DE3632876A1 - 2-OXO-1 - (((SUBSTITUTED SULFONYL) AMINO) CARBONYL) AZETIDINE - Google Patents

Description

The invention has for its object new drugs to combat bacterial infections in mammals, that have a broad spectrum of activity.

The invention relates to a process for the preparation of compounds of general formula I. and pharmacologically acceptable salts thereof, the symbols in the general formula I and in the further course of the description having the following meaning:

R means

R ₁ represents an acyl radical derived from a carboxylic acid;

R ₂ and R ₃ have the same or different meaning and each represent a hydrogen atom, an alkyl radical, an alkenyl radical, an alkynyl radical, a cycloalkyl radical, a phenyl group, a substituted phenyl group or a 4-, 5-, 6- or 7-membered heterocycle (hereinafter referred to as R _x ), or one of the radicals R ₂ and R ₃ denotes a hydrogen atom and the other an azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, Carboxyl-, -CH ₂ X ₁ - (where X _{1 is} an azido, amino, hydroxyl, carboxyl, alkoxycarbonyl, alkanoylamino, phenylcarbonylamino, (substituted phenyl) carbonylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted Phenyl) - sulfonyloxy, phenyl, substituted phenyl, cyano, represents, where A, X ₂ , X ₆ and X _{7 have} the meaning given below, an -SX ₂ - or -OX ₂ radical (where X _{2 is} an alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl -, substituted phenylalkyl, alkanoyl, phenylalkanoyl, substituted phenylalkanoyl, phenylcarbonyl, substituted phenylcarbonyl or a heteroarylcarbonyl radical), one (where one of X ₃ and X _{4 represents} a hydrogen atom and the other represents a hydrogen atom or an alkyl radical, or X ₃ and X ₄ together with the carbon atom to which they are attached represent a cycloalkyl radical, and X _{5 represents} a formyl- Represents alkanoyl, phenylcarbonyl, substituted phenylcarbonyl, phenylalkylcarbonyl, substituted phenylalkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, substituted aminocarbonyl or cyano radical), or a radical (where A is a -CH = CH-, - (CH ₂ ) _m -, - (CH ₂ ) _m -O-, - (CH ₂ ) _m -NH- or -CH ₂ S-CH ₂ group, m has the value 0, 1 or 2, and X ₆ and X _{7 are} identical or different and each represent a hydrogen atom, an alkyl radical, a phenyl group or a substituted phenyl group or X _{6 represents} a hydrogen atom and X _{7 represents} an amino, substituted amino Represents alkanoylamino or alkoxy, or X ₆ and X ₇ together with the nitrogen atom to which they are attached represent a 4-, 5-, 6- or 7-membered heterocycle);

A ₁ means a single bond,

A ₂ represents a single bond, dar;

A ₃ means - (CH ₂ ) _p -, where p is 0 or 1,

A ₄ represents wherein X represents a hydrogen atom, a carboxyl group or a carbamoyl group, p has the value 0 or 1 and y has the value 2, 3 or 4;

A ₅ represents a single bond, where q is 0 or 1;

A ₆ represents a single bond, -CH = CH- or - (CH ₂ ) _t -, where t has the value 1, 2, 3 or 4, characterized in that a compound of the general formula VII with a derived from a carboxylic acid R ₁ R ₁ acyl acylated or in that a -CO-NH-SO ₂ R-activating group to a compound of general formula IX introduces.

The symbols used above, such as A ₁ , A ₂ , A ₃ , A ₄ , A ₅ and A _6, represent residues with several atoms. These residues are introduced into the structural formulas shown in the order in which they are shown, ie from from left to right. For example, if R means and A ₁ then the remainder is R and not

Definitions of various terms are given below, those for the description of those produced according to the invention β-lactams can be used. These definitions apply when not otherwise specified in certain circumstances for which Terms throughout the description, either individually or as part of a larger group.

The terms "alkyl" and "alkoxy" both describe straight as also branched chains. Residues with 1 to 10 carbon atoms are preferred.  

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

The term "substituted alkyl group" refers to alkyl groups that with one or more (preferably 1, 2 or 3) azido, Amino, halogen, hydroxy, carboxy, cyano, alkoxycarbonyl, Aminocarbonyl, alkanoyloxy, alkoxy, phenyloxy, substituted Phenyloxy, mercapto, alkylthio, phenylthio, substituted Phenylthio, alkylsulfinyl or alkylsulfonyl residues are substituted.

The terms "alkanoyl", "alkenyl" and "alkynyl" both apply to straight chain as well as for branched groups. Leftovers with 2 to 10 carbon atoms are preferred.

The terms "halogen" and "halo" refer to fluorine, chlorine, bromine and iodine.

The term "substituted phenyl" relates to a phenyl radical which is substituted with 1, 2 or 3 amino, halogen, hydroxyl, trifluoromethyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, alkanoyloxy, Amine carbonyl or carboxyl radicals is substituted.

The term "4-, 5-, 6- or 7-membered heterocycle" (denoted by "R _x ") relates to substituted and unsubstituted aromatic and non-aromatic radicals which contain one or more (preferably 1, 2 or 3) nitrogen , Contain oxygen or sulfur atoms. Examples of substituents are oxo, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, alkylsulfonyl, phenyl, substituted Phenyl, 2-furfurylideneamino, benzylideneamino and substituted alkyl radicals, the alkyl group having 1 to 4 carbon atoms. An example of a "4-, 5-, 6- or 7-membered heterocycle" is the "heteroaryl radical". The term "heteroaryl" means 4-, 5-, 6- or 7-membered aromatic heterocycles. Examples of heteroaryl radicals are substituted and unsubstituted pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl -, Triazinyl- and tetrazolyl residues. Examples of non-aromatic heterocycles (ie fully or partially saturated heterocyclic radicals) are substituted and unsubstituted azetidinyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, imidazolidinyl, oxazolidinyl, pyrrolidinyl, tetrahydropyrimidinyl, dihydrothiazole. Examples of substituted 4-, 5-, 6- or 7-membered heterocycles are 1-alkyl-3-azetidinyl-, 2-oxo-1-imidazolidinyl-, 3-alkylsulfonyl-2-oxo-imidazolidinyl-, 3-benzylideneamino- 2-oxo-1-imidazolidinyl, 3-alkyl-2-oxo-1-imidazolidinyl, 3-phenyl (or substituted phenyl) -2-oxo-1-imidazolidinyl, 3-benzyl-2-oxo 1- imidazolidinyl-, 3- (2-aminoethyl) -2-oxo-1-imidazolidinyl-, 3-amino-2-oxo-1-imidazolidinyl-, 3 - [(alkoxycarbonyl) amino] - 2-oxo-1-imidazolidinyl -, 3- [2 - [(alkoxycarbonyl) amino] ethyl] 2-oxo-1-imidazolidinyl, 2-oxo-1-pyrrolidinyl, 2-oxo-3-oxazolidinyl, 4-hydroxy-6- methyl-2-pyrimidinyl, 2-oxo-1-hexahydroazepinyl, 2-oxo-3-pyrrolidinyl, 2-oxo-3-tetrahydrofuranyl, 2,3-dioxo-1-piperazinyl, 2,5-dioxo -1-piperazinyl, 4-alkyl-2,3-dioxo-1-piperazinyl and 4-phenyl-2,3-dioxo-1-piperazinyl residues.

The term "substituted amino" refers to a radical having the general formula -NX ₈ X ₉ , in which X _{8 represents} a hydrogen atom, an alkyl radical, a phenyl group, a substituted phenyl group, a phenylalkyl radical or a substituted phenylalkyl radical and X ₉ denotes an alkyl radical, a Phenyl group, substituted phenyl group, phenylalkyl radical, substituted phenylalkyl radical, hydroxyl group, cyano group, alkoxy radical, phenylalkoxy radical or an amino group.

The term "acyl" stands for all organic residues by an organic acid (i.e., a carboxylic acid) by removal  the hydroxyl group can be obtained. Certain acyl residues are preferred, of course, but this preference should be should not be considered as limiting the scope of the invention. Exemplary acyl residues are those acyl residues which are in the Past for acylation of β-lactam antibiotics including 6-aminopenicillanic acid and derivatives thereof and of 7-aminocephalosporanic acid and derivatives thereof were, cf. for example "Cephalosporins and Penicillins", edited by Flynn, Academic Press (1972), DE-OS 27 16 677, BE-PS 8 67 994, US-PS 41 52 432, US-PS 39 71 778, US-PS 41 72 199 and GB-PS 13 48 894. The following list Various acyl residues are further examples of the term "Acyl" but it is not meant to limit the term be seen. Examples of acyl residues are the following:

(a) Aliphatic radicals with the general formula in which R _A denotes an alkyl radical, cycloalkyl radical, alkoxy radical, alkenyl radical, cycloalkenyl radical or a cyclohexadienyl radical, or an alkyl or alkenyl radical which is substituted by one or more halogen atoms, cyano, nitro, amino, mercapto, alkylthio or cyanomethyl radicals are.

(b) Carbocyclic aromatic radicals with the general formula in which n has the value 0, 1, 2 or 3, R _b , R _c and R _d each independently of one another a hydrogen atom, halogen atom, a hydroxyl group, a nitro, amino, cyano, trifluoromethyl group, an alkyl radical with 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or an aminoethyl group, and R _e denotes an amino group, a hydroxyl group, a carboxyl salt, a protected carboxyl group, a formyloxy group, a sulfone salt, a sulfonamino salt, an azido group, a halogen atom, a hydrazino group, one Alkylhydrazino group, a phenylhydrazino group or a [(alkylthio) thioxomethyl] thio group.

Preferred carbocyclic aromatic acyl radicals are those with the formulas wherein R _{e is} preferably a carboxyl salt or a sulfonic salt, and wherein R _{e is} preferably a carboxyl salt or a sulfonic salt.

(c) Heteroaromatic radicals of the general formulas in which n is 0, 1, 2 or 3, R _{e has} the meaning given above, and R _{f is} a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring with 1, 2, 3 or 4 (preferably 1 or 2) means nitrogen, oxygen and sulfur atoms. Examples of heterocyclic rings are thienyl, furyl, pyrrolyl, pyridinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, thiadiazolyl and tetrazolyl. Examples of substituents are halogen, hydroxyl, nitro, amino, protected amino, cyano, trifluoromethyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or Preferred heteroaromatic acyl radicals are the radicals of the above formulas in which R _{f is} 2-amino-4-thiazolyl, 2-amino-5-halo-4-thiazolyl, 4-aminopyrimidin-2-yl, 5-amino 1,2,4-thiadiazol-3-yl, 2-thienyl, 2-furanyl or 6-aminopyridin-2-yl radical.

(d) [[(4-Substituted-2,3-dioxo-1-piperazinyl) carbonyl] amino] arylacetyl radicals of the general formula in which R _{g represents} an aromatic radical (including carbocyclic aromatic radicals such as those of the general formula and heteroaromatic radicals as included in the definition of R _f ), and R _{h is} an alkyl radical, substituted alkyl radical, where the alkyl radical is substituted by one or more halogen atoms, cyano, nitro, amino or mercapto groups, an arylmethylene amino radical ( ie -N = CH-R _g , where R _{g has} the meaning given above), an arylcarbonylamino radical (ie where R _{g has} the meaning given above) or represents an alkylcarbonylamino radical.

Preferred [[(4-substituted-2,3-dioxo-1-piperazinyl) carbonyl] amino] aryl acetyl radicals are those in which R _{h represents} an ethyl, phenylmethyleneamino or 2-furylmethyleneamino group.

(e) (Substituted oximino) aryl acetyl radicals of the general formula in which R _{g has} the meaning given above and R _{i is} a hydrogen atom, an alkyl radical, a cycloalkyl radical, a radical a 2-pyrrazolylmethyl group, a (2-oxo-3-pyrrolidinyl) methyl group, an alkylaminocarbonyl group, an arylaminocarbonyl group (ie where R _{g has} the meaning given above) or a substituted alkyl radical (where the alkyl radical has one or more halogen atoms, cyano, nitro, amino, mercapto, alkylthio, an aromatic radical defined by R _g , carboxyl ( including the salts thereof), amido, alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkoxyphosphinyl, dihydroxyphosphinyl, hydroxy (phenylmethoxy) phosphinyl, dialkoxyphosphinyl or tetrazolyl radicals).

Preferred (substituted oxyimino) aryl acetyl radicals are those in which R _{g represents} a 2-amino-4-thiazolyl group. Likewise preferred are the groups in which R _{i is} a methyl, ethyl, carboxylmethyl, 1-carboxy-1-methylethyl, 2,2,2-trifluoroethyl or 1-carboxycyclopropyl group.

(f) (Acylamino) aryl acetyl radicals of the general formula in which R _{g has} the meaning given above and R _{j has} a radical an amino group, an alkylamino group, a cyanoalkylamino group, an amido group, an alkylamido group, a cyanoalkylamido group or the groups means.

Preferred (acylamino) aryl acetyl radicals of the above formula are those in which R _{j represents} an amino or amido group. Likewise preferred are the radicals in which R _{g represents} a phenyl or 2-thienyl group.

(g) [[[3-Substituted-2-oxo-1-imdiazolidinyl] carbonyl] amino] arylacetyl radicals of the general formula in which R _{g has} the meaning given above and R _{k represents} a hydrogen atom, an alkylsulfonyl radical, arylmethylene amino radical (ie -N = CH-R _g , where R _{g has} the meaning indicated above), (where R _{m is} a hydrogen atom, an alkyl radical or an alkyl radical substituted by halogen), an aromatic radical as defined above by R _g , an alkyl radical or a substituted alkyl radical, the alkyl radical having one or more halogen atoms, cyano, nitro, Amino or mercapto groups is substituted.

Preferred [[[3-substituted-2-oxo-1-imidazolidinyl] carbonyl] amino] aryl acetyl radicals of the above formula are those radicals in which R _{g represents} a phenyl or 2-thienyl group. Also preferred are those radicals in which R _{k represents} a hydrogen atom, a methylsulfonyl, phenylmethylene amino or 2-furylmethylene amino group.

The compounds produced according to the invention form basic ones Salts with various inorganic and organic Bases that are also within the scope of the invention. Such salts are ammonium salts, alkali metal salts, alkaline earth metal salts, Salts with organic bases, such as dicyclohexylamine, Benzathine, N-methyl-D-glucamine or hydrabamine. The pharmacologically acceptable salts are preferred, though the other salts are also valuable, e.g. B. for insulation or cleaning the product.

Some of the compounds made according to the invention can crystallized or recrystallized from aqueous solvents will. In these cases, water of hydration can be formed will. The invention includes stoichiometric hydrates as well as compounds that contain variable amounts of water, that by methods such. B. Lyophilization occurs.

The β-lactams of the general formula I contain at least one chiral center, the carbon atom in the 3-position of the β-lactam nucleus, to which the acylamino substituent (R ₁ -NH) is linked. The invention is directed to the β-lactams described above, the stereochemistry at the chiral center in the 3-position of the β-lactam nucleus being the same as the configuration on the carbon atom in the 6-position of the naturally occurring penicillins (e.g. penicillin G ) and how the configuration on the carbon atom in the 7-position of the naturally occurring cephamycins (for example cephamycin C). The scope of the invention also includes racemic mixtures which contain the β-lactams described above.

The β-lactams of the general formula I and their pharmacological tolerable salts are effective against gram- positive and gram-negative organisms. The invention Manufactured compounds can be used as a means of control bacterial infections, including urinary tract and respiratory infections, in mammals such as pets (e.g. Dogs, cats, cows or horses) and humans will.

To combat bacterial infections in mammals, a A compound in accordance with the invention that requires treatment Mammals in an amount of about 1.4 mg / kg / day to about 350 mg / kg / day, preferably about 14 mg / kg / day to about 100 mg / kg / day can be administered. All types of administration, previously used for the administration of penicillin and cephalosporins on Infection focus can also be used for the invention manufactured β-lactams are used. Such The procedures are oral, intravenous, intramuscular and the gift as a suppository.

The β-lactams of the general formula I can be obtained from a 3-protected amino-2-azetidinone of the general formula II getting produced. In the general formula II and in the further course of the description, the symbol "R ₄ " means an amino protecting group. These groups are well known in the field of β-lactam chemistry and it is not critical which group is chosen. Examples are the benzyloxycarbonyl group, trityl group and tert-butoxycarbonyl group. The reaction of a β-lactam of the general formula II with an isocyanate of the general formula III

in which Y is a leaving group such as chlorine, gives the corresponding compound of general formula IV

The reaction is preferably carried out in an inert organic Solvents such as ethyl acetate, tetrahydrofuran, Dimethoxyethane, dichloromethane, acetonitrile or mixtures of these Solvent carried out. The replacement of the leaving group Y through the desired group R can be made using a suitable nucleophile of the general formula V

can be achieved, optionally in the presence of a base such as triethylamine, the corresponding compound having the general formula VI is obtained.

In another embodiment, the leaving group is replaced by implementing a compound of general Formula IV with a protected form of a compound of  general formula V. After the replacement reaction, the Protecting groups are removed by known methods, so that a compound of general formula VI is obtained.

Protected forms of a compound of general formula V and all the reactants described here that use a 3-hydroxy 4-pyridone group are the compounds in which the hydroxyl group is protected, the compounds in which the hydroxyl group and the ring nitrogen are protected and Compounds in which both pyridone oxygen atoms are protected are. Exemplary protective groups are silyl, such as trimethylsilyl, Benzyl and acyl, such as acetyl. If silyl is used, can later remove the protecting group by hydrolysis or fluoride-mediated cleavage. If Benzyl can be used later removal of the Protecting group done by hydrogenolysis. If used acyl the protective group can be removed later Hydrolysis.

Removal of a protecting group from a compound of general formula VI using conventional methods gives the corresponding important intermediate compound of general formula VII or a salt of it. The method for removing the protective group naturally depends on the respective protective group R ₄ . If, for example, R _{4 is} a tert-butoxycarbonyl protective group, the protective group can be removed by treating a compound of the general formula VI with an acid, such as formic acid or trifluoroacetic acid. For example, when R _{4 is} a benzyloxycarbonyl protecting group, the protecting group can be removed by catalytic hydrogenation of a compound of general formula VI. In another embodiment, the R ₄ protective group can be carried out simultaneously with the other pyridone protective groups immediately after the replacement reaction described above.

Conventional acylation methods can be used to convert an intermediate of general formula VII to the corresponding product of general formula I. Exemplary processes are the reaction of a compound of the general formula VII with a carboxylic acid R ₁ -OH or the corresponding carboxylic acid halide or the carboxylic anhydride. The reaction with a carboxylic acid is easily carried out in the presence of a carbodiimide such as dicyclohexylcarbodiimide and a substance which can form an active ester in situ such as N-hydroxybenzotriazole. If the acyl radical R _{1 contains} reactive functional groups, such as amino or carboxyl groups, it may be necessary to first protect these functional groups and only then to carry out the acylation reaction in order to finally remove the protective group from the product obtained.

Another embodiment for the preparation of the compounds of the general formula I consists in the acylation according to the acylation process described above of a 3-amino-2-azetidinone of the general formula VIII to an intermediate of the general formula IX

In the 1-position of a compound of general formula IX one can be carried out using the methods described above be introduced to obtain the corresponding products of the general formula I. If the acyl side chain R _{1 contains} reactive functional groups, such as amino groups, it may be necessary to first protect these functional groups, then to carry out the addition of the activating group in the 1-position and finally to remove the protective groups from the product obtained.

Another synthesis for the preparation of compounds of general formula I comprises the use of a 3-azido-2-azetidinone of general formula X.

In the 1-position of the compound of general formula X one can be carried out using the methods described above be introduced to the corresponding compound of general formula XI to obtain. The reduction of an intermediate of the general formula XI gives the corresponding intermediate of the general formula VII.

The reduction can be carried out by catalytic hydrogenation, for example with palladium-on-activated carbon or platinum oxide or by reducing agents such as zinc or triphenylphosphine. As described above, these important intermediates can (Compounds of the general formula VII) under Using common acylation processes the products of general formula I can be obtained.

In another embodiment, a 3-azido-2-azetidinone of the general formula X can correspond to the corresponding 3-amino-2-azetidinone of the general formula VIII be reduced. The reduction can be carried out by catalytic hydrogenation, for example using palladium-on-activated carbon or platinum oxide, or using reducing agents, such as zinc or triphenylphosphine. A 3-amino-2-azetidinone of the general formula VIII can, as described above, (ie first acylation and then treatment as described above) to introduce a in the 1-position) to be converted to the products of the general formula I.

In a further synthesis for the preparation of the compounds of the general formula I, in which R ₂ and R ₃ each represent hydrogen atoms, a 6-acylaminopenicillanic acid of the general formula XII is used or a salt thereof as a raw material. By adapting the processes described in the literature, 3-acylamino-2-azetidinone is obtained from the corresponding 6-acylaminopenicillanic acid of the general formula XII, cf. Chem. Soc. Special Publication No. 28, (1977), p. 288, "The Chemistry of Penicillins", Princeton University Press, p. 257, and Synthesis, 494 (1977).

As described in the literature, 6-acylaminopenicillanic acid or a salt thereof can be desulfurized by reduction with Raney nickel, to give a compound of the general formula XIII.

The reaction can be carried out in water under reflux conditions will.

The replacement of the carboxyl group of a compound of the general formula XIII by an acetate group and a subsequent hydrolysis yield the corresponding 3-acylamino-2-azetidinone with the general formula XIV.

Treatment of a compound of general formula XIII  with copper (II) acetate and lead tetraacetate in an organic Solvents such as acetonitrile replace the carboxyl group through an acetate group. Hydrolysis of the compound obtained can with potassium carbonate in the presence of sodium borohydride respectively.

In the 1-position of a compound of general formula XIV one can be introduced according to the processes described above, giving products of the general formula I in which R ₂ and R ₃ each represent a hydrogen atom.

Another embodiment of the synthetic routes described above for the preparation of a compound of general formula I, in which R ₂ and R ₃ each represent hydrogen atoms, consists in the desulfurization of 6-aminopenicillanic acid, the acylation of the compound obtained to a compound of general formula XIII and further reaction according to the processes described above to a 3-acylamino-2-azetidinone of the general formula XIV and then a product of the general formula I.

The azetidinones of the general formula I can also be derived from amino acids of the general formula XV getting produced. The amino group is first protected with a protective group R ₄ such as tert-butoxycarbonyl. The carboxyl group of the protected amino acid is then with an amine of the general formula XVI

implemented in the presence of a carbodiimide, where Z is an alkyl radical, a benzyl group or a triphenylmethyl group, so that a compound of the general formula XVII is obtained.

The hydroxyl group of a compound of general formula XVII is converted into a leaving group ("OL") using a reagent such as methanesulfonyl chloride or pyridine-SO ₃ complex.

The fully protected compound of general formula XVIII is cyclized by treatment with a base such as potassium carbonate. The reaction is preferably carried out in an organic solvent or a mixture of an organic solvent and water under reflux conditions and leads to a compound of the general formula XIX.

In another embodiment, the cyclization of a Compound of the general formula XVII take place without first the hydroxyl group is converted into a leaving group becomes. Treatment of a compound of the general formula XVII with triphenylphosphine and diethyl azodicarboxylate results a compound of the general formula XIX.  

Exemplary methods of converting a compound of general formula XVIII to a compound of general Formula XIX are described in J. Amer. Chem. Soc., 102 (1980), 7026, and in J. Org. Chem., 47 (1982), 5160.

Both of the above-described methods for ring closure of a compound of the general formula XVII lead to the inversion of the stereochemistry on the carbon which carries the radicals R ₂ and R ₃ when R ₂ and R _{3 are} not identical.

The protective group can be removed from the 1-position of an azetidinone of the general formula XIX by reduction with sodium if Z is an alkyl radical and leads to an intermediate of the general formula II, where at least one of the radicals R ₂ and R _{3 is} a hydrogen atom is. If Z is a benzyl group, the catalytic hydrogenation, for example with palladium-on-activated carbon, initially leads to the corresponding N-hydroxy compound which, after treatment with titanium trichloride, gives an intermediate of the general formula II. If Z is a triphenylmethyl group, treatment with formic acid or 70 percent acetic acid / water leads to the corresponding N-hydroxy compound.

In the 1-position of a compound of the general formula II, a be introduced. The protective groups can be split off from the compound obtained and it can be acylated.

The nucleophiles of the general formula V, in which R represents the rest means and A ₁ and A ₂ each represent a single bond, by reacting a silylated derivative of 2-imidazolidinone or the anion of 2-imidazolidinone formed with a strong non-nucleophilic base with an activated, suitably protected derivative of an acid of the general Formula XX are prepared, after removal of the protective group, the corresponding compound of the general formula XXI receives. The reaction can be carried out in an inert organic solvent, such as dimethylformamide, acetonitrile, dichloromethane or tetrahydrofuran. The acid of the general formula XX can be activated with dicyclohexylcarbodiimide or a combination of dicyclohexylcarbodiimide and hydroxybenzotriazole. An activated and suitably protected derivative of a compound of general formula XX can also be the corresponding acid chloride which has been prepared using reagents such as phosphorus pentachloride, thionyl chloride, oxalyl chloride or triphenylphosphine carbon tetrachloride, or a mixed anhydride which has been prepared using reagents such as diphenylphosphoryl chloride, pivaloyl chloride or Isobutyl chloroformate was produced.

The compound of the general formula XX, in which A _{6 is} a single bond, can be prepared according to the processes described in the literature, cf. Helv. Chem. Acta, 43 (1960), p. 469 and J. Med. Chem., 17 (1974), p. 1.

The compound of general formula XX, in which A _{6 is} -CH = CH-, can be obtained by oxidation of the suitably protected compound of formula XXII to the corresponding, suitably protected aldehyde of the formula XXIII and by reacting the aldehyde with a carboxyl-protected derivative of the formula XXIV and removal of the protective group, whereby the compound XXV receives. The compounds of the general formula XX, in which A _{6 is} - (CH ₂ ) _t -, where t is 2, 3 or 4, can be obtained by conjugation of a suitably protected compound of the formula XXIII with a Wittig reagent of the general Formula XXVI whose carboxyl group is protected in a suitable manner, can be prepared by subsequent hydrogenation of the exocyclic double bond obtained and by removal of the protective groups, a compound of the general formula XXVII in which t has the value 2, 3 or 4.

The compounds of the general formula XX, in which A is ₆ - (CH ₂ ) _t - and t has the value 1, can be reacted by reacting a suitably protected compound of the general formula XXVIII in which L _a denotes a leaving group, such as chloride, bromide, methanesulfonyloxy or toluenesulfonyloxy, are formed with cyanide and subsequent hydrolysis and removal of the protective group, giving the compound of the general formula XXVII in which t has the value 1. A compound of general formula XXVIII can be prepared from a compound of formula XXII which is suitably protected by conventional methods such as reaction with thionyl chloride or with methanesulfonyl chloride / triethylamine.

The nucleophiles of the general formula V, in which R represents the rest means, A _{1 represents} a single bond and A _{2 is} -NH-, can be prepared by reacting an activated and optionally protected derivative of a compound of general formula XX with 1-amino-2-imidazolidinone, the compound being removed after removal of the protective group of the general formula XXIX receives.

The nucleophiles of the general formula V, in which R represents the rest A _{1 represents} a single bond and A ₂ -CH ₂ -CH ₂ -NH- can be prepared by reacting an activated and optionally protected derivative of a compound of general formula XX with 1- (2-aminoethyl) -2-imidazolidinone , wherein after removal of the protective group, a compound of the general formula XXX receives.

The nucleophiles of the general formula V, in which R represents the rest means A _{1 represents} a single bond and A ₂ is, can by reacting the compound of formula XXXI with a silylated form of 2-imidazolidinone, the anion of 2-imidazolidinone formed with a strong non-nucleophilic base or with 2-imidazolidinone in the presence of an organic base, whereby the compound of formula XXXII receives.

Catalytic hydrogenation of the compound of formula XXXII gives the compound of formula XXXIII which can be coupled with an activated and optionally protected derivative of a compound of general formula XX, a compound of general formula XXXIV receives.

In another embodiment, the compound of formula XXXIII can be reacted with 1-chlorocarbonyl-2-imidazolidinone with tert-butoxycarbonyl-protected hydrazine to give the compound of formula XXXV and then removing the protecting group from the compound of formula XXXV.

The nucleophiles of the general formula V, in which R represents the rest means A ₁ is and A _{2 represents} a single bond, can by reacting a compound of general formula XXXVI which is protected in a suitable manner, be prepared with hexamethyldisilazane, a compound of the general formula XXXVII. being obtained after hydrolysis and removal of the protective group receives.

The suitably protected compounds of the general Formula XXXVI can be implemented by implementing a silylated Form of a compound of general formula XXI, the optionally protected, can be produced with phosgene.

In another embodiment, a connection of the general formula XXXVII by implementing a protected Form of a compound of general formula XXI with chlorosulfonyl isocyanate and subsequent hydrolysis of the obtained Intermediate and deprotection will.  

The nucelophiles of the general formula V, in which R represents the rest means A ₁ is and A ₂ means -NH-, can by reacting a silylated form of the compound of general formula XXXVIII in which the symbol Prot can denote an amino protecting group, such as tert-butoxycarbonyl or benzyloxycarbonyl, with phosgene, using a compound of the general formula XXXIX receives, which can be reacted with hexamethylsilazane, after removing the protective group, the compound of formula XL receives.

The reaction of the compound of the formula XL with an optionally protected, activated form of a compound of the general formula XX gives, after removal of the protective group, a compound of the general formula XLI

In another embodiment, a compound of formula XL can be prepared by reacting the compound of formula XLII be prepared with chlorosulfonyl isocyanate, the compound of the formula XLIII receives.

Treatment of this compound with aqueous acid gives a salt of the compound of formula XL.

The nucleophiles of the general formula V, in which R represents the rest means A ₁ and A _{2 represents} -CH ₂ -CH ₂ -NH-, can be removed by removing the protective group from 1- (aminocarbonyl) -3- [2- [[(tert-butoxy) carbonyl] amino] ethyl] - 2-imidazolidinone and coupling of the compound obtained with an activated form of a compound of the general formula XX, which is optionally protected, are prepared, with a compound of the general formula XLIV after removal of the protective group receives.

The nucleophiles of the general formula V, in which R represents the rest means A ₁ and A ₂ means can be obtained by reacting an isolylated form of a compound of general formula XXXIV, which is optionally protected, with phosgene and then hexamethyldisilazane, a compound of general formula XLV being obtained after hydrolysis and removal of the protective groups receives.

In another embodiment, a compound of the general formula XLV can be prepared by reacting a protected form of a compound of the general formula XXXIV with chlorosulfonyl isocyanate and subsequent hydrolysis of the intermediate product obtained and removal of the protective group. In another embodiment, a compound of the formula XXXII can be reacted with chlorosulfonyl isocyanate and subsequent hydrolysis of the intermediate product obtained, the compound of the formula XLVI receives.

Removal of the protecting group from the compound of formula XLVI by hydrogenolysis gives the compound of formula XLVII which can be coupled with an activated and optionally protected derivative of a compound of the general formula XX, a compound of the general formula XLV being obtained after removal of the protective group.

The nucleophiles of the general formula V, in which R represents the rest means, A _{1 is} -NH- and A _{2 represents} a single bond, can be prepared by coupling a compound of general formula XXXVIII to an activated form of a compound of general formula XX, which is optionally protected, and then splitting off the protective group, wherein a compound of the general formula XLVIII receives.

The nucleophiles of the general formula V, in which R represents the rest means, A _{1 is} -NH- and A _{2 is} -NH-, can be obtained by coupling a simply protected (preferably with tert-butoxycarbonyl or benzyloxycarbonyl) derivative of 1,3-diamino-2-imidazolidinone with an activated form of a compound of general formula XX, which is optionally protected, and subsequent removal of the protective groups, are prepared, the compound of the general formula XLIX receives.

In another embodiment, a connection of the general formula XLIX by nitrosing a protected Form of a compound of the general formula XXIX and subsequent Reduction of the nitroso group and elimination of the Protection group are formed.

The nucleophiles of the general formula V, in which R represents the rest A _{1 is} -NH- and A _{2 is} -CH ₂ -CH ₂ -NH- can be prepared by nitrosation of a compound of the general formula XXX which is suitably protected, whereby a suitably protected compound of the general formula L. obtained and, if this compound is reduced and the protective groups removed, a compound of the general formula LI receives.

The nucleophiles of the general formula V, in which R represents the rest means A _{1 is} -NH- and A ₂ represents, can be prepared by nitrosation, reduction and removal of the protective groups from a protected derivative of a compound of general formula XXXIV. The compound obtained has the general formula LII on.

In another embodiment, a compound of the general formula LII can be formed by reacting a compound of the general formula XXXVII with phosgene, a compound of the general formula LIII receives which, when reacted with a simply protected hydrazine in the presence of a base, the compound of the general formula LIV results (the two protective groups must be different).

The selective removal of the hydrazide protecting group gives a compound of general formula LV

The coupling of a compound of the general formula LV with an activated, possibly protected form of a connection of the general formula XX and the subsequent removal the protecting groups make a connection of the general Formula LII.  

The nucleophiles of the general formula V, in which R represents the rest means A ₁ and A _{2 represents} a single bond, can be prepared by reacting a compound of general formula XXXVI (preferably a protected derivative thereof) with hydrazine (preferably in a single protected form) in the presence of a base or with a silylated form of hydrazine or simply protected hydrazine be a protected derivative of the compound of general formula LVI receives, from which the protective groups can be removed by conventional methods.

In another embodiment, a connection of the formula XXXV (either a solylated derivative thereof or one formed by reaction with a strong base Anion thereof) with an activated form of a compound of the general formula XX, protected in a suitable manner is implemented and then the protective group is removed being a compound by general formula LVI receives.

The nucleophiles of the general formula V, in which R represents the rest means A ₁ and A _{2 represents} -NH-, can be formed by selective removal of the non-hydrazide protective groups of a compound of the general formula LIV and subsequent coupling with an activated, optionally protected compound of the general formula XX and subsequent removal of the protective group, whereby a compound of general formula LVII receives.

The nucleophiles of the general formula V, in which R represents the rest means A ₁ and A _{2 represents} -CH ₂ -CH ₂ -NH- can be obtained by successive reaction of a compound of general formula XXX or a protected derivative thereof with phosgene and then with hydrazine or a single-protected derivative thereof in the presence of a silylating agent such as methyl -N- (trimethylsilyl) trifluoroacetamide can be prepared, with a compound of the general formula LVIII after removal of the protective groups receives.

Alternatively, an amino-protected derivative of 1- (2-aminoethyl) -2-imidazolidinone, which is optionally silylated, can be reacted with phosgene and then with a single-protected derivative of hydrazine in the presence of a base or a silylating agent such as N- Methyl-N- (trimethylsilyl) trifluoroacetamide or bis (trimethylsilyl) acetamide to a protected derivative of the compound of formula LIX be implemented. The residues used to protect the terminal amino groups in a compound of the formula LIX should be chosen so that the protective group on the aminoethyl group can be removed selectively. The compounds obtained after removal of the protective group can be coupled with an activated form of an acid of the general formula XX or a protected derivative thereof, a compound of the general formula LVIII being obtained after removal of the protective groups.

The nucleophiles of the general formula V, in which R represents the rest means A ₁ and A ₂ represents, can be prepared by reacting the compound of formula XXXII, optionally in the form of the silylated derivative, with phosgene, with a protected derivative of the compound of formula LX receives, which can be coupled with a protected derivative of hydrazine, wherein a protected derivative with the formula LXI receives.

The residues used to protect the terminal amino groups in a compound of the general formula LXI should be chosen so that one of the protecting groups can be removed selectively. The compound obtained after removal of the protective group can be coupled with an optionally protected, activated form of an acid of the general formula XX, a compound of the general formula LXII receives.

The nucleophiles of the general formula V, in which R represents the rest means, according to the method described above for the preparation of the nucleophiles of the general formula V, in which R represents the rest means be prepared, but replacing the appropriate 2,3-piperazinedione reactants of the 2-imidazolidinone reactants.

The nucleophiles of the general formula V, in which R represents the rest A _{1 is} a single bond and A _{5 is} a single bond, using a suitably protected derivative of the compound LXIII getting produced. A compound of the formula LXIV can by converting a protected form of the compound of formula LXV to a protected form of the compound of formula LXIV according to the method of K. Heyns et al., Chem. Ber., 87 (1954), p. 1440, followed by removal of the protecting group, whereby the compound of formula LXIV receives per se.

A compound of formula LXV can be made from a suitably protected Form of a compound of formula LXIII by conversion in an ester, such as ethyl or methyl ester, reaction with hydrazine and removal of the protective groups will. In another embodiment, one can be suitable protected, activated form of a compound of the formula  LXIII implemented with a simply protected hydrazine be, one after removing the protecting groups Compound of formula LXV receives.

The reaction of the compound of formula LXIV or a suitably protected derivative thereof with 2- (chloroethyl) isocyanate, optionally in the presence of a base such as triethylamine or a silylating agent, gives the compound of formula LXVI after removal of the protective group.

Treatment of the compound of formula LXVI or a suitably protected derivative thereof with a base gives the compound of formula LXVII after removal of the protecting groups.

The nucleophiles of the general formula V, in which R represents the rest means, A _{1 is} a single bond and A _{5 represents} -CH-, can by reacting the compound of formula LXVIII or a derivative thereof in which the pyridone group is appropriately protected and the primary amino group is not protected, with 2- (chloroethyl) isocyanate, the compound of formula LXIX being removed after removal of the protecting groups receives.

Treatment of the compound of formula LXIX or a suitably protected derivative thereof with a base gives the compound of formula LXX.

A compound of formula LXVIII can be protected from a suitable Compound of general formula XXVIII by treatment with azide, reduction of the azide and removal of the Protective group can be produced.

The nucleophiles of the general formula V, in which R represents the rest means, A _{1 is} a single bond and A _{5 represents} -N = CH- or -NH-CH ₂ , can be prepared by condensation of 1-amino-2-imidazolidinone with the aldehyde of formula XXIII, which is optionally protected, where after removal of the protective group, the compound of the formula LXXI receives.

Reduction of the compound of formula LXXI, which is optionally protected, by catalytic hydrogenation with sodium cyanoborohydride gives the compound of formula LXXII.

The nucleophiles of the general formula V, in which R represents the rest means A _{1 is} a single bond and A ₅ represents, by reacting 1-chlorocarbonyl-2-imidazolidinone with a compound of general formula LXXIII or a suitably protected derivative thereof in the presence of a base or with a silylated derivative of a compound of the general formula LXXIII, the compound of the general formula LXXIV receives.

The nucleophiles of the general formula V, in which R represents the rest means and A ₁ is can be prepared by reacting a suitably protected derivative of a compound of the formulas LXVII, LXX, LXXI, LXXII or LXXIV with phosgene, a protected derivative of the general formula LXXV is obtained, which can be reacted with hexamethylsilazane, with a compound of the general formula LXXVI after removal of the protective groups and hydrolysis receives.

In another embodiment, nucleophiles of the general formula V, in which R the rest means and A ₁ is produced by reacting a suitably protected derivative of a compound of the formulas LXVII, LXX, LXXI, LXXII or LXXIV with chlorosulfonyl isocyanate, a compound of the general formula LXXVI being obtained after hydrolysis and removal of the protective group.

The nucleophiles of the general formula V, in which R represents the rest means and A _{1 is} -NH-, by nitrosation of a suitably protected derivative of a compound of the formulas LXVII, LXX, LXXI, LXXII or LXXIV with, for example, nitrous acid, reduction of the compound obtained with, for example, zinc under acidic conditions, and removal of the Protecting groups are prepared, using a compound of the general formula LXXVII receives. In another embodiment, the compounds of the general formula LXXVII, in which A ₅ means by reaction of a compound of general formula XXXIX with an optionally protected form of a compound of general formula LXIV or LXVIII in the presence of a base or a silylating agent, the compound of general formula LXXVIII being removed after removal of the protective groups receives.

In another embodiment, the compounds of the general formulas LXXVII, in which A ₅ denotes -N = CH- or -NH-CH ₂ -, can be reacted with simply protected 1,3-diamino-2-imidazolidinone with a compound of the formula XXIII or a protected derivative thereof and subsequent removal of the protective group to the derivative of the general formula LXXVII, in which A _{5 is} -NH = CH-. The reduction of this derivative gives the compound of the general formula LXXVII, in which A _{5 is} -NH-CH ₂ -.

The nucleophiles of the general formula V, in which R represents the rest means and A ₁ can be prepared by reacting a suitably protected compound of the general formula LXXV with a simply protected hydrazine in the presence of a base or a silylating agent.

After removing the protective groups, the products have the general formula LXXIX

The nucleophiles of the general formula V, in which R represents the rest A _{1 is} a single bond and A _{5 is} a single bond or -CH ₂ -, can be reacted by reacting a compound of the formula LXIV or LXVIII or a suitably protected derivative thereof with aziridine or an activated aziridine, with acyl or Sulfonyl radicals can be used, the compound of the formula LXXX being removed after the protective groups have been removed receives.

A compound of formula LXXX or a suitably protected derivative thereof can be obtained by reacting with a dialkyl oxalate and optionally removing the protecting groups to the desired piperazinedione with formula LXXXI being transformed.

The nucleophiles of the general formula V, in which R represents the rest means, A _{1 is} a single bond and A _{5 represents} -N = CH- or -NHCH ₂ -, according to the above for the preparation of the nucleophiles of the general formula V, in which R represents the rest means, A _{1 is} a single bond and A _{5 represents} -N = CH- or -NHCH ₂ -, described processes are prepared, but 1-amino-2,3-piperazinedione replaces the 1-amino-2-imidazolidinone. The compounds obtained have the formulas LXXXII and LXXXIII.

The nucleophiles of the general formula V, in which R represents the rest means A _{1 is} a single bond and A ₅ represents, by reacting an optionally protected derivative of the compound of formula LXXXIV with a compound of formula LXXIII or a suitably protected derivative thereof in the presence of a base or a silylating agent. The protective groups can be removed from the intermediate product obtained, a compound of the general formula LXXXV receives.

The nucleophiles of the general formula V, in which R represents the rest and A _{1 is} -NH-, can be prepared by nitrosation of a protected derivative of a compound of the general formulas LXXXI, LXXXII, LXXXIII or LXXXV with, for example, nitrous acid, reduction of the compound obtained, for example with zinc under acidic conditions, and by removal of the protective groups be, whereby a compound of the general formula LXXXVI receives.

In another embodiment, the compounds of the general formula LXXXVI, in which A ₅ denotes -N = CH- or -NH-CH ₂ -, can be reacted with simply protected 1,4-diamino-2,3-piperazinedione with a compound of Formula XXIII or a protected derivative thereof and by removing the protective groups from the product, whereby a compound of the general formula LXXXVI is obtained, in which A _{5 is} -NH-CH ₂ -, which are then reduced to a compound of the general formula LXXXVI can, in which A _{5 means} -NH-CH ₂ -. In another embodiment, the reduction of -N = CH- may precede the removal of the protecting groups.

The nucleophiles of the general formula V, in which R represents the rest means and A ₁ means can be prepared by reacting a suitably protected derivative of a compound of the formula LXXXI, LXXXII, LXXXIII or LXXXV with phosgene, the compound of the general formula LXXXVII is obtained, which can be reacted with hexamethyldisilazane, the compound of the general formula LXXXVIII after removal of the protective groups and hydrolysis receives.

In another embodiment, the nucleophiles of the general formula V, in which R the rest means and A ₁ is produced by reacting a suitably protected derivative of a compound of the formula LXXXI, LXXXII, LXXXIII or LXXXV with chlorosulfonyl isocanate, a compound of the general formula LXXXVIII being obtained after hydrolysis and removal of the protective groups.

The nucleophiles of the general formula V, in which R represents the rest means and A ₃ - (CH ₂ ) _p - have been described above, cf. the formulas LXIV and LXVIII.

The nucleophiles of the general formula V, in which R represents the rest means and A ₃ means can be prepared by reacting a compound of formula XXXI with an optionally protected compound of formula LXIV or LXVIII in the presence of a base or a silylating agent and the subsequent removal of protective groups.

In another embodiment, the nucleophiles of the general formula V, in which R the rest means and A ₃ represents, are prepared from a suitably protected form of a compound of formula LXIV or LXVIII by reaction with phosgene and subsequent treatment with a simply protected derivative of hydrazine in the presence of a base or a silylating agent and removal of the protective groups.

The nucleophiles of the general formula V, in which R represents the rest means and A ₃ or -CH ₂ -CO-NH-CH ₂ - can be prepared by coupling an activated N-protected glycine derivative with a compound of the formula LXIV or LXVIII, which is optionally protected, and then removing the protective groups.

The nucleophiles of the general formula V, in which R represents the rest means and A _{3 represents} -NH-CH ₂ - can be prepared by reacting an optionally protected derivative of the aldehyde of the formula XXIII with hydrazine or simply protected hydrazine and subsequent reduction of the carbon-nitrogen double bond and subsequent removal of the protective groups.

Alternatively, a mono-protected hydrazine on the free amino group can be monoalkylated with a compound of general formula XXVIII which is suitably protected and then the protecting groups removed to give a nucleophile of general formula V in which R the rest and A _{3 represents} -NH-CH ₂ -.

The nucleophiles of the general formula V, in which R represents the rest means and A _{3 represents} -O-CH ₂ -, can be prepared by reacting a suitably protected derivative of the compound of formula XXII with N-hydroxyphthalimide under Mitsunobu conditions (presence of triphenylphosphine and diethyl azodicarboxylate), whereby a protected derivative of LXXXIX connection is obtained, from which the protective groups can be removed, the compound XC receives.

In another embodiment, the connection of the Formula XC by reacting a compound of formula XXVIII, which is suitably protected with N-hydroxyphthalimide be prepared in the presence of a base.

The nucleophiles of the general formula V, in which R represents the rest and A _{4 represents} -NH- can be prepared by reacting a simply protected hydrazine with an activated, optionally protected derivative of an acid of the general formula XX, a compound of the general formula XCI being removed after the protective groups have been removed receives.

In another embodiment, the connections of general formula XCI by reacting a carboxylic acid ester a suitably protected derivative Compound of general formula XX with hydrazine and subsequent Removal of the protective groups can be made.

The nucleophiles of the general formula V, in which R represents the rest and A _{4 represents} - (CH ₂ ) _p -, where p is 0, can be prepared by reacting ammonia or hexamethyldisilizane with an activated, optionally protected derivative of an acid of the general formula XX, a compound being removed after the protective groups have been removed of the general formula XCII receives.

The nucleophiles of the general formula V, in which R represents the rest and A _{4 represents} - (CH ₂ ) _p -, where p is 1, can be prepared by treating a suitably protected, activated derivative of a compound of general formula XX with diazomethane and then with hydrochloric acid, whereby a protected derivative of a Compound of general formula XCIII receives, in which L _b means chlorine. A compound of general formula XCIII in which L _{b represents} chlorine can then be treated with an iodide or bromide salt such as sodium iodide or lithium bromide, being a protected derivative of a compound of general formula XCIII in which L _{b is} bromine or iodine is received. The replacement of the leaving group L _b , where L _{b is} chlorine, bromine or iodine, by azide and the subsequent reduction and removal of the protective group, gives a compound of the general formula XCIV

The nucleophiles of the general formula V, in which R represents the rest and A _{4 represents} - (CH ₂ ) _y -NH-, by reacting an optionally simply protected compound of the general formula XCV

be prepared with an activated, optionally protected derivative of an acid of the general formula XX, a compound of the general formula XCVI receives.

The nucleophiles of the general formula V, in which R represents the rest means and A ₄ represents, by reacting a compound of the general formula XCI, which is suitably protected, with a compound of the general formula XCVII in the presence of a silylating agent and subsequent removal of the protective groups.

The nucleophiles of the general formula V, in which R represents the rest means and A ₄ represents, by implementing in the presence of a base or a silylating agent with an activated, optionally protected derivative of the general formula XX, are prepared, with a compound of the general formula XCVIII receives.

The nucleophiles of the general formula V, in which R represents the rest means and A ₄ represents, by reaction of an optionally protected hydrazine derivative of the general formula XCIX

can be prepared with an activated, optionally protected derivative of an acid of the general formula XX, a compound of the general formula C receives.

In another embodiment, the connections of general formula C, in which X represents a hydrogen atom, by reacting methylhydrazine with a carboxylic ester derivative the acid of the general formula XX or one appropriately protected derivative thereof.

The compounds of general formula I in which R represents the remainder means are preferred. Most preferred are the compounds of the general formula I in which R represents the remainder represents. Also preferred are the compounds of general formula I in which R _{1 is} the rest means and R _{g represents} 2-amino-4-thiazolyl and R _{i represents} a methyl group, ethyl group, carboxymethyl group, 1-carboxy-1-methyl-ethyl group, 1-carboxy-1-ethyl group or the rest means, where s has the value 1, 2, or 3. The use of these preferred R ₁ acyl residues results in a product which is present as a syn or anti isomer or as a mixture of the isomers. The syn isomer is more potent than the anti isomer.

The examples illustrate the invention.

Examples: example 1

Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2- [[1 - [[[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - carbonyl] amino] 2-oxo-1-imidazolidinyl] sulfonyl] amino] - carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] - oxy] -2-methylpropionic acid

A) 2- (hydroxymethyl) -5- (phenylmethoxy) -4H-pyran-4-one

69 g ((3 mol) sodium are dissolved in 5 ml methanol and then with 425.3 g (3 mol) of 5-hydroxy-2- (hydroxymethyl) -4H- pyran-4-one added. The mixture is stirred at 30 ° C until a clear solution is obtained. The mixture is then with 595 g (3.5 mol) of benzyl bromide were added and the mixture was taken for 1 hour Reflux stirred. The very dark, warm solution comes in 15 ml Poured ice water. The product crystallizes out immediately. The collected crystals are first washed with 8 liters of water and then washed twice with 2.5 liters of ether. The product  is left overnight and finally 16 hours dried at 50 ° C. The yield is 646 g (92.6%).

B) 4-oxo-5- (phenylmethoxy) -4H-pyran-2-carboxylic acid

232 g (1 mol) of 2- (hydroxymethyl) -5- (phenylmethoxy) -4H-pyran-4-one are filled in a 10 liter stirred flask which contains 6.6 liters of acetone and 400 ml of water. The clear solution is cooled to + 5 ° C in an ice bath. While the temperature is kept at +5 to + 10 ° C, the solution is added dropwise with 640 ml of Jones reagent (202 g of CrO ₃ , 600 ml of water, 174 ml of H ₂ SO ₄ ) within 1 hour. Stirring is continued for 2 hours without cooling. The reaction mixture is filtered through a glass frit and the dark green residue is washed with 500 ml of acetone. The filtrate is evaporated until all acetone is removed. The aqueous, partially crystalline product is mixed with 1.2 liters of methanol and the mixture is then heated to its boiling point. The dark green clear solution obtained is placed in an ice bath and the product is allowed to crystallize. The crystalline product is filtered off and washed with 500 ml of a cold solvent mixture of 250 ml of methanol and 250 ml of water and finally dried. The yield is 195 g / 79%). A further 5% of the product can be isolated from the mother liquor.

C) 1,4-Dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinicarboxylic acid

300 g (1.22 mol) of 4-oxo-5- (phenylmethoxy) -4H-pyran-2-carboxylic acid are placed in a flask and 5 liters of 33% Na ₄ OH are carefully added with stirring. The reaction mixture is then stirred under reflux. After 3 hours, another liter of 33% NH ₄ OH is slowly added. The mixture is stirred under reflux for a further 2 hours. The reaction solution is then evaporated until the product crystallizes. The product is returned to the reaction flask and water is added until a clear solution is obtained (about 5 liters, pH 6.38). The solution is stirred vigorously and concentrated hydrochloric acid is added dropwise until a pH of 3 is reached. The precipitated white product is filtered off, washed thoroughly with water and dried. The yield is 273 g (1.12 mol, 91.8%).

D) 1,4-dihydro-4-oxo-N- (2-oxo-1-imidazolidinyl) -5-phenylmethoxy) - 2-pyridinecarboxamide

12.26 g (0.05 mol) of 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2- pyridinecarboxylic acid and 5.56 g (0.055 mol) of 1-amino-2-imidazolidinone are suspended in 120 ml of dimethylformamide. The Suspension is with 0.3 g of dimethylaminopyridine and 0.4 g N-hydroxybenzotriazole added. After stirring for 30 minutes The mixture is added dropwise to room temperature with a solution of 11.35 g (0.055 mol) of dicyclohexylcarbodiimide in 50 ml Dimethylformamide added and the mixture then overnight stirred at room temperature. The failed precipitation of dicyclohexylurea is filtered off and the filtrate evaporated under reduced pressure. The syrupy residue crystallizes on treatment with aqueous sodium hydrogen carbonate solution from, yielding 11.7 g of the Obtained title compound, mp 158 to 160 ° C. Additional 0.8 g crystallize the product with a melting point of 162 to 164 ° C from the aqueous filtrate.

E) 1,4-dihydro-5-hydroxy-4-oxo-N- (2-oxo-1-imidazolidinyl) - 2-pyridinecarboxamide

A suspension of 12 g (0.0365 mol) of 1,4-dihydro-4-oxo-N- (2-oxo-1-imidazolidinyl) -5- (phenylmethoxy) -2-pyridinecarboxamide in 150 ml of acetonitrile with 36.1 ml (0.146 mol) Bis- (trimethylsilyl) acetamide are added, one being easy receives cloudy solution. After filtering off, 6 g of 10%  Palladium on activated carbon added and hydrogen through the stirred reaction mixture passed. After hydrogenation for 60 minutes the catalyst is filtered off and the solution with 15 ml Methanol and 2 ml of acetic acid were added. It continues overnight stirred, the title compound in a yield of 6.6 g and a F. crystallized from 270 to 275 ° C.

F) (3S) - [1 - [[[[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - carbonyl] amino] -2-oxo-1-imidazolidinyl] sulfonyl] amino] - carbonyl] -2-oxo-3-azetidinyl] carbamic acid phenyl ester

A suspension of 13.8 g of (S) -2 - [[(phenylmethoxy-carbonyl] - amino] -2-azetidinone in 500 ml of ethyl acetate with 5.63 ml (0.0626 mol) of chlorosulfonyl isocyanate were added. The mixture is stirred for 1 hour at room temperature, one Solution of (S) -1 - [[(chlorosulfonyl) amino] carbonyl] -3 - [[(phenylmethoxy) - carbonyl] amino] -2-azetidinone is formed. The Solution is cooled to 0 ° C and slowly at this temperature with a solution of silylated 1,4-dihydro-5-hydroxy 4-oxo-N- (2-oxo-1-imidazolidinyl) -2-pyridinecarboxamide added. This was by adding 46.4 ml (0.25 mol) of N- Methyl-N- (trimethylsilyl) trifluoroacetamide to a suspension of 14.9 g (0.0626 mol) of 1,4-dihydro-5-hydroxy-4-oxo-N- (2-oxo-1-imidazolidinyl) -2-pyridinecarboxamide in 500 ml of ethyl acetate and stirring for 30 minutes. Subsequently the mixture is mixed with 150 ml of dichloromethane and over Stirred at room temperature overnight. The clear solution comes with 26.2 ml (0.188 mol) of triethylamine and then with 300 g Ice and 200 ml of water are added. The pH is 6.5. After stirring for 1 1/2 hours, the two phases are separated and the aqueous phase with three 200 ml portions of ethyl acetate washed. After removing the remaining ethyl acetate under reduced pressure the pH Value of the aqueous phase by slowly adding 2N hydrochloric acid (47 ml) adjusted to 2 with cooling. The crystals are filtered off, suspended in 200 ml of ethyl acetate  and stirred for 1 hour. Then the crystals are filtered off, twice with 30 ml of ethyl acetate and twice with 50 ml Washed petroleum ether and dried under reduced pressure. 28.6 g of the title compound with an F. of 190 to 200 ° C (dec.) Obtained.

G) (3S) -3-Amino-N - [[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2- pyridinyl) carbonyl] amino] -2-oxo-1-imidazolidinyl] sulfonyl] -2-oxo-1-azetidinecarboxamine trifluoroacetate salt (1: 2)

A mixture of 15 ml trifluoroacetic acid and 3.5 ml thioanisole is at room temperature with 4 g (0.00713 mol) (3S) - [1 - [[[[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] - amino] -2-oxo-1-imidazolidinyl] sulfonyl] amino] carbonyl] - 2-oxo-3-azetidinyl] -carbamic acid phenyl methyl ester added and cooled to 10 ° C. The clear solution is over Stirred at 10 ° C overnight. After evaporation under reduced The syrupy residue becomes with pressure at room temperature Treated ether so that the title compound as a yellowish Solid obtained. The yield is practically quantitative.

H) [3S (Z)] - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[3 - [[(1,4-dihydro- 5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] -2- oxo-1-imidazolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3- azetidinyl] -amino] -2-oxo-ethylidene] -amino] -oxy] -2- methyl propionic acid diphenyl methyl ester

A solution of 3.08 g (0.007 mol) of (Z) -2-amino-α - [[2- (diphenylmethoxy) - 1,1-dimethyl-2-oxoethoxy] imino] -4-thiazole acetic acid in 70 ml dimethylformamide with 2.9 ml (0.021 mol) Triethylamine added and after cooling to -30 ° C below Nitrogen with 1.55 ml (0.07 mol) of diphenyl chlorophosphate. The mixture is stirred at -30 ° C for 1 hour. Then 1.95 ml (0.014 mol) of triethylamine are added and then 0.07 mol (3S) -3-amino-N - [[3 - [[(1,4-dihydro-5-  hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-1-imidazolidinyl] - sulfonyl] -2-oxo-1-azetidinecarboxamide trifluoroacetate (1: 2) salt. The reaction mixture is at 2 hours -10 ° C and stirred at 0 ° C for 1 hour. Then the solvent removed under reduced pressure. Treatment of the Residue with water and ethyl acetate gives an insoluble Product, which after treatment with ether solidified. The yield of the pipe connection is 8.0 g.

I) Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) - 2 - [[1 - [[[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - carbonyl] amino] -2-oxo-1-imidazolidinyl] sulfonyl] amino] - carbonyl] -2-oxo-3-azetid-inyl] -amino] -2-oxo-ethylidene] - amino] -oxy] -2-methylpropionic acid

8 g crude [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[[3- [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] - 2-oxo-1-imidazolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3- azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] -2- methyl propionic acid diphenyl methyl ester are suspended in 15 ml of anisole. After cooling to - ⁹⁹⁹⁹⁹ ⁰⁰⁰⁷⁰ ⁵⁵² ⁰⁰¹⁰⁰⁰²⁸⁰⁰⁰⁰⁰00200012000285919988800040 0002003632876 00004 99880 10 ° C the suspension becomes added dropwise with 80 ml of trifluoroacetic acid and that The mixture was then stirred at -10 ° C. for 1 hour. After adding The trifluoroacetate salt of free acid falls ether at 0 ° C of the product from (4.1 g of the crude compound). The raw Compound is suspended in water and the pH adjusted Addition of sodium dicarbonate solution adjusted to 5.5. The the solution obtained is freeze-dried. The raw sodium salt is then determined by chromatography on HP-20 (a macroreticular Styrene-divinylbenzene copolymer resin, Mitsubishi Chemical Industries, Ltd.) cleaned. The product will eluted with water, 0.52 g of the product is obtained.

NMR (DMSOd ₆ ): δ = 1.35 (s, 3H); 1.40 (s, 3H), 3.37 (dd, 1H); 3.47 (t, 2H); 3.81 (t, 2H + dd, 1H); 5.05 (m, 1H); 6.75 (s, 1H); 7.27 (s, 1H); 7.72 (s, 1H); 1.52 (broad s, 1H).

Example 2

Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2- [[1 - [[[2 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] - hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] - amino] -2-oxoethylidene] amino] oxy] -2-methylpropionic acid

a) 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid- 2 - [(1,1-dimethylethoxy) carbonyl] hydrazide

61.3 g (0.25 mol) of 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2- Paridine carboxylic acid are in 500 ml of dimethylformamide at room temperature suspended and then with 39.65 g (0.3 mol) N- (tert-butoxycarbonyl) hydrazine, 1.5 g dimethylaminopyridine and 2.0 g of N-hydroxybenzotriazole were added. The mixture will Stirred for 30 minutes at room temperature. Then the mixture dropwise with stirring with 57.5 g within 30 minutes (0.28 mol) dicyclohexylcarbodiimide dissolved in 100 ml of dimethylformamide added and stirred overnight at room temperature. The precipitated dicyclohexylurea is filtered off and the filtrate evaporated under reduced pressure. The syrupy Residue crystallizes after treatment with dilute Sodium bicarbonate solution. The dried raw product is recrystallized from 2 liters of ethyl acetate. The Yield of the title compound is 69.5 g, mp 173 to 175 ° C. Another 3.2 g with a melting point of 160 to 165 ° C after evaporation of the mother liquor.

B) 1,4-Dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid hydrazide

370 ml of trifluoroacetic acid are mixed at 0 ° C. with 69 g (0.191 mol) 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid 2- [(1,1-dimethylethoxy) carbonyl] hydrazide added. The mixture is stirred for 1 hour at room temperature and then evaporated. The syrupy residue is treated with ether. 68.2 g of the crude 1,4-dihydro-4-oxo-5- (phenylmethoxy) - 2-pyridinecarboxylic acid.-hydrazide trifluoroacetate (1: 2) salt obtained as a solid.  

The crude 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid- hydrazide trifluoroacetate (1: 2) salt is dissolved in 52 ml of acetonitrile dissolved and stirred with cooling for 1 hour. The crystals are filtered off and again in 600 ml of acetone tril suspended. The suspension is mixed with 135 ml of bis (trimethylsilyl) acetamide and then with 28 g of 10% palladium on activated carbon. Then hydrogen is passed through the stirred solution passed. The hydrogenation is after 90 minutes completed. After filtering off, 70 ml of methanol and 2 ml of acetic acid were added. It is stirred overnight, the crystals formed are filtered off. You get 19.4 g of the title compound with an F. of 290 to 340 ° C (dec.).

C) (3S) - [1 - [[[[[[1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] - carbonyl] hydrazino] sulfonyl] amino] carbonyl] -2- phenyl methyl oxo-3-azetidinyl] carbamate

A suspension of 5.19 g (0.0236 mol) of (S) -3 - [[(phenylmethoxy) - carbonyl] amino] -2-azetidinone in 160 ml of ethyl acetate is stirred at room temperature with 2.05 g (0.0236 mol) chlorosulfonyl isocyanate added. The mixture is stirred for 1 hour at room temperature, being a solution of (S) -1 - [[(chlorosulfonyl) amino] carbonyl] -3 - [[(phenylmethoxy) - carbonyl] amino] -2-azetidinone is formed. The Solution is cooled to 0 ° C and with 80 ml dichloromethane, 9.9 ml (0.0707 mol) of triethylamine and a solution of silylated 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid hydrazide transferred. The latter was made from a suspension of 3.99 g (0.0236 mol) of 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid hydrazide in 50 ml of ethyl acetate and 8.75 ml N-methyl-N- (trimethylsilyl) trifluoroacetamide (0.0472 mol) receive. The mixture is stirred at room temperature overnight and then mixed with ice water, and there will be more Stirred for 30 minutes. The aqueous phase becomes ethyl acetate layered and acidified to a pH of 2.5.  The precipitate crystallizes out after stirring for 1 hour. The yield of the title compound is 6.6 g.

After evaporation of the ethyl acetate phase and treatment a further 1.4 g of the title compound are obtained with petroleum ether.

D) (3S) -3-Amino-N - [[2 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - carbonyl] hydrazino] sulfonyl] -2-oxo-1-azetidinecarboxamide- trifluoroacetate (1: 2) salt

A stirred mixture of 22 ml trifluoroacetic acid and 5.3 ml Thioanisole is mixed at room temperature with 6.6 g (0.0133 mol) (3S) - [1 - [[[[[[1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] - carbonyl] hydrazino] sulfonyl] amino] carbonyl] -2-oxo- 3-azetidinyl] -carbamic acid phenyl methyl ester and the mixture was stirred overnight at room temperature. The trifluoroacetic acid is removed under reduced pressure and the syrupy residue is treated with ether. It will be the Title compound obtained in quantitative yield.

E) [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[2 - [(1,4- dihydro-5-hydroxy-4-oxo-2-pyridinyl) -carbonyl] -hydr-azinosulfonyl] - amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2- oxoethylidene] -amino] -oxy] -2-methylpropionic acid diphenylmethyl ester

A solution of 5.84 g (0.0133 mol) of (Z) -2-amino-α - [[2- (diphenylmethoxy) - 1,1-dimethyl-2-oxoethoxy] imino] -4-thiazole acetic acid in 135 ml of dimethylformamide with 5.6 ml of triethylamine and after cooling to -30 ° C with 3.57 g (0.0133 mol) Diphenyl chlorophosphate added. The mixture is at 1 hour Stirred -30 ° C, mixed with 3.72 ml of triethylamine and then with 0.0133 mol (3S) -3-amino-N - [[2 - [(1,4-dihydro- 5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] sulfonyl] - 2-oxo-1-azetidinecarboxamide trifluoroacetate (1: 2) salt.  

The mixture is stirred at -10 ° C for 2 hours and at 1 hour 0 ° C. The solvent is removed under reduced pressure and the syrupy residue with 150 ml of ethyl acetate and 70 ml of ice water, which is added by adding 2N hydrochloric acid was adjusted to a pH of 1.5 to 2, treated. The insoluble part is removed and digested with ether, whereby 5.3 g of the crude product are obtained.

F) Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) - 2 - [[1 - [[[2 - [(1,4dihydro5-hydroxy-4-oxo-2-pyrid-inyl) - carbonyl] hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3- azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] -2-methylpropionic acid

5.3 g (0.0069 mol) [3S (Z)] - 2 - [[[1- (2-amino-e-thiazolyl) -2- [[1 - [[[2 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] - hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] - amino] -2-oxoethylidene] amino] oxy] -2-methylpropionic acid are suspended in 10.6 ml of anisole. The suspension is cooled to -10 ° C and with stirring with 53 ml of trifluoroacetic acid transferred. The mixture is at this temperature Stirred for 1 hour and then mixed with 200 ml @ ether at -10 ° C, the free acid tifluoroacetate salt of the title compound to fail. The yield is 7.3 g.

The crude product is in a mixture of 100 ml of water and 50 ml of acetone dissolved. The pH is adjusted to 5 to 5.5 and the acetone is removed under reduced pressure. The remaining aqueous solution is lyophilized. It will 8.1 g of the crude product obtained by chromatography on HP-20, eluting with water. The Chromatography gives 1.05 g of the product.

NMR (DMSOd ₆ ): δ = 1.40 (s, 3H); 1.42 (s, 3H); 3.25 (dd, 1H); 3.70 (dd, 1H); 5.10 (m, 1H); 6.75 (s, 1H); 7.40 (s, 1H); 7.80 (s, 1H); 11.32 (broad s, 1H).

Example 3

Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2- [[1 - [[[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-1-imidizolidinyl] sulfonyl] amino] carbonyl] - 2-oxo-3-azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] - 2-acetic acid

A) [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[3 - [[(1,4- dihydro-5-hydroxy-4-oxo-2-pyridinyl) -carbonyl] -amino] -2- oxo-1-imidizolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3- azetidinyl] -amino] -2-oxoäthyli-den] -amino] -oxy] -2-acetic acid- diphenylmethyl ester

A solution of 2.06 g (0.005 mol) of (Z) -2-amino-α - [[2- (diphenylmethoxy) - -oxoethoxy] -imino] -4-thiazole acetic acid in 100 ml of dimethylformamide is mixed with 2.1 ml (0.015 mol) of triethylamine transferred. The mixture is cooled to -30 ° C and below 1.1 ml (0.005 mol) of diphenyl chlorophosphate were added while stirring. After stirring for 1 hour at -30 ° C, additional 1.4 ml (0.1 mol) of triethylamine are added at -30 ° C. and then 2.7 g (3S) -3-amino-N - [[3 - [[(1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-1-imidazolidinyl] - sulfonyl] -2-oxo-1-azetidinecarboxamide trifluoroacetate- (1: 2) - Salt.

The reaction mixture is 2 hours at -10 ° C and 1 hour stirred at 0 ° C. The solvent is reduced Pressure evaporated. The oily residue is suspended in water and the pH of the suspension by adding 2N Hydrochloric acid set to 2. The suspension is 30 minutes stirred at room temperature, filtered off, the solid again suspended in water and filtered again. After this Drying under reduced pressure over phosphorus pentoxide Obtained 5.0 g of the crude product. The material is in used the next step without further cleaning.  

B) Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2- [[1 - [[[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - carbonyl] amino] -2-oxo-1-imidizolidinyl] sulfonyl] amino] - carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] - oxy] -2-acetic acid

5.0 g crude [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[[3- [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] - 2-oxo-1-imidizolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3- azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] -2- diphenyl methyl acetate are mixed at -10 ° C in a mixture 10 ml of anisole and 50 ml of trifluoroacetic acid are suspended. The Reaction mixture is stirred at -10 ° C for 1 hour and then carefully mixed with 100 ml ether to the crude trifluoroacetate salt of the title link to fail. The yield is 3.7 g. The crude compound is mixed dissolved from 30 ml water and 60 ml acetone and the pH Value of the mixture by adding 0.1N sodium hydroxide solution 5 to 5.5 set. The acetone is evaporated off and the aqueous phase lyophilized, 3.9 g of the crude product be preserved. The crude product is by chromatography cleaned on HP-20. The product is eluted with water, it fractions of 10 ml are collected. The the product containing fractions are lyophilized. It will be one Yield of 0.6 g of material obtained on HP-20 is re-chromatographed. 0.25 g of fine product are obtained.

Example 4

[3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[[(1,4-dihydro- 5-hydroxy-4-oxo-2-pyridinyl) methyl] amino] sulfonyl] - amino] -carbonyl] -2-oxo-3-azetidinyl] -amino] -2-oxoethylidene] - amino] -oxy] -2-methylpropionic acid

A) 2- (hydroxymethyl) -5- (phenylmethoxy) -4- (1H) pyridinone

A mixture of 9.65 g (41.59 ÅvmMol) 2- (hydroxymethyl) -5- (phenylmethoxy) -4H-pyran-4-one, 95 ml concentrated ammonia and 20 ml of ethanol is heated under reflux overnight. Subsequently an additional 75 ml of ammonium hydroxide are added and the mixture was heated under reflux for 2 hours and then chilled. The brown solid obtained is filtered off and washed with water until the washing liquids become neutral are. The crude product is suspended in methanol, filtered, washed with ethanol and hexane and under reduced pressure dried. The yield of the title compound is 7.1 g.

B) 2- (chloromethyl) -5- (phenylmethoxy) -4- (1H) -pyridinone monohydrochloride

A suspension of 3 g (12.99 mmol) of 2- (hydroxymethyl) -5- (phenylmethoxy) -4- (1H) pyridinone in 15 ml chloroform is added Cooled argon to 0 ° and with 6.1 ml (83.62 mmol) of thionyl chloride treated. You get within a few minutes a homogeneous solution. After stirring for an additional 5 minutes a cream-colored solid precipitates. The cooling bath is removed and the mixture was heated under reflux for 45 minutes. The Mixture is cooled to 0 ° and the white precipitate is filtered off, washed with chloroform and hexane and under reduced pressure Pressure dried. The yield of the title compound is 3.65 g.

C) 2- (Azidomethyl) -5- (phenylmethoxy) -4- (1H) pyridinone

A mixture of 3.50 g (12.54 mmol) of 2- (chloromethyl) -5- (phenylmethoxy) - 4- (1H) pyridinone monohydrochloride, 4.08 g (62.7 mmol) Sodium azide and 2.19 ml (12.54 mmol) diisopropylethylamine in 70 ml of dimethylformamide under argon for 3 1/2 days stirred at room temperature. The mixture is also with 4.08 g of sodium azide were added, and then 45 to 2 hours Heated to 50 ° C. After cooling, the reaction mixture becomes Poured 500 ml of water, becoming an insoluble white solid  is formed. The pH of the supernatant is measured with diluted hydrochloric acid decreased from 8.5 to 7.5 and the white Solid then filtered. After washing with water, acetone and hexane, the solid is dried under reduced pressure. The yield of the title compound is 2.81 g.

D) 2- (aminomethyl) -4- (phenylmethoxy) -4- (1H) pyridinone

A mixture of 2.03 g (7.93 mmol) of 2- (azidomethyl) -5- (phenylmethoxy) - 4- (1H) -pyridinone and 200 mg platinum oxide in 100 ml Dimethylformamide is kept under a nitrogen atmosphere for 6 hours stirred at room temperature. The catalyst is filtered off and concentrated the solution under reduced pressure. There are 1.5 g (82% yield) of the title compound as Obtained gray powder.

E) (3S) - [1 - [[[[[[[1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] - methyl] amino] sulfonyl] amino] car bonyl] -2-oxo-3- phenylmethyl ester of azetidinyl] carbamate

A stirred suspension of 2.330 g (10.13 mmol) of 2- (aminomethyl) - 5- (phenylmethoxy) -4- (1H) pyridinone in 60 ml of ethyl acetate is mixed with 3.76 ml (20.26 mmol) of N-methyl-N- (Trimethylsilyl) trifluoroacetamide added. The solution obtained is stirred for 30 minutes at room temperature and then on Cooled to 0 ° C. In parallel, a stirred suspension of 2.228 g (10.13 mmol) (S) -3 - [[(phenylmethoxy) carbonyl] - amino] -2-azetidinone in 60 ml ethyl acetate with 882 µ- Liter (10.13 mmol) of chlorosulfonyl isocyanate were added. The received Solution is stirred for 30 minutes at room temperature, cooled to 0 ° and finally with 4.23 ml (30.30 mmol) Triethylamine and then with the solution of the above described silylated 2- (aminomethyl) -5- (phenylmethoxy) - 4- (1H) -pyridinone added. The mixture is 2 days at room temperature touched.  

The mixture is concentrated under reduced pressure, the residue is dissolved in CH ₃ CN water (40:60) and the pH is reduced to 2.9, a thick oil separating off. After cooling to 5 ° C, the oil solidifies. The solid is separated off, washed four times with water and dried under reduced pressure. 3.4 g of crude product are obtained. The crude product is dissolved in a minimal volume of dimethylformamide and applied to a column (1 liter) of HP-20 resin. The column is gradually eluted with an acetone-water gradient. The desired substance is eluted at approximately 65% acetone. The appropriate fractions are collected and lyophilized. 2.69 g of the title compound are obtained.

F) [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[[(1,4-dihydro- 5-hydroxy-4-oxo-2-pyridinyl) methyl] amino] sulfonyl] - amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxo- ethylidene] amino] oxy] -2-methylpropionic acid re-diphenylmethyl ester (as a mixture of monopotassium and monotriethylammonium salt)

A mixture of 912 mg (1.64 mmol) (3S) - [1 - [[[[[[1,4-dihydro- 4-oxo-5- (phenylmethoxy) -2-pyridinyl] methyl] amino] sulfonyl] - amino] carbonyl] -2-oxo-3-azetidinyl] carbamic acid phenylmethyl ester, 625 mg (3.28 mmol) of p-toluenesulfonic acid monohydrate and 190 mg of 10% palladium-on-carbon in 16 ml of dimethylformamide is stirred in a hydrogen atom until 3.28 mmol (73 ml) of hydrogen have been consumed (approx. 3 hours).

A stirred solution of 846 mg (1804 mmol) of (Z) -2-amino- - [[2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy] imino] -4-thiazole acetic acid in 16 ml of dimethylformamide are added -20 ° C with 374 µLiter (1.804 mmol) diphenylchlorophosphate and then with 450 µLiter (3.28 mmol) triethylamine. The solution is stirred for 1 hour at -20 ° C. and then the mixture of hydrogenated (3S) - [1 - [[[[[1,4-dihydro-4-oxo-5- (phenylmethoxy) -2- described above pyridinyl] methyl] amino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] carbamic acid phenylmethyl ester added. The resulting mixture is stirred at -20 ° C for 1 hour and then at 5 ° C overnight. The catalyst is filtered off, the volatiles are removed under reduced pressure and the residual oil is dissolved in a small volume of acetone / water (75 to 25, pH 5.2) and added dropwise to a stirred suspension of 20 ml of Dowex 50x2-400 (K⁺ ) (Styrene-divinylbenzene copolymer gel with -SO ₃ - groups) in acetone / water (35:65) was added. After 40 minutes the mixture is filtered and the filtrate lyophilized. 2.1 g of a solid are obtained. The solid is dissolved in a small amount of acetonitrile / water (40 to 60, pH 5.6) and applied to a column (800 ml) of HP-20 resin. The column is gradually eluted with an acetonitrile / water gradient. The desired compound is eluted at about 30% acetonitrile. The appropriate fractions are collected and lyophilized. 254 mg of the impure title compound are obtained.

G) [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[[(1,4-dihydro- 5-hydroxy-4-oxo-2-pyridinyl) methyl] amino] sulfonyl] - amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxo- ethylidene] amino] oxy] -2-methylpropionic acid

A stirred suspension of 131 mg of the mixture of monopotassium and monotriethylammonium salt of the above impure [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[ [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl] amino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2 -oxoethylidene] -amino] - oxy] -2-methylpropionic acid diphenylmethyl ester in 3 ml dichloromethane and 0.3 ml anisole is added dropwise at 0 ° C with 4.7 ml trifluoroacetic acid. After stirring at 5 ° C. for 45 minutes, 2 ml of toluene are added and the volatiles are removed under reduced pressure. The remaining oil is washed three times with 4 ml of hexane and digested to a solid with 10 ml of ether. The solid is washed once with ether (10 ml) and dried under reduced pressure. The above reaction and working up is carried out with 166 mg [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1- [[[[(1,4-dihydro -5-hydroxy-4-oxo-2-pyridinyl) methyl] amino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] -oxy-2-methylpropionic acid diphenylmethyl ester (mixture of the monopotassium and monotriethylamine salt) is repeated. The crude products are combined, dissolved in 2 ml of CH ₃ CN water (40:60, pH 2.5) and chromatographed on a column (200 ml) of HP-20 resin using an acetonitrile / water gradient. The desired substance is eluted at a ratio of CH ₃ CN to water of 20:80. The appropriate fractions are pooled and lyophilized. 103 mg [3 (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[[(1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl) methyl] amino] sulfonyl] amino] - carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] - oxy] -2-methyl propionic acid obtained as a white solid.

Example 5

Disodium salt of [35 (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2- [[1 - [[[2 - [[2 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - carbonyl] hydrazino] carbonyl] hydrazino] sulfonyl] amino] - carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] - oxy] -2-methylpropionic acid

A) 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid- 2 - [[(4-methoxyphenyl) methoxy] carbonyl] hydrazide

A stirred suspension of 4.90 g (0.020 mol) of 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid, 4.50 g (0.022 mol) of 4-methoxybenzylcarbazate, 0.12 g (1st , 0 mmol) of 4-dimethylaminopyridine and 0.155 g (1.0 mmol) of 1-hydroxybenzotriazole hydrate in 25 ml of anhydrous dimethylformamide are mixed at room temperature with a solution of 4.45 g (0.022 mol) of dicyclohexylcarbodiimide in 25 ml of anhydrous dimethylformamide and stirring is continued overnight . The precipitate is filtered off and the filtrate is evaporated under reduced pressure. The residue becomes solid when stirred with ether and aqueous sodium hydrogen carbonate solution. The solid is collected, washed with water and finally dried under reduced pressure. The crude compound (8.14 g) is extracted in a Soxhlet with 800 ml CHCl _{3 for} 7 hours. 5.70 g (67%) of pure 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid 2 - [[(4-methoxyphenyl) methoxy] carbonyl] hydrazide crystallize directly from the cold CHCl ₃ extract. An additional 1.5 g (18%) of the impure title compound can be obtained by evaporating the CHCl ₃ solution under reduced pressure. M. 174.5 to 178 ° C.

B) 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid hydrazide- trifluoroacetate (1: 2) salt

An ice cold suspension of 3.71 g (8.76 mmol) of 1,4-dihydro 4-oxo-5- (phenylmethoxy) -1-pyridinecarboxylic acid 2 - [[(4-methoxyphenyl) - methoxy] carbonyl] hydrazide in 15 ml anhydrous Dichloromethane with a solution of -10 ° C of 3.81 ml (35.04 mmol) anisole in 38 ml trifluoroacetic acid. After stirring for 20 minutes at 0 ° C., the solution is reduced Evaporated pressure. It will be the title compound as Get solid. This is made with a few ml of anhydrous Aether stirred, collected by suction and under reduced pressure Pressure dried. The yield is 3.25 g (99%), F. 173 to 175 ° C (dec.).

C) 1,4-Dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid hydrazide

A suspension of 3.19 g (8.55 mmol) of 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid hydrazide trifluoroacetate (1: 2) salt in 35 ml of anhydrous acetonitrile is mixed with 3.84 ml  (19.64 mmol) N-methyl-N- (trimethylsilyl) trifluoroacetamide are added and stirring is continued for 30 minutes at room temperature. After evaporation under reduced pressure, the residue taken up in ether and added dropwise with 1 ml of methanol transferred. The precipitate is collected by suction, with Ether and petroleum ether washed and under reduced pressure dried. There are 2.05 g (92%) of the title compound an F. of 204 to 208 ° C (dec.) obtained.

D) 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid- 2 - [[[2- (phenylmethoxy) carbonyl] hydrazi-no] carbonyl] - hydrazide

With cooling, a suspension of 5.19 g (0.02 mol) of 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid hydrazide in 20 ml of anhydrous acetonitrile with 1.68 ml (0.060 mol) of N -Methyl-N-trimethylsilyltrifluoroacetamide added and stirring continued for 30 minutes at room temperature. The clear solution is evaporated under reduced pressure and the residue is redissolved in 30 ml of anhydrous dichloromethane. This solution is added dropwise to a stirred solution of 4.57 g (0.020 mol) (J. Gante, Chem. Ber. 97 (1964), 2551) in 60 ml of dichloromethane at 0 to 5 ° C. After stirring at this temperature for 2 1/2 hours, the solution is evaporated under reduced pressure and the solid foam is redissolved in 20 ml of methanol. Evaporation under reduced pressure gives the title compound as a solid foam, which becomes crystalline after stirring with anhydrous ether. The yield is 8.87 g (98%), F. ≦ λτ120 ° C (dec.).

E) 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid 2- (hydrazinocarbonyl) hydrazide dihydrochloride

A solution of 4.02 g (8.9 mmol) of 1,4-dihydro-4-oxo-5- (phenylmethoxy) - 2-pyridinecarboxylic acid-2 - [[[2- (phenylmethoxy) - carbonyl] hydrazino] carbonyl] hydrazide in 50 ml methanol,  which contains 2.94 ml (35.6 mmol) of concentrated hydrochloric acid, is in the presence of 0.4 g of palladium (10%) - on carbon Hydrogenated for 10 minutes. The catalyst is filtered off and the solvent was distilled off under reduced pressure. The title compound remains as a solid (2.58 g), which is stirred with a few ml of anhydrous ether Aspirate collected and dried under reduced pressure becomes. The yield is 2.47 g (92%), mp 235 to 236 ° C. (Dec.).

F) (3S) - [1 - [[[[2 - [[2 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - carbonyl] hydrazino] carbonyl] hydrazino] sulfonyl] - amino] carbonyl] -2-oxo-3-azetidinyl] carbamic acid phenylmethyl ester

A suspension of 1.5 g (5.0 mmol) of 1,4-dihydro-5-hydroxy 4-oxo-2-pyridinecarboxylic acid 2 (hydrazinocarbonyl) hydrazide dihydrochloride in 20 ml of anhydrous acetonitrile 4.86 ml (25.0 mmol) of N-methyl-N-trimethylsilyltrifluoroacetamide transferred. After stirring for 45 minutes at room temperature the clear solution is evaporated under reduced pressure and the residue in 20 ml of anhydrous ethyl acetate solved (solution A).

A suspension of 1.10 g (5.0 mmol) (S) -3 - [[(phenylmethoxy) - carbonyl] amino] -2-azetidinone in 40 ml of anhydrous ethyl acetate with 0.45 ml (5.0 mmol) of chlorosulfonyl isocyanate added with stirring. The mixture is 1 hour stirred at room temperature and then cooled to 0 ° C. To Add 10 ml of anhydrous dichloromethane and 2.09 ml (15.0 mmol) triethylamine becomes solution A at 0 ° C with stirring admitted. After stirring overnight at 0 ° C the reaction mixture poured into ice water and the organic layer separated. After acidifying the aqueous phase to a pH Value of 2 by adding 1N hydrochloric acid becomes the title compound obtained as a sticky precipitate by suction  is collected, washed with water and under reduced pressure Pressure is dried. The yield is 1.76 g (64%).

G) (3S) -3-Amino-N - [[2 - [[2 - [(1,4-dihydro-5-hydroxy-4-oxo-2- pyridinyl) carbonyl] hydrazino] carbonyl] hydrazino] - sulfonyl] -2-oxo-1-azetidinecarboxamide trifluoroacetate- (1: 2) - salt

A mixture of 5.13 ml trifluoroacetic acid and 1.21 ml thioanisole is at 0 ° C with 1.73 g (3.1 mmol) (3S) - [1 - [[[[2 - [[2- [(1,4-Diyhdro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] - carbonyl] hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3- azetidinyl] -carbamic acid phenyl methyl ester added. To Stir overnight at room temperature, the solution is under evaporated under reduced pressure and the residue with anhydrous Dichloromethane stirred. The precipitation is through Aspirate collected, washed with dichloromethane and under dried under reduced pressure. The yield of the title compound is 1.78 g (88%).

H) [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[2 - [[2 - [(1,4- dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] - carbonyl] hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3- azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] -2- methyl propionic acid diphenyl methyl ester

A solution of 1.10 g (2.5 mmol) of (Z) -2-amino- α - [[(2-diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy] imino] 4-thiazole acetic acid in 22 ml of anhydrous dimethylformamide with 1.05 ml (7.5 mmol) of triethylamine and 0.53 @ ml (2.5 mmol) Diphenyl chlorophosphate added. After stirring for 1 hour -30 ° C 1.05 ml (7.5 mmol) of triethylamine are added and then 1.62 g (2.5 mmol) (3S) -3-amino-N - [[2 - [[2 - [(1,4- dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] - carbonyl] hydrazino] sulfonyl] -2-oxo1-azetidinecarboxamide trifluoroacetate-  (1: 2) salt. The mixture is at 2 hours -10 ° C and stirred at 0 ° C for 1 hour. The solvent will removed under reduced pressure and the residue in some ml of ethyl acetate and ice water added. The The pH of the mixture is reduced to 2 with dilute hydrochloric acid set. The insoluble substances are collected by suction and stirred with a few ml of ethyl acetate until they become crystalline. The yield after drying under reduced pressure is 1.72 g (82%) of the title compound.

I) Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) - 2 - [[1 - [[[[2 - [[2 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridynyl) - carbonyl] hydrazino] carbonyl] hydrazino] sulfonyl] amino] - carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] - amino] -oxy] -2-methylpropionic acid

A suspension of 1.68 g (2.0 mmol) of crude [3S (Z)] - 2 - [[[1- (2-Amino-4-thiazolyl) -2 - [[1 - [[[[2 - [[2 - [(1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl) carbonyl] hydrazino] carbonyl] hydrazino] - sulfonyl] -amino] -carbonyl] -2-oxo-3-azetidinyl] -amino] -2-oxo- ethylidene] amino] oxy] -2-methylpropionic acid diphenylmethyl ester in 3 ml of anhydrous dichloromethane with 2.0 ml Anisole and then with 20 ml of trifluoroacetic acid -10 ° C offset. After stirring for 10 minutes at 0 ° C Solvent removed under reduced pressure at 0 to 5 ° C. The residue is taken up in ice water and ether and the pH value by adding 1% dilute sodium hydroxide solution set to 6.0. The organic phase and the insoluble Material (0.38 g) are separated and the aqueous phase freeze-dried (2.66 g). The residue from lyophilization XAD-2 resin (macroreticular styrene-divinylbenzene Copolymer), eluting with water. After lyophilization, 0.25 g (17%) of the title compound as a colorless powder with a melting point of ≦ λτ213 ° C (dec.). receive.  

Example 6

Disodium salt of [3S- [3α (Z), 4β]] - 2 - [[[1- (2-amino-4-thiazolyl) - 2 - [[1 - [[[2 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - carbonyl] hydrazino] sulfonyl] amino] carbonyl] -4-methyl-2- oxo-3-azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] -2- methyl propionic acid

A) (3S-trans) - [1 - [[[[2 - [[1,4-dihydro-4-oxo-5-hydroxy-2-pyridinyl] - carbonyl] hydrazino] sulfonyl] amino] carbonyl] -4- methyl-2-oxo-3-azetidinyl] carbamic acid phenylmethyl ester

A suspension of 2.34 g (3S-trans) - (4-methyl-2-oxo-3- azetidinyl) carbamic acid phenyl ester in 50 ml of anhydrous Ethyl acetate is mixed with 1.41 g of chlorosulfonylsiocyanate transferred. After stirring for 1 hour at room temperature a clear solution is formed (solution A).

A suspension of 1.70 g 1,4-dihydro-5-hydroxy-4-oxo-2- pyridinecarboxylic acid hydrazide in 50 ml of anhydrous ethyl acetate is with 6 g of N-methyl-N- (trimethylsilyl) trifluoroacetamide transferred. After stirring for 1 hour at 50 ° C get clear solution (solution B).

After cooling to -10 ° C, solution A is mixed with solution B. and the mixture was stirred overnight at room temperature. After cooling to -15 ° C, 3 g of triethylamine are added and then 150 ml ice water. After 1 hour Stirring at 0 ° C, the organic phase with 50 ml of water washed. The pH of the combined water phases is measured with 1N HCl set to 2 and these are three times with 100 ml Extracted ethyl acetate. The united organic Phases are dried and the solvent is evaporated. 3.64 g of the title compound are obtained.

B) (3S-trans-3-amino-N - [[2 - [(1,4-dihydro-5-hydroxy-4-oxo-2- pyridinyl) carbonyl] hydrazino] sulfonyl] -4-methyl-2-oxo  1-azetidinecarboxamide trifluoroacetate (1: 2) salt

3.5 g (3S-trans) - [1 - [[[[2 - [[1,4-dihydro-4-oxo-5-hydroxy-2- hydridinyl] carbonyl] hydrazino] sulfonyl] amino] carbonyl] - 4-methyl-2-oxo-3-azetidinyl] carbamic acid phenylmethyl ester in 20 ml of thioanisole at room temperature with 50 ml of trifluoroacetic acid added and the reaction mixture then 13th Hours stirred. After adding 100 ml of ether, 3.2 g a raw precipitate. This rainfall will then 1 hour in 50 ml isopropanol methylene chloride (1: 1) touched. 2.21 g of the title compound are obtained.

C) [3S- [3α (Z), 4β]] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1- [[[[2 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -carbonyl] - hydrazino] sulfonyl] amino] carbonyl] -4-methyl-2-oxo-3- azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] -2- methyl propionic acid diphenyl methyl ester

A solution of 1.8 g (Z) -2-amino-α - [[(diphenylmethoxy) -1,1- dimethyl-2-oxoethoxy] imino] -4-thiazole acetic acid and 1.2 g Triethylamine in 30 ml of dimethylformamide is at -30 ° C with 2.1 g of diphenyl chlorophosphate were added. After stirring for 45 minutes at -30 ° C 1.95 g (3S-trans) -3-amino-N - [[2 - [(1,4- dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] - sulfonyl] -4-methyl-2-oxo-1-azetidinecarboxamide trifluoroacetate (1: 2) salt in 10 ml of dimethylformamide added and then 0.8 g triethylamine. After stirring for 2 hours at -10 ° C and stirring for 1 hour at 0 ° C the dimethylformamide is added reduced pressure removed. The arrears with 250 ml of methyl acetate and 400 ml of ice water stirred. The pH of the water phase is adjusted to 1.5 with 2N HCl and this is done twice with 200 ml portions of ethyl acetate extracted. The organic phase is over Dried sodium sulfate and evaporated. There will be 1.3 g obtained the crude title compound.  

D) Disodium salt of [3S- [3α (Z), 4β]] - 2 - [[[1- (2-amino-4- thiazolyl) -2 - [[1 - [[[[2 - [(1,4-dihydro-t-hydroxy-4-oxo-2- pyridinyl) carbonyl] hydrazino] sulfonyl] amino] carbonyl] - 4-methyl-2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] - oxy] -2-methylpropionic acid

A solution of 1.2 g [3S- [3α (Z), 4β]] - 2 - [[[1- (2-amino-4- thiazolyl) -2 - [[1 - [[[[2 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - carbonyl] hydrazino] sulfonyl] amino] carbonyl] -4-methyl- 2-oxo-3-azididinyl] amino] -2-oxoethylidene] amino] oxy] - 2-methylpropionic acid diphenylmethyl ester in a mixture 10 ml of methylene chloride and 15 ml of anisole is mixed with 30 ml of trifluoroacetic acid offset at -5 ° C. After stirring for 30 minutes 100 ml of ether are added. There will be 0.8 g of a precipitate receive. This precipitate is suspended in 20 ml of water and the pH with sodium bicarbonate 6.5 set. The clear solution is then chromatographed on XAD-2, eluting with water. It becomes 0.28 g the pure title compound received.

Example 7

Disodium salt of [3S (Z)] - 1 - [[[1- (2-amino-4-thiazolyl) -2- [[1 - [[[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] - amino] -2-oxo-1-imidazolidinyl] sulfonyl] amino] carbonyl] - 2-oxo-3-azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] - cyclopentane carboxylic acid

A) [3S (Z)] - 1 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[3 - [[(1,4- dihydro-5-hydroxy-4-oxo-2-pyridinyl) -carbonyl] -amino] -2- oxo-1-imidazolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3- azetidinyl] -amino] -2-oxoäthyli-den] -amino] -oxy] - cyclopentane carboxylic acid diphenylmethyl ester

A suspension of 3.9 g (8.3 mmol) (Z) -2-amino-α - [[[[1- (diphenylmethoxy) carbonyl] cyclopentyl] oxo] imino] -4-thiazole acetic acid in 100 ml of anhydrous acetonitrile  3.5 ml (25 mmol) of triethylamine were added, giving a clear solution is obtained. After cooling to -30 ° C, 1.8 ml (8.3 mmol) diphenyl chlorophosphate added and the mixture Stirred for 1 hour at -30 ° C (solution A).

At the same time, 4.5 g (8.3 mmol) of (3S) -3-amino-N- [[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] - amino] -2-oxo-1-imidazolidinyl] sulfonyl] -2-oxo-1-azeitidine carboxamide trifluoroacetate (1: 2) salt in 100 ml anhydrous Suspended ethyl acetate. Then the suspension with 7.2 ml of bis (trimethylsilyl) acetamide at room temperature added, with a clear solution after 5 minutes receives. After stirring for 1 hour, the solution is brought to 0 ° C cooled (solution B).

Solution A is added dropwise at -30 ° C within 10 minutes added with solution B while stirring. The mixture is 1 hour stirred at -10 ° C and 1.5 hours at 0 ° C. The fleeting Fabrics are evaporated and the residue with water digested. The residue solidifies and the solids are collected and returned to water at pH about 2 resuspended. After stirring for 30 minutes, the solid becomes collected and dried. There are 12.0 g of the raw Received title link.

B) Disodium salt of [3S (Z)] - 1 - [[[1- (2-amino-4-thiazolyl) - 2 - [[1 - [[[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - carbonyl] amino] -2-oxo-1-imidazolidinyl] sulfonyl] amino] - carbonyl] -2-oxo-3-azetidinyl] ami-no] -2-oxoethylidene] - amino] -oxy] -cyclopentane carboxylic acid

12 g crude [3S (Z)] - 1 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[[3- [[1 - [[[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] - amino] -2-oxo-1-imidazolidinyl] sulfonyl] amino] carbonyl] - 2-oxo-3-azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] - Cyclopentanecarboxylic acid diphenyl methyl ester are in 20 ml  Suspended anisole and after cooling to -10 ° C with 100 ml Trifluoroacetic acid added. The mixture is at 1 hour Stirred at -10 ° C and then mixed with 300 ml of ether at -10 ° C, whereby a precipitation fails. After stirring for 1 hour the precipitate is filtered off. 5.7 g are obtained. This compound is in a mixture of 30 ml of water and 60 ml of acetone dissolved and the pH of the solution by addition from 0.1N NaOH at 0 ° with stirring to 5.5. The acetone is evaporated off under reduced pressure and the aqueous solution freeze-dried. There will be 5.7 g of a solid Received arrears. This residue is on HP-20 chromatographed, eluting with water. It will 1.69 g (27%) of the pure title compound obtained.

¹ H NMR (DMSO-d ₆ + CF ₃ COOH): δ = 1.67 (s, 4H); 2.07 (2, 4H); 3.65 (t, 2H); 3.75 (dd, 1H); 3.97 (dd, 1H); 4.07 (t. 2H); 5.07 (dd, 1H); 7.00 (s, 1H); 7.67 (s, 1H); 8.07 (s, 1H); ppm.

Example 8

Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2- [[1 - [[[3 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl] - 2-oxo-1-imdiazolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3- azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] -2-methylpropionic acid

A) 2- (azidomethyl) -5- (phenylmethoxy) -1- (phenylmethyl) -4- (1H) - pyridinone

A suspension of 2.0 g (6 mmol) of 2- (chloromethyl) -5- (phenylmethoxy) - 1- (phenylmethyl) -4- (1H) pyridinone in 20 ml acetonitrile is mixed with 3.9 g (60 mmol) sodium azide and 0.1 g [18] crown 6 offset. The mixture is heated under reflux for 4 hours. The salts are filtered off by suction and that The filtrate was evaporated under reduced pressure. The residue is by column chromatography on silica gel with ethyl acetate /  Methanol 8: 2 cleaned. There are 1.86 g of the title compound obtained with an F. of 120 ° C.

B) 2- (aminomethyl) -5- (phenylmethoxy) -1- (phenylmethyl) -4- (1H) pyridinone

1.0 g (2.89 mmol) 2- (azidomethyl) -5- (phenylmethoxy) -1- (phenylmethyl) - 4- (1H) -pyridinone are dissolved in 50 ml of methanol and mixed with 0.10 g of paltin oxide. Then 30 minutes long hydrogen passed through the mixture and the The catalyst is then filtered off by suction through Hyflo. The The filtrate is evaporated under reduced pressure and the oily residue digested with ether. There are 0.89 g of obtained crystalline title compound with a melting point of 207 ° C.

C) 2 - [[[[(2-chloroethyl) amino] carbonyl] amino] methyl] -5- (phenylmethoxy) -2- (phenylmethyl) -4- (1H) pyridinone

A suspension of 48.0 g (0.15 mol) of 2- (aminomethyl) -5- (phenylmethoxy) -1- (phenylmethyl) -4- (1H) pyridinone in 1.5 liters Ethyl acetate is mixed with 12.8 ml (0.15 mol) of 2-chloroethyl isocyanate transferred. The mixture is left overnight Stirred at room temperature and filtered off the product by suction. It is washed with ethyl acetate and then dried under reduced pressure. There will be 59.6 g of Obtain title compound with a melting point of 130 ° C.

D) 2 - [(2-Oxo-1-imidazolidinyl) methyl] -5- (phenylmethoxy) -1- (phenylmethyl) -4- (1H) pyridinone

A mixture of 60.8 g (0.13 mol) of 2 - [[[[(2-chloroethyl) amino] - carbonyl] amino] methyl] -5- (phenylmethoxy) -2- (phenylmethyl] - 4- (1H) -pyridinone and 1.3 liters of ethanol are added dropwise with a solution of 7.29 g (0.13 mol) of potassium hydroxide added in 500 ml of ethanol. The reaction mixture is under Reflux heated for 3 hours and then the solvent  evaporated under reduced pressure. The backlog will purified by column chromatography on silica gel, where a mixture of ethyl acetate and methanol (7: 3) is used as an eluent. There are 23.1 g of the product obtained by recrystallization from acetonitrile is further cleaned. There are 17.0 g of the title compound obtained with a F. of 190 ° C (dec.).

E) 5-Hydroxy-2 - [(2-oxo-1-imidazolidinyl) methyl] -4- (1H) - pyridinone-p-toluenesulfonic acid salt

A solution of 4.98 g (12.8 mmol) of 2 - [(2-oxo-1-imidazolidinyl) - methyl] -5- (phenylmethoxy) -1- (phenylmethyl) -4- (1H) pyridinone in 90 ml of dimethylformamide with 4.86 g (25.6 mmol) of p-toluenesulfonic acid monohydrate and 1.0 g palladium on activated carbon transferred. It then becomes hydrogen for 30 minutes passed through the mixture. The catalyst is suctioned off filtered off and the filtrate under reduced pressure evaporated. The residue is mixed with dichloromethane and ether digested. The product is filtered off by suction. It 4.12 g of the title compound are obtained with a melting point of 195 ° C.

F) 5-hydroxy-2 - [(2-oxo-1-imidazolidinyl) methyl] -4- (1H) - pyridinone

4.0 g (10.5 mmol) 5-hydroxy-2 - [(2-oxo-1-imidazolidinyl) - methyl] -4- (1H) -pyridinone-p-toluenesulfonic acid salt are in 50 ml of water dissolved and the pH of the solution by adding adjusted from 2N sodium hydroxide solution to 6.5. The precipitation is filtered off, washed with water and dried under reduced pressure. There will be 1.5 g of the title compound obtained with an F. of 280 ° C (dec.).  

G) (S) - [1 - [[[[3 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - methyl] -2-oxo-1-imidazolidinyl] sulfonyl] amino] carbonyl] - 2-oxo-3-azetidinyl] carbamic acid phenylmethyl ester

1.10 g (5 mmol) (S) -3 - [[(phenylmethoxy) carbonyl] amino] -2- Azetidinone are in 20 ml of anhydrous methyl acetate dissolved and mixed with 0.44 ml (5 mmol) of chlorosulfonyl isocyanate. The mixture is stirred at room temperature for 1 hour (Solution A).

A suspension of 1.04 g (5 mmol) of 5-hydroxy-2 - [(2-oxo-1- imidazolidinyl) methyl] -4- (1H) pyridinone in 10 ml of anhydrous Ethyl acetate is mixed with 3.70 ml (20 mmol) of N-methyl N- (trimethylsilyl) trifluoroacetamide and the mixture heated to 60 ° C. The clear solution obtained is under evaporated at 60 ° C and the residue dissolved in 10 ml of anhydrous ethyl acetate (solution B).

Solution A is mixed with solution B and the reaction mixture stirred overnight at room temperature. The solvent will evaporated under reduced pressure and the residue with Ether digested. There are 2.91 g of the title compound an F. of 180 ° C (dec.) obtained.

H) (S) -3-Amino-N - [[3 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - methyl] -2-oxo-1-imidazolidinyl] sulfonyl] -2-oxo-1- azetidinecarboxamide trifluoroacetate salt

A mixture of 0.5 ml thioanisole and 2 ml trifluoroacetic acid is mixed with 0.5 g (0.93 mmol) (S) - [1 - [[[[3 - [(1,4-dihydro- 5-hydroxy-4-oxo-2-pyridinyl) methyl] -2-oxo-1-imidazolidinyl] - sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] - carbamic acid phenyl methyl ester transferred. The solution is at overnight Stirred at room temperature and then evaporated under reduced pressure. The residue is digested with ether, by suction filtered off and dried under reduced pressure.  0.40 g of the title compound with a melting point of 155 ° C. receive.

I) [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[3 - [(1,4- dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl] -2-oxo-1-imidazolidinyl] - sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] - amino] -2-oxoethylidene] -amino] -oxy] -2- methyl prophenic acid diphenyl methyl ester

A suspension of 0.41 g (0.93 mmol) of (Z) -2-amino-α - [[2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy] imino] -4-thiazole acetic acid in 20 ml of anhydrous acetonitrile with 0.39 ml (2.8 mmol) triethylamine added. The mixture is brought to -30 ° C cooled and dropwise with 0.19 ml (0.93 mmol) of diphenyl chlorophosphate transferred. The reaction mixture is 1 hour stirred at -30 ° C (solution A).

0.48 g (0.93 mmol) (S) -3-amino-N - [[3 - [(1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl) methyl] -2-oxo-1-imidazolidinyl] sulfonyl] - 2-oxo-1-azetidinecarboxamide trifluoroacetate salt are in 20 ml anhydrous acetonitrile and suspended with 0.78 ml (3.2 mmol) Bis-trimethylsilylacetamide added. The suspension is stirred for 30 minutes at room temperature and then to the Solution A given.

The reaction mixture is stirred at -10 ° C for 1 hour and then 1.5 hours at 0 ° C. The clear solution obtained is evaporated under reduced pressure. The oily residue is mixed with 50 ml of water. The pH of the mixture is adjusted to 2 by adding 2N hydrochloric acid and the disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) - 2 - [[1 - [[[3 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - methyl] -2-oxo-1-imidazolidinyl] sulfonyl] amino] carbonyl] - 2-oxo-3-azetidinyl] -amino) -2-oxoethylidene] -amino] -oxy] -2- methyl propionic acid crystallizes out. The product is made by Filtered off, washed with water and under reduced pressure  Pressure dried. There will be 0.7 g of the title compound receive.

J) Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2- [[1 - [[[3 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl] - 2-oxo-1-imidazolidinyl] sulfonyl] amino] carbonyl] - 2-oxo-3-azetidinyl] -amino] -2-oxo-ethylidene] -amino] -oxy] - 2-methyl propionic acid

0.7 g (0.85 mmol) [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2- [[1 - [[[3 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl] - 2-oxo-1-imidazolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3- azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] -2-methylpropionic acid- Diphenylmethyl esters are suspended in 1.4 ml anisole and cooled to -10 ° C. The suspension comes with Trifluoroacetic acid was added and the solution was then added for 1 hour -10 ° C stirred. The solution is mixed with 100 ml of ether and the precipitate is filtered off with suction, washed with ether and dried under reduced pressure.

The trifluoroacetic acid salt is in a mixture of methanol and water and the pH of the solution by adding 2N sodium hydroxide solution set to 6.5. The methanol is under removed under reduced pressure and the aqueous solution freeze-dried. 0.5 g of the title compound are obtained. This is cleaned by MPLC. F. 250 ° C (dec.).

Example 9

Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2- [[1 - [[[4 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl] - 2,3-dioxo-1-piperazinyl] sulfonyl] amino] carbonyl] -2-oxo- 3-azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] -2-methylpropionic acid

A) 2- (chloromethyl) -5- (phenylmethoxy) -1- (phenylmethyl) -4- (1H) - pyridinone hydrochloride

A suspension of 3.21 g (10 mmol) of 2- (hydroxymethyl) -5- (phenylmethoxy) -1-phenylmethyl) -4- (1H) pyridinone in 20 ml Chloroform is cooled to 0 ° C and added dropwise 4.65 ml (64 mmol) of thionyl chloride were added. The mixture will Stirred at 0 ° C for 10 minutes and then under reflux for 1 hour warmed up. The solvent is evaporated off under reduced pressure and the residue washed with petroleum ether and under dried under reduced pressure. There are 3.66 g of the title compound obtained with an F. of 85 ° C (dec.).

B) 2- (chloromethyl) -5- (phenylmethoxy) -1- (phenylmethyl) -4- (1H) pyridinone

3.5 g (9.3 mmol) 2- (chloromethyl) -5- (phenylmethoxy) -1- (phenylmethyl) - 4- (1H) -pyridinone hydrochloride are mixed dissolved from water / ethyl acetate and the layers separated. The organic phase is washed twice with water washed, dried over magnesium sulfate and under reduced pressure Evaporated pressure. The residue is washed with petroleum ether digested, filtered off by suction and reduced Pressure dried. There are 2.27 g of the title compound an F. of 115 to 120 ° C (dec.) obtained.

C) N- (triphenylmethyl) piperazin-2,3-dione

A mixture of 11.4 g (100 mmol) of 2,3-piperazinedione, 55.7 g (270 mmol) bistrimethylsilylacetamide and 150 ml acetonitrile is heated under reflux for 1 hour. Within 30 minutes the mixture is added dropwise with 22.2 g (80 mmol) of triphenylmethyl chloride added and then under 2 hours Reflux heated. After stirring overnight at room temperature the clear solution is mixed with 21.6 ml of water. The precipitate obtained (3.13 g) is filtered off and the The filtrate was concentrated under reduced pressure. There will be 25.5 g the crude title compound obtained, which recrystallized from ethanol  becomes. The yield of the pure product with one F. from 230 to 235 ° C is 12.19 g.

D) 1 - [[1,4-Dihydro-4-oxo-5- (phenylmethoxy) -1- (phenylmethyl) -  2-pyridinyl] methyl] -4- (triphenylmethyl) -2,3-piperazinedione

A solution of 4.19 g (11.77 mmol) of N- (triphenylmethyl) - piperazin-2,3-dione in 95 ml of anhydrous dimethylformamide 0.35 g (11.77 mmol) of sodium hydride (80% oil) is added. After the evolution of hydrogen has ceased the thick suspension with 4.0 g (11.77 mmol) of 2- (chloromethyl) - 5- (phenyl-methoxy) -1- (phenylmethyl) -4- (1H) -pyridinone in 25 ml anhydrous dimethylformamide added, giving a clear solution arises. After stirring for 1 hour at room temperature precipitation starts to fall. After 2 hours the crystals are filtered off, washed and reduced Pressure dried. There are 5.13 g of the title compound obtained an F. of 165 to 68 ° C.

E) 1 - [[1,4-dihydro-4-oxo-5- (phenylmethoxy) -1- (phenylmethyl) - 2-pyridinyl] methyl] -2,3-piperazinedione

A solution of 8.77 g (13.23 mmol) of 1 - [[1,4-dihydro-4-oxo 5- (phenylmethoxy) -1- (phenylmethyl) -2-pyridinyl] methyl] -4- (triphenylmethyl) -2,3-piperazinedione in 65 ml dichloromethane is added dropwise at room temperature with 65 ml of formic acid transferred. After 3 days of stirring the volatiles distilled off under reduced pressure and the residue Digested twice with ether. 5.24 g of 1 - [[1,4-dihydro- 4-oxo-5- (phenylmethoxy) -1- (phenylmethyl) -2-pyridinyl] - methyl] -2,3-piperazinedione with a melting point of 260 to 265 ° C.

F) (S) - [1 - [[[[4 - [[1,4-dihydro-4-oxo-5- (phenylmethoxy) -1- (phenylmethyl) -2-pyridinyl] methyl] -2,3-dioxo-1-piper-azinyl] -  sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] - carbamic acid phenyl methyl ester

A solution of 0.44 g (2.0 mmol) (S) -3 - [[(phenylmethoxy) - carbonyl] amino] -2-azetidinone in 25 ml of anhydrous ethyl acetate with 0.28 g (2.0 mmol) of chlorosulfonyl isocyanate added and the solution for 30 minutes at room temperature touched. The solution is mixed with 12 ml dichloromethane, 0.61 g (6 mmol) of triethylamine and a previously stirred 3 hours Mixture of 0.83 g (2.0 mmol) of 1 - [[1,4-dihydro-4-oxo 5- (phenylmethoxy) -1- (phenylmethyl) -2-pyridinyl] methyl] - 2,3-piperazinedione and 1.59 g (8.0 mmol) of N-methyl-N- (trimethylsilyl) - trifluoroacetamide in 25 ml of anhydrous ethyl acetate transferred. After stirring for 3 days at room temperature the mixture is mixed with ice water and the pH adjusted to 1 with hydrochloric acid. The insoluble residue is filtered off and dried under reduced pressure. There are 1.15 g of the title compound with 72% purity receive.

G) (S) -3-Amino-N - [[4 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - methyl] -2,3-dioxo-1-piperazinyl] sulfonyl] -2-oxo- 1-azetidinecarboxamide-4-methylbenzenesulfonic acid salt

A solution of 0.98 g (1.32 mmol) (S) - [1 - [[[[4 - [[1,4-dihydro- 4-oxo-5- (phenylmethoxy) -1- (phenylmethyl) -2-pyridinyl] - methyl] -2,3-dioxo-1-piperazinyl] sulfonyl] amino] carbonyl] - 2-oxo-3-azetidinyl] -carbamic acid phenyl methyl ester in 20 ml Dimethylformamide is mixed with 0.5 g (2.64 mmol) of p-toluenesulfonic acid and 0.5 g palladium on activated carbon (10%) were added. Then hydrogen is bubbled through the mixture for 1 hour. The catalyst is filtered off, the solvent distilled off under reduced pressure and the residue with Dichloromethane digested. After drying, 0.82 g the title compound with a melting point of 160 to 185 ° C (dec.) receive.  

H) [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[4 - [(1,4- dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl] -2,3-di-oxo- 1-piperazinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] - amino] -2-oxoethylidene] -amino] -oxy] -2- methyl propionic acid diphenyl methyl ester

A solution of 0.57 g (13 mmol) (Z) -2-amino-α - [[2- (diphenylmethoxy) - 1,1-dimethyl-2-oxoethoxy] imino] -4-thiazole acetic acid in 30 ml of dimethylformamide at -30 ° C with 0.39 g (3.9 mmol) of triethylamine and 0.31 g (1.3 mmol) of triphenyl chlorophosphate transferred. After stirring for 1 hour 0.39 g (3.9 mmol) triethylamine and 0.98 g (1.3 mmol) (S) -3- Amino-N - [[4 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl] - 2,3-dioxo-1-piperazinyl] sulfonyl] -2-oxo-1-azetidinecarboxamine- 4-methylbenzenesulfonic acid salt added. The mixture is stirred for 2 hours at -10 ° C and 1.5 hours at 0 ° C. Then it is mixed with water and ethyl acetate and the pH was adjusted to 1 with 3N hydrochloric acid. The precipitate is filtered off with ethyl acetate washed and dried under reduced pressure. It will 0.86 g of the title compound with a melting point of 130 to 190 ° C Received (dec.).

I) Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) - 2 - [[1 - [[[4 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - methyl] -2,3-dioxo-1-piperazinyl] sulfonyl] amino] carbonyl] - 2-oxo-3-azetidinyl] -amino] -2-oxoäthy-liden] -amino] - oxy] -2-methylpropionic acid

A suspension of 0.8 g (0.94 mmol) [3S (Z)] - 2 - [[[1- (2-amino- 4-thiazolyl) -2 - [[1 - [[[[4 - [(1,4-dihydro-5-hydroxy-4-oxo 2-pyridinyl) methyl] -2,3-dioxo-1-piperazinyl] sulfonyl] amino] - carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] - amino] -oxy] -2-methylpropionic acid diphenylmethyl ester in 1.4 ml Anisole is mixed with 7 ml of trifluoroacetic acid at -10 ° C. After stirring for 1 hour, 30 ml of ether are added and the  the precipitate obtained is filtered off and reduced Pressure dried. This trifluoroacetic acid salt is in Suspended water and the pH of the solution with 2N sodium hydroxide solution set to 6.5. The solution is freeze-dried. 0.66 g of the crude product are obtained, which together with a second sample made in the same way (a total of 1.55 g) on a macroreticular styrene Chromatographed divinylbenzene copolymer under MPLC conditions becomes. 0.34 g of the title compound are obtained. A second column chromatography on macroreticular styrene Divinylbenzene copolymer gives 0.18 g of the title compound an F. of 242 to 270 ° C.

Example 10

Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2- [[1 - [[[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -methylene] - amino] -2-oxo-1-imidazolidinyl] sulfonyl] amino] carbonyl] - 2-oxo-3-azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] - 2-methyl propionic acid

A) 4,5-bis (phenylmethoxy) -2-pyridinecarboxylic acid phenylmethyl ester

A suspension of 29.4 g (120 mmol) of O-benzylcomenamic acid in 350 ml of dimethylformamide with 21.5 g (156 mmol) of potassium carbonate added and stirred for 1 hour at room temperature. 31 ml (264 mmol) of benzyl bromide are added to the mixture and heated to 100 ° C with stirring for 25 hours. After cooling the room temperature is below the dimethylformamide distilled off under reduced pressure and the residue with ethyl acetate digested with brief heating 60 ° C. 40 g of the inorganic salts are filtered off and the filtrate concentrated to about 75 ml. The concentrate will Chromatographed on silica gel, using ethyl acetate / petroleum ether 90: 10 is used as eluent. It will Obtained 35.5 g of the title compound with a melting point of 116.7 ° C.  

B) 4,5-bis (phenylmethoxy) -2-pyridine methanol

A suspension of 95 mg (25 mmol) lithium aluminum hydride in 10 ml ether and 10 ml tetrahydrofuran with 1.06 g (25 mmol) 4,5-bis- (phenylmethoxy) -2-pyridinecarboxylic acid phenylmethyl ester added in 3 portions at 0 ° C. After 20 minutes Stirring at 0 ° C the suspension becomes saturated with 0.2 ml Sodium bicarbonate solution, 0m2 ml 10% potassium hydroxide solution and additionally with saturated sodium bicarbonate solution added until the inorganic precipitate flocculates. The clear organic phase is poured off and evaporated under reduced pressure. An oil is obtained which slowly crystallizes out. The yield is 0.6 g, mp 96.6 ° C.

C) 4,5-bis (phenylmethoxy) -2-pyridinecarboxaldehyde

A solution of 0.54 g (1.7 mmol) of 4,5-bis (phenylmethoxy) - 2-pyridinemethanol in 15 ml acetone is mixed with 1.5 mg (17 mmol) Manganese dioxide added and the mixture overnight at room temperature touched. The mixture is then passed through a silica gel column (70 to 250 mesh, 60 to 200 µ) filtered and the Aldehyde eluted with acetone. The eluate is evaporated and the residue digested with petroleum ether. It becomes 0.3 g obtained the title compound with a melting point of 104.3 ° C.

D) 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxaldehyde

A solution of 1.9 g (6.0 mmol) of 4,5-bis (phenylmethoxy) - 2-pyridinecarboxaldehyde in 25 ml of anhydrous dimethylformamide is placed with 0.2 g of palladium on activated carbon catalyst and passed hydrogen through the mixture for 3 hours. The catalyst is filtered off, the solvent distilled off under reduced pressure and the residue with Ether digested. There are 0.64 g of the title compound an F. of 174 to 177 ° C (dec.) obtained.  

E) Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) - 2 - [[1 - [[[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - methylene] amino] -2-oxo-1-imidazolidinyl] sulfonyl] amino] - carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] - oxy] -2-methylpropionic acid

A solution of 0.64 g (1.1 mmol) [3S (Z)] - 2 - [[[2 - [[1 - [[[(3- Amino-2-oxo-1-imidazolidinyl) sulfonyl] amino] carbonyl] -2- oxo-3-azetidinyl] amino] -1- (2-amino-4-thiazolyl) -2-oxoethylidene] - amino] -oxy] -2-propionic acid in 15 ml of anhydrous dimethylformamide is mixed with 0.18 g (1.3 mmol) of 1,4-dihydro-5- hydroxy-4-oxo-2-pyridinexcarboxaldehyde added. After 4,5- hourly stirring, an additional 0.02 g (0.14 mmol) of added above compound. After stirring overnight at room temperature becomes the solvent under reduced pressure evaporated and the residue taken up in 30 ml of water, filtered and the solution freeze-dried. The raw product (0.82 g) is dissolved in 5 ml of water and macroreticular Chromatographed styrene-divinylbenzene copolymer resin, where Water is used as the eluent. It will 0.22 g of pure product with a melting point of 248 ° C (dec.) receive.

Example 11

Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2- [[1 - [[[4 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] - amino] -2,3-dioxo-1-piperazinyl] sulfonyl] amino] carbonyl] - 2-oxo-3-azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] - 2-methyl propionic acid

A) 4,5-bis (phenylmethoxy) -2-pyridinecarboxylic acid

A solution of 11.8 g (28 mmol) of 4,5-bis (phenylmethoxy) - 2-pyridinecarboxylic acid phenylmethyl ester in 115 ml tetrahydrofuran 16 ml of water and 35 ml of 1N potassium hydroxide solution are added. After stirring overnight at room temperature, 115 ml of water  added and the pH of the solution with 1N hydrochloric acid set to 2.5. The acid is filtered off with water washed and dried under reduced pressure. It will Obtain 8.6 g of the title compound with a melting point of 203.6 ° C.

B) N- (2,3-Dioxo-1-pierazinyl) -4,5-bis (phenylmethoxy) -2- pyridinecarboxamide

A suspension of 7.1 g (21.17 mmol) of 4,5-bis (phenylmethoxy) - 2-pyridinecarboxylic acid, 0.29 g (2.12 mmol) hydroxybenzotriazole and 2.73 g (21.17 mmol) of N-aminopiperazine-2,3-dione in 140 ml of anhydrous dimethylformamide after 15 minutes 4.8 g (23.3 mmol) of dicyclohexylcarbodiimide were added with stirring. After stirring for 21 hours at room temperature, the Filter cyclohexylurea (4.0 g) and the solvent evaporated under reduced pressure. The solid residue is digested with 240 ml of tetrahydrofuran for 40 minutes, filtered, washed with tetrahydrofuran and under reduced pressure Pressure dried. There are 7.76 g of the title compound obtained with an F. of 231.1 ° C.

C) (S) - [1 - [[[[4 - [[[4,5-bis- (phenylmethoxy) -2-pyridinyl] - carbonyl] aminop] -2,3-dioxo-1-piperazinyl] sulfonyl] amino] - carbonyl] -2-oxo-3-azetidinyl] carbamic acid phenylmethyl ester

A suspension of 2.02 g (9.18 mmol) (S) -3 - [[(phenylmethoxy) carbonyl] amino] -2-azetidinone in 130 ml of ethyl acetate with 1.43 g (10 mmol) of chlorosulfonyl isocyanate and after stirring for 1 hour at 0 ° C with 2.79 g (27.54 mmol) Triethylamine added. This mixture of 4.10 g (9.18 mmol) of N- (2,3- Dioxo-1-piperazinyl) -4,5-bis (phenylmethoxy) -2-pyridinecarboxamide and 5.4 g (27.54 mmol) of N-methyl-N- (trimethylsilyl) - trifluoroacetamide in 150 ml of ethyl acetate.  After stirring overnight at room temperature, the solution is mixed with 200 ml of ice water and the pH with 3N hydrochloric acid set from 10.3 to 2. If the separated organic Phase is treated with saline, the title compound falls out. The precipitate is filtered off with water washed and dried under reduced pressure. It 5.35 g are obtained. 2.5 g of this product are 1 hour long with a mixture of 25 ml of water and 37.5 ml Acetone digested at pH 6.3. There will be 2.12 g received the title link.

D) (S) -N- [4 - [[[(3-amino-2-oxo-1-azetidinyl) carbonyl] amino] - sulfonyl] -2,3-dioxo-1-piperazinyl] -1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinecarboxamide

A solution of 1.54 g (2 moles) (S) - [1 - [[[[4 - [[[4,5-bis- (phenylmethoxy) -2-pyridinyl] carbonyl] amino] -2,3-dioxo-1- piperazinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] - carbamic acid phenyl methyl ester in 30 ml of dimethylformamide is mixed with 0.77 g of palladium-on-carbon and that Mixture hydrogenated for 45 minutes. The catalyst is over hyflo filtered off and the solution obtained without the title compound isolate used in the next step.

E) [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[4 - [[(1,4- dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] - 2,3-dioxo-1-piperazinyl] sulfonyl] amino] carbonyl] -2- oxo-3-azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] -2- methyl propionic acid diphenylmethyl ester

A solution of 0.88 g (2.0 mmol) of (Z) -2-amino-α - [[2- (diphenylmethoxy) - 1,1-dimethyl-2-oxoethoxy] imino] -4-thiazole acetic acid in 20 ml of dimethylformamide with 0.60 g (6.0 mmol) triethylamine and at -30 ° C under nitrogen with 0.54 g (2.0 mmol) of triphenyl chlorophosphate were added. After 1- hourly stirring at -30 ° C, the mixture is added dropwise  0.20 g (2 mmol) of triethylamine and the dimethylformamide solution of (S) -N- [4 - [[[(3-amino-2-oxo-1-azetidinyl) carbonyl] amino] - sulfonyl] -2,3-dioxo-1-piperazinyl] -1,4-dihydro-5-hydroxy-4- oxo-2-pyridinecarboxamide added. The mixture is 2 hours stirred at -10 ° C and 17 hours at 0 ° C. The solvent is distilled off under reduced pressure and the residue shaken in 40 ml of ethyl acetate and 20 ml of ice water. When the pH of the solution with dilute hydrochloric acid is set to 1.5, an oil separates, which is separated from the solvent and under reduced pressure Pressure is dried. There are 1.35 g of the title compound receive.

F) Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) - 2 - [[1 - [[[4 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - carbonyl] amino] -2,3-dioxo-1-piperazinyl] sulfonyl] amino] - carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] - amino] -oxy] -2-methylpropionic acid

A mixture of 2.6 ml anisole and 13 ml trifluoroacetic acid is mixed with 1.3 g (1.48 mmol) [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) - 2 - [[1 - [[[4 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - carbonyl] amino] -2,3-dioxo-1-pierazinyl] sulfonyl] - amino] -carbonyl] -2-oxo-3-azetidinyl] -amino] -2-oxoethylidene] - amino] -oxy] -2-methylpropionic acid diphenylmethyl ester -10 ° C and the mixture was stirred at 0 ° C for 2 hours. The volatiles are distilled off under reduced pressure and the residue digested with ether. It will after drying 1.06 g of the trifluoroacetic acid salt receive. The trifluoroacetic acid salt is in 20 ml of water suspended and the pH of the suspension with 1N sodium hydroxide solution set to 6.5. The freeze-dried solution gives 1.10 g of the crude product. This becomes macroreticular Styrene-divinylbenzene copolymer under MPLC conditions chromatographed using water as the eluent. The yield is 0.48 g. The product is two more times  with other samples made in the same way chromatographed. The second column chromatography takes place on macroreticular styrene-divinylbenzene copolymer, the third organogen. Every time water is used as a solvent used. The final yield is 0.10 g. F. ≦ λτ300 ° C.

Example 12

[3S (Z)] - 3 - [[(2-amino-4-thiazolyl) - [(2-fluoroethoxy) imino] - acetyl] amino] -N - [[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2- pyridinyl) carbonyl] amino] -2-oxo-1-imidazolidinyl] sulfonyl] - 2-oxo-1-azetidinecarboxamidethyldiiospropylamine salt

A solution of 0.33 g (1.4 mmol) of (Z) -2-amino-α - [(2-fluoroethoxy) - imino] -4-thiazole acetic acid in 5 ml of anhydrous dimethylformamide with 0.19 g (1.4 mmol) of N-hydroxybenzotriazole and 0.18 g (1.4 mmol) of N-ethyl-diisopropylamine were added. The solution is at 0 ° C with 0.29 g (1.4 mmol) of dicyclohexylcarbodiimide added and the mixture stirred for 1 hour. Then it is mixed with a solution of 0.87 g (1.6 mmol) (3S) -3-amino-N - [[3 - [[(1,4-dihydro-5-hydroxy-4- oxo-2-pyridinyl) carbonyl] amino] -2-oxo-1-imidazolidinyl] - sulfonyl] -2-oxo-1-azetidinecarboxamide trifluoroacetet- (1: 2) - Salt (see Example 1 G) and 0.41 g (3.2 mmol) of N-ethyldiisopropylamine added in 3 ml of anhydrous dimethylformamide and stirred for 2 hours at 0 ° C. The mixture becomes more Stirred for 16 hours at room temperature. The dicyclohexylurea is filtered off and the solvent under evaporated under reduced pressure. The oily residue is with Water digested until the product crystallized completely is. The solid (0.82 g) is filtered and the Filtrate adjusted to pH 6.1 and freeze-dried. The Solid is suspended in 40 ml of water and the pH the suspension was adjusted to 6.0 with 0.25N sodium hydroxide solution. The insoluble material is filtered off and the filtrate freeze-dried. 2 servings of the freeze-dried product are combined (about 0.6 g) and on macroreticular  Chromatographed styrene-divinylbenzene copolymer, where Water and water / acetonitrile 95: 5 as eluent serve. After freeze-drying, the corresponding result Fractions 0.22 g of the title compound with an F. of 163 up to 165 ° C.

Example 13

Tri-sodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2- [[1 - [[[2- (carboxymethyl) -2 - [(1,4-dihydro-5-hydroxy-4-oxo 2-pyridinyl) -carbonyl] -hydrazino] -sulfonyl] -amino] -carbonyl] - 2-oxo-3-azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] -2- methyl propionic acid

A) N, O-dibenzyl-comenamyl chloride hydrochloride

A suspension of 16.77 g (50.0 mmol) of N, O-dibenzylcomenamic acid in 360 ml of anhydrous dichloromethane at 0 up to 5 ° C with 11.45 g (55.0 mmol) of phosphorus pentachloride transferred. After stirring for 1 hour at room temperature the precipitate is collected by suction, with 20 ml anhydrous dichloromethane and washed under reduced pressure Pressure dried. There are 15.02 g of the title compound an F. of 126 to 127 ° C (dec.) obtained.

B) [2 - [(phenylmethoxy) carbonyl] hydrazino] acetic acid-1,1- dimethyl ethyl ester

A stirred solution of 6.65 g (0.040 mol) of N - [(phenylmethoxy) - carbonyl] hydrazine in 40 ml of dimethylformamide a solution of 8.58 g (0.044 mol) of tert-butyl bromoacetate in 20 ml of dimethylformamide and a solution of 8.2 ml (0.048 mol) N, N-diisopropylethylamine in 8 ml dimethylformamide transferred. The mixture is kept at room temperature for one day stirred and the solvent then under reduced Pressure distilled off. The residue is in ether and Water added. The organic layer comes with three times  Washed water, dried over magnesium sulfate and under evaporated under reduced pressure. An oil remains (10.6 g) back, which was purified by column chromatography on silica gel is, with ethyl acetate / toluene (1: 1) as Eluent is used. The corresponding fractions are evaporated under reduced pressure and the residue stirred with petroleum ether. There will be 6.0 g of the title compound obtained with a melting point of 61 to 62 ° C.

C) [1 - [[1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] - carbonyl] -2 - [(phenylmethoxy) -carbonyl] -hydrazi-no] -acetic acid- 1,1-dimethyl ethyl ester

A solution of 11.2 g (40.0 mmol) [2 - [(phenylmethoxy) - 1,1-dimethylethyl carbonyl] hydrazino] acetic acid in 60 ml of anhydrous acetonitrile is mixed with 15.6 ml (80.0 mmol) N-methyl-N-trimethylsilyltrifluoroacetamide added. To 30 minutes stirring at room temperature becomes the clear solution evaporated under reduced pressure and the residue in 45 ml of anhydrous dichloromethane dissolved. This solution will at room temperature to a suspension of 15.61 g of N, O-dibenzylcomenamyl chloride hydrochloride in 60 ml anhydrous Given dichloromethane. After stirring overnight, the reaction mixture evaporated under reduced pressure. It stays a residue, which is stirred with 10 ml of methanol, under evaporated under reduced pressure and then on silica gel is chromatographed, with ethyl acetate and ethyl acetate / - Methanol (10: 1) was used as the eluent will. After evaporation under reduced pressure the corresponding fractions give a solid foam, which becomes crystalline when stirred with ether. The yield is 12.7 g, mp 177 to 178 ° C (dec.).

D) [1 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] - 1,1-dimethylethyl hydrazino] acetic acid

A suspension of 7.17 g (12.0 mmol) [1 - [[1,4-dihydro-4- oxo-5- (phenylmethoxy) -2-pyridinyl] carbonyl] -2 - [(phenylmethoxy) - 1,1-dimethylethyl carbonyl] hydrazino] acetic acid in 400 ml of methanol in the presence of 1.6 g of palladium hydrogenated on activated carbon (10%) for 40 minutes. The The catalyst and the precipitated product are filtered off and washed thoroughly with 300 ml of anhydrous dimethylformamide, to solve the precipitated product. From the united The solvents are filtered off under reduced pressure Pressure removed. There remains a backlog below Stirring crystallized with ether (1.68 g, mp 221 ° C, dec.) The recrystallization from methanol gives the pure compound in a yield of 1.26 g, mp 225 ° C, sintering point 229 ° C (dec.).

E) (3S) - [1 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] - 2 - [[[[2-oxo-3 - [[(phenylmethoxy) carbonyl] amino] - 1-azetidinyl] carbonyl] amino] sulfonyl] hydrazino] acetic acid 1,1-dimethyl ethyl ester

A suspension of 3.2 g (11.0 mmol) [1 - [(1,4-dihydro-5- hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] acetic acid - 1,1-dimethylethyl ester in 120 ml of anhydrous ethyl acetate with 9.0 ml (46.2 mmol) of N-methyl-N-trimethylsilyltrifluoroacetamide transferred. It will be 1 hour at room temperature stirred, giving a clear solution (solution A).

A suspension of 2.42 g (11.0 mmol) (S) -3 - [[(phenylmethoxy) - carbonyl] amino] -2-azetidinone in 80 ml of anhydrous Ethyl acetate is mixed with 0.99 ml (11.0 mmol) of chlorosulfonyl isocyanate added with stirring. The mixture will Stirred for 1 hour at room temperature and then cooled to 0 ° C. Solution A is added at 0 ° and overnight stirred further at room temperature. After adding 4 ml Triethylamine, the mixture is evaporated under reduced pressure.  The residue is dissolved in 10 ml of methanol / water (4: 1) solved. The solution is poured into a mixture of 30 ml methanol / - Poured water, keeping the pH at 2. It a residue (10.25 g) remains, which is stirred with some ml of water and methanol becomes crystalline. The precipitation by washing in succession with stirring Isopropanol / water (4: 1), methanol, methanol / ether (1: 1) and ether cleaned. The yield after drying under reduced pressure is 2.39 g.

F) (S) -3-Amino-1 - [[[[2- (carboxymethyl) -2 - [(1,4-dihydro-5- hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] sulfonyl] - amino] carbonyl] -2-azetidinone trifluoroacetate salt

A mixture of 7.0 ml trifluoroacetic acid and 1.66 ml thioanisole is mixed with 2.39 g (3.9 mmol) (3S) - [1 - [(1,4-dihydro- 5-hydroxy-4-oxo-2-pyridinyl) carbonyl] -2 - [[[[2-oxo-3- [[(phenylmethoxy) carbonyl] amino] -1-azetidinyl] carbonyl] - amino] -sulfonyl] -hydrazino] -acetic acid-1,1-dimethylethyl ester transferred. After stirring overnight at room temperature the solution is evaporated under reduced pressure. The The residue is washed in succession with ethyl acetate, Ethyl acetate / petroleum ether (1: 1), petroleum ether and dichloromethane, and then under reduced pressure dried. The raw salt is in without further purification used the next step. The yield is 2.15 g.

G) [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[2- (carboxymethyl) - 2 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - carbonyl] hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3- azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] -2- methyl propionic acid diphenyl methyl ester

A -30 ° C cold mixture of 1.42 g (3.24 mmol) (Z) -2-amino- α - [[2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy] imino] - 4-thiazole acetic acid and 1.81 ml (12.96 mmol) of triethylamine  in 30 ml of anhydrous acetonitrile with 0.70 ml (3.24 mmol) Diphenyl chlorophosphate added (solution A).

A suspension of 2.13 g (about 3.3 mmol) of crude (S) -3-amino- 1 - [[[[2- (carboxymethyl) -2 - [(1,4-dihydro-5-hydroxy-4-oxo 2-pyridinyl) -carbonyl] -hydrazino] -sulfonyl] -amino] -carbonyl] - 2-azetidinone trilfuoroacetate salt in 30 ml of anhydrous ethyl acetate is at room temperature with 3.27 ml (12.96 mmol) Bistrimethylsilylacetamide added. After 1- hours of stirring, the clear solution is cooled and poured into the -30 ° C cold solution A. The mixture is at 1 hour -10 ° C and 1 1/2 hours at 0 ° C and then under evaporated under reduced pressure. The arrears with a few ml of water and the pH of the solution Add diluted hydrochloric acid to 2. The precipitation is filtered off, washed with water, back in Water / acetone at pH 5.5 to 6.0 by adding dilute Sodium hydroxide solution dissolved and by MPLC on a macroreticular Styrene-divinylbenzene copolymer cleaned, with a water-methanol gradient (0 to 100%) is eluted. Freeze-drying the corresponding fractions gives 270 mg of the purified products. A suspension of the salt in a few ml of cold water with dilute hydrochloric acid Acidified to pH 2 to precipitate the free acid. These is collected by suction and under reduced pressure dried. There are 0.19 g with a F. of ≦ λτ180 ° C. Received (dec.).

H) [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[[2-carboxymethyl) - 2 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - carbonyl] hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3- azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] -2- methyl propionic acid trifluoroacetic acid salt

A -10 ° C stirred solution of 0.62 ml (8.0 mmol) Trifluoroacetic acid and 0.087 ml (0.8 mmol) thioanisole  slowly with 0.17 g (0.2 mmol) [3S (Z)] - 2 - [[[1- (2-amino-4- thiazolyl) -2 - [[1 - [[[[2- (carboxymethyl) -2 - [(1,4-dihydro-5- hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] sulfonyl] - amino] -carbonyl] -2-oxo-3-azetidinyl] -amino] -2-oxo-ethylidene] - amino] -oxy] -2-methylpropionic acid diphenylmethyl ester. The mixture is stirred at 0 ° C. for a further 15 minutes. The- Suspension is evaporated at -5 ° C under reduced pressure and the residue was stirred with anhydrous ether. The residue is collected by suction, with anhydrous water washed and dried under reduced pressure. It become 0.14 g with a melting point of ≦ λτ230 ° C (dec.). receive.

I) Tri-sodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) - 2 - [[1 - [[[2- (carboxymethyl) -2 - [(1,4-dihydro-5-hydroxy-4- oxo-2-pyridinyl) carbonyl] hydrazino] sulfonyl] amino] carbonyl] - 2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] - oxy] -2-methylpropionic acid

115 mg (0.146 mmol) of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) - 2 - [[1 - [[[2- (carboxymethyl) -2 - [(1,4-dihydro-5-hydroxy-4-oxo 2-pyridinyl) -carbonyl] -hydrazino] -sulfonyl] -amino] -carbonyl] - 2-oxo-3-azetidinyl] -amino] -2-oxo-ethylidene] -amino] -oxy] -2- methylpropionic acid trifluoroacetic acid salt are in 1.5 ml of water suspended and the pH of the suspension by the dropwise addition of dilute sodium hydroxide solution 5.5 set. The solution is successively over 2 columns from macroreticular styrene-divinylbenzene copolymer (0.05 up to 0.1 mm) and cross-linked dextran gel (25 to 100 µm) given and eluted with water. The corresponding fractions are combined and lyophilized. It becomes 100 mg received the title link.

Example 14

Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2- [[1 - [[[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - acetyl] amino] -2-oxo-1-imidazolidinyl] sulfonyl] amino] -  carbonyl] -2-oxo-3-acezitidinyl] amino] -2-oxoethylidene] amino] - oxy] -2-methylpropionic acid

A) 2- (cyanomethyl) -5- (phenylmethoxy) -1- (phenylmethyl) -4- (1H) - pyridinone

A suspension of 2.0 g (6 mmol) of 2- (chloromethyl) -5- (phenylmethoxy) - 1- (phenylmethyl) -4- (1H) pyridinone in 20 ml Acetonitrile is mixed with 3.9 g (60 mmol) of potassium cyanide and 0.1 g [18] crown-6 cross-linked. The mixture is under for 2.5 hours Reflux heated. The salts are filtered off by suction and the filtrate evaporated under reduced pressure. The remaining residue is by column chromatography Purified on silica gel, using ethyl acetate / methanol (8: 2) is used as the eluent. The yield the title compound is 0.55 g, mp 175 to 180 ° C.

B) 1,4-Dihydro-5-hydroxy-4-oxo-1- (phenylmethyl) -2-pyridine acetic acid

A mixture of 2.45 g (7.16 mmol) of 2- (cyanomethyl) -5- (phenylmethoxy) - 1- (phenylmethyl) -4- (1H) pyridinone and 40 ml Concentrated hydrochloric acid (37%) is stirred at 70 ° C for 4 hours and then evaporated under reduced pressure. The The residue is suspended in 15 ml of ice-cold water and the pH of the suspension by adding 5N sodium hydroxide solution set to 2.0. The precipitate is filtered off with Ice water and ether washed and under reduced pressure dried (1.71 g). The crude acid is dissolved in 20 ml of 0.5N sodium hydroxide solution dissolved by acidification with 2N hydrochloric acid to pH 1.8 precipitated again, collected by suction and with ice water washed. The yield is 1.52 g, mp 231 to 235 ° C.  

C) 1,4-dihydro-5-hydroxy-4-oxo-N- (2-oxo-1-imidazolidinyl) - 1- (phenylmethyl) -2-pyridineacetamide

A suspension of 9.29 g (35.83 mmol) of 1,4-dihydro-5-hydroxy 4-oxo-1- (phenylmethyl) -2-pyridine acetic acid, 0.28 g (1.79 mmol) N-hydroxybenzotriazole, 0.22 g (1.79 mmol) N-dimethylaminopyridine, 3.62 g (35.83 mmol) of N-aminoimidazolidinone and 8.13 g (39.31 mmol) of dicyclohexylcarbodiimide in 115 ml of anhydrous Dimethylformamide is mixed with 4.99 ml (35.83 mmol) Triethylamine added. It gets overnight at room temperature touched. The precipitated dicyclohexylurea is filtered off, washed with dimethylformamide and the filtrate under evaporated under reduced pressure. There is a backlog the crystalline becomes when it is stirred with 110 ml of dichloromethane becomes. The precipitate is collected by suction and dried under reduced pressure. A suspension of this crude product in 65 ml of anhydrous acetonitrile with 14.0 ml (71.6 mmol) of N-methyl-N-trimethylsilyltrifluoroacetamide transferred. After stirring for 30 minutes at room temperature the undissolved dicyclohexylurea is filtered off and the filtrate evaporated under reduced pressure. The oily residue is boiled in 70 ml of methanol for 15 minutes and then cooled. The precipitate is suctioned off collected, successively with methanol, methanol / ether (1: 1) and ether washed and dried under reduced pressure. The yield is 8.7 g, sintering point 242 ° C. F. 60 to 265 ° C (dec.).

D) Sodium salt of (S) - [1 - [[[[3 - [[[1,4-dihydro-5-hydroxy-4- oxo-1- (phenylmethyl) -2-pyridinyl] -acetyl] -ami-no] -2-oxo- 1-imidazolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3- phenyl azetidinyl] carbamate

A suspension of 3.42 g (10.0 mmol) of 1,4-dihydro-5-hydroxy 4-oxo-N- (2-oxo-1-imidazolidinyl) -1- (phenylmethyl) -2-pyridineacetamide in 50 ml of anhydrous ethyl acetate  

5.86 ml (30.0 mmol) of N-methyl-N-trimethylsilyltrifluoroacidamide added and stirred for 1 hour at room temperature (solution A).

A solution of 2.20 g (10.0 mmol) of (S) -3 - [[(phenylmethoxy) - carbonyl] amino] -2-azetidinone in 50 ml of anhydrous ethyl acetate is stirred with 0.90 ml (10.0 mmol) Chlorosulfonyl isocyanate added and the mixture at 1 hour Room temperature stirred. It is then cooled to 0 ° C and solution A was added with stirring at 0 ° C. After stirring overnight at room temperature the mixture evaporated under reduced pressure and the residue taken up in a few ml of methanol and water. The pH The value of the solution is increased by adding dilute sodium hydroxide solution set to 5.5 and the filtered solution is freeze-dried. There will be an MPLC on a macroreticular Styrene-divinylbenzene copolymer carried out with water / Acetone (8: 1) is eluted. Then the corresponding pure fractions freeze-dried. It will 0.40 g of the title compound was obtained. The not pure Fractions are subjected to a second MPLC, the same Conditions are met. The yield is 0.60 g.

E) (S) -N- [3 - [[[(3-amino-2-oxo-1-azetidinyl) carbonyl] amino] - sulfonyl] -2-oxo-1-imidazolidinyl] -1,4-dihydro-5-hydroxy- 4-oxo-2-pyridineacetamide trifluoroacetate salt

A solution of 0.90 g (1.3 mmol) of the sodium salt of (S) - [1 - [[[[3 - [[[1,4-dihydro-5-hydroxy-4-oxo-1- (phenylmethyl) - 2-pyridinyl] acetyl] amino] -2-oxo-1-imidazolidinyl] sulfonyl] - amino] carbonyl] -2-oxo-3-azetidinyl] carbamic acid phenylmethyl ester in 13 ml of anhydrous dimethylformamide, which contains 0.50 ml (6.5 mmol) of trifluoroacetic acid in the presence of 0.15 g palladium-on-carbon (10%) Hydrogenated for 20 minutes. The catalyst is filtered off  

and washed with a few ml of dimethylformamide. The filtrate is evaporated under reduced pressure. There remains one oily residue that becomes crystalline when combined with some ml of ethyl acetate is stirred. The yield is 0.675 g, F. ≦ λτ150 ° C (dec.)

Simply stir this crude title compound in anhydrous Ethyl acetate for 1 hour and subsequent Filtration, washing with ethyl acetate and drying under reduced pressure improves purity. The yield is 80%, F. ≦ λτ165 ° C (dec.).

F) [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[3 - [[(1,4- dihydro-5-hydroxy-4-oxo-2-pyridinyl) acetyl] amino] -2-oxo- 1-imidazolidiynl] sulfonyl] amino] carbonyl] -2-oxo-3- azetidinyl] -amino] -2-oxoethyli-den] -amino] -oxy] -2- methyl propionic acid diphenyl methyl ester

A suspension of 0.75 g (1.35 mmol) (S) -N- [3 - [[((3-amino- 2-oxo-1-azetidinyl) carbonyl] amino] sulfonyl] -2-oxo-1-imidaziolidinyl] - 1,4-dihydro-5-hydroxy-4-oxo-2-pyridineacetamide trifluoroacetate- Salt in 12 ml of anhydrous ethyl acetate with 1.1 ml (4.45 mmol) of bistrimethylsilylacetamide transferred. After stirring for 1 hour at room temperature the clear solution is evaporated under reduced pressure and the oily residue in 12 ml of anhydrous ethyl acetate solved (solution A).

A -30 ° C cold suspension of 0.60 g (1.35 mmol) (Z) -2- Amino-α - [[2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy] - imino] -4-thiazole acetic acid in 12 ml of anhydrous acetonitrile is with 0.57 ml (5.4 mmol) of triethylamine and then with 0.29 ml (1.35 mmol) of diphenyl chlorophosphate were added. It is 1 hour at -30 ° C and another hour at 0 ° C touched. The solvent is applied under reduced pressure removed and the residue by stirring with a few ml of water  failed at 0 ° C. The precipitate is suctioned off collected, washed with cold water, in water of pH Value 2 by adding a few drops of dilute hydrochloric acid suspended, filtered off, successively with water, methanol and ether washed and dried under reduced pressure. The yield is 1.07 g, F. ≦ λτ180 ° C (dec.). This raw product is in the next step without further cleaning used.

G) Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) - 2 - [[1 - [[[3 - [[(1,4-dihydro-5-hydroxy4-oxo-2-pyridinyl) - acetyl] amino] -2-oxo-1-imidazolidinyl] sulfonyl] amino] - carbonyl] -2-oxo-3-azetidinyl] -amino] -2-oxoäthy-liden] - amino] -oxy] -2-methylpropionic acid

A -10 ° C cold solution of 2.0 ml anisole in 10 ml trifluoroacetic acid is mixed with 1.01 g (1.17 mmol) of crude [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[[3 - [[(1,4-dihydro-5- hydroxy-4-oxo-2-pyridinyl) acetyl] amino] -2-oxo-1-imidazolidinyl] - sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] - amino] -2-oxoethylidene] -amino] -oxy] -2- methylpropionic acid diphenylmethyl ester added. After stirring for 20 minutes -10 ° C the solvent under reduced pressure Evaporated at + 10 ° C. The residue is mixed with a few ml of dichloromethane stirred, filtered and again with some ml of dichloromethane stirred. The residue is suctioned off collected, washed with hexane and under reduced pressure dried. The crude product (1.06 g) is dissolved in a few ml of water / Acetonitrile suspended and then by adjusting the pH to 6.0 by adding 1N sodium hydroxide solution. After concentrating under reduced pressure, the aqueous solution by MPLC on macroreticular styrene-divinylbenzene Copolymer chromatographed, eluting with water becomes. The appropriate fractions are combined and freeze-dried. The yield is 0.10 g, F. ≦ λτ255 ° C.  

Example 15

Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2- [[1 - [[[3 - [[3- (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -1- oxo-2-propenyl] amino) -2-oxo-1-imidazolidinyl] -2-sulfonyl] - amino] carbonyl] -2-oxo-3-azetidinyl] -2-amino] -2-oxoethylidene] - amino] -oxy] -2-methylpropionic acid

A) 2 - ((1-Hydroxy-1-methoxy) -1-methyl) -5- (phenylmethoxy) -4- (1H) pyridinone

9.0 g of 2- (hydroxymethyl) -5- (phenylmethoxy) -4- (1H) pyridinone and 26 g of manganese dioxide (activated) are in 100 ml of methanol stirred overnight at room temperature. Crystals fall of the product. After boiling the reaction mixture for 10 minutes and hot filtration by Hyflo Filter cake washed twice with 50 ml of boiling methanol. The combined filtrates are evaporated and the residue stirred with 50 ml of ethyl acetate. It fall white crystals of the product. The yield is 9.7 g, F. 156 ° C (dec.).

B) 3- [1,4-Dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] -2- ethyl propenate

0.5 g p-toluenesulfonic acid, 6.26 G 2- (1-hydroxy-1-methoxymethyl) - 5- (phenylmethoxy) -4- (1H) pyridinone and 8.35 g carbethoxymethylene triphenylphosphorane are 3 hours in 100 ml Dioxane stirred at 70 ° C. It forms a clear dark color Solution. After evaporation of the solvent under an oily residue of the title compound remains under reduced pressure and triphenylphosphine oxide. The backlog is in 30 ml of isopropanol dissolved, whereupon crystals of the product start failing. The solution is refrigerated overnight ditched. The crystals are then filtered off, washed with ether and recrystallized from isopropanol. The yield is 5.72 g, mp 188 ° C.  

C) 3- [1,4-Diyhdro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] -2- propenoic acid

1.5 g of 3- [1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] - Ethyl 2-propenate and 0.29 g of potassium hydroxide are dissolved in 30 ml Ethanol stirred at 50 ° C for 2 hours. After the steam has evaporated The residue is dissolved in 100 ml of water and filtered. The filtrate is mixed with 2N hydrochloric acid, until the pH reaches 5. The crystals of the title compound fall out of solution. They are filtered off with water washed and dried under reduced pressure. The Yield is 1.14 g, mp 236 ° C.

D) 3- [1,4-Dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] -N- (2-oxo-1-imidazolidinyl) -2-propenamide

10.85 g of 3- [1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] - 2-propenoic acid, 1 g N-hydroxybenzotriazole, 0.01 g N, N-dimethylaminopyridine and 8.24 g of dicyclohexalcarbodiimide Stirred for 30 minutes in 100 ml of dimethylformamide. After this Cooling to 0 ° C., 4 g of N-aminoimidazolidinone are added and 1 hour at 0 ° C and 10 hours at room temperature further stirred. The suspension obtained is heated to 60 ° C and filtered. It is again in 50 ml of dimethylformamide suspended, warmed to 60 ° C and filtered again. The combined filtrates are evaporated at 40 ° C (oil vacuum). The oily residue is washed with 50 ml of water containing 2 g Contains sodium bicarbonate, stirred. After filtering off the solid is washed with water, acetone and ether. After drying, 12.3 g of the solid are obtained. He together with 8 g of p-toluenesulfonic acid in 100 ml of dichloromethane Stirred for 1 hour. Filtration gives 12.98 g of a white solid. This connection is made in water suspended. The recrystallization from water / dimethylformamide gives 8.49 g of the title compound with an F. of 271 ° C.  

E) (3S) - [- [[[[3 - [[3- [1,4-dihydro-4-oxo-5- (phenylmethoxy) - 2-pyridinyl] -1-oxo-2-propenyl] amino] -2-oxo-1-imide-azolidinyl] - sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] - carbamic acid phenyl methyl ester

3.55 g of 3- [1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] - N-2- (2-oxo-1-imidazolidinyl) -2-propenamide are dissolved in 100 ml Ethyl acetate and suspended with 6.3 g of N-methyl-N- (Trimethylsilyl) trifluoroacetamide added. After 1 hour Stirring gives a clear solution. The solution will be then within 10 minutes to a solution cooled to 0 ° C of 3.3 g (S) -1 - [[(chlorosulfonyl) amino] carbonyl] -3- [[(phenylmethoxy) carbonyl] amino] -2-azetidinone in 50 ml Given ethyl acetate. After stirring overnight the solvent evaporated and the oily residue for 1 hour stirred with 50 ml of isopropanol. The precipitate obtained is filtered off and washed with isopropanol and ether. The yield is 5.91 g.

F) (3S) -3-Amino-N - [[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2- pyridinyl) -1-oxo-2-propenyl] amino] -2-oxo-1-imide-azolidinyl] - sulfonyl] -1-azetidinecarboxamide trifluoroacetate salt

6.8 g (3S) - [1 - [[[[3 - [[3- [1,4-dihydro-4-oxo-5- (phenylmethoxy) - 2-pyridinyl] -1-oxo-2-propenyl] amino] -2-oxo-1- imidazolidinyl] sulfonyl] amino] carbonyl] -2-oxo-2-azetidinyl] - carbamic acid phenyl methyl esters are overnight at Room temperature in 60 ml trifluoroacetic acid / thioanisole (3: 1) touched. After evaporation of the solution obtained 50 ml of isopropanol and 10 ml ether added. The (3S) -3-amino-N - [[3 - [[(1,4-dihydro- 5-hydroxy-4-oxo-2-pyridinyl) -1-oxo-2-propenyl] amino] - 2-oxo-1-imidazolidinyl] sulfonyl] -1-azetidinecarboxamide trifluoroacetate Salt precipitates as a white precipitate. It is washed several times with ether and dried. The Yield is 4.30 g.  

G) disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) - 2 - [[1 - [[[3 - [[3- (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - 1-oxo-2-propenyl] amino] -2-oxo-1-imidazolidinyl] sulfonyl] - amino] -carbonyl] -2-oxo-3-aze-tidinyl] -amino] -2-oxo- ethylidene] amino] oxy] -2-methylpropionic acid

2.2 g (Z) -2-amino-α - [[2- (diphenylmethoxy) -1,1-dimethyl-2- oxoethoxy] imino] -4-thiazole acetic acid and 1.5 g triethylamine are dissolved in 150 ml of acetonitrile. The solution will be 1.4 g of diphenyl chlorophosphate are added dropwise at -30 ° C. and the mixture was then stirred for 1 hour. 3.3 g (3S) -3- Amino-N - [[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - 1-oxo-2-propenyl] amino] -2-oxo-1-imidazolidinyl] sulfonyl] - 1-Azetidinecarboxamide-2.0-trifluoroacetate salt are dissolved in 100 ml Ethyl acetate and suspended with 6 ml of N-methyl-N- Treated (trimethylsilyl) trifluoroacetamide and then Stirred for 1 hour at room temperature. The solution will be at -30 ° C dropwise to the activated one within 15 minutes Given acid. It is then 1 hour at -10 ° C and stirred at 0 ° C for 30 minutes. The solvent is under evaporated under reduced pressure and the remaining oil stirred with ice water at pH 2 (2N phosphoric acid). The ice water is discarded and the residue again with ice water washed and then dissolved in 100 ml of tetrahydrofuran. The solution is dried over sodium sulfate and the filtrate then evaporated. The diphenylmethyl esters of the title compound is a solid foam in a yield of 1.81 g isolated.

1.5 g of the product are dissolved in 30 ml of trifluoroacetic acid / anisole stirred at 0 ° C for 30 minutes. After adding 100 ml of ether are 1.7 g of the trifluoroacetic acid salt Title compound isolated by filtration. This is in 10 ml of water dissolved and with sodium bicarbonate solution added until the pH reaches 5.5. The filtered solution is on macroreticular styrene-divinylbenzene copolymer  (400 g) chromatographed using water as the eluent is used. Contain the appropriate fractions 0.64 g of the product. A bioautography gives a low one Amount of a bioactive by-product. The product a second column chromatography on Merck Lobar C subjected to water as eluent. The corresponding Fractions contain 0.17 g of the title compound.

Example 16

Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2- [[1 - [[[[2- [3- (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -1- oxo-2-propenyl] hydrazino] sulfonyl] amino] carbonyl] -2- oxo - azetidinyl] amino] -2-oxoethylidene] amino] oxy] -2- methyl propionic acid

A) 3- [1,4-Dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] -2- propenoic acid 2 - [(1,1-dimethylethoxy) carbonyl] hydrazide

1.36 g of 3- [1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] - 2-propenoic acid, 0.75 g N-hydroxybenzotriazole, 0.01 g N, N-dimethylaminopyridine and 1.06 g dicyclohexylcarbodiimide are in 20 ml of dimethylformamide at 0 ° C for 20 minutes touched. Then 0.66 g of N- (tert-butoxycarbonyl) - hydrazine added. After stirring overnight, the resulting Dicyclohexylurea filtered off and the filtrate washed with 10 ml of dimethylformamide. The filtrate becomes Evaporated to dryness and the residue in 30 ml of water suspended. Then 1 g of sodium hydrogen carbonate added and after stirring the title compound filtered. The recrystallization from dimethylformamide / Water gives white crystals in one yield of 1.47 g with a melting point of 141 ° C.

B) 3- [1,4-Dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] -2- propenoic acid hydrazide

3.86 g of 3- [1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] - 2-propenoic acid 2 - [(1,1-dimethylethoxy) carbonyl] hydrazide be half at 0 to 5 ° C in 30 ml of trifluoroacetic acid Hour stirred. The trifluoroacetic acid salt of the title compound fails after the addition of 50 ml of diethyl ether. The Salt is suspended in 30 ml of water, with 2 g of sodium hydrogen carbonate Stirred for 20 minutes and then the title compound filtered off. It is washed with water and dried, yielding a beige powder in a 50380 00070 552 001000280000000200012000285915026900040 0002003632876 00004 50261 yield of 2.75 g.

C) (3S) -1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid- 2 - [[[[2-oxo-3 - [[(phenylmethoxy) carbonyl] - amino] -1-azetidinyl] carbonyl] amino] sulfonyl] hydrazide

2.86 g of 3- [1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] - 2-propenoic acid hydrazide and 8.1 g of N-methyl-N- (trimethylsilyl) - trifluoroacetamide are 1 hour in 50 ml of ethyl acetate touched. The clear solution obtained is within 10 minutes at 0 ° C with a solution of 3.27 g (S) -1 - [[(chlorosulfonyl) amino] carbonyl] -3 - [[(phenylmethoxy) - carbonyl] amino] -2-azetidinone added. After stirring over The solvent is evaporated overnight and the residue stirred with 50 ml isopropanol and a drop of acid. The The title compound is filtered off and with isopropanol and Ether washed. The yield is 5.42 g.

D) (3S) -3- [1,4-Dihydro-5-hydroxy-4-oxo-2-pyridinyl] -2- propenoic acid-2 - [[[(3-amino-2-oxo-1-azetidinyl) carbonyl] - amino] sulfonyl] hydrazide trifluoroacetate salt

5.2 g (3S) -1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid- 2 - [[[[2-oxo-3 - [[(phenylmethoxy) carbonyl] - amino] -1-azetidinyl] carbonyl] amino] sulfonyl] hydride are added in 50 ml trifluoroacetic acid / thioanisole (3: 1) Room temperature stirred overnight. The clear solution will be  with a mixture of 100 ml ether / isopropanol (8: 2 transferred. The precipitate obtained is filtered off and washed with ether. The yield is after drying 4.01 g.

E) Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) - 2 - [[1 - [[[[2- [3- (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - 1-oxo-2-propenyl] hydrazino] sulfonyl] amino] carbonyl] - 2-oxo-3-azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] - 2-methyl propionic acid

1.5 g (Z) -2-amino-α - [[2- (diphenylmethoxy) -1,1-dimethyl- 2-oxoethoxy] imino] -4-thiazole acetic acid and 1 g of triethylamine are dissolved in 100 ml of acetonitrile. The solution will be 1 g diphenyl chlorophosphate was added dropwise at -30 ° C and the mixture was then stirred for 1 hour.

2.0 g (3S) -3- [1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl] -2- propenoic acid-2 - [[[(3-amino-2-oxo-1-aztidinyl) carbonyl] - amino] sulfonyl] hydrazide trifluoroacetate salt and 5.5 ml N-methyl-N- (trimethylsilyl) trifluoroacetamide are described in 50 ml of ethyl acetate stirred at room temperature for 1 hour. The clear solution obtained is cooled and at -30 ° C added dropwise to the activated acid. The Mixture is 1 hour at -30 ° C, 30 minutes at -10 ° C and Stirred for 1 hour at 0 ° C. The solvents are then under evaporated under reduced pressure and the residue with 50 ml of isopropanol stirred. The resulting solid is filtered off and with 100 ml of ice water at pH 2 for 20 minutes (Phosphoric acid) stirred. After filtering you get the diphenylmethyl ester of the title compound, three times washed with 50 ml portions of ice water and dried (1.78 g). 1.5 g of the ester are mixed with 50 ml of trifluoroacetic acid / Anisole (4: 1) at 0 ° C for 30 minutes touched. After adding 150 ml of ether, the trifluoroacetic acid salt filtered off the free acid of the title compound  (1.65 g).

1 g of this product is suspended in 5 ml of water and the pH was adjusted to 6.0 with sodium hydrogen carbonate. The clear solution is then added to 400 g of macroreticular styrene Divinylbenzene copolymer with water as the eluent chromatographed. 413 g of the title compound are obtained. 400 mg of the product are added to Merck Lobar C. Rechromatographed water as eluent. The yield is 160 mg.

Example 17

Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2- [[1 - [[[[2 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - carbonyl] -amino] -ethyl] -amino] -sulfonyl] -amino] -carbonyl] - 2-oxo-3-azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] -2- methyl propionic acid

A) N- (4-methoxybenzyl) -O-benzylcomenamic acid

10 g of O-benzylcomenic acid and 10 ml of 4-methoxybenzylamine in 60 ml of water are heated under reflux for 4 hours. The The reaction mixture is mixed with 2N hydrochloric acid at room temperature adjusted to pH 2. 15 g of crystals are obtained. Recrystallization from dioxane gives 12.3 g of the title compound with a F. of 175 ° C.

B) 1,4-dihydro-1 - [(4-methoxyphenyl) methyl] -4-oxo-5- (phenylmethoxy) - N- [2 - [(phenylmethyl) amino] ethyl 2-pyridinecarboxamide

3.69 g of N - [(4-methoxyphenyl) methyl] -O-benzyl-comenamic acid, 1.50 g of N-hydroxybenzotriazole and 2.05 g of dicyclohexylcarbodiimide are in 1 hour at room temperature 50 ml of dioxane stirred. A solution of 1.35 g of N-benzylethylenediamine in 5 ml of dioxane is added dropwise. To  The dicyclohexylurea formed is stirred overnight filtered off and the dioxane evaporated from the filtrate. The oily residue is dissolved in 50 ml of dichloromethane and with two 50 ml portions of 10% sodium hydrogen carbonate extracted and then washed with water. To drying the dichloromethane solution over sodium sulfate the solution is evaporated. The remaining solid is recrystallized from ethanol. There will be 4.2 g Obtained crystals of the title compound with a melting point of 112 ° C.

C) N- (2-aminoethyl) -1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxamide- p-toluenesulfonate salt

9.95 g 1,4-dihydro-1 - [(4-methoxyphenyl) methyl] -4-oxo-5- (phenylmethoxy) -N- [2 - [(phenylmethyl) amino] ethyl] -2- pyridinecarboxamide and 7.7 g of p-toluenesulfonic acid in 100 ml Methanol with 3 g of palladium-on-carbon (10%) treated and hydrogen at 45 to 50 ° C for 6 hours passed through the reaction mixture. Then will Argon passed through the reaction mixture for 10 minutes. The mixture is filtered and the filtrate evaporated. There are beige crystals of the title compound obtained, first with 20 ml of cold methanol and then be washed with 50 ml ether. The yield is 10.5 g, mp 271 ° C.

D) N- (2-aminoethyl) -1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxamine- dihydrochloride

5.42 g N- (2-aminoethyl) -1,4-dihydro-5-hydroxy-4-oxo-2- pyridinycarboxamide p-toluosulfonic acid salt are in 50 ml Formic acid dissolved and then 7.5 ml formic acid / Hydrogen chloride gas (2.2 equivalents of hydrogen chloride) and 150 ml ether added. White crystals are obtained. To filtering and washing with 200 ml of ether becomes 2.60 g  obtained the title compound with a melting point of 287 ° C.

E) (3S) - [1 - [[[[[2 - [[(1,4-dihydro-5-hydroxy-4-oxo-2- pyridinyl) carbonyl] amino] ethyl] amino] sulfonyl] ami no] - carbonyl] -2-oxo-3-azetidinyl] carbamic acid phenylmethyl ester

4.38 g of (S) -3 - [[(phenylmethoxy) carbonyl] amino] -2-azetidinone are suspended in 50 ml of ethyl acetate and at room temperature with 2.83 g of chlorosulfonyl isocyanate. After stirring for 30 minutes, a clear solution is obtained.

5.40 g of N- (2-aminoethyl) -1,4-dihydro-5-hydroxy-4-oxo-2- pyridinecarboxamide dihydrochloride in 50 ml of acetonitrile together with 24 g (6 equivalents) of N-methyl-N- (trimethylsilyl) - trifluoroacetamide stirred at 50 ° C for 1 hour. The volatile substances are evaporated under reduced pressure. The remaining oily residue is with 50 ml Ethyl acetate added.

The solutions prepared as above are at 0 ° C cooled and the second solution with stirring to the first Solution given. After stirring overnight, 200 ml of isopropanol added with stirring at 0 ° C. It becomes the title link in the form of beige crystals in obtained a yield of 8.77 g with a melting point of 145 ° C.

F) (3S) -N - [[[[[(3-amino-2-oxo-1-azetidinyl) carbonyl] amino] - sulfonyl] amino] ethyl] -1,4-dihydro-5-hydroxy-4-oxo- 2-pyridinecarboxamide 2,0-trifluoroacetate salt

2 g (3S) - [1 - [[[[2 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - carbonyl] -amino] -ethyl] -amino] -sulfonyl] -amino] -carbonyl] - 2-oxo-3-azetidinyl] carbamic acid phenylmethyl ester are in 20 ml thioanisole / 40 ml trifluoroacetic acid at 0 ° C.  Stirred for 12 hours. After adding 100 ml of ether filtered off fine white crystals of the title compound. they are washed with 50 ml isopropanol and 100 ml ether. There are 2.12 g of the title compound with a melting point of 136 ° C. Received (dec.).

G) [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[[2- [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] ethyl] amino] sulfonyl] amino] carbonyl] -2-oxo-3- azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] -2- methyl propionic acid diphenyl methyl ester.

4.40 g of (Z) -2-amino-α - [[2- (diphenylmethoxy) -1,1-dimethyl-2- oxoethoxy] imino] -4-thiazole acetic acid and 3 g of triethylamine are dissolved in 150 ml of acetonitrile. The solution is at -30 ° C with 2.8 g of diphenyl chlorophosphate added dropwise and the mixture was then stirred for 1 hour.

6.13 g (3S) -N - [[[[[(3-amino-2-oxo-1-azetidinyl) carbonyl] - amino] sulfonyl] amino] ethyl] -1,4-dihydro-5-hydroxy-4- oxo-2-pyridinecarboxamide 2.0 trifluoroacetate salt and 17 g N-methyl-N- (trimethylsilyl) trilfuoracetamide are 2 hours stirred in 100 ml of ethyl acetate. The solvent the clear solution is made under reduced pressure distilled off and the remaining oily residue for 2 hours Evaporated at 30 ° C (oil vacuum ≦ ωτ0.01 mm). The residue is again dissolved in 100 ml of ethyl acetate and dropwise to the at -30 ° C within 30 minutes activated acid given. The mixture is at 1 hour -10 ° C and stirred at 0 ° C for 1 hour. The solvent will evaporated and the remaining oily residue with ice water stirred at pH 3 (2N phosphoric acid). The ice water is discarded and the residue washed again with ice water and dried. There are 7.8 g of beige crystals receive.  

H) Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) - [[1 - [[[[2 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - carbonyl] -amino] -ethyl] -amino] -sulfonyl] -amino] -carbonyl] - 2-oxo-3-azetidinyl] -amino] -2-oxo-ethylidene] -amino] -oxy] - 2-methyl propionic acid

3 g [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[[2 - [[(1,4- dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] ethyl] - aminine] -sulfonyl] -amino] -carbonyl] -2-oxo-3-azetidinyl] -amino] - 2-oxoethylidene] -amino] -oxy -] - 2-methylpropionic acid diphenylmethyl ester are soaked in 30 ml trifluoroacetic acid / Anisole stirred. The trifluoroacetic acid salt of the free Acid is isolated after precipitation with ether. 7.9 g of this Product are suspended in 20 ml water and the pH The value of the suspension was adjusted to 6.0 with sodium hydrogen carbonate. After stirring for half an hour the suspension filtered and the solution of macrireticular styrene-divinylbenzene Chromatograph copolymer with water as eluent. The yield is 0.24 g. This product will be again chromatographed on a Merck Lobar C-column. The Yield is 0.078 g, mp 275 ° C (dec.).

Example 18

Disodium salt of [2S [2α, 3β (Z)]] - 2 - [[[1- (2-amino-4-thiazolyl) - 2 - [[1 - [[[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - carbonyl] amino] -2-oxo-1-imidazolidinyl] sulfonyl] - amino] carbonyl] -2-methyl] -4-oxo-3-azetidinyl] amino] -2-oxo- ethylidene] amino] oxy] -2-methylpropionic acid

A) (2S-trans) - [1 - [[[[3 - [[[1,4-dihydro-4-oxo-5- (phenylmethoxy) - 2-pyridinyl] carbonyl] amino] -2-oxo-1-imidazo-lidinyl] - sulfonyl] amino] carbonyl] -2-methyl-4-oxo-3-azetidinyl] - carbamic acid phenyl methyl ester

2.35 g (3S-trans) - (4-methyl-2-oxo-3-azetidinyl) carbamic acid phenylmethyl ester and 1.41 g of chlorosulfonyl isocyanate  Stirred for 1 hour at 0 ° C to 5 ° C in 50 ml of ethyl acetate. A clear solution is obtained (solution A). 3.28 g 1,4-dihydro-4-oxo-N- (2-oxo-1-imidazolidinyl) -5- (phenylmethoxy) - 2-pyridinecarboxamide and 6 g of N-methyl-N- (trimethylsilyl) - trifluoroacetamide are 1 hour at 40 ° C in 50 ml of ethyl acetate stirred (solution B).

The cooled (0 ° C) solution A is within 30 minutes added with solution B while stirring. After stirring overnight the solvent is evaporated off and the oily residue stirred with 50 ml of isopropanol and 1 drop of acetic acid. The The title compound appears as a beige precipitate a F. of 163 ° (dec.) obtained in a yield of 4.3 g.

B) (2S-trans) -N- [3 - [[[(3-amino-2-methyl-4-oxo-1-azetidinyl) - carbonyl] amino] sulfonyl] -2-oxo-1-imidazo-lidinyl] -1,4- dihydro-5-hydroxy-4-oxo-2-pyridinecarboxamide di-p-toluenesulfonate

5.9 g (2S-trans) - [1 - [[[[3 - [[[1,4-dihydro-4-oxo-5- (phenylmethoxy) - 2-pyridinyl] carbonyl] amino] -2-oxo-1-imidazolidinyl] - sulfonyl] amino] carbonyl] -2-methyl-4-oxo-3-azetidinyl] - carbamic acid phenyl methyl ester in 50 ml of dimethylformamide and 3.8 g hydrated p-toluenesulfonic acid and 2.5 g Palladium on activated carbon (10%) are at room temperature Hydrogenated for 1 hour. After filtering through Hyflo it will Dimethylformamide distilled off under reduced pressure. The oily residue is stirred with 100 ml of dichloromethane. 5.8 g of the title compound immediately fall as white crystals out.

C) Disodium salt of [2S- [2α, 3β (Z)]] - 2 - [[[1- (2-amino-4- thiazolyl) -2 - [[1 - [[[[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2- pyridinyl) carbonyl] amino] -2-oxo-1-imidazolidinyl] sulfonyl] - amino] -carbonyl] -2-methyl-4-oxo-3-aze-tidinyl] -amino] - 2-oxoethylidene] amino] oxy] -2-methylpropionic acid

4.40 g of (Z) -2-amino-α - [[2- (diphenylmethoxy) -1,1-dimethyl-2- oxoethoxy] imino] -4-thiazole acetic acid and 3.0 g triethylamine are dissolved in 150 ml of acetonitrile. The solution will be 2.8 g of diphenyl chlorophosphate are added dropwise at -30 ° C. and stirred for 1 hour.

7.90 g (2S-trans) -N- [3 - [[[(3-amino-2-methyl-4-oxo-1-azetidinyl) - carbonyl] amino] sulfonyl] -2-oxo-1-imidazolidinyl] - 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxamide di-p-toluenesulfonate and 2.02 g of triethylamine are 5 minutes at -20 ° C. stirred in 50 ml of dimethylformamide.

The suspension prepared as described above and Solution are combined at -30 ° C and 1 hour at -30 ° C, Stirred for 1 hour at -10 ° C and overnight at 0 ° to 10 ° C. The solvents are then distilled off under reduced pressure and the residue with 100 ml of ice water at pH 3 (Phosphoric acid) stirred. The diphenylmethyl ester of the title compound is filtered off and washed with water. The yield of a beige powder is 6.13 g.

2 g of the ester are dissolved in 30 ml of trifluoroacetic acid / at 30 ° C for 30 minutes. Anisole (4: 1) stirred. After adding 100 ml The trifluoroacetic acid salt of the free acid precipitates ether. It is suspended in 10 ml of water and the pH of the Suspension adjusted to 6.0. After filtering off the filtrate over a macrireticular styrene-divinylbenzene Given a copolymer column with water as the eluent. The Yield is 0.48 g.

A second column chromatography on Merck Lobar C with water as eluent gives 0.17 g of the title compound.

Example 19

Potassium salt of [3S (Z)] - 2-amino-N- [1 - [[[[3 - [[(1,4-dihydro-5- hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-1-imidazolidinyl] -  sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] -α- (methoxyimino) -4-thiazole acetamids

A suspension of 0.6 g (Z) -2-amino- - (methoxyimino) -4- thiazole acetic acid (0.003 mol) is at room temperature with 2.14 ml (0.009 mol) of tributylamine were added. The suspension is cooled to -30 ° C and at this temperature 0.66 ml (0.003 mol) diphenyl chlorophosphate added. The reaction mixture is stirred for 1 hour at -30 ° C (mixture A).

A suspension of 1.62 g (0.003 mol) of (3S) -3-amino-N - [[3- [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] - 2-oxo-1-imidazolidinyl] sulfonyl] -2-oxo-1-azetidinecarboxamide in 20 ml of ethyl acetate at room temperature mixed with 2.6 ml of bis-trimethylsilylacetamide. It forms yourself a clear brownish solution that 1 hour at room temperature is stirred and then cooled to 0 ° C (Solution B).

Solution B is added dropwise to the mixture while stirring, keeping the temperature at -30 ° C (about 10 mins). The mixture is at -10 ° C for 1 hour and at 0 ° C stirred for a further 1 1/2 hours and then under reduced pressure Evaporated pressure. The syrupy residue is in 50 ml Dissolved acetone. The solution is mixed with 6 ml of 1M potassium ethyl hexanoate added to precipitate 3.0 g of the crude product. The Adding ether to the filtrate gives a further 0.2 g of the crude product. Chromatography of the crude product on macroreticular Styrene-divinylbenzene copolymer gives 1.85 g the title link.

Example 20

[3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[[3 - [[(1,4- dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo- 1-imidazolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] - amino] -2-oxoethylidene] amino] oxy] -2-methylpropionic acid  

2.2 g of the disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4- thiazolyl) -2 - [[1 - [[[[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2- pyridinyl) carbonyl] amino] -2-oxo-1-imidazolidinyl] sulfonyl] - amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxo- ethylidene] -amino] -oxo] -2-methylpropionic acid (see Example 1) are dissolved in 20 ml acetone / water (1: 1) and adjust the pH of the solution to 2 with 2N hydrochloric acid. Chromatography on macrireticular styrene-divinylbenzene Copolymer gives 0.7 g of the title compound.

Example 21

Sodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2- [[1 - [[[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - carbonyl] amino] -2-oxo-1-imidazolidinyl] sulfonyl] amino] - carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] - oxy] -N-hydroxy-2-methylpropanamids

4.72 g (Z) -2-amino-α - [[1,1-dimethyl-2-oxo-2 - [(triphenylmethoxy) - amino] ethoxy] imino] -4-thiazole acetic acid suspended in 65 ml acetonitrile and at -30 ° C with 3.72 ml Triethylamine added. After stirring for 10 minutes 1.97 ml of diphenyl chlorophosphate added. Then will stirred for a further 90 minutes (solution A).

8.9 ml (3S) -3-amino-N - [[3 - [[(1,4-dihydro-5-hydroxy-4-oxo 2-pyridinyl) carbonyl] amino] -2-oxo-1-1imidazolidinyl] - sulfonyl] -2-oxo-1-azetidinecarboxamide are dissolved in 70 ml of acetonitrile suspended and with 7.7 ml of bis-trimethylsilylacetamide transferred. After stirring for 1 hour at -10 ° C and 1 1/2 hours at 0 ° C a clear solution is obtained. The solvent and the resulting trifluoroacetic acid trimethylsilyl ester are evaporated under reduced pressure and that remaining oil dissolved in 70 ml of ethyl acetate (Solution B).

The stirred solution B is at -20 ° C within 30 minutes  mixed with solution A. After stirring for 1 1/2 hours at -10 ° C and stirring for 1 hour at 0 ° C the reaction is complete.

The solvents are distilled off under reduced pressure and the oily residue was stirred with 300 ml of ice water, whose pH is adjusted to 4.0 with 10% phosphoric acid had been. The solid formed is filtered off, washed with water and overnight under reduced pressure dried. The yield is 9 g of crude product.

4.5 g of the crude product are mixed with 45 ml of formic acid (98%) and 4.5 ml of dichloromethane were stirred at 0 ° C for 1 hour. By Precipitations with diethyl ether become 2.3 g of the title compound receive.

Example 22

Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2- [[1 - [[[[2 - [[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - carbonyl] amino] -2-oxo-1-imidazolidinyl] carbonyl] hydrazino] - sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] - 2-oxoethylidene] amino] oxy] -2-methylpropionic acid

A) 2 - [[(Phenylmethoxy) carbonyl] amino] -2-imidazolidinone

26 g (0.257 mol) of 1-amino-2-imidazolidinone are dissolved in 200 ml Dissolved water and then the solution with 200 ml of ethyl acetate overlaid. Then the solution with 43.8 g (0.257 mol) of chloroform / benzyl ester are added with stirring, taking the pH of the solution by adding saturated Sodium bicarbonate solution kept at 8.5 to 9 becomes. After stirring overnight at room temperature the title compound is filtered off, first with water and then washed with ethyl acetate. The yield is 46.7 g, mp 140-44 ° C.  

B) 1 - [[(phenylmethoxy) carbonyl] amino] -3- (chlorocarbonyl) - 2-imidazolidinone

A suspension of 69.9 g (0.297 mol) of 2 - [[(phenylmethoxy) - carbonyl] amino] -2-imidazolidinone in 1 liter of dichloromethane is with a solution of 35 g of phosgene in 200 ml of dichloromethane transferred. The mixture is left overnight at room temperature stirred, resulting in a clear solution. The solvent is removed under reduced pressure and the syrupy Residue digested with ether. The yield is 76.0 g, mp 102 to 05 ° C.

C) 3 - [[(Phenylmethoxy) carbonyl] amino] -2-oxo-1-imidazolidinecarboxylic acid- 2 - [(1,1-dimethylethoxy) carbonyl] hydrazide

1.5 liters of ethyl acetate are at room temperature with 76 g (0.255 mol) of 1 - [[(phenylmethoxy) carbonyl] amino] - 3- (chlorocarbonyl) -2-imidazolidinone added. After cooling to 0 ° to 5 ° C a solution of 39.6 g (0.9 mol) N- (tert-butoxycarbonyl) hydrazide and 41.8 ml (0.3 mol) Triethylamine in 150 ml of ethyl acetate within Added for 30 minutes. The mixture is stirred overnight. The precipitate is filtered off, dried, with 800 ml Stirred water to remove triethylamine hydrochloride, filtered, washed with water and dried. The yield is 71.2 g, mp 195 to 198 ° C.

D) 2 - [[3 - [[[1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] - carbonyl] -amino] -2-oxo-1-imidazolidinyl] -car-bonyl] -hydrazinecarboxylic acid- 1,1-dimethyl ethyl ester

31.5 g (0.08 mol) of 3 - [[(phenylmethoxy) carbonyl] amino] -2- oxo-1-imidazolidinecarboxylic acid 2 - [(1,1-dimethylethoxy) carbonyl] - hydrazide are dissolved in 400 ml of dimethylformamide. Subsequently the solution with 16 g palladium on activated carbon (10%) and hydrogen through the stirred  Reaction mixture passed. After 1 hour the catalyst filtered off. The filtrate is mixed with 19.62 g (0.08 mol) O-benzylcomenamic acid, 0.48 g dimethylaminopyridine and 0.64 g of N-hydroxybenzotriazole were added. The mixture is 1 hour stirred at room temperature and then with a solution of 18.13 g (0.088 mol) of dicyclohexylcarbodiimide at room temperature transferred. Then the mixture is left overnight touched. The precipitate of dicyclohexylurea is filtered off and the filtrate evaporated under reduced pressure. The residue is mixed with water to adjust the pH was added to 7.5 sodium bicarbonate, digested. The precipitate is filtered. There will be 36 g received the title link.

E) 3 - [[[1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] - carbonyl] amino] -2-oxo-1-imidazolidine carboxylic acid hydrazide

300 ml of trifluoroacetic acid are stirred at -10 ° C with 36 g 2 - [[3 - [[[1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] - carbonyl] amino] -2-oxo-1-imidazolidinyl] carbonyl] - hydrazine carboxylic acid added. The mixture is at 1 hour 0 ° C stirred and the trifluoroacetic acid under reduced Pressure removed. The residue is digested with ether, it 41 g of the trifluoroacetate salt of the title compound are obtained. The trifluoroacetate salt is cooled in water suspended and the pH of the suspension by adding 2N sodium hydroxide solution set to 7. The precipitate is filtered off. 21.9 g of the title compound are obtained.

F) 3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] - amino] -2-oxo-1-imidazolidine carboxylic acid hydrazide

21.9 g 3 - [[[1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] - carbonyl] amino] -2-oxo-1-imidazolidinecarboxylic acid hydrazide are suspended in 250 ml of acetonitrile. The suspension is mixed with 75 ml of bis-trimethylsilylacetamide and that  Mix the mixture until a solution is present. The solution will be mixed with 10 g palladium-on-carbon (10%) and hydrogen passed through the vigorously stirred mixture. The Debenzylation is complete after 1 hour. After filtering off the precipitate of the title compound with 15 ml Methanol and 10 drops of acetic acid are added. The yield is 10.8 g. This crude product is stirred with 150 ml of ethanol, 8.8 g of the title compound with an F. of ≦ ωτ205 ° C (dec.) Are formed.

G) (S) - [1 - [[[[2 - [[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl] - carbonyl] amino] -2-oxo-1-imidazolidinyl] carbonyl] - hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] - carbamic acid phenyl methyl ester

A suspension of 5.9 g (0.02 mol) of crude 3 - [[(1,4-dihydro- 5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-1- imidazolidine carboxylic acid hydrazide is mixed with 14.9 ml (0.08 mol) N-methyl-N- (trimethylsilyl) trifluoroacetamide added and the mixture is stirred at 50 ° C until a solution is formed (solution A).

A suspension of 4.4 g (S) -3 - [[(phenylmethoxy) carbonyl] - amino] -1-azetidinone (0.02 mol) in 160 ml of methyl acetate with 1.76 ml of chlorosulfonyl isocyanate at room temperature transferred. The mixture is stirred for 1 hour (solution B).

Solution B is mixed with solution A while cooling with ice. To Stirring for 1 hour, the mixture with 2.8 ml (0.02 mol) Triethylamine added and then overnight at room temperature touched. Another 2.8 ml (0.02 mol) of triethylamine added and then ice water. The mixture is stirred vigorously for 1 hour and then the layers Cut. The aqueous phase is acidified to pH 3 and the precipitate is filtered off. The yield on the raw  The title compound is 5.3 g.

The crude product is dissolved in acetone / water and the pH the solution adjusted to 6.5 by adding 2N sodium hydroxide solution. After removal of the acetone under reduced The aqueous solution is filtered under pressure and lyophilized. 5.5 g of the crude sodium salt of the title compound receive. Chromatography of the raw sodium salt Macroreticular styrene-divinylbenzene copolymer gives 0.64 g pure product. This is dissolved in water and with 2N Acidified hydrochloric acid, the title compound in a yield of 0.5 g fails.

H) (S) -N- [3 - [[2 - [[[(3-amino-2-oxo-1-azetidinyl) carbonyl] - amino] sulfonyl] hydrazino] carbonyl] -2-oxo-1-imide-azolidinyl] - 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxamide

A mixture of 0.5 ml thioanisole and 2 ml trifluoroacetic acid is mixed with 0.5 g (S) - [1 - [[[[2 - [[3 - [[(1,4-dihydro-5- hydroxy-4-oxopyridinyl) carbonyl] amino] -2-oxo-1-imidazolidinyl] - carbonyl] hydrazino] sulfonyl] amino] carbonyl] -2- oxo-3-azetidinyl] -carbamic acid phenyl methyl ester added. The mixture is stirred at room temperature overnight and then evaporated under reduced pressure. The residue is digested with ethyl acetate. It becomes the title link obtained in quantitative yield.

I) [3S (Z)] - 2 - [[[1- [2-amino-4-thiazolyl] -2 - [[1 - [[[2 - [[3- [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-1-imidazolidinyl] carbonyl] hydrazino] - sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2- oxoethylidene] -amino] -oxy] -2-methylpropionic acid diphenylmethyl ester

A solution of 0.35 g (0.0008 mol) of (Z) -2-amino-α - [[2- (diphenylmethoxy) - 1,1-dimethyl-2-oxoethoxy] imino] -4-thiazole acetic acid  in 10 ml of acetonitrile with 0.34 ml of triethylamine transferred. The mixture is cooled to -30 ° C and with 0.17 ml of diphenyl chlorophosphate added. The reaction mixture is stirred for 1 hour at -30 ° C (solution A).

A suspension of 0.008 mol (S) -N- [3 - [[2 - [[[(3-amino-2-oxo- 1-azetidinyl) carbonyl] amino] sulfonyl] hydrazino] carbonyl] - 2-oxo-1-imidazolidinyl] -1,4-dihydro-5-hydroxy-4-oxopyridinecarboxamide in 6 ml of ethyl acetate with 0.7 ml of bis- Trimethylsilylacetamide added (solution B).

Solution A is mixed with solution B at -30 ° C. The mixture is stirred for 2 hours at -10 ° C and 1 hour at 0 ° C and then evaporated under reduced pressure. After treatment the residue with water becomes 0.7 g of the title compound obtained with an F. of 155 ° C (dec.).

J) Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) - 2 - [[1 - [[[[2 - [[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - carbonyl] amino] -2-oxo-1-imidazolidinyl] carbonyl] - hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] - amino] -2-oxoethylidene] amino] oxy] -2-methylpropionic acid

A suspension of 0.7 g (0.00077 mol) [3S (Z)] - 2 - [[[1- [2- Amino-4-thiazolyl] -2 - [[1 - [[[[2 - [[3 - [[(1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-1-imidazolidinyl] - carbonyl] hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3- azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] -2- methylpropionic acid diphenylmethyl ester in 1 ml of anisole is mixed with 6 ml Trifluoroacetic acid added at -10 ° C. The mixture will Held at -10 ° C for 1 hour and then at -10 ° C with Ether displaced. The free trifluoroacetate falls Acid of the starting material in a yield of 0.5 g.

The precipitate is suspended in water with cooling and the pH of the suspension by adding 2N sodium hydroxide solution  set to 5.5. After freeze drying Obtained 0.55 g of the crude product. The raw product is through Chromatography on macroreticular styrene-divinylbenzene Copolymer cleaned. The yield of purified title compound is 0.1 g.

Example 23

Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2- [[1 - [[[2 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] - 2-methylhydrazino] sulfonyl] amino] carbonyl] -2-oxo- 3-azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] -2-methylpropionic acid

A) 1,4-dihydro-4-oxo-5- (phenylmethoxy) -1- (phenylmethyl) -2- pyridinecarboxylic acid 1-methylhydrazide

0.15 mol of N, O-dibenzylcomenamyl chloride are cooled with ice suspended in 150 ml dichloromethane. The suspension is with 26.2 ml (0.5 mol) of methylhydrazine and then treated with 150 ml of acetonitrile. The mixture is left overnight stirred at room temperature. The cloudy solution is reduced Evaporated pressure and the residue with 300 ml Water digested. The solid obtained is filtered off and dried to give 26.3 g of a crude product. The recrystallization of the crude product from water results 12.7 g of the pure title compound with an F. of 138 to 142 ° C.

B) (S) -1,4-dihydro-4-oxo-5- (phenylmethoxy) -1- (phenylmethyl) - 2-pyridinecarboxylic acid 1-methyl-2 - [[[[2-oxo-3 - [[(phenylmethoxy) - carbonyl] amino] -1-azetidinyl] carbonyl] amino] - sulfonyl] hydrazide

1.82 g (0.005 mol) of 1,4-dihydro-4-oxo-5- (phenylmethoxy) -1- (phenylmethyl) -2-pyridinecarboxylic acid 1-methylhydrazide suspended in 20 ml of ethyl acetate. The suspension  is at room temperature with a total of 1.85 ml (0.01 mol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide. The mixture is stirred for 4 hours at 60 ° C. (suspension A).

1.1 g (0.005 mol) (S) -3 - [[(phenylmethoxy -) - carbonyl] amino] - 2-azetidinone are at room temperature in 40 ml of ethyl acetate suspended and with 0.5 ml of chlorosulfonyl isocyanate transferred. The mixture is 1 hour at room temperature stirred, forming a solution (solution B).

Solution B is cooled with ice with 1.2 ml of triethylamine and then mixed with 20 ml dichloromethane and suspension A. The suspension is stirred overnight at room temperature. The slightly cloudy solution is mixed with 30 ml dichloromethane and 20 ml of water were added and the mixture was then added for 1 hour Room temperature stirred.

the pH of the aqueous phase is 6.5 to 7. It becomes mixed with 60 ml of ethyl acetate, the organic phase separated and the aqueous phase twice with a mixture washed from dichloromethane / ethyl acetate (1: 3). The combined organic phases are over magnesium sulfate dried and evaporated. There will be 4.5 g a syrup, which is obtained when standing over the weekend crystallized out. After treatment with ether 2.6 g of the title compound were obtained.

C) 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid 2- [[[((3 amino-2-oxo-1-azetidinyl) carbonyl] amino] sulfonyl] - 1-methylhydrazide trifluoroacetate salt

A solution of 2 g (S) -1,4-dihydro-4-oxo-5- (phenylmethoxy) - 1- (phenylmethyl) -2-pyridinecarboxylic acid 1-methyl-2 - [[[[2-oxo- 3 - [[(phenylmethoxy) carbonyl] amino] -1-azetidinyl] carbonyl] - amino] sulfonyl] hydrazide in 60 ml of dimethylformamide  1.1 ml trifluoroacetic acid and then with 1 g palladium on activated carbon (10%). After rinsing with Nitrogen becomes hydrogen with stirring for 60 minutes passed through the solution. The catalyst is filtered off and the filtrate evaporated under reduced pressure. The The residue is digested with ether, giving 1.1 g of the title compound can be obtained in a yield of 86.6%.

D) [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[2 - [(1,4- dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] -2-methylhydrazino] - sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] - amino] -2-oxoethylidene] -amino] -oxy] -2- methyl prophenic acid diphenyl methyl ester

A suspension of 0.88 g (0.002 mol) of (Z) -2-amino-α - [[2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy] imino] -4-thiazole acetic acid in 30 ml acetonitrile with 0.7 ml (0.005 mol) Triethylamine and then at -30 ° C with 0.44 ml (0.002 mol) of diphenyl chlorophosphate added. The mixture is stirred for 1 hour at -30 ° C (solution A).

A suspension of 1.2 g (0.002 mol) of 1,4-dihydro-5-hydroxy 4-oxo-2-pyridinecarboxylic acid 2 - [[[(3-amino-2-oxo-1-azetidinyl) - carbonyl] -amino] -sulfonyl] -1-methylhydrazide-trifluoroacetate- Salt in 30 ml of ethyl acetate is mixed with 2 ml (approx 0.008 mol) bis-trimethylsilylacetamide at room temperature added, a clear solution forming after 30 minutes (Solution B).

Solution A is added dropwise at -30 ° C within 10 minutes mixed with solution B. The temperature will be 1 hour held at -10 ° C for a further hour at 0 ° C. The solvent is evaporated off and the residue is washed with water treated. It is after filtering and drying 2.4 g of the crude title compound were obtained.  

E) Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) - 2 - [[1 - [[[2 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridynyl) - carbonyl] -2-methylhydrazino] sulfonyl] amino] carbonyl] - 2-oxo-3-azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] - 2-methyl propionic acid

A mixture of 20 ml trifluoroacetic acid and 4 ml anisole is at -10 ° C with 2.4 g of the crude [3S (Z)] - 2 - [[[1- (2-amino- 4-thiazolyl) -2 - [[1 - [[[[2 - [(1,4-dihydro-5-hydroxy-4-oxo-2- pyridinyl) carbonyl] -2-methylhydrazino] sulfonyl] amino] - carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] - oxy] -2-methylpropionic acid diphenylmethyl ester. The The mixture is stirred at -10 ° C for 1 hour and the reaction product then precipitated by adding ether at -10 ° C. The yield is 1.12 g of the crude trifluoroacetate Title link.

By adding 2N sodium hydroxide solution to a suspension in acetone / Water the raw product is converted into the sodium salt and lyophilized. The sodium salt is determined by chromatography on macroreticular styrene-divinylbenzene copolymer cleaned, eluting with water. The yield is 0.25 g.

Example 24

(3S) -2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[[(1,4-dihydro- 5-hydroxy-4-oxo-2-pyridinyl) methyl] amino] sulfonyl] amino] - carbonyl] -2-oxo3-azetidinyl] amino] -2-oxoethylidene] amino] - oxy] -2-methylpropionic acid

A) 2- (hydroxymethyl) -5- (phenylmethoxy) -4H-pyran-4-one

A suspension of 56.8 g (0.4 mol) of 5-hydroxy-2- (hydroxymethyl) - 4H-pyran-4-one in 400 ml of methanol is mixed with 16 g (0.4 mol) sodium hydroxide in 200 ml warm methanol and then treated with 50.6 g (46 ml, 0.4 mol) of benzyl chloride.  The mixture is heated under reflux for 3 1/2 hours, cooled and poured into 1 liter of water. The solid obtained is filtered and with about 1.5 liters of water, 200 ml Washed ethanol and 400 ml of hexane. After drying under a high vacuum, the weight of the product is 55.7 g.

B) 1,4-Dihydro-2- (hydroxymethyl) -5- (phenylmethoxy) -4-pyridinone

A mixture of 9.65 g (41.59 mmol) of 2-hydroxymethyl-5- (phenylmethoxy) - 4H-pyran-4-one, 95 ml concentrated ammonia and 20 ml of ethanol is heated under reflux overnight. Another 75 ml of ammonium hydroxide are added and the mixture was then refluxed for 2 hours and cooled. The brown solid obtained is filtered and with Washed water until the wash liquid is neutral. The Crude product is suspended in ethanol, filtered, with Washed ethanol and hexane and dried under reduced pressure. The yield of the Tiel compound is 7.61 g.

C) 1- (chloromethyl) -1,4-dihydro-5- (phenylmethoxy) -4-pyridinone hydrochloride

A suspension of 3 g (12.99 mmol) of 1,4-dihydro-2- (hydroxymethyl) - 5- (phenylmethoxy) -4-pyridinone in 15 ml chloroform is cooled to 0 ° C. under argon and with 6.1 ml (83.62 mmol) Treated thionyl chloride. Forms after a few minutes yourself a homogeneous solution. After stirring for a further 5 minutes a cream-colored solid precipitates. The cooling bath is removed and the mixture was heated under reflux for 45 minutes. The Mixture is cooled to 0 ° C and the white suspended Product filtered, washed with chloroform and hexane and dried under reduced pressure. The yield of the title compound is 3.65 g.  

D) 2- (azidomethyl) -1,4-dihydro-5- (phenoxymethyl) -4-pyridinone

A mixture of 3.59 g (12.54 mmol) of 1- (chloromethyl) -1,4- dihydro-5- (phenylmethoxy) -4-pyridinone hydrochloride, 4.08 g (62.7 mmol) sodium azide and 2.19 ml (12.54 mmol) diisopropylethylamine in 60 ml of dimethylformamide at room temperature Stirred under argon for 3 1/2 days. It will be again 4.08 g of sodium azide were added and the mixture was then added Heated to 45 to 50 ° C for 2 hours. After cooling down poured the reaction mixture into 500 ml of water, a insoluble white solid precipitates. The pH of the The supernatant is diluted with hydrochloric acid from 8.5 to 7.5 lowered and the white solid then filtered. After this Washing with water, acetone and hexane removes the solid dried under reduced pressure. The yield of the title compound is 2.81 g.

E) 2- (aminomethyl) -4-oxo-5- (phenylmethoxy) pyridine

A suspension of 2.030 g (7.93 mmol) of 2- (azidomethyl) - 1,4-dihydro-5- (phenoxymethyl) -4-pyridinone and 200 ml of platinum oxide is in 100 ml of dimethylformamide for 6 hours at room temperature stirred in a hydrogen atmosphere. The catalyst is filtered off and the solution under reduced pressure Concentrated pressure. There are 1.5 g of the title compound as Obtained gray powder.

F) (3S) -1 - [[[[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - methyl] amino] sulfonyl] amino] carbonyl] -2-oxo-3- [[(phenylmethoxy) carbonyl] amino] azetidine

A stirred suspension of 2.330 g (10.13 mmol) of 2- (aminomethyl) - 4-oxo-5- (phenylmethoxy) pyridine in 60 ml of ethyl acetate is mixed with 3.76 ml (20.26 mmol) of N-methyl-N- (trimethylsilyl) - trifluoroacetamide added. The solution obtained is stirred for 30 minutes at room temperature and then on  Cooled to 0 ° C. At the same time, a stirred suspension of 2.228 g (10.13 mmol) (S) -3 - [[(phenylmethoxy) carbonyl] - amino] -2-azetidinone in 60 ml of ethyl acetate 882 μl (10.13 mmol) of chlorosulfonyl isocyanate were added. The solution obtained is stirred for 30 minutes at room temperature and then cooled to 0 ° C and with 4.23 ml (30.39 mmol) Triethylamine and a solution of the above silylated 2- (aminomethyl) -4-oxo-5- (phenylmethoxy) pyridine transferred. The mixture is 2 days at room temperature touched.

The mixture is concentrated under reduced pressure and the residue was dissolved in acetonitrile / water (40:60). The The pH of the solution is adjusted to 2.9, with a separates thick oil. After cooling to 5 ° C solidifies the oil. The solid is separated off four times with water washed and dried under reduced pressure. It will 3.4 g of the crude title compound obtained. The raw product is dissolved in a small volume of dimethylformamide and on a column (1 liter) of macroreticular styrene-divinylbenzene Copolymer applied. The column comes with a gradual gradient eluted from acetone / water. The one you want Substance is eluted at approximately 65% acetone. The corresponding Fractions are pooled and lyophilized. 2.69 g of the title compound are obtained.

G) (3S) -2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[[(1,4-dihydro- 5-hydroxy-4-oxo-2-pyridinyl) methyl] amino] sulfonyl] - amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxo- ethylidene] amino] oxy] -2-methylpropionic acid rediphenylmethyl ester

912 mg (1.64 mmol) (3S) -1 - [[[[[(1,4-dihydro-5-hydroxy-4- oxo-2-pyridinyl) methyl] amino] sulfonyl] amino] carbonyl] - 2-oxo-3 - [[(phenylmethoxy) carbonyl] amino] azetidine, 625 mg (3.28 mmol) p-toluenesulfonic acid monohydrate and 190 mg 10%  Palladium on activated carbon in 16 ml of dimethylformamide are in stirred in a hydrogen atmosphere until 3.28 mmol (73 ml) Hydrogen are consumed (about 3 hours).

A stirred solution of 846 mg (1.804 mmol) (Z) -2-amino-α- [[2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy] imino] -4- tiazole acetic acid in 16 ml of dimethylformamide at -20 ° C. with 374 µL (1.804 mmol) of diphenyl chlorophosphate and 450 μl (3.28 mmol) of triethylamine were added.

The solution is stirred at -20 ° C for 1 hour and then with mixture of the hydrogenated compound described above transferred. Then 921 ul (6.6 mmol) of triethylamine admitted. The mixture obtained is 1 hour at -20 ° C and then stirred at 5 ° C overnight. The catalyst is filtered off, the volatile substances are reduced Pressure removed and there obtained oil in a low Volume acetone / water (75:25, pH 5.2) dissolved and dropwise to a stirred suspension of 20 ml Dowex 50x2-400 (K⁺) in acetone / water (35:65). After 40 Minutes, the mixture is filtered and the filtrate is lyophilized, to obtain 2.1 g of a solid. The Solid becomes in a small amount of acetonitrile / water (40:60, pH 5.6) dissolved and onto a column (800 ml) of macroreticular styrene-divinylbenzene copolymer. Elution is carried out in stages with an acetonitrile / Water gradient. The desired product is around 30% Acetonitrile eluted. The appropriate fractions will be combined and lyophilized, giving the title compound receives.

H) (3S) -2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[[(1,4-dihydro- 5-hydroxy-4-oxo-2-pyridinyl) methyl] amino] sulfonyl] - amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxo- ethylidene] amino] oxy] -2-methylpropionic acid

A stirred suspension of 131 mg (0.113 mmol) (3S) -2- [[[1- (2-Amino-4-thiazolyl) -2 - [[1 - [[[[[(1,4-dihydro-5- hydroxy-4-oxo-2-pyridinyl) methyl] amino] sulfonyl] amino] - carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino oxy] -2-methylpropionic acid diphenylmethyl ester in 3 ml Dichloromethane and 0.3 ml anisole are added dropwise at 0 ° C treated with 4.7 ml of trifluoroacetic acid. After 45 minutes Stirring at 5 ° C, 2 ml of toluene are added and the volatile Fabrics are then removed under reduced pressure. The oil obtained is washed three times with 4 ml of hexane and the Solid then digested with 10 ml ether. The solid is washed once with 10 ml of ether and then under reduced pressure Pressure dried. The above implementation and Workup is carried out with 0.166 mmol (3S) -2 - [[[1- (2-amino-4- thiazolyl) -2 - [[1 - [[[[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - methyl] amino] sulfonyl] amino] carbonyl] -2-oxo-3- azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] -2- repeated methyl propionate. The raw solids are combined in 2 ml of acetonitrile / water (40:60, pH 2.5) dissolved and on a column (200 ml) of macroreticular Chromatographed styrene-divinylbenzene copolymer. For elution an acetonitrile / water gradient is used. The wished Product is with acetonitrile / water (20:80) eluted. The appropriate fractions are pooled and lyophilized. 103 mg of the title compound are white Solid obtained with a melting point of 180 ° C (dec.).  

Invention claim:

• 1. Process for the preparation of compounds of general formula I. or pharmacologically acceptable salts thereof, in which means;
  R _{1 represents} an acyl radical derived from a carboxylic acid; R ₂ and R _{3 have} the same or different meaning and each represent a hydrogen atom, an alkyl radical, an alkenyl radical, an alkynyl radical, a cycloalkyl radical, a phenyl group, a substituted phenyl group or a 4-, 5-, 6- or 7-membered heterocycle ( hereinafter referred to as R _x ), or one of the radicals R ₂ and R _{3 is} a hydrogen atom and the other is an azido, halomethyl, dihalomethyl, trihalimethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl -, -CH ₂ X ₁ - (where X _{1 is} an azido, amino, hydroxyl, carboxyl, alkoxycarbonyl, alkanoylamino, phenylcarbonylamino, (substituted phenyl) carbonylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted Phenyl) sulfonyloxy, phenyl, substituted phenyl, cyano, SC ₂ or an -OX ₂ residue (where A, X ₂ , X ₆ and X ₇ are defined as described below), an -SX ₂ or -OX ₂ residue (where X _{2 is} an alkyl, substituted one Alkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, alkanoyl, phenylalkanoyl, substituted phenylalkanoyl, phenylcarbonyl, substituted phenylcarbonyl or a heteroarylcarbonyl radical) means one (where one of X ₃ and X _{4 is} a hydrogen atom and the other is a hydrogen atom or an alkyl group, or X ₃ and X ₄ together with the carbon atom to which they are attached represent a cycloalkyl group, and X _{5 is} a formyl, Alkanoyl, phenylcarbonyl, substituted phenylcarbonyl, phenylalkylcarbonyl, substituted phenylalkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, substituted aminocarbonyl or cyano radical), or one means means (where A is a -CH = CH-, - (CH ₂ ) _m -, - (CH ₂ ) _m -O-, - (CH ₂ ) _m NH- or -CH ₂ -S-CH ₂ group , m has the value 0, 1 or 2 and X ₆ and X _{7 are} identical or different and each represent a hydrogen atom, an alkyl radical, a phenyl group or a substituted phenyl group or X _{6 is} a hydrogen atom and X _{7 is} an amino group, substituted amino group, one Alkanoylamino or an alkoxy or X ₆ and X ₇ together with the nitrogen atom to which they are attached mean a 4-, 5-, 6- or 6-membered heterocycle);
  A _{1 is} a single bond, represents;
  A _{2 is} a single bond, means;
  A _{3 is} - (CH ₂ ) _p -, where p is 0 or 1, or means; where X is a hydrogen atom, a carboxyl group or a carbamoyl group, p is 0 or 1, and y is 2, 3 or 4;
  A ₅ a single bond, where q is 0 or 1; and
  A _{6 is} a single bond, -CH = CH- or - (CH ₂ ) _t -, where t has the value 1, 2, 3 or 4, characterized in that
  (1) a compound of the general formula VII acylated with an R ₁ acyl radical derived from an R ₁ carboxylic acid, or
  (2) a -CO-NH-SO ₂ R activation group in a compound of general formula IX introduces.

Claims (27)

1. Compound of the general formula or a pharmacologically acceptable salt thereof, in which R or R _{1 represents} an acyl radical derived from a carboxylic acid;
R ₂ and R _{3 are the} same or different and each represents a hydrogen atom, an alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl radical or a 4-, 5-, 6- or 7-membered heterocycle or one of the radicals R ₂ and R _{3 is} a hydrogen atom and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, means;
X _{1 is} an azido, amino, hydroxy, carboxyl, alkoxycarbonyl, alkanoylamino, phenylcarbonylamino, substituted phenylcarbonylamino, alkylsulfonyloxy, phenylsulfonyloxy, substituted phenylsulfonyloxy, phenyl, substituted phenyl, cyano radical, means;
X _{2 represents} an alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, alkanoyl, phenylalkanoyl, substituted phenylalkanoyl, phenylcarbonyl, substituted phenylcarbonyl or heteroarylcarbonyl radical;
one of X ₃ and X _{4 represents} a hydrogen atom and the other represents a hydrogen atom or an alkyl group, or X ₃ and X ₄ together with the carbon atom to which they are attached represent a cycloalkyl group;
X _{5 represents} a formyl, alkanoyl, phenylcarbonyl, substituted phenylcarbonyl, phenylalkylcarbonyl, substituted phenylalkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, substituted aminocarbonyl or cyano radical;
X ₆ and X _{7 are} identical or different and each represents a hydrogen atom, an alkyl, phenyl or substituted phenyl radical, or X _{6 represents} a hydrogen atom and X _{7 represents} an amino, substituted amino, alkanoylamino or alkoxy radical, or X ₆ and X ₇ together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycle;
A is -CH = CH-, - (CH ₂ ) _m -, - (CH ₂ ) _m -O-, - (CH ₂ ) _m -NH- or -CH ₂ -S-CH ₂ -;
m has the value 0, 1 or 2;
A _{1 is} a single bond, means;
A _{2 is} a single bond, represents; represents; represents;
A ₅ a single bond, means;
A _{6 represents} a single bond, -CH = CH- or - (CH ₂ ) _t -;
p has the value 0 or 1;
y is 2, 3 or 4;
q is 0 or 1;
t has the value 1, 2, 3 or 4 and
X represents a hydrogen atom, a carboxyl group or a carbamoyl group. 2. A compound according to claim 1, in which R is the rest means. 3. A compound according to claim 1, in which R is the rest means. 4. A compound according to claim 1, in which R is the rest means. 5. A compound according to claim 1, in which R is the rest means. 6. A compound according to claim 1, in which R is the rest means. 7. A compound according to claim 1, in which R is the rest means. 8. A compound according to claim 2, in which A _{1 represents} a single bond. 9. A compound according to claim 2, in which A ₂ means -NH-. 10. A compound according to claim 2, in which A _{6 represents} a single bond. 11. A compound according to claim 1, in which R _{1 is} the group means. 12. A compound according to claim 1, in which R ₂ and R ₃ each represent a hydrogen atom. 13. A compound according to claim 1, in which R _{1 represents} the rest and R _{g represents} 2-amino-4-thiazolyl and R _{i represents} a methyl group, ethyl group, carboxymethyl group, 1-carboxy-1-methylethyl group, a 1-carboxy-1-ethyl group or CH ₂ - (CH ₂ ) _s -C- COOH means, where s has the value 1, 2 or 3. 14. A compound according to claim 1, in which R _{1 is} the rest means R _{g represents} 2-amino-4-thiazolyl and R _{i represents} a carboxymethyl group, 1-carboxy-1-methylethyl group, 1-carboxy-1-ethyl group or the rest means, where s has the value 1, 2 or 3. 15. A compound according to claim 2, in which R _{1 represents} the rest means R _{g represents} 2-amino-4-thiazolyl and R _{i represents} a methyl group, ethyl group, carboxymethyl group, 1-carboxy-1-methylethyl group, 1-carboxy-1-ethyl group or the rest means, where s has the value 1, 2 or 3. 16. A compound according to claim 2, in which R _{1 represents} the rest means R _{g represents} 2-amino-4-thiazolyl and R _{i represents} a carboxymethyl group, 1-carboxy-1-methylethyl group, 1-carboxy-1-ethyl group or the rest means, where s has the value 1, 2 or 3. 17. A compound according to claim 11, in which R _{1 is} the rest means R _{g represents} 2-amino-4-thiazolyl and R _{i represents} a methyl group, ethyl group, carboxymethyl group, 1-carboxy-1-methylethyl group, 1-carboxy-1-ethyl group or the rest means, where s has the value 1, 2 or 3. 18. A compound according to claim 11, in which R _{1 represents} the rest means R _{g represents} 2-amino-4-thiazolyl and R _{i represents} a carboxymethyl group or a 1-carboxy-1-methylethyl group. 19. A compound according to claim 11, in which R ₂ and R ₃ each represent a hydrogen atom. 20. The compound of claim 1, namely [3S (Z)] - 2 - [[[1- (2-Amino-4-thiazolyl) -2 - [[1 - [[[3 - [[(1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-1-imidazolidinyl] - sulfonyl] -amino] -carbonyl] -2-oxo-3-azetidinyl] -amino] -2-oxo- ethylidene] -amino] -oxy] -2-methylpropionic acid or a pharmacologically tolerable salt of it. 21. A compound according to claim 1, namely [3S (Z)] - 2 - [[[1- (2-Amino-4-thiazolyl) -2 - [[1 - [[[2 - [(1,4-dihydro-5-hydroxy- 4-oxo2-pyridinyl) carbonyl] hydrazino] sulfonyl] amino] - carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] - oxy] -2-methylpropionic acid or a pharmacologically acceptable Salt of it.   22. A compound according to claim 1, namely [3S (Z)] - 2 - [[[1- (2-Amino-4-thiazolyl) -2 - [[1 - [[[3 - [[(1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-1-imidazolidinyl] - sulfonyl] -amino] -carbonyl] -2-oxo-3-azetidinyl] -amino] -2-oxo- ethylidene] -amino] -oxy] -2-acetic acid or a pahr-macologically tolerable salt of it. 23. A compound according to claim 1, namely [3S (Z)] - 2 - [[[1- (2-Amino-4-thiazolyl) -2 - [[1 - [[[[(1,4-dihydro-5-hydroxy-4- oxo-2-pyridinyl) methyl] amino] sulfonyl] amino] carbonyl] - 2-oxo-3-azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] -2- methyl propionic acid or a pharmacologically acceptable Salt of it. 24. The compound of claim 1, namely [3S (Z)] - 2 - [[[1- (2-Amino-4-thiazolyl) -2 - [[1 - [[[[2 - [[2 - [(1,4-dihydro-5- hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] carbonyl] - hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] - amino] -2-oxoethylidene] -amino] -oxy] -2-methylpropionic acid or a pharmaceutically acceptable salt thereof. 25. A compound according to claim 1, namely [3S- [3α (Z), 4β]] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[[2 - [(1,4-dihydro-5- hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] sulfonyl] - amino] carbonyl] -4-methyl-2-oxo-3-azetidinyl] amino] -2-oxo- ethylidene] -amino] -oxy] -2-methylpropionic acid or a pharmacologically tolerable salt of it. 26. The compound of claim 1, namely [3S (Z)] - 1 - [[[1- (2-Amino-4-thiazolyl) -2 - [[1 - [[[3 - [[(1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-1-imidazolidinyl] - sulfonyl] -amino] -carbonyl] -2-oxo-3-azetidinyl] -amino] -2-oxo- ethylidene] -amino] -oxy] -cyclopentanecarboxylic acid or a pharmacologically tolerable salt of it. 27. A method for producing a compound according to any one of claims 1 to 26, characterized in that
(1) a compound of the general formula acylated with an R ₁ acyl radical derived from an R ₁ carboxylic acid, or
(2) a -CO-NH-SO ₂ R activation group in a compound of the general formula introduces.