but does not mean carboxy-lower-alkyl, but furthermore can also be 'a <1> tri-lower alkylsilyl-lower-alkoxycarbonyl-lower-\ alkyl group or one in an easily hydrolyzable ester group transferred carboxy-lower alkyl group, and the group ^ NOR <10> is at least partially present in syn form, to a compound in racemic form or in the form of 3S-enantiomers with the general formula 10 20 3 in which R , R , R and Het have the above meaning, and the group =N0R<10> is at least partially present in syn-form, then sulphonates a product obtained, in which R 3 is hydrogen, transfers a possibly present 2,2-dimethyl-20' 1,3-dioxolan-4-yl group R in the hydroxyiminomethyl group, ; in a lower-alkoxyiminomethyl group or carbamoylvinyl group-j I pen, transfers -a possibly present trilower alkyl-i silyl-lower-alkoxycarbonyl-lower-alkyl group R <10> in carb-I <;> oxy-lower-alkyl, if desired, the substituent R10 transfers henh. R <1> in the sense of lower-alkylcarbonyl-lower-alkyl, j phenyl-lower-alkylcarbonyl-lower-alkyl or nitro-inyl-lower-alkoxycarbonyl-lower-alkyl i carboxy-lower-i alkyl, and if desired converts a product obtained into a pharma-Isø ytically acceptable salt. 2. Method according to claim 1 for the production of . compounds of formula I, in which Het is an amino-substituted, 5- or 6-membered, aromatic heterocyclic ring containing 1 or 2 nitrogen atoms, possibly also an oxygen or sulfur atom, R means hydrogen, lower alkyl, phenyl lower-alkyl, lower-alkanoyl, lower-alkoxycarbonyl, 1-lower-alkenyl-lower-alkyl, lower-alkoxycarbonyl-lower-alkyl-j alkyl, phenyl-lower-alkoxycarbonyl-lower-alkyl, nitrophenyl-,lower-alkoxycarbonyl-lower- alkyl or carboxy-lower alkyl, and R 2 lower-alkyl, lower-alkenyl, lower-alkynyl,, lower-alkoxycarbonyl, lower-alkanoyloxy-lower-alkyl, hydroxyiminomethyl, lower-alkoxyiminomethyl, carbamoyl or carbamoyloxy-lower-alkyl, in racemic form or in the form of the 3S-enantiomer, as well as of easily hydrolysable esters acc. pharmaceutically acceptable salts of these compounds, characterized by the use of correspondingly substituted starting compounds. 3. Process according to claim 2, characterized in that a starting compound with the formula II is used, where R<3> is sulfo. 4. Process according to claim 2 or 3, characterized in that the reaction of the starting compounds with formulas II and III is carried out in the presence of an organic amine, such as triethylamine. 5. Method according to one of claims 2-4, characterized by using an optically uniform 3,4-cis compound (in particular a 3S,4S-for bond) with formula II. f in 6. Method according to one of claims 2-5, characterized in that one as a thioester ■ with! formula III uses 2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(t-1 butoxycarbonyl)-1-methyl-ethoxy]-imino]-acetic acid 2-benzthiazolyl thioester, 2-(2-amino-4-thiazolyl)-2-[[(Z)-1-[2-(tri-jmethylsilyl)-ethoxycarbonyl]-1-methylethoxy]-imino]-acetic acid re-2-benz-thiazolyl-thioester, 2-(2-amino-4-thiazolyl)-2-[[(Z)-(p-nitrobenzyloxycarbonyl)-methoxy]-imino]-acetic acid-2-benz-thiazolyl- thioester, 2-(2-amino-4-thiazolyl)-2-[[(Z)-1-' (p-nitrobenzyloxycarbonyl)-1-methylethoxy]-imino]acetic acid- in 2-benzthiazolyl thioester and releases the carboxyl group in the reaction; tion product.\ 7. Method according to one of claims 1-5, | characterized in that 2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid-2-benzthiazolyl- thioester and releases the carboxyl group in the reaction product. 8. Method according to claim 6 or 7, characterized in that a t-butoxycarbonyl group is converted by treatment with hydrochloric acid or trifluoroacetic acid acid in carboxy group. 9. Method according to claim 6, characterized in that a trimethylsilylethoxycarbonyl group is converted by treatment with tetrabutylammonium fluoride into a carboxy group. 10. Method according to claim 6, characterized in that a p-nitrobenzyloxycarbonyl group is converted by catalytic hydrogenation into a carboxy group. 11. Method according to one of claims 2-9, characterized in that one reacts a (Z)-2-(2-amino-4-thiazolyl)-2-[[1-[R<1> 0CO]-1-methylethoxy ]-imino]-acetic acid 2-benzthiazolyl thioester, wherein R' is lower-al- | alkyl, phenyl-lower-alkyl, nitrophenyl-lower-alkyl or tri-p In lower-alkylsilyl-lower-alkyl, or a salt thereof with (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidin-;sulfonic acid and releases the carboxyl group in the reaction product. ; 12. Process according to one of claims 2-9, characterized in that one reacts a '2-(2-!amino-4-thiazolyl)-2-[[(Z)-(R"OCO)-methoxy]- imino]-acetic acid-' j 2-benzthiazolyl-thioester, in which R" is lower-alkyl, phenyl-i j lower-alkyl , nitrophenyl-lower-alkyl or tri-lower-alkyl-!silyl-loweralkyl, or a sali: thereof with (3S , 4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidinesulfonic acid and releases the carboxy group in the reaction product. i <!> i 13. Method according to one of claims 2-9, characterized in that (Z)-2-(2-amino-4-thiazolyl)-2-[[1-[t-butoxycarbonyl]-1-methylethoxy- •sy]-imino]-acetic acid-2-benzthiazolyl-thioester or a salt thereof with (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidine sulfonic acid and liberates the carboxyl group in the reaction product by treatment with a strong organic acid.. ! 14. Process according to one of claims 2-9, j characterized in that one reacts 2-(2-jamino-4-thiazolyl)-2-[[(Z)-(p-nitrobenzyloxycarbonyl)-methoxy]- imino]acetic acid 2-benzthiazol1-thioester with (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidine sulfonic acid and liberates the carboxy group in the reaction product by catalytic hydrogenation. 15. Process according to one of claims 1-9, characterized in that one reacts (Z)-2-(2-amino-4-thiazolyl)-2-[[1-[t-butoxycarbonyl]-methoxy]-imino]- acetic acid 2-benzthiazolyl thioester with (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidine sulfonic acid and liberates the carboxyl group in the reaction product by treatment with a strong organic acid. 16. Process for the production of 1-sulfone-2-oxo-j ; in azetidine derivatives of the general formula 1 ! IN in which R1 has the meaning stated in claim 1, j 4 I R has the same meaning as Het in claim 1, and ] 212 ' R has the meaning stated for R in claim 1, j with the group =NOR <1> at least partially present <1> in syn-form, with the proviso that at least one of the j in the following 4 meanings are fulfilled: 1 I I: a) R = 2-amino-4-oxazolyl, 2-amino-6-pyridyl, 2-amino-4-imidazolyl, 5-amino-3-(1,2,4-thiadia-i , 1 F zolyl or 2-pyrazol-3-yl, ] b) R = hydroxyiminomethyl, lower-alkoxyimino- i i methyl, lower-alkoxycarbonyl-lower-al kenyl or carbamoyl-lower-alkenyl, i in racemic form or in the form of the 3S enantiomer as well as easily hydrolyzable esters acc. pharmaceutical tolerable sal-! ter of these compounds, characterized by that mana) reacts a carboxylic acid with the general formula wherein R<1>^ has the same meaning as in claim 1, and R^ has the same meaning as R^ in formula Ic, in that an amino group present may be protected, and the group =NORx<^ exists at least partially in syn form, or a functional derivative thereof, with a compound of the general formula present in racemic form or in the form of the 3S enantiomer In i in i wherein R 21 has the same meaning as in formula Ic above, or with a salt thereof, and then cleaves off any amino protecting group, or that manb) sulphonates one in racemic form or in the form of den,3S-; enantiomeric present compound with the general formula 1 21 wherein R and R have the same meaning as above, and R 41 has the same meaning as R 4 above, however, a present amino group is protected, and the group =NOR <1> is at least partially present in vision form, or a salt thereof, and then cleaves off the amino protecting group, or that one c) in the preparation of a compound of formula Ic in racemic form or in the form of the 3S-enantiomeric compound, in which R 21 means hydroxyiminomethyl, lower-alkoxyiminomethyl or carbamoylvinyl, one reacts in racemic form or in the form of the 3S-enantiomeric compound with the general formula in which R 4 means the same as above, and R 1^ has the meaning stated in claim 1, and the group =NOR<10> is at least partially present in I syn-form, with hydroxylamine, an O-lower alkyl hydroxylamine or with carbamoylmethylenetriphenylphosphorane (and lower alkylates a 1 •i obtained product, or that one I!i d) in the preparation of a compound of formula Ic, in which R<1> is carboxy-lower alkyl, in a compound of the general formula in which R and R have the meanings given above, and 13 in R is tri-lower alkyl-silyl-lower-alkoxycarbon- nyl-lower-alkyl, lower-alkoxycarbonyl-lower-alkyl, phenyl-lower-alkoxycarbonyl-lower-alkyl or nitrophenyl-lower-alkoxycarbonyl-lower-alkyl, in that the group =NOR <1> is at least partially present in' i sight form, 13 transfers the group R in carboxy-lower alkyl, or that one e) transfers one in racemic form or in the form of the 3S-, enantiomeric present compound with formula Ic acc. a readily hydrolyzable ester thereof in a pharmaceutically acceptable salt. 17. Process according to claim 16 for the preparation of compounds according to claim 16 with the general formula 1 I 1 2 In which R and R have the same meaning as in formula I in claim 1, and R 4 is 2-amino-4-oxazolyl, 2-amino-6-pyridyl, 2-amino-4-imidazolyl, 5-amino- 3-(1,2,4-thiadiazolyl) i i ! or 2-pyrazol-3-yl, wherein the group =NOR in the min-; i ste is partly available in syn-form, ii in racemic form or in the form of the 3S-enantiomer as well as easily hydrolyzable esters acc. pharmaceutically acceptable salts .of these compounds, characterized by using correspondingly substituted starting compounds. 18. Process according to claim 17 for the preparation of compounds according to claim 17, in which R 4 is 2-amino-4-oxazolyl, 2-amino-6-pyridyl, 2-amino-4-imidazolyl or 5-ami-XLO- 3-(1, 2, 4-thiadiazolyl), characterized by using correspondingly substituted starting compounds. 19. Process according to claim 18 in the preparation of 3-[2-(2-amino-4-oxazolyl)-2-(methoxyimino)-acetamido]-4-|ethynyl-2-oxo-1-azetidinesulfonic acid in racemic form or in the form of the 3S-enantiomer as well as pharmaceutically acceptable salts of these compounds, characterized by the use of correspondingly substituted starting compounds. 20. Process according to claim 18 in the preparation of 3-[(Z)-2-(5-amino-1,2,4-thiadiazolyl-3-yl)-2-(methoxyimino)-acetamido]-4-(methoxycarbonyl) -2-oxo-1-azetidine sulfonic acid in racemic form or in the form of the 3S-enantiomer as well as pharmaceutically acceptable salts of these compounds, characterized by the use of correspondingly substituted starting compounds. 21. Method according to claim 18 in the production of 4-carbamoyloxymethyl-3-[(Z)-2-(methoxyimino)-2-pyrazol-3-'yl]-acetamido]-2-oxo-1-azetidine sulfonic acid in racemic form' or in the form of the 3S-enantiomeric as well as easily hydrolyzable esters acc. pharmaceutically acceptable salts of these compounds, characterized by ! 1 that correspondingly substituted starting compounds are used. || in ! 22. Process according to claim 18 for the production of trans-3-[(Z)-2-(methoxyimino)-2-pyrazol-3-yl-acetamido]-4-methyl-2-oxo-1-azetidinesulfonic acid in racemic form or in the form of the 3S-enantiomeric as well as easily hydrolyzable esters acc. pharmaceutically acceptable salts of these compounds, characterized by the use of correspondingly substituted starting compounds. j i 23. Process according to claim 18 in the preparation of bonyl)-methoxy]-imino]-acetamido]-4-carbamoyloxymethyl- in 2-oxo-1-azetidinesulfonic acid in racemic form or in the form of the 3S-enantiomer as well as easily hydrolyzable esters acc. pharmaceutically acceptable salts of these compounds,"characterized by using correspondingly substituted starting compounds. i 24. Process according to claim 18 in the preparation of 3-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(carboxymethoxy)-imino]-acetamido] -4-carbamoyloxymethyl-2-oxo-1-azetidinsulfonic acid in racemic form or in the form of the 3S-enantiomer as well as easily hydrolyzable esters acc. pharmaceutically acceptable salts of these compounds, characterized by the use of correspondingly substituted starting compounds. 25. Method according to claim 16 for the preparation of compounds according to claim 16 with the general formula in which R1- and Het have the same meaning as in mRe^l 1 I is in hkydrarov ks1y, imog inomethyl, lower-alkoxyiminome,tyl| lower alkoxycarbonyl-lower-alkenyl or carba- i 1 1 ■ ! moyl-lower-alkenyl, the group =NOR being the least part vis exists in syn-form, in racemic form or in the form of the 3S-enantiomer as well as easily hydrolyzable esters acc. pharmaceutical treaty- i. j in equal salts of these compounds, c a r a c t e r i sert by using correspondingly substituted i i ■ starting compounds. in j ! in 'I 26. Process according to claim 25 in the preparation of ay j compounds according to claim 25, in which R is hydroxyxmmqmethyl-: methyl or lower-alkoxyiminomethyl, characterized in that correspondingly substituted starting compounds are used. . 27. Process according to claim 26 in the preparation of 3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-acetamido]-4-[(E/Z)-(hydroxyimino)- methyl]-2-oxo-1-azetidine sulfonic acid, in racemic form or in the form of the 3S-enantiomer as well as pharmaceutically acceptable salts of these compounds, characterized by using correspondingly substituted starting compounds. 28. Process according to claim 26 in the preparation of 3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-acetamido]-4-methoxyiminomethyl-2-oxo-1-azetidinesulfonic acid in racemic | form or in the form of the 3S-enantiomer as well as pharmaceutically acceptable salts of these compounds, characterized by the use of corresponding substituents tease output connections. |29. Process according to claim 26 in the preparation of 3-[t(5-amino-3-(1,2,4-thiadiazolyl)]-2-(Z)-(methoxyiminoyl)-1;acetamido]-4-methoxyiminomethyl-2 -oxo-1-azetidine sulfonic acid in racemic form or in the form of the 3S enantiomer as well as pharmaceutically acceptable salts of these compounds, characterized by the use of correspondingly substituted starting compounds. |30. Method according to claim 25 in the production of ! I i |3-[(Z)-2-(2-amino-4-thiazolyl). -2-(Methoxyimino)-acetamido]-;4-[(E)-carbamylvinyl]-2-oxo-1-azetidinesulfonic acid in racemic form or in the form of the 3S-enantiomer as well as pharmaceutically acceptable salts of these compounds, characterized by the use of corresponding !sub-iS titrated ugout connections. in ; ! in; 3I. Process according to claim 25 in the preparation of avi 3-j i ' I t( Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-acetamido]- ii 4-[(Z)-2-(ethoxycarbonyl)-1-methylvinyl]-2-oxo-1-azetidine-' sulfonic acid in racemic form or in the form of the 3S-enantiomer as well as pharmaceutically acceptable salts of these compounds, characterized by the use of correspondingly substituted starting compounds. j i <1> i ! in ! . IN