MC1527A1 - PROCESS FOR THE PREPARATION OF 1-SULFO-2-OXOAZETIDINE DERIVATIVES - Google Patents

Description

The present invention relates to a process for preparing 1-sulfo-2-oxoazetidine derivatives of general formula

Het—C—CONH-II N

o

û

-R

-^N

SO3H

10

where Het represents a possibly amino-substituted, 5- or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms, and possibly also an oxygen or sulfur atom, R"*" represents a hydrogen, a lower alkyl, a lower phenyl alkyl, a lower alkanoyl, a lower alkoxycarbonyl, a lower alkenyl-lower alkyl, a lower alkoxycarbonyl-lower alkyl, a lower phenyl-alkoxy-carbonyl-lower alkyl, a lower nitrophenyl-alkoxy-carbonyl-lower alkyl, or a lower carboxy-alkyl, and R represents a hydrogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a lower alkoxy-carbonyl, a lower alkanoyloxy-lower alkyl, a lower alkoxy-carbonyl-lower alkyl, a hydroxyiminomethyl, an alkoxy inferior-iminomethyl, a carbamoyl, a carbamoyl-alkenyl

20

lower or a lower carbamoyloxy-alcohol, the =NOR^ group occurring at least partly in syn form, in racemic form or in the form of the 3S enantiomer,

as well as readily hydrolyzable esters or pharmaceutically acceptable salts of these compounds.

The heterocycle designated by "Het" comprises all 25 aromatic cyclic structures with 5 or 6 rings that possess 1 or 2 nitrogen atoms and are optionally substituted by an amino group, e.g., pyrazolyl groups

2

I

such as 2-pyrazol-3-yl, amino-pyridyl groups, such as 2-amino-6-pyridyl, amino-imidazolyl groups, such as 2-amino-4-imidazolyl. They may optionally contain an oxygen atom, as e.g. in amino-oxa-5-zolyl groups, e.g. 2-amino-4-oxazolyl, or a sulfur atom,

such as e.g. in amino-thiadiazolyl groups, such as 5-amino-3-(1,2,4-thiadiazolyl) or, in particular, amino-thiazolyl groups, such as 2-amino-4-thiazolyl.

The expression "lower alkyl" alone or in compounds 10 designates an aliphatic hydrocarbon group which can be

straight or branched chain 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 expression "lower alkoxy" has a similar meaning. The expression

"lower alkenyl" alone or compound denotes an olefinic hydrocarbon group, which may be straight-chain or branched and preferably contains up to 7 carbon atoms, such as vinyl, allyl, isopropenyl, 2-methyllyl, 20 2-butenyl, 3-butenyl, 2-hexenyl, 2-heptenyl, etc.

The term "lower alkynyl" refers to an acetylenic hydrocarbon group, which may be straight-chain or branched and preferably contains up to 7 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 2-hexynyl, 2-25-heptynyl, etc. The term "lower alkanoyl" or "lower alkanoyl oxy" refers to an aliphatic carboxylic acid radical preferably having up to 7 carbon atoms, such as acetyl, propionyl, isobutyryl, acetoxy, propionyloxy, isobutyryloxy.

30. The preferred R groups are: hydrogen, methyl,

ethyl, isopropyl, benzyl, 2-phenethyl, acetyl, propionyl, methoxycarbonyl, ethoxycarbonyl, methoxycarbonylmethyl, t-butoxycarbonylmethyl, 1-methyl-l-t-butoxycarbonylethyl, 1-methyl-l-benzhydryloxycarbonylethyl, 1-methyl-l-trityloxy-

carbonyl-ethyl, 1-methyl-l-(p-nitrobenzyloxycarbonyl)-ethyl

1-Methyl-l-carboxyethyl; particularly methyl,

carboxymethyl, and 1-methyl-l-carboxyethyl.

2

The preferred R groups are: methyl, ethyl, n-propyl, vinyl, allyl, ethynyl, 3-(acetoxy)-n-propyl, methoxycarbonyl, hydroxyiminomethyl, methoxyiminomethyl,

2-(ethoxycarbonyl)-1-methylvinyl, carbamoyl, carbamoyl-vinyl and carbamoyloxymethyl; especially carbamoyl and carbamoyloxymethyl.

Formula's favorite groups

Het—C—C0-

N

^OR1

are 2-pyrazol-3-yl-2-methoxyiminoacetyl, 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl, 2-(2-amino-4-thiazolyl)-2-(1-methyl-l-carboxyethoxyimino)-acetyl, 2-(2-amino-4-oxazolyl)-2-methoxyiminoacetyl, 2-[5-amino-3-(1,3,4-thia-diazolyl) ]-2-rnethoxyiminoacetyl, 2-(2-amino4-imidazolyl)-2-methoxyiminoacetyl and 2-(2-amino-6-pyridyl)-2-methoxyiminoacetyl; particularly 2-(2-amino-4-thiazolyl)-2-methoxyimino acetyl, 2-(2-amino-4-thiazolyl)-2-(1-methyl-l-carboxyethoxyimino)-acetyl and 2-(2-amino-4-thiazolyl)-2-(carboxymethoxyimino)-acetyl.

Compounds of formula I can exist in various isomeric forms [e.g., cis, trans; syn (Z form), anti (E form); as well as in the form of a 3S enantiomer]. The same applies to the starting compounds presented later.

Compounds of formula I can be in the form of free acids or betaine, or as pharmaceutically acceptable salts obtained by salification of the free 1-sulfo group or of a group

4

possible carboxy in the substituent at position 3 with a basic salifier. Examples of basic salifiers include: inorganic cations, such as sodium and potassium ions; basic amino acids, such as ar-5-ginine, ornithine, lysine, or histidine; polyhydroxy-

alkoylamines, such as N-methylglucamine, diethanolamine, and triethanolamine, etc.

The carboxy groups present in a compound of formula I or their salts can be transformed by corresponding esterification into easily hydrolyzed ester groups

sands. These readily hydrolyzable ester groups, which can be cleaved within the body to give the corresponding free carboxy groups, are, e.g., α-(lower alkoxy)-lower alkoxy-carbonyl groups, such as methoxy-15 methoxycarbonyl, α-methoxyethoxycarbonyl; α-(lower alkanoyl)-lower alkoxy-carbonyl groups, such as methylthiomethoxycarbonyl; α-(lower alkanoyl)-lower alkoxy-carbonyl groups, such as acetoxymethoxycarbonyl, pivaloyloxymethoxycarbonyl, α-pivaloyloxyethoxycarbonyl; α-(lower alkoxy-carbonyl)-20 lower alkoxy-carbonyl groups, such as ethoxycarbonyloxymethoxy-

carbonyl, t-butoxycarbonylmethoxycarbonyl or α-ethoxycarbonyloxycarbonyl; lactonyl groups, such as phthalidyl or thiophthalidyl; or the group

— COOCH2 r p"~ CH3

y

Examples of compounds of formula I that can be prepared according to the invention include the final products described in Examples 1-50 below, both in the form in which they appear according to the examples (3S enantiomers or racemates) and as readily hydrolyzable esters and pharmaceutically acceptable salts of these compounds.

h

Particularly valued compounds of formula I include compounds of general formula nh,

WZ.

■c-

ii n

-conh-

XOR11

O

R

21

-Ns

*so3h la

10

15

20

25

or R represents a methyl, a carboxymethyl, or a 1-

21

methyl-l-carboxyethyl and R represents a carbamoyl or a carbamoyloxymethyl,

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

Among these compounds, preference is given in particular to (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[Ll-carboxy-l-methylethoxy]imino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidine-sulfonic acid and (3S,4S)-3-[(Z )-2-(2-amino-4-thiazolyl)-2-[(carboxymethoxy)imino]acetamido]-4-carbamoyloxy-methyl-2-oxo-l-azetidine-sulfonic acid and their pharmaceutically acceptable salts.

Other subgroups of products of formula I according to the process are as follows:

1 2

- those where Het, R and R have the meaning given above, with this limitation that when simultaneously

2

Het represents a 2-amino-4-thiazolyl and R a lower alkyl, a lower alkanoyloxy-lower alkyl, a lower carbamoyloxy-alkyl, a lower alkoxy-carbonyl, a lower alkoxy-iminomethyl or a carbamoyl, R represents a hydrogen, a lower alkyl, a lower phenyl-alkyl, a lower alkanoyl, a lower alkoxy-carbonyl or a lower alkenyl-lower alkyl;

10

15

1 2

- those where Het, R and R have the meaning given above, with this limitation that when simultaneously

2

Het represents a 2-amino-4-thiazolyl and R a lower carbamoyloxy-alkoyl, R represents a hydrogen, a lower alkoyl, a lower phenyl-alkoyl, a lower alkanoyl, a lower alkoxy-carbonyl or a lower alkenyl-alkoyl;

each time in racemic form or in the form of 3S enantiomers, as well as the corresponding readily hydrolyzable esters and pharmaceutically acceptable salts of these compounds.

The compounds of formula I, as well as their readily hydrolyzable esters and pharmaceutically acceptable salts, are prepared according to the invention by a process characterized in that a compound, in racemic form or in the form of the 3S enantiomer, of general formula h2N-, is acyl-

O

,R

20

3

R

II

20

20 2

Where R has the same meaning as R or can still represent-

3

to represent a 2,2-dimethyl-1,3-dioxolan-4-yl group and R represents a hydrogen or a sulfo,

or one of its salts with a thioester of general formula

Het

III

' 10

where Het has the meaning given above and R has the same meaning as R^, but does not represent a lower carboxy-alkoxy group, but can also represent a lower tri-alkyl-lower silyl-alkoxy-lower carbonyl-alkoxy group or a transformed lower carboxy-alkyl group

into an easily hydrolyzable ester group, and the group

=NOR^^ appears at least partly in syn form,

to give a compound, appearing in racemic form or as the 3S enantiomer, of general formula

Het—Ç—CONH-

-R20

Ib

\„„10 /} \

OR G ^

R

10 20 3

Where R, R, R and Het have the meaning given above,

and the group =NOR"^ appears at least partly in the form

3

syn, then in that we sulfate a product obtained or R

represents a hydrogen, in that we transform a group

20

2,2-dimethyl-1,3-dioxolan-4-yl R possibly present in the hydroxyiminomethyl group, a lower alkoxy-iminomethyl group or the carbamoylvinyl group, in that a lower tri-alkoyl-silyl-lower alkoxy-lower carbonyl-alkoyl group possibly present R^ is transformed into a lower carboxy-alkoyl, if desired in that the substituent R^ or as the case may be R"*" representing a lower alkoxy-lower carbonyl-alkoyl, a lower phenyl-alkooxy-lower carbonyl-alkoyl or a lower nitrophenyl-alkooxy-lower carbonyl-alkoyl is transformed into a lower carboxy-alkoyl and if desired in that a product obtained is transformed into a pharmaceutically acceptable salt.

The reaction according to the invention of compounds of general formulas II and III is carried out in practice in an inert organic solvent, e.g. in a chlorinated hydrocarbon, such as methylene chloride or chloroform, in

An ether, e.g., tetrahydrofuran 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 practically between about -40 and +60°C, preferably between -15 and +25°C, particularly 0-20°C. The reagents are used in practice in an approximately stoichiometric ratio or with a slight excess of formula III thioester. The reaction is preferably carried out in the presence of a base, such as an organic amine, such as triethylamine or N-methylmorpholine, or an alkali metal bicarbonate, such as sodium bicarbonate.

3

Next, the products obtained are sulfonated, where R represents a hydrogen atom. Sulfonation can be carried out conventionally by reaction with sulfur trioxide or one of its reactive derivatives, e.g., with complexes of sulfur trioxide and an organic base, such as pyridine, dimethylformamide, picolin, etc. The reaction takes place, for example, at approximately -10 to +80°C in an inert organic solvent, e.g., in an ether, such as dioxane, or in an ester.

such as ethyl acetate, in a chlorinated hydrocarbon, such as methylene chloride; in acetonitrile, dimethylformamide or pyridine.

20

If in the product of the reaction formula Ib R represents the 2,2-dimethyl-1,3-dioxolan-4-yl group, it must be transformed into the hydroxyimino group or into a lower alkoxy-imino group according to the following scheme:

CHO

/ VI1 ^

fCH=lower NO-alkoyl .CH=CHCONH

i

IX

XIII

10

I

V >VI: in a lower alkanol, such as methanol, or in an aqueous ether, such as aqueous dioxane or tetrahydrofuran, in the presence of an acid catalyst, such as an ion exchanger sulfuric acid, p-toluenesulfonic acid, etc., preferably at a temperature up to about 60°C.

VI > VII: in an aqueous alkali metal metaperiodate,

e.g. sodium metaperiodate, at approximately room temperature.

VII-VIII: with hydroxylamine in an inert organic solvent, such as methylene chloride, preferably in the presence of an organic base, such as pyridine, and at approximately room temperature

VII ^IX: with a lower O-alcohol-hydroxylamine by analogy with VI >VIII.

VII >XIII ; with carbamoylmethylenetriphenylphosphorane in an inert solvent, e.g. methylene chloride and at around room temperature.

VIII } IX: with a lower alkyl iodide in an inert organic solvent, such as methylene chloride, preferably in the presence of an organic base, such as pyridine or N-diisopropylamine and at around room temperature.

If in the reaction product of formula Ib R"^ represents a lower tricarbonyl-lower silyl-alkoxy-lower carbonyl-alkoxy group (such as e.g. the [[2-(trimethylsilyl)ethoxy]-carbonyl]methyl group or the l-methyl-l-[[2-(trimethylsilyl)-ethoxy l-carbonyl]ethyl group)

This is transformed into the corresponding lower carboxy-alkyl group, in practice by treatment with a quaternary organic fluoride, such as tetrabutylammonium fluoride. The temperature is preferably close to room temperature, and the reaction is carried out in practice

in an inert organic solvent, such as tetrahydrofuran or methanol.

If in the reaction product of formula Ib or I or R^ represents a lower alkoxy-lower carbonyl-alkoyl group (such as e.g. the t-butoxycarbonyl-methyl group or the 1-methyl-l-(t-butoxycarbonyl)-ethyl group), this can, if desired, be transformed into the corresponding lower carboxy-alkoyl group by treatment with a strong acid, such as trifluoracetic acid (where appropriate in the presence of anisole), hydrochloric acid or p-toluenesulfonic acid, at low temperature, such as -10°C down to room temperature.

If in the reaction product of formula Ib or I R " or R^ represents a lower phenyl-alkoxy-lower carbonyl-alkyl group (such as e.g. the benzyloxy carbonylmethyl or 1-methyl-l-(benzyloxycarbonyl)-ethyl group) or a lower nitrophenyl-alkoxy-lower carbonyl-alkyl group (such as e.g. the p-nitrobenzyloxycarbonyl-methyl or 1-methyl-l-(p-nitrobenzyloxycarbonyl)-ethyl group), it can, if desired, be transformed into the corresponding lower carboxy-alkyl group by catalytic hydrogenation with e.g. palladium-carbon and palladium-kieselgur as a catalyst, e.g. in a lower alkanol, such as ethanol at about 0-80°C.

The preparation of the salts for the products of process formula I can be carried out conventionally, e.g., by reacting an acid of formula I with an equivalent amount of the desired base, optionally using an ion exchanger. In practice, this is done in a solvent, such as water, or in an organic solvent, such as ethanol, methanol, acetone, ethyl acetate, etc. The saltification temperature is not critical, but it is generally within a range of approximately 0 to 50°C, preferably at room temperature.

12

I

Thioesters of formula III can be prepared by reacting a carboxylic acid of general formula

Het—C—COOH

11 IV

N 1V

r10

where R"^ and Het have the meanings given above, with dithio-bis-benzthiazole in the presence of a tri-(lower alkyl) phosphite and a base, or in the presence of triphenylphosphine. The reaction temperature is practically between about -30 and +50°C, preferably between about -20 and +25°C. Esterification is preferably carried out in an organic solvent, e.g., acetonitrile or methylene chloride. The preferred variant is the reaction in the presence of a tri-(lower alkyl) phosphite and a base. Triethylphosphite is preferably used as the tri-(lower alkyl) phosphite, and an organic base, especially a tertiary organic base such as triethylamine, N-ethyldiisopropylamine, or preferably N-methylmorpholine, is preferred as the base.

The preparation of readily hydrolyzable esters of formula III thioesters can be carried out conventionally by releasing the lower carboxy-alkyl group R"^ (as described above for the final products of formula Ib or I) and then by reaction with an esterifying agent that delivers the readily hydrolyzable ester group, e.g., with the corresponding halide, e.g., iodide, in practice in the presence of a base, e.g., an alkali metal hydroxide or carbonate, or an organic amine, such as triethylamine. Esterification is preferably carried out in an inert organic solvent, such as dimethylacetamide, hexamethylphosphoric acid triamide, dimethyl sulfoxide, or dimethylformamide. The temperature is preferably within a range

13

I

of approximately 0-40°C.

Preferred formula III thioesters are those of formula

Illb

12

Where R represents a lower alkoxy-carbonyl-alkoyl-

5. rieur, a lower phenyl-alkoxy-lower carbonyl-alkyl,

a lower nitrophenyl-lower alkoxy-lower carbonyl-alkoxy or a lower tri-alkyl-lower silyl-alkoxy-carbonyl-

inferior alkyl.

Thioesters of formula IIb particularly 12

10 appreciated are those where R represents a lower alkoxy-

because bonylmethyl, a lower phenyl-alkoxy-carbonylmethyl,

a lower nitrophenyl-alkoxy-carbonylmethyl or a tri-

lower alkyl-silyl-lower alkyl-carbonylmethyl, in particular the 2-benzthiazolyl-thioester of the acid

15 2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(t-butoxycarbonyl)-methoxy]

imino-acetic acid and the 2-benzthiazolyl-thioester of the acid

2-(2-amino-4-thiazolyl)-2-LC(Z)-(p-ni trobenzyloxycarbonyl)-

methoxy]-imino]-acetic; or thioesters of formula 12

Illb where R represents a lower alkoxy-1-20-carbonyl methylethyl, a 1-(phenyl-lower alkoxy-carbonyl)-1-

methylethyl, a 1-(nitrophenyl-lower alkoxy-carbonyl)-1-methylethyl or a 1-(tri-alkyl-lower alkoxy-carbonyl)-1-methylethyl, in particular the 2-benzthiazolyl-thioester of 2-(2-amino-4-thiazolyl)-25 2-[[(z)-l-[2-(trimethylsilyl)-ethoxycarbonyl]-l-methylethoxy]

imino-acetic acid, the 2-benzthiazolyl-thioester of the acid

' 14

2-(2-amino-4-thiazolyl)-2-[[(Z)-l-(p-nitrobenzyloxycarbonyl) 1-methylethoxy]-imino]-acetic acid and the 2-benzthiazolyl-thioester of 2-(2-amino-4-thiazolyl)-2-[[(Z )-1-(t-butoxycarbonyl)-l-methyl-ethoxy]-imino]-acetic acid.

5. A particular problem arises in the preparation of acids of formula IV, where R represents the -Cf^-COOC(R)^ group, where R represents a C^ alkyl group. The usual method for obtaining such compounds, namely the reaction of the methyl or ethyl ester of the corresponding hydriximino compound with a C^Rj^-ester of halogenated acetic acid followed by saponification, does not, however, give the desired acid of formula IV with R~^ = -Ct^-COOC(R)^, because the -COOC(R)^ group is saponified. It is therefore necessary to find another synthetic route.

However, the acid of formula IV mentioned can be obtained with R^ = -CH2~COOC(R)^ in good yield when allyl- or p-nitrobenzylester is used instead of the methyl- or ethyl ester mentioned, that is, by separating it into an ester of general formula

5

Het—C—COOR

he x

N

och2-cooc(r)3

where Het has the meaning given above, R represents

5

an alkyl at C, at C, and R represents an allyl or a p-

5

nitrobenzyl, the R group.

"Alcoyl at C^" includes: methyl, ethyl, 25n-propyl, and isopropyl. The radical has the formula -COO-CMR)^

The preferred one is the one where R represents m methyl, that is, t-butoxycarbonyl.

According to a variant of the method of the invention,

C

cleaves by hydrogenolysis an ester of formula X where R represents

15

15

»

sends a p-nitrobenzyl. This cleavage is preferably carried out with hydrogen and a metal catalyst, preferably Raney nickel, and the reaction can be accelerated by the addition of an organic base, such as triethylamine.

A lower alkanool is preferably used as a solvent.

such as methanol or ethanol. The temperature is preferably between approximately 0 and 80°C, and work is typically carried out at ambient temperature.

According to another embodiment of the process of the invention, an ester of formula X, where R* represents an allyl, is catalytically cleaved. This cleavage can be carried out by the action of a palladium compound in the presence of triphenylphosphine or a tri-(lower alkyl)phosphite, e.g., triethylphosphite. Examples of palladium compounds include: palladium carbon, palladium salts, in particular salts formed with hydrohalic acids, such as hydrochloric acid or hydrobromic acid, or with lower alkane-carboxylic acids, such as acetic acid or propionic acid. Also noteworthy are organic palladium complexes with triphenylphosphine or a tri-(lower alkyl)phosphite, such as triethylphosphite, and the process can also be carried out without triphenylphosphine or tri-(lower alkyl)phosphite. (lower)-additional phosphite. Another reagent is an alkali metal alkanoate, e.g., sodium acetate or, preferably, sodium 2-ethylcaproate, or an organic base, such as triethylamine or N-methylmorpholine. The reaction temperature can range from about 0 to 100°C, but is preferably at room temperature (though slightly above when using palladium-carbon; about 50-80°C). Preferably, the reaction is carried out in an inert organic solvent, e.g., ethyl acetate or methylene chloride.

The p-nitrobenzylesters of formula X above can be prepared starting from a Het-2-(Z)-hydroxyimino- acid

20

25

30

4

acetic acid by the addition of p-nitrobenzyl bromide or chloride and an alkali metal iodide followed by a compound of general formula

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

where R has the meaning given above and Hal represents chlorine, bromine, or iodine,

In the presence of a base, such as an alkali carbonate, triethylamine, or N-ethyl-diisopropylamine, and an alkali metal iodide, allylesters of formula X can be prepared starting from diketens, chlorine gas, and allyl alcohol, which is transformed into allyl-4-chloroacetoacetate.

The latter is nitrated with nitric acid and then transformed with thiourea into the allylester of Het-2-(Z)-hydroxyimino-acetic acid, which is then transformed with the compound of formula XI above in the presence of a base, such as an alkali carbonate, triethylamine or N-ethyl-diisopropylamine, into the allylester of formula X.

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

Diagram I

Molecular sieve]e4A

I sopropyliden fcL-glyceraldehyde

MgS04,dmb-nh2

O H O

dmb'

Ft,

Ft-CH2~C0C1 Et3N,CH2Cl2'

y~i

CH3-NHNH

tr

-N

dmb h2N*

X

u

-N \

DMB

Z-Cl

Z—NH>

O^ H Q

r-f-

Butyien- ^

ox.yde (Y

-N \

DMB

TsOH

thf-h2o

Z —N H

HO OH

-N

V

dmb

Na 10

Z —NHv ^CHO

e

Q

N

H2NOH

Z -i—NHw aOH—noh

DMB PrOH

CX

rr

N

DMB

SEO

—NHv

,cn

PrOH

-N

dmb

K2S2°8

HAS

Z —NHv cr

>

CN

-N X

DMSO

H

Diagram I (continued)

•—NHk c/

CONH.

-N

\

1. Py;SO3 2- H2/Pd-C

H N 3 «

©

H

^CONH.

r ■

•N

SO

o

10

11

cc

Diagram II

Z—NHv

r

-N

CHO

NaBH

\

Z—NHw^

<¥

>*CH2OH

C1S02NC0

Z—NH

DMB

-N \

12

DMB

c/

13

Z—NHw

<y

-N \

CHOCOH,

H

14

l.Py.SO.

2.H2/Pd-C

H3N©

>*CH2OCONH2

-N

\

SO

0

15

Diagram III

Z—NHi y~i

K2S2°8

Z—NH-

&

-N \

y-/

1. • Py. SC>3

DMB

-N \

2. H2/Pd-C

© h3nw

H

j

-N

N-SO3G

16

17

Diagram IV

dmb

1.TsOH,THF-H20

2. NaJO,

Fty

>>

cho

-N \

18

dmb

1.AgO,THF-H ^0

2. CH2N2

Ft,

c/

r cooch.

-N \

19

dmb ch3-nhnh

¥v

^ cooch3

Z-Cl s

-N \

Butylene oxide dmb

Z—NHy j

^cooch.

K2S2°8

-N

\

Z—NHv kcooch

3 1.Py.SO- m J l—s o

-N

20

dmb

\

2-.H2/Pd-C

21

h

22

h-.n

©

V

y^coocH.

so

©

23

22

Diagram V

I

i! n ©

3 X-

rr

> N

C=CH

H..N 3 «

©

©

&

rh=ch, '

N

h3N ©

27 so3

1. Py • SC>3 , Dioxanne^

2.MeOH o hcooh/ch2ci2

\

28

SO

©

CT

^ch2-ch3

■N

\nO

HAS

hcooh/ch2c12

l-H2/cat. of

2.Py-S03 ,Dio^|ir

3. MeOH eu

TrtNH

S°2CH3

TrtNH

29 so3

1-H2/Pd-C

2.Py-S03,

Dioxanne

3.MeOH or hcooh/ch2ci2

TrtNH k ..C=CH

V ..•*

1.Py'S03,Dioxanne

2.MeOH or HCOOH/

CH2C12

1. H2/cat .de

Lindlar 2.Py-S03,,

3.MeOH or

HCOOH/CH_C1_

2 2 i cr

-N \

H

26

1.h /Pd-C

2.Py•S03,

Dioxanne

3.MeOH or hcooh/ch2ci2

h3N®

.... ch2-ch3

-N

\o©

32

TrtNH,

.so2ch3

Meofocil -c»CHgcl

-N

\,

24

Schoma VI

RAN 4 4lO/A-n-r

Picric acid in Et2O,H2O

34

Picric acid in

Et2o, h2o

M U)

Diagram VII

Z—NHv

e'

>CHO

-N

\

DMB

H 2 NO A Icoyle

19

CH2C12 Py

Z—NHy

CH=NOAlcoyl.

K2S2°8

O

-N \

DMB

47

Z NHv

CH=NOA Icoyle

-N

\

1.Py.SO

dLt,

2.H2/Pd-C

H-N

o «

©

CH=NOA Icoyle

M

g> N

H

\

48

SO

©

49

£

25

I

Legend for diagrams I-VII

DMB = 2,4-dimethoxybenzyl

Ft = phthalimido

And = 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 = trityle

Ac = lower alkanoyl, e.g. acetyl.

is the one

26

A subgroup of new compounds of compounds with the general formula of formula I

R

-c—conh-II n

^OR1

,r

21

THE

e

-"N

\

s03h

1, 4

or R has the meaning given in formula I, R has the

21

same meaning as Het in formula I and R has the

2

5. Meaning given for R in formula I, the group

=NOR"*" appearing at least partly in syn form, with the clarification that at least one of the following two conditions is met:

4

a) R = 2-amino-4-oxazolyl, 2-amino-6-pyridyl, 2-amino-10 4-imidazolyl, 5-amino-3-(1,2,4-thiadiazolyl or

2-pyrazol-3-yl,

21

b) R = hydroxyaminomethyl, lower alkoxy-iminomethyl,

lower alkoxy-lower carbonyl-lower alkenyl or lower carbamoyl-lower alkenyl,

15 in racemic form or as the 3S enantiomer,

as well as readily hydrolyzable esters or pharmaceutically acceptable salts of these compounds.

A subgroup of compounds with the formula ε is that of compounds with the general formula r —c—conh-II n

^OR1

O

Er

-R'

-"n

\

so3h

ID

20

1 2

where R and R have the same meaning as in formula I 4

above and R represents a 2-amino-4-oxazolyl, 2-amino-

27

I

&pyridyl, 2-amino-4-imidazolyl, 5-amino-3-(1,2,4-thia-diazolyl) or 2-pyrazol-3-yl, where the =NOR group is at least partly in syn form,

in racemic form or as the 3S enantiomer, as well as readily hydrolyzable esters or pharmaceutically acceptable salts of these compounds; and those of general formula

Het-

-conh-

N

^OR1

has

O

-R

21

-"N

\

s03h the

10

15

20

where R and Het have the same meaning as in formula I 21

and R represents a hydroxyiminomethyl, a lower alkoxy-iminomethyl, a lower alkoxy-lower carbonyl-alkenyl, or a lower carbamoyl-alkenyl, where the =N0R group is at least partly in syn form,

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

According to the invention, new derivatives of 1-sulfo-2-oxo-azetidine with the general formula le and their easily hydrolyzable esters or pharmaceutically acceptable salts can be prepared,

a) by reacting a carboxylic acid of general formula

40

R —C —COOH

N

IVb x0r10

10

where R has the same meaning as in formula III and

4

has the same meaning as R in the formula the, or

R

40

28

I

However, an existing amino group can be protected, and the 10

group =N0R appears at least partly in syn form, or one of its functional derivatives, with a compound of general formula h2N-

0

JR

21

\

so3h lia

21

where r has the same meaning as in the formula above,

appearing in racemic form or as the 3S enantiomer,

or with one of its salts and by separating a possible amino protecting group, or b) by sulfonating a compound, present in racemic form or as an 11S enantiomer, of general formula

41 ^R21

r —c—conh—

II n

XII - "NH

x0r1 £~

1 21

where R and R have the meanings given in the formulas

41 4

I or the above and R has the same meaning as R

in the formula where however an amino group is present is protected, and the group =N0R"'" appears at least partly in syn form,

or one of its salts, then separating the protecting group of 1-amino, or

21

(c) to prepare a compound of formula le, where R represents a hydroxyimino, a lower alkoxy-iminomethyl or a carbamoylvinyl, by reacting

29

I

a compound, appearing in racemic form or as an 11S enantiomer, with the general formula

R

-C—CONH-II N

X0R10

CHO

<f

Vlla

-"n

\

S03H

10

where R has the meaning given in formula I above and R"*"^ the meaning given in formula Ib above, and where the group =N0R"'"^ appears at least partly in syn form,

with 11-hydroxylamine, a lower 0-alkyl-hydroxylanine, or with carbamoylmethylene-triphenylphosphorane, and treating, where appropriate, with a lower alkyl product 21

obtained where R = hydizs<yiminornetyl, or d) to prepare a compound of formula le, where R^" represents a lower carboxy-alkoyl, by transforming into a compound, present in racemic form or as the 3S enantiomer, of general formula

40

r u—c—conh-

II N

x0ru cf

"r

21

-N

\

so3h

If

15

20

X n21, 1. ■r; ■ , • j ' • j . ,-,13

or R and R have the meaning given above and R

represents a lower tri-alkyl-lower silyl-alkyl-

because bonyl-lower alkyl, a lower alkoxy-carbonyl-

lower alkyl, a lower phenyl-alkoxy-carbonyl-

lower alkyl or a lower nitrophenyl-alkoxy-carbonyl-

lower alkyl, where the ^NOR"*" group is at least partly in syn form,

30

I

13

the R group into a lower carboxy-alkoyl group, or e) by transforming a compound of formula le or one of its readily hydrolyzable esters into a pharmaceutically acceptable salt.

The reaction according to the invention of 5-carboxylic acid of formula IVb (or one of its functional derivatives)

with the compound of formula lia can be carried out in the conventional manner. If the free carboxylic acid of formula IVb is used, it is preferable to work in the presence of a condensing agent, and the condensing agent used is, for example, a substituted carbodiimide, such as N,N-dicyclo-

hexylcarbodiimide; a quaternary salt of 2-halogenpyridinium, e.g., 2-chloro-1-methylpyridinium iodide; or 1-chloro-N,N-2-trimethyl-1-propeneamine. Functional derivatives of carboxylic acid of formula IVb include: acid halides, e.g., acid chlorides; acid anhydrides, e.g., mixed anhydrides with C1- to C1-carboxylic alkanes, such as acetic acid; acid azides; active amides, e.g., amides with pyrazole, imidazole, benztriazole; active esters, e.g., C1-alkyl, methoxy-

methyl-, 2-propynyl-, 4-nitro-phenyl- or hydroxysuccinimide esters; or active thioesters, such as esters with 2-pyridinethiol or 2-benzthiazolylthio. 2-Benzthiazolylthioesters are described above. 25 The reaction of the compound with general formula IVb

(or one of its functional derivatives) with the compound of formula lia is carried out in practice in an inert organic solvent, e.g., in a chlorinated hydrocarbon, such as methylene chloride or chloroform, in an ether, e.g., tetra-30 hydrofuran 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, in practice, [temperature range missing in original text].

between approximately -40° and +60°C, preferably between -15° and +25°C, particularly 0-20°C. In practice, the reagents are used in an approximately stoichiometric ratio or with a slight excess of a carboxylic acid of formula IVb or one of its reactive functional derivatives. The reaction is preferably carried out in the presence of a base, such as an organic amine like triethylamine or N-methylmorpholine, or in the presence of an alkali metal bicarbonate, such as sodium bicarbonate.

40

If the R group of the starting compound of formula

IVa or its functional derivative contains an amino substituent; this can preferably remain unprotected (because this saves a reaction step, the separation).

40

subsequent amino protecting group). However, R may also contain a protected amino group, and one can mention the usual amino protecting groups, e.g., acid-separable protecting groups such as t-butoxycarbonyl, benzhydryl, trityl, or formyl; basic-separable protecting groups such as trifluoracetyl or chlor-, bro-, or iodacetyl, which can be separated with thiourea. The amino group may also be protected by salification with a mineral acid, e.g., hydrochloric acid. After the reaction of the starting compounds IVb and lia, or the functional derivative of compound IVb, with compound lia, any amino protecting group is removed. Acid-separable protecting groups are preferably removed using a lower-carboxylic alkane, which may optionally be halogenated. In particular, hydrochloric acid, formic acid, or trifluoracetic acid (the latter sometimes in the presence of anisole) or pyridinium hydrochloride are used. The temperature is generally room temperature, although a slightly higher or lower temperature can also be applied, e.g., within a range of approximately 0°C to +40°C.

10

15

20

25

30

32

I

Alkali-separable protecting groups are generally hydrolyzed with diluted aqueous lye between 0° and 30°C. Chloracetyl, bromacetyl, and iodacetyl protecting groups can be separated using thiourea in acidic, neutral, or alkaline media at approximately 0-30°C.

According to variant b) of the process selcn 11 invention, a compound of formula XII is sulfonated. This sulfonation can be carried out conventionally by reaction with sulfur trioxide or one of its reactive derivatives, e.g. complexes of sulfur trioxide with an organic base, such as pyridine, dimethylformamide, picoline, etc. The reaction takes place, e.g., at about -10 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) of the method according to the invention,

41

The amino group of the radical R is protected. The amino protecting groups are of the same nature as in the case of the starting compounds of formula IVb; they are also separated in the same way as described in this regard.

The reaction according to the invention of the starting compound of formula VII with hydroxylamine gives a compound of

21

formula le, where R represents a 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 preferably around 0-60°C, and the work is carried out particularly at near room temperature. If hydroxylamine is used instead of a

Lower O-alkyl-hydroxylamine yields a compound of

21

formula le, where R represents a lower alkoxy-iminomethyl.

If the starting compound of formula Vlla is reacted with carbamoylmethylenetriphenylphosphorane, a compound of formula R^l is obtained, where R^l represents

a carbamoyl-vinyl. This reaction preferably takes place in an inert solvent, such as methylene chloride, tetrahydrofuran or dioxane, and at around room temperature up to the boiling point of the solvent.

If desired, treatment with an alcohol can be used.

21

a product of the formula thus obtained, where R represents a hydroxyimino. For this purpose, it is preferably reacted with a C1 to C2 alkyl iodide, preferably in an inert organic solvent, such as methylene chloride, and preferably in the presence of an organic base.

like pyridine. The temperature is preferably around 0-60°C, and work is carried out particularly at around room temperature.

13

The transformation according to the invention of the R group of compounds of formula If is carried out in the same way as is said above for compounds of formula Ib or I. The same applies to the preparation according to the invention of pharmaceutically acceptable salts of compounds of formula le.

The compounds of formula I, as well as their readily hydrolyzable esters and pharmaceutically acceptable salts, possess a broad range of antimicrobial activity, particularly against Gram-negative microorganisms, such as, e.g., germs of the Enterobacteriaceae family, e.g., Escherichia coli, Proteus spp., Serratia spp. and Pseudo-monas aeruginosa.

These products can therefore be used for the treatment and prevention of infectious diseases. For adults, a daily dose of approximately 10-600 mg/kg of body weight can be considered.

The minimum inhibitory concentration (MIC, pg/ml) in vitro of some representative compounds is given in the following table (reference is made to some of the compounds shown in the application examples below).

Painting

Organization

Example 7

Example link

Example 13

Example 27

Example 29

Example 31

E. cloacae 15M

0.4

3.1

1.6

0.5

0.12

0.25

S.marcescens 80315

0.4

3.1

3.1

0.5

0.12

0.25

Pr.mirabilis 2117

^.0.05

0.8

0.8

0.06

<£0.03

0.06

Pr.vulgaris 1028

40.05

0.8

0.4

£0.06

£0.03

0.12

Ps.aeruginosa 799/61

0.8

1.6

0.2

0.12

0.12

0.06

E.coli UB 1005

0.2

1.6

0.8

0.5

0.12

0.12

K. pneumoniae 418

0.1

0.8

0.8

1

0.12

0.12

K.oxytoca 22812

-

1.6

0.8

1

0.12

0.5

Table (continued)

Organization

Example 3 4

Example 3.5d

Example 36a

Example 44

Example 4 5

E. cloacae 15M

0.4

0.2

0.5

4

0.5

S.marcescens 80315

•0.4

0.2

2

8

1

Pr.mirabilis 2117

0.2

0.1

0.12

4

0.5

Pr.vulgaris 1028

0.2

0.1

0.25

2

0.25

Ps.aeruginosa 799/61

0.1

"0.1

m 0

1

0.12

E. coli UB 1005

0.4

0, 2

0.5

4

0.25

K. pneumoniae 418

0.8

"0.1

0.25

4

0.5

K.oxytoca 22812

0.2

0.4

2

4

0.5

■J-

Table (continued)

Organism e

Example 46

Example 47

Example 48

Example 49

Example 5 0

E. cloacae 15M

0.25

16

0.5

4

16

S.marcescens 80315

0.25

32

0.5

8

32

Pr.mirabilis 2117

0.12

4

0.5

2

16

Pr.vulgaris 1028

0.12

2

0.5

16

64

Ps.aeruginosa 799/61

0.5

4

0.12

0.5

8

E. coli UB 1005

0.25

4

0.25

2

8

K. pneumoniae 418

0.06

8

0.25

4

8

K.oxytoca 22812

4

4

0.5

64

> 128

J)

37

Painting

I

Organization

Example 27

Example 29

Ent.cloaceae 4W-142

2

4

C.freundii 4f52

4

8

P.vulgaris 10610

<0.25

S.0, 25

Ps.aeruginosa 5F 81-1

8

4

S.marcescens 1X172

2

0.5

38

I

The products according to the invention can be applied as drugs, e.g. in the form of pharmaceutical preparations which contain them, or their salts mixed with a pharmaceutical carrier suitable for parenteral application, 5 organic or inorganic, inert.

4i-

Example 1

a) 18 mg (0.087 mmol) of acid is stirred for 2 hours

[3S,4S]-3-amino-4-propyl-2-oxo-l-azetidinesulfonic acid, 32 mg (0.095 mM) of 2-benzthiazolyl thioester of 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyiminoacetic acid, and 14.5 mg (0.143 mM) of triethylamine in 1 mL of dichloromethane. After evaporating the solvent, the mixture is absorbed into 5 mL of water, washed 5 times with 5 mL of ether each time, and then lyophilized. 35 mg of triethylamine salt of [3S,4S]-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-acetamido]-4-propyl-2-oxo-l-azetidinesulfonic acid is obtained in the form of a colorless amorphous product.

IR: (KBr, cm-1): 3384, 3312, 3207, 1763, 1670, 1621, 1537, 1266, 1230, 1044 NMR: (DMSO, ppm): 9.24 (d, J = 8.5 Hz, 1H), 7.17 (s, 2H); 6.64 (s, 1H); 4.50 (dd, J = 2.5/8.5 Hz; 1H), 3.79 (s, 3H), 3.59 (m, 2H); 3.07 (q, J = 7.5 Hz, 6H), ca. 2 (m, br, 1H); 1.4 (m, width, 1H); 1.17 (t, J=7.5 Hz, 9H); 0.88 (m, 3H),

The 2-benzthiazolyl-thioester of 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyiminoacetic acid used as a starting compound can be prepared as follows:

b) 3.93 g of triphenylphosphine and 5 g of dithio-bis-benzthiazole are suspended in 50 mL of dichloromethane and stirred for 30 minutes at approximately room temperature. After cooling to 0°C, 2 g of 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyiminoacetic acid are added, and the mixture is stirred for another 3 to 4 hours at 0°C. For purification, the mixture is filtered through a filter funnel to separate insoluble fractions and washed with a small amount of cold methylene chloride. The solid is then suspended in 25 mL of ethyl acetate, stirred for 30 minutes at 0°C, filtered again by suction, and washed.

10

40

I

with ethyl acetate. After recrystallization from tetrahydrofuran/dichloromethane, the 2-benzthiazolyl-thioester of 2-(2-amino-4-thiazolyl)-2-(Z)-methoxy-imino-acetic acid is obtained at 128-130°C.

The [3S,4S]-3-amino-4-propyl-2-oxo-l-azetidine-sulfonic acid used as a starting compound can be prepared as follows:

c) 84 mL of a 1.0 N ethylmagnesium bromide solution is added dropwise to tetrahydrofuran in 10.8 g (84 mM) of 3-(2-methoxy-2-propoxy)-propine, dissolved in 80 mL of dry tetrahydrofuran. The reaction solution is kept at room temperature by cooling with an ice bath, and after adding 15% ethylmagnesium bromide, the mixture is stirred for 30 minutes at room temperature. The reaction mixture is poured between -70°C and -40°C into 8.5 g (20.9 mM) of (3R,4R)-4-methylsulfonyl-3-trityl-amino-2-azetidinone, dissolved in 50 mL of dry tetrahydrofuran, and the mixture is stirred for 30 minutes at -30°C and then for 1.5 hours at room temperature. The brown solution obtained is diluted with 1 liter of ether, and the ether phase is washed with 300 ml of saturated aqueous ammonium chloride solution, then three times with 300 ml of water each time. The mixture is then dried and concentrated. The residue is chromatographed with 25% of 1:1 t-butylmethyl ether:n-hexane on 500 g of silica gel.

After 1.8 liters of head, there follows 0.9 liters of eluate with 1.2 g (13%) of substance A, 0.9 liters of eluate with 3.0 g (32%) of mixture of substance A and substance B and finally 1.8 liters of eluate with 3.2 g (34%) of substance B.

41

I

Substance A: Acetorc-methyl-3-[(3S,4R)-2-oxo-3-trityl-

15

25

ara ino-4-az^tidinyl]-2-propynyl-acetal.

5 NMR (CDCl3, 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,

10 3318,

; !

Substance B: Acetonermethyl-3-C (3S, 4S)-2-oxo-3-trityl-

amino-4-azetidinyl]-2-prop^nyl-acetal.

NMR (CDC13, jbprn): 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 resp. 9 Hz, 1H), 5.82 (s, 1H), 7.15 -7.55 (m, 15H).

d) 2.4 g (5.3 mM) of 1-acetone-methyl-3-[(3S,4S),-2-oxo-3-tritylamino-4-azetidinyl]-2-propynyl acetal is stirred for 15 minutes at room temperature in 50 mL of ether and 50 mL of 1% aqueous pitric acid. The aqueous phase is separated, and the ether phase is washed with a saturated aqueous solution of sodium bicarbonate and with water, dried, and concentrated. The residue corresponds to 1.8 g (89%) of 3-[(3S,4S)-2-oxo-3-tritylamino-4-azetidinyl]-2-propinol.

NMR (CDC13, ppm): 2.3 (s, lar., 1H), 2.8 (s,!^-, 1H),

3.35 (1H), 4.0 (2H), 4.2 (1H), 6.45 (s, 1H), 7.0-7.8 (m, 15H).

42

I

0.88 g (1.9 mMole) of acetone-methyl1-3-[(3S,4R)-2-oxo-3-tritylamino-4-azetidinyl]-2-propynyl-acetal is transformed in the same manner as above with picric acid to give 0.67 g (90%) of 5 3-[(3S,4R)-2-oxo-3-tritylamino-4-azetidinyl]-2-propinol.

NMR (CDC13, ppm): 1.56 (1H), 3.0 (d, J = 11 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 resp. 11 Hz, 1H), 5.84 (s, 1H), 0 7.2-7.6 (m, 15H).

e) 2.03 g (5.31 mMoles) of 3-[(3S,4R)-2-oxo-3-tritylamino-4-azetidinyl]-2-propinol, 0.65 g (6.37 mMoles) of acetanhydride and 504 mg (6.38 mMoles) of pyridine are stirred for 3 h at room temperature. 15 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 twice with 50 ml of water each time, dried and concentrated. The residue consists of 1.15 g (51%) of 3-[(3S,4R) 20 2-oxo-3-tritylamino-4-azetidinyl]-2-propynyl-acetate.

NMR (CDC13, ppm): 1.91 (s, 3H), 3.01 (d, J = 11 Hz, 1H),

3.64 (d, lar., J = 2 Hz resp. 5 Hz, 1H), 4.4 6 (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).

IR (KBr, cm-1): 705, 744, 1236, 1488, 1595, 1732, 1757,

2239, 2336, 3336.

25

From 3-[(3S,4S)-2-oxo-3-tritylamino-4-azeti-dinyl ]-2-propinol we obtain in the same way 3-[(3S,4S) — 2-oxo-3-tritylamino-4-azeti-dinyl]-2-propynyl-acetate.

NMR (CDC13< ppm): 2.07 (s, 3H), 2.84 (d, J = 9 Hz, 1H),

3.39 (q, J = 2 Hz, 1H), 4.29 (dd, J = 2 resp. 9 Hz, 1H), 4.50 (d, J = 2 Hz, 2H), 5.81 (s, 1H), 7.2 - 7.6 (m,

3 PM).

IR (KBr, cm-1): Identical to 3-[(3S,4R)-2-oxo-3-tritylamino-

4-azetidinyl]-2-propynyl-acetate.

f) Hydrogen is used for 10 minutes on 100 mg of platinum oxide in 410 mg (0.97 mM) of 3-[(3S,4R)-2-oxo-3-tritylamino-4-azetidinyl]-2-propynyl acetate, dissolved in 40 mL of methanol. The catalyst is filtered with a filter funnel and the filtrate is concentrated. The residue is chromatographed with 2:1 t-butylmethyl ether:n-hexane on 70 g of silica gel. After 200 mL of head, 120 mL of eluate is obtained with 180 mg (50%) of (3S,4R)-4-propyl-3-tritylamino-2-azetidinone. After another 500 ml, 420 ml of eluate is obtained with 67 mg (16%) of 3-[(3S,4R)-2-oxo-3-tritylamino-4-azetidinyl propyl acetate.

3,_[(3S,4R)-2-Oxo-3-tritylamino-4-azetidiriyl]-propyl-ace tatç

NMR (CDC13, 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-azetidinore

NMR (CDC13, ppm): 0.5 - 1.3 (7H), 2.7 (1H), 3.1 (1H),

4.35 (1H), 6.1 (1H), 7.1 - 7.7 (15H).

44

I

420 mg (1 mM) of 3-[(3S,4S)-2-oxo-3-tritylamino-4-azetidinyl]-2-propynyl acetate is hydrogenated in the same way with platinum oxide, and the resulting mixture is chromatographed with 1:1 t-butyl methyl ether:n-hexane on 570 g of silica gel. After 125 mL, 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-4-azetidinyl ]-propyl-acetate.

3-C(3S,4S)-2-Oxo-3-tritylamino-4-azetidinyl]-propyl-acetate

10

NMR (CDC13, ppm): 0.5 - 1.4 (4H), 2.0 (s, 3H), 2.7 (1H),

3.0 (1H), 3.8 (1H), 6.15 (1H), 7.0 -7.7 (15H).

15 ^

(3S,4S)-4-Propyl-3-tritylamino-2-azetidinone:

NMR (CDCl3, ppm): 0.4 - 1.3 (7H), 3.0 (2H), 3.7 (1H),

6.3 (1H), 7.2 - 7.7 (15H).

g) 180 mg (0.49 mM) of (3S,4S)-4-propyl-3-tritylamino-2-azetidinone and 239 mg (1.5 mM) of sulfur trioxide-pyridine complex 20 are stirred for 21 h at room temperature in 2 ml of dry dioxane. The residue is separated by centrifugation.

For the gation, it is dissolved in 10 ml of water, neutralized with sodium bicarbonate, and the aqueous solution is extracted with methylene chloride. The methylene chloride phase is concentrated, the residue is dissolved in 1 ml of 25-methylene chloride, and mixed with 40-yl formic acid (98-

100%). The product precipitates and is filtered using a filter funnel. 18 mg (18%) of (3S,4S)-3-amino-2-oxo-4-propyl-l-azetidinesulfonic acid is obtained, which can be used directly for the reaction according to the first paragraph of

4 5

I

this example.

Similarly, from (3S,4R)-4-propyl-3-tritylamino-2-azetidinone, crude (3S,4R)-3-amino-2-oxo-4-propy1-1-azetidinone sulfonic acid is obtained, which is also used directly further on.

Example 2

a) Similar to what is stated in example a), 20 mg of [3S,4R]-3-amino-4-(3-acetoxypropyl)-2-oxo-16azetidinesulfonic acid yields 20 mg of the triethylamine salt of (3S,4R)-3-[(Z)-2-(2-amino-4-thia-zolyl)-2-(methoxyimino)acetamido]-4-(3-acetoxypropyl)-2-oxo-1-azetidinesulfonic acid. Purification is performed by reversed-phase silica gel chromatography (eluent H₂O-CH₂OH 4:1). 6 mg of pure product is obtained as a lyophilized powder.

IR: (KBr, cm"1) 3410, 3328, 3240, 1772, 1741, 1681,

1545, 1247, 1045.

NMR: (DMSO, ppm): 9.2 7 (d, J = 9 Hz, lH), 7.1 (s, lar.

2H); 6.6 9 (s, lH), 5.10 (dd, J = 5 and 9 Hz, 1H); That. 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 a starting compound can be prepared as follows:

b) 67 mg (0.16 mMole) of 3-[(3S,4R)-2-oxo-3-tritylamino-4-azetidinyl]-propylacetate is transformed by analogy with example 4d) with a sulfur trioxide-pyridine complex into (3S,4R)-3-amino-4-(3-acetoxypropyl)-2-oxo-1-azetidin-sulfonic acid, which is directly acylated as crude product in the reaction above.

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Example 3

a) In the same way as stated in example a), from 36 mg of [3S,4S)-3-amino-4-(3-acetoxypropyl)-2-oxo-l-azetidinesulfonic acid, 37 mg of triethylamine salt of (3S,4S)-3-[(Z)-(2-arnino-4-thiazolyl)2-(methoxyimino)acetamidol-4-(3-acetoxypropyl)-2-oxo-l-azetidinesulfonic acid is obtained in the form of an 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,

laç 1H); 6.68 (s, lH); 4.51 (dd, J = 2.5/8.5 Hz, 1H); That. 4.0 (m, 2H), 3.82 (s, 3H), 3.07 (q, j = ca. 7.5 Hz, 6H); 2.0 (s, 3H); That. 1.5 (m, 3H); 1.17 (t, J = 7.5 Hz, 9H).

The [3S,4S]-3-amino-4-(3-acetoxypropyl)-2-oxo-1-azetidinesulfonic acid used as a starting compound can be prepared as follows:

b) 87 mg (0.20 mMole) of 3-[ ( 3S,4 S)-2-oxo-3-tritylamino-4-azetidinyl]-propylacetate is transformed by analogy with example lg) or 4d) into (3S,4S)-3-amino-4-(3-acetoxypropyl)-2-oxo-l-azetidinesulfonic acid, which is reacted directly further in crude form.

Example 4

38 mg (0.2 mM) of [3S,4R]-3-amino-4-ethynyl-2-oxo-1-azetidine sulfonic acid, 77 mg (0.22 mM) of 2-benzthiazolyl thioester of 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyiminoacetic acid and 56 µl (0.4 mM) of triethylamine are shaken for 2 h at room temperature

1 ml of acetone-water (4:1) is then filtered and concentrated. The residue is chromatographed with H2O:CH3OH 2:1 on reversed-phase silica gel. After lyophilization, the following is obtained

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66 mg of triethylamine salt of (3S,4R)-3-[(Z) — 2— (2-amino-4-thiazolyl)-2-(methoxyimino)acetamido ]-4-ethynyl-2-oxo-l-azetidinesulfonic acid.

IR: (KBr, cm-1): 3440, 1771, 1672, 1601, 1531, 1282,

1253, 1055.

: (ppm, CDCl3): 9.50 (d, J = 8 Hz; lH); 7.18 (s,

2H); 6.80 (s, lH); 5.22 (dd, J = 5.5/8 Hz; lH), 4.61 (dd, J = 2/5.5 Hz, lH) 3.82 (s, 3H) 3.45 (d, J = 2 Hz, lH).

10 The acid [3S,4RJ-3-amino-4-ethynyl-2-oxo-l-

Azetidinesulfonic acid used as a starting compound can be prepared as follows:

b) 30.1 g (0.306 mol) of trimethylsilylacetyne is dissolved in 300 ml of dry tetrahydrofuran. After cooling with 15 ml of ice, the solution is added dropwise for 30 minutes at

At 20°C, 290 ml of a 1.05 N solution of ethylmagnesium bromide in tetrahydrofuran is stirred for 2 h at 20°C and then added dropwise between -70 and -40°C to 31.3 g (0.077 Mol) of (3R,4R)-4-methylsulfonyl-3-trityl 20 amino-2-azetidinone in 200 ml of 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 a saturated aqueous solution of ammonium chloride and then with water, dried, and concentrated. The residual concentration is chromatographed with 2:3 β-butylmethyl ether:n-hexane on 1.5 kg of silica gel. After 4 liters of head, 1 liter of eluate is obtained with substance A, and then 4 liters of eluate with substance B. The fractions are then concentrated.

48

»

Substance A:

10.3 g (32%) (3S,4R)-3-Tritylamino-4-[2-(trimethylsilyl)cth^nyl]-2-azetidinone.

R/ff/ ( CDCl , ppm):

0.08 (s, 9H), 3.23 (d, J = 10 Hz, lH), 3.59 (d, J = 5 Hz, 1H), 4.30 (dd, J = 5/10 Hz, 1H), 5.88 (1H)

10

7.2 - 7.6 ppm.

SubstanceB: 15.3 g (47%) (3S,4S)-3-Tritylamino-4-[2-

(trimethylsilyl)cthvjnyl]-2-az4tidinone.

15

20

NMR (CDC13, ppm): 0.10 (s, 9H), 2.8 (1H), 3.40 (d, J =

2Hz, 1H), 4.23 (1H), 5.86 (1H), 7.1 -7.5 (15H).

c) 10.0 g (0.024 Mole) of (3S,4S)-3-tritylamino- are stirred

4-L2-(trimethylsilyl)ethynyl]-2-azetidinone and 1.5 g (0.026 Mole)

of potassium fluoride in 100 ml of ethanol and 100 ml of dimethyl sulfoxide for 1 h at 20°C. The solution is diluted with ether, the ether phase is washed with water,

We dry and concentrate. We obtain 8.1 g (85%) of (3S,4S)-

Crude 4-ethynyl-3-.tritylamino-2-azetidinone.

NMR (CDC13, ppm)

IR (KBr, cm):

1.8 (1H), 2.16 (d, J = 2 Hz, lH), 3.33 (tr, J = 2 Hz, 1H), 4.30 (lH), 5.87 (1H), 7.2 - 7.5 (15H).

706, 751, 1490, 1599, 1625, 1769, 2124, 3306.

°h

49

Similarly, from 9.4 g of (3S,4R)-3-tritylamino-4-[2-(trimethylsilyl)ethynyl]-2-aze-tidinone, 8.8 g (91%) of (3S,4R)-4-ethynyl-3-tritylamino-2-azetidinone is obtained.

NMR (CDCl^, 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 Hz, 1H), 5.88 (1H), 7.1 - 7.6 (15H).

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

10 d) 3.5 g (10 mMoles) of

(3S,4R)-4-ethynyl-3-tritylamino-2-azetidinone and 4.0 g (25 mM) of sulfur trioxide-pyridine complex in 40 mL of pyridine. The reaction solution is mixed with 15,200 mL of ether, and the resulting precipitate is dissolved in 100 mL of methylene chloride. After the addition of 5 mL of concentrated formic acid, an oily precipitate appears, which, after separation from the solvent by decantation and the addition of ether, transforms into white crystals. 1.19 g (58%) of [3S,4R]-3-amino-4-ethynyl-2-oxo-l-azetidinone is isolated.

sulfonic acid.

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: Cal. C 31.58 H 3.18 N 14.73 S 16.86%

Tr. C 32.33 H 3.40 N 13.42 S 16.24 H20 1.46%

e) 530 mg (1.5 mM) of (3S,4S)-46-ethyl-3-tritylamino-2-azetidinone and 600 mg (3.75 mM) of sulfur trioxide-pyridine complex are stirred in 6 mL of dry dioxane for 21 h at room temperature. The undissolved residue is filtered through a filter funnel and the mixture is blended.

50

the filtrate with 30 ml of ether. The product precipitates as a gummy precipitate, which, after separation from the solvent by decantation and scraping, in the presence of a little ether, transforms into crystals. These are filtered with a black filter funnel and correspond to 481 mg of pyridi- salt

nium of (3S,4S)-4-ethynyl-2-oxo-3-tritylamino-1-azetidinesulfonic acid. The product is dissolved in 20 ml of methanol, kept at room temperature for 4 days, then the solution is concentrated and the residue is filtered with a little methanol through a filtering funnel.

We obtain 180 mg (63%) of (3S,4S)-3-amino-4-ethynyl-2-oxo-l-azetidinesulfonic acid.

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

2 Hz, 1H), 4.46 (d, J = 2 Hz, 1H). 15 IR (KBr, cm-1): 1256, 1621, 2125, 2654, 3217.

Example 5

a) 60 mg (0.31 mM) of C3S,4R]-3-amino-4-vinyl-2-oxo-l-azetidine-1-sulfonic acid, 120 mg (0.34 mM) of 2-benzthiazolylthioester 20 of 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyiminoacetic acid, and 63 mg (0.62 mM) of triethylamine are stirred in 1.5 mL of acetone-water (4:1) for 3 h at room temperature. The mixture is concentrated and reversed-phase silica gel chromatography is performed with acetonitrile as the eluent. After concentration, 63 mg of triethylamine salt 25 of (3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxy imino )acetamido]-2-oxo-4-vinyl-l-azetidinesulfonic acid is obtained in the form of a colorless amorphous powder.

°l

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IR (KBr, cm 1): 34 00; 1765, 1671, 1536, 1275, 1044.

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

6.64 (s, lH), ca. 5.75 (m, lH); That. 5.2 (m, 3H) 4.4 (dd, J = 6/8 Hz, lH), 3.80 (s, 3H), 3.08 (q, J = 7 Hz, 6H), 1.17 (t, J = 7 Hz, 9H).

The previous triethylamine salt is dissolved in 6 ml of water and diluted with 5 ml of Amberlite CG 120 (Na+ form) for 3 h. The product is filtered and lyophilized, yielding 26 mg of sodium salt of (3S,4R)-3-[2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-2-oxo-4-vinyl-l-azeti-dine-sulfonic acid.

NMR (DMSO, ppm): 9.22 (d, J = 9 Hz, 1H); 7.21 (s, 2H); 6.64

(s, 1H); 5.84 (m, lH), 5.38 (m, lH), 5.18 (m, 2H), 4.40 (m, lH), 3.80 (s,. 3H).

The [3S,4R]-3-amino-4-vinyl-2-oxo-l-azetidine-l sufonic acid used above as a starting compound can be prepared as follows:

b) 1.55 g (4.4 mM) of (3S,4R)-4-ethynyl-3-tritylamino-2-azetidinone is dissolved in 200 mL of MeOH and hydrogenated for 2 minutes over a 5% palladium-calcium carbonate catalyst (poisoned with lead). The catalyst is filtered using a filter funnel, the filtrate is concentrated, and chromatography is performed with 2:1 petroleum ether on 200 g of silica gel. After 1.5 L of head, 210 mL of eluate is obtained with 0.50 g of (3S,4R)-3-tritylamino-4-vinyl-2-azetidinone. The following 1.4 L of eluate contains 0.80 g of a mixture of (3S,4R)-3-tritylamino-4-vinyl-2-azetidinone and (3S,4R)-4-ethyl-3-tritylamino-2-azetidinone. This mixture is chromatographed on silica gel impregnated with 30 g of silver nitrate. 0.10 g of

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(3S,4R)-4-ethyl-3-tritylamino-2-azetidinone and, with 700 ml of ethyl acetate and 500 ml of acetone, 0.53 g of (3S,4R)-3-tritylamino-4-vinyl-2-azetidinone. Total yield: 66% of (3S,4R)-3-tritylamino-4-vinyl-2-azetidinone.

5 NMR (CDCl^/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.

10

15

c) 470 mg (1.33 mM) of (3S,4R)-3-tritylamino-4-vinyl-2-azetidinone is sulfonated in a manner analogous to example 4d) with a sulfur trioxide-pyridine complex and then detritylated with formic acid. This yields 63 mg (25%) of (3S,4R)-3-amino-2-oxo-4-vinyl-l-azetidinone sulfonic acid.

20

NMR (DMSO, ppm)

IR (KBr, cm 1 ) :

4.44 (tr, J = 6.5 Hz, 1H), 4.57 (d, J = 6.5 Hz, 1H), 5.39 (dd, J = 2 resp. 10 Hz, 1H), 5.54 (dd, J = 2 resp. 17 Hz, 1H), 5.74 - 6.13 (m, 1H), 8.51 -9 ppm (m, 3H).

951, 994, 1200, 1229, 1254, 1529, 1770, 2640.

Example 6

25 In the same way as what is said in the example

5. From 110 mg of [3S,4S]-3-amino-4-ethynyl-2-oxo-l-azetidinesulfonic acid, 58 mg of triethylamine salt of [3S,4R]-3-[(Z)-2-(2-amino-4-thiazoly1)-2-(methoxyimino)acetamido]-4-ethynyl-2-oxo-l-azetidine-sulfonic acid are obtained.

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Elemental analysis:

C17H26N6°6S2 (474.55): cal.; C43.03%,

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

N 17.48%.

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

1535, 1275, 1245, 1046.

NMR (DMSO, ppm): 9.41 (d, J = 8 Hz, 1H); 7.21 (s, 2H); 6.73

(s, 1H), 4.72 (dd, J = 3/8 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 (t, 7.5 Hz, 9H).

Example 7

a) In the same way as in example 5, from [3S,4R]-3-amino-4-ethyl-2-oxo-l-azetidinesulfonic acid, we obtain (3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyimino.)acetamido]-4-ethyl-2-oxo-1-azetidinesulfon sodium ate.

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, lH), 3.80 (s, 3H), 3.74 (m, lH), 1.87 (m, lH), 1.54 (m, 1H), 0.83 (t, J = 6.5 Hz, 3H).

The [3S,4R]-3-amino-4-ethyl-2-oxo-l-azetidine-sulfonic acid can be prepared as follows:

b) 2.0 g (5.7 mMoles) of (3S,4R)-4-ethynyl-3-trityl-2-amino-azetidinone is dissolved in 250 ml of MeOH and hydrogenated for 15 minutes over 2.0 g of 5% palladium-carbon.

54

The catalyst is removed by filtration, and the filtrate is concentrated. The residue corresponds to 1.4 g (69%) of (3S,4R)-4-ethyl-3-trityl-amino-2-azetidinone.

NMR (CDC13, ppm): 0.65 - 1.25 (5H), 2.61 (d, J = 8 Hz,

1H), 3.08 (1H), 4.38 (dd, J = 5 resp. 8 Hz, 1H), 5.89 (1H), 7.1 - 7.6 (15H). IR (KBr, cm-1): 703, 755, 1491, 1596, 1752, 3266.

c) By analogy with example 4, (3S,4R)~ 4-ethyl-3-tritylamino-2-azetidinone is transformed into (3S,4R)-3-amino 4-ethyl-2-oxo-l-azetidinone sulfonic acid, which is directly reacted further in crude form.

Example 8

a) In the same way as stated in example 5, from 80 mg of [3S,4S]-3-amino-4-vinyl oxo-1-azetidinesulfonic acid, 88 mg of triethylamine salt of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxy-imino)acetamido]-2-oxo-4-vinyl1-1-azetidinesulfonic acid is obtained in the form of an amorphous lyophilized product.

C'17^28^6°6S2 (476.57): cal.: C 42.85%

H 5.92%, N 17.63%; tr. : 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, lH), 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, 1H), 4.11 (dd, J = 3/7 Hz, 1H), 3.82 (s, 3H), 3.10 (m, 6H), 1.18 (t, J = 7 Hz, 9H).

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The [3S,4S]-3-amino-4-vinyl-2-oxo-l-azetidine-sulfonic acid used above as a starting compound can be prepared as follows:

b) 2.5 g (7.1 mM) of (3S,4S)-4-ethynyl-3-tritylamino-2-azetidinone is dissolved in 250 mL of methanol and hydrogenated for 10 minutes over 1.5 g of palladium catalyst in 5% calcium carbonate (poisoned with lead). The catalyst is separated by filtration, the filtrate is concentrated, and chromatographed with 1:2 n-hexane:t-butyl ether on 200 g of silica gel. Elution of 1.86 g (74%) of (3S,4S)-3-tritylamino-4-vinyl-2-azetidinone occurs from 600 to 900 mL.

NMR (CDCl3, 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 (2.83 mM) of (3S,4S)-3-tritylamino-4-vinyl-2-azetidinone is sulfonated by analogy with example 4d) with a sulfur trioxide-pyridine complex and detritylated with methanol. 87 mg (16%) of (3S,4S)-3-amino-4-vinyl-1-2-oxo-1-azetidinonesulfonic 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.

10

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Example 9

In the same way as stated in example 5, from 70 mg of [3S,4S]-3-amino-4-ethyl-2-oxo-l-azetidinesulfonic acid, 152 mg of triethylamine salt of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl1)-2-(methoxyimino)acetamido]-4-ethyl-2-oxo-l-azetidinesulfonic acid is obtained in the form of an amorphous lyophilized product.

IR: (KBr, cm-1): 3403, 3316, 3206, 1763, 1667,

1621, 1537, 1243, 1044.

NMR (DMSO, ppm): 9.27 (d, J = 8.5 Hz, lH), 7.18 (s, br.

2H), 6.66 (s, 1H), 4.52 (dd, J = 2.5/8.5 Hz, lH), ca. 3.5 (m, lH), 3.82 (s, 3H), 3.09 (q, J = 7.5 Hz, 6H), ca. 1.8 (m, lar, 2H), 1.17 (t, J = 7.5 Hz, 9H), 0.89 (tr, J = 8 Hz, 3H).

The [L3S,4S]-3-amino-4-ethyl-2-oxo-l-azetidine-sulfonic acid used above as a starting compound can be prepared as follows:

b) 2.5 g (7.1 mM) of 20(3S,4S)-4-ethynyl-3-tritylamino-2-azetidinone is hydrogenated for 10 minutes in 250 mL of methanol over 2.5 g of 5% depalladium-carbon. The catalyst is separated by filtration, the filtrate is concentrated, and chromatographed with 1:1 t-butylmethyl ether:n-hexane on 200 g of silica gel. After 750 mL of head, 25% of the product is isolated with 1 L of eluent containing 1.63 g (65%) of (3S,4S)-4-6-ethyl-3-

tritylamino-2-azetidinone.

NMR (CDC13, ppm): 0.53 - 0.58 (5H), 2.7 (1H), 2.9 (1H),

3.75 (1H), 6.0 (1H), 7.2 - 7.6 (15H).

IR (KBr, cm-1): 705, 747, 1490, 1596, 1753, 3260.

15

H

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0.94 g (2.64 mMoles) of (3S,4S)-4-ethyl-3-tritylamino-2-azetidinone is reacted by analogy with example 4d). 176 mg (34%) of (3S,4S)-3-amino-4-ethyl-2-oxo-1-azetidinesulfonic acid is obtained.

5

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

10 Also by analogy with example 5 we can obtain the sodium salt of (3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-acetamido]-2-oxo-4-propyl-1-azetidinesulfonic acid.

15

20

Elemental analysis:

Cal. • C12H16N5°6S2Na C 34'87' H 3'90' N 16.94%

Tr>: C 34.54, H 3.91, N 16.43%

IR: (KBr cm-1) 3423, 3281, 3219, 1762, 1656, 1236,

NMR

(dg-DMSO, ppm): 0.9 (3H, t, Cfi3), 1.10 -1.95 (4H, m, -CH2-CH2-), 3.85 (3H, s, OCH3), 3.85 (1H, dt, -CH-CH2-CH2CH3), 5.05 (lH, dd, 6 und 9 Hz, NH-CH) 6.73 (1H, s, S-CH=), 7.15 (2H, s, NH,), 9.25 (1H, d, 9 Hz, CONH).

Example 11

a) In the same way as in Example 1, from 224 mg of rac,cis-3-amino-4-methoxy-carbonyl-2-oxo-l-azetidinesulfonic acid and 367 mg of 2-benzthiazolyl-thioester of 2-(2-amino-4-oxazolyl)-

58

t

-2-methoxyiminoacetic acid (7:2 mixture of Z:E isomers) 259 mg triethylamine salt of rac,cis-3-[2-(2-amino-4-isoxazolyl)-2-(methoxyimino)acetamido]-4-(methoxy-carbonyl)-2-oxo-l-azetidinesulfonic acid as an amorphous lyophilisate (7:2 mixture of Z:E isomers).

IR: (KBr, cm-1): 3410, 3333, 3288, 3223, 1758,

1658, 1559, 1539, 1285, 1237, 1048. NMR (DMSO, ppm): 9, 41 (d, J = 8 Hz, lH), 7.37 (s, lH), 6.83

(s, br., 2H), 5.34 (dd, J = 5.5/8 Hz, lH). 4.44 (d, J = 5.5 Hz, lH), 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-benzthiazolyl-thioester of 2-(2-amino-4-oxazolyl)-2-methoxuimino-acetic acid used as a starting compound can be prepared as follows:

b) Ch heats for 30 minutes at 100°C a solution of 50.4 g (0.2 Mole) of ethyl ester of 2-methoxyimino-4-bromo-acetoacetic acid (M. Ochiai et al., Chem. Pharm. Bull.

25, 3115 (1977) and 60.1 g (1 Mole) of urea in 200 ml of dimethylformamide. The mixture is then concentrated, absorbed into 800 ml of water, neutralized with sodium bicarbonate, and extracted with ethyl acetate. The ethyl acetate extract is chromatographed with acrylonitrile:methylene chloride 1:1 on silica gel. The ethyl ester of 2-(2-amino-4-oxazolyl)-2-methoxyiminoacetic acid is obtained in a yield of 26%; P 120°C (dec.).

s X

NMR (DMSO, ppm): 7.77 (s, lH), 6.93 (s, 2H), 4.15 (q, J =

7 Hz, 2H), 3.90 (s, 3H), 1.28 (tr, J = 7 Hz, 3H).

c) 2.13 g (10 mMoles) of ethyl ester of 2-(2-amino-4-oxazolyl)-2-methoxy-imino-acetic acid is treated in 20 ml of methanol at -20°C with 10 ml of 1 N aqueous sodium hydroxide solution.

59

t

After the addition of 10 ml of 1 N aqueous hydrochloric acid, 2-(2-amino-4-oxazolyl)-2-methoxyiminoacetic acid precipitates with a yield of 54%; 190° (dec.).

Elemental analysis:

C5H7N304 cal. : C 38.93, H 3.81, N, 22, 70°/o tr. : C 38.40, H 4.01, N 22.33%.

d) 670 mg (4.05 mM) of triethylphosphite is added, after cooling with ice, to a solution of 560 mg (3 mM) of 2-(2-amino-4-oxazolyl)-2-methoxyiminoacetic acid, 1.2 g (3.6 mM) of 2,2-dithio-bis-benzthiazole, and 360 mg (3.6 mM) of N-methylmorpholine in 20 mL of absolute acetonitrile. The mixture is stirred for 3 h at room temperature. The precipitate is then filtered through a filter funnel, washed with water, and dried. The result is the 2-benzthiazolyl thioester of 2-(2-amino-4-oxazolyl)-2-methoxyiminoacetic acid (a 7:2 mixture of the Z:E isomers).

Yield 55%; P^ 139°C (dec.).

HMK (DMSO, ppm): 4.0 and 4.22 (s, 3H; Z + E isomer); 6.90 and

7.08 (s, width, 2H; (E+Z); 7.5 - 8.5 (m, 5H).

Example 12

Similar to what is said in the example

1. From 95 mg of [3S,4R]-3-amino-4-ethynyl-2-oxo-1-azetidinesulfonic acid, 192 mg of triethylamine salt of (3S,4R)-3-[2-(2-amino-4-oxazolyl)-2-(methoxyimino)acetamido]-4-ethynyl-2-oxo-1-azetidinesulfonic acid are obtained. The product is a 5:1 mixture of the Z:E isomers.

60

IR: (cm-1, KBr): 3339, 3263, 2683, 1773, 1659,

1541, 1277, 1254, 1045.

NMR (DMSO, ppm): 9.48 + 9.67 (d, J = 8.5, lH; Z + E) 8.07

+ 7.49 (s, lH; E + Z); 6.97 + 6.82 (s, lar., 2H; E + Z); 5.2 (dd, J = 6/8.5 Hz, 1H); 4.60 (dd, J = 2/6 Hz, lH); 4.01 + 3.82 (s, 3H; E + Z); 3.47 (d, J = 2 Hz, lH); 3.06 (q, J = 7.5 Hz, 6H); 1.17 (t, J = 7.5 Hz,

9 AM).

Example 13

291 mg (1.3 mM) of rac-cis-3-amino-4-methoxycarbonyl-2-oxo-l-azetidinesulfonic acid, 640 mg (1.8 mM) of 1-benzthiazolyl thioester of 2-[(5-amino-3-(1,2,4-thiadiazolyl)]-2-(Z)-methoxyiminoacetic acid, and 263 mg of triethylamine are shaken in 6 mL of dichloromethane. After evaporation of the solvent, the mixture is absorbed into 20 mL of water, washed 5 times with 10 mL of ether each time, and lyophilized. 610 mg of triethylamine salt of rac-cis-3-[(Z)-2-(5-amino-l,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetic acid is obtained. )acetamido]- 4- ( methoxycarbonyl)-2-oxo-1-azetidinesulfonice .

IR: (KBr, cm-1): 3397, 3305, 3204, 1755, 1688,

1622, 1530, 1281, 1235, 1207, 1047. nmr (DMSO, ppm): 9, 37 (d, J = 8.5 Hz, lH), 8.10 (s, lar., 2H),

5.37 (dd, J = 5.5/8.5 Hz, lH), 4.41 (d, J = 5.5 Hz, 1H), 3.86 (s, 3H), 3.61 (s, 3H), 3.04 (q, J = 7.2 Hz, 6H), 1.16 (t, J = 7.2 Hz, 9H).

61

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Example 14

a) 190 mg (1 mMole) of [3S,4R]-3-amino-4-ethynyl-2-oxo-l-azetidine-sulfonic acid, 526 mg (1.1 mMole) of 2-benzthiazolyl-thioester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(t-Putoxycarbonyl)-1-methylethoxy]-imino]-acetic acid and 0.280 ml (2 mMole) of triethylamine are mixed in 5 ml of 4:1 acetone-water. Then the mixture is concentrated, absorbed into 4 ml of methanol and filtered. The filtrate is reversed-phase silica gel chromatographed using 10:1 f^O-methanol; after lyophilization we obtain 213 mg of (3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[Ll-(tert-butoxycarbonyl)-1-methyl-ethoxy] imino ]acetamidoJ-4-ethynyl-2-oxo- 1-azetidinesulf on ique in the form of an amorphous powder.

IR: (KBr, cm-1): 3315, 1773, 1725, 1679, 1621,

1531, 1285, 1257, 1146, 1055.

NMR (DMSO, ppm): 9.17 (d, J = 9 Hz, lH), 7.22 (s, lar, 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, 15 H).

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

b) 43 g (200 mMoles) of ethyl ester of 2-(2-amino-4-thiazolyl)-2-(Z)-hydroxyiminoacetic acid are dissolved in

1.2 liters of dimethylformamide. In a nitrogen atmosphere, 89.2 g (400 mM) of 2-bromo-2-methylpropionic acid β-butyl ester is gradually added, followed by 110.6 g (800 mM) of finely powdered potassium carbonate. The reaction mixture is stirred for 12 h at 45°C. After cooling to room temperature, 4 liters are added.

of water, and the mixture is extracted with 3.5 liters of ethyl acetate. The organic phase is washed 3 times with 2 liters of water. The water is extracted once more with 1.5 liters of ethyl acetate. The combined ethyl acetate solutions are dried with magnesium sulfate and concentrated to dryness. After recrystallization from ether, 61.4 g (85.9%) of ethyl ester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-l-(t-butoxycarbonyl)-l-methyl-ethoxy]-imino]-acetic acid is obtained at a boiling point of 172°C.

c) 240 g (671.5 mM) of the ethyl ester of 2-(2-amino-4-thiazolyl-2-[C(Z)-l-(t-butoxycarbonyl)-1-methylethoxy]imino]acetic acid is stirred for 12 h at 50°C in 1.3 L of methanol and 1.34 L of 1 N aqueous sodium hydroxide solution. The methanol is evaporated and the aqueous phase is washed.

Twice with 1 liter of ethyl acetate. After the addition of 1.34 liters of 1 N aqueous hydrochloric acid, the product crystallizes. After cooling to 0°C, the crystals are separated, washed successively with water, 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 filtration and drying under reduced pressure at 40°C, 177.7 g (80.3%) of 2-(2-amino-4-thia-zolyl)-2-C C(Z)-l-(t-butoxycarbonyl)-1-methylethoxy]imino]-acetic acid is obtained at 178-179°C. Water content 0.4%.

d) 28.8 g (86.4 mMoles) of 2-(2-amino-4-thiazolyl)-2-[[(Z)-l-(t-butoxycarbonyl)-1-methylethoxy]imino]acetic acid is dispersed in 360 ml of acetonitrile. 14.4 ml

(130.5 mMoles) of N-methylmorpholine is added while stirring. After 10 minutes, 34.6 g (103.5 mMoles) of 2,2-dithio-bis-benzthiazole is added and the resulting suspension is cooled to 0°C. After the addition of 20.2 mL (117 mMoles) of triethylphosphite (slow addition over 2 h), the suspension is stirred for 12 h at 0°C. The product is separated by filtration and washed.

11-sulfated with cold acetonitrile, isopropyl ether and petroleum ether and dried at room temperature under reduced pressure. The 2-benzthiazolyl thioester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(t-butoxycarbonyl)-1-methyl-ethoxy]imino]-acetic acid (33.7 g = 81.5%) is obtained at P 139-140°C.

Example 15

At -10°C, 66 mg of (3S,4R)-3-[2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(tert-butoxycarbonyl)-1-methylethoxy]imino]acetamido]-4-ethynyl-2-oxo-1-azetidinesulfonic acid is added to 4 ml of trifluoracetic acid. After 4 h, the mixture is concentrated, a small amount of water is absorbed, and the solution is analyzed by MCI gel chromatography using water. Lyophilization yields 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-azetidinesulfonic acid.

IR: (KBr, cm-1): 3292, 1771, 1679, 1638, 1531,

1276, 1047.

NMR (DMSO, ppm): 9.38 (d, J = 8.5 Hz, lH), 6.90 (s, lH),

5.28 (dd, J = 5.5/8.5 Hz, 1H), 4.67 (dd, J = 2/5.5 Hz, lH), 3.44 (d, J = 2 Hz, lH), 1.36 (s, lajajj 6 H).

Example 16

By analogy with example 14 we obtain the (3S,4R) — 3—[(Z) — 2—(2-amino-4-thiazolyl)-2-[(1-carboxy-l-methylethoxy)imino jacetamido]-4-methyl-2-oxo-1-azetidine-sulfonate sodium.

IR: (KBr cm-1): 3297, 2984, 2683, 1763, 1675,

1631, 1535, 1276.

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

3.5 Hz, CH-CH3), 4.0 (lH, m, CH-CH3), 5.05 (1H, dd, 6 and 9 Hz, NH-CH) 6.75 (lH, s, S-CH=), 7.20 (3H, large NH3), 9.15 (lH,d, 9 Hz, CONH).

Example 17

0.16 mg (0.55 mM) of [3S,4S]-3-amino-4-ethyl-2-oxo-l-azetidinesulfonic acid, 288 mg (0.6 mM) of 2-benzthiazolyl thioester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(t-butoxycarbonyl)-1-methylethoxy]imino3-acetic acid, and 0.153 mL of triethylamine (1.1 mM) are stirred in 3 mL of acetone-water (4:1) for 3 h at room temperature. The mixture is concentrated, absorbed into 10 mL of water, washed three times with 20 mL of ether each time, and lyophilized. 270 mg of triethylamine salt is obtained from (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(1-(t-butoxycarbonyl)-1-methyl-eth-oxy]imino Acetamido]-4-ethyl-2-oxo-1-azetidinesulfonic acid.

C24H42N6°8S2 (6°6.75);

cal. : C 47.51 H 6.98 N 13.85%

tr. : C 47.29 H 6.96 N 13.68%

Example 18

At -10°C, 250 mg of triethylamine salt of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-(t-butoxycarbonyl)-1-methylethoxy]imino jacetamido]-4-ethyl-2-oxo-l-azetidinesulfonic acid is added to 3 ml of trifluoracetic acid. After 20 h at -10°C, the mixture is evaporated and purified using DCCC (countercurrent droplet chromatography: upward-moving droplets in a 7:13:8 chloroform-methanol-water mixture). 58 mg of triethylamine salt of amorphous (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(l-carboxy-l-methylethoxy)iminojacetamido]-4-ethyl-2-oxo-l-azetidinesulfonic acid is obtained.

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IR (KBr, cm-1) 1766, 1673, 1539, 1201, 1042

NMR (DMSO, ppm): 9.13 (d,J=9Hz,1H); 6.66 (s,lH); 4.58

(dd,J=2.5/9Hz); 3.58 (m,lH); 3.10 ( ,J=7Hz, 6H); 1.42 ( s , lar, 6H ); 1.19 (t, J=7Hz,9H); 0.89 (tr,J=7Hz,3H).

Example 19

224 mg (1 mM) of rac,cis-3-amino-4-methoxycarbonyl-2-oxo-l-azetidinesulfonic acid, 526 mg (1.1 mM) of 2-benz-thiazolyl thioester of (Z)-2-(2-amino-4-thiazolyl)-10 2-[[1-(t-butoxycarbonyl)-l-methyl-ethoxy]-imino]acetic acid and

261 mg of triethylamine in 5 ml of dichloromethane. After evaporating the solvent, 20 ml of water is absorbed, the mixture is washed 5 times with 20 ml of ether each time, and then lyophilized. 569 mg of rac-cis-3-[(Z)-2-(2-amino-4-thiazo-15 lyl)-2-[[l-(t-butoxycarbonyl)-1-methyl-ethoxy]-imino]-aceta-

mido]-4-methoxycarbonyl-2-oxo-1-azetidinesulfonic acid.

Example 20

At room temperature, 550 mg of rac-cis-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[l-( ,t-bu toxycarbonyl ) 20 1-methyl-ethoxy]-imino]-acetamido]-4-methoxycarbonyl-2-oxo-

1-azetidinesulfonic acid in 5.5 ml of trifluoracetic acid. After 45 minutes, it is concentrated and purified by reversed-phase silica gel chromatography with 4:1 water-methanol. 27 mg of rac-cis-3-[(Z)-2-25 (2-amino-4-thiazolyl)-2-[(l-carboxy-l-methylethoxy)imino]- acid is obtained.

acetamido-4-(methoxycarbonyl1)-2-oxo-1-azetidinesuifonic acid pure in the form of an amorphous lyophilized powder.

NMR (DMSO, ppm): 9.13 (d,J=8.5Hz,1H); 6.6 7 (s,lH);

5.44 (dd,J=6/8.5Hz,1H); 4.48 (d,J=6Hz, qn 1H); 3.60 (s, 3H); 1.42 (slar,6H).

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Example 21

a) 522 mg (1.0 mM) of 2-benzthiazolyl thioester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-1-[2-(trimethylsilyl)-ethoxycarbonyl]-l-methylethoxy]-imino-acetic acid and 224 mg (1.0 mM) of rac-cis-3-amino-4-methoxycarbonyl-2-oxo-l-azetidinesulfonic acid are suspended in 5.0 mL of absolute acetone and mixed with 0.278 mL (2.0 mM) of triethylamine. The resulting clear yellow solution is stirred at room temperature for 24 h and then concentrated. DCCC (countercurrent chromatography) is performed.

by upward dropleting in a mixture: CHCl₂/MeOH/E₂O₂ 7:13:8). The fractions of interest are collected, concentrated, and lyophilized. 211 mg (31%) of triethylamine salt of rac-cis-3-[(Z)-2-(2-amino-4-thiazolyl)-2 — C[1-[[2-(trimethylsilyl)ethoxy]-carbonyl]-1-methyl-15 ethoxy]imino]acetamido]-4-methoxycarbonyl-2-oxo-1-azetidine-

sulfonic (1:1).

NMR (DzO, ppm): 0, 0 3 (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, 3H), 5.66 (d, J = 20 6, 0.1H), 6.81 (s,1H)

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 mMole) of triethylamine salt of 25 is dissolved in rac-cis-3[(Z)-2-(2-amino-4-thiazolyl)-2-[[l-[[2-

(trimethylsilyl)ethoxy]carbonyl]-1-methylethoxy]imino ]acetamide]-4-methoxycarbonyl-2-oxo-l-azetidinesulfonic acid in 10 mL of tetrahydrofuran (dry) and mix with 130 mg (0.50 mM) of tetrabutylammonium fluoride (dry). The reaction mixture is stirred overnight at room temperature and then concentrated. The residue is dissolved in a small amount of saturated aqueous sodium bicarbonate solution and

Chromatography on Amberlite XAD-2 (eluent: water, then 30% ethanol in water). After lyophilization, 40 mg (32%) of sodium salt of rac-cis-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(l-carboxy-1-methylethoxy)imino]-acetamido]-4-(methoxycarbonyl)-2-oxo-l-azetidinesulfonic acid is obtained.

IR (KBr, cm-1): 1771, 1730.

2-(2-amino-4-thiazolyl)-2-[[(Z)-1-[2-(trimethylsilyl)-ethoxycarbonyl]- 2-benzthiazolyl-thioester

1-Methylethoxy-imino-acetic acid used as a starting compound can be prepared as follows:

c) 24.9 g (102 mMoles) of t-butyl ester of the acid are dissolved

2-(2-amino-4-thiazolyl)-2-(Z)-hydroxy-imino-acetic acid in 400 ml of dimethylformamide. After the addition of 54.7 g (205 mMoles) of (2-trimethylsilyl)-ethyl ester of 2-bromo-2-methylpropionic acid, followed by 56.6 g (410 mMoles) of finely ground potassium carbonate, the reaction mixture is stirred for 4 h at 25°C in a nitrogen atmosphere.

After adding 3 liters of water, the mixture is extracted with 1.5 liters of ethyl acetate. The organic phase is washed twice with 1.5 liters of water. The water is extracted again with 1.5 liters of ethyl acetate. The combined ethyl acetate solutions are dried over sodium sulfate and concentrated to dryness. The product is purified by instant chromatography on silica gel (hexane-ethyl acetate 2:1) and crystallized from methanol/water. 28.6 g (65.3%) of β-butyl ester of 2-(2-amino-4-thiazolyl)-2-[(Z)-1-(2-(trimethylsilyl)ethoxycarbonyl)-1-methylethoxy]imino]-acetic acid is obtained at 83°C.

d) 13.4 g (31.2 mM) of 2-(2-amino-4-thia-zolyl)-2-[(Z)-(1-(2-trimethylsilyl)ethoxycarbonyl)-1-methyl-ethoxyjimino]acetic acid is stirred for 1 h at room temperature in 210 mL of acetic acid and 13.4 mL (104.5 mM) of boron trifluoride etherate. The solution is poured over 650 mL of water and the pH is adjusted to 3.0 with

Sodium bicarbonate is used. The precipitated crystals are separated by filtration, and the mixture is dried at room temperature under reduced pressure. 7.6 g (65.5%) of 2-(2-amino-4-thiazolyl)-2-[[(Z)-l-[2-(trimethylsilyl)ethoxycarbonyl]-l-methylethoxy3-imino]acetic acid with a boiling point of 155°C (dec.) is obtained. (The compound contains 3.3% water.) After dispersing the compound (twice) in 50 mL of dry acetonitrile and concentrating the solvent, the water content after drying at room temperature (16 h under reduced pressure - 0.1 mm Torr) drops to 0.22%.

e) 10.9 g (22.2 mMoles) of 2-(2-amino-4-thiazolyl)-2-[[(Z)-l-[2-(trimethylsilyl)ethoxycarbonyl]-l-m-ethylethoxy Jimino]-acetic acid is dispersed in 195 ml of acetonitrile o

(dried with a 3A molecular sieve) and mixed while stirring with 4.09 mL (37.1 mM) of N-methylmorpholine, followed by 11.7 g (35 mM) of 2,2-di-thio-bis-benzothiazole and 6.7 mL (39.7 mM) of triethylphosphite. After stirring for 1 h at room temperature, the resulting light yellow solution is concentrated to dryness. The amorphous residue is purified by flash chromatography on silica gel (hexane-ethyl acetate 4:1) and the pure fractions are crystallized on acetonitrile. 4.6 g (30%) of 2-benzthiazolyl-thioester of 2-(2-amiiro-4-thiazolyl)-2-[[(Z)-l-[2-(trimethylsilyl)-ethoxycarbonyl]-1-methyl-ethoxy]imino]-acetic acid is obtained at Pf 92°C (dec.).

Example 22

a) 201 mg (0.38 mM) of 2-benzthiazolyl thioester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(p-nitrobenzyloxycarbonyl)-methoxy]-imino]-acetic acid and 85 mg (0.38 mM) of rac-cis-3-amino-4-(methoxycarbonyl)-2-oxo-1-azetidinesulfonic acid are suspended in 1.9 mL of absolute acetone and mixed with 0.11 mL (0.79 mM) of triethylamine. The mixture is shaken for 3 h at room temperature and then concentrated. DCCC (countercurrent chromatography) is performed.

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with ascending droplets of the CHC1 mixture ^ : MeOH : h^O. = 7:13:8). The fractions of interest are collected, concentrated, and lyophilized. 56 mg (21%) of triethyl- , amino salt of rac-cis-3-[2-(2-amino-4-thiazolyl)-2-[[( Z)-5 (p-nitrobenzyloxycarbonyl)methoxyimino ]acetamido ]-4-methoxy-

carbonyl-2-oxo-1-azetidinesulfonic acid.

NMR (D20,fçm)i, 26 (t, J=7, 0, 9H), 3.18 (q,J=7.0.6H), 3.71 (s,3H), 4.88 (s,2H), 4.96 (d,J=6.0, 1H), 5.31 (s,2H), 5.64 (d,J=6.0, 1H), 6.89 (s,lH), 7.50 (d,J=8.5, 10 2H), 8.07 (d,J=8.5, 2H)

IR (Kar,an-1): 334 0 (56%), 1756 (26%), 1682 (43%), 1609 (46%), 1348 (28%), 1281 (22%), 1213 (25%), 1046 (23%)

C19H18N6°12S2 + C6H15N <687.696)

15 Cal.: C 43.66 H 4.84 N 14.26 S 9.32%

Tr.: C 43.70 H 4.80 N 14.24 S 9.30%

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

20 b) 6.1 g (25 mMoles) of t-butylester of the acid are dispersed

2-(2-amino-4-thiazolyl)-2-(Z)-hydroxyiminoacetic acid in 250 ml of dry acetonitrile. Then, 13.7 g (50 mM) of 4-nitrobenzyl ester of bromacetic acid and 12.9 ml (75 mM) of N-ethyldiisopropylamine are added, stirring at room temperature. 5 minutes later, 7.5 g (50 mM) are added.

sodium iodide. The reaction mixture is stirred for 3 h in an argon atmosphere at room temperature. The solvent is then evaporated, and the residue is diluted with 500 mL of ethyl acetate. The resulting solution is washed 4 times with a total of 2 liters of water. The water is extracted with 300 mL of ethyl acetate, and the acetate solutions are dried.

S

70

t of ethyl on sodium sulfate and concentrate until dry. After crystallization from ethyl-hexane acetate, 8.2 g (15%) of t-butyl ester of 2-(2-amino-4-thiazolyl)-2-[[(p-nitrobenzyloxycarbonyl)-methoxy]-imino]-5 acetic acid is obtained at 146.8°C (dec.).

c) 5.0 g (11.4 mMoles) of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(p-nitrobenzyloxycarbonyl)-methoxy ]-imino]-acetic acid is stirred in 86 mL of acetic acid and mixed with 5.2 mL (38.4 mMoles) of trifluoride ether of

10 boron. The resulting solution is stirred for 5 hours at room temperature and then poured over 260 ml of water. The precipitate is separated by filtration and dried at 40°C under reduced pressure. 3.5 g (80%) of 2-(2-amino-4-thiazolyl)-2-[[(p-nitrobenzyloxycarbonyl)-methoxy]-imino]-15 acetic acid is obtained. P^ approximately 175°C (dec.).

d) 1.9 g (0.5 mMole) of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(p-nitrobenzyloxycarbonyl)-methoxy]-imino]-acetic acid is dispersed in 30 ml of acetonitrile (dried with a molecular sieve)

O

3 A cular). This suspension is mixed with 1.4 mL 20 (12.7 mMoles) of N-methylmorpholine while stirring, then with

2.0 g (6.0 mMoles) of 2,2-dithio-bis-benztriazole and 1.14 mL (6.7 mMoles) of triethylphosphite. After stirring for 1 h at room temperature, the reaction mixture is cooled to 0°C and filtered. The filtrate is concentrated, and the residue is crystallized from methylene chloride.

1.03 g (39%) of 2-benzthiazolyl-thioester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(p-nitrobenzyloxycarbonyl)-methoxy]-imino]-acetic acid is obtained at P^ 124-126°C.

Example 23

30. 343 mg (0.5 mMole) of triethylamine salt of rac-cis-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[C(p-nitrobenzyloxycarbonyl)-methoxyimino jacetamido]-4-methoxycarbonyl-2-oxo-l-azetidinesulfonic acid is dissolved in 20 ml of

'71

methanol and hydrogen for 3 h at room temperature with 230 mg of 5% palladium/kieselgur in a hydrogen atmosphere. The catalyst is removed by filtration and the solution is concentrated. The residue is absorbed into a small amount of saturated aqueous sodium carbonate solution and chromatographed on Amberlite XAD-2 (eluent: water, then 30% ethanol in water). After lyophilization, 120 mg (51%) of the sodium salt of rac-cis-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxymethoxyimino)acetamido]-4-methoxy-10 carbonyl-2-oxo-l-azetidinesulfonic acid is obtained.

IR (KBr, cm-1): 1775, 1730.

Example 24

265 mg (0.5 mM) of 2-benzthiazolyl thioester of (Z)-2-(2-amino-4-thiazolyl-15-zolyl)-2-[[(p-nitrobenzyloxycarbonyl)-methoxy]-imino]acetic acid and 104 mg (0.5 mM) of (3S,4S)-3-amino-4-carbamoyl-2-oxo-1-azetidinesulfonic acid are suspended in 2.5 mL of absolute acetone and mixed with 0.15 mL (1.1 mM) of triethylamine. After 30 minutes, the suspension dissolves to give a yellow solution. After 24 h at room temperature, the residue is concentrated and chromatographed by DCCC (countercurrent chromatography with rising droplets in a CHCl₂:MeOH mixture, fr₂O = 7:13:8). The fractions of interest are concentrated and lyophilized. 0.139 g 25 (41%) of triethylamine salt of (3S,4S)-3-[(Z)- acid is obtained.

2-(2-amino-4-thiazolyl) — 2— C C(p-nitrobenzyloxycarbonyl)-methoxyimino]acetamido]-4-carbamoyl-1-2-oxo-1-azetidinesulfonic.

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NMR (D2Of 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%)

C18H17N701;LS2 + C6H15N (672,698)

Cal.: C 42.85 H 4.80 N 16.66 S 9.53 H20%

Tr.: C 41.22 H 4.81 N 16.13 S 9.45 H20 1.84%

Example 25

336 mg (0.5 mM) of triethylamine salt of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(p-nitrobenzyloxycarbonyl)-methoxyimino]acetamido]-4-carba-15 moyl-2-oxo-l-azetidinesulfonic acid is dissolved in 20 mL of methanol and hydrogenated for 3–4 h at room temperature with 150 mg of 5% palladium on diatomaceous earth. The catalyst is removed by filtration and the solution concentrated. The residue is dissolved in a small amount of saturated aqueous sodium bicarbonate solution and chromatographed on Amberlite XAD-2 (eluent:

water, then 40% ethanol in water). After lyophilization, 150 mg (65%) of sodium salt of (3S,4S)-3 — [(Z)—2—(2-amino-4-thiazolyl) — 2 — C(carboxymethoxy)imino]-acetamido 3-4-carbamoyl-2-oxo-1-azetidinesulfonic acid is obtained.

25 IR (KBr,cm-1): 3421, 1769, 1731, 1690.

Example 26

a) 1.62 g (6.20 mMoles) of the sodium salt of (3S,4S)-3-amino-4-carbamoyloxy-methyl-2-oxo-1-azetidine-sulfonic acid is dissolved in 180 ml of acetone-water (2:1) and treated with

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3.27 g (6.83 mM) of 2-benzthiazolyl thioester of (Z)-2-(2-amino-4-thiazolyl)-2-Cl-(t-butoxycarbonyl)-1-methylethoxymino)-acetic acid. The reaction mixture is stirred for 12 h at room temperature. A further 60 mg (0.12 mM) of the latter compound is added, and stirring continues for another 3 h. The acetone is withdrawn under reduced pressure, and 50 mL of water is added. The resulting crystals are separated by filtration and washed with a little water. The stock solution is partially concentrated (37°C, 15 mmHg) and analyzed by chromatography (MCI gel, F₂O). After lyophilization, 2.28 g (77%) of the sodium salt of the acid is obtained. (3S,4S)-3-[2-amino-4-thiazolyl)-2-(Z)-[[1-(t-butoxycarbonyl)-l-methylethoxyjimino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulfonic acid.

15. _i

IR (KBr, cm): 1766, 1723, 1683, 1617, 1531, 1458,

1369

NMR (DMSO, ppm): 1.35 (15H,s), 4.0-4.15 (3H,H4 &fc CH2~

OCONH2) » 5.25 (lH,dd,H3), 6.5 (2H,large,

20

CONH2), 6.7 (1H,s,H-Thiazol), 7.25 (2H,s,NH2), 8.9 (1H,d,CO-NH).

The sodium salt of (3S,4S)-3-amino-4-carbamoyloxymethyl1-2-oxo-1-azetidinesuifonic acid used as a starting material can be prepared as follows:

25 b) To a solution, stirred at room temperature, of

0.9 g (5.4 mMoles) of 2,4-dimethoxybenzylamine in 100 ml of methylene chloride, 3 g of molecular sieve added

O

4 A and after 20 minutes, 0.7 g (5.4 mMoles) of isopropyl-idene-L-glyceraldehyde and 5 g of anhydrous magnesium sulfate 30. Then, shake for another 1 minute at room temperature.

ambient temperature. The organic solution of isopropylidene-L-glyceraldehyde-(2,4-dimethoxybenzyl)imine is cooled to -20°C under argon and, with stirring, mixed with 0.88 ml

1

(5.4 mMoles) of triethylamine. A solution of 1.25 g (5.6 mMoles) of β-taloylglycyl chloride is then added dropwise over 1 h to 20 mL of dry methylene chloride, and the mixture is stirred overnight at room temperature. The reaction mixture is washed three times, each time with 100 mL of water and 100 mL of table salt solution, and dried over sodium sulfate. The residue is concentrated and chromatographed on silica gel (0.062–0.031 mm mesh opening) by eluting with hexane/ethyl acetate (1:1). 1.77 g (70%) of N-[(3S,4S)-cis-1-(2,4-dimethoxy-benzyl)-4-[(R)-2,2-dimethyl-l,3-dioxalan-4-yl]-2-oxo-3-azetidinyl]-phthalimide is obtained in the form of a foam;

[o] = +41° (c = 0.8 in chloroform); SM: 466 (M+).

c) Ch mixes a solution of 149.3 g (0.32 mol) of N-[(3S,4S)-cis-1-(2,4-dimethoxybenzyl)-4-C(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-3-azetidinylphthalimide in 2.5 liters of methylene chloride with 34 mL (0.64 mol) of methylhydrazine. The mixture is shaken overnight at 28°C, the precipitate is separated by filtration, and the filtrate is concentrated under reduced pressure. The residue is absorbed into 1.2 liters of ethyl acetate, and the resulting suspension is filtered. The filtrate is washed three times, each time with 500 mL of water and 500 mL of table salt solution, and dried over sodium sulfate. After concentration of the solvent, 104.3 g (86.8%) of crude (3S,4S)-cis-3-amino-l-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-2-azetidinone is obtained, which is used in further purification in the next step.

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

(3S,4S)-cis-3-amino-l-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone and 104 ml (1.2 Mol) of butylated oxide in 1.5 liters of methylene chloride, dropwise, with 57.6 ml (0.4 Mol) of carbobenzoxychloride,

The mixture is stirred for 1 hour and then concentrated under reduced pressure. The resulting raw material is treated with 2 liters

of dry ether, and a crystalline material is obtained. 122.6 g (84%) of benzyl-(3S,4S)-cis-1-(2,4-dimethoxybenzyl) — 4 — C(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-3-azetidinecarbamate is obtained at 115-116°C; = +48° (c = 0.3 in methanol).

e) A solution of 160 g (0.34 mol) of benzyl-(3S,4s)-cis-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-2-azetidine-carbamate is stirred overnight at 60°C in 1000 mL of tetrahydrofuran and 400 mL of water in the presence of 8 g of p-toluenesulfonic acid. The reaction mixture is neutralized with saturated NaHOC and the tetrahydrofuran is concentrated. The aqueous solution is then extracted with 2 liters of ethyl acetate. After drying on ^£50^ and concentration we obtain 142 g (97.2%) of pure benzyl-(3S,4S)-cis-4-[(R)-1,2-dihydroxyethyl]-l-(2,4-dimethoxybenzyl)-2-oxo-3-azetidinecarbamate, Pf 177-178°C (MeOH).

f) A solution of 142 g (0.33 mol) of benzyl-(3S,4S)-cis-4-[(R)-1,2-dihydroxyethyl]-1-(2,4-dimethoxybenzyl)-2-oxo-3-azetidinecarbamate is mixed dropwise in 1000 mL of tetrahydrofuran, while stirring. This mixture is then stirred for 1 h, filtered, and concentrated under reduced pressure. The residue is absorbed into 400 mL of ethyl acetate and washed twice, each time with 100 mL of water and 50 mL of table salt solution. After drying and concentration, 105 g (87.8%) of pure benzyl-(3S,4S)-cis-1-(2-dimethoxybenzyl)-4-formyl-2-oxo-3-azetidine-carbamate is obtained at P^ 145-147°C (from ethyl acetate/hexane); ta]D = +13.7° (c = 1, CHC13).

g) 4.27 g (113 mMoles) of sodium borohydride is dissolved in 1.6 liters of absolute ethanol and cooled to 0°C. This solution is then mixed dropwise with a solution of

90 g (226 mMoles) of benzyl-(3S,4S)-cis-1-(2,4-dimethoxybenzyl) 4-formyl-2-oxo-3-azetidinecarbamate in 720 ml of ethanol-

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Tetrahydrofuran (1:1) is stirred for 2 h at 0°C, then treated with 350 mL of saturated aqueous sodium sulfate solution and stirred for 45 minutes. After filtration and evaporation of the solvent, the residue is absorbed into 1.5 L of ethyl acetate and washed until a neutral reaction is obtained. After drying over sodium sulfate and partial concentration, crystalline (3S,4S)-cis-3-benzyloxycarboxamido-l-(2,4-dimethoxybenzyl) 4-hydroxymethyl-2-azetidinone is obtained as 72.2 g of colorless crystals (79.6%) with a boiling point of 138°C and a boiling point of +41.6°C.

(c = 1 in methanol).

Elemental analysis: calculated for C21H24N2°6:

C 62.99, H 6.04, N 7.00% found C 62.76, H 6.09, N 6.96%

IR (KBr, cm-1): 1718, 1698, 1615, 1589

NMR (CDCl^, ppm): 2.45 (lH, dd, OH), 3.55-3.75 (3H, large,

CH-CH2-), 3.79 (6H,s,2xOCH3), 4.35 " (2H,s,N-CH2), 5.08 (2H,s,0-CH2), 5.11 (lH,dd,5 and 9 Hz,H3), 6.06 (lH,d, 9Hz,NH), 6.43 (2H,m,Ar), 7.15 (1H,m,Ar), 7.31 (5H,m,C6H5)

SM: 292 (M-BzOH).

h) A solution of 30 g (74.9 mM) of (3S,4S)-cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-hydroxy-methyl-2-azetidinone in 600 mL of methylene chloride at 0-5°C is treated with 21.22 g of chlorosulfonyl isocyanate (2 equivalents). After 15 minutes, the reaction mixture is added dropwise to an aqueous solution, cooled to 5°C, of 20.9 g (2.7 equivalents) of sodium sulfite. The reaction mixture is stirred for 2 h, then diluted with methylene chloride and the organic phase is separated and washed with an aqueous solution of

77

sodium chloride is applied and dried over sodium sulfate for 12 hours. The organic phase is then treated with magnesium sulfate and stirred for another 2 hours. After filtration and evaporation of the solvent, the residue is treated with ether, the resulting crystals are filtered, and the mixture is washed with ether.

We obtain 32.6 g (97%) of (3S,4S)-cis-3-benzyloxycarboxamido-4-carbamoyloxymethyl-l-(2,4-dimethoxybenzyl)-2-azetidinone from 178-179°C, = +84.7° (c = 0.8 in chloroform).

Elemental analysis: calculated for: C22H25N3°7:

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- is heated for 3 h at 95°C in an argon atmosphere.

15

3-benzyloxycarboxamido-4-carbamoyloxymethyl-l-(2,4-dimethoxybenzyl)-2-azetidinone, 14.5 g (53.5 mM) of potassium peroxydisulfate, 13.98 g (80.3 mM) of dipotassium acid phosphate and 1.33 g (5.36 mM) of copper(II) sulfate (SfO) in 270 ml of acetonitrile and

20,130 ml of water, at a pH between 6.5 and 7.0 (with occasional addition of 10 g of dipotassium acid sulfate). After cooling and filtration, the aqueous phase is discarded and the organic phase is concentrated. The residue is absorbed into ethyl acetate and washed with water and a solution

25 grams of table salt. After drying on sodium sulfate,

The solvent is filtered and evaporated; the residue is absorbed into ether and filtered. The crude crystals (8.9 g) are chromatographed on SiO2 (300 g, 40-63 µm, chloroform:methanol ethyl acetate 85:10:5). 5.5 g (70%) of (3S,4S)-cis-3-benzyloxy-carboxamido-4-carbamoyloxymethyl-2-azetidinone is obtained.

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in the form of colorless crystals, [<*3D = +61.2° (c = 1 in methanol). Pf 193-195°C.

Elemental analysis: calculated for

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 and 9Hz,H3), 5.06 (2H,s, 0-CH2), 6.53 (2H,lar.,NH2), 7.35 (5H,s,CgH5), 7.95 (1H,d,9Hz,CH3~ NH-CO), 8.35 (1H,s,NH-CO)

SM (CI with NH3): 251 (M+H)+ -CONH

k) 5.4 g (18.4 mM) of (3S,4S)-cis-3-benzyloxy-carboxamido-4-carbamoyloxymethyl-2-azetidinone is treated in 200 mL of absolute dioxane at room temperature with 4.3 g (1.3 equivalents) of pyridine-sulfur trioxide complex. The resulting suspension is stirred for 3 h, then treated with a further 0.99 g (0.3 equivalents) of pyridine-sulfur trioxide complex and the reaction mixture is stirred for another h. After adding a further 1.37 g (0.4 equivalents) of pyridine-sulfur trioxide complex and stirring for another 2 h, some of the solvent is withdrawn under reduced pressure and the residue is treated with 110 mL of saturated aqueous sodium bicarbonate solution. The resulting brown solution is left to stand for 12 h in a refrigerator and the crystals obtained are separated by filtration. The mother liquor (MCI gel, water-ethanol 1:1 to 9:1) is chromatographed. After lyophilization, 3.5 g (49%) of the sodium salt of (3S,4S)-cis-3-benzyloxycarboxamido-4-carbamoyloxy-methyl-2-azetidinone-l-sulfonic acid is obtained as a colorless powder, Cct]^ = + 29.6° (c = 0.5 in water).

Elemental analysis: calculated for C13H14N3°8SNa:

C 39.50, H 3.57, N 10.63%

found: c 39.41, H 3.45, N 10.36%

— 1

IR (KBr, cm): 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, large,NH2), 7.4 (5H,s,C6H5), 8.0 (1H,d,NH)

1) 3.065 g (7.75 mM) of the sodium salt of (3R,4S)-cis-benzyloxycarboxamido-4-carbamoyloxymethyl-2-azetidinone-l-sulfonic acid is dissolved in 180 mL of absolute methanol and hydrogenated for 1 h in the presence of 1.5 g of 10% palladium on carbon. The catalyst is removed by filtration and the resulting solution is concentrated. 2.02 g (100%) of the sodium salt of (3S,4S)-cis-3-amino-4-carbamoyl-oxymethyl-1,2-oxo-1-azetidinone-l-sulfonic acid is obtained.

IR (KBr, cm-1): 3444, 3207, 1754, 1725, 1611, 1249.

Example 27

2.28 g (3.98 mMol) of sodium salt are treated

1. (3S,4S)-3-[2-amino-4-thiazolyl)-2-(Z)-[[l-(t-butoxycarbonyl)-1-methylethoxy 3-imino 3-acetamido 3-4-carbamoyloxymethyl 2-oxo-l-azetidinesulfonic acid is cooled with ice in 5 mL of trifluoracetic acid. The ice bath is removed, and the reaction mixture is stirred at room temperature for 30 minutes. Excess trifluoracetic acid is removed under reduced pressure (20°C, 15 mmHg), and the resulting oil is treated with 100 mL of ether. The crystals obtained are separated by filtration, washed with ether, and dried under greatly reduced pressure. After aqueous reversed-phase chromatography, 1.51 g is obtained after lyophilization.

80

(76.6%) of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-carboxy-l-methylethoxy]imino]acetamido]-4-carbamoyloxy-methyl-2-oxo-l-azetidine-sulfonic acid; ^a]D = + 35.7° (c = 0.3 in water).

Elementary analysis: calculated for C, .Hn oN^0n nS_:

14 1 o 6 10 2

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 and 9Hz,H3), 6.50 (3H, large, NH3 or COOH, CONf^), 6.90 (lH,s, Thiazol-5H), 9.15 (lH,d,9Hz,CONH)

Example 28

By analogy with example 26, from the 2-benzthiazolyl-thioester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(p-nitrobenzyloxycarbonyl)-methoxy]-imino]-acetic acid and the sodium salt of (3S,4S)-3-amino-4-carbamoyloxy-methyl-2-oxo-1-azetidinesulfonic acid, the sodium salt of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(p-nitrobenzyloxycarbonyl)methoxyimino]acetamido] 4-carbamoyloxymethyl-2-oxo-1-azetidinesulfonic acid is obtained.

Calculated for C19H18N7°12S2Na

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, large,NH2), 6.9 (1H,s,S-CH=0, 7.10 (2H,large,NH2), 7.70 and 8.2 (2x2H, 2d,2x3Hz,Ar), 9.15 (1H,d,9Hz,NHCO)

Example 29

270 mg (0.43 mM) of the sodium salt of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-C[(p-nitrobenzyloxycarbonyl)methoxyimino]acetamido]-4-carbamoyloxy-methyl-2-oxo-l-azetidine-sulfonic acid is dissolved in 30 mL of methanol and hydrogenated over 5% palladium on silica gel (150 mg). The catalyst is separated by filtration and the solvent is evaporated. The residue is absorbed into 2.5 mL of water and washed twice with ethyl acetate. The aqueous phase is chromatographed (reversed phase, water as eluent). 115 mg (54%) of sodium salt of 3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxymethoxy)imino ]acetamido]-4-carbamoyl-loxymethyl-2-oxo-l-azetidine-sulfonic acid is obtained.

Elemental analysis: calculated for C12H13N6°10S2Na

C 29.51, H 2.68, N 17.21%

Found: C 27.09, H 2.35, N 15.33%

IR (KBr, cm"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 and 9Hz,NH-CH), 6.6 (2H,large,NH2), 6.78 (lH,s,S-CH=), 7.13 (2H,s,NH2), 10.90 (1H,d,9Hz,CONH)

Example 30

By analogy with example 26, we also obtain:

a) The sodium salt of (3S,4S)-3-[(5-amino-3-(1,2,4-thiadiazolyl)]-2-(Z)-(methoxyimino)acetamido]-4-carbamoyloxy-methyl-2-oxo-1-azetidine-sulfonic acid.

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Elemental analysis: calculated for c, .H, „N_0oS_Na

1 U 1 c. law.

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,OCH3), 3.90-4.30 (3H,m,

CH-CH2), 5.20 (1 H,dd,6 and 9Hz,NH-CH), 6.35 (2H,s,NH2), 8.10 (2H,s,NH2), 9.04 (lH,d,9Hz,CONH)

? 0

[alsgg = +32.5° (c = 0.4 in water).

The 2-benzthiazolyl-thioester of 2—C(5—amino-3-(l,2,4-thiadiazolyl)]-2-(Z)-methoxyimino-acetic acid used for this purpose as a starting material can be prepared as follows:

b) 2.0 g of 2-(5-amino-3-(1,2,4-thiadiazol-yl)] 2-(Z)-methoxyiminoacetic acid is mixed in 60 mL of acetonitrile at room temperature with 1.3 mL of N-methylmorpholine. After 5 minutes, 3.6 g of dithio-bis-benzthiazole is added, followed by the dropwise addition of 2.2 mL of triethylphosphite in 10 mL of acetonitrile over 1 h. The reaction mixture is stirred for 12 h at room temperature, 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-benzthiazolyl thioester of the acid is obtained. 2-[(5-amino-3-(1,2,4-thiadiazolyl)]-2-(Z)-methoxyimino-acetic acid with a Pf greater than 160°C (dec.).

Example 31

By analogy with example 26, we also obtain: the sodium salt of the acid (3S,4S)-3-C2-amino-4-thiazolyl)-2-(Z)-methoxyimino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-

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azetidine-tallow.

Elemental analysis: calculated for C^H^NgOgS^a

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,OCH3), 4.10 (3H,m,CH-CH2),

5.25 (1H,dd, 4.5 and 9Hz,CH-NH), 6.45 (2H,s,NH2), 6.70 (lH,s,S-CH=), 7.10 (2H,s,NH2), 9.10 (lH,d,9Hz,CONH)

Example 32

a) By analogy with example 26, we also obtain:

the sodium salt of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl )-2-(methoxyimino)-acetamido]-4-carbamoyl-2-oxo-1-azeti-dine-sulfonic acid.

Elemental analysis: calculated for c10H1LN6°7S2Na

C 28.99, H 2.68, N 20.68% found: C 31.20, H 3.26, N 16.41%

IR (KBr, cm-1): 3282, 1790, 1640, 1612, 1527, 1260,

1230

NMR (DMSO, ppm): 3.85 (3H,s,OCH3), 4.3 (lH,d,6Hz,

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

The sodium salt of (3S,4S)-cis-3-amino-4-carbamoyl-2-azetidinone-l-sulfonic acid used for this purpose can be prepared as follows:

b) 17 g (42.7 mMoles) of benzyl-(3S,4S)-cis-1-(2,4-dimethoxy-benzyl-4-formyl-2-oxo-3-azetidine-carbamate is dissolved in 100 mL of methylene chloride and 100 mL of n-propanol. This solution is mixed with 3.5 g of hydrochloride

d1-hydroxylamine (50.3 mM), followed by 4.2 mL of pyridine (52 mM). The reaction mixture is heated for 2 h under reflux conditions. The methylene chloride is then separated by distillation, and a solution of 6.3 g of selenium dioxide (57 mM) is added dropwise.

in 100 mL of n-propanol. The reaction mixture is heated under reflux for 2 h, cooled to room temperature, and the resulting solution is filtered and concentrated under reduced pressure. The oil obtained is dissolved in 100 mL of n-propanol and concentrated. This process is repeated twice. The resulting partially crystalline residue is absorbed into 250 mL of methylene chloride and washed twice successively with 200 mL of water and table salt solution.

After drying over sodium sulfate, filtration, and evaporation of the solvent, the residue is absorbed into 70 mL of n-propanol. The solution is left to stand for 12 h in a refrigerator. 16.4 g (97%) of benzyl-(3S,4S)-cis-1-(2,4-dimethoxybenzyl)-4-cyano-2-oxo-3-azetidine-carbamate is obtained at 152-153°C. (C = 1 in chloroform)

SM: 395 (M+).

c) 15.72 g of potassium peroxide sulfate (58.2 mMoles) and 9.5 g of potassium acid sulfate (54.8 mMoles) 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 sulfate in 10 ml of water. The resulting suspension is diluted with 180 mL of acetonitrile and treated dropwise with a solution of 14.4 g of benzyl-(3S,4S)-cis-1-(2,4-dimethoxybenzyl-4-cyano-2-oxo-3-azetidine-carbamate in 300 mL of acetonitrile. The reaction mixture is heated for 2 h under reflux conditions, then cooled, filtered, and partially concentrated. The resulting oily aqueous solution is extracted with ethyl acetate, and the organic phase is washed three times successively with a

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A saturated aqueous solution of sodium bicarbonate, water, and table salt was prepared. After drying and evaporation of the solvent, the resulting oil was chromatographed on silica gel (0.062–0.031 mm mesh opening, eluent ethyl acetate:n-hexane 1:1). 6.1 g (68.3%) of benzyl-(3S,4S)-cis-4-cyano-2-oxo-3-azetidine-carbamate was obtained at a boiling point of 163–165°C.

SM: 245 (M+).

d) 6.16 g (25 mM) of benzyl-(3S,4S)-cis-4-cyano-2-oxo-3-azetidine-carbamate is dissolved in 45 mL of dimethyl sulfoxide and treated with 5.58 mL of 30% aqueous hydrogen peroxide. When the temperature has returned to 25°C, the mixture is treated with 5 mL of 1 N aqueous sodium hydroxide solution. The temperature rises to 55°C. After stirring for 40 minutes, a precipitate appears. 20 mL of ethyl acetate is added, and the resulting crystals are separated by filtration. 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-

10

20

30

carbamate of Pf 248-249°C. Ca]D = +13* (c = 1 in dimethyl sulfoxide).

The mother liquor is partially evaporated, and a further 0.33 g of product is isolated. This mother liquor is then diluted with water and analyzed by MCI gel chromatography (ethanol-water 3:7 as the eluent). The total yield of the final product is 3.0 g (45.4%).

e) 7.9 g (30 mM) of benzyl-(3S,4S)-4-carbamoyl-2-oxo-3-azetidine-carbamate is dispersed in 470 mL of absolute dioxane and treated with 6.2 g (39 mM) of pyridine-sulfur dioxide complex. The resulting suspension is stirred for 2 h at room temperature, then treated with 1.41 g (8.8 mM) of pyridine-sulfur dioxide complex and stirred for another h. After adding 1.90 g (12 mM) of pyridine-sulfur dioxide complex

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After stirring for another 2 hours, the solvent is concentrated under reduced pressure and the residue is absorbed into 200 mL of water. The resulting aqueous solution is treated with 15 g (44.24 mM) of tetrabutylammonium acid sulfate. This aqueous solution is extracted twice, each time with

250 mL of methylene chloride is dissolved, then dried over sodium sulfate. After evaporating the solvent, the resulting oily residue is dissolved in 150 mL of absolute methanol and hydrogenated over 2.5 g of 10% palladium on activated carbon. The catalyst is separated by filtration, and the solution is concentrated and then redissolved 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. This yields 2.3 g (36%) of (3S,4S)-3-amino-15-4-carbamoyl-2-oxo-l-azetidine-sulfonic acid. The mother liquor is chromatographed on silica gel (eluent: water-ethanol 1:0 to 9:1), yielding 420 mg of product. Total yield 2.7 g (43.3%).

20

IR (KBr f cm-1): 1779, 1696, 1633, 1485, 1288, 1250

NMR (DMSO, ppm): 4.43 and 4.72 (2x lH, 2d, 6Hz, CH-CH),

7.88 (2H,d,lar, • NH2), 8.59 (3Hlar.,

NH* ) •

Example 33

By analogy with example 32 or example 26 25 we also obtain the sodium salt of the acid (3S,4S)-3-[( Z)- 2-[[5-amino-3-(l,2,4-thiadiazolyl)]-2-[methoxyimino]acetamido]-4-carbamoyl-2-oxo-1-azetidine-sulfonic .

°t!

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Analysis: calculated for CgH1C)N7O7S2Na

C 26.03, H 2.43, N 23.61%

Found: C 26.02, H 2.59, N 23.32%

IR (KBr cm"1): 3424, 3334, 1776, 1688, 1618, 1524,

1278

NMR (DHSO, ppm): 3.9 0 (3H, s, OCH3), 4.4 5 (lH, d, 6 Hz,

ÇH-CONH2), 5.40 (lH,dd,6 and 9Hz,NH-CH), 7.30 (2H,lar. » NH2), 8.10 (2H,lar., NH2), 8.8 (lH,d,9Hz,NH-CO).

Example 34

By analogy with example 32 or examples 26 and 27, we also obtain

1'acid (3S,4S)-3[(Z)-2-[2-amino-4-thiazolyl)-2-[[1-carboxy-l-methylethoxy]imino]acetamido]-4-carbamoyl-2-oxo-l-azetidine-sulfonic.

Elemental analysis: calculated for 13H16N6°9S2

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 (lH,d,6Hz,

ÇH-CONH2), 5.33 (1H,dd,6 and 9Hz,NH-CH-), 6.96 (lH,s,S-CH=), 7.40 (2H,lar., d, 7HZ,C0NH2), 8.95 (lH,d,9Hz,CONH) UV (EtOH): 292 nra (6846), 240 nm (12232).

88

10

Example 35

a) By analogy with example 32, from (3S,4S)-3-amino-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-1-azetidinesulfonic acid and the 2-benzthiazolyl-thioester of 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino-acetic acid, the sodium salt of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-acetamido]-4-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-oxo-1-azetidine-sulfonic acid is obtained.

IR (KBr, cm-1): 3429, 3345, 1770, 1673, 1620, 1531,

1253

NMR (DMSO, ppm): 1.23 and 1.33 (2x3H,2s,2xCH3), 3.83

(3H,s,OCH3), 3.8-4.15 (4H,m,CH-CH-CH2~), 5.22 (lH, dd, 5, 5 and 9Hz,NH-ÇH_), 6.75 (lH,s,S-CH=), 7.19 (2H,lar., NH2), 8.68 15 (lH,d,9Hz,NH-CO).

b) 740 mg (1.57 mM) of the sodium salt of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-acetamido]-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-1-azetidine-sulfonic acid is dissolved in 40 mL of methanol-water (1:1) and stirred for 12 h in the presence of 15 g of Arnberlite IR 120

(previously washed in methanol). The catalyst is separated by filtration and the solvent is concentrated. 300 mg (0.7 mMole, 44%) of sodium salt of (3S,4S)-2-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-25 acetamido]-4-[(R)-1,2-dihydroxyethyl 3-2-oxo-1-azetidine sulfonic acid is obtained.

Elemental analysis: calculated for ClH14N5°8S2Na

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

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IR (KBr, cm"1): 3290, 1772, 1742, 1678, 1638,

1270, 1227, 1045 NMR (DMSO, ppm): 3.2-4.15 (4H,m,CH-CH-CH2), 3.52

(3H,s,OCH3), 5.19 (1H,dd,6 and 9Hz, NH-CH), 6.98 (lH,s,S-CH=), 7.1 (4H,larNH2,2xOH), 9.23 (lH,d, 9Hz, CONH).

c) From the sodium salt of (3S,4S)-2-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-[(R)-1,2-10 dihydroxyethyl]-2-oxo-l-azetidine-sulfonic acid, by analogy with example 26, we obtain the sodium salt of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-acetamido]-4-formyl-2-oxo-1-azetidine-sulfonic acid.

15

20

Elemental analysis: calculated for C^qH^pN^07S2Na

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

IR (KBr, cm-1): 3177, 1771, 1636, 1524, 1271

NMR (DMSO, ppm): 3.93 (3H,s,OCH3), 4.30 (lH,dd,4.0 and

6Hz,CH-CHO), 5.14 (lH,dd,6.0 and 8.0Hz, NH-ÇH), 5.5 (2H,lar., NH2), 6.77 (lH,s, S-CH=), 9.61 (lH,d,8Hz,NH-CO), 9.65 (1H,d,4.0Hz, CHO).

d) Ch dissolves 400 ml (1 mMole) of sodium salt of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-

O c acetamido]-4-formyl-2-oxo-l-azetidine-sulfonic acid is dissolved in 400 ml of methanol and treated with 100 mg (1.4 mM) of hydroxylamine hydrochloride and 0.1 ml (1.24 mM) of pyridine. After stirring for 2 h, the reaction mixture is concentrated and the product is analyzed by gel chromatography.

30 of silica (0.062-0.031 mm mesh opening, methanol:

ethyl acetate 3:7 as the eluent). Chromatography then

The partially purified product is prepared on MCI gel (water as eluent). 45 mg (10%) of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-[(E/Z)-(hydroxyimino)methyl]-2-oxo-1-azetidine-sulfonic acid is obtained.

Elemental analysis: calculated for: C10^11

N607S2Na C 28.99, H 2.68, N 20.28% found: C 30.06, 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 (lH,dd,5.5et

8.0Hz,CH-CH=), 5.22 (lH,dd,6 and 9Hz, NH-CH), 6.57 (1H,s,S-CH=), 7.18 (2H, width, NH2), 7.32 (lH,d,8.0Hz,CH=N), 9.29 (lH,9Hz,NH-CO), 11.0 (lH,s,CH).

L1 acid (3S,4S)-3-amino-4-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-2-oxo-l-azetidine-sulfonic acid used as a starting compound can be prepared as follows:

e) 0.25 g (0.78 mM) of benzyl-(3S,4S)-cis-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-3-azetidine-carbamate is dispersed in 4 mL of pyridine and treated with 0.5 g (3.1 mM) of sulfur trioxide-pyridine complex. The reaction mixture is heated for 1 h. The solution is cooled and then treated with 50 mL of ether. The ether is separated by decantation, and the residue is mixed with 300 mL of water. The solution is stirred at room temperature for 12 h in the presence of a Dowex 50 W ion exchanger (Na form). The ion exchanger is separated by filtration, and the solution is concentrated under reduced pressure. 325 mg (100%) of sodium salt of crude (3S,4S)-cis-3-benzyloxy-formamido-3-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-2-oxo-1-azetidinesulfonic acid is obtained.

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IR: (KBr cm"1): 3329, 1775, 1724, 1698, 1526,

1257.

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

4.4 (4H, m, CH-CH-CH2), 4.99 (lH, dd, 6 and 10 Hz, NH-CH), 5.15 (2H, s, N-CH2), 7.45 (5H, s, C, Hc), 7.5 (lH, d, 10 Hz, CONH).

D ->

f) Hydrogenating the sodium salt of (3S,4S)-cis-3-benzyloxyformamido-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-

2-oxo-l-azetidinesulfonic acid by analogy with example 33 10 with palladium-carbon, and we obtain the (3S,4S)- acid

3-amino-4-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-2-oxo-1-azetidinesulfonice.

Example 36

a) From the acid (3S,4S)-3-amino-4-methoxyimino-

15-methyl-2-oxo-l-azetidinesulfonic acid and 2-benzthiazolyl-

thioester of 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyiminoacetic acid, we obtain by analogy with example 1 the sodium salt of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-acetamido]-4-methoxyimino-methyl-20 2-oxo-l-azetidinesulfonic acid.

Elemental analysis:

Cn,H-_Nc0_SoNa Cal.: C 30.84, H 3.06, N 19.62%

1 i 1 o b //

25

Tr.: C 30.88, H 3.19, N 19.52%

-1,

cm):

1532, 1274.

IR: (KBr cm -1): 3424, 3336, 1772, 1671, 1622,

The (3S,4S)-3-amino-4-methoxyiminomethyl-2-oxo-l-azetidinesulfonic acid used as a starting compound can be prepared as follows:

92

b) 3.0 g (7.5 mM) of benzyl-(3S,4S)-[1-(2,4-dimethoxybenzyl)-4-formyl-2-oxo-3-azetidinyl]carbamate is dissolved in 40 ml of methylene chloride and treated with 0.7 g (8.5 mM) of O-methylhydroxylamine hydrochloride and

5. 0.73 mL (9.0 mMoles) of pyridine. The reaction mixture is stirred for 2 days at room temperature and then washed with water and a salt solution. After drying over sodium sulfate and evaporation of the solvent, the material is chromatographed (0.062–0.031 mm aperture, 10 mesh, ethyl acetate:-n-hexane 6:4). 2.6 g (82%) is obtained.

of benzyl-(2S,4S)-l-(2,4-dimethoxybenzyl)-4-[(methoxyimino)-methyl]-2-oxo-3-azetidinecarbamate (mixture of E/Z isomers):

IR (KBr, cm-1): 3290, 1772, 1686, 1210 15 Sri: 319 (M-0-CH2OH).

c) 11.9 g of potassium peroxydisulfate (44 mMoles) and 9.6 g of dipotassium acid phosphate are dispersed in 100 mL of acetonitrile and 350 mL of water. The mixture is heated to 78°C and a solution of 11.8 g (27.6

20 mM of benzyl-(3S,4S)-1-(2,4-dimethoxybenzyl)-4-[(methoxyimino)methyl]-2-oxo-3-azetidinecarbamate (mixture of E/Z isomers) in 300 mL of acetonitrile. Adding dipotassium phosphate maintains the pH of the solution at 7.

After boiling for 6 h, the reaction mixture 25 is cooled, the aqueous phase is discarded, the organic phase is diluted with ethyl acetate, and the mixture is washed successively with water, an aqueous solution of sodium bicarbonate, and a solution of table salt. After drying over sodium sulfate, the solvent is evaporated, and the crude mixture (0.062-0.031 mm mesh opening, ethyl acetate:n-hexane 8:2) is chromatographed, yielding 1.7 g (27% of benzyl-(3S,4S)-4-[(methoxyimino)methyl]-2-oxo-3-azetidinecarbamate (mixture of E/Z isomers)). Melting point 170-171°C.

30

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

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

5 with 1.26 g (7.9 mMoles) of sulfur dioxide complex-

pyridine and stir for 1 h at room temperature. After adding another 0.29 g (1.8 mM) of sulfur trioxide-pyridine complex, the suspension is stirred for another 1 h. After adding 0.39 g (2.45 mM) of sulfur trioxide-pyridine complex and stirring for another

At 1 h, the solvent is concentrated under reduced pressure, and the residue is treated with 30 mL of saturated aqueous sodium bicarbonate solution. The resulting aqueous solution is extracted twice with ethyl acetate, and the organic phase is discarded. The aqueous phase is concentrated to 10 mL and analyzed by chromatography (MCI gel; 1% orethanol 1:0 to 9:1 to 7:3). 1.36 g (58.5%) of (3S,4S)-3-[(benzyloxy)-formamido]-4-[(methoxyimino)methyl]-2-oxo-l-azetidine-sulfonic acid (a mixture of E/Z isomers) is obtained.

20 Elemental Analysis:

C13H14N3°7SNa Cal* C 41'16' H 3>72' N i1/08 %

Tr.: C 40.21, H 3.81, N 10.12%

IR (KBr, cm"1): 3396, 3347, 1774, 1708, 1256

e) Hydrogenating (3S,4S)-3-[(benzyloxy)formamido]-25 4-[(methoxyimino)methyl]-2-oxo-l-azetidine-sulfonic acid by analogy with the last paragraph of example 26. This gives (3S,4S)-3-amino-4-methoxy-imino-methyl-2-oxo-l-azetidine-sulfonic acid.

30

Example 37

By analogy with example 1, we obtain from the acid (3S,4S)-3-amino-4-methoxyiminomethyl-2-oxo-l-

94

azetidine-sulfonic acid (mixture of E/Z isomers) and of

2-benzthiazolyl thioester of 2-[(5-amino-3-(1,2,4-thiadiazolyl)]-2-(Z)-methoxyiminoacetic acid, as the final product the sodium salt of (3S,4S)-3-[(5-amino-

3-(l,2,4-thiadiazolyl)]-2-(Z)-(methoxyimino)acetamido]-4-methoxy-iminomethyl-2-oxo-l-azetidinesulfonic acid.

Elemental analysis:

C10H12N7°7S2Na Cal": C 27'97' H 2'82' N 22>84> S 14'93

Tr.; C 28.50, H 3.37, N 24.07, S 14.79

IR (KBr, cm-1): 3419, 1771, 1671, 1622, 1523, 1278

Example 38

a) 378 mg (2.1 mM) of (3S,4R)-3-amino-4-methyl-2-oxo-l-azetidinesulfonic acid is dissolved in 60 mL of acetone/water 1:1 and treated with 1.3 g (2.3 mM) of 2-benzthiazolyl thioester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(p-nitro-benzyloxycarbonyl)-l-methylethoxy]imino]acetic acid and 176 mg (2.1 mM) of sodium bicarbonate. The reaction mixture is stirred for 12 h at room temperature. The acetone is evaporated under reduced pressure and the residue is filtered. The resulting aqueous solution is concentrated. 115 mg (10%) of sodium salt of (3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[C1-(p-nitro-benzyloxycarbonyl)-1-methylethoxy]-imino]acetamido]-

4-methyl-2-oxo-l-azetidinesulfonic acid in the form of an amorphous substance.

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

1236

NMR (DMSO, ppm): 1.24 (3H,d,J=6Hz,CH-CH3), 1.46 and 1.50

(2x3H,2 s,(CH3)2C), 3.99 (1H,m,CH-CH3), 5.10 (1 H,dd,J=6 and 9Hz,NH-CH), 5.33 (2H,s,0-CH2), 6.69 (1 H,s,S-CH=), 7.30 (2H,lar- / NH2), 7.59-8.18 (4H,m,Ar), 9.26 (1H,d,9 Hz,NHCO)

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The 2-benzthiazolyl-thioester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-l-(p-nitrobenzyloxycarbonyl)-1-methylethoxy ]imino ]-acetic acid used above can be prepared as follows:

5 b) 33.0 g (136 mMoles) of t-butyl ester of the acid are dissolved

2-(2-amino-4-thiazolyl)-2-(Z)-hydroxyiminoacetic acid in 500 mL of dimethylformamide. After adding 85.4 g (272 mM) of 4-nitrobenzyl ester of 2-bromo-2-methylpropionic acid and 75.2 g (544 mM) of finely powdered potassium-10 carbonate, the reaction mixture is stirred for 5 h at 45°C in a nitrogen atmosphere. The reaction mixture is cooled to room temperature and poured into a mixture of 5 L of water and 2.5 L of ethyl acetate. The organic phase is washed 3 times with a total of 2.5 L of water. The water is extracted with 2.5 L of ethyl acetate. The combined ethyl acetate solutions are dried on sodium sulfate and concentrated to dryness. 42 g (66.4%) of 150.3°C 2-(2-amino-4-thiazolyl)-2-[[(Z)-(p-nitrobenzyloxycarbonyl)-1-methyl-20 ethoxy]imino]-acetic acid is obtained.

c) 23.4 g (50.4 mM) of β-butyl ester of 2-(2-amino-4-thiazolyl)-2-[C(Z)-1-(p-nitrobenzyloxycarbonyl)-1-methylethoxy]imino]acetic acid is dispersed in 60 mL of trifluoroacetic acid and stirred for 30 minutes at room temperature. The resulting solution is concentrated, the residue is dissolved in 200 mL of toluene, and the solution is concentrated again. After the addition of 700 mL (280 mM) of a 0.4 M aqueous sodium bicarbonate solution, the pH is adjusted to 3.8 with acetic acid. The precipitated crystals are separated by filtration, and the solution is dried under reduced pressure (0.05 mm) at 50°C. 17.3 g (84%) of 2-(2-amino-4-thia-zolyl)-2-[[(Z)-l-(p-nitrobenzyloxycarbonyl)-1-methylethoxy]-imino)-acetic acid is obtained at Pf 194°C (dec.).

25

30

The water content of the product is lowered by suspending it twice in 100 ml of dry acetonitrile each time and evaporating the solvent, then drying it for 20 h at room temperature under reduced pressure (0.1 mm), down to 0.26%, which is of interest for the following reaction.

d) 16.4 g (40.2 mMoles) of 2-(2-amino-4-thiazolyl)-2-[[(Z)-l-(p-nitrobenzyloxycarbonyl)-1-methylethoxy]imino]-acetic acid is dispersed in 250 ml of acetonitrile (dried

O

(using a 3A molecular sieve). After adding 5.6 mL (50.8 mM) of N-methylmorpholine while stirring, 16.0 g (48 mM) of 2,2-dithio-bis-benzthiazole and 9.2 mL (44.4 mM) of triethylphosphite are added, also while stirring. The resulting suspension is intensely colored yellow. After stirring for 1 h at room temperature, the reaction mixture is cooled to 0°C. The crystals obtained are separated by filtration after 1 h and dried at 50°C under reduced pressure (0.1 mm). 16.1 g (72.2%) of 2-benzthiazolyl-thioester of 2-(2-amino-4-thiazolyl) — 2 — [C(Z)-l-(p-nitrobenzyl-oxycarbonyl)-l-methylethoxy]imino]-acetic acid is obtained at 162-164°C.

Example 39

115 mg (0.19 mM) of the sodium salt of (3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[l-(p-nitro-benzyloxycarbonyl)-1-methylethoxy]imino]acetamido]-4-methyl-2-oxo-l-azetidinesulfonic acid is dissolved in 40 mL of water/tetrahydrofuran 1:1 and hydrogen for 12 h over 300 mL of 10% palladium on carbon. The catalyst is separated by filtration, and the solvent is concentrated under reduced pressure. The resulting oil (0.062–0.031 mm mesh opening, chloroform:methanol:n-propanol:water 4:6:1:4 solvent) is chromatographed. We obtain 28.6 mg (33%) of sodium salt of (3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(l-carboxy-l-methylethoxy)imino]acetamido3-4-methyl-2-oxo-1-azetidinesulfonic acid.

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IR (KBr, cm *): 3297, 2984, 2683, 1763, 1675, 1631,

1535, 1276

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

3.5Hz,CH-CH3), 4.0 (lH,m,CH-CH3), 5.05 (lH,dd,6 and 9Hz,NH-CH), 6.75 (lH,s, S-CH=), 7.20 (3H,lar., NH+), 9.15 (lH,d, 9Hz,CONH).

Example 40

In the same way as described in example 101, we obtain from the acid (3S,4S)-3-amino-4-carbamoyl-

oxymethyl-2-oxo-l-azetidinesulfonic acid and 2-benzthiazolyl thioester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxyimino]-acetic acid, as reaction product the triethylamine salt of (3S,4S)-3-[(Z)-15 2-(2-amino-4-thiazolyl) — 2 — [C(t-butoxycarbonyl)methoxy]-imino]-

Acetamido-4-carbamoyloxymethyl-2-oxo-1-azetidinesulfonic acid is dissolved in ethanol (approximately 4%). By adding an equivalent amount of a 2 N solution of sodium 2-ethylcaproate in ethyl acetate, 2 volumes of acetone, and 4 volumes of diethyl ether, the product is precipitated as a sodium salt.

1h-NMR (DMSO, ppm): 9.15 (d,J=9.5 Hz, 1H); 7.20 (s,lie,

2H); 6.75 (s,1H); 6.46 (slar,2H); 5.28 (dd, J=4 Hz, J=9 Hz, lH); 25 4.53 (s,2H); 4.0-4.3 (m,3H); 1.43

(s,9H).

The 2-benzthiazolyl-thioester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxyjimino]-acetic acid used as a starting material can be prepared as follows:

30 A. 245 g (1.0 Mole) of 2-(2-amino-4-thia-) acid are dispersed

zolyl)-2-(Z)-(hydroxyimino)-acetic acid at room temperature in 2.2 liters of dimethylformamide and mix with

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245 g (1.13 mol) of p-nitrobenzyl bromide and 170 g (1.13 mol) of sodium iodide. The reaction mixture is stirred for 12 h in a nitrogen or argon atmosphere. The resulting brown solution is mixed with 190 mL (1.20 mol) of t-butyl bromacate and 386 mL (2.25 mol) of n-ethyl-

diisopropylamine. After stirring for 1 hour at room temperature, the reaction mixture is poured into 8 liters of water, and the mixture is extracted with 4 liters of ethyl acetate. The ethyl acetate phase is washed with 3 liters of water. The aqueous phases are extracted in two fractions with 5 liters of ethyl acetate. The combined ethyl acetate phases are concentrated to 1 liter and cooled in an ice bath. The crystals that have formed are separated by filtration, washed with cold ethyl acetate and ether, and dried under reduced pressure at 50°C. 248 g (57%) of p-nitrobenzyl ester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid is obtained.

Calculated for C18H2 0N4°7S (436,447):

C 49.54, H 4.62, N 12.84, S 7.35%

20

1t. : C 49.57, H 4.69, N 12.73, S 7.30%.

109 g (0.25 mol) of p-nitrobenzyl ester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid is dispersed in 2 liters of methanol. After the addition of 42 mL (0.30 mol) of triethylamine and 55 g of Raney's 25-nickel, the mixture is stirred in a nitrogen atmosphere for 1 h. 20.5 liters of hydrogen are consumed. The catalyst is removed by filtration through diatomaceous earth, and the filtrate is concentrated. 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 approximately 250 mL of 1 N aqueous hydrochloric acid (pH 3). The resulting crystals are separated by filtration, washed with acetonitrile and water, and dried under

99

The pressure was reduced to 45°C for 16 hours. The resulting crystalline material contained approximately 5% water. Treatment with isopropanol lowered the water content to 0.9%.

In addition, the crystals containing 5% water are dispersed in 5100 ml of dry isopropanol, and the mixture is stirred for 12 hours at room temperature.

ambient temperature and drying for 16 h under reduced pressure at 45°C. 64 g (89%) of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid is obtained.

Calculated for ^11^15^3^5S (301,324 ):

10 C 43.85, H, 5.02, N 13.95, S 10.64%

Tr.: C 43.73, H 5.06, N 13.73, S 10.42 H20 0.89%.

The starting product can also be prepared as follows:

B. 84 g of diketene is dissolved in 250 mL of carbon tetrachloride-15 and cooled to -27°C. The solution becomes cloudy. 71 g of chlorine gas is introduced over 5 h with slow stirring, and the temperature is maintained between -20 and -30°C while cooling. The resulting clear solution is slowly poured, over 1 h, into a solution of 58 g of allyl alcohol-20 in 250 mL of carbon tetrachloride and 80.4 mL of pyridine, stirring between 0 and -5°C. After stirring for a further 15 minutes without cooling, the precipitated pyridine hydrochloride is separated by filtration and washed with 100 mL of carbon tetrachloride. The carbon tetrachloride-25 solution is washed with 2 x 300 mL of water, dried over sodium sulfate, and concentrated under reduced pressure. The residue is distilled. 136 g (77%) of allyl-4-chloroacetoacetate is obtained in the form of a colorless liquid at P, 61-69°C (0.1 mm Hg).

eb

30. 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 for 45 minutes, while stirring and cooling.

10

30

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During the addition, the temperature gradually drops from 0 to -15°C. The mixture is then stirred for 2 hours at -15°C. A pre-warmed solution of 15.2 g of thiourea in 120 mL of water (preheated to 30°C) is mixed with the resulting solution at a rate that maintains the reaction temperature at approximately 30-35°C. After stirring for another 7 hours, the resulting crystalline precipitate is removed by filtration. It is then washed successively with water, acetonitrile, and ether, and crystallized from acetonitrile. 21.8 g (48%) of allylester of 2-(2-amino-4-thiazolyl)-2-(Z)-hydroxyiminoacetic acid (P_184-185) is obtained.

A solution of 20.4 g of allylester of 2-(2-amino-4-thia-zolyl)-2-(Z)-hydroxyimino-acetate in 100 ml of dimethyl tallow and 100 ml of acetone with 30 g of potassium carbonate and 19.5 ml of t-butyl bromacate is shaken for 5 h at room temperature. After evaporating the acetone under reduced pressure (bath temperature 50°C), 600 mL of ethyl acetate is added and the solution is washed with ice-cold water until a neutral reaction occurs. It is then dried and concentrated under reduced pressure. A yellowish crystalline residue is obtained, which is dispersed in diisopropyl ether, filtered, and dried under reduced pressure. This yields 20.1 g (65.5%) of the allylester of 2-(2-amino-4-thiazolyl)■ 2-[[(Z)-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid at Pf 135-136°C.

19 g of allylester of 2-(2-amino-4-thiazolyl)-2-[C(Z)-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid is mixed in 500 mL of ethyl acetate, by stirring, successively with 0.09 g of palladium chloride, 0.46 mL of triethylphosphite, and 30 mL of sodium 2-ethylcaproate solution (2 N solution in ethyl acetate). After stirring for 4 h at room temperature, 500 mL of water and 100 mL of saturated aqueous solution of

sodium bicarbonate. The aqueous solution is separated, washed with 100 mL of ethyl acetate, and acidified to pH 2 with 2 N aqueous hydrochloric acid. The crystalline precipitate is separated by filtration, 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 at 175-176°C (dec.) is obtained.

Other methods for preparing the starting product include:

C. The allylester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxy]-imino]acetic acid is reacted according to B above, but using 0.12 g of palladium acetate instead of palladium chloride. After identical treatment, 14.5 g (86.3%) of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxy]-imino]acetic acid at 171-172°C is obtained.

D. The allylester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid is reacted analogously to C above, but 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 is obtained.

167-169 °C.

E. A suspension of 1.4 g of allyl ester of 2-(2-amino-4-thiazolyl)-2-[C(Z)-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid, 86 mg of palladium carbon, is shaken for 12 h at 60°C

(at 5%), 0.033 mL of triethylphosphite and 2.25 mL of sodium 2-ethylcaproate solution (2 N solution in ethyl acetate) in 50 mL of ethyl acetate. After cooling to room temperature, the reaction mixture is treated according to B above. 0.81 g (65.5%) of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxy 3-imino]-acetic acid is obtained, Pf 174-175°C.

F. 3.41 g of allylester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid is dispersed in 100 mL of ethyl acetate and mixed with 250 mg of triphenylphosphine and 250 mg of tetrakis-(triphenylphosphine)-palladium. The resulting solution is mixed with 5.5 mL of sodium 2-ethylcaproate solution (2 N solution in ethyl acetate). A thick, unstirring slurry quickly forms. After allowing it to stand for 15 minutes at room temperature, it 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 aqueous solutions are brought to pH 2 with 2 N aqueous hydrochloric acid. The crystalline precipitate is separated by filtration and washed successively with water, acetonitrile, and ether. 2.4 g of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid with a boiling point of 167-169°C (dec.) is obtained.

G. 3.41 g of allylester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxy]-imino]-acetic acid is dispersed in 100 mL of ethyl acetate and mixed with 18 mg of palladium chloride and 0.084 mL of triethylphosphite. After the addition of 1.2 mL of N-methylmorpholine, the mixture is shaken for

After 48 hours at room temperature, crystallization may occur. The mixture is left to stand for 4 days, the precipitate is filtered using a filtering funnel, washed with ethyl acetate, and dried under vacuum. This yields 3.52 g of N-methylmorpholine salt of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid.

The crude salt is suspended in 100 ml of dry acetonitrile. 0.49 ml of N-methylmorpholine and 3.32 g of 2,2'-dithiobenzothiazole are added successively while stirring, and the resulting suspension is cooled to 5°C. Over 4 hours, a 2.5 ml solution is then added dropwise.

103

1 ml of triethylphosphite in 30 ml of dry acetonitrile. After stirring for another 30 minutes, the resulting yellow suspension is cooled to -10°C. The crystals are filtered with a filtering funnel and washed with dry acetonitrile and ether. The 2-benzthiazolylthioester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)methoxy]imino]-acetic acid is obtained at 142-143°C (dec.).

54.2 g (180 mM) of 2-(2-amino-4-thiazolyl)-2-[[(Z)-{t-butoxycarbonyl)-methoxy]-imino]-acetic acid is dispersed in 1.4 liters of dry acetonitrile. 29.6 mL (270 mM) of N-methylporpholine is added while stirring, followed by 72.1 g (216 mM) of 2,2'-dithiobisbenzothiazole. The resulting suspension is cooled to 0°C. A solution of 53.8 mL (314 mM) of triethylphosphite in 350 mL of dry acetonitrile is then added over 4 hours. After stirring for another 30 minutes, the resulting yellow suspension is cooled to -10°C. The crystals are separated by filtration and washed with cold acetonitrile and ether. 59.7 g (73.6%) of 2-benzthiazolyl-thioester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid is obtained.

Elemental analysis: calculated for C18H18N4^4S3 (450,561):

C 47.99, H 4.03, N 12.44, S 21.35% found: ^ 47.88, H 4.34, N 12.34, S 21.02%.

Example 41

71.8 g (0.3 mol) of (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidinesulfonic acid is dispersed in 1.5 liters of methylene chloride and mixed with 45.6 g (0.45 mol) of triethylamine and 148.6 g (0.33 mol) of 2-benzthiazolyl thioester of 3-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid] while stirring. The reaction mixture is stirred for 5 h at room temperature. Then, 1.5 liters of water is added, the aqueous phase is separated, and two extractions are performed with 250 ml of

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methylene chloride is added and acidified by adding 850 ml of 37% aqueous hydrochloric acid. After stirring for

After 2 hours at room temperature, the resulting suspension is cooled to 0°C and stirred for another 2 hours. The

5. The precipitate is collected by filtration, then washed successively with 1000 ml of cold water, 1000 ml of methanol, and 1000 ml of ether, and dried for 12 hours at 40°C/10 mmHg. 111 g (79.3%) is obtained.

acid (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxy-

methoxy)-imino ]-acetamido]-4-carbamoyloxymethyl-2-oxo-1-

70

10 crude azetidinesulfonic acid at 207°C, Cclp = -46.2°

(c = 1 in dimethyl sulfoxide).

Elemental analysis: calculated for ^12^14N6^10S2

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 H20 3.61%.

corrected for the anhydrous substance: C 29.29, H 3.53, N 16.79, S 12.72%

The analytical sample yields the following results:

20

20

[ex]D = +39° (c = 1 in water) • corrected for the anhydrous substance + 42.5° (c = 0.9 in water)

20 y

[ CL 3d 43.5° (c = 1 in oxidized Dimethylsul f; corrected for the anhydrous substance -47.4° (c = 0.9 in water).

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I

IR (KBr, cm-1): 3458, 3428, 3354, 3291, 1777, 1712, 1648,

1617, 1557, 1531 *H- NMR (DMSO, ppm): 3.9-4.4 (3H, m, CH-CH2-O), 4.79 (2 H,

s, 0-CH2-C00H), 5.30 (lH, dd, 5 and 9 Hz, NH-CH-CH); 6.5 (6H,iar-, NH3+, NH2, COOH), 6.90 (1H,s, H-Thiazol), 9.45 (lH,d,9 Hz, CO-NH).

Elemental analysis: calculated for p h m r> q •

12 14 6U10 2"

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%

H2O 8.14%

corrected for the anhydrous substance: C 30.91, H 2.74, N 17.90, S 13.5 8%.

Example 42

One hundred and ten hundred pounds (110 g) (0.235 mol) of crude (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxymethoxy)-imino-acetamido]-4-carbamoyloxymethyl-2-oxo-l-azetidinesulfonic acid, obtained according to Example 41, is dispersed in 4.7 liters of methanol and treated with 72.3 mL (0.518 mol) of triethylamine and 282.9 mL (0.566 mol) of a 2 N solution of sodium 2-ethylcaproate in ethyl acetate. The resulting solution is stirred for 10 minutes, diluted with 9 liters of acetone, and concentrated to 3 liters. The remaining suspension is diluted with 3 liters of acetone, filtered, and the crystalline salt is washed with ether and dried. 108.59 g (99.5%) of the disodium salt of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxymethoxy)-imino]-acetamido]-4-carbamoyloxymethyl-2-oxo-l-azetidinesuifonic acid is obtained. This crude salt is dissolved in 420 mL of water. 1050 mL of ethanol is added, followed (after a few minutes) by another 210 mL of ethanol. The solution becomes cloudy and is stirred for 1 hour. Then, 1770 mL of ethanol is added dropwise.

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for 2 h. After further stirring for 1 h and cooling to 0°C, the precipitate is separated by filtration and washed with ethanol. The crystals obtained are dispersed in 170 ml of ethanol and 680 ml of ether, separated by filtration and washed with ether. After drying under greatly reduced pressure and at 40°C, 102.9 g (85.5%) of the disodium salt of (3,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxymethoxy)-imino J-acetamido J-4-carbamoyloxymethyl-2-oxo-1-azetidinesulfonic acid is obtained.

Elemental analysis: calculated for C12H12N6°10S2Na2:

C 28.24, H 2.37, N 16.47, S 12.56% found: C 28.18, H 2.63, N 16.34, S 12.21

H2O 1.02%

corrected for the anhydrous substance: C 28.46, H 2.65, N 16.50, S 12.33%

[a]2^1 = +19° (c = 1 in water)

IR (KBr, cm-1): 1777, 1712, 1648, 1617, 1557, 1417

UV (HpO; X max (e)): 295 nm (6850), 233 nm (12330)

1

H-NMR (d2° » PPm): 4.2-4.8 (5H,m,CH-CH2-0-C0, 0-CH2~

COONa), 5.6 (1H,d,5.5 Hz, 0=C-CH), 7.05 (1H,s, H-Thiazol). ,

Example 43

In the same way as what is said in the example

1. From 191 mg of (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-l-azetidinesulfonic acid and 2-benzthiazolyl thioester, 2-[5-(1-t-butoxyformamido)-3-(1,2,4-thiadiazolyl)]-2-[[(Z)-(t-butoxycarbonyl)-methoxy]-imino]-acetic acid is obtained as a reaction product of 355 mg

107

t of triethylamine salt of acid (3S,4S) — 3 — [(Z)—2—[[(t — butoxycarbonyl)-methoxy]-imino]-2-[5-(l-t-butoxyformamido)-1,2,4-thiadiazol-3-yl]acetamido]-4-carbamoyloxymethyl-2-oxo-

1-azetidinesulfonic acid.

1H-NMR (DMSO, pprn): 9.1 (d, J = 9 Hz, 1H), 6.3 0 (s^ar.2H);

5.24 (dd,J=4 Hz,J=9 Hz,lH); 4.63 (s,2H); 4.0-4.3 (m,3H); 3.04 (q, J=7, 3 Hz, 6H); 1.53 (s.9H); 1.44

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

The 2-benzthiazolylthioester of 2-[5-(1-t-butoxyformamido)-3-[l,2,4-thiadiazolyl)] — 2L L(Z) — (t — butoxycarbonyl )-methoxy]-imino]-acetic acid used as a starting compound can be prepared as follows:

Two g of 2-[5-(1-t-butoxyformamido]-3-(1,2-thiadiazolyl)]-2-[[_(Z)-(t-butoxycarbonyl)-methoxy]-imino]acetic acid and 2 g of 2,2-dithio-bis-benzothiazole are suspended in 50 mL of acetonitrile and 0.7 mL of N-methylmorpholine. While stirring for 1 h, this mixture is combined with 1.1 mL of triethylphosphite in 10 mL of acetonitrile. The mixture is then absorbed into ethyl acetate, washed with water, dried, and concentrated. The remaining yellow oil is chromatographed on silica gel. The thioester crystallizes from hexane (0.8 g). The 2-benzthiazolylthioester of the acid is obtained.

2-[5-(l-t-butoxyformamido)-3-(l,2,4-thiadiazolyl)]-2-[[ ( Z ) -

(t-butoxycarbonyl)-methoxy]-imino3-acetic acid at 115-120°C.

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 17.77%.

Example 44

804 mg (2 mMoles) of 2-[[(5-(1-t-butoxyformamido)-3-(1,2,4-thiadiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxy]-irnino]-acetic acid is dissolved in 30 ml of chloride of

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methylene is treated with 0.25 mL (2.05 mM) of 1-chloro-N,N,2-trimethyl-l-propenamine, followed by 0.57 mL (2.05 mM) of triethylamine and 478 mg (2 mM) of (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-l-azetidinesulfonic acid. The reaction mixture is stirred for 2 h and then concentrated. The residue is treated with a solution of 370 mg of sodium bicarbonate in 30 mL of water. The crude mixture is chromatographed on MCI gel (25% aqueous methanol as the eluate); 406 mg (34%) of triethylamine salt of (3S,4S)-3-[(Z)-2-[5-amino-l,2,4-thiadiazol-3-yl]-2-[[(-t-butoxycarbonyl)-methoxy]-imino]-acetamido]-4-carbamoyloxymethyl-2-oxo-l-azetidinesulfonic acid is obtained.

15

Elemental analysis: calculated for

C21H36N8°10S2

find:

C 40.38, H 5.81, N 17.94% C 40.31, H 5.70, N 17.9 9%

20

"H-RMN (DMSO, ppm):

1.17 (9H,t,7.5 Hz,3xCH2CH3), 1.42 (9H,s,3xCH3), 3.09 (6H,q,J=7.5 Hz, 3xCH2), 4.10 (3H,m,CH-CH2), 4.60 (2H,s,N-0-CH2), 5.25 (lH,dd,J=5 and 9 Hz, NH-CH), 6.3 0 (2H,s,NH2), 8.10 (2H,s,NH2), 9.0 (lH,d,J=9 Hz, NH-CH).

25

30

Example 45

314 mg (0.502 mMole) of triethylamine salt of (3S,4S)-3-[(Z)-2-[5-amino-l,2,4-thiadiazol-3-yl]-2-[[(t-butoxycarbonyl)-methoxy]-imino]-acetamido]-4-carbamoyloxymethyl-2-oxo-l-azetidinesulfonic acid is dissolved at 0°C in

5 mL of 3.5 N aqueous hydrochloric acid. The reaction mixture is stirred for 2 days at 0°C. The solvent is evaporated under reduced pressure, and the residue is absorbed into 15 mL of ethanol/water (2:1) and treated with 2 mL of 2 N sodium 2-ethylcaproate in ethyl acetate. The reaction mixture is concentrated and analyzed by MCI gel chromatography.

S

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(water as eluent). 135 mg (53%) of disodium salt of (3S,4S)-3-[(Z)-2-(5-amino-l,2,4-thiadiazol-3-yl)-2-[(carboxymethoxy)-imino]-acetamido]-4-carbamoyloxymethyl-2-oxo-l-azetidinesulfonic acid is obtained.

Elemental analysis: calculated for Cl lHi iN7°ioS2Na2 * 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 11.15, Cl 6.2 2%

IR (KBr, cm-1): 1767, 1664, 1614

^H-NMR (DMSO, ppm): 4-4.20 (3H, m, CH-CH2). 4.30 (2H,s,

K-0-CH2), 5.27 (lH,dd,J=5 and 10 Hz, NH-CH), 6.50 (2H,larrNH2), 8.11 (2H,s,NH2), 10.90 (lH,d,J=10 Hz,NH-CH).

Example 46

In the same way as what is said in the example

1. From 352 mg (1.5 mMole) of (3S,4S)-3-amino-4-[(E)-2-carbamoylvinyl]-2-oxo-l-azetidinesulfonic acid and the 2-benzthiazolyl-thioester of 2-(2-amino-4-thia-zolyl)-2-(Z)-methoxyiminoacetic acid, 180 mg (27%) of sodium salt of (3S,4S)-3-[(Z)-2-(2-amino-4-thia-zolyl)-2-(methoxyimino)acetamido J — 4 —[(E)-carbamoylvinyl ]-2-oxo-1-azetidinesulfonic acid is obtained.

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10

Elemental analysis: calculated for c,-H., -N.-O-.S-Na

1 Z lob / Z

C 32.72, H 2.98, N 19.08%

found: c 32.68, H 2.91, N 18.9 3%

IR (KBr, cm-1): 1769, 1675, 1648, 1613

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

efc 7.5 Hz, NH-CH-CH), 5.30 (lH, dd,J=6 and 9 Hz, NH-CH-CH), 6.20 (1H,d,J =16 Hz, =CH-CONH2), 6.70 (lH,dd,J= 7, 5 and 16 Hz, CH=CH-CONH2) 6.80 (1H,s,H-Thiazol), 7.0-7.5 (4H, lar,.2xNH2), 9.40 (1H,d,J=9 Hz, NH-CH).

The (3S,4S)-3-amino-4-[(E)-2-carbamoylvinyl]-2-oxo-l-azetidinesulfonic acid used as the starting compound can be prepared as follows:

59.08 g (0.175 mM) of (3S,4S)-3-amino-1-(2,4-dimethoxybenzyl)-4[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone is treated in 1 liter of dioxane in the presence of 16.4 g of potassium carbonate with 46.9 g (0.215 M) of di-t-butyl dicarbonate. After stirring for 4 h at room temperature, the resulting precipitate is separated by filtration, and the filtrate is concentrated under reduced pressure. The remaining oily residue is recrystallized from methylene chloride/n-hexane. We obtain 64.5 g (84.4%) of t-butyl-(3S,4S)-l-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-azetidinecarbamate.

76.8 g (0.176 mol) of t-butyl-(3S,4S)-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-azetidinecarbamate is dissolved in 500 mL of tetrahydrofuran and 350 mL of water and heated for 24 h at 60°C with 13.0 g of p-toluenesulfonic acid. The reaction mixture is cooled and neutralized with a 10% aqueous solution of

30

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I

Potassium bicarbonate is added and concentrated. The residue is absorbed into 300 mL of dioxane and treated with 21.8 g (0.1 mol) of di-t-butyl dicarbonate and 7.63 g of potassium carbonate. The reaction mixture is stirred at room temperature for 24 h and filtered. The solvent is then concentrated.

The crude product is recrystallized from acetonitrile. 61.3 g (88%) of t-butyl-(3S,4S)-1-(2,4-dimethoxybenzyl )-4-[(R)-l, 2-dihydroxyethyl ]-2-oxo-3-azetidinecarba mate is obtained.

5.0 g (12.6 mMoles) of t-butyl-(3S,4S)-10 l-(2,4-dimethoxybenzyl)-4-[(R)-l,2-dihydroxyethyl]-2-oxo-

3-Azetidinecarbamate is dissolved in 50 mL of methanol and treated with a solution of 2.95 g (13.8 mM) of sodium metaperiodate in 30 mL of water. The pH of the solution is maintained at 6.9 by adding a saturated aqueous solution of sodium bicarbonate. After stirring for 30 h at room temperature, the sodium iodate formed is separated by filtration, and the filtrate is concentrated. The residue is absorbed into ethyl acetate and washed with an aqueous solution of table salt, dried over magnesium sulfate, and concentrated. The oily residue is crystallized from ether, yielding 2.70 g (58.8%) of δ-butyl-(3S,4S)-1-(2,4-dimethoxybenzyl)-4-formyl-2-oxo-3-azetidinecarbamate.

Elemental analysis: calculated for C18H24N2°6

C 59.33, H 6.64, N 7.69%

25 found: C 59.08, H 6.91, N 7.38%.

4.0 g (11 mM) of t-butyl-(3S,4S)-1-(2,4-dimethoxybenzyl)-4-formyl-2-oxo-3-azetidinecarbamate is dissolved in 300 mL of methylene chloride and treated dropwise with a solution of 3.9 g (12 mM) of carbamoyl-30 methylenetriphenylphosphorane in 100 mL of methylene chloride. After 1 h, the reaction mixture is filtered, and the resulting crystals are washed with methylene chloride. 3.6 g (81%) of t-butyl-(3S,4S)-1-(2,4-dimethoxy-

benzyl)-4-[(E)-2-carbamoylvinyl]-2-oxo-3-azetidinecarbamate of P 270°C.

IR (KBr, cm-1): 1767, 1719, 1684, 1644.

3.6 g (8.9 mM) of t-butyl-(3S,4S)-1-(2,4-dimethoxybenzyl)-4-[(E)-2-carbamoylvinyl]-2-oxo-3-azetidinecarbamate is dissolved in 80 mL of acetonitrile and 150 mL of water and treated dropwise under reflux with a solution of 4.9 g (17.8 mM) of potassium peroxodisulfate in 50 mL of water. The pH is maintained at 6.5 by adding a saturated aqueous solution of sodium bicarbonate. After 4 h, 40 mL of acetonitrile is removed by distillation. The crude reaction mixture is then partially concentrated and cooled to +5°C. The resulting crystals are separated by filtration. The filter is washed twice with 100 mL of ether each time. 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 concentrated. A brown residue is obtained, which, after recrystallization from methanol, yields 920 mg (41%) of t-butyl-(3R,4S)-4-[(E)-2-carbamoylvinyl]-2-oxo-3-azetidinecarbamate.

IR (KBr, cm-1): 1784, 1732, 1689, 1673

Analysis: calculated for C^H^N-^O^: C 51.76, H 6.71, N 16.46%

found: 051.88, H 6.81, N 16.41%.

1.45 g (5.68 mM) of t-butyl-(3R,4S)-4-[(E)-2-carbamoylvinyl]-2-oxo-3-azetidinecarbamate is dissolved in 80 mM of acetonitrile and treated with 1.86 g (11.6 mM) of pyridine-sulfur trioxide complex. The reaction mixture is stirred at 40°C for 20 h. The solvent is then evaporated, and the residue is absorbed into 100 mL of water. The pH is adjusted to 7–8 by adding a saturated aqueous solution of sodium bicarbonate. The volume is reduced to 30 mL by concentration, and the resulting solution is chromatographed on an MCI gel.

113

(water as eluent). We obtain 1.61 g (67.5%) of sodium salt of (3R,4S)-3-(1-t-butoxyformamido)-4-[(E)-2-carbamoyl-vinyl]-2-oxo-1-azetidinesulfonic acid.

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

C 36.98, H 4.51, N 11.76°/=

found: C 37.31, H 4.89, N 11.19%

IR (KBr, cm-1): 1768, 1692, 1645.

1.55 g (4.34 mM) of the sodium salt of (3R,4R)-3-(1-t-butoxyformamido)-4-[(E)-2-carba-moylvinyl]-2-oxo-l-azetidinesulfonic acid is dissolved in 5 mL of anisol, cooled to 0°C, and treated with 5 mL of trifluoroacetic acid. The resulting suspension is stirred for 1 h at 0°C and then for 2 h at room temperature. The reaction mixture is diluted with 100 mL of ether and 20 mL of den-hexane. The resulting crystals are separated by filtration and dried. The crude material thus obtained is dissolved in 10 mL of water and analyzed by MCI gel chromatography (water as eluent). We obtain 1.04 g (100%) of (3S,4S)-3-amino-4-[(E)-2-carbamoyl-vinyl]-2-oxo-1-azetidinesulfonic acid.

IR (KRb, cm-1): &779, 1683, 1648, 1608.

Example 47

278 mg (1 mM) of rac-cis-3-amino-4-[(Z)-2-ethoxycarbonyl]-l-methylvinyl]-2-oxo-l-azetidinesulfonic acid is dissolved in 10 mL of water and 10 mL of acetone and treated with 290 mg (1.1 mM) of sodium bicarbonate and 386 mg (1.1 mM) of 2-(2-benzthiazolylthioester of 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyiminoacetic acid. The reaction mixture is stirred for 48 h at room temperature. The organic solvent is withdrawn under reduced pressure, and the crystals that have formed are separated by filtration. The filtrate is chromatographed on MCI gel (water as eluent). 161 mg (43%) of the sodium salt of rac-cis-

114

f

3-[(Z) — 2 —(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-

4-[(Z)-2-(ethoxycarbonyl)-1-methylvinyl ]-2-oxo-1-azetidinesulfonice .

Elemental analysis: calculated for c. CH1 oNc0oS~Na * 1 d 1 o b o 2

5 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

1H-.NMR (DMSO, ppm): 1.21 (3H,t,J=7 Hz,CH3CH2), 2.03

10 (3H,d,J=1 Hz,CH3-C=0, 3.76 (3H,s,

OCH3), 4.08 (2H,q,J=7 Hz,CH3-CH2), 4.54 (lH,dd,J=6 and 1 Hz,NH-CH-CH), 5.28 (1H,dd,J=6 and 9 Hz,NH-CH), 6.05 (1H,t,J=1 Hz, =CH), 6.57 (lH, 15 s, H-Thiazol), 7.17 (2H, lar, NH2),

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

Rac-cis-3-amino-4[(Z)-2-(ethoxycarbonyl)-1-methylvinyl]-2-oxo-l-azetidinesulfonic acid used as a starting compound can be prepared as follows:

6.68 g (0.042 mol) of 2,4-dimethoxybenzylamine is treated in 150 mL of methylene chloride in the presence of magnesium sulfate with 5.97 g (0.04 mol) of 3-formylcrotonic acid ethyl ester. After stirring for 30 minutes, the resulting precipitate is separated by filtration. The resulting imine solution is cooled to 0°C and treated with 6.7 mL of triethylamine, then dropwise with a solution of 10.2 g (0.047 mol) of phthalimidoacetyl chloride in 50 mL of methylene chloride. The reaction mixture is stirred for 1 h at 0°C, then heated to room temperature and washed successively with dilute aqueous hydrochloric acid, water, and an aqueous solution of table salt. After drying and concentration, the crude mixture is recrystallized from the chloride of

20

30

115

1 methylene/n-hexane. 15.6 g (81.6%) of crude ethyl-rac-cis-l-(2,4-dimethoxybenzyl)-B-methyl-4-oxo-3-pht alimido-2-azetidinacrylate is obtained from 159-160°C.

IR (KBr, cm-1): 1766, 1723, 1656.

5. 37.0 g (77.3 mMoles) of ethyl-rac-cis-

1-(2,4-dimethoxybenzyl)-B-methyl-4-oxo-3-phthalimido-2-azeti-dinacrylate is reacted in 500 mL of methylene chloride and treated with 8.2 mL (0.15 mM) of N-methylhydrazine at 30°C for 48 h. The reaction mixture is filtered and concentrated. The residue is absorbed into ethyl acetate and filtered.

The filtrate is extracted with 200 mL of aqueous hydrochloric acid, and the aqueous phase is separated. This phase is neutralized with a saturated aqueous solution of sodium bicarbonate and extracted twice, each time with 200 mL of methylene chloride. After drying and concentration, the crude, colorless product is isolated. 25.1 g (93%) of ethyl-rac-cis-3-amino-l-(2,4-•dimethoxybenzyl)-β-methyl-2-oxo-4-azetidinacrylate is obtained at a boiling point of 83–93°C.

IR (KBr, cm-1): 1741, 1708, 1651, 1616.

20. 18.4 g (0.053 Mol) of ethyl-rac-cis-3-

amino-1-(2,4-dimethoxybenzyl)-B-methyl-2-oxo-4-azetidinacrylate is dissolved in 350 mL of dioxane and treated in the presence of 5 g of potassium carbonate with 15 mL (0.068 M) of di-t-butyl dicarbonate. The reaction mixture is stirred at room temperature for 12 h, then filtered and concentrated. The residue is absorbed in methylene chloride and washed with water and a salt solution.

After drying and concentration, the crude material is recrystallized from methylene chloride/n-hexane. This yields 30 18.4 g (77.5%) of ethyl-rac-cis-3-(1-t-butoxyformamido)-1-(2,4-

colorless dimethoxybenzyl )-B-methyl-2-oxo-4-azetidinacrylate of P 150-152°.

116

4.0 g (8.9 mMoles) of 1-ethyl-rac-cis-3-(1-

10

15

20

25

t-Butoxyformamido)-l-(2,4-dimethoxybenzyl)-B-methyl-2-oxo-4-azetidinacrylate is dissolved in 300 mL of acetonitrile and treated for 2 h at 90–95°C with 3.86 g (14.3 mM) of potassium peroxodisulfate and 2.31 g (13.3 mM) of potassium acid sulfate. The organic solvent is concentrated, and the aqueous phase is extracted with chloroform. The combined organic phases are washed with aqueous table salt and dried over sodium sulfate. The solution is concentrated and analyzed by silica gel chromatography (ethyl acetate as eluent). 990 mg (37%) of t-butyl-4-[2-(ethoxycarbonyl)-l-methylvinyl]-2-oxo-3-azetidincarbamate is obtained.

IR (KBr, cm-1): 1783, 1758, 1712, 1703, 1690.

2.25 g (7.5 mM) of t-butyl-4-[2-(ethoxycarbonyl)-1-methylvinyl]-2-oxo-3-azetidinecarbamate is dissolved in 20 mL of acetonitrile and treated at room temperature with 3.0 g (18.8 mM) of sulfur trioxide-pyridine complex. The reaction mixture is stirred at room temperature for 12 h. The acetonitrile is evaporated, and the residue is treated with 3.16 g (36 mM) of sodium bicarbonate in 60 mL of water. The solution is concentrated to 30 mL by evaporation and cooled to 6°C. We obtain 1.92 g (63%) of crystalline sodium salt of rac-cis-3-(1-t-butoxy-formamido) — 4—E(Z) — 2—(ethoxycarbonyl)-1-methylvinyl ]-2-oxo-1-azetidinesuifonic acid.

Elemental analysis: calculated for ci4H21N2°8SNa

Ch dissolves 1.755 g (4.38 mMoles) of sodium salt of rac-cis(3-(l-t-butoxyformamido)-4-[(Z)-2-(ethoxy-carbonyl)-1-methylvinyl]-2-oxo-1-azetidinesulfonic acid in

C 42.00, H 5.29, N 7.0 0% found: C 42.07, H 5.27, N 7.23%

IR (KBr, cm-1): 1774, 1715, 1692, 1668.

117

I

7.5 mL of anisol is reacted and treated at -20°C with 10 mL of trifluoracetic acid. After stirring for 30 minutes at -20°C and then for another 3 hours at room temperature, the reaction solution is diluted with 300 mL of 1:1 ether/n-hexane. The resulting crystals are separated by filtration, dissolved in 10 mL of water, and analyzed by MCI gel chromatography. 808 mg (60%) of rac-cis-3-amino-4-[(Z)-2-(ethoxycarbonyl)- acid is obtained.

1-methylvinyl]-2-oxo-1-azetidinesulfonic.

Example 48

717 mg (3 mM) of (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidinesulfonic acid is dispersed in 75 mL of methylene chloride and treated for 24 h with stirring at room temperature with 0.46 mL (3.3 mM) of triethylamine and 2.70 g (3.3 mM) of 2-benzthiazolylthioester of 2-(2-tritylamino-4-thiazolyl)-2-(Z)-trityloxyiminoacetic acid. The solvent is evaporated and the residue is chromatographed on silica gel (methylene chloride/methanol 92:8 as eluent). 1.58 g (53%) of (3S,4S)-3-[(Z)-2-(2-tritylamino-4-thiazolyl)-

2-(trityloxyimino)acetamido]-4-carbamoyloxymethyl-3-oxo-l-azetidinesulfonic acid.

1.42 g (1.43 mM) of (3S,4S)-3-[(Z)-2-(2-trity1-amino-4-thiazolyl)-2-(trityloxyimino)acetamido]-4-carbamoyloxy-methyl-3-oxo-l-azetidinesulfonic acid is stirred for 4 h at room temperature in 15 mL of formic acid with 0.01 mL of water. The solvent is evaporated, the residue is absorbed into water, and distilled azeotropically with toluene. The residue is recrystallized from water/ethanol 4:1. We obtain 296 mg (51%) of (3S,4S)-3-C(Z)-2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-4-carbamoyl-oxymethyl]-2-oxo-l-azetidinesulfonic acid.

The 2-benzthiazolyl-thioester of 2-(2-trityl-amino-4-thiazolyl)-2-(Z)-trityloxyiminoacetic acid used as a starting compound can be prepared as follows:

F

118

67.2 g of 2-(2-tritylamino-4-thiazolyl)-2-(Z)-trityloxy-iminoacetic acid and 40 g of 2,2-dithio-bis-benzthiazole are suspended in 1.6 liters of acetonitrile and 16.5 ml of 4-methylmorpholine and treated at 0°C by stirring with 30 ml of triethylphosphite in 200 ml of acetonitrile.

A small amount of undissolved material is removed by filtration. The solution is concentrated to a low volume and mixed with isopropanol. It is concentrated again to a low volume. The crystallized thioester is separated by filtration and dried. 75.0 g of 2-benzthiazolylthioester of the acid is obtained.

2-(2-tritylamino-4-thiazolyl)-2-(Z)-trityloxyiminoacetic with mp 111-112°C.

Example 49

Ch dissolves 478 mg of (3S,4S)-3-amino-4-carbamoyl-15-oxymethyl-2-oxo-l-azetidinesulfonic acid, 338 mg of 2-(pyra-

(3S,4S)-4-carbamoyloxymethyl-2-[2-(methoxyimino)-2-pyrazol-3-yl]acetamido]-2-oxo-1-azetidinesulfonic acid is reacted with 613 mg of 2-chloro-1-methylpyridinium iodide for 1 h. The reaction mixture is concentrated at 25°C under reduced pressure. The residue is absorbed into water and reversed-phase silica gel chromatography with water is performed. After lyophilization, 645 mg of triethylamine salt of (3S,4S)-4-carbamoyloxymethyl-2-[2-(methoxyimino)-2-pyrazol-3-yl]acetamido]-2-oxo-1-azetidinesulfonic acid is obtained.

25 Elemental analysis: calculated for: C^^gN^OgS ( 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%

4

119

I

Example 50

In the same way as stated in example 49, from 360 mg of (3S,4S)-trans-3-amino-4-methyl-2-oxo-l-azetidinesulfonic acid and 2-(pyrazol-3-5 yl)-2-(Z)-methoxyimino-acetic acid, 423 mg of triethylamine salt of (3S,4S)-trans-3-[2-(methoxyimino)-2-pyrazol-3-yl-acetamido]-4-methyl-2-oxo-l-azetidinesulfonic acid are obtained.

1H-NMR (DMSO, ppm). 9.25 (d,J=8 Hz,lH), 7.77 (m,lH),

6.45 (m,1H), 4.41 (dd,J=2.5 Hz 10 and 8 Hz, 1H), 3.85 (s,3H), 3.64

(dd,J=2.5 Hz and 6 Hz, lH), 3.69 (q,J=7 Hz,6H), 1.4 0 (d,J=6 Hz,3H), 1.16 (t,J=7 Hz,9H).

Example 51

15' Preparation of dry ampoules for intramuscular administration:

A 1 g lyophilized powder of the sodium salt of (3S,4S)-3-[(5-amino-3-(1,2,4-thiadiazolyl)]-2-(Z)-(methoxyimino)acetamido]-4-methoxyimino-20-methyl-2-oxo-l-azetidinesulfonic acid is prepared as usual and transferred to an ampoule. Before administration, the lyophilized powder is mixed with 2.5 mL of a 2% aqueous lidocaine hydrochloride solution.

120

Claims (73)

DEMANDS 1. Pre-process Preparation of 1-sulfo-2-oxoazetidine derivatives with general formula Het—C—CONH- ,R N ^OR1 J"1" 3 4 O \ so3H where Het represents a possibly amino-substituted, 5- or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms, and possibly also an oxygen or sulfur atom, R1 represents a hydrogen, a lower alkyl, a lower phenyl alkyl, a lower alkanoyl, a lower alkoxycarbonyl, a lower alkenyl-lower alkyl, a lower alkoxycarbonyl-lower alkyl, a lower phenyl-alkyl-carbonyl-lower alkyl, a lower nitrophenyl-alkyl-carbonyl-lower alkyl or 2 a lower carboxy-alkoyl group and R represents a hydrogen atom, i a lower alkyl, a lower alkenyl, a lower alkynyl, a lower alkoxy-carbonyl, a lower alkanoyloxy-lower alkyl, a lower alkoxy-carbonyl-lower alkenyl, a hydroxyiminomethyl, a lower alkoxy-iminomethyl, a carbamoyl, a lower carbamoyl-alkenyl or a lower carbamoyloxy-alkyl, the =N0R^ group being at least partly in syn form, in racemic form or in the form of the 3S enantiomer, as well as readily hydrolyzable esters or pharmaceutically acceptable salts of these compounds, 121 characterized in that it acylates a compound, appearing in racemic form or as the 3S enantiomer, of general formula h2n- ,R 20 II 0 -N V 20 ~ 2 Where R has the same meaning as R or can still represent- 3 to represent a group 2, 2-dimethyl-1,3-dioxolan-4-yl and R represents a hydrogen or a sulfo, or one of its salts with a thioester of general formula Het—jj—COS- N ^OR10 III 122 1 10 where Het has the meaning given above and R has the same meaning as R1, but does not represent a lower carboxy-alkyl group, but can still also represent a lower tri-alkyl-lower silyl-alkoxy-lower carbonyl-alkyl group or a transformed lower carboxy-alkyl group into an easily hydrolyzable ester group, and the group =NOR1^ is at least partly in syn form, to give a compound, appearing in racemic form or as an 11S enantiomer, with the general formula Het—Çj—CONH- ■ R20 N Ib OR \ 3 R Where R1^, R2^, R^ and Het have the meaning given above, and the group =NOR1^ appears at least partly in the form 3 syn, then in that we sulfate a product obtained where R represents a hydrogen, in that we transform a group 20 2,2-dimethyl-1,3-dioxolan-4-yl R possibly present in the hydroxyiminomethyl group, a lower alkoxy-iminomethyl group or the carbamoylvinyl group, in that a lower tri-alkoyl-silyl-lower alkoxy-lower carbonyl-alkoyl group possibly present R1^ is transformed into a lower carboxy-alkoyl, if desired in that the substituent R1^ or as the case may be R1 representing a lower alkoxy-lower carbonyl-alkoyl, a lower phenyl-alkooxy-lower carbonyl-alkoyl or a lower nitrophenyl-alkooxy-lower carbonyl-alkoyl is transformed into a lower carboxy-alkoyl and if desired in that a product obtained is transformed into a pharmaceutically acceptable salt. 123 2. A process according to claim 1 for preparing compounds of formula I where Het represents an amino-substituted heterocycle, with 5 or 6 links, aromatic, containing 1 or 2 nitrogen atoms, and possibly also an oxygen or sulfur atom, R1 represents a hydrogen, a lower alkyl, a lower phenyl-alkoyl, a lower alkanyl, a lower alkoxy-carbonyl, a lower alkenyl-lower alkoyl, a lower alkoxy-carbonyl-lower alkoyl, a lower phenyl-alkoxy-lower carbonyl-alkyl, a lower nitrophenyl-alkoxy-lower carbonyl-alkyl or 2 a lower carboxy-alkoyl and R represents a lower alkoyl, a lower alkenyl, a lower alkynyl, a lower alkoxy-carbonyl, a lower alkanoyloxy-lower alkoyl, a hydroxyiminomethyl, a lower alkoxy-iminomethyl, a carbamoyl or a lower carbamoyloxy-alkoyl, in racemic form or as the 3S enantiomer, as well as readily hydrolyzable esters or pharmaceutically acceptable salts of these compounds, characterized in that correspondingly substituted starting compounds are used. 3. A method according to claim 2, characterized in that a sulfo is used. uses a starting compound of formula II where R^ represents 4. A process according to any one of claims 2 or 3, characterized in that the reaction of the starting compounds of formulas II and III is carried out in the presence of an organic amine, such as triethylamine. 5. A method according to any one of claims 2 to 4, characterized in that a 3,4-cis compound (in particular a 3S,4S compound) of optically uniform formula II is used. 6. A method according to any one of claims 2 to 5, characterized 12 4 what is used as the thioester of formula III is the 2-benzthiazolyl thioester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(T-butoxycarbonyl)-1-methylethoxy]-imino]-acetic acid, the 2-benzthiazolyl thioester of 2-(2-amino-4-thiazolyl) 5 2-[[(Z)-1-[2-(trimethylsilyl)-ethoxycarbonyl]-1-methylethoxy]- imino]-acetic, the 2-benzthiazolyl-thioester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(p-nitrobenzyloxycarbonyl)-methoxy]-imino]-acetic, the 2-benzthiazolyl-thioester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-l-(p-nitrobenzyloxy-10 carbonyl)-1-methylethoxy]-iminoacetic acid and in that the carboxy group is released in the reaction product. 7. A process according to any one of claims 1-5, characterized in that the 2-hecvz-thiazolyl-thioester of 2-(2-amino-4-thiazolyl)-2- acid is used as the thioester of formula III. 15 [[(Z)-1-(t-butoxycarbonyl)-methoxy]-imino]-acetic and in that the carboxy group is released in the product of the reaction. 8. A process according to claim 6 or 7, characterized in that a t-butoxy- group is transformed into a carboxy- 20 carbonyl by treatment with hydrochloric acid or trifluoracetic acid. 9. A process according to claim 6, characterized in that a trimethylsilyl-ethoxy-carbonyl group is transformed into a carboxy by treatment with tetrabutyl- fluoride 25 ammonium. 10. A process according to claim 6, characterized in that a p-nitrobenzyloxycarbonyl group is transformed into a carboxy by catalytic hydrogenation. 11. A process according to any one of claims 2 to 9, characterized in that a 2-benzthiazolyl-thioester of 12 5 I 11 (Z)-2-(2-amino-4-thiazolyl)-2-[[l-[R'OCO]-l-methyl-ethoxy]-imino]-acetic acid, where R' represents a lower alkyl, a lower phenyl-alkyl, a lower nitrophenyl-alkyl or a lower tri-alkyl-silyl-alkyl, or one of its salts, with (3S,4S)-3-amino-4-carbamoyl-oxymethyl-2-oxo-l-azetidine-sulfonic acid and in that the carboxy group is released in the product of the reaction. 12. A process according to any one of claims 2 to 9, characterized in that a 2-benzthiazolyl-thioester is reacted with 1'2-(2-amino-4-thiazolyl)-2-[[(Z)-(R"OCO)-methoxy]-imino]-acetic acid, where R" represents a lower alkyl, a lower phenyl-alkyl, a lower nitrophenyl-alkyl or a lower tri-alkyl-silyl-alkyl, or one of its salts, with (3S,4S)-3-amino-4-carbamoyloxy-methyl-2-oxo-l-azetidinesulfonic acid and in that the carboxy group is released in the product of the reaction. 13. A process according to any one of claims 2 to 9, characterized in that the 2-benzthiazolyl-thioester of the acid (Z)-2-(2-amino-4-thiazolyl)-2-[[1-(t-butoxycarbonyl]- 1-methylethoxy]-imino]-acetic acid, or one of its salts, with (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-l-azetidinesulfonic acid and in that the carboxy group is released in the product of the reaction by treatment with a strong organic acid. 14. A process according to any one of claims 2 to 9, characterized in that the 2-benzthiazolyl-thioester of the acid is reacted 2-(2-amino-4-thiazolyl)-2-[[(Z)-(p-nitrobenzyloxycarbonyl)-methoxy]-imino]-acetic acid with (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidinesulfonic acid and in that the carboxy group is released into the product of the reaction by catalytic hydrogenation. 12 6 t 15. A process according to any one of claims 1 to 9, characterized in that the 2-benzthiazolyl-thioester of (Z)-2-(2-amino-4-thiazolyl) — 2 — C C1—(t-butoxycarbonyl-methoxy)-imino3-acetic acid is reacted with (3S,4S)-3-amino-4-carbamoyloxy-methyl-2-oxo-l-azetidinesulfonic acid and in that the carboxy group is released in the reaction product by treatment with a strong organic acid. 16. Process for preparing benzthiazolthioesters of general formula where Het represents an aromatic, possibly amino-substituted, 5- or 6-membered heterocycle containing 1 or 2 nitrogen atoms, and possibly an oxygen or sulfur atom, R1^ represents a hydrogen, a lower alkyl, a lower phenyl alkyl, a lower alkanoyl, a lower alkoxy-carbonyl, a lower alkenyl-lower alkyl, a lower alkoxy-carbonyl alkyl, a lower phenyl alkyl-carbonyl alkyl, a lower nitrophenyl alkyl-carbonyl alkyl or a lower trialkyl-silyl alkyl-carbonyl alkyl, and the =NOR"'"^ group is at least partly in syn form, characterized in that a carboxylic acid of general formula is reacted Het—C—COOH 1! R10 12 7 10 10 15 20 where R and Het have the meaning given above, and where the group =NOR1^ appears at least partly in syn form, with dithio-bis-benzthiazole in the presence of tri-(lower alkyl)phosphite and a base or in the presence of triphenyl-phosphine. 17. A process according to claim 16, characterized in that the reaction of the carboxylic acid of formula IV with dithio-bis-benzthiazole is carried out in the presence of a tri-(lower alkyl)-phosphite and a base. 18. A process according to claim 17, characterized in that triethylphosphite is used as the lower tri(alkoyl)phosphite. 19. A method according to any one of claims 17 or 18, characterized in that an organic base is used as a basis. 20. A process according to claim 19, characterized in that N-methylmorpholine is used as the organic base. 21. A process according to any one of claims 17-20, characterized in that a carboxylic acid of general formula IV is used, where R1^ represents a lower alkoxy-carbonylmethyl, a lower phenyl-alkoxy-carbonylmethyl, a lower nitrophenyl-alkoxy-carbonylmethyl or a lower tri-alkyl-silyl-alkoxy-carbonylmethyl. 22. A method according to any one of claims 16-21 for preparing thioesters of general formula III a 12 8 .10 where R has the same meaning as in formula III of the 4 claim 1 and R represents a 2-amino-4-oxazolyl, a 2-amino-6-pyridyl, a 2-amino-4-imidazolyl or a 5-amino- 3-(1,2,4-thiadiazolyl), where the group =N0R"^ is present at least partly in syn form, characterized in that starting compounds are used which are substituted in a corresponding manner. 10 23. A process according to any one of claims 16-22 for the preparation of 1-benzthiazolyl-thioester of 2-(2-amino-4-oxazolyl)-2-(methoxyimino)-acetic acid, characterized in that correspondingly substituted starting compounds are used. 15 24. A process according to any one of claims 16-22 for the preparation of 1-benzthiazolyl-thioester of 2-[(5-amino-3-(1,2,4-thiadiazolyl)]-2-(Z)-methoxyimino-acetic acid, characterized in that correspondingly substituted starting compounds are used. 25. A method according to any one of claims 16-22 for preparing compounds of general formula Illb 20 12 Where R represents a lower alkoxy-lower carbonyl-alkyl, a lower phenyl-alkoxy-lower carbonyl-alkyl, a lower nitrophenyl-alkoxy-lower carbonyl-alkyl, or a lower tri-alkyl-silyl-alkoxy-lower carbonyl-alkyl, where the =NOR1l group is present at least 12 9 partly in syntactic form, characterized in that starting compounds are used which are substituted in a corresponding manner. 26. A method according to any one of claims 16-21 and 25 of 12 preparation of thioesters according to claim 25, where R represents a lower alkoxy-carbonylmethyl, a lower phenyl-alkoxy-carbonylmethyl, a lower nitrophenyl-alkoxy-carbonylmethyl or a lower tri-alkyl-silyl-lower alkoxy-carbonylmethyl, characterized in that correspondingly substituted starting compounds are used. 27. A process according to any one of claims 16-21 and 26 for the preparation of 2-benzthiazolyl-thioester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(p-nitrobenzyloxycarbonyl)-methoxy]- 15 imino-acetic, characterized in that correspondingly substituted starting compounds are used. 28. A process according to any one of claims 16-21 and 26 for the preparation of 2-benzthiazolyl-thioester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxy]-imino]- 20 acetic, characterized in that correspondingly substituted starting compounds are used. 29. A method according to any one of claims 16-21 and 25 for preparing thioesters according to claim 25, wherein 12 R represents a lower alkoxy-carbonyl-1-methylethyl, 25 a 1-(phenyl-lower alkoxy-carbonyl)-1-methylethyl, a 1-(nitrophenyl-lower alkoxy-carbonyl)-1-methylethyl or a 1-(lower tri-alkyl-silyl-lower alkoxy-carbonyl)-1-methylethyl, characterized in that correspondingly substituted starting compounds are used. 5 10 130 30. A process according to any one of claims 16-21 and 29 of preparing 2-benzthiazolyl-thioester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-1-[2-(trimethylsilyl)-ethoxycarbonyl]-1-methylethoxy]-imino]-acetic acid, characterized in that correspondingly substituted starting compounds are used. 31. A process according to any one of claims 16-21 and 29 for the preparation of 2-benzthiazolyl-thioester of 2-(2-amino-4-thiazolyl)-2-[C(Z)-1-(p-nitrobenzyloxycarbonyl)-1-methylethoxy]-imino]acetic acid, characterized in that correspondingly substituted starting compounds are used. 32. A process according to any one of claims 16-21 and 29 of preparing 2-benzthiazolyl-thioester of 2-(2-amino-4~thiazolyl)-2-[[(Z)-l-(t-butoxycarbonyl)-1-methyl-ethoxy ]-imino ]-acetic acid, characterized in that correspondingly substituted starting compounds are used. 33. Process for preparing carboxylic acids of general formula Het—C—COOH I' N IVa \ OCH2-COOC(R) where Het represents a possibly amino-substituted, 5-qi6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms, and also, where applicable, an oxygen or sulfur atom, and R represents an alkyl group, and where the group =NOCH2COOC(R)^ is at least partly in syn form, 131 characterized in that in an ester of general formula Het—C—COOR5 I' X N \ OCH2-COOC(R)3 5 where Het and R have the meaning given above and R represents an allyl or a p-nitrobenzyl, and the group =NOCH2COOC(R)^ is at least partly in the form of the R^ group. 34. A method according to claim 33, characterized in that 5 that we cleave by hydrogenolysis an ester of formula X, where R represents a p-nitrobenzyl. 35. A process according to claim 34, characterized in that the cleavage is carried out by hydrogenolysis using hydrogen and Raney nickel. 36. A process according to one of the methods described, characterized in that the organic base is carried out, such as sorting. benefits 34 or 35, cleavage character in the presence of a thylaminate. 37. A process according to claim 33, characterized in that an ester of formula X, where R represents a methyl and R"* an allyl, is cleaved by catalysis. 38. A method according to claim 35, characterized in that the catalytic cleavage is carried out using a palladium compound in the presence of triphenylphosphine or a tri-(lower alkyl)-phosphite and furthermore in the presence of an alkali metal alkanoate or an organic base. 132 39. A process according to claim 38, characterized in that a palladium salt with a hydrohalic acid or a lower alkane-carboxylic acid is used as the palladium compound. 5 40. Process according to claim 39, characterized in that palladium-carbon, palladium chloride or palladium acetate are used as the palladium compound. 41. A process according to any one of claims 39-40, characterized in that the process is carried out in the presence of a lower tri(alkoyl)- 10 phosphite, such as triethylphosphite. 42. A process according to any one of claims 39-40, characterized in that it is carried out in the presence of triphenylphosphine. 43. A method according to any one of claims 39-42, characterized in that the cleavage is carried out in the presence of a base 15 organic. 44. A process according to claim 43, characterized in that N-methylmorpholine or triethylamine is used as the organic base. 45. A method according to any one of claims 33-34, characterized in that an ester of formula X is used where Het represents a 2-amino-4-thiazolyl. 46. Process for preparing 1-sulfo-2-oxo-azetidine derivatives of general formula HAS, 133 I R where R1 has the meaning given in claim 1, R4 has the same meaning as R1 in claim 1 and R4 has the 2 meaning given for R in the reveiiLcaticn I, the group = NOR appearing at least partly in syn form, with the clarification that at least one of the following two conditions is met: 4 a) R = 2-amino-4-oxazolyl, 2-amino-6-pyridyl, 2-amino- 4-imidazolyl, 5-amino-3-(1,2,4-thiadiazrolyl^ or 2-pyrazol-3-yl, 21 b) R = hydroxyaminomethyl, lower alkoxy-iminomethyl, lower alkoxy-lower carbonyl-lower alkenyl or lower carbamoyl-lower alkenyl, in racemic form or as the 3S enantiomer, as well as readily hydrolyzable esters or pharmaceutically acceptable salts of these compounds, characterized in that a) a carboxylic acid of general formula is reacted 40 R —C —COOH 11 IVb ^OR10 where R1^ has the same meaning as in formula III and 404 R has the same meaning as R in the formula le, where 134 I However, an existing amino group can be protected, and the 10 group =N0R appears at least partly in syn form, or one of its functional derivatives, with a compound of general formula h2n- 0 -r 21 -n \ so3h Ha 21 or R has the same meaning as in the formula above, appearing in racemic form or as the 3S enantiomer, or with one of its salts and by separating a possible amino protecting group, or b) by sulfonating a compound, present in racemic form or as the 3S enantiomer, of general formula r 41 -c—conh-II n ^OR1 ,r 21 XII O -"nh 1 21 where R and R have the same meaning as 41 4 above and R has the same meaning as R above, where however an amino group present is protected, and the group =N0R1 appears at least partly in syn form, or one of its salts, then separating the protecting group of 1-amino, or 21 (c) to prepare a compound of formula le, where R represents a hydroxyimino, a lower alkoxy-iminomethyl or a carbamoylvinyl, by reacting 135 a compound, appearing in racemic form or as an 11S enantiomer, with the general formula R — c—conh- II n X0R10 CHO Vlla 0^ -"N \ s03h 10 where R has the meaning given above and R1^ the meaning given in claim 1, and where the group =N0R1^ is at least partly in syn form, with hydroxylamine, a lower hydroxylamine (OH-hydroxylanine), or with carbamoylmethylenetriphenylphosphorane, and treating the resulting product, if necessary, with a lower hydroxylamine, or (d) to prepare a compound of formula R1, where R1 represents a lower carboxylamine, by transforming into a compound, present in racemic form or as the 3S enantiomer, of general formula R 40 -c—conh-II n X0RU O -r 21 -"N \ so3h If 15 20 where R^1 and R^ have the meaning given above and R1^ represents a lower tri-alkyl-lower silyl-alkoxy-lower carbonyl-alkyl, a lower alkoxy-lower carbonyl-alkyl, a lower phenyl-alkoxy-lower carbonyl-alkyl or a lower nitrophenyl-alkoxy-lower carbonyl-alkyl, where the group =N0R1 is at least partly in syn form, 136 13' the R group as a lower carboxy-alkoyl group, or e) by transforming a compound of formula le, present in racemic form or as an 11S enantiomer, or one of its readily hydrolyzable esters, into a pharmaceutically acceptable salt. 47. A method according to claim 46 for preparing compounds according to claim 46 of general formula 10 15 r —c—conh-II n ^OR1 -r ID 0^ -"n \ so3h 1 2 where R and R have the same meaning as in formula I 4 of claim 1 and R represents a 2-amino-4-oxazolyl, a 2-amino-6-pyridyl, a 2-amino-4-imidazolyl, a 5-amino-3-(1,2,4-thiadiazolyl) or a 2-pyrazol-3-yl, wherein the —NOR group is present at least partly in syn form, in racemic form or in the form of the 3S enantiomer as well as readily hydrolyzable esters or pharmaceutically acceptable salts of these compounds, characterized in that correspondingly substituted starting compounds are used. 48. Method according to claim 47 for preparing 4 compounds according to claim 47? where R represents a 2-amino-4-oxazolyl, a 2-amino-6-pyridyl, a 2-amino-4-imidazolyl or a 5-amino-3-(1,2,4-thiadiazolyl), characterized in that correspondingly substituted starting compounds are used. 49. A process according to claim 48 for preparing 3-[2-(2-amino-4-oxazolyl)-2-(methoxyimino)-acetamido]-4- 137 I ethynyl-2-oxo-l-azetidinesulfonic in racemic form or as a 3S enantiomer and pharmaceutically acceptable salts of these compounds, characterized in that correspondingly substituted starting compounds are used. 50. A process according to claim 48 for preparing 3-[(Z)-2-(5-amino-1,2,4-thiadiazolyl-3-yl)-2-(methoxyimino)-acetamido]-4-(methoxycarbonyl)-2-oxo-l-azetidine-sulfonic acid in racemic form or in the form of the 3S enantiomer, as well as pharmaceutically acceptable salts of these compounds, characterized in that correspondingly substituted starting compounds are used. 51. Process according to claim 48 of preparing 4-carbamoyloxymethyl-3-[(Z)-2-(methoxyimino)-2-pyrazol-3- yl ]-acetamido ]-2-oxo-l-azetidinesulfonic in racemic form or in the form of the 3S enantiomer as well as readily hydrolyzable esters or pharmaceutically acceptable salts of these compounds, characterized in that correspondingly substituted starting compounds are used. 52. A process according to claim 48 for preparing trans-3-[(Z)-2-(methoxyimino)-2-pyrazol-3-yl-acetamido]-4-methyl-2-oxo-l-azetidinesulfonic acid in racemic form or in the form of the 3S enantiomer, as well as readily hydrolyzable esters or pharmaceutically acceptable salts of these compounds, characterized in that correspondingly substituted starting compounds are used. 53. A process according to claim 48 for preparing 3-[(Z)-2-[5-amino-l,2,4-thiadiazol-3-yl]-2-[[(t-butoxycarbonyl )-methoxy]-imino]-acetamido]-4-carbamoyloxymethyl-2-oxo-l-azetidinesulfonic acid in racemic form or in the 138 form of the 3S enantiomer as well as readily hydrolyzable esters or pharmaceutically acceptable salts of these compounds, characterized in that correspondingly substituted starting compounds are prepared. 54. A process according to claim 48 for preparing 3-[(Z)-2-(5-amino-l,2,4-thiadiazol-3-yl)-2-[(carboxymethoxy)-imino]-acetamide ]-4-carbarnoyloxyrnethyl-2-oxo-1-azetidinesulfonic acid in racemic form or in the form of the 3S enantiomer, as well as readily hydrolyzable esters or pharmaceutically acceptable salts of these compounds, characterized in that correspondingly substituted starting compounds are used. 55. A process according to claim 46 for preparing compounds according to claim 46 of general formula r21 Het—C—CONH- " II N x0r1 j r the O \ so3h where R and Het have the same meaning as in formula I 21 of claim 1 and R represents a hydroxyiminomethyl, a lower alkoxy-iminomethyl, a lower alkoxy-lower carbonyl-alkenyl or a lower carbamoyl-alkenyl, where the =NOR1 group is at least partly in syn form, in racemic form or as the 3S enantiomer, as well as readily hydrolyzable esters or pharmaceutically acceptable salts of these compounds, characterized in that correspondingly substituted starting compounds are used. 139 I 56. Method according to claim 55 for preparing 21 compounds according to claim 55, where R represents a hydroxyiminomethyl or a lower alkoxy-iminomethyl, characterized in that correspondingly substituted starting compounds are used. 57. Method according to claim 56 for preparing acid 3-[(Z) — 2—(2-amino-4-thiazolyl)-2-(methoxyimino)-acetamido ]- 4-[(E/Z)-(hydroxyimino)-methyl]-2-oxo-1-azetidinesulfonic in racemic form or as the 3S enantiomer and pharmaceutically acceptable salts of these compounds, characterized in that correspondingly substituted starting compounds are used. 58. Method according to claim 56 for preparing acid 3-[(Z) — 2—(2-amino-4-thiazolyl)-2-(methoxyimino)-acetamido]- 4-methoxyiminomethyl-2-oxo-l-azetidinesulfonic in racemic form or as the 3S enantiomer and pharmaceutically acceptable salts of these compounds, characterized in that correspondingly substituted starting compounds are used. 59. A process according to claim 56 of preparing 3-[[(5-amino-3-(l,2,4-thiadiazolyl)]-2-(Z)-(methoxyimino)-acetamido]-4-methoxyiminomethyl-2-oxo-l-azetidinesulfonic acid in racemic form or in the form of the 3S enantiomer and pharmaceutically acceptable salts of these compounds, characterized in that correspondingly substituted starting compounds are used. 60. A process according to claim 55 for preparing 3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-acetamido]-4-[(E)-carbamoylvinyl]-2-oxo-l-azetidine-sulfonic acid in racemic form or as the 3S enantiomer, as well as pharmaceutically acceptable salts 140 of these compounds, characterized in that correspondingly substituted starting compounds are used. 61. A process according to claim 55 of preparing 3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-4-[(Z)-2-(ethoxycarbonyl)-1-methylvinyl]-2-oxo-l-azetidinesulfonic acid in racemic form or in the form of the 3S enantiomer and pharmaceutically acceptable salts of these compounds, characterized in that correspondingly substituted starting compounds are used. 62. A process for preparing medicinal products, characterized in that a derivative of 1-sulfo-2-oxoazetidine of general formula given above is put into a galenic administration form in racemic form or in the form of the 3S enantiomer as well as readily hydrolyzable esters or pharmaceutically acceptable salts of these compounds. 63. Thioesters of general formula where R has the same meaning as in formula III of the 4 claim 1 and R represents a 2-amino-4-oxazolyl, a 2-amino-6-pyridyl, a 2-amino-4-imidazolyl or a 5-amino-3-(1,2,4-thiadiazolyl), where the =NOR1^ group is at least partly in syn form. 64. 2-benzthiazolyl-thioester of 2-(2-amino-4-oxazo-lyl)-2-(methoxyimino)-acetic acid. 65. 2-benzthiazolyl-thioester of 2-[( 5-amino-3-(1,2,4-thiadiazolyl)]-2-(Z)-methoxyimino-acetic acid. 141 I 66. Thioesters of general formula Illb 12 where R represents a lower alkoxy-lower carbonyl-alkyl, a lower phenyl-alkoxy-lower carbonyl-alkyl, a lower nitrophenyl-alkoxy-lower carbonyl-alkyl, or a lower tri-alkyl-lower silyl-alkoxy- 12 lower carbonyl-alcoyl, where the = NOR group is present at least partly in syn form. "12 67. Thioester according to claim 66, where R represents a lower alkoxy-carbonylmethyl, a lower phenyl-alkoxy-car bonylmethyl, a lower nitrophenyl-alkoxy-carbonylmethyl or a lower tri-alkyl-silyl-alkoxy-car bonylmethyl. 68. 2-benzthiazolylthioester of 2-(2-amino-4-thia-zolyl)-2-[[(Z)-(p-nitrobenzyloxycarbonyl)-methoxy 3-imino]-acetic acid. 69. 2-benzthiazolyl-thioester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-(t-butoxycarbonyl)-methoxy]-imino-acetic acid. 12 70. Thioester according to claim 66, where R represents a lower alkoxy-carbonyl-1-methylethyl, an l-(phenyl-lower alkoxy-carbonyl)-1-methylethyl, an l-(nitro-phenyl-lower alkoxy-carbonyl)-1-methylethyl or a 142 5 10 1-(lower tri-alkyl-silyl-lower alkoxy-carbonyl)-1-methylethyl. 71. 2-benzthiazolyl-thioester of 2-(2-amino-4-thiazolyl)-2-[[(Z)-l-[2-(trimethylsilyl)-ethoxycarbonyl]-l-methylethoxy]-imino]-acetic acid. 72. 2-benzthiazolyl-thioester of 2-(2-amino-4-thia-zolyl)-2-[[(Z)-l-(p-nitrobenzyloxycarbonyl)-1-methylethoxy]-imino]-acetic acid. 73. 2-benzthiazolyl-thioester of 2-(2-amino-4-thiazo-lyl)-2-[[(Z)-l-( t-butoxycarbonyl ) -1-methyl-ethoxy ]-irnino]-acetic acid. ORIGINk containing K«nvoi% -fnoi sjo^.é —.—mol nsyS mxP Industrial Property Consultancy, 26b's, Princess Charlotte Blvd., Monte-Carlo