JPH0532671A - New cephem compound, its production and antibacterial agent - Google Patents

Abstract

PURPOSE:To provide the subject new compound useful as an antibacterial agent against Gram-positive bacteria, Gramnegative bacteria, Staphylococcus aureus, Pseudomonas aeruginosa, etc. CONSTITUTION:The compound of formula I [R<1> is (substituted) lower alkyl, trityl, H, etc.; R<2> is H, metal or carboxyl-protecting group; R<3> to R<6> are H, halogen, (substituted) lower alkyl, (substituted) mercapto, etc.; R<7> is H, cyano, halogen, etc.; R<9> is (protected) amino; Z is N or CH; n is 0 or 1], e.g. 7beta-(Z)-2-(2- aminothiazol-4-yl)-2-methoxyimidonoacetamido]-3-(3-ethoxycarbonyl-6,7,8- trifluoro-4-oxo-4H-1-benzothiopyran-2-yl)thiomethyl-3-cephem-4-carboxylic acid sodium salt. The compound of formula I can be produced by reacting a compound of formula II with a compound of formula III (M is H, metal or quaternary ammonium).

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel cephem compound useful as an antibacterial agent, a pharmaceutically acceptable salt thereof, a method for producing the same, and an antibacterial agent containing them as an active ingredient.

[0002]

2. Description of the Related Art Cephalosporin antibacterial agents have broad antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, and various cephalosporin compounds have already been synthesized. However, among these compounds, few therapeutic agents have antibacterial activity against Pseudomonas aeruginosa, and those showing a wide range of powerful antibacterial activity from Gram-positive bacteria including Staphylococcus to Gram-negative bacteria including Pseudomonas aeruginosa Absent.

Compounds having a thiochromone skeleton in cephem are disclosed in JP-A-54-109995 and JP-A-57-165389.
It is disclosed in JP-A-57-165390 and US Pat. No. 3,904,618. These are those in which the 2- or 3-position of the thiochromone skeleton is bonded to a part of the side chain of the cephem. The compound having the thiochromone skeleton in the side chain of the cephem 3 is not only synthesized but also disclosed and suggested in the specification. Not done at all.

[0004]

Since the cephalosporin antibacterial agent shows selective toxicity only to bacteria and does not affect animal cells, it is used as an antibiotic with few side effects for treating bacterial infectious diseases. It is a widely used and highly useful drug.

However, in recent years, glucose non-fermenting Gram-negative bacilli, especially Pseudomonas aeruginosa, have often been isolated as a causative bacterium of intractable infectious diseases from patients with weakened immunity. On the other hand, among Gram-positive bacteria, Staphylococcus aureus (MRSA), which is resistant to all antibacterial agents, has become a clinically serious social problem. Under such circumstances, an antibacterial agent that is well balanced against Gram-positive bacteria including MRSA and Gram-negative bacteria such as Pseudomonas aeruginosa and has a strong antibacterial activity is required.

[0006]

DISCLOSURE OF THE INVENTION The present inventor aims to provide a novel cephalosporin derivative having excellent antibacterial activity, and 2- (2-aminothiazol-4-yl) is present at the 7-position of the cephem skeleton. ) -2-Substituted oxyiminoacetamide group or 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-
A substituted oxyiminoacetamide group is unprecedented in the 3-position
A new cephalosporin derivative having a thiochromone skeleton with a sulfide bond was studied intensively. as a result,
The compound of the present invention has a strong antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, and has a well-balanced and wide-ranging antibacterial spectrum up to Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa which are resistant to all antibacterial agents However, the present invention has been completed based on the surprising fact that the antibacterial activity is also enhanced.

That is, 2- (2-aminothiazol-4-yl) -2-substituted oxyiminoacetamide group or 2- (5-amino-1,2,4-thiadiazol-3-yl) at the 7-position of the cephem skeleton. )
The compound of the present invention having a 2-substituted oxyiminoacetamide group at the 3-position (substituted thiochromon-2-yl) thiomethyl group is a novel compound not described in the literature, and includes MRSA-containing Gram-positive bacteria and Pseudomonas aeruginosa It has a broad spectrum and strong antibacterial activity with well-balanced Gram-negative bacteria.

The present invention has the general formula [I] [I] [In the formula, R ¹ is a linear or branched lower alkyl group optionally substituted with an optionally protected carboxyl group, a trityl group, a hydrogen atom or a fluorine-substituted lower alkyl group, R ² Is a hydrogen atom, a metal atom, a protecting group for a carboxyl group or an ester residue capable of forming a hydrolyzable ester in vivo, and R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different and are a hydrogen atom. , Halogen atom, optionally substituted linear or branched lower alkyl group, optionally substituted mercapto group, lower alkylamino group,
Optionally protected hydroxyl group, lower alkoxy group, lower alkanoyl group, lower alkoxycarbonyl group and R ³
And R ⁴ may form a lower alkylenedioxy group which may be substituted with R ⁴ , R ⁷ is a hydrogen atom, a cyano group, a halogen atom or COOR ⁸ (R ⁸ is hydrogen or a lower alkyl group), and R ⁹ is An optionally protected amino group, Z is N or CH, and n is 0 or 1. ] It is related with the compound represented by these, its manufacturing method, and the antibacterial agent containing this compound as an active ingredient.

Next, the symbols and terms used in this specification will be described.

The substituent R ¹ of the compound of the general formula [I] is a linear or branched lower alkyl group optionally substituted with an optionally protected carboxyl group, a trityl group, a hydrogen atom or a fluorine-substituted group. It means a lower alkyl group.

Here, the linear or branched lower alkyl group refers to an alkyl group having 1 to 6 carbon atoms, specifically, a methyl group, an ethyl group, an n-propyl group, an isopropyl group,
n-butyl group, isobutyl group, sec-butyl group, t-butyl group, n-pentyl group, n-hexyl group and the like,
Particularly preferred examples include, for example, methyl group, ethyl group,
Examples include n-propyl group and isopropyl group.

Fluorine-substituted lower alkyl groups include fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2,2-difluoroethyl group,
2,2,2-trifluoroethyl group, 1-fluoroethyl group, 1,
Examples thereof include 2-difluoroethyl group, and particularly preferable examples include fluoromethyl group and 2-fluoroethyl group.

Preferred examples of the substituent R ¹ which may be substituted with a carboxyl group are carboxymethyl group, 1-carboxy-1-methylethyl group and 1-carboxy-1.
-Methylpropyl group and 1-carboxy-1-methylbutyl group.

The substituent R ² of the compound of the general formula [I] means a hydrogen atom, a metal atom or an ester residue capable of forming a hydrolyzable ester in vivo.

Here, examples of the metal atom include alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and preferable examples include sodium and potassium.

The ester residue capable of forming a hydrolyzable ester in vivo may have a lower alkoxycarbonyloxyalkyl group, an alkanoyloxymethyl group and a substituent (2-oxo-1,3-dioxolene). -4-yl) methyl group and the like, and particularly preferred examples are 1-
Examples thereof include (ethoxycarbonyloxy) ethyl group, acetoxymethyl group, pivaloyloxymethyl group and 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl group.

The substituent R ³ of the compound of the general formula [I],
R ⁴ , R ⁵ and R ⁶ may be the same or different and each is a hydrogen atom, a halogen atom, an optionally substituted linear or branched lower alkyl group, an optionally substituted mercapto group, a lower alkyl. Means that an amino group, an optionally protected hydroxyl group, a lower alkoxy group, a lower alkanoyl group, a lower alkoxycarbonyl group and a lower alkylenedioxy group which may be substituted with R ³ and R ⁴ may be formed. To do.

Here, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The linear or branched lower alkyl group which may be substituted has 1 to 6 carbon atoms which may have a substituent.
Is an alkyl group. Here, the substituent means an amino group which may be substituted with an alkoxy group, a halogen atom, an optionally protected hydroxyl group, a lower alkyl group, a lower acyl group, etc., and an optionally substituted lower alkyl group. Particularly preferred examples of the group include a methyl group, an ethyl group,
n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group, methoxymethyl group, ethoxymethyl group, 1-methoxyethyl group, 2-methoxyethyl group, fluoromethyl group, 2-fluoroethyl group, 1-fluoroethyl group, chloromethyl group, 2-chloroethyl group, 1-chloroethyl group, hydroxymethyl group, 2-hydroxyethyl group, 1-hydroxyethyl group, 1,2-dihydroxyethyl group, Aminomethyl group, 2-aminoethyl group,
Examples thereof include 1-aminoethyl group, methylaminomethyl group, dimethylaminomethyl group, pyrrolidinylmethyl group, and cyclopropylaminomethyl group.

Particularly preferred examples of the optionally substituted mercapto group are a methylmercapto group, an ethylmercapto group, a phenylmercapto group and (4-methyl-1,2,4-
And triazol-3-yl) mercapto group and (1-methyltetrazol-5-yl) mercapto group.

The lower alkylamino group has 1 to 6 carbon atoms.
Represents an amino group substituted with an alkyl group of, and the substituent on the nitrogen may form a ring. Particularly preferred examples of the lower alkylamino group are methylamino group, dimethylamino group, ethylamino group, diethylamino group, cyclopropylamino group, n-propylamino group, isopropylamino group, pyrrolidinyl group, piperidinyl group, morpholinyl group, Examples thereof include a piperazinyl group and an N-methylpiperazinyl group.

The lower alkoxy group has a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, cyclopropoxy group, etc. And particularly preferable examples include a methoxy group and an ethoxy group.

The lower alkanoyl group refers to a linear or branched alkanoyl group having 1 to 6 carbon atoms, and particularly preferable examples thereof include acetyl group and pivaloyl group.

The lower alkoxycarbonyl group has a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples thereof include a methoxycarbonyl group and a t-butoxycarbonyl group.

Particularly preferred examples of the optionally substituted lower alkylenedioxy group formed by R ³ and R ⁴ include methylenedioxy group, ethylenedioxy group and dimethylmethylenedioxy group.

The substituent R ^{7 in} the compound of the formula [I] means a hydrogen atom, a cyano group, a halogen atom or COOR ⁸ (R ⁸ is hydrogen or a lower alkyl group). Here, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The lower alkyl group in COOR ⁸ is an alkyl group having 1 to 6 carbon atoms, specifically, methyl group, ethyl group, n-propyl, isopropyl group, n-butyl group, sec-butyl group, t-butyl group. Examples thereof include a group and the like, and particularly preferable examples include a methyl group and an ethyl group.

In the oximino group of the general formula [I], The syn isomer exhibits excellent antibacterial activity, and in the present specification, all OR ¹ groups are syn isomers. E / Z nomenclature is Journal of the American Chemical Society
(J. Am. Chem. Soc.) Vol. 90, Item 509 (1968).

The compound of general formula [I] can be converted into its pharmacologically acceptable salt or physiologically hydrolyzable non-toxic ester by a conventional method.

The non-toxic salt of the compound of the general formula [I] means a conventional pharmaceutically acceptable salt, which is substituted by the 4-position carboxyl group of the cephem skeleton and the group R ^{1 of the} 7-position of the cephem skeleton. Mention may be made of a salt in the 2-aminothiazole group or 5-amino-1,2,4-thiadiazole group at the 7-position of the carboxyl group or cephem skeleton. For example, metal salts such as sodium, potassium, calcium, magnesium, and aluminum, organic amine salts such as triethylamine salt, pyridine salt, ethanolamine salt, and triethanolamine salt, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, perchlorine. Inorganic acid salts such as acids, organic acid salts such as acetic acid, lactic acid, propionic acid, maleic acid, fumaric acid, malic acid, tartaric acid and citric acid, for example, sulfonic acids such as methanesulfonic acid, isethionic acid, p-toluenesulfonic acid and the like. Examples thereof include salts, amino acid salts such as glutamic acid, aspartic acid, lysine and arginine.

The non-toxic ester of the general formula [I] means a pharmaceutically acceptable conventional one in the 4-position carboxyl group of the cephem skeleton, for example, acetoxymethyl group,
Alkanoyloxymethyl groups such as pivaloyloxymethyl group, for example alkoxycarbonyloxyalkyl groups such as 1- (ethoxycarbonyloxy) ethyl group, for example 5-
Examples include 5-substituted-2-oxo-1,3-dioxol-4-ylmethyl groups such as methyl-2-oxo-1,3-dioxol-4-ylmethyl and the like.

Next, a method for producing the compound of the present invention will be described. The compound of the general formula [I] can be produced by either the production method A or the production method B shown below.

Manufacturing Method A General Formula [II] [Wherein R ¹ is a linear or branched lower alkyl group which may be substituted with an optionally protected carboxyl group, a trityl group, a hydrogen atom or a fluorine-substituted lower alkyl group, and R ² is a hydrogen atom , A metal atom, a protecting group for a carboxyl group or an ester residue capable of forming a hydrolyzable ester in vivo, R ⁹ is an amino group which may be protected, Z is N or CH, n is 0 or 1, A represents a leaving group. ] The compound represented by the general formula [III] [III] [In the formula, R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different, and are a hydrogen atom, a halogen atom, an optionally substituted linear or branched lower alkyl group, a substituent Optionally substituted mercapto group, lower alkylamino group, optionally protected hydroxyl group, lower alkoxy group, lower alkanoyl group, lower alkoxycarbonyl group and R ³ and R ⁴
May form a lower alkylenedioxy group which may be substituted with, R ⁷ is a hydrogen atom, a cyano group, a halogen atom or COOR ⁸ (R ⁸ is hydrogen or a lower alkyl group),
M represents a hydrogen atom, a metal atom or quaternary ammonium. ] The compound [I] of the present invention can be produced by reacting the compound represented by the formula [1] and, if necessary, reducing and / or removing the protecting group.

Here, the leaving group A of the compound of the general formula [II] is
Specific examples thereof include halogen atoms such as chlorine, bromine and iodine, or an acetoxy group, a carbamoyloxy group, a trifluoromethanesulfonyl group, a p-toluenesulfonyloxy group and the like, particularly a chlorine atom, a bromine atom, an iodine atom, An acetoxy group is preferred.

In the compound of the general formula [III], M means a hydrogen atom, a metal atom or a quaternary ammonium,
Examples of the metal atom include sodium, potassium, calcium, magnesium, aluminum and the like, and particularly preferable examples include sodium and potassium. Examples of the quaternary ammonium include triethyl hydrogen ammonium, tri-n-butyl hydrogen ammonium, tripropyl hydrogen ammonium, triisopropyl hydrogen ammonium, diisopropyl ethyl hydrogen ammonium, tetraethyl ammonium, tetra-n-butyl ammonium and hydrogen. Examples thereof include pyridinium, and particularly preferable examples include triethyl hydrogen ammonium, tri-n-butyl hydrogen ammonium, and hydrogen pyridinium.

The reaction of the compound of the general formula [II] with the thiochromone derivative of the general formula [III] can be carried out, for example, by methylene chloride, chloroform, ether, ethyl acetate, tetrahydrofuran, acetonitrile, N, N-dimethylformamide,
It can be carried out in an organic solvent such as dimethyl sulfoxide or a mixed solvent thereof. In the reaction, 1 to 2 mol of the thiochromone derivative of the general formula [III] is used per 1 mol of the compound of the general formula [II], the reaction temperature is 0 to 40 ° C., and the reaction time is 0.5 to 10 hours.

The reaction of the compound of the general formula [II] where A is an acetoxy group with the thiochromone derivative of the general formula [III] can be carried out, for example, by water, phosphate buffer, acetone, acetonitrile, methanol, ethanol, tetrahydrofuran,
It can be carried out in a solvent such as dioxane, N, N-dimethylformamide, dimethylsulfoxide, or a mixed solvent thereof. The reaction is preferably carried out in the vicinity of neutrality, the reaction temperature is room temperature to 90 ° C., and the reaction time is 1 to 10 hours. Further, this reaction is promoted by carrying out in the presence of an iodide such as sodium iodide or potassium iodide, or a thiocyanate such as sodium thiocyanate or potassium thiocyanate.

The compound of the general formula [I] in which n is 0 is
Journal of Organic Chemistry (J.0rg.
Chem), Vol. 36, Item 2430 (1974) and the like, and can be produced by reducing the sulfoxide group. That is, a compound of the general formula [I] in which n is 1 is added dropwise with acetyl chloride at −40 to 0 ° C. in an acetone solvent in the presence of sodium iodide or potassium iodide and reacted for 1 to 5 hours, or , The compound of the general formula [I] in which n is 1, N, N-dimethylformamide, methylene chloride,
Phosphorus tribromide at -40 to 0 ° C in a solvent such as ethyl acetate, or
It can be reduced by dropping phosphorus trichloride and reacting for 0.5 to 5 hours. In the reaction, 3.5 to 10 mol of iodide and 1.5 to 5 mol of acetyl chloride or 1.1 to 6 mol of phosphorus trisalt or phosphorus tribromide are used with respect to 1 mol of the compound of the general formula [I] in which n is 1.

In the compound [I] of the present invention, the protecting group can be removed if necessary. A carboxyl group in the above general formula,
As the protecting group for the amino group and the hydroxyl group, a protecting group usually used in the field of β-lactam synthesis can be appropriately selected and used.

The method of introducing and removing the protective group depends on the type of the protective group, for example, Protective Group in Organic Synthesis (Protective Group).
s inOrganic Synthesis: TWGreen, Wiley, 198
It can be performed by appropriately selecting the method described in (1 year issue).

As the carboxyl protecting group, for example, t-
Butyl group, 2,2,2-trichloroethyl group, acetoxymethyl group, propionyloxymethyl group, pivaloyloxymethyl group, 1-acetoxyethyl group, benzyl group, 4-methoxybenzyl group, 3,4-dimethoxybenzyl group Group, 4-nitrobenzyl group, benzhydryl group, bis (4-methoxyphenyl) methyl group, trialkylsilyl group and the like,
Particularly, 4-methoxybenzyl group, benzhydryl group, t-butyl group, trimethylsilyl group, t-butyldimethylsilyl group and the like are preferable.

Examples of the amino group protecting group include a trityl group, a formyl group, a chloroacetyl group, a trifluoroacetyl group, a t-butoxycarbonyl group, a trimethylsilyl group and a t-butyldimethylsilyl group.

Examples of the hydroxyl-protecting group include 2-methoxyethoxymethyl group, methoxymethyl group, methylthiomethyl group, tetrahydropyranyl group, phenacyl group, isopropyl group, t-butyl group, benzyl group, 4-nitrobenzyl group. , Acetyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, t-butoxycarbonyl group, trimethylsilyl group, t-butyldimethylsilyl group, and, for example, methoxy, which is formed by bonding protective groups to each other. Examples thereof include orthoesters such as methylidene and methoxyethylidene, cyclic acetals such as benzylidene acetal, methylene acetal and ethylene acetal, cyclic ketals such as acetonide, alkylenedioxy such as methylenedioxy group, and cyclic carbonic acid ester.

The method of removing the protecting group will be specifically described below.
Trityl group, formyl group, t-butoxycarbonyl group,
Removal of the protecting groups such as benzhydryl group, 2-methoxyethoxymethyl group, 4-methoxybenzyl group, etc. can be performed with inorganic or organic acid such as hydrochloric acid, formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. It can be carried out, and trifluoroacetic acid is particularly preferable. When trifluoroacetic acid is used as the acid, the reaction is promoted by adding anisole, thioanisole or phenol, and side reactions are also suppressed.

The reaction is, for example, water, methylene chloride,
It can be carried out in a solvent that does not participate in the reaction, such as chloroform or benzene, or a mixed solvent thereof.
The reaction temperature and the reaction time are appropriately selected according to the chemical properties of the compound [I] of the present invention and the type of the protecting group, and it is particularly preferable to carry out the conditions of ice cooling or heating.

The starting compound [II] of the production method A can be produced as follows. A general formula [n where n is 0]
The compound of [I] is a 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid derivative [eg, The Journal of Antibiotics, Vol. 38,
1738 (1985)], 7-aminocephalosporanic acid or its ester with the general formula [V] [V] [In the formula, R ¹ is a linear or branched lower alkyl group optionally substituted with an optionally protected carboxyl group, a trityl group, a hydrogen atom or a fluorine-substituted lower alkyl group, and Z is N, CH, or R ⁹ represents an optionally protected amino group. ] Or a reactive derivative thereof (eg, acid halide, mixed acid anhydride, active ester, etc.) can be reacted to produce the compound.

The compound of the general formula [II] in which n is 1 is a compound of The Journal of Organic Chemistry (J.Or).
g. Chem.), 35, 2430 (1970), the compound of the general formula [II] in which n is 0 is, for example, methylene chloride, ethylene chloride, chloroform, ether, acetic acid, etc. Can be produced by oxidizing with an equimolar amount of m-chloroperbenzoic acid, hydrogen peroxide or metaperiodic acid in an organic solvent that does not participate in the reaction or in a mixed solvent thereof under ice cooling or room temperature. .

The compound of the general formula [II] in which the group A is an iodine atom can be prepared by the method described in, for example, Synthetic Communications (Vol. 16, page 1029 (1981)). The compound of the general formula [II] in which is a chlorine atom is, for example, in an organic solvent such as acetone, N, N-dimethylformamide, dimethylsulfoxide or in a two-layer system under ice cooling or at room temperature, sodium iodide, potassium iodide, etc. Produced by reacting with iodide of Tetrahedron Letters (Tetrahedron Lett.), Vol. 22, 39
According to the method described on page 15 (1981), the compound [II] in which the group A is an acetoxy group is treated with, for example, methylene chloride, chloroform, ether, ethyl acetate, tetrahydrofuran,
It can also be produced by reacting iodotrimethylsilane in acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide or a mixed solvent thereof, and may be used in the next reaction without isolation or purification.

2- (2-aminothiazole-4 of the general formula [V]
-Yl) -2-substituted oxyiminoacetic acid derivative or 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-substituted oxyiminoacetic acid derivative is a chemical and pharmaceutical bulletin (Chem.Pharm.Bull .), Volume 25,
2 (2-aminothiazol-4-yl) glyoxylic acid derivative, 2- (5-amino-1,2,4-thiadiazol-3-yl) glyoxyl according to the method described on page 3115 (1977). Acid derivative or 2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetic acid derivative, 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-hydroxyiminoacetic acid derivative Can be used for manufacturing.

The thiochromone derivative represented by the general formula [III] is described in Tetrahedron, Vol. 34, p. 725 (1978).
Year) and the like.

Production Method B General Formula [IV] [IV] [In the formula, R ² is a hydrogen atom, a metal atom, a protecting group for a carboxyl group, hydrogen or an ester residue capable of forming a hydrolyzable ester in vivo, R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different, and a hydrogen atom, a halogen atom,
Optionally substituted linear or branched lower alkyl group, optionally substituted mercapto group, lower alkylamino group, optionally protected hydroxyl group, lower alkoxy group, lower alkanoyl group, lower alkoxycarbonyl group And R ³ and R ⁴ may form a lower alkylenedioxy group which may be substituted, R ⁷ is a hydrogen atom, a cyano group, a halogen atom or COOR ⁸ (R ⁸ is hydrogen or a lower alkyl group), n represents 0 or 1. ] The compound represented by the formula [V] or its salt is acylated with the compound represented by the general formula [V] or its reactive derivative, and the compound of the present invention [I] is optionally reduced and / or the protective group is removed. ] Can be manufactured.

More specifically, the compound represented by the general formula [IV] is reacted with water, acetone, dioxane, acetonitrile, tetrahydrofuran, methylene chloride, chloroform, benzene, ethyl acetate, N, N-dimethylformamide, dimethylsulfoxide and the like. In a solvent that does not affect,
Alternatively, it can be produced by reacting the compound of the general formula [V] or a reactive derivative thereof (for example, acid halide, mixed acid anhydride, active ester, etc.) in a mixed solvent thereof.

The reaction is carried out by reacting 1 mol of the compound of the general formula [IV] with the compound of the general formula [V] or its reactive derivative 1-1.
5 mol is used, the reaction temperature is -40 to 40 ° C, and the reaction time is
0.5 to 10 hours.

When an acid halide is used as a reactive derivative of the compound of the general formula [V], it is carried out in the presence of a deoxidizing agent such as triethylamine, N-methylmorpholine, N, N-dimethylaniline or pyridine. Is preferred.

The acid halide forming reaction is carried out by the compound [V]
1 to 10 mol, preferably 1 to 1.5 mol, of a halogenating agent such as thionyl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride, phosgene, etc. is used per 1 mole, The reaction temperature is -40 to 100 ° C, preferably -20 to 20 ° C, and the reaction time is 10 to 120 minutes.

The mixed acid anhydride forming reaction is carried out by the compound [V] 1.
For example, 1 to 1.2 mol of a deoxidizing agent such as triethylamine, N-methylmorpholine, N, N-dimethylaniline and pyridine and methyl chloroformate,
1 to 1.2 mol of chloroformates such as ethyl chloroformate and isobutyl chloroformate are used, the reaction temperature is -40 to 20 ° C, preferably -20 to 5 ° C, and the reaction time is 10 to 10 ° C.
60 minutes.

The active ester forming reaction is carried out by the compound [V] 1.
N-hydroxy compound (eg, N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc.) or phenol compound (eg, 4-nitrophenol, 2,4-dinitrophenol, 2,4,5-trichloro) per mol 1 to 1.2 moles of phenol, etc. and 1 to 1.4 moles of N, N-dicyclohexylcarbodiimide, and the reaction temperature is −
At 10 to 50 ° C, the reaction time is 0.5 to 2 hours.

In the acylation, when the compound of the general formula [V] is used in the form of a free acid, carbodiimides such as N, N-dicyclohexylcarbodiimide, phosphorus oxychloride, N, N-dimethylformamide / oxychloride. The compound of the general formula [I] can be produced even in the presence of a condensing agent such as a phosphorus adduct.

The raw material compound [IV] of the production method B is the compound Cephalosporins and Penicillins by Flynn, Academic Press (Cephalosporins and Penic).
illins, Academic Press), pp. 151-171, (1972)
It can be produced by the method described above. For example,
7-acylamino-3-halomethyl-3-cephem-4-carboxylic acid derivative (synthesized according to the method disclosed in JP-A-58-72590 and 58-154588) or 7-acylaminocephalosporanic acid derivative or 7 -By reacting a benzylidene aminocephalosporanic acid derivative with a thiochromone derivative of the general formula [III], the general formula [VI] [VI] [In the formula, R ² is a hydrogen atom, a metal atom, a protective group for a carboxyl group, hydrogen or an ester residue capable of forming a hydrolyzable ester in vivo, R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different, and a hydrogen atom, a halogen atom,
Optionally substituted linear or branched lower alkyl group, optionally substituted mercapto group, lower alkylamino group, optionally protected hydroxyl group, lower alkoxy group, lower alkanoyl group, lower alkoxycarbonyl group And R ³ and R ⁴ may form a lower alkylenedioxy group which may be substituted, R ⁷ is a hydrogen atom, a cyano group, a halogen atom or COOR ⁸ (R ⁸ is hydrogen or a lower alkyl group), R ¹⁰ is an acylamino group or a benzylideneamino group, and n is 0 or 1. ] The compound represented by the above formula, and then deacylation and debenzylidene conversion can be used for the production.

The deacylation reaction is already known in the art, and when R ¹⁰ is, for example, a phenylacetylamino group, a phenoxyacetylamino group or an aminoadipylamino group in the compound represented by the above general formula, it is particularly preferable. It can be removed according to the method described in JP-A-49-20319. That is, the compound is treated with a deoxidizing agent such as N, N-dimethylaniline, pyridine, triethylamine, sodium hydrogen carbonate or potassium hydrogen carbonate in benzene, toluene, ethyl acetate, methylene chloride, ethylene chloride or a mixed solvent thereof. In the presence of phosphorus pentachloride or phosphorus oxychloride at −80 to 50 ° C., preferably −65 to 0 ° C.
After reacting for 2 hours, for example, methanol, ethanol,
The acyl group in the acylamino group of R ¹⁰ can be removed by treatment with a lower alcohol such as propanol and subsequent hydrolysis.

Further, the phenylacetyl group, phenoxyacetyl group or aminoadipyl group in the acylamino group can be removed by the method described in JP-A-63-264487, that is, water such as acetone, acetonitrile, methanol, ethanol and tetrahydrofuran. It can also be carried out by treating penicillin G acylase or immobilized penicillin G acylase at pH 7 to 8, preferably pH 7.5 to 7.8 in a mixed solvent of an organic solvent and water at room temperature. The reaction is preferably carried out by adding a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, triethylamine, tripropylamine or pyridine to keep the pH constant.

Removal of a benzylidene group from an acylamino group is carried out by Protective Groups in Organic Synthes
is: TWGreen, published by Wiley, 1981), for example, in an acid such as hydrochloric acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, or in a mixture thereof, −20 to 60.
It can be carried out by treating at ℃, preferably under ice-cooling to room temperature.

[Antibacterial Activity] The compound [I] of the present invention or a salt thereof is a novel compound and exhibits high antibacterial activity for inhibiting the growth of a wide range of pathogenic microorganisms including Gram-positive and Gram-negative bacteria. In order to show the usefulness of the compound [I] of the present invention, cefotaxime (C) is used as a comparative compound.
Table 1 shows the in vitro antibacterial activity (MIC) measured using TX) and ceftazidime (CAZ) according to the standard method of the Japanese Society of Chemotherapy.

[0063]

[Table 1]

Therefore, the compound of the general formula [I] and its pharmacologically acceptable salt or physiologically hydrolyzable non-toxic ester are useful as antibacterial agents.

The compound of the present invention can be used in the form of a pharmaceutical preparation suitable for parenteral administration, oral administration or external administration by mixing with a carrier of a solid or liquid excipient known in the art. Examples of the pharmaceutical preparation include liquid preparations such as injections, syrups and emulsions, solid preparations such as tablets, capsules and granules, and external preparations such as ointments and suppositories. In addition, in these preparations, if necessary, auxiliary agents, stabilizers, lubricants, emulsifiers, absorption promoters,
A commonly used additive such as an interfacial lubricant may be included. Examples of the additive include distilled water for injection, Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cacao butter, ethylene glycol, sucrose, corn starch, magnesium stearate, talc and the like.

Furthermore, the compounds according to the invention can be used as antibacterial agents for the treatment and prevention of bacterial infections in humans or animals. Although the dose varies depending on the patient's age and sex, it is usually preferable to administer 1 to 1000 mg / kg per day in 1 to 5 divided doses.

[0067]

The present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Example 1 p-Methoxybenzyl 3-chloromethyl-7-[(Z) -2-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxy rate
1-oxide (Note) PMB: p-methoxybenzyl group p-methoxybenzyl 3-chloromethyl-7-[(Z) -2-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -3-cephem -4-carboxylate
A solution of 0.4 g (0.504 mmol) in 6 ml of dichloromethane was stirred at 0 ° C., and 137 mg (0.554 m) of 70% m-chloroperbenzoic acid was added.
5 ml of dichloromethane solution of (mol) was added, and the mixture was stirred at the same temperature for 15 minutes. The solution was poured into saturated sodium bicarbonate water, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. Silica gel column chromatography of the residue (CH
Cl ₃ -AcOEt 5: 1) to give the title compound 0.2
52 g (0.311 mmol) was obtained (yield 62%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 3.38 (1H, d, J = 18.6Hz), 3.78 (1H,
d, J = 18.6Hz), 3.81 (3H, s), 4.07 (3H,
s), 4.24 (1H, d, J = 12.7Hz), 4.54 (1H,
d, J = 4.9Hz), 4.97 (1H, d, J = 12.7Hz), 5.
25 (2H, s), 6.15 (1H, dd, J = 4.9, 10.3Hz),
6.69 (1H, s), 6.9 to 7.4 (19H, m).

Example 2 p-Methoxybenzyl 3- (3-ethoxycarbonyl-6,
7,8-Trifluoro-4-oxo-4H-1-benzothiopyran-2
-Yl) thiomethyl-7-[(Z) -2-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -3-
Cephem-4-carboxylate 1-oxide Ethyl 3- (2,3,4,5-tetrafluorophenyl) -3-oxopropionate 78.3 mg (0.297 mmol), dry dimethyl sulfoxide 0.2 ml, carbon disulfide 22.7 mg (0.298 mmol)
60.2 mg (0.595 mmol) of triethylamine was added to the solution of
Stir for 1 hour. (Liquid A)

Separately, p-methoxybenzyl 3-chloromethyl-7-[(Z) -2- (2-tritylaminothiazol-4-yl)
-2-Methoxyiminoacetamido] -3-cephem-4-carboxylate 1-oxide 241 mg (0.297 mmol), dried dimethyl sulfoxide 5 ml solution in sodium iodide 2
81 mg, (1,87 mmol) was added and stirred for 1 hour. (Liquid B)

Solution B was added dropwise to solution A, stirred for 3 hours, poured into ice water, and extracted twice with dichloromethane. The organic layer is water,
Washed with saturated saline, dried over anhydrous sodium sulfate,
The solvent was distilled off. The residue was subjected to silica gel column chromatography (CHCl ₃ -AcOEt 2: 1 → 1: 1) to obtain 192 mg (0.176 mmol) of the title compound (yield 59).
%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 1.37 (3H, t, J = 7.0 Hz), 3.59 (2H, br
s), 3.79 (3H, s), 4.07 (3H, s), 4.37 (2
H, q, J = 7.0 Hz), 4.76 (1 H, d, J = 4.8 H)
z), 4.9 to 5.3 (4H, m), 6.16 (1H, dd, J =
4.8, 10.0Hz), 6.77 (1H, s), 6.8 to 7.4 (19
H, m), 7.9 to 8.2 (1H, m,).

Example 3 p-Methoxybenzyl 3- (3-ethoxycarbonyl-6,
7,8-Trifluoro-4-oxo-4H-1-benzothiopyran-2-
Il) thiomethyl-7-[(Z) -2-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -3-
Cephem-4-carboxylate To a solution of 572 mg (0.523 mmol) of the compound of Example 2 in 7 ml of dimethylformamide was added 0.05 ml (0.523 mmo) of phosphorus tribromide under ice cooling.
l) was added dropwise, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was poured into ice water and extracted twice with dichloromethane, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. Silica gel column chromatography of the residue (C
HCl ₃ -AcOEt 10: 3) to give the title compound 4
02 mg (0.373 mmol) was obtained (yield 71%).

Example 4 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (3-ethoxycarbonyl-
6,7,8-Trifluoro-4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-3-cephem-4-carboxylic acid sodium salt 402 mg (0.373 mmol) of the compound of Example 3, 0.52 anisole
2.64 ml of trifluoroacetic acid was added dropwise to a 7 ml solution under ice cooling,
The mixture was stirred at the same temperature for 4 hours. The reaction solution was poured into 79 ml of ice-cooled isopropyl ether, and the precipitated crystals were collected by filtration and dried. Suspend the crystals in 3 ml of water, add saturated sodium bicarbonate water under ice cooling, and adjust the pH.
The solution was prepared at 7.6, insoluble matters were removed, and the residue was loaded on Lichroprep RP-8 Lobar column chromatography. CH ₃ CN-H ₂
The desired product was eluted with O 3: 7 and freeze-dried to obtain 153 mg (0.217 mmol) of the title compound (yield 58%).

¹ H-NMR (90 MHz, CD ₃ OD,
δ): 1.37 (3H, t, J = 7.0Hz), 3.32 (1H, d,
J = 7.0Hz), 3.82 (1H, d, J = 7.0Hz), 3.96
(3H, s), 4.39 (2H, q, J = 7.0Hz), 4.0-
4.8 (2H, m), 5.09 (1H, d, J = 4.4Hz), 5.
74 (1H, d, J = 4.4Hz), 6.81 (1H, s), 8.0
~ 8.2 (1H, m). IR (KBr, cm ^-1 ): 1750, 1600.

Example 5 p-Methoxybenzyl 3- (6,7,8-trifluoro-4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-7-
[(Z) -2-Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 1-oxide 2 ', 3', 4 ', 5'-Tetrafluoroacetophenone 300 mg (1.
56 mmol), dry dimethyl sulfoxide 3.17 ml, carbon disulfide 119 mg (1.56 mmol) in a solution of 60% sodium hydride 1
25 mg (3.13 mmol) was added little by little and stirred for 5 hours.
(Liquid A)

Separately, 1.27 g of the compound of Example 1 (1.56 mmo
l), 281 mg (1.87 mmol) of sodium iodide was added to a solution of 26 ml of dry dimethyl sulfoxide, and the mixture was stirred for 1.3 hours. (Liquid B)

Solution B was added dropwise to solution A and stirred for 1 hour, and ice water was added.
Poured into 1.5 liters and extracted twice with dichloromethane.
The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. Silica gel column chromatography of the residue (CHCl ₃ -AcOEt 2: 1
→ 1: 1) was carried out to obtain 363 mg (0.355 mmol) of the title compound (yield 23%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 3.7 to 3.8 (2H, m), 3.79 (3H, s), 3.
9 to 4.1 (1H, m), 4.07 (3H, s), 4.54 (1
H, d, J = 4.9Hz), 4.80 (1H, d, J = 14.0H)
z), 5.1 to 5.3 (2H, m), 6.14 (1H, dd, J =
4.9, 10.0Hz), 6.67 (1H, s), 6.8 to 7.4 (20
H, m), 8.0 to 8.2 (1H, m).

Example 6 p-Methoxybenzyl 3- (6,7,8-trifluoro-4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-7-
[(Z) -2-Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 363 mg (0.355 mmol) of the compound of Example 5 as in Example 3
The title compound (242 mg, 0.241 mmol) was obtained from the above (yield 68
%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 3.40 (1H, d, J = 18.0Hz), 3.6 to 3.8 (1
H, m), 3.78 (3H, s), 4.0 to 4.2 (1H,
m), 4.07 (3H, s), 4.10 (1H, d, J = 14.0H
z), 4.36 (1H, d, J = 14.0Hz), 5.01 (1H,
d, J = 4.8Hz), 5.14 (2H, s), 5.91 (1H, d
d, J = 4.8, 10.0 Hz), 6.71 (1 H, s), 6.8 to 7.
4 (19H, m), 7.0-7.3 (1H, m).

Example 7 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (6,7,8-trifluoro-4-)
Oxo-4H-1-benzothiopyran-2-yl) thiomethyl-3
-Cephem-4-carboxylic acid sodium salt 242 mg (0.241 mmol) of the compound of Example 6 as in Example 4.
The title compound (443 mg, 0.0699 mmol) was obtained from the
%).

¹ H-NMR (90 MHz, CD ₃ OD,
δ): 3.3 to 3.4 (1H, m), 3.78 (1H, d, J =
18.0Hz), 3.96 (3H, s), 4.16 (1H, d, J = 1
3.0Hz), 4.60 (1H, d, J = 13.0Hz), 5.08 (1
H, d, J = 4.8Hz, 5.74 (1H, d, J = 4.8H)
z), 6.82 (1H, s), 7.97 (1H, s), 8.0 to 8.
2 (1H, m). IR (KBr, cm ^-1 ): 1750, 1600.

Example 8 p-Methoxybenzyl 3- (4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-7-[(Z) -2-methoxyimino
-2- (2-Tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carbochelate 1-oxide 1.27 g (1.56 mmol) of the compound of Example 1 as in Example 5
And the title compound 401 mg (0.414 mmol) was obtained from 216 mg (1.56 mmol) of 2'-fluoroacetophenone (yield 27%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 3.6 to 3.8 (2H, m), 3.77 (3H, s), 3.
7 to 3.9 (1H, m), 4.06 (3H, s), 4.51 (1
H, d, J = 5.0Hz), 4.90 (1H, d, J = 15.0H)
z), 5.1 to 5.3 (2H, m), 6.12 (1H, dd, J =
5.0, 11.0Hz), 6.67 (1H, s), 6.8 to 7.6 (23
H, m), 8.4 to 8.6 (1H, m).

Example 9 p-Methoxybenzyl 3- (4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-7-[(Z) -2-methoxyimino
-2- (2-Tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 401 mg (0.414 mmol) of the compound of Example 8 as in Example 3
The title compound (305 mg, 0.32 mmol) was obtained from the above (yield 77
%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 3.40 (1H, d, J = 18.0Hz), 3.6 to 3.8 (1
H, m), 3.77 (3H, s), 3.9 to 4.1 (1H,
m), 4.06 (3H, s), 4.37 (1H, d, J = 13.0H
z), 5.00 (1H, d, J = 4.8Hz), 5.15 (2H,
s), 5.90 (1H, dd, J = 4.8, 8.0Hz), 6.71 (1
H, s), 6.8 to 7.6 (23H, m), 8.4 to 8.6 (1
H, m).

Example 10 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (4-oxo-4H-1-benzothiopyran-2-yl) Thiomethyl-3-cephem-4-carboxylic acid sodium salt 305 mg (0.321 mmol) of the compound of Example 9 as in Example 4
This gave 129 mg (0.223 mmol) of the title compound (yield 69
%).

¹ H-NMR (90 MHz, CD ₃ OD,
δ): 3.42 (1H, d, J = 17.0Hz), 3.78 (1H,
d, J = 17.0Hz), 3.96 (3H, s), 4.10 (1H,
d, J = 13.0Hz), 4.74 (1H, d, J = 13.0Hz), 5.
04 (1H, d, J = 4.8Hz), 5.74 (1H, d, J =
4.8Hz), 6.82 (1H, s), 7.04 (1H, s), 7.5
~ 7.9 (3H, m), 8.4 ~ 8.5 (1H, m). IR (KBr, cm ^-1 ): 1760, 1580.

Example 11 p-Methoxybenzyl 3- [3-ethoxycarbonyl-6,8
-Difluoro-4-oxo-7- (1-pyrrolidinyl) -4H-1-benzothiopyran-2-yl] thiomethyl-7-[(Z) -2-methoxyimino-2- (2-tritylaminothiazole-4- Il) acetamido] -3-cephem-4-carboxylate 1-oxide Ethyl 3- (2,3,5-trifluoro-4-pyrrolidinylphenyl) -3-oxopropionate as in Example 5 491 mg
The title compound (915 mg, 0.799 mmol) was obtained from (1.56 mmol) (yield 51%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 1.36 (3H, t, J = 7.0Hz), 1.8 to 2.0 (4)
H, m), 2.2 to 2.8 (6H, m), 3.79 (3H,
s), 4.06 (3H, s), 4.35 (2H, q, J = 7.0H
z), 4.8 to 5.4 (5H, m), 6.10 (1H, dd, J =
5.0, 10.0Hz), 6.67 (1H, s), 6.7 to 7.4 (19
H, m), 7.79 (1H, dd, J = 1.0, 13.0Hz).

Example 12 p-Methoxybenzyl 3- [3-ethoxycarbonyl-6,8
-Difluoro-4-oxo-7- (1-pyrrolidinyl) -4H-1-benzothiopyran-2-yl] thiomethyl-7-[(Z) -2-methoxyimino-2- (2-tritylaminothiazole-4- Ile) acetamide] -3-cephem-4-carboxylate 903 mg (0.788 mmol) of the compound of Example 11 as in Example 3.
From the above, the title compound (567 mg, 0.502 mmol) was obtained (yield 64
%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 1.38 (3H, t, J = 7.0Hz), 1.8 to 2.0 (4)
H, m), 3.30 (1H, d, J = 18.0Hz), 3.6 to 3.8
(4H, m), 3.78 (3H, s), 3.9 to 4.1 (1H,
m), 4.06 (3H, s), 4.1 to 4.8 (2H, m), 4.4
0 (2H, q, J = 7.0Hz), 4.9 to 5.3 (1H,
m), 5.11 (2H, d, J = 2.0Hz), 5.89 (1H, d
d, J = 4.8, 9.0Hz), 6.69 (1H, s), 6.8 to 7.4
(19H, m), 7.8 (1H, dd, J = 1.8, 15.0Hz).

Example 13 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [3-ethoxycarbonyl-
6,8-Difluoro-4-oxo-7- (1-pyrrolidinyl) -4H-1
-Benzothiopyran-2-yl] thiomethyl-3-cephem-
4-carboxylic acid sodium salt Similar to Example 4, the compound of Example 12 530.2 mg (0.470 mmo
From the above, 60.9 mg (0.0772 mmol) of the title compound was obtained (yield 16
%).

Example 14 p-Methoxybenzyl 3- [3-ethoxycarbonyl-6,8
-Difluoro-7- (4-methylpiperazin-1-yl) -4-
Oxo-4H-1-benzothiopyran-2-yl] thiomethyl-7
-[(Z) -2-Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 1-oxide Ethyl 3- [2,3,5-trifluoro-4-as in Example 5
(4-Methylpiperazine) -1-yl] -3-oxopropionate 429 mg (1.25 mmol) to the title compound 818 mg (0.69
7 mmol) was obtained (yield 56%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 1.36 (3H, t, J = 7.0Hz), 2.34 (3H,
s), 2.4 to 2.6 (8H, m), 3.6 to 4.0 (2H,
m), 3.79 (3H, s), 4.0 to 4.6 (4H, m), 4.
07 (3H, s), 4.8 to 5.3 (3H, m), 6.12 (1
H, dd, J = 5.0,10.0Hz), 6.67 (1H, s), 6.8
~ 7.4 (19H, m), 7.92 (1H, dd, J = 2.0, 12.0
Hz).

Example 15 p-Methoxybenzyl 3- [3-ethoxycarbonyl-6,8
-Difluoro-7- (4-methylpiperazin-1-yl) -4-oxo-4H-1-benzothiopyran-2-yl] thiomethyl-7-
[(Z) -2-Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 806 mg (0.686 mmol) of the compound of Example 14 as in Example 3.
The title compound (319 mg, 0.275 mmol) was obtained from the
%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 1.38 (3H, t, J = 7.0Hz), 2.34 (3H,
s), 2.4 to 2.6 (4H, m), 3.3 to 3.5 (4H,
m), 3.6 to 4.0 (2H, m), 3.78 (3H, s), 4.
0 to 4.6 (4H, m), 4.06 (3H, s), 5.0 to 5.2
(3H, m), 5.90 (1H, dd, J = 5.0,10.0Hz),
6.71 (1H, s), 6.8 to 7.4 (19H, m), 7.92 (1
H, dd, J = 2.0, 12.0 Hz).

Example 16 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [3-ethoxycarbonyl-
6,8-Difluoro-7- (4-methylpiperazin-1-yl) -4-
Oxo-4H-1-benzothiopyran-2-yl] thiomethyl-3
-Cephem-4-carboxylic acid sodium salt 319 mg (0.275 mmol) of the compound of Example 15 as in Example 4
From the above, 8.5 mg (0.0104 mmol) of the title compound was obtained (yield 4
%).

Example 17 3-Ethoxycarbonyl-2-methylthio-4-oxo-4H-1-
Benzothiopyran Suspension at room temperature in ethyl 2-fluorobenzoyl acetate 8.00g (38.1mmol), carbon disulfide 2.89g (38.0mmo
l), add a solution of 20 ml of dry dimethyl sulfoxide, and add 100 ℃
It was stirred for 2 hours. Then, allow to cool to room temperature and add methyl iodide.
6.48 g (45.7 mmol) was added and stirred for 2 hours. It was poured into ice water, extracted with dichloromethane, the organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (C
HCl ₃ → CHCl ₃ -AcOEt 40: 1) was performed to obtain 3.06 g (10.9 mmol) of the title compound (yield 29%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 1.41 (3H, t, J = 7.0Hz), 2.66 (3H,
s), 4.44 (2H, q, J = 7.0Hz), 7.4 to 7.6 (3
H, m), 8.4 to 8.6 (1H, m).

Example 18 3-Ethoxycarbonyl-2-methylsulfinyl-4-oxo-4H-1-benzothiopyran 3.06 g (10.0 mmol) of the compound of Example 17, dichloromethane
A solution of 2.35 g of 70% m-chloroperbenzoic acid in 52 ml of dichloromethane was added to 63 ml of the solution under ice cooling, and the mixture was stirred at the same temperature for 30 minutes.
Pour into saturated heavy soup water, wash the organic layer with water and saturated saline,
It was dried over anhydrous sodium sulfate and the solvent was distilled off. Silica gel column chromatography of the residue (CHCl ₃ −
AcOEt 10: 1) was performed to give 2.75 g (9.27 mm) of the title compound.
ol) was obtained (yield 85%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 1.42 (3H, t, J = 7.0Hz), 3.11 (3H,
s), 4.44 (2H, q, J = 7.0Hz), 7.6 to 7.8 (3
H, m), 8.4 to 8.6 (1H, m). MS (M / Z) 296 (M ⁺ ).

Example 19 3-Ethoxycarbonyl-2-mercapto-4-oxo-4H-1-
Benzothiopyran A solution of 100 mg (0.337 mmol) of the compound of Example 18 in 1.8 ml of tetrahydrofuran was stirred at room temperature for 1N sodium hydrogen sulfide (0.69).
(7 mmol) was added and stirred for 3 hours. The solvent was distilled off, a solution of 87 mg of heavy soda and 6.5 ml of water was added to the residue, and the mixture was washed with dichloromethane. 2.2 ml of 1N hydrochloric acid was added, the mixture was extracted with dichloromethane, the organic layer was washed with saturated brine, concentrated, and subjected to silica gel column chromatography (CHCl ₃ ) on the residue to obtain the title compound (yield 23%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 1.44 (3H, t, J = 7.0Hz), 4.49 (2H,
q, J = 7.0Hz), 7.2-7.7 (3H, m), 8.2-
8.4 (1H, m).

Example 20 Diphenylmethyl 3- (3-ethoxycarbonyl-4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-7-
[(Z) -2-Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 1-oxide (Note) DPM: diphenylmethyl group diphenylmethyl 3-chloromethyl-7-[(Z) -2-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -3-cephem-4-carboxy Rate 1-oxide
To a solution of 800 mg (0.934 mmol) and 2 ml of dimethylformamide was added 168 mg (1.12 mmol) of sodium iodide, and the mixture was stirred for 1 hour. The compound of Example 19 (274 mg (1.03 mmo)
l), a solution of dimethylformamide (2.4 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. It was poured into ice water and extracted with dichloromethane, the organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. Silica gel column chromatography of the residue (CHCl ₃ -AcOEt
This was carried out at 10: 3) to obtain 683 mg (0.628 mmol) of the title compound (yield 67%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 1.35 (3H, t, J = 7.0Hz), 3.5 to 3.7 (2)
H, m), 4.07 (3H, s), 4.35 (2H, q, J =
7.0Hz), 4.86 (1H, d, J = 5.0Hz), 5.0 to 5.3
(2H, m), 6.16 (1H, dd, J = 5.0, 10.0Hz),
6.64 (1H, m), 7.0 ~ 7.7 (29H, m), 8.3 ~
8.5 (1H, m).

Example 21 Diphenylmethyl 3- (3-ethoxycarbonyl-4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-7-
[(Z) -Methoxyimino-2- (2-tritylaminothiazole-
4-yl) acetamido] -3-cephem-4-carboxylate 678 mg (0.624 mmol) of the compound of Example 20 as in Example 3
320 mg (0.299 mmol) of the title compound was obtained from the above (yield 48
%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 1.35 (3H, t, J = 7.0Hz), 3.4 to 4.0 (2)
H, m), 4.07 (3H, s), 4.2 to 4.6 (2H,
m), 4.38 (2H, q, J = 7.0Hz), 5.15 (1H,
d, J = 5.0Hz), 6.00 (1H, dd, J = 5.0, 10H
z), 6.89 (1H, s), 6.9 to 7.6 (29H, m), 8.4
~ 8.6 (1H, m).

Example 22 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (3-ethoxycarbonyl-4-oxo-4H-1-benzothiopyran -2-yl) thiomethyl-3-cephem-4-carboxylic acid sodium salt 314 mg (0.293 mmol) of the compound of Example 21 as in Example 4.
From the above, the title compound (58.6 mg, 0.0899 mmol) was obtained (yield 31
%).

¹ H-NMR (90 MHz, CD ₃ OD,
δ): 1.38 (3H, t, J = 7.3Hz), 3.36 (1H,
d, J = 17.0Hz), 3.84 (1H, d, J = 17.0Hz), 3.
95 (3H, s), 4.0 to 4.8 (2H, m), 4.38 (2
H, q, J = 7.3Hz), 5.05 (1H, d, J = 4.8H)
z), 5.73 (1H, d, J = 4.8Hz), 6.81 (1H,
s), 7.4 to 7.9 (3H, m), 8.3 to 8.5 (1H,
m). IR (KBr, cm ^-1 ): 1750, 1600.

Example 23 7-Fluoro-2-methylthio-4-oxo-4H-1-benzothiopyran 2 ', 4'-Difluoroacetophenone 300 as in Example 17
385 mg (1.70 mmol) of the title compound was obtained from mg (1.92 mmol) (yield 89%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 2.62 (3H, s), 6.82 (1H, s), 7.1 to 7.
4 (2H, m), 8.4 to 8.6 (1H, m).

Example 24 7-Fluoro-2-methylsulfinyl-4-oxo-4H-1-benzothiopyran 2.00 g (8.84 mmol) of the compound of Example 23 as in Example 18
To give 2.20 g of the title compound.

Example 25 7-Fluoro-2-mercapto-4-oxo-4H-1-benzothiopyran 1.06 g (4.39 mmol) of the compound of Example 24 as in Example 19
This gave 947 mg of the title compound.

¹ H-NMR (90 MHz, d ₆ DMSO,
δ): 7.09 (1H, s), 7.40 (1H, ddd, J = 2.
6, 8.8, 9.2Hz), 7.67 (1H, dd, J = 2.6, 9.0H
z), 8.22 (1H, dd, J = 5.7, 9.2Hz).

Example 26 p-Methoxybenzyl 3- (7-fluoro-4-oxo-4H-
1-benzothiopyran-2-yl) thiomethyl-7-[(Z) -2-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 1
-Oxide 700 mg (0.864 mmol) of the compound of Example 1 as in Example 20
Also, the title compound (573 mg, 0.581 mmol) was obtained from the compound (202 mg, 0.950 mmol) of Example 25 (yield 69%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 3.4 to 3.9 (2H, m), 3.78 (3H, s), 3.
8 to 4.1 (1H, m), 4.06 (3H, s), 4.54 (1
H, d, J = 5.0Hz), 4.84 (1H, d, J = 14.0H)
z), 5.19 (2H, s), 6.14 (1H, dd, J = 5.0, 1
0.0Hz), 6.67 (1H, s), 6.8 to 7.4 (22H,
m), 8.43 (1H, dd, J = 5.7, 9.0Hz).

Example 27 p-Methoxybenzyl 3- (7-fluoro-4-oxo-4H-
1-benzothiopyran-2-yl) thiomethyl-7-[(Z) -2-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 265 mg (0.573 mmol) of the compound of Example 26 as in Example 3
The title compound (279 mg, 0.288 mmol) was obtained from the
%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 3.56 (1H, d, J = 11.0Hz), 3.8 to 4.2 (2)
H, m), 3.77 (3H, s), 4.06 (3H, s), 4.36
(1H, d, J = 13.0Hz), 5.00 (1H, d, J = 5.0
Hz), 5.03 (2H, s), 5.90 (1H, dd, J = 5.0,
10.0Hz), 6.70 (1H, s), 6.8 to 7.4 (22H,
m), 8.50 (1H, dd, J = 6.0, 9.0Hz).

Example 28 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (7-fluoro-4-oxo
-4H-1-benzothiopyran-2-yl) thiomethyl-3-cephem-4-carboxylate sodium 271 mg (0.280 mmol) of the compound of Example 27 as in Example 4.
From the above, 291 mg (0.0487 mmol) of the title compound was obtained (yield 17
%).

¹ H-NMR (90 MHz, CD ₃ OD,
δ): 3.40 (1H, d, J = 17.0Hz), 3.78 (1H,
d, J = 17.0Hz), 3.96 (3H, s), 4.08 (1H,
d, J = 13.0Hz), 4.72 (1H, d, J = 13.0Hz), 5.
07 (1H, d, J = 4.8Hz), 5.74 (1H, d, J = 4.
8Hz), 6.82 (1H, s), 7.02 (1H, s), 7.36
(1H, ddd, J = 2.6,9.0,9.0Hz), 7.55 (1H, d
d, J = 2.6, 9.0Hz), 8.41 (1H, dd, J = 5.7,
9.0Hz). IR (KBr, cm ^-1 ): 1750, 1600.

Example 29 6,7,8-Trifluoro-2-methylthio-4-oxo-4H-1-benzothiopyran In the same manner as in Example 17, 100 mg (0.521 mmol) of 2 ′, 3 ′, 4 ′, 5′-tetrafluoroacetophenone to 60.5 mg (0.2
31 mmol) was obtained (44% yield).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 2.66 (3H, s), 6.83 (1H, s), 8.0 to 8.
3 (1H, m).

Example 30 6,8-Difluoro-2-methylthio-7- (4-methyl-4H-1,2,
4-triazol-3-ylthio) -4-oxo-4H-1-benzothiopyran 50 mg (0.191 mmol) of the compound of Example 29, acetonitrile 1
3-mercapto-4-methyl-4H-1,2,4- in 50 ml solution at 50 ° C
Triazole 24.2mg (0.210mmol), 1,8-diazabicyclo
29.0 mg (0.191 mmol) of [5,4,0] -7-undecene was added, and the mixture was stirred for 2 hours. The mixture was allowed to cool, and the precipitated crystals were collected by filtration, washed with cold acetonitrile and dried to give the title compound (51 mg, 0.143 mmol) (yield 75%).

MS (M / Z): 357 (M ⁺ ).

Example 31 6,8-Difluoro-7- (4-methyl-4H-1,2,4-triazole
-3-ylthio) -2-methylsulfinyl-4-oxo-4H-1-
Benzothiopyran 38.2 mg (0.107 mmol) of the compound of Example 30 as in Example 18
From the above, the title compound 28.6 mg (0.0766 mmol) was obtained (yield 72
%).

¹ H-NMR (90 MHz, d ₆ DMSO,
δ): 2.94 (3H, s), 3.62 (3H, s), 7.29 (1
H, s), 7.89 (1H, dd, J = 1.8, 9.2Hz), 8.57
(1H, s). MS (M / Z): 357 (M ⁺ ).

Example 32 6,8-Difluoro-2-mercapto-7- (4-methyl-4H-1,2,
4-triazol-3-ylthio) -4-oxo-4H-1-benzothiopyran 566 mg (1.52 mmol) of the compound of Example 31 as in Example 19
The title compound (407 mg, 1.19 mmol) was obtained from the above (yield 78
%).

Example 33 p-Methoxybenzyl 3- [6,8-difluoro-7- (4-methyl-4H-1,2,4-triazol-3-ylthio) -4-oxo-4
H-1-benzothiopyran-2-yl] thiomethyl-7-[(Z) -2-
Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate
1-oxide 700 mg (0.864 mmol) of the compound of Example 1 as in Example 20
Also, 828 mg (0.741 mmol) of the title compound was obtained from 236 mg (0.950 mmol) of the compound of Example 32 (yield 86%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 3.4 to 4.8 (4H, m), 3.78 (3H, s), 3.
79 (3H, s), 4.06 (3H, s), 4.56 (1H, d,
J = 5.0Hz), 5.1 to 5.3 (2H, m), 6.40 (1H,
dd, J = 5.0, 10.0Hz), 6.68 (1H, s), 6.8-
7.4 (20H, m), 7.9 to 8.1 (1H, m), 8.21 (1
H, s).

Example 34 p-Methoxybenzyl 3- [6,8-difluoro-7- (4-methyl-4H-1,2,4-thiazol-3-ylthio) -4-oxo-4H-1-
Benzothiopyran-2-yl] thiomethyl-7-[(Z) -2-methoxyimino-2- (2-tritylaminothiazol-4-yl)
Acetamide] -3-cephem-4-carboxylate 820 mg (0.734 mmol) of the compound of Example 33 as in Example 3
The title compound (203 mg, 0.185 mmol) was obtained from the above (yield 25
%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 3.77 (3H, s), 3.80 (3H, s), 3.4 to 4.
6 (4H, m), 4.04 (3H, s), 5.06 (1H, d,
J = 5.0Hz), 5.1 to 5.3 (2H, m), 5.92 (1H,
dd, J = 5.0, 10.0Hz), 6.71 (1H, s), 6.8 ~
7.4 (20H, m), 8.0 to 8.2 (1H, m), 8.22 (1
H, s).

Example 35 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [6,8-difluoro-7- (4-methyl-4H -1,2,4-triazol-3-ylthio) -4-oxo-4
H-1-benzothiopyran-2-yl] thiomethyl-3-cephem-4-carboxylic acid sodium salt 203 mg (0.185 mmol) of the compound of Example 34 as in Example 4.
From the above, the title compound (70.7 mg, 0.0953 mmol) was obtained (yield 52
%).

¹ H-NMR (90 MHz, CD ₃ OD,
δ): 3.4 to 4.4 (4H, m), 3.85 (3H, s), 3.
96 (3H, s), 5.07 (1H, d, J = 5.0Hz), 5.80
(1H, d, J = 5.0Hz), 6.82 (1H, s), 7.09
(1H, s), 7.9 to 8.1 (1H, m), 8.5 to 8.7
(1H, m).

Example 36 p-Methoxybenzyl 3- (7-fluoro-4-oxo-4H-
1-benzothiopyran-2-yl) thiomethyl-7-[(Z) -2-
(2-Tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido) -3-cephem-4-carboxylate 1-oxide P-Methoxybenzyl 3-chloromethyl-7-[(Z) -2- (2-tritylaminothiazol-4-yl)-as in Example 20
2-Trityloxyiminoacetamido] -3-cephem-4-
1.37 g (1.13 mmol) of the title compound was obtained from 1.48 g (1.43 mmol) of carboxylate 1-oxide (yield 79%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 3.32 (1H, d, J = 18.0Hz), 3.5 to 3.9 (2
H, m), 3.79 (3H, s), 4.40 (1H, d, J =
5.0Hz), 4.80 (1H, d, J = 14.0Hz), 5.20 (2
H, s), 6.24 (1H, dd, J = 5.0, 10.0Hz), 6.82
(1H, s), 6.9 to 7.6 (37H, m), 8.44 (1H,
dd, J = 5.7, 8.7 Hz).

Example 37 p-Methoxybenzyl 3- (7-fluoro-4-oxo-4H-
1-benzothiopyran-2-yl) thiomethyl-7-[(Z) -2- (2
-Tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3-cephem-4-carboxylate 1.36 g (1.12 mmol) of the compound of Example 36 as in Example 3
The title compound (357 mg, 0.298 mmol) was obtained from the
%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 3.20 (1H, d, J = 18.0Hz), 3.64 (1H,
d, J = 18.0Hz), 3.78 (3H, s), 3.8 to 4.4 (2
H, m), 5.04 (1H, d, J = 5.0Hz), 5.28 (2
H, s), 6.04 (1H, dd, J = 5.0, 10.0Hz), 6.8
~ 7.8 (38H, m), 8.4 ~ 8.6 (1H, m).

Example 38 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (7-fluoro-4-oxo
-4H-1-benzothiopyran-2-yl) thiomethyl-3-cephem-4-carboxylic acid sodium salt 347 mg (0.289 mmol) of the compound of Example 37 as in Example 4.
From the above, the title compound (88.0 mg, 0.143 mmol) was obtained (yield 49
%).

¹ H-NMR (90 MHz, CD ₃ OD,
δ): 3.3 to 3.5 (1H, m), 3.72 (1H, d, J =
18.0Hz), 4.08 (1H, d, J = 13.0Hz), 4.6 to 4.9
(1H, m), 5.08 (1H, d, J = 4.8Hz), 5.77
(1H, d, J = 4.8Hz), 6.77 (1H, s), 6.0-
6.7 (2H, m), 7.03 (1H, s), 8.2 to 8.6 (1
H, m). IR (KBr, cm ^-1 ): 1740, 1600.

Example 39 p-Methoxybenzyl 7-[(Z) -2- (1-tert-butoxycarbonyl-1-methylethoxy) imino-2- (2-tritylaminothiazol-4-yl) acetamide]- 3- (7-Fluoro-4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-3-cephem-4-carboxylate 1-oxide P-Methoxybenzyl 7-[(Z) -2-as in Example 20
(1-tert-Butoxycarbonyl-1-methylethoxyimino) -2- (2-tritylaminothiazol-4-yl) acetamido] -3-chloromethyl-3-cephem-4-carboxylate 1-oxide 1.00 g ( 1.07 mmol) to the title compound 601
mg (0.540 mmol) was obtained (yield 50%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 1.41 (9H, s), 1.55 (3H, s), 1.57 (3
H, s), 3.40 (1H, d, J = 18.0Hz), 3.6 to 3.9
(2H, m), 3.79 (3H, s), 4.52 (1H, d, J
= 5.0Hz), 4.92 (1H, d, J = 14.0Hz), 5.20 (2
H, s), 6.96 (1H, dd, J = 5.0, 10.0Hz), 6.67
(1H, s), 6.8 to 7.4 (22H, m), 8.46 (1H,
dd, J = 5.7, 9.0 Hz).

Example 40 p-Methoxybenzyl 7-[(Z) -2- (1-tert-butoxycarbonyl-1-methylethoxy) imino-2- (2-tritylaminothiazol-4-yl) acetamide]- 3- (7-Fluoro-4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-3-cephem-4-carboxylate 591 mg (0.630 mmol) of the compound of Example 39 as in Example 3.
To give 208 mg (0.225 mmol) of the title compound (yield 36
%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 1.42 (9H, s), 1.58 (3H, s), 1.63 (3)
H, s), 3.36 (1H, d, J = 18.0Hz), 3.6 to 3.9
(1H, m), 3.78 (3H, s), 4.0 to 4.7 (2H,
m), 5.00 (1H, d, J = 5.0Hz), 5.17 (2H,
s), 5.96 (1H, dd, J = 5.0, 10.0Hz), 6.71 (1
H, s), 6.8 to 7.4 (22H, m), 8.48 (1H, dd,
J = 6.0, 9.0 Hz).

Example 41 7β-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-
Carboxy-1-methylethoxy) iminoacetamide]
-3- (7-Fluoro-4-oxo-4H-1-benzothiopyran-2-
I) Thiomethyl-3-cephem-4-carboxylic acid disodium salt 200 mg (0.217 mmol) of the compound of Example 40 as in Example 4.
From the above, the title compound (73.9 mg, 0.102 mmol) was obtained (yield 47
%).

¹ H-NMR (90 MHz, CD ₃ OD,
δ): 1.53 (6H, s), 3.3 to 3.5 (1H, m), 3.
76 (1H, d, J = 17.0Hz), 4.08 (1H, d, J = 1
3.0Hz), 4.7 to 4.9 (1H, m), 5.07 (1H, d,
J = 4.8Hz), 5.74 (1H, d, J = 4.8Hz), 6.81
(1H, s), 7.05 (1H, s), 7.36 (1H, ddd,
J = 2.6,9.0,9.0Hz), 7.56 (1H, dd, J = 2.6,
9.0Hz), 8.41 (1H, dd, J = 5.7, 9.0Hz). IR (KBr, cm ^-1 ): 1750, 1500.

Example 42 p-Methoxybenzyl 7-[(Z) -2-tert-butoxycarbonylmethoxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -3- (7-fluoro-4 -Oxo-4H-1-benzothiopyran-2-yl) thiomethyl-3-cephem-4-carboxylate 1-oxide P-Methoxybenzyl 7-[(Z) -2-te as in Example 20.
rt-Butoxycarbonylmethoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-chloromethyl-3-cephem-4-carboxylate 1-oxide 9
The title compound 400 mg (0.368 mmol) was obtained from 60 mg (1.05 mmol) (yield 35%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 1.43 (9H, s), 3.36 (1H, d, J = 19.0H)
z), 3.5 to 3.8 (2H, m), 3.77 (3H, s), 4.5
2 (1H, d, J = 5.0Hz), 4.70 (2H, s), 4.8
~ 5.2 (1H, m), 5.19 (2H, s), 5.96 (1H,
dd, J = 5.0, 10.0Hz), 6.72 (1H, s), 6.8-
7.4 (22H, m), 8.42 (1H, dd, J = 5.7, 9.0H
z).

Example 43 p-Methoxybenzyl 7-[(Z) -2-tert-butoxycarbonylmethoxyimino-2- (2-tritylaminothiazole)
-4-yl) acetamido] -3- (7-fluoro-4-oxo-4H
-1-Benzothiopyran-2-yl) thiomethyl-3-cephem-4-carboxylate 383 mg (0.352 mmol) of the compound of Example 42 as in Example 3.
The title compound (137 mg, 0.128 mmol) was obtained from the
%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 1.44 (9H, s), 3.36 (1H, d, J = 18.0H)
z), 3.5 to 3.8 (1H, m), 3.77 (3H, s), 4.0
0 (1H, d, J = 13.0Hz), 4.36 (1H, d, J = 13.)
0Hz), 4.75 (2H, s), 5.00 (1H, dd, J = 5.0H
z), 5.17 (2H, s), 5.88 (1H, dd, J = 5.0, 1
0.0Hz), 6.79 (1H, s), 6.8 to 7.4 (22H,
m), 8.48 (1H, dd, J = 6.0, 9.0Hz).

Example 44 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-carboxymethoxyiminoacetamido] -3- (7-fluoro-4)
-Oxo-4H-1-benzothiopyran-2-yl) thiomethyl
-3-Cephem-4-carboxylic acid disodium salt 130 mg (0.122 mmol) of the compound of Example 43 as in Example 4.
From the above, the title compound (45.2 mg, 0.0650 mmol) was obtained (yield 53
%).

¹ H-NMR (90 MHz, CD ₃ OD,
δ): 3.0 to 4.8 (4H, m), 4.32 (2H, s), 5.
04 (1H, d, J = 5.0Hz), 5.6 to 5.8 (1H,
m), 6.83 (1H, s), 6.97 (1H, s), 7.48 (1
H, ddd, J = 3.0,9.0,9.0Hz), 7.84 (1H, dd, J
= 3.0, 9.0Hz), 8.36 (1H, dd, J = 6.0, 9.0H
z). IR (KBr, cm ^-1 ): 1740, 1580.

Example 45 p-Methoxybenzyl 3- (4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-7-[(Z) -2- (2-tritylaminothiazol-4-yl)- 2-Trityloxyiminoacetamido] -3-cephem-4-carboxylate 1-oxide P-Methoxybenzyl 3-chloromethyl-7-[(Z) -2- (2-tritylaminothiazol-4-yl) -as in Example 20.
2-Trityloxyiminoacetamido] -3-cephem-4-
The title compound (669 mg, 0.559 mmol) was obtained from the carboxylate 1-oxide (898 mg, 0.865 mmol) (yield 65%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 3.12 (1H, d, J = 18.0Hz), 3.38 (3H,
s), 3.48 (1H, m), 4.36 (1H, d, J = 5.0H
z), 4.64 (1H, d, J = 13.0Hz), 4.96 (1H,
d, J = 13.0Hz), 5.1 to 5.3 (2H, m), 6.20 (1
H, dd, J = 5.0, 10.0Hz), 6.80 (1H, s), 6.8
~ 7.6 (38H, m), 8.3 ~ 8.5 (1H, m).

Example 46 p-Methoxybenzyl 3- (4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-7-[(Z) -2- (2-tritylaminothiazol-4-yl)- 2-Trityloxyiminoacetamide] -3-cephem-4-carboxylate 653 mg (0.546 mmol) of the compound of Example 45 as in Example 3
From the above, the title compound (360 mg, 0.305 mmol) was obtained (yield 56
%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 3.20 (1H, d, J = 18.0Hz), 3.60 (1H,
d, J = 18.0Hz), 3.77 (3H, s), 3.96 (1H,
d, J = 13.0Hz), 4.36 (1H, d, J = 13.0Hz), 5.
00 (1H, d, J = 4.8Hz), 5.1 to 5.2 (2H,
m), 5.96 (1H, dd, J = 4.8, 10.0Hz), 6.80 (1
H, s), 6.8 to 7.6 (38H, m), 8.3 to 8.5 (1
H, m).

Example 47 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (4-oxo-4H-1-benzothiopyran-2-yl) Thiomethyl-3-cephem-4-carboxylic acid sodium salt 349 mg (0.296 mmol) of the compound of Example 46 as in Example 4.
The title compound (82.7 mg, 0.138 mmol) was obtained from the
%).

¹ H-NMR (90 MHz, CD ₃ OD,
δ): 3.3 to 3.5 (1H, m), 3.76 (1H, d, J =
17.0Hz), 4.08 (1H, d, J = 13.0Hz), 4.68 (1
H, d, J = 13.0Hz), 5.09 (1H, d, J = 4.8H
z), 5.77 (1H, d, J = 4.8Hz), 6.76 (1H,
s), 7.04 (1H, s), 7.3 to 7.8 (3H, m), 8.2
~ 8.4 (1H, m). IR (KBr, cm ^-1 ): 1750, 1600.

Example 48 6,7-Dimethoxy-2-methylthio-4-oxo-4H-1-benzothiopyran Similarly to Example 17, the title compound 150 mg from 2'-fluoro-4 ', 5'-dimethoxyacetophenone 200 mg (1.0 mmol).
(0.559 mmol) was obtained (yield 56%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 2.62 (3H, s), 3.97 (3H, s), 3.99 (3)
H, s), 6.85 (1H, s), 6.86 (1H, s), 7.88
(1H, s). MS (M / Z): 268 (M ⁺ ).

Example 49 6,7-Dimethoxy-2-methylsulfinyl-4-oxo-4H-
1-benzothiopyran 1.00 g (3.73 mmol) of the compound of Example 48 as in Example 18
The title compound (1.25 g) was obtained from.

¹ H-NMR (90 MHz, d ₆ DMSO,
δ): 2.49 (3H, s), 3.01 (3H, s), 3.33 (3)
H, s), 7.24 (1H, s), 7.57 (1H, s), 7.71
(1H, s).

Example 50 2-Mercapto-6,7-dimethoxy-4-oxo-4H-1-benzothiopyran 1.25 g (4.40 mmol) of the compound of Example 49 as in Example 19
To give 1.15 g of the title compound.

MS (M / Z): 254 (M ⁺ )

Example 51 p-Methoxybenzyl 3- (6,7-dimethoxy-4-oxo
-4H-1-benzothiopyran-2-yl) thiomethyl-7-[(Z)-
2-methoxyimino-2- (2-tritylaminothiazole-4-
Ile) acetamide] -3-cephem-4-carboxylate
1-oxide 2.10 g (2.59 mmol) of the compound of Example 1 as in Example 20
And 1.64 g (1.59 mmo) of the title compound from the compound of Example 50
l) was obtained (yield 62%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 3.73 (3H, s), 3.89 (3H, s), 3.94 (3)
H, s), 4.01 (3H, s), 3.4 to 4.2 (2H,
m), 4.64 (1H, d, J = 5.0Hz), 4.4 to 4.9 (2
H, m), 4.7 to 5.3 (2H, m), 6.00 (1H, dd,
J = 5.0, 10.0Hz), 6.64 (1H, s), 6.7 to 7.8
(22H, m).

Example 52 p-Methoxybenzyl 3- (6,7-dimethoxy-4-oxo
-4H-1-benzothiopyran-2-yl) thiomethyl-7-[(Z)-
2-methoxyimino-2- (2-tritylaminothiazole-4-
Iyl) acetamide) -3-cephem-4-carboxylate 1.64 g (1.59 mmol) of the compound of Example 51 as in Example 3
The title compound (664 mg, 0.656 mmol) was obtained from the
%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 3.2 to 4.3 (1H, m), 3.76 (3H, s), 3.
95 (3H, s), 3.98 (3H, s), 4.05 (3H,
s), 4.48 (1H, d, J = 17.0Hz), 4.96 (1H,
d, J = 5.0Hz), 5.0 to 5.3 (4H, m), 5.94 (1
H, dd, J = 5.0,10.0Hz), 6.69 (1H, s), 6.7
~ 7.4 (22H, m).

Example 53 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (6,7-dimethoxy-4-oxo-4H-1- Benzothiopyran-2-yl) thiomethyl-3-cephem-4-carboxylic acid sodium salt 154 mg (0.152 mmol) of the compound of Example 52 as in Example 4.
To give 21.1 mg (0.0314 mmol) of the title compound (yield 21
%).

¹ H-NMR (400 MHz, CD ₃ OD,
δ): 3.42 (1H, d, J = 17.6Hz), 3.77 (1H,
d, J = 17.6Hz), 3.90 (3H, s), 3.93 (3H,
s), 3.97 (3H, s), 4.04 (1H, d, J = 13.2H
z), 4.72 (1H, d, J = 13.2Hz), 5.08 (1H,
d, J = 4.4Hz), 5.56 (1H, d, J = 4.4Hz), 6.8
3 (1H, s), 7.01 (1H, s), 7.30 (1H,
s), 7.81 (1H, s). SIMS (M / Z): 672 (M + 1) ⁺ . IR (KBr, cm ^-1 ): 1740, 1620.

Example 54 6,7-Dihydroxy-2-methylthio-4-oxo-4H-1-benzothiopyran To a solution of the compound of Example 48 (2.31 g, 8.61 mmol) and dry dichloromethane (28 ml) at -78 ° C was added 3.67 g (14.8 g) of boron tribromide.
mmol) and a solution of 9 ml of dichloromethane, and the mixture was stirred at room temperature overnight. Ice water (31 ml) was added to the solution at 0 ° C to adjust the pH to 11 with a 1N aqueous sodium hydroxide solution, and the mixture was washed with ether. The aqueous layer was acidified with 1N hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water and dried to give 1.64 g (6.83 mmol) of the title compound (yield 79
%).

MS (M / Z): 240 (M ⁺ ).

Example 55 6,7-Isopropylidenedioxy-2-methylthio-4-oxo-4H-1-benzothiopyran A mixture of 97.4 mg (0.405 mmol) of the compound of Example 54, phosphorus pentoxide, acetone, and benzene was heated under reflux at 120 ° C. for 21 hours. After distilling off the solvent, dichloromethane was added, and the organic layer was washed with saturated sodium bicarbonate water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (CHCl ₃ -AcOEt 10: 1) to obtain 41 mg (0.146 mmol) of the title compound (yield 36
%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 1.73 (6H, s), 2.60 (3H, s), 6.78 (1
H, s), 6.81 (1H, s), 7.77 (1H, s). MS (M / Z): 280 (M ⁺ ).

Example 56 6,7-Isopropylidenedioxy-2-methylsulfinyl
-4-oxo-4H-1-benzothiopyran 297 mg (1.06 mmol) of the compound of Example 55 as in Example 18
This gave 345 mg of the title compound.

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 1.75 (6H, s), 2.95 (3H, s), 6.96 (1
H, s), 7.19 (1H, s), 7.80 (1H, s). MS (M / Z): 296 (M ⁺ ).

Example 57 6,7-Isopropylidenedioxy-2-mercapto-4-oxo-4H-1-benzothiopyran 345 mg (1.16 mmol) of the compound of Example 56 as in Example 19
This gave 280 mg of the title compound.

MS (M / Z): 266 (M ⁺ ).

Example 58 p-Methoxybenzyl 3- (6,7-isopropylidenedioxy-4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-7-[(Z) -2-methoxyimino- 2- (2-Tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 1-oxide 726 mg (0.895 mmol) of the compound of Example 1 as in Example 20
And the title compound 634 mg (0.609 mmol) was obtained from the compound 239 mg (0.896 mmol) of Example 57 (yield 71%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 1.73 (6H, s), 3.45 (1H, d, J = 18.4H
z), 3.66 (1H, d, J = 14.2Hz), 3.73 (1H,
d, J = 18.4Hz), 3.79 (3H, s), 4.07 (3H,
s), 4.50 (1H, d, J = 4.9Hz), 4.90 (1H,
d, J = 14.2Hz), 5.12 (1H, d, J = 11.7Hz), 5.
21 (1H, d, J = 11.7Hz), 6.11 (1H, dd, J =
4.9, 10.3Hz), 6.68 (1H, s), 6.7 to 7.4 (21
H, m), 7.76 (1H, s).

Example 59 p-Methoxybenzyl 3- (6,7-isopropylidenedioxy-4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-7-[(Z) -2-methoxyimino- 2- (2-Tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 630 mg (0.606 mmol) of the compound of example 58 as in example 3
The title compound (328 mg, 0.321 mmol) was obtained from
%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 1.73 (6H, s), 3.40 (1H, d, J = 18.6H)
z), 3.70 (1H, d, J = 18.6Hz), 3.79 (3H,
s), 3.95 (1H, d, J = 13.5Hz), 4.07 (3H,
s), 4.37 (1H, d, J = 13.5Hz), 5.00 (1H,
d, J = 4.9Hz), 5.10 (1H, d, J = 11.7Hz), 5.
18 (1H, d, J = 11.7Hz), 5.88 (1H, dd, J =
4.9, 8.3Hz), 6.72 (1H, s), 6.74 (1H,
s), 6.8 to 6.9 (3H, m), 6.99 (1H, s), 7.
01 (1H, s), 7.26 to 7.29 (15H, m), 7.77 (1
H, s).

Example 60 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (6,7-isopropylidenedioxy-4-oxo-4H -1-Benzothiopyran-2-yl) thiomethyl-3-cephem-4-carboxylic acid sodium salt 137 mg (0.134 mmol) of the compound of Example 59 as in Example 4.
From the above, the title compound (38.6 mg, 0.0565 mmol) was obtained (yield 42
%).

¹ H-NMR (400 MHz, CD ₃ OD,
δ): 1.64 (6H, s), 3.31 (1H, d, J = 17.3H
z), 3.66 (1H, d, J = 17.3Hz), 3.87 (3H,
s), 3.93 (1H, d, J = 13.2Hz), 4.59 (1H,
d, J = 13.2Hz), 4.97 (1H, d, J = 4.9Hz), 5.
65 (1H, d, J = 4.9Hz), 6.73 (1H, s), 6.90
(1H, s), 7.05 (1H, s), 7.55 (1H, s).

Example 61 6,7-Methylenedioxy-2-methylthio-4-oxo-4H-1-
Benzothiopyran In the same manner as in Example 23, 99.9 mg (0.396 mmol) of the title compound was obtained from 300 mg (1.23 mmol) of 2′-bromo-4 ′, 5′-methylenedioxyacetophenone (yield 32%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 2.61 (3H, s), 6.09 (2H, s), 6.82 (1
H, s), 6.87 (1H, s), 7.85 (1H, s). MS (M / Z): 252 (M ⁺ ).

Example 62 6,7-Methylenedioxy-2-methylsulfinyl-4-oxo-4H-1-benzothiopyran 2.00 g (7.93 mmol) of the compound of Example 61 as in Example 18.
From the above, 1.72 g (6.41 mmol) of the title compound was obtained (yield 81
%).

MS (M / Z): 268 (M ⁺ ).

Example 63 6,7-Methylenedioxy-2-mercapto-4-oxo-4H-1-
Benzothiopyran 1.72 g (6.41 mmol) of the compound of Example 62 as in Example 19
To give 1.20 g (5.04 mmol) of the title compound (yield 79
%).

MS (M / Z): 238 (M ⁺ ).

Example 64 p-Methoxybenzyl 3- (6,7-methylenedioxy-4-
Oxo-4H-1-benzothiopyran-2-yl) thiomethyl-7
-[(Z) -2- (2-Tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3-cephem-4-carboxylate 1-oxide P-Methoxybenzyl 3-chloromethyl-7-[(Z) -2- (tritylaminothiazol-4-yl) -2- as in Example 20
Trityloxyiminoacetamido] -3-cephem-4-carboxylate 1-oxide 900 mg (0.867 mmol) and the compound of Example 63 gave the title compound 341 mg (0.279 mmol) (yield 32%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 3.14 (1H, d, J = 19.0Hz), 3.45 (1H,
d, J = 19.0Hz), 3.63 (1H, d, J = 14.0Hz), 3.
80 (3H, s), 4.36 (1H, d, J = 4.9Hz), 4.84
(1H, d, J = 14.0Hz), 5.14 (1H, d, J = 11.7)
Hz), 5.21 (1H, d, J = 11.7Hz), 6.11 (2H,
s), 6.24 (1H, dd, J = 4.9, 10.3Hz), 6.76 (1
H, s), 6.9 to 7.4 (36H, m), 7.84 (1H,
s).

Example 65 p-Methoxybenzyl 3- (6,7-methylenedioxy-4-
Oxo-4H-1-benzothiopyran-2-yl) thiomethyl-7
-[(Z) -2- (2-Tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3-cephem-4-carboxylate 437 mg (0.352 mmol) of the compound of Example 64 as in Example 3.
The title compound (341 mg, 0.279 mmol) was obtained from the
%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 3.24 (1H, d, J = 18.1Hz), 3.60 (1H,
d, J = 18.1Hz), 3.79 (3H, s), 3.94 (1H,
d, J = 13.5Hz), 4.34 (1H, d, J = 13.5Hz), 5.
01 (1H, d, J = 4.9Hz), 5.13 (1H, d, J = 1)
2.2Hz), 5.18 (1H, d, J = 12.2Hz), 6.00 (1
H, dd, J = 4.9, 8.8Hz), 6.10 (2H, s), 6.4
~ 7.9 (38H, m).

Example 66 7β-[(Z) -2- (2-Aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3- (6,7-methylenedioxy
-4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-3-cephem-4-carboxylic acid sodium salt 335 mg (0.274 mmol) of the compound of example 65 as in example 4
The title compound (109 mg, 0.169 mmol) was obtained from the
%).

¹ H-NMR (400 MHz, CD ₃ OD,
δ): 3.40 (1H, d, J = 17.6Hz), 3.75 (1H,
d, J = 17.6Hz), 4.04 (1H, d, J = 13.5Hz), 4.
67 (1H, d, J = 13.5Hz), 5.09 (1H, d, J =
4.4Hz), 5.78 (1H, d, J = 4.4Hz), 6.15 (2
H, s), 6.77 (1H, s), 6.99 (1H, s), 7.23
(1H, s), 7.72 (1H, s). IR (KBr, cm ^-1 ): 1750, 1590.

Example 67 p-Methoxybenzyl 3- (6,7-methylenedioxy-4-
Oxo-4H-1-benzothiopyran-2-yl) thiomethyl-7
-[(Z) -2-Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 1-oxide 700 mg (0.864 mmol) of the compound of Example 1 as in Example 20
The title compound (511 mg, 0.504 mmol) was obtained from the compound (226 mg, 0.950 mmol) of Example 63 (yield 58%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 3.45 (1H, d, J = 18.4Hz), 3.68 (1H,
d, J = 14.2Hz), 3.74 (1H, d, J = 18.4Hz), 3.
79 (3H, s), 4.07 (3H, s), 4.51 (1H, d,
J = 4.4Hz), 4.87 (1H, d, J = 14.2Hz), 5.13
(1H, d, J = 11.7Hz), 5.19 (1H, d, J = 11.7Hz)
Hz), 6.10 (2H, s), 6.1 to 6.2 (1H, m), 6.
68 (1H, s), 6.8 to 7.3 (21H, m), 7.83 (1
H, s).

Example 68 p-Methoxybenzyl 3- (6,7-methylenedioxy-4-
Oxo-4H-1-benzothiopyran-2-yl) thiomethyl-7
-[(Z) -2-Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 506 mg (0.500 mmol) of the compound of Example 67 as in Example 3.
From the above, the title compound (424 mg, 0.425 mmol) was obtained (yield 85
%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 3.41 (1H, d, J = 18.1Hz), 3.70 (1H,
d, J = 18.1Hz), 3.79 (3H, s), 3.97 (1H,
d, J = 13.5Hz), 4.07 (3H, s), 4.34 (1H,
d, J = 13.5Hz), 5.00 (1H, d, J = 4.9Hz), 5.
11 (1H, d, J = 12.0Hz), 5.16 (1H, d, J = 1
2.0Hz), 5.88 (1H, dd, J = 4.9, 8.8Hz), 6.10
(2H, s), 6.7 to 7.3 (23H, m).

Example 69 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3- (6,7-methylenedioxy
-4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-3-cephem-4-carboxylic acid sodium salt 419 mg (0.421 mmol) of the compound of Example 68 as in Example 4.
From the above, 131 mg (0.199 mmol) of the title compound was obtained (yield 47
%).

¹ H-NMR (400 MHz, CD ₃ OD,
δ): 3.41 (1H, d, J = 17.4Hz), 3.75 (1H,
d, J = 17.4Hz), 3.96 (3H, s), 4.04 (1H,
d, J = 13.5Hz), 4.67 (1H, d, J = 13.5Hz), 5.
07 (1H, d, J = 4.9Hz), 5.75 (1H, d, J =
4.9Hz), 6.15 (2H, s), 6.83 (1H, s), 7.00
(1H, s), 7.23 (1H, s), 7.72 (1H, s). IR (KBr, cm ^-1 ): 1750, 1590.

Example 70 6,7-Di-tert-butoxycarbonyloxy-2-methylthio
-4-oxo-4H-1-benzothiopyran 300 mg (1.25 mmol) of the compound of Example 54, dichloromethane
21.4 mg of 4-dimethylaminopyridine in a 10 ml suspension at room temperature
(0.175mmol), di-tert-butyl dicarbonate 599mg
(2.75 mmol) was added and stirred for 30 minutes. The solvent was concentrated and the residue was subjected to silica gel column chromatography (CHCl ₃
-AcOEt 40: 1) to give 319 mg (0.
725 mmol) was obtained (yield 58%).

Melting point 110 to 111 ° C. Elemental analysis value (%): Calculated value as C ₂₀ H ₂₄ O ₇ S ₂ C: 54.53; H: 5.49 Measured value C: 54.61; H: 5.46

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 1.55 (18H, s), 2.61 (3H, s), 6.82 (1
H, s), 7.48 (1H, s), 8.32 (1H, s). MS (M / Z): 440 (M ⁺ ).

Example 71 6,7-Di-tert-butoxycarbonyloxy-2-methylsulfinyl-4-oxo-4H-1-benzothiopyran 276 mg (0.625 mmol) of the compound of Example 70 as in Example 18.
This gave 310 mg of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 1.57 (18H, s), 2.96 (3H, s), 7.25 (1
H, s), 7.69 (1H, s), 8.40 (1H, s).

Example 72 6,7-Di-tert-butoxycarbonyloxy-2-mercapto
-4-oxo-4H-1-benzothiopyran 310 mg (0.678 mmol) of the compound of Example 71 as in Example 19
The title compound (241 mg, 0.564 mmol) was obtained from the
%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 1.57 (18H, s), 7.18 (1H, s), 7.38 (1
H, s), 8.13 (1H, s).

Example 73 p-Methoxybenzyl 3- (6,7-di-tert-butoxycarbonyloxy-4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-7-[(Z) -2- Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 1-oxide 834 mg (1.03 mmol) of the compound of Example 1 as in Example 20.
Also, 783 mg (0.652 mmol) of the title compound was obtained from 483 mg (1.13 mmol) of the compound of Example 72 (yield 63%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 1.57 (18H, s), 3.41 (1H, d, J = 18.6H
z), 3.7 to 3.8 (2H, m), 3.78 (3H, s), 4.0
7 (3H, s), 4.52 (1H, d, J = 4.9Hz), 4.84
(1H, d, J = 14.2Hz), 5.16 (1H, d, J = 11.7)
Hz), 5.25 (1H, d, J = 11.7Hz), 6.13 (1H, d
d, J = 4.9, 10.0 Hz), 6.69 (1H, s), 6.9 to 7.
4 (21H, m), 8.32 (1H, s).

Example 74 p-Methoxybenzyl 3- (6,7-di-tert-butoxycarbonyloxy-4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-7-[(Z) -2- Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 778 mg (0.648 mmol) of the compound of Example 73 as in Example 3
The title compound (484 mg, 0.408 mmol) was obtained from the above (yield 63
%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 1.56 (18H, s), 3.41 (1H, d, J = 18.1H
z), 3.68 (1H, d, J = 18.1Hz), 3.77 (3H,
s), 4.02 (1H, d, J = 13.5Hz), 4.07 (3H,
s), 4.34 (1H, d, J = 13.5Hz), 5.01 (1H,
d, J = 4.9Hz), 5.13 (1H, d, J = 11.7Hz), 5.
21 (1H, d, J = 11.7Hz), 5.89 (1H, dd, J =
4.9, 8.8Hz), 6.73 (1H, s), 6.8 to 7.4 (21
H, m), 8.33 (1H, s).

Example 75 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (6,7-dihydroxy-4-oxo-4H-1- Benzothiopyran-2-yl) thiomethyl-3-
Cephem-4-carboxylic acid sodium salt 266 mg (0.224 mmol) of the compound of Example 74 as in Example 4.
The title compound (96.8 mg, 0.150 mmol) was obtained from the above (yield 67
%).

¹ H-NMR (400 MHz, CD ₃ OD,
δ): 3.40 (1H, d, J = 17.4Hz), 3.75 (1H,
d, J = 17.4Hz), 3.96 (3H, s), 4.02 (1H,
d, J = 13.7Hz), 4.66 (1H, d, J = 13.7Hz), 5.
07 (1H, d, J = 4.9Hz), 5.75 (1H, d, J =
4.9Hz), 6.83 (1H, s), 6.94 (1H, s), 7.00
(1H, s), 7.71 (1H, s). IR (KBr, cm ^-1 ): 1750, 1550.

Example 76 p-Methoxybenzyl 3- (6,7-di-tert-butoxycarbonyloxy-4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-7-[(Z) -2- (2-Tritylaminothiazol-4-yl) -2-trityloxyiminoacetamide) -3-
Cephem-4-carboxylate 1-oxide P-Methoxybenzyl 3-chloromethyl-7-[(Z) -2-trityloxyimino-2- (tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate as in Example 20 The title compound 461m from 1.07 g (1.03 mmol) of 1-oxide and 483 mg (1.13 mmol) of the compound of Example 72.
g (0.323 mmol) was obtained (yield 31%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 1.57 (18H, s), 3.12 (1H, d, J = 18.4H
z), 3.47 (1H, d, J = 18.4Hz), 3.71 (1H,
d, J = 14.2Hz), 3.78 (3H, s), 4.39 (1H,
d, J = 4.9Hz), 4.82 (1H, d, J = 14.2Hz), 5.
17 (1H, d, J = 11.7Hz), 5.27 (1H, d, J = 1
1.7Hz), 6.26 (1H, d, J = 4.9, 10.3Hz), 6.87
(1H, s), 6.9 to 7.4 (36H, m), 8.33 (1H,
s).

Example 77 p-Methoxybenzyl 3- (6,7-di-tert-butoxycarbonyloxy-4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-7-[(Z) -2- (2-Tritylaminothiazol-4-yl) -2-trityloxyiminoacetamide] -3-
Cephem-4-carboxylate 457 mg (0.320 mmol) of the compound of Example 76 as in Example 3.
From the above, 353 mg (0.250 mmol) of the title compound was obtained (yield 78
%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 1.56 (18H, s), 3.23 (1H, d, J = 18.4H
z), 3.59 (1H, d, J = 18.4Hz), 3.77 (3H,
s), 3.98 (1H, d, J = 12.7Hz), 4.34 (1H,
d, J = 12.7Hz), 5.02 (1H, d, J = 4.9Hz), 5.
14 (1H, d, J = 11.7Hz), 5.23 (1H, d, J = 1
1.7Hz), 6.01 (1H, dd, J = 4.9, 8.8Hz), 6.86
(1H, s), 6.9 to 7.4 (36H, m), 8.32 (1H,
s).

Example 78 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3- (6,7-dihydroxy-4-
Oxo-4H-1-benzothiopyran-2-yl) thiomethyl-3
-Cephem-4-carboxylic acid sodium salt 349 mg (0.247 mmol) of the compound of Example 77 as in Example 4.
The title compound (101 mg, 0.160 mmol) was obtained from the
%).

¹ H-NMR (400 MHz, CD ₃ OD,
δ): 3.40 (1H, d, J = 17.4Hz), 3.73 (1H,
d, J = 17.4Hz), 4.06 (1H, d, J = 13.0Hz), 4.
55 (1H, d, J = 13.0Hz), 5.08 (1H, d, J =
4.9Hz), 5.78 (1H, d, J = 4.9Hz), 6.76 (1
H, s), 6.84 (1H, s), 6.91 (1H, s), 7.64
(1H, s). IR (KBr, cm ^-1 ): 1750, 1540. SIMS (M / Z): 630 (M + 1) ⁺ .

Example 79 2-Bromo-3-chloro-4,5-dimethoxybenzaldehyde 5.39 g (20.3 mmol) of 6-bromo-5-chlorovanillin was suspended in 50 ml of acetonitrile, and 1.8-diazabicyclo [5,4,0]-
3.04 ml (20.3 mmol) 7-undecene, 2.53 ml methyl iodide
(40.6 mmol) is added dropwise under ice cooling. After stirring at room temperature for 5 hours, 3.9 ml of diisopropylethylamine (22.33 mmo
l) and 2.53 ml (40.6 mmol) of methyl iodide are added under ice cooling and the mixture is stirred at room temperature for 20 hours. After distilling off the solvent, 200 ml of dichloromethane is added to the residue and washed with water. After drying over anhydrous magnesium sulfate, the concentrated residue was purified by silica gel column chromatography (Hex: AcOEt = 5: 1) to give the title compound as colorless needles. 4.04g (Yield 71
%). Melting point 118.5-119.1 ° C.

Elemental analysis value (%): C ₉ H ₈ Br ClO ₃
Calculated as C: 38.67; H: 2.88 Found C: 38.65; H: 2.75

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 3.93 (3H, s), 3.96 (3H, s), 7.44 (1
H, s), 10.28 (1H, s).

Example 80 2-Bromo-3-chloro-4,5-dimethoxyacetophenone To a solution of 3.90 g (14 mmol) of the compound of Example 79 in 20 ml of THF, 3.40 g (14 mmol) of magnesium and 1.05 of methyl iodide were added.
The Grignard reagent prepared from ml (16.8 mmol) and 5.7 ml of diethyl ether is added dropwise under ice cooling. After stirring for 40 minutes at room temperature, 8.5 ml of saturated NH ₄ Cl aqueous solution is added and the mixture is stirred for another 10 minutes. The organic layer was separated and the aqueous layer was extracted with ether (50 ml).
X2). The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the concentrated residue was purified by silica gel column chromatography (Hex: AcOEt = 4: 1) to obtain a pale yellow powder. The obtained pale yellow powder was dissolved in 2.7 ml of dichloromethane and then added dropwise to 55 ml of dichloromethane containing 4.81 g (22.32 mmol) of pyridinium chlorochromate and 5.58 g of molecular sieve powder. After stirring at room temperature for 50 minutes, the organic layer is separated. 50 ml of diethyl ether was added to the residue and the mixture was vigorously stirred, and then the ether layer was separated. This operation is repeated 3 times, and the ether layer and the above dichloromethane layer are combined and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. After drying over anhydrous magnesium sulfate, the concentrated residue was subjected to silica gel column chromatography (Hex: AcOEt =
4: 1) to obtain the title compound as a pale yellow powder. 2.
86 g (yield 70%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 2.64 (3H, s), 3.88 (6H, s), 6.88 (1
H, s).

Example 81 8-Chloro-6,7-dimethoxy-2-methylthio-4-oxo-4
H-1-benzothiopyran 2.85 g (9.70 mmol) of the compound of Example 80 as in Example 17
To give the title compound as a white powder. 2.50 g (yield 85
%).

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 2.65 (3H, s), 3.98 (6H, s), 6.84 (1)
H, s), 7.93 (1H, s).

Example 82 8-Chloro-6,7-dihydroxy-2-methylthio-4-oxo
-4H-1-benzothiopyran 2.03 g (6.69 mmol) of the compound of Example 81 as in Example 54
To give the title compound as a pale yellow powder. 0.947 g (yield 52
%).

¹ H-NMR (90 MHz, DMSO-d6,
δ): 2.69 (3H, s), 6.76 (1H, s), 7.70 (1
H, s).

Example 83 8-Chloro-6,7-di-tert-butoxycarbonyloxy-2-
Methylthio-4-oxo-4H-1-benzothiopyran 0.947 g (3.45 mmo) of the compound of Example 82 as in Example 70
The title compound was obtained as a colorless oil from l). 1.43 g (yield 8
7%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 1.55 (9H, s), 1.57 (9H, s), 2.66 (3
H, s), 6.84 (1H, s), 8.33 (1H, s).

Example 84 8-Chloro-6,7-di-tert-butoxycarbonyloxy-2-
Methylsulfinyl-4-oxo-4H-1-benzothiopyran 1.37 g (2.88 mmol) of the compound of Example 83 as in Example 18
To give the title compound as a white powder. 1.40 g (yield 99
%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 1.56 (9H, s), 1.58 (9H, s), 2.98 (3)
H, s), 7.30 (1H, s), 8.40 (1H, s).

Example 85 p-Methoxybenzyl 3- (8-chloro-6,7-di-tert-butoxycarbonyloxy-4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-7-[(Z ) -Methoxyimino
-2- (2-Tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 0.446 g (0.912 mmol) of the compound of Example 84 was added to THF 5.0
After dissolving in 1 ml, 1.82 ml of 1N-NaSH aqueous solution was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution is concentrated under reduced pressure, and the residue is dissolved in 2.0 ml of dimethylformamide. The pH was adjusted to 3.0 with 3N-HCl under ice cooling to obtain an orange solution. (Liquid A). p-Methoxybenzyl 3-chloromethyl-7-[(Z) -2-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 0.60 g (0.76 mmol ) Was dissolved in 1.5 ml of dimethylformamide, and sodium iodide 136.8 mg (
0.912 mmol) and then stirred at room temperature for 30 minutes. Next, the above solution A was added dropwise to this reaction solution under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution is poured into 40 ml of ice water and the precipitate is collected by filtration. The obtained precipitate is dissolved in 200 ml of dichloromethane, washed with water and then with saturated saline. After drying over anhydrous magnesium sulfate, the concentrated residue was purified by column (MeOH: CH ₂ Cl ₂ = 1: 9).
9) Then, a light yellow caramel-like title compound was obtained. 0.290 g
(Yield 31%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 1.56 (9H, s), 1.57 (9H, s), 3.56 (2
H, ABq, J = 18.1Hz), 3.77 (3H, s), 4.21
(2H, ABq, J = 13.2Hz), 4.07 (3H, s), 5.
02 (1H, d, J = 4.9Hz), 5.18 (2H, ABq, J
= 11.7Hz), 5.89 (1H, dd, J = 4.9Hz, 9.3Hz),
6.73 (1H, s), 6.85 (2H, d, J = 8.8Hz), 6.
98 (1H, s), 7.28 to 7.31 (17H, m), 8.33 (1
H, s).

Example 86 7β-[(Z) -2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (8-chloro-6,7-dihydroxy-4-oxo- 4H-1-benzothiopyran-2-yl) thiomethyl-3-cephem-4-carboxylic acid sodium salt 0.284 g (0.233 mm) of the compound of Example 85 as in Example 4
ol) to give the title compound as a pale yellow powder. 71.6 mg (yield
45%).

¹ H-NMR (400 MHz, D ₂ O, δ): 3.
63 (2H, ABq, J = 17.6Hz), 4.18 (2H, AB
q, J = 13.7Hz), 3.98 (3H, s), 5.16 (1H,
d, J = 4.4Hz), 5.73 (1H, d, J = 4.4Hz), 6.9
7 (1H, s), 7.00 (1H, s), 7.52 (1H, s)
s). IR (KBr, cm ^-1 ): 1740, 1600.

Example 87 p-Methoxybenzyl 7-[(Z) -2-tert-butoxycarbonylmethoxyimino-2- (2-tritylaminothiazole-4)
-Yl) acetamido] -3- (8-chloro-6,7-di-tert-butoxycarbonyloxy-4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-3-cephem-4-carboxylate Similar to Example 85, 0.151 g (0.307 mm) of the compound of Example 84
ol) and p-methoxybenzyl 7-[(Z) -2-tert-butoxycarbonylmethoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-chloromethyl-3-cephem-4- A pale yellow caramel-like title compound was obtained using 0.229 g (0.256 mmol) of carboxylate. 0.177 g
(Yield 52%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 1.44 (9H, s), 1.56 (9H, s), 1.57 (9
H, s), 3.52 (2H, ABq, J = 18.1Hz), 3.77
(3H, s), 4.20 (2H, ABq, J = 13.2Hz), 4.
76 (2H, ABq, J = 17.1Hz), 5.01 (1H, d, J
= 4.9Hz), 5.18 (2H, ABq, J = 11.7Hz), 5.87
(1H, dd, J = 4.9Hz, 8.8Hz), 6.80 (1H,
s), 6.85 (2H, d, J = 8.3Hz), 6.96 (1H,
s), 7.27 to 7.32 (17H, m), 8.33 (1H, s), 8.
70 (1H, d, J = 8.8Hz).

Example 88 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-carboxymethoxyiminoacetamide] -3- (8-chloro-6,7-
Dihydroxy-4-oxo-4H-1-benzothiopyran-2-
Il) Thiomethyl-3-cephem-4-carboxylic acid disodium salt Similar to Example 4, the compound of Example 87 0.169 g (0.128 mm
ol) to give the title compound as a pale yellow powder. 87.8 mg (yield
92%).

¹ H-NMR (400 MHz, D ₂ O, δ): 3.
63 (2H, ABq, J = 17.6Hz), 4.22 (2H, AB
q, J = 13.7Hz), 4.57 (2H, s), 5.17 (1H,
d, J = 4.9Hz), 5.75 (1H, d, J = 4.9Hz), 7.0
4 (1H, s), 7.05 (1H, s), 7.54 (1H,
s). IR (KBr, cm ^-1 ): 1760, 1690.

Example 89 p-Methoxybenzyl 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- (6,7 -Di-tert-butoxycarbonyloxy-4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-3
-Cephem-4-carboxylate 0.493 g (1.08 mmo) of the compound of Example 71 as in Example 85
l) and p-methoxybenzyl 7-[(Z) -2- (5-amino-1,
2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3-chloromethyl-3-cephem-4-carboxylate (0.50 g, 0.90 mmol) was used to obtain the title compound as a pale yellow caramel. 0.724 g (yield 85%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 1.56 (18H, s), 3.55 (2H, ABq, J = 1
8.6Hz), 3.76 (3H, s), 4.09 (3H, s), 4.21
(2H, ABq, J = 13.2Hz), 5.06 (1H, d, J =
4.9Hz), 5.16 (2H, ABq, J = 11.7Hz), 6.10
(1H, dd, J = 4.9Hz, 8.8Hz), 6.63 (2H, br
s), 6.85 (2H, d, J = 8.8Hz), 6.95 (1H,
s), 7.29 (2H, d, J = 8.8Hz), 7.44 (1H,
s), 8.31 (1H, s), 8.45 (1H, d, J = 8.8H
z).

Example 90 7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- (6,7-dihydroxy-4 -Oxo-4H-1-benzothiopyran-2-yl)
Thiomethyl-3-cephem-4-carboxylic acid sodium salt 0.691 g (0.73 mmo) of the compound of Example 89 as in Example 4.
l) The title compound was obtained as a pale yellow powder. 191.8 mg (41% yield
%).

¹ H-NMR (400 MHz, CD ₃ OD,
δ): 3.56 (2H, ABq, J = 17.6Hz), 4.04 (3
H, s), 4.28 (2H, ABq, J = 12.7Hz), 5.07
(1H, d, J = 4.9Hz), 5.79 (1H, d, J = 4.9Hz)
Hz), 6.71 (1H, s), 6.91 (1H, s), 7.60 (1
H, s). IR (KBr, cm ^-1 ): 1755, 1590.

Example 91 p-Methoxybenzyl 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamide] -3- (6,7 -Di-tert-butoxycarbonyloxy-4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-3
-Cephem-4-carboxylate 0.482 g (1.06 mmo) of the compound of Example 71 as in Example 85
l) and p-methoxybenzyl 7-[(Z) -2- (5-amino-1,
2,0-thiadiazol-3-yl) -2-ethoxyiminoacetamido] -3-chloromethyl-3-cephem-4-carboxylate 0.50 g (0.88 mmol) was used to obtain the title compound as a pale yellow caramel. 0.631 g (75% yield).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 1.32 (3H, t), 1.56 (18H, s), 3.55 (2
H, ABq, J = 18.1Hz), 3.77 (3H, s), 4.20
(2H, ABq, J = 13.2Hz), 4.37 (2H, q), 5.
06 (1H, d, J = 4.9Hz), 5.16 (2H, ABq, J
= 11.7Hz), 6.08 (1H, dd, J = 4.9Hz, 9.3Hz),
6.51 (2H, br s), 6.86 (2H, d, J = 8.8H
z), 6.96 (1H, s), 7.29 (2H, d, J = 8.8H
z), 7.44 (1H, s), 8.05 (1H, d, J = 9.3H
z), 8.32 (1H, s).

Example 92 7β-[(Z) -2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamide] -3- (6,7-dihydroxy-4 -Oxo-4H-1-benzothiopyran-2-yl)
Thiomethyl-3-cephem-4-carboxylic acid sodium salt Similar to Example 4, 0.620 g (0.647 mmo) of the compound of Example 91
The title compound as a pale yellow powder was obtained from l). 171.2 mg (yield 40%).

¹ H-NMR (400 MHz, CD ₃ OD,
δ): 1.34 (3H, t), 3.56 (2H, ABq, J = 1
7.6Hz), 4.299 (2H, ABq, J = 13.2Hz), 4.304
(2H, q), 5.08 (1H, d, J = 4.9Hz), 5.79
(1H, d, J = 4.9Hz), 6.82 (1H, s), 6.92
(1H, s), 7.64 (1H, s). IR (KBr, cm ^-1 ): 1760, 1600.

Example 93 3-Bromo-6,7-methylenedioxy-2-methylthio-4-oxo-4H-1-benzothiopyran To a suspension of 600 mg (2.38 mmol) of the compound of Example 61 in 6 ml of acetic acid, 0.227 ml (2.38 mmol) of bromine was added at room temperature, and the mixture was stirred at 50 ° C for 3 hours. The precipitated crystals were collected by filtration and washed with ethyl acetate to give the title compound (935 mg).

¹ H-NMR (400 MHz, d ₆ DMSO,
δ): 2.74 (3H, s), 6.25 (2H, s), 7.58 (1
H, s), 7.68 (1H, s). MS (M / Z): 330 (M ⁺ ).

Example 94 3-Bromo-6,7-dihydroxy-2-methylthio-4-oxo
-4H-1-benzothiopyran 935 mg (2.82 mmol) of the compound of Example 93 as in Example 54
The title compound (232 mg, 0.726 mmol) was obtained from the above (yield 26
%).

¹ H-NMR (400 MHz, d ₆ DMSO,
δ): 2.71 (3H, s), 7.13 (1H, s), 7.70 (1
H, s). MS (M / Z): 318 (M ⁺ ).

Example 95 3-Bromo-6,7-di-tert-butoxycarbonyloxy-2-
Methylthio-4-oxo-4H-1-benzothiopyran 232 mg (0.726 mmo) of the compound of Example 94 as in Example 70
189 mg (0.365 mmol) of the title compound was obtained from (l) (yield 5
0%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 1.56 (18H, s), 2.68 (3H, s), 7.59 (1)
H, s), 8.39 (1H, s).

Example 96 3-Bromo-6,7-di-tert-butoxycarbonyloxy-2-
Methylsulfinyl-4-oxo-4H-1-benzothiopyran 189 mg (0.365 mmo) of the compound of Example 95 as in Example 18
204 mg of the title compound was obtained from l).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 1.57 (18H, s), 3.08 (3H, s), 7.75 (1
H, s), 8.43 (1H, s).

Example 97 p-Methoxybenzyl 3- (3-bromo-6,7-di-tert-butoxycarbonyloxy-4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-7-[(Z ) -2-Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate At room temperature, add 1N sodium hydrogen sulfide (0.358 mmol) and
Stir for minutes. The solvent was distilled off, and heavy residue 44.7 mg of water and water
3.4 ml of solution was added and washed with dichloromethane. 1N
Hydrochloric acid 0.7 ml was added, and the mixture was extracted with dichloromethane 1 ml to obtain a dichloromethane solution. (Liquid A)

P-Methoxybenzyl 3-chloromethyl-7
-[(Z) -2-Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 138 mg (0.173 mmol), dimethylformamide
Sodium iodide (31.2 mg, 1.12 mmol) was added to the 0.4 ml solution, and the mixture was stirred for 1 hour. (Liquid B)

Solution A was added to solution B under ice cooling, and the mixture was stirred at room temperature for 2 hours. It was poured into ice water and extracted with dichloromethane, the organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. Silica gel column chromatography of the residue (dichloromethane-ethyl acetate 20:
1) was carried out to obtain 54.0 mg (0.0428 mmol) of the title compound (yield 25%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 1.57 (18H, s), 3.44 (1H, d, J = 18.1H
z), 3.70 (3H, s), 3.7 to 3.8 (1H, m), 4.0
~ 4.1 (1H, m), 4.06 (3H, s), 4.44 (1
H, d, J = 12.7Hz), 5.04 (1H, d, J = 4.9H)
z), 5.17 (1H, d, J = 11.7Hz), 5.22 (1H,
d, J = 11.7Hz), 5.92 (1H, dd, J = 4.9, 8.8H
z), 6.8 to 7.3 (20H, m), 7.41 (1H, s), 8.3
7 (1H, s).

Example 98 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (3-bromo-6,7-dihydroxy-4-oxo- 4H-1-benzothiopyran-2-yl) thiomethyl-3-cephem-4-carboxylic acid sodium salt Similar to Example 4, the compound of Example 97 204 mg (0.162 mmo
The title compound (94.3 mg, 0.131 mmol) was obtained from (l) (yield 8
1%).

¹ H-NMR (400 MHz, CD ₃ OD,
δ): 3.45 (1H, d, J = 17.3Hz), 3.78 (1H,
d, J = 17.3Hz), 3.97 (3H, s), 4.14 (1H,
d, J = 12.2Hz), 4.59 (1H, d, J = 12.2Hz), 5.
11 (1H, d, J = 4.9Hz), 5.78 (1H, d, J =
4.9Hz), 6.68 (1H, s), 6.84 (1H, s), 7.60
(1H, s). IR (KBr, cm ^-1 ): 1750, 1620.

Example 99 p-Methoxybenzyl 3- (3-bromo-6,7-di-tert-butoxycarbonyloxy-4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-7-[(Z ) -2-tert-Butoxycarbonylmethoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate P-Methoxybenzyl 7-[(Z) -2-ter as in Example 97
t-Butoxycarbonylmethoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-chloromethyl-3-cephem-4-carboxylate 301 mg (0.336mm
ol) to give 262 mg (0.192 mmol) of the title compound (yield
57%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 1.45 (9H, s), 1.57 (18H, s), 3.44 (1)
H, d, J = 18.1Hz), 3.67 (1H, d, J = 18.1H)
z), 3.71 (3H, s), 4.10 (1H, d, J = 12.2H
z), 4.32 (1H, d, J = 12.2Hz), 4.73 (1H,
d, J = 17.1Hz), 4.79 (1H, d, J = 17.1Hz), 5.
04 (1H, d, J = 4.9Hz), 5.20 (1H, d, J = 1)
1.7Hz), 5.25 (1H, d, J = 11.7Hz), 5.90 (1
H, dd, J = 4.9, 8.8Hz), 6.8 to 7.3 (20H,
m), 7.43 (1H, s), 8.37 (1H, s).

Example 100 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-carboxymethoxyiminoacetamido] -3- (3-bromo-6,7
-Dihydroxy-4-oxo-4H-1-benzothiopyran-2
-Yl) thiomethyl-3-cephem-4-carboxylic acid disodium salt Similar to Example 4, the compound of Example 99 260 mg (0.191 mmo
113 mg (0.146 mmol) of the title compound was obtained from (l) (yield 7
7%).

¹ H-NMR (400 MHz, CD ₃ OD,
δ): 3.46 (1H, d, J = 17.8Hz), 3.78 (1H,
d, J = 17.8Hz), 4.12 (1H, d, J = 12.2Hz), 4.
54 (2H, s), 4.69 (1H, d, J = 12.2Hz), 5.12
(1H, d, J = 4.9Hz), 5.76 (1H, d, J = 4.9Hz)
Hz), 6.68 (1H, s), 6.89 (1H, s), 7.59 (1
H, s). IR (KBr, cm ^-1 ): 1750, 1600.

Example 101 3-Cyano-2-methylsulfinyl-4-oxo-4H-1-benzothiopyran 3-Cyano-2-methylthio-4-oxo-4 as in Example 18
H-1- Benzothiopyran (WDRudorf, Tetrahedron, 3
4, 725 (1978).) The title compound from 100 mg (0.429 mmol)
106 mg (0.423 mmol) was obtained (yield 99%).

¹ H-NMR (400 MHz, d ₆ DMSO,
δ): 3.14 (3H, s), 7.81 (1H, dd, J = 7.3,
7.8Hz), 7.93 (1H, dd, J = 7.3, 8.3Hz), 8.23
(1H, d, J = 8.3Hz), 8.40 (1H, d, J = 7.8)
Hz). MS (M / Z): 249 (M ⁺ ).

Example 102 3-Cyano-2-mercapto-4-oxo-4H-1-benzothiopyran In the same manner as in Example 19, the compound of Example 101 92.9 mg (0.373 mm
The title compound (70.0 mg, 0.319 mmol) was obtained from
86%).

¹ H = NMR (400 MHz, d ₆ DMSO,
δ): 7.3 to 7.5 (2H, m), 7.54 (1H, dd, J =
7.3, 7.8Hz), 8.13 (1H, d, J = 7.8Hz). MS (M / Z): 219 (M ⁺ ).

Example 103 p-Methoxybenzyl 3- (3-cyano-4-oxo-4H-1)
-Benzothiopyran-2-yl) thiomethyl-7-[(Z) -2-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate P-Methoxybenzyl 3-chloromethyl-7-[(Z) -2-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxy as in Example 20. Rate 300 mg (0.378 mmol) and compound of Example 102
91.1 mg (0.416 mmol) to the title compound 276 mg (0.282 mm
ol) was obtained (yield 75%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 3.44 (1H, d, J = 18.1Hz), 3.74 (3H,
s), 3.79 (1H, d, J = 18.1Hz), 4.08 (3H,
s), 4.19 (1H, d, J = 12.7Hz), 4.58 (1H,
d, J = 12.7Hz), 5.07 (1H, d, J = 4.9Hz), 5.
16 (1H, d, J = 11.7Hz), 5.20 (1H, d, J = 1
1.7Hz), 5.93 (1H, dd, J = 4.9, 8.8Hz), 6.8
~ 7.6 (24H, m).

Example 104 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (3-cyano-4-oxo-4H
-1-Benzothiopyran-2-yl) thiomethyl-3-cephem-4-carboxylic acid sodium salt Similar to Example 4, the compound of Example 103 269 mg (0.275 mm
63.6 mg (0.0999 mmol) of the title compound was obtained from
36%).

¹ H-NMR (400 MHz, CD ₃ OD,
δ): 3.45 (1H, d, J = 17.6Hz), 3.82 (1H,
d, J = 17.6Hz), 3.97 (3H, s), 4.22 (1H,
d, J = 13.7Hz), 5.04 (1H, d, J = 13.7Hz), 5.
12 (1H, d, J = 4.9Hz), 5.78 (1H, d, J =
4.9 Hz), 6.83 (1 H, s), 7.3 to 8.4 (4 H, m). SIMS (M / Z): 637 (M + 1) ⁺ . IR (KBr, cm ^-1 ): 1750, 1600.

Example 105 p-Methoxybenzyl 3- (3-cyano-4-oxo-4H-1)
-Benzothiopyran-2-yl) thiomethyl-7-[(Z) -2- (2
-Tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3-cephem-4-carboxylate P-Methoxybenzyl 3-chloromethyl-7-[(Z) -2- (2-tritylaminothiazol-4-yl) as in Example 20.
-2-Trityloxyiminoacetamide-3-cephem-4
-Carboxylate 386 mg (0.378 mmol) and Example 102
From the compound of 91.1mg (0.416mmol) to the title compound of 200mg
(0.166 mmol) was obtained (yield 44%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 3.25 (1H, d, J = 18.1Hz), 3.67 (1H,
d, J = 18.1Hz), 3.74 (3H, s), 4.1 to 4.2 (1
H, m), 4.60 (1H, d, J = 13.2Hz), 5.06 (1
H, d, J = 4.9Hz), 5.19 (1H, d, J = 11.7H)
z), 5.23 (1H, d, J = 11.7Hz), 6.05 (1H, d
d, J = 4.9, 8.8 Hz), 6.8 to 7.7 (39 H, m).

Example 106 7β-[(Z) -2- (2-Aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (3-cyano-4-oxo-4
H-1-benzothiopyran-2-yl) thiomethyl-3-cephem-4-carboxylic acid sodium salt 196 mg (0.162 mm) of the compound of Example 105 as in Example 4.
ol) to obtain 52.8 mg (0.0848 mmol) of the title compound (yield
52%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 3.43 (1H, d, J = 17.6Hz), 3.81 (1H,
d, J = 17.6Hz), 4.21 (1H, d, J = 13.7Hz), 5.
05 (1H, d, J = 13.7Hz), 5.13 (1H, d, J =
4.9Hz), 5.81 (1H, d, J = 4.9Hz), 6.77 (1
H, s), 7.3 to 8.4 (4H, m). SIMS (M / Z): 623 (M + 1) ⁺ . IR (KBr, cm ^-1 ): 1760, 1600.

Example 107 p-Methoxybenzyl 7-[(Z) -2-tert-butoxycarbonylmethoxyimino-2- (2-tritylaminothiazole-4)
-Yl) acetamido] -3- (6,7-di-tert-butoxycarbonyloxy-4-oxo-4H-1-benzothiopyran-2-
Il) Thiomethyl-3-cephem-4-carboxylate P-Methoxybenzyl 7-[(Z) -2-ter as in Example 20.
t-Butoxycarbonylmethoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-chloromethyl-3-cephem-4-carboxylate 262mg (0.293mm
ol) and the compound of Example 72 (138 mg, 0.323 mmol) to give the title compound (230 mg, 0.179 mmol) (yield 61%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 1.43 (9H, s), 1.56 (18H, s), 3.38 (1)
H, d, J = 18.3Hz), 3.63 (1H, d, J = 18.3H)
z), 3.77 (3H, s), 4.02 (1H, d, J = 13.2H
z), 4.32 (1H, d, J = 13.2Hz), 4.72 (1H,
d, J = 17.1Hz), 4.78 (1H, d, J = 17.1Hz), 5.
01 (1H, d, J = 4.9Hz), 5.15 (1H, d, J = 1)
2.0Hz), 5.21 (1H, d, J = 12.0Hz), 5.86 (1
H, dd, J = 4.9, 8.3Hz), 6.8 to 7.4 (22H,
m), 8.33 (1H, s).

Example 108 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-carboxymethoxyiminoacetamido] -3- (6,7-dihydroxy-4-oxo-4H-1 -Benzothiopyran-2-yl) thiomethyl-3-cephem-4-carboxylic acid disodium salt 230 mg (0.179 mm) of the compound of Example 107 as in Example 4
84.0 mg (0.118 mmol) of the title compound was obtained from
66%).

¹ H-NMR (400 MHz, CD ₃ OD,
δ): 3.42 (1H, d, J = 17.3Hz), 3.74 (1H,
d, J = 17.3Hz), 4.05 (1H, d, J = 13.7Hz), 4.
54 (2H, s), 4.72 (1H, d, J = 13.7Hz), 5.07
(1H, d, J = 4.9Hz), 5.74 (1H, d, J = 4.9Hz)
Hz), 6.87 (1H, s), 6.96 (1H, s), 7.05 (1
H, s), 7.73 (1H, s). IR (KBr, cm ^-1 ): 1760, 1580.

Example 109 p-Methoxybenzyl 7-[(Z) -2- (1-tert-butoxycarbonyl-1-methylethoxy) imino-2- (2-tritylaminothiazol-4-yl) acetamide]- 3- (6,7- di-t
ert-Butoxycarbonyloxy-4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-3-cephem-4-carboxylate P-Methoxybenzyl 7-[(Z) -2- (1-
tert-butoxycarbonyl-1-methylethoxyimino)
-2- (2-Tritylaminothiazol-4-yl) acetamido] -3-chloromethyl-3-cephem-4-carboxylate
232 mg (0.752 mmol) and the compound of Example 72 118 mg (0.2
The title compound (239 mg, 0.182 mmol) was obtained from 77 mmol) (yield 72%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 1.42 (9H, s), 1.56 (18H, s), 1.58 (3
H, s), 1.62 (3H, s), 3.38 (1H, d, J = 1
8.1Hz), 3.65 (1H, d, J = 18.1Hz), 3.77 (3
H, s), 4.00 (1H, d, J = 12.9Hz), 4.37 (1
H, d, J = 12.9Hz), 5.00 (1H, d, J = 4.9H)
z), 5.16 (1H, d, J = 11.7Hz), 5.20 (1H,
d, J = 11.7Hz), 5.96 (1H, dd, J = 4.9, 8.8H
z), 6.7 to 7.4 (22H, m), 8.33 (1H, s).

Example 110 7β-[(Z) -2- (2-Aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxy) iminoacetamide] -3-
(6,7-Dihydroxy-4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-3-cephem-4-carboxylic acid disodium salt Similar to Example 4, compound of Example 109 120 mg (0.0914 mm
ol) to give 35.1 mg (0.0476 mmol) of the title compound (yield
52%).

¹ H-NMR (400 MHz, CD ₃ OD,
δ): 1.52 (3H, s), 1.55 (3H, s), 3.43 (1)
H, d, J = 17.6Hz), 3.74 (1H, d, J = 17.6H)
z), 4.06 (1H, d, J = 13.2Hz), 4.63 (1H,
d, J = 13.2Hz), 5.08 (1H, d, J = 4.9Hz), 5.
75 (1H, d, J = 4.9Hz), 6.81 (1H, s), 6.82
(1H, s), 6.92 (1H, s), 7.63 (1H, s). IR (KBr, cm ^-1 ): 1760, 1580.

Example 111 3-Ethoxycarbonyl-2-methylthio-4-oxo-6,7,8
-Trifluoro-4H-1-benzothiopyran Ethyl 2,3,4,5-tetrafluorobenzoyl acetate
3.00 g (11.4 mmol), carbon disulfide 870 mg (11.4 mmol),
2.31 g (22.8 mmol) of triethylamine was added to a solution of 9 ml of dry dimethyl sulfoxide at room temperature, and the mixture was stirred at room temperature for 1 hour. Then, 3.24 g (22.8 mmol) of methyl iodide was added at room temperature, and the mixture was stirred for 2 hours. It was poured into ice water, and the precipitated crystals were collected by filtration and dried to obtain 2.81 g (8.41 mmol) of the title compound (yield 74
%). Melting point 113 ~ 5 ℃

¹ H-NMR (90 MHz, CDCl ₃ ,
δ): 1.40 (3H, t, J = 7.0Hz), 2.71 (3H,
s), 4.44 (2H, q, J = 7.0Hz), 8.11 (1H, d
dd, J = 2.2, 7.5, 10.3Hz).

Elemental analysis value (%): C ₁₃ H ₉ F ₃ O ₃ S ₂
Calculated as C: 46.70; H: 2.71 Found C: 46.66; H: 2.69

Example 112 3-Carboxy-2-methylthio-4-oxo-6,7,8-trifluoro-4H-1-benzothiopyran 300 mg (0.897 mmol) of the compound of Example 111, 0.54 m of acetic acid
A mixture of l, concentrated sulfuric acid 0.072 ml and water 0.36 ml was stirred at 100 ° C. for 3 hours. The mixture was allowed to cool, the precipitated crystals were collected by filtration, washed with water and dried to obtain 147 mg (0.481 mmol) of the title compound (yield 54
%).

¹ H-NMR (90 MHz, d ₆ DMSO,
δ): 2.77 (3H, s), 8.12 (1H, ddd, J = 2.
2, 7.5, 10.8Hz). MS (M / Z): 306 (M ⁺ ).

Example 113 3- (4-Methoxybenzyloxycarbonyl) -2-methylthio-4-oxo-6,7,8-trifluoro-4H-1-benzothiopyran 50 mg (0.163 mmol) of the compound of Example 112, chloroform
30.7 mg of p-methoxybenzyl chloride in 0.2 ml suspension
(0.196mmol), triethylamine 16.5mg (0.163mmo
l), sodium iodide 29.4mg (0.196mmol) was added,
Stir at room temperature for 5 hours. The mixture was poured into ice water and extracted with dichloromethane, the organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue is subjected to silica gel column chromatography (CHCl ₃ ) to give the title compound 2
2.5 mg (0.0528 mmol) was obtained (yield 32%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 2.66 (3H, s), 3.81 (3H, s), 5.34 (2)
H, s), 6.90 (2H, d, J = 8.6Hz), 7.40 (2
H, d, J = 8.6Hz), 8.12 (1H, ddd, J = 2.2,
7.6, 10.0 Hz).

Example 114 3- (4-Methoxybenzylcarbonyl) -2-methylsulfinyl-4-oxo-6,7,8-trifluoro-4-oxo-4H-1
-Benzothiopyran 55.8 mg (0.131 mm) of the compound of Example 113 as in Example 18
ol) to give 53.7 mg (0.121 mmol) of the title compound (yield
93%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 3.00 (3H, s), 3.82 (3H, s), 5.31 (1)
H, d, J = 11.5Hz), 5.37 (1H, d, J = 11.5H)
z), 6.92 (2H, d, J = 8.8Hz), 7.39 (2H,
d, J = 8.8Hz), 8.15 (1H, ddd, J = 2.4, 7.
5, 9.9Hz).

Example 115 2-Mercapto-3- (4-methoxybenzyloxycarbonyl) -4-oxo-6,7,8-trifluoro-4H-1-benzothiopyran 53.7 mg (0.121 mm) of the compound of Example 114 as in Example 19
ol) to obtain 40.2 mg (0.0975 mmol) of the title compound (yield
80%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 3.81 (3H, s), 5.41 (2H, s), 6.91 (2)
H, d, J = 8.8Hz, 7.42 (2H, d, J = 8.8H)
z), 7.9 to 8.0 (1H, m).

Example 116 p-Methoxybenzyl 3- [3- (4-methoxybenzyloxycarbonyl) -4-oxo-6,7,8-trifluoro-4H-1-
Benzothiopyran-2-yl] thiomethyl-7-[(Z) -2-methoxyimino-2- (2-tritylaminothiazol-4-yl)
Acetamide] -3-cephem-4-carboxylate P-Methoxybenzyl 3-chloromethyl-7-[(Z) -2-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxy as in Example 20. Rate 157 mg (0.198 mmol) and compound of Example 115
89.7 mg (0.218 mmol) to the title compound 139 mg (0.119 mm
ol) was obtained (60% yield).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 3.14 (1H, d, J = 18.3Hz), 3.52 (1H,
d, J = 18.3Hz), 3.76 (3H, s), 3.77 (3H,
s), 3.84 (1H, d, J = 13.7Hz), 4.07 (3H,
s), 4.45 (1H, d, J = 13.7Hz), 4.95 (1H,
d, J = 4.9Hz), 5.06 (1H, d, J = 12.0Hz), 5.
12 (1H, d, J = 12.0Hz), 5.32 (2H, s), 5.85
(1H, dd, J = 4.9, 9.0Hz), 6.8 to 7.4 (24H,
m), 8.0 to 8.1 (1H, m).

Example 117 7β-[(Z) -2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (3-carboxy-4-oxo
-6,7,8-Trifluoro-4H-1-benzothiopyran-2-yl) thiomethyl-3-cephem-4-carboxylic acid sodium salt Similar to Example 4, the compound of Example 116 139 mg (0.119 mm
ol) to obtain 64.1 mg (0.0903 mmol) of the title compound (yield
76%).

¹ H-NMR (400 MHz, CD ₃ OD,
δ): 3.46 (1H, d, J = 17.6Hz), 3.86 (1H,
d, J = 17.6Hz), 3.96 (3H, s), 4.09 (1H,
d, J = 12.7Hz), 4.68 (1H, d, J = 12.7Hz), 5.
11 (1H, d, J = 4.9Hz), 5.74 (1H, d, J =
4.9 Hz), 6.83 (1 H, s), 8.0 to 8.2 (1 H, m). IR (KBr, cm ^-1 ): 1760, 1600.

Example 118 p-Methoxybenzyl 3- [3- (4-methoxybenzyloxycarbonyl) -4-oxo-6,7,8-trifluoro-4H-1-
Benzothiopyran-2-yl] thiomethyl-7-[(Z) -2- (2-
Tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3-cephem-4-carboxylate P-Methoxybenzyl 3-chloromethyl-7-[(Z) -2- (2-tritylaminothiazol-4-yl) as in Example 20.
-2-Trityloxyiminoacetamido] -3-cephem-4
-Carboxylate 209 mg (0.204 mmol) and Example 115
From the compound of 92.5 mg (0.224 mmol) of the title compound 163 mg
(0.116 mmol) was obtained (yield 57%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 3.00 (1H, d, J = 18.6Hz), 3.46 (1H,
d, J = 18.6Hz), 3.69 (3H, s), 3.78 (3H,
s), 3.8 to 3.9 (1H, m), 4.44 (1H, d, J =
13.2Hz), 4.97 (1H, d, J = 4.9Hz), 5.09 (1
H, d, J = 11.7Hz), 5.18 (1H, d, J = 11.7H)
z), 5.30 (2H, d, J = 2.93Hz), 6.00 (1H, d
d, J = 4.9, 9.0Hz), 6.8 to 7.4 (39H, m), 8.0
~ 8.1 (1H, m).

Example 119 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (3-carboxy-4-oxo-6,7,8- Trifluoro-4H-1-benzothiopyran-2-
Il) Thiomethyl-3-cephem-4-carboxylic acid sodium salt In the same manner as in Example 4, 160 mg of the compound of Example 118 (0.1
The title compound (50.3 mg, 0.0723 mmol) was obtained from 15 mmol) (yield 63%).

¹ H-NMR (400 MHz, CD ₃ OD,
δ): 3.46 (1H, d, J = 17.6Hz), 3.86 (1H,
d, J = 17.6Hz), 4.10 (1H, d, J = 12.7Hz), 4.
67 (1H, d, J = 12.7Hz), 5.13 (1H, d, J =
4.9Hz), 5.77 (1H, d, J = 4.9Hz), 6.77 (1
H, s), 8.0-8.2 (1H, m). IR (KBr, cm ^-1 ): 1760, 1600.

Example 120 2,3-Dibromo-4,5-dimethoxybenzaldehyde 5,6-Dibromovanillin (Isao Kuboet.
al., Journal of Natural Products, 53 , 50 (1990).)
From 9.99 g (32.2 mmol), the title compound 8.30 g (25.6 mmo
l) was obtained (yield 79%). Melting point 126-7 ℃

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 3.93 (3H, s), 3.95 (3H, s), 7.49 (1
H, s). MS (M / Z): 322 (M ⁺ ).

Example 121 2,3-Dibromo-4,5-dimethoxyacetophenone Similar to Example 80, 8.30 g of the compound of Example 120 (25.6 mmo
4.52 g (13.4 mmol) of the title compound was obtained from (l) (yield 52
%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 2.64 (3H, s), 3.88 (3H, s), 3.88 (3
H, s), 6.91 (1H, s). MS (M / Z): 336 (M ⁺ ).

Example 122 8-Bromo-6,7-dimethoxy-2-methylthio-4-oxo-4
H-1-benzothiopyra 3.00 g (8.88 mmo) of the compound of Example 121 as in Example 17.
2.52 g (7.26 mmol) of the title compound was obtained from (l) (yield 82
%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 2.66 (3H, s), 3.98 (3H, s), 4.00 (3
H, s), 6.85 (1H, s), 8.01 (1H, s). MS (M / Z): 346 (M ⁺ ).

Example 123 8-Bromo-6,7-dihydroxy-2-methylthio-4-oxo
-4H-1-benzothiopyran 2.23 g (6.42 mmo) of the compound of Example 122 as in Example 54
2.28 g of the title compound are obtained from l).

¹ H-NMR (400 MHz, d ₆ DMSO,
δ): 2.69 (3H, s), 6.75 (1H, s), 7.76 (1)
H, s). MS (M / Z): 318 (M ⁺ ).

Example 124 8-Bromo-6,7-di-tert-butoxycarbonyloxy-2-
Methylthio-4-oxo-4H-1-benzothiopyran 1.98 g (6.19 mmo) of the compound of Example 123 as in Example 70
2.43 g (4.68 mmol) of the title compound was obtained from (l) (yield 76
%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 1.55 (9H, s), 1.57 (9H, s), 2.66 (3
H, s), 6.83 (1H, s), 8.39 (1H, s).

Example 125 8-Bromo-6,7-di-tert-butoxycarbonyloxy-2-
Methylsulfinyl-4-oxo-4H-1-benzothiopyran As in Example 18, 1.86 g (3.58 mmo) of the compound of Example 124
1.96 g of the title compound are obtained from l).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 1.56 (9H, s), 1.58 (9H, s), 2.99 (3
H, s), 7.28 (1H, s), 8.45 (1H, s).

Example 126 p-methoxybenzyl 3- (8-bromo-6,7-di-tert-butoxycarbonyloxy-4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-7-[(Z ) -2-Methoxyimino
-2- (2-Tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate P-Methoxybenzyl 3-chloromethyl-7-[(Z) -2-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxy as in Example 85 Rate 267 mg (0.336 mmol) and compound of Example 125
180 mg (0.336 mmol) to the title compound 307 mg (0.243 mm
ol) was obtained (yield 72%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 1.56 (9H, s), 1.57 (9H, s), 3.43 (1
H, d, J = 18.1Hz), 3.70 (1H, d, J = 18.1H)
z), 3.77 (3H, s), 4.0 to 4.1 (1H, m), 4.0
7 (3H, s), 4.36 (1H, d, J = 13.2Hz), 5.02
(1H, d, J = 4.9Hz), 5.13 (1H, d, J = 11.7)
Hz), 5.23 (1H, d, J = 11.7Hz), 5.90 (1H, d
d, J = 4.9, 8.6Hz), 6.8 to 7.4 (21H, m), 8.3
8 (1H, s).

Example 127 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3- (8-bromo-6,7-dihydroxy-4-oxo- 4H-1-benzothiopyran-2-yl) thiomethyl-3-cephem-4-carboxylic acid sodium salt 302 mg (0.239 mm) of the compound of Example 126 as in Example 4.
ol) to obtain 130 mg (0.181 mmol) of the title compound (yield 7
Five%).

¹ H-NMR (400 MHz, CD ₃ OD,
δ): 3.44 (1H, d, J = 17.3Hz), 3.75 (1H,
d, J = 17.3Hz), 3.96 (3H, s), 4.17 (1H,
d, J = 12.7Hz), 4.43 (1H, d, J = 12.7Hz), 5.
10 (1H, d, J = 4.9Hz), 5.76 (1H, d, J =
4.9Hz), 6.83 (1H, s), 6.95 (1H, s), 7.63
(1H, s). IR (KBr, cm ^-1 ): 1760, 1600.

Example 128 p-Methoxybenzyl 3- (8-bromo-6,7-di-tert-butoxycarbonyloxy-4-oxo-4H-1-benzothiopyran-2-yl) thiomethyl-7-[(Z ) -2-tert-Butoxycarbonylmethoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate P-Methoxybenzyl 7-[(Z) -2-ter as in Example 85.
t-Butoxycarbonylmethoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-chloromethyl-3-cephem-4-carboxylate 227mg (0.254mm
ol) and 136 mg (0.254 mmol) of the compound of Example 125 to obtain 291 mg (0.213 mmol) of the title compound (yield 84%).

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 1.44 (9H, s), 1.56 (9H, s), 1.57 (9
H, s), 3.40 (1H, d, J = 18.1Hz), 3.65 (1
H, d, J = 18.1Hz), 3.77 (3H, s), 4.06 (1
H, d, J = 12.7Hz), 4.35 (1H, d, J = 12.7H)
z), 4.7 to 4.8 (2H, m), 5.02 (1H, d, J =
4.9Hz), 5.15 (1H, d, J = 11.7Hz), 5.22 (1
H, d, J = 11.7Hz), 5.8-5.9 (1H, m), 6.8
~ 7.4 (21H, m), 8.38 (1H, s).

Example 129 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-carboxymethoxyiminoacetamide] -3- (8-bromo-6,7-
Dihydroxy-4-oxo-4H-1-benzothiopyran-2-
Il) Thiomethyl-3-cephem-4-carboxylic acid disodium salt 288 mg (0.211 mm) of the compound of Example 128 as in Example 4.
ol) to give 117 mg (0.148 mmol) of the title compound (yield 7
0%).

¹ H-NMR (400 MHz, CD ₃ OD,
δ): 3.44 (1H, d, J = 17.6Hz), 3.75 (1H,
d, J = 17.6Hz), 4.12 (1H, d, J = 12.7Hz), 4.
53 (2H, s), 4.33 (1H, d, J = 12.7Hz), 5.10
(1H, d, J = 4.9Hz), 5.73 (1H, d, J = 4.9Hz)
Hz), 6.87 (1H, s), 6.93 (1H, s), 7.62 (1
H, s). IR (KBr, cm ^-1 ): 1760, 1600.

Example 130 6,7-Dimethoxy-2-methylthio-4-oxo-4H-1-benzothiopyran 2-Bromo-4,5-dimethoxyacetophenone as in Example 17 (Edward McDonald and Paul Smith, JCS Perkin
I, 837 (1979).) 1.00 g (3.86 mmol) from the title compound
802 mg (2.99 mmol) was obtained (yield 77%).

Melting point 161 to 162 ° C. Elemental analysis value (%): Calculated value as C ₁₂ H ₁₂ O ₃ S ₂ C: 53.70; H: 4.51 Found value C: 53.60; H: 4.37 Of the compound.

Example 131 6,7-Dihydroxy-2-methylthio-4-oxo-4H-1-benzothiopyran 33.6 g (133 mmol) of the compound of Example 61 as in Example 54
The title compound (6.81 g, 28.3 mmol) was obtained from the above (yield 21
%).

Melting point 164-166 ° C. The spectral data of this product was in agreement with the compound of Example 54.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Hideyuki Fukuda             4-20-11-201 Suzumiya, Utsunomiya City, Tochigi Prefecture

Claims (4)

[Claims] 1. A novel cephem compound represented by the formula [I] and a pharmacologically acceptable salt thereof or a physiologically hydrolyzable non-toxic ester. [I] [In the formula, R ¹ is a linear or branched lower alkyl group optionally substituted by an optionally protected carboxyl group, a trityl group, a hydrogen atom or a fluorine-substituted lower alkyl group, and R ² is A hydrogen atom, a metal atom, a protecting group for a carboxyl group or an ester residue capable of forming a hydrolyzable ester in vivo, R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different and a hydrogen atom , Halogen atom, optionally substituted linear or branched lower alkyl group, optionally substituted mercapto group, lower alkylamino group,
Optionally protected hydroxyl group, lower alkoxy group, lower alkanoyl group, lower alkoxycarbonyl group and R ³
And R ⁴ may form a lower alkylenedioxy group which may be substituted with R ⁴ , R ⁷ is a hydrogen atom, a cyano group, a halogen atom or COOR ⁸ (R ⁸ is hydrogen or a lower alkyl group), and R ⁹ is An optionally protected amino group, Z is N or CH, and n is 0 or 1. ] 2. A compound represented by the formula [II] [II] [wherein R ¹ is a linear or branched lower alkyl group optionally substituted with an optionally protected carboxyl group, a trityl group, a hydrogen atom or a fluorine-substituted lower alkyl group, R ² Is a hydrogen atom, a metal atom, a protecting group for a carboxyl group or an ester residue capable of forming a hydrolyzable ester in vivo, R ⁹ is an amino group which may be protected, Z is N or CH, and n is 0. Alternatively, 1 and A represent a leaving group. ] The compound represented by the formula [III] [III] [In the formula, R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different, and are a hydrogen atom, a halogen atom, an optionally substituted linear or branched lower alkyl group, a substituent Optionally substituted mercapto group, lower alkylamino group, optionally protected hydroxyl group, lower alkoxy group, lower alkanoyl group, lower alkoxycarbonyl group and R ³ and R ⁴
May form a lower alkylenedioxy group which may be substituted with, R ⁷ is a hydrogen atom, a cyano group, a halogen atom or COOR ⁸ (R ⁸ is hydrogen or a lower alkyl group),
M represents a hydrogen atom, a metal atom or quaternary ammonium. ] The reaction product and, if necessary after reduction, the protecting group is removed from the reaction product.
A method for producing the novel cephem compound described. 3. A compound represented by the formula [IV] [IV] [wherein R ² is a hydrogen atom, a metal atom, a protective group for a carboxyl group, hydrogen or an ester residue capable of forming a hydrolyzable ester in vivo, R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different, and a hydrogen atom, a halogen atom,
Optionally substituted linear or branched lower alkyl group, optionally substituted mercapto group, lower alkylamino group, optionally protected hydroxyl group, lower alkoxy group, lower alkanoyl group, lower alkoxycarbonyl group And R ³ and R ⁴ may form a lower alkylenedioxy group which may be substituted, R ⁷ is a hydrogen atom, a cyano group, a halogen atom or COOR ⁸ (R ⁸ is hydrogen or a lower alkyl group), n Indicates 0 or 1. ] Or its reactive derivative at the amino group or a salt thereof with the formula [V]
Compound represented by [V] [In the formula, R ¹ is a linear or branched lower alkyl group optionally substituted with an optionally protected carboxyl group, a trityl group, a hydrogen atom or a fluorine-substituted lower alkyl group, and Z is N, CH, or R ⁹ represents an optionally protected amino group. ] Or a reactive derivative thereof at the carboxyl group or a salt thereof is reacted, and if necessary, a protecting group is removed from the reaction product, to prepare a novel cephem compound. 4. An antibacterial agent containing the novel cephem compound according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.