JPH07316163A - Cephalosporin derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound having excellent antibacterial activity in a wide range of spectrum, effective even against an antibiotic-resistant bacterium such as MRS and useful as an antibacterial agent. CONSTITUTION:This is a compound of formula I [R<1> is H, a lower alkenyl, etc.; R<2> is H, an ester residue, etc.; R<3> is formula H or formula III (R<4> and R<5> are each a lower alkoxy, a not-substituted amino, etc., R<6> and R<7> are each H, a halogen, etc.; A-ring is 4- or 5-membered nitrogen-containing heterocyclic ring), etc.; X is a methine or N] or its salt, e.g. 7beta-[(Z)-2-(2-amino-4- thiazolyl)-2-(methoxyimino)acetamido]-3-[(E)-2-(2,2-dimethyl-5- isoxazolidinio]vinyl]-3-cephem-4-carboxylate. The compound is obtained, e.g. by cyclizing a butadiene compound of formula IV (R<3> is H, a negative electric charge, etc.; R<1a> is R<1> except H or a hydroxyl-protecting group; R<9> is an amino- protective group) with an azodicarboxylate compound in an inert solvent under stirring followed by deblocking the obtained product.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a cephalosporin derivative or a salt thereof which is useful as a medicine, especially as an antibacterial agent, and an intermediate of the cephalosporin derivative or a salt thereof.

[0002]

2. Description of the Related Art Since cephalosporin antibacterial agents show a wide range of antibacterial activities against Gram-positive bacteria and Gram-negative bacteria, many synthetic studies of cephalosporins have been conducted. Among them, a compound in which an isoxazolidine ring is bonded to the 3-position of a cephalosporin skeleton in JP-A-3-232891 is a vinyl group in which a lower alkoxycarbonyl group or a cyano group is substituted in JP-A-56-55392. Compounds having are described. further,
JP-A-1-156984 describes a compound in which a 3- (carbamoylmethylethylmethylammonio) -1-propen-1-yl group is introduced at the 3-position of the cephalosporin skeleton. However, a better cephalosporin antibacterial agent is desired.

[0003]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a cephalosporin derivative which has a wide range of excellent antibacterial activities and is effective against antibiotic resistant bacteria such as MRSA.

[0004]

Means for Solving the Problems As a result of repeated studies on the synthesis of cephalosporin derivatives, the present inventors have found that they contain an oxygen atom at the 3-position of cephalosporin, which has a different chemical structure from conventional compounds. A compound having a vinyl group substituted with a nitrogen-containing heterocycle or a quaternary salt thereof or a compound having a 6-membered heterocyclic group containing two nitrogen atoms is excellent against a wide range of Gram-positive and Gram-negative bacteria. The present invention has been completed by finding out that it has antibacterial activity. The present invention has the general formula (I)

[0005]

[Chemical 9]

(The symbols in the formulas have the following meanings: R ¹ : hydrogen atom, lower alkenyl group, lower alkynyl group, cycloalkyl group, protective group for hydroxyl group or substituted or unsubstituted lower alkyl group R ² : Hydrogen atom, ester residue or negatively charged R ³ : (1) Group represented by the following formula

[0007]

[Chemical 10]

R ⁴ and R ^{5 are the} same or different and each is a lower alkoxy group, a substituted or unsubstituted amino group, or a substituted or unsubstituted R ⁴ and R ^{5 which} are integrally formed with an adjacent tetrahydropyridazinyl group. Unsubstituted fused 5- or 6-membered ring group (2) Group represented by the following formula

[0009]

[Chemical 11]

R ⁶ , R ^{7 are the} same or different hydrogen atoms,
Halogen atom, amino group, azido group, unsubstituted or amino group, azido group, carbamoyl group or halogen atom-substituted lower alkyl group, carbamoyl group, or substituted or unsubstituted 5- or 6-membered heterocyclic group (heterocyclic nitrogen The atom can be a quaternary amine together with a substituent.) A ring: 4- to 5-membered nitrogen-containing heterocycle which may contain an oxygen atom X: methine group (-CH =) or nitrogen atom, and so on)
The cephalosporin derivative represented by or its salt, and the intermediate body of this cephalosporin derivative represented by the following general formula (II).

[0011]

[Chemical 12]

(The symbols in the formulas have the following meanings. R ³ is as described above, R ⁸ is a hydrogen atom, a negative charge or a protecting group for a carboxyl group. The same applies hereinafter.) Less than,
The compounds (I) and (II) of the present invention will be described in detail. In the present specification, unless otherwise specified, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms.

Here, as the "lower alkyl group", specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, t
ert-butyl group, pentyl (amyl) group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group Group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3- Dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-
A trimethylpropyl group, a 1-ethyl-1-methylpropyl group, a 1-ethyl-2-methylpropyl group and the like can be mentioned. Of these groups, a methyl group, an ethyl group and a propyl group are preferable.

The "lower alkenyl group" is a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, vinyl group, propenyl group, butenyl group, methylpropenyl group, methylpropenyl group. Group, dimethylvinyl group, pentenyl group, methylbutenyl group, dimethylpropenyl group, ethylpropenyl group, hexenyl group, dimethylbutenyl group, methylpentenyl group and the like. The "lower alkynyl group" is a linear or branched alkynyl group having 2 to 6 carbon atoms, and specifically, an ethynyl group, a propynyl group, a butynyl group, a methylpropynyl group, a pentynyl group, a methylbutynyl group. Group, hexynyl group and the like. Examples of the “cycloalkyl group” include those having 3 to 8 carbon atoms, and specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and a cyclooctyl group.

The "substituted lower alkyl group" means substituted with one or more halogen atoms, a carboxyl group, a lower alkoxycarbonyl group, a cycloalkyl group and the like, and is a substituent. The cycloalkyl group may be unsubstituted or substituted with one or more lower alkyl groups, lower alkoxy groups, halogen atoms, carboxyl groups or lower alkoxycarbonyl groups. Here, the “lower alkyl group” and the “lower alkoxy group” are as described above, and the “lower alkoxycarbonyl group” includes a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group,
Butoxycarbonyl group, isobutoxycarbonyl group, s
ec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxy (amyloxy) carbonyl group, isopentyloxycarbonyl group, tert-pentyloxycarbonyl group, neopentyloxycarbonyl group, 2-methylbutoxycarbonyl group, 1,2- Examples thereof include a dimethylpropoxycarbonyl group, a 1-ethylpropoxycarbonyl group, a hexyloxycarbonyl group, and the "lower alkoxy group" includes a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, sec-butoxy group, te
rt-butoxy group, pentyloxy (amyloxy)
Group, isopentyloxy group, tert-pentyloxy group, neopentyloxy group, 2-methylbutoxy group,
1,2-dimethylpropoxy group, 1-ethylpropoxy group, hexyloxy group and the like can be mentioned.

Examples of the "hydroxyl protecting group" include lower alkylsilyl groups such as trimethylsilyl group and tert-butyldimethylsilyl group, such as methoxymethyl group, 2
-Lower alkoxymethyl group such as methoxyethoxymethyl group, for example, tetrahydropyranyl group, for example, benzyl group, p-methoxybenzyl group, 2,4-dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, trityl group Aralkyl groups, such as formyl groups,
Acyl group such as acetyl group, for example, tert-butoxycarbonyl group, 2-iodoethoxycarbonyl group, 2,
Lower alkoxycarbonyl group such as 2,2-trichloroethoxycarbonyl group, for example, 2-propenyloxycarbonyl group, 2-chloro-2-propenyloxycarbonyl group, 3-methoxycarbonyl-2-propenyloxycarbonyl group, 2-methyl- Alkenyloxycarbonyl groups such as 2-propenyloxycarbonyl group, 2-butenyloxycarbonyl group, cinnamyloxycarbonyl group, for example, benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, o-nitrobenzyloxycarbonyl group, p Examples thereof include an aralkyloxycarbonyl group such as a -nitrobenzyloxycarbonyl group and the like, and a 2-propenyloxycarbonyl group and a p-nitrobenzyloxycarbonyl group are preferable. Further, the “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The "ester residue" in R ² is
An ester residue that is metabolized and hydrolyzed in the living body, for example, a lower alkanoyloxy lower alkyl group,
Lower alkenoyl lower alkyl group, cycloalkylcarbonyloxy lower alkyl group, lower alkenoyloxy lower alkyl group, lower alkoxy lower alkanoyloxy lower alkyl group, lower alkoxy lower alkyl group, lower alkoxy lower alkoxy lower alkyl group, lower alkoxycarbonyloxy lower Alkyl group, lower alkoxy lower carbonyloxy lower alkyl group, benzoyloxy lower alkyl group, 2-oxotetrahydrofuran-
5-yl group, 2-oxo-5-alkyl-1,3-dioxolen-4-ylmethyl group,

[0018]

[Chemical 13]

Examples include common ester residues such as a tetrahydrofuranylcarbonyloxymethyl group and a 3-phthalidyl group. The following formula for R ³

[0020]

[Chemical 14]

In the group represented by, the "substituted amino group" of R ⁴ and R ⁵ is, for example, an amino group in which one or two lower alkyl groups described above are substituted, and specifically, Methylamino group, ethylamino group, propylamino group,
Examples thereof include a dimethylamino group, a diethylamino group and a methylethylamino group. Also, "lower alkoxy group"
Is as described above, but among these groups, a methoxy group, an ethoxy group, and a propoxy group are preferable.
Examples of the “substituted or unsubstituted fused 5- or 6-membered ring group in which R ⁴ and R ⁵ are integrally formed with the adjacent tetrahydropyridazinyl group” include

[0022]

[Chemical 15]

And the like. These rings may have a "lower alkyl group" as a substituent at any position, and the "lower alkyl group" is as described above. , And preferably a methyl group, an ethyl group and a propyl group. Also, the following formula

[0024]

[Chemical 16]

In the group represented by, the "halogen atom" for R ⁶ or R ⁷ is a fluorine atom, a chlorine atom, an iodine atom or an iodine atom. "Lower alkyl group"
Is as described above, preferably a methyl group, an ethyl group and a propyl group. "Replaced or not replaced 5
Examples of the "to 6-membered heterocyclic group" include a pyridyl group, a furyl group, a 1-methylpyridinio group, a trimethylpyridinio group and a 2-nitrofuryl group. The "4- to 5-membered nitrogen-containing heterocycle which may contain an oxygen atom" represented by "A ring" includes an azetidinyl group, a pyridyl group, an oxazolyl group, an oxazolinyl group, an oxazolidinyl group,
Examples thereof include an isoxazolyl group, an isoxazolinyl group, an isoxazolidinyl group, a pyridinio group, an oxazolinio group, an oxazolidinio group, an isoxazolinio group, and an isoxazolidinio group. Any oxygen-containing 5-membered nitrogen-containing heterocycle is preferable, and a non-aromatized group is particularly preferable, and isoxazolinyl group, isoxazolidinyl group, isoxazolinio group,
Examples thereof include isoxazolidinio group. The "amino group-protecting group" in the compound of the present invention means a protecting group usually used by those skilled in the art, and typical examples thereof include a formyl group, an acetyl group, a propionyl group and the like as an acyl-based amino group protecting group. Lower alkanoyl group, methoxycarbonyl group, ethoxycarbonyl group, lower alkoxycarbonyl group such as tert-butoxycarbonyl group (hereinafter referred to as BOC), lower alkanesulfonyl group such as methanesulfonyl group, ethanesulfonyl group, methoxyacetyl group, methoxypropionyl group , Benzoyl group, benzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group or other aliphatic acyl group, or thienylacetyl group, thiazolylacetyl group, tetrazolylacetyl group or other heterocyclic lower alkanoyl group, azo Rylglyoxyloyl group, thienyl Okishiroiru heterocyclic acyl group such as a group.
Examples of the aralkyl-based amino group-protecting group include a benzyl group, a p-nitrobenzyl group, a benzhydryl group and a trityl group. Further, a tri-lower alkylsilyl group such as trimethylsilyl group can be mentioned.

Examples of the protective group for the carboxyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group and te.
lower alkyl groups such as rt-butyl group, eg 2,2,2
-Halo-substituted lower alkyl groups such as trichloroethyl group, 2,2,2-trifluoroethyl group, etc., such as acetoxymethyl group, propionyloxymethyl group, pivaloyloxymethyl group, 1-acetoxyethyl group, 1-propionyloxy Lower alkanoyloxyalkyl group such as ethyl group, for example, 1- (methoxycarbonyloxy) ethyl group, 1- (ethoxycarbonyloxy) ethyl group, 1-
Lower alkoxycarbonyloxyalkyl group such as (isopropoxycarbonyloxy) ethyl group, for example, 2-propenyl group, 2-chloro-2-propenyl group, 3-methoxycarbonyl-2-propenyl group, 2-methyl-2-
Lower alkenyl groups such as propenyl group, 2-butenyl group, cinnamyl group, for example, benzyl group, p-methoxybenzyl group (hereinafter referred to as PMB), 3,4-dimethoxybenzyl group, o-nitrobenzil group, p-nitrobenzyl group , Benzhydryl group, bis (p = methoxyphenyl)
Aralkyl groups such as methyl group, for example (5-methyl-2-
(5-substituted-2-oxo-1,3-dioxole-4-, such as oxo1,3-dioxol-4-yl) methyl group
Yl) methyl group, eg trimethylsilyl group, tert
Examples include tri (lower) alkylsilyl groups such as -butyldimethylsilyl group, indanyl group, phthalidyl group, methoxymethyl, and the like, and particularly 2-propenyl group, p-nitrobenzyl group, PMB, benzhydryl group, tert-butylmethylsilyl. A group and the like are preferable.

The compound (I) or (II) of the present invention may form an inner salt with the carboxyl group at the 4-position, depending on the kind of the substituent at the 3-position. In addition, it may have a carboxyl group at the 4-position or may form a salt with another acid or base depending on the kind of the substituent at the 3-position. Such salts are salts with acids or bases, and as salts with acids, mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, Oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid,
Examples thereof include acid addition salts with organic acids such as methanesulfonic acid, ethanesulfonic acid and glutamic acid. Examples of salts with bases include inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, organic bases such as methylamine, ethylamine, and ethanolamine, or salts with basic amino acids such as lysine, arginine, ornithine, and ammonium salts. To be

The compound (I) of the present invention has a 2-aminothiazolyl group, a 5-aminothiadiazolyl group or the like at the 7-position, and has an iminoether type oxime. It includes all geometrical isomers such as anti, optical isomers and tautomers. Also,
Since it has a double bond in the substituent at the 3-position, cis (Z),
There are trans (E) forms of geometric isomers. There is also an optical isomer showing R, S, or RS due to the carbon atom of the 4- to 5-membered nitrogen-containing heterocycle which may contain an oxygen atom and which is bonded to the vinyl group at the 3-position. The compound of the present invention (I
I) includes all Z- and E-form geometrical isomers, optical isomers and mixtures thereof based on the substituent at the 3-position. Further, the compound of the present invention can also form a hydrate, a solvate such as ethanol, or a polymorph.

Further, 7β- [2- (2-amino-4-thiazolyl) -2- (hydroxyimino) acetamide]
-3-[(E) -2- (2,2-Dimethyl-5-isooxazolidinio) vinyl] -3-cephem-4-carboxylate and 7β- [2- (5-amino-1,2). ，
4-thiadiazol-3-yl) -2-hydroxyiminoacetamide] -3-[(E) -2-((RS)-
2,2-Dimethyl-5-isooxazolidinio) vinyl] -3-cephem-4-carboxylate includes Z and E geometric isomers based on the 7-position substituent and mixtures thereof. . Inventive Compounds (I) and (II)
Of these, R3 is preferably a group represented by the following general formula

[Chemical 17] And more preferably in the following general formula

[Chemical 18] (The dotted line may form a double bond.). (Production Method) The compound of the present invention and the intermediate can be produced by applying various synthetic methods. The typical manufacturing method will be described below. First manufacturing method

[0030]

[Chemical 18]

(In the formula, R ¹ , R ² , R ⁴ , R ⁵ , R ⁸ and X have the above-mentioned meanings. R ^1a represents a group excluding a hydrogen atom in R ¹ and a protective group for a hydroxyl group, and R ⁹ Means an amino-protecting group.) The compound (VI) of the present invention undergoes a cyclization reaction with a butadiene compound represented by the general formula (III) and an azodicarboxylate represented by the general formula (IV). , A tetrahydropyridazinyl compound represented by the general formula (V) is obtained (first step), and the protective group of the compound (V) is removed (second step). The first step is carried out by stirring the compound (III) and a corresponding amount of the compound (IV) in an inert solvent under cooling or heating with stirring. Examples of the inert solvent include organic solvents such as methylene chloride, chloroform, acetonitrile, benzene and toluene. The removal of the protecting group in the second step may be carried out by a conventional method. For example, when the protecting group is a tri-lower alkylsilyl group, it can be easily carried out by treating with water. Also, a benzhydryl group,
When it is a protective group such as p-methoxybenzyl group, trityl group, tert-butyl group, and formyl group, formic acid, trifluoroacetic acid, trifluoroacetic acid-anisole mixed solution,
It is easily removed by treatment with an acid such as a hydrobromic acid-acetic acid mixed solution or a hydrochloric acid-dioxane mixed solution. Second manufacturing method

[0032]

[Chemical 19]

(Wherein R ^1a , R ¹ , R ² , R ⁶ , R ⁷ , R
⁸ , R ⁹ and X are as described above. The second production method is a method for producing a compound having a nitrogen-containing 5-membered heterocyclic-substituted vinyl group at the 3-position of the cephalosporin skeleton.
The target compound (IX) of the present invention in the production method A is the butadiene compound represented by the general formula (III) and the general formula (V)
A cyclization reaction with a nitrone compound represented by II),
The compound can be produced by obtaining an isoxazolidinyl compound represented by the general formula (VIII) (first step) and removing the protecting group of the obtained compound (VIII) (second step).

The first step is carried out by heating the compound (III) and the corresponding amount of the compound (VII) in an inert solvent at room temperature or under heating. Examples of the inert solvent include methylene chloride, chloroform, acetonitrile, ethyl acetate, tetrahydrofuran and the like. Removal of the protecting group in the second step is as described above. The compound (XII) of the present invention in the production method B can be obtained by using the nitrile oxide compound (X) in place of the nitrone compound (VII) used in the production method A and performing a cyclization reaction to give a compound of the general formula (X
It can be produced by obtaining an isoxazolinyl compound represented by I) (first step) and removing the protecting group of the obtained compound (XI) (second step). In the first step, a butadiene compound represented by the general formula (III) and a reaction-corresponding amount of the compound (X) are cooled or heated, and an inert gas such as methylene chloride, chloroform, acetonitrile, ethyl acetate or dioxane. It can be reacted in a solvent. Third method

[0035]

[Chemical 20]

(In the formula, R ^1a , R ¹ , R ² , R ⁸ , R ⁹ and X have the above-mentioned meanings. Z means a halogenosulfonyl group.) The third production method is cephalosporin. It is a method for producing a compound having a nitrogen-containing 4-membered heterocyclic-substituted vinyl group at the 3-position of the skeleton.
The compound (XV) of the present invention undergoes a cyclization reaction with the butadiene compound represented by the general formula (III) and the isocyanate compound represented by the general formula (XIII) to obtain the compound represented by the general formula (XI
The compound can be produced by obtaining a lactam compound represented by V) (first step) and removing the protecting group of the obtained compound (XIV) (second step). In addition, the lower alkyl group can be introduced by N-alkylating the lactam compound before removing the protecting group. In the first step, the compound (III) and a corresponding amount of the compound (XI
II) and is stirred in an inert solvent under cooling to room temperature. Examples of the inert solvent include methylene chloride, acetonitrile, chloroform, ethyl ether, aliphatic hydrocarbons, aromatic hydrocarbons and the like. The N-alkylation reaction is performed by a conventional method.
For example, according to the below-mentioned 5th manufacturing method. Removal of the protecting group is as described above. Fourth manufacturing method

[0037]

[Chemical 21]

(In the formula, R ¹ , R ² , R ³ , R ⁸ and X are as described above. R ¹⁰ is a protecting group for an acyl amino group in R ^9. ) Object of the present invention Compound (I) can be prepared by converting 3-substituted-7-amino-3-cephem-4-carboxylic acid (or protected carboxylic acid) represented by general formula (XVI) into general formula (XVII).
Α- (thiazolyl or thiadiazolyl)-
It can be produced by reacting α-substituted iminoacetic acid or a reactive derivative thereof, and optionally removing a protecting group from the reaction product. The reaction of compound (XVI) with compound (XVII) or its reactive derivative is usually carried out in a solvent under cooling to room temperature. The solvent is not particularly limited as long as it does not participate in the reaction. Commonly used solvents include acetone, dioxane, ethyl ether, tetrahydrofuran, methyl ethyl ketone, chloroform, dichloroethane, methylene chloride, ethyl acetate,
Examples include ethyl formate, dimethylformamide, dimethylsulfoxide, water and the like. These solvents may be appropriately mixed and used.

The compound (XVII) is used in the form of a free carboxylic acid and is also used in the reaction as a reactive derivative of the carboxylic acid. As the reactive derivative of carboxylic acid, active ester (for example, benzotriazole ester), mixed acid anhydride, acid halide, active amide, acid anhydride, acid azide and the like are used. Compound (XVII)
When N is used in the form of a free carboxylic acid, N, N-
It is preferable to use a condensing agent such as dicyclohexylcarbodiimide or N, N-diethylcarbodiimide. In addition, depending on the type of the reactive derivative of the carboxylic acid used, it may be preferable to react in the presence of a base in order to allow the reaction to proceed smoothly. Examples of such a base include inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate and potassium carbonate, and organic bases such as trimethylamine, triethylamine, dimethylaniline and pyridine. Removal of the protecting group from the product thus obtained can be easily carried out by treating with water when the protecting group is a tri-lower alkylsilyl group or the like. When it is a protective group such as benzhydryl group, p-methoxybenzyl group, trityl group, tert-butyl group, and formyl group, formic acid, trifluoroacetic acid-anisole mixed solution, hydrobromic acid-acetic acid mixed solution, hydrochloric acid-
It is easily removed by treating with an acid such as a mixed solution of dioxane.

Fifth Production Method (Betaine Production Method) In the case where the ring A is betaine, the nitrogen-containing heterocyclic compound and the lower alkyl halide or lower alkyl triflate are mixed in an inert solvent such as dimethylformamide, chloroform or benzene at room temperature. It can be produced by stirring under heating. Method 6

[0041]

[Chemical formula 22]

(In the formula, R ^1a , R ¹ , R ² , R ⁸ , R ⁹ and Y are as described above. Hal means a halogen atom.) The object compound (XXII) of the present invention has the general formula (XVII
A phosphorane compound represented by the general formula (XIX) produced from a triphenylphosphine compound represented by the formula (I) in the presence of a base is reacted with a carbonyl compound represented by the general formula (XX) to give a compound represented by the general formula (XXI) It can be prepared by obtaining the lactam compound shown and removing the protecting group of the obtained compound. The first step is Wittig
In the reaction, a compound represented by the general formula (XIX) is obtained by reacting the compound represented by the general formula (XVIII) with a commonly used base such as sodium hydroxide and a lithium compound.
A phosphorane compound represented by is obtained. The obtained compound (XIX) and an amount of the compound corresponding to the reaction thereof represented by the general formula (XX) are stirred under cooling or heating in an insoluble solvent to obtain the compound represented by the general formula (XXI).
As an inert solvent, methylene chloride, chloroform, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide,
Examples thereof include benzene, toluene and hexane. Removal of the protecting group is as described above.

Seventh Production Method (Salt Making Reaction) The compound of the present invention forming a salt can be produced by applying a conventional salt making reaction. For example, 2
-Add a butanol solution of alkali ethylhexanoate,
Next, an alkali metal salt is added by adding an organic solvent such as ethyl ether or ethyl acetate having different solubilities, and an equal amount or a small amount of an organic base such as dicyclohexylamine, triethylamine, cyclohexylamine, diethanolamine, arginine or lysine or a basic amino acid. It is possible to produce an organic base drug salt with a basic amino acid by adding an excess amount of the mixture, and an ammonium salt by adding aqueous ammonia. Isolation and purification of the compound (I) of the present invention and a salt thereof are carried out by a conventional method, and extraction, crystallization, and
Separation and purification by column chromatography is used. Eighth manufacturing method (manufacturing method of intermediate)

[0044]

[Chemical formula 23]

(Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ ,
R ⁷ , Z, R ⁸ and R ¹⁰ are as described above. The compound (XXIX) which is an intermediate of the compound of the present invention is 7-acylamino-3-, instead of the butadiene compound (III) which is the starting material in the above-mentioned first to third production methods.
Other than using the butadiene cephem compound (XXIV),
It can be manufactured in a similar manner. Therefore, this 7th
In the production method, only the acylation reaction of the 7-acylamino-3-butadiene cephem compound (XXIV) will be described. The acylation reaction is carried out by stirring the 7-amino-3-butadienecephem compound (XXIII) and the corresponding amount of the carboxylic acid or its reactive derivative (XXX) in an inert solvent at room temperature or under heating. be able to. Examples of the inert organic solvent include tetrahydrofuran, dioxane, ethyl ether, benzene, toluene, xylene, methylene chloride, dichloroethane, chloroform, dimethylformamide, ethyl acetate, acetonitrile and the like.

When the compound (XXX) is reacted as a free carboxylic acid, it is advantageous to carry out it in the presence of a condensing agent such as dicyclohexylcarbodiimide or 1,1'-carbonyldiimidazole. Examples of the reactive derivative of the compound (XXX) include acid halides such as acid chloride and acid bromide; acid azides; active esters with N-hydroxybenzotriazole and N-hydroxysuccinimide; symmetrical acid anhydrides; alkyl carbonates or p- Examples thereof include a mixed acid anhydride with toluenesulfonic acid. Depending on the type of reactive derivative, triethylamine,
It may be advantageous to add an organic base such as pyridine, picoline, lutidine, N, N'-dimethylaniline or the like or an inorganic base such as potassium carbonate, sodium hydroxide or the like to smoothly proceed the reaction. Pyridine can also serve as a solvent. The present invention has been described in detail above. The typical compounds included in the general formulas (I) and (II) of the present invention are listed below.

[0047]

[Table 1]

[0048]

[Table 2]

[0049]

[Table 3]

[0050]

[Table 4]

[0051]

[Table 5]

[0052]

[Table 6]

[0053]

[Table 7]

[0054]

[Table 8]

[0055]

[Table 9]

[0056]

[Table 10]

[0057]

[Table 11]

[0058]

[Table 12]

[0059]

[Table 13]

[0060]

[Table 14]

[0061]

[Table 15]

[0062]

[Table 16]

[0063]

[Table 17]

[0064]

[Table 18]

[0065]

[Table 19]

[0066]

[Table 20]

[0067]

[Table 21]

[0068]

[Table 22]

[0069]

[Table 23]

[0070]

[Table 24]

[0071]

[Table 25]

[0072]

[Table 26]

[0073]

[Table 27]

[0074]

[Table 28]

[0075]

INDUSTRIAL APPLICABILITY The compound of the present invention is a wide range of bacteria belonging to Gram-positive and Gram-negative bacteria, especially M which is a Gram-positive bacteria.
Excellent antibacterial activity against antibiotic resistant bacteria such as RSA.
As test substances, the inventive compound of the present invention described later, and ceftazidime and flomoxef as control compounds were used.

[0076]

[Table 29]

Therapeutic Effect on Intraperitoneal Infection of Mice The bacterial cells cultured overnight at 37 ° C. were suspended in mucin, and 0.5 ml of the suspension was added to mice (ICR or ddy strain mice,
4-5 weeks old), the strain was infected by inoculation by a conventional method. Two hours after the infection, 0.2 ml of the test solution was subcutaneously administered, and after observing life and death for 7 days, the ED ₅₀ was calculated by the Probit method or Weil method. In addition,
A group of 10 mice was prepared, and the test substance was dissolved in physiological saline. As a test compound, isomer B of the compound of Example 6 of the present invention was used as a control compound for the therapeutic effect on systemic infections caused by Staphylococcus aureus Smith (JP-A-1-159).
The compound described in Example 1 of JP-A-84 (hereinafter, E-107
7) and Flomoxef,
Pseudomonas aeruginosa
No. 10) and ceftazidime (Cefta) as control compounds for the therapeutic effect on systemic infections caused by nosa).
zidim) was used. Results: The compound of the present invention was about 10-fold higher in E-1077 and Flomoxef than Staphylococcus aureus Smith, and in Pseudomonas aeruginosa (P.
aeruginosa), E-1077 is about 2
Double, about 8 for ceftazidime
It showed a double infection protection effect.

The above ceftazidime (Ceftazidim)
e) is a compound that is effective against gram-negative bacteria, and particularly effective against Pseudomonas aeruginosa, which has been a problem as a causative bacterium of opportunistic infections, and is widely used clinically. The compound has a more excellent effect. Of the compounds of the present invention, the compound of the general formula (II) synthesizes the compound of the general formula (I) which is the compound of the present invention having excellent antibacterial activity by the method described in the fourth production method. Is useful as an intermediate. A preparation containing one or more kinds of the compound of the present invention as an active ingredient is prepared by using a carrier, an excipient and other additives which are usually used for preparation. The carrier or excipient for the preparation may be either solid or liquid, for example, lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa butter, ethylene glycol, etc. Examples include regular ones. The administration may be in any form of oral administration such as tablets, pills, capsules, granules, powders, solutions, etc., or parenteral administration such as intravenous injection, intramuscular injections, suppositories, transdermal agents, etc. Good. The dose is appropriately determined according to each case in consideration of symptoms, age of the administration subject, sex, etc.,
Generally, it is about 200 to 400 mg per day.

[0079]

The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. A production example of the raw material compound used in the examples will be described as a reference example.

Reference Example 1 (1) Under an argon atmosphere, dry tetrahydrofuran (6
4 ml) with p-methoxybenzyl 7β-[(Z) -2.
-(2-Tritylamino-4-thiazolyl-2- (methoxyimino) acetamido] -3-chloromethyl-3-
Cephem-4-carboxylate 6.36 g (8 mmo
l), (E) -3-Hydroxy-1-tributylstannyl-1-propene 2.78 g (8.03 mmol), bis (dibenzylideneacetone) palladium (0) 92 m
g (0.16 mmol) and tri (2-furyl) phosphine 74.4 mg (0.32 mmol) were added, and the mixture was heated under reflux for 2 hours. After completion, 50 ml of acetonitrile was added to the residue obtained by distilling off the solvent under reduced pressure, and adding 50 ml of hexane to the residue.
It was washed twice with 1 and the acetonitrile layer was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (2: 3, v / v) to collect fractions containing the desired product. The solvent was evaporated under reduced pressure to obtain a foamy product, which was ethyl acetate. Solidify with ether-hexane to give p-methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide] -3-[(E) -4-hydroxy. -2-butenyl] -3-cephem-4-carboxylate 6 g (92
%) Was obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard); δ (ppm): 2.88 (1H, dd, J = 14.2,7.3Hz), 3.17 (1H, dd, J = 14.
2,4.9Hz), 3.56 (1H, d, J = 18.1Hz), 3.74 (3H, s), 3.80 (3H,
s), 3.86 (2H, d, J = 4.9Hz), 4.66 (1H, t, J = 5.4Hz), 5.1-5.63
(3H, m), 6.71 (1H, s), 6.92 (2H, d, J = 8.3Hz), 7.2-7.3 (17H,
m), 8.82 (1H, s), 9.51 (1H, d, J = 7.8Hz) Positive ion-FAB-mass spectrum: m / z; 816
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 1784,1522,1250,70
2 cm ^-1

(2) The obtained p-methoxybenzyl 7
β-[(Z) -2- (2-tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide] -3-
[(E) -4-Hydroxy-2-butenyl] -3-cephem-4-carboxylate (3.26 g) was dissolved in methylene chloride (25 ml) under an argon atmosphere, and -5
After cooling to 0 ° C., N, N-dimethylaminopyridine (73
3 mg) and diphenylphosphoric acid chloride (1.2 ml) were added, and the mixture was stirred at -50 ° C for 80 minutes. After the completion, pour into methylene chloride (200 ml), and use 10% sodium dihydrogen phosphate aqueous solution (100 ml, 2 times), saturated sodium hydrogen carbonate aqueous solution (100 ml), water (100 ml, 2 times), saturated saline solution (100 ml). After washing each, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (3: 4, v / v) to collect fractions containing the desired product. The solvent was evaporated under reduced pressure to give a foamy product with ethyl ether- Hexane is added to solidify,
p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4-thiazolyl) -2- (methoxyimino) acetamido] -3-[(E) -4-diphenylphosphoryloxy-2-butenyl] -3-Cephem-4-
The carboxylate (3.30 g, 79%) was obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 2.94 (1H, dd, J = 13.4,6.7Hz), 3.19 (1H, dd, J = 13.
4,4.8Hz), 3.26 (1H, d, J = 18.3Hz), 3.45 (1H, d, J = 18.3Hz),
3.73 (3H, s), 3.80 (3H, s), 4.71 (2H, t, J = 6.7Hz), 5.10 (1H,
d, J = 4.3Hz), 5.16 (2H, dd, J = 19.5,12.2Hz), 5.64 (1H, dt, J =
10.4,5.5Hz), 5.69 (1H, t, J = 6.1Hz), 5.75-5.79 (1H, m), 6.7
1 (1H, s), 6.91 (2H, d, J = 7.9Hz), 7.22-7.43 (27H, m), 8.83 (1
H, s), 9.53 (1H, d, J = 7.9Hz) Positive ion-FAB-mass spectrum: m / z; 1048
(M) ⁺ infrared absorption spectrum ν _max (KBr); 1784,1520,1492,11
90,1168,956cm ^-1

(3) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4) obtained in (2)
-Thiazolyl) -2- (methoxyimino) acetamide] -3-[(E) -4-diphenylphosphoryloxy-2-butenyl] -3-cephem-4-carboxylate 3.03 g (2.89 mmol) in acetonitrile 6
Dissolve in 0 ml and diisopropylethylamine (1.5
(ml) was added dropwise under ice cooling. After stirring at the same temperature for 24 hours, the solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography to obtain methylene chloride-ethyl acetate (1
5: 1, v / v) and the fractions containing the desired product were collected, the solvent was distilled off under reduced pressure, and the resulting foam was solidified with ethyl ether-hexane to give p-methoxybenzyl 7β.
-[(Z) -2- (2-Tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide] -3-
[(E) -1,3-Butadienyl] -3-cephem-4
-2.19 g (94%) of the carboxylate was obtained.

Nuclear magnetic resonance spectrum (DMSO-d
₆ , TMS internal standard) δ (ppm): 3.61 (1H, d, J = 17.6Hz), 3.75 (3H, s), 3.81 (3H, s),
3.89 (1H, d, J = 17.6Hz), 5.18 (1H, d, J = 4.9Hz), 5.20 (2H, s),
5.26 (1H, d, J = 11.5Hz), 5.39 (1H, d, J = 17.1Hz), 5.69 (1H, d
d, J = 8.0,4.9Hz), 6.3-6.4 (1H, m), 6.7-6.8 (3H, m), 6.94 (2
H, d, J = 9.2Hz), 7.2-7.4 (17H, m), 8.85 (1H, s), 9.59 (1H, d, J
= 7.9 Hz) Positive ion-FAB-mass spectrum: m / z; 799
(M + 2) ⁺ infrared absorption spectrum ν _max (KBr); 330
4,1780, 1724, 1686, 1520, 130
6,1248,1168,1038,702 cm ^-1

Reference Example 2 (1) Under an argon stream, 400 ml of dry N, N-dimethylformamide was added to p-methoxybenzyl 7β- (2
-Phenylacetamide) -3-chloromethyl-3-cephem-4-carboxylate 38.96 g (80 mm
ol), (E) -3-hydroxy-1-tributylstannyl-1-propene 27.69 g (80 mmol), bis (dibenzylideneacetone) palladium (0) 920
mg (1.6 mmol) and tri (2-furyl) phosphine 743 mg (3.2 mmol) were added, and the mixture was heated under reflux for 3 hours. After the completion, 400 ml of acetonitrile was added to the residue obtained by distilling off the solvent under reduced pressure, and adding 400 ml of hexane to the residue.
It was washed 3 times with 1 and the acetonitrile layer was distilled off under reduced pressure. Ethyl acetate-benzene (1: 1, v / v) was added to the obtained residue.
400 ml was added, this was washed with 400 ml of water three times,
The organic layer was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, chloroform-methanol (100: 1, v / v).
The fractions containing the desired compound were eluted and the solvent was distilled off under reduced pressure to remove p-methoxybenzyl 7β- (2-phenylacetamido) -3-[(E) -4-hydroxy-
There were obtained 38.5 g, (94.6%) of 2-butenyl] -3-cephem-4-carboxylate. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 2.88 (1H, dd, J = 14.2,7.3Hz), 3.18 (1H, dd, J = 14.
2,4.9Hz), 3.36 (1H, d, J = 18.1Hz), 3.52 (2H, dd, J = 28.8,14.
2Hz), 3.57 (1H, d, J = 18.1Hz), 3.75 (3H, s), 3.88 (2H, brs),
4.67 (1H, t, J = 5.4Hz), 5.08 (1H, d, J = 4.4Hz), 5.12 (1H, d, J =
12.2Hz), 5.22 (1H, d, J = 12.2Hz), 5.51-5.57 (1H, m), 5.59-
5.65 (2H, m), 6.93 (2H, d, J = 8.8Hz), 7.2-7.3 (5H, m), 7.34 (2
H, d, J = 8.8Hz), 9.09 (1H, d, J = 8.3Hz) Positive ion-FAB-mass spectrum: m / z; 509
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 3292,3048,2972,17
84,1718,1654,1618,1540,1520,1366,1252,1174,700cm ^-1

(2) p-Methoxybenzyl 7β- (2-phenylacetamido) -3-obtained in (1)
[(E) -4-hydroxy-2-butenyl] -3-cephem-4-carboxylate 33.3 g (66 mmo
l) was dissolved in 350 ml of methylene chloride under an argon atmosphere, cooled to -70 ° C, 32.0 g (262 mmol) of N, N-dimethylaminopyridine was added, and then -70.
54.6 ml of diphenylphosphoric acid chloride at ℃ -65 ℃
(262 mmol) was added dropwise over 50 minutes, and-
Stir for 10 minutes at 65 ° C. After completion, methylene chloride 65
Pour into 0 ml, saturated ammonium chloride aqueous solution 500 m
1, twice, 500 ml of saturated aqueous sodium hydrogen carbonate solution,
After washing with 500 ml of water and 500 ml of saturated saline respectively, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and methylene chloride-ethyl acetate (10: 1, v
/ V) and the fractions containing the desired product were collected and the solvent was distilled off under reduced pressure to obtain p-methoxybenzyl 7β- (2-
Phenylacetamide) -3-[(E) -4-diphenylphosphoryloxy-2-butenyl] -3-cephem-
32.9 g of 4-carboxylate were obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 2.93 (1H, dd, J = 14.7,7.3Hz), 3.21 (1H, dd, J = 14.
0,5.5Hz), 3.29 (1H, d, J = 18.3Hz), 3.53 (2H, dd, J = 36.0,14.
0Hz), 3.54 (1H, d, J = 18.3Hz), 3.73 (3H, s), 4.73 (2H, dd, J =
8.5,6.1Hz), 5.07 (1H, d, J = 4.9Hz), 5.18 (2H, dd, J = 35.4,1
2.2Hz), 5.65-5.68 (1H, m), 5.70-5.73 (1H, m), 5.77-5.83 (1
H, m), 6.92 (2H, d, J = 8.5Hz), 7.1-7.4 (17H, m), 9.10 (1H, d, J
= 8.5Hz) Positive ion-FAB-Mass spectrum: m / z; 741
(M + 1) ⁺ infrared absorption spectrum ν _max (CHCl ₃ ); 3440,301
2,2976,1788,1728,1688,1616,1594,1494,1286,1168,101
4,964 cm ^-1

(3) p-methoxybenzyl 7β- (2
-Phenylacetamido) -3-[(E) -4-diphenylphosphoryloxy-2-butenyl] -3-cephem-4-carboxylate (32.1 g, 43 mmol) was dissolved in 480 ml of acetonitrile, and 14.6 ml of diisopropylethylamine ( (86 mmol) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 24 hours. After the completion, the precipitate was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure.
5.1 g of -methoxybenzyl 7β- (2-phenylacetamido) -3-[(E) -1,3-butadienyl] -3-cephem-4-carboxylate were obtained. Further, the above filtrate was distilled off under reduced pressure, the obtained residue was subjected to silica gel column chromatography, and eluted with methylene chloride-ethyl acetate (10: 1, v / v) to collect fractions containing the desired product. The solvent was distilled off under reduced pressure and p-methoxybenzyl 7β- (2-phenylacetamide) -3-
[(E) -1,3-Butadienyl] -3-cephem-4
-4.9 g of carboxylate are obtained.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ (ppm): 3.53 (2H, dd, J = 25.9,14.2Hz), 3.62 (1H, d,
J = 17.6Hz), 3.75 (3H, s), 3.94 (1H, d, J = 17.6Hz), 5.15 (1H,
d, J = 4.9Hz), 5.17-5.27 (3H, m), 5.39 (1H, d, J = 17.1Hz), 5.7
0 (1H, dd, J = 8.3,4.9Hz), 6.66-6.77 (2H, m), 6.94 (2H, d, J =
8.8Hz), 7.21-7.32 (5H, m), 7.36 (2H, d, J = 8.8Hz), 9.16 (1H,
d, J = 8.3Hz) Positive ion-FAB-mass spectrum: m / z; 491
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 3284,3048,2976,17
80,1718,1660,1538,1520,1388,1360,1234,1170,698cm ^-1

Alternative Method of Reference Example 2 p-Methoxybenzyl 7β- (2-
Phenylacetamide) -3-trifluoromethanesulfonyloxy-3-cephem-4-carboxylate 586 mg (1 mmol) was dissolved in 1-methyl-2-pyrrolidinone 2 ml, and zinc chloride 273 mg (2 m
mol), 12 mg of tri (2-furyl) phosphine
(0.05 mmol) and bis (dibenzylideneacetone) palladium (0) 15 mg (0.025 mmo
l) was added. After stirring for 10 minutes, (E) -3-hydroxy-1-tributylstannyl-1,3-butadiene (377 mg, 1.1 mmol) was added together with 1-methyl-2-pyrrolidine (2 ml) and reacted at room temperature for 4 hours. It was The reaction solution was diluted with 30 ml of ethyl acetate, and then diluted with water three times,
After washing once with a saturated saline solution, it was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain a residue. This residue was dissolved in 80 ml of acetonitrile and washed with hexane three times. The acetonitrile layer was concentrated, and the obtained crude product (608 mg) was purified by subjecting it to silica gel column chromatography to obtain 385 mg (79%) of the desired product. The physicochemical properties of this compound are p-methoxybenzyl obtained in Reference Example 2 (3).
7β- (2-phenylacetamide) -3-[(E)-
Identical to 1,3-butadienyl] -3-cephem-4-carboxylate.

Reference Example 3 (1) 80 m of dry tetrahydrofuran under argon flow
p-methoxybenzyl 7β-[(Z) -2- (5
-Tritylamino-1,2,4-thiadiazole-3-
Ii) -2-Methoxyiminoacetamido] -3-chloromethyl-3-cephem-4-carboxylate 7.
95 g (10 mmol), (E) -3-hydroxy-1
-Tributylstannyl-1-propene 3.47 g (10
mmol), bis (dibenzylideneacetone) palladium (0) 115 mg (0.2 mmol), and tri (2-furyl) phosphine 93 mg (0.4 mmol), and added 3
Reflux for hours. After the completion, the solvent was distilled off under reduced pressure, and 200 ml of acetonitrile was added to the obtained residue. This was washed with 200 ml of hexane and then 100 ml, and the acetonitrile layer was separated and distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and hexane-ethyl acetate (1: 1)
To 3: 7 in different ratios (v / v) and the fractions containing the desired product were collected, the solvent was distilled off under reduced pressure, and the resulting foam was solidified with ethyl ether-hexane to give p-methoxy. Benzyl 7β-[(Z) -2- (5-tritylamino-1,2,4-thiadiazol-3-yl) -2-
(Methoxyimino) acetamide] -3-[(E) -4
5.94 g (72.7%) of -hydroxy-2-buten-1-yl] -3-cephem-4-carboxylate were obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 2.87 (1H, dd, J = 13.7,6.8Hz), 3.16 (1H, dd,
J = 13.7,4.6Hz), 3.54 (1H, d, J = 18.6Hz), 3.75 (3H, s), 3.88
(5H, m), 3.86 (2H, d, J = 4.9Hz), 4.66 (1H, t, J = 5.5Hz), 5.1-
5.21 (3H, m), 5.49-5.70 (2H, m), 5.72 (1H, m), 6.92 (2H, d, J =
8.8Hz), 7.2-7.4 (17H, m), 9.50 (1H, d, J = 8.8Hz), 9.99 (1H,
s) Positive ion-FAB-mass spectrum: m / z; 817
(M + H) ⁺ infrared absorption spectrum: ν _max (KBr); 3416,3316,2952,17
78,1726,1690,1520,1248,1042,702cm ^-1

(2) p-Methoxybenzyl 7β-[(Z) -2- (5-tritylamino-) obtained in (1)
1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3-[(E) -4-hydroxy-2-butenyl] -3-cephem-4-carboxylate 5 g (6. 1 mmol) was dissolved in methylene chloride (40 ml) under an argon atmosphere, cooled to -50 ° C, and then N, N-dimethylaminopyridine (826 m) was added.
g) and diphenylphosphoric acid chloride (1.55 ml) were added and the mixture was stirred at -45 ° C for 60 minutes. After the completion, pour into methylene chloride (200 ml), and use 10% sodium dihydrogen phosphate aqueous solution (100 ml, 2 times), saturated sodium hydrogen carbonate aqueous solution (100 ml), water (100 ml, 2 times), saturated saline solution (100 ml). After washing each, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (2: 3 to 3: 7, v / v) to collect the fractions containing the target compound. The solvent was evaporated under reduced pressure to give a foam. Ethyl ether-hexane was added to solidify,
p-Methoxybenzyl 7β-[(Z) -2- (5-tritylamino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamide] -3-
[(E) -4-diphenylphosphoryloxy-2-butenyl] -3-cephem-4-carboxylate (5.1
7g, 80.5%) was obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 2.91 (1H, dd, J = 14.2,6.8Hz), 3.18 (1H, dd,
J = 14.2,5.1Hz), 3.24 (1H, d, J = 18.6Hz), 3.51 (1H, d, J = 18.6
Hz), 3.73 (3H, s), 3.89 (3H, s), 4.71 (2H, t, J = 5.9Hz), 5.07-
5.2 (3H, m), 5.65-5.8 (3H, m), 6.91 (2H, d, J = 8.3Hz), 7.21-
7.44 (27H, m), 9.51 (1H, d, J = 8.3Hz), 9.99 (1H, s) Positive ion-FAB-Mass spectrum: m / z; 1049
(M) ⁺ infrared absorption spectrum ν _max (KBr); 3300,2952,1778,17
26,1686,1520,1492,1394,1248,1188,1168,1094,1040,95
2,754,702,690 cm ^-1

(3) p-Methoxybenzyl 7β-[(Z) -2- (5-tritylamino-) obtained in (2)
1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3-[(E) -4-diphenylphosphoryloxy-2-butenyl] -3-cephem-4-carboxylate 5 g ( 4.76 mmol) was dissolved in 100 ml of acetonitrile, and diisopropylethylamine (2.6 ml) was added dropwise at room temperature. After stirring at room temperature for 24 hours, the solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography.
Fractions containing the desired product were collected by elution with ethyl acetate (15: 1, v / v), and the solvent was evaporated under reduced pressure to give a foam, which was solidified with ethyl ether-hexane to give p-methoxybenzyl 7β. -[(Z) -2- (5-Tritylamino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamide] -3-[(E) -1,3
3.4 g (89.5%) of -butadienyl] -3-cephem-4-carboxylate were obtained.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ (ppm): 3.58 (1H, dd, J = 17.6Hz), 3.74 (3H, s), 3.85
-3.93 (5H, s, d), 5.17 (2H, m), 5.21 (1H, d, J = 11.72Hz), 5.38
(1H, d, J = 17.1Hz), 5.77 (1H, m), 6.3-6.5 (1H, m), 6.6-6.8 (2
H, m), 6.94 (2H, d, J = 8.7Hz), 7.2-7.4 (17H, m), 9.57 (1H, d, J
= 8.3Hz), 9.99 (1H, s) Positive ion-FAB-Mass spectrum: m / z; 799
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 3296,2952,1778,17
24,1688,1520,1388,1364,1248,1220,1160,1042,702cm ^-1

Reference Example 4 (1) Dry tetrahydrofuran 8 under argon atmosphere
0 ml of p-methoxybenzyl 7β-[(Z) -2-
(2-Tritylamino-4-thiazolyl) -2- (1-
tert-Butoxycarbonyl-1-methylethoxyimino) acetamido] -3-chloromethyl-3-cephem-4-carboxylate 9.23 g (10 mmo
l), (E) -3-hydroxy-1-tributylstannyl-1-propene 3.47 g (10 mmol), bis (dibenzylideneacetone) palladium (0) 115 m.
g (0.2 mmol) and tri (2-furyl) phosphine 93 mg (0.4 mmol) were added, and the mixture was heated under reflux for 3 hours. After the completion, 200 ml of acetonitrile was added to the residue obtained by distilling off the solvent under reduced pressure, and adding 100 m of hexane to the residue.
It was washed twice with 1 and the acetonitrile layer was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and hexane-ethyl acetate (1: 1 to 2: 3, v / v).
The fractions containing the desired product were eluted, and the solvent was distilled off under reduced pressure. The resulting foam was solidified with ethyl ether-hexane and p-methoxybenzyl 7β-[(Z) -2-
(2-Tritylamino-4-thiazolyl) -2- (1-
tert-Butoxycarbonyl-1-methylethoxyimino) acetamido] -3-[(E) -4-hydroxy-2-butenyl] -3-cephem-4-carboxylate (9.15 g, 96.9%) was obtained. .

Nuclear magnetic resonance spectrum (DMSOd ₆ , T
MS internal standard) δ (ppm): 1.35 (15H, s), 2.90 (1H, dd, J = 14.2,7.3H
z), 3.18 (1H, dd, J = 14.2,4.9Hz), 3.35 (1H, d, J = 8.6Hz), 3.
55 (1H, d, J = 18,6Hz), 3.74 (3H, s), 3.86 (2H, m), 4.66 (1H, t,
J = 5.5Hz), 5.1-5.21 (3H, m), 5.49-5.67 (3H, m), 6.69 (1H,
s), 6.92 (2H, d, J = 8.8Hz), 7.1-7.4 (17H, m), 8.79 (1H, s), 9.
29 (1H, d, J = 8.3) Positive ion FAB mass spectrum: m / z; 944
(M) ⁺ infrared absorption spectrum; ν _max (KBr); 3416,3072,2992,1
790,1728,1690,1520,1372,1302,1248,1174,1144,702cm
^-1

(2) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4) obtained in (1)
-Thiazolyl) -2- (1-tert-butoxycarbonyl-1-methylethoxyimino) acetamide] -3
-[(E) -4-hydroxy-2-butenyl] -3-cephem-4-carboxylate 9.1 g (9.6 mmo)
l) was dissolved in 62 ml of methylene chloride under an argon atmosphere, cooled to -50 ° C, and then 1.28 g of N, N-dimethylaminopyridine and 2.39 m of diphenylphosphoric acid chloride.
1 was added and the mixture was stirred at -45 ° C for 2 hours. After the completion, the mixture was poured into 200 ml of methylene chloride, twice with 100 ml of 10% sodium dihydrogen phosphate aqueous solution, 100 ml of saturated sodium hydrogen carbonate aqueous solution, twice with 100 ml of water, and 100 ml of saturated saline solution.
After washing with ml respectively, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (3: 2 to 2: 3, v / v) to collect fractions containing the desired product, and the solvent was distilled off under reduced pressure to obtain a foamy product. Ethyl ether-hexane was added to and solidified, and p-methoxybenzyl 7β-[(Z) -2- (2-tritylamino-
4-thiazolyl) -2- (1-tert-butoxycarbonyl-1-methylethoxyimino) acetamide]-
3-[(E) -4-diphenylphosphoryloxy-2-
Butenyl] -3-cephem-4-carboxylate 1
0.21 g (90%) was obtained.

Nuclear magnetic resonance spectrum (DMSOd ₆ , T
MS internal standard) δ (ppm): 1.34 (15H, s), 2.95 (1H, dd, J = 14.6,7.4H
z), 3.19 (1H, m), 3.52 (1H, d, J = 18.3Hz), 3.72 (3H, s), 4.71
(2H, t, J = 6.1Hz), 5.1-5.2 (3H, m), 5.6-5.8 (3H, m), 6.69 (1
H, s), 6.91 (2H, d, J = 8.6Hz), 7.18-7.43 (27H, m), 8.79 (1H,
s), 9.28 (1H, d, J = 8.5Hz) positive ion FAB mass spectrum; m / z: 1176
(M) ⁺ infrared absorption spectrum; ν _max (KBr); 3412,3072,2988,178
8,1728,1692,1520,1494,1368,1300,1192,1172,1144,101
2,954,759,702cm ^-1

(3) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4) obtained in (2)
-Thiazolyl) -2- (1-tert-butoxycarbonyl-1-methylethoxyimino) acetamide] -3
-[(E) -4-Diphenylphosphoryloxy-2-butenyl] -3-cephem-4-carboxylate 9.9
5 g (8.46 mmol) of 177 ml of acetonitrile
Dissolved in diisopyropyrethylamine (4.6 ml)
Was added dropwise under ice cooling. After stirring at the same temperature for 24 hours, the solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography to obtain methylene chloride-ethyl acetate (15:
1, v / v) and the fractions containing the desired product were collected, the solvent was distilled off under reduced pressure, and the resulting foam was solidified with ethyl ether-hexane to give p-methoxybenzyl 7β-.
[(Z) -2- (2-Tritylamino-4-thiazolyl) -2- (1-tert-butoxycarbonyl-1-
Methylethoxyimino) acetamide] -3-[(E)
7.53 g (96.3%) of -1,3-butadienyl] -3-cephem-4-carboxylate was obtained.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ (ppm): 1.35 (15H, s), 3.60 (1H, d, J = 17.6Hz), 3.91
(1H, d, J = 15.8Hz), 5.09-5.20 (1H, m), 5.20 (2H, s), 5.25 (1
H, d, J = 11.2Hz), 5.38 (1H, d, J = 16.6Hz), 5.70 (1H, m), 6.3-
6.45 (1H, m), 6.69-6.78 (3H, m), 6.93 (2H, d, J = 8.8Hz), 7.2-
7.4 (17H, m), 8.80 (1H, s), 9.36 (1H, d, J = 8.3Hz) Positive ion FAB mass spectrum; m / z: 926 (M
+1) ⁺ infrared absorption spectrum; ν _max (KBr); 3408,2922,2952,178
8,1726,1696,1520,1386,1368,1304,1252,1220,1168,114
6,100 6,702 cm ^-1

Reference Example 5 (1) 5.15 g (12 mmo) of (Z) -2-hydroxyimino-2- (tritylamino-4-thiazolyl) acetic acid
1) is suspended in 60 ml of methylene chloride and 5.2 ml of 2-methoxypropene is added at 4 ° C. After stirring at room temperature for 30 minutes, the solvent is distilled off under reduced pressure. 50 ml of methylene chloride in the residue
Was added, 2.63 g of phosphorus pentachloride was added at -25 ° C, and -4
Stir for 60 minutes at 5--20 ° C to obtain a solution of (Z) -2- (1-methoxy-1-methyl) ethoxyimino-2- (2-tritylamino-4-thiazolyl) acetic acid chloride. On the other hand, p-methoxybenzyl 7β-amino-3-
Chloromethyl-3-cephem-4-carboxylate
The hydrochloride salt (ACLE.HCl) is suspended in 50 ml of methylene chloride and 2.8 ml of bis (trimethylsilyl) acetamide is added at 10 ° C. After stirring at room temperature for 30 minutes, -60
At 0 ° C., 4 ml of pyridine and the above acetic acid chloride solution are sequentially added. After stirring at −35 to −20 ° C. for 30 minutes, the mixture is poured into 150 ml of a saturated aqueous solution of monopotassium phosphate, and 100 ml of methylene chloride is added.
Extract twice with ml. The extract was washed with a saturated potassium monophosphate solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography to give hexane-ethyl acetate (3: 2).
˜1: 1, v / v), and the fractions containing the desired product were collected and the solvent was evaporated under reduced pressure to give the foam compound p-methoxybenzyl 3-chloromethyl-7β-[(Z) -2.
-(2-Tritylamino-4-thiazolyl) -2- (1
-Methoxy-1-methyl) ethoxyiminoacetamide] -3-cephem-4-carboxylate 7.65 g
(81.5%) was obtained.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ (ppm): 3.11 (3H, s), 3.53 (1H, d, J = 18.1Hz), 3.70
(11, d, J = 18.6Hz), 3.74 (3H, s), 4.50 (2H, q, J = 23.4, J = 11.2
Hz), 5.1-5.3 (3H, m), 5.73 (1H, q, J = 4.9Hz), 6.71 (1H, s), 6.
92 (2H, d, J = 6.8Hz), 7.2-7.4 (17H, m), 8.86 (1H, s), 9.53 (1
H, d, J = 8.3) Positive ion-FAB-mass spectrum: m / z; 852
(M) ⁺ , infrared absorption spectrum ν _max (KBr); 3416,3072,2948,17
94,1730,1692,1630,1618,1522,1386,1374,1250,1178,11
64,1068,956,924,702cm ^-1

(2) Under an argon atmosphere, p-methoxybenzyl 3-chloromethyl-7β-[(Z) -2- (2-tritylamino-4-thiazolyl) -2- (1-methoxy) was added to 80 ml of dry tetrahydrofuran. -1-Methyl) ethoxyiminoacetamide] -3-cephem-4
-Carboxylate 8.53 g (0.01 mol),
(E) -3-Hydroxy-1-tributylstannyl-1
-Propene 3.47 g (0.01 mol), bis (dibenzylideneacetone) palladium (0) 115 mg
(0.2 mmol), tri (2-furyl) phosphine 9
3 mg (0.4 mmol) was added and the mixture was heated under reflux for 23 hours. After completion, 100 ml of acetonitrile was added to the residue obtained by distilling off the solvent under reduced pressure, and adding 100 ml of hexane to the residue.
It was washed twice with and the acetonitrile layer was evaporated under reduced pressure.
The residue was subjected to silica gel column chromatography, eluted with hexane-ethyl acetate (3: 2 to 2: 3, v / v) to collect fractions containing the target compound, and the solvent was distilled off under reduced pressure to give a foam. The solid was solidified with ethyl ether-hexane to give p-methoxybenzyl 7β-[(Z) -2- (2-
Tritylamino-4-thiazolyl) -2- (1-methoxy-1-methyl) ethoxyiminoacetamide] -3-
2.54 g (29.2%) of [(E) -4-hydroxy-2-butenyl] -3-cephem-4-carboxylate.
Got

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ (ppm): 1.38 (6H, s), 2.89 (1H, dd, J = 14.2,6.8Hz),
3.17 (1H, dd, J = 14.2,5.4Hz), 3.31 (3H, s), 3.35 (1H, d, J = 1
8.6Hz), 3.55 (1H, d, J = 18.6Hz), 3.74 (3H, s), 3.86 (2H, m),
4.65 (1H, t, J = 5.4Hz), 5.1-5.2 (3H, m), 5.5-5.7 (4H, m), 6.7
1 (1H, s), 6.92 (2H, d, J = 6.8Hz), 7.1-7.4 (17H, m), 8.85 (1H,
s), 9.45 (1H, d, J = 7.8) positive ion-FAB-mass spectrum: m / z; 874
(M) ⁺ , 802 (MC (CH ₃ ) ₂ OCH ₃ +1) ⁺ infrared absorption spectrum ν _max (KBr); 3416,3072,3008,29
52,2848,1788,1728,1686,1618,1520,1376,1300,1248,11
76,1072,1034,978,902,848,824,754,702cm ^-1

(3) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4) obtained in (2)
1.6 g (1.-thiazolyl) -2- (1-methoxy-1-methyl) ethoxyiminoacetamide] -3-[(E) -4-hydroxy-2-butenyl] -3-cephem-4-carboxylate. (83 mmol) was dissolved in 12 ml of methylene chloride under an argon atmosphere, and after cooling to -50 ° C, 0.27 g (2 of N, N-dimethylaminopyridine)
mmol), 0.455 ml of diphenylphosphoric acid chloride
Was added and the mixture was stirred at −45 to −20 ° C. for 2 hours. After the end 1
Pour into 100 ml of 0% aqueous solution of sodium dihydrogen phosphate,
It was extracted twice with 50 ml of methylene chloride. The extract was mixed with 20 ml of saturated aqueous sodium hydrogen carbonate solution and 20 ml of water twice,
The organic layer was washed with 20 ml of saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with hexane-ethyl acetate (3: 2-1: 1-2: 3, v / v) to collect fractions containing the desired product, and the solvent was evaporated under reduced pressure. The foam obtained was solidified with ethyl ether-hexane to give p-methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4-thiazolyl) -2- (1-methoxy-1-methyl). Ethoxyiminoacetamide] -3-
[(E) -4-Diphenylphosphoryloxy-2-butenyl] -3-cephem-4-carboxylate 1.46
g (71.9%) were obtained.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ (ppm): 1.37 (6H, s), 2.95 (1H, dd, J = 14.7,6.8Hz),
3.10 (3H, s), 3.18 (1H, dd, J = 14.7,9.3Hz), 3.29 (1H, d, J = 1
8.6Hz), 3.54 (1H, d, J = 18.6Hz), 3.72 (3H, s), 4.70 (2H, dd, J
= 9.3,8.8Hz), 5.1-5.2 (3H, m), 5.6-5.8 (3H, m), 6.71 (1H,
s), 6.90 (2H, d, J = 8.8Hz), 7.19-7.44 (27H, m), 8.86 (1H, s),
9.47 (1H, d, J = 7.8Hz) positive ion-FAB-mass spectrum: m / z; 1106
(M) ⁺ , 1034 (MC (CH ₃ ) ₂ OCH ₃ +1) ⁺ infrared absorption spectrum ν _max (KBr); 3420,3072,2954,28
84,1788,1728,1686,1592,1520,1492,1376,1286,1248,12
20,1190,1166,1072,1012,954,772,754,702,692cm ^-1

(4) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4) obtained in (3)
-Thiazolyl) -2- (1-methoxy-1-methyl) ethoxyiminoacetamide] -3-[(E) -4-diphenylphosphoryloxy-2-butenyl] -3-cephem-4-carboxylate 1.4 g ( 1.27mmo
l) was dissolved in 20 ml of acetonitrile, and 0.69 ml of diisopropylethylamine was added under ice cooling. After stirring under ice-cooling for 3 days, the solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography and eluted with methylene chloride-ethyl acetate (15: 1, v / v) to obtain the desired product. The fractions containing were collected. The solvent was distilled off under reduced pressure and the obtained foam was solidified with ethyl ether-hexane to give p-
Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4-thiazolyl) -2- (1-methoxy-1
-Methyl) ethoxyiminoacetamide] -3-
[(E) -4-Diphenylphosphoryloxy-2-butenyl]-[(E) -1,3-butadienyl] -3-cephem-4-carboxylate 896 mg (82.7%)
Got

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ (ppm): 1.39 (6H, s), 3.11 (3H, s), 3.60 (1H, d, J = 1
7.6Hz), 3.74 (3H, s), 3.91 (1H, d, J = 17.6Hz), 5.06-5.49 (5
H, m), 5.69 (1H, d, J = 7.8Hz), 6.39 (1H, m), 6.66-6.78 (3H,
m), 6.93 (2H, d, J = 8.79Hz), 7.20-7.4 (17H, m), 8.87 (1H, s),
9.77 (1H, d, J = 8.3Hz) Positive ion-FAB-Mass spectrum: m / z; 856
(M) ⁺ , 784 (MC (CH ₃ ) ₂ OCH ₃ +1) ⁺ infrared absorption spectrum ν _max (KBr); 3336,3072,3004,29
52,2844,1790,1722,1692,1618,1516,1450,1384,1306,12
48,1220,1170,1106,1070,1034,1004,978,892,848,824,8
08,754,702 cm ^-1

Reference Example 6 (1) 312 mg of phosphorus pentachloride under an argon atmosphere
(1.5 mmol) was dissolved in 5 ml of methylene chloride, and 122 μl of pyridine (1.5 mmo) was added to the solution at 5 ° C.
1) was added and stirred for 1 hour. 245 m of p-methoxybenzyl 7β- (2-phenylacetamido) -3-[(E) -1,3-butadienyl] -3-cephem-4-carboxylate obtained in Reference Example 2 in the obtained reaction liquid.
g (0.5 mmol) was added, and the mixture was stirred at 8 ° C. for 1.5 hours. The reaction solution was further cooled to -30 ° C, and then methanol 2m
1 was added and the mixture was stirred at -15 ° C for 1.5 hours. After the completion, 5 ml of methylene chloride and 10 ml of water were added. The aqueous layer was separated from the reaction solution, the organic layer was extracted with water, the aqueous layers were combined, neutralized with a saturated aqueous sodium hydrogen carbonate solution under ice cooling, and the resulting aqueous solution was extracted with chloroform. After the chloroform extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to remove p-methoxybenzyl 7β-amino-3-[(E) -1,3-butadienyl] -3-cephem-4-carboxylate. 175 mg
Was obtained as a crude product.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ (ppm): 3.32 (2H, brs), 4.82 (1H, d, J = 4.9Hz), 5.04
(1H, d, J = 5.4Hz), 5.19 (2H, d, J = 2.4Hz), 5.23 (1H, d, J = 11.7
Hz), 5.97 (1H, d, J = 16.6Hz), 6.38 (1H, dt, J = 17.1,9.8Hz),
6.63-6.75 (2H, m) positive ion-FAB-mass spectrum: m / z; 372
(M + 1) ⁺ ,

(2) (Z) -2-hydroxyimino-2
2.1 g of-(tritylamino-4-thiazolyl) acetic acid
(4.9 mmol) was suspended in 25 ml of methylene chloride,
Add 2.1 ml of 2-methoxypropene at 4 ° C. After stirring at room temperature for 30 minutes, the solvent is distilled off under reduced pressure. 20 ml of methylene chloride was added to the residue, and phosphorus pentachloride 1.05 was added at -21 ° C.
g, and stirred at −45 to −20 ° C. for 50 minutes, (Z)
-2- (1-methoxy-1-methyl) ethoxyimino-
A solution of 2- (2-tritylamino-4-thiazolyl) acetic acid chloride is obtained. On the other hand, p-methoxybenzyl 7β
-Amino-3-[(E) -1,3-butadienyl] -3
-Cephem-4-carboxylate / hydrochloride 1.82 g
(4.45 mmol) was suspended in 20 ml of methylene chloride, and bis (trimethylsilyl) acetamide 1.
Add 12 ml. After stirring for 30 minutes at room temperature, 1.6 ml of pyridine and the above acetic acid chloride solution are sequentially added at -60 ° C. After stirring at −35 to −20 ° C. for 30 minutes, the mixture is poured into 100 ml of a saturated aqueous solution of monopotassium phosphate, and 100 ml of methylene chloride is added.
Extract twice with ml. The extract was washed with a saturated monopotassium phosphate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and hexane-ethyl acetate (3: 2
˜1: 1, v / v), collect the fractions containing the desired product, evaporate the solvent under reduced pressure to remove the foam compound p-methoxybenzyl 7β-[(Z) -2- (2-trityl). Amino-4-thiazolyl) -2- (1-methoxy-1-methyl) ethoxyiminoacetamide] -3-[(E)-
625 mg (16.4%) of 1,3-butadienyl] -3-cephem-4-carboxylate were obtained. The physicochemical properties are the same as in Reference Example 5.

Reference Example 7 (1) 1.38 g of (Z) -2- (2-tritylamino-4-thiazolyl) -2-fluoromethoxyiminoacetic acid
(3.0 mmol) in 30 ml of methylene chloride,
Under cooling to -10 ° C, phosphorus pentachloride 621 mg (3.0 mm
ol) was added and the mixture was stirred at the same temperature for 30 minutes to obtain an acid chloride solution. On the other hand, ACLE hydrochloride 1.22 g (3.0 mm
Ol) was suspended in 30 ml of methylene chloride, 1.5 ml of N, O-bistri (methylsilyl) acetamide and 1.5 ml of pyridine were added, and the mixture was stirred for 10 minutes. This solution was cooled to −50 ° C., the acid chloride solution prepared above was added, and the mixture was stirred at the same temperature for 30 minutes. This reaction solution was poured into 160 ml of a saturated sodium dihydrogenphosphate aqueous solution, the organic layer was separated, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (20: 1), the fractions containing the target substance were collected, and the solvent was evaporated under reduced pressure to obtain a foamy substance with ethyl ether. Solidify to p-methoxybenzyl 3-chloromethyl-7β-[(Z) -2- (2-tritylamino-4-thiazolyl) -2-fluoromethoxyimino)
Acetamide] -3-cephem-4-carboxylate (1.87 g, 76.8%) was obtained.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ (ppm): 3.53 (1H, d, J = 17.6Hz), 3.70 (1H, d, J = 17.6)
Hz), 3.76 (3H, s), 4.46 (1H, d, J = 11.2Hz), 4.53 (1H, d, J = 11.
2Hz), 5.10-5.25 (3H, m), 5.70 (2H, d, J = 55.2Hz), 5.72 (1H,
m), 6.88 (1H, s), 6.93 (1H, d), 7.20-7.40 (17H, m), 8.92 (1H,
s), 9.77 (1H, m) positive ion-FAB-mass spectrum: m / z; 812
(M + 1) ⁺ , infrared absorption spectrum; ν _max (KBr): 1792,1730,1692,
1522,1496,1366,1250,1176,1098,1068,702cm ^-1

(2) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4-thiazolyl) -2-fluoromethoxyimino) acetamide] -in dry tetrahydrofuran (80 ml) under an argon atmosphere.
3-Chloromethyl-3-cephem-4-carboxylate 1.7 g (2.1 mmol), (E) -3-Hydroxy-1-tributylstannyl-1-propene 724
mg (2.1 mmol), bis (dibenzylideneacetone) palladium (0) 24 mg (0.042 mmo
l), tri (2-furyl) phosphine 20 mg (0.
(086 mmol) was added and the mixture was heated under reflux for 4 hours. After the end,
Acetonitrile was added to the residue obtained by distilling off the solvent under reduced pressure.
5 ml was added, and this was washed twice with 20 ml of hexane,
The acetonitrile layer was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with hexane-ethyl acetate (3: 2 to 2: 3, v / v) to collect fractions containing the target compound, and the solvent was distilled off under reduced pressure to give a foam. The solid was solidified with ethyl ether-hexane to give p-methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4-thiazolyl) -2-fluoromethoxyimino) acetamide] -3-[(E). -4-Hydroxy-2-butenyl] -3-cephem-4-carboxylate 1.4
8 g (84.8%) were obtained.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ (ppm): 2.89 (1H, dd, J = 14.2,6.8Hz), 3.17 (1H, d
d, J = 14.2, 5.4Hz), 3.34 (1H, d, J = 18.6Hz), 3.55 (1H, d, J = 1
8,6Hz), 3.74 (3H, s), 3.86 (2H, m), 4.65 (1H, t, J = 5.5Hz), 5.
1-5.2 (3H, m), 5.51-5.65 (4H, m), 5.76 (1H, s), 6.88 (1H, s),
6.92 (2H, d, J = 8.8Hz), 7.1-7.4 (17H, m), 8.91 (1H, s), 9.71
(1H, d, J = 7.8) Positive ion-FAB-mass spectrum: m / z; 834
(M + 1) ⁺ infrared absorption spectrum; ν _max (KBr): 3416,3320,3068,3
040,2972,1784,1728,1686,1520,1368,1302,1248,1174,1
096,1034,966,754,702cm ^-1

(3) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4) obtained in (2)
-Thiazolyl) -2-fluoromethoxyimino) acetamido] -3-[(E) -4-hydroxy-2-butenyl] -3-cephem-4-carboxylate 1.4 g
(1.68 mmol) was dissolved in methylene chloride (11 ml) under an argon atmosphere, cooled to 50 ° C, and then N, N-.
Dimethylaminopyridine 0.25 g (2 mmol),
Add 0.42 ml of diphenylphosphoric chloride-45-
The mixture was stirred at -35 ° C for 5 hours. After the completion, pour into 100 ml of 10% sodium dihydrogen phosphate aqueous solution and add 5 methylene chloride.
Extracted twice with 0 ml. The extract was mixed with 20 ml of saturated aqueous sodium hydrogen carbonate solution and 20 ml of water twice, and saturated saline solution 20
After washing with ml respectively, it was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and hexane-ethyl acetate (3:
Fractions containing the desired product were collected by elution (2-1: 1-2: 3, v / v), the solvent was distilled off under reduced pressure, and ethyl ether-hexane was added to the resulting foam to solidify it. Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4-thiazolyl) -2-fluoromethoxyimino) acetamido] -3-[(E) -4-diphenylphosphoryloxy-2-butenyl] -3 -1.34 g (74.8%) of cephem-4-carboxylate were obtained.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ (ppm): 2.95 (1H, dd, J = 14.7,7.3Hz), 3.20 (1H, d
d, J = 14.7, 5.4Hz), 3.25 (1H, d, J = 18.1Hz), 3.51 (1H, d, J = 1
8.6Hz), 3.73 (3H, s), 4.70 (2H, dd, J = 8.8, 5.9Hz), 5.1-5.2
(3H, m), 5.6-5.8 (6H, m), 6.80-6.94 (3H, m), 7.2-7.44 (27H,
m), 8.91 (1H, s), 9.72 (1H, d, J = 8.3Hz) positive ion-FAB-mass spectrum; m / z: 106
6 (M) ⁺ infrared absorption spectrum; ν _max (KBr): 3420,3300,3072,297
6,1786,1728,1686,1592,1520,1492,1370,1286,1248,122
4,1190,1168,1096,1070,1012,952,754,702,690cm ^-1

(4) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4) obtained in (3)
-Thiazolyl) -2-fluoromethoxyimino) acetamido] -3-[(E) -4-diphenylphosphoryloxy-2-butenyl] -3-cephem-4-carboxylate 1.32 g (1.24 mmol) in acetonitrile 20 ml. Was dissolved in water and 0.67 ml of diisopyropyrethylamine was added under ice cooling. After stirring under ice-cooling for 2 days and night, the solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography to obtain methylene chloride-ethyl acetate (1
5: 1, v / v) and the fractions containing the desired product were collected, the solvent was distilled off under reduced pressure, and the resulting foam was solidified with ethyl ether-hexane to give p-methoxybenzyl 7β.
-[(Z) -2- (2-Tritylamino-4-thiazolyl) -2-fluoromethoxyimino) acetamide]-
966 mg (95.6%) of 3-[(E) -1,3-butadienyl] -3-cephem-4-carboxylate was obtained.

Nuclear magnetic resonance spectrum (DMSOd ₆ , T
MS internal standard) δ (ppm): 3.62 (1H, d, J = 17.6Hz), 3.88 (1H, d, J = 17.6)
Hz), 5.09-5.30 (4H, m), 5.39 (1H, d, J = 17.1Hz), 5.63 (1H,
s), 5.70 (1H, dd, J = 7.8,4.9Hz), 5.77 (1H, s), 6.3-6.5 (1H,
m), 6.65-6.8 (2H, m), 6.89 (1H, s), 6.93 (2H, d, J = 8.8Hz), 7.
2-7.4 (17H, m), 8.92 (1H, s), 9.77 (1H, d, J = 7.8Hz) positive ion-FAB-mass spectrum; m / z: 816
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 3312,3068,3040,298
0,2844,1788,1726,1692,1616,1520,1466,1386,1364,130
6,1248,1220,1168,1098,1068,1034,1004,770,702cm ^-1

Reference Example 8 (Z) -2- (5-tert-Butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-hydroxyiminoacetic acid 5.69 g and methylene chloride 60 ml.
And 8.5 ml of 2-methoxypropene were added to the mixture at room temperature for 3
After stirring for 0 minutes, the solvent was distilled off to obtain 7.22 g of (Z) -2.
-(5-tert-butoxycarbonylamino-1,
2,4-thiadiazol-3-yl) -2- (1-methoxy-1-methyl) ethoxyiminoacetic acid was obtained as a foam compound. Of these, 1.72 g (4.77 mmo)
l) was taken and dissolved in 20 ml of methylene chloride.
1.03 g (4.95 mmol) of phosphorus pentachloride was added at 20 ° C. and stirred for 1 hour to prepare an acid chloride. On the other hand, 4-methoxybenzyl 7-amino-3- (1,3-butadienyl) -3-cephem-4-carboxylate hydrochloride 1.601 g (4.30 mmol) was added to methylene chloride 20.
ml and bis (trimethylsilyl) acetamide (BS
A) 1.12 ml was added and stirred at room temperature for 85 minutes to form a uniform solution. This solution was cooled to −40 ° C., 1.6 ml of pyridine and then the above-mentioned acid chloride were added, and the reaction was carried out for 1.5 hours. The reaction solution was poured into 100 ml of a saturated aqueous solution of sodium hydrogen phosphate, extracted twice with 100 ml of chloroform, and the organic layer was collected. It was dried over magnesium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography to obtain hexane-ethyl acetate (1: 1, v / v).
Eluted with p-methoxybenzyl 7β-[(Z) -2-
(5-tert-butoxycarbonylamino-1,2,
4-Thiadiazol-3-yl) -2- (1-methoxy-1-methyl) ethoxyiminoacetamide] -3-
[(E) -1,3-Butadienyl] -3-cephem-4
368 mg of carboxylate were obtained.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ (ppm): 1.46 (6H, s), 1.50 (9H, s), 3.17 (3H, s), 3.6
3 and 3.95 (2H, ABq), 3.76 (3H, s), 5.21 (1H, d, J = 6Hz), 5.23
-5.27 (2H, m), 5.38 (1H, d, J = 17Hz), 5.88 (1H, q, J = 6,8Hz),
6.38-6.42 (1H, m), 6.7 (1H, m), 6.94 and 7.36 (4H, ABq), 9.6
9 (1H, d) positive ion -FAB- mass spectrum: m / z; 643 (M -C (CH 3) 2 OCH 3 + H) + Infrared absorption spectrum ν _max (KBr); 2996,1788,1722,1
548,1386,1374,1250,1154cm ^-1

Reference Example 9 (1) p-Methoxybenzyl 7β-[(Z) -2- (5-
Tritylamino-1,2,4-thiadiazol-3-yl)
-2-Fluoromethoxyimino) acetamido] -3-chloromethyl-3-cephem-4-carboxylate 1.34 g
Using (1.65 mmol) as a starting material, Reference Example 3
Using the same method as in (1), p-methoxybenzyl
7β-[(Z) -2- (5-Tritylamino-1,2,4-thiadiazol-3-yl) -2-fluoromethoxyimino) acetamido] -3-[(E) -4-hydroxy-2- Butenyl] -3-cephem-4-carboxylate 1.25 g
(91.0%) was obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 2.87 (1H, dd, J = 7.3,14.2Hz), 3.16 (1H, dd, J = 4.9,
13.7Hz), 3.32 (1H, d, J = 18.6Hz), 3.55 (1H, d, J = 18,6Hz), 3.
75 (3H, s), 3.86 (2H, m), 4.65 (1H, t, J = 5.5Hz), 5.1-5.21 (3
H, m), 5.49-5.75 (4H, m), 5.83 (1H, s), 6.92 (2H, d, J = 8.3H
z), 7.2-7.5 (17H, m), 9.68 (1H, d, J = 8.3Hz), 10.08 (1H, s). Positive ion-FAB-mass spectrum: m / z; 835 (M + 1) ⁺ Infrared absorption spectrum νmax (KBr) ； 3416,3044,2972,17
80,1724,1692,1618,1532,1520,1450,1394,1368,1304,12
48,1174,1124,1076,1004,754,702cm ^-1 .

(2) p-Methoxybenzyl 7β-[(Z) -2- (5-tritylamino-1,1 obtained in (1)
2,4-thiadiazol-3-yl) -2-fluoromethoxyimino) acetamido] -3-[(E) -4-hydroxy
-2-Butenyl] -3-cephem-4-carboxylate
Starting from 25 g (1.5 mmol) as a starting material, Reference Example 3
Using the same procedure as in (2), p-methoxybenzyl
7β-[(Z) -2- (5-tritylamino-1,2,4-thiadiazol-3-yl) -2-fluoromethoxyimino)
Acetamide] -3-[(E) -4-diphenylphosphoryloxy-2-butenyl] -3-cephem-4-carboxylate 1.4 g (87.5%) was obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 2.92 (1H, dd, J = 7.3,14.7Hz), 3.19 (1H, m), 3.24
(1H, d, J = 18.6Hz), 3.52 (1H, d, J = 18.6Hz), 3.73 (3H, s), 4.7
0 (2H, dd, J = 5.9,8.8Hz), 5.1-5.2 (3H, m), 5.6-5.9 (5H, m),
6.91 (2H, d, J = 8.5Hz), 7.1-7.5 (27H, m), 9.68 (1H, d, J = 8.3H
z), 10.08 (1H, s). Positive ion-FAB-mass spectrum; m / z: 1067 (M + 1)
⁺ Infrared absorption spectrum νmax (KBr) ； 3416,3280,3072,297
6,1784,1726,1692,1616,1592,1522,1492,1452,1392,136
8,1286,1250,1222,1188,1164,1124,1076,1012,954,756,
702,690,522 cm ^-1 .

(3) p-Methoxybenzyl 7β-[(Z) -2- (5-tritylamino-1,1, obtained in (2)
2,4-thiadiazol-3-yl) -2-fluoromethoxyimino) acetamido] -3-[(E) -4-diphenylphosphoryloxy-2-butenyl] -3-cephem-4-carboxylate 1.4 g ( 1.3 mmol) as a starting material and using the same method as in Reference Example 3 (3), p-methoxybenzyl 7β-[(Z) -2- (5-tritylamino-
1,2,4-Thiadiazol-3-yl) -2-fluoromethoxyimino) acetamido] -3-[(E) -1,3-butadienyl] -3-cephem-4-carboxylate 840
mg (79.1%) was obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 3.60 (1H, d, J = 17.6Hz), 3.75 (3H, s), 3.90 (1H, d,
J = 17.6Hz), 5.09-5.20 (1H, m), 5.19 (2H, s), 5.25 (1H, d, J = 1
0.7Hz), 5.38 (1H, d, J = 17.1Hz), 5.70 (1H, s), 5.80 (1H, m),
5.84 (1H, s), 6.3-6.45 (1H, m), 6.34-6.76 (2H, m), 6.94 (2H,
d, J = 8.3Hz), 7.2-7.4 (17H, m), 9.75 (1H, d, J = 8.3Hz), 10.08
(1H, s). Positive ion-FAB-mass spectrum m / z; 817 (M + 1) ⁺ infrared absorption spectrum; νmax (KBr): 3308,3040,2980,17
80,1698,1616,1520,1450,1390,1366,1306,1250,1222,11
68,1124,1076,1004,756,702 cm ^-1 . Example 1

[0123]

[Chemical formula 24]

(1) p-methoxybenzyl 7β- (2
-Phenylacetamido) -3-[(E) -1,3-butadienyl] -3-cephem-4-carboxylate 4.9 g (10 mmol), sodium acetate 1.23 g
(15 mmol), 38% formalin water 1.58 mg
(20 mmol) was dissolved in 150 ml of tetrahydrofuran, and N-methylhydroxyamine hydrochloride 1.2 was added thereto.
A solution prepared by dissolving 5 g (15 mmol) in 20% 80% ethanol water was added dropwise, and the mixture was heated under reflux for 4.5 hours. After completion, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in methylene chloride, washed with saturated aqueous sodium hydrogen carbonate solution, saturated aqueous ammonium chloride solution, water and saturated brine, dried over anhydrous magnesium sulfate, and then reduced pressure. The lower solvent was distilled off.
The obtained residue was subjected to silica gel column chromatography, and methylene chloride-methanol (50: 1, v / v).
The fractions containing the desired product were collected, and the solvent was evaporated under reduced pressure to remove p-methoxybenzyl 7β- (2-phenylacetamido) -3-[(E) -2- (2-methyl-5-iso). 5.35 g of oxazolidinyl) vinyl] -3-cephem-4-carboxylate were obtained as a mixture of isomers.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ (ppm): 1.9 (1H, m), 2.3 (1H, m), 2.54 (3H, brs), 2.6
7 (1H, m), 3.1 (1H, m), 3.5-3.6 (3H, m), 3.75 (3H, s), 3.88 (1
H, brd), 4.34and4.59 (1H), 5.1-5.3 (3H, m), 5.7 (1H, m), 6.1
(1H, m), 6.6-6.7 (1H, m), 6.94 (2H, m), 7.2-7.4 (7H, m), 9.15
(1H, m) positive ion-FAB-mass spectrum: m / z; 550
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 3296,1780,1720,16
70,1618,1590,1536,1520,1390,828,698cm ^-1

(2) Phosphorus pentachloride 62 under argon atmosphere
5 mg (3 mmol) was dissolved in 10 ml of chloroform, and 243 μl of pyridine (3 mm
ol) was added and the mixture was stirred for 1 hour. In the obtained reaction solution,
P-Methoxybenzyl 7β- (2-obtained in (1)
Phenylacetamide) -3-[(E) -2- (2-methyl-5-isoxazolidinyl) vinyl] -3-cephem-4-carboxylate 550 mg (1 mmol)
Was added and the mixture was stirred at 8 ° C. for 1.5 hours. The reaction solution is further -3.
After cooling to 0 ° C, 4.1 ml of methanol was added, and the mixture was stirred at -15 ° C for 1.5 hours. After the completion, 10 ml of chloroform and 20 ml of saturated saline were added. The aqueous layer was separated from the reaction solution, the organic layer was extracted with water, the aqueous layers were combined, neutralized with a saturated aqueous sodium hydrogen carbonate solution under ice cooling, and the resulting aqueous solution was extracted with chloroform.
After drying the chloroform extract over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure to give p-methoxybenzyl 7β-amino-3-[(E) -2- (2-methyl-5-isoxazolidinyl) vinyl] -3-cephem-4-carboxylate. Obtained.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ (ppm): 3.75 (3H, s), 4.79 (1H, d, J = 4.9Hz), 5.01 (1
H, m), 6.04 (1H, brs), 6.63 (1H, m), 6.93 (2H, m), 7.37 (2H, m) Positive ion-FAB-mass spectrum: m / z; 432
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 2848,1780,1726,16
18,1394,1358,1304,1248,1176 cm ^-1 Example 2

[0128]

[Chemical 25]

(1) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-) obtained in Reference Example 1
4-thiazolyl) -2- (methoxyimino) acetamido] -3-[(E) -1,3-butadienyl] -3-cephem-4-carboxylate 208 mg (0.26 m
(mol) was dissolved in 2.6 ml of benzene under an argon atmosphere, diethyl azodicarboxylate (32 μl) was added, and the mixture was heated under reflux for 10.5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography to obtain methylene chloride-ethyl acetate (50
(0:40, v / v), the fractions containing the desired product were collected, the solvent was distilled off under reduced pressure, and the resulting foam was solidified with ethyl ether-hexane to obtain p-methoxybenzyl 7β- [. (Z) -2- (2-Tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide]-
3- [1,2-bis (ethoxycarbonyl) -1,2,
87 mg of 3,6-tetrahydro-3-pyridazinyl] -3-cephem-4-carboxylate were obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 3.75 (3H, s), 3.79 (3H, s) Positive ion-FAB-mass spectrum: m / z; 972
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 3320,1792,1728,16
18,1520,1218,702cm ^-1

(2) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4) obtained in (1)
-Thiazolyl) -2- (methoxyimino) acetamide] -3- [1,2-bis (ethoxycarbonyl)-
1,2,3,6-Tetrahydro-3-pyridazinyl]-
160 mg of 3-cephem-4-carboxylate was dissolved in methylene chloride (3 ml) and anisole (2 ml) under an argon atmosphere, cooled to 10 ° C, and trifluoroacetic acid (5 ml) was added dropwise. After stirring for 60 minutes at 10 ° C. to room temperature, the solvent and trifluoroacetic acid were distilled off under reduced pressure, ethyl ether-hexane was added to the residue, which was solidified and collected by filtration. Trifluoroacetic acid (10 m
In addition to 1), water (5 ml) was further added dropwise. 60 at room temperature
After stirring for a minute, ethyl alcohol was added to the residue obtained by distilling off trifluoroacetic acid under reduced pressure, and water was azeotropically distilled off. Ethyl ether was added to the residue to solidify and collect by filtration. The obtained powder was dissolved in a saturated aqueous solution of sodium hydrogen carbonate to prepare HP-
20 column purified, sodium 7β-[(Z) -2-
(2-Amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3- [1,2-bis (ethoxycarbonyl) -1,2,3,6-tetrahydro-3-pyridazinyl] -3-cephem -4-carboxylate (7
1 mg) was obtained.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ (ppm): 3.82 (3H, s), 7.20 (2H, brs) Positive ion-FAB-Mass spectrum: m / z; 608
(M-Na) ⁺ infrared absorption spectrum ν _max (KBr); 177
2,1694,1618,1540,1386,134
4,1220,1076,1040 cm ^-1 Example 3

[0132]

[Chemical formula 26]

(1) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-) obtained in Reference Example 1
4-thiazolyl) -2- (methoxyimino) acetamido] -3-[(E) -1,3-butadienyl] -3-cephem-4-carboxylate 160 mg (0.2 mm
was dissolved in methylene chloride (1 ml) under an argon atmosphere, and 4-methyl-1,2,4-triazole-3,5-dione (15 mg, 0.13 mmol) was added in an ice bath. After stirring for 30 minutes in an ice bath, dilute with methylene chloride, subject to thin-layer preparative chromatography, develop with methylene chloride-ethyl acetate (100: 8, v / v), collect the desired product, and depressurize the solvent. Diisopropyl ether was added to the foam obtained by evaporation to solidify, and p-methoxybenzyl 7β
-[(Z) -2- (2-Tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide] -3-
[1,3-Dioxo-2-methyl-2,3,5,8-tetrahydro-1H- [1,2,4] triazolo [1,2
90 mg of -a] pyridazin-5-yl] -3-cephem-4-carboxylate was obtained.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ (ppm): 2.90 (3H, s), 3.3-3.4 (2H, m), 3.75 (3H, s),
3.79 (3H, s), 4.01 (1H, brd, J = 14.6Hz), 4.20 (1H, brd, J = 15.
9Hz), 5.14 (1H, d, J = 4.9Hz), 5.21 (2H, dd, J = 26.9,12.2Hz),
5.58 (1H, brs), 5.7 (2H, m), 6.19 (1H, brd, J = 10.4Hz), 6.70
(1H, s), 6.93 (2H, d, J = 8.5Hz), 7.2-7.4 (17H, m), 8.82 (1H,
s), 9.51 (1H, d, J = 7.9Hz) positive ion-FAB-mass spectrum: m / z; 911
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 1780,1712,1520,14
72,1250,1220,1178,1036,702cm ^-1

(2) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4) obtained in (1)
-Thiazolyl) -2- (methoxyimino) acetamide] -3- [1,3-dioxo-2-methyl-2,3
160 mg (0.18 mmo) 5,8-tetrahydro-1H- [1,2,4] triazolo [1,2-a] pyridazin-5-yl] -3-cephem-4-carboxylate
l) was dissolved in methylene chloride (3 ml) and anisole (2 ml) under an argon atmosphere, cooled to 10 ° C., and trifluoroacetic acid (5 ml) was added dropwise. 60 at 10 ℃ ~ room temperature
After stirring for a minute, the solvent and trifluoroacetic acid were distilled off under reduced pressure, ethyl ether-hexane was added to the residue, which was solidified and collected by filtration. This was added to trifluoroacetic acid (10 ml) cooled to 10 ° C., and water (5 ml) was further added dropwise.
After stirring at room temperature for 60 minutes, trifluoroacetic acid was distilled off under reduced pressure, and ethyl alcohol was added to the resulting residue to azeotropically distill off water. Ethyl ether was added to the residue to solidify and collect by filtration. The obtained powder was dissolved in saturated aqueous sodium hydrogen carbonate solution and purified by HP-20 column chromatography to give sodium 7β-[(Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamide]-. Three
-[1,3-dioxo-2-methyl-2,3,5,8-
Tetrahydro-1H- [1,2,4] triazolo [1.
2-a] -pyridazin-5-yl] -3-cephem-4
-Carboxylate (74 mg) was obtained.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ (ppm): 2.92 (3H, s), 3.08 (1H, d, J = 17.1Hz), 3.17
(1H, d, J = 17.1Hz), 3.82 (3H, s), 3.94 (1H, d, J = 14Hz), 4.18
(1H, d, J = 14Hz), 4.95 (1H, d, J = 4.9Hz), 5.57 (1H, m), 5.89 (1
H, m), 6.0 (2H, m), 6.72 (1H, s), 7.20 (2H, s), 9.45 (1H, d, J =
7.9 Hz) Positive ion-FAB-mass spectrum: m / z; 547
(M-Na) ⁺ infrared absorption spectrum ν _max (KBr); 1764,1698,1614,15
40,1488,1398,1362,1284,1038 cm ^-1 Example 4

[0137]

[Chemical 27]

(1) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-) obtained in Reference Example 1
4-thiazolyl) -2- (methoxyimino) acetamido] -3-[(E) -1,3-butadienyl] -3-cephem-4-carboxylate 5.59 g (7 mmo
l), sodium acetate 861 mg (10.5 mmol)
And 1.1 ml (14 mmol) of 38% formalin water was dissolved in 112 ml of tetrahydrofuran, and 878 mg (10.5 mm) of N-methylhydroxyamine hydrochloride was added thereto.
ol) was dissolved in 80% ethanol water (18 ml) and added dropwise, and the mixture was heated under reflux for 2.5 hours. After completion, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in methylene chloride, washed with saturated aqueous sodium hydrogen carbonate solution, saturated aqueous ammonium chloride solution, water and saturated brine, dried over anhydrous magnesium sulfate, and then reduced pressure. The lower solvent was distilled off. The obtained residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (100: 1, v / v) to collect fractions containing the desired product, and the solvent was evaporated under reduced pressure to give p-methoxybenzyl 7β. -[(Z) -2- (2-
Tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide] -3-[(E) -2- (2-methyl-5-isoxazolidinyl) vinyl] -3-cephem-4-carboxylate 5.97 g were obtained as a mixture of isomers.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ (ppm): 1.8-2.0 (1H, m), 2.3-2.8 (5H, m), 3.14 (1H, m), 3.5
6 (1H, m), 3.75 (3H, s), 3.81 (3H, s), 3.87 (1H, m), 4.2-4.7 (1
H, m), 5.1-5.2 (3H, m), 5.7 (1H, m), 6.1 (1H, m), 6.7 (1H, m),
6.72 (1H, s), 6.9 (2H, m), 7.2-7.4 (17H, m), 8.84 (1H, s), 9.5
9 (1H, m) positive ion-FAB-mass spectrum: m / z; 857
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 3352,2944,2860,17
84,1724,1632,1580,1518,1246cm ^-1

Alternative method of (1) (Z) -2- (2-tritylamino-4-thiazolyl)
-2- (methoxyimino) acetic acid 310 mg (0.7 mm
ol) was dissolved in 9 ml of a mixed solution of methylene chloride-N, N-dimethylformamide (2: 1, v / v), and 95 mg (0.7 mmo) of 1-hydroxybenzotriazole was dissolved therein.
l), 1,3-dicyclohexylcarbodiimide 144
mg (0.7 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours to obtain an ester form. This was obtained from p-methoxybenzyl 7β-amino-3-[(E) -2-obtained in Example 1.
(2-Methyl-5-isooxazolidinyl) vinyl]-
280 mg of 3-cephem-4-carboxylate was mixed with methylene chloride-N, N-dimethylformamide (2:
1, v / v) was added to the solution dissolved in 9 ml under ice-cooling, and the mixture was further stirred from ice-cooling temperature to room temperature for 15 hours. After completion, the solvent was distilled off under reduced pressure, and the resulting residue was mixed with 50 ml of chloroform.
And washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, chloroform-methanol (100: 0 to 0: 0).
100: 3, v / v) and the fractions containing the desired product were collected and the solvent was evaporated under reduced pressure to remove p-methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4-).
Thiazolyl) -2- (methoxyimino) acetamide]
-3-[(E) -2- (2-Methyl-5-isooxazolidinyl) vinyl] -3-cephem-4-carboxylate was obtained.

(2) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4) obtained in (1)
-Thiazolyl) -2- (methoxyimino) acetamido] -3-[(E) -2- (2-methyl-5-isooxazolidinyl) vinyl] -3-cephem-4-carboxylate 170 mg, argon In an atmosphere, dissolve in 3 ml of methylene chloride and 2 ml of anisole, cool to 10 ° C, add 5 ml of trifluoroacetic acid, and add 6 at 10 ° C to room temperature
Stir for 0 minutes. After cooling to 10 ° C. again, 5 ml of water was added, and the mixture was further stirred for 60 minutes. After the completion, the solvent was distilled off under reduced pressure, and ethanol was added to the residue to remove water by azeotropic distillation. Diisopropyl ether was added to the obtained ethyl ether solution, and the precipitated insoluble material was collected by filtration. The obtained powder was purified by high performance liquid preparative chromatography to obtain 7
[(Z) -2- (2-amino-4-thiazolyl) -2-
(Methoxyimino) acetamide] -3-[(E) -2
-(2-Methyl-5-isooxazolidinyl) vinyl]
Two isomers of 4--3-cephem-4-carboxylic acid (4
A, 4B) was obtained.

4A: Nuclear magnetic resonance spectrum (DMSO
-D ₆ , TMS internal standard) δ (ppm): 1.9 (1, m), 2.3-2.8 (4H, m), 3.84 (3H, s), 4.
33and4.62 (1H), 5.09 (1H, d, J = 4.6Hz), 5.6 (1H, m), 5.75 (1
H, m), 6.74 (1H, s), 6.84 (1H, d, J = 15.9Hz), 7.19 (2H, brd),
9.56 (1H, d, J = 8.2Hz) Positive ion-FAB-Mass spectrum: m / z; 495
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 1770,1676,1608,15
38,1388,1038cm ^-1

4B: Nuclear magnetic resonance spectrum (DMSO
-D ₆ , TMS internal standard) δ (ppm): 1.9 (1, m), 2.3-2.8 (4H, m), 3.84 (3H, s), 4.
32and4.59 (1H), 5.03 (1H, brd), 5.6 (3H, m), 6.74 (1H, s), 6.
87 (1H, d, J = 15.9Hz), 7.19 (2H, brs), 9.55 (1H, d, J = 7.9Hz) Positive ion-FAB-mass spectrum: m / z; 495
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 176
8, 1674, 1612, 1542, 1388, 103
8 cm ^-1 Example 5

[0144]

[Chemical 28]

P-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide] -3- [obtained in (1) of Example 4] 5.84 g of (E) -2- (2-methyl-5-isooxazolidinyl) vinyl] -3-cephem-4-carboxylate was dissolved in 117 ml of N, N-dimethylformamide, and methyl iodide 2 was added thereto. .12 ml
Was added and the mixture was stirred at room temperature for 24 hours. After completion, the solvent and excess methyl iodide were distilled off under reduced pressure, and the resulting foam was solidified with diisopropyl ether to give p-methoxybenzyl 7β-.
[(Z) -2- (2-Tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide] -3-
5.83 g of [(E) -2- (2,2-dimethyl-5-isooxazolidinio) vinyl] -3-cephem-4-carboxylate iodide were obtained as a mixture of isomers.

Nuclear magnetic resonance spectrum (DMSO-d
₆ , TMS internal standard) δ (ppm): 2.56 (1H, m), 2.82 (1H, m), 4.1 (1H, m), 4.2
(1H, m), 5.1-5.3 (3H, m), 5.7 (1H, m), 6.2 (1H, m), 6.7 (1H,
s), 6.85 (1H, d, J = 16.1Hz), 6.94 (2H, m), 7.2-7.4 (17H, m),
8.85 (1H, brs), 9.59 (1H, d, J = 7.8Hz) positive ion-FAB-mass spectrum: m / z; 871
(MI) ⁺ infrared absorption spectrum ν _max (KBr); 1786,1724,1670,15
20,1390,1248,1222,1036,704cm ^-1

(2) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4) obtained in (1)
-Thiazolyl) -2- (methoxyimino) acetamide] -3-[(E) -2- (2,2-dimethyl-5-isooxazolidinio) vinyl] -3-cephem-4-carboxylate iodide 5.72 g was dissolved in 30 ml of methylene chloride and 20 ml of anisole under argon atmosphere, cooled to 4 ° C., and added with 50 ml of trifluoroacetic acid.
The mixture was stirred at 4 ° C to room temperature for 60 minutes. After cooling to 4 ° C. again, 50 ml of trifluoroacetic acid and 50 ml of water were added, and the mixture was further stirred for 60 minutes. After the completion, the solvent was distilled off under reduced pressure, and then ethanol was added to the solution to remove water by azeotropic distillation, diisopropyl ether was added to the obtained ethanol solution, and the precipitated insoluble material was collected by filtration. The obtained powder was purified by HP-20 column chromatography and further high performance liquid preparative chromatography to obtain 7β-[(Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamide]. -3-[(E) -2- (2,2-dimethyl-5
-Isoxazolidinio) vinyl] -3-cephem-4
-Two isomers of carboxylates (5A, 5B) were obtained.

5A: Nuclear magnetic resonance spectrum (DMSO
-D ₆ , TMS internal standard) δ (ppm): 2.5 (1H, m), 2.7 (1H, m), 3.4 (2H, brs), 3.52
(3H, s), 3.55 (3H, s), 3.84 (3H, s), 4.0-4.1 (1H, m), 4.1-4.2
(1H, m), 5.02 (1H, d, J = 4.9Hz), 5.19 (1H, m), 5.5-5.6 (2H,
m), 6.74 (1H, s), 7.10 (1H, d, J = 15.6Hz), 7.21 (2H, brs), 9.5
5 (1H, d, J = 7.8Hz) Positive ion-FAB-Mass spectrum: m / z; 509
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 1770,1668,1610,15
40,1390,1356,1038cm ^-1 5B: Nuclear magnetic resonance spectrum (DMSO-d ₆ , TM
S internal standard) δ (ppm): 2.5 (1H, m), 2.7 (1H, m), 3.51 (3H, s), 3.54
(3H, s), 3.84 (3H, s), 4.0-4.1 (1H, m), 4.1-4.2 (1H, m), 5.03
(1H, d, J = 4.9Hz), 5.18 (1H, m), 5.5-5.6 (2H, m), 6.74 (1H, s) Example 6

[0149]

[Chemical 29]

(1) Compound 800 obtained in Reference Example 3
mg (1 mmol) was dissolved in 16 ml of tetrahydrofuran, and 123 mg of sodium acetate (1.5 mmo
l), 0.16 ml (2 mmol) of 38% formalin water
Was added. N-methylhydroxylamine hydrochloride 125
What melt | dissolved mg (1.5 mmol) in 80% ethanol water was dripped at the said solution under ice-cooling, and it heated and refluxed for 3.25 hours after that. After completion, the solvent was distilled off and the obtained residue was subjected to silica gel column chromatography and eluted with chloroform-methanol- (100: 1, v / v) to collect fractions containing the target substance, and the solvent was distilled off. P-methoxybenzyl 7β-[(Z) -2- (5-tritylamino-1,2,4-thiadiazol-3-yl) -2-
Methoxyiminoacetamide] -3-[(E) -2-
(2-Methyl-5-isooxazolidinyl) vinyl]-
774 mg of 3-cephem-4-carboxylate was obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 1.8-2.0 (1H, m), 2.3-2.7 (2H, m), 2.5 (3H,
m), 3.14 (2H, m), 3.31 (3H, s), 3.52 (1H, ABq), 3.86 (lH, AB
q), 3.75 (3H, s), 3.90 (3H, s), 4.2-4.6 (1H, m), 5.1-5.2 (3H,
m), 5.7 (1H, m), 6.1 (1H, m), 6.64 (1H, d, J = 15Hz), 6.93 (2H, A
Bq, J = 8Hz), 7.2-7.4 (17H, m), 9.57 (1H, m), 9.90 (1H, brs) Positive ion-FAB-Mass spectrum: m / z; 858
(M + H) ⁺ infrared absorption spectrum ν _max (KBr); 295
2,1784,1724,1688,1520,139
0,1220,1042,752,702cm ^-1

(2) Compound 76 obtained in the above (1)
6 mg (0.89 mmol) was dissolved in 4 ml of DMF, 277 μl (4.5 mmol) of methyl iodide was added thereto, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, ethyl ether was added to the residue, and the solid was collected by filtration and dried to obtain p.
-Methoxybenzyl 7β-[(Z) -2- (5-tritylamino-1,2,4-thiadiazol-3-yl)
2-Methoxyiminoacetamide] -3-[(E)-
2- (2,2-dimethyl-5-isooxazolidinio)
Obtained 827 mg (93%) of vinyl] -3-cephem-4-carboxylate iodide. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 2.5-2.9 (2H, m), 3.4-3.6 (9H, m), 3.75 (3H,
s), 3.8 (2H, ABq), 3.90 (3H, s), 4.0-4.2 (2H, m), 5.1-5.2 (3
H, m), 5.8 (1H, m), 6.2 (1H, m), 6.83 (1H, d, J = 16Hz), 6.94 (2
H, ABq, J = 8Hz), 7.2-7.5 (17H, m), 9.56 (1H, d, J = 8Hz), 10.0
(1H, s) positive ion-FAB-mass spectrum: m / z; 872
(MI) ⁺ infrared absorption spectrum ν _max (KBr); 3456,2952,1784,17
24,1670,1520,1392,1039cm ^-1

(3) Compound 785m obtained in (2)
g (0.79 mmol) was dissolved in 9 ml of methylene chloride and 2 ml of anisole, cooled to 10 ° C, added with 15 ml of trifluoroacetic acid, and stirred at 10 ° C to room temperature for 1.5 hours.
After the completion, 5 ml of water was added thereto while cooling with ice, and the mixture was further stirred for 1 hour. 50 ml of n-hexane is added to the reaction solution, and the aqueous layer is separated. The organic layer was extracted twice with water and combined with the previous aqueous layer. The aqueous layer was concentrated under reduced pressure, the residue was subjected to HP-20 column chromatography, and eluted with water-acetonitrile to collect fractions containing the desired product. After concentration under reduced pressure and freeze-drying, 7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3-[(E)- 2- (2,
2-Dimethyl-5-isooxazolidinio) vinyl]-
270 mg of 3-cephem-4-carboxylate (68
%) Was obtained. Since this was a 1: 1 mixture of isomers (6A, 6B) derived from the 5-position of isoxazole,
Both isomers were purified by high performance liquid chromatography to obtain each isomer.

6A: Nuclear magnetic resonance spectrum (DMSO
-D ₆ , TMS internal standard) δ (ppm): 2.5-2.7 (1H, m), 3.3-3.5 (2H, m), 3.52 (3H,
m), 3.55 (3H, s), 3.91 (3H, s), 4.07-4.16 (2H, m), 5.01 (1H,
d, J = 5Hz), 5.18 (1H, m), 5.54-5.62 (2H, m), 7.10 (1H, d, J = 16
Hz), 8.14 (1H, s), 9.51 (1H, d, J = 8.5Hz) Positive ion-FAB-mass spectrum: m / z; 510
(M + H) ⁺ infrared absorption spectrum ν _max (KBr); 3428,1770,1670,16
08,1532,1394,1354,1042cm ^-1

6B: Nuclear magnetic resonance spectrum (DMSO
-D ₆ , TMS internal standard) δ (ppm): 2.5-2.7 (2H, m), 3.4-3.5 (2H, m), 3.51 (3H,
s), 3.55 (1H, s), 3.91 (3H, s), 4.07-4.19 (2H, m), 5.04 (1H,
d, J = 5Hz), 5.17 (1H, m), 5.5-5.6 (2H, m), 7.10 (1H, d, J = 16H
z), 8.13 (1H, s), 9.51 (1H, d, J = 8.5Hz) Positive ion-FAB-mass spectrum: m / z; 510
(M + H) ⁺ infrared absorption spectrum ν _max (KBr); 3424,1770,1670,16
10,1530,1464,1356,1040 cm ^-1 Example 7

[0155]

[Chemical 30]

600 m of the compound obtained in Example 6 (1)
g (0.70 mmol) was deprotected in the same manner as in Example 6 and purified by HP-20 column chromatography to give 7β-[(Z) -2- (5-amino-1,
2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido) -3-[(E) -2- (2-methyl-5-isoxazolidinyl) vinyl] -3-cephem-4-carboxylic 269 mg (78%) of the acid were obtained. This is an isomer derived from the 5-position of isoxazolidine (7A,
Since it was a 1: 1 mixture of 7B), both isomers were purified by high performance liquid chromatography to obtain each isomer.

7A: Nuclear magnetic resonance spectrum (DMSO
-D ₆ , TMS internal standard) δ (ppm): 1.9-2.0 (1H, m), 2.3-2.7 (6H, m), 3.52 (1H,
ABq, J = 17Hz), 3.72 (lH, ABq, J = 17Hz), 3.91 (3H, s), 4.36 and 4.63 (1H, m), 5.11 (1H, d, J = 5Hz), 5.72 (2H, q , J = 8.5H
z), 5.9 (1H, m), 6.82 (1H, d, J = 15Hz), 8.13 (2H, brs), 9.56 (1
H, d, J = 8 Hz) Positive ion-FAB-mass spectrum: m / z; 496
(M + H) ⁺ infrared absorption spectrum: ν _max (KBr); 3432,1772,1
678,1604,1530,1398,1042cm ^-1

7B: Nuclear magnetic resonance spectrum (DMSO
-D ₆ , TMS internal standard) δ (ppm): 1.8-2.0 (1H, m), 2.3-2.7 (6H, m), 3.50 (1H,
ABq, J = 16Hz), 3.68 (lH, ABq, J = 16Hz), 4.37 and 4.63 (1H,
m), 5.09 (1H, d, J = 5Hz), 5.72 (2H, q, J = 9.5Hz), 5.86 (1H, m),
6.82 (1H, d, J = 16Hz) 8.13 (2H, brs), 9.56 (1H, d, J = 9Hz) Positive ion-FAB-Mass spectrum: m / z; 496
(M + H) ⁺ infrared absorption spectrum ν _max (KBr): 3432,1772,1678,15
30,1396,1042 cm ^-1 Example 8

[0159]

[Chemical 31]

(1) p-methoxybenzyl 7β-
[(Z) -2- (2-Tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide] -3-
[(E) -1,3-Butadienyl] -3-cephem-4
-Carboxylate 1.2 g (1.5 mmol), dibromoformaldoxime 308 mg (1.5 mmo
l), sodium hydrogencarbonate 638 mg (7.5 mmo
l) was suspended in 20 ml of methylene chloride and stirred at room temperature for 5 hours. After the completion, a saturated ammonium chloride aqueous solution was added, and further washed twice with a saturated ammonium chloride aqueous solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated, and the obtained residue was subjected to silica gel column chromatography to obtain methylene chloride-ethyl acetate (10: 1, v
/ V) and collect the fractions containing the desired product, evaporate the solvent and remove p-methoxybenzyl 7β-[(Z)-
2- (2-Tritylamino-4-thiazolyl) -2-
(Methoxyimino) acetamide] -3-[(E) -2
-(4H, 5H-3-Bromo-5-isoxazolyl)
Vinyl] -3-cephem-4-carboxylate 1.0
4 g (76%) were obtained as a mixture of isomers. Nuclear magnetic resonance spectrum (DMSO-d ₆ ) δ (ppm): 3.1 (1H, m), 3.5-3.6 (2H, m), 3.75 (3H, s),
3.81 (3H, s), 3.9 (1H, m), 5.70 (1H, dd, J = 7.8,4.9Hz), 6.17
(1H, dd, J = 15.6,7.3Hz), 6.71 (1H, s), 6.77 (1H, d, 15.6Hz),
6.93 (2H, m), 7.2-7.4 (17H, m), 8.84 (1H, brs), 9.6 (1H, m) positive ion-FAB-mass spectrum: m / z; 920
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 3320,1788,1728,16
88,1518,1250,1220,1038,702cm ^-1

(2) p-methoxybenzyl 7β-
[(Z) -2- (2-Tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide] -3-
200 mg of [(E) -2- (4H, 5H-3-bromo-5-isoxazolinyl) vinyl] -3-cephem-4-carboxylate was dissolved in 2 ml of methylene chloride and 1 ml of anisole under an argon atmosphere, 5 ml of trifluoroacetic acid was added dropwise at 10 ° C to room temperature. After stirring at room temperature for 60 minutes, the solvent and trifluoroacetic acid were distilled off, ethyl ether-hexane was added to the obtained residue to solidify it, and the solid was collected by filtration. Add this to 5 ml of trifluoroacetic acid cooled to 10 ° C
Further, 2.5 ml of water was added dropwise at room temperature or below. After stirring for 60 minutes at room temperature, 10 ml of ethyl alcohol was added to the residue obtained by distilling off trifluoroacetic acid, and water was azeotropically distilled off. 10 ml of ethyl ether was added to the residue, solidified and collected by filtration. The obtained powder was dissolved in a saturated aqueous solution of sodium hydrogen carbonate and purified by HP-20 column chromatography to obtain sodium 7β-[(Z) -2- (2-tritylamino-).
4-thiazolyl) -2- (methoxyimino) acetamido] -3-[(E) -2- (4H, 5H-3-bromo-
5-Isoxazolinyl) vinyl] -3-cephem-4
-56 mg of carboxylate were obtained as a mixture of isomers. Nuclear magnetic resonance spectrum (DMSO-d ₆ ) δ (ppm): 3.0-3.1 (1H, m), 3.84 (3H, s), 5.59 (1H, dd,
J = 7.3, 4.4Hz), 7.23 (2H, brs), 9.57 (1H, m) Positive ion-FAB-mass spectrum: m / z; 581
(M + 2) ⁺ infrared absorption spectrum ν _max (KBr); 3448,1766,1670,16
12,1538,1386,1040 cm ^-1 Example 9

[0162]

[Chemical 32]

(1) p-methoxybenzyl 7β-
[(Z) -2- (2-Tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide] -3-
[(E) -1,3-Butadienyl] -3-cephem-4
-Carboxylate 485 mg (0.61 mmol),
4-Pyridylhydroxamoyl chloride hydrochloride 236
mg (1.22 mmol) was suspended in 5 ml of dioxane, and 338 μl of triethylamine (2.
2 ml of a dioxane solution of 44 mmol) was added dropwise over 15 minutes. After completion of dropping, the mixture was further stirred at room temperature for 1 hour,
The insoluble material was filtered off, and the filtrate was concentrated. The obtained residue was subjected to silica gel column chromatography, eluted with chloroform, the fractions containing the target compound were collected, the solvent was evaporated, and p-methoxybenzyl 7β-[(Z) -2-
(2-Tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide] -3-[(E) -2- (4
275 mg (49%) of H, 5H-3- (4-pyridinyl) -5-isoxazolinyl) vinyl] -3-cephem-4-carboxylate were obtained as a mixture of isomers. Nuclear magnetic resonance spectrum (DMSO-d ₆ ) δ (ppm): 3.1-3.3 (2H, m), 3.5-3.7 (3H, m), 3.74 (3H,
s), 3.81 (3H, s), 5.3 (1H, m), 5.7 (1H, m), 6.2-6.3 (1H, m), 7.
6 (2H, m), 8.68 (2H, m), 8.84 (1H, brs), 9.6 (1H, m) Positive ion-FAB-mass spectrum: m / z; 918
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 1786,1724,1686,16
00,1520,1218,1038,754,702cm ^-1

(2) p-methoxybenzyl 7β-
[(Z) -2- (2-Tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide] -3-
[(E) -2- (4H, 5H-3- (4-pyridinyl))
-5-isoxazolinyl) vinyl] -3-cephem-
92 mg of 4-carboxylate was dissolved in 2 ml of methylene chloride and 1 ml of anisole under an argon atmosphere, and 5 ml of trifluoroacetic acid was added dropwise at 10 ° C to room temperature. 6 at room temperature
After stirring for 0 minutes, the solvent and trifluoroacetic acid were distilled off, ethyl ether-hexane was added to the residue, and the mixture was solidified and collected by filtration. 5m of trifluoroacetic acid cooled to 10 ° C
2.5 ml of water was added dropwise at room temperature or below. After stirring for 60 minutes at room temperature, 10 ml of ethyl alcohol was added to the residue obtained by distilling off trifluoroacetic acid, and water was azeotropically distilled off. 10 ml of ethyl ether was added to the residue, solidified and collected by filtration. The obtained powder was dissolved in a saturated aqueous solution of sodium hydrogen carbonate and purified by HP-20 column chromatography to obtain sodium 7β-[(Z) -2- (2-tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide. ] -3-[(E) -2- (4H, 5H-3-
(4-Pyridinyl) -5-isoxazolyl) vinyl]
21 mg of -3-cephem-4-carboxylate were obtained as a mixture of isomers. Nuclear magnetic resonance spectrum (DMSO-d ₆ ) δ (ppm): 5.2 (1H, m), 7.2 (2H, brs), 7.6 (2H, m), 8.6
(2H, m), 9.6 (1H, m) positive ion-FAB-mass spectrum: m / z; 556
(M + 2) ⁺ , 278 (M + Na + 2) ⁺ , 600 (M +
Na + Na + 2) ⁺ infrared absorption spectrum ν _max (KBr); 3432,1766,1672,16
08,1540,1386,1040 cm ^-1 Example 10

[0165]

[Chemical 33]

(1) p-methoxybenzyl 7β-
[(Z) -2- (2-Tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide] -3-
[(E) -2- (4H, 5H-3- (4-pyridinyl))
-5-isoxazolinyl) vinyl] -3-cephem-
4-carboxylate 148 mg (0.16 mmol)
Was dissolved in 2 ml of dimethylformamide under an argon atmosphere, methyl iodide was added, and the mixture was stirred at room temperature for 17 hours.
After the completion, the solvent was distilled off, and ethyl ether-hexane was added to the obtained foam to solidify it, and p-methoxybenzyl 7
β-[(Z) -2- (2-tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide] -3-
[(E) -2- (4H, 5H-3- (1-methyl-4-
Pyridinio) -5-isoxazolinyl) vinyl] -3
-Cephem-4-carboxylate iodide 166m
g was obtained almost quantitatively as a mixture of isomers. Nuclear magnetic resonance spectrum (DMSO-d ₆ ) δ (ppm): 3.75 (3H, s), 3.81 (3H, s), 4.35 (3H, s), 5.4
8 (1H, m), 6.24 (1H, m), 8.28 (2H, dd, J = 14.6,6.7Hz), 8.84 (1
H, s), 9.02 (2H, d, J = 6.7Hz), 9.59 (1H, m) positive ion-FAB-mass spectrum: m / z; 932
(M) ⁺ infrared absorption spectrum ν _max (KBr); 3432,1784,1684,15
20,1250,1220,1176,1036,704cm ^-1

(2) p-methoxybenzyl 7β-
[(Z) -2- (2-Tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide] -3-
[(E) -2- (4H, 5H-3- (1-methyl-4-
Pyridinio) -5-isoxazolinyl) vinyl] -3
-Cephem-4-carboxylate iodide 154m
g was dissolved in 2 ml of methylene chloride and 1 ml of anisole under an argon atmosphere, and 5 ml of trifluoroacetic acid was added at 10 ° C.
~ Dropped at room temperature. After stirring at room temperature for 60 minutes, the solvent and trifluoroacetic acid were distilled off, ethyl ether-hexane was added to the obtained residue to solidify it, and the solid was collected by filtration. This was added to 5 ml of trifluoroacetic acid cooled to 10 ° C, and water of 2.5 m was added.
1 was added dropwise at room temperature or below. After stirring for 60 minutes at room temperature,
10 ml of ethyl alcohol was added to the residue obtained by distilling off trifluoroacetic acid, and water was azeotropically distilled off. 10 ml of ethyl ether was added to the residue, solidified and collected by filtration. The obtained powder was dissolved in a saturated sodium hydrogen carbonate aqueous solution and purified by HP-20 column chromatography to obtain 7β-[(Z) -2-
(2-Tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide] -3-[(E) -2- (4
H, 5H-3- (1-methyl-4-pyridinio) -5-
53 mg of isoxazolinyl) vinyl] -3-cephem-4-carboxylate were obtained as a mixture of isomers. Nuclear magnetic resonance spectrum (DMSO-d ₆ ) δ (ppm): 3.83 (3H, s), 4.35 (3H, s), 5.03 (1H, m), 5.3
-5.5 (2H, m), 5.58 (1H, dd, J = 8.3,4.9Hz), 5.72 (1H, m), 6.7
3,6.79 (1H, s), 7.0-7.1 (1H, m), 7.24 (2H, brs), 8.28 (2H,
m), 9.04 (2H, m), 9.56 (1H, m) positive ion-FAB-mass spectrum: m / z; 570
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 3416,1770,1642,16
08,1534,1386,1036,932 cm ^-1 Example 11

[0168]

[Chemical 34]

(1) p-Methoxybenzyl 7β-
[(Z) -2- (2-Tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide] -3-
[(E) -1,3-Butadienyl] -3-cephem-4
-Carboxylate 400 mg, anhydrous sodium acetate 6
To 80 ml of a tetrahydrofuran solution containing 2 mg and 0.09 ml of 38% formalin water, 127 mg of 80% ethanol solution of N-carbamoylmethylhydroxylamine hydrochloride was added dropwise, and the mixture was heated under reflux for 5 hours. After completion, the solvent was distilled off and the obtained residue was dissolved in methylene chloride. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (20: 1, v / v), fractions containing the desired product were collected, the solvent was evaporated, and p-methoxybenzyl was added.
7β-[(Z) -2- (2-Tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide] -3
280 mg of-[(E) -2- (2-carbamoylmethyl-5-isooxazolidinyl) vinyl)]-3-cephem-4-carboxylate were obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 1.8-2.0 (1H, m), 2.3-2.5 (1H, m), 2.8-3.4
(4H, m), 3.56 (1H, m), 3.75 (3H, s), 3.81 (3H, s), 3.85 (1H,
m), 4.52 (1H, m), 5.1-5.3 (3H, m), 5.7 (1H, m), 6.1 (1H, m), 6.
67 (1H, d, J = 16Hz), 6.71 (1H, s), 6.93 (2H, d, J = 8.6Hz), 7.2-
7.4 (17H, m), 8.83 (1H, s), 9.58 (1H, m). Positive ion-FAB-mass spectrum: m / z; 900
(M + H) ⁺ infrared absorption spectrum ν _max (KBr); 3400,2952,1786,16
84,1520,1036,704cm ^-1

(2) 260 mg of the compound obtained in (1) was dissolved in 6 ml of methylene chloride and 4 ml of anisole, 10 ml of trifluoroacetic acid was added under ice cooling, and the mixture was stirred at 0 ° C to room temperature for 1 hr. After the solvent was distilled off, ethyl ether was added and the resulting precipitate was collected by filtration. The obtained powder is water 10m
10 ml of trifluoroacetic acid was added under ice-cooling, and the mixture was stirred at 0 ° C to room temperature for 1 hr. After distilling off the solvent,
Ethyl ether was added and the resulting precipitate was collected by filtration. The obtained powder was dissolved in saturated aqueous sodium hydrogen carbonate solution,
Purified by -20 column chromatography and high performance liquid preparative chromatography to obtain 7β-[(Z) -2- (2
-Amino-4-thiazolyl) -2- (methoxyimino)
Acetamide] -3-[(E) -2- (2-carbamoylmethyl-5-isoxazolidinyl) vinyl)]-3
-Two isomers of the sodium salt of cephem-4-carboxylic acid 11A (30 mg), 11B (25 mg) were obtained.

11A: Nuclear magnetic resonance spectrum (DMS
O-d ₆ , TMS internal standard) δ (ppm): 1.96 (1H, m), 2.46 (1H, m), 2.8-3.4 (4H, m),
3.50 (1H, d, J = 17.1Hz), 3.66 (1H, d, J = 17.1Hz), 3.84 (3H,
s), 4.4-4.6 (1H, m), 5.10 (1H, d, J = 4.9Hz), 5.66 (1H, m), 5.7
-5.9 (1H, m), 6.67 (1H, d, J = 16Hz), 6.75 (1H, s), 6.85 (2H, d,
J = 16.1Hz), 7.12 (2H, d, J = 14.2Hz), 7.21 (1H, m), 9.58 (1H,
d, J = 8.3Hz) Positive ion-FAB-mass spectrum: m / z; 538
(M + H) ⁺ infrared absorption vector ν _max (KBr); 3546,1768,1670,1394,1
040cm ^-1 11B: Nuclear magnetic resonance spectrum (DMSO-d ₆ , T
MS internal standard) δ (ppm): 1.94 (1H, m), 2.3-2.6
(1H, m), 2.8-3.4 (4H, m), 3.52
(1H, d, J = 17.1 Hz), 3.69 (1H,
d, J = 17.1 Hz), 3.84 (3H, s), 4.
58 (1H, m), 5.11 (1H, d, J = 4.4H
z), 5.69 (1H, m), 5.89 (1H, m),
6.74 (1H, s), 6.87 (1H, d, J = 16)
Hz), 7.12 (2H, d, J = 15.1Hz),
7.21 (1H, m), 9.58 (1H, d, J = 8.
3 Hz) Positive ion-FAB-mass spectrum: m / z; 538
(M + H) ⁺ infrared absorption vector ν _max (KBr); 3480,1774,1676,1388,1
040 cm ^-1 Example 12

[0172]

[Chemical 35]

(1) p-methoxybenzyl 7β-
[(Z) -2- (2-Tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide] -3-
[(E) -1,3-Butadienyl] -3-cephem-4
-Carboxylate 400 mg acetonitrile 5 ml
Was dissolved in water, 4- (R, S)-(t-butoxycarbonylamino) -3-oxo-1- (methylene) -1,2-pyrazolidinium ylide 213 mg was added, and the mixture was heated under reflux for 5 hours. After completion, the solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography, chloroform-
Elute with methanol (20: 1, v / v), collect the fractions containing the desired product, evaporate the solvent, and remove p-methoxybenzyl-3-[(E) -2- (1R or 1S, 6.
R or 6S) -6- (t-butoxycarbonylamino) -7-oxo-2,3,7,6-1H, 5H-pyrazolo [1,2-a] pyrazol-1-yl) vinyl]-
7β-[(Z) -2- (2-Tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide] -3
-215 mg of cephem-4-carboxylate were obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 1.38 (9H, s), 1.8-2.0 (1H, m), 2.3-2.7 (3H,
m), 3.1-3.2 (1H, m), 3.4-3.9 (9H, m), 4.2-4.6 (2H, m), 5.1-
5.3 (3H, m), 5.68 (1H, m), 5.9-6.1 (1H, m), 6.6-6.8 (2H, m),
6.93 (2H, d, J = 8.6Hz), 7.1-7.6 (17H, m), 8.83 (1H, m), 9.59
(1H, m) positive ion-FAB-mass spectrum: m / z; 1011
(M + H) ⁺ infrared absorption spectrum ν _max (KBr); 3424,2988,1786,16
96,1520,1166,1038,704cm ^-1

(2) Using the same procedure as in Example 11 (2), 320 mg of the compound obtained in (1) was treated with 3-[(E)-.
2- (1R or 1S, 6R or 6S) -6-amino-7-oxo-2,3,7,6-1H, 5H-pyrazolo [1,2-a] pyrazol-1-yl) vinyl]-
7β-[(Z) -2- (2-amino-4-thiazolyl)
2- (Methoxyimino) acetamido] -3-cephem-4-carboxylic acid isomer 12A (30 mg), 12
B (28 mg) and a 36:64 mixture 12C (58 mg) of two isomers different from 12A and 12B were obtained. 12A: Nuclear magnetic resonance spectrum (DMSO-d ₆ , T
MS internal standard) δ (ppm): 1.98 (1H, m), 2.3-2.7 (3H, m), 3.23 (1H, m),
3.47 (1H, d, J = 17.1Hz), 3.60 (1H, d, J = 17.1Hz), 3.81 (1H,
m), 3.84 (3H, s), 4.01 (1H, m), 4.45 (1H, m), 5.08 (1H, d, J = 4.
9Hz), 5.6-5.8 (2H, m), 6.74 (1H, s), 6.90 (2H, d, J = 8.6Hz), 7
(1H, d, J = 15.6Hz), 7.22 (2H, s), 9.58 (1H, d, J = 7.9Hz). Positive ion-FAB-mass spectrum: m / z; 549
(M + H) ⁺ infrared absorption spectrum ν _max (KBr); 3424,2988,1786,16
96,1520,1166,1038,704 cm ⁻¹ 12B: Nuclear magnetic resonance spectrum (DMSO-d ₆ , T
MS internal standard) δ (ppm): 1.94 (1H, m), 2.4-3.2 (4H, m), 3.48 (1H, d, J
= 17.1Hz), 3.63 (1H, d, J = 17.1Hz), 3.84 (3H, s), 4.06 (1H,
m), 4.39 (1H, m), 5.10 (1H, d, J = 4.9Hz), 5.65 (1H, m), 5.76 (1
H, dd, J = 6.7,9.1Hz), 6.74 (1H, s), 6.90 (1H, d, J = 16.1Hz),
7.21 (1H, m), 9.58 (1H, d, J = 7.9Hz) Positive ion-FAB-Mass spectrum: m / z; 549
(M + H) ⁺ infrared absorption spectrum ν _max (KBr); 3452,1768,1674,15
40,1388,1040cm ^-1

12C: Nuclear magnetic resonance spectrum (DMS
O-d ₆ , TMS internal standard) δ (ppm): 1.8-2.0 (1H, m), 2.3-
3.1 (4H, m), 3.2-4.0 (7H, m),
4.3-4.5 (1H, m), 5.0-5.1 (1H,
m), 5.6-5.8 (2H, m), 6.74 (1H,
s), 6.8-7.1 (1H, m), 7.2 (2H,
s), 9.5-9.6 (1H, m) positive ion-FAB-mass spectrum: m / z; 549
(M + H) ⁺ infrared absorption spectrum ν _max (KBr); 3456,1768,1684,15
38,1390,1038 cm ^-1 Example 13

[0176]

[Chemical 36]

(1) [7- (2-Tritylaminothiazol-4-yl) -2-methoxyimino-2-acetamido-4- (p-methoxybenzyloxycarbonyl)]
-3-Cephem-3-ylmethyl] triphenylphosphonium iodide 3441 mg was added to chloroform 100 m.
Dissolve in 1 l, add 12 ml of 1N-NaOH to this,
Stir for 0 minutes. After adding saturated saline to this, the organic layer was separated and dried over anhydrous sodium sulfate. 5-formyl-
A chloroform solution of 1.38 g of 2-isoxazoline was added to the above solution, and the mixture was stirred overnight at room temperature. The reaction solution was washed with water and saturated saline and then dried over anhydrous magnesium sulfate.
The crude product obtained by concentrating the solvent under reduced pressure was subjected to silica gel column chromatography and eluted with chloroform-methanol (100: 0 to 99: 1 to 95: 5, v / v) to give a fraction containing the desired product. Collect and evaporate the solvent to remove p-
Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4-thiazolyl) -2- (methoxyimino)
Acetamide] -3-[(E, Z) -2- (2-methyl-5-isoxazolidinyl) vinyl] -3-cephem-4-carboxylate (517 mg) was obtained. This was a mixture of isomers derived from (RS) at the 5-position of (E, Z) and isoxazole.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ (ppm): 1.7-2.0 (1H, m), 2.3-2.7 (5H, m), 3.1 (1H, m), 3.50
(1H, m), 3.74 (3H, s), 3.80 (3H, s), 4.2-4.7 (1H, m), 5.1-5.2
(2H, m), 5.20-5.25 (1H, m), 5.48-5.57 (1H, m), 5.70 (1H, m),
6.2 (1H, m), 6.71 (1H, s), 6.9 (2H, m), 7.2-7.7 (17H, m), 8.84
(1H, s), 9.56 (1H, d) positive ion-FAB-mass spectrum: m / z; 857
(M + H) ⁺

(2) 261 mg of the compound obtained in (1)
Was dissolved in 5 ml of methylene chloride and 0.2 ml of anisole under an argon atmosphere, cooled to 10 ° C, added with 5 ml of trifluoroacetic acid, and stirred at 10 ° C to room temperature for 60 minutes.
After distilling off methylene chloride and trifluoroacetic acid under reduced pressure, the temperature was again set to 10 ° C. and trifluoroacetic acid 5
ml and 3 ml of water were added and stirred for 1 hour. After the completion, the solvent was distilled off, and ethyl ether was added to the residue to obtain a crude product. The E / Z ratio in the crude product was 1: 4 by analytical high performance liquid preparative chromatography. The crude product was purified by high performance liquid preparative chromatography to give 7β
-[(Z) -2- (2-amino-4-thiazolyl) -2
-(Methoxyimino) acetamide] -3-[(Z)-
2- (2-Methyl-5-isooxazolidinyl) vinyl] -3-cephem-4-carboxylic acid isomers (13
A, 13B) was obtained. At room temperature, two conformers were observed in each case on NMR. 13A: Nuclear magnetic resonance spectrum (DMSO-d ₆ , T
MS internal standard) δ (ppm): 1.85 (1H, m), 2.30 (1H, m), 2.51 (3H, s), 3.13 (1H,
m) 3.45 (1H, m), 3.46 (1H, ABq, J = 17Hz), 3.60 (1H, ABq, J = 17H
z), 3.84 (3H, s), 4.51 and 4.76 (0.5H, m each), 5.17 (1H, d, J
= 5Hz), 5.43 (1H, dd, J = 12,10Hz), 5.73 (1H, dd, J = 8,5Hz), 6.
31 (1H, m), 6.74 (1H, s), 7.2 (1H, m), 9.59 (1H, d, J = 8Hz) Positive ion-FAB-Mass spectrum: m / z; 495
(M + H) ⁺ infrared absorption spectrum ν _max (KBr); 3424,1722,1670,16
10,1538,1388,1354,1040 cm ⁻¹ 13B: Nuclear magnetic resonance spectrum (DMSO-d ₆ , T
MS internal standard) δ (ppm): 1.90 (1H, m), 2.3 (1H, m), 2.50 (3H, m), 2.55 (1H,
m), 3.14 (1H, m), 3.37 (2H, m), 3.71 (2H, m), 3.85 (3H, s), 4.5
8 and 4.86 (0.5H, m each), 5.09 (1H, d, J = 5Hz), 5.30 (1H, m),
5.61 (1H, dd, J = 8,5Hz), 6.52 (1H, m; 1H under heating at 80 ℃,
d, J = 13 Hz), 6.75 (1H, s), 7.21
(1H, m), 9.55 (1H, d, J = 8Hz) Positive ion-FAB-mass spectrum: m / z; 495
(M + H) ⁺ infrared absorption spectrum ν _max (KBr); 3432,1772,1670,16
06,1540,1394,1356,1040 cm ^-1 Example 14

[0180]

[Chemical 37]

Mixture 227 obtained in Example 13 (1)
mg was dissolved in 4 ml of DMF, and methyl iodide 50
μl was added and the mixture was stirred at room temperature overnight. The solid obtained by evaporating the solvent under reduced pressure was dissolved in 5 ml of methylene chloride, and 0.2 g of anisole and 5 ml of trifluoroacetic acid were added.
ml was added, and the mixture was stirred at room temperature for 1 hour. Then, methylene chloride is distilled off under reduced pressure, the reaction solution is cooled to 10 ° C., 8 ml of trifluoroacetic acid and 3 ml of water are added, and the mixture is stirred for 1 hour. Water and trifluoroacetic acid were distilled off, and ethyl ether was added to the obtained residue to solidify it, followed by filtration and drying.
5 mg of crude product was obtained. This product was purified by high performance liquid chromatography to give 7β-[(Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamide] -3-[(Z) -2- (2. , 2-dimethyl-5
-Isoxazolidinio) vinyl] -3-cephem-4
-Carboxylate isomers (14A, 14B) were obtained.

14A: Nuclear magnetic resonance spectrum (DMSO
-D ₆ + CD ₃ OD, TMS internal standard) δ (ppm): 2.5-2.8 (2H, m), 3.36 (1H, ABq, J = 17Hz), 3.53 (3H,
s), 3.56 (3H, s), 3.69 (1H, ABq, J = 17Hz), 3.90 (3H, s), 4.07
(1H, m), 4.20 (1H, m), 5.10 (1H, d, J = 5Hz), 5.39 (1H, m), 5.44
(1H, m), 5.68 (1H, d, J = 5Hz), 6.70 (1H, d, J = 12Hz), 6.80 (1H,
s) Positive ion-FAB-mass spectrum: m / z; 509
(M + H) ⁺ infrared absorption spectrum ν _max (KBr); 348
8, 1770, 1666, 1608, 1538, 138
8,1356,1038 cm ⁻¹ 14B: Nuclear magnetic resonance spectrum (DMSO-d ₆ , T
MS internal standard) δ (ppm): 2.5-2.8 (2H, m), 3.30 (1H, ABq, J = 17Hz), 3.51 (3H,
s), 3.54 (3H, s), 3.61 (1H, ABq, J = 17Hz), 3.83 (1H, s), 4.03
(1H, m), 4.18 (1H, m), 5.07 (1H, d, 1H, d, J = 5Hz), 5.34 (1H,
m), 5.48 (1H, m), 5.62 (1H, dd, J = 8,5Hz), 6.62 (1H, d, J = 12H
z), 7.21 (1H, s), 9.57 (1H, d, J = 8Hz) Positive ion-FAB-mass spectrum: m / z; 509
(M + H) ⁺ infrared absorption spectrum ν _max (KBr); 3432,1776,1662,160
8,1540,1464,1392,1360,1040 cm ^-1 Example 15

[0183]

[Chemical 38]

(1) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-) obtained in Reference Example 4
4-thiazolyl) -2- (1-tert-butoxycarbonyl-1-methylethoxyimino) acetamide]-
3-[(E) -1,3-butadienyl] -3-cephem-4-carboxylate 925 mg (1 mmol), sodium acetate 123 mg (1 mmol), and 38%
To 20 ml of tetrahydrofuran solution of 0.17 ml (2 mmol) of formalin aqueous solution, 2.5 ml of 80% ethanol aqueous solution of 126 mg (1.5 mmol) of N-methylhydroxylamine hydrochloride was added dropwise, 30 minutes at room temperature and 3 hours under heating and refluxing. It was stirred. After the completion, the resulting insoluble matter was filtered off, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (15: 1, v / v), the fractions containing the desired product were collected, and the solvent was evaporated to remove p-methoxybenzyl 7β- [. (Z) -2- (2-tritylamino-4
-Thiazolyl) -2- (1-tert-butoxycarbonyl-1 methylethoxyimino) acetamide] -3-
[(E) -2- (2-Methyl-5-isooxazolidinyl) vinyl] -3-cephem-4-carboxylate 8
Obtained 00 mg (81.3%). Nuclear magnetic resonance spectrum (DMSOd ₆ , TMS internal standard) δ (ppm): 1.3-1.4 (15H, m), 1.8-2.1 (1H, m), 2.3-2.7 (5H,
m), 3.13 (1H, m), 3.55 (1H, m), 3.74 (3H, s), 3.84 (1H, m), 4.3
-4.7 (1H, m), 5.1-5.3 (3H, m), 5.7 (1H, m), 6.0-6.2 (1H, m),
6.66 (1H, d, J = 15.6Hz), 6.69 (1H, s), 6.93 (2H, d, J = 6.8Hz),
7.1-7.4 (17H, m), 8.80 (1H, s), 9.35 (1H, m) positive ion-FAB-mass spectrum; m / z: 999
(MI) ⁺ infrared absorption spectrum ν _max (KBr); 3420,2992,1790,172
8,1690,1520,1372,1306,1252,1146,704cm ^-1

(2) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4) obtained in (1)
-Thiazolyl) -2- (1-tert-butoxycarbonyl-1-methylethoxyimino) acetamide] -3
-[(E) -2- (2-Methyl-5-isooxazolidinyl) vinyl] -3-cephem-4-carboxylate 492 mg (0.5 mmol) in dimethylformamide solution 6 ml, methyl iodide 355 mg ( 2.5 mmo
1) was added dropwise, and the mixture was stirred overnight at room temperature. The solvent was evaporated, and the obtained residue was solidified with ethyl ether to give p-methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4-thiazolyl) -2- (1-tert-butoxy). Carbonyl-1-methylethoxyimino) acetamide]
560 mg of -3-[(E) -2- (2,2-dimethyl-5-isooxazolidinio) vinyl] -3-cephem-4-carboxylate iodide was quantitatively obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 1.2-1.6 (15H, m), 2.5-2.6 (1H, m), 2.7-3.0 (1H,
m), 3.4-3.7 (8H, m), 3.76 (3H, m), 3.88 (1H, d, J = 16.0), 4.0-
4.3 (2H, m), 5.1-5.3 (3H, m), 5.73 (1H, m), 6.21 (1H, m), 6.69
(1H, s), 6.84 (1H, d, J = 15.6Hz), 6.94 (2H, d, J = 8.3Hz), 7.1-
7.5 (17H, m), 8.80 (1H, s), 9.37 (1H, d, J = 7.8Hz). Positive ion-FAB-mass spectrum; m / z: 999
(MI) ⁺ infrared absorption spectrum ν _max (KBr); 3432,2992,1788,172
6,1686,1520,1388,1372,1306,1250,1222,1178,1146,97
0,704cm ^-1

(3) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4) obtained in (2)
-Thiazolyl) -2- (1-tert-butoxycarbonyl-1-methylethoxyimino) acetamide] -3
530 mg (0.47 mmol) of-[(E) -2- (2,2-dimethyl-5-isooxazolidinio) vinyl] -3-cephem-4-carboxylate iodide in 9 ml of methylene chloride and 6 ml of anisole. It melt | dissolved, 15 ml of trifluoroacetic acids were added under ice-cooling, and it stirred at 0 degreeC-room temperature for 1 hour. After distilling off the solvent, ethyl ether was added to the obtained residue, and the resulting solid was collected by filtration. The obtained powder was suspended in 15 ml of water, 15 ml of trifluoroacetic acid was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. After distilling off the solvent, ethyl ether was added to the obtained residue, and the resulting powder was collected by filtration. The obtained powder is dissolved in water and HP-2
0, 7β-purified by high performance liquid chromatography
[(Z) -2- (2-amino-4-thiazolyl) -2-
(1-Carboxy-1-methylethoxyimino) acetamide] -3-[(E) -2- (2,2-dimethyl-5)
-Isoxazolidinio) vinyl] -3-cephem-4
-Two isomers of carboxylate 15A 52 mg, 1
37 mg of 5B was obtained.

15A: Nuclear magnetic resonance spectrum (DMS
O-d ₆ , TMS internal standard) δ (ppm): 1.44 (3H, s), 1.46 (3H, s), 2.4-2.6 (1H, m), 2.75 (1
H, m), 3.3-3.7 (9H, m), 4.0-4.3 (2H, m), 5.08 (1H, d, J = 4,9H
z), 5.21 (1H, m), 5.6-5.8 (2H, m), 6.73 (1H, s), 7.07 (1H, d, J
= 15.6 Hz), 7.26 (2H, brs), 9.7-10.0 (1H, brs). Positive ion-FAB-mass spectrum; m / z: 581
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 3452,3052,1774,1670,
1598,1540,1470,1392,1164,980cm ^-1 15B: Nuclear magnetic resonance spectrum (DMSO-d ₆ , T
MS internal standard) δ (ppm): 1.42 (3H, s), 1.47 (3H, s), 2.4-2.7 (2H, m), 3.4-3.
7 (9H, m), 4.07 (1H, m), 4.25 (1H, m), 5.12 (1H, d, J = 4,9Hz),
5.35 (1H, m), 5.63 (1H, m), 5.70 (1H, m), 6.72 (1H, s) 7.05 (1
H, d, J = 15.6Hz), 7.23 (2H, brs) positive ion-FAB-mass spectrum; m / z: 581
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 3448,3052,1772,1672,
1598, 1538, 1470, 1394, 1164, 980 cm ^-1 Example 16

[0188]

[Chemical Formula 39]

(1) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-) obtained in Reference Example 7
4-thiazolyl) -2-fluoromethoxyimino) acetamido] -3-[(E) -1,3-butadienyl]-
3-Cephem-4-carboxylate 816 mg (1 m
mol) as a starting material and using the same method as in Example 4 (1), p-methoxybenzyl 7β-[(Z)-
2- (2-Tritylamino-4-thiazolyl) -2-fluoromethoxyimino) acetamido] -3-[(E)
-2- (2-Methyl-5-isooxazolidinyl) vinyl] -3-cephem-4-carboxylate 630 mg
(72.0%) was obtained. Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) δ (ppm): 1.7-2.1 ( 1H, m), 2.3-2.8 (5H, m), 3.13 (1H, m), 3.5
7 (1H, d, J = 17.6Hz), 3.75 (3H, s), 3.83 (1H, d, J = 17.6Hz), 4.
2-4.7 (1H, m), 5.1-5.3 (3H, m), 5.62 (1H, s), 5.69 (1H, m), 5.
76 (1H, s), 6.09 (1H, m), 6.6-6.8 (1H, m), 6.89 (1H, s), 6.93
(2H, d, J = 7.8Hz), 7.2-7.5 (17H, m), 8.92 (1H, s), 9.7-9.9 (1
H, m) positive ion-FAB-mass spectrum; m / z: 875
(M + 1) ⁺ infrared absorption spectrum νmax (KBr); 3412,2972,1786,1726,
1684,1616,1520,1388,1306,1250,1220,1098,988,702cm
^-1

(2) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4) obtained in (1)
-Thiazolyl) -1-methyl-1-methoxy-ethoxyimino) acetamide] -3-[(E) -2- (2-methyl-5-isoxazolidinyl) vinyl] -3-cephem-4-carboxy Rat 438mg (0.5mmo
Using l) as a starting material and a method similar to that in Example 5 (1), p-methoxybenzyl 7β-[(Z) -2-
(2-Tritylamino-4-thiazolyl) -2-fluoromethoxyimino) acetamido] -3-[(E) -2
510 mg of-(2,2-dimethyl-5-isooxazolidinio) vinyl] -3-cephem-4-carboxylate iodide was quantitatively obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 2.5-3.0 (2H, m), 3.4-3.7 (8H, m), 3.75 (3H, s), 3.8
6 (1H, d, J = 17.6Hz), 4.0-4.3 (2H, m), 5.1-5.3 (3H, m), 5.63
(1H, s), 5.73 (1H, m), 5.77 (1H, s), 6.19 (1H, m), 6.89 (1H,
s), 6.95 (2H, d, J = 7.8Hz), 7.1-7.5 (17H, m), 8.93 (1H, s), 9.
78 (1H, d, J = 7.8Hz) positive ion-FAB-mass spectrum; m / z: 88
9 (MI) ⁺ infrared absorption spectrum ν _max (KBr); 3456,2976,1786,1724,
1670,1616,1520,1390,1250,1220,1222,1178,1098,984,7
04 cm ^-1

(3) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4) obtained in (2)
-Thiazolyl) -2-fluoromethoxyimino) acetamide] -3-[(E) -2- (2,2-dimethyl-5)
-Isoxazolidinio) vinyl] -3-cephem-4
-500 mg of carboxylate iodide (0.49 m
mol) as a starting material and using the same method as in Example 5 (2), 7β-[(Z) -2- (2-amino-4-).
Thiazolyl) -2-fluoromethoxyimino) acetamide] -3-[(E) -2- (2,2-dimethyl-5-
Isoxazolidinio) vinyl] -3-cephem-4-
85 mg and 87 mg of two isomers of carboxylate, 16A and 16B, were obtained. 16A: Nuclear magnetic resonance spectrum (DMSO-d ₆ , T
MS internal standard) δ (ppm): 2.4-3.0 (2H, m), 3.2-3.6 (8H, m), 4.0-4.3 (2H, m),
5.07 (1H, d, J = 4.9Hz), 5.21 (1H, m), 5.5-5.7 (3H, m), 5.80 (1
H, s), 6.19 (1H, m), 6.91 (1H, s), 7.10 (1H, d, J = 15.6Hz), 7.3
0 (2H, brs), 9.77 (1H, d, J = 8.4Hz) Positive ion-FAB-mass spectrum; m / z: 52
7 (M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 3448,1770,1670,161
2,1540,1388,1098,984 cm ^-1 16B: Nuclear magnetic resonance spectrum (DMSO-d ₆ , T
MS internal standard) δ (ppm): 2.4-3.0 (2H, m), 3.2-3.6 (8H, m), 4.0-4.3
(2H, m), 5.08 (1H, d), J = 4.9Hz), 5.20 (1H, m), 5.5-5.7 (3H,
m), 5.80 (1H, s), 6.19 (1H, m), 6.90 (1H, s), 7.10 (1H, d, J = 1
5.6Hz), 7.29 (2H, brs), 9.77 (1H, d, J = 8.4Hz). Positive ion-FAB-mass spectrum; m / z: 52
7 (M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 3456,2940,1774,167
4,1612,1540,1390,1098,970 cm ^-1 Example 17

[0192]

[Chemical 40]

(1) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4-thiazolyl) -2- (1-methoxy-1-methyl) obtained in Reference Example 5 or 6 Ethoxyiminoacetamide] -3-[(E)-
1,3-butadienyl] -3-cephem-4-carboxylate 856 mg (1 mmol) as a starting material,
Using a method similar to that in Example 4 (1), p-methoxybenzyl 7β-[(Z) -2- (2-tritylamino-).
4-thiazolyl) -2- (1-methoxy-1-methyl)
Ethoxyiminoacetamide] -3-[(E) -2-
((RS) -2-methyl-5-isoxazolidinyl)
Vinyl] -3-cephem-4-carboxylate 640
mg (70.0%) was obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 1.39 (6H, s), 1.7-2.1 (1H, m), 2.2-2.8 (5H, m), 3.0
-3.3 (4H, m), 3.5-3.7 (1H, m), 3.75 (3H, s), 3.86 (1H, d, J = 1
7.6Hz), 4.2-4.7 (1H, m), 5.1-5.3 (3H, m), 5.68 (1H, s), 6.09
(1H, m), 6.6-6.8 (2H, m), 6.93 (2H, d, J = 7.8Hz), 7.2-7.5 (17
H, m), 8.86 (1H, s), 9.5-9.6 (1H, m). Positive ion-FAB-mass spectrum; m / z: 91
5 (M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 3416,3072,3004,296
8,1788,1726,1688,1618,1520,1376,1306,1452,1376,130
6,1250,1218,1178,1156,1070,958,894,754,702cm ^-1

(2) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4) obtained in (1)
-Thiazolyl) -2- (1-methoxy-1-methyl) ethoxyiminoacetamide] -3-[(E) -2- (2
-Methyl-5-isooxazolidinyl) vinyl] -3-
Cephem-4-carboxylate 458 mg (0.5 m
mol) as a starting material and using a method similar to that in Example 5 (1), p-methoxybenzyl 7β-[(Z)-
2- (2-Tritylamino-4-thiazolyl) -2-
(1-Methoxy-1-methyl) ethoxyiminoacetamido) acetamido] -3-[(E) -2-((RS))
520 mg of 2,2,2-dimethyl-5-isooxazolidinio) vinyl] -3-cephem-4-carboxylate iodide was quantitatively obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 1.39 (6H, s), 2.5-2.9 (2H, m), 3.11 (3H, s), 3.4-3.
7 (8H, m), 3.76 (3H, s), 3.93 (1H, d, J = 17.6Hz), 4.0-4.3 (2H,
m), 5.1-5.3 (3H, m), 5.70 (1H, m), 6.20 (1H, m), 6.73 (1H, s),
6.84 (1H, d, J = 15.6Hz), 6.94 (2H, d, J = 7.8Hz), 7.1-7.5 (17
H, m), 8.87 (1H, s), 9.54 (1H, d, J = 7.8Hz). Positive ion-FAB-mass spectrum; m / z: 92
9 (MI) ⁺ infrared absorption spectrum ν _max (KBr); 3448,
3012, 1786, 1728, 1672, 1618,
1520, 1388, 1250, 1220, 1180,
1068,976,894,754,704 cm ^-1

(3) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4) obtained in (2)
-Thiazolyl) -2- (1-methoxy-1-methyl) ethoxyiminoacetamido) acetamido] -3-
[(E) -2-((RS) -2,2-Dimethyl-5-isooxazolidinio) vinyl] -3-cephem-4-carboxylate iodide 500 mg (0.47 mmo
7β-[(Z) -2- (2-amino-4-thiazolyl) -2- (hydroxyimino) acetamide] -using the same method as in Example 5 (2), using 1) as the starting material.
3-[(E) -2- (2,2-Dimethyl-5-isooxazolidinio) vinyl] -3-cephem-4-carboxylate (Compound 17A) 35 mg, 7β-[(E)-
2- (2-amino-4-thiazolyl) -2- (hydroxyimino) acetamide] -3-[(E) -2- (2,
2-Dimethyl-5-isooxazolidinio) vinyl]-
3-Cephem-4-carboxylate (Compound 17B)
20 mg was obtained.

17A: Nuclear magnetic resonance spectrum (DMS
O-d ₆ , TMS internal standard) δ (ppm): 2.4-2.6 (1H, m), 2.7-2.9 (1H, m), 3.2-3.6 (8H, m),
4.0-4.3 (2H, m), 5.03 (1H, m), 5.18 (1H, m), 5.5-5.7 (2H, m),
5.80 (1H, s), 6.65 (1H, s), 6.91 (1H, s), 7.0-7.2 (3H, s), 9.4
0 (1H, d, J = 7.8Hz), 11.33 (1H, brs). Positive ion-FAB-mass spectrum; m / z: 495
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 3448,3048,1772,1608,
1540,1394,1184,1048,970cm ^-1 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 2.4-2.6 (1H, m), 2.6-2.9 (1H, m), 3.2- 3.6 (8H, m),
4.0-4.3 (2H, m), 5.04 (1H, m), 5.21 (1H, m), 5.5-5.7 (2H, m),
7.11 (1H, d, J = 15.6Hz), 7.20 (2H, s), 7.50 (1H, s), 9.27 (1H,
m), 12.61 (1H, m). Positive ion-FAB-mass spectrum; m / z: 495
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 3448,2360,1768,167
2,1610,1534,1394,1180,1004,970 cm ^-1 Example 18

[0197]

[Chemical 41]

(1) Compound 351m obtained in Reference Example 8
g (0.49 mmol) was dissolved in 8 ml of tetrahydrofuran, and 60 mg of sodium acetate (0.735 m
mol), 0.077 ml of 38% formalin water (0.9
8 mmol) was added. A solution of 62 mg (0.735 mmol) of N-methylhydroxylamine hydrochloride dissolved in 80% ethanol water was added dropwise to the above solution under ice cooling, and then heated under reflux for 3 hours. After the completion, the solvent was distilled off and the obtained residue was subjected to silica gel chromatography and eluted with chloroform-methanol (100: 2, v / v) to collect fractions containing the target compound. -Methoxybenzyl 7β-[(Z) -2- (5-tert
-Butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2- (1-methyl-1-methoxy)
Ethoxyiminoacetamide] -3-[(E) -2-
((RS) -2-methyl-5-isoxazolidinyl)
Vinyl] -3-cephem-4-carboxylate 244
mg was obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 1.46 (6H, s), 1.51 (9H, s), 1.8-2.0 (1H, m), 2.3-2.
7 (3H, m), 2.5 (3H, s), 3.16 (2H, m), 3.28 and 3.31 (3H, each
s), 3.58 (1H, ABq), 3.76 (3H, s), 3.90 (1H, ABq), 4.2-4.6 (1
H, m), 5.19-5.24 (3H, m), 5.88 (1H, q, J = 5,8Hz), 6.1 (1H, m),
6.64 (1H, d, J = 15Hz), 6.94,7.36 (4H, ABq), 9.68 (1H, m), 12.
4 (1H, brs) positive ion-FAB-mass spectrum: m / z; 774
(M + H) ⁺ infrared absorption spectrum ν _max (KBr); 179
0,1722,1548,1520,1374,125
0,1222,1176,1156cm ^-1

(2) 230 mg of the compound obtained in (1)
(0.30 mmol) was dissolved in 4 ml of DMF, 93 μl (1.5 mmol) of methyl iodide was added thereto, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, ethyl ether was added to the residue, and the solid was collected by filtration and dried to give p-methoxybenzyl 7β-[(Z) -2- (5-tert-butoxycarbonylamino-1,2,2. 4-thiadiazol-3-yl) -2- (1-methoxy-1-methyl) ethoxyiminoacetamide] -3-[(E) -2-((R
S) -2,2-Dimethyl-5-isooxazolidinio)
Vinyl] -3-cephem-4-carboxylate 251 mg of iodide was obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 1.46 (6H, s), 1.51 (9H, s), 2.5 (1H, m), 2.8 (1H, m),
3.16 (3H, s), 3.54 (1H, ABq), 3.6 (6H, m), 3.76 (3H, s), 3.9 (1
H, ABq), 4.0-4.3 (2H, m), 5.1-5.2 (4H, m), 5.9 (1H, m), 6.2 (1
H, m), 6.84 (1H, d, J = 16Hz), 6.95 (2H, ABq, J = 8Hz), 7.36 (2H,
ABq, J = 8Hz), 9.70 (1H, d, J = 8Hz) Positive ion-FAB-Mass spectrum: m / z; 788
(MI) ⁺ infrared absorption spectrum ν _max (KBr); 1788,1720,1552,13
88,1248,1154cm ^-1

(3) 251 mg of the compound obtained in (2)
(0.27 mmol) and anisole (0.2 ml) were dissolved in methylene chloride (2 ml), and trifluoroacetic acid (2 m) was added.
1 was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, 2 ml of trifluoroacetic acid and 4 ml of methylene chloride were added to the residue again, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and ethyl ether was added to the residue to give a crude product 16
7 mg was obtained. This product was purified by HP-20 column chromatography to obtain 7β-[(EZ) -2-
(5-Amino-1,2,4-thiadiazol-3-yl) -2-hydroxyiminoacetamide] -3-
135 mg of [(E) -2-((RS) -2,2-dimethyl-5-isooxazolidinio) vinyl] -3-cephem-4-carboxylate were obtained. This was further purified by high performance liquid chromatography to obtain two components (18A, 18B) derived from E and Z of the above compound oxime. These were a mixture of diastereomers derived from the 5-position of isoxazolidine.

18A: Nuclear magnetic resonance spectrum (DMS
O-d ₆ , TMS internal standard) δ (ppm): 2.6-2.7 (2H, m), 3.3-3.6 (8H, m), 4.0-4.18 (2H,
m), 5.01,5.04 (1H, each d, J = 5Hz), 5.18-5.20 (1H, m), 5.56-
5.66 (1H, m), 7.08 (1H, d, J = 16Hz), 8.06 (2H, brs), 9.38 (1
H, d, J = 8Hz), 11.95 (1H, brs) positive ion-FAB-mass spectrum: m / z; 496
(M + H) ⁺ infrared absorption spectrum ν _max (KBr); 3416,1770,1670,16
04,1526,1392,1178cm ^-1 18B: Nuclear magnetic resonance spectrum (DMSO-d ₆ , T
MS internal standard) δ (ppm): 2.7-2.8 (2H, m), 3.4-3.7 (8H, m), 4.07-4.18 (2H,
m), 5.04 and 5.05 (1H, each d, J = 5Hz), 5.19-5.21 (1H, m), 5.
19-5.21 (1H, m), 5.58-5.66 (2H, m), 7.10 (1H, d, J = 16Hz), 8.
07 (1H, s), 8.78 (1H, d, J = 8Hz), 12.7 (1H, brs) Positive ion-FAB-Mass spectrum: m / z; 496
(M + H) ⁺ infrared absorption spectrum ν _max (KBr); 3432,1770,1680,160
6,1518,1394,1356 cm ^-1 Example 19

[0202]

[Chemical 42]

P-Methoxybenzyl obtained in Reference Example 9
7β-[(Z) -2- (5-tritylamino-1,2,4-thiadiazol-3-yl) -2-fluoromethoxyimino)
Acetamide] -3-[(E) -1,3-butadienyl]-
3-Cephem-4-carboxylate 810 mg (0.9
9 mmol) as a starting material and using the same method as in Example 6 (1), p-methoxybenzyl 7β-[(Z)
-2- (5-Tritylamino-1,2,4-thiadiazole-
3-yl) -2-fluoromethoxyimino) acetamido] -3-[(E) -2- (2-methyl-5-isoxazolidinyl) vinyl] -3-cephem-4-carboxylate 678 mg (78 .2%). Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 1.7-2.1 (1H, m), 2.2-2.8 (5H, m), 3.13 (1H, m), 3.
55 (1H, m), 3.75 (3H, s), 3.84 (1H, m), 4.2-4.7 (1H, m), 5.0-
5.3 (3H, m), 5.70 (1H, s), 5.79 (1H, m), 5.84 (1H, s), 6.08 (1
H, m), 6.6-6.7 (1H, m), 6.93 (2H, d, J = 8.8Hz), 7.1-7.4 (17H,
m), 9.75 (1H, m), 10.08 (1H, s). Positive ion-FAB-mass spectrum; m / z: 876 (M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 3416,2976, 1788,172
4,1696,1616,1520,1450,1392,1372,1306,1250,1222,117
8,1124,1076,1006,754,702cm ^-1 .

(2) p-Methoxybenzyl 7β-[(Z) -2- (5-tritylamino-1,1 obtained in (1)
2,4-thiadiazol-3-yl) -2-fluoromethoxyimino) acetamido] -3-[(E) -2- (2-methyl-5-isooxazolidinyl) vinyl] -3-cephem-
4-carboxylate 640 mg (0.73 mmol)
Was used as a starting material and p-methoxybenzyl 7β-[(Z) -2- (5-tritylamino-1,2,4-thiadiazol-3-yl) was prepared in the same manner as in Example 6 (2). -2-
Fluoromethoxyimino) acetamide] -3-[(E)
700 mg (94.2%) of -2- (2,2-dimethyl-5-isooxazolidinio) vinyl] -3-cephem-4-carboxylate iodide was obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 2.4-2.6 (1H, m), 2.7-2.9 (1H, m), 3.4-3.7 (7H,
m), 3.75 (3H, m), 3.8-3.9 (1H, m), 4.0-4.3 (2H, m), 5.1-5.3
(3H, m), 5.70 (1H, s), 5.8-5.9 (2H, m), 6.1-6.3 (1H, m), 6.84
(1H, d, J = 15.6Hz), 6.94 (2H, m), 7.2-7.5 (17H, m), 9.76 (1H,
m), 10.09 (1H, s). Positive ion-FAB-mass spectrum; m / z: 890 (MI) ⁺ infrared absorption spectrum ν _max (KBr); 3464,304
0,2976,1786,1724,1684,161
8, 1520, 1452, 1394, 1366, 130
6,1250,1222,1178,1124,107
4,1004,860,756,704 cm ^-1 .

(3) p-Methoxybenzyl-7β-[(Z) -2- (5-tritylamino-1,1 obtained in (2)
2,4-thiadiazol-3-yl) -2-fluoromethoxyimino) acetamido] -3-[(E) -2- (2,2-
Dimethyl-5-isooxazolidinio) vinyl] -3-cephem-4-carboxylate iodide 690 mg
Example 6 using (0.68 mmol) as a starting material.
Using the same method as in (2), 7β-[(Z) -2- (5-
Amino-1,2,4-thiadiazol-3-yl) -2-fluoromethoxyimino) acetamido] -3-[(E) -2-
Two isomers of (2,2-dimethyl-5-isooxazolidinio) vinyl] -3-cephem-4-carboxylate, 19A81 mg and 19B115 mg, were obtained.

19A: Nuclear magnetic resonance spectrum (DMS
O-d ₆ , TMS internal standard) δ (ppm): 2.43-2.6 (1H, m), 2.65-2.8 (1H, m), 3.3-3.6 (8H,
m), 4.0-4.23 (2H, m), 5.04 (1H, d, J = 4.9Hz), 5.20 (1H, m), 5.
55-5.65 (2H, m), 5.72 (1H, s), 5.86 (1H, s), 7.10 (1H, d, J = 1
5.6Hz), 8.24 (2H, s), 9.71 (1H, d, J = 8.3Hz). Positive ion-FAB-mass spectrum; m / z: 528 (M + 1) ⁺ infrared absorption spectrum; ν _max ( KBr): 3448,3056,1772,167
6,1610,1532,1464,1398,1354,1180,1144,1086,1064,99
2,864 cm ^-1 19B: Nuclear magnetic resonance spectrum (DMSO-d ₆ , TM
S internal standard) δ (ppm): 2.45-2.6 (1H, m), 2.68-2.8 (1H, m), 3.3-3.7 (8H,
m), 4.0-4.23 (2H, m), 5.05 (1H, d, J = 4.9Hz), 5.19 (1H, m), 5.
55-5.66 (2H, m), 5.72 (1H, s), 5.86 (1H, s), 7.09 (1H, d, J = 1
5.6Hz), 8.26 (2H, s), 9.72 (1H, d, J = 8.3Hz). Positive ion-FAB-mass spectrum; m / z: 528 (M + 1) ⁺ infrared absorption spectrum; ν _max ( KBr): 345
2,1770,1674,1610,1532,146
4,1398,1354,1182,1140,108
8,1062,998,860 cm ^-1

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Hiroyuki Kudō 2-37 Kasuga, Tsukuba City, Ibaraki Building No. 2 402 (72) Inventor Noriaki Nagano 6-16-3 Nagayama, Ryugasaki City, Ibaraki Prefecture

Claims (13)

[Claims] 1. A compound represented by the general formula (I): (The symbols in the formulas have the following meanings: R ¹ : hydrogen atom, lower alkenyl group, lower alkynyl group, cycloalkyl group, hydroxyl-protecting group or substituted or unsubstituted lower alkyl group R ² : hydrogen atom, Ester residue or negatively charged R ³ : (1) group represented by the following formula: R ⁴ and R ^{5 are the} same or different and each is a lower alkoxy group, a substituted or unsubstituted amino group, or a substituted or unsubstituted R ⁴ and R ⁵ are integrally formed with an adjacent tetrahydropyridazinyl group. Fused 5- or 6-membered cyclic group (2) Group represented by the following formula: R ⁶ , R ^{7 are the} same or different and each is a hydrogen atom, a halogen atom, an amino group, an azido group, an unsubstituted or amino group, an azido group, a carbamoyl group or a halogen atom-substituted lower alkyl group, a carbamoyl group, or a substituted or unsubstituted Substituted 5- to 6-membered heterocyclic group (the nitrogen atom of the heterocyclic ring can be a quaternary amine together with the substituent) A ring: 4- to 5-membered nitrogen-containing heterocyclic ring which may contain an oxygen atom X: methine group A cephalosporin derivative represented by (-CH =) or a nitrogen atom) or a salt thereof. 2. The compound according to claim 1, wherein R ³ is represented by the following formula. [Chemical 4] (R ^6, R ^7: identical or different, a hydrogen atom, a halogen atom, an amino group, an azido group, an unsubstituted or amino group,
Azido group, carbamoyl group or halogen atom-substituted lower alkyl group, carbamoyl group, or substituted or unsubstituted 5- or 6-membered heterocyclic group (the nitrogen atom of the heterocyclic ring may become a quaternary amine together with the substituent) A ring : 4- to 5-membered nitrogen-containing heterocycle which may contain an oxygen atom X: a cephalosporin derivative represented by a methine group (-CH =) or a nitrogen atom) or a salt thereof. 3. The compound according to claim 1, wherein R ³ has the formula —CH═CH—Y. (The symbols in the formulas have the following meanings: Y: a group represented by the following formula: The dotted line may form a double bond. R ⁶ , R ^{7 are the} same or different and each is a hydrogen atom, a halogen atom, an amino group, an azido group, an unsubstituted or amino group, an azido group, a carbamoyl group or a halogen atom-substituted lower alkyl group, a carbamoyl group, or a substituted or unsubstituted A cephalosporin derivative represented by a substituted 5- to 6-membered heterocyclic group (the nitrogen atom of the heterocycle may become a quaternary amine with a substituent) or a salt thereof. 4. The compound according to claim ¹ , wherein R ¹ is hydrogen, a lower alkyl group, a halogeno lower alkyl group or a carboxy lower alkyl group. 5. 7β-[(Z) -2- (2-amino-4-)
Thiazolyl) -2- (methoxyimino) acetamide]
-3-[(E) -2- (2,2-Dimethyl-5-isooxazolidinio) vinyl] -3-cephem-4-carboxylate or a salt thereof. 6. β-[(Z) -5-amino-1,2,4
-Thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3-[(E) -2- (2,2-dimethyl-5-isoxazolidinio) vinyl] -3-cephem-4- Carboxylate or its salt. 7. 7β-[(Z) -2- (2-amino-4)
-Thiazolyl) -2- (fluoromethoxyimino) acetamide] -3-[(E) -2- (2,2-dimethyl-
5-Isoxazolidinio) vinyl] -3-cephem-
4-carboxylate or a salt thereof. 8. β- [2- (2-Amino-4-thiazolyl) -2- (hydroxyimino) acetamide] -3-
[(E) -2- (2,2-Dimethyl-5-isooxazolidinio) vinyl] -3-cephem-4-carboxylate or a salt thereof. 9. β- [2- (5-amino-1,2,4-)
Thiadiazol-3-yl) -2- (hydroxyimino) acetamido] -3-[(E) -2-((RS)-
2,2-Dimethyl-5-isooxazolidinio) vinyl] -3-cephem-4-carboxylate or a salt thereof. 10. β-[(Z) -2- (2-amino-4)
-Thiazolyl) -2- (methoxyimino) acetamide] -3-[(E) -2- (2-methyl-5-isoxazolidinyl) vinyl] -3-cephem-4-carboxylic acid or a salt thereof. 11. β-[(Z) -2- (5-amino-)
1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3-[(E) -2- (2
-Methyl-5-isooxazolidinyl) vinyl] -3-
Cephem-4-carboxylic acid or a salt thereof. 12. β-[(Z) -2- (5-amino-)
1,2,4-thiadiazol-3-yl) -2- (fluoromethoxyimino) acetamido-3-[(E) -2
-(2,2-Dimethyl-5-isooxazolidinio) vinyl] -3-cephem-4-carboxylate or a salt thereof. 13. A compound represented by the general formula (II): (The symbols in the formulas have the following meanings. R ⁸ : Protecting group for hydrogen atom, negative charge or carboxyl group R ³ : (1) Group represented by the following formula: R ⁴ and R ^{5 are the} same or different and each is a lower alkoxy group, a substituted or unsubstituted amino group, or a substituted or unsubstituted R ⁴ and R ⁵ are integrally formed with an adjacent tetrahydropyridazinyl group. Fused 5- to 6-membered ring group (2) Group represented by the following formula: R ⁶ , R ^{7 are the} same or different and each is a hydrogen atom, a halogen atom, an amino group, an azido group, an unsubstituted or amino group, an azido group, a carbamoyl group or a halogen atom-substituted lower alkyl group, a carbamoyl group, or a substituted or unsubstituted Substituted 5- to 6-membered heterocyclic group (the nitrogen atom of the heterocycle may become a quaternary amine together with the substituent) A ring: A 4- to 5-membered nitrogen-containing heterocyclic ring which may contain an oxygen atom) A cephalosporin derivative or a salt thereof.