NL8100571A - ANTIBIOTIC BETA-LACTAMS. - Google Patents

Description

Antibiotic β-lactams

The invention relates to β-lactams with a sulfonic acid substituent in the 1-position and an amine function in the 3-position and to their use as antibiotics.

The compounds of the invention form a new family of antibiotic β-lactams, which may be used in particular as antibacterial agents.

It has been found that one can biologically activate the β-lactam core through a sulfonic acid salt substituent bonded to the nitrogen atom in the core.

β-Lactams with a sulfonic acid salt (including "internal salt") substituent in the 1-position and an acylamino substituent in the 3-position show activity against a range of gram-negative and gram-positive bacteria.

Preferred members of the novel antibiotic β-lactams family of the invention are of formula 1.

In addition to the above-described β-lactams with a sulfonic acid salt substituent in the 1-position and an acylamino substituent in the 3-position, the invention also relates to β-lactams with a sulfonic acid salt (including "internal salt") substituent on the 1 position and an amino substituent in the 3 position.

The preferred compounds of this type have the formula la. These compounds are intermediates for the preparation of corresponding 3-acylamino compounds.

In the formulas 1 and la and throughout the description, the symbols have the following meanings:

Rj is acyl.

Rj is hydrogen or alkoxy of 1-4 carbon atoms.

R 1 and R 2 are the same or different and are each hydrogen, alkyl, cycloalkyl, phenyl or substituted phenyl, or one of R 3 and R 2 is hydrogen and the other is alkoxycarbonyl, alkenyl-1, alkynyl-1,2-phenylethenyl or 2-phenylethynyl.

J * 2 M + is hydrogen or a cation.

The terms "alkyl" * and "alkoxy" refer to both straight chain and branched chain groups, such groups having 1-10 carbon atoms are preferred.

The terms "cycloalkyl" and "cycloalkenyl" refer to cycloalkyl and cycloalkenyl groups having 3, 4, 5, 6 or 7 carbon atoms.

The term "alkenyl" refers to both straight chain and branched chain groups.

Such groups with 2-10 carbon atoms are preferred.

The term "halogen" refers to fluorine, chlorine, bromine and iodine,

The term "substituted phenyl" refers to a phenyl group which is substituted 1,2 or 3 amino, halogen, hydroxyl, trifluoromethyl and / or lower alkyl and / or alkoxy groups.

The "protected carboxyl" pit print refers to a cafboxyl group esterified with a conventional protective ester group. These groups are well known, see, for example, U.S. Patent 4,144,333. The preferred protected carboxyl groups are benzyl, a zhydryl and t-butyl esters.

w

The term "acyl" includes all organic radicals derived from an organic acid (ie a carboxylic acid} by removing the hydroxyl group. Certain acyl groups are of course preferred, but this preference should not be construed as limiting the scope of the invention Examples of acyl groups are the acyl groups which have been used in the past to acylate antibiotic β-lactams including 6-aminopenicillanic acid and derivatives and 7-aminocephalosporanic acid and derivatives (see, for example, Cephalosporins and Penicellina, published by Flynn, Academie Press (1972), German Offenlegungsschrift 2,716,677, Belgian Patent No. 867,994, U.S. Patent Nos. 4,152,432, 3,971,778 and 4,172,199 and British Patent No. 1,348,894.

8100571 - 3 -

The following list of acyl groups is provided to further illustrate the term "acyl". Examples of acyl groups are: a. Aliphatic groups of the formula (CO) -, where R <. alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, cyclohexadienyl, or alkyl or alkenyl, substituted with 1 or more halogen, cyano, nitro, amino, mercapto, alkylthio or cyanomethyl thio groups.

b. Carbocyclic aromatic groups of any one of formulas 35 to 40, wherein n is 0, 1, 2 or 3, Rg, Rl and Rg each independently hydrogen, halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon or aminomethyl and Rg amino, hydroxyl, a carboxylic acid salt, protected carboxyl, formyloxy, a sulfo salt, a sulfoamino salt, azido, halogen, hydrazino, alkyl hydrazino, phenylhydrazino, or [((alkylthio) thioxomethyl / thio.

Preferred carbocyclic aromatic acyl groups are those of formulas 41, 42, 43, (wherein 20 Rg preferably represents a carboxylic acid salt or sulfo salt) and 44, (wherein Rg preferably represents a carboxylic acid salt or sulfo salt.

c. Heteroaromatic groups of any one of formulas 45 to 49, wherein n is 0, 1, 2 or 3, Rg has the above meaning and Rg has a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring represents 1, 2, 3 or 4 (preferably 1 or 2) nitrogen, oxygen and / or sulfur atoms. Examples of heterocyclic rings are thienyl, furyl, pyrrolyl, pyridinyl, pyrazynyl, thiazolyl, morpholinyl, pyrimidinyl, and tetrazolyl. Examples of substituents are halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, alkyl of 1-4 carbon atoms or alkoxy of 1-4 carbon atoms.

Preferred heteroaromatic acyl groups are those groups of the above formulas, wherein R 2 g 2-amino-4-thiazolyl, 2-amino-5-halo-4-thiazolyl, 4-aminopyrimi-35-dinyl-2, j5- amino-1,2,4-thiadiazolyl-5, 2-thienyl or 2-furanyl represents 81 00 57 1-4.

d. (4-Substituted-2,3-dioxo-1-piperazinyl) carbonyl / amino / arylacetyl groups of the formula 50 wherein Rj represents an aromatic group (including carbonyl aromatics such as the formula 51 and heteroaromatics included in the definition of Rjq) and alkyl, substituted alkyl (wherein the alkyl group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups) arylmethyleneamino (i.e. -N = CH-R ^ j, in which R ^ has the above meaning), aryΙ-ΙΟ carbonylamino (i.e. -NH- (CO) -R ^, where R ^ has the above meaning), or represents alkylcarbonylamino.

(/ (4R-Substituted-2,3-dioxo-1-piperazinyl) -carbonyl / amino / arylacetyl groups are preferred where R 1 represents ethyl, phenylmethyleneamino or 2-furylmethyleneamino.

e. (Substituted oxyimino) arylacetyl groups of formula 52, wherein R 2 has the above meaning and R 2 is hydrogen, alkyl, cycloalkyl, alkylaminocarbonyl, arylaminocarbonyl (i.e., - (CO) -Nh-Rj, where R 3 has the above meaning / - - V). {,, V 'has V-Jf 20) or represents substituted alkyl (in which case the alkyl group is substituted with one or more halogen, cyano, nitro, amino, mercapto, alkylthio, aromatic group ( as defined by Rjj> carboxyl (including its salts), amido, alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkoxyphosphinyl, dihydroxyphosphinyl, hydroxy (phenylmethoxy) -phosphinyl, or dialkoxyphosphinyl substituents).

Preferred (substituted oxyimino) arylacetyl groups are those wherein R 1 represents 2-amino-4-thiazolyl. Also preferred are groups wherein R 1 represents methyl, ethyl, carboxymethyl or 2-carboxyisopropyl.

f. (Acylamino) arylacetyl groups of the formula 53, wherein R ^ has the above meaning and R ^ a group of the formula 54, amino, alkylamino, (cyanoalkyl) amino, amido, alkyl amido, (cyanoalkyl) amido, or a group with one of formulas 55 to 35 represents 60.

Preferred are the groups wherein R 1 represents amino or amido. The preferred groups are 1 -5- 5- (Acylamino) arylacetylic groups of the above formula. Preference is also given to the groups in which phenyl represents or 2-thienyl.

5 g, LL 3 -Substituted-2-oxo-1-imidazolidinyl / carbonyl / amino / arylacetyl groups of formula 61, wherein R 2 is as defined above and R 2 is hydrogen, alkylsulfonyl, arylmethyleneamino (i.e. -N = CH-R ^, where R ^ has the above meaning), - (CO) -Rlg (where Rlg represents hydrogen, alkyl 10 or haloalkyl), an aromatic group (as defined above by Rj ^), alkyl or substituted alkyl, (in which latter case the alkyl group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups).

/ / / 3-Substituted-2-oxo-1-imidazolidinyl-15-carbonyl-7-amino-arylacetylic groups of the above formula are preferred where R 1 represents phenyl or 2-thienyl. Also preferred are the groups wherein R 1 represents hydrogen, methylsulfonyl, phenylmethyleneamino or 2-furylmethyleneamino.

The expression "cation" used throughout the description refers to all kinds of positively charged atoms or atomic groups. The "-SO 2 M +" substituent on the nitrogen atom of the β-lactams of the invention refers to all sulfonic acid salts. Pharmaceutically acceptable salts are of course preferred, although other salts may also be used in purifying the products of the invention or as intermediates for the preparation of pharmaceutically acceptable salts. The cationic portion of the sulfonic acid salts of the invention can be obtained from either organic or inorganic bases. Such a cationic moiety comprises, for example, the following ions: ammonium, substituted ammonium, for example alkyl ammonium (also called tetra-n-butylammonium, hereinafter referred to as tetrabutylammonium), alkali metal, for example lithium, sodium and potassium, alkaline metal, for example calcium and mag-35 nesium, pyridinium, dicyclohexylammonium, hydrabaminium, benzathi 81 0 0 5 7 i 6 6

nium and N-me thy1-D-glucaminium.

As shown in formula 3 and in the definitions of formula 3, M + may be hydrogen.

As will be further described, the β-lac-5 grains of the invention can be prepared synthetically. The non-alkoxylated 4-unsubstituted β-lactams of the formula 3, ie the compounds of the formula 1, wherein R 1 and R 2 are hydrogen can be used using 6-aminopenicillanic acid or an acyl aminopenicillanic acid as a starting material . The β-lactams of formula 1, wherein R 2 is alkoxy, can be prepared from the corresponding non-alkoxylated β-lactam. Some compounds of the invention can be crystallized or recrystallized from aqueous solvents. In such cases, hydrate water can be formed. The present invention relates to stoichiometric hydrates, as well as compounds containing varying amounts of water and leanings are prepared by methods such as freeze drying.

Some β-lactams of the formula 1 have also been prepared organically. Culture of a strain of the microorganism Cfaromobacterium violaceum SC 13,378 yields a salt of (R) -3- (acetylamino) -3-methoxy-2-oxo-3-azethidine sulfonic acid. Culture of various acetic acid bacteria, for example Gluconobacter species SC 33,435 provides a salt of (R) -3- (3) -R-25 (Dy-glutamyl) -D-alanylJ7 aminoJ7-3-methoxy-2-oxo-3-azethidine- sulfonic acid.

β-Lactams with a sulfonic acid salt substituent in the 3-position and an amino- or acylaraino substituent in the 3-position contain at least one chiral center - the carbon-30 atom (in the 3-position of the β-lactam nucleus) to which the amino or acylamino substituent is attached. The invention relates to those β-lactams described above, in which the stereoi 81 00 57 1 - 7 -

chemistry at the chiral center at the 3-position of the β-lactam nucleus is the same as the configuration at the same carbon atom at the 6-position of naturally occurring penicillins (e.g. penicillin G) and as the configuration at the carbon at 5 7 -place of naturally occurring cefamycin (eg cefamycin C).

With regard to the preferred 3-lactars of formulas 1 and 1a, the structural formulas are drawn so that they represent the stereochemistry at the chiral center in the 3-position. Because of the nomenclature convention, the compounds of formulas 1 and 1a, wherein R 2 hydrogen is the S configuration, and the compounds of formulas 1 and 1a, wherein R is alkoxy, have the R configuration.

Also included in the invention are racemic mixes containing 3-lactams described above.

β-Lactams with a sulfonic acid salt substituent at the 1-position of the β-lactam nucleus and an amino or acylamino substituent at the 3-position of the β-lactam nucleus have activity against a range of gram-negative and gram-positive organisms. The sulfonic acid salt substituent is essential for the action of the compounds of the invention. The compounds in which R 1 and / or R 2 are hydrogen or alkyl, in particular methyl, have a particularly valuable effect.

The compounds of the invention can be used as agents to combat bacterial infections (including urinary and respiratory tract infections) in mammalian animal species (eg dogs, cats, cattle, horses, etc.) and in humans.

To combat bacterial infections in mammals, a compound of the invention can be administered to a mammal as needed in the amount of 1.4 mg / kg / day to 350 mg / kg / day, preferably 14 mg / kg / day to 100 mg / kg / day. All modes of administration which have been used in the past to deliver penicillins and cephalosporins to the site of infection also apply using the new 81 00 57 1-8 family of β-lactams of the invention. Such routes of administration include oral, intravenous, intramuscular and as a suppository.

The β-lactam products of the invention are generally prepared by introducing a sulfonic acid substituent (a sulfo group -SO 2 -) on the nitrogen atom at the 1-position of the β-lactam nucleus. The sulfonation reaction is easily carried out by the β treat lactam with a sulfur trioxide complex or with an equivalent sulfonating reagent, for example a chlorine sulfonate.

The most commonly used sulfur trioxide complexes are pyridine sulfur trioxide, lutidine sulfur trioxide, dimethylformamide sulfur trioxide and pikoline sulfur trioxide. Instead of using a preformed complex, the complex can also be formed in situ, for example using chlorosulfonyl-trimethylsilyl ester and pyridine as reagents. Optionally, the sulfonation can be carried out via an intermediate, for example by first silylating the nitrogen atom on the β-lactam core and then subjecting the silylated compound to a silyl exchange reaction with trimethylsilyl chlorosulfonate or a similar reagent. Examples of silylating agents are monosilyltrifluoroacetamide, trimethylsilyl chloride / triethylamine and bis-trimethylsilyltrifluoroacetamide.

Generally, the sulfonation reaction is carried out in the presence of an organic solvent, for example pyridine or a mixture of organic solvents, preferably a mixture of a polar solvent such as dimethylformamide and a halohydrocarbon such as dichloromethane.

The product originally formed in the sulfonation reaction is a salt of the sulfonated β-lactam. When pyridine sulfur trioxide is the sulfonating complex, the product initially formed is the β-lactam sulfonated pyridinium salt of the sulfonated β-lactam, where M + in the formula 62 represents a pyridinium ion. These complexes can be converted into other sulfonic acid salts in the usual ways (eg, 8 1 0 0 5 7 1 f; - 9 - ion exchange resins, crystallization or ion pair extraction). These conversion methods are also suitable for purifying the products. Conversion of the pyridine salt to the potassium salt using potassium phosphate or potassium ethyl hexanate, in the tetrabutylsanium salt or using tetrabutyl ammonium hydrogen sulfate or in a Zwitter ion (M + = hydrogen) using formic acid are particularly valuable.

The sulfation reaction, which introduces the sulfo group to the nitrogen atom of the β-lactam core, may of course be carried out in 10 different stages of the synthesis, including incorporation into the formation of the β-lactam core, following such a procedure as set forth below. . The sulfonation reaction is carried out in the presence of solvents previously described and usually at room temperature. When the amino function 15 is present, the reaction is preferably carried out with the protected amino function.

Using a benzyl oxycarbonyl protecting group as an example, the sulfation reaction can be represented by reaction scheme A.

Other protecting groups can be used to protect the amine function, for example a p-butyloxy-carbonyl group, a simple acyl group such as acetyl or benzoyl or phenylacetyl, a triphenylmethyl group, or a group having the amino function in the form of an azide group. The desired acyl group (R ^) 25 can then be confirmed with an ordinary acylation reaction.

Examples of acylation methods for converting a compound of Formula 3 into a product of Formula 1 involve reaction with a carboxylic acid (R 1 -OH), or corresponding carboxylic acid halide or carboxylic anhydride. The acylation is best carried out with an acid chloride or acid bromide when R 1 is oxyoxy 30. The reaction with a carboxylic acid proceeds most easily in the presence of a carbodiimide, for example dicyclohexylcarbodiimide and a substance, which can form an active ester in situ, for example N-hydroxybenztriazole. In those cases where the acyl group (R ^) contains a reactive function (eg amino 81 0 0 5 7 1

£ X

Or carboxyl groups), it may be necessary to protect these functional groups first, then carry out the acylation reaction and finally deprotect the product obtained. Optionally, the sulfonation reaction can be carried out, while the acyl group is already on site, i.e. according to reaction scheme B.

In case R 2 represents lower alkoxy, there may be an additional variation, because the lower alkoxy group can be introduced both before and after the sulfonation using the ordinary method, chlorinating the acylated nitrogen atom at the 10 3 position by reaction with a lower alkoxide, as shown in Reaction Scheme C.

The acyl groups also contain easily removable groups in the above reaction, which function as a protecting group and can be removed after the reaction to obtain the "deacylated" product.

Furthermore, the (3-lactam ring can be formed via a ring closure reaction and the sulfonation reaction can be carried out both before and after the ring closure as shown, for example, in reaction scheme D.

The acyl group in this reaction can also be an easily removable group, which acts as a protecting group and yields the -NHj product upon removal,

The starting azetidinones in which R 2 is hydrogen and at least one of the symbols and R 1 is hydrogen can also be prepared from amino acids of the formula 12 (in which at least one of the symbols R 1 and R 4 is hydrogen). The amino group is first protected with a classic protecting group, for example p-butoxycarbonyl (hereinafter referred to as "BOC"). The carboxyl group of the protected amino acid is then reacted in the presence of a carbodiimide with an amine salt of the formula 13 to obtain a compound of the formula 14 (at least one of the symbols R 1 and R 1 is hydrogen). The hydroxy1 group of a compound of the formula 14 is converted into a leaving group (V) with a conventional reagent, for example methane-35 sulfonyl chloride (methanesulfonyl is hereinafter referred to as 81 00 57 1 - 11 - κ

a

as "Ms" !. Other leaving groups (V) which can be used are benzenesulfonyl, toluenesulfonyl, chlorine, bromine and iodine.

The fully protected compound of formula 15 (wherein at least one of the symbols and R 4 is hydrogen) is cyclized by treatment with a base, for example potassium carbonate. The reaction is preferably carried out under reflux in an organic solvent such as acetone to yield a compound of the formula (at least one of the symbols and R 1 is hydrogen).

Optionally, cyclization of a compound of the formula 14 can be effected without first converting the hydroxy group to a leaving group. Treatment of a compound of formula 14 with triphenylphosphine and diethyl azodicar boxylate yields a compound of formula 16 wherein at least one of the synbole and R 2 is hydrogen.

Removal of the protecting group from the 1-position of an azetidinone of the formula 16 can be accomplished via sodium reduction when Y is alkyl and yields an intermediate of the formula 17, wherein at least one of the symbols is R (and hydrogen). When Y is benzyl, catalytic (i.e., palladium on carbon) hydrogenation initially yields the corresponding N-hydroxy compound which, when treated with titanium trichloride, yields an intermediate of formula 17 wherein at least one of the symbols R1 and R4 is hydrogen is.

A synthesis, in which ring closure of the type described above has been discussed, leads to inversion of the stereochemical configuration of the R3 and R4 substituents.

As already mentioned, the above-mentioned azetidinone can be sulfonated to form a compound of the formula 18 (at least one of the symbols R 3 and R 3 is hydrogen).

An optional other process for preparing a compound of the formula 1, wherein R 2 is hydrogen and at least one of the symbols R 3 and R 3 is hydrogen, starts from an amino acid amide of the formula 19 (in which at least one of the symbols R 3 and R 3 is R ^ is hydrogen). Protection of the amino group 81 00 57 1 Μ · ^ - 12 - with a classic protecting group, for example benzyloxycarbonyl (hereinafter referred to as 2) or BOC and conversion of the hydroxyl group to a leaving group (for example V) for example Ms yields a compound of the formula 20 (wherein at least one of the symbols is R 1 and hydrogen), wherein A represents the protecting group.

Sulfonation of a compound of formula 20 yields a compound of formula 21 (wherein at least one of the symbols R 1 and R 2 is hydrogen).

Ring closure of a compound of the formula V) 21 is effected with a base, for example potassium carbonate. The reaction is preferably carried out in a mixture of water and an organic solvent (eg a halohydrocarbon such as 1,2-dichloroethane) under reflux with heating to give a compound of the formula (22 wherein at least one of the symbols R ^ and R ^ is hydrogen).

Ο

Deprotection of a sulfonated azetidinone of the formula 22, wherein A represents a protecting group, as well as of the above-described counterparts having an R 1 alkoxy group, by catalytic hydrogenation yields a compound of the formula 23 (wherein at least one of the symbols R 1 and is hydrogen) wherein R 1 is hydrogen or alkoxy can be converted to the corresponding Zwitterion of formula 24 (wherein at least one of the symbols R 1 and R 2 is hydrogen) by treatment with an acid such as formic acid.

Deprotection of a sulfonated azetidinone of formula 22, wherein A represents a protecting BOC group using acidic conditions (eg using formic acid) to yield the corresponding Zwitterion of formula J4 ·

An excellent source of the starting β-lactams are the 6-aminopenicillanic acids and the 7-aminocephalosporanoic acids, which may optionally carry a 6-alkoxy substituent or 7-alkoxy substituent, respectively. These compounds have formulas 25a and 25b, respectively, wherein Rj is hydrogen or alkoxy 81 00 57 1

It represents 13 and Rj represents hydrogen or acyl. By adapting methods described in the literature, 3-amino-2-azetindinones can be prepared; see, for example, Chem.Soc. Special Publication No. 28, 288 (1977); The Chemistry of Penicillins, Princeton üniv.

5 Press, 257, and Synthesis, 494 (1977).

Thus, 6-aminopenicillanic acid or 7-amino-cephalosporanic acid is first desulfurized by reduction with Raney nickel. The reaction can be carried out under reflux in water under heating and the resulting compound has the formula 26.

Replacement of the carboxyl group of the compound of formula 26 with an acetate group followed by hydrolysis yields a 3-amino-3-alkaxy-2-azetidinone of the formula 1 wherein R 1 is hydrogen or acyl and R is hydrogen or lower alkoxy 15 and R 1 and R 2 represent hydrogen. Treatment of a compound of formula 26 with cupric acetate and lead tetraacetate in an organic solvent (e.g. acetic nitrile) replaces the carboxyl group with an acetate group. Hydrolysis of the resulting compound can be accomplished with potassium carbonate in the presence of sodium hydride.

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

A 3-azido-2-azetidinone used as starting material can be prepared by first reacting an olefin of the formula 27 with a halosulfononyl isocyanate (preferably chlorosulfonyl isocyanate) of the formula 28 to obtain an azetidinone of the formula 29. Reductive hydrolysis of a 3Q azetidinone of formula 29 yields an N-unsubstituted g-lactam of formula 30. For a more detailed description of reaction series described above, reference may be made to the literature, see for example Chem, Soc. Rev. " 51818 (1976) and J.Qrg. Chem. , ^ 35 ^, 2043 (1970), 35 An azido group can be introduced into the 3-position of an azetidinone of the formula 30 (or its sulfonated counterpart) 81 00 57 1 - 14 - by reacting the compound with an arylsulfonyl azide (eg toluenesulfonylazide) to obtain an azetidinone of the formula 31 to be used as starting material. The reaction proceeds best by first protecting the azetidinone nitrogen with a silyl residue (eg t-butyldimethylsilyl, or p-butyldiphenylsilyl), then the anion 3-forming the core with a strong organic base (e.g. lithium diisopropylamine) at low temperature and then treating the anion with toluene sulfonyl azide. The resulting intermediate 10 is quenched with trimethylsilyl chloride and subsequent acid hydrolysis or fluoride sulphysis of the N-protecting group affords the compound of formula 31.

Optionally, the compound of formula 31 may be obtained by first reacting a primary amine of formula 63 or 64 with an aldehyde of formula R 1 CH 2 O to give the corresponding base of Schiff. A / 2 + 2 / cyclo addition with an activated form of azidoacetic acid yields a 3-azido-2-azetidinone of the formula 65, wherein Q represents a group of the formula 66 or 67, oxidative contamination of the 20 Q substituent gives the compound of formula 31.

The 3-acylamino-2-azetidinones can be obtained by first reducing a 3-azido-2-azetidinone of the formula 31 to yield the corresponding 3-amino-2-aze-tidinone and then the 3-amino-2- acylidinone. As already mentioned, when R 1 represents lower alkoxy, the product can be prepared from the counterpart in which R 1 is hydrogen. Chlorination of the amide nitrogen of a non-alkoxylated compound yields an intermediate of formula 32. Reagents and processes for N-chlorination of amides are known in the art. Examples of reagents are t-butyl hypochlorite, sodium hypochlorite and chlorine. The reaction can be carried out in an organic solvent (for example a lower alkanol such as methanol) or in a biphasic solvent system (for example water / methylene chloride) in the presence of a base such as sodium 35-borate decahydrate. The reaction is preferably carried out at a reduced temperature of 81 DEG-57 DEG-5-15.

Reaction of an intermediate of formula 31 with an alkoxylating agent, for example an alkali metal alkoxide, yields a product of formula 1, wherein R 2 represents alkoxy, in combination with its enantiomer. The reaction can be carried out in an organic solvent, for example a polar organic solvent such as dimethylformamide, at a reduced temperature.

10 15 20 25

An optional other synthetic route to prepare the compounds of formula I, wherein alkoxy is, is to first alkoxylate an intermediate of formula 6, wherein R 1 NH is a carbamate (R 1 is, for example, benzyloxycarbonyl) and R 2 is hydrogen and then introducing a sulfo group at the 1-position of the resulting compound. Chlorination of a compound of the formula 6 by the above-described method (for chlorination of a non-alkoxylated compound of the formula 1 to a compound of the formula 22) yields an intermediate of the formula 33. According to the above-described alkoxylation method (for converting a compound of the formula 32 into a product of the formula 1), followed by addition of a reducing agent, for example trimethylphosphite, the compound of the formula 33 can be converted into an intermediate of the formula 34 in combination with its enantiomer.

The above-described processes yield the products of formula I, wherein R2 is alkoxy, as a racemic mixture. If desired, the R-enantiomer can be recovered from the racemic mixture in the usual ways, for example, by fractional crystallization of a suitable salt with an optically active organic amine or by ion pair chromatography using an optically active cation.

30

Organic production of the antibiotic EM5117.

35

Salts of (R) -3- (acetylamino) -3-methoxy-2-oxo-1-azetidine sulfonic acid (Formula 1, Rj is acetyl and R2 is methoxy, hereinafter referred to as EM5117) can also be prepared by 81 00 57 1 culture of a strain of the microorganism Chromobacterium violaceum SC 11,378 deposited in the American Type Culture Collection as ATCC No. 3153-2. - 16 - r * 5 The micro-organism »

The microorganism used for the production of EM5117 is a strain of Chromobacterium violaceum SC 11.378. A subculture of the microorganism can be obtained from the permanent collection of the American Type Culture Collection, Rock-10 ville, Maryland. His order number is A.T.C.C. No. 31532. In addition to the specific microorganism described and characterized herein, mutants of the microorganism (for example, mutants obtained by use of X-rays, ultraviolet rays or nitrogen mustard) can of course also be cultivated to produce EM5117.

Chromobacterium violaceum SC 11378, A.T.C.C.

No. 31532 can be recovered from a moist soil sample containing the micro-organism by first stamping the moden sample on a medium containing: 20 Soil extract 400 ml

Distilled water 400 ml

Yeast extract 5.0 g

Glucose 10.0 g

Agar 17.5 g

The medium is adjusted to pH 6.0 and 20 min.

sterilized in an autoclave at 121 ° C. After 24-72 hours of incubation at 25 ° C, colonies of Chromobacterium violaceum SC 11,378 are collected from the streaked soil. These isolated colonies are then grown on a medium containing:

Yeast extract 1 g Beef extract 1 g NZ amine A 22 g Glucose 10 g Agar 15 g Distilled water to 1 1 8100571 17

The medium is adjusted to pH 7.3 and heated in an autoclave at 121 ° C for 30 min.

Chromobacterium violaceum SC 11,378 is a Gram-negative rod, often exhibiting transverse, bipolar spotting, and lipid inclusions. It is a single polar flagellum motile with occasionally lateral fllagella, which are smaller in size.

Chromobacterium violaceum SC produces 11,378 violet colonies on nutrient agar. The pigment is enhanced on tryptophan rich media and yeast extract. In nutrient fluid, it produces a violet ring on the wall of the tube, but not a confluent pellicle. The violet pigment is soluble in ethanol, but insoluble in water and chloroform.

Chromobacterium violaceum SC 11,378 is mesophilic 15 and grows over a range of 15-37 ° C, but no growth occurs at 4 ° C or above 37 ° C. Casein is highly hydrolyzed by the microorganism, which is oxidase positive. In the presence of Chromobacterium violaceum SC 11,378, glucose, fructose and trehalose are fermented (method of Hugh & Leifson, 1953).

L-Arabinose is used by the microorganism neither fermentatively nor oxidatively. Hydrogen cyanide is produced by the microorganism and aesculin hydrolysis is negative.

The key properties described above provide the basis for the identification of the microorganism as Chromobacterium violaceum to distinguish Chromobacterium lividum, the only other species of the genus Chromobacterium, which is distinguished in the 8th edition of Bergey's Manual of Determinative Bacteriology.

Still other strains of Chromobacterium violaceum 30 can also be grown to produce EM5117.

The antibiotic.

To obtain the antibiotic EM5117, Chromobacterium violaceum SC 11378 A.T.C.C. No. 31532 35 at or at about 25 ° C under submerse aerobic conditions 81 0 0 5 7 1 * - 18 - growing on an aqueous nutrient medium containing an assimilable carbon and nitrogen source. The fermentation is carried out until the medium has acquired significant antibiotic activity, usually 18-24 hours, preferably 20 hours.

EM5117 can be separated and purified from the fermentation broth using the following procedure. After the fermentation is complete, the liquid can be centrifuged to remove the mycelium, or optionally also filtered to remove the mycelium from the liquid. After removal of the mycelium from the liquid, EM5117 can be extracted from the liquid. Preferably, the liquid is extracted at pH 5 by ion pair extraction with cetyldimethylbenzylammonium chloride in methylene chloride and extracted back into aqueous sodium iodide (adjusted to pH 5 with acetic acid). After concentration of the sodium 15 iodide extract in vacuum, a solution of the residue in water can be washed with butanol. Concentration of the resulting aqueous solution to dryness gives a residue which is dissolved in methanol as far as possible. The insolubles can be centrifuged off, then washed with methanol and then discarded.

Purification of the antibiotic can be done by dissolving the methanol concentrate in methanol / water (1: 1) and passing it over a chromatography column, for example a column of Sephadex G-10 in the same solvent mixture. After eluting the same mixture, the active fractions are combined and concentrated to dryness. The residue is mixed with methanol and the insoluble matter is filtered off and discarded.

Further purification is obtained by passing the methanol-soluble substance over a column of DEAE cellulose. The column can be eluted with a linear gradient prepared from pH 5 sodium 0.0 M phosphate buffer and pH 5 sodium 0.1 M phosphate buffer. The active fractions are combined and concentrated and the methanol insolubles are removed and discarded.

Still further purification of EM5117 is obtained 81 00 57 1 i, t-19 - by dissolving this substance in water and passing the solution over a column of Sephadex LH-20 and eluting the column with water. The active fractions are combined and concentrated. Further purification of EM5117 is then obtained by dissolving the substance in water, passing the solution over a column of Diaion HP-20AG and eluting with water. The active fractions are combined and concentrated. The concentrate is dissolved in water and passed through a column of Dowe 50W-X2, potassium form under washing with water. The effluent can be concentrated to a crystalline substance, which is the relatively pure potassium salt of EM5117.

The recovery and purification described above yields the potassium salt of EM5117. Other salts can be prepared in accordance with the shape of the ion exchange resin used in the final purification step.

15

Organic production of the antibiotic EM5210.

Salts of (R) -3 - / - (N - (D-γ-glutamyl) -D-alanyl / / - amino / -3-methoxy-2-oxo-1-azetidine sulfonic acid (Formula 1, wherein 20 Rj Dy- glutamyl-D-alanyl and methoxy, hereinafter referred to as EM5210) can also be prepared by cultivation of various acetic acid bacteria.

The microorganism.

The microorganism Gluconobacter species SC

11,435 can be used for the production of EM5210. A subculture of the microorganism can be obtained from the permanent collection of the American Type Culture Collection, Rockville, Maryland. His order number in the collection is A.T.C.C. No.

Of course, in addition to the specific microorganism described and characterized here, mutants of the microorganism (eg mutants obtained by use of X-rays, ultraviolet rays or nitrogen mustard) can also be cultivated to produce EM5210.

Gluconobacter species SC 11.435, A.T.C.C. No.

81 00571 - 20 - 10 15 20 25 30 35 31 581 can be recovered from soil moss containing the microorganism by first incubating the soil moss in a 10 * pectin solution in water at 25 ° C for 7 days ( pH 2.5). The organism can then be isolated by spreading on a medium containing: χ Spartina patens grass extract 400 ml Distilled water 600 ml Yeast extract 5 g Glucose 10 g Crude agar flakes 17.5 g * Spartina patens grass extract is prepared by 500 g add finely chopped dried grass to 3 l of tap water, which has been brought to the boil and simmered for 30 minutes. The medium is adjusted to pH 6.0 and sterilized in an autoclave at 121 ° C for 20 min. After 18 hours of incubation at 25 ° C, colonies of Gluconobacter species SC 11.435 are recovered from the streaked pectin enrichment solution. This isolated colony is then grown on a medium containing: Yeast Extract 1 g Beef Extract 1 g NZ Amine A 2 g Glucose 10 g Agar 15 g Distilled water to 1 liter. The medium is adjusted to pH 7.3 and heated in an autoclave at 121 ° C for 30 minutes. Gluconobacter species SC 11.435 is a pleiomorphic gram-negative rod, which is motile with 1-3 polar flagella. It is inevitably aerobic, catalase positive and oxidative. It differs from Pseudomonas in that the cytochrome oxidase is negative and tolerant under extremely acidic conditions. These properties indicate that the microorganism is more closely related to the acetic acid bacteria than to true Pseudomonas. Gluconobacter species SC 11.435 grows on BBL Trypticase soy agar as a mixture of rough and smooth colony types.

81 00 57 1 * _ Λ - 21 -

The rough type is accompanied by a slightly yellow soluble pigment, while the smooth type is mucoid and pigmentless. Dissociation between the two types is affected by media, temperature and storage conditions. The action of EM5210 tends to decrease in cultures in which the crude component predominates.

On BBL Wart agar (pH 4.8), Gluconobacter species SC 11.435 grows abundantly as heaped mucoloid colonies. A similar growth is obtained on malt yeast extract agar (1% each) adjusted to pH 4.5.

On medium containing 1% yeast extract, 10% glucose, 3% calcium carbonate and 2.5% agar, sufficient acid is produced from the glucose to produce a clarification zone of the calcium carbonate for growth. This is a characteristic aspect of Acetobacter and Gluconobacter.

In the presence of Gluconobacter species SC 11.435, I. a brown soluble pigment is produced on yeast extract glycerol and yeast extract calcium lactate agar plates and II. acid produced on glucose, fructose, galactose, mannose, xylose, mannitol and arabinose, but no growth or acid production occurs on rhamnose, lactose, sucrose or maltose when these sugars are incorporated in Hugh and Leifson's medium.

The organic production of EM5210 is not limited to Gluconobacter species SC 11.435, but is widely distributed among the acetic acid bacteria. The following cultures can each be used for the production of EM 5210:

Acetobacter pasteurianus subsp. pasteurianum A.T.C.C.6033.

Acetobacter aceti subsp. aceti A.T.C.C. 15973.

Gluconobacter oxydans subsp. oxydans A.T.C.C. 19357.

Gluconobacter oxvdans subsp. suboxy dance A.T.C.C. 23773.

30 Gluconobacter oxydans subsp. oxydans A.T.C.C. 15178.

Acetobacter aceti subsp. liquefaciens A.T.C.C. 23751.

Acetobacter peroxydans A.T.C.C. 12874.

Gluconobacter oxydans subsp. suboxy dance A.T.C.C. 19441.

Acetobacter sp. A.T.C.C. 21780.

Gluconobacter oxydans subsp. industralis A.T.C.C. 11894.

81 00 57 1

The antibiotic.

To obtain the antibiotic EM5210, Gluconobacter species SC 11,435 A.T.C.C. No. 31581 or any of the microorganisms listed above at or at about 25 ° C under submerged aerobic conditions, grow on an aqueous nutrient medium containing an assimilable source of carbon and nitrogen. The fermentation is carried out until the medium has acquired significant antibiotic activity, usually 16-24 hours, preferably 20 hours.

EM 5210 can be separated and purified from the fermentation medium in the following manner. After the fermentation is complete, the liquid to remove the bacteria is centrifuged and the antibiotic is removed from the supernatant by absorption at pH 3.7 on an anion exchange resin, for example Dowex 1-X2. The antibiotic is eluted from the resin at pH 4 with sodium chloride and the eluate is concentrated and passed over an activated carbon column. EM 5210 is then eluted from the activated carbon with methanol: water, 1: 1. The active fractions are collected and dried and then passed through an anion exchange column, for example Dowex 1-X2 and eluted with a gradient of sodium chloride, buffered at pH 4.

The active fractions are concentrated and desalted on a macro-reticular styrene-divinylbenzene copolymer resin column (Dianion HF 20AG). The active fractions are eluted with water and concentrated and lyophilized and this material is the sodium salt of EM5210.

The purification method described above gives the sodium salt of EM5210. Other salts can be obtained by changing the salt used to elute EM5210 in the ion exchange chromatography as described above, for example, using potassium chloride to obtain the potassium salt.

The following examples illustrate the invention.

81 00 57 1 35

Example 1 (S) -N- (2-Oxo-1-sulfo-3-zetidinyl) -2-phenylacetamide, potassium salt.

Method I: A) -1 - / - <1R) -carboxy-2-methyl (propyl) - / - 2-oxo (3S) - / phenyl / acetyl (amino) / / / azetidine.

Raney nickel is washed with water by decanting it for several hours until the pH of the water (5-6 times the volume of the Raney nickel) is 7.6.

54 g or 90 ml of Raney nickel are added to a solution of 9.0 g of penicillin G (Na +) in 500 ml of water. The flask equipped with a reflux condenser is immersed in a 155 ° C bath. When the reflux starts, this is continued for 15 minutes.

The flask is immediately cooled in an ice-water bath and the Raney nickel is removed by filtration through Celite. The pH is adjusted to 3 with dilute HCl and the aqueous solution is concentrated to about 150 ml and cooled. The oil layer crystallizes when scratched. After washing with water and drying in vacuo at 50 ° C for 3 hours, 3.83 g of the title compound are obtained.

B) 1- / Acetyloxy-2-methyl (propyl) -1/2-oxo (3S) -phenyl / acetyl (amino) -1 / 1 / azetidine.

Nitrogen is bubbled under stirring for 15 min through a suspension of 608 mg or 2 mmol of the above compound in 20 ml of dry acetic nitrile. A water bath of 40-45 ° C is used for several minutes to dissolve all the acid. The water bath is removed and 182 mg or 1 mmol of powdered cupric acetate monohydrate is added, followed by stirring for 1 min with 886 mg or 2 mmol of lead tetraacetate. The mixture is stirred at room temperature for 20 min. The acetic acid nitrile solution is decanted from the precipitate and the solids are washed with ethyl acetate. The combined acetic acid nitrile-ethyl acetate solution is evaporated to a residue which is taken up in ethyl acetate-water.

The ethyl acetate layer is washed successively with water (three times), aqueous sodium bicarbonate (pH 7) and water. The ethyl acetate layer is dried over sodium sulfate and discarded to 515 mg of residue, which is used in the next reaction without further purification.

C) 2-0xo (3S) - / - phenyl acetyl (amino) - / _ / azetidine.

To a solution of 911 mg or 2.86 mmol of the above compound in 21 ml of methanol, 3.5 ml of water is added, followed by 383 mg or 2.86 mmol of potassium carbonate. The mixture is stirred under nitrogen for 1 min, after which 160 mg or 4.30 mmol sodium borohydride is added. The reaction is stirred at room temperature for 20 minutes. The methanol is removed in vacuo and the residue is taken up in ethyl acetate and a small amount of water. This is adjusted to pH 2.5. The ethyl acetate layer is washed at pH 7.0 with aqueous sodium bicarbonate and then with a small volume of water and finally dried over sodium sulfate and evaporated to 493 mg of crude product. Addition of a small amount of ethyl acetate provides 250 mg (43% yield) of desired crystalline product. More amounts of product can be obtained by crystallization or chromatography.

D) (S) -N- (2-Oxo-1-sulfo-3-azetidinyl) -2-phenyl-acetamide, potassium salt.

215 mg or 1.35 mmol of pyridine.SO 2 complex under nitrogen at room temperature is added with stirring to a solution of 251 mg or 1.23 mmol of the above product in 2 ml of dry dimethylformamide and 2 ml of dry methylene chloride. The mixture is stirred for 3 hours. The solvents are removed in vacuo and the residue is taken up in methylene chloride water. The pH is adjusted to 6.5 with 2N potassium hydroxide. The water layer is washed with methylene chloride (three times), filtered and evaporated to a residue. The residue is stirred with 20 ml of methanol and the potassium sulfate is filtered off. The filtrate is evaporated to a residue, which is stirred with 10-15 ml of methanol. The solids 10057 1 - 25 - are collected to 49 mg of the title compound, mp 189 ° C with decomposition.

Analysis: Calculated for cuHuN2 O5®K: C 40.99; H 3.44; N 8.69; S 9.93; 5 Found: C 45.96; H 3.83; N 9.86; S 8.99.

The compound exhibits identical spectral properties to the product obtained in Method II.

Method II:

A solution of 660 mg (S) -2-oxo-3-V {_ (phenylmethoxy) carbonyl / amino __ / - 1-azetidine sulfonic acid, potassium salt (see example 3) in 13 ml of water is placed in a hydrogen atmosphere for 2 hours stirred with 200 mg of 10% palladium on charcoal. The catalyst is filtered off and the filtrate diluted with an equal volume of acetone and cooled in an ice bath. Phenylacetyl chloride in 8 portions of 40 µl and 10% potassium bicarbonate is added over 30 minutes (keeping the pH between 5.2-5.8). After 40 min, the solution is concentrated in vacuo to remove acetone and passed over a 200 ml HP-20 column. Elution with water and then with water-acetone (9: 1) yields 160 mg of crude product after thin-layer chromatography of Rhydon-positive fractions, followed by bundling and evaporation. Crystallization from methanol-ether gives 101 mg of the title compound, mp 210 ° C with decomposition.

Analysis: Calculated for εΐ1Η11Ν2 ° 5δΚΛ H20: 25 C 39.86; H 3.65; N 8.45; S 9.68; K 11.80;

Found: C 40.01; H 3.37; N 8.59; S 9.59; K 11.98.

NMR (D20) 3.66 (s, 3), 3.67 (d of d, / = 6.4), 3.90 (tj = j), 4.90 (d of d, j = 6.4 ), 7.36 ppm (m. 5),

Method III: 30 To a solution of 120 mg (S) -3-amino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 6A) in 3 ml dry methylene chloride, 40 mg phenylacetic acid and 61 mg dicyclohexylcarbodiimide are added. The mixture is stirred at room temperature for 48 hours and filtered to remove dicyclohexylurea. The solvent is removed in vacuo and the residue 81 0057 1C-26 - is taken up in acetone, filtered and the title compound is precipitated by adding 5 ml of acetone saturated with potassium iodide. The supernatant is poured off and the residue is washed with acetone (three times) and after drying 5, 48 mg of product with spectral properties corresponding to those of the products of Methods I and II are obtained.

Method IV;

A solution of 2.83 g of (S) -2-oxo-3-1 / (phenylmethoxy) carbonyl / amino-1-azetidine sulfonic acid, pyridine-10 salt (see example 2) is stirred in 36 ml of water in a water cool atmosphere with 707.5 mg of 10% palladium on carbon (hydrogen uptake 175 ml). After 2 hours, the slurry is filtered and the filtrate cooled to 0 ° C and diluted with 46 ml of acetone (starting pH = 4.25, adjusted to pH 6.7 with cold 10% potassium bicarbonate solution). A solution of 2.4 ml of phenylacetyl chloride in 10 ml of acetone is added dropwise

15 min. The pH is kept between 5.2 and 5.8 by simultaneous addition of 10% potassium bicarbonate solution. After 45 min, the slurry is diluted with 93 ml of 0.5M potassium phosphate (pH = 4.2) and concentrated to remove acetone. The slurry is filtered and washed with water. Filtrate and washings are combined and passed over a 450 ml HP-20 column. Elution with 1 1 0.5M potassium phosphate (pH = 4.2), 1 1 water then 2.5 1 9: 1 water acetone gives 1.285 g of the title compound in fractions 14-19 (fractions 1-15 were 200 ml, fractions 16-21 were 100 ml). The spectral data are in accordance with what was obtained in the previous methods.

Example 2, (S) -2-Oxo-3 - / ^, / (phenylmethoxy) carbony 1 / amino / -1-aetidine sulfonic acid, pyridine (1: 1) salt.

Method I: A) 1 - / - (IR) -Carboxy-2-methyl (propyl) - / - 2-oxo (3S) - / / - (phenylmethoxy) carbonyl / amino / azetidine.

A slurry of 12.98 g or 0.06 mole of 6-aminopenlcil- 81 00 57 1 * Jt-27-lanoic acid in 140 al water containing 5.1 g of sodium carbonate (cyl. Stirred for 10 min without complete solution) is stirred added in one portion to a well stirred (mechanical stirrer) suspension of Raney nickel (washed with water to pH 8.0, 260 ml of slurry = 130 5 g) in an oil bath of 70 ° C. After 15 min. the slurry is cooled , filtered and the filtrate treated with 5.18 g of sodium carbonate and a solution of 11.94 g or 0.07 mole of benzyl chloroformate in 12 ml of acetone. After 30 min, the solution is acidified to pH 2.5 and extracted with methylene chloride. The organic layer is dried, evaporated and triturated with ether-hexane to give a total of 6.83 g of the title compound.

B) 1- / (Acetyloxy) -2-methyl (propyl) - / - 2-oxo (3S) - / / (phenylmethoxy) carbonyl / amino / azetidine.

A solution of 6.83 g or 0.0213 mol of the above acid in 213 ml of acetic nitrile is treated with 1.95 g or 0.0107 mol of cupric acetate monohydrate and 9.5 g or 0.0213 mol of lead tetraacetate. The slurry is immersed in a 65 ° C oil bath and stirred with a nitrogen stream bubbling through the slurry until the starting material is consumed. The slurry is filtered and the solids are washed with ethyl acetate. The combination of filtrate and washings is evaporated in vacuo and the residue taken up in 100 ml of ethyl acetate plus 100 ml of water and adjusted to pH 7. The ethyl acetate layer is separated, dried and evaporated to 6.235 g of the title compound.

C) (S) - (2-Oxo-3-azetidinyl) carbamic acid, phenyl methyl ester.

A solution of 3.12 g or 0.0093 mole of the above acetate in 70 ml of methanol and 7 ml of water is cooled to -15 ° C and 1.33 g of potassium carbonate and 349 mg of sodium borohydride are added. The reaction mixture is stirred at -15 - 0 ° C. After the reaction is completed (about 2 hours), the mixture is neutralized to pH 7 with 2N HCl and concentrated in vacuo. Concentrate 35 is adjusted to pH 5.8, saturated with salt and extracted with ethyl acetate 81 00 57 1 4L> 28 (three times). The organic layer is dried and evaporated in vacuo. The residue is combined with material of a similar test and triturated with ether to give 3.30 g of the title compound.

5 D) (S) -2-Oxo-3 - / - / - (phenylmethoxy) carbonyl - / - amino / -1-azetidine sulfonic acid, pyridine salt.

Method Is

A solution of 440 mg or 0.002 mol of the above azetidinone is stirred in a mixture of 2 ml of dry methylene chloride and 2 ml of dry dimethylformamide under nitrogen for 2 hours under nitrogen with 350 mg or 0.0022 mol of pyridine sulfur trioxide complex. The mass of the solvent is then removed in vacuo and the residue triturated with ethyl acetate to give 758 mg of a solid which is essentially the title compound.

NMR <D20-CD30D) 3.63 (1H, d of d,} = 6.4), 3.90 (1H, t, j = 6), 4.85 (1H, d of d, j = 6, 4), 5.10 (2H, S), 7.27 (5H, s), 8-0-9.0 ppm (m's 5H).

Method II; 18.87 g of chlorosulfonyltrimethylsilyl ester are added dropwise at -20 ° C with stirring and under a nitrogen atmosphere to 7.9 g of anhydrous pyridine. After everything has been added, stirring is continued for 30 minutes at room temperature and trimethylchlorosilan is then removed in vacuo. A solution of 20 g of the above azetidinone (Method I, Part C) in 120 ml of dimethylformamide and 120 ml of methylene chloride is added and stirring is continued at room temperature for 3.5 hours. The solvent is distilled off in vacuo and the oily residue is crystallized by addition of ethyl acetate to give 31 g of the title compound. The NMR data is identical to that of the product of Method 1. Example 3 (S) -2-Oxo-3 - / - (phenylmethoxy) carbonyl / amino - / 1-azetidine sulfonic acid, potassium salt.

35 8100571-2-29 Method I;

135 mg of (S) -2-oxo-3- / / (phenylmethoxy) -carbonyl-7-amino-7-a-azetidine sulfonic acid, pyridine salt (see example 2) are dissolved in 2 ml of 0.5 M monobasic potassium phosphate (adjusted to pH 5.5) with 2N potassium hydroxide) and pass the solution over a 25 ml HP-20 AG column. The column is eluted with 100 ml buffer, 200 ml water and 100 ml 1: 1 acetone water. Fractions (25 ml) 14-15 are strongly Rydon positive. Evaporation yields 80 mg of material which is essentially the title compound (the spectral data is identical to that of the product prepared below).

Method II: 600 Mg (S) -2-oxo-3- / / (phenylmethoxy) carbonyl _ / - amino __ / - l-azetidine sulfonic acid pyridine salt (see example 2) is dissolved in 2 ml water and mixed with 15 ml pH 5.5 monobasic potassium phosphate buffer. A solid forms and the slurry is cooled to 0 ° C, filtered, washed with cold buffer, cold 50% ethanol, ethanol and ether to give 370 mg of the title compound (analysis of which contains excess potassium ions ). A solution of 280 mg of the salt in 20 ml of water is passed over a 100 ml HP-20 column. The column is eluted with 200 ml of water and then with water-acetone (9: 1).

Fractions (50 ml) are collected and evaporation of fraction 7 yields a solid. Trituration with acetone, filtration and vacuum drying affords 164 mg of the title compound 25, mp 193-196 ° C.

Analysis: Calculated for cnHuN2 ° gSK, 3I H 2 O: C 38.02; H 3.48; N 8.06; S 9.23; K 11.25;

Found: C 38.19; H 3.24; N 8.15; S 9.12; K 11.53.

NMR (D2Q) 3.69 (1H, d of d, j = 6.4), 3.91 (1H, t, j - 6), 4.76 (1H, m), 5.16 (2h, S), 7.43 ppm (5H, S).

Method III:

20.0 g of (S) - (2-oxo-3-azetidinyl) -carbamic acid, phenylmethyl ester (see example 2C) are suspended in 200 ml of vinegar-vacuum nitrile, 21.6 ml or 25.3 g of monotrimethylsilyl-trifluoro-acetamide are added and heat the mixture at 50 ° C with stirring for 1 hour.

81 00 57 1 ΐ * - 30 -

After cooling in an ice bath to 0 ° C, 17.2 g of trimethylsilylchlorosulfonate are dripped in and the solution is stirred at room temperature for 6 hours. 24.2 g of potassium ethylhexanate in 100 ml of butanol are added to the solution and stirring is continued for an additional hour. The slurry is poured into 1 l of dry diethyl ether and the precipitate is filtered off and dried in vacuo. The compound is dissolved in 500 ml of water, the pH is adjusted to 5.0 with potassium carbonate, insoluble material is filtered off and the mother liquor is freeze-dried. The crude compound yield is 19.4 g. The compound contains small amounts of potassium chloride, which is removed by chromatography. The spectral data is identical to that of Method II.

Example 4 (S) -2-Oxo-3V / _ (phenylmethoxy) carbonyl / amino-1/1-azetidine sulfonic acid, tetrabutyl ammonium salt. (1: 1) 15

Method I:

34.3 g of (S) -2-oxo-3- / / (phenylmethoxy) -carbonyl / amino / -1-aetidine sulfonic acid, pyridine salt (III) (see example 2) are dissolved in 800 ml of water. The solution is clarified with activated carbon, 30.7 g of tetrabutyl ammonium hydrogen sulfate in 80 ml of water are added and the pH is adjusted to 5.5 with 1N potassium hydroxide.

The solvent is removed in vacuo until a volume of 200 ml is reached. The precipitated tetrabutyl ammonium salt is filtered off and dried in vacuum. The compound can be recrystallized from water or dissolved in methylene chloride, filtered and precipitated by addition of ether. Yield 34.3 g, melting point 108-110 ° C.

Method II:

20.2 g of (S) -2-oxo-3 ~> 7 [(phenylmethoxy) -30 carbonyl / amino / -1-azetidine sulfonic acid, potassium salt (1: 1) (see example 3) are dissolved in 500 ml of water, filter and add 20.3 g of tetrabu-tylammoniura hydrogen sulfate in 100 ml of water. The pH is adjusted to 5.5 with 1N potassium hydroxide. The volume is reduced to 100 ml in vacuo and the precipitated tetrabutyl ammonium salt is filtered off. The compound is dissolved in 30 ml of methylene-8100571-3-chloride, filtered and precipitated by addition of ether to yield 21 g of the title compound, mp 109-111 ° C.

Example 5 5 (3S) α-α / 2 (2-x-1-sulfo-3-azetidinyl) amino / carbonyl / benzene acetic acid, phenyl methyl ester, potassium salt (1: 1).

A) (S) -3-Amino-2-azetidinone.

3 g of (S) - (2-oxo-3-azetidinyl) -carbamic acid, phenylmethyl ester (see example 2C) are hydrogenated in 100 ml of methanol in the presence of 1 g of palladium on carbon as a catalyst.

When the theoretical amount of hydrogen has been absorbed, the catalyst is filtered off and the filtrate is evaporated to dryness.

On standing, 1.1 g of the title compound crystallize out.

B) (3S) -α - / - (2-Oxo-3-azetidinyl) amino / carbonyl / benzeneacetic acid, phenylmethyl ester.

3.0 g of the above azetidinone are dissolved in 100 ml of dimethylmethylformamide. The solution is cooled to 0 ° C and 4.5 g of N-methylmorpholine is added, followed by (dropwise) 10.8 g of a- (chlorocarbonyl) benzenacetic acid, phenylmethyl ester in 50 ml of acetic acid nitrile with stirring. The mixture is stirred at 5 ° C for 16 hours. The solvent is distilled off in vacuo and 100 ml of water are added to the residue. The aqueous suspension is extracted twice, each time with 100 ml of methylene chloride. The organic layers are combined, washed with sodium bicarbonate, 2N phosphoric acid and water, dried with sodium sulfate, filtered and evaporated to dryness. The residue is recrystallized from ethyl acetate and petroleum ether, whereby 8.7 g of melting point 164-166 ° C are obtained.

C) (3S) -a - / - (2-Oxb-1-sulfo-3-azetidinyl) amine / carbonyl / benzeneacetic acid, phenylmethyl ester, potassium salt (1: 1). 35 81 0 0 5 7 1 - 32 -

6.9 g of the above compound are suspended in 150 ml of acetic nitrile. 5.7 g of monotrimethylsilyltrifluoroacetamide are added and the solution is heated at 50 ° C with stirring for 30 min. The solution is cooled to 0 ° C and 3.9 g of trimethylsilylchlorosulfonate are added dropwise. When everything has been added, the mixture is heated at 50 ° C for 5 hours. After cooling to 20 ° C, 7.6 g of potassium ethyl hexanate in 10 ml of butanol are added and the mixture is stirred for an additional 30 minutes. On addition of 300 ml of ether, the title compound precipitates and this compound is filtered off. The crude product is stirred with 100 ml of dry acetic nitrile for 30 min and filtered to give 4.5 g of the title compound, m.p. 118-120 ° C. Further purification of the crude product by HP-20 chromatography, followed by freeze drying, yields pure material with melting point 15 188-190 ° C.

Example 6 (S) - 3 - [- (2-Amino-4-thiazolyl) acetyl / amino-2 / oxo-1-azetidine sulfonic acid, potassium salt.

20 A) (S) -3-Araino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt.

2 g of (S) -2-oxo-3V / (phenylmethoxy) carbonyl / amino 7-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see Example 4) are dissolved in 100 ml of dimethylformamide and hydrogenated with 1 g for 30 min. palladium on carbon (10%) as a catalyst.

The catalyst is filtered off and the dimethylformamide is removed leaving the title compound as an oil. NMR (Cl> Cl 3) 3.82 (1H, t = 5.5), 4.05 (d, 1H, 30 d of d, j = 5.5, 2.5 cps.).

B) (S) -3- / / (2-Amino-4-thiazolyl) acetyl / - amino T-2-oxo-1-azetidine sulfonic acid, potassium salt.

2 g of the above compound, 0.5 g of aminothiazole acetic acid and 0.4 g of hydroxybenztriazole are stirred at 0 ° C in 8100571 - 33 - 100 ml of dry dimethylformamide, while dropwise dissolving a solution of 0.7 g of dicyclohexylcarbodiimide in 10 ml of dimethylformamide. adds. After everything has been added, 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 perfluorobutane sulfonate in 20 ml of acetone at room temperature for 15 min. After addition of 200 ml of dimethyl ether, the title compound precipitates and this compound is filtered, dried and purified through a 300 ml HP-20 chromatography column using water as an eluent. The yield is 850 mg of the title compound, melting point> 300 ° C. Example 7 f_ 3S (+) - / - 3 "(_ L (F ° rmyloxy) phenylacetyl / amino _ / - 2-oxo-1-azetidine-15 sulfic acid, potassium salt.

1.5 g of (S) -3-amino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 6A) in 100 ml dimethylformamide and 2 ml propylene oxide are cooled to 0 ° C. A solution of O-formylamandelic acid chloride in 10 ml of acetic nitrile is added dropwise with stirring. The temperature is maintained for 1 hour and the solvent is then distilled off in vacuo. The oily residue is treated with a solution of 2 g of potassium perfluorobutane sulfonate in 15 ml of acetone. After addition of 200 ml of ether, the title compound crystallizes out and this compound is filtered off to obtain 1.5 g of product. The product is purified by HP-20 chromatography. Melting point 180-185 ° C with decomposition.

Example 8 30 / 3S (+) / 3-V / (Formyloxy) phenylacetyl / amino / 2-oxo-1-azetidine sulfonic acid, potassium salt.

If the procedure of Example 7 is followed, but using DO-formyl-mandelic acid chloride instead of O-formyl-35-mandelic acid chloride, the title 81 00 57 1 I-34- compound having melting point 120-125 ° C after freeze-drying is obtained .

Example 9 / ~ 3S (~) 7-3- / / (Formyloxy) phenylacetyl / amino-2-oxo-1-azetidine sulfonic acid, potassium salt.

5 10

Following the procedure of Example 7, but using LO-formyl-mandelic acid chloride instead of O-formyl-mandelic acid chloride, the title compound, containing 1 mole of water, mp 203-205 ° C is obtained. After careful drying, melt the product at 228-230 ° C.

Example 10 (S) -2-Oxo-3- / (1-oxooctyl) amino / -1-azetidine sulfonic acid, potassium salt.

1.5 g of (S) -3-Amino-2-oxo-1-azetidine sulfonic acid, 15 tetrabutyl ammonium salt (see example 6A) in 100 ml of dimethyl formamide and 2 ml of propylene oxide are cooled to 0 ° C. A solution of 0.8 g caprylic acid chloride in 200 ml dry acetone is added dropwise at this temperature and stirring is continued for 30 minutes. The solvent is evaporated in vacuo and the oily residue is treated with 2 g of potassium perfluorobutane sulfonate in 15 ml of acetone. The acetone is distilled off in vacuo. The residue is dissolved in 5 ml of water and chromatographed using HP-20 resin and water / acetone (9: 1) as an eluent to yield 0.9 g of the title compound, mp 173-180 ° C after freeze drying.

Example 11 / 3S (Z) - 3 - 3 / (2-Amino-4-thiazolyl) / hydroxy hydroxy (phenylmethoxy) -phosphinyl / methoxy / imino / acetyl / amino / 2-oxo-1-azetidine sulfonic acid, potassium salt.

0.8 g (S) -3-Amino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 6A) in 30 ml dimethylformamide, 0.9 g (Z) -2-amino-α / hydroxy hydroxy (phenylmethoxy) phosphinyl / methoxy / imino / 4-thiazole acetic acid, 0.3 g of hydroxybenztriazole and 0.7 g of dicyclohexylcarbodiimide are stirred at room temperature for 24 hours.

81 0 0 57 1% - 35 -

The precipitated urea is filtered off and the solvent is removed in vacuo. The residual oil is treated with an equivalent amount of potassium perfluorobutane sulfonate in 10 ml of acetone. The title compound is filtered and purified using HP-20 resin and water as an eluent to give 500 mg, mp 210-215 ° C with decomposition.

Example 12 / 3S (Z) _ / - 3- / (_ (2-Amino-4-thiazolyl) (ethoxyimino) -acetyl / amino-10-2-oxo-1-azetidine sulfonic acid, potassium salt.

1.5 g (S) -3-Amino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 6A) in 100 ml dimethylformamide, 0.6 g hydroxybenztriazole, 1 g dicyclohexylcarbodiimide and 0.8 g (Z -2-amino-α- (ethosyimino) -4-thiazole acetic acid are stirred at room temperature for 24 hours. The solvent is filtered off and the residue is dissolved in 30 ml of acetone. Urea is filtered off and the mother liquor is treated with a solution of 2 g of potassium perfluorobutane sulfonate in 20 ml of acetone. After the addition of 200 ml of ether, the title compound precipitates, which is filtered off and dried. Purification is by chromatography using an HP-20 column and water as an eluent to give 1.1 g of the title compound, m.p. 180-185 ° C with decomposition.

Example 13 / 3S (E) / 3-V / (2-Amino-4-thiazolyl) (ethoxyimino) acetyl / amino / 2-oxo-1-azetidine sulfonic acid, potassium salt.

Following the procedure of Example 12, but using (E) -2-amino-a- (ethoxyimino) -4-thiazole acetic acid instead of (Z) -2-amino-a- (ethoxyimino) -4-thiazole acetic acid, the title compound having melting point 160-170 ° C after freeze drying

λ

Example 14 / ~ 3S (Z) _ / - 3-V / (2-Amino-4-thiazolyl) ((2,2,2-trifluoroethoxy) amino / acetyl / amino / -2-oxo-1-azetidine sulfonic acid, potassium salt .

Following the procedure of Example 12, use (Z) -2-amino-α- / (2,2,2-trifluoroethoxy) imino---4-thiazole acetic acid instead of (Z) -2-amino -a- (ethoxyimino) -4-thiazole-acetic acid, the title compound, m.p. 160-170 ° C, is obtained after; freeze drying.

Example 15 (S) -2-Oxo-3- / (1-oxopropyl) amino / -1-azetidine sulfonic acid, potassium salt.

Method I: 1.5 g (S) -3-Amino-2-oxo-1-azetidine sulfonic acid, 15 tetrabutyl ammonium salt (see example 6A) in 100 ml dry dimethyl formamide and 4 ml propylene oxide are cooled to 0 ° C with stirring. 0.5 g of propionic acid chloride in 10 ml of acetic nitrile are added dropwise at this temperature and the mixture is stirred for an additional 2 hours. The solvent is distilled off in vacuo and the oil-active residue is treated with an equivalent amount of potassium perfluorobutane sulfonate in 5 ml of acetone. On addition of ether, the title compound crystallizes out, which is filtered off, yielding 0.8 g of product mp 135-140 ° C after freeze drying.

25 Method II:

4 g of (S) -2-oxo-3 - / (phenyl-methoxy) carbonyl / amino / 1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 4) are hydrogenated in 100 ml diglyme with 1 g palladium on carbon. The hydrogenation is completed after 2.5 hours. The catalyst is filtered off and 2 ml of propylene oxide is added. After cooling to 0 ° C, 0.5 g of propionic acid chloride in 10 ml of dry diglyme are added with stirring. After 30 minutes, the solvent is removed in vacuo and the oily residue is treated with an equivalent amount of potassium perfluorobutane sulfonate in 20 ml of acetone. After addition of ether, the title compound crystallizes from, which is filtered off 8100571-37 and recrystallized from water / acetone, yielding 0.9 g of product mp 156-160 ° C with decomposition. Example 16 L (+,) - / - 3- / (Hydroxyphenylacetyl) amino - / - 2-oxo-1-azetidine sulfonic acid, potassium salt.

1.5 g of (S) -3-amino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 6A) are stirred in 100 ml of dry dimethylformamide for 16 hours with 1.5 g of dicyclohexylcarbodiimide, 0.5 g of hydroxybenztriazole and 0.6 g of mandelic acid. The solvent is removed in vacuo and the residue dissolved in 20 ml of acetone.

The precipitated urea is filtered off and the mother liquor is treated with an equivalent amount of potassium perfluobutane sulfonate. After addition of ether, the title compound precipitates, which is filtered off, yielding 1.4 g of crude product. After recrystallization from water, the product has a melting point of 138-140 ° C.

Example 17 (S) -3 - / - / - (Cyanomethyl) thio / acetyiyamino / - 2-oxo-1-azetidine-20 sulfonic acid, potassium salt.

1.5 g of (S) -3-amino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 6Ά) and 0.72 g / (cyanomethyl) thio / acetic acid are dissolved in 70 ml of acetic acid nitrile and Add a solution of 1.04 g of dicyclohexylcarbodiimide in vinegar vacuum nitrile dropwise. The mixture is stirred at 0 ° C for 16 hours and the precipitated dicyclohexylurea is filtered off, the filtrate is evaporated and the oily residue is dissolved in benzene. On addition of a saturated solution of potassium iodide in acetone, the title compound precipitates to give 1.1 g of product mp 150-155 ° C.

Example 18 (S) -2-Oxo-3- / (1H-tetrazol-1-ylacetyl) amino / -1-azetidine sulfonic acid, potassium salt.

35 81 00 57 1 I% - 38 - 5 To a solution of 0.005 mol (S) -3-amino-2-oxo-1-azetidine sulfonic acid, tetrabutylammonium salt (see example 6A) in 70 ml dimethylformamide, 0.77 g 1H is added -tetrazCol-1-acetic acid and a solution of 1.13 g of dicyclohexylcarbodiimide in 5 ml of dimethylformamide. The mixture is stirred at room temperature for 16 hours and the solvent is removed in vacuo. The residual oil is dissolved in 20 ml of acetone and treated with 0.006 mole solution of potassium perfluorobutane sulfonate in acetone to obtain 1.5 g of the title compound, m.p. 170-175 ° C, with decomposition. Example 19 (S) -2-Oxo-3- / (2H-tetrazol-2-ylacetyl) amino-1-azetidine sulfonic acid, potassium salt. Following the procedure of Example 18, but using 2H-tetrazole-2-acetic acid instead of 1H-tetrazole-1-acetic acid, the title compound, m.p. 175-177 ° C is obtained with decomposition. Example 20 20 (S) -2-OXO-3V (2-thienylacetyl) amino-1 / -1-azetidine sulfonic acid, potassium salt. in CM Following the procedure of Example 18, but using 2-thiophenoacetic acid in place of 1H-tetrazole-1-acetic acid, the title compound, m.p. 180-190 ° C, is obtained with decomposition. Example 21 / 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 tetrabutyl ammonium salt (prepared as described in example 6A) is cooled from 7.9 g (S) -2-oxo-3- (phenylmethoxy) carbonyl amino _ / - 1-aze tidine sulfonic acid, tetrabutyl ammonium salt) to 0 ° G and add 3.53 g (Z) -2-amino-a- (methoxyimino) -4-thiazole acetic acid, followed by 81 00 57 1

ΐ- X

- 39 - a solution of 3.27 g of dicyclohexylcarbodiimide in 10 ml of dimethylformamide. The mixture is stirred at 5 ° C for 16 hours, filtered and the solvent is removed in vacuo. The residue is dissolved in acetone and filtered. Upon addition of 60 ml of a 10% solution of potassium perfluorobutane sulfonate in acetone, 4.7 g of crude product crystallize out. The crude product is purified by chromatography on HP-20, 0.074-0.0149 mm, whereby 3.0 g of the title compound are obtained, m.p. 235 ° C. Example 22 (3S) -a ~ / _ / _ (2-Oxo-1-sulfo-3-azetidinyl) amino> carbonyl / benzene acetic acid, dipotassium salt.

100 mg (3S) -α / / / (2-Oxo-1-sulfo-3-azetidinyl) amino / carbonyl / benzeneacetic acid, phenylmethyl ester, potassium salt (see example 5) are dissolved in 20 ml of anhydrous methanol. 10 mg of 10% palladium on charcoal are added and the mixture is treated with hydrogen for 15 min. The catalyst is filtered off and the methanol is evaporated in vacuo. The residue is dissolved in 5 ml of water and the pH is adjusted to 6 with 1N potassium hydroxide. After freeze-drying, crude product is obtained. The crude material is chromatographed on HP-20 resin (water as an eluent) to give 60 mg of the title compound, mp 80-85 ° C. Example 23.

(S) -3- (Acetylamino) -2-oxo-1-azetidine sulfonic acid, potassium salt, 25

Method I; A) (S) -3-Amino-2-oxo-1-azetidine sulfonic acid, potassium salt.

169 Mg (S) -3- (benzyloxycarbonylamino) -2-oxo-1-azetidine sulfonic acid, potassium salt (see example 3) are dissolved in 4.0 ml water and hydrogenated on 37 mg 10% palladium on charcoal for 1 hour 40 min. . The catalyst is filtered off and washed with 1 ml of 50% aqueous acetone.

35 81 00 57 1 - 40 - B) (S) -3- (Acetylamino) -2-oxo-l-azetidine sulfonic acid potassium salt

The above solution of the free amine 5 is diluted with 3.5 ml of acetone and stirred in an ice bath. About 320 liters of acetyl chloride are added in small portions over about 15 minutes alternating with solid potassium bicarbonate to maintain the pH at 6.5-7.2. After 30 minutes, a silica gel thin layer chromatography in acetone: acetic acid (19: 1) and the Rydon test indicate that the reaction has essentially ended. 6 ml of 0.5 M pH 5.5 monobasic potassium phosphate buffer are added and the solution is acidified with 2N hydrochloric acid to pH 4.8. The acetone is removed in vacuo and the aqueous solution thus obtained is passed over a 50 ml HP-20AG column to obtain 2.197 g of solid. This is digested with methanol to obtain 282 mg of extractable material still containing some salt. The product is further purified by passing over an IKC-50 column followed by acidification to pH 3.8 with subsequent stripping to dryness in vacuum. Trituration with acetone gives 64 mg of the desired product, which contains about 0.5 equivalent of inorganic potassium salts. Finally, passing through a 200 ml AP-20AG column followed by lyophilization from 0.5 ml of water yields 22 mg of product as an amorphous powder, which is dried in vacuo at 50 ° C for 2 hours, melting point 170-180 ° C after softening at 100 ° C.

Analysis: Calculated for C 5 H 7 O 5 N 2 SK: C 24.38; H 2.87; N 11.37; K 15.9;

Found: C 26.06; H 3.14; N 9.96; K 18.04.

Method II: ^ A solution of 2.0 g (S) -2-oxo-3- / / (phenyl-

Methoxy) carbonyl / amino / -1-azetidine sulfonic acid, pyridine salt (see example 2) in 25 ml of water is hydrogenated over 500 mg of 10% palladium on carbon. After 2 hours, the solution is filtered, cooled to 0 ° C and 40 ml of acetone are added. The pH of the solution is kept between 5.2-5.8 by simultaneously adding acetyl chloride and cold 10% potassium bicarbonate solution. The pH

8100571-41 - of the solution is adjusted to 4.2 with acetyl chloride and the solution is concentrated on a rotary evaporator to remove acetone. Chromatography on 300 ml HP-20AG column (water as eluent - 25 ml fractions) yields 900 mg of the title compound in fractions 13 and 14 / contaminated with some potassium acetate. Chromatography on HP-20AG provides an analytical sample with melting point 205-210 ° C. Analysis: Calculated for C 8 H 15 OgSK: C 24/38; H 2.86; N 11.38; S 13.02; K 15.88; Found: C, 24.23; H 2; 81; N 11.25; S 12.86; K 15.74.

Example 24 (S) -2-Oxo-3 - / - (phenoxyacetyl) amino - / - 1-azetidine sulfonic acid, potassium salt.

1.5 g of (S) -3-Amino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 6A) in 100 ml of dry dimethyl formamide are cooled to 0 ° C. 2 ml of propylene oxide are added and 1 g of phenoxyacetyl chloride is added dropwise with stirring. The reaction is completed within 1 hour. The solvent is removed in vacuo and the residue treated with an equivalent amount of potassium perfluorobutane sulfonate in 20 ml of acetone. When ether is added, 1 g of the title compound crystallizes out, which is filtered off and dried. After recrystallization from boiling water, the title compound has a melting point of 176-180 ° C.

Example 25 / 3S (RX) _ / - 3 - / _ / / / /. 3- / (2-Furanylmethylene) amino / 2-oxo-1-azetidinyl / carbonyl / amino / phenylacetyl / amino / 2-oxo-1-azetidinesulfonic acid, potassium salt.

30 g (S) -2-Oxo-3 - / "" / (phenylmethoxy) carbonyl - / - amino - / - 1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 4) is hydrogenated in 100 ml dimethylformamide with 1.5 g palladium on carbon . After 0.5 hours, the catalyst is filtered off and 1.8 g of dicyclohexylcarbodiimide, 2 g of (R) -O- / / / 3- / (2-fura-81 00 57 -1-methyl-methylene J) are added. amino-2-oxo-1-imidazolidinyl / carbonyl / amino-benzenacetic acid and 0.9 g of hydroxybenztriazole After 3 hours the reaction mixture is evaporated to dryness, dissolved in 50 ml of dry acetone and the precipitated urea is filtered off. Add an equivalent amount of potassium perfluorobutane sulfonate in 20 ml of acetone and the title compound precipitates.

Crystallization is completed by adding 200 ml of ether. After filtration, the title compound is recrystallized from water, whereby 2 g of melting point 220-225 ° C, 10 are obtained with decomposition.

Example 26 £ 3S (RX) _ / - 2-Oxo-3 - / _ (_! _ (_ (2-oxo-1-imidazolidiny 1) carbony 1 _ / - amino __ / phenylacetyl_ / amino _ / - l-azetidine sulfonic acid, potassium salt .

15 g (S) -2-Oxo-3V / _ (phenylmethoxy) carbony 1 __ / - amino _ / - l-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 4) is hydrogenated in 100 ml dry direthylformamide with 1.5 g palladium on carbon, The catalyst is filtered off after 30 minutes. 1.8 g of (R) -aV / (2-oxo-1-imidazolidinyl) -20 carbonyl / amino / benzeneacetic acid, 1.3 g of dicyclohexylcarbodiimide and 0.9 g of hydroxybenztriazole are added and the solution is stirred for 2.5 hours.

The solvent is removed in vacuo and the residue 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 in 20 ml of acetone. The title compound crystallizes out and is filtered off after adding 200 ml of ether to yield 1.8 g of product mp 210-215 ° C after recrystallization from water / acetone. Example 27 30 / 3S (Z) - / - 3 - 1 - ((Methoxyimino) phenylacetyl / amino - / - 2-oxo-1-azetidinesulfonic acid, potassium salt.

A) 3S (Z) - 3 - / 7 (Methoxyimino) phenylacetyl / amino - 2-azetidinone.

35 81 00 57 1 Μ -y - 43 - 3.58 g (Z) -a- (Methoxyimino) benzenacetic acid is dissolved in methylene chloride, cooled to 5 ° C and treated with a solution of 4.53 g of dicyclohexylcarbodiimide in 50 ml of methylene chloride . The mixture is stirred at 5 ° C for 30 min and a solution of 1.72 g of 3-amino-2-azetidinone (see example 5A) in 100 ml of methylene chloride is added. The reaction mixture is kept at 5 ° C for 1 hour and at room temperature for 2 hours. After filtration of dicyclohexylurea, the filtrate is evaporated and 6.6 g of crude product are obtained. This material is purified by chromatography on 750 g of silica gel using a mixture of methylene chloride / ethyl acetate (7: 3) as an eluent to yield 2.9 g of product.

B) (- 3S (Z) - / - 3 (Methoxyimino) phenylacetyl - / - amino / -2-oxo-1-azetidine sulfonic acid, potassium salt.

0.5 ml of Pyridine is dissolved in 5 ml of absolute methylene chloride, cooled to -30 ° C and a solution of 0.93 ml of trimethylsilylchlorosulfonate in 5 ml of methylene chloride is added. The mixture is stirred at room temperature for 30 min and evaporated in vacuo to dryness. The residue is dissolved in 10 ml of dimethylformamide and treated at room temperature with a solution of 1.23 g of the above azetidinone in 10 ml of dimethylformamide.

25

After stirring for 2 hours at room temperature, the solution is evaporated to dryness, yielding 2.1 g of crude / 3S (Z) 3 / 3V (methoxyimino) phenylacetyl / amino / 2-oxo-1-azetidine sulfonic acid, pyridine salt .

30

Treatment of the pyridine salt with tetra-butylammonium hydrogen sulfate gives the corresponding tetrabutyl ammonium salt, which is extracted with methylene chloride and remains as an oil after evaporation.

35

Treatment of the tetrabutyl ammonium salt with an equimolar amount of potassium perfluorobutane sulfonate in acetone, evaporation and treatment of the residue with ether afford 1.6 g of the title potassium salt, which is purified by chromatography on HP-20. The elution is carried out with water / acetone 90:10 and yields 81 00 57 1 - 44 - a product with melting point 220 ° C, with decomposition.

Example 28 / 3S (Z) _ / - 3 - / _ / _ (2-Araino-4-thiazolyl) // 2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy_ / imino_ / acetyl_ / amino __ / - 2-oxo-1-azetidin-5 sulfonic acid, potassium salt. (1: 1).

A solution of 0.005 mol (S) -3-amino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 6A) and 0.006 mol (Z) -2-amino-a- / / 2- (diphenylmethoxy) -1, 1-Dimethyl-2-10 oxoethoxy / imino / 4-thiazole acetic acid in 60 ml dimethylformamide is treated with 0.7 g hydroxybenztriazole and 1.13 g dicyclohexyl carbodiimide. The mixture is stirred at room temperature for 16 hours, filtered and the filtrate evaporated. The residue is dissolved in 30 ml of acetone, filtered and treated with 20 ml of a solution of 10% potassium perfluorobutane sulfonate in acetone. After addition of petroleum ether, the title compound, which is treated with ether and filtered, yields 3.8 g of product, m.p. 190 ° C with decomposition.

Example 29 20 f_S (Z) _ / - 3-V / _ 2-Amino-4-thiazolyl) / _ (1-carboxy-1-methylethoxy) -imino_ / acetyl_ / amino _ / - 2-oxo-1-azetidine sulfonic acid , dipotassium salt.

25 30 35

2 g / 3S (Z) - / - 3- / / (2-amino-4-thiazolyl) / 2- (diphenylmethoxy) -1,1-dimethy 1-2-oxoethoxy / / imino / acetyl / / amino / -2-oxo-1-azetidine sulfonic acid, potassium salt (see example 28) in 5 ml anisole and add 25 ml trifluoroacetic acid at -10 ° C. The mixture is stirred at -10 ° C for 10 min. 10 ° C slowly add 100 ml of ether and then 50 ml of petroleum ether. The precipitate is filtered off to obtain 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 under decomposition.

Example 30 81 0 0 5 7 1 (_ 3Ξ (Z) / —3— (2-Amino-4-thiazolyl) - / _ / _ 2- (diphenylmethoxy) -2-oxoethoxy __ / imino_ / acetyl_ / amino _ / - 2 -oxo-l-azetidine sulfonic acid, potassium salt.

Following the procedure of Example 28, use (Z) -2-amino-α- / / 2- (diphenylmethoxy) -2-oxoethoxy / imino-4-thiazole acetic acid instead of (Z) -2-amino- α- / / 2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy / imino / 4-thiazole acetic acid, the title compound, m.p. 180 ° C, is obtained with decomposition.

Example 31 / 3S {+) - / - 3 - (Azidophenylacetyl) amino - / - 2-oxo-1-azetidine sulfonic acid, potassium salt.

Method I; A) (+, S) -α-Azido-N- (2-oxo-3-azetidinyl) benzene acetamide.

2.15 g of (S) -3-amino-2-azetidinone (see example 5A) and 2.1 g of sodium bicarbonate are dissolved in 50 ml of acetone / water (2: 1). 5 g of (+) - α-azidobenzene acetyl chloride, dissolved in 10 ml of acetone, are added dropwise while maintaining the temperature at 0-5 ° C and the pH at 6.8 with sodium bicarbonate. After stirring for 1 hour, the acetone is distilled off and the remaining aqueous solution is adjusted to pH 8 with sodium carbonate and extracted with three 50 ml portions of methylene chloride. Evaporation of the organic layers dried with sodium sulfate gives 3.6 g of the title compound as an oil which crystallizes after trituration with ether. Recrystallization from methylene chloride / ether gives the title compound, mp 97-100 ° C.

B) / _ 3S (+) _ / “3V (Azidophenylacetyl) amino _ / - 2-oxo-1-azetidine sulfonic acid, potassium salt _

A solution of 2.45 g of the above azetidinone

t X

46 and 3 g of monosilyltrifluoroacetamide in 20 ml of acetic nitrile 1 are kept at 40 ° C for 1 hour. After cooling to 0 ° C, the solution is treated with 1.88 g of trimethylsilylchlorosulfonate and stirred under argon for 5 hours. Finally, 6.12 ml of a 2N solution of potassium 5-2-ethylhexanate in n-butanol are added and the stirring is continued for an additional 45 min.

on. The solution is poured into 300 ml of ether and the precipitate is filtered off. A filtered solution of 1.2 g of precipitate in phosphate buffer (pH 5.5) is chromatographed on 100 ml of HP-20. Elution takes place with: 1) 20 ml buffer, 2) 200 ml HjO, 10 3) 20 ml water: acetone (9: 1), 4) 200 ml water acetone (3: 1). The elution is monitored by thin layer chromatography (Rydon test on SK ^). Fractions of 25 ml are taken, and from fractions 15 and 16, 280 mg of the title compound are obtained. A second column chromatography of this material yields 120 mg of the title compound, m.p. 148 ° C, with decomposition.

Method II:

2.0 g of (S) -3-amino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 6A) and 0.9 g (+) - α-azidobenzeneacetic acid are dissolved in 30 ml of acetic nitrile and 20 a solution of 1.03 g of dicyclohexylcarbodiimide in 10 ml of acetic nitrile. The temperature is kept at 0 ° C for 1 hour and at room temperature for 10 hours. After the resulting precipitate has been filtered off, the solvent is distilled off in vacuo and the oily residue is dissolved in 20 ml of acetone and treated with 1.70 g of potassium perfluorobutane sulfonate in acetone. After addition of 10 ml of ether, the title compound crystallizes out. Melting point 149 ° C, with decomposition.

Method III:

2.5 g of α-azidophenylacetyl chloride 30 are added to a solution of 4.06 g of 3-amino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 6A) and 5 g of propylene oxide in 30 ml of acetic nitrile. After stirring for 2 hours, the solvent is distilled off in vacuo and the oily residue is treated with 1 equivalent of potassium perfluorobutane sulfonate in acetone. After addition of ether, the title compound crystallizes from 8100571 47 which is filtered off. Melting point 148-149 ° C, with decomposition. Example 32 / _ 3S (D) _ / - 3- / / / / (4-Methoxypheny 1) methoxy / carbonyl 1 / amino _ / - phenylacetyl / amino / -2-oxo-1-azetidine sulfonic acid, potassium salt.

5 10 15

In a solution of 2.03 g of 3-amino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 6A) and 1.58 g of Da - / _ (_ f_ (4-methoxypheny 1) methoxy __ / carbonyl_ / amino __ / Benzene acetic acid in 50 ml of acetic nitrile is added dropwise a solution of 1.03 g of dicyclohexylcarbodiimide in 10 ml of acetic nitrile, the temperature is kept at 5 ° C for 1 hour and at room temperature for 6 hours, separating the formed dicyclohexyl urea and distilling off the solvent. the title compound as an oily residue Treatment of this oil in acetone with potassium perfluorobutane sulfonate and ether yields 2.4 g of product mp 108-111 ° C under decomposition Examples 33-37.

20

Following the procedure of Example 32, but using the compound specified in column 1 of the table below instead of (D) -a - / _ / _ f_ (4-methoxyphenyl) methoxy_ / carbonyl_ / amino_ / benzenacetic acid, the corresponding compound mentioned in column 2 of the table below.

25 8100571 CS I Η s

a o I — I

I Η I, 10 1 NS 3 SA "0, IP SNS ii ο a 8 GP λ · Η Η I S '^ I * 4-1 H *> i> 1 Ή XP 3 a) 0 Ο N id g H 3 HGHV

• ns I H o> i N 1 -. + * I S. © * —l - cl 'o 5 v f ff

- O '<c • rl - Ό P (U

3 3 N C 0 44 H 3., W I φ

Shi ill l \, H 'β> 1 H * - C Ό CJ a g h - Λ P 0, W P Φ CO lm, id n' ί o id «-t

II - cs Η, I SN οι o H c & § o, id JSS, + JO) H a> ip IC 3 O '0 3 I, ¾ fi N, S5 i "NS Ί * & § Ö 0 44 1 Jc o PH SIS

IO co> i H o.i n1 \.

U H <d H oU c -

Ic ..HO JC> 1 44 2 3 d 0 3 Λ WP 0) id C Ο H INS? As cs 0, - -c Ni Vh CO> 1 * 1 Ci l "v, © CS P l * n. I a + * Jft

id H

I rf I 0 c, NO idO 'I io - CS I I 0 cs X co 0 cs 1 O W Λ, co p. © "via 0 P c H H 0) 1 §

I> 1 X Λ P P, I 3 axis, 3 a n I H c O '> 1 ΤΊ - C H Ί «CU

N id H o o I N N

I cs I

-Tl0 + 1 a) ν '4-1 O P a I P O' <U, I ^ K1 Η O ts C Ή

CO

8 1 0 0 57 1 IHII -VOI Η XO '> 1 ocs CI - * Φ CS 4-1 IP SNS i SB1 P Η H 1.11 3N "ki & S, 00 NS I> Nl> ι Ο H §G Id Η X lil - 11 Ί3 cs H 3 1,> t NN ss, 00 "v | P 44 IP to id I. O

I iH I I 1 0 K, x I! o co> t I o * Ü N H O, I 5NS U o 3 H-X f} rH S δ s C \ .S © to 4-t H> 1> i * X P H Φ 3 O O id N

>> 0 0 Λ XPP 0 c ai I 3 S cs a - IP Hj \ HN _lg cos VC to 4-1 H X. I -P 0 h's, 3 Λ 0 p Η N a> Ss e O 'B -P 3 β 1 β »Η HO 'Ο Η Ό w id id tu S i rH ^ rH Sj> ♦ -P kiS ps I .Ή 3 SK, 3 P, In φ, ν, ΐο CO 1, coc vJh <po I SH n, id 3 ·, ΐΚ, Μϋ K, 1 © H CO -. > iH m Pi G Ό t "- Ο Η H 01 API .CO p 01 cs 1 .dot 's | u id h 5 * rH 0) 0 5 ai a 1 O' & ai β Λ" Ιθ J, C, w "ν1 · Η 44 1 1 d IO. id 3. 1 K.05 N-'S 3 & S u O 'c • H Ό P 0)" HP co P 0) Ό c 0 3 to ©. · C tlx Ό Ü '-'OH 01 J3 P O rn P ai co, o n cs sis «η

N

O «Λ, co p \ u

* iH PO <u ω N O 'id H

I <*** Η I SN 0) o 4-t C &! In (UH a> ip IC 3 f O 3 Nf NI, P c NSS NN8 NS'S Ö 0 PI Λ 3 -, P 44 + | φ I - a cs I djv! C "Ti 0) o 44 C> <H xa £ jK! (UH a> ip I c 3 O '0 3, - 43 N c

NS

I, Ο H N ^ S i X 0) Ö 0 Φ I Λ N - PC P) Φ Φ - a λ

I Η. 1 φ o 44 C> <H §, l SN Φ Η P a> i 3 1 C 3 Ο · Ο N .- Λ C 1, ΡΐΊ NS d NNS \> 1 Φ IX Φ ao 44 I Λ O - PH ► 3 Φ P - BP

in co co O 'co co y - 49 -

Example 38 (3S) -3- / / "" "/ / (Methylthio) thioxomethyl / thio / phenylacetyl / amino / - 2-oxo-1-azetidine sulfonic acid, trabutyl ammonium salt, 5 A solution of 1.0 g (+) - a - / - / - (methylthio) - thioxomethyl / thio / / benzeneacetic acid and 1.63 g of 3-amino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 6A) in 30 ml of acetic nitrile are treated with -5 ° C 0.8 g of dicyclohexylcarbodiimide dissolved in 10 ml of acetic nitrile After stirring for 16 hours, the dicyclohexylurea formed is filtered off and the mother liquor is evaporated The resulting oily residue is chromatographed on a column of 400 g of silica (ethyl acetate / methanol / water (8.5: 1: 0.5 is the eluent), whereby 1.3 g of the title compound are obtained.

Example 39 3 (S) -3- / [- {((Methylthio) thioxomethyl / thio / phenylacetyl / amino] - 2-oxo-1-azetidine sulfonic acid, potassium salt.

1.3 g (3S) -3- / / / / (Methylthio) thioxomethyl _ / - 20 thio_ / phenylacetyl / amino _ / - 2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 38) is dissolved in acetone and treated with an equivalent amount of potassium perfluorobutane sulfonate. When ether is added, the title compound crystallizes out which is filtered off. Yield 0.18 g of product, melting point 157 ° C, with decomposition.

Example 40 / 3S (D) V-3- / / / / (4-Ethyl-2,3-dioxo-1-piperazinyl) carbonyl-amino-2-thienylacetyl / amino-2-oxo-1-azetidine sulfonic acid , potassium salt.

3.25 g (D) -aV / (4-Ethyl-2,3-dioxo-1-piperazinyl) carbonyl / amino-2-thiophenoacetic acid, 4.20 g 3-amino-2-oxo-1 -azetidine sulfonic acid, tetrabutyl ammonium salt (see example 6A) and 1.3 g of N-hydroxybenztriazole are dissolved in 25 ml of acetic acid-35 nitrile. Dropwise addition of 2.06 g of dicyclohexylcarbodi-81 00 57 1 h * -50-imide, dissolved in 10 ml of acetic nitrile at -10 ° C, takes 20 min and stirring is continued for another 16 hours. The urea formed is filtered off and the solvent is evaporated in vacuo. The residual oil is dissolved in 50 ml of acetone and after treatment with an equivalent amount of potassium perfluorobutane sulfonate, the title compound crystallizes out. Melting point 185-187 ° C, with decomposition.

Example 41 / 3S (+) ^ / - 3- / (Bromophenylacetyl) amino __ / - 2-oxo-1-azetidine sulfonic acid, potassium salt.

1.4 g of a-bromophenylacetyl chloride in 10 ml of acetic nitrile are added dropwise to a solution of 5mM

3-amino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt and 3 g of propylene oxide in acetic nitrile at 0 ° C. After stirring for 3 hours, the solvent is filtered off and the remaining oily residue is dissolved in 30 ml of acetone. The equivalent amount of potassium perfluorobutane sulfonate in acetone is added. By addition of ether, the title compound 20 crystallizes out. Melting point 135-137 ° C, with decomposition.

Example 42 L 3S (+ W-3- /, //, (Aminocarbonyl) amino-2-thienylacetyl / amino-2-oxo-1-azetidine sulfonic acid, potassium salt.

25 Method I:

To a solution of 2 g (S) -3-amino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt and 1.5 g propylene oxide in acetic nitrile, 1.1 g (+) - 2-amino-4- (2- thienyl) -5- (4H) -oxazolone, hydrochloride. After stirring for 3 hours at 0 ° C and 1 hour at room temperature, the solvent is distilled off and the oily residue is dissolved in 30 ml of acetone. By adding an equivalent amount of potassium perfluorobutane sulfonate in acetone, the title compound crystallizes out. purification by column chromatography on HP-20 using water as an eluent affords the title compound with 81 00 57 1 - 51 mp 218-222 ° C, decomposition.

Method II:

In a suspension of 2 g (+) - a- / (aminocarbonyl) -amino __ / - 2-thiophenoacetic acid, 10 mM (S) -3-amino-2-oxo-1-azetidine-5 sulfonic acid, tetrabutyl ammonium salt and 10 mM N Hydroxybenztriazole in 50 ml of acetic acid nitrile is added at 0 ° C (with stirring) 10 mM dicyclohexylcarbodiimide dissolved in 15 ml of acetic acid nitrile. Stirring is continued for 1 hour at -15 ° C and 16 hours at room temperature. After the dicyclohexylurea has been filtered off, the solvent is evaporated and the oily residue is dissolved in 50 ml of acetone. Addition of the equivalent amount of potassium perfluorobutane sulfonate in acetone yields crystalline product. Purification by column chromatography on HP-20 with water as an eluent affords the title compound, mp 220-223 ° C. Example 43 {_ 3S (+) __ / - 3- / / / / (Methylamino) carbonyl / amino - / - 2-thienylacetyl / - amino / -2-oxo-1-azetidine sulfonic acid, potassium salt.

0.54 g of (+) "<* - // (methylamino) carbonyl-20 amino-2-thiophenoacetic acid and 1.00 g of (S) -3-amino-2-oxo-1-azetidine sulfonic acid , tetrabutyl ammonium salt (see example 6A) in 20 ml of acetic acid nitrile and add 0.5 g of dicyclohexylcarbodiimide at a temperature of 0 ° C. After stirring for 8 hours, dicyclohexylurea is filtered off and after the solvent has been distilled off, the oily residue is dissolved in 50 ml of acetone and the equivalent amount of potassium perfluorobutane sulfonate is added. The crystalline product is filtered off and the purification is done over HP-20 using water as an eluent. Melting point 205 ° C, with decomposition.

Example 44 / 3S (+) / -3 "/././ (Aminooxoacetyl) amino-2-thienylacetyl / amino-2-oxo-1-azetidine sulfonic acid, potassium salt.

Following the procedure of Example 35 42, method II, but (+) -a - / _ (aminooxoacetyl) amino __ / - 2- 81 00 57 1

X

Using thiophic enacetic acid instead of (+) - α- / (aminocarbonyl) -amino-2-thiophene acetic acid, the title compound of melting point 218-222 ° C is obtained. 45 / 3S (RX) _ / - 3 -, / (_ / _ / (4-Ethyl-2,3-dioxo-1-piperazinyl) carbonyl __ / - amino_ / phenylacetyl_ / amino __ / - 2-oxo-1-azetidine sulfonic acid, potassium salt: When following the procedure of Example 40, but using (R) -a- / / (4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl / amino / / - benzeneacetic acid instead of (D) -aV / (4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl / araino / 2-thiophenoacetic acid, the title compound is obtained, m.p. 155-157 ° C, with decomposition. 46. 15 3- (Acetylamino) -3-methoxy-2-oxo-1-azetidine sulfonic acid, potassium salt 20 Method I: A) 3- / (N-Acetyl-N-chloro) amino __ / - 2-oxo-1- azetidine sulfonic acid, mixed sodium and potassium salt. To a solution of 172 mg of 3- (acetylamino) -2-oxo-1-azetidine sulfonic acid, potassium salt (see example 23) in 17 ml of methanol containing 4% sodium borate decahydrate and cooled to -15 to -10 ° C is added 110 µl t-butyl hypochlorite. The mixture is stirred in the cold for 1 hour and 45 minutes, poured into 50 ml of 0.5 M monobasic potassium phosphate solution and the pH is lowered to 5.5. The solvent is removed in vacuo and the residue is dissolved in a minimum amount of water and chromatographed on 140 ml of HP-20 AG, 0.074-0.149 mm. Elution with water yields 63 mg of oil, which crystallizes on standing. Trituration with methanol / ether and then with ether gives 53 g of a solid, m.p. 124 ° C under slow decomposition B) 3- (Acetylamino) -3-methoxy-2-oxo-1-azetidine sulfonic acid, potassium salt. 35 8100571 X.

- 53% 37 mg 3- / (N-Acety1-N-chloro) amino-2-oxo-1-azetidine sulfonic acid, mixed salt is dissolved in 1.5 ml dry dimethylformamide and added to a solution of 50 mg lithium- methanolate in 1 ml of methanol at -78 ° C. After 15 min, stirring at 5 -78 ° C, 10 ml of 0.5 M monobasic potassium phosphate solution are added and the solution is then acidified with 1 N hydrochloric acid to pH 4. the solution 70 mg tetrabutyl ammonium hydrogen sulfate and extract the solution four times with methylene chloride. The combined extracts are dried (sodium sulfate) and the solvent is removed in vacuo to give 55 mg of oil. Chromatography on 5.5 g of silica gel yields 41 mg of an oily product as the tetrabutyl ammonium salt (eluted with 8% methanol: 92% methylene chloride). 31 mg of the oil is dissolved in water and passed through an ion exchange column (5 mg AG 50W-X2, K + Form, 0.037-0.074 mm, 0.6 meq / ml). Removal of water in vacuum yields an oil which crystallizes out from methanol-ether.

Trituration with ether yields the product as 11 mg of colorless powder, mp 182-183 ° C with decomposition.

Method II? A) 3-Amino-3-methoxy-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt.

100 4% sodium borate decahydrate solution in methanol is added to a suspension of 30 mg of 10% palladium on charcoal in 2 ml of methanol and the mixture is stirred under a hydrogen atmosphere for 15 min. 60 mg of 3-methoxy-2-oxo-3- (phenylraethoxy) carbonyl / amino-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 49) are added in 2 ml of methanol and the mixture is stirred vigorously for 15 min. under a hydrogen atmosphere. The catalyst is filtered through Celite on a millipore filter (0.5 ml), the solvent is removed from the filtrate in vacuo and the residue is extracted with methylene chloride. Removal of solvent under reduced pressure affords 35 mg of the title compound as an oil.

8100571 B) 3- (Acetylamino) -3-methoxy-2-oxo-1-azetidine sulfonic acid, potassium salt.

To a solution of 35 mg of 3-amino-3-methoxy-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt in 10 ml of methylene chloride at 0 ° C, 2 ml of propylene oxide and 74 l of acetyl chloride are added. After 2 hours, the solvent is removed under reduced pressure and the residual oil is chromatographed on 4 g of silica gel. Elution with 6-8% methanol in methylene chloride yields 18 mg of oil, which is dissolved in water and passed over 3 ml of ion exchange resin (AG 50W-X2, K + form, 0.6 meq / ml). Removal of water from the eluate in vacuo gives 10 mg of the desired product.

Example 47 N- (3-Methoxy-2-oxo-1-sulfo-3-azetidinyl) -2-phenylacetamide, tetrabutyl ammonium salt.

A) N-Chloro-N- (2-oxo-1-sulfo-3-azetidinyl) -2-phenylacetamide, potassium salt.

In a solution of 50 mg (S) -N- (2-oxo-1-sulfo-3-azetidinyl) -2-phenylacetamide, potassium salt (see example 1) in methanol, containing 5 ml 4% sodium borate decahydrate and cooled in a -5 ° C bath, add 20 µl of t-butyl hypochlorite. After stirring for 32 min, the mixture is poured into 0.5 M pH 5.5 potassium phosphate buffer at 0 ° C. Resulting solution (pH 5.9) is adjusted to pH

4.5 adjusted, concentrated in vacuo to remove methanol and chromatographed on 100 ml HP-20AG, 0.074 ^ 0.149 mm.

After washing the column with 100 ml of 0.5 M pH 5.5 buffer and water, the desired product is eluted with 9 µl of water: acetone. Concentration in vacuum provides 50 mg of the title compound.

B) N- (3-Methoxy-2-oxo-1-sulfo-3-azetidinyl) -2-phenylacetamide, tetrabutyl ammonium salt.

A solution of 149 mg of N-chloro-N- (2-oxo-1-sulfo-3-) is added, with stirring, to a solution of - 55-160 mg of lithium methoxide in 5 ml of methanol, which is cooled to -78 ° C. azetidinyl) -2-phenylacetamide, potassium salt in 10 ml dry dimethyl formamide. After everything has been added, the mixture is stirred at -78 ° C for 5 min., Poured into 100 ml of 0.5 N monobasic potassium phosphate solution and washed three times with methylene chloride. 213 mg of tetrabutyl ammonium bisulfate are added to the aqueous layer, which is then extracted three times with methylene chloride. The combined extracts are dried (sodium sulfate) and the solvent is removed in vacuo to give 271 rag oil. Chromatography of the oil on 25 g of silica gel and eluting with 4% methanol 96% methylene chloride yields 149 mg of product as an oil.

Example 48 N- (3-Methoxy-2-oxo-1-sulfo-3-azetidinyl) -2-phenylacetamide, potassium salt.

91 mg of N- (3-Methoxy-2-oxo-1-sulfo-3-azetidinyl) -2-phenylacetamide, tetrabutyl ammonium salt (see example 47) is dissolved in water and passed over 10 ml ion exchange column (AG 50W-X2 K + shape). The eluate is concentrated in vacuo and the residual oil solidifies upon scratching with a methanol-acetone ether mixture. After rubbing twice with ether, the product is obtained as 53 mg solid with the following properties: 25 v 1762, 1665 cm -1, NMR (CD, GD) δ 3.41 (s, 3H, OCH,), 3, 59 (S, max J 3 2H, CH 3), 3.84 (ABq, J = * 6.3 Hz, 2H, H 4), 7.30 (m, 5H, aromatic) Analysis calculated for: C 39, 88, H 3.62, N 7.75;

Found: C 39.62; H 3.65; N 7.60.

Example 49 3-Methoxy-2-oxo-3- / / (phenylmethoxy) carbonyl- / amino- / -1-azetidine-sulfonic acid, tetrabutyl ammonium salt.

Method I: 35 81 00 57 1 - 56 - A) 2-Oxo-3 - / - N-chloro-N-y (phenylmethoxy) carbonyl Zamino / -1-azetidine sulfonic acid, tetrabutyl ammonium salt.

0.9 g (S) -2-Oxo-3- / / (phenylmethoxy) carbonyl _ / - 5 amino _ / - 1-aze-tidinesulfonic acid, tetrabutyl ammonium salt (see for example 4) dissolved in 80 ml methylene chloride and added to a mixture (cooled to 0-5 ° C) 3.17 g sodium borate decahydrate and 11.8 ml 5.25% sodium hypochlorite solution in 70 ml water. The reaction mixture is stirred vigorously for 55 min while cooling in an ice bath. After diluting the mixture with 0.5 M monobasic potassium phosphate solution, the product is extracted with methylene chloride (three 150 ml portions). Combination of the extracts, drying (sodium sulfate) and removal of solvent in vacuo afford the title compound as 0.94 g of oil.

B) 3-Methoxy-2-oxo-3V / (phenylmethoxy) carbonyl / araino / -1-azetidine sulfonic acid, tetrabutyl ammonium salt.

667 mg of lithium methoxide in 10 ml of anhydrous methanol are added at -78 ° C to a solution of 0.94 g of 2-oxo-3 - / - N-chloro-N - / - (phenylmethoxy) carbonyl / amino / / with stirring. -1-azetidine sulfonic acid tetrabutyl ammonium salt in 10 ml dry dimethyl formamide. After stirring the mixture at -78 ° C for 1 hour, it is poured into 0.5 M monobasic potassium phosphate solution and extracted with methylene chloride (three 150 ml portions). The combined extracts are dried (sodium sulfate) and the solvent is removed in vacuo to give 0.83 g of oil. The desired product is obtained by chromatographing the oil on 100 ml of silica gel and eluting with 4-5% methanol in methylene chloride to obtain 513 mg of oil: v (net)

luaX

1767, 1720 cm-1; NMR (CDCl 3) 6 3.40 (S, OCH 3), 3.03 (ABq, J - 6.5

Hz, H4), 508 (S, CH2), 6.00 (S, NH), 7.27 (S, aromatic).

Method II:

To a solution of 400 mg of 3-benzyloxycarbonyl-amino-3-methoxy-2-oxo-1-azetidine sulfonic acid, potassium salt in water is added 10.9 ml of 0.1 M tetrabutyl ammonium bisulfate solution, which is 8100571 * * - 57 - with potassium hydroxide adjusted to pH 4.3. The mixture is extracted three times with methylene chloride, the extracts are combined, dried (^ 2 ^ 0 ^) and the solvent is removed in vacuo to give 625 mg of foam with spectral properties approaching that of the product of Method I. Example 50 3-Methoxy-2-oxo-3 - / - (phenylmethoxy) carbonyl / amino / 1-azetidine sulfonic acid, potassium salt.

Method I: A) 2-Oxo-3V N-chloro-N- / (phenylmethoxy) carbonyl / amino / -1-azetidine sulfonic acid, potassium salt.

In a solution of 1.00 g of (S) -2-oxo-3- / ((phenylmethoxy) carbonyl-amino-1-a-azetidine sulfonic acid, potassium salt (see example 3) in 90 ml of methanol, containing 4 % sodium borate decahydrate, 420 t-butyl hypochlorite is added at -10 ° C. After stirring at -10 ° C for 2 hours, 100 ml of 0.5 M monobasic potassium phosphate solution are added and the pH is adjusted with 1N hydrochloric acid. at 6. After concentrating the solvent in vacuo to 30 ml, the aqueous solution is chromatographed on 200 ml of HP-20AG, 0.074-0.149 mm After passing a solution of 50 g of basic potassium phosphate in 1000 ml of water, followed by 2000 ml of water, the product is eluted with 10% acetone-90% water, the solvent is removed in vacuo and the title compound is recrystallized from water to give 530 mg of solid, mp 173-175 ° C. .

B) 3-Methoxy-2-oxo-3V [_ (phenylmethoxy) carbonyl] / amino] -1-azetidine sulfonic acid, potassium salt.

30

To a solution of 874 mg of lithium methanolate in 10 ml of dry methanol, 857 mg of 2-oxo-3- / N-chloro-N- / "(phenylmethoxy) carbonyl / amino-1-azetidine sulfonic acid, potassium salt are added at -78 ° C 13 ml of dry dimethylformamide After 15 min at -78 ° C, the mixture is poured into 200 ml of 0.5 M monobasic potassium phosphate-81 00 57 1 f * -58 solution and adjust the pH to 5.5 with IN hydrochloric acid The aqueous mixture is washed with methylene chloride (three 100 ml portions) and 1.169 g of tetrabutyl ammonium bisulfate are added The product is extracted with methylene chloride (three 5 200 ml portions), dried (sodium sulfate), filtered and concentrated in vacuo The remaining oil is chromatographed on 150 g of silica gel and the product is eluted with 2-4% methanol in methylene chloride to give the tetrabutyl ammonium salt of the product as 701 mg of oil. the oil is dissolved in water and passed over an ion out ssel column (3 ml AG 50W-X2, 0.037-0.074 mm, K + form 0.6 meq / ml). Concentration of the eluate in vacuum yields 30 mg of oil which is crystallized by scratching with acetone: v (KBr) 1760, max 1725 cm -1; NMR (D20) 6 3.48 (S, 3H, OCH3), 392 (S, 2H, H4); 5.20 (S, 2H, CH2), 7.42 (S, 5H, aromatic); mp 196-198 ° C.

Method II; A) 1-Chloro-3- / N-chloro-N- / (phenylmethoxy) carbonyl / -2razetidinone.

A solution of 440 mg 3- / f (phenyl-methoxy) carbonyl / amino-2-azetidinone (see example 2C) in 40 ml 40% methanolic borax is cooled to 0 ° C and 0.5 ml t- butyl hypochlorite. After 30 min. At 0 ° C, the solution is poured into 200 ml of cold water and extracted with two 100 ml portions of ethyl acetate. The combined ethyl acetate layer is washed with water, dried and evaporated in vacuo to give 546 mg of the title compound as an oil.

B) 3-Methoxy-3V / (phenylmethoxy) carbonyl / amino / 2-azetidinone.

30

A solution of 730 mg or 0.0025 mol of 1-chloro-3- / N-chloro-N- / (phenylmethoxy) carbonyl / amino-2 / azetidinone in 5 ml of tetrahydrofuran is cooled to -78 ° C and add 4 ml of methanol containing 285 mg of lithiumraethoxide. After 20 min. At -78 ° C, 0.6 ml of acetic acid and 0.6 ml of trimethylphosphite are added. The 8100571 - 59 - 5 solution is stirred at -18 ° C for 5 min, allowed to warm to room temperature and stirred for 30 min. The resulting solution is diluted with ethyl acetate, washed with 5% sodium bicarbonate, water, 5% potassium bic sulfate, water and saturated brine and dried. Solvent removal yields an oil which is passed over four 20 x 20 cm x 1 mm silica gel plates. Development with benzene-ethyl acetate (1: 1) and recovery of the main UV-active band of Rf = 0.25 gives 91 mg of oil which crystallizes from ether to a solid of 10 t. Recrystallization from ether gives the title compound, m.p. 112-114 ° C. C) 3-Methoxy-2-oxo-3- / (phenylmethoxy) carbonyl-amino-1-azetidine sulfonic acid, potassium salt. A solution of 25 mg of 3-methoxy-3- / / (phenylmethoxy) carbonyl / amino-2-azetidinone in 0.175 ml of dichloromethane and 0.175 ml of dimethylformamide is stirred with 55.4 mg of a pyridine sulfur trioxide complex for 24 hours. The resulting slurry is diluted with 5 ml of cold 0.5 M monobasic potassium phosphate (adjusted to pH 4.5) and extracted with ethyl acetate. The water layer is passed over a 40 ml HP-20AG column. Elution with more buffer, water and water-acetone (9: 1) yields 32 mg of the title compound as an oil, which slowly solidifies, recrystallization from acetone yields the title compound, mp 196-198 ° C under decomposition. f "25 λ» Example 51 3- / -1 / 1,3-Dioxo-2-pheny 1-3- (phenylmethoxy) propyl-yamino-3-methoxy-2-oxo-1-azetidine sulfonic acid, potassium salt. 30 A) 3- / / 1,3-Dioxo-2-phenyl-3- (phenylmethoxy) -propyl / amino / -3-methoxy-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt 351 mg of crude 3-amino-3 are dissolved -methoxy-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 74), containing borax, in 30 ml dry acetic nitrile, add 81 00 57 1 - 60 - 317 μΐ dry pyridine and stir the solution at -10 ° C good under dry nitrogen 568 mg of a- (benzyl-oxycarbonyD-phenylacetyl chloride in 3 ml of dry acetic nitrile are added dropwise). Thin layer chromatography indicates that the reaction is complete after 15 min. potassium phosphate buffer pH 5.5 and removes most of the acetic nitrile in vacuo The residue is diluted with water and extracted three times with equal volumes of methylene chloride The extract is dried over anhydrous sodium sulfate and evaporated in vacuo to give 1.032 g of crude product, which is dissolved in 3 ml of methylene chloride and chromatographed on a silica column using methylene chloride-methanol to give 470 mg of the title compound.

B) 3-1 / 1,3-Dioxo-2-phenyl-3- (phenylmethoxy) -15 propyl / amino 7-3-methoxy-2-oxo-1-azetidine sulfonic acid, potassium salt.

470 mg of 3- / 1 / 1,3-dioxo-2-phenyl-3- (phenyl-methoxy) propyl / amino-3-methoxy-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt are dissolved in 15 ml of 30% acetone water and pass the solution over a Dowex 50W-X2 (K + form) column using the same solvent as the eluent. The total eluate is evaporated in vacuo to 345 mg of an amorphous solid, which is lyophilized to an amorphous powder, mp 100-120 ° C.

Analysis Calculated for C 20 H 19 ° 8 N 2 SK 25 C 49.37; H 3.94; N 5.76; S 6.59;

Found: C 49.08; H 4.00; N 5.58; S 6.29.

Example 52 (+) - 3 - / - / (Cyanomethyl) thio / acetyl / amino / / 3-methoxy-2-oxo-1-azetidine sulfonic acid, potassium salt. 3.

30

To a solution of 414 mg of 3-amino-3-methoxy-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 74) in 50 ml of dry acetic nitrile, 210 l of diethylaniline and 169 mg of cyanomethylthioacetyl chloride are added at -20 ° C. After 10 minutes, the solvent is removed under reduced pressure and 22.8 ml of 8 1 0 0 57 1 - 61 - 0/1 Μ tetrabutyl ammonium sulfate solution, which has been adjusted to pH 4.3 with potassium hydroxide, are added and extracted. product with three 50 ml portions of methylene chloride, dried, filtered and concentrated under reduced pressure. The oily residue is purified over 60 g of silica gel and the product (294 mg) is eluted with 4% methanol-methylene chloride. The purified product is passed over 16 ml of ion exchange resin (AG50 W-X2 K + form), 0.6 meq / ml, 0.037-0.074 mm. Removal of water yields 164 mg of partially purified product. The product is further purified over 100 ml of Diaion AG HP 20 using water as an eluent. The solvent is removed under reduced pressure to give 126 mg of the product, which is triturated with ether to 76 mg of the title product, mp 110-125 ° C.

15 Analysis calculated for C8H10N3S2 ° 6K! C, 27.66; H 2.88; N 12.10; S 18.44;

Found it; C, 27.25; H 3.00; N 10.84; S 17.53.

Examples 53-56

Following the procedure of Example 42, Method II, but using a compound listed in column I of the table below instead of (+) - c * V (aminocarbonyl) -amino / -2-thiophenoacetic acid, the resulting connection from colossus II behind it.

81 00 57 1 I 62 f H H 8 H & H H O —I £

II ρ a> 1 3 CP (OP Ρ (0 3 MPI - CN PO »I 1 3 C 3 PN T3 OG d) GOH P lp pahg (0 3 0 <- * W rM) H> i (! ® Ρ Ρ Ό (DOG ü PO (0 P 0 <D * XNU 0 (0 0 I 0 C Η ΙΛ Ρ IP ε o (n (0 XI 0 CN I, i 'vltN CN hfSs>' ë E Cl fl D BH 'X ? + h -> 1 * WPP, ci 41 3, 00 vj «JN

IHII io in ox σι X o * h Λ 4J ok§ S o'8 sef (0 P <D - • BH P, 3 W JS I * P PP 0)> i 3 BPO §0 NO g (O (O 3 > | H Ή O SnP _ - sn) B> I, OJ MC> Jp Ή NV \ JCN § l, · N kh | '• x O <PIGH _ ro P 3 Ό i-Li S § -hS - + 1 -1 <0 o W 4J +> 0, η eor * I, on σ> \ | (tj | Q p T3 P 0)

P 1 P P> 0 Sn * G <P P Ki3 O N C G P O E <P (O P - 3 -I M Sn d) P G

I> 1 G <D c • ft

§ ft P <0 M

• ft Ό P +> 0) N 10 I o 01

CJ

o CN t Γ "o I o X Γ"! <Ν CN l ^ \ P> V§ n c ft! Si | V-? "- SN - W Ρ P, <Ί O 3 I, ο o s | id n

r-l & o X) P <0 o o G

P 1 1 P 3 n <v c • η Ό -t p P 0) <D Ό N G (O O I

(P c • ft Ό 0) -P G O

aiu (O o, - xo l, O m, \ i I CN, CN CN I "vP · co 3 C 0+ p + r 4-1,1 *, 1« K —t -> i * W Ρ P , n dl 3 1, oo vjlj N

I co k

- P P 3 Sn 3 P N G

O) o (O o X o o G P

I I - o P P> t JS P P P I (D CN b, i

• η N 3 G (O P 3 + t (O I> '^ l Ö o I c —ip ± ‘S

§H (O o> t c O P - SP .3 3 '• xK., 3

I P P Sn 2 P 3 (1) N O G β - -> O P X N

i - P P 3> i 3 G N 'C

,. N t, Sn · η \ | P P I <U N Ö O (0 I (0 G O dl + | X (U -, O P ï)

(0 0 G C dl P o g N 3 G rj} Ö o 1 G - * P «H

P P (0 N O (0 O G G 0) P d) H N 3 c Γ, Λ> K! 0 O 1 G - · p Pi H

«P <D dl fi O!> N in -d * in in in 10 in 8100571 £, Τ - 63 -

Example 57 L 3S (+)) / - 3V / 2- 2- (Methylthio) -1-oxopropyl / amino---2-oxo-1-azetidinesulfonic acid, potassium salt.

Following the procedure of Example 31, metho II, but using (+) - 2- (methylthio) propanoic acid instead of (+) - α-azidobenzenoacetic acid, the title compound, m.p. 173 °, is obtained. C, under decomposition.

Example 58 10 (_ 3S (R *) _ / - 3- / (_ (_ / _ (_ (2,3-Dioxo-4- / (phenylmethylene) amino _ / - 1-piperazinyl_ / carbonyl_ / amino_ / phenylacetyl __ / amino __ / - 2-oxo-1-azetidinesulfonic acid, potassium salt.

0.7 g of (R) -α / / / 2,3-Dioxo-4V (phenyl-15 methylene) amino-1-piperazinyl-1 / carbonyl / amino-benzenoic acid and 0.8 g of (S) - are dissolved 3-Emino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 6A) in 20 ml of acetic nitrile. 0.4 g of dicyclohexylcarbodiimide are added dropwise at 0 ° C with stirring. Stirring is continued for 18 hours and after filtration the solvent is distilled off leaving an oily residue.

The residue is dissolved in acetone and treated with potassium perfluobutane sulfonate to precipitate the title compound. Purification by column chromatography on HP-20 using water as an eluent gives the title compound of mp 193-194 ° C.

Example 59 / * 3S (Z) 7-3- / / (2-Amino-4-thiazoly-1) / (2-methoxy-2-oxoethoxy) imino / acetyl 7amino / -2-oxo-1-aze t idine sulf on acid, potassium salt.

1.3 g (Z) -2-amino-oV (2-methoxy-2-oxo-) are dissolved

ethoxy) imino-4-thiazole acetic acid and 2.03 g (S) -3-amino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 6A) in 50 ml of acetic nitrile and added dropwise at 0 ° C

Add 1.03 g of dicyclohexylcarbodiimide dissolved in 5 ml of acetic nitrile 35. After stirring for 15 hours and after filtering off dicyclohexylurea, the solvent is distilled off. The residual oily residue is dissolved in acetone and treated with the equivalent amount of potassium perfluorobutane sulfonate. The title compound is recovered and purified by column chromatography over HP-20 using water as an eluent to afford the title compound, mp 195-198 ° C.

Example 60 (_ 3S (rX) _ / ~ 3 - / _ /./././. 3 V / _ (4-Chlorophenyl) methylene / / amino __ / - 2-10 oxo-1-imidazolidinyl __ / carbonyl_ / amino_ / phenylacate ty / amino / -1-azeididine sulfonic acid, potassium salt.

1.5 g of (S) -3-amino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 6A) are stirred in 100 ml of absolute diglyme (diethylene glycol dimethyl ether), 1.5 g (R) -c < - / f_ (_ 3 - / _ / _ (4-chlorophenyl) methylene __ / amino _ / - 2-oxo-1-imidazolidinyl / carbonyl / amino_ / benzeneacetic acid, an equivalent amount of dicyclohexylcarbodiimide and 0.5 g of hydroxybenztriazole for 12 hours The solvent is removed in vacuo and the residue is dissolved in 50 ml of acetone and filtered, the acetone is distilled and the residue is dissolved in 200 ml of methylene chloride The solution is dissolved with sodium bicarbonate in water and then with sodium chloride solution in water washed The methylene chloride layer is dried over sodium sulfate, evaporated to dryness and crystallized by addition of ether The compound is recrystallized from acetone-ether The resulting white crystalline powder is dissolved in acetone and treated with an equivalent amount of potassium perfluorobutane ulphonate in acetone. The title compound precipitates and is filtered to yield 1.4 g of product mp 217-222 ° C.

Example 61 / 3S (R *) _ / - 3 - / _ / / / /. 2-Oxo-3V (phenylmethylene) amino-1-l-imidazolidiny 1 / carbony 1 / amino-f / enylacetyl / amino-7-1-azetidine sulfonic acid, potassium salt.

35 "8 1 0 0 5 7 1 f. Λ - 65 -

2.25 g of (S) -3-amino-2-oxo-1-azetidine-sulfonic acid, tetrabutylammoniura salt (see example 6Ά) are stirred in 100 ml of dry dimethylformamide (DMF), an equivalent of dicyclohexylcarbodiimide, 2.5 g ( R) -a- / / / 2-oxo-3- / (phenylmethylene) amino -1-5 iraidazolidinyl / carbonyl / amino / benzenacetic acid and 0.85 g of hydroxybenztriazole for 12 hours at room temperature. At this time, DMF is removed in vacuo and the residue is dissolved in 50 ral acetone. The precipitated urea is filtered off and the mother liquor is treated with an equivalent amount of potassium perfluorobutane sulphonate in 20 ral acetone. After addition of 100 ml of ether, the title compound precipitates, which is filtered off. The product is purified by dissolving the compound in DMF / acetone and precipitating with water to obtain 1.5 g of product mp 224 ° -226 ° C under decomposition.

Example 62 / 3S (Rx) _ / - 3 - / _ / _ / _ (_ / _ 3- (Methylsulfonyl) -2-oxo-1-imidazolidinyl_ / ~ carbony1 / amino_ / phenylacetyl_ / amino _ / - 2-oxo -1-azetidine sulfonic acid, ~ kaliura salt.

2.25 g of (S) -3-amino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 6A) are stirred in 60 ml dimethylformamide for 12 hours with 1.9 g (R) -a- / [alpha] 3- (methylsulfonyl) -2-oxo-1-imidazolidinyl / carbonyl / amino-benzeneacetic acid, 0.75 g hydroxybenztriazole and 2.3 g dicyclohexylcarbodiimide. The solvent is removed in vacuo and the residue dissolved in 20 ml of acetone and filtered. The mother liquor is treated with 1.87 g of potassium perfluorobutane sulfonate in 20 ml of acetone. After addition of ether, the title compound precipitates to yield 2.0 g of material. The compound is purified by recrystallization from water and has a melting point of 240-245 ° C, with decomposition.

35 81 0 0 57 1 i- τ - 66 -

Example 63 3S (RX) 3 / 3- (hydroxyphenylacetyl) amino / 2-oxo-1-azetidinesulfonic acid, potassium salt.

1.5 g (S) -3-amino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 6Ά) are stirred in 100 ml dry dimethylformamide for 16 hours with 1.5 g dicyclohexylcarbodiimide, 0.5 g hydroxybenztriazole and 0.6 g of Ra-hydroxybenzene acetic acid. The solvent is removed in vacuo and the residue dissolved in 20 ml of acetone. The precipitated urea is filtered off and the mother liquor treated with an equivalent amount of potassium perfluorobutane sulfonate. After addition of ether, the title compound precipitates, which is filtered off to give 1.3 g of crude product. The product is purified by chromatography using HP-20 and water / acetone (9: 1) as an eluent. It has a melting point of 145-150 ° C with decomposition.

Example 64 3 3S (SX) / / - 3- ((Hydroxyphenylacety 1) amino / - 2-oxo-1-azetidinesulphonic acid, potassium salt.

Following the procedure of Example 63, but using (S) -a-hydroxybenzeneacetic acid in place of (R) -a-hydroxybenzeneacetic acid, the title compound mp 195-197 ° C is obtained.

Example 65 3 3S (+) 2 / - 2-Oxo-3- ((phenylsulfoacetyl) amino---1-azetidine sulfonic acid, potassium salt (1: 2).

2.25 g (S) -3-Amino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 6A) in 100 ml dry diglyme, 2.4 g triethylamine and 0.3 g dimethylaminopyridine are cooled to 0 ° C . 1.8 g of (R) -a- (chlorocarbonyl) -benzenemethanesulfonic acid in 20 ml of diglyme are added dropwise. The temperature is maintained for 2 hours, the solvent is distilled off in vacuo 8100571 - 67 - and the residue is dissolved in acetone. The insoluble precipitate is filtered off and the mother liquor treated with an equivalent amount of potassium perfluorobutane sulfonate. After addition of ether, the title compound, which is filtered to yield 1.4 g of crude product, mp 240-245 ° C, precipitates under decomposition, after recrystallization from water / acetone. Example 66 / 3S (Z) 3/3 / (2-Amino-4-thiazolyl) / (diethoxyphosphinyl) methoxy / imino / acetyl / amino / 2-oxo-1-azetidine sulfonic acid, potassium salt.

10

2.25 g of (S) -3-amino-2-oxo-1-azetidinesulfonic acid, tetrabutyl ammonium salt (see example 6A) are treated in 100 ml of dry dimethylformamide for 12 hours while stirring with 1.87 g of (Z) -2 -amino-αV / (diethoxyphosphinyl) methoxy / imino-4-thiazole acetic acid, 0.75 g of hydroxybenztriazole and 2.29 g of dicyclohexylcarbodiimide. The precipitated urea is filtered off and the solvent is removed in vacuo. The residual oil is treated with an equivalent amount of potassium perfluorobutane sulfonate in 20 ml of acetone. After addition of ether, the title compound precipitates, which is filtered off to give 2.77 g of crude product. Purification of this crude product by column chromatography using HP-20 and water / acetone (9: 1) as an eluent affords the title compound, m.p. 155-160 ° C, with decomposition.

Example 67 / 3S (Z) __ 7-3 - / / / ~ (2-Amino-4-thiazolyl) / _ / _ 2- (1,1-dimethylethoxy) -2-oxo-1-phentlethoxy __ / iminp / acetyl_ / aminq / - 2-oxo-1-azetidine sulfonic acid, potassium salt.

2.2 g of (S) -3-amino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 6A) are stirred in 60 ml dimethylformamide at room temperature for 12 hours with 2.4 g (Z) -2- amino-α- / 2- (1,1-dimethylethoxy) -2-oxo-1-phenylethoxy / imino-4-thiazole acetic acid, 1 g hydroxybenztriazole and 1.5 g dicyclohexyl-35 carbodiimide. The solvent is removed in vacuo and the 81 0 0 5 7 1 * 1 - 68 residue dissolved in 50 ml of acetone. The precipitated urea is filtered off and the mother liquor treated with an equivalent amount of potassium perfluorobutane sulfonate. After addition of ether, the title compound crystallizes out, which is filtered off. Purification of the compound is accomplished by HP-20 column chromatography using water / acetone (7: 3) as an eluent, to give 1 g of product, m.p.> 250 ° C, with decomposition. Example 68 / 3S (Z) 3 / 3- (2-Amino-4-thiazolyl) / (1H-tetrazol-5-ylmethoxy) -10 imino / acetyl / amino / 2-oxo-1- azetidine sulfonic acid, potassium salt.

1.9 g of (S) -3-amino-2-oxo-1-azetidinesulfonic acid, tetrabutyl ammonium salt (see example 6A) in 60 ml of dimethylformamide are treated with 1.4 g of (Z) -2-amino under stirring for 24 hours. -av (1H-15-tetrazol-5-ylmethoxy) imino-4-thiazole acetic acid, 0.7 g of hydroxybenztriazole and 1.4 g of dicyclohexylcarbodiimide. 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 perfluorobutane sulfonate in 10 ml of acetone. The title compound is precipitated by adding 200 ml of ether. Purification is achieved by HP-20 column chromatography using HP-20 resin and water as an eluent to yield 1.05 g of product, mp 250 ° C, with decomposition.

Example 69 / 3S (Z) 7-3- / Γ (2-Amino-4-thiazolyl) / (phenylmethoxy) imino / acetyl / - amino / -2-oxo-1-azetidine sulfonic acid, potassium salt.

1.5 g of (S) -3-amino-2-oxo-1-azetidine-30 sulfonic acid, tetrabutyl ammonium salt (see example 6A), 1.23 g (2) -2-amino-a- / (phenylmethoxy) are stirred imino-4-thiazole acetic acid, 0.57 g of hydroxybenztriazole and 1.14 g of dicyclohexylcarbodiimide at room temperature in 60 ml of dimethylformamide for 24 hours. The precipitated urea is filtered off, the solvent is removed and the residue is treated with an equivalent amount of potassium perfluorobutane sulphate in 10 ml of acetone. After addition of 200 ml of ether, the title compound, which is filtered and purified by HP-20 column chromatography with water / acetone (9: 1) as eluent, precipitates to give 1 g of material, mp 200 ° C # 5 under decomposition.

Example 70 / 3S (Z) 7 * "3- / / (2-phmino-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 are mixed -oxo-1-azetidine sulfonic acid, potassium salt (1: 1) (see example 30) with 5 ml of anisole. 25 ml of trifluoro-acetic acid are added at -15 ° C and the mixture is stirred for 10 min. 100 ml of ether are slowly added at -10 ° C and then 50 ml of petroleum ether. The precipitate is suspended in 20 ml of water with cooling and adjusted to pH 5.0 with dilute potassium hydroxide. The product is purified by chromatography on an HP-20 column to obtain 3.0 g of the title compound, mp 230-20, 235 ° C, with decomposition.

Example 71 f_ 3S (Z) _ / - 3 - / _ / (2-Amino-4-thiazoly 1) / ^ [_ 2-oxo-2- (phenylmethoxy) -ethoxy __ / imino_ / acetyl_ / amino _ / - 2- oxo-1-azetidine sulfonic acid, potassium salt.

25

Following the procedure of Example 28, use (Z) -2-amino-α- / / 2-oxo-2- (phenylmethoxy) ethoxy / imino / - 4-thiazole acetic acid instead of (Z) -2-amino -C - [2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy] / imino / 4-thiazole acetic acid, the title compound, m.p. 170 DEG C., decomposition, is obtained. .

Example 72 / 3S (Z) - / - 3 - / _ / / (2-Amino-2-oxoethoxy) imino / / (2-amino-4-thiazolyl) -acetyl / / amino __ / - 2-oxo-1-azetidine sulfonic acid , potassium salt.

35 81 00 57 1

When following the procedure of Example 28, but using (2) -2-amino-aV (2-amino-2-oxoethoxy) imi-c-4-di-acetic acid instead of (Z) -2-amino-α - / - / - 2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy-7-amino-5% by weight thiazole acetic acid, the title compound having melting point is obtained 205-210 ° C, with decomposition.

Example 73 / 3S (zW-3- / / (2-Amino-4-thiazolyl) (tydroxyimino) -acetyl / amino_ / ~ 2-oxo-1-azetidine sulfonic acid, potassium salt,

A solution of 0.6 g of 90% hydroxy-benztriazole in 100 ml of dimethylformamide is stirred with 10 g of 4A molecular sieves for 1 hour, filtered and the filtrate is added to a solution of 0.004 mol (S) -3-amino-2-oxo -1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 6Ά) in dimethylformamide. 0.89 g of (Z) -2-amino-α- (hydroxyimino) -4-thiazole acetic acid are added and then 0.91 g of dicyclohexylcarbodiimide. The mixture is stirred for 16 hours, evaporated in vacuo and the residue dissolved in 20 ml of acetone and filtered. Addition of a potassium perfluorobutane sulfonate solution precipitates the title compound. Chromatography on HP-20 resin yields 0.44 g of product with melting point> 240 ° C.

Example 74 3-Methoxy-2-oxo-3V (2-thienylacetyl) araino / -1-azetidine sulfonic acid, potassium salt.

A) 3-Amino-3-methoxy-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt.

143 mg of (+) -S-methoxy-SV / _ (phenylmethoxy) carbonyl / amino / -2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 49) are dissolved in 15 ml of dry methanol. 2 mg or 0.1 equivalent of Na2B4O · .10 HgO is added, followed by 72 mg of 10% palladium on carbon. The mixture is hydrogenated at 1 atmosphere pressure for 15 min. The catalyst is filtered off and the filtrate in 5

ir A

--71- evaporated in vacuo to give * 114 mg of the title compound, - B) 3-Methoxy-2-oxo-3- / (2'Hienylacetyl) amino __ / - 1-azetidine sulfonic acid tetrabutyl ammonium salt, 10 15 20

102 mg of 3-methoxy-3-amino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt are dissolved in 10 ml of dry acetic acid nitrile. 56.5 µl dry pyridine is added and the solution is stirred well under dry nitrogen at -10 ° C. 44 μl of thienylacetyl chloride in 1 ml of dry acetic acid nitrile are added dropwise. The reaction is completed in 15 min by thin layer chromatography.

4.2 ml of 0.5 M potassium phosphate buffer, pH 5.5 and 8.5 mg or 0.1 equivalent of tetrabutyl ammonium sulfate are added and the majority of the acetic acid nitrile is removed in vacuo. The residue is diluted with water and extracted with three 20 ml portions of methylene chloride. The extract is dried over anhydrous sodium sulfate and evaporated in vacuo to 107 mg of gum. The crude product is purified by silica gel chromatography using methylene chloride-methanol to give 66 mg of the title compound.

C) 3-Methoxy-2-oxo-3 - [(2-thienylacetyl) amino] / - 1-azetidine sulfonic acid, potassium salt.

154 mg of 3-methoxy-2-oxo-3- (2-thienyl-acetyl) amino-1-a-azetidine sulfonic acid, tetrabutyl ammonium salt are dissolved in 3 ml of 30% acetone water, the solution is passed through a column of

Dowex 50W-X2 (K + form) and elutes with the same solvent. The total eluate is evaporated in vacuo to 95 mg of product, which is freeze-dried to an amorphous powder, mp 120-135 ° C.

Analysis calculated for C, nH, N 0, S-K: IU 11 2 o 2 C 33.51; H 3.09; N 7.82; S 17.89;

Found: C 33.46; H 3.08; N 7.92; S 17.64.

35 81 00 57 1 - 72 -

Example 75 / / 3 3S (Z) 7-3- / 7 (2-Amino-4-thiazolyl) / (carboa ethoxx) Jnino / acetyl 7 amino-7-2-oxo-1-azetidinesulfonic acid / kaolin salt, "5 0.1 g / 3S (25) 7-3-77 (2-amino-4-thiazolyl) / _ / _ 2-oxo-2- (phenylmethoxy ethoxy / imino / acetyl / amino / 2-oxo-1-azetidinesulfonic acid potassium salt (see example 71) 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 carbon.

After 2 hours, the catalyst is filtered off and the residual solution is lyophilized to afford the title compound, mp 235 ° C, with decomposition.

Example 76 3 - / "/" (S) - / (Aminocarbonyl) amino_y-2-thienylacetyl_ / araino_ / - 3-15 methoxy-2-oxo-1-azetidine sulfonic acid, potassium salt, isomer A.

To a solution of 277 mg of 3-amino-3-methoxy-2-oxo-1-azetidine sulfonic acid, tetrabutylammonium salt (see example 46, method II, part A) in 15 ml of dry acetic acid atrile, 71 µm is added at 20 -20 ° C 1 or 0.888 mmol of pyridine and 166 mg of (D) -2-amino-4- (2-thienyl) -5- (4H) -oxazoline hydrochloride. The mixture is stirred for 10 minutes and a second amount of 71/1 pyridine and 166 mg oxazoline is added. After a further 10 minutes, the solvent is removed under reduced pressure and the residue is dissolved in a water-acetone mixture and passed over 20 ml of ion exchange resin (AG 50W-X2, K + form, 0.073-0.074 mm). Removal of water from fractions 2-3 gives 248 mg of the diastereomer mixture.

The product is purified and the diastereomers are separated over 130 ml of Diaion AG HP 20 and eluted with water. Isomer A is eluted in fractions 23-28 (30 mg) and isomer B in fractions 35-45 (30 mg) (8 ml fractions). The intermediate fractions (10 mg) are combined with fractions from other courses and a total of 35 mg isomer A and 59 mg isomer B are recovered.

Analysis for isomer A, melting point 158-165 ° C.

35 Calculated for C ^ H ^ N ^ S ^ K. ^ O

81 0 0 57 1 5 - 73 - 10 15 20 25 30 35 C 31.05? Η 3.29; N 13.18; Found: C 30.95; H 2.97; N 12.93.4¾¾¾ 'Analysis for isomer B, melting point 160-170 ° C (decomposition) Calculated for -,> C 31.05; H 3.29; N 13.18; S 15.05; Found: C 31.17; H 3.09; N 13.13; S 15.09. Example 77 3-Methoxy-2-oxo-3- / (phenylsufloacetyl) amino / -1-azetidine sulfone di-acid, / potassium salt.

To a solution of 366 mg of crude 3-amino-3-methoxy-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 74A) and 38 mg of borax in 35 grams of dry acetic acid nitrile at 0.5 ° C under nitrogen is added 0.53 ml of dry pyridine, followed by 2 min. addition of a solution of 348 mg of α-sulfophenylacetyl chloride monoetherate in 8 ml of acetic acid nitrile. After 20 min, the solvent is removed in vacuo and the residue treated with 35 ml of 0.5 M potassium phosphate buffer pH 5.5. 383 mg of tetrabutyl ammonium hydrogen sulfate are added and the mixture is extracted three times with methylene chloride. The methylene chloride is dried (sodium sulfate) and evaporated to 685 mg of crude product. The crude product is combined with 115 mg of second pass crude and the combined material is purified on a column of SiliCAR CC-4 using methylene chloride and then 2, 4, 6, 8 and 10% methanol in methylene chloride as an eluent. The product, a mixture (about 6: 1) of racemic diastereomers in the tetrabutyl ammonium salt form, is converted to the potassium salt by passing it over Dowex 50W-X2 (K + form) resin using 20% acetone in water as a solvent. The product is lyophilized to 171 mg of the title compound, mp 205-210 ° C with decomposition. Analysis calculated for C 21 H 21 N 2 ° 9 S 2 K 2 * H 2 ° C 29.51; H 2.89; N 5.74; S 13.10; Found: C 29.45; H 2.74; N 5.51; S 12.82.

81 00 57 1 * - 74 -

Example 78. 3- / (Carboxyphenylacetyl) amino __ / - 3-methoxy-2-oxi-azetldinesulfonic acid, dipotassium salt.

5 KtfMen dissolves 39 mg 3- / l, 3-dioxo-2-phenyl-3 (phenyl-methoxy) propyl-7-amino-3-methoxy-2-oxo-1-azetidine sulfonic acid, potassium salt (see example 51} in 5 ml of methanol 3.9 mg of anhydrous potassium carbonate and 19 mg of 10% palladium on charcoal are added and the mixture is hydrogenated at atmospheric pressure for 20 minutes, the catalyst is filtered off and the filtrate is evaporated in vacuo to give 34 mg of glassy residue, which is lyophilized to an amorphous powder, mp 178-190 ° C, with decomposition.

Analysis for C13 H12 ° 8 N2 S K2 * 0.5 H2 O C 35.20; H 3.18; N 6.32; S 7.23; Found: C, 35.51; H 2.96; N 6.29; S 6.92.

Example 79 3 3S (Z) / / - 3 - / / / (2-Amino-4-thiazolyl) / / 2- (1,1-dimethylethoxy) -1- (inethylthio) -2-oxoethoxy_ / iniino_ / acetyl_ / amino-2-oxo-1-azetidinin sulfonic acid, potassium salt.

Following the procedure of Example 73, but (Z) -2-amino-α-β-2- (1,1-dimethylethoxy) -1- (methylthio) -2-oxo-ethoxy / imino-4-thiazole acetic acid used in place of (Z) -2-amino-α- (hydroxyimino) -4-thiazole acetic acid, the title compound, m.p. 130 ° C, is obtained with decomposition. Example 80 (+) - 3-Butoxy-3- (phenylmethoxy) carbonyl / amino-2-oxo-1-azetidinic sulfosonic acid, potassium salt. 4 A solution of 185 mg of 2-oxo-3- N-chloro-N- (phenylmethoxy) carbonyl / amino-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 49A) in 1 ml dimethylformamide is added at -78 ° Cooled to 3.8 ° C. 3.8 ml of 0.73 N lithium n-butanolate in n-butanol are added. After 15 min, 0.5 M one-35 basic potassium phosphate buffer is added and the product extracted 8100571

r. a

- 75 - 5 in dichloromethane: (three ml of 40 ml) dried over sodium sulfate, filtered and concentrated in vacuo to 179 mg corresponding to tetrabutyl ammonium salt of the irH bond.

ver 10

To a solution of 109 mg of this tetrabtuyl ammonium salt in acetone, 60 mg of perfluorobutyl sulfonic acid, potassium salt in acetone are added. They remove the solvent in vacuo and add ethyl acetate. The product crystallizes out and is recovered and dried to 66 mg of the title compound, mp 186.5-187.5 ° C under decomposition.

Example 81 {_ 3+ (E) _ / - 3-Methoxy-3 - / _ / _ (methoxyimino) - / 2 - /, /, (phenylmethoxy) -carbonyl / amino _ / - 4-thiazolyl_ / acetyl_ / amino_ -2-oxo-1-azetidine sulfonic acid, potassium salt.

15 20 25

Them treats a suspension of 0.175 mmol 3-amino-3-methoxy-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (Example 46, method II, part Ά) and 0.0175 mmol sodium borate in 2 ml dichloromethane at 28 ° C with 28 1 pyridine and 0.175 mmol (E) -a- (methoxyimino) -2 - / - / - (phenylmethoxy) carbonyl / amino - / - 4-thiazolylacetyl chloride * After 1 hour, the mixture is diluted with dichloromethane and quenched with water. The organic layer is washed with water, saturated salt, dried and evaporated in vacuo. The residue is purified on 20 g of Mallinckrodt SiliCAR CC-4 silica gel to obtain 43 mg of corresponding tetrabutyl ammonium salt of the title compound.

30

43 mg of this tetrabutyl ammonium salt are dissolved in 0.5 ml of acetone and 20 mg of potassium perfluorobutane sulfonate in 0.5 ml of acetone are added. After adding 3 ml of ether, the solid is collected and dried in vacuo to 28 mg of the title compound, mp 144-146 ° C with decomposition.

Example 82 35 / 3+ (Z) __ / - 3-Methoxy-3- / / (methoxyimino) / 2- / / (phenylmethoxy) carbonyl_ / amino _ / - 4-thiazolyl__ / acetyl_ / amino _ / - 2-oxo -1-azetidine sulfonic acid, potassium salt.

81 00 57 1 - 76 -

When the procedure of Example 81 follows, but (Z) -a- (methoxyimino) -2- (phenylmethoxy) carbonyl / amino-4-thiazolylacetyl chloride is used in platinum carbon (methoxyimino) - 2 - / (phenylmethoxy) carbonyl / amino / 4-thiazolylacety 1-5 chloride, the inditely named compound, m.p. 168 DEG-170 DEG C., is obtained with decomposition.

Example 83 3- / / "(R) -a - / _ / _ (4-Ethyl-2,3-dioxo-1-piperazinyl) carbonyl / amino-/ / phenylacetyl / amino / / -3-methoxy-2-oxo- 1-azetidine sulfonic acid, potassium-10 salt.

To a solution of 0.69 mmol of 3-amino-3-methoxy-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (example 46, method II, part A) in 30 ml of dry acetic nitrile, 15 are added at -20 ° C with stirring and under nitrogen 242 l of dry pyridine, followed by a solution of 352 mg of (R) -a- / / (4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl / amino / phenylacetyl chloride in 4 ml of acetic nitrile . After 1 hour, 84 liters of pyridine are added, followed by a further 117 mg of the above acid chloride in 1 ml of acetic nitrile. The reaction is stirred for 20 min, diluted with 24 ml 0.5 M pH 5.5 potassium phosphate monobasic buffer and concentrated in vacuo to remove acetic nitrile. The aqueous residue is extracted three times with methylene chloride and the combined extracts are dried (Na 2 O 3) and evaporated to leave 546 mg of residue. Passing the residue through an ovum gel column using methylene chloride and then 2%, 4% and 6% methanol in methylene chloride, two fractions (285mg and 173mg) of the corresponding tetrabutyl ammonium salt of the title link. Passing the 173 mg fraction through 4.5 mg of Dowex 50-X2 (K +) resin with acetone-water as an eluent yields 119 mg of the title compound.

104 mg of this material are passed over a column of HP-20AG resin in water. Subsequent elution with water, 5% acetone in water and 10% acetone in water, yields 60 mg of product 35 as a mixture (about 1; 1) of diastereomers. Freeze drying of 810057 1

.A

- 77 - the fraction of 60 mg yields a solid "with melting point 171-172 ° C with decomposition. ......--- -

Example 84 N- {3-Butoxy-2-oxo-1-sulfo-3-azefeM ± nyl) -2-phenylacetamide, tetra-buty lammonium salt, = -

Following the procedure of Example 80, but N-chloro-N- (2-oxo-1-sulfo-3-azetidinyl) -2-phenylacetamide, tetrabutyl ammonium salt (see Example 47A for the preparation of the corresponding potassium salt) is used in Instead of 2-OXO-3V N-chloro-N- / (phenylmethoxy) carbonyl / amino-1-azetidine sulfonic acid, tetrabutyl ammonium salt, the title compound is obtained as an oil: nmr (CDCl 3) 3.62 (s .2H, C ^ -H ^ C ^), 4.03 (ABq, 2H, V = 7 cps, C-4 CH2), 6.98 (s, 1H, NH) and 7.30 ppm (S, 15H, CgH5).

Example 85 (R) -3-Methoxy-2-oxo-3 - / - (phenylacetyl) amino - / - 1-azetidine sulfonic acid, potassium salt.

A 1M solution of dimethylformamide sulfur trioxide complex is prepared by slowly adding trimethylsilyl chlorosulfonate to dimethylformamide at 0 ° C followed by applying a vacuum of 0.1 mm for 30 min at 0-25 ° C. Under a nitrogen atmosphere, 50 mg of (R) -N- (3-methoxy-2-oxo-25-1-azetidinyl) phenylacetamide are dissolved in 0.2 ml of anhydrous dimethylformamide and cooled to 0 ° C. 0.428 ml of cold 1M dimethylformamide sulfur trioxide solution is added, the mixture is stirred for 2 hours and poured into 15 ml of 0.5 N monobasic potassium phosphate. The solution is extracted twice with dichloromethane (discarded) and 73 mg of tetrabutyl ammonium bisulfate are added. Extraction with dichloromethane (three 10 ml portions) yields a viscous oil after drying and evaporation in vacuo. Chromatography on Mallinckrodt CC-4 silica gel (50: 1) using 2% methanol in dichloromethane as the eluent yields 43 mg (R) -3-methoxy-2-oxo-3 - / - (phenylacetyl) ami-35 no / - 1-azetidine sulfonic acid, tetrabutyl ammonium salt op. Ions 81 00 57 1 exchange over 50W-X2-H *! » 10 equivalents) after freeze-drying of the aqueous eluate yields the title potassium salt having melting point 130 ° C, with decomposition (C = 0.5, water), - * 1 '

Example 86 rtSigS

(S) -3- / /// "" "(1-Ethyl-4-hydroxy-3-methyl-1H-pyrazolo / 3,4-b-pyridin-5-yl) carbonyl / amino> 7-phenylacetyl / amino_ / -2-oxo-1-azetidine sulfonic acid, potassium salt.

Following the procedure of Example 73, but a- / / <1-ethyl-4-hydroxy-3-methyl-1H-pyrazolo / 3,4-b / pyridin-S-ylcarbonyl / amino / benzenacetic acid is used in instead of (Z) -2-amino- (hydroxyimino) -4-thiazole acetic acid, the title compound, m.p. 233-236 ° C, is obtained with decomposition.

Example 87 (R) -3-Acetylamino-3-methoxy-2-oxo-1-azetidine sulfonic acid, potassium salt.

A) 3-Acetylamino-1 - / - 1 -carboxy-2-methyl (propyl) - / - (3R) -3-methoxy-2-oxoazetidine.

With a solution of 650 mg (6R-cis) -7-acetyl-amino-7-methoxy-3-methyl-8-oxo-5-thia-1-azabicyclo £ 4,2,0 / oct-2-en- 2-carboxylic acid and 191 mg of sodium bicarbonate in water are added 11 ml of technical grade Raney nickel slurry (0.6 g / ml), which is washed with water until neutral. The mixture is lowered into an oil bath which has been preheated to 170 ° C and it begins to reflux within 2-3 min while maintaining the bath temperature at 150-170 ° C. After refluxing for 15 minutes, the reaction is quenched by cooling in an ice bath. The catalyst is filtered through Celite and the filtrate (pH 11) is adjusted to pH 2 with 1N hydrochloric acid. After the aqueous solution is extracted five times with ethyl acetate, the combined extracts are dried (Na 2 SO 2) and the solvent is removed in vacuo to give 487 mg of oil. Chromatography # 79 - 5 on silica gel yields the product (eluted in chloroform) as 381 mg of oil. B) 3-Acetylamino-1- (acetyloxy) -2-methyl- (propyl / - (3R) -3-methooyl-2-oxoazetidine.

10

IS

20

464 mg of the above azetidinone are dissolved in 15 ml of dry acetic acid nitrile and the solution is sprayed with argon for 15 min. 359 mg of copper acetate are added, stirred for 1 min to dissolve the salt and 797 mg of lead tetraacetate are added. While the argon is bubbling through the mixture, the reaction temperature is raised by dropping the flask in an oil bath which has been preheated and held at 55-65 ° C for 15 min. The mixture is allowed to cool to room temperature, filtered through Celite and the filter pad washed well with acetic acid nitrile. The solvent is removed in vacuo from the combination of filtrate and washings. The residue is taken up in water and extracted four times with

ethyl acetate. The combined extracts are dried (Na.SOJ

λ 4 and the solvent is removed in vacuo to give 382 mg of the desired product as an oil.

C) (R) -N— (3-Methoxy-2-oxo-1-azetidinyl) acetamide.

The above oil is dissolved in a mixture of 10 ml of methanol and 1 ml of water, cooled in an ice-methanol bath at -10 to -15 ° C and 194 mg of potassium carbonate are added, followed by 53 mg of sodium borohydride. After stirring at -15 to -8 ° C for 110 min, the solvent is removed in vacuo, the residue taken up in water and the solution adjusted to pH 6 with 1N hydrochloric acid. Exhaustive extraction with ethyl acetate, drying (Na2 SO4) and removal of solvent in vacuo yield 224 mg of oil. Chromatography of the oil on silica gel followed by elution with 5% methanol: 95% methylene chloride provides 169 mg of oil. The title compound crystallizes from ether pentane to give 131 mg of material, mp 106-112 ° C (sintering 103.5 ° C).

81 00 57 1 80 - * * D) (R) -3 ^ Acetylamino-3-raefhoxy-2-oxo-1-azetidi-

nesulfonic acid, potassium salt

50 mg of (R) -5-3-acetylamino-3-methoxy-2-oxo-1-azetidine are placed in a flask and cooled to 0 ° C under an argophil atmosphere. 0.95 ml of 1M solution of dimethylformamide sulfur trioxide complex are then added. in dimethylformamide and stir the solution for 15 min. The flask content is then poured into 40 ml of 0.5 N KjHPO 2 solution and extracted twice with 10 ml of methylene chloride. 1.2 equivalents of tetrabutyl ammonium sulfate are added to the aqueous solution and the resulting mixture is extracted with four 10 ml portions of methylene chloride. The extracts are dried over Na2SO4 and concentrated to 39 mg of product. The tetrabu tylammonium salt is converted to the title potassium salt by passing it through a column of Dowex 50-X2 (K +).

Concentration of the water fraction yields 19 mg of potassium salt with identical NMR spectrum data as the products prepared according to Example 46 Method I, B and as recovered from natural sources (Example 165).

Example 88 (+) - 3V (Azidophenylacetyl) amino-3-methoxy-2-oxo-1-azetidinesulfonic acid, potassium salt.

A) (+) - 3 - / (Azidophenylacetyl) amino - / - 3-methoxy-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt.

202 mg of 3-amino-3-methoxy-2-oxo-1-azetidinesulfonic acid, tetrabutyl ammonium salt (see example 74A) are dissolved in 20 ml of dry acetic acid nitrile. The solution is added at -20 ° C under dry nitrogen under Stir well 167 μΐ dry pyridine and 96 μΐ o-azidophenylacetyl chloride. After 20 min, 12 ml of 0.5 M monobasic potassium phosphate buffer pH 5.5 are added and the vinegar vacuum nitrile is removed in vacuo. The aqueous residue is extracted three times with methylene chloride. The extract is dried over anhydrous sodium sulfate and evaporated in vacuo to give 8100571

81 - of 281 mg of crude product as a gum. This is purified by chromatography through a column of 30 g of silica, 1 part by volume of methylene chloride and mixtures of methylene chloride-methanol to 6% methanol. 231 me ^ g. gives the title compound 5.

B) (+) - 3- / (Azidophenylacetyl) amino-3-methoxy-2-oxo-1-azetidine sulfonic acid, potassium salt.

231 Mg (+) - 3 - / - (azidophenylacetyl) amino - / - 3-10 methoxy-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt in 15 ml 30% acetone: water is passed through a column of 3 ml Dowex 50W-X2 ( K + form) and eluted with water. The total eluate is vacuum-sealed to 168 mg of colorless glass as a 1: 1 mixture of diastereomers. When this mixture is passed through a 60 ml column 15 of HP-20-A6 using water and water: 10% acetone, 71 mg of 1: 1 mixture of racemic diastereomers and 70 mg of 1: 3 mixture of racemic diastereomers are obtained. The 1: 1 mixture is lyophilized and dried in vacuo at 40 ° C to yield the dried product as hemihydrate, melting point 130 ° C.

Analysis for Cj2Hi2N5 ° 6 * K * SHjO:

Calculated: C 35.90; H 3.26; N 17.45; S 7.98;

Found: C 35.94; H 3.07; N 17.24; S 8.02.

Example 89 3- / (Azidophenylacetyl) amino-3-methoxy-2-oxo-1-azetidine sulfonic acid, potassium salt, isomer A.

The 1: 3 mixture of racemic distereomers obtained in Example 88 B is left in deuterated water at room temperature and isomer A crystallizes out. After cooling in a refrigerator, the mother liquor is removed and the crystals (28 mg) are dried in vacuo at 40 ° C. They have a melting point of 130 ° C with decomposition as monodeuterate.

81 00 57 1% i 5 10 15 20 25 30 35

Example 90 -. ____.- = «» - ·· / ~ 3 + _ (RK) {_ / (4-Ethyl-2,3-dioxo-l-piB & baz ^^ l) carbonyl _ / - amino_ / phenylacetyl_ / amino _ / - 3- methoxy-2-oxo-1-azetidine sulfonic acid, potassium salt. —..... ®

To a solution of 0.69 mmol of 3-amino-3-methoxy-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 74A) in 30 ml of dry acetic nitrile is added at -20 ° C with stirring and 242 µl dry under nitrogen pyridine, followed by a solution of 352 mg (R) -a- / / (4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl / amino / phenylacetyl chloride in 4 ml of acetic nitrile. After 1 hour, 84 μl of pyridine is added, followed by another 117 mg of the acid chloride in 1 ml of acetic nitrile. The reaction is stirred for 20 min, diluted with 24 ml of 0.5 M pH 5.5 monobasic potassium phosphate buffer and concentrated in vacuo to remove acetic nitrile. The aqueous residue is extracted three times with methylene chloride and the combined methylene chloride extracts are dried (Na 2 SO 4) and evaporated to 546 mg residue. When passing this material through a column of SiliCAR CC-4 using methylene chloride and then. 2%, 4% and finally 6% methanol in methylene chloride, two fractions (285 mg and 173 mg) of purified product are obtained in the tetrabutyl ammonium salt form. When the 173 mg portion is passed through 4.5 g of Dowex 50-X2 (K +) resin using acetone water, 119 mg of potassium salt are obtained. A 104 mg portion of this material is passed through a column of HP-20-AG resin in water. Subsequent elution with water, 5% acetone in water and finally 10% acetone in water yields 60 mg of product as a mixture (about 9) of diastereomers and 21 mg of product as a mixture (about 9: 1) of diastereomers. Freeze drying of the 60 mg fraction affords the title compound, mp 171-172 ° C, with decomposition. Analysis for cigH22N5 ° 9SK * H2 °! Calculated: C 41.23; H 4.37; N 12.65; S 5.78; Found: C 41.39; H 4.12; N 12.58; S 5.63.

81 00 57 1 - 83 - t *

Freeze drying, of the 21 mg fraction, affords the title compound with melting gun Effi-1720 C, with decomposition. .. ··.

Analysis for C ^ E22U ^ Q-SK.B2Qi ^ m 5 Calculated: C 41.23? H 4.37? N 12.65?

Found: C 41.43? H 4.11? N 12.28.

Treatment of the 285 mg fraction of tetrabutyl ammonium salt with Dowex 50-X2 (K +) yields 145 mg of potassium salt, which is combined with the remaining 15 mg of the above amount of 119 mg of Dowex resin obtained from Dowex resin. When this material is passed through HP-20AG as already described, 31 mg of product as mixture (about 1: 1) of diastereomers and 42 mg of product as mixture (about 9: 1) of diasteromers are obtained. The total amount (1: 1) mixture of diastereomers is 91 mg and the total amount (9: 1) mixture of diastereomers is 63 mg.

Example 91 f-3S (Z) -3- / / (Methoxyimino) / ^ 2-V / _ (phenylmethoxy) carbonyl _ / - araino _ / - 4-thiazolyl / acetyl_ / amino _ / - 2-oxo-1-azetidine sulfonic acid, 20 potassium salt.

To a solution of 0.170 mmol (S) -3-amino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 6A) and 0.170 mmol sodium borate in 2 ml methylene chloride at 0 ° C, 62 µl pyridine and 0, 51 mmol (Z) -a- (Methoxyimino) -2- / / (phenylmethoxy) caxbonyl / amino-4-thiazole acetyl chloride. The reaction mixture is diluted after 40 min with methylene chloride and water, followed by 5.1 ml of 0.1 M tetrabutyl ammonium sulfate buffered to pH 4. The organic layer is separated and washed with water, adjusted to pH 2, water adjusted to pH 7 and water saturated with sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified on 10 g of SiliCAR CC-4 silica gel and the product eluted with 10% methanol / methylene chloride.

The tetrabutyl ammonium salt is passed after solution 81 00 57 1: -84-. ΒΕγί! Ί8ΒΕ in acetone / water by one-ion exchange resin (8 ml, AG 50W-X2, K + form, 0.074-0.149 ma), Heat water in fractions 1-2. 40 mg of the title compound on m.p. 172-174 ° C-7 under piping.

5 Analysis for C ^ 7H ^ gN ^ .OgS. H ^ O: ~

Calculated: C, 37.84; H 3.33; N 12.99; S 11.87;

Found: C 37.95; H 3.30; N 12.73; S 11.53.

Example 92 (+) - 3-Butoxy-2-oxo-3V (phenylacetyl) amino / 1-azetidine sulfonic acid, potassium salt.

A) 3 - / - Chloro (phenylacetyl) amino - / - 2-oxo-1-azetidinesulfonic acid, tetrabutyl ammonium salt.

A solution of 350 mg (S) -2-oxo-3 - / - (phenylmethoxy) carbonyl / amino - / -a-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 4) in 3 ml of methylene chloride at 0 ° C is added to a suspension of 1.27 g of sodium borate in 4.72 ml of 5.25% sodium hypochlorite solution and 20 ml of water. After 1 hour, 25 ml of 0.5 M monobasic potassium phosphate are added and the mixture extracted three times with methylene chloride (50 ml portions). The organic extracts are dried over sodium sulfate, filtered and concentrated in vacuo to 344 mg of the title link.

B) (+) -3-Butoxy-2-oxo-3- (phenylacetyl) amino-1-azetidine sulfonic acid, tetrabutyl ammonium salt.

A solution of 344 mg of 3- / / ch chlorob (phenylmethoxy) carbonyl / / amino / 1-azetidine sulfonic acid, tetrabutyl ammonium salt in 5 ml dimethylformamide at -78 ° C under an inert atmosphere is added to 6 ml 0.73 N n-lithium butoxide in n-butanol in 1 ml of dimethylformamide. After 10 min, the mixture is diluted with 175 ml of 0.5 M monobasic potassium phosphate solution. After extracting three times with methylene chloride, the organic extract is dried over sodium 35 sulfate, filtered and the solvent is evaporated in vacuo. 81 00 57 1 5 I. ψ.

- 85 - deleted. The residue is purified on 80 g of SiliCAR CC-4 silica gel and 130 mg of the title compound are eluted with 4-8% methanol in methylene chloride.

C) (+). -3-Acute-2-oxo-3- / (phenylacetyl) amino-1-a-azetidine sulfonic acid, potassium salt.

10 15 43 mg (+) - 3-Butoxy-2-oxo-3- / {phenylacetyl) -amino-l-azetidine sulfonic acid, tetrabutyl ammonium salt is dissolved in a water-acetone mixture (9: 1) and passed over a cation exchange 5g column (Dowk AGMP 50W-X2, 0.074-0.149mm, K + shape).

The product is eluted with water and the eluate concentrated in vacuo to give 20 mg of the title compound, mp 122-125 ° C.

Analysis for Ο ^, - Η ^ Ν ^ εκΛΗ ,, Ο:

Calculated: C 44.66; H 4.96; N 6.95; S 7.94;

Found: C 44.77; H 4.76; N 6.76; S 7.75.

Example 93 (+) -3-Ethoxy-2-oxo-3 (phenylacetyl) amino-1 / -1-azetidine sulfonic acid, potassium salt.

20 25 30

200 mg of 3- / chloro (phenylacetyl) amino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 92A) in 4 ml of dimethylformamide at -78 ° C under an inert atmosphere are added to 12.20 ml of 0.5 N lithium ethanolate in ethanol. After 10 min., The mixture is diluted with 15 ml of 0.5 M monobasic potassium phosphate solution. After extracting three times with methylene chloride, the organic layer is dried over sodium sulfate, filtered and the solvent is removed in vacuo. The residue is purified on 20 g of SiliCAR CC-4 silica gel and 40 mg of tetrabutyl ammonium salt of the product are eluted with 2% methanol in methylene chloride.

35

The tetrabutyl ammonium salt is dissolved in a 9: 1 water-acetone mixture and passed over 5 g of the cation exchange column (Dowex AGMP 50W-X2, 0.074-0.149 mm, K + form). The product is eluted with water and the eluate concentrated in vacuo to 25 mg of the title compound, mp 94-8100571 * β # 86-96 ° C.

Analysis calculated for ci3H15N2 ° 6SK:

Found: Example 94 C 42.62; H 4.10; N 7.65; S 8.74; C 40.36, N 6.77; S 8.44.

L 3+ <Z) 3 - / - / (2-Ainino-4-thiazolyl) (methoxyimino) acetyl / amino_ / 3-methoxy-2-oxo-1-azetidine sulfonic acid, potassium salt.

3-Amino-3-methoxy-2-oxo-1-azetidine sulphonic acid, tetrabutyl ammonium salt (see example 46, method II, part A) is dissolved in 20 ml acetic nitrile and 1 ml pyridine and the solution is added with vigorous stirring to a suspension of (Z) -a- (methoxy-imino) -2-amino-4-thiazole acetyl chloride in 20 ml of acetic nitrile cooled to 0-5 ° C. After cold stirring for 1 hour, the mixture is diluted with 100 ml of 0.5 M monobasic potassium phosphate solution (pH of the mixture is 4.8) and the solvent is removed in vacuo. The residue is taken up in a minimum amount of water, which contains a small amount of acetone. Chromatography on 200 ml ion exchange resin (AG 50W-X2, 0.074-0.149 mm, K + form) yields the crude product as the potassium salt upon elution with water.

Further purification over 200 ml of HP-20 resin with water as an eluent yields 59 mg of product as a powder after trituration with acetic acid nitrile ether and then twice with ether. The product is an amorphous powder, which melts slowly and decomposes above 150 ° C.

25 Analysis calculated for C10H12N5 ° 7SK! 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.

Example 95 "/ 3R (RX) and 3S (Sx) __ / - 3- / / _ / fAminocarbonyl) amino" / phenylacetyl "/ - 30 amino" / 3-methoxy-2-oxo-1-azetidine sulfonic acid, potassium salt.

A) (+) - 3 .- / (Aminophenylacetyl) amino _ / - 3-methoxy-2-oxo-1-azetidine sulfonic acid, internal salt »35 209 mg (+) - 3- / (Azidophenylacetyl) amino _ / - 3- 8100571 methoxy-2-oxo-1-azetidine with phosphon 2 hours, potassium salt (see example 88) is dissolved in 60 ml of dry methanol. 0.6 ml of anhydrous trifluoroacetic acid and 105 mg of 10% palladium-opgpSSar are added and the mixture is hydrogenated for 1 hour. The catalyst is filtered off and the filtrate evaporated in vacuo to 71 mg of crude product.

B) / - 3R (RX) of 3S (SX) - / - 3 '/ / [_ (Aminocarbonyl) · amino_ / phenylacetyl / amino_ / - 3-methoxy-2-oxo-1-azetidine sulfonic acid, potassium salt.

271 mg (+) - 3- / (aminophenylacetyl) amino-3-methoxy-2-oxo-1-azetidine sulfonic acid, potassium salt, are dissolved in 6.5 ml of water. 87 mg of potassium cyanate are added and the mixture is stirred at room temperature for 3 hours. The solution is concentrated in vacuo to about 2 ml and chromatographed on a 100 ml column of HP-20AG with water as the eluent. After freeze-drying, 29 mg of isomer A with melting point 160 [deg.] C. are recovered, with decomposition.

Analysis calculated for C 19 H 25 N 5 O-ySK monohydrate C 36.44; H 3.99; N 13.07; S 7.48;

Found: C 36.35; H 3.79; N 12.81; S 7.32,

Example 96 / 3R (SX) and 3S (RX) - 3 - / - (Aminocarbonyl) amino - / phenylacetyl - / - amino - / - 3-methoxy-2-oxo-1-azetidine sulfonic acid, potassium salt.

In addition to / 3R (R) and 3S (SX) _ / - 3 - / _ / £ (aminocarbonyl) amino_ / phenylacetyl_ / amino _ / - 3-methoxy-2-oxo-1-azetidine sulfonic acid, potassium salt produced in Example 95 mg / ”3R (SX) and 3s (RX) __ / - 3- / /” V "" (aminocarbonyl) araino-7phenylacetyl _ / - aunino _ / - 3-methoxy-2-oxo-1-azetidine sulfonic acid, potassium salt produced as freeze-dried product with melting point 160 ° C with decomposition.

Analysis for sesquihydrate:

Calculated: C, 35.69; H 4.14; N 12.81; S 7.33;

Found: C 35.98; H 3.87; N 12.50; S 7.32.

88 - at * ~ ......... ............ Example 97 _______ / 3; + (SX) _ / - 3-Methoxy-3- / / / / 7 (2-oxo-3 - ^^^^ 5-ethylene) ainino / - 1-imidazolidinyl / carbonyl Vamino / - 2-thieny lace tyl / amino / -2-oxo-1-azetidine sulfonic acid, potassium salt. 5 In a solution of 3-amino-3-methoxy-2-oxo-azetidine sulfonic acid, tetrabutyl ammonium salt (306 mg of raw material, which is believed to contain 274 mg of organic material and prepared as described in Example 74) in 20 ml of dry acetic acid-nitrile is added at -20 ° C with stirring and under nitrogen 0.30 / - S V..V · ml or 3.72 moles of dry pyridine, followed by 484 mg (S) - / /./.2 -oxo-3-phenylmethylene) amino / 1-imidazolidinyl / carbonyl / amino / 2-thienylacetyl chloride, partially dissolved and suspended in 10 ml of dry acetic nitrile. The reaction is stirred and the temperature is allowed to rise to 0 ° C over 1 hour. The reaction is diluted with a large volume of methylene chloride and then treated with 22 ml of 0.5 M + pH 5.5 monobasic potassium phosphate buffer. The water layer is washed with methylene chloride and the combined methylene chloride extract is washed with water, dried (Na 2 SO 4) and evaporated to 508 mg residue. This residue is chromatographed on 50 g of SiliCAR CC-4 using methylene chloride and then 2% and 4% methanol in methylene chloride to give 251 mg of tetrabutyl ammonium salt of the title compound. t · '25 To 251 mg of this salt in acetone is added a solution of 107 mg of perfluorobutanesulfonic acid potassium salt in a few ml of acetone. The ethyl acetate is added and the precipitate is washed three times with ethyl acetate by centrifugation and dried in vacuo at 40 ° C / mm for 2 hours to obtain 95 mg of the desired potassium salt as a mixture (about 1: 2) of diastereomers. with a melting point of 200 ° C, with decomposition. Analysis for c2iH2lN6 ° 8S2K! Calculated: C 42.85? H 3.60? N 14.28? S 10.87? Found: C 43.02? H 3.74? N 13.94? S 10.71. 35 81 00 57 1

Example 98 (+ -cis) -4-Methyl-2-oxo-3 - / - (phenylmethoxy) c azetidine sulfonic acid, potassium salt *

1 / amino / -1 A) N-Benzyloxy-t-bocallotreonineamine

A solution of 6.9 gd, lt-box-allotreonine and the free amine from 5.3 g of o-benzylhydroxylamine.HCl (~ 0.033 mol, ethyl acetate-sodium bicarbonate release) in 80 ml of tetrahydrofuran is treated with 4.82 g N-hydroxybenztriazole and 6.5 g of dicyclohexylcarbodiimide in 20 ml of tetrahydrofuran. After stirring at room temperature for 16 hours, the slurry is filtered, concentrated in vacuo and chromatographed on 400 µl silica gel column. Elution with 5-10% ethyl acetate in chloroform gives 6.8 g of the title compound in fractions 7-22 (200 ml each).

31 "boe" means butoxycarbonyl, B) (+ -cis) -N-benzyloxy-3-t-butoxycarbonylamino-4-methylaze tidinone.

A solution of 6.8 g of N-benzyloxy-t-boc-allo-threonine amide in 200 ml of tetrahydrofuran is stirred with 5.24 g of triphenylphosphine and 3.2 ml of diethylazodicarboxylate for 16 hours. The solvents are diluted in vacuo and the residue is chromatographed on a 500 ml silica gel column. Elution with methylene chloride followed by crystallization from ether gives a total of 2.65 g of azetidinone. Chromatography of the mother liquors and mixed fractions yields 0.6 g. Twice recrystallization of an amount from ether (-20 ° C) gives the analytical sample of the title compound, mp 140-142 ° C.

C) (+ ^ cis) -3-t-Butoxycarbonylamino-1-hydroxy-4-methylzetidinone.

A solution of 3.2 g of cis-N-benzyloxy-3-t-butoxycarbonylamino-4-methylazetidinone in 200 ml of 95% ethanol is added 5 90 - "..........." ~ "... In a hydrogen atmosphere stirred with 0.7 g of 10% palladium on charcoal. After 40 minutes, the slurry is filtered (249 ml) and the filtrate is evaporated and the ether is triturated to give of, in two portions, 2.05 g of solid, m.p. 134-136 ° C. φρ D) (+ -cis) -3-t-Butoxycarbonylamino-4-methyl-azetidinone.

One solution of 2.05 g of cis-3-t-butyloxycarbo-10-ylamino-1-hydroxy-4-methylazetidinone in 60 ml of methanol is treated with a total of 90 ml of 4.5M ammonium acetate (40, 20 and 30 ml portions ) and 45 ml of 1.5 M titanium trichloride (20, 10 and 15 ml portions), the second and third additions being made after 15 and 120 minutes, respectively. After 135 min., The solution is diluted with an equal volume of 8% sodium chloride and extracted with three 300 ml portions of ethyl acetate. The combined organic layer is washed with a mixture of 100 ml of 5% sodium bicarbonate solution and 100 ml of saturated brine, dried and evaporated. Trituration with ether yields in two portions 1.65 g of solid. Part of the first amount is recrystallized from ether to the analytical sample, m.p. 176-178.5 ° C.

E) (+ -cis) -3-Benzyloxycarbonylamino-4-methyl-azetidinone.

A solution of 1.55 g of cis-3-t-butoxycarbonyl-amino-4-methylazetidinone in 4 ml of methylene chloride and 4 ml of anisole is cooled to 0 ° C and 50 ml of cold trifluoroacetic acid are added. After 90 minutes, the solvents are evaporated in vacuo (three times benzene is added and evaporated). The residue is dissolved in 25 ml of acetone, the initial pH (2.5) is adjusted to 7 with 5% sodium bicarbonate and 2 ml of benzyl chloroformate are added.

The solution is kept at 0 ° C and pH 7 for 4 and the acetone is removed in vacuo to obtain a slurry which is filtered. The filtrate is saturated with salt and with 81 00 57 1 i. ï 5 - 91 - i. ï 5 - 91 - 10 15 20 25 30 .....- ......

methylene chloride extracted. The solid is dissolved in methylene chloride and dried. The organic layers were combined, concentrated and the residue chromatographed on a 200 ml silica gel column. Elution with 3: 1 chloroform, ethyl acetate gives 850 mg of the title compound in fractions 4-11 (100 ml each). Crystallization of a small sample from ether gives the analytical sample with melting point 165-166 ° C.

F) (1-cis) -4-Methyl-2-oxo-3 - / - / - (phenylmethoxy) -carbonyl / amino / -1-azetidine sulfonic acid, potassium salt.

In a suspension of 0.75 g of cis-3-benzyloxy-carbonylamino-4-methylazetidinone in 7 ml of dimethylformamide (dried with 4Ά sieves activated under argon flow at 320 ° C for 15 hours and 7 ml of methylene chloride (dried by basic Al 2 O ^) 1.66 g of pyridine sulfur trioxide complex is added After stirring at room temperature under nitrogen for 3 hours, 1.66 g of pyridine sulfur trioxide complex is added, the reaction mixture is then stirred at room temperature under nitrogen for 16 hours. vacuum removed to give 4.6 g of residue, which is dissolved in 300 ml of 0.5 M monobasic potassium phosphate solution (40 ° C for 10-15 min.) The solution is cooled, through a column of HP-20 resin (3 cm x 60 cm) guided with 400 ml of 0.5 M monobasic potassium phosphate, 1 l of distilled water and (14: 1) water: acetone to obtain 280 mg of product in fractions 13-26 (100 ml each) Recrystallization from methyl alcohol: petroleum ether yields 757.5 mg of analytical sample with melt point 214-215.5 ° C, under decomposition. Analysis for C12H13N2S ° 6K: Calculated: C 40.90, H 3.72; N 7.95; S 9.10; K 11.10. Found: C 40.43; H 3.60; N 7.89; S 8.69; K 10.82. Example 99 (3S-trans) -4-Methyl-2-oxo-3 - / - (phenylmethoxy) carbonyl / amino - / 1-azetidine sulfonic acid, potassium salt.

35

Following the procedure of Example 98, using 1-t-boc threonine instead of, d, 1-t-boc allotreonine, yields the title compound of melted point 133-135 ° C. #

Analysis calculated for; C, 40.90; H- * 3.72; N 7.95; S 9.10; K 11.10;

Found: C 40.72; H 3.60; N 7.99; S 8.80; K 10.82,

Example 100 (3S-trans) -4-Methyl-2-oxo-3- (phenylacetyl) amino-1-azetidine sulfonic acid, potassium salt.

10 A) (3S) -3-Amino-4-methyl-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt.

352.4 mg (4S-trans) -4-Methyl-2-oxo-3- / / (fe-15-methylthoxy) carbonyl / amino-1-azetidine sulfonic acid, potassium salt

(see Example 99) is dissolved in 20 ml of distilled water and treated with 373.5 mg or 1 mmol tetrabutyl ammonium hydrogen sulfate. After stirring at room temperature for 10 min, the solution is extracted three times with 10 ml portions of methylene chloride after saturation with sodium chloride. The methylene chloride is dried over sodium sulfate and evaporated in vacuo to give 536 mg of tetrabutyl ammonium salt, which is hydrogenated with 270 mg of 10% palladium on carbon in 25 ml of dimethylformamide. The mixture is filtered through Celite and washed twice with 2.5 ml. Portions of dimethylformamide to give the title compound in solution, B) (3S-trans) -4-Methyl-2-oxo-3- / (phenylacetyl) -amino / -1-azetidine sulfonic acid, potassium salt.

The crude (3S) -3-amino-4-methyl-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt of Part A (the combination of filtrate and washes) is treated with 206 mg of dicyclohexylcarbodiimide at 0 ° C, 153 mg of N-hydroxybenztriazole and 138 mg of phenylacetic acid. The reaction mixture is stirred at 0 ° C for 1 hour and then at room temperature for 2 hours. The precipitate obtained 81 00 57 1

Jr * .-- 93-.

** "'RF! S8U

is filtered, the filtrate is evaporated in vacuo and the residue is dissolved in 10 ml of acetone and fictitious. The filtrate is treated with 25 ml of potassium iodide saturated acetone and then with 200 ml of ether. The rain solid (752.7 mg) is a mixture of the potassium and tetgrabutyl ammonium salt of the title compound. The solid is dissolved in 50 ml of 0.5 monobasic potassium phosphate and passed through an HP-20 column. Elution with water and then with water-acetone gives different fractions, which are combined and evaporated to the purified tetrabutyl-10 ammonium salt. An aqueous solution of this material is passed through Dowex 50W-X2 (K + form) to give 121.4 mg of the title potassium salt. Trituration with acetone-hexane affords -104.6 mg of the title compound, m.p. 211-213 ° C. Analysis calculated for C 21: 15 C, 41.72; H 4.09; N 8.11; S 9.28; K 11.32;

Found: C 41.70; H 4.01; N 8.07; S 9.01; K 11.02.

Example 101 (cis) -4-Methyl-2-oxo-3- (phenylacetyl) araino-1-azetidine sulfonic acid, potassium salt.

20

A solution of 320 mg (+ -cis) -4-methyl-2-oxo-3 - /> / - (phenylmethoxy) carbonyl / / amino - / - 1-azetidinesulfonic acid, potassium salt (see example 98) in 20 ml is prepared water, which contains 483 mg of tetrabutyl ammonium hydrogen sulfate and adjusts it to pH 5.5. Extraction with six 25 ml portions of methylene chloride provides 517.3 mg of oil. A solution of this material in 15 ml of dimethylformamide is stirred in a hydrogen atmosphere for 90 min with 400 mg of 10% palladium on carbon. The catalyst is filtered off and the filtrate stirred for 7.5 hours with 150 mg of phenylacetic acid, 169 mg of N-hydroxy-30 benztriazole and 247 mg of dicyclohexylcarbodiimide. The solvent is removed in vacuo and the residue dissolved in 20 ml of acetone and filtered. The filtrate is treated with 25 ml of 0.044 M potassium iodide in acetone. Dilution with an equal volume of ether gives 330 mg of solid, which is passed over a 50 ml HP-20 column in 20 ml of 0.05 M monobasic potassium phosphate. Elution with 200 ml 81 0 0 5 7 1 »- 94 - - •« "iSSu.

water followed by 1: 9 acetort water yields Rydon positive material in fractions 6-10 (50 ml). Evaporation of -phoses 7-9 yields 81 mg of solid. Recrystallization from acetic nitrile water gives 46 mg of the title compound, which decomposes at> 205 ° C. A second amount of 6 mg is obtained from the filtrate. Another 5 mg is obtained from fractions 6 and 10 by evaporation and recrystallization.

Analysis calculated for C 12 H 13 N 2 O 5 SK: 10 C 42.84; H 3.89; N 8.33; S 9.53; K 11.62; Found: C 42.75; H 3.82; N 8.32; S 9.26; K 11.63.

Example 102 / "3S- / ~ 3a- (2), 4β_Τ_7-3 - /" / "(2-Amino-4-thiazolyl) (methoxyimino) acetyl / amino / -4-methyl-2-oxo-1-azetidine sulfonic acid , potassium salt.

15 A) (3S-trans) -4-Methyl-2-oxo-3- (phenylmethoxy) carbonyl / amino / -1-azetidine sulfonic acid, tetrabutyl ammonium salt.

352.4 mg (3S-trans) -4-Methyl-2-oxo-3- / f_ (phenyl-methoxy) carbonyl / amino-1-azetidine sulfonic acid, potassium salt (see 20 example 99) is dissolved in 20 ml of water and 373.5 mg of tetrabutyl ammonium hydrogen sulfate are added. The aqueous solution is extracted three times with methylene chloride and the combined extracts are dried over sodium sulfate. After removal of the solvent, 534.6 mg of the title compound are obtained.

B) / ~ 3S- / ~ 3a (Z) # 48j ^ 7-3- / V '(2-Amino-4-thia-zolyl) (methoxyimino) acetyl / amino_7-4-methyl-2-oxo-1- azetidine sulfonic acid, potassium salt.

A solution of 534.6 mg (3S-trans -) - 4-methyl-2-oxo-3- / f (phenylmethoxy) carbonyl / amino-1-azetidine sulfonic acid, tetrabutyl ammonium salt in 20 ml of dimethylformamide is added at atmospheric pressure 2. Hydrogenated for 75 hours with 220 mg of 10% palladium on carbon; the hydrogen uptake is 26.3 ml. The mixture is filtered and washed twice with 2.5 ml of dimethylformamide. The 8100571 - 95 - filtrate and the washings (total about 25 ml) are stirred under nitrogen with 161 mg (Z) -a- (methoxyimino) rino-4-thiazole acetic acid, 136 mg N-hydroxybenztriazole and 164 1.8 mg of tricyclohexyl carbodiimide. The mixture is stirred under nitrogen for 6 hours. The dimethylformamide is removed in vacuo and the gummy residue dissolved in acetone and filtered to remove urea. To the filtrate is added a solution containing 272 mg or 0.8 mmol perfluorobutanesulfonic acid, potassium salt 0.8 ml of acetone The slurry is diluted with an equal volume of ether and filtered to 325.5 mg of crude product which is chromatographed on 75 ml of ΗΡ-20Ά6 Elution with 400 ml of water and 400 ml (9: 1 water: acetone mixture (50 ml fractions) yields 335 mg in fractions 3-10. After trituration with acetone-hexane, 97.3 mg of analytical sample from fractions 3-5 are obtained. Similar trituration of fractions 6-10 gives still 90.4 mg of product as a solid.

Analysis calculated for cigHi2N5 ° 6S2Ki 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 (D2q) 1.57 (3H, d, y «7), 3.97 (3H, S), 4.30 1H, d of q, 20 y - 7.3), 4.70 (1H, d , = 7), 6.95 ppm (1H, S).

Example 103 f_ 3S- / 3α (Ζ), 4β _ / - / - 3 - / _ £ (2-Amino-4-thiazolyl) / _ (1-carboxy-1-methyl ethyloxy) imino_ / acetyl_ / amino _ / - 4- methyl 2-oxo-1-azetidine sulfonic acid, dipotassium salt.

A) N-Benzyloxy-t-boc threonine amide.

A solution of 8.76 g of t-bocthronine and the free amine from 6.4 g of O-benzylhydroxylamine HCl (ethyl acetate-30 sodium bicarbonate release) in 100 ml of tetrahydrofuran is treated with 6.12 g of N-hydroxybenztriazole and 8.24 g dicyclohexylcarbodiimide in 20 ml tetrahydrofuran. The mixture is stirred under nitrogen for 26 hours, filtered and evaporated in vacuo.

The residue is chromatographed on 300 g of silica gel column (elution with chloroform and chloroform-ethyl acetate (3: 1)) to give 81 00 57 1 20

A solution of 9.18 g of (3S-trans) -N-benzyl-oxy-3-t-butoxycarbonylamino-4-methylazetidinone in 300 ml of 95% ethanol is stirred in a hydrogen atmosphere with 1.85 g of 10% palladium on carbon . After 141 minutes, the slurry is filtered and evaporated in vacuo. The residue is recrystallized from ether-hexane to obtain 5.12 g of the title compound.

D) (3S-trans -) - 3-t-Butoxycarbonylamino-4-methylazetidinone.

• · Λ 15 5 10 (

- 96 - 7.2 g of compound are obtained. Recrystallization from ether-hexane gives 4.18 g of the title compound compound | §§5p. B) (3S-trans-N-Benzyloxy-3-t-butoxycarbonyl-amino-4-methylazetidinone; A solution of 12.67 g of N-benzyloxy-t-bocthonone amide, 11.5 g of triphenylphosphine and 6.23 ml of diethylazodicarboxylate in 380 ml of tetrahydrofuran are stirred under nitrogen for 16 hours The solution is evaporated and chromatographed on a 900 g silica gel column Elution with chloroform-ethyl acetate (3: 1) yields 13.69 g of a compound from ether-hexane crystallizes to 9.18 g of the title compound C) (3S-trans) -3-t-Butoxycarbonylamino-1-hydroxy-4-methylazetidinone.

A solution of 4.98 g of (3S-trans) -3-t-butoxy-carbonylamino-1-hydroxy-4-methylazetidinone in 200 ral ethanol is treated with 132 ml of 4.5 M ammonium acetate and then 66 ml of 1.5 M titanium trichloride and stirred for 4.5 hours. The aqueous solution is diluted with an equal volume of 8% sodium chloride and extracted with ethyl acetate to obtain 3.48 g of crude product. Recrystallization from ether-hexane gives 3.3 g of the title compound.

E) (3S-trans) -3-Benzyloxycarbonylamino-4-methyl-azetidinone.

81 0057 1 τ - 97 -

A solution of 3.3 g (3S-trans) -3-t-butoxy-carbonylaminor4-methylzetidinone in 10 ml of dichloromethane and 10

ml of anisole are cooled to 0 ° C and 112 ml of trifluoroacetic acid are added. The solution is stirred for 90 min and evaporated in vacuo (benzene added three times and evaporated). 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 an hour at pH 6.5-7.5.

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

15 P) (3S-trans) -4-Methyl-2-oxo-3 - / "/ (phenylmethoxy) - carbonyl / amino / -1-azetidine sulfonic acid, tetrabutyl ammonium salt.

A solution of 600 mg (3S-trans) -3-benzyl-oxycarbonylamino-4-methylazetidinone in 2 ml of dimethylformamide is cooled to 20 ° C and 4 ml of 0.8 M sulfur trioxide in dimethylformamide are added. The solution is stirred at room temperature under nitrogen for 1 hour and poured into 80 ml of cold 0.5 M 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 tetrabutyl ammonium bisulfate are added. The resulting solution is extracted with four 75 ml portions of methylene chloride. The combined organic layer is washed with 8% aqueous sodium chloride, dried and evaporated in vacuo to give 1.54 g of the title compound.

30 G) / 3S- / 3α (Ζ), 4β / - / - 3- / / (2-Amino-4-thiazoleyl 1) - / _ (1-diphenylmethoxycarbony 1-1 -methyl-ethoxy) imino __ / acetyl_ / -amino / -4-methyl-2-oxo-1-azetidine sulfonic acid, potassium salt.

A solution of 1.54 g (3S-trans) -4-methyl-2-35 oxo-3- / / (phenylmethoxy) carbonyl / amino / -1-azetidine sulfonic acid, 81 00 57 1 J: * - 98 - tetrabutyl ammonium salt in 4 µl dimethylformamide is stirred in a hydrogen atmosphere for two hours with 800 mg / ml of alladladium on carbon. The catalyst is filtered and the filtrate stirred for 16 hours with 1.24 g (Z) -2-amino-α- ((1-diphydomethoxycarbonyl-1-methylethoxy) -5 imino-4-thiazole acetic acid, Q> 4 g N-hydroxybenztriazole 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 washes) is treated with 868 mg of potassium perfluorobutane sulfonate in 3 ml of acetone. Dilution with 75 ml ether gives 10 a solid, which is recovered by decanting the mother liquor,

triturating with ether and filtering to give 0.91 g of the title compound. The mother liquor is diluted with an additional 100 ml of ether to give a second amount of 0.45 g of the title compound.

15 H) / ~ 3S ~ / "” 3a (Z)> 45_7_7 ~ 3 (2-Amino-4-thiazolyl) / (1-carboxy-1-methylethoxy) imino_ / acetyl __ / amino _ / - 4-methy1-2- oxo-l-azetidine sulfonic acid, dipotassium salt.

A slurry of 140 mg of J_ 3S- / 3α (Z), 4β __ / _ / - 20 3-V (_ (2-amino-4-thiazolyl) / _ (1-diphenylmethoxycarbonyl-1-methyl- ¢ - *) is stirred ethoxy) imino / acetyl / amino / 4-methyl-1-2-oxo-1-azetidine sulfonic acid, potassium salt (first amount) in 0.5 ml anisole at -12 ° C under nitrogen and add 2.5 ml cold (-10 ° C) trifluoroacetic acid After 10 min, 10 ml ether and 5 ml hexane are added and the resulting slurry is stirred at -12 ° C for 5 min and allowed to warm to room temperature. centrifuged and washed twice with ether A solution of this solid in 5 ml of cold water is immediately adjusted to pH 5.5 with 0.4 N potassium hydroxide and then passed through an 80 ml HP-20AG column. Water provides 72 mg of the title compound in fractions 7-11 (10 ml) after evaporation (acetic nitrile added three times and evaporated) and trituration with ether, mp about 250 ° C (with decomposition).

Analysis calculated for C ,, H._Nc0oS „K_:

1y 15 D o Z Z.

35 C, 30.51; H 2.95; N, 13.69; S 12.53; K 15.28.

81 00 57 1

Ir - 99 -

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

NMR (D20) 1.46 (S, 6H), 1.58 (1H, d, j = 7} JÊf28 (1H, d, from q, = 7, 2.5), 4.67 (1H, d , £ 2 £ 6.95 ppm (S, 1H).

The remaining 1.22 g / "~ 3S - /" "3 (Z), 4 77" 3-5 / "/ (2-amino-4-thiazolyl) / (1-diphenylmethoxycarbonyl-1-methylethoxy) imino_ / acetyl / amino __ / - 4-methy1-2-oxo-1-azetidine sulfonic acid, potassium salt (harvests 1 and 2) is treated as above (4.2 ml anisole, 16 ml trifluoroacetic acid, 13 min. at -15 ° C Chromatography on a 300 ml HP-20AG column yields 694 mg of the title compound 10 in fractions 6-9 (60 ml) after treatment as above.

Examples 104-133

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Examples 134-135

When following the procedure of Example 70, but a compound listed in column I "uses" instead of / "~ 3S (Z) J-3 - /" / "(2-amino-4-thiazdyl) /" "/ 2 (diphenylmethoxy) -2-oxo-5-ethoxy / imino / acetyl / amino / 5-oxo-1-azetidine sulfonic acid, potassium salt, the corresponding compound of column II is obtained.

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Example 136.

/ ~ 3α (Ζ), 4α_7-3 - / "/ Γ (2-Amino-4-thiazolyl) (methoxyimino) acetyl _ / - amino / -4-methy1-2-oxo-1-aze tidinesulfonzqj | r, potassium salt .

5 A solution of 51.8 mg (cis) -4-methyl-2-oxo-3- / / (phenylmethoxy) carbonyl / amino-1-azetidine sulfonic acid, potassium salt and 51 mg of tetra-n-butylammonium bisulfate in 5 ml of water is added extracted with methylene chloride (four 10 ml portions) to give 41 mg of oil. It is stirred in a hydrogen atmosphere for 10 hours with 40 mg of 10% palladium on carbon in 4 ml of dimethylformamide. The catalyst is filtered and washed with 1 ml of dime thyformamide. Filtrate and washings are combined and stirred with 31 mg (Z) -2-amino-α- (methoxyimino) -4-thiazole acetic acid, 27 mg N-hydroxybenztriazole and 31.5 mg dicyclohexylcarbo-15 diimide for 16 hours. 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 41 mg of potassium perfluorobutane sulfonate. Dilution with 5 ml ether and filtration yields a solid. Chromatography on 40 ml HP-20AG provides Rydon positive material 20 in fractions 3-5 (20 ml) (elution with water). Evaporation and trituration with ether yield 23 mg of product as a hygroscopic solid.

Analysis calculated for ci () H12N506S2K: C 29.91; H 3.01; N 17.44; Found: C 29.30; H 3.31; N 16.66.

NMR (D2Q) 1.40 (3H, d, j = 7), 3.97 (3H, S), 4.46 (1H, apparent pentet,} = 7), 5.37 (1H, d,; 7), 6.97 ppm (1H, S).

Example 137 (3S-cis) -3-Amino-4-methyl-2-oxo-1-azetidine sulfonic acid.

A) t-Boc-1 allotreonine.

A suspension of 6.72 g of 1-allotreonine in 70 ml of 50% aqueous dioxane is treated with 9.45 ml of triethylamine and 18.1 g of t-butyl pyrocarbonate. The resulting mixture is stirred at 81 00 57 1 room temperature for 4 hours and then diluted with 70 ml of water and 140 ml of ethyl acetate. After thorough shaking, the layers are separated and the organic layer is washed with 3 ml of 2: 1 water: brine The combined water layers are then back extracted with 70 ml of ethyl acetate The water layer is cooled in an ice bath and 10% potassium bisulfite solution is added to pH 2.3 The acidified solution is extracted with ethyl acetate (four 150 ml portions). layers are dried over anhydrous sodium sulfate and the solvent is stripped to give 9.13 g of the title compound.

B) N-Methoxy-t-boc-1-allotreonine amide.

9.13 g of t-boc-1-allotreonine are dissolved in 85 ml of water and 41 ml of 1N potassium hydroxide solution. 5.22 g of methyl-xyaraine hydroxychloride and 8.67 g of 1-ethyl-3,3- (dimethylamino-propyl-1) -carbodiimide.HCl are added. The mixture is stirred at room temperature for 4 hours and then saturated with sodium potassium tartrate. The resulting mixture is extracted with ethyl acetate (four 150 ml portions) and the organic layer is dried over anhydrous sodium sulfate and the solvent is stripped to give 7.38 g of the title compound as a solid.

C) Met-Methanesulfony1-N-methoxy-t-boc-1-allotreonine amide.

7.32 g of N-Methoxy-t-boc-1-allotreonine amide is dissolved in 40 ml of pyridine and cooled to -20 ° C under nitrogen. 3 ml of methanesulfonyl chloride are added dropwise with a syringe over a period of 5 min. The resulting mixture is slowly warmed to 0 ° C and stirred at this temperature for 3 hours. 500 ml of ethyl acetate are added and the solution is washed with 250 ml of ice-cold 3N HCl solution and then with 100 ml of 5% NaHCO 2 solution. The ethyl acetate layer is dried over anhydrous sodium sulfate, the solvent is stripped off, and 8.64 g of the title compound are obtained as a white solid.

* - 109 - D}. (3S-cis) -3-t-Butoxycarbonylamino-1-methoxy-4-methylazetidinone,

8.64 g of O-methanesulfonyl-N-methoxy-t-5 boc-1-allotreonine amide are dissolved in 30 ml of acetone and solid potassium carbonate is added. The mixture is slowly heated to 65 ° C under nitrogen and stirred at this temperature for 1 hour. The reaction mixture is then filtered through Celite and the filter cake is washed with ethyl acetate. The filtrate is concentrated and the residue is taken up in 250 ml of ethyl acetate. The ethyl acetate solution is washed with 100 ml of 1N hydrochloric acid solution and 100 ml of 5% sodium bicarbonate solution. The ethyl acetate layer is dried over anhydrous sodium sulfate and the solvent is stripped to yield 6.63 g of crude product.

E) (3S-cis) -3-t-butoxycarbonylamino-4-methylsaturidinone.

1.35 g of sodium are dissolved at -50 ° C in 300 ml of liquid ammonia and 5.87 g of (3S-cis) -3-t-butoxycarbonylamino-1-methoxy-4-methylazetidinone are added dropwise via syringe. in 35 ml of tetrahydrofuran. Another 10 ml of tetrahydrofuran is used for rinsing. At the end of the addition, 100 mg of sodium are added. The mixture is stirred for an additional 5 min and then quenched by adding 3.35 g of solid ammonium chloride in one portion. The ammonia is blown off with a stream of nitrogen and 250 ml of ethyl acetate are added to the residue. After the solid is filtered off and washed with ethyl acetate, the solvent is stripped from the combined filtrate to yield 4.82 g of the title compound.

30 P) (3S-cis) -3-t-Butoxycarbonylamino-4-methyl-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt.

4.98 g / 3S, 4R-7-3-t-butoxycarbonyl-araino-4-methylzetidinone is dissolved in 30 ml of dimethylformamide. 11.9 g of pyridine sulfur trioxide complex are added and the mixture is stirred at room temperature under nitrogen at 81 0057. After stirring for 14 hours, an additional 1.8 g of pyridine sulfur trioxide complex is added. and stir for another 80 hours. The reaction mixture is poured into 75% pil 0.5 M monobasic potassium phosphate solution and washed with methylene chloride (three 5 ml portions of 300 ml). 8.45 g of t-butylammonium bisulfate is added to the aqueous solution and the mixture is extracted with methylene chloride. (four 300 ml portions) The combined methylene chloride layers are dried over anhydrous sodium sulfate and the solvent is stripped to give 10.76 g of the title compound as a gum.

G) (3S-cis) -3-Amino-4-methyl-2-oxo-1-azetidine-. ƒ sulfonic acid.

10.76 g (3S-cis) -3-t-Butoxycarbonylamino-4-15 methyl-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt, are dissolved in 50 ml of 95-97% formic acid and stirred under nitrogen for 4 hours. A small amount of product from a previous reaction is added as a seed and the mixture is stirred for an additional hour. The mixture is kept in a freezer for 16 hours and the frozen mixture is warmed to room temperature and stirred for an additional hour. The solid formed is filtered and washed with methylene chloride to give 982 mg of the title compound. The filtrate is diluted with 1 L of methylene chloride and kept at -20 ° C for 4 hours. The precipitate that forms is recrystallized from water-raethanol-acetone to give an additional 167 mg of the title compound. NMR (D4) 1.63 (3H, d, j = 6.5 cps), 1R (nujol) 1775cmV.

Example 138 (_ 3SV 3α (Z), 4a _ / - / - 3- £ / _ 2-Amino-4-thiazolyl) methoxyimino) acetyl _ / - 30 amino / - 4-methyl-2-oxo-1-azetidine sulfonic acid, potassium salt .

A solution of 201 mg (Z) -2-amino-α- (methoxyiraino) -4-thiazole acetic acid and 153 mg N-hydroxybenz-triazole monohydrate in 3 ml dimethylformamide with 206 mg dicyclo-35 hexylcarbodiimide is treated. The mixture is stirred at room temperature for 20 min. 81 0 0 5 7 1

* X

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stirred under nitrogen and a solution of 180 mg (3S-cis) -3-amino-4-methyl-2-oxo-1-azetidines-1-acidic acid and 0.14 ml of triis. ** ethylamine in 2 ml of dimethylformamide (use 1 ml more

* ... jC

- dimethylformamide before rinsing) and stir the mixture for 16 hours. The slurry is evaporated in vacuo, triturated with 12 ml of acetone, centrifuged and the liquid is treated with 338 mg of potassium perfluorobutane sulfonate. Dilution with 10 ml of ether and filtration yields a solid product which is chromatographed on 200 ml of HP-20 resin eluting with water. Fractions 18-30 (10 20 ml each) are combined and lyophilized to 274 mg of the title compound as hygroscopic solid.

Analysis calculated for ^ ¢) ^ 12 ^^ 6 ^ 2 ^ C 29.91; H 3.01? N 17.44?

Found: C 30.03; H 3.21; N 17.06.

NMR (D2Q) 1.40 (3H, d,} = 6.5), 3.98 (3H, S), 4.48 (1H, d of t, j - 6.4, 5.5), 5.36 (1H, d, j = 5.5) 6.97 (1H, S).

Example 139 (3S-trans) -3-Amino-4-methyl-2-oxo-1-azetidine sulfonic acid.

A) Treonine, methyl ester, hydrochloride.

Under a nitrogen atmosphere, a flask containing 500 ml of methanol is cooled to -5 ° C (ice / brine) and 130 ml of thionyl chloride (excess) is added to such an extent that the reaction temperature is between 0 and 10 ° C is held. After cooling again to -5 ° C, 59.5 g of 1-threonine are added and the mixture is allowed to come to room temperature and stir for 16 hours. The mixture is concentrated and vacuumed at 10 * torr for 2 hours to obtain a viscous oil. This material is used directly for the next step.

B) Treonine amide,

The crude product of part A is dissolved in 2.5 l of methanol and cooled to -5 ° C (ice / brine). The solution is saturated with ammonia gas, the cooling bath is removed and the sealed vessel is left to stand for 3 days. After removing most of the unreacted ammonia through the blower, add 100

g sodium bicarbonate and 50 ml water transfer the mixture to a viscous ol

The crude product of part B (which already contains the required amount of sodium bicarbonate) is diluted with water to a volume of 1 1. To this solution, 94 g (88 ml of 90% pure material) are added with rapid stirring over a period of 1 hour. benzyloxycarbonyl chloride as a solution in 80 ml of tetrahydrofuran. The reaction mixture is then stirred for an additional 16 hours and extracted with ethyl acetate (one 500 ml portion, two 250 ml portions). The combined extracts are dried over magnesium sulfate and concentrated. The crystalline residue is then dissolved in 250 ml of hot ethyl acetate and 300 ml of hexane are added and boiling is carried out until a clear solution is reached. Cooling and filtration of the crystalline mass after drying yield 104 g of the title compound.

D) Benzyloxycarbonyltreonine amide, O-mesylate.

Under an argon atmosphere, 100 g of benzyl oxycarbonyltreonine amide are dissolved in 400 ml of anhydrous pyridine and cooled in an ice / salt bath. To this solution is added 36.8 ml (54.5 g) of methanesulfonyl chloride over a period of 25 minutes while stirring. After stirring for 2 hours, 0.3 equivalents of methanesulfonyl chloride are added. The reaction is then stirred for 1 hour and poured into a mixture of 1.5 l of ice and 2 l of water. The resulting slurry is stirred for 30 min.

o stirred and filtered. Drying the crude product at 60 ° C for 16 hours in a vacuum oven yields 109 g of the title compound.

E) N-Sulfonylbenzyloxycarbonyltreonine aride O-mesylate, tetrabutyl ammonium salt 35

A solution of 17.8 ml of 2-pikoline in 90 ml of 81 00 57 1 * J5 - 113 - methylene chloride is cooled at -5 ° C (ice brine) and 5.97 ml of chlorosulfonic acid are added to such an extent that the internal reaction temperature is kept below 5 ° C. The resulting solution is added via cannula to a suspension of 7.56 g of 5-benzyloxycarbonyltreonine-one-half-mesylate in 120 ml of methylene chloride. The resulting heterogeneous mixture is refluxed for 16 hours to obtain of a clear solution. The solution is poured into 500 ml of pH 4.5 phosphate buffer (0.5 M) and further diluted with 120 ml of methylene chloride. The separated organic layer is then washed once with 100 ml of buffer solution and the combined aqueous phases are treated with 10.2 g of tetra-n-butylammonium hydrogen sulfate and extracted with methylene chloride (one 300 ml portion and two 150 ml portions), After drying of the combined organic extracts on sodium sulfate, the solution is concentrated to give 12.7 g of foam.

F) (3S-trans) -3-amino-4-methyl-2-oxo-1-azetidinesulfonic acid.

A mixture consisting of 5.52 g of potassium carbonate in 20 ml of water and 160 ml of 1,2-dichloroethane is heated to a reflux condenser and 15.5 mmol of N-sulfonylbenzyloxycarbonyltreonine amide, O-mesylate, tetrabutyl ammonium salt are added in 20 ml of 1,2-dichloroethane (20 ml is used as a rinse).

After heating to a reflux condenser for 30 minutes, the mixture is poured into a separatory funnel, diluted with 50 ml of water and 100 ml of methylene chloride and the phases are split. The resulting organic phase is dried over sodium sulfate and concentrated to crude (3S-trans) -3-benzyloxycarbonylamino-4-methyl-2-oxo-1-azetidin-30-sulfonic acid, tetrabutyl ammonium salt. The crude azetidinone is treated in 250 ml of ethanol with 0.8 g of 5% palladium on carbon catalyst and hydrogen is bubbled through the solution. After 90 minutes, the mixture is filtered through Celite using 50 ml of ethanol as a rinse. Addition of 1.2 ml of formic acid 35 to this solution causes an immediate precipitation of 8 1 00 57 1 - 114 - - 114 -

the title zwitterion, which is filtered after stirring for 1 hour to obtain 1.1 g of product, which is scented for 1 hour after drying. A second crop of product is obtained upon concentration of the filtrate and addition of more formic acid 5 to give 1.3 g of the title zwitterion.

Melting point> 218 ° C (decomposition), / aJQ = -41.1 (Ol, H 2 O). NMR (D2Q) 1.58 (3H, d, j * 7), 4.80 (2H, M).

Examples 140-143

Following the procedure of Example 138, but use (3S-trans -) - 3-amino-4-methyl-2-oxo-1-azetidine sulfonic acid instead of (3S-cis) -3-amino-4-methyl -2-oxo-1-azetidine-sulfonic acid and an acid listed in column I of the table below used instead of (Z) -2-araino-a- (methoxyimino) -4-thiazole-acetic acid, the corresponding compound is obtained from column 15 II of the table below.

i ".

81 00 57 1 - 115 - I 8 0 1 Μ Ir * HO> ιΛ S g Ρ, 0.3l \ * WI Η>, + »N> ιΛ Η I, -Η 03 Η S 03 ΓΉ I, η Η ' Τ * §hL 3 I o X Θ H Ό.

ι o

0 »G H Ό 0) H P G O

ι; a ms S ms a Ν 11B 'vïK η x i \, ° K7 - K.H αα I>, COG

§ H ι — Ϊ lx

H X ΕΚ. οι 0) «3 I 03 Ό w O G G Ö G G -Η O n j) η Ό i, 0) S H - \ h, a +> u ι> K o) 03 Λ 1 NO m 4J H id m ®> t I

G - »H, AKi3> H 3 M> 1 NI + JGH 0) O> ι Ο <H 43 a H 33 H 3> t WP GOO), 0) G · 0« Η -HG l JV .. * » J Ki Ji ι Ο +) * Ma δ ° Mi ft Mm? 5 m Η O, I> 1 X hS f MS '? CQ. (d «H Ü> i« H J V & 8 ^ * W) 8 N ^ O), mK m «

0! I

λ to Η «Η O> ι ι n Η Ο <N 0 X, NO +) <C ι G Ή N 3 λ ι a +) H +) 1> 1H ^ ί ® ι -pa ο 0) to hole ι * ^ U "I 00 - XW * +> g il

Mia G cm I ft O CO HGH, n CrjH I, i § «H CM> i I -P +> hc Φ> | 3 g 43 ft a +> +) o 0) HX a 0) ο ι a Ο Ό * 03 «G. I * * - hK,« · e -¾1 +> a Jp 3, I 3 3 O 3 IK, O, - GO CM N 1, Η N r, s ι Mi § kilft A * V AS · "K>, u K gu, 1+) 3. Yes 3 K, ® 3 K, H 3 i Ü N out c 0«. 0 <w - GHNH 3 ^ a οι bho> cn> tc. XH n | 0 Ό IPH CO Ό +), n> i ffl i S3 mK a}> i N CQ. C CO '·> * 0) OG «Η <HH«, Λ Η Ό + +) 3 0) WI 03 H 8 CM 0) +), n, t GC UM3 0 I Ο Η P CO G -P 0), η Η 0) Ό Mi S § I ι a,) saK * s § s * a - «ani, 3 3 ON , (MXI) Ο H CM I> i 1 ~ MO MMS, η oan I, 3.0 C MlK? M * ft S MSc - ρ G 0) 8 0) Ό 0) 1 Η H>, HKX o NG. 0) «+) Μ Λ I 0 X 0 Ή. I« Κ, ι Ip WAS *> i 3 CM GN) OG Η xn> »yh λ an 33 ao Q) ~ e ι H 0) 'tf> i 0 ), w GN ίκ NI \ I Pl \ .ι ο) I Ö ft 0 1 H c ft H «ra id oc • H a • H> 1 X 0 M T3 ->« 3 Λ H - G 1 τ »8 H> N oach ft 8 an ι a CM -w) x - »+) NI w M 3 U 3) 3 ~ NHG> t τι +) H 0) N ao X 0) Ο Ή oo ö τ! Η 43 ε -ρ r.7> κι 8 Ο) G λ Η Τ3 Η 0) Ο β ο!> Ο wr

CM

00 81 00 57 1 * t - 116 - 5 Example 144 / 3S- / 3α (Ζ), 4β _ / _ / - 3- / 7 (2-Amino-4-thiazolyl) / '7 1,1-dimethyl-2 - / (4-nitrophenyl ') methoxy / -2-oxoethoxy / jajino / acetyl / amino / -4-thy1-2-oxo-1-azetidine sulfonic acid, potassium salt. - Μ & β To a slurry of 0.36 g (3S-trans) -3-amino-4-methyl-2-oxo-1-azetidine sulfonic acid (see example 139) in 30 ml dry dimethylformamide, add under nitrogen at 26 ° C 309 p.1 triethylamine. After about 5 minutes a clear solution is obtained and 0.816 g of (Z) -2-amino-aV / 1,1-dimethyl-1-2- / (4-nitrophenyl) methoxy-2-oxoethoxy / imino is added. Β-thiazole acetic acid, followed by 0.334 g of N-hydroxybenztriazole and 0.453 g of dicyclohexyl carbodiimide. The mixture is stirred at 26 ° C for 12 hours, after which the solvent is removed in vacuo and the residue is triturated with 30 ml of acetone. After stirring for 5 min, the solid is removed and the filtrate treated with 3.680 g of potassium perfluorobutane sulfonate in 5 ml of acetone. Addition of about 40 ml of ether gives a precipitate which is collected and dried in vacuo. Yield 1.073 g, second crop, 0.066 g, total 1.14 g. Analysis calculated for C-H-N-N-O-S-K 1 H-O 2U 21 b 1U 2 2 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. Example 145 25 w / _ 3a (Z), 4 <x _ / - 3- / / (2-Amino-4-thiazolyl) ((1-carboxy-1-methyl-ethoxy) imino / acetyl / amino-4-methyl- 2-oxo-1-azetidine sulfonic acid, potassium salt. 30 A) 3 3a (Z), 4a __ / - 3- / ((2-Amino-4-thiazolyl) /> (1-diphenylmethoxycarbonyl-1-methylethoxy) imino> _ / acetyl> J / ainino-4-methyl- 2-oxo-1-azetidine sulfonic acid, potassium salt. A solution of 201 mg (cis) -4-methyl-2-oxo-3-LL (phenylmethoxy) carbonyl / amino / -1-azetidine sulfonic acid, tetra-butylammonium salt (prepared from the corresponding potassium salt of Example 98 as described in Example 136 ) in 5 ml dimethyl-8100571 ♦ 117-formamide is stirred in a hydrogen atmosphere with 90 mg 10% palladium on calcium carbonate for 2 hours. The pipette is filtered and the filtrate stirred under nitrogen for 16 hours with 146 mg of (Z) -2-amino-> mm a - / (1-diphenylmethoxycarbonyl-1-methyl thyoxy) imino-4-thiazoleazine Acid, 73 mg dicyclohexylcarbodiimide and 51 mg N-hydroxybenztriazole. The slurry is evaporated in vacuo and triturated with 4 ml acetone.

The slurry is filtered and the solid washed twice with 2 ml portions of acetone. Filtrate and washings are combined and treated with 113 mg of potassium perfluorobutane sulfonate. Dilution of 10 with 24 ml of ether yields a solid which is centrifuged off and washed three times with ether to yield 186 mg of the title compound.

B) / _ 3α (Z), 4a _ / - 3- / / _ (2-Amino-4-thiazolyl) / _ 1-carboxy-1-methylethoxy_ / imino __ / acetyl_ / amino _ / - 2-methyl-4-oxo -1-15 azetidine sulfonic acid, potassium acid (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 20 in 0.6 ml distilled anisole is cooled to -12 ° C and 3.0 ml distilled trifluoroacetic acid is added at -10 ° C. The solution is stirred for 10 minutes and 12 ml of ether are added, followed by 6 ml of hexane. After 5 min at -10 ° C and 15 min stirring at room temperature, the solid is centrifuged and washed four times with ether to give 141 rag.

This is dried in vacuo, powdered, dissolved in 5 ml of cold water and immediately adjusted to pH 5.6 with 0.4 N potassium hydroxide. The solution is passed over a 100 ml HP-20AG column and eluted with water. Fractions 8-12 (10 ml) are combined and evaporated in vacuo (acetic nitrile is added three times and evaporated). The residue is triturated with ether to give 101.7 mg of product as a hygroscopic solid.

Analysis calculated for C ^ Hj ^ NgOgS ^ K: C 30.51? H 2.95; N 13.69? S 12.53; K 15.28; 35 Found: C 30.11? H 3.26? N 13.35; S 12.12? K 15.02.

81 0 0 5 7 1 ï - 118 - 5

Example 146 ^ ½. / 3S- / 3α (Z), 4g / / -3- / / (^ amino- ^ thi ^ zolyl) / (1-carboxy-1-methyl-

87.3 mg 7 / 3S ~ / _ 3α (Z), 4β __ / - 3- / £ (2-Amino-4-thia-zolyl) / (1-carboxy-1-methylethoxy) imino_ / acetyl_ / amino _ / - 4-methyl-2-oxo-1-azetidine sulfonic acid, dipotassium salt (see example 103) is dissolved in 1.38 ml water, cooled to 0 ° C, treated with 0.34 ml

IN hydrochloric acid and the resulting crystals are centrifuged off. The wet solid is dissolved in methanol, filtered, concentrated to about 0.5 ml and mixed with 1 ml of water to give 55.9 mg of the title compound.

Example 147 / _ 3S-f_ 3α (Z), 4β __ / _ / - 3- / (2-Amino-4-thiazolyl) / (1-carboxy-1-me-15 thylethoxy) imino _ / - 4-methy 1- 2-oxo-1-azetidine sulfonic acid, sodium salt.

A sample contains 99.7 mg 3SV 3α (Z), 4β __ / - 3 - / _ / (2-amino-4-thiazolyl) / _ (1-carboxy-1-methyl-ethoxy) imino_ / ace-20 tyl / amino / -4-methyl-2-oxo-1-azetidine sulfonic acid is mixed with 0.207 ml of 1N sodium hydroxide and the resulting mixture is gently heated to dissolve the residual solid. Water is azeotrope removed with acetic nitrile and the residue is recrystallized from a mixture of 0.5 ml methanol (ter

Solution of the residue) and 1 ml of acetic nitrile, whereby 81.8 mg of a solid are obtained. A second recrystallization from 0.8 ml of methanol yields 47.9 mg, a third from 0.24 ml methanol and 0.24 ml absolute ethanol yields 44.8 mg and a fourth from 0.225 ml methanol and 0.225 ml absolute ethanol yields 38.8 mg op. The solid is dried at 20 ° C and 0.01 mm Hg for 18 hours and then equilibrated with atmospheric moisture for 24 hours to give the title compound 40.9 mg.

8 1 0 0 57 1 .35 119 - t

Example 148! _ 3S - / _ 3aj [Z) »43 _ / __ / - 3 - / _ / _ (2-Amino-4-thiazolyl) / _ (1-carboxy-1-methyl-ethoxy) imino __ / - 4 -methyl-2-oxo-1-azetidium-sulfononic acid, disodium salt.

5 A sample assivan 3.00 g (_ 3S- / 3α (ζ), 4β _ / _ / - 3- / _ / _ (2-amino-4-thiazolyl) [_ (1-carboxy-1-methyl-ethoxy) imino_ / -acetyl / amino-4-methyl-2-oxo-1-azetidine sulfonic acid (see example 146), is suspended in 30 ml of water and triturated with 1 N sodium hydroxide, which requires 12.0 ml and is obtained in 10 title disodium salt The pH is lowered to 6.5 by adding a little Dowex 50W-X2 (H +) The mixture is filtered and the filtrate diluted to 66.3 g with water An amount of 6.63 g is added removed for other purposes The residual filtrate is lyophilized to give 2.38 g of solid Partial equilibration (24 hours) with atmospheric moisture yields 2.54 g of the title compound.

Examples 149-151

Following the procedure of Example 138, but using a compound listed in column I of the table below instead of (Z) -2-amino-α- (methoxyimino) -4-thiazole acetic acid, the corresponding compound specified in column II.

81 00 57 1 - 120 £ Example i s ,, fKii CM Η Λ I> i P> 1 5 U. . 5 3K | i ai> 1 h w S C> 1 i ai β Mi Ή · Ρ I N 3 P ai (¾ 3 * H -H ïï x l <

P 8 N

v | I CM 8 M? CS Λ1 Vo'S .mts o | -p -p ^ 17. i «η Η Ή | V, P -> 1 * 0. > 1 CM A a »Ν, β, I P H HKs + i 3 Ό SC Η H 0> i>. 3 3 P 0 Λ P 3 O

P 0) P co ai

Mi - 4J -, <]) X N «al - I β CO, co I, -, oK

ai ai ιρ Ό 3 * 3 U N 0) 0 3 1H P σ »ε * ί w o, m m I I 1 vj« p i 0) lp * - I Sj o ». V CV I -PI cj * ε hp I, 3> i 3 OVC 3 X ON 0> P Λ 3 • H> t P · η fl C β Ή 1 O. ON m λΚ 3 * · p lc, nmp ci kii & 8 VI S? N § I .0 3, Λ • vkc PV i -pa) I ea) ft oie i4 e rH fij Ή «> 1“ E - fi »P 3 II 0 0.> ιΛ X §PO <0 IP, U CM 3V I lp HIH>, CM>, A, - 3 P, ρ ai VS? , fO Η Ί I, ο.ι VS'V * VS gg, Vi 8 * PN 1, -h ε g I, 'Ρΐ'ν,' Ρ VI h I Ο Η (β ro X> ix, I 0 - PK, i »-. | CM Ο P Γν, I Its 3 K, H 3 3 1> i N ίγ o fi s - sa> o -. -P.ip ip *« g'vs ^ - «Ο w β aaa>, co 3 · Ρ c I. 3 ε -p \ | h. 3 Ό I W'V.'HWA | P mpha) 1, 0)> i N \ | S c «0 o X 3 P Ο Ή 3 Ή 8 O Ό, ίο N Ακι! »Η · Ρ CM> i H 1 4-1 (0 h axis x> 1 o A itS * P Η P a)> 1 3 I 3 3 P <φ N 1 N., °, vl 1¾ i. Ο HV -η a ViS> K | 3 ro η ή, I> i P VB 8 Ki «1 3 (0 * p Mi Ü I o -PXX> 1 0 (¾ 3 I - -P CM 8 NI, η ( 0 rP I. p> 1> | 4) AI ft PW -P <u, η ft ε Ι, ιι VJ * P Mi | <H> 1 <p I 3> ι Ο Ο P β X Λ 3 3 Ο P 3 PI 3 N 3 cm, O 3 <P, I kn 11—., 1-p CM | ip NO> 1 ItS ν | · ρ -P § kiSS 8 kï5 3 SI, 3 Ν, Λ vj 0) it! V, I Η Ό i 8 -POIAE 3 p -P -P tf a) I ε «g« -Η 3 I s P, YK | P co ip 3 k> i 3 CM CNIO 3 P Λ · η> i P -P Λ 3 .NPO 3 3 3 I Η 3 Mi> i 3 3 NI, * P 3 Λνΐ N 3 II «, Λ \ PN, I 3 8 ft O 1 * ri 5 ΪΒ ψ * (Ö

σι o H Mi in in H H H

8100571 5 r s 121 -.

Example 152 ν-:: / 3S- / 3α (Ζ), 4α_ / / -3- / / (2-Amino-4-th £ azolyl) / ~ C 1-carboxy-1-me-_-_. Thylethoxy) imino / acetyl / amino / 4 * -methyl-2-oxo-1-azetidine sulfonic acid, potassium salt (1: 2). , -7 'A) / _ 3S- / 3α (Z), 4a __ / _ / - 3- / / _ (2-Amino-4-thiazolyl) / (1-diphenylmethoxycarbony 1-1 -methyl-ethoxy) imino_ / acety 1 / amino-4-methyl-2-oxo-1-azetidine sulfonic acid, potassium salt.

10

O

15 20 s - 25

A solution of 440 mg (Z) -2-amino-aV (1-carboxy-1-methylethoxy) imino-4-thiazole acetic acid and 153 mg N-hydroxybenztriazole monohydrate in 3 ml dimethylformamide is treated with 206 mg dicyclohexylcarbodiimide. The mixture is stirred at room temperature for 30 min under nitrogen and a solution of 180 mg (3s-cis) -3-amino-4-methyl-2-oxo-1-azetidinesulfonic acid (see example 137) and 0 is added. Add 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 about 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 3 ml portions). The filtrate and washes combination is treated with 338 mg of potassium perfluorobutane sulfonate. Dilution with 30 ml of ether gives a gummy solid which slowly solidifies. The solid is filtered off and washed with ether to give 656 mg of the title compound. B) ΓBS - / "* 3 α (Z), 4 * 7 Ί-1-ΓΓ (2-Amino-4-thiazolyl) / _ (1-carboxy-1-methylethoxy) imino_ / acety 1_ / amino __ / - 4 -methyl-2-oxo-1-azetidine sulfonic acid, potassium salt (1: 2).

A slurry of 656 mg / _ 3S-V 3α (Z), 4a _ / _ / - 3- / f_ (2-amino-4-thiazolyl) / _ (1-diphenylmethoxycarbony-1-methyl-ethoxy) imino / acetyl_ is cooled / amino-4-methyl-2-oxo-1-azetidine sulfonic acid, potassium salt in 2.3 ml of distilled anisole to -12 ° C and add 11.5 ml of trifluoroacetic acid (pre-cooled to -10 ° C). The solution is stirred for 15 minutes and 46 ml of ether are added, followed by 23 ml of 81 00 57 1 of 122-hexane. After 5 min. At -10 ° C and 15 min. Stirring at room temperature, the solid is filtered off and washed with ether under ......: ¾

obtaining 457 mg of very hygroscopic gum. This is dissolved in 6 ml of cold water and immediately adjusted to pH 5.6 with 0.4 N

iSfrir - potassium hydroxide solution. The solution is passed over 200 ml of HP-20 resin and eluted with water. Fractions 7-11 (50 ml each) are combined and lyophilized to 239 mg of the title compound as a solid.

Analysis calculated for C 13 H 15 O g N 5 S 2 K 2 * Js H 2 O: 10 Ο 15 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, d,; = 75), 1.46 (6H, S), 4.48 (1H, d of t, - - 75, 5.5), 5.34 (1H , d, j - 5.5), 6.96 ppm (1H, S).

Example 153 (+) - 3-Amino-4,4-dimethyl-2-oxo-1-azetidine sulfonic acid.

A) (+) - 4,4-Dimethyl-2-oxo-1-azetidine-tert-butyl diphenylsilan.

A solution of 40.5 ml of t-butyl chlorodiphenyl-vsilane in 112 ml of dimethylformamide is cooled to 0 ° C. 22 ml of triethylamine are added to this. A solution of 12.87 g of 4,4-dimethyl-2-azetidinone in 25 ml of dimethylformamide is added dropwise over 10 minutes to the cooled triethylamine solution. The resulting cloudy solution is stirred at 5 ° C under argon for 18 hours. The mixture is poured into 400 ml of ice water and extracted with three 150 ml portions of 2: 1 ether ethyl acetate. The combined extracts are washed with four 100 ml portions of 0.5M potassium phosphate monobasic buffer, one 150 ml portion of sodium bicarbonate solution, two 150 ml portions of water and one 150 ml portion of saturated sodium chloride solution. The solution is dried over sodium sulfate and concentrated in vacuo to 33.03 g of the title compound as a solid.

B) (+) - 3-Azido-4,4-dimethyl-2-oxo-1-azetidine-35 t-butyldiphenylsilan.

81 0 0 5 7 1 - 123 - - 123 - ir 4

The mixture is stirred at -50 ° C under argon in a 100 ml three-necked flask, a solution of 4.25 ml of J. 6M n-butyl lithium in hexane and 11 ml of dry tetrahydrofuran. A solution of 0.083 g of triphenylmethane in 1 ml of tetrahydrofuran is added. The resulting solution is cooled to -60 ° C and 1.0 ml of diisopropylamine is added dropwise with a syringe. It is stirred for 15 minutes and then cooled to -78 ° C. A solution of 2.3 g (+) - 4,4-dimethyl-2-oxo-1-azetidine-t-butyl-diphenylsilane in 8 ml of tetrahydrofuran is slowly added with a syringe. The resulting solution is stirred at -78 ° C for 20 min, during which time heavy precipitation occurs and uniform stirring becomes difficult. A solution of 1.33 g of p-toluenesulfonyl azide in 5 ml of tetrahydrofuran is added dropwise. The resulting mixture is allowed to stir at -78 ° C for 20 min and 2 ml of trimethylsilyl-15 chloride are added dropwise. The reaction mixture is warmed to room temperature and stirred for 1 hour. The mixture is then cooled to 0 ° C and poured into 150 ml of 0 ° C ethyl acetate. Sufficient 0.5 M monobasic potassium phosphate buffer is added to clarify both the water layer and the organic layer. The two layers are separated and the organic layer is washed with three 150 ml portions of 0.5 M monobasic potassium phosphate solution, one 150 ml portion of sodium chloride solution and one 150 ml portion of saturated sodium chloride solution and dried over sodium sulfate. The solution is concentrated in vacuo to 2.83 g of oil, which, upon rubbing with hexane, yields 1.67 g of the title compound as a solid.

C) (+) - 3-Azido-4,4-dimethyl-2-oxo-1-azetidine.

1.52 g (+) - 3-30 azido-4,4-dimethyl-2-oxo-1-azetidine-t-butyldiphenylsilane are dissolved in 25 ml vinegar vacuum nitrile in a 50 ml three-necked flask. 0.25 ml of 48% hydrofluoric acid is added to this solution with stirring. The mixture is stirred at room temperature and a portion of 0.5 ml of 48% hydrofluoric acid is added every 60 minutes until a total of 3.25 ml of 48% hydrofluoric acid is added after 6.5 hours. The reaction mixture is then cooled to 0 ° C, neutralized 81 00 57 1 with saturated sodium bicarbonate and extracted with 120 ml ethyl acetate. The organic layer is then washed with 100 ml of water and 100 ml of saturated sodium chloride solution and dried over sodium sulfate. The dry solution is concentrated in vacuo to 1.34 g of oil. This crude oil is chromatographed on 27 g of silica gel with hexane followed by 33% ethyl acetate in hexane to obtain 0.358 g of the title compound as a solid.

D) (+) - 3-Azido-4,4-dimethyl-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt.

At 0.100 g (+) - 3-azido-4,4-dimethyl-2-oxo-1-azetidine, 2.8 ml of 0.5 M dimethylformamide sulfur trioxide complex are added at 0 ° C under argon. This mixture is allowed to warm to room temperature and stirred for 45 min. Then the solution is poured into 20 ml of 0.5 M pH 5.5 monobasic potassium phosphate buffer.

It is washed with three 20 ml portions of methylene chloride (discarded) and 0.237 g of tetrabutyl ammonium hydrogen sulfate are added to the aqueous solution. It is extracted with four 20 ml portions of methylene chloride and the combined organic extracts are washed with 20 ml of 8% sodium chloride. The methylene chloride solution is dried (sodium sulfate) and concentrated in vacuo to 0.31 g of oil, which is 50% dimethylformamide and 50% title compound by nmr.

E) (+) - 3-Amino-4,4-dimethyl-2-oxo-1-azetidine sulfonic acid.

A solution of 0.155 g (+) - 3-azido-4,4-dimethyl-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium in 0.6 mol of methanol is hydrogenated for 20 min. At 1 atmosphere above 10% palladium on carbon . The catalyst is filtered off and rinsed with methylene chloride, which is combined with the methanol solution. This clear solution is treated with 0.123 ml of 97% formic acid. When the acid is added, the solution immediately becomes cloudy. After standing at 5 ° C for 1 hour, the solid is filtered off to give 0.066 g of the title compound with melt

point 200-202 ° C (with decomposition) NMR (D20) 1.64 (3H, S), 1.68 (3H, S), 4.42 (1H, S), IR (KBr) 1765 cm 5 Example 154 / ~ 3 + (Z W-3 -f ~ [_ (2-Amino-4-thiazolyl) (methoxyimino) acetyl] / amino --- 4,4-dimethyl-2-oxo-1-azetidine sulfonic acid, potassium salt.

A solution of 50 mg N-hydroxybenztriazole hydrate and 0.323 mmol (Z) -2-amino-α- (methoxyimino) -4-thiazole acetic acid in 0.5 ml dimethylformamide is treated with 67 mg dicyclohexylcarbodiimide at room temperature under argon. The resulting mixture is stirred for 1 hour, to which 57 mg (+) - 3-amino-4,4-dimethyl-2-oxo-1-azetidine sulfonic acid (see example 153) is added as a solid, followed by dropwise addition of 0.05 ml of triethylamine. The reaction is stirred at room temperature for 16 hours. The dimethylformamide is removed under high vacuum at 30 ° C and the residue is slurried with 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 followed by ether are added to the filtrate. Trituration of the resulting gum with ether yields 40 mg of a tan solid which is chromatographed on a 70 ml HP-20AG column. Elution with water gives 20 mg of the title compound in fractions 16-40 (5 ml) after evaporation, trituration with 1: 1 acetone-hexane and drying. Melting point 225 ° C (with decomposition).

Analysis calculated for C ^ jH ^^ N ^ OgS ^ K

Found: C 31.80; H 3.40, N 16.86; S 15.43; C, 29.47; H 3.48; N 14.98; S 13.35.

Example 155 (+) - 4,4-Dimethyl-2-oxo-3- / (phenylacetyl) amino / / - 1-azetidine sulfonic acid, potassium salt.

A solution of 45 mg of N-hydroxy-benztriazole hydrate and 40 mg of phenylacetic acid in 0.5 ml of dimethyl-81 00 57 1 <- 126-5 formamide under argon is treated at room temperature with 61 mg of dicyclohexyl carbodiimide. The resulting mixture is stirred for 1 hour and 52 mg (+) - 3-amino-4,4-dimethyl-% oxo-1-azetidine sulfonic acid (see Example 153) is added as the first ester, followed by dropwise addition of 0.04 ml of triethylamine. The reaction is stirred at room temperature for 24 hours. The dimethylformamide is removed under high vacuum at 30 ° C and the residue is slurried with acetone and filtered. Potassium perfluorobutane sulfonate is added to the filtrate, ether is added and the mixture is cooled. The resulting solid is washed with acetone and hexane and dried to yield the title compound as a powder. (/) Analysis calculated for C 13 H 15 N 2 O 5 SK: C 44.55, H 4.32; N 8.00; S 9.15; K 11.16; Found: C 43.83; H 4.16; N 7.96; S 8.76; K 11.43. NMR (D2Q) 1.33 (S, 3H), 1.58 (S, 3H), 3.68 (S, 3H), 4.70 (S, 1H), 7.56 ppm (Wide S, 5H) . Example 156. (3S-trans) -3 - / - (2-Amino-4-thiazolyl) oxoacetyl / amino - / - 4-methyl-2-oxo-1-azeididine sulfonic acid, potassium salt. r ~> 25 O 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), 2.14 g (2-amino-4) are added. -thiazolyl) glyoxylic acid, triethylamine salt. After stirring for 0.5 hour, a solution of 1.08 g (3S-trans) -3-araino-4-methyl-2-oxo-1-azetidine-sulfonic acid is added (see example 139) and 1.92 ml of triethylamine in 5 ml of dry dimethylformamide to 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 chromatographs on 200 ml Dowex 50 X 2-400 resin (K + form). When eluted with water (15 ml fractions), the crude product is collected in fractions 13-27 (3.37 g). Chromatography on 200 ml HP-20 resin and elution with water (15 ml fractions) yields the desired product in fractions 18-25. Removal of water in 8100571 4 * -127 vacuum yields the title compound as an amorphous powder.

• aisar- · ,,.

Analysis calculated for C 8 H 19 N 2 OG S K (37 ^ 42): C 29.02; Η Τ, 44} 1 ^ 5.04; S 17.22; K 10.50; Found: C 28.87; H 2.62; N 14.85; S 15.09; K 10.81.

- Mr.

Example 157 3S (RX) / -3V / / (Aminoacetyl) amino / phenylacetyl / amino / - 2-oxo-1-azetidine sulfonic acid, potassium salt trifluoroacetate (1: 1).

Deprotection of / 3S (RX) _ / - 3- / ////.//. (4-methoxyphenyl) methoxy / carbonyl / amino / acety l / amino / phenylacety 1 / amino-2-oxo-1-azetidine sulfonic acid, potassium salt (see Example 127) using trifluoroacetic acid and anisole to provide the title compound at melting point 165 ° C, with decomposition.

Example 158 (3S-trans-) -3-Methoxy-4-methyl-2-oxo-3- / f- (phenylmethoxy) carbonyl-amino-1-azetidine sulfonic acid, potassium salt.

A) (3S-trans) -4-Methyl-3-methoxy-2-oxo-4 - / - (phenylmethoxy) carbonyl / amino / azetidine.

A solution of 2.5 g or 0.0106 mol (3R-trans) -4-methyl-2-oxo-3- / / (phenylmethoxy) carbonyl / amino-azetidine (prepared from d-threonine containing 12, 6% yield, essentially as described for the racemic cis isomer in Example 98C) in 112 ml 4% borax in methanol to 0 ° C and add 3.0 ml t-butyl hypochlorite. After 20 minutes, the solution is poured into 1 L of cold water and extracted with two 750 ml portions of cold ethyl acetate. The organic layer is washed with cold water (two 750 ml portions), saturated brine, dried and evaporated to 3.05 g of crude N, N * dichloramide.

A solution of 426 mg of lithium methanolate in 20 ml of dry methanol is cooled to -78 ° C and diluted with 40 ml of dry tetrahydrofuran. In the course of 00 57, 1 - 128 -% is added via a syringe. -x of 30 sec. at -78 ° C add a solution of the above chloramide in 20 ml of tetrahydrofuran. After 20 minutes at -78 ° C, 2 ml of acetic acid and 2 ml of trimethylphosphorus rt are added. After 40 min. At room temperature, the solution is poured into 500 ml of water and extracted with two portions of 300 ml of gath acetate. The organic layer is washed with water, dried and evaporated to an oil. Chromatography on a 200 ml silica gel column and eluting with 3 s of chloroform sethylacetate gives a total of 1.25 g of the title compound.

10 ', b) (3s-trans) -3-Methoxy-4-methyl-2-oxo-3- / / (phenylmethoxy) carbonyl / amino / -1-azetidine sulfonic acid, potassium salt.

Q

A solution of 800 mg or 0.00303 mol (3S-trans -) - 4-methyl-3-methoxy-2-oxo-4 - / - {(phenylmethoxy) -15 carbonyl / amino / azetidine in 2 ml is cooled dimethylformamide to 0 ° C and add 4 ml of dimethylformamide sulfur trioxide complex. After 1 hour at 0 ° C and 4 hours at room temperature, the solution is poured into 80 ml of 0.5 M monobasic potassium phosphate (adjusted to pH 5.5) and extracted with methylene chloride (two 50 ml portions discarded). The water layer is treated with 1.04 g of tetrabutyl ammonium sulfate and extracted with dichloromethane to obtain 1.42 g of oil. This is dissolved in acetone and treated with 1.04 g of potassium perfluorobutane sulfonate in 10 ml of acetone. Dilution with 250 ml of ether and extensive rubbing of the oily solid yields 584 mg of crude product. Chromatography on 200 ml HP-20AG yields 418 mg purified product in fractions 13-16 (100 ml) eluting with 1 L water and then 9: 1 water acetone. Trituration of 114 rag of this material with ether gives 104 mg of the analytical sample.

Analysis calculated for H14N2O7SK.H2O: C 39.06; H 4.04; N 7.01; S 8.03; K 9.78.

Found: C 38.91; H 3.62; N 6.91; S 8.06; K 9.51.

NMR (D20) 1.33 (3H, d, j = 7), 3.46 (3H, S), 4.22 (2H, d of d, j = 6), 5.18 (2H, S), 7.43 ppm (5H, S).

-35 8 1 0 0 57 1 * - 129 -

Example 159 (3-S-trans) -3-Methoxy-4-methyl-2-oxo-3- / (phenylacetyl) amino-1-a-azetidine sulfonic acid, potassium salt. -¾

(3S-trans) -3-amino-3-methoxy-4-methyl 1-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt is prepared by catalytic hydrogenation of (3S-trans) -3-methoxy-4-methyl-2 -oxo-3 - / - / (phenylmethoxy) carbonyl / amino - / - 1-azetidine sulfonic acid, potassium salt (see example 158) after conversion into the tetrabutyl ammonium salt. Following the procedure of Example 88, but using (3S-trans) -3-amino-3-methoxy-4-methyl-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt and phenylacetyl chloride, the title compound is obtained .

Analysis calculated for C ^ H ^^ OgSKs C 42.61? H 4.31? N 7.65?

Found: C 39.67? H 4.09? N 7.30.

NMR (D2Q) 1.29 (BH, d, j »7), 3.45 (3H, S), 3.73 (2H, S), 4.36 (2H, d of d, j = 6), 7.38 ppm (5H, S).

Example 160 / _ 3S- / 3α (Z), 4β _ / _ / - 3- / / (2-Amino-4-thiazolyl) / _ / 2- (diphenyl-methoxy) -2-oxoethoxy __ / imino_ / acetyl __ / amino_ -2-methyl-4-oxo-1-azeididine sulfonic acid, potassium salt.

Following the procedure of Example 138, use (Z) -2-amino-aV / 2- (diphenylmethoxy) -2-oxoethoxy / imino / - 4-thiazole acetic acid instead of (Z) -2-amino-a- (methoxyimino) -4-thiazole acetic acid and first treating the (3S-cis) -3-amino-4-methyl-2-oxo-1-azetidinesulfonic acid with triethylamine, the title compound m.p. 155-160 ° is obtained C, under decomposition.

Example 161 / 3S- / 3α (Z), 4β_Τ / / - 3 - / _ / (Carboxymethoxy) imino / (2-amino-4-thiazolyl) acetyl 7-amino-2-oxo-1-azetidine sulfonic acid, dipotassium salt.

*; * - 130 - 5

10 15 20 25 30

Deprotection of (_ 3S- / 3α (Z), 48 _ / _ / - 3- / / (2-amino-4-thiazolyl) / </ 2- (diphenylmethoxy) -2-oxoethoxy_ / imino _ / - acetyl __ / amino / -2-methyl-4-oxo-1-azetidine sulfonic acid, potassium salt (see example 160) using trifluoroacetic acid and anisole gives the title compound which decomposes at> 250 ° C. Example 162 (S) -3 - / - (- (2,6-Dichloro-4-pyridinyl) thio / acetyl / amino / / 2-oxo-1-azetidine sulfonic acid, potassium salt.

Acylation of (S) -3-amino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see example 6A) with / (2,6-dichloro-4-pyridinyl) thio / acetic acid, 4-nitrophenyl ester, followed by treatment with potassium perfluorobutane sulfonate, gives the title compound, mp 212-214 ° C. Example 163 (_ 3S (RX) __ / - 3 "/.//./. (4-Amino-2,3) -dioxo-1-piperazinyl) -carbonyl __ / - amino_ / phenylacetyl_ / amino _ / - 4-methyl-2-oxo-1-azetidine sulfonic acid, potassium salt When using / _ 3S (RX) _ / - / 4 - / _ / f_ 2 - (_ (4-methyl-2-oxo-1-sulfo-3-azetidinyl) amino _ / - 2-oxo-1-phenylethyl / amino __ / - carbonyl __ / - 2,3-dioxo-1-piperaziny 1 __ / carbamic acid , phenylraethyl ester, potassium salt (see example 149) hydrogenates with hydrogen gas and 10% palladium on carbon as a catalyst, the title compound, m.p. 165 ° C, is obtained under decomposition Example 164 / 3S (Z) 3 / 3- / / (2-Amino-4-thiazolyl) / (1-carboxy-1-methylethoxy) -imino / acetyl / amino / - 2-oxo-1-azetidine sulfonic acid, sodium salt (1: 2).

When (_ 3S (Z) _ / - 3- / / _ (2-amino-4-thiazolyl) - / (_ 2- (diphenylraethoxy) -1,1-dimethyl-2-oxoethoxy __ / imino __ / acetyl_ -amino-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (see Example 28) deprotects using trifluoroacetic acid 81 0057-131 and anisole to give the title compound of O-4 f melting point 185 DEG C., decomposed - post-conversion into the disodium - - ***. - - salt with aqueous sodium hydroxide and purification over HP-20. Examples 165-168-5 Following the procedure of Example 11, but a In the column I of the table below, the acid used instead of (Z) -2-amino-α - / - {- hydroxy (phenylmethoxy) phosphinyl - / - methoxy / imino / -4-thiazole acetic acid, the corresponding column II is obtained. link.

10 81 0057 1 132 8 Ρ f i, 7 * K.H gj o a e «o is ρ ~ 3 H O> 1 N o e N P C H O rH Λ fÖ & ï * 'o 5 c Ή * Ό P (1). PH Φ PPSN β • HCO Ό OIP p (£ Η Φ «P Ό (N 1/1 β, '·' φ o 1. β ν, Ι-Η ·> I Ό U co · γ) I 4JO φ ο Ui Ν 00 - <β »-ι 1 Ή • Η Ρ Ό Ο ^ Ν I, I § rhl ιν & 1 \ Ιρ χ _ φ ϋ> Η U 'β> ι id Ρ Η Η | \ Ρ Ό ο 3 φ Ν Ο Ν Γ-Ι id β β Ρ • Η · Η Ο β Λ S Ή Ο Ρ, Η Η IV3 Ρ VI 0) Φ I> ι Φ Ό Ο X fi Ü β Ο -Η Ο Η Ρ Ό Β 3 · Η - ( Ö Λ Ρ UI Ο Φ (Ν X NO Ο Φ Ο I, ι ι «, -νΙ'ϋ '« Η * Η Ι.ι> ι \ 1 ^ ο ιη t> 1 κ οι Μ X Ο Η, ιοι cm Ρ | ρ, · c Λ Sl \ 3 Ν S JQ, "-HOP W> ι β Η .η ö -η Φ kj« § ϊ a? • Η I Ό, I β Φ Ο Η 1 · ρ ρ ι— i Η Ν 3 β UJ Ο Φ Λ β -Ρ Η Ό »Ό β ϋ Η Ο -Ρ Ntl 'Ss Ν U Ο Φ Α I Ο Ρ ι- ΙΛ φ, I - SK. ^ Η | ro> ι 0 CM β β, φ Η Ρ <n ε β I Ν, H-'s l'H & S Va Β CM φ * If ,! Λ J? Β I Ρ Η S i 5? 'V CM Ο ι β Η ui a 8 Ρ φ Ρ 3 3 Ν

I -; • Ρ I Ν HP id 3 Φ Ρ, ι Μ; Ό φ -V φ .β ft Ι-Ρ *** Ή Η Ή ft> ιΌ * I β Η Ο Η Ο +1 I Λ ΦΟ Η Ρ Ν Ο> ι id <ΰ Γ "8, Ο I CM Phv. ^ H ι ο ι m <PHO Vfl I> 1 κ CM <a · ι o - VO III CM N fi, I s I TlK ft> ιΌ P κ η ο hpa β φ Ρ Η · Η B Ό P 8 tn> i> <, «Cl Qj'S. TKJtj h 3 I fl> io, xl ι -pn, η Φ a * u 3 I .cm id n, \ I Η H i,>!> 1 «1, Ό Φ Dl Vj-P IP - CIP \, PH co> i 1 3 Ό I ft 0 3 Φ ffi λ β Ν H Ui Η Η β P η> ia ο β" β ld IHO

-Ρ β 3

P ï N> Φ O N β Φ £ 5? o 5 φ a • H o (vo CM

. 1 U • K, 3 Φ, 1 3 <W> i N rj κ c Ό 0 · η «· Ρ Tl I 3 N .Μ1 Λ ld, IH NO O, κ o slo n ι ι id Ö Mil H ι IA 0 P • 5 1 v «l CM φ O ι a β Η τΗ n>, aw fi * H

I 0 I Λ! Φ P O id Ν Ο β * · <* α) & ν «ο ι Α Η Ρ> ι Φ A 1¾ Sl-ί,« ο1, '- β f 0¾ 1> ι 3 CM β Ν 1. * & ΚΙ fifi-L 0 co | lp «H 1, CN>, P ^ iS 3- w" v.1 o 1 2 -9 CM Ό PI Ή ld η> 1 P, OHS ^ Nlïï p ft -12 P * "» Η β Ό H> i Φ> 1> t I Λ β VO I Η I .lil Η Β I, id η, _ Ρ Ό V., 0) Η, \ Ι ft Β ο 1, Η Η β νΡΪ, Ι ö -ι ft id 3 Ν β Φ Ν β Φ, Λ 2 ω φ ιΛ Ό r- φ U3 VO νο νο fl 0:> Η Η Η 81 0 0 57 1 (transl) -3-Amino-4-ethyl-2-oxo-l -azetidine sulfonic acid.

4 - * - 133 -

Example 169

A) t-Boc-N-methyl-1-g-threoethylserinamide.

1.33 g of treo-D-L-g-ethylserine are dissolved in 10 ml of 2N potassium hydroxide and 5 ml of t-butanol. After adding 2.46 g of di-t-butyl pyrocarbonate to the biphasic mixture, the mixture is stirred at room temperature for 4 hours. 1.25 g of O-methylhydroxylammonium-10 chloride are added and the pH is adjusted to 4 with 1N hydrochloric acid. 1.92 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride is added and the pH is adjusted again to 4. After stirring for 1 hour, the reaction mixture is saturated with sodium chloride and extracted with four 50 ml portions of ethyl acetate. . The ethyl acetate extracts are combined and dried over MgSO4. Removal of the solvent in vacuo gives 1 g of the title compound.

B) t-Boc-O-methanesulfonyl-N-methoxy-g-threopropionamide.

10.5 g of t-Boc-N-methoxy-g-threoethyl serinamide are dissolved in 65 ml of pyridine. 4.65 ml of methanesulfonyl chloride are added dropwise at 0 ° C. After stirring at room temperature for 3 hours, the reaction mixture is poured into 200 g of ice and 300 ml of 1N hydrochloric acid. The pH is adjusted to 25 with concentrated hydrochloric acid. After extraction with three 85 ml portions of ethyl acetate, the combined extracts are dried over MgSO 4 and concentrated in vacuo. The residue is treated with carbon tetrachloride and concentrated again. Stirring with ether followed by filtration yields 6.9 g of the title compound.

C) (trans) -3-t-Butoxycarbonylamino-4-ethyl-1-methoxy-2-azetidinone.

4.15 g of anhydrous potassium carbonate and 125 ml of dry acetone are heated to a reflux condenser and 3.4 g of t-boc-35 O-methanesulfonyl-N-methoxy-g-treopropionamide in 25 ml of acetone are added.

8100571 - 134 -

After 1 hour, the reaction mixture is cooled and filtered and the filtrate concentrated in vacuo. The oily residue is stirred with hexane to 2.2 g. ij || the title named compound.

D) (trans) -3-t-Butoxycarbonylamino-4-ethyl-2-azetidinone.

3 g of (trans) -3-t-butoxycarbonylamino-4-ethyl-1-methoxy-2-azetidinone are added to 170 ml of liquid ammonia at -78 ° C under nitrogen and 1.68 g are added over a period of 5 min. Add sodium in five portions while stirring. Stirring is continued for an additional 30 minutes. Ammonium chloride is then added slowly until the blue color of the reaction mixture disappears. After removal of the ammonia under nitrogen, the solid is extracted with two 100 ml portions of ethyl acetate. Removal of the solvent followed by drying in vacuum affords 2.7 g of the title compound.

E) (trans) -3-t-Butoxycarbonylamino-4-ethyl-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt.

To 2 ml of absolute pyridine in 20 ml of dry dichloromethane, 3.7 ml of trimethylsilylsulfonyl chloride in 5 ml of dry dichloromethane are added. The addition is made over a period of 10 min. Under nitrogen at -30 ° C. After stirring for 30 min. the flask is placed under vacuum at room temperature to obtain a pyridine sulfur trioxide complex. 2.67 g of (trans -) - 3-t-butoxycarbonylamino-4-ethyl-2-azetidinone and 20 ml of dry pyridine are placed in the flask, which is then placed in an oil bath preheated at 90 ° C. After 15 minutes, a clear solution is obtained, which is poured into 200 ml of 1M dibasic potassium phosphate solution. A clear solution is obtained after adding 27 g of dibasic potassium phosphate and 100 ml of water. The solution is extracted with two 60 ml portions of ethyl acetate. Tetrabutyl ammonium hydrogen sulfate is added to the water layer and the aqueous solution is extracted with three 100 ml portions of dichloromethane and the combined organic layers are dried over MgSO 4. Concentration in vacuum provides 6.9 g in the 81 00 57 1

St * - 135 - title mentioned link on.

F.) (tran3-3-Amino-4-ethyl-2-oxo-1-azetidinesulphonic acid.

5. 6.75 g of (trans) -3-t-butoxycarbonylamino-4-ethyl-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt are stirred in 40 ml of 98% formic acid for 3 hours at room temperature. 60 ml of dichloromethane are added and the mixture is cooled in a refrigerator for 16 hours.

The resulting precipitant is filtered off and then dried in vacuo to 0.85 g of the title compound, mp 185 ° C, with decomposition.

Example 170 (trans, Z) -3- / / (2-Amino-4-thiazoly-1) {_ (1-carboxy-1-methylethoxy) -imino_ / acetyl_ / amino_ / - 4-ethyl-2-oxo-1 -azetidine sulfonic acid, dika-15 lium salt.

A) (trans, Z) -3 - / _ [_ (2-Amino-4-thiazolyl) / _ (1-diphenylmethoxycarbonyl-1-methylethoxy) imino / acetyl] / amino _ / - 4-ethyl-2-oxo-1 -azetidine sulfonic acid, dipotassium salt.

20 25 30 35

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 dimethylformamide. 1.14 g of (Z) -2-amino-α- ((1-diphenylmethoxycarbonyl-1-methylethoxy) imino / / - 4-thiazole acetic acid, followed by 450 mg of hydroxybenztriazole and then 0, are added with stirring at 0 ° C. 69 g of dicyclohexylcarbodiimide. After stirring at 0 ° C for 16 hours, the flask is placed under vacuum. 25 ml of dry acetone are added to the solid with stirring. The mixture is filtered and 0.94 g of potassium perfluorobutane sulfonate is added to the filtrate, followed by 100 ml of ether. After standing at 0 ° C for 1 hour, the solid is filtered off, washed with ether and dried in vacuo to give 1.58 g of the title compound.

B) (trans, Z) -3- / / (Z-Amino ^ -thiazolyl) / ^ (1-carboxy-1-methylethoxy) imino / acetyl / amino / 4-ethyl-2-oxo-1-azetidine sulfonic acid , dipotassium salt.

81 00 57 1 - 136 - 5 For a suspension of 1.31 g of (trans, Z) -3- / / (2-amino-4-thiazolyl) / _ (1-diphenylmethoxycarbonyl-1-methylethoxy) iraino _ / - acetyl / amino / -4-ethyl-2-oxo-1-ylidenesulfonic acid, dipotassium salt in 10 ml of anisole is added over a period of 10 min. at 15 DEG C. of trifluoroacetic acid. After stirring for 2 hours at -10 ° C, a clear solution is obtained. 80 ml of dry ether are added at -30 ° C 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 to remove unreacted starting material. The filtrate is chromatographed on HP-20 with water as the eluent. Freeze drying provides 185 mg of the title compound, m.p. 160 ° C with decomposition. Example 171. 15 /> (Z) J-3- / / (2-Amino-4-thiazolyl) / (4-hydroxy-4-oxobutoxy) -imino / acetyl / amino-2-oxo-1-azetidi . esulfonic acid, potassium salt. Deprotection of / 3S (Z) _ / - 3-V / (2-amino-4-thiazolyl) / / 4- (diphenylmethoxy) -4-oxobutoxy_ / imino_ / acetyl _ / - amino _ / - 2-oxo-l- azetidine sulfonic acid, potassium salt (see example 166) using trifluoroacetic acid and anisole gives the title compound with melting point> 200 ° C. Example 172 (S) -3 - / - 2 - (Aminomethyl) benzoyl / araino / - 2-oxo-1-azetidine sulfonic acid 25, internal salt. Deprotection of (S) -2-oxo-3-V / _ 2- / / _ / _ (phenyl-methoxy) carbonyl / amino_ / methyl_ / benzoyl_ / amino __ / - 1-azetidinesulfonic acid, potassium salt using hydrogen gas palladium on carbon and hydrochloric acid affords the title compound, m.p. 162-165 ° C. Example 173 (S) -3- / / / 2- (4-Formyl-1-piperazinyl) -5-hydroxypyrido / _ 2,3-d / pyri-midin-6-yl / carbonyl / amino / -2-oxo-1-azetidine sulfonic acid, potassium salt.

8 i OO 5 7 1 '* - 137 - (S) -3-Amino-2-oxo-1-azetidine sulfonic acid, tetra-butylammonium salt (see example 6jp is coupled with 2— (4-formyl-1-piperazinyl) - 5-hydroxy-6- (4-nitrophenoxy) carbonyl / pyrido / 2,3-d-tpyriraidin treated with potassium perfluorobutane-5-sulfonate in acetone to give the title compound, mp 290 ° C , under decomposition.

Example 174 (3S, trans) -a- / ((4-Methyl-2-oxo-1-sulfo-3-azetidinyl) amino / carbonyl / benzenoacetic acid, dipotassium salt.

10 (3S-trans) -3-amino-4-methyl-2-oxo-1-azetidine-sulfonic acid (see example 139) is coupled with a- (carboxyl) -benzene acetyl chloride and treated with triethylamine and potassium perfluorobutane sulfonate to give the title compound, m.p. 147 ° C, with decomposition. Example 175 / 3S-trans 7-3-Amino-4-cyclohexyl-2-oxo-1-azetidine sulfonic acid.

A) a- (t-Butoxycarbonylamino) -6-cyclohexyl-3-20 hydroxy-treopropionzutir.

15 g of B-cyclohexyl-α-amino-β-hydroxytreopropionic acid are suspended in 150 ml of acetic acid triitrile and 70 ml of water. 17.8 g of triethylamine are added and the mixture is heated to 60 [deg.] C. with stirring, at this temperature a clear solution is obtained, 21.0 g of di-t-butyl pyrocarbonate are added and the stirring is continued at 60 [deg.] C. , 5 hours on. The solvent is removed in vacuo and 50 ml of water are added. The water layer is extracted with ethyl acetate at pH 2, which is adjusted by adding 3N HCl. The organic layer is separated, dried over Na2SO4 and evaporated to dryness. The remaining crystalline material is filtered with petroleum ether to obtain 20.4 g of the title compound, mp 113-115 ° C.

B) a- (t-Butoxycarbonylamino) -5-cyclohexyl-3-35 hydroxy-N-methoxy-treopropionamide.

81 00 57 1 - 138 -

20.2 g of α- (t-butoxycarbonylaini.no) -8-cyclohexyl-8-hydroxytreppropionic acid and 7.6 g of O-methylhydroxyamine hydrochloride are suspended in 350 ml of water, 171 ml of t-butanol. The pH of the mixture is adjusted to 4 with potassium carbonate. 16.4 g of 5 l-ethyl-3- (3-dimethylaminopropyl) carbodiimide is added and the pH is kept at 1.5 with stirring for 4 hours. T-butanol is removed in vacuo and saturates the remaining aqueous solution with sodium chloride and extracts twice with 100 ml portions of ethyl acetate. The organic layers are combined, dried over Na2O4 and evaporated to dryness. The remaining crystals are filtered with petroleum ether to obtain 18.6 g of the title compound, m.p. 125-127 ° C.

C) a- (t-Butoxycarbonylamino) -β-cyclohexyl-B- (methanesulfonyloxy) -N-methoxy-treopropionamide.

15

18.3 g of a- (t-butoxycarbonylamino) -6-cyclohexyl-B-hydroxy-N-methoxytreopropionamide are dissolved with stirring in 100 ml of dry pyridine. The solution is cooled to 0 ° C with stirring and 9.3 g of methanesulfonyl chloride are added dropwise. After 1 hour, 3.3 g of methanesulfonyl chloride are added at 0 ° C and stirring is continued for an additional hour. The solution is poured into 300 ml of ice water, 200 ml of ethyl acetate are added and the pH is adjusted to 3 with dilute hydrochloric acid. The organic layer is separated, dried over Na 2 SO 4 and the solvent is removed in vacuo.

The residual solid is recovered with petroleum ether to give 19.0 g of the title compound, m.p. 150-552 C.

D) / "* 3S-trans-3- (t-Butoxycarbonylamino) -4-cyclohexyl-1-methoxy-2-azetidinone, 30

18.7 g of cx- (t-butoxycarbonylamino) - $ - cylochexyl-β- (methanesulfonyloxy) -N-methoxytreopropionamide are dissolved in 500 ml of dry acetone. 9.8 g of potassium carbonate are added and the suspension is heated under reflux for 5 hours with stirring.

The insoluble inorganic material is filtered off and the solvent is removed in vacuo and the residual oil is dissolved in 30 ml of ethyl acetate. The addition of petroleum ether precipitates the title compound, which is filtered off. Up- •. Q yields 12.9 g with melting point 110-112 C.

5 E) / § 3 ^ trans-/-3- (t-Butoxycarbonylamino) -4-cyclohexyl-2-azetidinone.

1 g / 3S-trans-3- (t-butoxycarbonylamino) -4-cyclohexyl-1-methoxy-2-aze-tidinone is added with stirring to 50 ml of liquid ammonia. 0.154 g of sodium is added in five to six portions over 5 minutes. An additional 0.025 g of sodium is then added and stirring is continued for a further 5 minutes. 0.89 g of ammonium chloride are added and the ammonia is removed. The residue is extracted with warm ethyl acetate. The organic extract is evaporated to dryness and the remaining crystals of the title compound are filtered off with petroleum ether. Yield 0.5 g with melting point 130-132 ° C.

F) / 3S-trans-3- (t-Butoxycarbonylamino) -4-cyclohexyl-2-oxo-1-azetidine sulfonic acid, pyridine salt.

5.3 g / 3S-trans-3- (t-Butoxycarbonylamino) -4-cyclohexyl-2-azetidinone is dissolved in 20 ml of methylene chloride and 80 ml of dimethylformamide. After adding 60 mmol of pyridine sulfur trioxide complex, the solution is stirred at room temperature for 6 hours. Removal of the solvent in vacuo affords 11.3 g of the title compound as an oil.

G) / 3S-trans __ / - 3- (t-Butoxycarbonylamino) -4-cyclohexy1-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt.

11.3 g of 3S-trans-3- (t-butoxycarbonyl-amino) -4-cyclohexyl-2-oxo-1-azetidine sulfonic acid, pyridine salt are dissolved in 250 ml of water. 9.0 g of tetrabutyl ammonium hydrogen sulfate are added with stirring and the pH is adjusted to 6.5 with 1N potassium hydroxide.

The aqueous solution is extracted twice with 200 ml portions of methylene chloride. The organic portions are dried at 81 0 0 57 1 140

Na 2 SO 4, filtered and the solvent is distilled off to give 8 g of the title compound, mp 135-138 ° C.

H) [3 3S-trans-3-3-Amino-4-cyclohexyl-2-oxo-1-azetidine sulfonic acid.

10 Θ

3.8 g / 3S-trans-3- (t-butoxycarbonyl-amino) -4-cyclohexyl-2-oxo-1-azetidine sulfonic acid tetrabutyl ammonium salt is stirred in 20 ml formic acid for 3 hours, followed by addition of 20 ml methylene chloride . The precipitated title compound (1.0 g) is filtered off. Melting point 217-219 ° C.

Example 176 3SV 3α (Ζ), 4β / / -3 - / [((2-Amino-4-thiazolyl) phenoxyimino) acetyl] / amino / -4-cyclohexyl-2-oxo-1-azetidine sulfonic acid, potassium salt.

15

0.25 g / 3S-trans-3-amino-4-cyclohexyl-2-oxo-1-azetidine sulfonic acid is dissolved with stirring in 30 ml of dry dimethylformamide and 0.12 g of triethylamine. When a clear solution is obtained, 0.2 g of (Z) -2-amino-α-(methoxyimino) -4-thiazole acetic acid, 0.16 g of hydroxybenztriazole and 0.42 g of dicyclohexylcarbodiimide are added. Stirring is continued for an additional 48 hours at room temperature. The precipitated urea is filtered off and the solvent is removed in vacuo. The residue is dissolved in 10 ml of acetone and 0.41 g of potassium perfluorobutane sulfonate are added. After adding 50 ml of ether, the title compound precipitates, which is filtered off. Column chromatography using HP-20 and water / acetone (9: 1) as an eluent yields 0.36 g of product mp 200-205 ° C (after freeze drying).

30

Example 177 f_ 3S - / _ 3α (Z), 43 __ / _ / - 3- / / (2-Amino-4-thiazolyl) / (1-carboxy-1-me-thylethoxy) imino __ / ace ty 1 __ / amino __ / -4-cyclohexyl-2-oxo-1-azetidine sulfonic acid, dipotassium salt.

35 81 00 57 1 * - «- 141 - A) / 3S- / 3α (Z), 4β __ / __ / - 3-Υ / _ (2-Amino-4-thiazolyl) / (1-diphenylmethoxycarbonyl-1 -methyl-ethoxy) imino / acetyl / - 1 · = · "" 1 amino / -4-cyclohexyl-2-oxo-1-azetionesulfonic acid, potassium salt.

5 € 0.2 g / 3S-trans-3-amino-4-cyclohexyl-2-oxo-1-azetidine sulfonic acid (see example 175) are stirred in 30 ml of dimethylformamide and 0.09 g of triethylamine. 0.12 g of hydroxybenztriazole, 0.3 g of (Z) -2-amino-α - / (1-diphenylmethoxycarbonyl-1-methylethoxy) imino / 4-thiazole acetic acid and 0.33 g of dicyclo-10 hexylcarbodiimide are added and continue stirring at room temperature for an additional 12 hours. The precipitated urea is filtered off and the mother liquor evaporated to dryness. The residual oil is dissolved in 5 ml of acetone, treated with 0.3 g of potassium perfluorobutane sulfonate and poured into 100 ml of ether with stirring. 0.61 g of 15 / 3S- / 3α (Ζ), 4β __ / _ / - 3- / / (2-amino-4-thiazolyl) - / (1-diphenylmethoxycarbonyl-1-methylethoxy) imino __ / acetyl_ precipitate / amino-4-cyclohexyl-2-oxo-1-azetidine sulfonic acid, potassium salt, which is filtered off.

B) S3S- / ~ 3α (Z), (2-Amino-4-thiazolyl) (_ (1-carboxy-1-methylethoxy) imino __ / acetyl __ / amino __ / - 4-cyclo-20 hexyl-2-oxo -1-azetidine sulfonic acid, dipotassium salt.

0.61 g / 3S - / - 3α (Z), 43 _ / __ / - 3 - / _ / _ (2-amino-4-thiazolyl) - / _ (1-diphenylmethoxycarbony 1-1-methyl-1-) ethoxy) imino / acetyl / amino / 4-cyclohexyl-2-oxo-1-azetidinesulphonic acid, potassium salt in 6 ml of anisole, cooled to -15 ° C and instilled with 5 ml of trifluoroacetic acid with stirring. The temperature is maintained for 1 hour and then lowered to -30 ° C. 100 ml of dry ether are added at such a rate that the temperature does not rise above -10 ° C. The precipitated compound is filtered and chromatographed using HP-20 resin and water / acetone (9: 1) as an eluent to give 3.0 g of the title compound, mp 117-120 ° C, with decomposition, (after freeze drying).

35 81 00 57 1 έ - 142 -

Example 178.

[_ 3S- / 3α, 43 _ / _ / - 4-Cyclohexy / / 3- / (2-furanylmethylene) -amino _ / - 2-oxo-1-imidazolidinyl_ / carbonyl_ / amino __ / phenylacetyl __ / amino 7-2-oxo- 1-azetidine sulfonic acid, potassium salt.

5 10 15 20

0.1 g / 3S-trans / -3-amino-4-cyclohexyl-2-oxo-1-azetidine sulfonic acid (see example 175) is dissolved with stirring in a mixture of 30 ml of dry dimethylformamide and 0.05 g of triethyl- amine. 0.14 g of [_ / _ (_ / (2-furanylmethyl-amylamino] / -2-oxo-1-imidazolidinyl / carbonyl / amino / f-enylacetic acid, 0.06 g of hydroxybenz-triazole and 0.17 g of dicyclohexylcarbodiimide are added and stirred the solution at room temperature for 5 days The solvent is removed in vacuo, the residue is dissolved in 10 ml of acetone and the precipitated urea is filtered off. The mother liquor is stirred with 0.15 g of potassium perfluorobutane sulfonate and diluted with 50 ml of ether. The precipitate is filtered. and chromatographed with HP-20 resin with water / acetone (9: 1), as an eluent using 0.14 g of product mp 195-200 ° C, with decomposition (after freeze drying).

Example 179 (_ 3S - / _ 3a (R5 *) 243 __ / _ / - 4-Cyclohexyl-3 - / _ {_ 3- (4-ethyl 1-2,3-dioxo-1-piperaz iny 1) -1 3-dioxo-2-phenylpropyl / amino-2-oxo-1-aze tidine-sulfonic acid, potassium salt.

0.1 g of 3-trans-3-amino-4-cyclohexyl-2-oxo-1-azetidine sulfonic acid (see example 175) are dissolved with stirring in 30 ml of dimethylformamide and 0.5 g of triethylamine. (R) -a-LL (4-ethyl 1-2,3-dioxo-1-piperazinyl) carbonyl / amino / benzene acetic acid, 0.06 g hydroxybenztriazole and 0.17 g dicyclohexylcarbo-30 diimide are added and stirred the mixture at room temperature for 16 hours. The solvent is distilled off in vacuo and the remaining oil is dissolved in 10 ml of acetone. The precipitated urea is filtered off and the mother liquor is stirred with 0.15 g of potassium perfluorobutane sulfonate and diluted with 50 ml of ether. The precipitate is filtered off and chromatographed on HP-20 resin with water / acetone 8 1 0 0 57 1 - 143 - (9: 1) as an eluent to yield 0.15 g of the title compound with melting point, 175-180 ° C (after freeze drying). Example 180 '(trans, Z) -3- / f (2-Amino-4-thiazolyl) (methoxyimino) acetyl / amino / m 2 2-4-ethyl-2-oxo-1-azetidine sulfonic acid, potassium salt.

Following the procedure of Example 170, Part A, but using (Z) -2-amino-a- (methoxyimino) -4-thiazole acetic acid instead of (Z) -2-araino-aV (1-diphenylmethoxycarbonyl-1-) Methyl ethyl) imino-4-thiazole acetic acid, the title compound, m.p. 190 ° C, is obtained, with decomposition. Example 181 ((+) - (trans) -3-Amino-2-oxo-4-phenyl-1-azetidine sulfonic acid.

A) (+) - (trans) -2-oxo-4-phenyl-1-azetidine-t-butyl-diphenylsilane.

A solution of 20.56 g of t-butyl chlorodiphenyl silane in 45 ml of dimethylformamide is cooled to 0 ° C under argon and treated with 10.4 ml of triethylamine and then (+) - 2-oxo-4-pheny1- 1-azetidine. After a few hours at 0 ° C, the resulting mixture is treated with an additional 1 ml of triethylamine and 12.1 g of t-butylchlorophenylsilane and left to stir at 5 ° C for 65 hours. The reaction mixture is poured into 300 ml of ice water and extracted with 3: 1 ethyl ethyl acetate (three 125 ml portions). The organic extracts are washed with pH 4.5 phosphate buffer (three 50 ml portions), 50 ml of saturated sodium bicarbonate solution, two 50 ml portions of water, saturated sodium chloride solution and dried over Na 2 SO 4. Filtration and concentration in vacuo give a solid which is washed with hexane, after which 15 g of the title compound are obtained as a solid after drying (high vacuum).

B) (+) - (trans -) - 3-azido-2-oxo-4-phenyl-1-azetidine-t-butyldiphenylsilane.

35 81 00 57 1 4 - 144 -

A 50 ml flask equipped with stir bar, gas inlet and septum is flame-dried under argon and charged with 0.65 ml of 1.6 M n-butyl lithium solution hexane, cooled to -40 ° C and dissolved in 2 ml of tetrahydrofuran. 0.16 ml of diisopropylamine is added dropwise and the resulting mixture is stirred for 30 min and cooled to -78 ° C. A solution of 400 mg (+) - (trans) -2-oxo-4-phenyl-1-azetidine-t-butyl-diphenylsilane in 1.5 ml of tetrahydrofuran is added dropwise over 5 minutes. After stirring for an additional 20 minutes, the solution is treated with 204 mg of p-toluenesulfonyl azide in 0.5 ml of tetrahydrofuran. The resulting mixture is stirred at -78 ° C for 10 min and treated dropwise with 0.4 ml of chlorotrimethylsilane. After an additional 10 minutes of stirring, the cooling bath is removed and the reaction mixture is stirred at room temperature for 2.5 hours. Then, while cooling at 0 ° C, 20 ml of ethyl acetate are added, followed by 8 ml of pH 4.5 phosphate buffer. The organic layer is washed with even more buffer (two 8 ml portions), three 10 ml portions of 5% sodium bicarbonate solution, 10 ml of 50% sodium chloride solution, 10 ml of saturated sodium chloride solution and dried over Na 2 SO 4. Filtration and concentration in vacuo give 500 mg of oil 20, which is flash chromatographed with 5% ethyl acetate-hexane to give 253 mg of the title compound.

C) (+) - (trans) -3-azido-2-oxo-4-phenyl-1-azetidine.

A solution of 17 g of crude (+) - (trans) -3-azido-2-oxo-4-phenyl-1-azetidine-t-butyldiphenylsilane is dissolved in 250 ml of methanol and treated dropwise with 35 ml at 0 ° C concentrated hydrochloric acid. The cooling bath is removed, the reaction is stirred at room temperature for 1 hour and it is cooled again to 0 °, whereupon sodium bicarbonate solution is added to neutral. The resulting mixture is extracted with ethyl acetate (one 300ml portion and four 100ml portions) and the organic extracts are washed with 1: 1 5% sodium bicarbonate, 50% sodium chloride solution, saturated sodium chloride solution and dried over (Na_SO ,). Filtration and concentration in vacuum yields 15 g of heavy 2 4 35 oil, which is chromatographed on 100 g of silica gel with 81 00 57 1 5 *? 145 - 20% ethyl acetate-hexane to give 460 mg of the title compound. ^. - * g, D) (+) - (trans) Azido-4-phenyl-1-azetidine sulfonic acid, tetrabutyl ammonium salt.

10 15 20

A solution of 300 mg (+) - (trans) -3-azido-2-oxo-4-phenyl-1-azetidine in 3 ml dimethylformamide is cooled to 0 ° C under argon and treated dropwise with a dimethylformamide complex and sulfur trioxide (7.78 ml of a 0.5 M solution in dimethylformamide). The cooling bath is removed, the reaction mixture is stirred at room temperature for 2 hours and poured into 80 ml of 0.5 M monobasic potassium phosphate (pH 5.5). The solution is extracted with dichloromethane (discarded) and 541 mg of tetrabutyl ammonium bisulfate is added. The resulting mixture is extracted with dichloromethane and the organic extracts are washed with 10% sodium chloride solution and dried (Na 2 SO 4). Filtration and concentration in vacuum gives 800 mg of oil, about 40% of the desired product, the remainder dimethylformamide. This mixture is used in the next step without purification.

E) (+) - (trans) -3-Amino-4-phenyl-1-azetidine sulfonic acid.

A solution of (+) - (trans) - 3-amino-4-phenyl-1-azetidine sulfonic acid, tetrabutyl ammonium salt in 25 ml of methanol over 30 mg of platinum oxide at 1 atmosphere and room temperature is hydrogenated. under vacuum and introduces fresh hydrogen. After a further 45 minutes, the reaction is completed and the system is flashed with nitrogen. After a few days at room temperature in dichloromethane-methanol (4: 1), 200 ml, the catalyst aggregation is complete and the filtration is complete. The filtrate is concentrated in vacuo to 18 ml and 0.2 ml of 97% formic acid is added. After cooling at 5 ° C for several hours, the resulting solid is filtered and washed with dichloromethane to give 150 mg of the title compound as a solid after drying.

35 61 00 57 1 i-% - 146 -

Analysis calculated for C 8 H 25 t O 2 S: C 44.62; H 4.1% N 11.57; S, 13.23;

Found: C 43.36; H ~ 4.31; N 11.09; S 13.02.

Example 182 -. -...-.---------------- 5 (+) - (trans) -2-Oxo-4-phenyl-3- / (phenylacetyl) amino-1-azetidine sulfonic acid, potassium salt.

A) (+) - trans-2-oxo-4-phenyl-3'V (phenylacetyl) -amino / -1-azetidine sulfonic acid tetrabutyl ammonium salt.

10

A solution of 52 mg of N-hydroxy-benztriazole monohydrate and 46 mg of phenylacetic acid in 0.3 ml of dimethylformamide under argon is treated at 0 ° C with 70 mg of solid dicyclohexylcarbodiimide. The cooling bath is removed and the resulting mixture is stirred at room temperature for 1 hour. After dilution with an additional 0.3 ml of dimethylformamide, 75 rag (+) - (trans) -3-amino-2-oxo-4-phenyl-1-azetidine sulfonic acid is added as a solid (see example 181), followed by dropwise addition of 0.05 ml of triethylamine. The reaction is stirred at room temperature for 23 hours, filtered and the filter cake washed with dimethylformamide. The filtrate is added to 20 ml of 0.5 M monobasic potassium phosphate of pH 4.5, the mixture is washed with three 8 ml portions of ethyl acetate (discarded) and 105 mg or 0.31 mmol of tetrabutyl ammonium bisulfate are added. The resulting mixture is extracted with three 15 ml portions of dichloromethane. The extracts are washed with 10% sodium chloride solution (two 15 ml portions) and 10 ml of saturated sodium chloride solution and dried over sodium sulfate. Filtration and concentration in vacuum yields (after heating at 32 ° C under high vacuum) 165 mg of oil, of which about 40% is the desired compound and 60% dimethylformamide.

B) (+) - trans-2-Oxo-4-phenyl-3-V (phenylacetyl) -amino / -1-azetidine sulfonic acid, potassium salt.

A solution of (+) - trans-2-oxo-4-phenyl-3-35 / (phenylacetyl) amino / -1-azetidine sulfonic acid, tetrabutylammonium salt 8100571-147 in 1.5 ml acetone is treated with 41 mg or 0.121 mmol potassium per -Fluorobutane sulfonate. Dilution with 12 ml of ether yields a glass which, when triturated with ether, yields .43 solid, containing 20% impurity, containing a tetrabutyl ammonium residue. The solid is dissolved in 50% aqueous acetone and passed over 1 ml

Dowex 50W-X2 K + ion exchange resin. Solvent removal yields a solid, which is washed with acetone and hexane and dried under high vacuum at 60 ° C. The yield of the title compound is 15 mg.

Analysis calculated for C 21 H N N O S S. K: C 51.23; H 3.80; N 7.03; S 8.05; K 9.81;

Found: C 50.44; H 4.20; N 7.01; S 7.59; K 9.40.

Example 183 (+) - (trans, Z) -3- / / (2-Amino-4-thiazolyl) (methoxyimino) acetyl-15-amino / -2-oxo-4-phenyl-1-azetidine sulfonic acid, potassium salt.

A solution of 52 mg of N-hydroxy-benztriazole hydrate and 69 mg of (Z) -2-alino-α- (methoxyimino) -4-thiazole acetic acid in 0.3 ml of dimethylformamide is treated with argon at room temperature with 70 mg of solid dicyclohexylcarbodiimide. The resulting mixture is stirred for 1 hour, 75 mg (+) - (trans) -3-amino-2-oxo-4-phenyl-1-azetidine sulfonic acid (see example 181) is added as solid and then 0.05 ml dropwise triethylamine. The reaction is stirred at room temperature for 23 hours. The dimethylformamide is removed under high vacuum at 30 ° C and the residue triturated with 2 ml of acetone and filtered. The filter cake is washed with more acetone (two 3 ml portions) and 86 mg of potassium perfluorobutane sulfonate are added to the filtrate. Dilution with 10 ml of ether yields a gummy solid, which is triturated and washed with acetone and hexane to give, after drying, 82 mg of the title compound as a solid.

Analysis for ci5Hi4N5 ° 6S2'K

Calculated: C 40.26; H 3.16; N 15.65; S, 14.33; K 8.74;

Found it; C, 38.60; H 3.19; N 15.07; S 13.87; K 7.5 35 81 0057 1 * - 148 -

Example 184 (cis) -2-Oxo-4-phenyl-3 / potassium salt.

A) N-Ijenzylidene-2,4-dimethoxybenzylamine.

12.0 g of 2,4-dimethoxybenzylamine hydrochloride are added to 100 ml of 1N sodium hydroxide solution and the mixture is extracted with 125 ml of ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and the solvent is stripped to give 10.2 g of 2,4-dimethoxybenzylamine as an oil. This amine is dissolved in 150 ml of benzene and 6.47 g of benzaldehyde and 0.6 g of p-toluenesulfonic acid raohydrate are added.

The mixture is heated to reflux with water removal with a Dean-Stark separator and the calculated 1.1 ml amount of water is separated over 2 hours. The mixture is cooled to room temperature. After further cooling, the benzene solution deposits some precipitate. Benzene is removed under reduced pressure and 60 ml of petroleum ether are added to the residue.

An oil layer with more precipitate separates. 10 ml of benzene are added to make the layers homogeneous and the remaining precipitate is filtered off. The solvent is stripped from the filtrate to obtain 14.2 g of the title compound as an oil.

(Phenylacetyl) amino __ / l-azetidine sulfonic acid,

B) (+) - (cis -) - 4-Phenyl-1- (2,4-dimethoxybenzyl) -2-oxo-3-azidoazetidine.

1.62 g of a-azidoacetic acid are dissolved in 25 ml of methylene chloride under nitrogen. 3.24 g of triethylamine and 1.02 g or 4.0 mmol of the imine N-benzylidene-2,4-dimethoxybenzylamine dissolved in 10 ml of methylene chloride are added to this solution. The mixture is cooled in an ice bath and 3.36 g of trifluoroacetic anhydride are slowly added, the solution being colored dark. After stirring in an ice bath for 1 hour, the mixture is warmed to room temperature and stirred for a further 15 minutes. The solution is then washed with 60 ml of water, two portions of 50 ml of 5% sodium bicarbonate solution and 81 0057 1 * * - 149. 60 ml IN hydrochloric acid. The organic layer is dried over anhydrous sodium sulfate and the solvent is stripped to give 1.72 g of crude product as dark gum.

The gum is treated with activated charcoal several times and the resulting brown mixture is chromatographed on 40 g of silica gel eluting with 1: 1 petroleum ether: ethyl acetate. The combined fractions yield crystals upon rapid freezing in a dry ice acetone bath. Using this as a graft, the product is recrystallized from petroleum ether-ethyl acetate to give 817 mg of the title compound as needles, which melt upon warming to room temperature.

C) (+) - (cis) -4-Phenyl-2-oxo-3-azidoazetidine.

737 mg (+) - (cis) -4-Phenyl-1- (2,4-dimethoxybenzyl) -2-oxo-3-azidoazetidine is dissolved in 25 ml of acetic acid nitrile and heated to 80-83 ° C under nitrogen. To the resulting solution are added over a period of 1 hour 943 mg of potassium persulfate and 570 mg of potassium monohydrogen sulfate, both dissolved in 25 ml of water.

After addition, the mixture is further heated at 80-83 ° C for 7 hours.

The mixture is cooled and the pH adjusted to 6-7 by addition of solid potassium monohydrogen sulfate. Most of the vinegar vacuum nitrile is removed under reduced pressure and the resulting mixture is extracted with 60 ml of chloroform. The chloroform form layer is washed with 60 ml of water, dried over anhydrous sodium sulfate and the solvent is stripped to give a crude product as an oil. The crude product is chromatographed on 40 g of silica gel, eluting with 1: 1 petroleum ether-ethyl acetate. The combined fractions yield crystals and the product is recrystallized from petroleum ether-ethyl acetate to give 267 mg of the title compound.

D) (+) - (cis) -4-Phenyl-2-oxo-3-azido-1-azetidine sulfonic acid, tetrabutyl ammonium salt.

35 81 0057 1

*

L

- 150 -

162 mg (+) - (cis) -4-phenyl-2-oxo-3- azidoazetidine are cooled to 0 ° C under nitrogen and 3.5 ml of cirica 0.5M dimethylformamide sulfur trioxide complex are added dropwise via syringe. solution in dimethylformamide. The resulting clear solution is stirred at 0 ° C for 15 min. The mixture is then poured into 50 ml of 0.5M monobasic potassium phosphate solution and washed with three 50 ml portions of methylene chloride. 292 mg of t-n-butylammonium bisulfate is added to the aqueous solution and the mixture is extracted with six portions of 50 µl of 10 methylene chloride. The combined methylene chloride layers are dried over anhydrous sodium sulfate and the solvent is stripped to give 272 mg of the title compound as a gum.

E) (+) - (cis) -2-Oxo-4-phenyl-3 - / (phenylacetyl) -15 amino / -1-azetidine sulfonic acid, potassium salt.

293 mg of Jj - (cis) -4-phenyl-2-oxo-3-azido-1-azetidinesulfonic acid, tetrabutyl ammonium salt, is dissolved in 4 ml of ethanol and hydrogenated with 80 mg of platinum oxide as a catalyst in 20 1 atmosphere. After stirring for 1 hour, the catalyst is filtered through a Millipore filter with Celite, some catalyst particles passing through the filter to obtain a black filtrate. The ethanol is removed under reduced pressure and the residue is dissolved in 4 ml of dimethylformamide. 81 mg of N-hydroxy-25 benztriazole raohydrate, 78 mg of phenylacetic acid and 117 mg of dicyclohexylcarbodiimide are added and the mixture is stirred under nitrogen for 16 hours.

The slurry is evaporated in vacuo and triturated with 10 ml of acetone. The resulting slurry is filtered through a Millipore filter with a Celite top and the brown filtrate is treated with 193 30 mg of potassium perfluorobutane sulfonate. After adding 20 ml of ether, a gum separates. The liquid is removed and the gum is washed with ether. The gum is dissolved in 10 ml of methanol. A small amount of precipitate forms after addition of ether.

The mixture is filtered and the colored filtrate treated with more ether. The precipitate formed is filtered and recrystallized twice from ether-methanol to give 26 mg of the title compound.

C, 46.99; H 4.41; N 6.45; 5 Found; C 47 ^ 24; H 4.19; N 6.34.

Example 185 (cis, Z) -3-V / - (2-Amino-4-thiazolyl) (methoxyimino) acetyl / amino-2-oxo-4-phenyl-1-azeididine sulfonic acid, potassium salt.

10 560 mg (cis) -2-Oxo-4-phenyl-3- / (phenylacetyl) - amino __ / - l-azetidine sulfonic acid, potassium salt (see example 184, part O) is dissolved in 5 ml ethanol and hydrogenated with 110 mg platinum oxide as a catalyst at 1 atmosphere. After stirring for 1 hour, the catalyst is filtered through a Millipore filter with Celite, whereby catalyst particles pass through the filter and a black filtrate is obtained. The ethanol is removed under reduced pressure and the residue dissolved in 4 ral dimethylformamide. 168 mg of N-hydroxybenztriazole monohydrate, 221 mg (Z) -2-amino-α- (methoxyimino) -4-thiazole acetic acid and 227 mg dicyclohexylcarbodiiride-20 are added and the mixture is stirred under nitrogen for 16 hours. The slurry is evaporated in vacuo and triturated with 15 ml of acetone. The resulting slurry is filtered through a Millipore with Celite and the filtrate treated with 372 mg of potassium perfluorobutane sulfonate. On addition of 15 ml of ether, a gum separates. The liquid is removed and the gum washed with ether. The gum is dissolved in 5 ml of water and passed over 150 ml of HP-20 resin eluting with water. Fractions 16-34 (30 ml each) are combined and lyophilized to 201 mg of the title compound as a solid.

} Analysis calculated for 1½ h ^ O; 30

Found: C 36.73; H 3.49; N 14.28; S 13.07; K 7.97; C, 36.65; H 3.00; N, 13.99; S, 13.48; K 8.30.

Example 186 (cis) -3-Amino-2-oxo-4- (2-phenylethenyl) -1-azetidine sulfonic acid 35 A) N- (3-Phenyl-2-propenylidene) -4-methoxyaniline 81 00 57 1 - 152 - »*

12.32 g of p-anisidine are dissolved in 160 ml of methylene. chloride and adds 20 g of anhydrous magnesium sulfate. The mixture is cooled in an ice bath and 13.22 g of trans-cinnamaldehyde are added. The mixture is stirred under nitrogen for 2 hours and then filtered.

The filtrate is evaporated to a solid. The crude product is recrystallized from methylene chloride-petroleum ether to give 20.96 g of the title compound as a solid. B) (+) - (cis) -3-Azido-1- (4-methoxyphenyl) - 2-oxo-10 4- (2-phenylethenyl) azetidine.

24.26 g of 2-azidoacetic acid are dissolved in 100 ml of methylene chloride and cooled in an ice bath. To this solution are added 48.57 g of triethylamine and 14.24 g of N- (3-phenyl-2-propylidene) -15 4-methoxyaniline dissolved in 250 ml of methylene chloride. 50.41 g of trifluoroacetic anhydride are added dropwise to the resulting solution over a period of 1 hour. After stirring in an ice bath for 1 hour, the mixture is warmed to room temperature and stirred for 16 hours. The mixture is then diluted with 250 ml of methylene chloride and washed with 750 ml of water, two portions of 750 ml of 5% sodium bicarbonate solution and 750 ml of 1N hydrochloric acid. The organic layer is dried over anhydrous sodium sulfate and the solvent is stripped off to obtain a solid. The crude product is recrystallized from ethyl acetate to give 11.39 g of the title compound as a solid.

C) (+) - (cis) -3-Azido-2-oxo-4- (2-phenylethenyl) azetidine.

To a solution of 10.22 g ceriammonium ni-30 trate in 13 ml water is added at 0 ° C over a period of 15 min. 1.99 g (+) - (cis) -3-azido-1- (4- methoxyphenyl) -2-oxo-4- (2-phenylethenyl) azetidine, dissolved in 65 ml of acetic acid nitrile, using an additional 10 ml of acetic acid nitrile for rinsing. The mixture is stirred for an additional 15 min at 0 ° C, diluted with 750 ral ethyl acetate, washed with six 600 ml portions of water, dried over anhydrous sodium 81 00 57 1 - 153 sulfate and the solvent is stripped to give an oil. The crude product is chromatographed on 90 g of silica gel, using one elute with 250 ml of 30% ethyl acetate / petroleum ether and then with 50% ethyl acetate / petroleum ether. Fractions 11-16 (each of 50 ml) are combined and evaporated to 802 mg of the title compound as an oil.

D) (+) - (cis) -3-Azido-2-oxo-4- (2-phenylethenyl) -1-azetidine sulfonic acid, tetra-n-butylammonium salt.

10 Dissolve 334 mg (+) - (cis) -3-azido-2-oxo-4- (2-

phenylethenyl) -azetidine in 3 ml of dimethylformamide and add 868 mg of pyridine sulfur trioxide. The mixture is stirred at room temperature under nitrogen for 40 hours and then poured into 200 ml of 0.5 M monobasic potassium phosphate solution and washed with 30 ml of methylene chloride. 530 mg of t-n-butylammonium bisulfate are added to the aqueous solution and the mixture is extracted with four 50 ml portions of methylene chloride. The combined organic layers are washed with two 100 ml portions of water, dried over anhydrous magnesium sulfate, and the solvent is stripped to give 824 mg of the title compound as a gum.

E) (+) - (cis) -3-Azido-2-oxo-4- (2-phenylethenyl) -1-azetidine sulfonic acid.

300 mg (+) - (cis) -3-azido-2-oxo-4- (2-phenyl-ethenyl) -1-azetidine sulfonic acid, tetrabutyl ammonium salt is dissolved in 4 ml of tetrahydrofuran and stirred quickly. 600 mg of zinc dust are added to the mixture, followed by 0.8 ml of 1N basic potassium phosphate solution. The mixture is heated to 45 ° C and stirred at this temperature for 3 hours. The mixture is then filtered and the filtrate is taken up in 40 ml of methylene chloride and 10 ml of water. The water layer is further extracted with three 40 ml portions of methylene chloride and the combined methyl chloride layers are freed by solvent stripping to give 256 mg of foam. This crude product is dissolved in a small amount of approximately 30% acetone-water and passed over 7.5 ml of Dowex (k +) · jis (0.7 meq / vnl) under elution with 40 ml of water. The eluent is evaporated to yield. of 151 mg of foam, which is dissolved in 2 ml of water and acidified to pH 2 with 1N hydrochloric acid. A small amount of acetic nitrile is added to dissolve the precipitate and the resulting solution is passed over 15 ml of HP-20 resin eluting with 150 ml of water and then 10% acetone water. Fractions 2-13 (15 ml each) are combined and evaporated to 101 mg of the title compound as a foam.

10 o

Example 187 (+) - (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 (Z) -2-amino-α- (methoxyimino) -4-thiazole acetic acid and 51 mg N-hydroxybenz-triazole monohydrate in 2 ml dimethylformamide with 69 mg dicyclohexylcarbodiimide is treated. The mixture is stirred at room temperature under nitrogen for 30 minutes. 90 mg (cis) -3-amino-2-oxo-4- (2-20 phenylethenyl) -1-azetidine sulfonic acid (see example 186) and 34 mg triethylamine are added and the mixture is stirred under nitrogen for 20 hours. The slurry is evaporated in vacuo and triturated with 10 ml of acetone.

The slurry is filtered and the filtrate treated with 113 mg of potassium perfluorobutane sulfonate. Dilution with 30 ml ether and filtration yields 169 mg of solid product, which is dissolved in a small amount of about 10% acetic nitrile / water and passed over 34 ml of HP-20 resin eluting with 150 ml of water and then with 10% acetone / water. Fractions 16-19 (15 ml each) are combined and liberated by stripping solvent to give 110 mg of the title compound as a solid.

Analysis calculated for C 18 H 20 OgNg 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.

35 8 1 0 0 5 7 1

Example 188 2-oxo-1-azetidine sulfonic acid.

(cis) -3-Amino-4-A) / (4-Methoxyphenyl) imino / acetic acid, raethyl ester.

A 1 L dry three-necked flask equipped with nitrogen inlet and stir bar is charged with 56.88 g of MgSO 2 followed by a solution of 19.43 g of recrystallized anisidine in 250 ml of dichloromethane. After cooling to 0 ° C, a solution of 19.92 g of methyl glyoxylate hemiacetal in 250 ml of dichloromethane is added over 1.5 hours. After stirring for an additional 20 minutes at 0 ° C, the reaction mixture is filtered off, dried over sodium sulfate, filtered and concentrated in vacuo to a quarter volume. 300 ml of hexane are added and the solution is concentrated to an oil which is semi-solidified on standing under high vacuum at 5 ° C. B) (cis) -3- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) -4-methoxycarbonyl-2-oxo-1- (4-methoxyphenyl) azetidine.

A 500 ml dry three-necked flask fitted with a stir bar, addition funnel, septum and nitrogen inlet is charged with a solution of 21.09 g / (4-methoxyphenyl) imino / acetic acid, methyl ester in 150 ml of dichloromethane and cooled to 0 ° C. 19.2 ml or 0.14 mol of triethylamine are added dropwise, followed by a solution of 28.4 g of (N-phthalimido) acetyl chloride in 150 ml of dichloromethane over 1 hour. The resulting mixture is stirred at 0 ° C for 1.5 hours and diluted with 2.5 L of dichloromethane. The organic solution is washed with two 500 ml portions of monobasic potassium phosphate pH 4.5, two 500 ml portions of 5% sodium bicarbonate and 500 ml of saturated sodium chloride solution and dried over sodium sulfate. Filtration and concentration in vacuo give a solid which is washed with ethyl acetate, cold acetone and hexane to obtain 18.65 g of product. C) (cis) -4- (Methoxycarbonyl) -1- (4-methoxyphenyl) -2-oxo-3 - / - / - (phenylmethoxy) carbonyl / amino / azetidine.

- 156 - *

A dry 500 ml flask equipped with a nitrogen inlet, stirring rod and septum is filled with 18.65 g (cis) -3- (1,3-dioxo-2H-isoindol-2-yl) -4-methoxycarbonyl-2-oxo-1 (4-methoxyphenyl) azetidine and 325 ml of dichloromethane. The resulting suspension is cooled to -30 ° C and 3.52 ml of methyl hydrazine is added dropwise. The reaction is warmed to 0 ° C and stirred for 1 hour. An additional 0.4 ml of methylhydrazine is added and the mixture is stirred for 10 min. This sequence is repeated until a total of 2.9 equivalents of methylhydrazine or 7.7 ml is added. . The solvent is removed in vacuo, 200 ml of fresh dichloromethane is added and the mixture is concentrated again. This sequence is repeated two more times and the resulting foam is dried under high vacuum for 20 l) min, redissolved in 225 ml of dichloromethane and left at room temperature for 16 hours during which time a significant amount of solid precipitates. The mixture is filtered under nitrogen, the filtrate cooled to 0 ° C (under nitrogen atmosphere) and treated dropwise with 17 ml of diisopropylethylamine followed by 7 ml of benzyl chloroformate. The reaction is stirred at 0 ° C for 30 min and then 20 l, 5 hours at room temperature. The mixture is washed with two 300 ml portions of pH 4.5 monobasic potassium phosphate buffer, two 300 ml portions of 5% sodium bicarbonate and 300 ml of saturated sodium chloride, dried over sodium sulfate and filtered. Concentration in vacuum yields a foam which "upon rubbing with {T) 25 ether yields 9.9 g of the title compound as a solid, D) (cis) -4- (Methoxycarbonyl) -2-oxo-3 - / ^ / _ (phenylmethoxy) carbonyl / amino / -1-azetidine.

A solution of 8.59 g of cerium ammonium nitrate in 60 ml of 1: 1 acetic nitrile water is treated in 10 min with a slurry of 2 g of (cis) -4- (methoxycarbonyl) -1- (4-methoxyphenyl) - 2-oxo-3- / ((phenylmethoxy) carbonyl-7-amino-azetidine in 50 ml of acetic acid nitrile. The reaction mixture is stirred for an additional 10 hours at room temperature and diluted with 100 ml of ethyl acetate. The separated 8100571 5 - r - 157 - water layer is washed with three 40 ml portions of ethyl acetate and the combined organic extracts are washed with three 70 ml portions of 50% sodium bicarbonate. The basic washings are washed with 50 ml of ethyl acetate and the combined organic extracts. are washed with aqueous sodium bisulfite, 100 ml of 5% aqueous sodium carbonate, two 100 ml portions of 5% sodium chloride solution and two 50 ml portions of saturated sodium chloride and stirred over activated charcoal (Darco G-60) for 30 min. Sodium sulfate is added and the mixture is filtered and concentrated in vacuo to an oil which, when triturated with ether, yields 685 mg of the title compound as a solid.

10 ί; E) (cis) -4- (Methoxycarbonyl) -2-oxo-3- / (phenyl-methoxy) carbonyl / amino-1-azetidine sulfonic acid, tetrabutyl ammonium salt.

15 20 / ί ν,> 25

A mixture of 100 mg (cis) -4- (methoxycarbonyl) -2-OXO-3- / / (phenylmethoxy) carbonyl / amino-1-azetididine and 172 mg pyridine sulfur trioxide complex in 1 ml pyridine is stirred under argon at 80 ° C for 3 hours. The reaction mixture is poured into 70 ml of 0.5 M monobasic potassium phosphate pH 5.5 and extracted with four portions of 30 ml of dichloromethane (discarded). 122 mg of tetrabutyl ammonium hydrogen sulfate are added to the aqueous layer, which is then extracted with four 30 ml portions of dichloromethane. The organic extracts are washed with 8% sodium chloride solution, dried over sodium sulfate and filtered. Concentration in vacuum provides 186 mg of the title compound as a viscous oil.

F) (cis) -3-Amino-4- (methoxycarbonyl) -2-oxo-1-azetidine sulfonic acid.

30 35

A solution of 186 mg (cis) -4- (methoxycarbonyl) -2-oxo-3- (phenylmethoxy) carbonyl / amino-1-azetidine sulfonic acid, tetrabutyl ammonium salt in 2 ml of methanol is hydrogenated at 1 atmosphere for 1.5 hours about 95 mg of 10% palladium on charcoal. The catalyst is filtered off and rinsed with dichloromethane. 81 00 57 1 ΐ-158 - and the filtrate is treated with 97% formic acid and cooled to -50 ° C (at this stage the presence of a seed crystal is necessary to initiate crystallization). After crystallization begins, the mixture is allowed to stand at 10 ° C for 16 hours. The resulting solid is washed with dichloromethane and hexane and dried in vacuo to give 50mg of the title compound.

Example 189 (cis) -3- / / (2-Amino-4-thiazolyl) / _ / _ 1- (diphenylmethoxycarbonyl-1-10 methylethoxy) imino_ / acetyl_ / amino _ / - 4- (methoxycarbonyl) -2-oxo- l-azetidine sulfonic acid, potassium salt.

A solution of 34 mg of N-hydroxy-benztriazole hydrate and 101 mg of 2-amino-α - / - / - 1- (diphenylmethoxycarbonyl) -1-methylethoxy / imino-4-thiazole acetic acid in 0.5 ml of dimethyl is treated - formamide with 45 mg of solid dicyclohexylcarbodiimide and stir the mixture under argon at room temperature for 45 min. 45 mg (cis) -3-amino-4- (methoxycarbonyl) -2-oxo-1-azetidine sulfonic acid (see example 188) are then added as a solid, followed by dropwise administration of 0.03 ml triethylamine. The reaction mixture is stirred at room temperature for 16 hours. The dimethylformamide is removed at 30 ° C under high vacuum and the residue triturated with acetone.

The supernatant is treated with 67 mg of potassium perfluorobutane sulfonate. Dilution with ether gives a solid, which is washed with ether and dried in vacuo to give 93 mg of the title compound.

Example 190 (cis) -3 - / ^ (_ (2-Amino-4-thiazolyl) / (1-carboxy-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 / (diphenylmethoxycarbonyl) -1-methylethoxy / imino-acety1 7-amino-4- (methoxycarbonyl) -2-oxo is stirred -1-azetidine sulfonic acid, 35 potassium salt in 0.4 ml anisole at -12 ° C under argon and add 0.9 ml 81 00 57 1 - 159 - * cold (-10 ° C) trifluoroacetic acid. After 1.5 hours, 4 ml of ether and 2 ml of hexane are added and the resulting slurry is stirred at -10 ° C for 15 min and then at room temperature for 15 min. The solid is centrifuged off and washed with ether. The pH of a suspension of this material in 0.5 ml of cold water is adjusted to 6 with 1 N potassium hydroxide and the whole is passed through a column of 30 ml of HP-20AG. Elution with water after evaporation gives 30 mg of the title compound (two times acetic nitrile added and evaporated).

Analysis calculated for c14H15K2N5 ° gS2: C 31.15; H 2.81; N 12.98;

Found: C 29.08; H 3.03; N 12.19.

Example 191 (S) - (trans) -3-Amino-4-ethynyl-2-oxo-1-azetidine sulfonic acid.

A) 2- (Trimethylsilyl) ethynylmagnesium bromide.

50 ml of dry tetrahydrofuran, 2.20 ml of trimethylsilylacetylene and 5.05 ml of 3.06 M solution of methyl magnesium bromide in ether are placed in a flame-dried 50 ml flask, which is kept under an overpressure of nitrogen. The mixture is stirred for 140 minutes to give the title compound.

B) (S) - (trans) -4 - / - 2- (trimethylsilyl) ethynyl / - 2-OXO-3- / (triphenylmethyl) amino / azetidine.

6.00 g of (S) - (cis) -4- (methylsulfonyl) -2-oxo-3- / (triphenylmethyl) amino / azetidine are placed in a 250 ml flame-dried three-necked flask. purged and then kept under an excess of nitrogen.

After the reaction mixture has been cooled in a dry ice / isopropanol bath, 4.65 ml of a 3.06 M solution of methyl magnesium bromide in ether are added dropwise with rapid stirring via a syringe.

The solution of 2- (trimethylsilyl) -35 ethynylmagnesium bromide prepared according to part A is added via a Teflon tube under nitrogen 8100571 9 * - 160 - r * · '•' • «Λ * 5 10 15 20 positive pressure (the flask is rinsed containing the reagent with 7 ml of tetrahydrofuran). When everything has been added, the cooling bath is removed. After 45 minutes, a solution of 3.5 g of potassium bisulfate in 20 ml of water is added. Most of the tetrahydrofuran is removed on the rotary evaporator. The residue is transferred to a separatory funnel with ether and water. The water layer is separated and extracted twice with ether. The combined ether layers are washed once with saturated aqueous sodium chloride, dried over sodium sulfate and filtered. Removal of the solvent produces a foam, which is chromatographed on a silica column. Elution with 2 1 dichloromethane, 111% ether / dichloromethane, 212% dichloromethane and 1.5 1 10% ether / dichloromethane (fraction 1 = * 1000 ml, fraction 2.3 = 500 ral, fraction 4 - end «250 ml) 1.30 g of the title compound in fractions 2-8 and 1.80 g of corresponding trans isomer in fractions 12-19. Fractions 9-11 contained 1.19 g of a. mixture of cis and trans isomer. C) (S) - (trans) -4-ethynyl-2-oxo-3- (triphenylmethyl) amino / azetidine.

25 30

2.97 g of (S) - (trans) -4 - / - 2- (trimethylsilyl) ethynyl / - 2-oxo-3 - / (triphenylmethyl) amino / azetidine are dissolved in 30 ml of dichloromethane and 330 mg of tetrabutyl ammonium fluoride (containing 20-25% water). After 20 min. The solvent is removed in vacuo. The residue is taken up in ethyl acetate and water. The organic layer is separated, washed once with water and once with saturated sodium chloride in water, dried over sodium sulfate and filtered. Removal of the solvent gives an oil, which is stirred with 60 ml of pentane for 15 min. To obtain 2.35 g of the title compound as a powder (after drying in vacuum).

D) (S) - (trans) -3-amino-4-ethynyl-2-oxo-1-azetidinine sulfonic acid.

404 mg (S) - (trans) -4-ethynyl-2-oxo-3- 81 00 57 1 * - 161 - [_ (triphenylmethyl) amino / azetidine and 560 mg complex of pyridine and sulfur trioxide in a 25 ml flask. After purging the flask with nitrogen, 4 * 13 ml of dry pyridine is added and the mixture is heated at 80-85 ° C for three hours. The mixture is added with rapid stirring to a mixture of 4.0 ml of concentrated hydrochloric acid, 50 ml of water and 50 ml of ethyl acetate. The pH is adjusted to 3.15 with sodium carbonate. The water layer is separated and extracted once with ethyl acetate. The combined organic layer is washed once with saturated aqueous sodium chloride, dried over sodium sulfate and filtered. Removal of solvent in vacuum gives a foam, which is taken up in 10 ml of dichloromethane. 8 ml of 98% formic acid are added and the mixture is concentrated to 4 ml after 15 minutes and 10 ml of dichloromethane are added to obtain a solid suspended in solution. Filtration provides 100 ml of the title compound as a solid (marked discoloration upon melting> 180 ° C).

Example 192 / 3S- / 3 x (Z) / -3- / / (2-Amino-4-thiazolyl) (methoxyimino) acet-4-ethynyl-2-oxo-1-azeididine sulfonic acid, potassium salt.

20 ------------------------------------------------- -----------------

100 mg (Z) -2-amino-α- (methoxyimino) -4-thiazole acetic acid, 85 mg N-hydroxybenztriazole monohydrate and 113 mg dicyclohexylcarbodiimide are weighed into a 10 ml flask. The flask is purged with nitrogen and cooled in an ice-water bath. Then 0.6 ml of dimethylformamide is added and the mixture is stirred for 10 minutes, to which 0.6 ml of dimethylformamide is added. 95 mg (S) - (trans) -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 cooling bath is removed and the mixture stirred for 22 hours. 3 ml of acetone are added and the solids present are filtered off and washed with a further 4 ml of acetone. All solvents are removed in vacuo and the residue is taken up in 5 ml of methanol and 162 mg of potassium perfluorobutane sulfonate are added and dissolved. After standing a solid is deposited, which is centrifuged off to obtain 68 mg of the title compound, m.p. 81 00 57 1

Vi - 162 - *> 230 C.

EXAMPLE 193 - (FIG.) - (S) -3- (3-Dichlorophenyl) thio / acetyl / amino / 2-oxo-1-azetidinesulfonic acid, potassium salt.

100 mg of 3-amino-2-oxo-1-azetidine sulfonic acid are dissolved in 2 ml of dimethylformamide with 0.083 ml of triethylamine. 123 mg or 0.602 mmol of 2,5-dichlorophenylthioacetic acid, 61 mg of N-hydroxybenztriazole hydrate and 124 mg of dicyclohexylcarbodiimide are added, the mixture is stirred at room temperature for 2 hours and then at 5 ° C for 2 days, the solvent is removed and the mixture is then removed. residue in water, filtered through Celite and the filtrate was washed with ethyl acetate. The water layer is combined with dichloromethane, 612 mg of tetrabutyl ammonium bisulfate is added, the pH is raised to 3 with 1N potassium hydroxide solution and, after extracting a total of three times with 15 dichloromethane, dried, the combined extracts are taken over sodium sulfate and the solvent is removed in vacuo. of an oil. A solution of the oil in acetone is added to a solution of 612 mg of potassium perfluorobutane sulfonate in acetone, whereby the product is precipitated. After adding a small amount of ether, the solid is filtered off, washed several times with acetone and dried to obtain 206 mg of powder.

Analysis calculated for C 21 Hg O 2 C C K: C 31.21; H 2.14; N 6.62; Cl 16.75; Found: C 27.90; H 2.11; N 5.84; Cl 18.04.

Example 194 (3S-trans) -3% (2,5-Dichlorophenyl) thio- / acetyl-amino-4-methyl-2-oxo-1-azetidine sulfonic acid, potassium salt.

250 mg (3S-trans) -3-amino-4-methyl-2-oxo-1-azetidine sulfonic acid (see example 139) are dissolved in 2 ml of dimethylformamide with 193 µl triethylamine. 285 mg of 2,5-dichlorophenylthioacetic acid, 213 mg of N-hydroxybenztriazole hydrate and 287 mg of dicyclohexylcarbodiimide are added. After stirring for 16 hours at room temperature 35 ............ .............. ...........

8 1 0 0 57 1

If Mi - 163 - the mixture is filtered and the solvent is removed in vacuo. The residue is taken up in water and filtered. The filtrate is washed with ethyl acetate, covered with a layer of dichloromethane and 4.2 mmol of tetrabutyl ammonium bisulfate is added.

After a total of three extractions with dichloromethane, the combined extracts are dried over sodium sulfate and the solvent is removed in vacuo to give 920 mg of oil. To a solution of the oil in acetone is added 946 mg of potassium perfluorobutane sulfonate dissolved in acetone. A solid is slowly precipitated, which is collected, washed twice with ether and dried to 306 mg of powder. Chromatography on a column of 100 ml HP-20 resin and eluting with 20% acetic nitrile: 80% water, yields the desired product which crystallizes after evaporation of a water: methanol mixture. Trituration of the residue with acetone gives 233 mg of powder, mp 212-213 ° C with decomposition.

Analysis calculated for C12H11N2 ° 5C12S2K: C 32.95) B 2.54; N 6.41; Cl, 16.21; S, 14.66;

Found: C 32.91; H 2.60; N 6.42; Cl, 16.50; S 13.77.

Examples 195-196 When following the procedure of Example 138, use (3S-trans) -3-amino-4-methyl-2-oxo-1-azetidine sulfonic acid instead of (3S-cis) -3-amino- 4-methyl-2-oxo-1-azetidine sulfonic acid and an acid from column I of the table below used instead of (Z) -2-amino-α- (methoxyimino) -4-thiazole acetic acid, the corresponding compound is obtained of column II of the table below.

30 81 00 57 1

* * - 164 - Example Column I Column II

i H • I> 1 ps PIVI ü <Ö, IP o \ s Pi o 0 0 N 0 CI c -π 3 • H g -H 4-i3 I, -r f- & n 'Γ- 8 l N. 1 «JN 1 -» fi m H o, 1> ιΉ K, β HK p oi s'srs 0 A • HO Ή> i P Pi Λ <ΰ —- I Μ a · * · (ö P0, w I KH \ I 10 0 M β X, η · ι-ι o kilA

'ί • 5 p 1 § N H G Ss · η P Ή O) N O lö a O H Pi> 1 O β O 0) 5¾ § 3 .w P VI C? * in <nuo IC "« I CO Η Η H. & OP oacoo 3 aia 0 CN P Pi IH OHO) 0> i B β Λ W • Η P 6 <D * SBP, '-' IO 1 · 7 | O 1 \ | CH 1 -ri «(O g M 1¾¾ Ki * s ca PN if ® C Öi 'OO β G <W -rl * Η Η Ό Pi Ss 3 V - C 01 H a <d <up, nmcc khS ° I o -wuwgpo · Ρ dl T3 kil S §

* c • H

iH * O o «J O Pi o o β • H

io Ή .w N 1, <«\ | Ή I Ss o Pi dl * - M-i vo σι 8100571 * * - 165 -

Example 197 / 3S (RX) _ / - 3- / / / _ (Arainooxoacetyl) amino _ / (4-hydroxyphenyl) acetyl _ / - amino / -2-oxo-1-azetidine sulfonic acid, potassium salt.

_____ ”----------------------: -: ¾ ---------------------- --------------- 5 Following the procedure of Example 28, but using (R) - / - (aminooxoacetyl) amino_ / (4-hydroxyphenyl) acetic acid instead of (Z) -2-amino-α-/ / 2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy / imino / -4-thiazole acetic acid, the title compound, m.p. 128 ° C, is obtained with decomposition.

Example 198 f_ 3S (RX) _ / - 3-V / (2-Amino-4-thiazolyl) / / / 3- / (2-furanylmethylene) -amino __ / - 2-oxo-1-imidazolidinyl_ / carbony amino __ / acetyl / amino-2-oxo-1-azetidine sulfonic acid, potassium salt.

Following the procedure of Example 6, but using (R) -2-amino-ay / / 3-V (2-furanylmethylene) amino-2-oxo-1-imidazolidinyl / carbonyl / amino-4-thiazole acetic acid instead of aminothiazole acetic acid, the title compound having melting point> 250 ° C is obtained.

Example 199

Organic production of EM5117.

9 liters of fermentation.

Chromobacterium violaceum SC 11,378, A.T.C.C. No. 31532 is held on the sterilized agar medium 25 (A):

Gram

Yeast extract 1

Beef extract 1 NZ Amine A 2 30 Glucose 10

Agar 15

Distilled water up to 1 liter

The pH is adjusted to 7.3 before sterilization at 121 ° C for 30 min.

A loop of surface growth of the 81 00 57 1 - 166 - * fe 5 10 15 20 25 30 35 microorganism is taken to inoculate each of three 500 ml Erlenmeyer flasks, each containing 100 ml of the following sterilized medium. (B): Gram Oatmeal 20 Tomato Paste 20 Tap water to 1 liter. The pH is adjusted to 7.0 before sterilizing at 121 ° C for 15 min. The flasks are then incubated at 25 ° C on a rotary shaker (300 rpm, stroke 5 cm) for 24 hours. After approximately incubating as described above, make 1 vol.% Transfers from the growth culture flasks onto 100 500 ml Erlenmeyer flasks, each containing 100 ml of the following sterilized medium (C): Gram Oatmeal 20 Tomato paste 20 Glucose 30 Tap water 1 liter The pH is adjusted to 7.0 before sterilizing at 121 ° C for 15 min. After inoculation, the flasks are incubated at 25 ° C for 18-24 hours on a rotary shaker (300 rpm, stroke 5 cm). The flask contents are then combined and the liquid is centrifuged to yield about 9 liters of supernatant. 250 liters of fermentation. A surface growth loop of an oblique agar culture (medium A) of Chromobacterium violaceum SC 11.738 A.T.C.C. is used. No. 31532 to inoculate each of five 500 ml Erlenmeyer flasks, each containing 100 ml sterilized medium (B). The flasks are then incubated on a rotary shaker (300 rpm, stroke 5 cm) at 25 ° C for 24 hours. After 81 0 0 57 1

* V

Incubation approximately as described above, transfers of 1% by volume from the growth culture flasks to five Erlenmeyer sr 4-liter flasks each containing 1.5 liters of sterilized medium B are made. After inoculation, the flasks are then incubated on a rotary shaker (300 rpm, stroke 5 cm) at 25 ° C for 24 hours. After incubation approximately as described above, a 1% by volume transfer is made to a stirred fermentation tank containing 250 liters of sterilized medium (C). After inoculation, the fermentation is continued under the following conditions: temperature 25 ° C, pressure 70 kPa overpressure, aeration 280 Ι / min, stir 155 rpm. Ucon is added as an anti-fumigant if necessary. Fermentation is complete after 18-24 hours. The fermentation liquid is then adjusted to pH 5.0 with hydrochloric acid and the liquid content of the tank is centrifuged to yield 230 liters of supernatant.

Extraction and purification.

The 250 liter fermentation supernatant is adjusted to pH 5 with sulfuric acid and filtered using 3-5% diatomaceous earth (Celite). The liquid filtrate is extracted with two 30 ml. Portions of 0.005 M cetyldimethylbenzylammonium chloride in methylene chloride.

The combined lower phase is extracted with 6 liters of 0.05 M sodium iodide, which is adjusted to pH 5 with acetic acid. The bottom phase is discarded and the top phase concentrated to 500 ml in vacuo.

The concentrated material is extracted with 400 ml of n-butanol. The top phase is discarded and the bottom phase is concentrated in vacuo to dryness. The residue is dissolved as far as possible in 150 ml of methanol. The insoluble matter is discarded and the methanol solution is concentrated in vacuo to dryness to yield 38.6 g of crude antibiotic.

The crude product is dissolved in 10 ml of metha-35 nol water (1: 1) and chromatographed on a 500 ml column of 81 00 57 1 '- w - 168 - cross-linked dextrangel (Sephadex G-10) in the same solvent mixture. sel, eluting at 2 ml / min. and 20 ml fractions. The active fractions (19r26) are combined and concentrated in vacuo. The 5.23 g residue is mixed with 50 ml of methanol. Insoluble material is filtered and discarded.

The filtrate is concentrated in vacuo.

The 5.0 g material residue is dissolved in 10 ml of sodium 0.01 M phosphate buffer pH 5 and passed over a column of DEAE cellulose (Whatman DE52 cellulose), which is filled and equilibrated with the same buffer. The column is eluted fc'-Λ V; 1 at 5 ml / min. with a linear gradient, prepared from 4 liters of 0.01 M sodium phosphate buffer pH 5 and 4 liters of 0.1 M sodium phosphate buffer pH 5 while receiving 20 ml fractions. The active fractions (192-222) are combined and concentrated in vacuo and material insoluble in methanol is removed with good washing out with methanol. Solvent removal yields 576 mg of material.

This 576 mg residue is dissolved in 4 ml of water and the pH is adjusted to 5 with 1 ml of 0.1 N sodium hydroxide. The solution is chromatographed on a column of alkylated, cross-linked dextrangel (Sephadex LH-20) in water. eluting at 1 ml / min. and collects 10 ml fractions. The active fractions (38-44) are combined and concentrated to give 459 mg of residue.

348 mg of this residue are dissolved in water and passed over a column of macroreticular styrene-divinylbenzene copolymer resin (Diaion HP20AG), which column is first prepared by washing with methanolic potassium hydroxide, methanol, methanolic hydrochloric acid, methanol and water and then is filled with water. The column is eluted with water at 1 ml / min. under-30 catch of 10 ml fractions. The active fractions (36-43) are combined and concentrated to 186.4 mg of material. Chromatography in the same manner of another 100 mg of the 459 mg residue from the previous step yields 51.5 mg of material. At this stage, the 186.4 mg material and 51.5 mg material are substantially pure EM5117 as evidenced by thin layer chromatography and nuclear magnetic resonance spectra. ----------------- - - ............................... ........... - ........................... -.......... ......-........

8100571 w * - 169 - 5 10 15 20 25 30 35

The 186.4 mg portion of EM5117 obtained as above is dissolved in water and passed through an ion exchange resin column (Dowex 50 W ^ 2, 0.074-0.037 mm, potassium form) washing with two bed volumes of water. Concentration of the effluent gives 189.0 mg of crystalline solid. Recrystallization of this material is done by dissolving it in 0.38 ml of water and adding 3.42 ml of methanol. The resulting mixture is cooled on ice and filtered to give 145 mg of crystals. Two further recrystallizations in this manner from water-methanol, 1: 9, yield 95.9 mg of EM 5117, potassium salt, mp 194 ° C with decomposition. Optical rotation in water at 21 ° C (c = 1).

λ (nm) 589 579 546 436 365 L aJ + 94.3 ° +98.6 +113.1 +203 +348

The following fermentation media are effective for the production of EM5117 and can be used in place of media B and C of the above example: Medium D

Nutritional Flower Glucose Gistamine

Grams 30 50 2.5

CaCO3 7 Distilled water up to 1 liter. Medium E

Gram

Yeast Extract 4 Malt Extract 10 Glucose 30 Glycerol 2

Distilled water to 1 liter 81 00 57 1 t - 170 - Adjusted to pH 7.3 for sterilization Medium F Gram Glycerol 10 5 L-Asparagine 5 kh2po4 1 Na „HPO. 2 4 2 Glucose 50 MgSO 4 „7H20 0.2 10 Yeast extract 2.5 Tap water up to 1 liter. Medium G Grams <NH4> 2S04 2 15 L-Asparagine 5 Glucose 50 Glycerol 10 Kh2P ° 4 3 K2HP04 7 20 MgS04.7H20 0.2 Yeast Extract 2.5 Distilled water to 1 liter. pH adjusted to 7.0 • Medium H 25 Grams k2hpo4 7 kh2po4 3 Na citrate 0.5 MgS04 0.1 30 <NH4> 2s04 1 Glucose 30 Yeast Extract 2.5 Distilled water to 1 liter. Medium I 35 Grams 8 1 0 0 57 1 171

Gram

Nutrient flower 10 <HH4> 2S0 * 5

Glucose 50 5

Yeast extract 2.5

CaCO3 5

Distilled water up to 1 liter. Medium J

10 15 20

Gram Baby oatmeal. van Gerber 20 Tomato paste from Contadina 5 Glucose 20 Tap water to 1 liter pH adjusted to 7.0. Medium K Gram Baby oatmeal from Gerber 5 Tomato paste from Contadina 20 Glucose 20 Tap water to 1 liter pH set at 7.0.

Medium L.

Gram

Yeast extract 4 25

Malt extract 10

Glucose 34

Medium M

Gram

Amberex (1003) 5 30

Glucose 30

Tap water up to 1 liter 8 1 0 0 5 7 1 35

X

Medium N.

- 172 -

Amberex Cerelose 5

Tap water up to 1 liter

Example 200

Organic production of EM 5210.

Gluconobacter species SC 11.435 A.T.C.C. No. 31581 is held on the following sterilized agar medium (A): 10

Gram 15

Yeast Extract 1 Beef Extract 1 NZ Amine A 2 Glucose 10 Agar 15

Distilled water to 1 liter. The pH is adjusted to 7.3 before sterilization at 121 ° C for 20 min.

20

A surface growth loop of the slant agar culture (medium A) of Gluconobacter species SC 11,435 is used to inoculate each of three 500 ml Erlenmeyer flasks, each containing 100 ml of the following sterilized medium (B):

Gram

Yeast extract 4 25

Malt extract 10

Dextrose 4

Distilled water to 1 liter. The pH is adjusted to 7.3 before sterilizing at 121 ° C for 15 min.

30 35

Gram 5 33

After the inoculation, the flasks are incubated for 24 hours at 25 ° C on a rotary shaker (300 rpm, stroke 5 cm). After incubating approximately as described above transfers of 1% by volume from the growth culture flasks to 100 Erlenmeyer flasks of 500 ml each containing 100 ml of the following sterilized medium (C): 8100571 * - ï

Grams - 173 - 5 Yeast Extract 5 Glucose ^ 10 Distilled Water 1 liter The medium is sterilized at 121 ° C for 15 min. After inoculation, the flasks are incubated for 18 hours at 25 ° C on a rotary shaker (300 rpm, stroke 5 cm). The flask contents are then collected and the liquid centrifuged to yield about 9 liters of supernatant. f> Extraction and purification (small scale). The active substance from the supernatant 15 · * (10 1) is absorbed into a 500 g column of strong basic anion exchange resin with guaternary ammonium groups, which are bound to a styrene-divinylbenzene copolymer lattice (Dowex AG1-X2 (Cl-) ), washed with water and eluted with 5% sodium chloride in aqueous 0.01 M NaH 2 PO 3. The eluate is concentrated in vacuo. The residue is adsorbed on 250 g of activated carbon, which is washed with water. EM5210 is eluted with methanol-water (1: 1). The active fractions are combined and concentrated in vacuo to give crude EM5210. m CN The crude EM5210 is chromatographed on a 280 ml column of strongly basic anion exchange heirs (Bio.Rad AG 1-X2 (Cl-)) using a linear gradient prepared from 1 liter of water and 1 liter of 2N pyridinium acetate (pH 4.5). The active fractions are combined and concentrated in vacuo. The partially purified EM5210 is further purified by gel filtration of the residue over a 500 ml column of cross-linked dextran gel (Sephadex G-10) eluting with water. The active fractions are combined and concentrated to obtain 26 mg of EM5210. The potassium salt of EM5210 is prepared 81 00 57 1 V t - 174 - by passing EM5210 through a column of cation exchange resin (Dowex 50-X2) in the potassium form.

%

Extraction and purification (large scale).

The liquid filtrate from a 250 liter fermentation (pH 3.7) of Gluconobacter species SC 11.435 is absorbed on 10.8 kg strongly basic anion exchange resin (Dowex 1-X8 (Cl-)). The resin is washed with water and eluted with 5% sodium chloride in 0.01 M sodium dihydrogen phosphate. The 10 active fractions are combined and concentrated to a small volume. The precipitated salt is removed and the filtrate is freed from salt by passing it through an activated carbon column (1.1 kg 0.42-0.84 mm Darco) in water. The column is washed with water and the EM5210 is eluted with methanol-water, 1: 1.

The active fractions are combined and concentrated. The 16 g residue is dissolved in water and chromatographed on a column of 600 ml strong basic ion exchange resin (Bio. Rad AG 1-X2 (Cl "), 0.037-0.074 mm), eluting with a linear gradient prepared from 1 liter of water and 1 liter of 10% sodium 20 chloride in 0.01 M sodium dihydrogen phosphate The active fractions are combined, concentrated in vacuo to a small volume and the precipitated salts are filtered off. The filtrate is passed over a column of macroreticular styrene. divinyl benzene copolymer resin The column is eluted with water The active fractions are combined, concentrated to a small volume and freeze dried, to give 120 mg of sodium salt of EM5210.

In order to convert the sodium salt to the lithium salt, an ion exchange resin column (Dowex 30 50 W-X2, lithium form) is used. 100 mg of the sodium salt is dissolved in 0.5 ml of water, passed over the column and eluted with water. The active fractions are combined and lyophilized directly to give 95 mg of lithium salt of EM5210 as an amorphous solid.

The free acid (internal salt) of EM5210 is prepared by passing a basic salt of EM5210 over a column of weakly acidic ion exchange resin in the H + form. For example, 2 mg of the lithium salt can be passed over a column of Bio. Rad Bio. Rex 70 (H j and elute with water to give 1r45 mg of the free acid (internal salt).

Chemical properties of EM5210.

1) Ninhydrin positive 2) Acid hydrolysis (6N HCl at 115 ° C for 16 hours) yields two major ninhydrin positive stains on paper chromatography (Whatman No. 1, butanol acetic acid water (5: 1: 4) and one weak ninhydrin positive stain, which scares off UV-excited fluorescence The two main ninhydrin positive stains are D-glutamic acid and D-alanine.

15 Physical properties of EM5210.

1) UV spectrum of the sodium salt in water: final absorption.

2) IR. - Main peaks of the lithium salt in KBr: 1770, 1640, 1530, 1384, 1242 and 1051 cm "" 1.

20 3) PMR. - Chemical shifts of the lithium salt in deuterated water, ppm, down from TSP: 1.40 (d, J = 7Hz), approx.2.14 (m), approx.2.44 (m), 3.49 (s), 3.73 (t, J = 6Hz), 3.94 (s), 4.28 (m).

Optical rotation of the free acid (internal salt) in water at 24 ° C (00.15%) (pH 2.7): λ (nm) / o_ / 589 + 73 ° 578 + 79 ° 546 + 91 ° 30 436 + 159 ° 365 + 263 °

The following fermentation media have been found effective for the production of EM5210 and can be used in place of medium (B) and (C) mentioned in the text.

35 81 00 57 1

Medium D.

- 176 -

Gram

Oatmeal 20

Tomato paste 20

Tap water up to 1 liter.

The pH is adjusted to 7.0 before sterilizing at 121 ° C for 15 min.

Medium E

Grams Θ 10 Gistamine 5 Cerelose Tap water up to 1 liter. 11 Sterilization for 15 Medium F min. At 12 15 Grams Glucose 5 Tartaric Acid 2 Yeast Extract 0.5 (iffl4) 2ro4 1 20 «V2S ° 4 2 K2HP04 0.5 NaH ^ PO. 2 4 0.5 MgSO4.7H20 0.2 CaCO3 ^ 1 25 Distilled water to 1 liter. The pH is adjusted to 6.0 121 ° C to sterilize. Medium G before 15. Grams 30 Food Soy Flour 30 Glucose 50 Gistamine 2.5 CaCO3 ^ 7 Distilled Water to 1 L Sterilization at 121 ° C for 30 min.

35 8100571 5 ï β

Medium Η

Gram - 177 - NZ Amine A 10

Cerelose 33

Yeast amine 2.5

Tap water up to 1 liter.

Sterilization at 121 ° C for 15 min. Medium I.

Gram 10

Food soy flour 15

Soluble starch 15

Glucose 50

CoCl2.6H20 0.005

CaCO3 10 15

Distilled water to 1 liter Sterilization at 121 ° C for 30 min. Biological activity 20

The following methodology is used to determine the minimum inhibitory concentration (hereinafter referred to as MIC) of the β-lactams of the invention.

The test organisms are grown in approximately 15-20 ml of antibiotic test liquid (Difco) by inoculating the liquid (in tubes) with a loop of the organism of a BHI (Difco) slant agar culture. The seeded tubes are incubated at 37 ° C for 18-20 hours. These cultures are believed to contain 10 colony-forming units (hereinafter referred to as CFU) per ml. The cultures are diluted at 1: 100 to obtain a final graft content of 10 CFU. The dilutions are made with K-10 liquid (the composition of which will be explained in more detail).

35

The compounds are dissolved in the appropriate diluent at a concentration of 1000 µg / ml. Two-fold dilutions in K-10 liquid are made, resulting in a range from 1000 µg / ml to 0.5 µg / ml. 1.5 ml of each dilution is placed in separate square Petri dishes, into which 81.0 0 57 1 178 - 13.5 ml of K-10 agar is added. (The composition of K-10 agar will be detailed later). The final concentration of the active substance in the agar ranges from 100 µg / ml to 0.05 g / ml. Organism growth control plates containing only agar are prepared and seeded before and after the test plates. The organisms are applied to the agar surface of each plate with a Denley Multipoint Inoculator (which delivers approximately 0.001 ml of each organism), resulting in a final graft of 4 10 CFU on the agar surface.

The plates are incubated at 37 ° C for 18 hours and the MlCs are determined. The MIC is the lowest concentration of the compound that inhibits growth of the organism.

K-10 Liquid is a yeast beef liquid, which contains: 15 Beef extract 1.5 g

Yeast extract 3.0 g

Pepton 6.0 g

Dextrose 1.0 g

Distilled water as needed up to 1 liter.

20 K-10 agar consists of:

Beef extract 1.5 g

Yeast extract 3.0 g

Pepton 6.0 g ^ 25 Dextrose 1.0 g

Agar 15.0 g

Distilled water as needed up to 1 liter. The following tables are the tabulated results obtained when the β-lactams of the invention were tested on various organisms. The number behind each organism refers to the number of the organism in the collection of E.R. Squibb & Sons, Inc., Princeton, New Jersey. A dash (-) in the tables means that the tested compound showed no activity against the organism concerned at 35 100 µg / m.1. The symbol "N.T" means not tested.

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1 · 1 H rp 000 • lotninmooin · 0 0 0 1 1 0 1 1 1 ai oool 1 ncoocNCNtNoocNfoininm 1 0 rlHH H rH rH rH n OOOO in in O in 1 1 0 in in m in 1 CN CN 1 1 I 1 1 1 1 0 1 1 1 1 1 1 1 CN H CN 1 1 1 1 1 1 O 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 I 1 1 σι OH ΗΗΠ co 10 • · · in 0 • · 0 0 O rH 3 3 6 2 0 oh 1 m 1 1 1 1 1 1 0 1 1 1 1 1 1 O 1 1 σ rH rH rH in • * in 5 5 5 8 3 6 5 6 2 1 1 6 1 co in in CO rH • in in 0 • 0 o CN CN OJ O 1 CN CN CN O l £> 1—1 CN 1 6 3 0 1 3 10 CN CN IO co m 1 0 «H rH rH f — i rH rH fH H • LD N · LD σ \ LD LD OO • · · OO 0 0 o 0 0 in co CN CN LD LD 1 cn 0 1 cn in LD 1 OO LD LD LD 1 1 1 1 1 CN 1 1 Η H rH H LD LD LD in 00 in co * · * O • · * O 0 OOOOO in co CN CN CN in 1 cn 0 1 cn m 0 1 0 0 in 0 0 1 1 1 1 1 CN 1 1 (—1 1— | 1 rH H. iH rH rH rH jH - voiOMnm ^ inm ^ cooonincnn c \ o, * i, CNinr ^ r-iOT ,, 3, tr> n «Hco'si'CNro com ^ inro ^ 'jH'iCNOinrMnnn

oooff> noomHcoooff> wffiooco iH rH rH rH I

I 03 • H c m tJi n

ujmotDiHr'LDrrr ^ Γ * σ \ ονοΗωσιθΜΛ CNCOrPr-IOlNrl'CNOO HNNOCnoitNCOq iH

μ -tJ «-u co« α 03 or 81 0 0 57 1 GCl55f -Ί89-

F-10

o o rH

cn σι tn tntnoo · · o o o o o o o o o NNino i Nifloinoifl l o | o I o o I rH iH rH rH r-i r-i r-i r-i I I I I I (

o o o o ininooomooooooo ooo tninmoinicNotntnnroooinoinini lotntni i i — 1 rH rH rH rH rH iH

Γ * {ε x C7i 3.

H .H Φ (!) A U O O> co cn

OOO O O OOO I f O O I I I I 1 I I I I I I I I I I I I I f — 11 — t <—I H rH

O O O O O tn tn o 1 o i ι i H rH rH

I I I I I I I I I 1 1 I I III

Ό -JJ o 3 Ό O U Pk r- cn vo σι tn cn

E co -H C (0 Cr HO

tn nnm ifl (onN> i05 <* nürino (OHninHui ro • · «tn ................... · o tOtOCMCN I ΗΠΌΟΗΟΙΟΗΠΙΟΟΗΠΙΟΜΙΌΜ VO OI ι — IV i — 1 rH ι—)

tn and • · ooo oo oooooo o I ι ι ι ι «ίο ι o tnw ι tanning itnmomtninlin lH lH rH rH rH

co co m and tn o o o o · «mm · · o o o tn o o> ooom ro o tn tn tn o i votoMMNOtntnincsinMtntntnN ^ tn'l tn rH rH rH .......

(omotnHMr'ThtooioMnn'otnmUJcommncin r'ffiotoHcocicninmoo'Ninr'Hai ^ nr'rHco'vriNn cNoi ^ THo (N '> 3in! racQcJiirincoH''fHHΉrHo rCrrncrocnCoNrCoNrCoNrCoNrCrNrCrNrCrNrCrNrCrCrNrCo

0) <U V β JO O 8 * 8 * 8 * § * 2 HA HA HA HA HA 44 CQ CQ CQ tQ 0J

0 0 5 7 t>, * GC155f 00 o

in m mm VO Η H 00 0000 ONHMONOOH «flO io oo io oo in • · · LD O · i i ··········· · · iQ η co m cnj m o oo ooooooooooh hohonki V V V H

HUOlfl fflrlrl Η Ό «ï rl'Ï« p Η Η «ί CO tOOOHOOCNU") p. R · »o ** # ·········· ..... * in o whh irt l dnnoHönoooooowiomooNN H

in in mrotn οοίηοοΗΐοΝοοΝΗΟΟΗ'ίοοιβηιηοιΛ ιο · · »· o» · »·» · * · »····· · · *».

r- (S \ cr η

u * H

0 0) yes n o o> §>, 4J O 3 Ό O S-i CU

in in rH iHH lOH «JHCOHsrHHOOHspcO (aiOHfMH in * * ♦ o ........... · · •••• - •• in O OOrOrOtnOHPOOOOOOOOOOOOOOr-lfOOrOCM rH i — I V V

«Sp o rH

n o rH

mnn vo ic n <n ro vo h «3 m oo oo m imn r-t ••• oo .... ·. ........ m · · · o NiouininHriiooiOHNnHooon'flNNNnm l rH Η H in m in in in m in in rponjO'i'OOOOOCN'a 'f vnoh o · .......... ...... ol ii i lincsooooooooooooooooroo HVVVVVVVV iH

in m m in m m m ooo HrlHOHOOlHHOOOHl'lsrHOCOO · o οοιηιι .................. o <n Η H rH ooco. OOOOOOOOOÖOOOOO. OrlH. VV _VVV_ ιοσιοιηΗΜη · ρΜθ £ ηοΜησιΐοιησΜοωσ3Πΐησιη iN-mon> HcocriOuncno, p <Ninr'Hoi «i 'oho oin« THO (N ^ MCOCDcn «rinco« tr}' H «rNOinMnmn riiNNOOioiOKoooooftnoocnHcoooocncnincoco rH rH rH i-I rI Ή 0) e co • H β cd uo

·> *> Λ n to 05 05 05 3 3 3 3 05 ¢) 05 05 5m & fi 3 3 3 3 O ö o ö 05 05 05 05 3 3 3 3 OQ C5 C5 Ü 0 C3 C5 OOOOO CJ 0 O 3 OT * i OO r ~ J r ~ 5 § · § · § · §- U. «+ L -U CQ CQ CO CO

C3 «T'-i 0 r-5 V ® tt 3 V · ♦» _ sa «co ΛΛΛΛ O CJ ® 05 q qnm Cq & J S <i

0) 0) V β ® O ft * Αι 81 0 0 57 1 GC155f <in

co «H

VO 00 CO iH CO rH co co in • · · · · · · ö Ö · · Hoo noon i vo i i ι © ι © vo ι ι ι \ f l cm i i H rH rH H

in m wtnci cdmoncommomo o η π η n cj ·. · Tind · ....... · · ......... (/) cNiNtecsinddricid o'cn hoo oonn uveudn ι hh v v

rH H iH CO * «3.00 -M * in CO CO CO rf VO .H UO H .... © ..in ·. · ιη · *. · * · In m in in * o nncucindoctocnocniuoo wcocmcmcmcncmcooj rH rH rH

rH E cr o

+ J o 3 Ό O CU

01 E tn * H c 10 crj o

CM iH

iH r—! rH

O iH rH

O O H

tn m VO V0 VO rICOOOOCMHOCMM'CDOM'M'VDHCOHO • · · o o ........ ········. «Mm HH H lil OOOOÖOO rHOOÖOOOi — ICOOCOOCM CM rH V V

in ίο ίο h CMtnnouJcnnvDvoHifH η π in h co oo m • · ino ................. * * m Hrinoilf, ΟΟΙΟΟΗΟΙΟΗΗΠΟΟ Cl VO CM fO VO O CM CM V rH rH

vo vo vo tn ^ TfincMcoiH co vo co tn in co .... in ····. ·· /) ··· ••• mm * tn * in rHiHiHCMCMOOCNOMOfOCNVOrHO O VO CM CM CM CM CMOCM I rH rH rH rH

tn tn tn CO VOCOCOCMCOCMVOCNCMOCMrHOOVOrHVOlOrrtn ··· © © ··· ............. ... o CMCMVOOinrHO © OOOHOOOO OOtHCOHCMOCNO rlH Η V r4 rH rH

vomoiiiHt ^ inMT'VocrioMnmvoinm'ocoraroincrici r "cnovDiHcoo \ cnin <Tio'M, CMinr-Hcri'a, cr> r-'rHco'3, cMCO CMHM'HOClM'NCOCOtnO'oXnCom'M'HN'NMCN'N'MNHN'NCOCOtnM'iniXIM'M'HN''NCOC rH rH rH Η Ή

p * o, ^ MMMlM _ _ a> +> ΛΛΛΛ CV, Ctr 8 · § · 8 · 2 2 -u + i 43 co oj oa oj or cq 81 00 57 1 GCl55f K ο -Ί92- rH ε tP α Ό, H α) I <u • so 8 cj

+ you 3 CU

d) ε W • H c «5 Cr H

CN o CN H cn co vo rH iH t uo uo CO VO H CO co n * co o 6 4 3 2 6 8 0 8 6 1 5 1 3 1 • · · · · · · UO uo OH CO VO 1 oo vo o 1 0 6 0 1 0 0 OH CO CN 3 6 3 2 2 VV rH in η co iH vo 1 6 3 1 1 2 1 6 1 3 5 CO uo uo · o · · · 3. 1. 6. 3. 3.0. 3. Ö UO · α o CN CN CN O 1 CO CO CO H 1 3 6 2 uo cn vo σ α r — 1 rH rH rH rH in LD Η Η H OfflHO CO CN CO 00 Η Η H 6 6 1 3 6 3 2 1 3 • · · OO * · · cococooooocoo 0 0 6 0 3 3 0 1 1 3 6 1 6 0 3 6 H rH VV in ÜO uo uo CO fO iH o co CN o 2 0 4 1 4 2 0 CN CN CD co 4 8 4 co • · · ö o · · · VDVOCOOOOOOO ooooo σ o OO oo 0 0 0 vo uo HH VVVV VO VO H UO *> r rH UO rH VO CO UO co rH CO CN co co co uo vo •••• o ··· o uo HHCOCNOOCOCN o 1 0 2 6 3 6 0 VO VO vo CN VO CN rH UO CN Η Η Ή rH uo uo ΗΗΠ CN VC r — 1 o 8 2 1 6 8 6 0 VO VO rH co 6 6 3 * · * LD O · · · oo COCOVO cn vn O Ή coo 0 0 3 1 0 1 0 rH i — 1 cn vo 1 1 6 oo VV rH rH co co co uo h in uo uo • · · · »· o σ ooo oo uo o σ oo • · o VO VO VO CN | CO CN O uo UO uo O O O CN O O O o 1 1 CN CN 1 uo rH rH rH Η pH Η Η Η H rH. H · H

amomHP-in'a'r ^ vocnoMncnvoinm ^ coco nmm fo ι> ^ ονοΗθ3σιθΜησιό, 3'ίνιΐΛΐ ^ Ησι, ίΠΓΉθ3, ί, οιπ NM'iHoM'J'Ncocom'a'incDrr ^ ri ^ NoinMno-Noo 'NooNNo' ~ NMNNNO '~ NMNNNOO' ~ - r — 1 Η HH r) cocoocncncnoocD

§ · § · § * § * HA + »+ i H4 co CQ CO tQ

8f 0 0 57 1

-193- GCl55f tn m tn cy o in · o o ................. .. cm ιηο4θ4ΐηιητ-ιοσοοοοοοοοοοοβι-ΗοθΝ I rH V V rH

coi-icn oh now rH tr> in oo in in in m rH oo · · · οσ · * m · »-o ...... .0» w * 0 cm οΜΌΐηιηαηΝΟ ιο i-rm mrjtNd ojrjojintN moo i Η H rH iH rH rH rH

HHH VO Π f »» · · · 10 o · · in CJ ΓΟΓΟΠΟΙΟΗΦ I CM f · 1 Η H

in in 11 (0411 (11 (0411 M.I.C. (uq / ml) Product of Example

HHH co rH in tji 0 vo ο h rH 04 0 0 in vo 10 ••• mo ··· »· · in ...... -o in in · in 0 cm nnniNoonNo id η ιί ο η η o uj iooj m «cm« -h cm in rH 1 —I rH rH in moo 'iriOH HCoineorf ^ OriHin in in in m in · · · 0 0 ....... * ....... 0 CM lOlOlOinOOfniOOOOCMOOiHOOOCNmCMCMCMCNI rH rH rH VrHrHiHi — 1 — 4 in in in co-H o in in o is η n in • · · in · · in · · · in tn ·. · · Ό ο o in CM Ol CM CM I Ο Ο Γ4 VO <MCMCMCMVOrHOVCC4 000CM04 II HHH Η H (—it — II — II—! In mm rH Η O VO VO VO O * 3 "rH VO 04 CM Ο © CM TP CO rH CO VOOO O o. .M ···. ············ · * · ο 04 OOlDCM I 1-HrHrHO OOrHOOO OOOOOO HO VOin rH VVV

«3CM rH

01 • H G ns & n O

io <xiotnrHf''io> '3 * r' * io <nor-incniotncniocoajotncno 0'OOvor-ico (Ticnmoo'3'CMmr'rHcn'vror ~ iHco'3'CNO niO'THoiNTjnromcjiYrinro ^ rrH'rnionhncnncnnncnncn r — i rH i — 4 r!

MM M _ _ 3iHi Hi Λ Λ Λ Λ CU CU Ο Λ O O O QQQ -.- .- to to to to to Ö 5 »5) CQ T-i TM

§ · § · § · & £ 8 δ + i -u · «-u ΰ -B y 03 CO CQ 03 Ö3 & 3% § CO 09 Q) TM 3 3CN 3-SS 8 §, O O O TM · Μ

ö Ί * 1 03 CO O 1 S, -Ji ö> ti S _ Hi tS-C 3 Sr Hi tM O M 51 3 ^ CO

51 V to O cu m: 0 0 57 1 GC155f

* - 194- tn in m in in (ΗΓΟ (N Ö <NH TJ1 rH OOO α CN <N · ** ÏN rr 00 «5 OOO ....... * .......... Cf co oom ι öoaoooaoaoooooöö tin iHrlH V VVVV hhh conncoifleoHo ^ 'i'iOHHoifi com in · · · OÖ · * · ► ··· * · »··» * »· lO · · lO η oonimnclO'ociNdocloooNouh« r m rlOOH COrlOO ^ 1 O'f'iWOOrHrinO tj <oa ................. ..o η II ii iindnortoodaoodHonovo «iin i rl -H v MIC (yig / ml) Product of example

r) H m m m vo 4 4 ** · · OO m VOntNtN ((N rH I in o I rH Η Ή rH

O O O (i o LO i i i i i i o i lH rH

tn tnton ^ HricoHcDn «nflo'flH '«' fi <',) uiinH cm · · · o o ................... o fO NNUJini / lOMMO ποόηηοηοηηόγίνπ cno

ro rH

MM O H * rH £ Ν (Ή U5 Η Μ Μ Η1 ΙΟ tn • · · o o · · ld · · · o · · · · · · m o m m m m o vovovom oortnotCHinovotoomMiN un oj cm γή cnlo i — I rH rH

m voc'ivo'ftocjcoNtNH'raHHMMOtn o iflifiifiö · m ·· ............... Γ0 CM CM CM O I NMHOHOHOOOOOOmrUflWON | rH rH rH ...... rH

tDmoinHn'tn ^ n-tooior'incji'ntnm'ncocDMinoiM f'motDrHoocriCfuniTiovNLn r ~ rH oi.h'M ^ hcoh'NM MMVHONH, nlCOCOmr} M / lCOHl ^ rlH, (NainMnMm

cocoooicnfficoco i — I

0) B CQ • H c (0 Oi M O

HNtNOCtOlNfflOOOOmMtDoi rH H rH rl H 3 δ I 3 «ö 6 ö

n r n co ca to ® 3 3 3 3 03 ca ca g • »CS <3 1. to Q v ¢ 1 ο ί o ‘H Λ Η ΤΗ ca k ex m b +? ÖJ-S5 C Sr +3 τη o o> 3 »tt -H 3 tH O TH ö ö Q Q to Η A 3 3 C τη O to (0 O to Ü

0) α * h «eo Oi Ri -¾ 81 00 57 1 GCl55f -195 - ir in m in mifl Tf NNO CO HOO OOrf 00 OQ CO V CO H om · ...... .... ... ... o I l II itncNOooooooooooooooocnm vvvvv

rjmm co vo ττηη mnvovocn m. . .o · «o». . ...... moifl o * io m cn in [onto OW l mu> hhv> m non ion i i rH H I-H rH

M.I.C. (ijq / ml) Product of example

there TT rH

NRH

O TT rH

00 co

HinCOVCOCOHCOOCOOJODejHrICOHH ooo ... ..... ....... ... oops WWO I I nMHOrlOflrlOOOOCifOMrlflflöO rH rH iH rH

• in in E-i · in in CN · CN CN | CNnHHrIOHHHOOOHHfCOO® J CN 3 Ή rH

rHlOVOlOOOlOlOVOrHCOCOlOVOrHCOCOCO

in

in in n oho o co i — i co HvvoiNcocoH co cocoinin moo .................... CN m ΙΟ I I LOVDrHOrHOrHOOOOOOi-HCOrHrHOCNCN V V HH

in tn Cf ηβο ^ rH 00 rH WO CN V 00 CO 00 ΟΟΌΙΠίη in in in- ..................... CN CN CN II ΟΌιΗΟΟ OO ΟΟΟΟΟΟΟιΗ O OrHCNCN VV rH H

in in in in in in Ό01ΗΟΗ OCN OOOOOrlHN rH CN "T ο σ c> .................. o in O in in I [rHOCSOOOOGOOOOOoOOOOOOOCN rH V * V VVVVVV. ..... IH

lomoinHMnvMDmoMncncoinmOcomninmn> mocoHCDmcriinmovNinr'rHcnN '(r) rTHooN | iNcn NrtTfHONVMCOCOmH'lilCOH'ctrHVNOLnMnOin HNtNommiNcooocnmnncoooDCnm

81 0057 1

m ε (0 t4 G «3 oi M O

* 3) 5) * 3) Η »Hi Hi Hi Cq CO CQ CO

o§ «“ CJ C3 CJ cj o ~ CJ _ _ o o o o

§§ · is is Co CO

CJ rH t-n OMM r »« q> sh v · * »0) co Q ΛΛΛΛ O O ¢ 1« 03 0) ri rJ &} & J S * i * <i

HO O OMV

e§ * il O f, 3 O Ti Q5 01 CO α δ S s, § Hi Hi a ε Ο Ο + i ö Ö Q ¢ 3 H5 Λ CJ M Ο Ο Λ Η »S <JC, 'CO 3 CJ Μ »1. Hi CJ CJ 03 ¢ 0 CO C3 O CJ CJ s: sc o Μ Cj Cn Crjri 3 3 CJ f, SH C3 03 03 CJ CJ SH 03 CO + i

Cj Co Λ »τζ -_196, - Ή

-_196, - Ή vo in rH

GCX55f in mHrUommH ^ PiriHHMiHH ♦ O ····· ..... · · · · · O I I I I lNO «dcirnew <no« nn (* nonnii) i l rH e tr 3.

YOU

H

Ό H φ αί sx. M <O O> £> 4J ü 3 Ό O M (¾

ID oo in 1 1 1 1 1 1 1 i in iiiiioo 1 1 1 1 1 1 1 1 1 1 rH rH H po ro in oo in moimn o · · tn oomo tn 1 1 1 1 1 1 1 in vo chcnovocnocncncn oocno 1 1 1 rH rH rH rH rH rH rH rH • mmm in in in 5 2 1 2 T 4 0 0 0 oo rH rH 8 4 2 T VO CN ΙΠ LH 1 1 1 1 CN 2 0 0 0 N 0 0 0 0 oooo 0 0 0 o rH CN rH rH H in mm mrOrHrHVD ^ .inrH'tfCN o -sP vo co 3 1 3 PO in tn rH • · mo tn KO vo CN O 1 VD VOfOOrHOCNOOO oo rH O 6 3 6 VD <N CN rH rH rH V rH rH in in rH rH ro n * ΗΛ0ΟΌ · Ρ110ΓΝ0ΰ10 o co vö 1 6 1 m in o • è • OO in mm VD O 1 O COrHOOOrHOOrH oo O rH 3 1 3 CN 04 in * H rH VV rH rH in m ro ro rH ΗΗΟΟΟ'ίΐη'ίΌΐΰ o to VO VO 3 1 1 rH σι • 1 moon <VO VO CN 1 in 3 3 0 0 0 2 0 1 1 0 1 1 1 6 3 3 P0 o in rH V rH V rH

^ οσίοιηΗΜη-ίΓΊΌσιΟΜησιωιη ^ νοωαιπιησιη Γ'σιθ'ΰΗα3οιθΜηαιο · 'ΓΜΐπΓΉσι, ίΠΓ'Ηο, τΝ (θ

cnooocncricncoco rH

NMii'HOCS'fl'NCOCOOl ^ intD ^ 'TH'TNOinMiinn HN (NoiTimtsmoooooi (ricD (n-Jmmr''T' "'' T'mm rH Η H Hrl <Ί • 1 CO • i ca Ί O co CS a SS ca ** »i cs Cü s £ i cs o Co ca O co * i <i co CS o Cn P co O i O SC,

φ e tn • H C n) Oi M O

§ * 8 · 8 * § * • ü - »« + »co to CO tQ ft ft n; 8 f 0 0 57 1 * Μ. -.197- GCl55f # «- * Λ iH u CS) ε 0 CO \ tn 0>« H ne <β> • iH u + l SO «O · —i HD • Ό S 0 U Οι cn in ri <u ε co • Ή c fij oi uo in ri in in in tn in in 4 1 8 0 2 0 0 0 0 0 1 1 8 4 8 4 6 * at ···· ........ 1! 1 1 I mcsoooooooooooo OOOOHOVVVVVV ri m nnri'rincD'fitNN'N'NMnnnHHn in · m CS) CN CN 1 I loiocoocNOr-ioooooioiosomcotöin in ri iH ι-l ri CN N * o * •om · o ooo · in ooo ι I tn i cn oll I f I CN 1 t iH ri m Ό * CNi-lHCOCNCNOCNCN- ^ CN 4 2 4 8 5 O ......... · · · 1 II 1 I OIOOOOOOOOOOOO OOOO CN O iH ri ri ooo 1 1 1 t I II1IOOIOIIIIII 1 I ((f I r-tl — t 1-t in in in m vo tn • · · oo • · om tn tn o ooooomoo oo · oo cNCNCNinosOiHtncNcNCNin inmininmcNino tnincNino Η Η Η Η Η H rH. Ri. Ri. Η Ή

§ * § * § * § * · »+> +> +» Co CQ CQ to O O O m co co PO PO PO

03 C3 3 3

¢) r-3 rQ k NO 1-i • 1 · »63 1 ·» CQ ö co O ·> O r-3 3 ri -tJ rJ M tt> Fi fX 0) C3: § & C33-S3 3 es ca ___sill 8.SO o ® OO οώνί! 81 0 0 57 1

Claims (41)

1. β-Lactam with a sulfonic acid salt substituent ~ 2 ° M + »in which M + represents hydrogen or a cation at the 1-position and with an amino substituent -Ni ^ or a protected form thereof at the 3-position. la. β-Lactam with a sulfonic acid salt substituent -SO ^ M +, in which M + represents hydrogen or a cation at the 1-position and with an azido substituent -N ^ at the 3-position. 2. β-Lactam according to claim 1, with a sulfonic acid salt substituent -SO ^ M +, wherein M + represents hydrogen or a cation at the 1-position and with an amino substituent -NHj or a protected form thereof at the 3-position and an alkyl substituent at the 4-position. 2a. β-Lactam according to claim 1 with a sulfone-* * f · | · 15 acid salt substituent -SO ^ M, wherein M represents hydrogen or a cation at the 1-position and with an amino substituent -NHj or a protected form thereof at the 3-position and cycloalkyl, phenyl or substituted phenyl in the 4-position. 2b. β-Lactam according to claim 1 with a sulfone-mm * J20 acid salt substituent -SO ^ M, wherein M represents hydrogen or a cation at the 1-position and with an amino substituent -NI ^ or a protected form thereof at the 3 site and alkoxycarbonyl, alken-1-yl, alkyne-1-yl, 2-phenylethenyl or 2-phenylethynyl in the 4-position. 2c. β-Lactam according to claim 1, with a sulfonic acid salt substituent -SO ^ M, wherein M represents hydrogen or a cation in the 1-position and with an azido substituent -N ^ in the 3-position and an alkyl substituent in the 4-position -place. 2d. β-Lactam according to claim 1 with a sulfonic acid salt substituent -SO ^ M, wherein M represents hydrogen or a cation in the 1-position and with an azido substituent -N ^ in the 3-position and cycloalkyl, phenyl or substituted phenyl in 4th place 2nd. β-Lactam according to claim 1 with a sulfonic acid salt substituent -SO ^ ~ M +, wherein M + represents hydrogen or a cation 00 57 1 t '3è - 199 - in the 1-position and with an azido substituent -N ^ in the 3-position and alkoxycarbonyl, alken-1-yl, alkyne-1-yl, 2-phenylethenyl or 2-phenylethynyl in the 4-position. 3. β-Lactam according to claim 2 with a sulfonic acid salt substituent -SO ^ M, wherein M represents hydrogen or a cation at the 1-position, an amino substituent -N ^ or a protected form thereof at the 3-position and a methyl substituent in the 4-position. Β-Lactam according to claim 1 of formula 11a, wherein hydrogen or alkoxy represents 1-4 carbon atoms and and are the same or different and each represent hydrogen, alkyl, cycloalkyl, phenyl or substituted phenyl, or one of Rg and hydrogen and the other alkoxycarbonyl, alken-1-yl, alkyne-1-yl, 2-phenylethenyl or 2-phenylethynyl and M + represents hydrogen or a cation. 4a. β-Lactam according to claim 1 of the formula la, wherein the symbols have the same meaning as in claim 4, with the proviso that the amino group has been replaced by an azido group. 5. β-Lactam according to claim 4 or 4a, characterized in that it represents hydrogen. Β-Lactam according to claim 5, characterized in that R 1 and R 1 represent methyl. 7. β-Lactam according to claim 5, characterized in that R 1 and R 1 represent hydrogen. Β-Lactam according to claim 5, characterized in that R 1 represents hydrogen and R 4 represents methyl. Β-Lactam according to claim 5, characterized in that R 3 represents methyl and R 1 represents hydrogen. 10. β-Lactam according to claims 4-9, characterized in that the amino substituent (-N ^) is protected in the 3-position. Β-lactam according to claim 10, characterized in that the amino substituent is in the form of an azido group. 12. β-Lactam according to claim 11, characterized 81 0 0 57 1 - 200 - mark. that it has the formula 68, wherein R 1 and R 3 are the same or-3 4 different and each represents hydrogen or alkyl and M represents hydrogen or a cation. 13. β-Lactam according to claim 12, characterized in that R 1 and R 1 are the same or different and each represents hydrogen or methyl. 14. β-Lactam with a sulfonic acid salt substituent -SO 3 M +, wherein M + represents hydrogen or a cation at the 1-position and with an acylamino substituent at the 3-position. 15. β-Lactam according to claim 14 with a sulfonic acid salt substituent -SO ^ M +, wherein M + represents hydrogen or a cation at the 1 position and with an acylamino substituent at the 3 position and an alkyl substituent at the 4 position. 16. β-Lactam according to claim 14, with a sulfonic acid salt substituent -SO ^ M, wherein M represents hydrogen or a cation in the 1-position and with an acylamino substituent in the 3-position and a methyl substituent in the 4-position -place. 17. β-Lactam according to claim 14 of the formula 1, wherein R 1 represents acyl, R 2 represents hydrogen or alkoxy with 1-4 carbon atoms, and R 1 represents the same or different and each represents hydrogen or alkyl, cycloalkyl or phenyl in addition, when one of the symbols R 1 and R 1 represents hydrogen, the other alkenyl, styryl, alkynyl, alkoxy, alkylthio, carboxyl or an alkyl ester thereof, hydroxymethyl, lower alkylsulfonylmethyl, phenylsulfonylmethyl, wherein the phenyl group is methyl or halogen substituted, halomethyl, mercaptomethyl or a benzyl or triphenylmethylthio derivative thereof, may represent azidomethyl or aminomethyl and M represents hydrogen or a cation. 18. β-Lactam according to claim 17, characterized in that R2 represents hydrogen. Β-Lactam according to claim 18, characterized in that R 1 and R 1 represent methyl. 20. β-Lactam according to claim 18, characterized in that R. and R, represent hydrogen, -3 4 81 00 57 1 5 & V - 201 - 21. 8-Lactam according to claim 18, characterized which R1 represents hydrogen and methyl. 8. Lactam according to claim 18, characterized in that R 1 represents methyl and hydrogen. G-Lactam according to claims 17-22, characterized in that R 1 represents an aliphatic group of the formula R (CO) - in which R 1. alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, cyclohexadienyl or alkyl or alkenyl substituted with one or more halogen, cyano, nitro, amino, mercapto, alkylthio or cyano-methylthio groups. Β-Lactam according to claims 17-22, characterized in that R 1 represents a carbocyclic aromatic group of one of formulas 35 to 40, wherein n is 0, 1, 2 or 3, Rg, and Rq each independently from each other hydrogen, halogen, hydroxyl, O nitro, amino, cyano, trifluoromethyl, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms or amino and Rg amino, hydroxyl, a carboxyl salt, protected carboxyl, formyloxy, a sulfo salt, a sulfoamino salt, azido, halogen, hydrazino, alkyl hydrazino, phenylhydrazino or f (alkylthio) thioxomethyl / thio. Lactam according to claims 17-22, characterized in that R 1 represents a heteroaromatic group of one of formulas 45 to 49, wherein n is 0, 1, 2 or 3, R 9 amino, hydroxyl, a carboxyl salt protected carboxyl, formyloxy, a sulfo salt, a sulfoamino salt, azido, halogen, hydrazino, alkylhydrazino, phenylhydrazino or / _ (alkylthio) thioxomethyl / thio and R ^ represents an unsubstituted or substituted 5-, 6- or 7-membered heterocyclic aromatic ring with 1, 2, 3 or 4 nitrogen, oxygen and / or sulfur atoms. 26. β-Lactam according to claims 17-22, characterized in that R 1 represents a group of the formula 50, wherein R 1 (1) represents a group of the formula 51, wherein R 8, R 8 and Rg each independently represent hydrogen, halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms or aminomethyl, or (II) an al or 1 00 57 1 s. I * - 202 - represents unsubstituted 5-, 6- or 7-membered heterocyclic ring with 1, 2, 3 or 4 nitrogen, oxygen and / or sulfur atoms and R12 -NH (CO) -Rjj, alkylcarbonylamino, alkyl or alkyl, substituted with one or more halogen, cyano, nitro, amino and / or 5 mercapto groups. 27. β-Lactam according to claims 17-22, characterized in that R 1 represents a group of the formula 52, wherein R 1 (I) represents a group of the formula 51, wherein R 1, R 1 and R 1 each independently represents hydrogen, halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms or aminomethyl or (II) an unsubstituted or substituted 5-6 - or 7-membered heterocyclic ring with C 1, 2, 3 or 4 nitrogen, oxygen and / or sulfur atoms and R 1 hydrogen, alkyl, cycloalkyl, alkylaminocarbonyl, - (CO 3 NH-R 1, or alkyl, substituted with one or more halogen, cyano, nitro, amino, mercapto, alkylthio, R 1, carboxyl, carboxyl salt, amido, alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkoxyphinyl, dihydroxyphosphinyl, hydroxy (phenylmethoxy) phosphinyl or dialkoxyphosphinyl substituents β. -Lactam according to claims 17-22, characterized in that R 1 represents a group of frontal groups of formula 53, w aarin R ^ (I) represents a group of formula 51, wherein Rg, R ^ and Rg are each independently hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1-4 carbon atoms, alkoxy of x 25 1- Represent 4 carbon atoms or aminomethyl, or (II) represents an unsubstituted or substituted 5-, 6- or 7-membered heterocyclic ring with 1, 2, 3 or 4 nitrogen, sulfur and / or sulfur atoms and R 1 a group of the formula 54 (wherein n is 0, 1, 2 or 3), amino, alkylamino, (cyanoalkyl) araino, amido, alkylamido, (cyanoalky.1) -30 amido, or a group of any one of formulas 55 to 60. 29.-Lactam according to claims 17-22, characterized in that R 1 represents a group of the formula 61, wherein R 1 (I) represents a group of the formula 51, wherein R 8, R 1 and R 8 each independently hydrogen , halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon 810057 1 5 - 203 - ί * V atoms or aminomethyl represent or (II) an or not substituted 5-, 6- or 7-membered heterocyclic ring with 1,2, 3 or 4 nitrogen, oxygen and / or sulfur atoms and hydrogen, alkylsulfonyl, -N = CH-R ,,, - (CO) -R ( wherein R 1 represents hydrogen, 11 10 alkyl, or haloalkyl), alkyl or alkyl substituted with one or more halogen, cyano, nitro, amino and / or mercapto groups. 30. Lactam according to claim 27, characterized in that R 1 represents 2-amino-4-thiazolyl. 10-Lactam according to claim 30, characterized in that it is a salt of 3 3S (Z) /-3- / / (2-amino-4-thiazolyl) - (methoxyimino) acetyl-amino-2-oxo-1-azetidine sulfonic acid. 32. Lactam according to claim 30, characterized in that it is a salt of 3 3S (Z) / - 3-£ (2-amino-4-thiazolyl) - ((carboxymethoxy) imino / acetyl / amino. / -2-oxo-1-azetidine sulfonic acid. 33. Lactam according to claim 30, characterized in that it is a salt of 3 3S (Z) /-3- / ((2-amino-4-thiazolyl) - ((1-carboxy-1-methyl-ethoxy) imino / acetyl / amino / 2-oxo-1-azetidinesulfonic acid. 34. Lactam according to claim 30, characterized in that it is a salt of £ 3S £ 3a (z), 40-3 £ ((2-amino-4-thiazolyl) (methoxyimino) acetyl / amino_ / -4-methyl-2-oxo-1-azetidin-sulfonic acid. 35.-Lactam according to claim 30, characterized in that it is a salt of 3 3 S £ 3 α (Z), 40 / / 3 3 £ £ ((carboxymethoxy) imino / (2-amino-4- thiazolyl) acetyl / amino / -4-methyl-2-oxo-1-azetidine sulfonic acid. 36.-Lactam according to claim 30, characterized in that it is a salt of £ 3S-£ 3α (Z), 40% / -3- £ (2-amino-4-thiazolyl) £ (1- carboxy-1-methylethoxy) imino / acetyl / amino / 4-methyl-2-oxo-1-azetidine sulfonic acid. 37.-Lactam according to claim 30, characterized in that it is the dipotassium salt of £ 3S-£ 3α (Z), 4β / -3- £ (2-amino-4-thiazolyl) £ (1- carboxy-1-methylethoxy) imino / acetyl / amino-4-methyl-2-oxo-1-azetidine sulfonic acid. 8100571-204 - 10 O 15 20 25 30 35 38. -Lactam according to claim 30, characterized in that it is a salt of 3S- / 3a (Z), 4a _ / _ / - 3 - / _ / _ (2-amino-4-thiazolyl) (methoxyimino) acetyl / amino-4-methyl-2-oxo-1-azetidinesulfonic acid. 39.-Lactam according to claim 30, characterized in that it is a salt of f-3S - / - 3a (Z), 4α - / / - 3 - / - A- (2-amino-4-thiazolyl) / (1-carboxy-1-methylethoxy) imino / acetyl / amino-4-methyl-2-oxo-1-azetidine sulfonic acid. Β-Lactam according to claim 29, characterized in that R 1 represents a group of the formula 69, 41. β-Lactam according to claim 40, characterized in that R 1 represents a group of the formula 70. 42 β-Lactam according to claim 40, characterized in that it is a salt of / ^ 33 (^) ^ / - 3 - / ^ / £ / / ~ 3- / ~ (2-furanyl-methylene) amino - / - 2-oxo-1-imidazolidinyl / carbonyl / amino / phenyl-acetyl / amino / 2-oxo-1-azetidine sulfonic acid. Β-Lactam according to claim 40, characterized in that it is a salt of / "* 3S- / ~ 3a (RX) 7-3-Γ" Γ "/ ^ 3- / (2-furanylmethylene) amino_ / -2-oxo-1-imidazolidinyl / carbonyl / -amino / phenylacetyl / amino-4-methyl-2-oxo-1-azetidine sulfonic acid 44.-Lactam according to claim 40, characterized in that it is a salt of / 3S - / _ 3a (R *), 4a _ / _ / - 3- / /, ///. 3- / (2-furanylmethylene) amino_7-2-oxo-1-imidazolidinyl_ / carbonyl _ / - amino_ / phenylacetyl_ / amino-4-methyl-2-oxo-1-azeididine sulfonic acid 45. -Lactam according to claim 26, characterized in that R 1 represents a group of formula 71. 46. β-Lactam according to claim 45, characterized in that it is a salt of / _ 3S (RX) _ / - 3 - / _ / _ [_ / _ (4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl / amino_ / phenylacetyl / amino / -2-oxo-1-azetidine sulfonic acid 47. β-Lactam according to claim 45, characterized in that it is a salt of / 3S - / - 3a (RX), 4β - / - / - 3 - / _ / _ / _ / _ (4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl_ / amino_ / phenylacetyl _ / - amino _ / - 4-methyl-2-oxo-1-azetidine sulfo acid. 48. β-Lactam according to claim 45, characterized in that it is a salt of / 3S- / 3a (RX), 4a / / -3- / / ~ ~ / * "" / - (4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl / amino / phenylacetyl / amino / 4-methyl-2-oxo-1-azetidine sulfonic acid. 49. A method of treating bacterial infections in mammals, characterized in that an mammal is administered as required with an effective amount of an O-lactam of the formula I wherein acyl represents R2 hydrogen or alkoxy of 1-4 carbon atoms R4 and R4 are the same or different and each represents hydrogen or alkyl and M + represents hydrogen or a cation. 50. A composition characterized in that it contains an effective amount of 0-lactam of the formula 1 wherein acyl represents R2 represents hydrogen or an alkoxy of 1-4 carbon atoms, R1 and R2 are the same or different and each represents hydrogen or alkyl, cycloalkyl or phenyl, in addition, when one of the symbols R 1 and R 1 represents hydrogen, the other represents alkenyl, styryl, alkynyl, alkoxy, alkylthio, carboxyl or an alkyl ester thereof, hydroxymethyl, lower alkylsulfonylmethyl, phenylsulfonyl-methyl, wherein the phenyl group may be substituted with methyl or halogen, halomethyl, mercaptomethyl or a benzyl or triphenyl-methylthio derivative thereof represents azidomethyl or aminomethyl and M + represents hydrogen or a cation. 51, A compound of formula 72 wherein R 1 -NH- represents a protected amino group, or wherein R 1 represents acyl, V represents a leaving group, such as methanesulfonyl, benzenesulfonyl, toluenesulfonyl, chlorine, bromine or iodine, while R 3 and R 4 above meaning and the free amino group may be in sulfonic acid salt form. 52. A compound of formula 24, wherein the corresponding symbols have the same meaning as in claim 4. 53. A compound of formula 32, wherein the corresponding symbols have the same meaning as in claim 4. 54. A process for preparing a 0-lactam 81 00 57 1 - 206 - with a sulfonic acid salt substituent -SO ^ M +, wherein M + represents hydrogen or a cation in the 1-position and an amino substituent -NH2 or a protected form thereof in the 3-position, with the characterized in that a corresponding β-lactam with a hydrogen substituent in the 1-position and a protected amino substituent in the 3-position is sulfonated and the protecting group is removed from the amino. 55. Process according to claim 54, characterized in that the amino substituent is acylated in the 3-position and this acylation is carried out before or after the sulfonation reaction. 56. Process according to claim 54 or 55, characterized in that the product contains an alkyl substituent in the 4-position. 57. Process according to claims 54-56, characterized in that the product has the formula I, wherein R 1 represents hydrogen or 15 acyl or the group -NH-protected amino, r 2 represents hydrogen or alkoxy of 1-4 carbon atoms, R 1 and R 2 are the same or different and each represent hydrogen, alkyl, cycloalkyl, phenyl or substituted phenyl, or wherein one of the symbols R 1 and R 2 represents hydrogen and the other alkoxycarbonyl, 1, 20-olken-1-yl, alkyn-1 -yl, 2-phenylethenyl or 2-phenylethynyl and M + represents hydrogen or a cation and the sulfonation is carried out on a compound of the formula 73, or a precursor thereof of the formula 72, which is cyclized while the sulfonation reaction is carried out before or after the cyclization and R 1 -NH- in reagents represents a protecting amino group or R 7 acyl, V represents a leaving group as methanesulfonyl, benzenesulfonyl, toluenesulfonyl, chlorine, bromine or iodine and R 2, R 3 and R 3 top-notch m have the meaning. 58. A process according to claim 57, characterized in that R 1 represents hydrogen or the group R 1 -NH- represents a protected amino group. 59. Process according to claim 57, characterized in that R 1 represents acyl. 60. Process according to claim 57, characterized in that the acyl group is selected from: 10057 1 - 207 - <5 ΪΓ a. Represents an aliphatic group of the formula Rg (CO) - wherein R <-alkyl, cycloalkyl alkoxy, alkenyl, cycloalkenyl, cyclohexadienyl or alkyl or alkenyl substituted with one or more halogen, cyano, nitro, amino, mercapto, alkylthio or cyano-methylthio groups, b. a carboxylic aromatic group of any one of formulas 35 to 40, wherein n is 0, 1, 2 or 3, R_, R5 and R_ each independently hydrogen, halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms or amino and Rg represents amino, hydroxyl, a carboxyl salt, protected carboxyl, formyloxy, a sulfo salt, a sulfoamino salt, azido, halogen, hydrazino, alkylhydrazino, phenylhydrazino or / (alkylthio ) represents thioxomethyl / thio, c. a heteroaromatic groups of any one of formulas 45 to 49, wherein n is 0, 1, 2 or 3, RQ amino, hydroxyl, a carboxylic acid salt, protected carboxyl, formyloxy, a sulfo salt, a sulfoamino salt, azido, halogen, hydrazino, alkylhydrazino, phenylhydrazino or [- (alkylthio) thioxomethyl / thio and R 1 represents an unsubstituted or substituted 5-, 6- or 7-membered heterocyclic ring containing 1,2, 3 or 4 nitrogen, oxygen and / or sulfur atom. men, d. groups of the formula 50, wherein R ^ (I) represents a group of the formula 51, wherein Rg, and Rg are each independently hydrogen, halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms or aminomethyl, or (II) represents an unsubstituted or substituted 5-, 6- or 7-membered heterocyclic ring with 1, 2, 3 or 4 nitrogen, oxygen and / or sulfur atoms and R ^ - N = CH-R 1, -NH (CO) R 1, alkylcarbonylamino, alkyl or alkyl substituted with one or more halogen, cyano, nitro, amino and / or mercapto groups, e. groups of the formula 52, wherein R (I) represents a group of the formula 51, wherein Rg, Rl and Rg each independently hydrogen, halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, alkyl of 1-4 carbon atoms , alkoxy with 1-4 carbon 81 00 57 1% by weight - 208 - material atoms or aminomethyl, or (II) represents an unsubstituted or substituted 5-, 6- or 7-membered heterocyclic ring with 1, 2, 3 or 4 nitrogen, oxygen and / or sulfur atoms and hydrogen, alkyl, cycloalkyl, alkylaminocarbonyl, - (CO) -NH-R 3, or 5 alkyl, substituted with one or more halogen, cyano, nitro, amino, mercapto, alkylthio, R 4 represents carboxyl, carboxyl salt, amido, alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkoxyphosphinyl, dihydroxyphosphinyl, hydroxy (phenylmethoxy) phosphinyl or dialkoxyphosphinyl substituents. 10 f. groups of the formula 53, wherein R ^ (I) Ο represents a group of the formula 51, wherein Rg, R ^ and Rg are each independently hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1-4 carbon atoms , alkoxy of 1-4 carbon atoms or aminomethyl or (II) represents a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring with 1, 2, 3 or 4 nitrogen, oxygen and / or sulfur atoms and R ^ represents a group of formula 54, wherein n is 0, 1, 2 or 3, amino, alkylamino, (cyanoalkyl) amino, amido, alkylamido, (cyanoalkyl) -araido or a group of any one of formulas 55 to 60 , 20 g. groups of the formula 61, wherein R ^ (I) r · -. tv represents a group of formula 51 wherein Rg, Rl and Rg independently represent hydrogen, halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms or aminomethyl or (II) represents an unsubstituted or substituted 5-, 6- or 7-membered heterocyclic ring with 1,2, 3 or 4 nitrogen, oxygen, and / or sulfur atoms and R 1 hydrogen, alkylsulfonyl, -N = CH-R . ,, - (CO) R, ct where R.,. water represents 11 lb lb of substance, alkyl or haloalkyl, R 1 alkyl, or alkyl substituted with one or more halogen, cyano, nitro, amino or mercap-30 groups. 61. Process according to claim 60, characterized in that R 1 represents 2-amino-4-thiazolyl. 62. Process according to claim 61, characterized in that the product is a salt of / 3S (2) ^ / - 3 - / _ / (2-amino-4 ~ 35 thiazolyl) (methoxyimino) acetyl / amino _ / - 2 -oxo-1-azetidine sulfonic acid. 8 1 0 0 5 7 1 ^ * - 209 - 63. Process according to claim 61, characterized in that the product is a salt of / 3S (Z) _ / - 3 - / * ~ / (2-amino-4-thiazolyl) (carboxymethoxy) imino / acetyl / amino_ / -2-oxo-1-azetidine sulfonic acid. 64. Process according to claim 61, characterized in that the product is a salt of / 3S (Z) / -3-V / (2-amino-4-thiazolyl) f_ (1-carboxy-1-methyl-ethoxy) imino_ / acetyl / amino / 2-oxo-1-azetidine sulfonic acid. 65. Process according to claim 61, characterized in that the product is a salt of / 3S- / 3α (Z), 4β / __ / - 3- / / (2-amino-4-thiazolyl) (methoxyimino acetyl / amino-4-methyl-2-oxo-1-azetidine sulfonic acid. 66. Process according to claim 61, characterized in that the product is a salt of / 3S- / 3a (z), 48 __ / _ / - 3 - * / / / "" (carboxymethoxy) imino __ / (2 -amino-4-thiazolyl) acetyl / amino-4-methyl-2-oxo-1-azetidine sulfonic acid. 67. Process according to claim 61, characterized in that the product is a salt of / 3S- / 3a (z), 4β / / - 3 - / _ / (2-amino-4-thiazoly1) / {1- carboxy-1-methylethoxy) imino / acetyl / 20 amino / 4-methyl-2-oxo-1-azetidine sulfonic acid. 68. Process according to claim 67, characterized in that the product is the dipotassium salt of / _ 3S- / 3α (Z), 48 / / -3 - / _ / _ (2-amino-4-thiazolyl) (1- carboxy-1-methylethoxy) imino / acetyl / amino / 4-methyl-2-oxo-1-azetidine sulfonic acid. 69. Process according to claim 61, characterized in that the product is a salt of / 3SV 3α (Z), 4a / / - 3- / ~ V (2-amino-4-thiazolyl) (methoxyimino) acetyl_ / amino / 4-methyl-2-oxo-1-azetidine sulfonic acid. 70. Process according to claim 61, characterized in that the product is a salt of / 3S- / 3α (Z), 4a-/ - / - 3- / / (2-amino-4-thiazoly 1) / (1-carboxy-1-methyl-lethoxy) imino / acetyl / amino-4 / methyl-2-oxo-1-azetidine sulfonic acid. 71. Process according to claim 61, characterized in that the product is a salt of 3S (RK) - / - 3 - / - //././, 3 - 35 [- (2-furanylmethylene) amino - / - 2 -oxo-1-imidazolidinyl / carbonyl / - 81 0 0 57 1 - 210 - amino / phenylacetyl / amino / / - 2-oxo-1-aze tidine sulfonic acid. 72. A process according to claim 61, characterized in that the product is a salt of / - 3S - / - 3a (RX), 4β - / - / - 3-LLLLL-L (2-furanylmethylene) amino-2- oxo-1-imidazolidinyl / 5-carbonyl / amino-phenylacetyl / amino / 4-methyl-2-oxo-1-azetidine sulfonic acid. 73. Process according to claim 61, characterized in that the product is a salt of [_ 3S- / 3a (RX), 4a _ / __ / - 3 - // £ / _ / 3 - / _ (2-furanylmethylene) amino-2-oxo-1-imidazolidinyl-10-carbonyl / amino / phenylacetyl / amino-4-methyl-2-oxo-1-azetidine sulfonic acid. 74. A process according to claim 61, characterized in that the product is a salt of / 3S (RX) __ / - 3- / /./,/. (4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl / amino / phenylacetyl / amino / 15 2-oxo-1-azetidine sulfonic acid. 75. Process according to claim 61, characterized in that the product is a salt of β-3S - / - 3a (RX) _ / .43- / / / / (4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl / amino / phenyl-acetyl / amino / 4-methyl-2-oxo-1-azetidine sulfonic acid. mm mm 76. Process according to claim 61, characterized in that the product is a salt of / _ 3S - / _ 3a (RX), 4a / / -3 - [_ / _ / _ / _ (4-ethyl-2 3-dioxo-1-piperazinyl) carbonyl / amino / phenyl-acetyl / amino / 4-methyl-2-oxo-1-azetidine sulfonic acid, 77. Process according to any one of claims 54-2576, characterized in that the sulfonation is carried out by treatment with a sulfur trioxide complex or an equivalent sulfonating agent. 78. Process according to claim 77, characterized in that the sulfonating complex is pyridine-sulfur trioxide complex. 79. Process according to claim 77, characterized in that the sulfonating complex is dimethylformamide sulfur trioxide complex. 80. A method according to claim 54, characterized in that the amino substituent at the 3-position in the azide form is protected 1 0 0 57 1 - 211 -. 81. A process according to claim 57, characterized in that the group R 1 -NH is an amino group protected in the azide form. 82. Process according to claim 80 or 81, characterized in that the protective azide group is reduced to form the amino substituent (-nh2). 83. A process according to claim 54 or 57, characterized in that the amino protecting group is benzyloxycarbonyl or butyloxycarbonyl. A method according to claims 54, 56 and 57, characterized in that the product has the formula la, wherein the different groups have the same meaning as in claim 57, wherein the amino group can be in protected form. 85. A process according to claim 57, characterized in that R 2 represents hydrogen and R 1 and R 1 are the same or different and can represent hydrogen or alkyl. 86. A process according to claim 85, characterized in that the alkyl group is methyl. 87, Process according to claims 54-87, characterized in that the cation M + is a pyridinium ion or a tetrabtuyl ammonium ion or an alkium ion. 88. Process for preparing a salt of (R) -3- (acetylamino) -3-methoxy-2-oxo-1-azetidine sulfonic acid, characterized in that a strain of the microorganism Chromobacterium violaceum ATCC, 31532 cultures in a water medium containing yeast extract, beef extract, NZ amine, glucose and agar. 89. Process for preparing a salt of (R) ~ 3 ~ / _ / _ N- (ϋ-γ-glutamyl) -D-alanyl / amino-3-methoxy-2-oxo-azetidine sulfonic acid characterized by that a strain of the microorganism Gluconobacter ATCC 31581 grown in a water medium containing yeast extract, beef extract, NZ amine A, glucose and agar. 90. Process for preparing a new compound, characterized in that a compound is prepared with the 81 00 57 1 * 'φ - 212 - formula 21 as defined above, it being understood that OMs now has the meaning of V in formula 15, by a sulfonation compound of formula 20, wherein OMs also has the same meaning as V in formula 15. 91. A compound of formula 21, wherein the symbols have the same meaning as in claim 90. 92. A compound of formula 32, wherein the symbols have the above meanings. 93. A compound of the formula I, with the proviso that the group R 1 -NH- is replaced by an azido group N 2 -. 81 00 57 f * β Rx? X? «R, - Ntf- C-C-R-s 0Λ —-n-so; m + 1 Nhj _ C o * c C - R * 1 - * N. SO M 9 la -A. R * Rii CAH5-CHi oco-nh r-Rj. H ^ N R, liit 1) sulfonation r aj deprotection N-SO'M * 3 -B- R, Rk Rr NH 4-R, NH sulfonation R-NH 1 R »R * 1-R» n-so'm * -C. Cl 1 H R; Rx? <> Acyl. N-i-R »acyl-NH-N-SO * M * (RSW <nolate, <* f— Rj N.SOM *) -D. acyl. NH- / R <acyl. NHNPIQUE ^ R, R> • ιΛ • NH-SCTM 8 N-SO'M * \ E.R. Squibb & Sons, Inc., Princeton, New Jersey, USA St. America 81 00 57 1 * * * now NHX i. Ra 'CH —c (n I Nr5 BOC-NH-CH OH "' / R * C o * 12 BOC-NH-CH I N.SO ~ M + 3 Y-O-NH 2 Cl OH 13 0 V r, R; BOC-NH-rr-—r R * C nRj I I n «c - N-O-Y u BOC.NH-NH-O-Y * k 1-R: NH NH 4 CH. 19 16 17 / \ R. NH. ANH-CH I n.C OMs 1 C NR, NH. 20 ANH-CH I o * c ' NHSO “M * ANH. R4 Ri HjN-? Λ 4 — R · • N. SCf M * 21 22 23 n-so; m * R »NH. Ri • R. -N-SO, R-NH-1 2L CH; R "f'CH, - N - C-COOH 25a R-NH. r -Nv ^ CH3 CO OH 25b R-NH -N-CH.CH (CH ^ 26 cooh * R4 ch-c-r3 27 O = C - N -SO ^ - halogen 28 Or • N.SO halogen 29 o? A f *. .NH .30 8100571 ER, Squibb & Sons, lac., Princeton, New Jersey, USA St. America Cl ^ I Η Ra CL Ra RfN -R, CH * CH -O-CO.N 6 1 .R 0. alkyl R *. 3. HO.CO.NH (, s 32 N-SoV * 33 N-CL NH 34 45. R ^ CCH ^ -C- E.R. Squibb S Soos, Inc., Princeton, New Jersey, USA St.Aerika 8 1 0 0 5 7 1 ' OH ^ O / V ii N-CH O O O i -CCH-NH-C-N 'nN.R, _ • \ I Rn CHi-CH * 61 n.so'm * O-aLkyl? 4 HiN '^ °' aLky 1 0.alkyl 63 O.aLkyl 68 o π o V o N, CN 70 R-NH-CH 1 NN = CH -C-CH-NH-CN 1 CH, IN 0 71 V „Rx 1 yRk P MM Γ -C \ Rj Γν - ΙΗΓ1- U, '1 * ΝΗλ cx 1' 0 "R * m Φ CR. Λ 3 73 72 ER Squibb & Sons, Inc., Princeton, New Jersey, USA St. 8100571