JPS6284082A - 2-oxo-1- ((substituted sulfonyl) amino) carbonyl azetidines - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to 2-oxo-1-(((substituted sulfonyl)amino)carbonyl)azetidines, more specifically, as described below, a 3-acylamino substituent and a The present invention relates to a novel 2-azetidinone compound (β-lactam compound) having an active group of the formula: -C-NH-Sot-R and exhibiting antibacterial activity, and a method for producing the same.

Structure and Effects of the Invention The novel compound according to the present invention is represented by the following formula CI), and also includes pharmaceutically acceptable salts thereof.

t In the above formula CI) and throughout the present invention, the definitions of various symbols are as follows.

R is □ R1 is an acyl group derived from carboxylic acid, R7 and R3 are the same or different, and each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or 4゜5.6 or 7-membered heterocyclic group (hereinafter referred to as RX), or one of R7 and R3 is hydrogen and the other is azide, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethynyl, 2-phenylethynyl, carboxyl, - CH2X
,.

-9X2, x, X3 0X2, OCX4, -5-c-x.

X s X 5 or -A-C-NX8X? , X is azido, amino (-NH2), hydroxy, carboxyl, alkoxycarbonyl, alkanoylamino, phenylcarbonylamino, (substituted phenyl)carbonylamino, alkylsulfonyloxy, phenylcarbonyloxine, (substituted phenyl)sulfonyloxy ,
Phenyl, substituted phenyl, ano, A CNXIIX? , -5-X, or OXt, X is alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, alkanoyl, phenylalkanoyl, (substituted phenyl)
Alkanoyl, phenylcarbonyl, (substituted phenyl)
carbonyl or heteroarylcarbonyl, one of X3 and X4 is hydrogen and the other is hydrogen or alkyl, or X3 and X4 together with the carbon atom to which they are attached is cycloalkyl, X5 is formyl, alkanoyl, phenylcarbonyl,
(Substituted phenyl)carbonyl, phenylalkylcarbonyl, (substituted phenyl)alkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl (NH
t-C-), (substituted amino) carbonyl, or cyano (-CE N), X8 and X7 are the same or different, each hydrogen, alkyl, phenyl or substituted phenyl, or X8 is hydrogen and X7 is amino, substituted Amino, alkanoylamino or alkoxy, or x6 and (CHt)m
-〇-1(CHz)m NH- or -CH, -5
-CH, -1 m is 0, 1 or 2, I AI is a single bond, -NH-C-1-NH-1 or -NH
-NH-C-1 A is a single bond, -NH-1CHt CHt NH-
1 or -〇-NH-NH-1 A, is-(CHJp-1-N H-C-NH-1NH
CNHCHy-1-NH-CH2-1l -0-CHt-1-CHt-C-NH-1 or -CH
2-C-NH-CH, -1 A, is -NH-1(CHt)p-1(CHt)yNH-
1-NH-C-NH-NH-1-C-NH-NH-1H
2X or -N-1 A is a single bond, -CH, -1-NH-CHt-1-N=
CH-1 or 10 NH(CHt)q-1Ae is a single bond, -CH=CH- or i;i -(CI,)t-1
p is O or 11 y is 2.3 or 4, q is 0 or 11 t is 1, 2.3 or 4, and X is hydrogen, carfoquinol or carbamoyl.

The symbols mentioned above (e.g. A I, A 2 , A s
, A-, A a and A,) are used to represent multiatomic groups.

These groups are inserted in the structural formulas shown herein in the manner in which they are present (ie, from left to right). For example, if R is and A,7!1(-NH-C-, the R group is and not.

Definitions of terms used to describe the β-lactam compounds of the present invention are listed below. These definitions apply throughout this specification to terms used individually or as part of a larger group, unless specifically limited otherwise.

"Alkyl" and "alkoxy" refer to both straight and branched chain groups. A group having 1 to IO carbon atoms is preferred.

"Cycloalkyl" and "cycloalkenyl" are
Refers to cycloalkyl and cycloalkenyl groups having 3,4,5,6 or 7 carbon atoms.

"Substituted alkyl" means one or more (preferably 1, 2 or 3) azide, amino (-NHt)
, halogen, hydroxy, carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenyloxo, (substituted phenyl)oxy, mercapto, alkylthio, phenylthio, (substituted phenyl)thio, alkylsulfinyl or alkylsulfonyl group refers to an alkyl group.

"Alkanoyl", "alkenyl" and "alkynyl" refer to both straight and branched chain groups. A group having 2 to IO carbon atoms is preferred.

"Halogen" and "halo" refer to fluorine, chlorine, bromine and iodine.

1-substituted phenyl" means 1, 2 or 3 amino (
-N Hz), halogen, hydroxyl, trifluoromethyl, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkanoyloxy, aminocarbonyl, or a phenyl group substituted with a carboxyl group.

“4.5.6- or 7-membered heterocyclic group (RX) J means 1
refers to substituted and unsubstituted aromatic and non-aromatic groups containing one or more (preferably 1.2 or 3) nitrogen, oxygen or sulfur.

Specific examples of substituents include oxo (=0), halogen, hydroxy, nitro, amino, cyano, trifluoromethyl,
Alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms,
They are alkylsulfonyl, phenyl, substituted phenyl, 2-furfurylideneamino and substituted alkyl (alkyl having 1 to 4 carbon atoms) groups. 1 type 4.5.6 or 7
A membered heterocyclic group is a heteroaryl group. "Heteroaryl" refers to an aromatic 4, 5, 6 or 7 membered heterocyclic group. Specific examples of heteroaryl groups include substituted and unsubstituted pyridinyl, furanyl, pyrrolyl, chenyl,
1,2,3-triazolyl, l.

2.4-) riazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxasilyl, triazinyl and tetrazolyl. Specific examples of non-aromatic heterocyclic groups (i.e., fully or partially saturated heterocyclic groups) include substituted and unsubstituted azetidinyl, oxetanyl, cetanyl, piperidinyl, piperazinyl, imidazolidinyl, oxazolidinyl, virozolidinyl, tetrahydropyrimidinyl, dihydrothiazolyl. Or hexahydroazepinyl. Specific examples of substituted 4.5.6- or 7-membered heterocyclic groups include l-alkyl-3-azetidinyl, 2-
Oxo-1-imidazolidinyl, 3-alkylsulfonyl-2-oxo-1-imidazolidinyl, 3-benzylideneamino-2-oxo-1-imidazolidinyl, 3-
Alkyl-2-oxo-l-imidazolidinyl, 3-phenyl (or substituted phenyl)-2-oxo-1-imidazolidinyl, 3-benzyl-2-oxo-l-imidazolidinyl, 3-(2-aminoethyl)-2-oxo −
1-imidazolidinyl, 3-amino-2-oxo-1-
imidazolidinyl, 3-[(alkoxycarbonyl)aminoco-2-oxo-1-imidazolidinyl, 3-[2
-[(alkoxycarbonyl)aminoconitylyo2-
Oxo-1-imidazolidinyl, 2-oxo-1-pyrrolidinyl, 2-oxo-3-oxazolidinyl, 4-hydroquine-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 1-phenyl-2,3-
Dioxo-1-piperazinyl.

"Substituted amino" means a compound of the formula: NXaXe (Xs is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl, and
(Substituted phenyl)alkyl, hydroxy, cyano, alkoxy, phenylalkoxy or amino (-NH2)
) refers to the group.

"Acyl" refers to any organic group derived from an organic acid (ie, a carboxylic acid) by removing the hydroxyl group.

Of course, certain acyl groups are selected, but this selection should not be seen as limiting the scope of the invention. Specific examples of acyl groups include those traditionally used to acylate β-lactam antibiotics, including 6-aminopenicillanic acid and derivatives and 7-aminosephalosboranic acid and derivatives. (For example, Flynn's r C
ephalosporins and penicil
linsJ (academic.

Press, 1972), West German Patent Publication No. 2716677, published on IO, 1978, 1978
Belgian Patent No. 867994, published February 11th, 19
U.S. Patent No. 4,152,432, issued May 1, 1979, 1
U.S. Patent No. 3,971,778 issued on July 27, 19976; ■U.S. Patent No. 41721 issued on July 23, 1979
No. 99 and British Patent No. 1348894, issued 27 March 1974). Reference sections describing these various acyl groups are incorporated herein by reference. The following is a list of acyl groups to further exemplify the term "acyl", but this should not be considered as limiting the term. Specific acyl groups are as follows.

(a) An aliphatic group represented by the formula: [wherein Ra is alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, cyclohexagenyl, or substituted alkyl or substituted alkenyl (the substituents are halogen, cyano, nitro, amino , mercapto,
Alkylthio is one or more substituents selected from cyanomethylthio] (b) Formula.

Carbocyclic aromatic group represented by Rc or Rc [where n is 0.1, 2 or 3, Rh, Rc and R
d each independently represents hydrogen, halogen, hydroxyl,
Nitro, amino, cyano, trifluoromethyl, alkyl having 1 to 4 carbon atoms, alkoxy or aminomethyl having 1 to 4 carbon atoms, Re is amino, hydroxyl, carboxyl salt, protected carboxyl, formyloxy, sulfo salt,
A preferred carbocyclic aromatic acyl group is Re (Re is preferably a carboxyl salt or a sulfo salt). ),
and Re (Re is preferably carboxyl salt or sulfo salt).

(c) Equation.

Rf (CH7)n C=, Rf-CH-C-1□ Re Rf-0-CH2-C-1Rf-3-CH, -(, - or Rf-(, -C-) a group [wherein n is 0.1, 2 or 3, Rf is a substituted or unsubstituted 5.6 or 4 (preferably 1 or 2) nitrogen, oxygen and sulfur atom] 7-membered heterocyclic group, Re has the same meaning as above] Examples of the heterocyclic group include chenyl, furyl, pyrrolyl, pyridinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, thiadiazolyl, and tetrazolyl. Examples of the substituent include: Examples include halogen, hydroxyl, nitro, amino, protected amino, cyano, trifluoromethyl, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or a group represented by NH2 represented by IHOOCCHCH20CNH-.

A preferred heterocyclic aromatic acyl group is one in which Rf is 2-amino-
4-thiazolyl, 2-amino-5-halo 4-thiazolyl, 4-aminopyrimidin-2=yl, 5-amino-1
, 2,4-thiadiazol-3-yl, 2-chenyl,
Includes those groups which are 2-furanyl or 6-aminopyridin-2-yl.

(d) Formula: [[(4-substituted-2,3-dioxo-1-piperazinyl)carbonyl]amino]arylacetyl group [wherein Rg is an aromatic group (such as a group represented by c Rh is alkyl, substituted alkyl (one or more substituents selected from halogen, cyano, nitro, amino or mercapto); ), arylmethyleneamino: -N=CH-Rg (Rg has the same meaning as above), arylcarbonylamino: -NH-C-Rg (Rg
is the same meaning as above), or alkylcarbonylamino] Preferred [[(4-substituted-2,3-dioxo-1
-piperazinyl)carbonyl]amino]arylacetyl groups include groups in which Rh is ethyl, phenylmethyleneamino or 2-furylmethyleneamino.

(e) Formula.

-C-C=N-0-Ri (substituted oxyimino)arylacetyl group represented by Rg [wherein Rg has the same meaning as above, Ri is hydrogen, alkyl,
Cycloalkyl, 2-pyrazolylmethyl, (2-oxo-3-pyrrolidinyl)methyl, alkylaminocarnyl, arylaminocarbonyl: -C-NH-Rg (Rg has the same meaning as above), or substituted alkyl (halogen, cyano , nitro, amino, mercapto, alkylthio, aromatic group (Rg
), carboxyl (including its salts), amido, alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroquinalkoxyphosphinyl, dihydroxyphosphinyl, hydroxy(phenylmethoxy)phosphinyl, dialkoxy Phosphinyl is an alkyl substituted with one or more substituents selected from tetrazolyl] Preferred (substituted oxyimino)arylacetyl groups are:
including groups where Rg is 2-amino-4-thiazolyl,
Also preferred are groups in which R1 is methyl, ethyl, carboxymethyl, l-carboxy-1-methylethyl, 2.2.2-)lifluoroethyl or I-carboxycycloprobyl.

(f) Formula: (acylamino)arylacetyl group represented by the formula % [wherein, Rg has the same meaning as above, Rj is the group shown, ami-8 alkylamino, (cyanoalkyl) amino, amide, alkylamino , (cyanoalkyl)amide, NH NH,Q l] CHCH2CNHCH3, or ] Preferred (acylamino)arylacetyl groups include the above groups in which Rj is amino or amide, and Rg is phenyl or 2 Also preferred are groups which are -chenyl.

(g) Formula: [[[3-Substituted-2-oxo-1-imidazolidinyl]carbonyl]amino]arylacetyl group [wherein Rg has the same meaning as above, Rk is hydrogen, alkylsulfonyl, arylmethylene Aminony N=CH-R
g (Rg has the same meaning as above), -C-Rm (Rm is hydrogen, alkyl or halogen-substituted alkyl), aromatic group (as shown by Rg above), alkyl or substituted alkyl (halogen, cyano, nitro [[3-substituted-2-oxo-1-imidazolidinyl]carbonyl]amino]arylacetyl group is R
The above groups are included where g is phenyl or 2-chenyl, and also groups where Rk is hydrogen, methylsulfonyl, phenylmethyleneamino or 2-furylmethyleneamino are preferred.

The compounds of the present invention form basic salts with various inorganic and organic bases, and these also fall within the technical scope of the present invention. Such salts include ammonium salts, alkali metal salts, alkaline earth metal salts, salts with organic bases (eg, dicyclohexylamine salts, benzathine salts, N-methyl-D-glucamine salts, hydrabamine salts), and the like. Although pharmaceutically acceptable salts are preferred, other salts are also useful in isolating or purifying the desired product.

Some of the compounds of the present invention can be crystallized or recrystallized from aqueous solvents. In this case, water of hydration may be formed.

The present invention contemplates stoichiometric hydrates and compounds containing varying amounts of water, which can be produced by methods such as lyophilization.

The β-lactam compound (1) of the present invention has at least one chiral center, i.e. an acylamino substituent (R, -N
H-) is bonded to the carbon atom at the 3-position of the β-lactam nucleus). The present invention relates to β-lactam compounds as described above, wherein the stereochemistry of the chiral center at position 3 of the β-lactam nucleus is similar to the configuration of the carbon atom at position 6 of naturally occurring penicillins (e.g. penicillin G). and the configuration of the carbon atom at position 7 of naturally occurring cephamycins (eg, cephamycin C). Racemic mixtures containing the β-lactam compounds are also included within the technical scope of the present invention.

The β-lactam compound [II and its pharmaceutically acceptable salts of the present invention have activity against Durham positive and negative bacteria. Such compounds of the present invention can be used to treat bacterial infections (
It can be used as an agent to combat infections (including urinary tract infections and respiratory infections).

To combat bacterial infections in mammals, the compound of the present invention is administered to the mammal in need of the compound in an amount of about 1°4 to 350m9.
It can be administered for 7 to 97 days, preferably in an amount of about 14-100 n/ky/day. The β-lactam compound (1) of the present invention can also be produced from a 3-protected amino-2-azetidinone of the formula:

In formula CII) above, and throughout this specification, R4
refers to an amino protecting group. These groups are well known in the beta-lactam art and are not limited to the specifically selected groups. Examples of such protecting groups are penzyloquinecarbonyl, trityl and t-butoxycarbonyl.

The β-lactam (II) above is reacted with an isocyanate of formula: %formula%([] (Y is a leavingable group such as chlorine) to give the corresponding compound of formula: The reaction is carried out in an inert organic solvent (e.g. Ethyl acetate, tetrahydrofuran, dimethoxyethane,
Preference is given to working in dichloromethane, acetonitrile or mixtures thereof). The substitution of the leaving group Y with the desired group R can be carried out using a suitable nucleophile of the formula: % formula % (), optionally in the presence of a base (for example, triethylamine), and such substitution gives the corresponding compound of formula: Alternatively, substitution of the leaving group can be carried out by reacting compound (rV) with a protected form of compound (V). After performing the substitution reaction,
Compound [■] can be obtained by removing the protecting group by a conventional method.

Protectors for compound (V) and all reactants having a 3-hydroxy-4-pyridone moiety include compounds in which the hydroxyl group is protected, compounds in which the hydroxyl group and ring nitrogen are protected, and compounds in which both the pyridone oxygens are protected. is included. Examples of protecting groups are silyl (eg trimethylsilyl), benzyl and acyl (eg acetyl). When using silyl, subsequent deprotection can be carried out by hydrolysis or fluoride cleavage.

When benzyl is used, subsequent deprotection can be carried out by hydrogenolysis. When using acyls, subsequent deprotection can be carried out by hydrolysis.

Compound (Vl) is deprotected in a conventional manner to obtain the corresponding basic intermediate of formula: or a salt thereof. The particular deprotection reaction employed will, of course, depend on the protecting groups R4 present. For example, when R4 is a t-butoxycarbonyl protecting group, deprotection can be effected by treating compound (V[) with an acid (eg, formic acid or trifluoroacetic acid). R4
When is a benzyloxycarbonyl protecting group, deprotection can be achieved by catalytic hydrogenation of the compound (l).

Alternatively, the R9 protecting group can be removed at the same time as the other pyridone protecting group, followed immediately by the substitution reaction described above.

The intermediate [■] can be converted into the corresponding target compound (4) using a well-known acylation method.

As a specific method, compound [■] and carboxylic acid (R
, -0H) or its corresponding carboxylic acid halide or anhydride.

Reactions with carboxylic acids proceed most readily in the presence of carbodiimides (eg dicyclohexylcarbodiimide) and substances capable of forming active esters in situ (eg N-hydroxybenzotriazole). If the acyl group (R1) contains reactive functional groups (e.g. amino or carboxyl groups), it is possible to first protect these functional groups, then carry out the acylation reaction and finally deprotect the resulting product. is necessary.

Another method for producing the compound (1) of the present invention is to first acylate 3-amino-2-azetidinone of formula: (the acylation method is the same as above), and then add 10-NH-So to , -R active group can be introduced (using the procedure described above) to obtain the corresponding target compound (1). If the acyl side chain R+ has reactive functional groups (e.g. amino groups), these functional groups can be protected first, followed by the addition of the active group at position 1, and finally the resulting product can be deprotected. is necessary.

Furthermore, another synthetic method for producing the compound (I) of the present invention is represented by the formula: of 3-azido-2-azetidinone.

A -C-NH-Sot-R active group is introduced at the 1-position of compound (X) (using the procedure described above) to give the formula.

R6 The corresponding compound can be obtained.

Reduction of intermediate (XI) gives the corresponding intermediate of formula: Reduction can be achieved by catalytic hydrogenation (e.g. palladium/activated carbon or platinum oxide) or by reducing agents (
For example, zinc or triphenylphosphine) may be used. As mentioned above, these basic intermediates (
The target compound (1) can be produced from the compound [■]) using a conventional acylation method.

Alternatively, 3-azido-2-azetidinone [X] can be reduced to the corresponding 3-amino-2-azetidinone of formula: Reduction can be achieved by catalytic hydrogenation (e.g. palladium/
activated carbon or platinum oxide) or reducing agents (eg zinc or triphenylphosphine). 3-Amino-2-azetidinone [■] is reacted as described above (i.e., first acylated and then treated as described above to introduce -C-NH-Sot-R active group at the l position).
In this way, the target compound CI) can be obtained.

Furthermore, the synthetic method for producing the compound (1) of the present invention in which R2 and R8 are each hydrogen utilizes 6-acylaminopenicillanic acid of the formula: or a salt thereof as a starting material. 3-Anolamino-
2-azetidinone can be obtained (e.g. Ch
em, Soc, 5specialP publicat
ion No. 28, p. 288, 1977, T
he Chemistry of Pen1ci
llins, Princeton University Press,
p. 257 and 5ynthesis, 494, I
977).

As described in the literature, 6-acylaminopenicillanic acid or its salts can be desulfurized (by reduction using Raney nickel) to give compounds of formula: The reaction can be carried out in water under reflux conditions.

After substitution of compound (XI[I) with an acetate group, hydrolysis is performed to obtain the corresponding 3-acylamino-2-azetidinone of formula: Compound (XI) is treated with cupric acetate and lead tetraacetate in an organic solvent (eg acetonitrile) to replace the carboxyl group with an acetate group. Hydrolysis of the resulting compound can be carried out using potassium carbonate in the presence of sodium borohydride.

Using the above procedure, -C- is added to the 1-position of compound (X1'V).
An NH-8ow-R active group can be introduced, which gives the target compound CI) in which R7 and R3 are each hydrogen.

Furthermore, an alternative method of the above synthetic method for producing the compound of the present invention (13) in which R2 and R3 are each hydrogen consists of the following steps: First, 6-aminopenicillanic acid is desulfurized and the resulting compound is acylated. to obtain compound [XIII),
The reaction was then carried out as described above, first with 3-acylamino-2-azetidinone [:X■), then with the target compound [1
).

The azetidinones CI) of the present invention can also be produced from the amino acid of the formula: That is, first the amino group is protected (with a protecting group R such as t-butoxycarbonyl). The carboxyl group of the protected amino acid is then reacted with an amine of formula: %formula% ((Z is alkyl, benzyl or triphenylmethyl)) in the presence of carbodiimide to obtain a compound of formula: Compound [X■] The hydroxyl group of
It is converted to a leaving group (o) with reagents such as methanesulfonyl chloride or pyridine SO complex.

A fully protected compound of formula: is cyclized by treatment with a base (eg potassium carbonate). The reaction is preferably carried out under reflux conditions in an organic solvent or an organic solvent/water mixture, thereby giving a compound of formula: U.

Alternatively, the cyclization of compound [X■] can be carried out without first converting the hydroxyl group into a leaving group. Compound [X■] is treated with triphenylphosphine and diethyl azodicarboxylate to obtain compound (XIX)
get.

Regarding the specific operation of converting compound [X■] to compound (XIX), see J., Am6r, Chem, S.
oc,.

102.7026.1980, and J, Org.

Chem, 47, 5160.1982.

By the double ring closure method of the above compound [X■], R3 and R
When 3 are not identical, a stereochemical inversion of the carbon atoms bearing the R2 and R3 substituents occurs.

Removal of the protecting group from the 1-position of azetidinone (XIX) is
This can be done via sodium reduction when Z is alkyl, thereby giving the formula.

(At least one of R2 and R3 is hydrogen) is obtained. When Z is benzyl, first catalytic hydrogenation (e.g. palladium/activated carbon) gives the corresponding N-hydroxy compound, which is treated with titanium trichloride to give the intermediate (I
obtain f). When Z is triphenylmethyl, the corresponding N-hydroxy compound is first obtained with formic acid or 70% acetic acid/water.

Using the above procedure, an I -c'-NH-sot-R active group is introduced into the 1-position of the compound [■], and the resulting compound is deprotected and acylated.

Nucleophile where R is A and A2 is each a single bond [■]
is deprotected by reacting the silylated derivative of 2-imidazolidinone or the anion of 2-imidazolidinone formed with a strong non-nucleophilic base with an appropriately protected activated derivative of the acid of formula : It can be produced by obtaining the corresponding compound. The reaction can be carried out in an inert organic solvent such as dimethylformamide, acetonitrile, dichloromethane or tetrahydrofuran. Acid (XX) can be activated with dicyclohexylcarbonimide or a mixture of dicyclohexylcarbodiimide and hydroxybenzotriazole. Suitably protected activated derivatives of compound (XX) can be prepared using the corresponding acid chloride (prepared using reagents such as phosphorus pentachloride, thionyl chloride, oxalyl chloride or triphenylphosphine/carbon tetrachloride) or mixed acid anhydride ( (produced using reagents such as diphenylphosphoryl chloride, pivaloyl chloride or isobutyl chloroformate).

Compound (XX) in which A is a single bond can be produced according to the description in the literature (Helv, Chem.

Acta, 43,469.1960 and J. Med.
.

Chem, 17.1.1974).

The compound (, X X ) in which 80 is -CH=CH-,
It can be manufactured using the following procedure. That is, a compound of formula (suitably protected) is oxidized to the corresponding aldehyde of formula (suitably protected), and the aldehyde is reacted with a carboxyl protected derivative of formula: and deprotected to form a compound of formula: get.

Compound [XX) in which 80 is -(CHz)t-1t is 2.3 or 4 can be produced by the following procedure. That is, the compound (XXI[I] (suitably protected) is converted into a Witttig reagent of the formula (with the carboxyl group suitably protected).
The resulting exocyclic double bond is then hydrogenated and deprotected to form the formula.

(t is 2.3 or 4) The compound is obtained.

A compound (X
X) can be produced by the following procedure. That is,
A suitably protected compound of the formula: (La is a leaving group such as chlorine, bromine, methanesulfonyloxy or toluenesulfonyloxy) is reacted with cyanide, followed by hydrolysis and deprotection to form a compound CXX with t of 1. ■].

Compound [XX■] can be produced from compound (XXII) (suitably protected) by methods known in the art (eg thionyl chloride or methanesulfonyl chloride/triethylamine).

The nucleophilic reagent (V) in which R is A1 is a single bond and A is -NH- can be produced by the following procedure. That is, an optionally protected activated derivative of compound (XX) is converted into a 1-amino-
Reaction with 2-imidazolidinone and deprotection yields a compound of formula:

The nucleophilic reagent (V) in which R is A, is a single bond, and A is -CHt CHt NH- can be produced by the following procedure. That is, an optionally protected activated derivative of compound (XX) is reacted with 1-(2-aminoethyl)-2-imidazolidinone and deprotected to yield a compound of formula:

A nucleophilic reagent [■] in which R is A1 is a single bond and A2 is -C-NH-NH- can be produced by the following procedure. That is, a compound of the formula: is reacted with a silylated product of 2-imidazolidinone, an anion of 2-imidazolidinone formed with a non-nucleophilic strong base, or 2-imidazolidinone in the presence of an organic base, A compound of formula: is obtained. Catalytic hydrogenation of compound (XXXn) gives a compound of formula: which is coupled with an optionally protected activated derivative of compound (XX) and deprotected to give a compound of formula:

Alternatively, compound CXXXIII) is prepared by first reacting l-chlorocarbonyl-2-imidazolidinone with t-butoxycarbonyl protected hydrazine to obtain a compound of formula: and deprotecting compound (XXXV). can do.

The nucleophile (V) in which R is a single bond of NHC-1A2 can be produced by the following procedure. That is, a compound of formula: (suitably protected) is reacted with hexamethyldisilazane, hydrolyzed and deprotected to yield a compound of formula: Compound (XXXVI) (suitably protected) is compound (XXXVI) (suitably protected).
It can be produced by reacting a silylated product of XI) (optionally protected) with phosgene.

Alternatively, compound (XXX■) is compound [XXI]
It can be produced by reacting the protected form of with chlorosulfonyl isocyanate and then hydrolyzing the resulting intermediate to cleave the protecting group.

The nucleophilic reagent [■] in which R is A1 or -NH-C-1A, and is -NH- can be produced by the following procedure. That is, a silylated form of a compound of the formula (Prot may be an amino protecting group such as t-butoxycarbonyl or benzyloxycarbonyl) is reacted with phosgene to form a compound of the formula.

can be reacted with hexamethylsilazane and deprotected to give a compound of formula: Compound CXL) is reacted with an optionally protected active form of compound (XX) and deprotected to yield a compound of formula.

Alternatively, compound (XL) can be produced by the following procedure. That is, a compound of formula: % formula % [ is reacted with chlorosulfonyl isocyanate and hydrolyzed to obtain a compound of formula: 0 [XLnl]. The compound is treated with aqueous acid to obtain the salt of compound (XL).

The nucleophile (V) in which R is -NH-C-1A2 is -CH and -CHl-NH- can be produced by the following procedure.

That is, first, 1-(aminocarbonyl)-3-(2-
((Q-butoxy)carbonyl]amino]ethyl]-2
- deprotecting the imidazolidinone and coupling the resulting compound with the active form of compound (XX) (optionally protected);
Deprotection yields a compound of formula:%formula%].

The nucleophile (V) in which R is A, is 11]1 -NH-C-1A, and is -C-NH-NH- can be produced by the following procedure. That is, the silylated form of compound (XXXIV) (optionally protected) is reacted with phosgene, and then reacted with hexamethyldisilazane, hydrolyzed and deprotected to form the formula: %formula% Alternatively, compound (XLV ) can be manufactured by the following procedure. That is, after reacting the protected form of compound (XXXIV) with chlorosulfonyl isocyanate,
The resulting intermediate is hydrolyzed to cleave the protecting group. Alternatively, compound (XXXI[) can be reacted with chlorosulfonyl isocyanate and then the resulting intermediate can be hydrolyzed to produce a compound of formula: % formula %. Compound (XL■) is deprotected by hydrogenolysis to obtain a compound of formula:, which is coupled with an optionally protected activated derivative of compound (XX) and deprotected to yield compound (XLV). get.

The nucleophilic reagent (V) in which R is a single bond, AI is -NH-1A, and AI is a single bond can be produced by the following procedure. That is, the compound (XX
X■] with an activated form of compound (XX) (optionally protected) and cleavage of the protecting group yields a compound of formula 20H.

The nucleophile (V) in which R is -NH-1A, and AI is -NH- can be produced by the following procedure. That is, a monoprotected (preferably with t-butoxycarbonyl or benzyloxycarbonyl) derivative of 1,3-diamino-2-imidazolidinone is coupled with an active form of compound [XX] (optionally protected) to obtain Deprotection of the compound yields a compound of formula:

Alternatively, compound (XLIX) is compound (XXIX)
It can be produced by nitrosating the protected form of , then reducing the nitroso group and cleaving the protecting group.

The nucleophile (V) in which R is -NH-1A and AI is -CH2CHtNH- can be produced by the following procedure. That is, compound (XXX) (appropriately protected) is nitrosated to obtain a compound of formula: (appropriately protected), and this compound is reduced and deprotected to obtain a compound of formula:

A nucleophile in which R is -NH-1A2 is -C-NH-NH- (
V) can be prepared by nitrosation, reduction and deprotection of compound (XXXIV), and the resulting compound has the formula: %Formula% Alternatively, compound (Ln) can be prepared by the following procedure. I can do it. That is, the compound (XXX■) is reacted with phosgene to obtain a compound of formula: This is reacted with monoprotected hydrazine in the presence of a base to obtain a compound of formula: (the two Prots (protecting groups) are different) The hydrazide protecting group is selectively removed to obtain a compound of the formula: Compound (LV) is coupled with an optionally protected active form of compound (XX), followed by deprotection to obtain compound [L ].

A nucleophile in which R is A1 and NH-NH-C-1A2 is a single bond (V
) can be manufactured by the following procedure.

That is, compound (XXXVI) (preferably a protected derivative thereof) is reacted with hydrazine (preferably in a monoprotected form) in the presence of a base, or with a silylated form of hydrazine or a monoprotected hydrazine to obtain a protected derivative of the formula, This can be deprotected using conventional methods.

Alternatively, compound (XXXV) (either its silylated derivative or its anion formed by reaction with a strong base) can be reacted with the active form of compound [Xχ] (suitably protected) and deprotected to form the compound (LVI) can be obtained.

A nucleophile in which R is -NH-NH-C-1A, is -NH- (
V) can be produced by the following procedure.

That is, after selectively removing the non-hydrazide protecting group of compound [L■], it is coupled with an optionally protected active form of compound (XX), and then deprotected to obtain a compound of the formula:

R is -NH-NH-C-1A, is -CH, -CH, -NH-
The nucleophilic reagent [■] can be produced by the following procedure. That is, compound (XXX) (or a protected derivative thereof) is sequentially reacted with phosgene and then hydrazine (or a monoprotected derivative thereof) in the presence of a silylating agent such as N-methyl-N-(trimethylsilyl)trifluoroacetamide. and deprotection to obtain a compound of formula:

Alternatively, the amino-protected derivative of 1-(2-aminoethyl)-2-imidazolidinone (optionally silylated) can be combined with a base or a silylating agent (e.g. N-methyl-N-()limethylsilyl)trifluoroacetamide or (bis(trimethylsilyl)acetamide)), phosgene,
Reaction with a monoprotected derivative of hydrazine then yields a protected derivative of the compound of formula: The group used to protect the terminal amino group of compound (LIX) should be selected so that the protecting group for the aminoethyl group can be selectively removed. The resulting mono-deprotected compound is treated with acid (XX) (or its protected derivative)
Coupling with the active form of and deprotecting the compound [L■]
can be obtained.

The nucleophilic reagent [■] in which R is -NH-NH-C-1A and A1 is -C-NH-NH- can be produced by the following procedure.

That is, compound (XXXII) (optionally as a silylated derivative thereof) is reacted with phosgene to obtain a protected derivative of the compound of formula: which is coupled with a protected derivative of hydrazine to obtain a protected derivative of formula: get. The group used to protect the terminal amino group of compound (LXI) should be selected so that one of the protecting groups can be selectively removed. The resulting mono-deprotected compound is coupled with an optionally protected active form of acid (XX) and deprotected to yield a compound of formula;

The nucleophile (V) in which R is prepared using the method described above for the production of the nucleophile (V) in which R is 2.
-Can be prepared by substituting a suitable 2,3-piperazinedione reactant for the imidazolidinone reactant.

The nucleophile (V) in which R is A, is a single bond, and A is a single bond, can be prepared using an appropriately protected derivative of a compound of formula: H.

formula: The compound can be produced by the following procedure.

That is, the formula: The protected form of the compound of K. Haynes et al. in Chem.

After converting the compound (LXI) into a protected form according to the procedure described in J. Ber., 87, 1440. 1954, the compound (LXI) is deprotected to obtain the compound (LXR') itself.

Compound (LXV) can be produced from a suitable protected form of compound (LXIII) by reacting it with hydrazine, deprotecting it, and converting it into an ester (eg, ethyl or methyl ester). Instead of this,
The appropriately protected active form of compound (LXI [
can be obtained.

Compound (LXI) (or a suitable protected derivative thereof) is reacted with 2-(chloroethyl)isocyanate, optionally in the presence of a base (e.g. triethylamine) or a silylating agent, and deprotected to give a compound of formula 20. obtain. Compound (LXVu) (or a suitable protected derivative thereof) is treated with base and deprotected to provide a compound of formula:

R is a nucleophile where A1 is a single bond and A is -CH - [■]
can be manufactured using the following procedure. That is, a compound of formula (or a derivative with appropriate protection of the pyridone and no protection of the primary amine) is reacted with 2-(chloroethyl)isocyanate and deprotected to yield a compound of formula: Treatment of compound (LXIX) (or a suitable protected derivative thereof) with a base provides a compound of formula:

Compound (LX■) is compound [XX■] (appropriately protected)
It can be produced by treating this with azide, reducing the azide, and deprotecting it.

R is A, is a single bond, A is -N=CH- or -NH-CH
The t-nucleophile (V) can be produced by the following procedure. That is, ■-Amino-2-imidazolidinone is condensed with aldehyde (XXm) (optionally protected) and deprotected to obtain a compound of formula:

Compound (LXXI) (optionally protected) is reduced using catalytic hydrogenation or sodium cyanoborohydride to provide a compound of formula:

Nucleophile where R is A and is -C-NH(CHt)q- [■]
can be manufactured using the following procedure. That is, l-
Chlorocarbonyl-2-imidazolidinone is reacted with a compound of the formula (or a suitably protected derivative thereof) in the presence of a base or with a silylated derivative of the compound (LXXI[[), followed by deprotection to give the formula : Obtain the compound.

The nucleophilic reagent (V) in which R is A and is -NHC- can be produced by the following procedure. That is, the compound (LX■),
Reaction of a suitable protected derivative of (LXX), (LXX I ), (LXXII) or (LXXIV) with phosgene yields a protected derivative of formula: which is reacted with hexamethylsilazane for deprotection and hydrolysis. to obtain a compound of formula:

Alternatively, the nucleophile (V) in which R is OA, is NH-C-
X■〕, (L, XX), (LXXI), [LXXII)
Alternatively, it can be produced by reacting a suitable protected derivative of (LXXW) with chlorosulfonyl isocyanate, followed by hydrolysis and deprotection to obtain compound (LXXW).

The nucleophilic reagent (V) in which R is A and is -NH- can be produced by the following procedure. That is, the compound [LX■], (
LXX), (LXXI), (LXXII) or (LX
A suitable protected derivative of XIV) is nitrosated (eg using nitrous acid) and the resulting compound is reduced (eg using zinc under acidic conditions) and deprotected to give a compound of formula: O Alternatively, a compound (LXXW) in which A is -C-NH(CHt)q- can be produced by the following procedure. That is, compound (XXXIK) is reacted with any protected form of compound (LXIV) or [LX■] in the presence of a base or a silylating agent, and deprotected to obtain a compound of the formula:

Alternatively, A5 may be -N=CH- or -NH-CH,
- Compound CLXX■] can be produced by the following procedure. That is, monoprotected 1,3-diamino-2
- reacting the imidazolidinone with compound (XXIII) (or a protected derivative thereof) and deprotecting the product,
A derivative (LXX■) in which A5 is -N=CH- is obtained.

The derivative is reduced to obtain a compound (LXX■) in which A5 is -NHCHt-.

The nucleophile (V) in which R is -NH-NH-C- is a compound (
LXXV) (suitably protected) with a monoprotected hydrazine in the presence of a base or silylating agent. The product after deprotection has the formula: % Formula % A nucleophile (V) in which A1 is a single bond and A is a single bond or 10H, - can be produced by the following procedure. That is, compound (LXIV) or [LX■] (or a suitable protected derivative thereof) is reacted with aziridine or activated aziridine (activated with a group such as acyl or sulfonyl) and deprotected to yield a compound of formula: . reacting compound (LXXX) (or a suitable protected derivative thereof) with a dialkyl oxalate;
If necessary, it can then be deprotected and converted to the desired piperazinedione of the formula.

R is A, is a single bond, A is -N=CH- or -NHCHt
The nucleophile (V) is -, R is A, is a single bond, A is -N=CH- or -NHCH1
- using the method described above for the production of the nucleophile (V),
It can be produced by using 1-amino-2,3-piperazinedione instead of 1-amino-2-imidazolidinone. The resulting compound has the formula: %Formula% A6 is a nucleophile [■
] can be prepared by reacting an optionally protected derivative of formula: with compound (LXXI[I) (or a suitable protected derivative thereof) in the presence of a base or a silylating agent. The resulting intermediate can be deprotected to provide compounds of formula:

The nucleophilic reagent (V) in which R is A and is -NH- can be produced by the following procedure. That is, the compound [LXXXI]
, CLXXXI[), (LXXXI[[) or (LX
The protected derivative of XXV) is nitrosated (eg using nitrous acid) and the resulting compound is reduced (eg using zinc under acidic conditions) and deprotected to give the compound of formula:

Alternatively, A is -N=CH- or -NH-CH,
- Compound (t, XXXVI) can be produced by the following procedure. That is, monoprotected 1,4-diamino-2,3-piperazinedione is converted into compound (XXII[)
(or a protected derivative thereof) and deprotect the product to form a compound (LXX
XVI), which can then be reduced to compounds (LXXXVI) in which A is -NHCHt-. Alternatively, reduction of -N=CH- can be carried out before deprotection.

The nucleophile (V) in which R is -NH-NH-C- can be produced by the following procedure. That is, the compound (LXXX
I), (LXXXII), (LXXX■] or (LX
XXV) by reacting a suitable protected derivative of XXV) with phosgene,
A compound of formula: is obtained, which is reacted with hexamethyldisilazane, deprotected and hydrolyzed to obtain a compound of formula 20.

Alternatively, the nucleophile (V) in which R is A and is -NHC- can be prepared by the following procedure. That is, the compound (LXXXI), (
t, XXXII ), (LXXXII[) or (LX
A suitable protected derivative of XXV) is reacted with chlorosulfonyl isocyanate, hydrolyzed and deprotected to yield the compound (LXXX■).

The nucleophile (V) in which R is and A3 is -(CHt)p- has already been described (see compounds (LX■) and (LX■)).

The nucleophile (V) in which R is or -NHCNHCHl- is
It can be produced by reacting compound (XXX I) with compound (LXIV) or [LX■] (optionally protected) in the presence of a base or silylating agent, and then removing any of the protecting groups. .

Alternatively, R is a nucleophile where A3 is -NH-C-NH- or -NH-C-NH-CH2- [■
] can be obtained from a suitable protected form of compound (LXIV) or [Lx■] by reacting it with phosgene and then deprotecting it by treating it with a monoprotected derivative of hydrazine in the presence of a base or a silylating agent. can be manufactured.

A nucleophile (V) in which R is A, is -CHt-C-NH- or -CHl-CO-NH-CHl-, can be used to convert the activated N-protected glycine derivative into a compound (L
-XIV) or (LX■) (optionally protected), followed by deprotection.

R is ■, A3 is -NH-CH! - The nucleophile (V) is an aldehyde (XXIII)
It can be produced by reacting any protected derivative of with hydrazine or monoprotected hydrazine followed by reduction of the carbon-nitrogen double bond and then deprotection.

Alternatively, the free amino group of the monoprotected hydrazine is monoalkylated with the compound (XX■) (preferably protected), followed by deprotection, so that R is a nucleophile (where A3 is -NH-CH2-) V) may be obtained.

The nucleophilic reagent (V) in which R is A3 is 10-CH2- can be produced by the following procedure. That is, by reacting a suitable protected derivative of compound (XXII) with N-hydroxyphthalimide under Mitsunobu conditions (presence of triphenylphosphine and diethyl azodicarboxylate), a protected derivative of a compound of formula: %formula%] is prepared. This is deprotected to give a compound of formula H.

Alternatively, compound (XCI) can be prepared by reacting compound [XX■] (suitably protected) with N-hydroxyphthalimide in the presence of a base.

The nucleophilic reagent (V) in which R is and A4 is -NH- can be produced by the following procedure. That is, a monoprotected hydrazine is reacted with an optionally protected activated derivative of acid (XX) and deprotected to provide a compound of formula:

Alternatively, compound (XC[]) can be prepared by reacting a carboxylic acid ester of a suitable protected derivative of compound (XX) with hydrazine followed by deprotection.

The nucleophile (V) in which R is A4 and (CHt)p-1p is 0 can be produced by the following procedure. That is, ammonia or hexamethyldisilazane is reacted with an optionally protected activated derivative of acid [XX] and deprotected to provide a compound of formula:

The nucleophile (V) in which R is A4 is (CH2)p-1p is 1 can be produced by the following procedure. That is, the compound (XX
Treatment of the suitably protected activated derivative of ) with diazomethane followed by treatment with hydrochloric acid gives the protected derivative of the compound of formula: %formula%). The compound in which Lb is chlorine (XCI[) is then treated with an iodide or bromide salt (e.g. sodium iodide or lithium bromide),
Protected derivatives of compounds (XCII[) in which Lb is bromine or iodine can be obtained.

Replacement of the leaving group L b (L b being chlorine, bromine or iodo) with azide is followed by reduction and deprotection to yield compounds of formula.

The nucleophile (V) in which R is 1l -NH-C-NH-NH- can be obtained by treating compound (XCI) (suitably protected) in the presence of a silylating agent.
It can be produced by reacting with a compound of the formula: % and then removing the protecting group.

The nucleophile [■] in which R is and A4 is -C-NH-NH- can be produced by the following procedure. That is, NH*CNH
NHt is reacted with an optionally protected activated derivative of acid (XX) in the presence of a base or silylating agent and deprotected to provide a compound of formula:

The nucleophilic reagent (V) in which R is C1 and X A4 is -N- can be produced by the following procedure. That is, an optionally protected hydrazine derivative of formula: %formula% is reacted with an optionally protected activated derivative of acid (XXI) and deprotected to yield a compound of formula: %formula%.

Alternatively, compounds (C) where
It can be produced by reacting with a carboxylic acid ester derivative.

The compound (1) of the present invention in which R is preferred. Most preferred are compounds CI) in which R is. Also preferred compound (1) is:
R8 is I-C-C=N-0-Ri, Rg is 2-amino-4-R
g Thiazolyl, a compound in which Ri is methyl, ethyl, carboxymethyl, l-carboxy-1-methylethyl, and ■S is 1, 2 or 3. The use of these preferred R, acyl groups results in the desired products existing as syn or anti isomers or mixed isomers. The syn isomer is more active than the act isomer.

The following examples are specific illustrations of the invention.

(Space below) Example 1 [3(Z)co2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[3-[[(1,4-dihydro -5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonylcoamino]carbonyl]-2-oxo-3-azetidinyl]aminoco2-oxoethylidene]amino]oxy ]-2-Methylpropionate disodium salt preparation A) 2-(hydroxymethyl)-5-(phenylmethoxy)-4H-pyran-4-one 699 (3 mol) of sodium was dissolved in 5 (2) methanol. Dissolve and then add 425.3 g (3 mol) of 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one and stir at 30° C. until the solution becomes clear. Then 5959 (3 mol) , 5 mol) of benzyl bromide and stirred under reflux for 1 hour. This very dark hot solution was heated to 151
Pour into ice water from step 2. The product crystallizes out immediately. The crystals are collected and washed twice, first with 8Q of water and then with 2.51 of ether. The product is allowed to stand overnight and finally dried for 16 hours at 50°C.

Yield 646g (92.6%).

B) IOρ with 4-year-old xo-5-(phenylmethoxy)-4H-pyran-2-carboxylic acid 6.6Q of acetone and 400Q of water
A stirred flask is charged with 232 g (1 mole) of 2-(hydroxymethyl)-5-(phenylmethoxy)-4H-pyran-4-one. The clear solution is cooled to 5°C in a water bath. 640 i (l
Jones reagent (Cr03202g)
, 600 R12 of water, 174 m of H2SO are added dropwise over 1 hour. Continue stirring for 2 hours without cooling. The reaction mixture was filtered through a glass filter plate and the dark green residue was filtered at 500xN.
Wash with acetone. The filtrate is then evaporated until all the acetone has been removed.

1.2 c of methanol is added to the partially crystalline aqueous product and the mixture is heated to its boiling point. The resulting dark green clear solution is placed in a water bath and the product crystallizes out. The crystalline product is filtered, washed with 500 m of a cold solvent mixture consisting of 250 mQ methanol and 250xR water and finally dried. Yield t 959 (79%). A further 5% of product can be isolated from the mother liquor.

C) 1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid 3001? (1,2
2 mol) of 4-oxo-5-(phenylmethoxy)-4
H-pyran-2-carboxylic acid was added to the flask and 512
of 33% NH,OH is carefully added under stirring. The reaction mixture is then stirred under reflux. After 3 hours, slowly add 33% NF (40H) of IQ.
Continue stirring for an hour. The reaction solution is evaporated until the product crystallizes out. Return the product to the reaction flask and add water (approximately 5QSI) H6,38) until a clear solution is obtained.

This solution is vigorously stirred, and during this time concentrated hydrochloric acid is added dropwise until the solution reaches pet3. The precipitated white product is filtered off, washed thoroughly with water and dried. Yield ff12739 (1°12 mol, 91.8%).

D) 1,4-dihydro-4-oxo-N-(2-oxo-1-imidazolidinyl)-5-(phenylmethoxy)
-2-Vyridinecarpoxamide 1,4-dihydro-4-
Oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid (12,269,0,05 mol) and 1-amino-2-imidazolidinone (5,56 g, 0.055 mol) were dissolved in 120 g of dimethylformamide. Suspend in The suspension contains 0.39 dimethylaminopyridine and 0.4
Add 9 of N-hydroxybenzotriazole. After stirring for 30 minutes at room temperature, a solution of 11.359 (0.055 mol) dicyclohexylcarbodiimide in 50 MQ dimethylformamide is added dropwise and the mixture is stirred overnight at room temperature. The precipitate (dicyclohexylurea) is filtered off and the filtrate is evaporated under reduced pressure. The remaining syrup is crystallized by treatment with aqueous sodium bicarbonate to give 11.7 g of the title compound (mp 158-160 DEG C.). A further product of 0.89 is obtained which crystallizes from the aqueous filtrate (melting point 162-164°C).
).

E) 1,4-dihydro-5-hydroxy-4-oxo-
N-(2-oxo-1-imidazolidinyl)=2-pyridinecarboxamide 129 (0,0365
36. mol) of 1.4-dihydro-4-oxo-N-(2-oxo-1-imidazolidinyl)-5-(phenylmethoxy)-2-pyridinecarboxamide.
Add 12 parts (0,146 mol) of bis(trimethylsilyl)acetamide to form a slightly cloudy solution. After filtration, 6 g of 10% palladium on activated carbon are added and hydrogen is passed through the stirred reaction mixture.

After 60 minutes of hydrogenation, the catalyst is filtered off and 15 mN methanol and 2IIIQ acetic acid are added. Stirring is continued overnight and the title compound crystallizes out. Yield i46.69, melting point 27
0-275℃.

F) (3S)-[1-[[[[3-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)
carbonyl]aminoco2-oxo-1-imidazolidinylcosulfonylcoamino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid phenylmethyl ester 13.89 of (S)-3-[ in 500 ml of ethyl acetate
To the suspension of [(phenylmethoxy)carbonyl]amino]-2-azetidinone are added 5.63 d (0,0626 mol) of chlorosulfonyl isocyanate. The mixture is stirred at room temperature for 1 hour to form a solution of (S)-1-[[(chlorosulfonyl)aminococarbonyl]-3-[[(phenylmethoxy)carbonylcoamino]-2-azetidinone. The solution was cooled to 0 °C and at this temperature the silylated 1,4-dihydro-5-hydroxy-4-oxo-
N-(2-oxo-1-imidazolidinyl)-2-pyridinecarboxamide solution [14°99 (0,0626 mol) of 1,4-dihydro- in ethyl acetate of 500zσ
5-hydroxy-4-oxo-N-(2-oxo-1-
46.4 (0.25 mol) of N-methyl-N-(trimethylsilyl)trifluoroacetamide was added to a suspension of (imidazolidinyl)-2-pyridinecarboxamide, and the mixture was stirred for 30 minutes. . Then 150 z12 of dichloromethane are added and the mixture is stirred at room temperature overnight. 26.2 m12 (0,18
After adding 8 mol) of triethylamine, 3009 of ice and 20 (11!) of water are added.l)H is 65°1.
After stirring for 5 hours, the two phases were separated and the aqueous phase was washed three times with 200 m(! parts) of ethyl acetate. After removing the residual ethyl acetate under reduced pressure, 2N-hydrochloric acid (47 ff12) was slowly added while cooling. The pt of the phase is adjusted to 2. The crystals are filtered off and suspended in 200 x Q ethyl acetate and stirred for 1 hour. The crystals are then filtered off and suspended twice in 30 mQ ethyl acetate and 50 mQ petroleum ether. Wash twice, dry under reduced pressure,
The title compound of 28°69 is obtained. Melting point 190-200℃
(Disassembly).

GX3S)-3-amino-N-[[3-[[(1,,s
-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]-2-oxo-1-azetidinecarboxamide trifluoroacetate salt (l.2
) 49 (0°00713 mol) of (3S)-[+-[[[[3-[
[(1.

4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonylcoamino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2
-oxo-3-azetidinyl]carbamic acid phenylmethyl ester. Stir the clear solution overnight at lOoC. After evaporation under reduced pressure at room temperature, the remaining syrup is treated with ether to give the title compound as a yellowish solid. Yield is almost quantitative.

H) [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-azetidinylcoamino]-2-oxoethylidene]amino]oxyco-2-methylpropionic acid diphenylmethyl ester of 3.089 (0,007 mol) in 70 m (l) of dimethylformamide (Z)- 2
-amino-α-[[2-(diphenylmethoxy)-1,
In a solution of 1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid, 2.9 mQ (0,021 mol)
of triethylamine is added, then cooled to -30°C under nitrogen and 1°55iQ (0,007 mol) of diphenylchlorophosphate is added. The mixture is stirred at -30°C for 1 hour. Then 1.95 m12 (0,014 mol) of triethylamine was added followed by 0.007 mol of (3S)-3-amino-N-[[3=[[(1,4-dihydro-5-hydroxy- Add 4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonylco-2-oxo-1-azetidinecarboxamide trifluoroacetate salt (1:2). The reaction mixture was stirred at -10°C for 2 hours and at 0°C for 1 hour. The solvent is then removed under reduced pressure. The residue is treated with water and ethyl acetate to give an insoluble product which is solidified by treatment with ether to give crude compound 8.09.

1 ) [3S (Z)Co2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[3-[[(
1,4-dihydro-5-hydroxy-4-oxo-2-
pyridinyl)carbonyl]aminoco2-oxo-1=
imidazolidinyl]sulfonyl]amino]carbonyl]
-2-oxo-3-azetidinylcoamino]-2-oxoethylidene]amino]oxy]-2-methylpropionate disodium salt [35(Z)]-2-[[[1-(2-amino -4-
Thiazolyl)-2-[[1-4[[[3-[[(1,4
-dihydro-5-hydroxy-4-oxo-2-pyrinonyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonylco2-
Oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylprozeonic acid diphenylmethyl ester (89) is suspended in 15Il12 of anisole. After cooling to -10°C, 80w (l) of trifluoroacetic acid is added dropwise and the mixture is stirred at -10°C for 1 hour. Ether is added at 0°C and the trifluoroacetate salt of the free acid product (4,19 The suspension of the suspension in water is adjusted to I) H5.5 by addition of sodium bicarbonate solution, and the solution formed is lyophilized. The crude sodium salt is then purified by chromatography on HP-20*.

Note*: The macroreticular styrene-divinylbenzene copolymer resin product manufactured by Mitsubishi Chemical Corporation is eluted with water to yield a product of 0.529.

NMR (DMSO-ds): δ1.35 (s, 3H),
1°40 (s, 3H), 3', 37 (dd, ,
I H), 3.47 (t, 2H), 3.81 (t, 2H
+dd, IH), 5, 05 (m, IH), 6.75
(s, IH), 7.27(s, lH), 7.72(
s, IH), 11.52 (Broad s, IH) Example 2 [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]-
Preparation of 2-oxoethylidene]amino]oxy]-2-methylpropionic acid disodium salt = A) 1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid 2-[( 1,1-dimethylethoxy)carbonyl]hydrazi 1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid (61.3 g, 0.25 mol) was dissolved in 500 ml of dimethylformamide at room temperature. 39.65y (0,3
mol) of N-(t-butoxycarbonyl)hydrazine,
1,59 dimethylaminopyridine and 2.09 N
-Hydroxybenzotriazole is added and the mixture is stirred at room temperature for 30 minutes. 57 g (0.28 mol) of dicyclohexylcarbodiimide are then dissolved in 100 g of dimethylformamide, which are added dropwise over 30 minutes with stirring, and the mixture is stirred overnight at room temperature. The precipitate (dicyclohexylurea) was filtered off, and the solution 'a' was evaporated under reduced pressure.

Treat the remaining syrup with dilute sodium bicarbonate solution and
Let it crystallize.

The dried crude product was recrystallized from 2 g of ethyl acetate,
69.5 g of the title compound are obtained (melting point 173-175°C
). Evaporation of the mother liquor gives a second crop of 3,29 (melting point 160-165°C).

B) 1,4-dihydro-5-hydroxy-4-oxo-
2-Pyridinecarboxylic acid hydrazide 1,4-dihydro-4-oxo-
5-(phenylmethoxy)-2-pyridinecarboxylic acid.
2-[(1,1-dimethylethoxy)carbonylcohydrazide (699,0,191 mol) is added. The mixture is stirred at room temperature for 1 hour and then evaporated. The remaining syrup was treated with ether to give 68.29 crude 1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid hydrazide trifluoroacetate salt (1:2) as a solid. obtain.

Coarse! , 4-dihydro 4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid hydrazide trifluoroacetate salt (1:2) is dissolved in 250 x I2 acetonitrile and stirred for 1 hour while cooling. The crystals are then filtered and resuspended in acetonitrile at 600 mC. Bis(trimethylsilyl)acetamide (135
xN), then add 28 g of 10% palladium/activated carbon. Hydrogen is then passed through the stirred solution. Hydrogenation is completed after 90 minutes. After filtration, 70 methanol and 2
Add MI2 acetic acid. - Filtering off the crystals formed after stirring overnight gives 19.49 of the title compound. Melting point 290-3
40℃.

CX3S)-[1-[[[[[[1,4-dihydro-4
=oxo-5-(phenylmethoxy)-2-pyridinylcocarbonyl]hydrazino]sulfonylcoamino]carbonyl]-2-year-old xo-3-azetidinylcocarbamic acid phenylmethyl ester 5.199 in ethyl acetate of 160 (0,0236t
2.059 (0,0236 mol) of chlorosulfonyl isocyanate are added to the suspension of (S)-3-[I[(phenylmethoxy)carbonylkoamino]-2-azetidinone of The mixture is stirred at room temperature for 1 hour to form a solution of (S)-1-[[(chlorosulfonyl)aminococarbonyl]-3-[[(phenylmethoxy)carbonylcoamino]-2-azetidinone. After cooling the solution to 0° C. and adding 80 mQ of dichloromethane, 9.9 zQ (0,0707 mol) of triethylamine and silylation! .

4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid hydrazide solution [5 (Lo2 of ethyl acetate and 8.75x12 (0,0472 mol) of N-methyl-N-()limethylsilyl)trifluoroacetamide] 3.99 g (0,0236 mol) of 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid hydrazide] is added thereto. The mixture is stirred at room temperature overnight, then ice water is added and stirring is continued for an additional 30 minutes. Separate the aqueous layer with ethyl acetate and adjust the pH.
Acidify to 2,5. After stirring for 1 hour, the precipitate crystallizes out to give the title compound, 6°69.

Evaporation of the ethyl acetate phase and treatment with petroleum ether gives a second crop of the title compound, 1.49.

D) (3S)-3-amino-N-[[2-[(1,4-
dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]hydrazino]sulfonyl]-2-oxo-1-azetidinecarboxamide trifluoroacetate salt (1:2) 22 mQ of trifluoroacetic acid and 5.3 A mixture of thioanisole was stirred at room temperature and added to (3s)-[
l-[[[[[[t, 4-dihydro-4-oxo-5
-(phenylmethoxy)-2-pyridinyl]carbonylcohydrazinocosulfonylcoamino]carbonyl]-2
-oxo-3-azetidinylcocarbamic acid phenylmethyl ester (6.6 g, 0.0133 mol) was added;
Stir overnight at room temperature. Trifluoroacetic acid was removed under reduced pressure,
Treatment of the remaining syrup with ether gives the title compound in constant yield.

E) [3S (Z) Knee2 [C[1-(2-amino-4-thiazolyl)-2-[[1-[[[[2-[(1
,4-dihydro-5-hydroxy-4-oxo-2-pyrinonyl)carbonyl]hydrazinocosulfonyl]aminococarbonylco-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]- 2
- 5.84 g of methylpropionic acid diphenylmethyl ester 135j112 in dimethylformamide
(0,0133 mol) of (Z)-2-amino-α-[[
2-(diphenylmethoxy)-1,1-dimethyl-2-
Add 5,6 mQ of triethylamine to a solution of -30
After cooling to 0.degree. C., 3.579 (0.0133 mol) of diphenylchlorophosphate are added. Heat the mixture at -30°C.
After stirring for an hour and then adding 3.72 m(l) of triethylamine, 0.0133 mol of (3S)-3-amino-N-[[2-[(1,4-dihydro-5-hydroxy-4- Add oxo-2-pyridinyl)carbonyl]hydrazino]sulfonyl]-2-oxo-1-azetidine carboxamide trifluoroacetate salt (1:2).

The mixture was stirred for 2 hours at -lO<0>C and 1 hour at 0<0>C, the solvent was removed under reduced pressure and the remaining syrup was treated with 150xQ ethyl acetate and 70mQ ice water, to which was added 2N-HCl , adjust to 5-2.

5. Remove insoluble material and triturate with ether.
39 crude products are obtained.

F) [3S (Z) nee 2-[[[1-(2-amino-
4-thiazolyl)-2-[[1-[[[[2-[(1,
4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]hydrazinocosulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2 −
Methylpropionate disodium salt [35(Z)]-2
-[[[+-(2-amino-4-thiazolyl)-2-[
[1-[[[C2-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonylcohydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino] -2-oxoethylidene]aminocooxy]-2-methylpropionic acid diphenylmethyl ester <5.39.0.0069 mol) is suspended in anisole of IO,6+.
Cool to 200 °C and add 53i (2) of trifluoroacetic acid under stirring. The mixture is stirred at this temperature for 1 hour, then 200 °C
The ether of R(2) is added at -10°C to precipitate the free acid trifluoroacetate of the title compound. Yield 7°3.
g.

The crude material is dissolved in a mixture of 100 ml of water and 50 ml of acetone. pl (adjusted to 5-55, and acetone was removed under reduced pressure. The remaining aqueous solution was lyophilized to 8.1
A crude product of 9 is obtained which is purified by HP-20 chromatography eluting with water. This chromatography gives a 1.05y product.

NMR (DMSOdo): δ1.40 (s, 3H
),! .

42 (s, 3H), 3.25 (dd, IH), 3.
70 (dd.

IH), 5.10 (m, IH), 6.75 (s, IH)
, 7°40 (s, lH), 7.80 (s, lH),
11.32 (Broad s, l H) Example 3 [3S(Z)nee 2-[[[1-(2-amino-4-deazolyl)-2-[[1-[[[[3-[[ (1,4-
dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonylcoamino]-2-oxo-1-imidizolidinyl]sulfonyl]aminococarbonyl]-2-oxo3-azetidinyl]amino]-2-oxoethylidene Preparation of disodium salt of 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-oxoethylidenecoamino]oxy]-2-acetic acid diphenylmethyl ester of 10.0 m (2.069 m) in dimethylformamide
0,005 mol) of (Z)-2-amino-α-[[2-
2.1 mC (0,0
15 mol) of triethylamine are added.

The mixture was cooled to -30°C and stirred 1. Ld(0゜00
5 mol) of diphenylchlorophosphate are added. −
After stirring at 30°C for 1 hour, the temperature was further increased to 1.4+7! at -30°C. (
After adding 0.1 mol) of triethylamine, 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-year-old xo-1-azetidinecarboxamide trifluoroacetate salt (1:2)
Add.

The reaction mixture was stirred at -10°C for 2 hours and at 0°C for 1 hour. The solvent was evaporated under reduced pressure and the oily residue was suspended in water and 2N-
The pH of the suspension is adjusted to 2 by adding hydrochloric acid. The suspension is stirred at room temperature for 30 minutes and the solid is filtered off, which is resuspended in water and filtered off again. After drying under reduced pressure over phosphorus pentoxide, 50 g
A crude product is obtained. This material is used in the next step without purification.

B) [35(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 disodium salt 5.09
Amino-4-thiazolyl)-2-[[1-[[[[3-
[[(1.

4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-■-imidizolidinylcosulfonyl]amino]carbonyl]-2
-Oxo-3-azetidinyl]amino]-2-oxoethylidene]aminocooxy]-2-acetic acid diphenylmethyl ester is suspended at -lO<0>C in a mixture of 10*C of anisole and 50ml of triple oroacetic acid.

After stirring the reaction mixture at -10°C for 1 hour, lOOmσ
of ether is carefully added to precipitate the crude trifluoroacetate salt of the title compound. The material having an aggregation of 3.79° is dissolved in a mixture of 30*C water and 60*C acetone and O,IN-sodium hydroxide is added to adjust the pH of the mixture to 5-5.5. Evaporate the acetone and lyophilize the aqueous phase to obtain 3.9 g of crude product.

The combined material is purified by chromatography on HP-20. The product is eluted with water (10 i of each fraction).

The product-containing fractions were lyophilized to obtain 0.6 g of material;
This was again subjected to chromatography on HP-20,
025 g of pure product are obtained.

Example 4 [3S (Z)]-2-[[[1-(2-amino-4-
Thiazolyl)-2-[[1-[[[[(1,4-dihydro-5-hydroxy-4-dihydro-2-pyridinyl)
Production of methyl]amino]sulfonyl]amino]carbonyl-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropionic acid A) 2-(hydroquinemethyl)-5 -(phenylmethoxy)-4(lH)-viridinone 2-(hydroxymethyl)-5-(phenylmethoxy)
A mixture of -4H-bilan-4-one (9,659,41°59 mol), 95*C concentrated ammonia and 20*C ethanol is heated to reflux for -night. Another 75 inches of ammonium hydroxide is added and the mixture is refluxed for 2 hours and cooled. The resulting brown solid is filtered and washed with water until the washings are neutral. The crude product is suspended in ethanol, filtered, washed with ethanol and hexane, and dried under vacuum. Yield of title compound: 7.61!11°B) 2-(chloromethyl)-5-(phenylmethoxy)
-4(IH)-Viridinone monohydrochloride chloroform (
2-(hydroxymethyl)-5- in 1'5ff12)
(phenylmethoxy)-4(IH)-viridinone (39
, 12,99 mmol) is cooled to 0 °C under argon and treated with thionyl chloride (6,Ii (,83,62 mmol). Within a few minutes, a homogeneous solution is obtained. After stirring for minutes, a cream solid precipitates out. The cooling bath is removed and the mixture is heated to reflux for 45 minutes. The mixture is cooled to 0° C. and the white precipitate is filtered off, washed with chloroform and hexane, and dried under vacuum. . Collection of the title compound fi3,6
59°C) 2-(azidomethyl)-5-(phenylmethoxy)-4(IH)-pyridinone 2-(chloromethyl)-5-(phenylmethoxy)-4(IH)-pyridinone in 70% dimethylformamide・Monohydrochloride (3,591/, 12.54 mmol)
, sodium azide (4.08 g, 62°7 mmol)
and diisopropylethylamine (2,19mQ, 1
2.54 mmol) at room temperature under argon.
Stir for 5 days. Another 4.89 g of sodium azide is added and the mixture is heated at 45-50° C. for 2 hours. After cooling,
Pour the reaction mixture into 500×Q water to produce an insoluble white solid. The pal of the supernatant was lowered from 8.5 to 7.5 with dilute hydrochloric acid, and the white solid was collected by filtration. After washing with water, acetone and hexane, the solid is dried under vacuum. Yield of the title compound: 281 g.

D) 2-(aminomethyl)-4-(phenylmethoxy)
-4(IH)-Viridinone A mixture of 2-(azidomethyl)-5-(phenylmethoxy)-4(IH)-viridinone (2,03 g, 7.93 mmol) and platinum oxide (200B) in 100 mC of dimethylformamide. is stirred at room temperature over 1 atmosphere of hydrogen for 6 hours. The crystals were filtered off, and the solution was concentrated under reduced pressure to give 1
．． 59 (82%) of the title compound are obtained as a gray powder.

EX3 S )-[1-[[[[[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]methyl]amino]sulfonyl]aminococarbonyl]-2-oxo-3 -azetidinyl]carbamic acid phenylmethyl ester 60 mQ, 2-(aminomethyl) = 5 in ethyl acetate
-(phenylmethokino)-4(IH)-viridinone (2
, 3309, 1013 mmol) of N-
Add methyl-N-(trimethylsilyl)trifluoroacetamide (3,7611!L 20.26 mmol). The resulting solution was stirred at room temperature for 30 minutes, then 0.
Cool to ℃. Meanwhile, in parallel, (S)-3-[[(phenylmethquin)carbonyl]amino]-2-azetidinone (2,228 g, 10
．． overnight, chlorosulfonyl isocyanate (882 μρ, IO, 13 mmol)
Add. The resulting solution was stirred at room temperature for 30 minutes and then heated to 0°C.
Finally, add triethylamine (4.23 mn, 30 mn.
．． After treatment with 39 mmol), the previously unlylated 2-(aminomethyl)-5-(phenylmethoxy)-4(IH)
- Treat with viridinone solution. These mixtures are stirred at room temperature for 2 days.

The mixture was concentrated under reduced pressure and the residue was dissolved in CH3CN/water (40/
60) and lowering the pH to 29, a thick oil separates. Upon cooling to 5°C, the oil solidifies. The solid was separated, washed with water 4 times, and dried under reduced pressure to give 3.4 g.
A crude product is obtained. The crude product was dissolved in a minimum amount of methylformamide and applied to a HP-20 resin column (lρ).
load on. The column is eluted with a stepwise acetone/water gradient. The desired material is eluted with approximately 65% acetone. The relevant fractions are combined and lyophilized to yield 2.69 g of the title compound.

F) [3S(Z)]-2-[[[1-(2-amino-4
-thiazolyl)-2-[[1-[[[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyrinonyl)methyl]amino]sulfonyl]amino]carbonyl]
-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]okyne]-2-methylpropionic acid diphenylmethyl ester (as a mixture of monopotassium and monotriethylammonium salts) in 16 m&gt; 3S)-[1-
[[[[[l, 4-dihydro-4-oxo-5-
(]enylmethoxy)-2-pyridinyl]methyl]amino]sulfonyl]amino]carbonyl]-2-oxo-
3-azetidinyl]carbamic acid phenylmethyl ester (912II + 9.1.64 mmol), p-1 luenesulfonic acid monohydrate (625 mg, 3.28 mmol), and 10% palladium on activated carbon (190119
) under 1 atm of hydrogen at 3.28 mmol (73
Stir until the hydrogen in mC) is consumed (approximately 3 hours).

(Z)-2 in dimethylformamide of 16'/l12
-Amino-α-C[2-(diphenylmethoxy)-1゜1-dimethyl-2-oxoethoxycoimino]-4-thiazoleacetic acid (846 mg, 1.804 mmol) -
Diphenyl chlorophosphate (
374 μm2, 1.804 mmol) and then triethylamine (450μC13,28 mmol).

The solution was stirred at -20° C. for 1 hour and added to the hydrogenolyzed (3S)-[1-[[[[[1,4-dihydro-4-oxo-5-(phenylmethoxy)-]. Add the mixture of 2-pyridinyl]methyl]amino]sulfonyl]aminococarbonyl]-2-oxo-3-azetidinyl]carbamic acid phenylmethyl ester. The resulting mixture is stirred at -20°C for 1 hour and at 5°C overnight. The catalyst was filtered off, the volatiles were removed under reduced pressure and the resulting oil was dissolved in a minimum amount of acetone/water (75/25, I)H5,2) and dissolved in acetone/water (35/65). 20mQ of D
Add dropwise to the stirred suspension of owex50X2-40Q*(K+).

Note *) Dowex 50X2-400: -Styrene-divinylbenzene copolymer gel with -S Os- groups, manufactured by Dow Chemical Co. After 40 minutes, the mixture was filtered, and the filtrate was freeze-dried to obtain 2.1
9 solids are obtained. Dissolve the solids in a minimum amount of acetonitrile/water (
HP-20
Load onto a resin column (800 mg) and elute with a stepwise acetonitrile/water gradient. The desired material is eluted with approximately 30% acetonitrile. The relevant fractions are combined and lyophilized to yield the impure title compound. (2541119).

G) [35(Z)]-2-[[[1-(2-amino-4
-thiazolyl)-2-[[1-[[[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)methyl]amino]sulfonyl]amino]carbonyl]
The above impurity [3S(Z)]-2-[[ [1-(2
-amino-4-thiazolyl)-2-[[1-[[[[[
(1.

4-dihydro-5-hydroquine-4-oxo-2=pyridinyl)methyl]amino]sulfonyl]aminococarbonyl]-2-oxo-3-azetidinyl]amino]-2
-oxoethylidene]amino]okyne]-2-methylpropionic acid diphenylmethyl ester (as a mixture of monopotassium and monotriethylammonium salts,
C4.7m of trifluoroacetic acid is added dropwise at 0° C. to a stirred suspension of 1 31 x g). After stirring for 45 minutes at 5°C, 2
Add mQ of toluene and remove volatiles under reduced pressure. The resulting oil was washed with hexane (4if2X3) and 10 mQ
Tritrate with ether to form a solid. The solid was washed once with Gothyl' (101C) and dried under reduced pressure. 16
6o [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-oxoethylidenecoamino]oxy]-2-methylpropion Repeat the reaction and work-up described above for the acid diphenyl methyl ester (mixture of monopotassium and monotriethylammonium salts).

The crude products were combined and 2 mQ of CH,CN/water (4
0/60, pH 2,5) and chromatographed using an acetonitrile/water gradient on an HP-20 resin column (200 m). The desired material is eluted with CH3CN/water (20/80). Related images Combine the minutes,
Freeze-dry and produce 103m9 of [3S(Z)Go2-[[[
1-(2-amino-4-thiazolyl)-2”[[l −
[[[[(1,4-dihydro-5-hydroxy-4-
Oxo2-pyrinyl)methylcoamino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinylcoamino]-2-oxoethylidene]amino]oxyco-2-methylpropionic acid is obtained as a white solid.

Example 5 [35(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[2-[[2-[(1
,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonylcohydrazinococarbonylcohydrazinocosulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene] Production of disodium salt of aminocooxy]-2-methylpropionic acid, - A) 1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid 2-[[(4-methoxyphenyl) 4.549 of carbonylcohydrazide 25FIQ in dry dimethylformamide
A solution of (0,022 mol) of dicyclohexylcarbodiimide in 25 mQ of dry dimethylformamide was prepared by
．． 90 g (0,020 mol) of 1,4-dihydro-4-
Oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid, 4.509 (0,022 mol) of 4-methoxybenzylcarbazate, 0.129 (l, 0 mmol)
of 4-dimethylaminopyridine and 0.1559(1
,0 mmol) of 1-hydroxybenzotriazole hydrate at room temperature and stirring continued overnight. The precipitate is filtered off and the filtrate is evaporated under reduced pressure. The residue was stirred with ether and aqueous sodium bicarbonate to solidify;
The solids are collected, washed with water and finally dried under vacuum. Group material (8
, 149) with 80011f2 CHC123 in a Soxhlet extractor (7 hours). This cold CHCf2
Directly from the 3 extract, 5.709 (67%) pure 1.4-
Dihydro 4-oxo-5-(phenylmethoxy)-2
-Pyridinecarboxylic acid 2-[[(4-methoxyphenyl)methquin]carbonyl]hydrazide was crystallized, and further mixed with jl(1,
5 g, 18%) of the title compound can be obtained. Melting point: 174.5-178°C.

B) 1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid hydrazide trifluoroacetate salt (1:2) 3.81 mC (35°04 mmol) in 38 mQ trifluoroacetic acid ) of anisole in 15 ml of dry dichloromethane was prepared as follows: 3.71y (8, furimmol) of 1,4-dihydro-4-oxo-5-(phenylmethoxy)-1-pyridinecarboxylic acid 2- [[(4-methquinphenyl)
Water cooling of methoxy]carbonyl]hydrazide! @Add to topical solution. After stirring for 20 minutes at 0°C, the solution is evaporated under reduced pressure to give the title compound as a solid, which is stirred with a few mQ of dry ether, collected under suction and dried under reduced pressure. Yield 3.259
(99%), melting point 173-175°C (decomposition).

C) 1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid hydrazide 3.199 (85
5 mmol) of 1,4-dihydro-4-oxo-5-(
phenylmethquine)-2-pyridinecarboxylic acid hydrazide trifluoroacetate salt (1:2) suspension,
3.84iQ (19.64 mmol) of N-methyl-N
-(Trimethylsilyl)trifluoroacetamide is added and stirring is continued for 30 minutes at room temperature. After evaporation under reduced pressure, the residue is dissolved in ether and then Lm (l of methanol is added dropwise). The precipitate is collected by suction, washed with ether and petroleum ether and dried under reduced pressure to give the title compound of 2.059C92%.

Melting point 204-208°C (decomposed).

D) 1.4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid 2-[[2-(phenylmethoxy)carbonyl]hydrazino]carbonyl]hydrazide 5. 199 (0゜0
@i! iB eL while cooling 11.69z (!
(0,060 mol) of N-methyl-N-trimethylsilyltrifluoroacetamide was added and stirring continued at room temperature for 30 min.
Continue for a minute. The clear solution is evaporated under reduced pressure and the residue is redissolved in 30 mQ of dry dichloromethane.

This solution was then diluted with 4.0 ml of dichloromethane at 60 πa.
57y (0,020 moJlz) (7) PhCHzOCN
HNHCOCI2 (J, Gangte's Chem, Ber,
97, 2551, 1964) in a stirred solution of
Add dropwise at 5°C. After stirring at this temperature for 2.5 hours, the solution was evaporated in vacuo and the solid foam was redissolved in 20 mL methanol. Evaporation in vacuo gave the title compound as a solid foam, which was dried Stir with ether to form crystals.

Yield 8.879 (98%), melting point > 120°C (decomposition).

E) 1,4-dihydro-5-hydroxy-4-oxo-
2-Pyridinecarboxylic acid 2-(hydrazinocarbonyl)hydrazide dihydrochloride 1.4 of 4.029 (8.9 mmol) in 50 mg of methanol with 2.94 ml (35.6 mmol) of concentrated hydrochloric acid -dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid 2-'[[2=(
A solution of phenylmethoxy)carbonyl]hydrazino]carbonyl]hydrazide was mixed with 0.49 palladium (10
%)/hydrogenate for 10 minutes in the presence of carbon. The catalyst was filtered off and the solvent was distilled off under reduced pressure to obtain the title compound as a solid (2,
589), stirred with several m (l) of dry ether, collected by suction and dried under reduced pressure. Yield 2.479 (92
%), melting point 235-236°C (decomposition).

FX3 S)-[1-[[[[2-[[2-[(1,4
-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonylcohydrazino]carbonyl]hydrazino]sulfonyl]amino]carbonyl]-2-oxo-
3-Azetidinyl]carbamic acid phenylmethyl ester in 20 tons of dry acetonitrile. ! In a suspension of M (5.0 mmol) of 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid 2-(hydrazinocarbonyl)hydrazide dihydrochloride, 4.861 (
25,0 mmol) of N-methyl-N-trimethylsilyltrifluoroacetamide are added. After stirring for 45 minutes at room temperature, the clear solution is evaporated under reduced pressure and the residue is dissolved in 20 m(!) of dry ethyl acetate (solution A).

40. To a suspension of 1.10 g (5.0 mmol) of (S')-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone in 1.40 kg of dry ethyl acetate was added 0.4 m of dry ethyl acetate under stirring. 45 uC (5,0 mmol) of chlorosulfonylisonoanaate are added and the mixture is stirred at room temperature for 1 hour and then cooled to 0°C. After addition of If) +σ of dry dichloromethane and 2.09 mC (15.0 mmol) of triethylamine, solution A is added dropwise with stirring at 0°C. After stirring overnight at 0°C, the reaction mixture is poured into ice water and the organic layer is separated. The aqueous phase is acidified to pH 2 by addition of IN-hydrochloric acid to give the title compound as a thick precipitate which is collected by suction, poured with 1 portion of water and dried under reduced pressure. Yield 1.7
6g (64%).

GX3S:)-3-Amino-N-[[2-[[2-[(
114-Novitro-5-hydroxy-4-oxo-2-
pyridinyl]sulfonyl]hydrano]carbonyl]hydrazino]sulfonyl 1-2-oxo-1-azetidine carboxamide trifluoroacetate salt (1:2) 5.13 mQ of trifluoroacetic acid and 1.2171 c
1.7.1 (3,
(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. After stirring overnight at room temperature, the solution is evaporated under reduced pressure and the residue is stirred with dry dichloromethane. The precipitate is collected by suction, washed with dichloromethane, and dried under vacuum to yield 1.789 (88%) of the title compound.

H) [3S(Z)]-2-[[[1-(2-amino-4
-thiazolyl 1-2-[[1-[[[[2-[[1-[
(1.

4-dihydro-5-hydroquine-4-oxo-2-pyridinyl)carbonyl]hydrazino]carbonyl]hydrazino]sulfonyl]amino]carbonyl]-2-axo3-azetidinyl]amino]-2-oxoethylidene]amino]oxy ]-2-Methylpropionic acid diphenylmethyl ester 221 (1.10 g (2,5 mmol) of (Z)-2-amino-α-[(2-diphenylmethoxy)-1,1 in dry dimethylformamide of Q) -To a 30° C. solution of -dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid is added 1.051 (7.5 mmol) of triethylamine followed by 0.53 mg (2.5 mmol) of diphenylchlorophosphate. .

After stirring for 1 hour at -30°C, 1.05JI112 (7,
After dropping 1.6 mmol of triethylamine
29 (2.5 mmol) of (3S)-3-amino-N-
[[2-[[2-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl]carbonyl]hydrazino]carbonylcohydrazino]sulfonyl]-2-oxo-1-azetidinecarboxamide. Add trifluoroacetate salt (1:2). Mixture = 2 at 10°C.
Stir for an additional 1 hour at 0°C.

The solvent is removed under reduced pressure and the residue is dissolved in several mQ of ethyl acetate and ice water. Adjust the pH of the mixture to 2 by adding dilute hydrochloric acid. The insoluble materials were collected by suction, stirred with several mQ of ethyl acetate until crystallization, and dried under reduced pressure to yield 1.72y (8
2%) of the title compound is obtained.

I ) [3S (Z) nee 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-oxoethylidenecoamino]oxy]-2-methylpropionic acid disodium salt 1.68y (2.0 mmol) of crude [35( Z)]-2-[L[1-(2-amino-4-thiazolyl)-2-[[1-[[[[2-[
[2-[(1,4-dihydro-5-hydroquine-4-xo-2-pyridinyl)carbonyl]hydrazino]carbonyl]hydrazino]sulfonyl]aminococarbonyl]-2-oxo-3-azetidinyl]amino]-2 -oxoethylidenecoamino]oxo]-2-methylpropionic acid diphenylmethyl ester suspension, 2
After adding OmQ of anisole, 20 mQ of trifluoroacetic acid is added at -1O<0>C. After stirring for 10 minutes at 0°C, the solvent is removed under reduced pressure at 0-5°C. The residue was dissolved in ice water and ether and diluted with dilute sodium hydroxide (1%).
Adjust to H6, 0.

The organic phase and insoluble material (0,389) are separated and the aqueous phase is lyophilized (2.6 fNJ). XAD of freeze-drying residue
Purified with -2 resin* (eluted with water) and lyophilized to 0.
25y (17%) of the title compound is obtained as a colorless powder. Melting point>213°C (decomposed).

Note *) XAD-2 resin: macroreticular styrene-divinylbenzene Example 6 [3S -[3α(Z), 4β]]-2-[[[1-(
2-amino-4-thiazolyl)-2-[[1-[[[
2=[(l,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]hydrazino]sulbonyl]amino]carbonyl]-4-methyl-2-axo3-azetidinyl1aminoco-2-oxo Preparation of disodium salt of ethylidene]amino]oxy]-2-methylpropionate A) (3S-trans)-[1-[[[[2-4[1
,4=dihydro-4-oxo-5-hydroxy-2-pyridinyl]carbonyl]hydrazino]sulfonyl]amino]carbonyl]-4-methyl-2-oxo-3-azetidinyl]carbamic acid phenylmethyl ester 50H in dry ethyl acetate To the suspension solution of 2.349 (3S-trans)-(4-methyl-2-oxo-3-azetidinyl)carbamic acid phenylmethyl ester, 1
．． Add 419 chlorosulfonyl isocyanate.

After stirring for 1 hour at room temperature, a clear solution forms (solution A).

To a suspension of 1.709 of 1,4-dihydro-5-hydroquine-4-oxo-2-pyridinecarboxylic acid hydrazide in 50 mQ of dry ethyl acetate was added 6 N-methyl-N
-(Trimethylnoryl)trifluoroacetamide is added. After stirring for 1 hour at 50° C., a clear solution forms (solution B).

Solution B is added to solution A after cooling to -10°C and the mixture is stirred at room temperature overnight. After cooling to -15°C and adding 3 parts of triethylamine, add 150z(l of ice water).
After stirring for 1 hour at .degree. C., the organic phase is washed with 50.pi.Q water. The combined aqueous phases were adjusted to I)H2 with IN-Hce, and 1
Extract three times with ethyl acetate at 0 (lo2). The combined organic phase is dried and the solvent is evaporated to give the title compound 3.649.

B) (3S-trans)-3-amino-N-[[2-[
(1,4-dihydro-5-hydroxy-4-oxo-2
-pyridinyl)carbonyl]hydrazino]sulfonylco-4-methyl-2-oxo-1-azetidinecarboxamide trifluoroacetate salt (1.2) 2011Q in thioanisole (1) 3.59 (DC3
5- trans 2-year-old xo-3-azetidinyl]
50πQ trifluoroacetic acid is added to the carbamic acid phenylmethyl ester at room temperature, and the reaction is then stirred for 13 hours. After adding 100o2 ether, 3.2g
Obtain the original precipitate. This precipitate was stirred for 1 hour in 50πQ isopropanol/methylene chloride (1:1).2.
The title compound 219 is 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]sulfonylcoaminocorponyl]-4-methyl-2-oxo-3-azetidinylcoaminocor (Z) of 1.89 in dimethylformamide of 30*Q
-2-amino-α-[[(2-diphenylmethoxy)-
1,1-dimethyl-2-oxoethoxykoimino]-4
- To a solution of thiazole acetic acid and 100 g of triethylamine at -30° C. add 2.19 g of diphenylchlorophosphate. After stirring for 45 min at -30°C, 1.959 (3S-trans)-3-amino-N-[C2-[(1,4-dihydro-5-hydroxy-4-oxo- 2-pyridinyl)carbonyl]hydrazinocosulfonyl]-4-methyl-2-
Add 1-azetidine carboxamide trifluoroacetate salt (1:2) followed by 0.89 triethylamine. After stirring for 2 hours at −10° C. and 1 hour at 0° C., the dimethylformamide is removed under reduced pressure and the residue is stirred with 250 μQ of ethyl acetate and 400 μm of ice water. The aqueous phase is adjusted to pH 1.5 with 2N-1 (C12) and extracted twice with 20 Off C portions of ethyl acetate. The organic phase is dried over sodium sulfate and evaporated to give 1.39 of the crude title compound.

D) [3S −[3α(Z), 4β]]−2−[[[1
-(2-amino-4-thiazolyl)-2-[[1-[[
[[2-[(1,4-dihydro-5-hydroxy-4-
oxo-2-pyrinyl)carbonyl]hydrazinocosulfonyl]amino]carbonyl]-4-methyl-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]okushroom-2-methylpropionic acid disodium salt 1.29 [3S-[3α(Z),4β] in a mixture of LOmQ methylene chloride and 15ml anisole
]co-2-[[[1-(2-amino-4-thiazolyl)
=2-[[1-[[[[2-[(1,4-dihydro-5
-human, uxi4-oxo-2-pyridinyl)carbonyl]hydrazino]sulfonyl]amino]carbonyl]
-4-methyl-2-oxo-3-azetidinyl]amino]-2-xoethylidenecoaminocooxy]-2-methylpropionic acid diphenylmethyl ester solution,
Add 30ml (l) of trifluoroacetic acid at -5°C.
After stirring for 1 minute, 100 mN of ether is added to obtain 0.8 g of precipitate. This precipitate is suspended in 20ml of water and adjusted to 86.5% with sodium bicarbonate. The clear solution is then chromatographed on XAD-2 with water as eluent to give 0.289 pure title compound.

Example 7 [35(Z)]-1-[[[1-(2-amino-4-thiazolyl)-2-II[1-[[[[3-[[(1,4
-dihydro5-hydroxy-4-oxo-2-pyridinyl)carbonyl]aminoco2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-
Preparation of oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]cyclopentanecarboxylic acid disodium salt A) [3S (Z)
[[1-(2-amino-4-thiazolyl)-2-[[1
-[[[3-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1=imidazolidinylcosulfonyl]
aminococarbonyl]-2-oxo-3-azetidinylcoamino]-2-oxoethylidenecoaminocooxy]
Cyclopentanecarboxylic acid diphenylmethyl ester 1
00i (3.99 (8°3) in dry acetonitrile of 7
3.5 mmol) of (Z)-2-amino-α-[[[1-(diphenylmethoxy)carbonyl]cyclopentylcoxy]iminoco-4-thiazoleacetic acid.
Add uQ (25 mmol) of triethylamine to form a clear solution. After cooling to -30°C, ■.

8 m&(8.3 mmol) of phenylchlorophosphate are added and the mixture is stirred at -30° C. for 1 hour (solution A).

On the other hand, at the same time, 4.5? (8,3 mmol) of (3S)
-3-amino-N-[[3-[[(1,4-dihydro-
5-hydroxy-4-oxo-2-pyridinyl)carbonyl]aminoco-2-oxo-1-imidazolidinyl]
sulfonyl]-2-oxo-1-azetidine carboxamide trifluoroacetate salt (1:2) at 1001
Add to dry ethyl acetate.

Then 7.2 tn (l) of bis(trimethylsilyl)acetamide are added at room temperature to obtain a clear solution after 5 minutes.

After stirring for 1 hour, the solution is cooled to 0° C. (Solution B).

Solution B is added dropwise to solution A over 10 minutes at −30° C. under stirring. The mixture is stirred at -10° C. for 1 hour and at 0° C. for 1.5 hours. Evaporate the volatiles and triturate the residue with water. The residue is allowed to solidify and the solid is collected and resuspended in water at approximately pH 2. After stirring for 30 minutes, the solid was collected and dried for 12 minutes.
．． The crude title compound 09 is obtained.

B) [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-oxoethylidenecoamino]oxy]cyclopencunecarboxylic acid disodium salt [3S(Z)nee1-[[[1-(2-amino-4-
Thiazolyl)-2-[[+-[[[[3-[[(1,4
-dihydro-5-hydroxy-4-oxo-2-bilinonyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]aminococarbonyl"-2-
Oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxycocyclopencune carboxylic acid diphenylmethyl ester (129) was suspended in 20 molar anisole, cooled to -10°C, and 100 Add acetic acid.

The mixture was stirred at -10°C for 1 hour, and 300% of ether was added at -10°C to obtain a precipitate. After stirring for 1 hour, filter off the precipitate to obtain 5.79 material.

This material was dissolved in a mixture of 30 mQ of water and 60 rttQ of acetone and 0.1N Na
Adjust the l)H of the solution to 5.5 by adding OH.

Acetone was evaporated under reduced pressure, and the aqueous solution was lyophilized to 5°79
A solid residue is obtained. This residue was chromatographed (eluted with water) on P-20 (1699 (27%)).
The pure title compound is obtained.

'H-NMR (DMSO-d6+CF3CO0H)・δ
1.67 (s, 4H), 2.07 (2, 4H), 3.6
5(t, 2H), 3.75(dd, lH), 3.9
7 (dd, I H), 4.07 (t, 2H), 5.
07(dd, II-(), 7.00(s.

IH), 7.67 (s, IH), 8, 07 (s,
I H) ppm Example 8 [35(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[3=[(1,4-dihydro -5-hydroxy-4-oxo-2-pyrinonyl)methyl]-2-oxo1-imidazolidinyl]sulfonylcoamino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]
Preparation of disodium salt of oxo]-2-methylpropionate A) 2-(azidomethyl)-5-(phenylmethoxy)
-1-(phenylmethyl)-4(IH)-Viridinone 2.09 (6 mmol) of 2-(chloromethyl)-5-(phenylmethquine)-1 in 20 ml of acetonitrile
To the suspension of -(phenylmethyl)-4(IH)-viridinone, 3.99 (60 mmol) of sodium azide and 18-crown-6 of 08I9 are added and the mixture is heated to reflux for 4 hours. . Remove the salt by suction filtration,
The filtrate is evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/methanol = 8+2) to give a concentration of 1.861? The title compound is obtained. Melting point 120
℃.

B) 2-(aminomethyl)-5-(phenylmethquine)
-1-(phenylmethyl)-4(IH)-pyridinone 2-(azidomethyl)-5-(phenylmethoxy)-1
-(phenylmethyl)-4(IH)-viridinone (1,
09,2,89 mmol) is dissolved in 50*(2) of methanol and Q, 1O!7 of platinum oxide is added.

Hydrogen was bubbled into the mixture for 30 minutes, and Hyflo
) and filter off the catalyst with suction. The filtrate is evaporated under reduced pressure and the oily residue is triturated with ether to give the crystalline title compound (o,s9g). Melting point: 207°C.

C) 2-[[[[(2-chloroethyl)amino]carbonyl]amino]methyl]-5-(phenylmethoxy)-
2-(phenylmethyl)-4(IH)-viridinone 1.
48.09 (0,t 5 mol) in 5f2 ethyl acetate
2-(aminomethyl)-5-(phenylmethoxy)-
12.8 m (0.15 mol) of 2-chloroethyl isocyanate are added to the suspension of 1-(phenylmethyl)-4(IH)-pyridinone. The mixture is stirred at room temperature overnight and the product is filtered off with suction, washed with ethyl acetate and dried under reduced pressure to give 59.69 of the title compound. Melting point: 130°C.

D) 2-[(2-oxo-1-imidazolidinyl)methyl]-5-(phenylmethoxy')-1-(phenylmethyl)-4(IH)-pyridinone 7.299(0,13 A solution of 60.89 (0.13 mol) of potassium hydroxide is dissolved in a solution of 60.89 (0.13 mol) of 2- -(phenylmethyl)-4(IH)-pyridinone and 1.312 ethanol dropwise. The reaction mixture is heated to reflux for 3 hours and the solvent is evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate/methanol (7:3) as an eluent to obtain the product 23.19, which was further purified by recrystallization from acetonitrile. 17.0y
The title compound is obtained.

Melting point: 190°C (decomposed).

E) 5-hydroxy-2-[(2-oxo-!-imidazolidinyl)methyl]-4(IH)-viridinone p-
2-[(2-oxo-1-imidazolidinyl)methyl]-5-(phenylmethquin)-1-(phenylmethyl)-4(IH)- in toluenesulfonate salt dimethylformamide (90πQ)
To a solution of pyridinone (4,989,12,8 mmol) was added p-toluenesulfonic acid monohydrate (4°869.2
5.6 mmol) and palladium/activated carbon (1.0 g
) and bubble hydrogen through the mixture for 30 minutes. The catalyst is filtered off with suction and the filtrate is evaporated under reduced pressure.

The residue is triturated with dichloromethane and ether and the product is filtered off with suction to give 4.129 of the title compound. Melting point: 195°C.

F) 5-Hydroxy-2-[(2-oxo-1=imidazolidinyl)methyl]-4(IH)-Viridinone 5-hydroxy-2-[(2-oxo-1-imidazolidinyl)methyl]-4(IH) -Viridinone p-toluenesulfonate salt (4,09,1O55 mmol) is dissolved in water (50,w&) and adjusted to pH 6,5 by adding 2N-sodium hydroxide. The precipitate is filtered off with suction, washed with water and dried under reduced pressure to obtain 1.5 g of the title compound. Melting point: 280°C (decomposed).

GXS)-[1-[[[[3-[(1,4-dihydro-
5-Hydroxy-4-oxo-2-pyridinyl)methylco-2-oxo-1-imidazolidinylcosulfonyl]
Aminococarbonylco-2-oxo-3-azetinonyl]carbamic acid phenylmethyl ester 1.109 (5 mmol) of (S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone was dried in 20 mQ. Suspend in ethyl acetate and add 0.44sQ (
5 mmol) of chlorosulfonyl isocyanate are added. The mixture is stirred for 1 hour at room temperature (solution a).

On the other hand, IOm(! of 1.049(5) in dry ethyl acetate
mmol) of 5-hydroxy-2-[(2-oxo-1
-imidazolidinyl)methyl]-4(IH)-pyridinone, 3.70 mQ (20 mmol) of N-methyl-N-()limethylsilyl)trifluoroacetamide are added and the mixture is heated to 60<0>C. The resulting clear solution is evaporated under reduced pressure at 60° C. and the residue is dissolved in 10 mQ of dry ethyl acetate (solution b). Solution (b) is added to solution (a) and the reaction mixture is stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was triturated with ether to give 2.91
The title compound 9 is obtained. Melting point: 180°C (decomposed).

HXS)-3-Amino-N-[['3-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)methyl]-2-oxo1-imidazolidinyl]sulfonyl]-2-oxo -1-azetinone carboxamide trifluoroacetate salt (S) -[1-4[[[3
-ECI, 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)methyl]-2-oxo1-imidazolidinylcosulfonyl]amino]carbonylco2
-oxo-3-azetidinyl]carbamic acid phenylmethyl ester (0.50 g, 0.93 mmol)
．． Add to a mixture of 5 parts thioanisole and 2 mQ trifluoroacetic acid. The solution was stirred at room temperature overnight and evaporated under reduced pressure. The residue is triturated with ether, filtered off with suction and dried under reduced pressure to give 0.499 of the title compound. Melting point: 155°C.

I ) [35(Z)]-2-[[[1-(2-amino-
4-thiazolyl)-2-[['l-[[[[3-[(1
,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)methylio2-oxo-1-imidazolidinylcosulfonyl]aminococarbonyl]-2=oxo-
3-Azetidinyl] aminoco-2-oxoethylidene]
Amino]oxy]-2-methylpropionic acid diphenylmethyl ester of (Z)-2-amino-α-:[2-(
diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid,
0.39. Add zσ (2.8 mmol) of triethylamine. The mixture was cooled to -30°C and heated to 0°19m (2
(0.93 mmol) of diphenylchlorophosphate are added dropwise. The reaction mixture was stirred at -30°C for 1 hour (
Solution a).

On the other hand, (S)-3-amino-N-[[3-[(1,4=
dihydro-5-hydroxy-4-oxo-2-pyridinyl)methyl]-2-oxo1-imidazolidinylsulfonyl]-2-oxo1-azetidine carboxamide trifluoroacetate salt (0,489,0,93
mmol) in 20 tQ of dry acetonitrile,
0.78 ml (3.2 mmol) of bis-trimethylsilylacetamide are added. Stir the suspension for 30 minutes at room temperature and add it to solution (a).

The reaction mixture is stirred at -10°C for 1 hour and at 0°C for 1.5 hours. The resulting clear solution was evaporated under reduced pressure to an oily residue.
Add water at 0xC. Add 2N-hydrochloric acid to the mixture to adjust the pH.
2, and from the solution [3S(Z)]-2-[[[1
-(2-amino-4-thiazolyl)-'2-[[1-[
[[[3-[(1,4-dihydro-5-hydroxy-4
-oxo-2-pyridinyl)methyl]-2-oxo 1
-imidabridinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-medylpropionic acid nonodium salt is crystallized. The product is filtered off with suction, washed with water and dried under reduced pressure to give 0.79 of the title compound.

J) [3S(Z)co2-[[[1-(2-amino-4
-thiazolyl)-2~[[l -[[[[3-[(1,
4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)methylio2-oxo-1-imidazolidinylcosulfonylcoamino]carbonyl]-2-oxo-3
-azetidinyl]aminoco2-oxo-ethylidenecoamino]oxy]-2-methylpropionic acid disodium salt [3S (Z)]-2-[[[1-(2-amino-4-
Thiazolyl)-2-[[1-[[[[3-[(1,4-
dihydro-5-hydroxy-4-oxo-2-pyridinyl)methyl]-2-oxo! -imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinylcoamino]-2-oxoethylidene]aminocooxy]-2-methylpropionic acid diphenylmethyl ester (0,79,0,85 mmol) .4if
f in anisole and cooled to -10°C. Trifluoroacetic acid is added and the solution is stirred at -10°C for 1 hour.

Ether (100 ml) is added and the precipitate is filtered off with suction, washed with ether and dried under reduced pressure.

Dissolve this trifluoroacetate in a mixture of methanol and water and add 2N-sodium hydroxide to p) (6,
Adjust to 5. The methanol is removed in vacuo and the aqueous solution is lyophilized to yield 0.59 of the title compound. MPLC
Refine with. Melting point 2506C (decomposed).

Example 9 [3S(Z)nee 2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[4-[(1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl)methyl]-2.3-dioxo1-piperazinyl]sulfonyl]aminococarbonyl]-2-oxo-3-azetidinylcoamino]-2-oxoethylidene]amino]oxyco-2- Preparation of methylpropionate disodium salt A) 2-(chloromethyl)-5-(phenylmethoxy)
-1-(phenylmethyl)-4(IH)-viridinone
3.21 g (10 mmol) of hydrochloride 20 g in chloroform
A suspension of 2-(hydroxymethyl)-5-(phenylmethoxy)-1-(phenylmethyl)-4(I H)-pyridinone was cooled to 0 °C and 4.65+Q (64 mmol) was chlorinated. Add thionyl dropwise. 1 of the mixture at 0°C.
Stir for 0 minutes, then heat to reflux for 1 hour. The solvent was evaporated under reduced pressure and the residue was washed with petroleum ether and dried under reduced pressure.
69 of the title compound is obtained.

Melting point: 85°C (decomposed).

B) 2-(chloromethyl)-5-C phenylmethokino)
-1-(phenylmethyl)-4(IH)-viridinone 2-(chloromethyl)-5-(phenylmethoxy)-1
-(Phenylmethyl)-4(IH)-pyridinone hydrochloride (3,59,9,3 mmol) is dissolved in the water/ethyl acetate mixture and the layers are separated. Wash the organic phase twice with water,
Dry over magnesium sulfate and evaporate under reduced pressure. The residue is triturated with petroleum ether, filtered off with suction and dried under reduced pressure to give 2.27 g of the title compound. Melting point 115-12
0°C (decomposition).

C) N-()liphenylmethyl)piperazine-2゜3-
dione 2,3-piperazinedione (11,49,100 mmol), bistrimethylsilylacetamide (55,7 g
, 270 mmol) and 150 x c acetonitrile is heated under reflux for 1 hour.

Triphenylmethyl chloride (22゜2g) within 30 minutes
, 80 mmol) are added dropwise and the mixture is refluxed again for 2 hours. After stirring overnight at room temperature, 21°61112 of water is added to the clear solution. The resulting precipitate was filtered off (3.13 g),
Concentrate the filtrate under reduced pressure. The residue is triturated with water and dried to give 25.59 of the crude title compound, which is recrystallized from ethanol. Yield of pure product 12.199, melting point 230-235°C.

D) l -[[1,4-dihydro-4-oxo-5-(
phenylmethoxy)-1-(phenylmethyl)-2-pyridinylcomethyl]-4-()liphenylmethyl)-2
,3-piperazinedione N-()liphenylmethyl)piperazine-2,3-dione (4,19
0.359 (11
, 77 mmol) of sodium hydride (80% oil)
Add. After the evolution of hydrogen had ceased, the thick suspension was dissolved in 2-(chloromethyl)-5-(phenylmethoxy)-1-(phenylmethyl)-4(IH)-pyridinone ( 4.0g, 11
．． 77 mmol) to give a clear solution. After stirring for 1 hour at room temperature, precipitation begins. After 2 hours, the crystals are collected by filtration, washed and dried under reduced pressure to obtain the title compound 5.139. Melting point 165-168°C.

E) 1-[[1,4-dihydro-4-xo-5-(phenylmethoxy)-1-(phenylmethyl)-2-pyridinyl]methyl]-2,3-piperazinedione 65H in dichloromethane [[1,4-dihydro-4-oxo-5-(phenylmethoxy)-1-(phenylmethyl)-2-pyridinylcomethylco-4-(triphenylmethyl)-2,3-piperazinedione (8 ,7
7y, 13.23 mmol) at room temperature.
Add formic acid (2) dropwise. After stirring for 3 days, volatiles were removed under reduced pressure and the residue was triturated twice with ether to give 5.2
49 of 1-[[1,4-dihydro-4-oxo-5-(
phenylmethoxy)-1-(phenylmethyl)-2-pyridinyl]methyl]-2,3-biperanonedione is obtained. Melting point 260-265°C.

FXS)-[1-[[[[4-[[1,4-dihydro-
4-oxo-5-(phenylmethoxy)-1-(phenylmethyl)-2-pyridinylcomethyl]-2,3-dioxo-1-piperazinylJsulfonylcoaminococarbonyl]-2-oxo-3-azetidinyl ] Carbamic acid phenyl methyl ester 25 iC of (S)-3-[[(phenylmethoxy)carbonylcoaminoco-2-azetidinone (0,449,2,0 mmol) in a solution of 0.28
g (2.0 mmol) of chlorosulfonyl isocyanate are added and the solution is stirred for 30 minutes at room temperature. 12z for this
1-[[[1,4-dihydro-4-oxo-5-(phenylmethoxy)-1(phenylmethyl) )-2-pyridinyl]methyl]-2,3-piperazinedione (0,83
9,2,0 mmol) and N-methyl-N-(trimethylsilyl)trifluoroacetamide (Summer, 599.
8.0 mmol) (previously stirred for 3 hours). After stirring at room temperature for 3 days, ice water is added and the pH is adjusted to 1 with hydrochloric acid.

The insoluble residue is filtered and dried under reduced pressure to obtain 1.15 g of the title compound (72% purity).

GXS)-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-methylbenzenesulfonate (S)-[1-[
[[[4-[[1,4-dihydro-4-xo-5-(
phenylmethoxy)-1=(phenylmethyl)-2-pyridinyl]methyl]-2,3-dioxo-1-piperazinyl]sulfonyl]amino]carbonylco-2-oxo-3-azetidinylcorubamate phenylmethyl ester (0 , 989, 1,32 mmol).
! M (2,64 mmol) of p-toluenesulfonic acid and 0.5 g of palladium/activated carbon (10%) are added. Bubble the mixture with hydrogen for 1 hour. The catalyst is filtered off, the solvent is removed under reduced pressure and the residue is triturated with dichloromethane to give the title compound 0829 after drying. melting point 16
0-185°C (decomposition).

H) [3S(Z)]-2-[[[1-(2-amino-4
-thiazolyl)-2-[[1-4[[[4-[(1,4
-dihydro-5-human axy4-oxo-2-pyridinyl)methyl]-2,3-dioxo1-piperazinyl]sulfonyl]aminococarbonyl]-2-oxo-3
-azetidinyl]amino]-2-oxoethylidenecoamino]oxy]-2-methylpropionic acid diphenylmethyl ester (Z)-2-amino-α-[C2(diphenylmethoxy)-1°1 in 30 mg of dimethylformamide -dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid (0.57 g, 1.3 mmol) in a solution of -30
Triethylamine (0.39 g, 3.9 mmol) at °C
and triphenylchlorophosphate (0,3+9.
1.3 mmol) is added. After stirring for 1 hour, triethylamine (0.39 g, 3.9 mmol) and (S)-
3-Amino-N-[[4-[(1,4-dihydro-5-
hydroxy-4-oxo-2-pyridinyl)methyl]-
2,3-dioxo-1-piperazinyl]sulfonyl]-
Add 2-oxo-l-azetidine lupoxamide 4-methylbenzenesulfonate (0.98 g, 1.3 mmol). The mixture was heated at -10°C for 2 hours and at 0°C for 1.5 hours.
Stir for an hour. Water and ethyl acetate are added, and the pH is adjusted to 1 with 3N hydrochloric acid. The precipitate was collected by filtration and washed with ethyl acetate.
Drying under reduced pressure yields 0.869 of the title compound. Melting point 13
0-190°C (decomposition).

[)[3S(Z)]-2-[[[1-(2-amino-4
-thiazolyl)-2-[[1-[[[[4-[(1,4
-dihydro-5-hydroxy-4-oxo-2-pyridinyl)methyl]-2,3-dioxo -piperazinyl]sulfonyl]amino]carbonyl]-2-oxo-3
-azetidinylcoamino]-2-oxoethylidenecoamino]oxy]-2-methylpropionic acid disodium salt 1.4πQ of [35(Z)]-2-E[
[1-(2-amino-4-thiazolyl)-2-[[1
-C[[[4-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)methyl]-2,3-dioxo=■-piperazinyl]sulfonyl]amino]carbonylco2-oxo- 3-Azetidinylcoaminony2-oxoethylidene]amino]oxyco-2-methylpropionic acid diphenylmethyl ester (0.8 g, 0
．． To a suspension of 94 mmol), 7 ml of trifluoroacetic acid are added at =10°C. After stirring for 1 hour, 30 liters of ether was added, and the resulting precipitate was collected by filtration and dried under reduced pressure. This trifluoroacetate is suspended in water and adjusted to pH 6.5 with 2N sodium hydroxide. The solution was lyophilized to 0
．． A crude product of 669 was obtained, which was combined with a second sample prepared in a similar manner (total 1.559) and subjected to MPL with macroreticular styrene-divinylbenzene copolymer.
Chromatography under C conditions yields 0.349 of the title compound. A second column chromatography on the macroreticular styrene-divinylbenzene copolymer yields 0.18 g of the title compound. Melting point 242-270
℃.

Example IO [3S(Z)nee 2-[[[1-(2-amino-4-thiazolyl)-2-[[1-
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 disodium salt preparation A) 4.5-bis(phenylmethoxy)-2-pyridinecarboxylic acid phenylmethyl ester 29.49 (120 mmol) of 0 in 350 mQ of dimethylformamide
- 21.59 (15
Add 6 mmol of potassium carbonate and stir at room temperature for 1 hour. Benzylbromide (31 mg, 264 mmol)
is added and the mixture is heated under stirring to 100° C. for 25 hours.

After cooling to room temperature, the dimethylformamide is distilled off under reduced pressure and the residue is triturated with ethyl acetate with slight heating to 60°C. 409 inorganic salts were removed by filtration, and the filtrate was approximately 751
Chromatography on silica gel using ethyl acetate/petroleum ether (90:10) as eluent gives 35.59 of the title compound. Melting point 116.
7℃.

B) 4.5-bis(phenylmethoxy)-2-pyridinemethanol 1.069 (25 mmol) of 95+y (25 mmol) of lithium aluminum hydride in suspension in 10 ml of ether and 10 ml of tetrahydrofuran 4.5-bis(phenylmethoxy)-2-pyridinecarboxylic acid phenylmethyl ester was added at 0°C in three portions. After stirring for 20 minutes at 0° C., 0.2 mQ of saturated sodium bicarbonate solution, 0.2 mg of 10% potassium hydroxide solution and more saturated sodium bicarbonate solution are added until the inorganic precipitate coagulates. The clear organic phase is decanted and evaporated under reduced pressure to give an oil which is slowly drained. 0.6g, melting point 966℃.

C) 4,5-bis(phenylmethoxy)-2-pyridinecarboxaldehyde 15 mC A solution of 0.549 (1,7 mmol) of 4,5-bis(phenylmethoxy)-2-pyridine in methanol in acetone; 1.5 mg (17 mmol) of manganese dioxide are added and the mixture is stirred at room temperature overnight. The mixture is then filtered on a silica gel column (70-250 Metz) and the aldehyde is eluted with acetone. The eluate is evaporated and the residue is triturated with petroleum ether to give 0.39 of the title compound. Melting point: 104.3°C.

D) 1,4-dihydro-5-hydroxy-4-oxo-
2-Pyridinecarboxaldehyde 4,5-bis(phenylmethoxy)-2-pyridinecarboxaldehyde (1,99,6
, 0 mmol) is added with 0.2 g of palladium/activated carbon catalyst and the mixture is bubbled with hydrogen for 3 hours. The catalyst is filtered off, the solvent is removed under reduced pressure and the residue is triturated with ether to give 0.649 of the title compound. Melting point 174
~177°C (decomposed).

E) [35(Z)]-2-[[[1-(2-amino-4
-thiazolyl)-2-[[1-[[[[3-[[(1,
4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)methylene]aminocor2=oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-
[3S (Z)
]-2-[[[2-[[1-[[[(3-amino-2-
1-imidazolidinyl)sulfonyl]amino]
Carbonylco-2-oxo-3-azetidinyl]aminoco-■-(2-amino-4-thiacylyl)-2-oxoethylidenecoaminocooxyco-2-propionic acid monosodium salt (0.64 g, 1.-1 mmol ), 1,4-dihydro-5-hydroxy-4-oxo-
2-Pyridinecarboxaldehyde (o, ts9.1.
3 mmol) was added, and after stirring for 4.5 hours, an additional 0.029
(0.14 mmol) of 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxaldehyde are added. After stirring overnight at room temperature, the solvent is evaporated under reduced pressure, the residue is dissolved in 30 m(l) of water, filtered, and the solution is lyophilized. Chromatography was performed on a styrene-divinylbenzene copolymer resin using water as an eluent.
．． 229 pure product is obtained. Melting point: 248°C (decomposed).

Example II C3S(Z)nee 2-[:[[I-(2-amino-4-
Thiazolyl)-2-[[1-[[[[4-[[(1,4
-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonylkoamino]-'2,3-dioxo-1
-piperazinylcosulfonyl]amino]carbonyl]-
Preparation of 2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropionic acid disodium salt A) 4.5-bis(phenylmethoxy)-2-pyridinecarboxylic acid tetrahydrofuran A solution of 11.1 (28 mmol) of 4,5-bis(phenylmethoxy)-2-pyridinecarboxylic acid phenylmethyl ester in 115 ml of water
Add 35 m of IN potassium hydroxide and 35 m of IN potassium hydroxide. After stirring overnight at room temperature, add 15 m of water and adjust the pH to 2.5 with IN hydrochloric acid. Filter this acidic solution, wash with water and dry under reduced pressure. 8.6 of the title compound with a melting point of 203°6°C.
I got a 9.

B) N-(2,3-dioxo-1-piperazinyl)-4
, 5-bis(phenylmethoxy)-2-pyridinecarboxamide 4° 5-bis(phenylmethoxy)-2-pyridinecarboxylic acid (7
, 19,21,17 mmol), hydroxybenzotriazole (0,29 g, 2.12 mmol) and N-
Aminopiperazine-2,3-dione (2,73g, 21
．． After stirring the suspension of 17 mmol) for 15 minutes, 4.809 (23.3 mmol) of dicyclohexylcarbodiimide are added. After stirring at room temperature for 21 hours, dicyclohexylurea (4,.

9) is filtered off and the solvent is evaporated under reduced pressure. solid residue 2
Trituration with 401 of tetrahydrofuran for 40 minutes, filtering, washing with tetrahydrofuran and drying under vacuum gives the title compound 7.769, mp 231.1°C.

C)(S)-[1-[[[[4-[[[4,5-bis(phenylmethoxy)-2-pyridinyl]carbonylkoamino]-2,3-dioxo-1-piperazinyl]sulfonyl]amino ]carbonyl]-2-oxo-3-azetidinyl]carbamic acid phenylmethyl ester (S)-3-[[(phenylmethoxy)carbonylcoaminocoke-azetidinone (2,02 g, 9.18 mmol) in ethyl acetate 1301112 Chlorosulfonyl isocyanate (1.43 g, 10 mmol) was added to the suspension, and after stirring for 1 hour, triethylamine (2
, 799, 27, 54 mmol). To this mixture was added 150 ml of ethyl acetate, stirred (1.5 hours).
(in N-(2,3-dioxo-1-piperazinyl)-
A solution of 4,5-bis(phenylmethoxy)-2-pyridinecarboxamide (4.10 g, 9.18 mmol) and N-methyl-N-(trimethylsilyl)trifluoroacetamide (5.49, 27.54 mmol) was prepared. Add. After stirring overnight at room temperature, ice water 22011Q is added and the pH is adjusted to 2 (from pH 10.3) with 3N hydrochloric acid. The organic phase was separated and treated with brine and the precipitated title compound was filtered, washed with water and dried under vacuum to yield 5.359. Combine 2.59 of this substance with 25R12 of water and 37.5j112 of acetone.
Triturate for 1 hour at pH 6.3 with a mixture of
．． 12 g of the title compound were obtained.

D)(S)-N-[4-[:[[(3-amino-2-oxo-1-azetidinyl)carbonylcoamino]sulfonyl]-2,3-dioxo-1-piperazinyl]-1,
(S)-[1-[[
[[4-[[[4,5-bis(phenylmethoxy)-2
-pyridinyl]carbonylcoamino]-2,3-dioxo-1-piperazinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid phenylmethyl ester (1,54 g, 2 mmol) @
0.779 palladium on carbon is added to the suspension and the mixture is then hydrogenated for 45 minutes.

The catalyst was removed by filtration through Hyflo, and the resulting solution was used in the next step without identifying the title compound.

E) [35(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
-biperazinylcosulfonyl]aminococarbonyl]-
2-oxo-3-azetidinylcoamino]-2-oxoethylidene]amino]oxy]-2-methylpropionic acid diphenylmethyl ester dimethylformamide 20
(Z)-2-Amino-α-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid (0.88 g, 2.0
Triethylamine (0,609 mmol) was added to a suspension of triethylamine (0,609,
Then triphenylchlorophosphate (0.54 g, 2.0
mmol). After stirring for 1 hour at -30°C, triethylamine (0,209,2 mmol) and (S)-
N -[4-[[[(3-amino-2-oxo-1-azetidinyl)carbonyl]amino]sulfonyl]-2゜3-dioxo-1-piperazinyl]-1,4-dihydro-5-hydroxy-4 - A solution of oxo-2-pyridinecarboxamide in dimethylformamide is added dropwise. The mixture was stirred at -10° C. for 2 hours and at 0° C. for 17 minutes. The solvent was distilled off under reduced pressure and the residue was partitioned between 40 tttQ of ethyl acetate and 20 ml of ice water. The pH was adjusted to 1.5 with dilute hydrochloric acid and the oil separated from the solvent was dried under reduced pressure to give the title compound, 1.359.

F) [3S(Z)]-2-[[[1-(2-amino-4
-thiazolyl)-2-[[1-[[[[4-[[(1,
4-dihydro-5-hydroxy-4-dioxo2-pyridinyl)carbonylcoamino]-2,3-dioxo-■
-piperazinyl]sulfonylcoamino]carbonyl]-
2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropionic acid disodium salt anisole 2,6 mQ and trifluoroacetic acid 13
[35(Z)]-2-[[[1-(2
,-amino-4-thiazolyl)-2-[[1-[[[
4-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonylcoamino]-2,3
-dioxo-1-piperazinylcosulfonyl]amino]
carbonyl-2-oxo-3-azetidinylco-amino]-2-oxoethylidene]amino]oxy]-2-methylpropionic acid diphenylmethyl ester (l, 39
．． 1.48 mmol) were added at -10°C, and the mixture was then stirred at 0°C for 2 hours. The volatiles were removed under reduced pressure and the residue was triturated with ether and dried to 1.0
The trifluoroacetate of 69 is obtained. This trifluoroacetate was suspended in 20xff of water, and! Adjust to I)86.5 with N sodium hydroxide.

The solution is lyophilized to give a crude product of 1.109, which is subjected to MPLC chromatography of macroreticular styrene-divinylbenzene copolymer using water as eluent. Collection ff10.48@. This material is chromatographed two more times with other samples prepared using a similar procedure. The second column chromatography was carried out on macroreticular styrene-divinylbenzene copolymer and the third on organoken, each with water as the eluent. Final yield: 0.10t, melting point>300°C.

Example 12 [3S (Z)]-3-[[(2-amino-4-thiazolyl)[(2-fluoroethoxy)iminocoacetylcoamino]-N-[[3-[[(1,4- dihydro-5-
Preparation of hydroxy-4-oxo-2-pyridinyl)carbonylcoamino]-2-oxo-1-imidazolidinyl]sulfonyl]-2-oxo-1-azetidine carboxamide ethyldiisopropylamine salt. A solution of (Z)-2-amino-α-[(2-fluoroethoxy)iminoco-4-thiazoleacetic acid (0.33 g, 1.4 mmol) was added with N
-Hydroxybenzotriazole (0°199.1.4
mmol) and N-ethyl-diisopropylamine (
o, ts9.1.4 mmol). Dicyclohexylcarbodiimide (0,299,1,4 mmol) is added at 0° C. and the mixture is stirred for 1 hour. (3S)-3-Amino-N-[[ in dry dimethylformamide SzQ
3-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]-2-oxo-1-azetidinecarboxamide tri Fluoroacetate (1:2) (0,879,1,6 mmol; Example I
(see G) and N-ethyl-diisopropylamine (0°4
After adding a solution of 1 g, 3.2 mmol) and stirring for 2 hours at 0° C., the mixture is stirred for a further 16 hours at room temperature. Dicyclohexylurea is filtered off and the solvent is distilled off under reduced pressure.

The remaining oil is triturated with water until completely crystallized. The solids are collected by filtration and the filtrate is lyophilized to pH 6.1. This solid was suspended in 40 liters of water and 0.25
Adjust the pH to 6.5 with N sodium hydroxide. Insoluble matter is filtered off, and the filtrate is freeze-dried. Combine 2 parts of the freeze-dried product (
0,69) and then chromatography of the macroreticular styrene-divinylbenzene copolymer using water, water and niacetonitrile 95:5 as eluent. After drying under reduced pressure, the title compound from the appropriate fractions (melting point 163-16
The yield at 5° C.) was 0.229.

Example 13 [35(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[2-(carboxymethyl)-2-[(1, 4-dihydro-5-hydroxy-
4-oxo-2-pyridinyl)carbonylcohydrazino]sulfonylcoamino]carbonyl]-2-oxo-3
-azetidinyl]amino]-2-oxoethylidene]aminocooxyco-2-methylpropionic acid trisodium salt preparation A) N,O-dibenzyl-comenamyl chloride hydrochloride N,O-dibenzyl in 360 mQ of dry dichloromethane To a suspension of 16.779 (50.0 mmol) leucomenamic acid was added 11.459 (55.0 mmol) of phosphorous pentachloride at 0-5°C.
(mmol) little by little. After stirring for 1 hour at room temperature, the precipitate was collected by suction, washed with 20 d of dry dichloromethane, and dried under reduced pressure to yield 15.029 of the title compound. Melting point 126-127°C (decomposed).

B) [2-[(phenylmethoxy)carbonyl]hydrazino]acetic acid/1,1-dimethylethyl ester N-[(phenylmethoxy) in 40 mQ of dimethylformamide
Carbonylcohydrazine 6.659 (0°040 mol)
A solution of 8.58 sJ (0,044 mol) of t-butylbromoacetic acid in 20 Q of dimethylformamide,
A solution of 8.21 .rho. (0.048 mol) of N,N-diisopropylethylamine in dimethylformamide BRQ is then added dropwise with stirring.

After stirring the mixture for one day at room temperature, the solvent is evaporated under reduced pressure and the residue is partitioned between ether and water. The organic layer is washed three times with water, dried (magnesium sulfate) and evaporated under reduced pressure leaving an oil (10,69). This is purified by column chromatography on silica gel, eluting with ethyl acetate/toluene (1:1). Both appropriate portions were evaporated under reduced pressure and the residue was stirred with petroleum ether to give the title compound 6.09. Melting point 61-62°C.

C) [1-[[1,4-dihydro-4-oxo-5-(
phenylmethoxy)-2-pyridinyl]carbonyl]-
2-[(phenylmethoxy)carbonyl]hydrazinocoacetic acid! , 1-dimethylethyl ester N-methyl-N
-trimethylsilyltrifluoroacetamide 15.6
3! (2 (80,0 mmol)) in dry acetonitrile 6
[2-[(phenylmethoxy)carbonyl]hydrazino]acetic acid/1,1-dimethylethyl ester 11 in 0 sake
．． 29 (40,0 mmol). 3 at room temperature
After stirring for 0 min, the clear solution is evaporated under reduced pressure and the residue is dissolved in dry dichloromethane. This solution is added dropwise at room temperature to a suspension of 15.61 parts of N,O-dibenzyl-comenamyl chloride hydrochloride in 60 parts of dry dichloromethane. - After stirring overnight, the reaction mixture is evaporated under reduced pressure and the resulting residue is stirred with methanol LOxQ, evaporated again under reduced pressure and then eluted with ethyl acetate and ethyl acetate/methanol (10:1) on silica gel. Subject to chromatography. After evaporation under reduced pressure, the appropriate fractions are crystallized by stirring with ether to obtain a solid foam. Yield 112
．． 7 g, melting point 177-178°C (decomposed).

D) [1-[(1,4-dihydro-5-hydroxy-4
-oxo-2-pyridinyl)carbonylcohydrazino]
Acetic acid/1,1-dimethylethyl ester methanol 40
[1-[[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinylcocarbonyl]-2-[(phenylmethoxy)carbonyl]hydrazino]acetic acid, 1,1-dimethyl in 0m12 Ethyl ester 7.1
A suspension of 7i12 (12.0 mmol) was mixed with palladium/
Hydrogenate in the presence of carbon (10%) for 40 minutes. The catalyst and precipitated product are filtered off and washed thoroughly with dry dimethylformamide 300JIQ to dissolve the precipitated product. The solvent from the combined filtrates is evaporated under reduced pressure and the resulting residue is crystallized by stirring with ether (1.68 g, mp 221° C., decomposed). Recrystallize from methanol to obtain the pure compound. Yield 1J1.26? , melting point 225°C, sintering point 229°C (decomposition).

EX3S)-[1-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]-2
-[[[[2-oxo-3-[[(phenylmethoxy)
9.0 m (46.2 mmol) of N-methyl-N-trimethylsilyl trifluoroacetamide was dissolved in dry ethyl acetate. 12. [1-[(1,4-dihydro-
Add to a suspension of 3.29 (11.0 mmol) of 5-hydroxy-4-year-old xo-2-pyridinyl)carbonyl]hydrazino]acetic acid 1,1-dimethylethyl ester.

Continue stirring for 1 hour at room temperature to obtain a clear solution (solution A).

A suspension of 2.421? (11.0 mmol) of (S)-3-[[(phenylmethoxy)carbonylkoamino]-2''-azetidinone in dry ethyl acetate SmQ was added with 0.99 mQ (11.0 mmol) of chlorosulfonyl isocyanate. , 0 mmol) is added with stirring. The mixture is stirred at room temperature for 1 hour and then cooled to 0 °C. At 0 °C solution A is added dropwise and then stirred at room temperature overnight. 4 mol of triethylamine are added. Afterwards, the mixture is evaporated under reduced pressure. The residue is dissolved in methanol/water (4:1) lOiQ. This solution is
The resulting residue (10,025 g) was stirred with a small amount of water and methanol to crystallize it. The precipitate was dissolved in isopropanol/water (
4:1), methanol, methanol/water (1:l) and ether with successive stirring washes and purification. Yield after vacuum drying: 239 g.

F) (S)-3-amino-1-[[[[2-(carboxinmethyl)-2-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]hydrazi (3S)-[1-[(
1.

4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]-2-[[[[2-oxo-3-
[[(phenylmethoxy)carbonyl]amino]-1-
Azetidinyl]carbonyl]aminocosulfonyl]hydrazino]acetic acid 1,1-dimethyl ester was added at 0°C to 7.0 ml of trifluoroacetic acid and 1.0 ml of thioanisole.
Add to 66ml of mixture. After stirring overnight at room temperature,
The solution is evaporated under reduced pressure. The residue is washed (stirred) successively with ethyl acetate, ethyl acetate/petroleum ether (1:1), petroleum ether and dichloromethane and then dried under reduced pressure. This crude salt is used in the next step without further purification. Yield: 2.15g.

G) [3S(Z)]-2-[[[1-(2-amino-4
-thiazolyl)-2-[[1-[[[[2-(carboxymethyl)-2-[(1,4-dihydro, a-5-hydroxy-4=oxo-2-pyridinyl)carbonyl]hydrazino]sulfonyl] Amino]carbonyl]-2=oxo-3-azetidinyl]aminoco2-oxoethylidenecoaminocooxyco-2-methylpropionic acid diphenylmethyl ester 0.70+Q (3.24 mmol) of diphenylchlorophosphate was dissolved in 30 iQ of dry acetonitrile ( Z)-
2-amino-α-[[2-(diphenylmethoxy)-1
，! -dimethyl-2-oxoethoxy]imino]-4-
Add dropwise to a cold mixture (-30 DEG C.) of 1.429 (3.24 mmol) of thiazoleacetic acid and 1.81 m (2 (12.96 mmol)) of triethylamine (solution A).

Bistrimethylsilylacetamide 3.27xC (12
96 mmol) in 30 ml of dry ethyl acetate (S)
-3~amino-1-[[[[2-(carboxymethyl)
-2-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]hydrazino]sulfonyl]amino]carbonyl]-2=azetidinone trifluoroacetate 2.139 (~3°3 millimolar) suspension at room temperature. After stirring for 1 hour, the clear solution was cooled and
Then, solution A at -30°C is added dropwise. Heat the mixture to 10°
Stir for 1 hour at 0°C and 1.5 hours at 0°C, then evaporate under reduced pressure. The residue is stirred with a little water and adjusted to I) H2 by addition of dilute hydrochloric acid. The precipitate was filtered off, washed with water, redissolved in water/acetone at 5-6.0 (added dilute sodium hydroxide), and dissolved in a water/methanol gradient (
Purification by MPLC of a macroreticular styrene-divinylbenzene copolymer eluting at 0-100%). Lyophilize the appropriate fractions to obtain 270 mg of purified product. A suspension of this salt (a small amount of cold aqueous solution) is acidified to pi (2) with dilute hydrochloric acid to precipitate the free acid.

This is collected with suction and dried under reduced pressure. Yield 0゜19
9゜Melting point〉180℃ (decomposition).

H)[3S (Z)Co2-[[[1-(2-amino-
4-thiazolyl)-2-[[1-[[[[2-(carboxymethyl)-,2-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]hydrazino]sulfonyl 0.179 (0.2 mmol) of [3S (Z)]- 2
-[[[(2-amino-4-thiazolyl)-2-[[
1-[[[[2-(carboxymethyl)-2-[(1,
4-dihydro-5-hydroxy-4-oxo2-pyridinyl)carbonyl]hydrazino]sulfonylcoaminococarbonyl]-2-oxo-3-azetidinylcoamino]-2-oxoethylidenecoamino]oxy]-2 −
Methyl propionic acid diphenylmethyl ester is slowly added to a cold stirred solution (-100C) of 0.62i12 (8.0 mmol) of trifluoroacetic acid and 0.087iQ (0.8 mmol) of thioanisole. Stir for 15 minutes at 0°C. The suspension is evaporated under reduced pressure at 0-5° C., the residue is stirred with dry ether, collected with suction, washed with dry ether and dried under reduced pressure. Yield 0.14Li
, melting point>230°C (decomposition).

I ) [3S (Z) nee 2-[[rho(2-amino-
4-thiazolyl)-2-[[1-[[[[2-(carboxymethyl)-2-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonylcohydrazinocosulfonyl] ]Amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]aminocooxy]-2-methylpropionic acid trisodium salt 115 (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]hydrazinocosulponylcoaminococarbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]aminocooxyco-2
-Methylpropionic acid trifluoroacetic acid- to water 1,5
Suspend in ttrQ and dropwise add dilute sodium hydroxide to p
) (adjust to 5.5. This solution is mixed with macroreticular styrene-divinylbenzene copolymer (0.05~0, l
1jF) and cross-linked dextran gel (25-100
Water is passed as eluent through two consecutive columns of μ-pass. Both appropriate portions are combined and lyophilized to yield 100xy of the title compound.

Example 14 [35(Z)]-2-[[[1-(2-amino-4-thiazolyl')-2-[[1-[[[[3-[[(1,4
-dihydro-5-hydroxy-4-oxo-2-pyridinyl)acetyl]amino]-2-oxo-1-imidazolidinylcosulfonyl]aminococarbonyl]-2-oxo-3-azetidinyl]aminoco2-oxoethylidene] Preparation of disodium salt of amino]oxyco-2-methylpropionate A) 2-(cyanomethyl)-5-(phenylmethoxy)
-1-(phenylmethyl)-4(IH)-2-(chloromethyl)-5- in 20 tons of pyridinone acetonitrile
(phenylmethoxy)-1-(phenylmethyl)-4(
A suspension of 2.09 (6 mmol) of IH)-pyridinone with 3.9 g (60 mmol) of potassium cyanide and 0.1
Add 18-crown-6 of 9. The mixture is heated to reflux for 2.5 hours. The salts are filtered off with suction and the filtrate is then evaporated under reduced pressure. The resulting residue is purified by silica gel column chromatography using ethyl acetate/methanol (8:2) as eluent. Yield of the title compound: 0.55 g, melting point: 175-180°C.

B) 1,4-dihydro-5-hydroxy-4-oxo-
1-(phenylmethyl)-2-pyridineacetic acid 2-(cyanomethyl)-5-(phenylmethoxy)-1-(phenylmethyl)-4(IH)-viridinone 2.459(7,
A mixture of 16 mmol) and 40 tttQ of concentrated hydrochloric acid (37%) is stirred at 70° C. for 4 hours and then dried under reduced pressure.

The residue is suspended in 1511Q ice-cold water and 5N sodium hydroxide is added to bring the pH to 2.0.

The precipitate was filtered off, washed with ice water and ether, and dried under reduced pressure (1.71 g). The crude acid was dissolved in 20 μm of 0.5N sodium hydroxide and acidified with 2N hydrochloric acid (pH 1).

8) Collect the reprecipitated material using suction and wash with ice water. Yield fi 1.829, melting point 231-235°C.

C) 1,4-dihydro-5-hydroxy-4-oxo-
N-(2-oxo-1-imidazolidinyl)-1-(phenylmethyl)-2-pyridineacetamide = 1.4 in dry dimethylformamide 11511IQ
Dihydro-5-hydroxy-4-oxoto-(phenylmethyl)-2-pyridineacetic acid 9.299 (35,83
mmol), N-hydroxybenzotriazole 0.2
1 (1,79 mmol), N-dimethylaminopyridine 0.229 (1,79 mmol), N-aminoimidazolidinone 3.629 (35,83 mmol) and dicyclohexylcarbodiimide 8.139 (39,41 Triethylamine 4.99i12
(35.83 mmol) is added. Continue stirring overnight at room temperature. The precipitated dicyclohexylurea is filtered off, washed with dimethylformamide, and the filtrate is then evaporated under reduced pressure to crystallize the resulting residue by stirring with 110 av of dichloromethane. The precipitate is collected with suction and dried under reduced pressure. .

To a suspension of this compound in 65 ml of dry acetonitrile is added 14.0 ml of N-methyl-N-trimethylsilyltrifluoroacetamide (71.6 x I2). After stirring for 30 minutes at room temperature, the undissolved dicyclohexylurea is filtered off and the filtrate is evaporated under reduced pressure.

The oily residue is boiled in 70 methanol for 15 minutes and cooled. Collect the precipitate with suction, methanol,
Wash successively with methanol/ether (1:1) then ether and dry under vacuum.

Yield 8.7g, sintering point 242℃, melting point 260-265℃
(Disassembly).

DOS)-[1-1:[[[3-[[[1,4-dihydro-5-hydroxy-4-oxo-1-(phenylmethyl)-2-pyridinylcoacetylcoamino]-2-oxo -1-imidazolidinyl]sulfonyl]aminococarbonyl-2-oxo-3-azetidinyl]carbamic acid phenylmethyl ester monosodium salt 1,4-dihydro-5-hydroxy-4-oxo-N in 50 ml of dry ethyl acetate -(2-oxo-1-imidazolidinyl)-1-(phenylmethyl)-2-pyridineacetamide 3.429 (10.0 mmol) in a suspension of N-methyl-N-)limethylsilyltrifluoroacetamide 5 Add .86JI12 (30゜0 mmol),
Stir for 1 hour at room temperature (solution A).

A solution of 2.20 g (10,0 mmol) of (S)-3-[[(phenylmethoxy)carbonylkoamino]-2-azetidinone in 501 (10,0 mmol) of chlorosulfonyl isocyanate in 501 (10,0 mmol) is added with stirring and the mixture is stirred at room temperature for 1 hour and then cooled to 0° C. Solution A is added dropwise with stirring at 0° C. After stirring overnight at room temperature, the mixture is evaporated under reduced pressure and The residue is then treated with a small amount of methanol and water. The pH is adjusted to 5.5 by adding dilute sodium hydroxide and the filtered solution is lyophilized. Divinylbenzene copolymer was subjected to MPLC, and the resulting pure fraction was lyophilized to 0.
．． The title compound 409 is obtained. Both fractions containing impurities are purified by a second MPLC under the same conditions. Yield 0
．． 60g.

EXS)-N-[3-[[[(3-amino-2-oxo-azetidinyl)carbonyl]amino]sulfonylco-
2-oxo-1-imidazolidinyl]-1.

4-dihydro-5-hydroxy-4-oxo-2=pyridineacetamide trifluoroacetate (S)-[1-[[ [[
3-[[[1,4-dihydro-5-hydroxy-4-oxo-1-(phenylmethyl)-2-pyridinylcoacetylcoamino]-2-oxo-1-imidazolidinyl]
sulfonylcoamino]carbonylco2-oxo-3-
[azetidinyl]carbamic acid phenylmethyl ester/
A solution of the monosodium salt 0.909 (1.3 mmol) in the presence of palladium/carbon (10%) 0.159
Hydrogenate for 0 minutes. The catalyst is filtered off and washed with a small amount of dimethylformamide. The filtrate is evaporated under reduced pressure to give an oily residue, which is crystallized by stirring with a small amount of ethyl acetate.

Yield 0.6759, melting point>150°C (decomposed).

This crude title compound was stirred in dry ethyl acetate for 1 hour,
Then, it is purified by washing with ethyl acetate and drying under reduced pressure. Yield 80%, melting point>165°C (decomposition).

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-imidazolidinyl]sulfonylcoamino]carbonyl]-2-
(S
)-N-[3-[[[(3-amino-2-oxo-azetidinyl)carbonyl]amino]sulfonylco-2-oxo-! -imidazolidinyl]-1,4-dihydro-5
-Hydroxy-4-oxo-2-pyridineacetamide trifluoroacetate 0.75y (1.35 mmol)
bistrimethylsilylacetamide l in a suspension.

Add 1iQ (4.45 mmol). After stirring for 1 hour at room temperature, the clear solution is evaporated under reduced pressure and the oily residue is dissolved in 12 ml of dry ethyl acetate (solution A).

(Z)-2-Amino-α-[[2-(diphenylmethoxy)-Ll-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid 0.609 (1,35 mmol) in dry acetonitrile of 12i12 A cold suspension of (-3
0.57112 (5.4 mmol) of triethylamine at 0°C) followed by 0.2 (diphenylchlorophosphate)
Add 9 ml (1.35 ml J%) dropwise. -30℃
Stir for 1 hour at 0° C. and an additional 1 hour at 0°C. The solvent is removed under reduced pressure and the residue is stirred with a small amount of water (0° C.) to form a precipitate. The precipitate was collected by suction, washed with cold water, and I) H2
of water (add 2.3 drops of diluted hydrochloric acid), filter, remove water,
Wash successively with methanol and then ether and dry under vacuum. yield! .

079, melting point>180°C (decomposed). This group of materials is used in the next step without further purification.

G) [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-imidazolidinylcosulfonyl]amino]carbonylco2
1.019 (1, 17 mmol)
crude [35(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]aminococarbonyl]-2-
Add oxo-3-azetidinyl]amino]-2-oxoethylidene]aminocooxy]-2-methylpropionic acid diphenylmethyl ester. After stirring for 20 minutes at -10°C, the solvent is removed under reduced pressure at +10°C. The residue is stirred with a small amount of dichloromethane, filtered, stirred once more with a small amount of dichloromethane, collected in a saccitane, washed with hexane and dried under vacuum. The crude product (t, 06 g) is suspended in a small amount of water/acetonitrile and then dissolved by adding IN sodium hydroxide to bring the I)H to 6.5. After concentration under reduced pressure, the aqueous solution is subjected to macroreticular styrene-divinylbenzene copolymer chromatography (MPLC), eluting with water.

Combine appropriate amounts and freeze-dry. Yield 0.10g,
Melting point>255°C.

Example 15 [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
-oxol-imidazolidinyl]sulfonyl]amino]
Preparation of disodium salt of carbonyl]-2-oxo-3-azetidinyl]-2-oxoethylidenecoamino]oxy]-2-methylpropionate )
-5-(Phenylmethoxy)-4(IH)-Viridinone 9.0 g of 2-(hydroxymethyl)-5-(phenylmethoxy)-4(IH)-Viridinone and 26 g of manganese dioxide (active) in 100 mg of methanol. Add and stir overnight at room temperature. Crystals of the product form. After boiling the reaction mixture for 10 minutes, it is filtered hot over Hyflo, the filter cake is washed twice with 50 mQ of boiling methanol, the combined filtrates are evaporated and the residue is stirred with 50 mQ of ethyl acetate. White crystals of product form. Revenue
9.79, melting point 156°C (decomposition).

B) 3-[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]-2-propenoic acid ethyl ester 100 mQ of dioxane and 0.0 m of I)-toluenesulfonic acid.
5g, 2-(l-hydroxy-1-methoxymethyl)-
5-(phenylmethoxy)-4(IH)-viridinone 6
．． 269 and carbethoxymethylenetriphenylphosphorane 8.359 are added and stirred at 70°C for 3 hours. The result is a clear dark solution. Evaporation of the solvent under reduced pressure yields an oily residue of the title compound and triphenylphosphine oxide.

When the residue is dissolved in 30 tt (l) of isopropanol, the crystals of the product begin to separate. After leaving it in the refrigerator overnight,
The crystals are filtered off, washed with ether and recrystallized from isopropanol. Yield 5.729, melting point 188°C.

C) 3-[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]-2-propenoic acid methanol 3011Q, 3-[1,4-dihydro-4
-Oxo-5-(phenylmethoxy)-2-pyridinyl]-2-propenoic acid ethyl ester (1,59) and 0.299% of potassium hydroxide are added and stirred at 50°C for 2 hours. After evaporating the solvent, the residue is dissolved in 1 OOIRQ of water and filtered. Add 2N hydrochloric acid to the filtrate until the pH reaches 5.0. Crystals of the title compound separate from the solution. It is filtered, washed with water and dried under vacuum. Yield 1.14g, melting point 236°C.

D) 3-lo,4-dihydro4-oxo-5-(phenylmethoxy)-2-pyridinyl]-N-(2-oxo-
1-imidazolidinyl)-2-propenamide dimethylformamide 100x (7 to 3-[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-
pyridinyl]-2-propenoic acid (10,851F), N
Add 1 g of -hydroxybenzotriazole, 0.019 of N,N-dimethylaminopyridine and 8.249 of dicyclohexylcarbodiimide and stir for 30 minutes. 0
After cooling to ℃, add 4 g of N-amidoimidazolidinone,
Stirring is continued for 1 hour at 0°C and 10 hours at room temperature. Then,
The resulting suspension is heated to 60°C and filtered. This was resuspended in 50m(2) of dimethylformamide and 60°C.
Heat to and filter. The combined filtrates are evaporated at 40° C. (oil vacuum). The oily residue is stirred with 50 g of water containing 29 g of sodium bicarbonate. After filtration, the solid is washed with mmol, acetone and ether. Dry to obtain 12.39 solids. 89 in 100 mQ of dichloromethane
Stir with p-)luenesulfonic acid. Filter to obtain 12.989 white solid.

This material is suspended in water. Recrystallization from water/dimethylformamide gives 8.499 of the title compound. Melting point 2
71℃.

EX3 S)-[1-[[[[3-[[3-[1,4-
Dihydro-4-oxo-5-(phenylmethoxy)-2
-pyridinyl]-1-oxo2-propenyl]amino]-2-oxo-1-imidazolidinylcosulfonyl]
Aminococarbonylco-2-oxo-3-azetidinyl]carbamic acid phenylmethyl ester 3-[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]-N-(2-oxo- 1
-imidazolidinyl)-2-propenamide (3,55
9) is suspended in 100x (2) of ethyl acetate and 6.39 of N-methyl-N-(trimethylsilyl)trifluoroacetamide is added. After stirring for 1 hour, a clear solution is obtained.

The solution was dissolved (S) in ethyl acetate 50i12 within 10 minutes.
-1-[[(chlorosulfonyl)aminococarbonyl]
-3-[[(phenylmethoxy)carbonyl]amino]
Add to a cold solution (0°C) of 3.39 -2-azetidinone. - After stirring overnight, the solvent is evaporated and the oily residue is stirred with 50112 isopropanol.

The resulting precipitate is separated by filtration and washed with isopropanol and ether. Yield: 5.91g.

F) (3S)-3-amino-N-[[3-[[(1,4
-dihydro-4-oxo-2-pyridinyl)-1-oxo-2-propenyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]-1-azetidinecarboxamide trifluoroacetate (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-3-azetidinyl]carbamic acid phenylmethyl ester ( 6,89) in trifluoroacetic acid/thioanisole (1:3) 60112 overnight at room temperature. After evaporating the resulting solution to 1/3 volume,
Add 50xQ isopropanol and 10xQ ether.

(3S)-3-Amino-N-[[3-[[(1,4-dihydro-4-oxo-2-pyridinyl)-1oxo-2
White crystals of -propenylcoamino]-2-oxo-1-imidazolidinyl]sulfonylco-1-azetidine carboxamide trifluoroacetate are obtained. This is washed several times with ether and dried.

Yield 4.309゜G)[35(Z)co2-[[[1-(2-amino-4
-thiazolyl”)-2-[[1-[[[[3-[[3-
(1.

4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)-1-oxo-2-propenyl]aminoco 2
-oxo-1-imidazolidinyl]sulfonylcoaminococarbonylco-2-oxo-3-azeticinyl]amino]-2-oxoethylidene]amino]oxy]-2-
Methylpropionic acid disodium salt (Z)-2-amino-α-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]iminoco4-thiazoleacetic acid (2,29) and triethylamine 1. Dissolve 59 in 150xN acetonitrile.

At −30° C., 1.49 g of diphenylchlorophosphate is added dropwise and the mixture is stirred overnight.

(3S)-3-Amino-N-[[3-[[(1,4-dihydro-4-oxo-2-pyridinyl)-1-oxo-2-propenyl]amino]- suspended in ethyl acetate 10011Q 2-oxo-1-imidazolidinyl]sulfonylco-1-azetidinecarboxamide 2.0 trifluoroacetate (3,39) was converted to 6RQ's N-methyl-N-(
Trimethylsilyl)trifluoroacetamide and stir for 1 hour at room temperature.

The solution is added dropwise (in 15 minutes) to the active acid at -30°C.

The mixture was then stirred for 1 hour at -10°C and 30 minutes at 0°C. The solvent was evaporated under reduced pressure and the remaining oil was purified to pH 2 (2N sulfuric acid).
Stir with ice water. The ice water is discarded and the residue is washed again with ice water and then dissolved in tetrahydrofuran of 1001 (2). The solution is dried over sodium sulfate and the filtrate is evaporated. Diphenyl methyl ester of the title compound 1.819
is obtained as a solid foam. 1.59 of this material was stirred in trifluoroacetic acid/anisole 30RQ at θ°C for 30 minutes, 100i (J) of ether was added and the trifluoroacetate of the title compound was filtered off. This was dissolved in 1OjIQ of water. , and sodium bicarbonate until pH 5.5.The filtrate is chromatographed on macroreticular styrene-divinylbenzene copolymer (4009) using water as eluent.The product at 0.649 is extracted from the appropriate fractions. Bioautography reveals the presence of another biologically active by-product in small amounts. This material is subjected to secondary column chromatography on a Merck Lorber C, eluting with water. 0.17 g of the title compound are obtained.

Example 16 [3S(Z)co2-[[[1-(2~amino-4-thiazolyl)-2-[[1-[[[[2-[3-(1,4
-dihydro-5-hydroxy-4-oxo-2-pyridinyl)-1-oxo-2-propenyl]hydrazino]sulfonylcoamino]carbonyl]-2-oxo-3-azetidinyl]aminoco-2-oxoethylidene]amino]oxy ]-2-Methylpropionic acid disodium salt preparation A) 3-[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]-2-propionic acid 2-[(1 ,1-dimethylethoxy)carbonylcohydrazide 3-[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl coke-propionic acid (1
, 369), N-hydroxybenzotriazole 0.7
51F,N,N-dimethylaminopyridine o, ot9 and dicyclohexylcarbodiimide t, oe9 are stirred in 20 mQ of dimethylformamide at 0°C for 20 minutes. Add 0.669 N-(t-butoxycarbonyl)hydrazine. - After stirring overnight, the dicyclohexylurea formed was filtered off and the filtrate was dissolved in dimethylformamide 101
The filtrate was evaporated to dryness and the residue was washed with 30 t (l
After adding 19 parts of sodium bicarbonate and stirring, the title compound is filtered off. Recrystallization from dimethylformamide/water gives white crystals. Yield 1.479, melting point 141'C0 B) 3-[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl-2-propionic acid hydrazide 3-[1,4-dihydro-4- Oxo-5-(phenylmethoxy)-2-pyridinyl]-2-propionic acid 2
-[(1,1-dimethylethoxy)carbonyl]hydrazide (3,869) in 301 g of trifluoroacetic acid
Stir for 1.5 hours at ~5°C. diethyl ether 50
Addition of x(2 precipitates the trifluoroacetate salt of the title compound. The salt is suspended in 30zQ of water, 2 g of sodium bicarbonate is added, stirred for 20 minutes, and the title compound is filtered off.
Wash with water and dry to obtain a beige powder. Yield 2.
759°C) (3S)-1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid 2-[,[[[2-oxo-3-[[(phenylmethoxy) carbonyl]amino]-1-azetidinylcocarbonyl]aminocosulfonyl]hydrazide 3-[1,
4-dihydro-4-oxo-5-(phenylmethoxy)
-2-pyridinyl]-2-propionic acid hydrazide (2
, 869) and N-methyl-N-(trimethylsilyl)trifluoroacetamide 8.12 in ethyl acetate 50RQ
Stir inside for 1 hour. Add 3 ethyl acetate to the resulting clear solution.
03112 (added within 10 minutes) Add at 0°C. - After stirring overnight, the solvent is evaporated and the residue is stirred with 50 grams of isopropanol and 1 drop of acid. The title compound is filtered off and washed with isopropanol and ether. Yield 5
．． 429゜DX3S)-3-[1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl-2-propionic acid.
2- [[[(3-Amino-2-oxo-1-azetidinyl)carbonyl]amino]sulfonyl]hydrazide.
Trifluoroacetic acid salt 50 mQ trifluoroacetic acid/thioanisole (3:l
) in (3S)-1,4-dihydro-4-oxo-5-
(Phenylmethoxy)-2-pyridinecarboxylic acid 2-
[[[[2-oxo-3-[[(phenylmethoxy)carbonyl]amino]-1-azetidinyl]carbonyl]
Stir the amino]sulfonyl]hydrazide (5°29) at room temperature overnight. A mixture of ether/isopropanol (8:2) 100xQ is added to this clear solution. The precipitate obtained is filtered off and washed with ether. Yield after drying4.
01g.

E) [3S(Z)]-2-[[[1-(2-amino-4
-thiazolyl)-2-[[1-[[[[2-[3-(1
,4-dihydro-5-hydroxy-4-oxo-2-re' II - ++bar 1-→Toyo-・] -
9- Propeni 11no 1k "Radino]sulfonylcoamino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]
-2-Methylpropionic acid disodium salt (Z) -2-amino-α-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid (1,59 ) and 1 g of triethylamine in 100 m of acetonitrile (-30
℃, diphenylchlorophosphate! 2 was added dropwise and the mixture was stirred for 1 hour.

(3S')-3-[1,4- in 50 mQ ethyl acetate
Dihydro-5-hydroxy-4-oxo-2-pyridinyl-2-propionic acid 2-[[[(3amino-2
-oxo-■-azetidinyl)carbonyl]aminocosulfonylcohydrazide trifluoroacetate (2,09
) and 5.5πe of N-methyl-N-(trimethylsilyl)trifluoroacetamide are stirred at room temperature for 1 hour. A clear solution forms which, after cooling to =30° C., the active acid is added dropwise. The mixture is stirred for i hours at -30°C, for 30 minutes at -to°C, and for 1 hour at 0°C. The solvent is then evaporated under reduced pressure and the residue is stirred with 50 molar of isopropanol.

A solid is formed. This was separated by filtration and treated with pH 2 (sulfuric acid) for 20 minutes in 100xL of ice water! : Stir. Filtration gave the diphenyl methyl ester of the title compound, 5011a.
Wash 3 times with ice water and dry (1.789). 1.59 of this ester was mixed with trifluoroacetic acid/asol (4
: 1) Add 50 zQ and stir at 0°C for 30 minutes. After adding ether 150xQ, the trifluoroacetate salt of the free acid of the title compound (1,659) is separated by filtration.

1 g of this material is suspended in 5 ml of water and the pH is adjusted to 6.0 (sodium bicarbonate). This clear solution is then chromatographed on 400 g of macroreticular styrene-divinylbenzene copolymer using water as an eluent to obtain 413 x g of the title compound.

400 ay of this material is rechromatographed on a Merck Rover C using water as the eluent.

Yield 16019° Example 17 [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]aminoco2-oxoethylidene]aminocooxy]
Preparation of -2-methylpropionate disodium salt A) (2S-trans)-[1-[[[[3-[[[
1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]carbonyl]aminoco-2-oxo-1-imidazolidinyl]sulfonyl]aminococarbonyl]-2-methyl-4-oxo-3- azetidinyl]carbamic acid phenylmethyl ester (3S-)lance)-(4-methyl-2-oxo-3-
azetidinyl)carbamic acid phenylmethyl ester (
2,359) and chlorosulfonyl isocyanate 1
, 419G in 50 mQ of ethyl acetate at 0-5°C for 1 hour. A clear solution (solution A) is obtained. 1,4-dihydro-4-oxo-N-(2-oxo-1-imidazolidinyl)-5-(phenylmethoxy)-2-pyridinecarboxamide (3,28 g) and N-methyl-N-(trimethylsilyl)trifluoro 6 g of acetamide are stirred in 50×Q ethyl acetate at 40° C. for 1 hour (solution B).

Add solution B to the cooled (0° C.) solution A with stirring for 30 minutes. -After stirring overnight, the solvent was evaporated and the residue (oil)
is stirred with 50 mQ of isopropanol and 1 drop of acetic acid. The title compound is obtained as a beige precipitate. Melting point 163℃
(decomposition), yield i14.39°B) (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-toluenesulfonic acid (2S-) lance in 50 mQ of dimethylformamide)
-[1-[[[[3-[[[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]carbonyl]aminoco-2-oxo-1-imidazolidinyl]sulfonylcoamino] carbonyl]-2-methyl-
4-year-old xo-3-azetidinyl]carbamic acid phenylmethyl ester (5,91i+), 3.8 g of hydrated p-toluenesulfonic acid and palladium/carbon (10%)2
．． 59 is hydrogenated for 1 hour at room temperature. After filtration through Hyflo, dimethylformamide is distilled off under reduced pressure. The oily residue is stirred with 100 g of dichloromethane. The title compound (5.8 g) forms rapidly as a white crystalline material.

C) [2S [2α, 3β(Z)]l-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-oxoethylidene]amino]oxy]-2-methylpropionic acid disodium salt (Z)-2-amino-α-[[2- (diphenylmethoxy)-t,t-ymethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid (4,409) and triethylamine (3.09) are dissolved in 15 (1!) acetonitrile.

Add 2.89 g of diphenylchlorophosphate dropwise at −30° C. and stir for 1 hour.

(2S-)lance)-N-[3-[[[(3-amino-2-methyl-4-oxo-1-azetidinyl)carbonyl]aminocosulfonyl]-2-oxo-1-imidazolinonyl]- 1,4-dihydro-5-hydroxy-4
-oxo-2-pyridinecarboxamide p-)luenesulfonic acid (7,909) and triethylamine 2.029 in 50 mQ of dimethylformamide at -20°C.
Stir for 5 minutes.

The suspension and solution prepared above were combined at -30°C, then at -30°C for 1 hour, at -10°C for 1 hour, and at 0-10°C.
Stir overnight. The solvent is then distilled off under reduced pressure and the residue is stirred with 100x (2) of ice water at pH 3 (sulfuric acid).

The diphenylmethyl ester of the title compound is filtered off and washed with water. Yield 6.13g, beige powder.

2 g of this ester was mixed with trifluoroacetic acid/anisole (4
:1) Add to 1 g of 30°C and stir at 0°C for 30 minutes. 1
The trifluoroacetate salt of the free acid is precipitated by adding 00 ml of ether. It is suspended in 1031 (!) water and adjusted to pH 6.0. After filtration, the filtrate is passed through a macroreticular styrene-divinylbenzene copolymer column (water is the eluent). Yield 0°489° Elution with water Secondary column chromatography on Merck Rover C gives 0.179 of the title compound.

Example 19 [3S (Z)]-]2-aminoN-1-[[[3
-[[(1,4-dihydro-5-hydroxy-4-xo-2-pyridinyl)carbonylcoamino]-2-oxo-1-imidazolidinyl]sulfonylcoamino]carbonyl]-2-xo-3-azetidinyl] -Preparation of α-(methoxyimino)-4-thiazoleacetamide monopotassium salt Suspension of 0.69 ni(Z)-2-amino-α-(methoxyimino)-4-thiazoleacetic acid (0.03 mol) Add 2.14 IIC (0,009 mol) of tributylamine to the solution at room temperature.
Add. The suspension is cooled to -30 DEG C. and 0.66" of diphenylchlorophosphate (0,003 mol) is added. Stir the reaction mixture at -30°C for 1 hour (Mixture A)
.

(3S)-3-Amino-N- in 20 mQ ethyl acetate
[[3-[[(1,4-dihydro-5-hydroxy-4
-oxo-2-pyridinyl)carbonyl]amino]-2
-oxo-1-imidazolidinyl]sulfonyl]-2-
To a suspension of 1.629 oxo-1-azetidine carboxamide (0,003 mol) was added 2,6 nQ of bis-trimethylsilylacetamide at room temperature to produce a clear brown solution, which was stirred for 1 h at room temperature. , then cooled to 0° C. (solution B).

Solution B is added dropwise to mixture A with stirring (approximately 10 minutes), maintaining the temperature at -30°C. The mixture was heated to -10°C.
Stir for a further 1.5 hours at 0° C. and evaporate under reduced pressure. Dissolve the remaining syrup in 501 acetone. 1 mol potassium ethylhexanoate BmQ is added to this solution to precipitate 3.0 g of crude product. Addition of ether to the filtrate gives an additional 0.29 of crude product. The crude product is chromatographed on macroreticular styrene-divinylbenzene copolymer to give the title compound, t, ss9.

Example 20 [3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[c[5-cc(1,t-
dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonylcoamino]-2-oxo-1-imidazolidinylcosulfonyl]aminococarbonyl]-2-oxo-3-azetidinyl]aminoco2=oxoethylidene]amino ] Oxy]-2-methylpropionic acid production nee[35(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[ (1,4-
dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinylcoaminoco-2-oxoethylidene ]amino]oxy]-2-methylpropionic acid disodium salt (2.2 g, see Example 1) in acetone/water (1:l) 20y! Dissolve Q and adjust the pH to 2 with 2N hydrochloric acid. Chromatography using a macroreticular styrene-divinylbenzene copolymer yielded 0.0% of the title compound.
Get 79.

Example 21 [3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[3-[[(1,4-
dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]aminoco2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo3-azetidinyl]amino]-2=oxoethylidene]amino] Preparation of monosodium salt of oxy]-N-hydroxy-2-methylpropionic acid amide (Z)-2-amino-α-[[1,1-dimethyl-2-
Oxo-2-[()riphenylmethoxy)aminocoethoxy]imino]-4-thiazoleacetic acid (4.72 g) is suspended in 65.times.Q of acetonitrile, and 3.72 mQ of triethylamine is added at -30.degree. After stirring for 10 minutes, 1°97 mQ of diphenyl chlorophosphate was added dropwise.

Stirring is then continued for 90 minutes (solution A).

(3S)-3-Amino-N-[[3-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]aminoco-2-oxo-1-imidazolidinyl]sulfonylco-2 -Oxo-1-azetidine carboxamide (8,9 m) was suspended in 70 d of acetonitrile, and bis-trimethylsilylacetamide 7,7
Add zQ. Stir at -1θ°C for 1 hour and at 0°C for 1.5 hours to obtain a clear solution.

The solvent and trifluoroacetic acid trimethylsilyl ester formed are evaporated under reduced pressure and the residual oil is dissolved in ethyl acetate of 70jII2 (solution B).

Next, solution A is added dropwise to solution B over 30 minutes while stirring at -20°C. The reaction was completed by stirring at −10° C. for 1.5 hours and at 0° C. for 1 hour.

The solvent was then distilled off under reduced pressure and the oily residue was dissolved in sulfuric acid (10%
) and stir with 300 ml of ice water adjusted to pH 4.0. The solid formed is then filtered off, washed with water and dried under reduced pressure overnight. Yield 199 (crude product).

The crude product (4,59) was dissolved in formic acid (98%) 45. Stir at 0° C. for 1 hour with 4.5 m of wQ and dichloromethane.

Precipitation with diethyl ether gives the title compound (2,39).

Example 22 [35(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-
Preparation of disodium salt of imidazolidinyl]carbonyl]hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxyco-2-methylpropionic acid A) 2-[ [(phenylmethoxy)carbonylcoamino]-2-imidazolidinone 1-amino-2-imidazolidinone (2
69,0,257 mol) is dissolved. This solution was added to 200 ml of ethyl acetate, and the mixture was stirred with saturated sodium bicarbonate solution and maintained at pH 8, 5-9.
3.89 chloroformic acid benzyl ester (0,257 mol) are added dropwise. After stirring overnight at room temperature, the title compound is filtered off and washed with water and then with ethyl acetate. Yield 46.79
, melting point 140-144°C.

B) 1-[[(phenylmethoxy)carbonylcoamino]-3-(chlorocarbonyl)-2-imidazolidinone 2-[[(phenylmethoxy)carbonyl]amino]-2-imidazolidinone in dichloromethane 112 69
．． 99C0,297 mol) dichloromethane 2
Add a solution of phosgene 359 in 00 sake.

The mixture is stirred at room temperature overnight to form a clear solution.

The solvent is removed under reduced pressure and the remaining syrup is triturated with ether. Yield 7G, 09, melting point 102~1
05℃.

c) 3-[[(phenylmethoxy)carbonyl]aminoco-2-oxo-1-imidazolidinecarboxylic acid 2-
[(1,1-dimethylethoxy)carbonyl]hydrazide To 1.5 f2 of ethyl acetate was added 1-[[(phenylmethoxy)carbonylcoamino]-3'-(chlorocarbonyl)-2-imidazolidinone (769,0 , 255 mol). After cooling to 0-5 DEG C., 39.69 (0.9 mol) of N-(t-butoxycarbonyl)hydrazide and 41.8 mol of triethylamine (0.3 mol) are added dropwise within 30 minutes. Stir the mixture overnight. The precipitate is filtered off, dried, stirred with 800 g of water to remove triethylamine hydrochloride, filtered, washed with water and dried.

Yield fi 71.29, melting point 195-198°C.

D) 2-[[3-[[(1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]carbonyl]amino]-2-oxo-1-imidazolidinyl]
carbonyl]hydrazinecarboxylic acid 1゜l-dimethylethyl ester 3-[[(phenylmethoxy)carbonyl]amino]-
2-oxo-1-imidazolidinecarboxylic acid 2-[(
1,1-dimethylethoxy)carbonyl]hydrazide (
31.5 g, 0.08 mol) in dimethylformamide 4
Palladium/activated carbon (10%) dissolved in 00xQ16
g and hydrogen was passed through the reaction mixture with stirring. After 1 hour, the catalyst is filtered off. 19.629 (0.08 mol) of 0-penzylcomenamic acid, 0.48 g of dimethylaminopyridine and 0.64 g of n-hydroxybenzotriazole are added to the filtrate. The mixture is stirred at room temperature for 1 hour. Dicyclohexylcarbodiimide 18.139 (0,
088 mol) is added at room temperature and the mixture is stirred overnight. The precipitate (dicyclohexylurea) was filtered off, the filtrate was evaporated under reduced pressure and then adjusted to pH 7.5 with sodium bicarbonate.
Triturate the residue with water adjusted to . The precipitate is filtered off to give the title compound 369.

E) 3-[[[1,4-dihydro-4-oxo-5-(
phenylmethoxy)-2-pyridinyl]carbonylcoaminoco-2-oxo-1-imidazolidinecarboxylic acid.
2-[[3-[[(
1.

4-dihydro-4-xo-5-(phenylmethoxy)
-2-pyridinylcocarbonylcoamino]-2-oxo-1-imidazolidinyl]carbonyl]hydrazinecarboxylic acid 1,1-dimethylethyl ester (36 g) is added at -10°C with stirring.

The mixture is stirred at 0° C. for 1 hour, the trifluoroacetic acid is removed under reduced pressure and the residue is triturated with ether to give the trifluoroacetate salt 419 of the title compound. The trifluoroacetate is suspended in water with cooling and adjusted to pH 7 with 2N sodium hydroxide. The precipitate was filtered to obtain the title compound 2.
Get 1.99.

F) 3-[[(1,4-dihydro-5-hydroxy-4
-oxo-2-pyridinyl)carbonyl]amino]-2
-Oxo-1-imidazolidinecarboxylic acid/hydrazide In 250 mQ of acetonitrile, 3-[[[1,4-dihydro-4-oxo-5-(phenylmethquine)-2-pyridinyl]carbonyl]amino]-2-oxo- 1-Imidazolidinecarboxylic acid hydrazide (21.9 g) is suspended. Add 75 mQ of bis-trimethylsilylacetamide to the suspension and stir the mixture into solution. 10 g of palladium/activated carbon (10%) are added to the solution and hydrogen is passed through the mixture with vigorous stirring. Debenzylation is complete after 1 hour.

After filtration, 15 m+2 methanol and 10 drops of acetic acid are added to precipitate the title compound. Yield t 0.8g. Stirring this mixture with 150 iQ of ethanol yields 8.87 of the title compound. Melting point: 205°C (decomposition).

G)(S)-[1-[[[[2-[[3-[[(1,4
-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-I-imidazolidinyl]carbonylcosulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid phenylmethyl ester Crude 3-[[(1,4-dihydro-5-hydroxy-4-
2-pyridinyl)carbonyl]amino]-2-
Oxo-1-imidazolidinecarboxylic acid/hydrazide 5
．． N-methyl-N-(
trimethylsilyl)trifluoroacetamide 14.9
++o2 (0.08 mol) is added and the mixture is stirred into solution at 50° C. (solution A).

To a suspension of 4.49 C0.02 mol of (S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone) in 160 ml of ethyl acetate is added 1.76 m of chlorosulfonyl isocyanate at room temperature.

The mixture is stirred for 1 hour (solution B).

Add solution A to solution B (water cooling). After stirring for 1 hour, 2.8 ml (0.02 mol) of triethylamine are added to the mixture and then stirred overnight at room temperature. Another 2°8m (!
of triethylamine followed by ice water. Stir the mixture thoroughly for 1 hour and separate the layers. pH the aqueous phase
3 and separate the precipitate.

Crude product yield 5.3g.

Dissolve the compound in acetone/water and adjust the pH of the solution to 6.5 by adding 2N sodium hydroxide.

After removing the acetone under reduced pressure, the aqueous solution is filtered and lyophilized to yield 5.59 g of the crude sodium salt of the title compound. The crude sodium salt was chromatographed on a macroreticular styrene-divinylbenzene copolymer to yield a purified material of 0.64
Get 9. This is dissolved in water and acidified with 2N hydrochloric acid to precipitate the title compound. Yield 0.5g.

HXS )-N-[3-[[2-[[[(3-amino-2-oxo-1-azetidinyl)carbonyl]amino]sulfonyl]hydrazino]carbonyl]-2-oxo-■-imidazolidinyl]-1, 0.59 (S)-[1-[[[2-[[3
-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo'/-1~imidazolidinyl]carbonyl]sulfonyl]aminococarbonyl]-2-oxo- Add 3-azetidinyl]carbamic acid phenylmethyl ester. The mixture is stirred at room temperature overnight and evaporated under reduced pressure. Trituration of the residue with ethyl acetate yields a substantial amount of the title compound.

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-oxo1-imidazolidinyl]carbonylcohydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino
oxy]-2-methylpropionic acid diphenylmethyl ester 0.359 (0,0008
(mol) of (Z)-2-amino-α-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid with triethylamine 0
．． Add 34m12. Cool the mixture to -30°C,
Add 0.171 of diphenylchlorophosphate. The reaction mixture is stirred at -30° C. for 1 hour (solution A).

(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-oxo-2- Add 0.7 molecules of bis-trimethylsilylacetamide to the suspension of pyridine carboxamide (solution B). At -30℃,
Add solution B to solution A.

The mixture is stirred at -10°C for 2 hours and at 0°C for 1 hour and evaporated under reduced pressure. Treatment of the residue with water gives 0.79 crude title compound. Melting point: 155°C (decomposed). J) [35(
Z)]-2-[[[1-('2-amino-4-thiazolyl)-2-[[1-[[[[2-[[3-[[(1,4
-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-l-imidazolidinyl]carbonyl]hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]
amino]-2-oxoethylidene]amino]oxy]-
[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 0.79 (0,00077 mol) suspension was added with 6 mQ of trifluoroacetic acid at -10°C. Add with . The mixture is stirred at -10°C for 1 hour. Addition of ether at -10°C precipitates the trifluoroacetate of the starting free acid.

The precipitate was suspended in cooled water and the I)H was adjusted with 2N sodium hydroxide at 5.5. Freeze-dry to 0.5! l
A mixture of materials is obtained. This complex is purified by macroreticular styrene-divinylbenzene copolymer chromatography to yield 0.19 pure title compound.

Example 23 [35(Z)]-2-[[[1-(2-Amino-4-thiazolyl)-2-[[1-[[[[2-[(1,4-dihydro-5-hydroxy -4-oxo-2-pyridinyl)carbonyl]-2-methylhydrazino]sulfonyl]
[amino]carbonylco-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]
-Production of 2-methylpropionic acid disodium salt A) 1,4-dihydro-4-oxo-5-(phenylmethoxy)-1-(phenylmethyl)-2-pyridinecarboxylic acid 1-methylhydrazide dichloromethane 150x
N, O-dibenzylcomenamyl chloride (0,15
ff12). 26.2 d (0.5 mol) of methylhydrazine are added to this suspension followed by 150 d of acetonitrile. The mixture is stirred at room temperature overnight. The cloudy solution is evaporated under reduced pressure and triturated with 300 ml of water. The resulting solid material was filtered and dried at 26
A composite material of ゜39 was obtained. Recrystallization of the compound from water yields the pure title compound. Melting point: 138-142°C.

B) (S)-1,4-dihydro-4-oxo-5-(phenylmethoxy)-1-(phenylmethyl)-2=pyridinecarboxylic acid/l-methyl-2-[[[2-oxo- 3-[[(phenylmethoxy)carbonyl]amino]
-1-azetidinyl]carbonyl]amino]sulfonyl]hydrazide 1,4-dihydro-4-oxo-5-(phenylmethquin)-t-<phenylmethyl)-2-pyridinocarboxylic acid/l-methylhydrazide (1 , 82 g, 0.005 mol) in ethyl acetate 2011Q.

A total of 1.85x (2 (0.01 mol)) of N-methyl-N-(trimethylsilyl)trifluoroacetamide is added at room temperature. The mixture is stirred at 60° C. for 4 hours (suspension A).

(S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone (1.1 g, 0.00
5 mol) was suspended in 40 mQ of ethyl acetate, and 0.5 mQ of chlorosulfonyl isocyanate was added. The mixture is stirred at room temperature for 1 hour to obtain a solution (solution B).

Add 1.2ml of triethylamine to solution B (water cooling)
, then 20 mσ of dichloromethane and! 8 Add suspension A. Stir the suspension overnight at room temperature. Dichloromethane 30 to a slightly cloudy solution! lσ and 20 rtt (l) of water are added and the mixture is stirred at room temperature for 1 hour.

The pI of the aqueous phase (is 6,5-7. 60 g of ethyl acetate is added and the aqueous phase is washed twice with a mixture of dichloromethane/ethyl acetate (1:3). The organic phases are combined and dried (magnesium sulfate). ), evaporated to give a syrup of 4.59, which was allowed to stand and crystallize over the weekend.

Treatment with ether gives 2.69 of the crude title compound.

C) 1,4-dihydro-5-hydroxy-4-oxo-
2-Pyridinecarboxylic acid 2-[[[(3-amino-2
-oxo-azetidinyl)carbonyl]amino]sulfonyl]-1-methylhydrazide trifluoroacetate dimethylformamide 60 (S)-1,4-dihydro-4=oxo-5-(phenylmethoxy)-1- (
2 g of phenylmethyl)-2-pyridinecarboxylic acid/l-methyl-2-[[[2-oxo-3-[[(phenylmethoxy)carbonylkoamino]-1-azetidinyl]carbonyl]amino]sulfonyl]hydrazide. 1.1 mρ of trifluoroacetic acid is added to the suspension, followed by 1 g of palladium/charcoal (10%). After bubbling nitrogen through the solution, hydrogen was passed through the solution for 60 minutes with stirring, the catalyst was filtered off, the filtrate was evaporated under reduced pressure, and the residue was triturated with ether to give the crude title compound of 1.19. obtain.

Yield 96.6%.

D) [3S(Z)]-2-[[[1-(2-amino-4
-thiazolyl)-2-[[1-[[[[2-[(1,4
-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]-2-methylhydrazino]sulfonylcoamino]carbonyl]-2-oxo-3-azetidinyl]aminoco2-oxoethylidene]aminocooxyco2 -Methylpropionate diphenylmethyl ester acetonitrile 30j! (Z)-2-amino- in 12
A suspension of 0.889 (0,002 mol) of α-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxykoimino]-4-thiazoleacetic acid was added with 0.711Q (0,000 mol) of triethylamine. 0.005 mol) and then 0.44 x 12 (0.002 mol) diphenyl chlorophosphate at 30°C. The mixture is stirred at -30° C. for 1 hour (solution A).

1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid 2-[[
A suspension of 1.29 (0,002 mol) of [(3-amino-2-oxo-azetidinyl)carbonyl]amino]sulfonyl]-1-methylhydrazide trifluoroacetate was added with 2 portions of bis-trimethylsilylacetamide (approx. o, o
osmol) at room temperature to form a clear solution after 30 minutes (solution B).

Add solution B to solution A dropwise (about 10 minutes) at -30°C.

The temperature is maintained at -10°C for 1 hour and at 0°C for an additional hour.

The solvent was evaporated and the residue was treated with water, filtered and dried.2.
49 crude title compound is obtained.

E) [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-azetidinylcoaminoco2-oxoethylidene]amino]oxy ]-2-Methylpropionic acid disodium salt A mixture of 20 mQ of trifluoroacetic acid and 4 liters of anisole was mixed with crude [3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)] at 1θ°C. -2-[[1-[[[[2-[
(1,4-dihydro-5-hydroxy-4-oxo-2
-pyridinyl)carbonyl-2-methylhydrazinocosulfonyl]amino]carbonyl]-2-oxo-3-
2.4 g of azetidinyl]amino]-2-oxoethylidenecoamino]oxy]-2-methylpropionic acid diphenylmethyl ester are added. The mixture is stirred at -10°C for 1 hour and ether is added at -10°C to precipitate the reaction product. Yield: 1 crude trifluoroacetate of the title compound
．． 12g.

An acetone/water suspension of this compound is converted to the sodium salt by adding 2N sodium hydroxide and lyophilizing. The sodium salt is purified by chromatography on a macroreticular styrene-divinylbenzene copolymer (M in water). Example 24 (3S)-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[[(1,4-dihydro-5
-Hydroxy-4-oxo-2-pyridinyl)methylcoamino]sulfonylcoaminoco-luponylco-2-oxo-3-azetidinylcoaminoco2-oxoethylidene]aminocooxy]-2-methylpropionic acid preparation A) 2 -(Hydroxymethyl)-5-(phenylmethoxy)-4H-pyran-4-one 5-hydroxy-2-(hydroxymethyl)-4H-bilan-4-one (56,8 g) in 400 mQ methanol
. The mixture was heated to reflux for 3.5 h, cooled and IQ
Pour into water. The resulting solid is filtered and contains approximately 1.51 parts water,
Wash with 200 mQ of ethanol and 400 mQ of hexane. After drying under high vacuum, the weight of the product is 55.79
Met.

B) 1,4-dihydro-2-(hydroxymethyl)-5
-(Phenylmethoxy)-4-pyridinone 2-(hydroxymethyl)-5-(phenylmethoxy)-4H-pyran-4-one (9,659,4159 mmol), 95 inches of concentrated ammonia and 20 parts of ethanol were heated overnight. Reflux. Ammonium hydroxide 7F++12 is added and the mixture is refluxed for 2 hours and cooled. The resulting brown solid is filtered and washed with water until the washings are neutral. The crude product is suspended in ethanol, filtered, washed with ethanol and hexane, and dried under reduced pressure. The description of the title compound is 7.6
It is 1g.

C) 1-(chloromethyl)-1,4-dihydro-5-(
phenylmethoxy)-4-viridinone hydrochloride 1,4-dihydro- in chloroform (15ylf2)
2-(Hydroquinemethyl)-5-(phenylmethoxy)
A suspension of -4-pyridinone (3 g, 12.99 mmol) was cooled to 0°C under argon and thionyl chloride (6,
1i (2,83,62 mmol).

A homogeneous solution forms within a few minutes. After stirring for an additional 5 minutes, a cream colored solid precipitates out. Remove the cooling bath and heat the mixture to reflux for 45 minutes. The mixture is cooled to O'C and the white suspended material is filtered, washed with chloroform and hexane and dried under reduced pressure. The profile of the title compound is 3.65y.

D) 2-(azidomethyl)-1,4-dihydro-5-(
l-(chloromethyl)-1,4- in 70 ml of phenylmethoxy)-4-pyridinone dimethylformamide.
Dihydro-5-(phenylmethoxy)-4-viridinone hydrochloride (3°599.12.54 mmol)
, sodium and (4,089,62,7 mmol)
and noisopropylethylamine (2,19xL
12.54 mmol) at room temperature under argon.
Stir for 5 days.

An additional 4.089 ml of sodium azide was added and the mixture was reduced to 4.089 ml of sodium azide.
Heat at 5-50°C for 2 hours. After cooling, the reactants were heated to 500 ml.
Pour into 1RQ of water to obtain an insoluble white solid.

Lower the l)H of the supernatant liquid from 8.5 to 7.5 with dilute hydrochloric acid,
Filter the white solid. After washing with water, acetone and hexane, the solid is dried under reduced pressure. Yield of the title compound is 2.81 g.

E) 2-(,azidomethyl)-1,4-')hydro-5-(phenylmethoxy)-4- in 2-(aminoethyl)-4-oxo-5-(phenylmethquine)pyridinedimethylformamide 100xC A suspension of pyridinone (2,030 g, 7.93 mmol) and platinum oxide (200 mg) was added under a hydrogen atmosphere.
Stir at room temperature for 6 hours. The catalyst was filtered off and the solution was concentrated under reduced pressure to yield the title compound I.

59 is obtained as a gray powder.

FX3 S)-1-[[C[[(1,4-dihydro-5
-Hydroquine-4-year-old xo-2-pyridinyl)methyl]
[amino]sulfonyl]amino]carbonyl]-2-oxo-3-[[(phenylmethoxy)carbonyl]amino]azetidine 2-(aminoethyl)-4=oxo-5-(phenylmethoxy)pyridine ( 2゜330
N-methyl-
N=(trimethylsilyl)trifluoroacetamide (
3,711σ, 20.26 mmol). The resulting solution is stirred at room temperature for 30 minutes and then cooled to 0°C. At the same time, (S)-3-C[(
Chlorosulfonyl isocyanate (882 μm 2
, 10.13 mmol). The resulting solution was stirred at room temperature for 30 min, then cooled to 0 °C and treated with triethylamine (4,23 mQ, 30.39 mmol), followed by the silylated 2-(aminoethyl)-4-
Treat with oxo-5-(phenylmethoxy)pyridine.

The mixture is stirred at room temperature for three days.

The mixture was concentrated under reduced pressure and the residue was dissolved in acetonitrile/water (
40/60) and reduce the I)H to 2.9 to separate a dark oil. Cool to 5°C to solidify the oil.

The solid was separated, washed four times with water and dried under reduced pressure.3.
49 crude title compound is obtained.

The crude title compound is dissolved in minimal dimethylformamide and passed through a macroreticular styrene-divinylbenzene copolymer column (IQ). The column is eluted stepwise with an acetone/water gradient. The pickled material elutes at approximately 65% acetone. Combine appropriate amounts and freeze-dry.
2.699 of the title compound is obtained.

GX3S) -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 dimethylformamide 16 x g
(3S)-1-[[[[(1,4-dihydro-5
-hydroxy-4-oxo-2-pyridinyl)methyl]
aminocosulfonyl]amino]carbonyl]-2-oxo-3-[[(phenylmethoxy)carbonyl]amino]azetidine (912 mg, l, 64 mmol), p-
Toluenesulfonic acid monohydrate (625u, 3.28
mmol) and 10% palladium/activated carbon (t90o
) under a hydrogen atmosphere until 3.28 mmol (73 molecules) of hydrogen is consumed (approximately 3 hours).

(Z)-2-Amino-α-[[2-(nophenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid (846 mg, 1.804 mmol) in dimethylformamide 1BmQ ) diphenyl chlorophosphate (374 μm
2,1.804 mmol), then triethylamine (
450 μm2, 3.28 mmol). The solution is stirred at -20°C for 1 hour and the above hydrogenation mixture is added. Triethylamine (921 μm2, 6.6 mmol) is then added. The resulting solution was heated at -20°C for 1 hour.
Stir overnight at 5°C.

The catalyst was filtered off, the volatiles were removed under reduced pressure and the resulting oil was washed with a minimum amount of acetone/water (75/25XI).
) (5,2) and added dropwise to a stirred suspension of 20 mQ of 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 solid. This solid is dissolved in a minimum amount of acetonitrile/water (40/60) and passed through a macroreticular styrene-divinylbenzene copolymer column (800 uC) eluting with an acetonitrile/water gradient. .

The desired substance elutes at approximately 30% acetonitrile. Both appropriate portions are combined and lyophilized to yield the title compound.

HX3S)-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 dichloromethane (3S)-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[(1,4-dihydro-5
-Hydroxy-4-oxo-2-pyridinyl)medyl]
Stirred suspension of diphenylmethyl]-2-methylpropionic acid diphenylmethyl ester (131 mg, 0.113 mmol) Add trifluoroacetic acid C4,7m to the solution at 0°C.
Add Q). After stirring at 5℃ for 45 minutes, add 2mQ of toluene.
is added and the volatiles are removed under reduced pressure. The resulting oil is washed with hexane (3x4xQ) and triturated with ether lOmQ to give a solid. The solid is dissolved in ether (l
Wash once with Omρ) and dry under reduced pressure. The above reaction and preparation procedure was carried out using 0.166 mmol of (3S)-2-[[
[1-(2-amino-4-thiazolyl)-2-[[1-
[[[[[(1,4-dihydro-5-hydroxy-4-
Repeat for oxo-2-pyridinyl)methyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropionic acid diphenylmethyl ester. Combine the crude solids and add acetonitrile/
Dissolve in water (40/60X pH 2,5) and chromatograph on a column (200 mg) of macroreticular styrene-divinylbenzene copolymer 0 using an acetonitrile/water gradient. The desired substance is acetonitrile/water (20
/80).

Combine the appropriate portions and lyophilize to yield 103x9 of the title compound as a white solid. Melting point: 180°C (decomposition).

Claims (1)

[Claims] 1. Formula, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R is ▲ There are ▲ Numerical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas There are , chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ R_1 is acyl derived from carboxylic acid The groups R_2 and R_3 are the same or different and are each hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or a 4, 5, 6 or 7-membered heterocyclic group, or one of R_2 and R_3 is hydrogen, The other is azide, halomethyl, dihalomethyl, trihalomethyl,
Alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -CH_2X_1, -
S-X_2, -O-X_2, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Or -A-C-NX_6X_7, Amino, (substituted phenyl)carbonylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyloxy, phenyl, substituted phenyl, cyano, ▲Numerical formula, chemical formula, table, etc.▼, -S-X_2, or -O -X_2, X_2 is alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl,
alkanoyl, phenylalkanoyl, (substituted phenyl)alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, or heteroarylcarbonyl, one of X_3 and X_4 is hydrogen and the other is hydrogen or alkyl, or X_3 and X_4 are the carbons to which they are bonded Combined with the atom, cycloalkyl,
substituted amino) carbonyl, or cyano; X_6 and X_7 are the same or different, each hydrogen, alkyl, phenyl or substituted phenyl; or
A is a 4-, 5-, 6- or 7-membered heterocyclic group when combined with the nitrogen atom to which they are bonded, A is -CH=CH-, -(CH_2)m-, -(CH_
2) m-O-, -(CH_2)m-NH- or -CH
＿2-S-CH_2-, m is 0, 1 or 2, A is a single bond, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, -
NH-, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, A_2 is a single bond, -NH-, -CH_2-CH_2-N
H-, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, A_3 is -(CH_2)p-, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, -NH-CH_2
-, -O-CH_2-, ▲There are mathematical formulas, chemical formulas, tables, etc.▼
, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, A_4 is -NH-, -(CH_2)p-, -(CH_2
)y-NH-, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲
There are mathematical formulas, chemical formulas, tables, etc.▼, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, A_5 is a single bond, -CH_2-, -NH-CH_2-,
-N=CH-, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, A_6 is a single bond, -CH=CH- or -(CH_2)
t-, p is 0 or 1, y is 2, 3 or 4, q is 0 or 1, t is 1, 2, 3 or 4, and X is hydrogen, carboxyl or carbamoyl], or A pharmaceutically acceptable salt thereof. 2. The compound according to item 1 above, wherein R is ▲a mathematical formula, a chemical formula, a table, etc.▼. 3. The compound according to item 1 above, wherein R is ▲a mathematical formula, a chemical formula, a table, etc.▼. 4. The compound according to item 1 above, wherein R is ▲Numerical formula, chemical formula, table, etc.▼. 5. The compound according to item 1 above, wherein R is ▲Numerical formula, chemical formula, table, etc.▼. 6. The compound according to item 1 above, wherein R is ▲a mathematical formula, a chemical formula, a table, etc.▼. 7. The compound according to item 1 above, wherein R is ▲a mathematical formula, a chemical formula, a table, etc.▼. 8. The compound according to item 2 above, wherein A_1 is a single bond. 9. The compound according to item 2 above, wherein A_2 is -NH-. 10. The compound according to item 2 above, wherein A_8 is a single bond. 11. The compound according to item 1 above, wherein R is ▲a mathematical formula, a chemical formula, a table, etc.▼. 12. The compound according to item 1 above, wherein R_2 and R_3 are each hydrogen. 13. R_1 is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Rg is 2-amino-4-thiazolyl, Ri is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 1-carboxy-1-ethyl , or -CH_2-(CH_2)s-
The compound according to item 1 above, wherein C-COOH, s is 1, 2 or 3). 14, R_1 is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Rg is 2-amino)-4-thiazolyl, Ri is carboxymethyl, 1-carboxy-1-methylethyl, 1-carboxy-1-ethyl,
or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, s is 1, 2, or 3), the compound described in item 1 above. 15. R_1 is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Rg is 2-amino)-4-thiazolyl, Ri is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 1-carboxy-1- The compound according to item 2 above, wherein ethyl or ▲ has a mathematical formula, chemical formula, table, etc. ▼, s is 1, 2 or 3). 16, R_1 is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Rg is 2-amino)-4-thiazolyl, Ri is carboxymethyl, 1-carboxy-1-methylethyl, 1-carboxy-1-ethyl,
or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, s is 1, 2, or 3), the compound according to the above item 2. 17. R_1 is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Rg is 2-amino)-4-thiazolyl, Ri is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 1-carboxy-1- The compound according to item 11 above, which is ethyl or ▲ where there is a mathematical formula, chemical formula, table, etc. ▼, s is 1, 2 or 3). 18. The compound according to item 11 above, wherein R_1 is ▲Numerical formula, chemical formula, table, etc.▼ (Rg is 2-amino)-4-thiazolyl, Ri is carboxymethyl or 1-carboxy-1-methylethyl) . 19. The compound according to item 11 above, wherein R_2 and R_3 are each hydrogen. 20, [3S(Z)]-2-[[[1-(2-amino-
4-thiazolyl)-2-[[1-[[[[3-[[(1
,4-dihydro-5-hydroxy-4-oxo-2-pyrimidinyl)carbonyl]amino]-2-oxo-1-
imidazolidinyl]sulfonyl]amino]carbonyl]
-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropionic acid, or a pharmaceutically acceptable salt thereof. 21, [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-
The compound according to item 1 above, which is methylpropionic acid, or a pharmaceutically acceptable salt thereof. 22, [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]-
The compound according to item 1 above, which is 2-oxo-3-azetidinyl]amino]-2-oxo-ethylidene]amino]oxy]-2-acetic acid, or a pharmaceutically acceptable salt thereof. 23, [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-methylpropion The compound according to item 1 above, which is an acid or a pharmaceutically acceptable salt thereof. 24, [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, [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-methylpropionic acid; A compound according to item 1 or a pharmaceutically acceptable salt thereof. 26, [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]cyclopentanecarboxylic acid, or a pharmaceutically acceptable salt thereof. 27. The compound of formula (1), ▲mathematical formula, chemical formula, table, etc. is acylated with an R_1 acyl group derived from R_1-carboxylic acid, or the compound of formula (2), ▲mathematical formula, chemical formula, table, etc. There is a formula characterized by introducing a -CO-NH-SO_2R active group into the compound of ▼ ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ A method for producing a compound represented by ▼ or a pharmaceutically acceptable salt thereof [In the formula, R is ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ R_1 is an acyl group derived from carboxylic acid, R_2 and R_3 are the same or different and are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or 4-, 5-, 6- or 7-membered heterocyclic group, or one of R_2 and R_3 is hydrogen and the other is azide, halomethyl, dihalomethyl, trihalomethyl,
Alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -CH_2X_1, -
S - carboxyl,
Alkoxycarbonyl, alkanoylamino, phenylcarbonylamino, (substituted phenyl)carbonylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyloxy, phenyl, substituted phenyl, cyano, ▲Mathematical formula, chemical formula, table, etc.▼, -S-X_2, or -O-X_2, X_2 is alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl,
alkanoyl, phenylalkanoyl, (substituted phenyl)alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, or heteroarylcarbonyl, one of X_3 and X_4 is hydrogen and the other is hydrogen or alkyl, or X_3 and X_4 are the carbons to which they are bonded Combined with the atom, cycloalkyl,
substituted amino) carbonyl, or cyano, X_6 and X_7 are the same or different, each hydrogen, alkyl, phenyl or substituted phenyl or
_6 is hydrogen; −, −(CH_2)m−, −(CH_
2) m-O-, -(CH_2)m-NH- or -CH
＿2-S-CH_2-, m is 0, 1 or 2, A_1 is a single bond, ▲There are mathematical formulas, chemical formulas, tables, etc.▼,
-NH-, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, A_2 is a single bond, -NH-, -CH_2-CH_2-N
H-, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, A_3 is -(CH_2)p-, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, -NH-CH_2
-, -O-CH_2-, ▲There are mathematical formulas, chemical formulas, tables, etc.▼
, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, A_4 is -NH-, -(CH_2)p-, -(CH_2
)y-NH-, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲
There are mathematical formulas, chemical formulas, tables, etc.▼, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, A_5 is a single bond, -CH_2-, -NH-CH_2-,
-N=CH-, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, A_6 is a single bond, -CH=CH- or -(CH_2)
t-, p is 0 or 1, y is 2, 3 or 4, q is 0 or 1, t is 1, 2, 3 or 4, and X is hydrogen, carboxyl or carbamoyl].