DK166280B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 2-AZETIDINONES - Google Patents

Description

DK 166280B

The present invention relates to an analogous method for the preparation of therapeutically active 2-azetidinones of the general formula j 4th

fc.NH-C₅-(i)

0 / - 'N-SOjH

Wherein R 1 is hydrogen or C 1-4 alkyl containing a carboxyl group or a C 1-4 alkyl or benzyl ester thereof, R 2 is hydrogen or C 1-4 alkoxy, and R 3 and R 4 is the same or different and means hydrogen or alkyl, or salts or stereoisomeric forms thereof.

Salts of the substituent on the nitrogen atom of the β-lactams prepared by the process of the invention include all sulfonic acid salts. Pharmaceutically acceptable salts are of course preferred, although other salts may also be used to purify the products prepared by the process of the invention or as intermediates in the manufacture of pharmaceutically acceptable salts. The cationic portion of the present sulfonic acid salts can be obtained from either organic or inorganic bases.

Such a cationic moiety includes, but is not limited to, the following ions: ammonium, substituted ammonium such as alkyl amraonium (e.g. tetra-n-butylammonium, hereinafter referred to as tetrabutylammonium), alkali metal such as lithium, sodium and potassium, alkaline earth metal such as calcium and magnesium, pyridinium, dicyclohexylammonium, hydrabaminium, benzathinium and

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2 N-methyl-D-glucaminium.

As described below, the β-lactams are made synthetically according to the invention. The non-alkoxylated 4-unsubstituted / 3-lactams of formula I, i. those compounds of formula I wherein R 2 / R 3 and R 4 are hydrogen can be prepared using 6-amino-penicillanic acid or a 6-acylaminopenicillanic acid as starting material. The β-layers of the formula I wherein R 2 is alkoxy can be prepared from the corresponding non-alkoxylated β-lactams. Some of the compounds of this invention may be crystallized or recrystallized from solvents containing water. In these cases, hydration water can be formed. The compounds of this invention comprise stoichiometric hydrates as well as compounds containing variable amounts of water and which can be prepared by methods such as lyophilization.

9-Laetams having a sulfonic acid salt substituent in the 1-position and an amino or acylamino substituent in the 3-position contain at least one chiral center, namely the carbon atom (in the 3-position of the β-lactam nucleus) to which the amino or acylamino substituent is attached. The invention relates to the preparation of such β-lactams described above, wherein the stereochemistry in the chiral center in the β-position of the β-lactam nucleus is the same as the configuration at the carbon atom in the 6-position of naturally occurring penicillins (e.g.

And the configuration at the carbon atom in the 7-position of naturally occurring cephamycins (e.g., cephamycin G).

The invention also encompasses a process for preparing racemic mixtures containing the above-described β-lactams.

β-Lactams with a sulfonic acid salt substituent in the β-lactam nucleus 1 position and an amino or acylamino substituent in the β-lactam nucleus 3 position exhibit activity against a variety of gram-negative and gram-positive organisms. The sulfonic acid salt substituent is essential for those of invention 3

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the activity of late compounds. The compounds wherein R 3 and / or R 4 are hydrogen or alkyl, especially methyl, exhibit a particularly favorable activity.

The present compounds can be used as agents for controlling bacterial infections (including urinary tract infections and respiratory tract infections) in mammals such as domestic animals (e.g., dogs, cats, cows, horses, and the like) and in humans.

For the control of bacterial infections in mammals, a compound prepared by the method of the invention can be administered to a mammal in need thereof in an amount of approx. 1.4 mg / kg / day to approx. 350 mg / kg / day, preferably approx. 14 mg / kg / day to approx. 100 mg / kg / day. All modes of administration previously used to deliver penicillins and cephalosporins to the site of infection may also be used in the context of the novel family of β-lactams. Such methods of administration include oral, intravenous and intramuscular administration as well as suppositories.

The β-lactam products are prepared in accordance with the process of the invention by a) sulfonating a corresponding intermediate with a hydrogen atom at the 1-position with a pyridine-sulfur trioxide complex or equivalent thereof under conventional conditions or b) acylating a corresponding intermediate in which R 1 is hydrogen, with an acyl group as defined by R 2 above by conventional methods and, if desired, converting acid groups to salts and / or, if desired, dividing racemic mixtures into stereoisomeric forms.

The most commonly used sulfur trioxide complexes are pyridine sulfur trioxide, lutidine sulfur trioxide, dimethylformamide sulfur trioxide and picoline sulfur trioxide. Instead of using a pre-formed complex, the complex can be formed in situ, e.g. using chlorosulfonyltrimethylsilyl ester and pyridine as reactants. Alternatively, the sulfonation may be by means of an intermediate, e.g. at 4

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first, to silylate the nitrogen atom in the β-lactam nucleus and then subject the silylated compound to a silyl exchange reaction with trimethylsilyl chlorosulfonate or a similar reactant. Silylating agents are e.g. monosilyl trifluoroacetamide, trimethylsilyl chloride / triethylamine and bis-trimethylsilyltrifluoroacetamide.

As a rule, the sulfonation reaction is carried out in the presence of an organic solvent such as pyridine or a mixture of organic solvents, preferably a mixture of a polar solvent such as dimethylformamide and a halogenated hydrocarbon such as dichloromethane.

The product initially formed by the sulfonation reaction is a salt of the sulfonated β-lactam.

When pyridine-sulfur trioxide is the sulfonation complex, the product formed to begin with is the β-lactam sulfone -gyrated pyridinium salt of the sulfonated β-lactam, where M in the formula below is the pyridinium ion: 20 - + / yn - so3 mo

These complexes can be converted to other sulfonic acid salts using conventional techniques (e.g., using ion exchange resins, crystallization or ion-pair extraction). These conversion methods are also useful for purifying the products. Conversion of the pyridine salt to the potassium salt using potassium phosphate or potassium ethyl hexanoate, to the tetrabutylammonium salt using tetrabutylammonium hydrogen sulfate, or to a zwitterion (M + = hydrogen) using formic acid are particularly useful.

It should be noted that the sulfonation reaction which causes the introduction of the sulfo group to nitrogen atoms in the β-lactam nucleus can be carried out at various stages of the synthesis, including introduction before formation of a β-lactam nucleus, following such a procedure as set forth below. . The sulfonation reaction 5

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occurs in the presence of solvents described above and usually at room temperature. When the amino function is present, it is preferably carried out with the amino function protected.

Using, for example, a benzyloxycarbonyl protecting group, the sulfonation reaction can be illustrated as follows:

2 4 R R

κ2 τΑ 10 CgHgCfLjOCO-NH - t-R3 H2N - T “R3] \ sulfcneridg _.

-NH 2) £ inhibition of J-N-SO3 M

protection σ

Other protecting groups may be used to protect the amine function, e.g. a t-butyloxycarbonyl group, a simple acyl group such as acetyl or benzoyl, or phenylacetyl, a triphenylmethyl group, or with the amino function in the form of an azide group. The desired acyl group (R 2) can then be joined by a conventional acylation reaction.

Examples of acylation technique for converting a compound of formula III into a product of formula I include reaction with a carboxylic acid (R 2 -OH) or a corresponding carboxylic acid halide or carboxylic anhydride.

When R 2 is alkoxy, the acylation is best performed using an acid chloride or an acid bromide. The reaction with a carboxylic acid is most easily carried out in the presence of a carbodiimide such as dicyclohexylcarbodiimide and a substance capable of forming an active ester in situ such as N-hydroxybenzotriazole.

In such cases where the acyl group (R 2) contains reactive functionality (such as amino or carboxyl groups), it may be necessary first to protect these functional groups, then to perform the acylation reaction and finally to remove the protecting group from the resulting product. Alternatively, the sulfonation reaction may be carried out with the acyl group 35 in place, i.

0

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6 2 4 .24 R1-NH - ^ - R3 v R, -NH - f-R3. suiranuig '.

/; - ip J-n-soZm o o 3. When R3 is lower alkoxy, a further variation can be carried out in that the lower alkoxy group R2 can be introduced both after and before the sulfonation using the usual technique of chlorinating the acylated nitrogen atom at 3-positions followed by reaction. with a lower alkoxide H H 4 (R 2) alkoxide R 2 R 4 acyl-N -? - r 3 _ ^ acyl-NH - i-R 3. -N-SO ~ M * J-N-SO ~ M + (j 3 o ** 3

WE V

The acyl groups of the above reaction also include readily removable groups which act as a protecting group and which the male is removed after the reaction to give the "deacylated" product (-NH 2).

An excellent source of the β-lactam starting materials 25 are the 6-aminopenicillanoic acids and the 7-aminocephalosporanoic acids, which may have an optional 6-alkoxy or 7-alkoxy substituent, respectively. These compounds have the formulas: 30 35 0

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7 2 R -NH - S> I I CH3 XXVa

I - N-C-C00H

0 '5 and R3 R ^ -NH --- J ^ "S' | 10 oJ-« sJ CH3 XXVb

COOH

wherein R 2 is hydrogen or alkoxy and is hydrogen or acyl. Using the methods described in the literature, 3-amino-2-azetidinones can be prepared, see f.

Chem. Soc. Special Publication No. 28, page 288 (1977),

The Chemistry of Penicillins, Princeton Univ. Press, page 257, and Synthesis, 494 (1977).

The 6-aminopenicillanoic acid or 7-amino-cephalosporanoic acid is first desulfurized by reduction using

Raney nickel. The reaction can be carried out in water under reflux conditions and the resulting compound has the structural formula: R 2 R, -NH-- 25! ; xxvi J-H-CH-CH1CH,) - cT I 32

COOH

Exchanging the carboxyl group of the compound of formula XXVI with an acetate group followed by hydrolysis gives a 3-amino-3-alkoxy-2-azetidinone of formula I wherein R 1 is hydrogen or acyl, R 2 is hydrogen or lower alkoxy, and R and is hydrogen. Treatment of a compound of formula XXVI with cupriacetate and lead tetraacetate in an organic solvent (e.g. acetonitrile) causes the carboxyl group to be replaced by an acetate group. Hydrolysis of the resultant compound can take place using potassium carbonate in the presence of sodium borohydride.

0

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8

Introduction of a sulfo group at the 1-position to the above-mentioned 3-amino-3-alkoxy-2-azetidinone compound can be effected by reacting the intermediate with a complex of dimethylformamide and sulfur trioxide.

A 3-azido-2-azetidinone starting material may be prepared by first reacting an olefin of formula 4

CH2 = C-R3 XXVII

With a halogen sulfonyl isocyanate (preferably chlorosulfonyl isocyanate) of the formula

0 = C = N-SO2 ~ halogen XXVIII

15 to give an azetidinone of formula 24 -f "R3

XXIX

20-N-SO 2 -halogen.

Reducing hydrolysis of an azetidinone of formula XXIX gives an N-unsubstituted β-lactam of formula * 4 R3

25 XXX

J-NH

For a more detailed description of the reaction sequence described above, reference is made to the literature, see e.g. Chem. Soc. Rev. , 181 (1976) and J. Org. Chem. 35, 20, 2043 (1970).

An azido group at the 3-position can be introduced into an azetidinone of formula XXX (or the sulfonated corresponding compound) by reacting the compound with an aryl sulfonylazide (such as toluene sulfonylazide) to give an starting azézeidinone of formula 0

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9 r4 n3 -r ~ R3

J J XXXI

J-NH

5

The reaction is best done by first protecting the azetidinone nitrogen with a silyl residue (e.g. t-butyldimethylsilyl or t-butylphenylsilyl), then forming the anion at the 3-position of the nucleus with a strong organic base (e.g., lithium diisopropylamine ) at low temperature and then treated ten

le the anion with toluene sulfonylazide. The resulting intermediate is cooled with trimethylsilyl chloride, followed by acid J

hydrolysis or fluoride solvolysis of the N-protecting group affords the compound of formula XXXI.

Alternatively, the compound of formula XXXI can be obtained by first reacting a primary amine of formula H2N-CH2-O-alkyl or H2N- -O-alkyl 20 in O-alkyl with an aldehyde of formula R3CH = 0, giving the similar Schiff base. A [2 + 2] cyclization addition with an activated form of -azido acetic acid gives a 3-azido-2-azetidinone of the formula R4 N3 -] - t ~ R3

J-N Q

30 CK

wherein Q is -CH 2 - O - O-alkyl or -O-alkyl O-alkyl

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10

Oxidative removal of the Q substituent gives the compound of formula XXXI.

3-Acylamino-2-azetidinones can be obtained by first reducing a 3-azido-2-azetidinone of formula XXXI to give the corresponding 3-amino-2-azetidinone, and then acylating the 3-amino-2-azetidinone.

As previously mentioned, in the case where 1 * 2 is lower alkoxy, the product can be prepared from the corresponding product where R 2 is hydrogen. Chlorination of the amide nitro-10 gene in a non-alkoxylated compound gives an intermediate of the formula

CjlH R4 R.-N -? - R3

XXXII

15 J-N-SO 3'M +

Reagents and methods for N-chlorination of amides are known in the art. Such reagents are tert-butyl hypochlorite, sodium hypochlorite and chlorine. The reaction may take place in an organic solvent (e.g., a lower alkanol such as methanol) or in a two-phase solvent system (e.g., water / methylene chloride) in the presence of a base such as sodium borate decahydrate. The reaction preferably proceeds at a reduced temperature.

The reaction of an intermediate of formula XXXI with an alkoxylating agent, e.g. an alkali metal alkoxide, gives a product of formula I wherein R 2 is alkoxy, combined with its enantiomers. The reaction may take place in an organic solvent, e.g. a polar organic solvent such as dimethylformamide at reduced temperature.

An alternative synthesis for the preparation of compounds of formula I wherein R 2 is alkoxy first comprises alkoxylation of an intermediate of formula VI wherein R 1 NH is a carbamate (e.g. R 1 is benzyloxycarbonyl) and R 2 is hydroxy. -35 gene, and then introducing a sulfo group into the resulting compound 1 position. Chlorination of a compound of formula VI using the method described above

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n (for chlorination of a non-alkoxylated compound of formula I to give a compound of formula XXXII) gives an intermediate of formula c 5 j _ 4 c6h5-ch2-o-co-n-j-i-r3 i

XXXIII

JN-Cl o * · 0 Using the above-described alkoxylation method (to convert a compound of formula XXXII into one in product of formula I) and then adding a reducing agent such as trimethylphosphite, the compound of formula XXXIII can be converted to an intermediate of formula 15-alkyl R 4

C6H50-C0 "NH" R3 XXXIV

j 5.8 20 combined with its enantiomers.

The above methods give such products of formula I wherein R 2 is alkoxy as a racemic mixture. If desired, the R-configuration enantiomer can be isolated from the racemic mixture by conventional techniques such as fractionated crystallization of a suitable salt with an optically active organic amine or by ion-paired chromatography using an optically active cation.

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Example 1 (S) -3- [[(2-Amino-4-thiazolyl) acetyl] amino] -2-oxo-1-azetidine sulfonic acid potassium salt A) (S) -3-Amino-2-oxo-1 -azetidine sulfonic acid tetrabutylammonium salt 2 g (S) -2-OXO-3- [[(phenylmethoxy) carbonyl] amino] -1-azetidine sulfonic acid tetrabutylammonium salt (see Example 4) are dissolved in 100 ml of dimethylformamide and hydrogenated in ca.

3 minutes with 1 g of palladium-on-charcoal (10%) as catalyst. The catalyst is filtered off and the dimethylformamide is removed leaving the title compound as an oil. NMR (CDCl 3) 3.82 (1H, t, - 5.5), 4.05 (d, 1H, d of d, J = 5.5, 2.5 Hz).

B) (S) -3- [[(2-Amino-4-thiazolyl) acetyl] amino] -2-oxo-1-azadidine sulfonic acid potassium salt 2 g of the above compound, 0.5 g aminothiazole acetic acid and 0.4 g of hydroxybenzotriazole is stirred at 0 ° C in 100 ml of dry dimethylformamide, while a solution of 0.7 g of dicyclohexylcarbodiimide in 10 ml of dimethylformamide is added dropwise. After the addition is complete, stirring is continued for 12 hours at 20 ° C. Insoluble urea is filtered off and the solvent is evaporated in vacuo. The oily residue is treated with a solution of potassium perfluorobutanesulfonate in 2 ml of acetone at room temperature for 15 minutes. After the addition of 200 ml of dimethyl ether, the title compound is precipitated and filtered, dried and purified by means of a 300 ml HP-20 chromatography column using water as the eluent. The yield is 850 mg of the title compound, mp> 300 ° C.

35 13

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Example 2 [3S (Z) 3-3- [[(2-Amino-4-thiazolyl) [[(hydroxy (phenylmethoxy) -phosphinyl) methoxy] imino] acetyl] amino 1 -2-oxo-1-azetidine insul in phonic acid potassium salt j 0.8 g (S) -3-amino-2-oxo-1-azetidine sulfonic acid tetra-butylammonium salt (see Example 1A) in 30 ml of dimethylformamide, 1 0.9 g (Z) - 2-Amino-α ~ [[hydroxy (phenylmethoxy) phosphinyl] methoxy] imino] -4-thiazole acetic acid, 0.3 g hydroxybenzotriazole i and 0.7 g dicyclohexylcarbodiimide are stirred for 24 hours at room temperature. The precipitated urea is filtered off The residual oil is treated with an equivalent amount of potassium perfluorobutane sulphonate in 10 ml of acetone. The title compound is filtered off and purified using HP-20 resin and water as eluent to give 500 mg which melting at 210-215 ° C with decomposition.

Example 3 [3S (Z)] -3- [[(2-Amino-4-thiazolyl) (ethoxyimino) acetyl] amino] -2-oxo-1-azetidine sulfonic acid potassium salt 1.5 g (S) -3 -amino-2-oxo-1-azetidine sulfonic acid tetrabutylammonium salt (see Example 1A) in 100 ml of dimethylformamide, 0.6 g of hydroxybenzotriazole, 1 g of dicyclohexylcarbo-diimide and 0.8 g of (Z) -2-amino -a- (ethoxyimino) -4-thiazole acetic acid is stirred at room temperature for 24 hours. The solvent is distilled off and the residue is dissolved in 30 ml of acetone. The urea is filtered off and the mother liquor is treated with a solution of 2 g of potassium perfluorobutanesulfonate in 20 ml of acetone.

After the addition of 200 ml of ether, the title compound is precipitated, filtered off and dried. Purification is by chromatography using an HP-20 column and water as the eluent, yielding 1.1 g of the title compound, mp 180-185 ° C, with decomposition.

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Example 4 [3S (E)] - 3 - [[(2-Amino-4-thiazolyl) (ethoxyimino) acetyl] amino] -2-oxo-1-azetidine sulfonic acid potassium salt

By the method of Examples 3, 5 but using (E) -2-amino-α- (ethoxyimino) -4-thiazole acetic acid instead of (Z) -2-amino-α- (ethoxyimino) -4 -thiazoleacetic acid, the title compound is obtained, which melts at 160-170 ° C after freeze-drying.

Example 5 [3S (Z) -3 - [[(2-Amino-4-thiazolyl)] (2,2,2-trifluoroethoxy) imino] acetyl] amino] -2-oxo-1-azetidine sulfonic acid potassium salt of the procedure of Example 3 but using (Z) -2-amino-α - [(2,2,2-trifluoroethoxy) -imino] -4-thiazole acetic acid instead of (Z) -2-amino-α (ethoxyimino) - 4-thiazole acetic acid, the title compound is obtained, which melts at 160-170 ° C after freeze-drying.

20

Example 6 [3S (Z)] - 3 - [[(2-Amino-4-thiazolyl) (methoxyimino) acetyl] amino] -. 2-oxo-1-azetidine sulfonic acid potassium salt (S) -3-Amino-2-oxo-1-azetidine sulfonic acid tetrabutylammonium salt (prepared as described in Example 1A out of 7.9 g (S) -2-oxo -3 - [[(phenylmethoxy) carbonyl] amino] -1 - azetidine sulfonic acid tetrabutylammonium salt) is cooled to 0 ° C and 3.53 g of (Z) -2-amino-α- (methoxyimino) -4-thiazole acetic acid is added. followed by a solution of 3.27 g of dicyclohexylcarbodiimide in 10 ml of dimethylformamide. The mixture is stirred for 16 hours at 5 ° C, filtered and the solvent removed in vacuo. The residue is dissolved in acetone and filtered. After the addition of 60 ml of a 10% solution of potassium perfluorobutane sulfonate in acetone, 35 g of crude product crystallize. The crude product is purified by chromatography on HP -20, 100-200 mesh, yielding 3.0 g of the title compound which melts at 235 ° C.

0 15

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Example 7 [3S (Z)] -3- [[(2-Arino-4-thiazolyl) - [[2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy] imino] acetyl] amino] -2 -oxo-1-azetidine sulfonic acid potassium salt (1: 1) A solution of 0.005 mole (S) -3-amino-2-oxo-1-azetidine

idinsulfonic acid tetrabutylammonium salt (see Example 1A) and 0.006 mol (Z) -2-amino-α - [[2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy] imino] -4-thiazole acetic acid in 60 ml of dimethyl -formamide is treated with 0.7 g of hydroxybenzotriazole and 1.13 g of dicyclohexylcarbodiimide. The mixture is stirred for approx. 16 hours at room temperature, filter and evaporate the filtrate. The residue is dissolved in 30 ml of acetone, filtered and treated with 20 ml solution of 10% potassium perfluorobutanesulfonate in acetone. After the addition of petroleum ether, the title compound is precipitated and treated with ether and filtered to give 3.8 g of product, mp 190 ° C

during decomposition.

Example 8 [3S (Z)] - 3 - [[(2-Amino-4-thiazolyl) [(1-carboxy-1-methylethoxy) -amino] acetyl] amino] -2-oxo-1-azetidaric sulfonic acid dipotassium salt 2 g (3S (Z)] - 3 - [[(2-Amino-4-thiazolyl) [[2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy] imino] acetyl] amino] -2- -oxo-1-azetidine sulfonic acid potassium salt (see Example 7) was suspended in 5 ml of anisole and 25 ml of trifluoroacetic acid was added at -10 ° C. The mixture was stirred for 10 minutes at -10 ° C.

100 ml of ether are slowly added at -10 ° C and then 50 ml of petroleum ether is added. The precipitate is filtered off to give 1.6 g of trifluoroacetic acid salt. This is suspended in 20 ml of water at 0 ° C, adjusted to pH 5.5 with dilute potassium hydroxide and purified on an HP-20 column. The title compound is eluted with water and has a melting point of 225 ° C during decomposition.

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Example 9 [3S (Z)] - 3- [C (2-Amino-4-thiazolyl) [[2- (diphenylmethoxy) -2-oxo-ethoxy] imino] acetyl] amino] -2-oxo-1-azetidine sulfonic acid -potassium salt 5 By the procedure described in Example 7, but using (Z) -2-amino-α - [[2- (diphenylmethoxy) -2-oxoethoxy] imino] -4-thiazole acetic acid instead for (Z) - 2-amino-α - [[2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy] imino] -4-thiazole acetic acid gives the title compound, m.p. 180 ° C during decomposition.

Example 10 [3S (Z)] - 3 - [[(2-Amino-4-thiazolyl) - [(2-methoxy-2-oxoethoxy) imino] acetyl] amino] -2-oxo-1-azetidine sulfonic acid potassium salt 1.3 g (Z) -2-amino-α - [(2-methoxy-2-oxoethoxy) imino] -4-thiazole acetic acid and -2.03 g (S) -3-amino-2-oxo 1-azetidine sulfonic acid tetrabutylammonium salt (see Example 1A) is dissolved in 50 ml of acetonitrile and 1.03 g of dicyclohexylcarbodiimide dissolved in 5 ml of acetonitrile is added dropwise at 0 ° C. After stirring for 15 hours and filtering off dicyclohexylurin, the solvent is distilled off. The remaining oily residue is dissolved in acetone and treated with an equivalent amount of potassium perfluorobutanesulfonate. The title compound is isolated and purified by column chromatography on HP-20 with water as the eluent to give the title compound, mp 195-198 ° C.

30 35 0 17

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Example 11 [3S (Z) -3 - [[(2-Amino-4-thiazolyl) [I (diethoxyphosphinyl) methoxyxyimino] acetyl] amino-2-oxo-1-azetidine sulfonic acid potassium salt 2.25 g ( S) -3-Amino-2-oxo-1-azetidine sulfonic acid tetrabutylammonium salt (see Example 1A) in 100 ml of dry dimethylformamide is treated with 1.87 g of (Z) -2-amino-at [(diethoxyphosphinylmethoxy) ] imino] -4-thiazole acetic acid, 0.75 g of hydroxy-benzotriazole and 2.29 g of dicyclohexylcarbodiimide for 12 hours with stirring The filtered urea is filtered off and the solvent removed in vacuo. The remaining oil is treated with an equivalent amount of potassium perfluorobutane After addition of ether, the title compound is precipitated and filtered off, yielding 2.77 g of crude product. Purification of this crude product by column chromatography using HP-20 and water. acetone (9: 1) as eluent yields the title compound, mp 155-160 ° C, with decomposition Ling.

20

Example 12 [3S (Z)] - 3 - [[(2-Amino-4-thiazolyl) [[2- (1,1-dimethylethoxy) -2-oxo-1-phenylethoxy] imino] acetyl] amino] -2 -oxo-1-az ethidine sulfonic acid potassium salt 2.25 g (S) -3-amino-2-oxo-1-azetidine sulfonic acid tetrabutylammonium salt (see Example 1A) in 60 ml of dimethylformamide is stirred at room temperature with 2 4 g (Z) -2-amino-α - [[2- (1,1-dimethylethoxy) -2-oxo-1-phenylethoxy] imino] -4-thiazole acetic acid, 1 g hydroxybenzotriazole and 1.5 g dicyclohexyl-3q carbodiimide for 12 hours. The solvent is removed in vacuo and the residue is dissolved in 50 ml of acetone. The precipitated urea is filtered off and the mother liquor is treated with an equivalent amount of potassium perfluorobutane sulfonate. After the addition of ether, the title compound crystallizes and is filtered off. The compound is purified by HP-20 column chromatography using water / acetone (7: 3) as the eluent to yield 1 g of 0 18

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of the product, melting point> 250 ° C with decomposition.

Example 13 [3S (Z)] -3- [[(2-Amino-4-thiazolyl) [(1H-tetrazol-5-ylmethoxy) -imino] acetyl] amino] -2-oxo-1-azetidine sulfonic acid potassium salt 1.9 g of (S) -3-amino-2-oxo-1-azetidine sulfonic acid tetra-butylammonium salt (see Example 1A) in 60 ml of dimethylformamide are treated with 1.4 g of (Z) -2-amino-α - [( 1H-tetrazol-5-ylmethoxy) imino] -4-thiazole acetic acid, 0.7 g hydroxybenzotriazole and 1.4 g dicyclohexylcarbodiimide with stirring for 24 hours.

After the solvent is removed in vacuo, the residue is dissolved in acetone and the precipitated urea is filtered off. The mother liquor is treated with an equivalent amount of potassium perfluorobutanesulfonate in 10 ml of acetone. The title compound 1 · * is precipitated by the addition of 200 ml of ether. Purification is performed by HP-20 column chromatography using HP-20 resin and water as the eluent to yield 1.05 g of product, mp 250 ° C (dec.).

Example 14 [3S (Z)] -3- [[(2-Amino-4-thiazolyl) [(phenylmethoxy) imino] acetyl] amino] -2-oxo-1-azetidine sulfonic acid potassium salt 1.5 g (S) -3-amino-2-oxo-1-azetidine sulfonic acid tetra-butylammonium salt (see Example 1A), 1.23 g (Z) -2-amino-α - [(phenylmethoxy) imino] -4- thiazole acetic acid, 0.57 g of hydroxybenzotriazole and 1.14 g of dicyclohexylcarbodiimide are stirred in 60 ml of dimethylformamide at room temperature for 24 hours. The precipitated urea is filtered off, the solvent is removed and the residue is treated with an equivalent amount of potassium perfluorobutanesulfonate in 10 ml of acetone. After the addition of 200 ml of ether, the title compound is precipitated and purified by HP-20 column chromatography using water / acetone (9: 1) as eluent to yield 1 g of material, m.p. 200 ° C (decomp.).

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Example 15 [3S (Z)] -3- [[(2-Amino-4-thiazolyl) [carboxymethoxy) imino] acetyl] amino] -2-oxo-1-azetidine sulfonic acid potassium salt (1: 1) 1.3 g [3S (Z)] 3- [[(2-Amino-4-thiazolyl) [[2- (diphenylmethoxy) -2-oxoethoxy] imino] acetyl] amino] -2-oxo-1-aceti disinsulfonic acid - Potassium salt (1: 1) (see Example 9) is mixed with 5 ml of anisole. 25 ml of trifluoroacetic acid are added at -15 ° C and the mixture is stirred for 10 minutes. 100 ml of ether are slowly added at -10 ° C and then 50 ml of petroleum ether. The precipitate is suspended under cooling in 20 ml of water and adjusted to pH 5.0 with dilute potassium hydroxide. The product is purified by chromatography on an HP-20 column yielding 3.0 g of the title compound, mp 230-235 ° C (decomposition).

15

Example 16 [3S (Z)] -3- [[(2-Amino-4-thiazolyl) [[2-oxo-2-phenylmethoxy) ethoxy] imino] acetyl] amino] -2-oxo-1-azetidine sulfonic acid potassium - salted 20 Using the procedure of Example 7, but using (Z) -2-amino-α- [[2-oxo-2- (phenylmethoxy) -ethoxy] imino] -4-thiazole acetic acid instead of (Z ) -2-Amino - α - [[2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy] imino] -4-thiazole acetic acid yields the yield of the title compound, m.p. 170 ° C (dec.).

Example 17 [3S (Z)] - 3 - [[(2-Amino-4-thiazolyl) (hydroxyimino) acetyl] amino] -2-oxo-1-azetidine sulfonic acid potassium salt

A solution of 0.6 g of 90% hydroxybenzotriazole in 100 ml of dimethylformamide is stirred for one hour with 10 g of 4A molecular sieves, filtered and the filtrate is added to a solution of 0.004 mol (S) -3-amino-2-oxo -1-azetidine sulfonic acid tetrabutylammonium salt (see Example 1A) in dimethyl

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o formamide. 0.89 g of (Z) -2-amino-α- (hydroxyimino) -4-thiazole acetic acid is added followed by the addition of 0.91 g of dicyclohexylcarbodiimide. The mixture is stirred for approx. 16 hours, evaporate in vacuo and dissolve the residue in 20 ml of acetone 5 and filter. Addition of a solution of potassium perfluorobutane sulfonate causes the title compound to precipitate. Chromatography on HP-20 resin yields 0.44 g of product, m.p. 240 ° C.

10

Example 18 [3S (Z)] -3- [[(2-Amino-4-thiazolyl) [(carboxymethoxy) imino] acetyl] amino] -2-oxo-1-azetidine sulfonic acid potassium salt 0.1 g [3S (Z) ] -3 - [[(2-amino-4-thiazolyl) [[2-oxo-2-15 (phenylmethoxy) ethoxy] imino] acetyl] amino] -2-oxo-1-azetidine sulfonic acid potassium salt (see Example 16) is dissolved in a mixture of 5 ml of ethanol and 5 ml of water and hydrogenated at room temperature in the presence of 0.2 g of 10% palladium on charcoal.

After 2 hours, the catalyst is filtered off and the 20 remaining solution is freeze-dried, yielding the title compound, m.p. 235 ° C (dec.).

Example 19 [3S (Z)] -3- [[(2-Amino-4-thiazolyl ([[2- (1,1-dimethyl ethoxy) -1- (methylthio) -2-oxoethoxy] imino] acetyl] amino] -2-oxo-1-azetidine sulfonic acid potassium salt

By the procedure of Example 17, but using (Z) -2-amino-α- (hydroxyimino) -4-thiazoleacetic acid instead of (Z) -2-amino-α- [[2- ( 1,1-Dimethylethoxy) -1- (methylthio) -2-oxoethoxy] imino] -4-thiazole acetic acid yields the title compound, mp 130 ° C (dec.).

35 21

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Example 20 [3+ (Z)] -3- [{(2-Amino-4-thiazolyl) (methoxyimino) acetyl] amino] -3-methoxy-2-oxo-1-azetidine sulfonic acid potassium salt 3-Amino Dissolve -3-methoxy-2-oxo-1-azetidine sulfonic acid tetra-butylammonium salt in 20 ml of acetonitrile and 1 ml of pyridine and add to a vigorously stirred suspension of (Z) -a- (meth-oxyimino) -2-amino 4-thiazole acetyl chloride in acetonitrile (20 ml) cooled to 0-50 ° C. After cooling with stirring for 1 hour, the mixture is diluted with 100 ml of 0.5 molar monobasic potassium phosphate solution (the pH of the mixture is 4.8) and the solvent removed in vacuo. The residue is taken up in a little water containing some acetone. Chromatography on 200 ml ion exchange resin ("AG 50W-X2", 100-200 mesh, K + form) gives a crude product as the potassium salt after elution with water. Further purification of 200 ml of "HP-20" resin with water as eluent gives 59 mg of product as powder after trituration with acetonitrile / ether and then twice with ether. The product is an amorphous powder which melts slowly and decomposes above 150 ° C.

Analysis:

Calculated for C 10 H 12 N 5 O 7 SK: C 28.77, H 2.90, N 16.78, S 15.36, K 9.37 Found: C 27.77, H 2.82, N 15.87, S 13.63, K 10.11.

25

Example 21 [3S- [3α (Z), 4β] 1-3- [[(2-Amino-4-thiazolyl) (methoxyimino) acetyl] amino] -4-methyl-2-oxo-1-azetidine sulfonic acid potassium salt A ) (3S-trans) -4-Methyl-2-oxo-3- [[(phenylmethoxy) carbonyl] -amino] -1-azetidine sulfonic acid tetrabutylammonium salt 352.4 mg (3S-trans) -4-methyl-2 -oxo-3 - [[(phenylmethoxy) carbonyl] amino] -1-azetidine sulfonic acid potassium salt is dissolved in 20 ml of water and 373.5 mg of tetrabutylammonium hydrogen sulfate are added. The aqueous solution 35 is extracted three times with methylene chloride and

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Dry extracts are dried over sodium sulfate. After removal of the solvent, 534.6 mg of the title compound is obtained.

B) [3S- [3α (Z), 4β]] - 3 - [[(2-Amino-4-thiazolyl) (methoxyimino) -acetyl] amino] -4-methyl-2-oxo-1-azetidine sulfonic acid potassium salt

A solution of 534.6 mg (3S-trans) -4-methyl-2-oxo-3- [[(phenylmethoxy) carbonyl] amino] -1-azetidine sulfonic acid tetrabutylammonium salt in 20 ml of dimethylformamide is hydrogenated with 220 mg 10% palladium on charcoal at atmospheric pressure for 2.75 hours in hydrogen uptake is 26.3 ml. The mixture is filtered and washed twice with 2.5 µl of dimethylformamide. The filtrate and washings (a total of about 25 ml) are stirred under nitrogen with 161 mg of (Z) -a- (methoxyimino) -2-amino-4-thiazoleacetic acid, 136 mg of N-hydroxybenzotriazole and 164.8 mg of dicyclohexylcarbodiimide. The mixture is stirred under nitrogen for approx. 16 hours. The dimethylformamide is removed in vacuo and the rubbery residue is dissolved in acetone and filtered to remove urea. To the filtrate is added a solution containing 272 mg (0.8 mmol) of perfluorobutanesulfonic acid potassium salt in 0.8 ml of acetone. The slurry is diluted with a similar volume of ether and filtered to give 325.5 mg of crude product which is purified by chromatography on 75 ml of "HP-20r 25 AG". Elution with 400 ml of water and 400 ml (9: 1) of water / acetone mixture (50 ml of fractions) gives 335 mg in fractions 3-10. After trituration with acetone / hexane, 97.3 mg of an analytical sample of fractions 3-5 is obtained. A similar trituration of fractions 6-10 yields an additional 90.4 mg of product as solid 30.

Analysis:

Calcd for C 18 H 20 N 5 O 6 S 2 K: C 29.92, H 3.01, N 17.45, S 15.97, K 9.74.

Found: C 30.32, H 3.49, N 15.82, S 13.95, K 10.45.

NMR (D 2 O) 1.57 (3H, α, J = 7), 3.97 (3H, s), 4.30 (1H, d of q, J = 7.3), 4.70 (1H) , i.e., J = 7), 6.95 ppm (1H, S).

23 0

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Example 22 [3S- [3α (Z), 4β]] - 3- [[(2-Amino-4-thiazolyl) [(1-carboxy-1-methylethoxy) imino] acetyl] amino] -4-methyl -2-oxo-1-azetidine sulfonic acid dicalcium salt A) N-Benzyloxy-t-boc-threoninamide

A solution of 8.76 g of t-boc-threonine and the free amine of 6.4 g of O-benzylhydroxyamine HCl (ethyl acetate / sodium bicabonate release) in 100 ml of tetrahydrofuran is treated with 6.12 g of N-hydroxybenzotriazole and 8 , 24 g of dicyclohexylcarbodiimide in 20 ml of tetrahydrofuran. The mixture is stirred under nitrogen for 26 hours, filtered and evaporated in vacuo. The residue is chromatographed on a 300 g silica gel column (elution with chloroform and chloroform / ethyl acetate (3: 1)) to yield 4.18 g of the title compound.

B) (3S-trans) -N-Benzyloxy-3-t-butoxycarbonylamino-4-methyl-azetidinone

A solution of 12.67 9 N-benzyloxy-t-boc-threoninamide, 11.5 g of triphenylphosphine and 6.23 ml of diethyl azodi-carboxylate in 380 ml of tetrahydrofuran is stirred under nitrogen for approx. 16 hours. The solution is evaporated and chromatographed on a 900 g silica gel column. Elution with chloroform / ethyl acetate (3: 1) gives 13.69 g of compound crystallizing from ether / hexane to yield 9.18 g of the title compound.

C) (3S-trans) -3-t-Butoxycarbonylamino-1-hydroxy-4-methyl-azetidinone

A solution of 9.18 g (3S-trans) -N-benzyloxy-3β-t-butoxycarbonylamino-4-methyllazetidinone in 300 ml of 95% ethanol is stirred in hydrogen atom with 1.85 g of 10% palladium charcoal. After 141 minutes, the slurry is filtered and evaporated in vacuo. The residue is recrystallized from ether / hexane to yield 5.12 g of the title compound.

D) (3S-trans) -3-t-Butoxycarbonylamino-4-methyllazetidinone

A solution of 4.98 g (3S-trans) -3-t-butoxycarbonylamino-1-hydroxy-4-methyllazetidinone in 200 ml of methanol

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Treat with 132 ml of 4.5 molar ammonium acetate and then 66 ml of 1.5 molar titanium trichloride and stir for 4.5 hours.

The aqueous solution is diluted with a corresponding volume of 8% sodium chloride and extracted with ethyl acetate to give 3.48 g of crude product. Recrystallization from ether / hexane yields 3.3 g of the title compound.

E) (3S-trans) -3-Benzyloxycarbonylamino-4-methyllazetidinone

A solution of 3.3 g of (3S-trans) -3-t-butoxycarbonylamino-4-methyllazetidinone in 10 ml of dichloromethane as well

as anisole is cooled to 0 ° C and 112 ml of trifluoroacetic acid is added. The solution is stirred for 90 minutes and evaporated in vacuo (benzene is added and evaporated three times). The residue is dissolved in 70 ml of acetone and the solution is adjusted to pH 7 with 5% sodium bicarbonate solution. A total of 5.33 g of benzyl chloroformate is added over one hour at pH

6.5-7.5. The mixture is stirred for 30 minutes at pH 7, diluted with 100 ml of saturated salt and extracted with ethyl acetate (three times 400 ml portions). The residue obtained by evaporation is chromatographed on a 1 liter silica gel column. . Elution with chloroform / ethyl acetate (4: 1) gives 2.19 g of compound. Crystallization from ether / hexane yields 1.125 g of the title compound.

F) (3S-trans) -4-Methyl-2-oxo-3 - [[(phenylmethoxy) carbonyl] amino] -1-azetidine sulfonic acid tetrabutylammonium salt

A solution of 600 mg (3S-trans) -3-benzyloxycarbonylamino-4-methyllazetidinone in 2 ml of dimethylformamide is cooled to 0 ° C and 4 ml of 0.8 molar sulfur trioxide in dimethylformamide is added. The solution is stirred at room temperature 3q under nitrogen for one hour and poured into 80 ml of cold 0.5 molar monobasic potassium phosphate (adjusted to pH 5.5). The solution is extracted with three 50 ml portions of methylene chloride (discarded) and 868 mg of tetrabutylammonium bisulfate added.

The resulting solution is extracted with four 75 ml portions of 35 methylene chloride. The combined organic layer is washed with aqueous sodium chloride 81, dried and evaporated in vacuo to give 1.54 g of the title compound.

0 25

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G) [3S- [3α (Z), 4β]] - 3 - [[(2-Amino-4-thiazolyl) - [(1-diphenylmethoxycarbonyl-1-methylethoxy) imino] acetyl] amino] -4- methyl 2-oxo-1-azetidine sulfonic acid potassium salt

A solution of 1.54 g (3s-trans) -4-methyl-2-oxo-5 -3 - [[(phenylmethoxy) carbonyl] amino] -1-azetidine sulfonic acid tetrabutylammonium salt in 45 ml of dimethylformamide is stirred in a hydrogen atmosphere with 800 mg 10% palladium on charcoal for 2 hours. The catalyst is filtered off and the filtrate is stirred for approx. 16 hours with 1.24 g of (Z) -2-amino-α - [(1-diphenylmethoxycarbonyl-1-methylethoxy) imino] -4-thiazole acetic acid, 0.4 g of N-hydroxybenzotriazole and 580 mg of dicyclohexylcarbodiimide . The slurry is evaporated in vacuo and the residue is triturated with 20 ml of acetone and filtered. The filtrate (plus 2 ml of washings) is treated with 868 mg of potassium perfluorobutane sulfonate in 3 ml of α-15 cetone. Dilution with 75 ml of ether gives a solid which is isolated by decanting the mother liquor, trituration with ether and filtration to give 0.91 g of the title compound. The mother liquor is diluted with an additional 100 ml of ether to give a next yield of 0.45 g of the title compound.

H) [3S- [3a (Z), 4β]] - 3 - [[(2-Amino-4-thiazolyl) [(1-carboxy-1-methylethoxy) imino] -acetyl] amino] -4-methyl -2-oxo-l-Aze-tidinsulfonsyre dipotassium salt

A slurry of 140 mg of [3S- [3α (Z), 4β] J-3 - [[(2-α-25-mino-4-thiazolyl) [(1-diphenylmethoxycarbonyl-1-methylethoxy) -imino] acetyl] amino ] -4-methyl-2-oxo-1-azetidine fulphonic acid potassium salt (first yield) in 0.5 ml of anisole is stirred at -12 ° C under nitrogen and 2.5 ml cold (-10 ° C) is added. triflusulfuron-oreddikesyre. After 10 minutes, add 10 ml of e-3Q ther and 5 ml of hexane, and the resulting slurry is stirred for 5 minutes at -12 ° C and allowed to warm to room temperature. The solid is isolated by centrifugation and washed twice with ether. A solution of this solid in 5 ml of cold water is immediately adjusted to pH 5.5 with 0.4N potassium hydroxide and then an 80 ml HP-20AG column is applied. Elution with water gives 72 mg of the title compound in the fractions (10 ml) 7-11 after evaporation (there 26

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acetonitrile and evaporated three times) and trituration with ether, m.p. 250 ° C (dec.).

Analysis:

Calculated for C C ^H ^NgOgS ^^ 5 C 30.51, H 2.95, N 13.69, S 12.53, K 15.28.

Found: C 29.63, H 3.20, N 12.96, S 11.94, K 12.78.

NMR (D 2 Q) 1.46 (S, 6H), 1.58 (1H, d, δ 7), 4.28 (1H, d of q, J = 7, 2.5), 4.67 ( 1H, d, 2), 6.95 ppm (S, 1H).

The remaining 1.22 g of [3S- [3α (Z), 4β]] - 3- [[(2-amino-4-thiazolyl) - [(1-diphenylmethoxycarbonyl-1-methylethoxy) imino] acetyl ] Amino-4-methyl-2-oxo-1-azetidine sulfonic acid potassium salt (yields 1 and 2) is treated as above (4.2 ml of anisole, 16 ml of trifluoroacetic acid, 13 minutes at 15-15 ° C). Chromatography on a 300 ml HP-20AG column gives 694 mg of the title compound in fractions (60 ml) 6-9 after treatment as above.

Example 23 20 Using the procedure of Example 15, but substituting 3S (Z) -3 - [[(2-amino-4-thiazolyl) [[2- (diphenylmethoxy) -2-oxyethoxy] imino] acetyl ] amino-2-oxo-1-azetidine sulfonic acid potassium salt with A is obtained Compound B: A = [3S (Z) -3 - [[2-amino-4-thiazolyl) [[2- (1,1-dimethylethane) oxy) -1- (methylthio) -2-oxoethoxyimino] acetyl] amino-2-oxo-1-azetidine sulfonic acid potassium salt (see Example 18) B = [3S (Z) -3 - [[2-amino-4-thiazolyl ) [[carboxy (methylthio) methoxy] imino] acetyl] amino] -2-oxo-1-azetidine sulfonic acid potassium salt (1: 2), m.p. 165 ° C under decomposition.

30

Example 24 [3α (Z), 4a] -3 - [[(2-Amino-4-thiazolyl) (methoxyimino) acetyl] amino] -4-methyl-2-oxo-1-azetidine sulfonic acid potassium salt

A solution of 51.8 mg (ci-s) -4-methyl-2-oxo-3- [[(phenylmethoxy) carbonyl] amino] -1-azetidine sulfonic acid potassium salt and 51 mg of tetra-n-butylammoniurabisulfate in Extract 5 ml of water with 0

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27 methylene chloride (four 10 ml portions) to give 81 mg of oil. This is stirred in an atmosphere of hydrogen for 2 hours with 40 mg of 10% palladium on charcoal in 4 ml of dimethylformamide. The catalyst is filtered and washed with 1 ml of dimethylformamide.

5 The filtrate and washings are combined and stirred for approx. 16 tips with 31 mg of (Z) -2-amino-α- (methoxyimino) -4-thiazole acetic acid, 27 mg of N-hydroxybenzotriazole and 31.5 mg of dicyclohexylcarbodiimide. The solution is evaporated in vacuo and the residue is triturated with 3 ml of acetone. The resulting slurry is centrifuged and the liquid is treated with 51 mg of potassium perfluorobutane sulfonate. Dilution with 5 ml of ether and filtration gives a solid. Chromatography on HP-20 AG (4 ml) gives Ry-don positive material in the fractions (20 ml) 3-5 (elution with water). Evaporation and ether trituration give 23.15 mg of product as a hygroscopic solid.

Analysis:

Calcd. For C10 H12 N5 N2 O2: C 29.91, H 3.01, N 17.44 Found: C 29.30, H 3.31, H 16.66.

NMR (D 2 O) 1.40 (3H, d, J = 7), 3.97 (3H, S), 4.46 (1H, apparently pentane, J - 7), 5.37 (1H, d, J) = 7), 6.97 ppm (1H, S).

Example 25 [3S- [3a (Z), 4a]] - 3 - [[2-Amino-4-thiazolyl) methoxyimino) acetyl] amino-4-methyl-2-oxo-1-azetidine sulfonic acid potassium

A solution of 201 mg of (Z) -2-amino-α- (methoxyimino) -4-thiazole acetic acid and 153 mg of N-hydroxybenzotriazole monohydrate in 3 ml of dimethylformamide is treated with 206 mg of dicyclohex-30-ylcarbodiimide. The mixture is stirred at room temperature for 20 minutes under nitrogen and a solution of 180 mg of (3S-cis) -3-amino-4-methyl-2-oxo-1-azetidine sulfonic acid and 0.14 ml of triethylamine in 2 ml of dimethylformamide ( an additional 1 ml of dimethylformamide is used for rinsing) and the mixture is stirred for approx. 16 hours. The slurry is evaporated in vacuo, triturated with 12 ml of acetone, centrifuged and the liquid treated with 338 mg of potassium perfluorobutanesulfonate. Dilution with 0

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28 10 ml of ether and filtration give a solid product which is chromatographed on 200 ml of HP-20 resin, eluting with water. Fractions (20 ml each) 18-30 are combined and lyophilized to give 274 mg of the title compound as a hygroscopic solid.

Analysis: Calculated for C HH₂NN5 ° 6S₂K: C-29/91, H 3.01, N 17.44 Found: C 30.03, H 3.21, N 17.06.

NMR (D 2 O) 1.40 (3H, d, J = 6.5), 3.78 (3H, S), 4.48 1H, d for t, J = 6.4, 5.5), δ, 36 (1H, d, _ / 5.5), 6.97 (1H, S).

10

Example 26 [3S- [3ct (Z), 4β]] -3- [[(2-Amino-4-thiazolyl) - [[1,1-dimethyl-2 - [(4-nitrophenyl) methoxy] -2 -oxoethoxy] imino) acetyl] amino] -4-15-methyl-2-oxo-1-azetidine sulfonic acid potassium salt

To a slurry of 0.36 g of (3S-trans) -3-amino-4-methyl-2-oxo-1-azetidine sulfonic acid (see Example 139) in 30 ml of dry dimethylformamide under nitrogen is added at 26 ° C 309 µl of triethylamine. . After approx. A clear solution was obtained over 5 minutes and 0.816 g of (Z) -2-amino-α - [[1,1-dimethyl-3 - [(4-nitrophenyl) methoxy] -2-oxoethoxy) was added. ] imino] -4-thiazole acetic acid followed by 0.334 g of N-hydroxybenzotriazole and 0.453 g of dicyclohexylcarbodiimide. The mixture is stirred for 12 hours at 26 ° C, then the solvent is removed in vacuo and the residue is triturated with 30 ml of acetone. After stirring for five minutes, the solids are removed and the filtrate is treated with 3,680 g of potassium perfluorobutanesulfonate in 5 ml of acetone. Addition of approx. 40 ml of ether gives a precipitate which is collected and dried in vacuo (1.073 g, second yield 0.066 g, 1.14 g total).

Analysis:

Calcd for C 20 H 21 N 6 ° 10S 2 K 2 H 2 O: C 38.33, H 3.70, N 13.41, S 10.23, K 6.24.

Found: C, 38.30; H, 3.63; N, 13.41; S, 9.88; K, 5.98.

35 29 0

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Example 27 [3a (Z), 4a] -3- [[(2-Amino-4-thiazolyl) [(1-carboxy-1-methylethoxy) imino] acetyl] amino] -4-methyl-2-oxo -1-azetidine sulfonic acid potassium salt (1: 2) A) [3α (Ζ), 4a] -3 - [[2-Amino-4-thiazolyl) [(1-diphenylmethoxy-carbonyl-1-methylethoxy) imino] acetyl] amino] -4-methyl-2 - oxo-l-azetidinesulfonic acid, potassium salt

A solution of 201 mg (cis) -4-methyl-2-oxo-3-10 - [[(phenylmethoxy) carbonyl] amino] -1-azetidine sulfonic acid tetrabutylammonium salt (prepared from the corresponding potassium salt as described in Example 24 in 5 ml of dimethylformamide is stirred with 90 mg of 10% palladium on calcium carbonate in hydrogen atmosphere for 2 hours, the slurry is filtered and the filtrate is stirred for about 16 hours with 146 mg of (Z) -2-amino-α- [1 -diphenylmethoxycarbonyl-1-methylethoxyimino] -4-thiazole acetic acid, 73 mg dicyclohexylcarbodiimide and 51 mg N-hydroxybenzotriazole under nitrogen. The slurry is evaporated in vacuo and triturated with 4 ml of acetone. The slurry is filtered and the solid washed twice with 2 ml portions of acetone. The filtrate and washings are combined and treated with 113 mg of potassium perfluorobutane sulfonate. Dilution with 24 ml of ether gives a solid which is isolated by centrifugation and washed three times with ether 25 to give 186 mg of the title compound.

B) [3α (Z), 4a] -3 - [[(2-Amino-4-thiazolyl) [1-carboxy-1-methyl-ethoxy] imino] acetyl] amino] -2-methyl-4-oxo- 1-azetidine sulfonic acid potassium salt (1: 2) A slurry of 186 mg [3α (Z), 4a] -3 - [[2-amino-4-thiazolyl) [(1-diphenylmethoxycarbonyl-1-methylethoxy) imino] -acetyl] amino] -4-methyl-2-oxo-1-azetidine sulfonic acid potassium salt in 0.6 ml of distilled trifluoroacetic acid (at -10 ° C) is added. The solution is stirred for 10 minutes and 12 ml of ether is added followed by 6 ml of hexane. After 5 minutes at 30

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ISLAND

-10 ° C and stirring for 15 minutes at ambient temperature, the solid is isolated by centrifugation and washed four times with ether to give 141 mg of material. This is dried in vacuo, pulverized, dissolved in 5 ml of cold water 5 and immediately adjusted to pH 5.6 with 0.4N potassium hydroxide.

The solution is applied to a 100 ml HP-20AG column and eluted with water. The fractions (10 ml) 8-12 are combined and evaporated in vacuo (acetonitrile is added three times and evaporated). The residue is triturated with ether to give 101.7 mg of product as a hygroscopic solid.

Analysis:

Calc'd for ΐ3ΐ] Ν5Ν508δ2 C 30.51, H 2.95, N 13.69, S 12.53, K 15.28 Found: C 30.11, H 3.26, N 13.35, S 12 , 12, K 15.02.

15

Example 28 [3S- [3α (Z), 4 (5] 3 -3- [[(2-Amino-4-thiazolyl) - [(1-carboxy-1-methylethoxy) imino] acetyl] amino] - 4-methyl-2-oxo-1-azetidine sulfonic acid 87.3 mg [3S- [3a (Z), 4β] -3 - [[(2-Amino-4-thiazolyl) - [(1-carboxy) -1-Methylethoxy) imino] acetyl] amino] -4-methyl-2-oxo-1-azetidine sulfonic acid dicalcium salt (see Example 22) is dissolved in 1.38 ml of water, cooled to 0 ° C, treated with 0.34 The hydrochloric acid is dissolved in methanol, filtered, evaporated to about 0.5 ml and mixed with 1 ml of water to give 55.9 mg of the title connection.

30

Example 29

[3S- [3a (Z), 4β] -3 - [[(2-Amino-4-thiazolyl) [1-carboxyl-1-methyl-ethoxy) imino] -4-methyl-2-oxo-1-azetidine sulf Acetic acid sodium salt A sample of 99.7 mg of [3S- [3α (Z), 43]] - 3 - [[(2-amino-4-3β-thizolyl) [(1-carboxy-1-methylethoxy) imino ] acetyl] amino] -4-methyl-2-oxo-1-azetidine sulfonic acid is mixed with 0.207 ml of IN

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31 sodium hydroxide and the resulting mixture is gently heated to dissolve the remaining solid. Water is azeotropically removed with acetonitrile and the residue is crystallized from a mixture of 0.5 ml of methanol (to dissolve the residue) and 1 ml of acetonitrile. giving 81.8 mg in solid. A recrystallization # 2 from 0.8 mL of methanol yields 47.9 mg, # 3 from 0.24 mL of methanol, and 0.24 mL of absolute ethanol yields 44.8 mg and # 4 from 0.225 mL of methanol and 0.225 ml of absolute ethanol give 38.8 mg. The solid 10 is dried at 20 ° C and 0.01 mm Hg for 18 hours and then equilibrated with atmospheric humidity for 24 hours to give 40.9 mg of the title compound.

Example 30 [3S- [3α (Z), 4a]] - 3 - [[(2-Amino-4-thiazolyl) [(1-carboxy-1-methylethoxy) imino] acetyl] amino] -4- methyl 2-oxo-1-azetidine sulfonic acid potassium salt (1: 2) A) [3S- [3α (Z), 4aJ] -3- [[(2-Amino-4-thiazolyl) [(1-diphenylmine) -thoxycarbonyl-1-methylethoxyimino] acetyl] amino] -4-methyl-20-2-oxo-1-azetidine sulfonic acid potassium salt

A solution of 440 mg of (Z) -2-amino-α - [(1-carboxy-1-methylethoxy) imino] -4-thiazole acetic acid and 153 mg of N-hydroxy-benzotriazole monohydrate in 3 ml of dimethyl fomamide is treated with 206 mg of dicyclohexylcarbodiimide. The mixture is stirred at room temperature for 30 minutes under nitrogen and a solution of 180 mg of (3S-cis) -3-amino-4-methyl-2-oxo-1-azetidine sulfonic acid and 0.14 ml of triethylamine is added. in 2 ml of dimethylformamide (an additional 1 ml of dimethylformamide is used for rinsing) and the mixture is stirred for approx. 16 hours. The slurry is evaporated in vacuo and triturated with 12 ml of acetone. The slurry is filtered and the solid washed with acetone (two 3ml portions). The combined filtrate and washings are treated with 338 mg of potassium perfluorobutanesulfonate. Dilution with 30 ml of ether gives a gurai-like solid which slowly solidifies. The solid is filtered and washed with ether to give 656 mg of the title compound.

0

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32 B) [3S- [3α (Z), 4a]] - 3- [[(2-Amino-4-thizolyl) [(1-carboxy-1-methylethoxy) imino] acetyl] amino] -4- methyl 2-oxo-1-azetidine sulfonic acid potassium salt (1; 2)

A slurry of 656 mg of [3S- [3α (Z), 4a] -3 - [[(2-amino-4-thiazolyl) [(1-diphenylmethoxycarbonyl-1-methylethoxy) -imino] acetyl] amino] -4-Methyl-2-oxo-1-azetidine sulfonic acid potassium salt in 2.3 ml of distilled anisole is cooled to -12 ° C and 11.5 ml of trifluoroacetic acid is added (pre-cooled to -10 ° C). The solution is stirred for 15 minutes and 46 ml of ether are added followed by 23 ml of hexane. After 5 minutes at -10 ° C and stirring for 15 minutes at room temperature, the solid is filtered off and washed with ether to give 457 mg of a very hygroscopic gum. This is dissolved in 6 ml of cold water and adjusted to pH 5.6 with 0.4N potassium hydroxide solution. The solution is applied to a 200 ml HP-20 resin and eluted with water. The fractions (50 ml each) 7-11 are combined and lyophilized to give 239 mg of the title compound as a solid.

Analysis:

Calcd for C0: C 29.99, H 3.10, N 13.45, S 12.32 Found: C 29.94, H 3.30, N 13.30, S 11.93.

NMR (D2q) 1.44 (3H, Å, J - 75), 1.46 (6H, S), 4.48 (1H, d of t J = 75, 5.5), 5.34 (1H) , d, J = 5.5) 6.96 ppm (1H, S).

Example 31 [3 (-) (Z)] -3- [[(2-Amino-4-thiazolyl) (methoxyimino) acetyl] amino] -4,4-dimethyl-2-oxo-1-azetidine sulfonic acid potassium salt A solution of 50 mg of N-hydroxybenzotriazole hydrate and 0.323 mmol (Z) -2-amino-α- (methoxyimino) -4-thiazole acetic acid in 0.5 ml of dimethylformamide is treated with 67 mg of dicyclohexylcarbodiimide under argon at ambient conditions. temperature. The resulting mixture is stirred for one hour, at which time 57 mg (+) - 3-amino-4,4-dimethyl-2-oxo-1-

DK 166280 B

-acetidine sulfonic acid is added as a solid followed by a drop of 0.05 ml of triethylamine. The reaction mixture is stirred at ambient temperature for 16 hours. The dimethylformamide is removed under high vacuum at 30 ° C and the residue is slurried in 4 ml of acetone and filtered. The filter cake is washed with an additional 4 ml of acetone and 85 mg of potassium perfluorobutane sulfonate is added to the filtrate followed by ether. Trituration of the resulting rubber with ether gives 40 mg of a light brown solid which is chromatographed on a 70 ml column of HP-10 -2OAG. Elution with water gives 20 mg of the title compound in the fractions (5 ml) 16-40 after evaporation, trituration with 1: 1 acetone / hexane and drying, m.p. 225 ° C (dec.).

Calcd for: K: C 31.80 / H 3.40, N 16.86, S 15.43 Found: C 29.47, H 3.48, N 14.98, S 13.35.

Example 32 (3S-trans) -3 - [[(2-Amino-4-thiazolyl) oxoacetyl] amino] -4-methyl-2-oxo-1-azetidine sulfonic acid potassium salt

To a solution of 1.85 g of diphenylphosphinyl chloride in 15 ml of dry dimethylformamide cooled in an ice / methanol bath (-15 to -20 ° C) is added 2.14 g (2-amino-4-thiazolyl) gly-25 oxylic acid triethylamine salt. After stirring for 0.5 hour, a solution of 1.08 g of (3S-trans) -3-amino-4-methyl-2-oxo-1-azetidine sulfonic acid and 1.92 ml of triethylamine in 5 ml of dry dimethylformamide is added. the cold mixed anhydride solution and the reaction mixture is stirred at 5 ° C for 24 hours.

The solvent is removed in vacuo, the remaining dark oil is dissolved in water and chromatographed on "Dowex" 50 X 2-400 resin (K-form, 200 ml). After elution with water (15 ml fractions), the crude product is collected in fractions 13-27 (3.37 g). Chromatography on HP-20 resin (200 ml), elution with water (15 ml fractions) gives the desired product in fractions 18-26. Removal of water in vacuo gives the title compound as an amorphous powder.

DK 166280B

34 o

Analysis: Calculated for CgHgN40OgS2K (372.42): C 29.02, H 2.44, N 15.04, S 17.22, K 10.50 Found: C 28.87, H 2.62, N 14, 85, S 15.09, K 10.81.

5

Example 33 [3S- [3α (Z), 4β] 3-3 - [[(2-Amino-4-thiazolyl) [[2- (diphenylmethoxy) -2-oxoethoxy] imino] acetyl] amino] -2- methyl 4-oxo-1-aze-tidinsulfonic acid potassium salt 10 By the procedure of Example 25, but using (Z) -2-amino- <x- [[2- (diphenylmethoxy) -2-oxo- ethoxy] imino] -4-thiazole acetic acid instead of (Z) -2-amino-no- (methoxyimino) -4-thiazole acetic acid and first treat (3S-cis) -3-amino-4-methyl-2-oxo -1-azetidine sulfonic acid with triethylamine gives the title compound, mp 155-160 ° (decomposition).

Example 34 [3S (R *)] - 3 - [[[[(4-Amino-2,3-dioxo-1-piperazinyl) carbonyl] -20 amino] phenylacetyl] amino] -4-methyl-2-oxo-1- azetidine sulfonic acid potassium salt [3S (R *)] - [4 - [[[2 - [(4-methyl-2-oxo-1-sulfo-3-azetidinyl) amino] -2-oxo-1- phenylethyl] amino] carbonyl] -2,3-dioxo-1-piperazinyl] carbamic acid phenylmethyl ester potassium salt is hydrogenated by gaseous hydrogen and 10% palladium-on-charcoal as catalyst to give the title compound, mp 165 ° C (dec.).

Example 35 [3S (Z)] -3- [[(2-Amino-4-thiazolyl)] [(1-carboxy-1-methylethoxy) imino] acetyl] amino] -2-oxo-1-azetidine sulfonic acid sodium salt (1: 2) [3S (Z)] - 3 - [((2-Amino-4-thiazolyl) - [[2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy ] imino] acetyl] amino] -2- -oxo-1-azetidine sulfonic acid tetrabutylammonium salt (see Example 7)

DK 166280 B

35 is liberated for protecting groups using trifluoroacetic acid and anisole to give the title compound, mp 185 ° C (decomposition), after conversion to the disodium salt with aqueous sodium hydroxide and purification on HP-20.

Example 36 (trans, Z) -3 - [[(2-Amino-4-thiazolyl) [(1-carboxy-1-methylethoxy) -imino] acetyl] amino] -4-ethyl-2-oxo-1α, zetidine sulfonic acid -decali-io salt A) (trans, Z) -3 - [[(2-Amino-4-thiazolyl) [(1-diphenylmethoxycarbonyl-1-methylethoxy) imino] acetyl] amino] -4-ethyl-2 -oxo-1-azetidine sulfonic acid dicalcium salt 0.55 g of (trans) -3-amino-4-ethyl-2-oxo-1-azetidine sulfonic acid and 335 mg of triethylamine are dissolved in 50 ml of dry dimethyl formaride. 1.14 g of (Z) -2-amino-α - [(1-diphenylmethoxycarbonyl-1-methylethoxy) imino] -4-thiazole acetic acid is added with stirring at 0 ° C followed by 450 mg of hydroxybenzotriazole and then 0 , 69 g of dicyclohexylcarbodiimide. After stirring for approx. For 16 hours at 0 ° C, the flask is evacuated. 25 ml of dry acetone is added to the solid with stirring. The mixture is filtered and 0/94 g of potassium perfluorobutanesulfonate is added to the filtrate followed by 100 ml of ether.

After standing for one hour at 0 ° C, the solid is filtered, washed with ether and dried in vacuo to give 1.58 g of the title compound.

B) (trans, Z) -3 - [[(2-Amino-4-thiazolyl) [(1-carboxy-1-methyl-ethoxy) imino] acetyl] amino] -4-ethyl-2-oxo-1- azetidine sulfonic acid dicalcium salt To a suspension of 1.31 g (trans, Z) -3- [[(2-amine)

No-4-thiazolyl)] (1-diphenylmethoxycarbonyl-1-methylethoxy) -imino] acetyl] amino] -4-ethyl-2-oxo-1-azetidine sulfonic acid di-potassium salt in 10 ml of anisole is added 5 ml of trifluoroacetic acid for a period of 10 minutes at -15 ° C. After stirring for 2 hours at -10 ° C, a clear solution is obtained. At -30 ° C

80 ml of dry ether is added and the resulting precipitate is filtered and then treated with 5 ml of water. The pH is adjusted to 5.5 with 1N potassium hydroxide at 0 ° C and the mixture is filtered 36 0

DK 166280 B

to remove unconverted starting material. The filtrate is chromatographed on HP-20 with water as the eluent. Lyophilization gives 185 mg of the title compound, mp 160 ° C (decomposition).

5

Example 37 [3S (Z)] - 3 - [[(2-Amino-4-thiazolyl) [(4-hydroxy-4-oxobutoxy) imino] acetyl] amino] -2-oxo-1-azetidine sulfonic acid potassium salt

Removal of the protection from [3S (Z) 3-3 - [[(2-Amino-4-thiazolyl) [[4- (diphenylmethoxy) -4-oxobutoxy] imino] acetyl] amino] -2-oxo- 1-azetidine sulfonic acid potassium salt by trifluoroacetic acid and anisole gives the title compound, melting point,> 200 ° C.

15

Example 38 [3S- [3α (Z), 4β]] - 3 - [[(2-Amino-4-thiazolyl) - (methoxyimino) acetyl] amino] -4-cyclohexyl-2-oxo-1-azetidine sulfonic acid potassium salt Dissolve 0.25 g of [3S-trans] -3-amino-4-cyclohexy-2-oxo-1-azazide insulin form in 30 ml of dry dimethylformamide and 0.12 g of triethylamine with stirring. When a clear solution is obtained, 0.2 g of (Z) -2-amino-α- (methoxyimino) -4-thiazole acetic acid, 0.16 g of hydroxybenzotriazole and 0.42 g of di-cyclohexylcarbodiimide are added. Stirring is continued for 48 hours at ambient temperature. The precipitated urea file; is removed and the solvent is removed in vacuo. The residue is dissolved in 10 ml of acetone and 0.41 g of potassium per fluorobutane sulfate is added. After the addition of 50 ml of ether, the title compound precipitates and is filtered off. Column chromatography with HP-20 and water / acetone (9: 1) as the eluent yields 0.36 g of product, mp 200-205 ° C (after lyophilization).

35 37 0

DK 166280B

Example 39 [3S- [3α (Z), 4β]] - 3 - [[(2-Amino-4-thiazolyl) [(1-carboxy-1-methyl-ethoxy) imino] acetyl] amino] -4-cyclohexyl -2-oxo-1-azetidine sulfonic acid dicalcium salt A) [3S- [3α (Z), 4β]] - 3 - [[(2-Amino-4-thiazolyl) [1-diphenylmethoxycarbonyl-1 methylethoxy) imino] acetyl] amino] -cyclohexyl-2-oxo-1-azide insulphonic acid potassium salt 0.2 g of [3S-trans] -3-amino-4-cyclohexyl-2-oxo-1- Azetidine sulfonic acid is dissolved in 30 ml of dimethylformamide and 0.09 g of triethylamine with stirring. 0.12 g of hydroxybenzotriazole, 0.30 g of (Z) -2-amino-α - [(1-di-phenylmethoxycarbonyl-1-methylethoxy) imino] -4-thiazole acetic acid and 0.33 g of dicyclohexylcarbodiimide are added. and stirring is continued at ambient temperature for 12 hours. The precipitated urea is filtered off and the mother liquor is evaporated to dryness. The remaining oil is dissolved in 5 ml of acetone, treated with 0.3 g of potassium perfluorobutanesulfonate and poured into 100 ml of ether with stirring. 0.61 g of the title compound is precipitated and filtered off.

B) [3S- [3α (Z), 4β] 3-3 - [[(2-Amino-4-thiazolyl) [1-carboxy-1-methylthoxy) imino] acetyl] amino] -4 -cyclohexyl-2-oxo-1- azetidine sulfonic acid dicalcium salt 0.61 g [3S- [3a (Z), 4fJ]] - 3 - [[(2-amino-4-thiazolyl) -25 [(1-diphenylmethoxycarbonyl) -1-methylethoxy) imino] acetyl] amino] -4-cyclohexyl-2-oxo-1-azetidine sulfonic acid potassium salt is suspended in 6 ml of anisole, cooled to -15 ° C and 5 ml of trifluoroacetic acid are added dropwise with stirring.

The temperature is kept for one hour and then lowered to -30 ° C.

30 Add approx. 100 ml of dry ether at a rate such that the temperature does not exceed -10 ° C. The precipitated compound is filtered off and chromatographed using HP-20 resin and water / acetone (9: 1) as eluent to yield 0.3 g of the title compound, mp 118-120 ° C (decomposition) (post-lyophilization.

0 38

DK 166280 B

Example 40 (trans), Z) -3- [[(2-Amino-4-thiazolyl) (methoxyimino) acetyl] amino] -4-ethyl-2-oxo-1-azetidine sulfonic acid potassium salt

By the method of Example 36, where instead of (Z) -2-amino-ot- [(1-diphenylmethoxycarbonyl-1-methylethoxy) imino] -4-thiazole acetic acid is used (Z) -2-amino -a- (methoxyimino) -4-thiazole acetic acid, obtained as yield the title compound, melting point 190 ° C (decomposition) - 10

Example 41 (-) - (trans, Z) -3- [[2-Amino-4-thiazolyl) (methoxyimino) acetyl] amino] -2-oxo-4-phenyl-1-azetidine sulfonic acid potassium salt A solution of 52 mg of N-hydroxybenzotriazo] hydrate and 69 mg of (Z) -2-amino-ct- (methoxyimino) -4-thiazole acetic acid in 0.3 ml of dimethylformamide are treated with 70 mg of solid dicyclohexylcarbodiimide under argon at ambient temperature.

The resulting mixture is stirred for one hour, with 75 mg of (+) - (trans) -3-amino-2-oxo-4-phenyl-1-azetidine sulfonic acid added as a solid followed by a drop of 0.05 ml of triethylamine. . The reaction is stirred at ambient temperature for 23 hours. The dimethylformamide is removed under high vacuum at 30 ° C and the residue is triturated with 2 ml of acetone and filtered. The filter cake is washed with additional acetone (two 3 ml portions) and 86 mg of potassium perfluorobutanesulfonate added to the filtrate. Dilution with 10 ml of ether gives a rubbery solid which is triturated, washed with acetone and hexane, which yields, after drying, 82 mg of the title compound as a solid.

Analysis:

Calcd. For δ 5 ^ 4 ^ 50 ^ 2-K: C 40.26, H 3.16, N 15.65, S 14.33, K 8.74.

Found: C, 38.60; H, 3.19; N, 15.07; S, 13.87; K, 7.5.

39 0

DK 166280B

Example 42 (cis, Z) -3 - [[(2-Amino-4-thiazolyl) (methoxyimino) acetyl] amino] -2-oxo-4-phenyl-1-azetidine sulfonic acid potassium salt 560 mg (cis) -2 -oxo-4-phenyl-3 - [(phenyl-5-acetyl) amino] -1-azetidine sulfonic acid potassium salt is dissolved in 5 ml of ethanol and hydrogenated with 110 mg of platinoxide catalyst at 1 atm. After one hour of stirring, the catalyst is filtered through a "Millipore" filter with "Celite", catalyst particles pass through the filter to give a black filtrate, ethanol is removed under reduced pressure and the residue is dissolved in 4 ml of dimethylformamide. -Droxybenzotriazole monohydrate, 221 mg of the (Z) -2-amino-α- (methoxyoxy) -4-thiazole acetic acid and 227 mg of dicyclohexylcarbodiimide are added and the mixture is stirred for about 16 hours under the nitrolene gene. in vacuo and triturated with 15 ml of acetone, the resulting slurry is filtered through "Millipore" with "Celite" and the filtrate is treated with 372 mg of potassium perfluorobutanesulfonate. After the addition of 15 ml of ether, a gum is separated and the gum removed The rubber is dissolved in 5 ml of water and applied to 150 ml of HP-20 resin, eluting with water. The fractions (30 ml each) are combined 16-34 and lyophilized to give 201 mg of the title compound. said compound as a solid.

Analysis:

Calculated for C C ]HH l406O40N5S₂K 1 1 1/2 0 0: C 36.73, H 3.49, N 14.28, S 13.07, K 7.97 Found: C 36.65, H 3.00 , N 13.99, S 13.48, K 8.30.

30

Example 43 + (-) - (cis, Z) -3 - [[(2-Amino-4-thiazolyl) (methoxyimino) acetyl] amino] -2-OXO-4- (2-phenylethenyl) -1-azetidine sulfonic acid - potassium salt | A solution of 68 mg of (Z) -2-amino-α- (methoxyimino) -4-thiazole acetic acid and 51 mg of N-hydroxybenzotriazole monohydrate in 2 ml of dimethylformamide is treated with 69 mg of dicyclohex-40

DK 166280 B

ISLAND

ylcarbodiimid. The mixture is stirred at room temperature for 30 minutes under nitrogen. 90 mg (cis) -3-amino-2-OXO-4- (2-phenylethenyl) -1-azetidine sulfonic acid and 34 mg triethylamine are added and the mixture is stirred for 20 hours under nitrogen. The slurry is evaporated in vacuo and triturated. The slurry is filtered and the filtrate is treated with 113 mg of potassium perfluorobutanesulfonate. Dilution with 30 ml of ether and filtration gives 169 mg of a solid product which dissolves to a degree of approx. 10% acetone-10 tril / water and applied to 34 ml HP-20 resin, eluting with 150 ml water and then 10% acetone / water. The fractions (15 ml each) 16-19 are combined and freed of solvent to give 110 mg of the title compound as a solid.

Analysis:

Calcd for C 17 H 16 O 6 N 5 S 2 K, H 2 O: C 40.23, H 3.57, N 13.80, S 12.63, K 7.70.

Found: C 40.03, H 3.05, N 13.61, S 12.31, K 7.56.

20

Example 44 (cis) -3 - [[(2-Amino-4-thiazolyl) [[1- (diphenylmethoxycarbonyl) -1-methylethoxy] imino] acetyl] amino] -4- (methoxycarbonyl) -2-oxo- 1-azetidine sulfonic acid potassium salt 25 - * -

A solution of 34 rag N-hydroxybenzotriazole hydrate and 101 mg of 2-amino-α - [[1- (diphenylmethoxycarbonyl) -1-methylethoxy] imino] -4-thiazole acetic acid in 0.5 ml of dimethylformamide is treated with 45 mg of solid dicyclohexylcarbodiimide and the mixture is stirred under argon for 45 minutes (ambient temperature) then 45 mg (cis) -3-amino-4-carbonyl) -2-oxo-1-azetidine sulfonic acid is added as a solid followed by 0.03 ml of triethylamine dropwise. The reaction is stirred at ambient temperature for approx. 16 hours. The dimethylformamide is removed under high vacuum at 35 ° C and the residue is triturated with acetone. The upstairs flight 0 41

DK 166280 B

the same layer is treated with 67 mg of potassium perfluorobutanesulfonate. Dilution with ether gives a solid which is washed with ether and dried in vacuo to yield 93 mg of the title compound.

5

Example 45 (cis) -3- [[(2-Amino-4-thiazolyl) [(1-carboxyl-1-methylethoxy) -imino] acetyl] amino] -4- (methoxycarbonyl) -2-oxo-1- azetidine sulfonic acid dipotassium salt

A slurry of (cis) -3 - [[(2-amino-4-thiazolyl) - [[(1-carboxy-1-methylethoxy) imino] acetyl] amino] -4- (methoxy-carbonyl) -2-oxo -1-azetidine sulfonic acid potassium salt in 0.4 ml of anisole is stirred at -12 ° C under argon and 0.9 ml of cold (-10 ° C) trifluoroacetic acid is added. After 1.5 hours, 4 ml of ether and 2 ml of hexane are added and the resulting slurry is stirred for 15 minutes at -10 ° C and then 15 minutes at ambient temperature. The solid is isolated by centrifugation and washed with ether. A suspension j of this material in 0.5 ml of cold water is adjusted to pH 6 j with 1 N potassium hydroxide and then a 30 ml HP-20AG column is applied. Elution with water yields 30 mg of the title compound after evaporation (acetonitrile is added and evaporated twice). j

Analysis:

Calcd for c14 H15 K2 N5 ° 9S2: C1 / 15, H 2.81, N 12.98. 1

Found: C 29.08, H 3.03, N 12.19. i 30

Example 46 [3S- [3a (Z), 4β]] - 3 - [[(2-Amino-4-thiazolyl) (methoxyimino) acetyl] amino] -4-ethynyl-2-oxo-1-azetidine sulfonic acid potassium salt 100 Weigh in mg (Z) -2-amino-α- (methoxyimino) -4-thiazole acetic acid, 85 mg of N-hydroxybenzotriazole monohydrate and 113 mg of dicyclohexylcarbodiimide into a 10 ml flask. Col- 42

DK 166280 B

ISLAND

legs are rinsed with nitrogen and cooled in ice / water bath. Then 0.6 ml of dimethylformamide is added and the mixture is stirred for 10 minutes, at which time another 0.6 ml of dimethylformamide is added. 95 mg of (S) - (trans) -5 -3-amino-4-ethynyl-2-oxo-1-azetidine sulfonic acid (see Example 191) is added as a solid with 1.0 ml of dimethylformamide and 56 µl of triethylamine. The cold bath is removed and the mixture is stirred for 22 hours. 3 ml of acetone is added and the resulting solids are removed by filtration and washed with a further 4 ml of acetone. All solvents are removed in vacuo and the residue is taken up in 4 ml of methanol, and 162 mg of potassium perfluorobutanesulfonate is added and dissolved. After standing, a solid is then deposited by centrifugation to give 68 mg of the title compound, mp 23 ° C.

Example 47 [3S (R *) 3 -3- [[(2-Amino-4-thiazolyl) [[[3- [(2-furanylmethylene) -20 amino] -2-oxo-1-imidazolidinyl] carbonyl] amino ] acetyl] amino] - 2-oxo-1-azetidine sulfonic acid potassium salt By the procedure of Example 1, but by replacing aminothiazole acetic acid with (R) -2-amino-α - [[[3 - [(2- furanylmethylene (amino) -2-oxo-1-imidazolidinyl] carbonyl] amino] -4-thiazole acetic acid gives the title compound, m.p. 250 ° C.

Biological Activity 30 The following methodology is used to determine the minimum inhibitory concentration (hereinafter called MIC) of the β-lactams produced by the method of the invention.

The test organisms are grown for approx. 15-20 ml "Antibiotic Assay Broth" (Difco) by inoculation (in glass) of nutrient medium with an eye needle full of the organism from an obliquely stiffened DK 166280 B! 43 ί 0 BHI (Difco) agar. The inoculated glass is incubated at 37 ° C for 18-20 hours. These cultures are thought to contain 10 colony forming units (hereafter referred to as CFUs) per day. ml. The cultures are diluted 1: 100 to give a final graft 5 level of 10 ^ CFU; dilutions are made with K-10 nutrient liquid '.

The compounds are dissolved in a suitable diluent at a concentration of 1000 pg / ml. Two-fold dilutions are made in K-10 nutrient liquid, giving a range from 1000 µg / ml to 0.5 µg / ml. 1 * 5 ml of each dilution is placed in individual square petri dishes to which 13.5 ml of K-10 agar are added. * The final preparation concentration in the agar ranges from 100 µg / ml to 0.05 µg / ml. Organic growth control plates containing only agar are prepared and inoculated before and after the test plates. The organisms are applied to the agar surface of each plate with a "Denley Multipoint Inoculator" (delivering approximately 0.001 ml of each organism), giving a final graft level 4 of 10 CFU on the agar surface.

The plates are incubated at 37 ° C for 18 hours and MIC

is determined. MIC is the lowest compound concentration that inhibits the growth of the organism.

25 30 35

DK 166280B

44 Λ) K-10 nutrient liquid contains: Meat extract 1.5 g Yeast extract 3.0 g 5 Pepton 6.0 g

Dextrose 1.0 g

Distilled water until 1 liter JMi) K-10 agar Meat extract 1.5 g Yeast extract 3.0 g

Peptone 6.0 g

Dextrose 1.0 g ^ Agar 15.0 g

Distilled water up to 1 liter

The following tables indicate, in tabular form, the results obtained when a series of 3-lactams, i.a. those produced by the process of the invention are tested for various organisms. The number after each organism refers to the organism's number in the collection at E.R. Squibb & Sons, Inc., Princeton,

New Jersey. A dash (-) in the tables means that the 25 compound tested did not exhibit activity to the particular organism at 100 µg / ml. "N.T." means "not tested".

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Claims (2)

An analogous process for the preparation of therapeutically active 2-azetidinones of the general formula 5 = Κ, ΝΗ-C;, OR (()) CI 0 * c-10. which R ^ is vOT 15 wherein R3 is hydrogen or C1_ alkyl alkyl containing a carboxyl group or a C 1-4 alkyl or benzyl ester thereof, R 2 is hydrogen or C 1-4 alkoxy, and R 3 and R 4 are the same or different and represent hydrogen or C 1-4 alkyl, or salts or stereoisomeric forms thereof characterized in that a) sulfonates a corresponding intermediate with a hydrogen atom at the 1-position with a pyridine-sulfur trioxide complex 25 or an equivalent thereof under conventional conditions or b) acylates a corresponding intermediate wherein R 1 is hydrogen with an acyl group as defined by R 2 above by conventional methods and, if desired, converting acid groups to salts and / or, if desired, cleavage of racemic mixtures into stereoisomeric forms. A process according to claim 1 for the preparation of [3S- [3a (Z), 4/3]] - 3 - [[(2-amino-4-thiazolyl) - [(1-carboxy-1-methyl-ethoxy) ) -imino] -acetyl] -amino] -4-methyl-2-oxo-1-azetidine-sulfonic acid or salts or C 1-4 alkyl or benzyl esters thereof, characterized in that corresponding substituted starting materials are used. .