JPH0645630B2 - New cephalosporin derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel cephalosporin derivative, more specifically 7- [2- (2-aminothiazol-4-yl) -2.
-(Substituted oxyimino) acetamide] -3-[(2-
Methyl-2-isoindolinio) methol] -3-cephem-4-carboxylate derivative, its production method and its use.

Problems to be Solved by the Prior Art and Invention β-lactam antibiotics show selective toxicity only to bacteria,
Since it does not affect animal cells, it plays an important role in the prevention and treatment of bacterial infections as an antibiotic with few side effects. In particular, cephalosporin derivatives are generally stable against penicillinase, have a broad antibacterial spectrum, and are often used for prevention and treatment of bacterial infections. However, on the other hand, for the treatment of intractable infections caused by non-fermentative gram-negative bacilli of glucose, such as resistant staphylococci having various resistance mechanisms or resistant Pseudomonas esginosa, Acinetobacter calcoaceticus, etc. There is a need for new cephalosporin derivatives with a broad spectrum.

Cephalosporin derivatives having a quaternary ammonium salt structure are disclosed in JP-A-53-53690, JP-A-55-59196, and JP-A-58-174387.
No. 58-198490, No. 59-219292, etc. In particular, JP-A-59-219292 discloses a compound similar to the compound of the present invention [Example 14: 7-[(Z) -2- (2
-Aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(2-methyl-2-benzo [c] pyrrolinio) methyl] -3-cephem-4-carboxylate] and the like, that is, of the cephem nucleus. A compound in which a mono-substituted or unsubstituted isoindoliniomethyl group is introduced as a 3-side chain is disclosed. However, no compound having two or more substituents on the isoindoline nucleus is shown. Currently Cefotaxim [Anti-Microbial Agent and Chemotherapy 14
Vol. 749, (1987)], etc., the third-generation cephalosporin derivatives show excellent antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, especially intestinal bacterial groups, but are potent against Pseudomonas, Acinetobacter, etc. It rarely exhibits a strong antibacterial effect. Therefore, a more potent and effective therapeutic agent is desired for the treatment of serious infectious diseases caused by these bacteria or a mixed infection of these bacteria and other bacteria. Ceftazidime [Antimicrobial Agent and Chemotherapy, 17: 876, (1980
Year)] against Pseudomonas and Acinetobacter,
It is the best compound among existing cephalosporin compounds, but it is not always satisfactory because various resistant bacteria exist.

Means for Solving the Problems The present inventors have studied a novel cephem compound having a 2-methyl-2-isoindoliniomethyl group as the 3-side chain of the cephem nucleus, and as a result, adjoined the isoindoline nucleus, A compound having a dihydroxy group or a diacetoxy group has a gram-negative bacterium, particularly Pseudomonas aeruginosa, Pseudomonas cepacia, and other glucose non-compounds, as compared with a known cephalosporin derivative in which the isoindoline nucleus is unsubstituted or mono-substituted. The inventors have found that the antibacterial activity is extremely strong against fermentative Gram-negative bacilli and completed the present invention.

The present invention has the general formula (In the formula, R ¹ is a linear or branched lower alkyl group which may be substituted with a carboxyl group, R ² is a hydrogen atom, a hydroxy group or an acetoxy group, and R ³ and R ⁴ are the same, And a salt thereof or a physiologically hydrolyzable ester thereof, a process for producing the same and a use thereof.

The compound [I] of the present invention shows an excellent antibacterial action, and also shows an excellent antibacterial action against Pseudomonas and Acinetobacter which are resistant to ceftazidime.

The compound of the present invention has a 2- (2-aminothiazol-4-yl) -2- (substituted oxyimino) acetamide group as a side chain at the 7-position, and 2-methyl-5,6-disubstituted- at the 3-position.
The compound having a 2-isoindoliniomethyl group is particularly excellent in antibacterial action.

Generally, the substitution on the oximino group can take the geometrical isomeric structure of E or Z, but the substitution on the oximino group contained in the acylamino moiety at the 7-position of the compound of the general formula [I] is Z.
It has the structure of.

Next, various terms and symbols referred to in this specification will be described.

The lower alkyl group refers to an alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group,
Examples include isopropyl group and n-butyl group.

Examples of the amino protecting group include trityl group, formyl group, chloroacetyl group, trifluoroacetyl group, t-
Examples thereof include a butoxycarbonyl group, a trimethylsilyl group, a t-butyldimethylsilyl group and the like, and a trityl group which can be easily removed by an acid treatment is particularly preferable.

Examples of the carboxyl protecting group include the following groups. Lower alkyl group such as t-butyl group; haloalkyl group such as 2,2,2-trichloroethyl group; alkanoyloxyalkyl group such as acetoxymethyl group, propionyloxymethyl group, pivaloyloxymethyl group, 2-
Acetoxyethyl group, 1-propionyloxyethyl group; 1- (ethoxycarbonyloxy) ethyl group; phthalidyl group; alkanesulfonylalkyl group such as methanesulfonylmethyl group, 1-methanesulfonylethyl group;
Aralkyl groups such as benzyl group, 4-methoxybenzyl group, 4-nitrobenzyl group, phenethyl group, trityl group, benzhydryl group, bis (4-methoxyphenyl)
Methyl group, 3,4-dimethoxybenzyl group; (5-substituted-
2-oxo-1,3-dioxol-4-yl) methyl group such as (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group; alkylsilyl group such as trimethylsilyl group, t-butyldimethyl Examples thereof include a silyl group, and a benzhydryl group and a t-butyl group, which can be easily removed by an acid treatment, are particularly preferable.

Examples of the protective group for the hydroxy 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, acetonide, trimethylsilyl group, t-butyldimethylsilyl group and the like.

Examples of the halogen atom for X include chlorine, bromine, iodine and the like. Examples of the leaving group include an acetoxy group,
Examples thereof include a trifluoroacetoxy group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a phenylsulfonyloxy group and a p-toluenesulfonyloxy group. X is particularly preferably a bromine atom or an iodine atom.

X Examples of the anions include chlorine ion and bromine ion.
And halogen ions such as iodine ion, sulfate ion, and sulfur ion
Acid hydrogen ion, methyl sulfate ion, p-toluenesulfo
Nitrate ion, methanesulfonate ion, trifluoroacetic acid
Anion such as acid ion may be used.

R ² , R ³ and R ^{4 of the} general formula [I] and the general formula [II
I], general formula [IV], general formula [V] and general formula [VII]
The substitution positions of R ⁸ , R ⁹ and R ¹⁰ are not particularly limited as long as they are on the condensed benzene ring of the isoindoline skeleton,
A compound having a dihydroxy group or a diacetoxy group adjacent to the 5th and 6th positions of the isoindoline skeleton is particularly preferable.

The compound of the general formula [I] can be produced by any of the following Method A and Method B.

Method A general formula(In the formula, R⁵Is a hydrogen atom or an amino protecting group, R⁶Is hydrogen
Atom or carboxyl protecting group, R⁷Is protected carbo
Linear or branched, optionally substituted by a xyl group
-Like lower alkyl group, X is a halogen atom or a leaving group, Y
Represents S or SO) or a salt thereof
And the general formula(In the formula, R⁸Is a hydrogen atom, optionally protected hydro
Xy group or acetoxy group, R⁹And R^TenAre the same,
An optionally protected hydride bound to an adjacent carbon atom.
Roxy group or acetoxy group, R¹¹Is a hydrogen atom or methyl
(Representing a group) is reacted with an amine represented by the general formula(In the formula, R⁵, R⁶, R⁷, R⁸, R⁹, R^Ten, R¹¹Over
And Y have the meanings given above and X Is an anion)
Compound and, if necessary, methylation and / or
Is reduced and then the protecting group is removed.

When the compound of the general formula [I] is produced by the method A, the compound of the general formula [II] is first prepared in a solvent.
I] or a salt thereof. When a hydrochloride, hydrobromide, sulfate or acetate is used as the salt of the compound of the general formula [III], the reaction is carried out in the presence of a neutralizing amount of a tertiary amine such as triethylamine. Examples of the solvent include methylene chloride, chloroform, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran,
A non-aqueous organic solvent such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, or a mixture thereof is used. In the solvent, the compound of the general formula [III] is
It can also be used after being silylated with a silylating agent such as N, O-bis (trimethylsilyl) acetamide. The amount of the compound of the general formula [III] used is the amount of the compound 1 of the general formula [II].
It is 1 to 2 mol with respect to mol. Reaction temperature is 0 ~ 35 ℃
Then, the reaction is completed in 0.5 to 5 hours.

Further, after reacting the compound of the general formula [III] in which the substituent R ¹¹ is a hydrogen atom with the compound of the general formula [II], the product is isolated or is isolated without isolation, for example, methylation with methyl iodide. An ammonio compound [IV] in which R ¹¹ is a methyl group can be obtained by the reaction.

When this methylation reaction is carried out in the above non-aqueous organic solvent,
The amount of methyl iodide used is 1 to 30 mol, preferably 3 to 15 mol, per 1 mol of the product, and the reaction temperature is -30 to + 35 ° C.
The reaction is completed in 5 to 48 hours. Further, an ammonio compound [IV] in which R ⁹ is a methyl group can also be obtained by reacting the product with excess methyl iodide at 10 to 35 ° C. for 5 to 20 hours in the absence of a solvent.

When the compound of the general formula [II] in which the group Y is SO is used, the compound of the general formula [IV] is prepared by a known method, for example, Journal of Organic Chemistry, Vol.
430, (1970), Synthesis, 58, (19
1979) or Journal Chemical Research)
(S), page 341, (1979) and the like. For example, the compound of the general formula [IV] in which the group Y is SO is dissolved in an inert organic solvent such as acetone, methylene chloride, chloroform, tetrahydrofuran, ethyl acetate and the like, potassium iodide or sodium iodide is added, and -4
Acetyl chloride was added dropwise at 0 to 0 ° C, and 1 at -20 to -10 ° C.
It can be reduced by reacting for ~ 2 hours. The amount of iodide used is 3.5 to 10 with respect to 1 mol of the compound of the general formula [IV].
The amount of mol and acetyl chloride used is 1.5 to 5 mol. The compound thus obtained is a carboxyl protecting group,
When it has an amino-protecting group or a hydroxy-protecting group, removal of the protecting group gives a compound of the general formula [I].

As a method for removing the protecting group, a commonly used method can be appropriately selected according to the type of the protecting group. Removal of the protecting group
For example, a method using an acid is preferable, and examples of the acid include inorganic or organic acids such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and hydrochloric acid, and trifluoroacetic acid is particularly preferable. When trifluoroacetic acid is used as the acid, the reaction is promoted by adding anisole. Further, this reaction is preferably carried out in an inert solvent, for example, an organic solvent such as methylene chloride, ethylene chloride, benzene or the like, or a mixed solvent thereof, particularly methylene chloride. The reaction temperature is not particularly limited, and may be appropriately selected according to the chemical properties of the raw material compound and the reaction product, the type of protective group, the type of removal method, or the like, or the reaction is performed under mild conditions such as cooling or heating. Is preferred.

The compound of the general formula [III] is described in Journal of American Chemical Society, Volume 72, page 2889,
(1950) and Organic Synthesis Volume 5, 4
It can be synthesized according to the method described on pages 06 and 1064.

The compound of the general formula [II] in which the group Y is S has the general formula (Wherein, R ⁶ and X have the above-mentioned meanings, and Z represents a hydrogen atom or an acyl group), and a compound represented by the general formula [V
It is obtained by acylation using the carboxylic acid of [I] or its reactive derivative. The compound of the general formula [II] in which the group Y is SO is the compound of the general formula [II] in which the group Y is S in an organic solvent such as methylene chloride, ethylene chloride or chloroform which does not participate in the reaction under ice cooling. It is obtained by oxidation with equimolar m-chloroperbenzoic acid. The compound of the general formula [II] in which the substituent X is an iodine atom can be produced by reacting the compound of the general formula [II] in which X is a chlorine atom with sodium iodide.

The compound of the general formula [V] is the compound of the general formula [VIII] in which Z is an acyl group, and the compound of the general formula [II] in which R ¹¹ is a methyl group.
It is obtained by reacting with the compound of [I] and then deacylating.

The compound of the general formula [VIII] has the general formula Compounds represented by the formula (wherein R ⁶ and Z have the above-mentioned meanings) can be prepared by, for example, JP-A Nos. 50-76089 and 56-86187.
It can be easily produced by treating it according to the method described in the publication.

Method B general formula(In the formula, R⁶, R⁸, R⁹, R^TenAnd X Means the above
Represented by the formula), a salt thereof or a silyl thereof.
The compound is represented by the general formula(In the formula, R⁵And R⁷Has the above meaning)
Acylated with carboxylic acid or its reactive derivative
General formula(In the formula, R⁵, R⁶, R⁷, R⁸, R⁹, R^TenAnd X
Has the above-mentioned meaning).
And remove the protecting group as needed.

When the compound of the general formula [I] is produced by the method B, the compound of the general formula [V] is first added to the compound of the general formula [VI] in a solvent.
The carboxylic acid or the reactive derivative thereof is reacted, but it is particularly preferable to use the reactive derivative. The reaction is carried out in an inert solvent such as water, acetone, dioxane, acetonitrile, tetrahydrofuran, methylene chloride, chloroform, benzene, ethyl acetate, N, N-dithymerformamide, etc. or a mixture thereof. General formula [VI]
The amount of the reactive derivative of the compound (1) to be used is 1 to 1.5 mol with respect to 1 mol of the compound of the general formula [V]. Reaction temperature is -40
It is + 40 ° C, preferably -20 to + 30 ° C. General formula [VI]
When the acid chloride of the compound is used, it is preferable to react in the presence of an alkali metal carbonate or an organic amine such as trimethylamine, triethylamine and N-methylmorpholine.

Examples of the reactive derivative of the compound of the general formula [VI] include acid halides, mixed acid anhydrides, active esters and the like. The acid halide of the compound of general formula [VI] is obtained by reacting the compound of general formula [VI] with a halogenating agent. The reaction is carried out in an inert solvent such as methylene chloride, chloroform, dichloroethane, benzene, toluene and the like or a mixture thereof. Examples of the halogenating agent include thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, oxalyl chloride, phosgene and the like. The amount of halogenating agent used is represented by the general formula [V
1 to 10 mol, preferably 1 to 1 mol of the compound [I]
~ 1.5 mol, the reaction temperature is -40 ~ +100 ℃, preferably -20 ~ +
20 ° C.

The mixed acid anhydride of the compound of the general formula [VI] has the general formula [VI]
It can be obtained by reacting the compound (1) with an alkyl chlorocarbonate, an aliphatic carboxylic acid chloride or the like. The reaction is carried out in an inert solvent such as acetone, dioxane, acetonitrile, tetrahydrofuran, methylene chloride, chloroform, benzene, ethyl acetate, N, N-dimethylformamide, etc. or a mixture thereof. The reaction is preferably carried out in the presence of a tertiary amine such as triethylamine or N-methylmorpholine, and the reaction temperature is -30 to +20.
C., preferably -15 to 0.degree.

The active ester of the compound of general formula [VI] has the general formula [VI]
It is obtainable by reacting the compound of 1) with preferably 1 to 1.2 mol of N-hydroxy compound or phenol compound. The reaction is carried out in an inert solvent such as acetone, dioxane, acetonitrile, tetrahydrofuran, methylene chloride, chloroform, ethyl acetate, N, N-dimethylformamide and the like or a mixture thereof. Examples of the N-hydroxy compound include N-hydroxysuccinimide, N-hydroxyphthalimide and 1-hydroxybenzotriazole, and examples of the phenol compound include 4-nitrophenol, 2,4-dinitrophenol,
2,4,5-Trichlorophenol, pentachlorophenol and the like are used. The reaction is preferably carried out in the presence of 1-1.2 mol of a condensing agent such as N, N'-dicyclohexylcarbodiimide. The reaction temperature is -30 to + 40 ° C, preferably -10 to + 25 ° C, and the reaction time is 30 to 120 minutes.

After completion of the reaction, the product [VII] is separated, and if necessary, the protecting group is removed in the same manner as in the method A to obtain the compound of the general formula [I].

The compound of general formula [I] can be converted into a salt or a physiologically hydrolyzable ester by a conventional method.

The salt of the compound of the general formula [I] is a pharmaceutically acceptable conventional salt, for example, a salt with an alkali metal such as sodium and potassium; a salt with an alkaline earth metal such as calcium and magnesium; N, N ′. -Dibenzylethylenediamine,
Salts with organic amines such as procaine; hydrochloric acid, sulfuric acid, nitric acid,
Salts with inorganic acids such as perchloric acid and hydrobromic acid; salts with organic acids such as acetic acid, lactic acid, propionic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid; methanesulfonic acid, isethionic acid , Salts with organic sulfonic acids such as p-toluenesulfonic acid; salts with amino acids such as aspartic acid and glutamic acid. Examples of the physiologically hydrolyzable ester of the general formula [I] include alkanoyloxyalkyl esters such as acetoxymethyl ester and pivaloyloxymethyl, and alkoxycarbonyloxyalkyl esters such as 1- (ethoxycarbonyloxy) ethyl. (5-substituted-2-oxo-1,3-dioxole-4 such as phthalidyl ester, (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl, etc.
-Yl) methyl esters and the like are preferable.

The minimum inhibitory concentration (MIC: μ / m) of the compound of the present invention against various bacteria is cefotaxime, ceftazidime and Reference Example 3 (the compound of Example 14 of JP-A-59-219292) and Reference Example 1-F, 2-D was used as a comparative compound and measured by the agar plate dilution method using Sensitivity Disc Agall (Nissui) (bacteria number: 10 ⁶ CFU / m
). The results are shown in the table below.

As is clear from this result, among the compounds of the general formula [I], the compounds having two substituents in the isoindoline nucleus are gram-negative bacteria, particularly glucose-nonfermenting gram-negative bacilli, such as Pseudomonas aeruginosa and Pseudomonas.・ Exhibits excellent antibacterial activity against Sepacia, Pseudomonas maltophilia, Acinetobacter calcoaceticus, etc. In particular, these compounds are excellent in that they also exhibit strong antibacterial activity against Pseudomonas aeruginosa AKR17 resistant to known cephalosporin derivatives and Pseudomonas maltophilia II D1275 resistant to ceftazidime.

Introducing a hydroxy group or an acetoxy group at the 5- and 6-positions of the isoindoline nucleus dramatically increases the antibacterial activity against Gram-negative bacteria in general, and Pseudomonas and Acinetobacter, for example, against Pseudomonas aeruginosa AK109. The compounds of Examples 1D, 2D, 3D and 5E, which are derivatives or 5,6-dihydroxy derivatives, are compared with compounds having no substituents on the isoindoline nucleus or mono-substituted compounds (Reference Examples 1 to 3), respectively. 16
It showed antibacterial activity of 2-fold, 32-fold, 32-fold and 64-fold or more. The compounds of Examples 1D, 2D, 3D and 5E are 32 times, 32 times, 64 times and 500 times or more of Reference Examples 1 to 3 against Pseudomonas aeruginosa AKR17 which is resistant to all cephalosporins including ceftazidime. Showed antibacterial activity. Example 1 for Pseudomonas cepacia 23
The compounds of D, 2D, 3D and 5E are 16 times to 32 times, 31 to 64 times, 63 to 125 times the compounds of Reference Examples 1 to 3, respectively.
The antibacterial activity was doubled and 125 to 250 times or more higher. Examples 1D, 2 for Acinetobacter calcoaceticus
The compounds D, 3D and 5E exhibited 125 times, 125 times, 125 times and 250 times the antibacterial activity of the compounds of Reference Examples 1 to 3, respectively. The compound of Example 5E exhibited antibacterial activity of 8 times or more against Pseudomonas maltophilia resistant to ceftazidime.

The results of the mouse infection treatment experiment of the compound of the present invention are shown below as ED ₅₀ (mg / kg) in comparison with ceftazidime.

The compound of Example 2D was tested against experimental infections in mice by S. aureus Smith, E. coli Juhl and P. aeruginosa D15.
The therapeutic effect was about twice as high as that of ceftazidime.

The compounds of the present invention showed strong antibacterial activity against sensitive and resistant Gram-positive and Gram-negative bacteria, particularly resistant Pseudomonas aeruginosa, Pseudomonas cepacia, Acinetobacter calcoaceticus and the like.

Here, using the compound of Example 5 as a representative compound, "GLP
4 weeks IC according to “Standards and Toxicity Test Law Guideline” (supervised by the Ministry of Health and Welfare Pharmaceutical Affairs Bureau Examination Division; Pharmaceutical Affairs Daily)
R Female mice (n = 5) were treated as a group, and the concentration of the drug solution was 100 m with distilled water for injection containing a neutralizing amount of sodium hydrogen carbonate.
It was diluted to g / ml and a single tail vein administration was performed at a dose rate of 1 ml / min. As a result, 2 g / kg of the compound of Example 5 was administered to the mouse, but no death of the mouse for 3 days including the administration day was observed.

Therefore, the compound of the present invention is a compound of the general formula [I]:
An antibacterial agent containing a salt thereof or a physiologically hydrolyzable ester thereof as an active ingredient.

The compound of the present invention can be used in the form of a pharmaceutical preparation suitable for oral administration, parenteral administration or external administration, by mixing with a carrier of a solid or liquid excipient. Examples of the pharmaceutical preparation include injections, syrups, liquids such as emulsions, solid preparations such as tablets, capsules and granules, and external preparations such as ointments and suppositories.

The above-mentioned preparations may contain commonly used additives such as auxiliaries, stabilizers, wetting agents and emulsifiers. For example, the injection may contain additives such as distilled water for injection, physiological saline, a solution such as Ringer's solution, a preservative such as methyl paraoxybenzoate and propyl paraoxybenzoate. Liquids such as syrups and emulsions include sorbitol syrup, methyl cellulose, glucose, sucrose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, edible oil, tonsil oil, coconut oil, oily ester, sorbitan monooleate, In addition to propylene glycol, glycerin, ethyl alcohol, water and the like, emulsifiers such as gum arabic, gelatin and lecithin, and surfactants such as tween and span may be contained. As the solid agent, lactose, sucrose, corn starch, calcium phosphate, magnesium stearate, talc, silicic acid, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, polyethylene glycol, sodium lauryl sulfate and the like are used. As bases for ointments and suppositories, for example, cocoa butter, glycerides, polyethylene glycols, white vaseline and the like are used. You may contain a surfactant and an absorption promoter as needed.

The compound [I] of the present invention can be used for the treatment and prevention of bacterial infections such as respiratory infections, urinary tract infections, obstetrics and gynecologic infections, purulent diseases, and surgical infections. The dose varies depending on the age and condition of the patient, but it is usually used in the range of 1 to 100 mg / kg per day, and 5 to 30 mg / k per day.
It is preferable to administer in 2 to 4 divided doses in g.

Next, the present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited thereto.

Example 1 (A) Benzhydryl 3-[(5,6-diacetoxyisoindoline-2-yl) methyl] -7-[(Z) -2-methoxyimino-2- (2-tritylaminothiazole-4)
-Yl) acetamido] -3-cephem-4-carboxylate 1-oxide 2.1 g (2.2 mmo) of the powder obtained in Reference Example 1 (B) was dissolved in 40 m of methylene chloride to give 5,6-diacetoxyisoindoline. 1.3 g (4.1 mmo) of hydrobromide and 0.6 m (4.3 mmo) of triethylamine were added and the solution was stirred at room temperature for 1 hour. After distilling off methylene chloride, the residue was subjected to flash silica gel column chromatography (1
% Methanol / methylene chloride) to give the title compound 1.89
g (80% yield) of powder was obtained.

NMR (CDC ₃ ) δ: 2.30 (6H, s), 3.65 to 4.2 (8H,
m), 4.05 (3H, s), 4.56 (1H, d, J = 4Hz), 6.15 (1H, dd, J = 4 and 10Hz), 6.70 (1H, s), 6.90 (1H, s), 7.0〜 7.8 (27H, m) (B) Benzhydryl 3-[(5,6-diacetoxy-2-
Methyl-2-isoindolinio) methyl] -7-[(Z)
2-Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4
-Carboxylate 1.8 g (1.71 mmo) of powder obtained from 1-oxide iodide (A) was dissolved in 20 m (321 mmo) of methyl iodide (alumina treated), and this solution was left for 12 hours at room temperature in the dark. did. The reaction mixture was subjected to flash silica gel column chromatography (5% methanol / methylene chloride), 1.21 g of the title compound powder.
(Yield 59%) was obtained.

NMR (DMSO-d ₆ ) δ: 2.35 (6H, s), 3.10 (3H, br
s), 3.35 (2H, br s), 3.90 (3H, s), 4.6 ~ 5.2 (6H, m), 5.16 (1
H, d, J = 4Hz), 6.0 (1H, m), 6.85 (1H, s), 7.08 (1H, s), 7.1〜
7.8 (27H, m), 8.75 (1H, br s), 9.12 (1H, br s) (C) Benzhydryl 3-[(5,6-diacetoxy-2-
Methyl-2-isoindolinio) methyl] -7-[(Z)
2-Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4
-1.2 g (1.0 mmo) of powder obtained from carboxylate iodide (B) was added to 12 m of acetone.
Dissolved in water, 0.67 g (4.0 mmo) of potassium iodide was added, and then acetyl chloride 0.14 m (1.97 m
mo) was added dropwise. After 30 minutes, add more potassium iodide.
67 g (4.0 mmo) and acetyl chloride 0.14 m
(1.97mmo) was added. After stirring for 30 minutes, the reaction solution was poured into 1% sodium metabisulfite / saturated saline and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off to give 1.0 g of the title compound (yield 89
%) Was obtained.

NMR (DMSO-d ₆ ) δ: 2.40 (6H, s), 3.05 (5H, br
s), 3.90 (3H, s), 4.5〜5.2 (6H, m), 5.40 (1H, d, J = 4Hz), 5.9
(1H, m), 6.82 (1H, s), 7.10 (1H, s), 7.0〜8.0 (27H, m), 8.9 (1
H, m), 9.65 (1H, br d) (D) 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(5,
6-diacetoxy-2-methyl-2-isoindolinio) methyl] -3-cephem-4-carboxylate 1.0 g (0.84 mmo) of the powder obtained from (C) was added to methylene chloride 2
m and anisole 2 m, and at 0 ° C. trifluoroacetic acid 5 m was added. After stirring for 1 hour, the reaction solution was concentrated under reduced pressure, 20 m of methylene chloride was added, and this solution was extracted 4 times with water. The aqueous layer was purified by reverse phase column chromatography (Waters Pre Pack 500 / C-18,80m; 2-5% tetrahydrofuran / water), and the fractions containing the target compound were collected, concentrated under reduced pressure, freeze-dried, and Target compound 134 mg
(Yield (24.5%) was obtained.

Melting point: 161 ° C. (decomposition) IR (KBr): 3400,1760,1605 cm ⁻¹ NMR (CF ₃ COOH) δ: 2.00 (6H, s), 3.07 (3H, br
s), 3.30 (2H, br s), 3.77 (3H, s), 4.2〜4.8 (6H, m), 4.90 (1
H, d, J = 5Hz), 5.5 (1H, dd, J = 5 and 7Hz), 6.87 (2H, s), 6.90
(1H, s), 7.0 to 7.6 (2H, m), 8.08 (1H, d, J = 7Hz) Example 2 (A) Benzhydryl 3-[(5,6-dihydroxyisoindoline-2-yl) methyl] -7-[(Z) -2-Methoxyimino-2- (2-tritylaminothiazole-4)
-Yl) acetamido] -3-cephem-4-carboxylate 1-oxide 3.0 g (3.16 mmo) of the powder obtained in Reference Example 1 (B) was added to N, N
-Dissolved in 15m of dimethylformamide, 1.2g of 5,6-dihydroxyisoindoline hydrobromide (5.17mm
o) and triethylamine 0.8m (5.73mmo)
Was added. After stirring at room temperature for 90 minutes, the reaction solution was concentrated under reduced pressure, and the residue was flash silica gel column chromatography (ethyl acetate / n-hexane = 3: 1 → 1: 0).
Then, 2.35 g of the title compound (yield: 76%) was obtained as a powder.

NMR (CDC ₃ ) δ: 3.4 to 3.9 (8H, m), 4.05 (3H, s),
4.68 (1H, d, J = 5Hz), 6.12 (1H, m), 6.63 (2H, s), 6.75 (1H,
s), 6.98 (1H, s), 7.1-7.9 (27H, m) (B) Benzhydryl 3-[(5,6-dihydroxy-2-
Methyl-2-isoindolinio) methyl] -7-[(Z)
2-Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -3-cephem-4
-Carboxylate 2.3 g (2.37 mmo) of the compound obtained from 1-oxide iodide (A) was dissolved in 20 m (321 mmo) of methyl iodide (alumina treated), and this solution was left for 12 hours at room temperature in the dark. did. The reaction solution was subjected to flash silica gel column chromatography (10% methanol / methylene chloride) to obtain 1.29 g (yield 49%) of the title compound.

NMR (DMSO-d ₆ ) δ: 2.94 (3H, br s), 3.48 (2H,
br s), 3.90 (3H, s), 4.2〜5.3 (6H, m), 5.30 (1H, d, J = 5Hz),
6.05 (1H, dd, J = 5 and 8Hz), 6.83 (1H, s), 6.90 (1H, s), 7.08
(1H, s), 6.9 to 7.9 (27H, m), 9.2 (1H, br d, J = 8Hz), 9.40 (1
H, br s) (C) Benzhydryl 3-[(5,6-dihydroxy-2-
Methyl-2-isoindolinio) methyl] -7-[(Z)
2-Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4
-Carboxylate iodide (B) powder 1.29g (1.16mmo) in acetone 13m
Dissolve in, add 0.7 g (4.2 mmo) of potassium iodide, and then add acetyl chloride 0.15 m (2.11 m) at -10 ° C.
mo) was added dropwise. After stirring for 40 minutes, the reaction solution is 2%
It was poured into sodium metabisulfite / saturated saline and extracted with ethyl acetate. The organic layer was dehydrated with anhydrous sodium sulfate,
The solvent was distilled off. The residue is again subjected to the same reaction and workup to give 1.8 g of the title compound, which is used in the next step without purification.

NMR (DMSO-d ₆ ) δ: 2.88 (3H, br s), 2.9 (2H, b
rs), 3.88 (3H, s), 4.3 to 5.1 (6H, m), 5.40 (1H, d, J = 5Hz),
5.90 (1H, dd, J = 5 and 8Hz), 6.81 (3H, s), 7.03 (1H, s), 7.0
~ 7.8 (27H, m), 9.00 (1H, br s), 9.68 (1H, d, J = 8Hz) (D) 7-[(Z) -2- (2-aminothiazol-4-yl) -2 -Methoxyiminoacetamide] -3-[(5,
6-dihydroxy-2-methyl-2-isoindolinio) methyl] -3-cephem-4-carboxylate (C) The crude compound obtained in (C) was dissolved in 2 m of methylene chloride and 2 m of anisole, and 5 m of trifluoroacetic acid was added at 0 ° C. added. After stirring for 1 hour, the reaction solution was concentrated under reduced pressure, methylene chloride was added to the residue, and this solution was extracted 5 times with water.
Reversed phase column chromatography (Waters Pre Pack)
(500 / C-18; 0.5% tetrahydrofuran / water), the fractions containing the target compound are collected, concentrated under reduced pressure and freeze-dried to obtain 261 mg of the target compound (40% yield from the previous step). It was

Melting point: 152 ° C. (decomposition) IR (KBr): 3400, 1775, 1670, 1615 cm ⁻¹ NMR (CF ₃ COOH) δ: 2.98 (3H, br s), 3.27 (2H,
br s), 3.80 (3H, s), 4.2〜4.8 (6H, m), 4.90 (1H, d, J = 5Hz),
5.45 (1H, dd, J = 5 and 8Hz), 6.50 (2H, s), 6.92 (1H, s), 7.0
~ 7.7 (2H, m), 8.05 (1H, d, J = 8Hz) Example 3 (A) Benzhydryl 3-[(5,6-dihydroxyisoindoline-2-yl) methyl] -7-[(Z) -2-Ethoxyimino-2- (2-tritylaminothiazole-4
-Yl) acetamido] -3-cephem-4-carboxylate 1-oxide benzhydryl 3-chloromethyl-7-[(Z) -2-
Ethoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 1-oxide 3 g (3.45) mmo) was dissolved in acetone 60 m and sodium iodide 1.14 g (7 .
6 mmo) was added. After stirring for 15 minutes at room temperature, the reaction solution was added to a 10% sodium thiosulfate aqueous solution, and this solution was extracted with ethyl acetate. After the organic layer was dehydrated with anhydrous sodium sulfate, the solvent was distilled off. The concentrated residue was dissolved in 15 m of N, N-dimethylformamide, and 1.2 g of 5.6-dihydroxyisoindoline hydrobromide (5.17 mmo
) And triethylamine 0.7 m (5.0 mmo) were added and the solution was stirred at room temperature for 3 hours. N, N− under reduced pressure
Dimethylformamide was distilled off, and the residue was subjected to flash silica gel column chromatography (ethyl acetate / n-hexane = 1: 3 → 1.0) to obtain 2.33 g (yield 69%) of the title compound.

NMR (DMSO-d ₆ ) δ: 1.25 (3H, t, J = 6Hz), 3.3
~ 3.9 (8H, m), 4.03 (2H, q, J = 6Hz), 5.09 (1H, d, J = 4Hz), 5.
92 (1H, dd, J = 4 and 8Hz), 6.60 (1H, m), 6.85 (1H, s), 7.01 (2
H, s), 7.0 to 7.8 (25H, m), 8.7 (1H, br d, J = 8Hz), 8.76 (1H, b
rs) (B) Benzhydryl 3-[(5,6-dihydroxy-2-
Methyl-2-isoindolinio) methyl] -7-[(Z)
2-Ethoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4
-Carboxylate 1-Oxide-iodide (A) Compound 2.39g (2.48mmo) dissolved in methyl iodide (alumina treated) 20m (321mmo),
It was left for 12 hours at room temperature in the dark. The reaction solution was subjected to flash silica gel column chromatography (5% methanol / methylene chloride) to obtain 2.06 g (yield 75%) of the title compound.

NMR (DMSO-d ₆ ) δ: 1.25 (3H, t, J = 6Hz), 2.90
(3H, br s), 3.30 (2H, br s), 4.13 (2H, q, J = 6Hz), 4.1 ~ 5.0
(6H, m), 5.20 (1H, d, J = 5Hz), 6.00 (1H, m), 6.75 (2H, br s),
6.81 (1H, s), 7.01 (1H, s), 7.0〜7.6 (25H, m), 8.75 (1H, br
s), 9.00 (1H, br d, J = 8Hz), 9.3 (1H, br s) (C) Benzhydryl 3-[(5,6-dihydroxy-2-
Methyl-2-isoindolinio) methyl] -7-[(Z)
2-Ethoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4
-2.06 g (2.1 mmo) of the compound obtained from carboxylate iodide (B) was added to 20 m of acetone.
, 1.21 g (7.28 mmo) of potassium iodide was added, and acetyl chloride 0.26 m (3.65 mmo) at -10 ° C.
) Was added dropwise. After stirring for 40 minutes, the reaction solution was poured into 2% sodium metabisulfite / saturated saline, and this solution was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was again subjected to the same reaction and post-treatment to give 2.6 g of the title compound, which was used in the next step without purification.

NMR (DMSO-d ₆ ) δ: 1.25 (3H, t, J = 6Hz), 2.9
(2H, m), 3.00 (3H, s), 4.15 (2H, q, J = 6Hz), 4.3 ~ 5.0 (6H,
m), 5.40 (1H, d, J = 5Hz), 5.92 (1H, m), 6.78 (2H, br s), 6.90
(1H, br s), 7.01 (1H, br s), 7.1〜7.8 (25H, m), 9.0 (1H, m),
9.6 (1H, m) (D) 7-[(Z) -2- (2-aminothiazol-4-yl) -2-ethoxyiminoacetamide] -3-[(5,
6-Dihydroxy-2-methyl-2-isoindolinio) methyl] -3-cephem-4-carboxylate (C) 2.6 g of the crude compound obtained was dissolved in 4 m of methylene chloride and 4 m of anisole, and trifluoroacetic acid was added at 0 ° C. 10m
Was added. After stirring for 1 hour, the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and this solution was extracted 5 times with water. Reversed phase column chromatography (Waters Pre
Pack 500 / C-18,200m; Tetrahydrofuran / water 0: 1 → 5: 95), collect the fractions containing the target compound, concentrate under reduced pressure, freeze-dry, and obtain 460 mg of the target compound (from the previous step). Yield of 43%) was obtained.

Melting point: 148 ° C (decomposition) IR (KBr): 3400, 1770, 1610, 1340 cm ^-1 NMR (CF ₃ COOH) δ: 1.03 (3H, t, J = 7Hz), 3.06
(3H, br s), 3.36 (2H, br s), 4.14 (2H, q, J = 7Hz), 4.2 to 4.9
(6H, m), 5.00 (1H, d, J = 5Hz), 5.52 (1H, dd, J = 5 and 8Hz),
6.59 (2H, s), 6.99 (1H, s), 8.18 (1H, br d, J = 8Hz) Example 4 (A) Benzhydryl 3-[(5,6-dihydroxy-2-
Methyl-2-isoindolinio) methyl] -7-[(Z)
2-Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4
-Carboxylate 1-oxide iodide 5,6-dihydroxy-2-methylisoindoline 460 mg
N, O-bis (trimethylsilyl) acetamide 1.6m (6.6mm)
o) was added. After stirring and dissolving at 50 ° C. for 1 hour, this solution was cooled to room temperature and benzhydryl 3-iodomethyl-7-[(Z) -2-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -3
-Cephem-4-carboxylate 1-oxide 2.84
g (3 mmo) in a solution of 20 m ethyl acetate was added at once. After stirring at room temperature for 4 hours, chloroform 150m
And 30 m of water were added, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was separated and purified by flash silica gel column chromatography (3-5% methanol / methylene chloride) to give 1.78 g of the title compound as a powder.
(Yield 53.3%) was obtained.

(B) Benzhydryl 3-[(5,6-dihydroxy-2-
Methyl-2-isoindolinio) methyl] -7-[(Z)
2-Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4
-To 1.78 g (1.6 mmo) of the compound obtained from carboxylate iodide (A) and 1.33 g (8 mmo) of potassium iodide, 35 m of acetone was added, and then acetyl chloride 0.28 m (4 mmo) at -20 ° C.
Was dripped. After stirring at -20 to -10 ° C for 2 hours, 1.33 g of potassium iodide and 0.28 m of acetyl chloride were added, and this solution was further stirred at the same temperature for 2 hours. The reaction solution was cooled to 10%.
Aqueous sodium metabisulfite solution-saturated saline solution (1: 1)
100 m and 100 m of methylene chloride were added for liquid separation, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a powder.

(C) 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(5,
6-Dihydroxy-2-methyl-2-isoindolinio) methyl] -3-cephem-4-carboxylate The compound obtained in (B) was dissolved in 18 m of methylene chloride, and 1.8 m of anisole was added. After cooling the solution, 18m of cold trifluoroacetic acid was added. Reaction solution at the same temperature 5
After stirring for an hour, the solvent was distilled off under reduced pressure. 20 m of ethyl acetate was added to the residue, and the mixture was concentrated under reduced pressure. After repeating this operation twice, 40 m of diethyl ether was added and the insoluble material was collected by filtration. The insoluble matter was suspended and stirred in 200 m of water, the insoluble matter was collected by filtration, and the aqueous layer was subjected to reverse phase column chromatography (Wa
Separation and purification with ters Pre Pack 500 / C-18; 100m (water 300)
m and a 1% tetrahydrofuran aqueous solution 1). The fraction wrapping the desired product was concentrated under reduced pressure and freeze-dried to obtain 330 mg of the target compound.

The IR and NMR of this product were consistent with those of the compound obtained in Example 2 (D).

Example 5 (A) Benzhydryl 7-[(Z) -2- (1-t-butoxycarbonyl-1-methylethoxyimino) -2- (2
-Tritylaminothiazol-4-yl) acetamido] -3-chloromethyl-3-cephem-4-carboxylate 1-oxide benzhydryl 7-[(Z) -2- (1-t-butoxycarbonyl-1-methylethoxy) Imino) -2- (2-
Tritylaminothiazol-4-yl) acetamide]
10 g (10.3 mmo) of 3-chloromethyl-3-cephem-4-carboxylate was dissolved in 200 m of methylene chloride, and 80% m-chloroperbenzoic acid 1.78 g (1
0.3 mmo) was added over 10 minutes and the reaction solution was stirred for 20 minutes. 40 m of a 10% sodium thiosulfate aqueous solution was added to the reaction solution, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a powder.

IR (KBr): 1795,1720,1680,1500,1365,1300,125
0,1170,1140,1050 cm ^-1 NMR (DMSO-d ₆ ) δ: 1.36 (9H, s), 1.45 (6H, s),
3.9 (2H, m), 4.55 (2H, m), 5.1 (1H, d, J = 5Hz), 6.0 (1H, dd, J
= 5 and 9 Hz), 6.81 (1H, s), 7.0 (1H, s), 7.3 (25H, br s), 8.1
5 (1H, d, J = 9Hz), 8.7 (1H, s) (B) Benzhydryl 7-[(Z) -2- (1-t-butoxycarbonyl-1-methylethoxyimino) -2- (2
-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate 1-Oxide The compound obtained in (A) was dissolved in 200 m of acetone and 3.38 g (22.5 mmo) of sodium iodide. Was added and the solution was stirred at room temperature for 30 minutes. Ethyl acetate 600m and 1 in the reaction solution
200 m of 0% sodium thiosulfate aqueous solution was added and the layers were separated. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by flash silica gel column chromatography (ethyl acetate / n-hexane = 1: 2), concentrated under reduced pressure, and added with diisopropyl ether.
The powdery title compound (7.0 g, yield 63.0%) was collected by filtration.

IR (KBr): 1795,1720,1680,1500,1370,1300,125
0,1170,1140,1050 cm ^-1 NMR (DMSO-d ₆ ) δ: 1.35 (9H, s), 1.45 (6H, s),
3.95 (2H, m), 4.45 (2H, m), 5.1 (1H, d, J = 5Hz), 6.0 (1H, dd, J
= 5 and 9Hz), 6.8 (1H, s), 7.0 (1H, s), 7.3 (25H, br s), 8.15
(1H, d, J = 9Hz), 8.7 (1H, s) (C) Benzhydryl 7-[(Z) -2- (1-t-butoxycarbonyl-1-methylethoxyimino) -2- (2
-Tritylaminothiazol-4-yl) acetamido] -3-[(5,6-dihydroxy-2-methyl-2-
Isoindolinio) methyl] -3-cephem-4-carboxylate 1-oxide iodide 5,6-dihydroxy-2-methylisoindoline 340 mg
(2.1mmo) in butyl acetate 25m suspension in N, O
-Bis (trimethylsilyl) acetamide 1.0m (4.1
mmo) was added. After stirring and dissolving at 50 ° C. for 1 hour, this solution was cooled to room temperature, and 2 g of the compound obtained in (B) (1.9 m
Mo) was added to a solution of 20 m of butyl acetate in one portion. After stirring at room temperature for 6 hours, the solvent was removed under reduced pressure,
The residue was separated and purified by flash silica gel column chromatography (3-4% methanol / methylene chloride),
1.84 g (yield 79.8%) of the title compound was obtained as a powder.

IR (KBr): 1795,1720,1650,1510,1300,1140cm ^-1 (D) benzhydryl 7-[(Z) -2- (1-t-butoxycarbonyl-1-methylethoxyimino) -2- (2)
-Tritylaminothiazol-4-yl) acetamido] -3-[(5,6-dihydroxy-2-methyl-2-
Isoindolinio) methyl] -3-cephem-4-carboxylate iodide (C) 1.84 g (1.48 mmo) of the compound obtained and 1.23 g (7.4 mmo) of potassium iodide, 28 m of acetone was added, and acetyl was added at -20 ° C. Chloride 0.26m (3.7mmo)
Was dripped. After stirring at -20 to -10 ° C for 2 hours, 600 mg of potassium iodide and 0.13 m of acetyl chloride were added, and this solution was stirred at the same temperature for 4 hours. The reaction mixture was cooled with 10% aqueous sodium metabisulfite solution-saturated saline solution (1: 1) 100.
m and 100 m of methylene chloride were added and the layers were separated. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a powder.

IR (KBr): 1790,1720,1680,1510,1360,1300,122
0,1140 cm ^-1 (E) 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxyimino) acetamide] -3-[(5, 6-dihydroxy-2
-Methyl-2-isoindolinio) methyl] -3-cephem-4-carboxylate The compound obtained in (D) was dissolved in 18 m of methylene chloride and added to 1.8 m of anisole. Cold trifluoroacetic acid under ice cooling 1
8 m was added, and this solution was stirred at the same temperature for 5 hours. After the solvent was distilled off under reduced pressure, 20 m of ethyl acetate was added, and this solution was concentrated under reduced pressure again (this operation was repeated twice). 40 m of diethyl ether was added, and the insoluble material was collected by filtration. This insoluble matter was suspended and stirred in 200 m of water, and the insoluble matter was filtered off. Reversed phase column chromatography (Waters P
Separation and purification with re Pack 500 / C-18, 100m (water 300m,
2%, 3% tetrahydrofuran aqueous solution 500m each),
The organic solvent was removed under reduced pressure and freeze-dried to obtain 300 mg (yield 32%) of the title target compound.

Melting point: 145 ° C (decomposition) IR (KBr): 1770,1650,1600,1520,1460,1390,134
0,1190,1155 cm ^-1 NMR (DMSO-d ₆ ) δ: 1.48 (6H, br s), 3.05 (3H,
br s), 5.12 (1H, d, J = 5Hz), 5.75 (1H, dd, J = 5 and 9Hz), 6.
86 (3H, br s), 9.8 (1H, d, J = 9Hz) Example 6 (A) Benzhydryl 7-[(Z) -2- (benzhydryloxycarbonylmethoxyimino) -2- (2-trityl) Aminothiazol-4-yl) acetamide] -3-
Chloromethyl-3-cephem-4-carboxylate
1-oxide benzhydryl 7-[(Z) -2- (benzhydryloxycarbonylmethoxyimino) -2- (2-tritylaminothiazol-4-yl) acetamido] -3-chloromethyl-3-cephem-4- Carboxylate 23.4
g (22.3mmo) is dissolved in 500m of methylene chloride,
80% m-chloroperbenzoic acid under ice cooling 4.8g (22.3mm
o) was added in 10 minutes and the solution was stirred for 20 minutes. 150m of 10% sodium thiosulfate aqueous solution was added to the reaction solution,
The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a powder (used in the next reaction without purification).

IR (KBr): 1800,1730,1680,1520,1490,1450,137
5,1250,1180,1090,1060,1010,750,700cm ^-1 (B) Benzhydryl 7-[(Z) -2- (Benzhydryloxycarbonylmethoxyimino) -2- (2-tritylaminothiazole-4- Il) acetamide] -3-
Iodomethyl-3-cephem-4-carboxylate
The compound obtained with 1-oxide (A) was dissolved in 380 m of acetone, 7.4 g (49 mmo) of sodium iodide was added, and the mixture was stirred at room temperature for 30 minutes. 300m of 10% sodium thiosulfate aqueous solution in the reaction solution
And 1150 m of ethyl acetate were added, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by flash silica gel column chromatography (ethyl acetate / n-hexane = 1: 1) to give the title compound 2 as a powder.
2.4 g (86.7% yield from the previous step) was obtained.

IR (KBr): 1795,1725,1685,1520,1495,1450,137
0,1290,1230,1180,1085,1060,750,700 cm ^-1 NMR (DMSO-d ₆ ) δ: 3.9 (2H, br s), 4.5 (2H,
m), 4.9 (2H, br s), 5.08 (1H, d, J = 5Hz), 5.93 (1H, dd, J = 5
And 8Hz), 6.87 (1H, s), 6.92 (1H, s), 7.0 (1H, s), 7.35 (36H,
m), 8.85 (2H, m) (C) Benzhydryl 7-[(Z) -2- (benzhydryloxycarbonylmethoxyimino) -2- (2-tritylaminothiazol-4-yl) acetamide] -3-
[5,6-Dihydroxy-2-methyl-2-isoindolinio) methyl] -3-cephem-4-carboxylate 1-oxide iodide 5,6-dihydroxy-2-methylisoindoline 410 mg
(2.48mmo) in butyl acetate 20m suspension in N,
O-bis (trimethylsilyl) acetamide 1.2 m (4.
96 mmo) was added. After stirring and dissolving at 60 ℃ for 1 hour,
The solution was cooled to room temperature and the compound obtained in (B) 1.82 g
A solution of (1.57 mmo) in 20 m of butyl acetate was added at once and the solution was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, 50 m of diethyl ether was added to the residue, the insoluble matter was collected, and purified by flash silica gel column chromatography (4% methanol / methylene chloride) to obtain 1.42 g of the title compound in powder form (yield 68%). ) Got.

IR (KBr): 1800,1730,1660,1610,1520,1450,134
5,1300,1220,1180,1090,1070,1035,750,700cm ^-1 (D) Benzhydryl 7-[(Z) -2- (Benzhydryloxycarbonylmethoxyimino) -2- (2-tritylaminothiazole- 4-yl) acetamide] -3-
[5,6-Dihydroxy-2-methyl-2-isoindolinio) methyl] -3-cephem-4-carboxylate iodide 1.42 g (1.01 mmo) of the compound obtained in (C) and potassium iodide 890 mg (5.04 mmo) 23m of acetone was added to), and acetyl chloride 0.19m (2.68mmo at -20 ℃).
) Was added dropwise. The reaction solution was stirred at -10 ° C, and after 1 hour and 2 hours, 890 mg of potassium iodide (5.04 mm)
o) and acetyl chloride 0.19m (2.68mmo)
Was added. After stirring the reaction solution for 1 hour, cold 10% sodium metabisulfite aqueous solution / saturated saline solution (1: 1) 50m
And methylene chloride 100 m were added. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a powder (used in the next reaction without purification).

IR (KBr): 1790,1720,1690,1515,1490,1450,136
0,1250,1220,1180,1090,1020,750,700 cm ^-1 (E) 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (carboxymethoxyimino) acetamide] -3 -[(5,6-Dihydroxy-2-methyl-2-
The compound obtained as isoindolinio) methyl] -3-cephem-4-carboxylate (D) was dissolved in 8 m of methylene chloride and added to 1.6 m of anisole. Cold trifluoroacetic acid under ice cooling 1
A solution of 6 m and methylene chloride 8 m was added dropwise over 30 minutes, and the solution was stirred at the same temperature for 3 hours. The solvent was distilled off under reduced pressure, and 20% of 95% formic acid was added to the residue.
It was left at 12 ° C for 12 hours. After distilling off the solvent under reduced pressure, water
200 m and 50 m of ethyl acetate were added, the aqueous layer was washed again with 50 m of ethyl acetate, and the organic solvent was distilled off under reduced pressure. Reversed phase column chromatography (Waters Pre P
ack 500 / C-18, 100m; 1% tetrahydrofuran ・
Water). The organic solvent was distilled off under reduced pressure and freeze-dried to obtain 210 mg of the title compound (yield 34% from the previous step).

Melting point: 143 ° C (decomposition) IR (KBr): 1770,1650,1600,1530,1390,1340,119
5,1070,1035 cm ^-1 NMR (DMSO-d ₆ · H ₂ O) δ: 3.05 (3H, br s),
4.5 (2H, br s), 5.1 (1H, d, J = 5Hz), 5.7 (1H, d, J = 5Hz), 6.8
(2H, br s), 6.83 (1H, s) Example 7 (A) Benzhydryl 3-[(5,6-dihydroxyisoindoline-2-yl) methyl] -7-[(Z) -2-isopropoxy Imino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 1-oxide benzhydryl 3-chloromethyl-7-[(Z) -2-
Isopropoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4
-Carboxylate 1-oxide 2.0 g (2.26 mmo
) Was dissolved in 40 m of acetone, and 750 m (5 mmo) of sodium iodide was added under ice cooling. After stirring for 30 minutes, the reaction solution was concentrated under reduced pressure, and ethyl acetate and water were added to the residue. The organic layer was washed with an aqueous solution of sodium metabisulfite and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This oily residue was treated with N, N-dimethylformamide 1
After dissolving in 0 m, 790 mg of 5,6-dihydroxyisoindoline hydrobromide (3.4 mmo was added, and then 0.47 m (3.38 mmo) of triethylamine was added dropwise at room temperature.
The reaction solution was stirred at the same temperature for 2 hours, N, N-dimethylformamide was distilled off under reduced pressure, and chloroform and water were added to the residue. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography (5% methanol / chloroform) to give 1.74 g (yield 78%) of the title compound.

IR (KBr): 1790,1660,1490,1290 cm ^-1 (B) Benzhydryl 3-[(5,6-dihydroxy-2-
Methyl-2-isoindolinio) methyl] -7-[(Z)
2-Isopropoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 1-oxide • iodide 1.74 g (1.74 mmo) of the compound obtained in (A) Methyl iodide (10 m, 160 mmo) and N, N-dimethylformamide (0.15 m) were added. After stirring at room temperature for 18 hours, the reaction solution was concentrated under reduced pressure, and the residue was subjected to flash silica gel chromatography (4-5% methanol / chloroform) to obtain 1.0 g of the title compound (yield 50%).

NMR (DMSO-d ₆ ) δ: 1.25 (6H, d, J = 6.0Hz), 2.
87 (2H, br s), 5.15 (1H, d, J = 4.0Hz), 6.00 (1H, m), 6.73 (1
H, s), 6.78 (1H, s), 7.00 (1H, s), 7.1〜7.6 (25H, br s), 8.75
(1H, m), 9.28 (1H, br s) (C) 7-[(Z) -2- (2-aminothiazol-4-yl) -2-isopropoxyiminoacetamide] -3-
[(5,6-Dihydroxy-2-methyl-2-isoindolinio) methyl] -3-cephem-4-carboxylate 1.0 g (0.87 mmo) of the compound obtained in (B) was added to 20 m of acetone.
, 1.45 g (8.7 mmo) of potassium iodide was added, and then acetyl chloride 0.31 m (4.37 m
MMO) was added dropwise. The reaction solution was stirred at −10 ° C. for 3 hours, poured into an ice-cooled 2% sodium metabisulfite aqueous solution, and the precipitate was collected by filtration. This precipitate was dissolved in chloroform and washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. This residue was dissolved in 2 m of methylene chloride and 0.8 m of anisole, and 6 m of trifluoroacetic acid was added dropwise under ice cooling. The reaction solution was stirred at the same temperature for 2 hours, concentrated under reduced pressure, and ethyl acetate and water were added to the residue. The aqueous layer was adjusted to pH 2.3 and subjected to reverse-phase column chromatography (Waters Pre Pack 500 / C-18; 2% tetrahydrofuran / water). Fractions containing the desired product were collected, concentrated under reduced pressure, and then freeze-dried. And the target compound, 83.8 mg
(Yield 17%) was obtained.

Melting point: 170 ° C. (decomposition) IR (KBr): 1770, 1610, 1510, 1340 cm ⁻¹ NMR (DMSO-d ₆ ) δ: 1.25 (6H, d, J = 6.0 Hz), 5.
10 (1H, d, J = 4.5Hz), 5.70 (1H, m), 6.71 (1H, s), 6.77 (2H,
s), 9.45 (1H, d, J = 9.0Hz) Reference Example 1 (A) Benzhydryl 3-chloromethyl-7-[(Z) -2
-Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 1-oxide benzhydryl 3-chloromethyl-7-[(Z) -2-
Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 2.5 g (2.97 mmo) was added to benzene 25 m.
Dissolve in 80% m-chloroperbenzoic acid 640mg under ice cooling
(3.27 mmo) was added. After stirring for 1 hour at room temperature,
The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium sulfite solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a powder.

NMR (CDC ₃ ) δ: 3.25 and 3.70 (2H, ABq, J = 18H
z), 4.03 (3H, s), 4.13 and 4.70 (2H, ABq, J = 12Hz), 4.47 (1
H, d, J = 5Hz), 6.07 (1H, dd, J = 5 and 9Hz), 6.67 (1H, s), 6.9
2 (1H, s), 7.3 (27H, m) (B) Benzhydryl 3-iodomethyl-7-[(Z) -2
-Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 1-oxide The compound obtained in (A) was dissolved in 50 m of acetone and 670 mg of sodium iodide ( 4.47 mmo) was added. After stirring at room temperature for 30 minutes, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium thiosulfate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a powder.

IR (KBr): 1790,1720,1680,1510,1370,1290,123
0,1160,1040 cm ^-1 NMR (CDC ₃ ) δ: 3.4 and 3.68 (2H, ABq, J = 18H
z), 4.03 (3H, s), 4.48 (3H, m), 6.0 (1H, dd, J = 5 and 9Hz), 6.
67 (1H, s), 6.95 (1H, s), 7.3 (27H, m) (C) Benzhydryl 3- [5-acetoxyisoindoline-2-yl) methyl] -7-[(Z) -2-methoxy Imino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 1-oxide (B) 2.32 g (2.45 mmo) of the powder obtained in methylene chloride 2
Dissolve in 3m, 1.2g (4.65mmo) 5-acetoxyisoindoline hydrobromide and triethylamine
0.8 m (5.7 mmo) was added and the solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to flash silica gel column chromatography (ethyl acetate / n-
Hexane = 3: 1) to obtain 2.62 g of the crude title compound.

NMR (DMSO-d ₆ ) δ: 2.26 (3H, s), 3.5 to 3.9 (8
H, m), 3.88 (3H, s), 5.08 (1H, d, J = 4Hz), 5.90 (1H, dd, J = 4
And 8Hz), 6.86 (1H, s), 6.98 (1H, s), 7.03 (1H, s), 7.0 ~ 7.9
(27H, m), 8.74 (1H.br s), 8.88 (1H, br d, J = 8Hz) (D) Benzhydryl 3- [5-acetoxy-2-methyl-2-isoindolinio) methyl] -7- [ (Z) -2
-Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 1-oxide iodide 2.6 g of the compound obtained with methyl iodide (alumina treatment) )
It dissolved in 20 m. After standing at room temperature for 18 hours, the reaction solution was flash silica gel column chromatography (2-5
% Methanol / methylene chloride) to give the title compound 2.34
g (yield 79% from the previous step) was obtained.

NMR (DMSO-d ₆ ) δ: 2.31 (3H, s), 3.00 (3H, br
s), 3.38 (2H, br s), 3.90 (3H, s), 4.5〜5.1 (6H, m), 5.15 (1
H, m) 6.00 (1H, dd, J = 5 and 7Hz), 6.85 (1H, s), 7.05 (1H, s), 7.0
~ 7.8 (28H, m), 8.75 (1H, br s), 9.11 (1H, br d, J = 7Hz) (E) Benzhydryl 3-[(5-acetoxy-2-methyl-2-isoindolinio) methyl]- 7-[(Z)-
2-Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-
2.3 g (2.0 mmo) of the compound obtained with carboxylate iodide (D) was added to 23 m of acetone.
Dissolved in water, 1.34 g (8.0 mmo) of potassium iodide was added, and then acetyl chloride 0.29 m (4.07
mmo) was added dropwise. After stirring for 1 hour, the reaction solution was poured into 2% sodium metabisulfite / saturated saline and extracted with ethyl acetate. The organic layer was dehydrated with anhydrous sodium sulfate and the solvent was distilled off to obtain 2.68 g of the title compound (yield 100%).

NMR (DMSO-d ₆ ) δ: 2.30 (3H, s), 3.00 (3H, br
s), 3.88 (3H, s), 4.0 (2H, m), 4.5〜5.1 (6H.m), 5.35 (1H, d),
5.90 (1H, m), 6.79 (1H, s), 7.01 (1H, s), 7.1〜7.8 (28H, m),
8.85 (1H, br s), 9.65 (1H, br d, J = 8Hz) (F) 3-[(5-acetoxy-2-methyl-2-isoindolinio) methyl] -7-[(Z) -2- Aminothiazol-4-yl) -2-methoxyiminoacetamide]
2.6 g (2.32 mmo) of the compound obtained from -3-cephem-4-carboxylate (E) was dissolved in 5 m of methylene chloride and 5 m of anisole, and 13 m of trifluoroacetic acid was added dropwise at 0 ° C. After stirring for 1 hour, the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was extracted with water. Reversed phase column chromatography (Waters Pre P
ack 500 / C-18,60m; 2% tetrahydrofuran / water)
The fractions containing the desired product were collected, concentrated under reduced pressure and freeze-dried to obtain 579 mg (yield 48.8%) of the target compound.

Melting point: 153 ° C. (decomposition) IR (KBr): 3400,1760,1610 ^-1 NMR (CF ₃ COOH) δ: 2.00 (3H, s), 3.04 (3H, br
s), 3.34 (2H, br s), 3.78 (3H, s), 4.2〜4.9 (6H, m), 4.92 (1
H, d, J = 5Hz), 5.5 (1H, m), 6.72 (1H, s), 6.78 (1H, d, J = 9H
z), 6.80 (1H, s), 6.95 (1H, d, J = 9Hz), 7.0〜7.6 (2H, m), 8.0
6 (1H, br d) Reference Example 2 (A) Benzhydryl 3-[(5-hydroxyisoindoline-2-yl)]-7-[(Z) -2-methoxyimino-2- (2-tritylaminothiazole) -4-yl)
Acetamide] -3-cephem-4-carboxylate 1-oxide 2.4 g (2.53 mmo) of the powder obtained in Reference Example 1 (B) was added to N, N-
Dissolved in 20m of dimethylformamide, 0.77g (3.56mmo) of 5-hydroxyisoindoline hydrobromide
And triethylamine 0.6m (4.3mmo) were added,
The solution was stirred at room temperature for 1 hour. N, N-dimethylformamide was distilled off under reduced pressure, and the residue was subjected to flash silica gel column chromatography (ethyl acetate / n-hexane = 3: 1 → 1: 0) to give 2.1 g of the title compound (yield 87
%) Was obtained.

_{NMR (DMSO-d 6) δ} : 3.38 (2H, br s), 3.40~4.
00 (6H, m), 3.89 (3H, s), 5.08 (1H, d, J = 4Hz), 5.89 (1H, dd, J
= 4 and 8 Hz), 6.85 (1H, s), 7.00 (1H, s), 7.0 to 7.8 (28H, m),
8.70 (1H, br s), 8.9 (1H, br d, J = 8Hz) (B) Benzhydryl 3-[(5-hydroxy-2-methyl-2-isoindolinio) methyl] -7-[(Z)-
2-Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-
2.1 g (2.2 mmo) of the compound obtained from carboxylate 1-oxide iodide (A) was dissolved in 20 m (321 mmo) of methyl iodide (treated with alumina).
After leaving it in the dark at room temperature for 12 hours, the reaction solution was subjected to flash silica gel column chromatography (2-5% methanol / methylene chloride) to give 1.9 g of the title compound (yield 79
%) Was obtained.

NMR (DMSO-d ₆ ) δ: 2.92 (3H, br s), 3.49 (2H,
br s), 3.89 (3H, s), 4.3〜5.2 (6H, m), 5.21 (1H, d, J = 4Hz),
6.00 (1H, dd, J = 4 and 8Hz), 6.86 (1H, s), 7.05 (1H, s), 7.0
~ 7.8 (27H, m), 8.80 (1H, br s), 9.16 (1H, br d, J = 8Hz) (C) Benzhydryl 3-[(5-hydroxy-2-methyl-2-isoindolinio) methyl]- 7-[(Z)-
2-Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-
1.9 g (1.73 mmo) of the compound obtained with carboxylate iodide (B) was added to 19 m of acetone.
Dissolved in water, 1.13 g (6.8 mmo) of potassium iodide was added, and then at -10 ° C acetyl chloride 0.25 m (3.5 m)
mo) was added. After stirring for 45 minutes, the reaction solution is 5%
It was poured into sodium metabisulfite / saturated saline and extracted with ethyl acetate. The organic layer was dehydrated with anhydrous sodium sulfate,
The solvent was distilled off to obtain 2.18 g of the crude title compound, which was used in the next step without purification.

NMR (DMSO-d ₆ ) δ: 2.90 (2H, br s), 3.00 (3H,
br s), 3.90 (3H, s), 4.3 to 5.1 (6H, m), 5.42 (1H, br d, J = 5H
z), 5.90 (1H, dd, J = 5 and 8Hz), 6.80 (1H, s), 6.85 (2H, br
s), 7.02 (1H, s), 7.0〜7.8 (26H, m), 8.9 (1H, br s), 9.65 (1
H, br d, J = 8 Hz) (D) 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(5
2.1 g of powder obtained with -hydroxy-2-methyl-2-isoindolinio) methyl] -3-cephem-4-carboxylate (C) was dissolved in 4 m of methylene chloride and 4 m of anisole, and 10 m of trifluoroacetic acid was added at 0 ° C. added. After stirring for 1 hour, the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was extracted 5 times with water. Reversed phase column chromatography (Waters Pre Pack 500 / C-18; 2)
% Tetrahydrofuran / water) and the fractions containing the desired product are collected, concentrated under reduced pressure, freeze-dried, and
1 mg (48% yield from the previous step) was obtained.

Melting point: 160 ° C. (decomposition) IR (KBr): 3400, 1768, 1610 cm ⁻¹ NMR (CF ₃ COOH) δ: 3.02 (3H, br s), 3.38 (2H,
br s), 3.85 (3H, s), 4.2〜4.9 (6H, m), 4.98 (1H, d, J = 5Hz),
5.5 (1H, dd, J = 5 and 8Hz), 6.60 (1H, s), 6.65 (1H, d, J = 7H
z), 6.88 (1H, dd, J = 7Hz) .6.96 (1H, s), 7.1〜7.7 (2H, m), 8.
08 (1H, d, J = 8Hz) Reference Example 3 Benzhydryl 3-chloromethyl-7-[(Z) -2-
Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 1-oxide Using sodium iodide and 2-methylisoindoline in the same manner as in Reference Example 1, 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(2-methyl-2-isoindolinio) methyl] -3-cephem-4-carboxylate Got

Melting point: 150 ° C. (decomposition) IR (KBr): 1770, 1660, 1620, 1530, 1345, 1030 cm ^-1 NMR (D ₂ O) δ: 3.23 (3H, s), 3.98 (3H, s), 5.16 (1H) ,
d, J = 4.5Hz), 5.76 (1H, d, J = 4.5Hz), 6.93 (1H, s), 7.38 (4
H, br s) Effect of the Invention The compound of the present invention is a novel compound not described in the literature, exhibits a strong antibacterial activity against susceptible and resistant Gram-positive bacteria and Gram-negative bacteria, and is useful as an antibacterial agent.

Claims (4)

[Claims] 1. A general formula (In the formula, R ¹ is a linear or branched lower alkyl group which may be substituted with a carboxyl group, R ² is a hydrogen atom, a hydroxy group or an acetoxy group, and R ³ and R ⁴ are the same, A compound represented by a hydroxy group or an acetoxy group bonded to adjacent carbon atoms), a salt thereof, or a physiologically hydrolyzable ester thereof. 2. General formula(In the formula, R⁵Is a hydrogen atom or an amino protecting group, R⁶Is hydrogen
Atom or carboxyl protecting group, R⁷Is protected carbo
Linear or branched, optionally substituted by a xyl group
-Like lower alkyl group, X is a halogen atom or a leaving group, Y
Represents S or SO) or a salt thereof
And the general formula(In the formula, R⁸Is a hydrogen atom, optionally protected hydro
Xy group or acetoxy group, R⁹And R^TenAre the same,
An optionally protected hydride bound to an adjacent carbon atom.
Roxy group or acetoxy group, R¹¹Is a hydrogen atom or methyl
(Representing a group) is reacted with an amine represented by the general formula(In the formula, R⁵, R⁶, R⁷, R⁸, R⁹, R^Ten, R¹¹Over
And Y have the meanings given above and X Is an anion)
Compound and, if necessary, methylation and / or
Is characterized by reducing and then removing the protecting group,
General formula(In the formula, R¹Is substituted by a carboxyl group
Good, linear or branched lower alkyl group, R^TwoIs hydrogen
Atom, hydroxy group or acetoxy group, R^ThreeAnd R^FourIs
Hydroxy groups that are the same and that are attached to adjacent carbon atoms
Or a salt thereof)
Alternatively, a method for producing a physiologically hydrolyzable ester thereof. 3. General formula(In the formula, R⁶Is a hydrogen atom or a carboxyl protecting group, R⁸
Is a hydrogen atom, an optionally protected hydroxy group or an
Setoxy group, R⁹And R^TenAre the same and adjacent carbons
An optionally protected hydroxy group attached to an atom or
Acetoxy group, X Is an anion)
Compound, its salt or its silyl compound(In the formula, R⁵Is a hydrogen atom or an amino protecting group, R⁷Is protected
Optionally substituted by a carboxyl group
Represents a chain or branched lower alkyl group)
Acylating with a carboxylic acid or its reactive derivative,
General formula(In the formula, R⁵, R⁶, R⁷, R⁸, R⁹, R^TenAnd X
Has the above-mentioned meaning).
And removing the protecting group if necessary.
General formula(In the formula, R¹Is substituted by a carboxyl group
Good, linear or branched lower alkyl group, R^TwoIs hydrogen
Atom, hydroxy group or acetoxy group, R^ThreeAnd R^FourIs
Hydroxy groups that are the same and that are attached to adjacent carbon atoms
Or a salt thereof)
Alternatively, a method for producing a physiologically hydrolyzable ester thereof. 4. A general formula (In the formula, R ¹ is a linear or branched lower alkyl group which may be substituted with a carboxyl group, R ² is a hydrogen atom, a hydroxy group or an acetoxy group, and R ³ and R ⁴ are the same, An antibacterial agent comprising a compound represented by a hydroxy group or an acetoxy group bonded to adjacent carbon atoms), a salt thereof, or a physiologically hydrolyzable ester thereof as an active ingredient.