KR950011746B1 - 3-propenylcephem derivative, preparation thereof, chemica intermediates therein, pharmaceutical composition and use - Google Patents

Abstract

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Description

3-propenyl cefem derivative

The present invention relates to novel cefem derivatives useful as antibacterial agents. More specifically, the present invention relates to 3-propenyl cefem derivatives. The present invention also provides a method for producing the 3-propenyl cefem derivative antibacterial agent and an intermediate of the 3-propenyl cefem derivative and a method for producing the intermediate.

Sepemide derivatives having ammoniagi are Japanese Patent Application Publication Nos. 174,387 / 83, 198,490 / 83, 130,295 / 84, 172,493 / 84, 219,292 / 84, 97,983 / 85 and 197,693. / 85 and 5,084 / 86 and the like.

In particular, cefem derivatives having ammonio propenyl groups at three-branch similar to the compounds of the present invention are described in Japanese Patent Application Laid-Open Nos. 172,493 / 84 and 5,084 / 86.

The present inventors have found that a cefe derivative having an ammonioprophenyl group at 3-point and a fluorine-substituted lower alkoxyimino group or a cyano-substituted lower alkoxyimino group at the 7-side side chain has excellent antibacterial action. It was completed.

It is therefore an object of the present invention to provide novel cefem compounds useful as antibacterial agents, methods for their preparation, pharmaceutical compositions containing them, intermediates of their derivatives and methods of preparing these intermediates.

The present invention relates to 3-propenyl cefem derivatives represented by the following general formula (I) and pharmaceutically acceptable salts thereof.

In the above formula, R ₁ is a fluorine-substituted lower alkyl group or a cyano-substituted lower alkyl group, and A is a cyclic or acyclic ammonium group.

Formula (I) is a fluoromethyl, difluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-tri as a specific example of the fluorine-substituted lower alkyl group represented by R ₁ . Fluoroethyl, 1-fluoroethyl, 2-fluoropropyl, 2- (fluoromethyl) -2-fluoroethyl, 3-fluoropropyl, and the like, among which fluoromethyl is particularly suitable. .

Cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, etc. are mentioned as an example of the cyano substituted lower alkyl group represented by R <_1> of general formula (I).

As an example of the acyclic ammonia group represented by A of General formula (I), group represented by following structural formula is mentioned.

Wherein R ₂ , R ₃ and R ₄ are the same as or different from each other, lower alkyl, hydroxyl substituted lower alkyl, carbamoyl substituted lower alkyl, cyano substituted lower alkyl, amino, (lower alkyl) carbonylamino Substituted lower alkyl, aminosulfonylaminocarbonyl substituted lower alkyl, (lower alkyl) sulfonylamino carbonyl substituted lower alkyl, (lower alkyl) aminocarbonyl substituted lower alkyl, hydroxyl and carbamoyl substituted lower alkyl, hydroxyl And hydroxy (lower alkyl) aminocarbonyl substituted lower alkyl, (lower alkaloxy) aminocarbonyl substituted lower alkyl, hydroxy aminocarbonyl substituted lower alkyl, carbamoyl (lower alkyl) aminocarbonyl substituted lower alkyl, hydride Roxy (lower alkyl) aminocarbonyl substituted lower alkyl, (lower alkyl) amino substituted lower alkyl, carboxylate (lower alkyl) di (lower alkyl) ammonio substituted low Lower alkyl, di (lower alkyl) amino substituted lower alkyl, di (lower alkyl) amino and hydroxyl substituted lower alkyl, ureido, hydroxyl, carboxyl substituted lower alkyl, hydroxyl and carbamoyl substituted lower alkyl, lower alkyl Oxy substituted lower alkyl, di (lower alkyl) amino carbonyl substituted lower alkyl, dicarbamoyl substituted lower alkyl, bis [hydroxy (lower alkyl) aminocarbonyl substituted lower alkyl, dihydroxy substituted lower alkyl, trihydroxy substituted Lower alkyl, bis [hydroxy (lower alkyl) amino substituted lower alkyl, amino substituted lower alkyl, oxo substituted lower alkyl, di lower alkyl substituted lower alkyl, 5-membered heterocycle substituted lower alkyl (where the heterocycle is pyrazolyl, Individual groups selected from the group consisting of dazolyl, oxadiazolyl or tetrazolyl).

Further, as an example of the cyclic ammonium group represented by A of general formula (I),

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Wherein R ₅ is lower alkyl, carbamoyl substituted lower alkyl, amino substituted lower alkyl, hydroxyl substituted lower alkyl, carboxyl substituted lower alkyl, cyano substituted lower alkyl, dihydroxy substituted lower alkyl and ureido substituted Group which is selected from the group consisting of lower alkyl group), and the cyclic ammonium group includes hydroxyl substituted lower alkyl, hydroxyl, formyl, sulfonic, carboxyl substituted lower alkyl, carbamoyl, sulfa in the ring. Moyl, carboxyl, hydroxyimino substituted lower alkyl, imino substituted lower alkyl, bis [hydroxy (lower alkyl)] aminocarbonyl, hydroxy (lower alkyl) aminocarbonyl, amino, morpholino carbonyl, carboxy (Lower alkyloxy) substituted optionally one or more substituents selected from the group consisting of lower alkyl, carboxy lower alkylthio and lower alkyl groups.

Examples of lower alkyl groups represented by A (R ₂ -R ₅ ) in Formula (I) include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl; And the same C ₁ -C ₄ alkyl.

Non-toxic salts of the compounds of formula (I) include pharmaceutically acceptable salts thereof, such as alkali metal salts such as sodium salts and potassium salts; Ammonium salts; Quaternary ammonium salts such as tetraethyl ammonium salt and betaine salt; Alkaline earth metal salts such as calcium salts and magnesium salts; Inorganic acid salts such as hydrochloride, hydrobromide, iodide bromide, sulfate, carbonate and bicarbonate; Organic carboxylates such as acetates, maleates, lactates and tartarates; Organic sulfonates such as methanesulfonate, hydroxymethanesulfonate, hydroxyethanesulfonate, taurine salt, benzenesulfonate and toluene sulfonate; Amino acid salts such as arginine salts, lysine salts, serine salts, aspartate and glutamate; Trimethylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, N-methyllucamine salt, diethanolamine salt, triethanol Amine salts such as amine salt, tris (hydroxymethylamino) methane salt and phenethylbenzylamine salt, and the like.

The compounds of the following general formula (I) of the present invention each have their syn-isomer (Z) and anti-isomer (E) according to the steric configuration in the next moiety.

Although all of the isomers are included in the present invention, syn-isomers are suitable because of their antibacterial action.

The compound of this invention can be manufactured by the following method.

That is, the compounds of formula (I) and their pharmaceutically acceptable salts are compounds of formula (II), compounds in which amino and (or) carboxyl groups are protected by a protecting group or salts thereof The functional groups can be obtained by reacting with a compound protected by the protecting group (s) or a salt thereof and then optionally removing the protecting group.

In formula, R <_1> is a fluorine substituted alkyl group or a cyano substituted lower alkyl group, X is a halogen atom, and A 'is an amine corresponding to A.

Examples of the halogen atom represented by X in the general formula (II) include iodine atom, bromine atom and chlorine atom.

The reaction is carried out at 0 ° to 40 ° C, preferably at -10 to 60 ° C. As the reaction solvent, anhydrous organic solvent is suitable. Useful organic solvents include lower alkylnitriles such as acetonitrile and propionitrile; Halogenated lower alkanes such as chloromethane, dichloromethane and chloroform; Ethers such as tetrahydrofuran, dioxane and ethyl ether; Amides such as dimethylformamide; Esters such as ethyl acetate; Ketones such as acetone; Hydrocarbons such as benzene, alcohols such as methanol and ethanol, and sulfoxides such as dimethyl sulfoxide and mixed solvents thereof.

Removal of the protecting group is carried out by methods known in the art such as hydrolysis or reduction depending on the type of protecting group used.

As salts of the compounds of the general formulas (II) and (III) and protecting groups of these compounds, those conventionally used can be used as long as the reaction is not impaired.

Examples of protecting groups for amino groups include formyl, acetyl, chloroacetyl, dichloroacetyl, phenylacetyl, thienylacetyl, t-butoxycarbonyl, benzyloxycarbonyl, trityl, p-methoxybenzyl and di A phenylmethyl group, a benzylidene group, p-nitrobenzylidene group, and m-chlorobenzylidene group are mentioned. Examples of the protecting group for the carboxyl group include p-methoxybenzyl group, p-nitrobenzyl group, t-butyl group, methyl group, 2,2,2-trichloroethyl group, diphenylmethyl group and pivaloyl oxymethyl group. In the present invention, N, O-bis (trimethylsilyl) acetamide, N-methyl-N- (trimethylsilyl) acetamide, N-methyl-N- (trimethylsilyl) trifluoroacetamide or N- (trimethyl It is easy to use a silylating agent such as silyl) acetamide since such silylating agent can protect the amino group and the carboxyl group at the same time.

Alkali metal salts such as sodium salts and potassium salts as salts of the compounds of general formulas (II) and (III); Alkaline earth metal salts such as calcium salts and magnesium salts; Ammonium salts; Quaternary ammonium salts such as triethylammonium salt and betaine salt; Inorganic acid salts such as hydrochloride, hydrobromide, sulfate, carbonate, iodide bromide and bicarbonate; Organic carboxylates such as acetates, trifluoroacetates, maleates, lactates and tartarates; Organic sulfonates such as methane sulfonate, hydroxymethane sulfonate, hydroxyethane sulfonate, taurine salt, benzene sulfonate and toluene sulfonate; Trimethylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanol Amine salts such as amine salts, tris (hydroxymethylamino) methane salts and phenethylbenzylamine salts; And amino acid salts such as arginine salt, aspartate salt, lysine salt, glutamate salt, serine salt and glycine salt.

The compounds of the present invention exhibit strong antibacterial action against both gram positive and gram negative bacteria and are therefore useful as anti bacterial agents. These compounds are useful for the treatment of diseases caused by bacteria.

When the compounds of the present invention are used as injections, they can generally be administered intravenously or intramuscularly by dividing the dose of 100 mg-10 g daily into 1-4 times. The dosage can be increased or decreased depending on the age of the patient and the symptoms of the disease.

Injection is carried out according to methods known in the art. For example, each compound of the present invention may be dissolved in distilled water in the presence of an isotonic agent, a solubilizer, or the like, if necessary, to prepare an injection solution. They can be filled with vials and powdered to dissolve and inject before use. Thus, these injection solutions can be dissolved and injected into distilled water for injection, physiological saline, glucose injection or amino acid injection.

A compound of formula (II), ie, an intermediate, amino and / or carboxyl group protected with a protecting group; Or salts of these compounds are all novel compounds. These compounds can be manufactured by the following method. That is, these compounds are represented by the following general formula (IV)

Wherein R ₁ is as defined above, a reactive acid derivative thereof, a compound in which an amino group is protected with a protecting group, or a salt of this compound.

Wherein the compound of formula (X is as defined above), a compound in which the carboxyl group is protected with a protecting group or a salt thereof, and then optionally removed the protecting group and / or converts the halogen atom represented by X to another halogen atom can do.

The reaction can be carried out under the usual reaction conditions for N-acylation. For example, the reaction can be carried out in an inert solvent such as tetrahydrofuran, ethyl acetate, acetone, N, N-dimethylformamide, acetonitrile, dioxane or a mixed solvent thereof at a temperature of -50 ° to 50 ° C. .

Reactive acid derivatives of the compounds of formula (IV) include acid halides such as acid chlorides, acid bromides, symmetric acid anhydrides, mixed acid anhydrides, mixed acid anhydrides, active esters, active acid amides and the like.

When using the free carboxylic acid of formula (IV) or a salt thereof, the reaction is suitably carried out in the presence of a conventional condensing agent such as N, N'-dicyclohexylcarbodiimide, p-toluenesulfonic acid and the like.

The process of converting the halogen atom represented by X into another halogen atom is performed by a conventional method. For example, a compound of formula (II) wherein X is an iodine atom can be prepared by reacting a compound of formula (II) wherein X is a chlorine atom with an alkali metal iodide.

Moreover, the compound or its salt whose intermediate, amino, and / or carboxyl group of the following general formula (VI) is protected by the protecting group is also a novel compound.

In said formula, R <_6> is a carboxyl group, a halogenocarbonyl group, a carbamoyl group, and a cyano group.

Examples of protecting groups for the amoni and carboxyl groups include groups similar to those exemplified for the protecting group of the compound of formula (II).

The compounds can be prepared by the following illustrated process.

Compounds of formula (VIII) can be prepared by reacting compounds of formula (VII) with halogeno fluoromethane in an inert solvent.

Examples of the halogeno fluoromethane include bromo fluoromethane, iodine fluoromethane and the like.

The reaction is carried out at -30 ° to 100 ° C.

Compounds of formula (IX) may be prepared by reacting compounds of formula (VIII) with a dehydrating agent in an inert solvent. Room temperature or more is suitable as the reaction temperature. Dehydrating agents include phosphorus oxychloride, thionyl chloride and the like.

Compounds of formula (X) may be prepared by reacting compounds of formula (IX) with ammonia and / or ammonium salts in an inert solvent such as water, lower alcohols, acetone, chloroform and the like. The reaction temperature is preferably -20 ° C to room temperature. Ammonium salts include ammonium chloride, ammonium acetate, ammonium sulfate and the like.

Compounds of formula (XI) may be prepared by reacting compounds of formula (X) with halogenating agents such as bromine gas, chlorine gas and the like, followed by reaction with alkali metal thiocyanates in the presence of a base to suitably Can be. The reaction temperature is preferably -20 ° C to room temperature. Examples of the alkali metal thiocyanate include potassium thiocyanate and sodium thiocyanate.

A compound of formula (XII), a compound in which an amino group is protected with a protecting group or a salt thereof, hydrolyzes a compound of formula (XII), a compound in which an amino group is protected with a protecting group in the presence of an oxidizing agent and a base, and then optionally It can be prepared by removing the protecting group.

The reaction can be carried out in water, a buffer solution or a mixed solvent of these with lower alcohols at a temperature of 0 ° -07 ° C.

Hydrogen peroxide, oxygen, etc. can be used as an oxidizing agent, and sodium hydroxide, potassium hydroxide, etc. can be used as a base.

A compound of formula (XIII), a compound in which an amino group is protected with a protecting group or a salt thereof, hydrolyzes a compound of formula (XII), a compound in which an amino group is protected with a protecting group, or a salt thereof in the presence of a base, and then optionally a protecting group Can be manufactured by removal.

It is the same as what was described about reaction from general formula (XI) to the compound of general formula (XII) in the form of a base, a solvent, reaction temperature, etc.

Further, the compound of formula (XIII), the compound whose amino group is protected with a protecting group or a salt thereof, reacts the compound of formula (XIV) with amino and / or carboxyl group protected with a protecting group with halogeno fluoromethane, and It can be prepared by optionally removing the protecting group.

Halogeno fluoromethane includes bromo fluoromethane, iodine fluoromethane, chloro fluoromethane.

The reaction can be carried out in an inert solvent at a temperature in the range of -30 ° to 100 ° C.

Examples of inert solvents include sulfoxides such as dimethyl sulfoxide and the like; Amides such as N, N'-dimethylacetamide, formamide, hexamethylphosphoryl triamide and the like, ketones such as acetone and the like or a mixed solvent thereof.

The compound of the general formula (XV), the compound in which the amino group is protected with a protecting group, or a salt thereof may be prepared by reacting the compound of the general formula (XIII), the compound in which the amino group is protected with a protecting group, or a salt thereof with a halogenating agent.

Examples of the halogenating agent include phosphorus pentoxide, thionyl chloride, thionyl bromide, phosphorus oxachloride and the like.

The reaction can be carried out at an inert solvent such as dichloromethane, tetrahydrofuran, ethyl acetate, chloroform or a mixed solvent thereof at a temperature of -50 ° to 50 ° C.

The present invention will be described in more detail with the following experimental examples and examples.

Example 1

[Synthesis of Compound of Raw Material]

Ethyl 2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxy imino acetate

60.4 g of ethyl 2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z) -2-hydroxyimino acetate are dissolved in 210 ml of dimethyl sulfoxide, followed by carbonic acid 96.48 g of potassium were added under ice cooling. This solution was stirred for 10 min. Then 19 g of bromo fluoromethane were added thereto, and the solution was stirred at room temperature for 3 hours. 1 liter of ethyl acetate was added to the reaction solution, which was washed with water, then with saturated brine, and dried by adding anhydrous magnesium sulfate. The solvent was distilled off and 120 ml of ethanol was added to the residue. The precipitated crystals were collected by filtration and washed with ethanol to give 58.2 g of the desired product.

Example 2

[Synthesis of Raw Material Compounds]

2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxy imino acetic acid

17.87 g of the compound prepared in Experiment 1 was added to a mixed solution containing 2.04 g of sodium hydroxide, 146 ml of ethanol, and 29 ml of water, and the solution was stirred at reflux for 20 minutes. This solution was concentrated under reduced pressure, to which 200 ml of ethyl acetate and 77 ml of 1N hydrochloric acid were added. The ethyl acetate layer was separated and collected, washed with saturated brine, and then dried by adding anhydrous magnesium sulfate. The solvent was distilled off to obtain crystals. The crystals were triturated with the addition of petroleum ether and then filtered to recover 16.55 g of the desired product.

Example 3

[Synthesis of Raw Material Compounds]

p-methoxybenzyl 7β- [2- (5-tritylamino) -1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyamino acetoamido] -3- [(Z) -3-chloro-1-propen-1-yl] -3-cepem-4-carboxylate

348 μl of dimethylformamide and 4.1 mL of tetrahydrofuran, were cooled to −10 ° C., to which 418 μl of phosphorus oxychloride was added and stirred under ice cooling for 90 minutes. A solution of 1.73 g of the compound of Experiment 2 dissolved in 5.5 ml of tetrahydrofuran was added to this solution while cooling the solution to -10 ° C, and the resulting solution was stirred for 90 minutes under ice-cooling. The reaction solution is cooled to -20 ° C, to which p-methoxybenzyl 7β-amino-3-[(Z) -3-chloro-1-propen-1-yl] -3-cepem-4-carboxyl A mixed solution containing 1.78 g of late hydrochloride, 2.95 g of N (-trimethylsilyl) acetamide, 18 ml of ethyl acetate and 5.5 ml of tetrahydrofuran was added, and the resulting solution was stirred at -10 ° C for 1 hour. 100 ml of ethyl acetate was added to the reaction solution, and the resulting solution was continuously washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried by adding anhydrous MgSO ₄ . The solvent was distilled off and the residue was purified by silica gel column chromatography to give 2.65 g of the desired product.

Example 4

[Synthesis of Raw Material Compounds]

p-methoxybenzyl 7β- [2- (5-tritylamino) -1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3- [(E) -3-iodod-1-propen-1-yl] -3-cepem-4-carboxylate

10.11 g of the compound prepared in Experimental Example 3 was dissolved in 212 ml of acetone, and 9.03 g of sodium iodide was added thereto under ice cooling. The resulting solution was stirred under ice cooling for 15 minutes and further stirred at room temperature for 90 minutes. The solvent was distilled off and the residue was extracted with 500 ml of ethyl acetate. The extract was washed with saturated aqueous sodium thiosulfate solution and saturated brine, and then dried by adding anhydrous MgSO ₄ . The dried extract was concentrated under reduced pressure, to which n-hexane was added. The resulting precipitate was filtered to give 10.92 g of the desired product.

Example 5

[Synthesis of Raw Material Compounds]

p-methoxybenzyl 7β- [2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z) -difluoromethoxyimino acetamido] -3-[( Z) -3-chloro-1-propen-1-yl] -3-cefe-4-carboxylate

2.00 g of 2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z) -difluoromethoxyimino-acetic acid in the same manner as described in Experimental Example 3 The reaction product was reacted with 1.795 g of oxybenzyl 7β-amino-3-[(Z) -3-chloro-1-propen-1 yl] -3-cef-4-carboxylate hydrochloride to obtain 3.17 g of the desired product.

Example 6

[Synthesis of Raw Material Compounds]

p-methoxybenzyl 7β- [2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z) -2-difluoromethoxyimino acetamido] -3- [(E) -3-iodo-1-propen-1-yl] -3-cepem-4-carboxylate

3.00 g of the compound prepared in Experiment 5 was reacted with 2.62 g of sodium iodide in the same manner as described in Experiment 4 to obtain 2.92 g of the desired product.

Example 1

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- ( Carbamoylmethylethyl methylammonia) -1-propen-1-yl] -3-cepem-4-carboxylate

550 mg of the compound prepared in Experimental Example 4 was dissolved in a mixed solution containing 20 ml of ethyl acetate and 10 ml of ethyl ether, followed by addition of 117 mg of ethylmethylaminoacetamide. The resulting solution was stirred at room temperature for 4 hours 30 minutes. Isopropyl ether was added to the reaction solution, and the resulting precipitate was collected by filtration and dried to give 400 mg of a tan powder.

The powder was stirred under ice cooling for 1 hour with a mixed solution of 4.5 ml of trifluoroacetic acid-4 ml of anisole, and ethyl ether was added thereto. The resulting precipitate was collected by filtration and washed with ethyl ether. The precipitate was suspended in 5 ml of water. Sodium acetate was added to this suspension to adjust the pH to 5.5-6.2. The insoluble material was filtered off and the filtrate was purified by reverse phase chromatography to give 49 mg of the desired product.

Example 2

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyamino acetamido] -3-[(E) -3- [ 1- (2-hydroxyethyl) -4-carbamoyl] -1-piperazinio] -1-propen-1-yl] -3-cepem-4-carboxylate

700 mg of the compound prepared in Experimental Example 4 was dissolved in 3 ml of dimethylformamide, and to this was added a solution of 194 mg of 1- (2-hydroxyethyl) isonifcortamide dissolved in 0.5 ml of dimethylformamide. The solution was stirred overnight. The reaction solution was added to 120 ml of ethyl ether, and the resulting precipitate was collected by filtration to give 680 mg of a yellow powder.

4.5 ml of anisole was added to the powder, and 5.3 ml of trifluoro acetic acid was added dropwise over 30 minutes with stirring under ice cooling. After completion of the dropwise addition, the mixture was stirred for an additional 1 hour 30 minutes. 50 ml of isopropyl ether was added to the reaction solution, and the resulting precipitate was collected by filtration. The precipitate was suspended in 30 ml of water, and the suspension was adjusted to pH 7.0 by addition of sodium acetate. The resulting insoluble substance was filtered off, and the filtrate was purified by reverse phase silica gel column chromatography to obtain two isomers of the following title compound.

21 mg of isomers (2-1)

20 mg of isomers (2-2)

50 mg of two isomeric 1: 1 mixtures

Example 3

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- [ (1S-carbamoylethyl) dimethylammonio] 3-1-propen-1-yl] -3-cepem-4-carboxylate (3-1)

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- [ 1R-carbamoylethyl] dimethylammonio] -1-propen-1-yl] -3-cepem-4-carboxylate (3-2)

600 mg of the compound prepared in Experimental Example 4 was dissolved in a mixed solution containing 20 ml of ethyl acetate and 10 ml of ethyl ether, and then 150 mg of 2-dimethylaminopropylamide was added thereto. The resulting solution was stirred at rt for 3 h. Isopropyl ether was added to the reaction solution, and the resulting precipitate was collected by filtration and then dried to give 50 mg of a tan powder.

The powder was stirred under ice cooling in a mixed solution containing 5.5 ml of trifluoroacetic acid and 5 ml of anisole for 1 hour, and then ethyl ether was added thereto. The resulting precipitate was collected by filtration and washed with ethyl ether. The precipitate was suspended in 5 ml of water, and the suspension was adjusted to pH 5.5-6.5 by addition of sodium acetate. Insoluble matter was removed by filtration, and the filtrate was purified by reversed-phase silica gel column chromatography. 1: 1) 4 mg was obtained.

Example 4

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- [ 1- (2-hydroxypropyl) dimethylammonia] -1-propen-1-yl] -3-cepem-4-carboxylate

550 mg of the compound prepared in Experimental Example 4 was dissolved in a mixed solution containing 20 ml of ethyl acetate and 10 ml of ethyl ether, followed by addition of 0.124 ml of 3-dimethylamino-2-propanol. The resulting solution was stirred for 1 hour 30 minutes at room temperature. Isopropanol was added to the reaction solution. The resulting precipitate was collected by filtration and dried to give 530 mg of a tan powder.

The powder was stirred for 1 hour in a mixed solution containing 5.5 ml of trifluoroacetic acid and 5 ml of anisole under ice cooling. Thereafter, ethyl ether was added thereto. The resulting precipitate was collected by filtration and washed with ethyl ether. The precipitate was suspended in 5 ml of water. Sodium acetate was added to this suspension to adjust the pH to 5.5-6.5. The insoluble material was filtered off and the filtrate was purified by reverse phase silica gel column chromatography to give 70 mg of the desired product.

Example 5

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- [ 1R-carbamoyl-2-hydroxyethyl) dimethylammonio] -1-propen-1-yl] -3-cepem-4-carboxylate

1.00 g of the compound prepared in Experimental Example 4 was dissolved in 2 ml of dimethylformamide. 590 mg of N, N-dimethyl-D-serineamide trifluoroacetate was dissolved in 5 ml of methanol, to which 2.4 ml of 1N-sodium hydroxide aqueous solution was added, and then the solvent was distilled off under reduced pressure, and the residue was acetonitrile. Extraction to 2 ml produced a N, N-dimethyl-D-serineamide solution. The N, N-dimethyl-D-serineamide solution was added to the solution of the compound prepared in Experimental Example 4 dissolved in dimethylformamide under ice-cooling. The resulting solution was stirred for 30 minutes. The reaction solution was added to ethyl ether and the resulting precipitate was collected by filtration to give 1.1 g of a yellow powder.

8 ml of anisole was added to the powder, and 9 ml of trifluoroacetic acid was added dropwise over 30 minutes while stirring under ice cooling, followed by stirring for an additional 1 hour and 30 minutes. Ethyl ether was added to the reaction solution and the resulting precipitate was collected by filtration. The precipitate was suspended in 10 ml of water. This suspension was then adjusted to pH 7 by addition of sodium acetate. The insoluble material was filtered off and the filtrate was purified by reverse phase silica gel column chromatography to afford 30 mg of the desired product.

Example 6

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- [ 4R-hydroxy-2R-hydroxymethyl-1-methyl-1-pyrrolidinio) -1-propen-1-yl] -3-cefe-4-carboxylate

700 mg of the compound prepared in Experimental Example 4 was dissolved in 4 ml of acetone, and a solution of 89 mg of N-methyl-cis-4-hydroxy-D-prolinol dissolved in acetone 2 was added thereto. The resulting solution was stirred overnight. The reaction solution was added to 100 ml of ethyl ether, and the resultant precipitate was collected by filtration to obtain 700 mg of a yellow powder.

4.5 ml of anisole was added to the powder, and trifluoro acetic acid was added dropwise over 30 minutes while stirring under ice cooling, and further stirred for 1 hour 30 minutes. 50 ml of isopropyl ether was added to the reaction solution. The resulting precipitate was collected by filtration. The precipitate was suspended in 30 ml of water, and the suspension was adjusted to pH 7 by addition of sodium acetate. Insoluble matter was removed by filtration, and the filtrate was purified by reversed-phase silica gel column chromatography to obtain the following two types of isomers (relative to the nitrogen atom of pyrrolidine).

27 mg of isomers (6-1)

100 mg of isomers (5-2)

Example 7

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- ( 4R-hydroxy-1- (2-hydroxyethyl-2S-hydroxymethyl-1-pyrrolidinio) -1-propen-1-yl] -3-cepem-4-carboxylate

2.0 g of the compound prepared in Experiment 4 contains 450 mg of (R) -4-hydroxy-1- (2-hydroxyethyl)-(S) -2-hydroxymethylpyrrolidine in 5 ml of dimethylformamide. To the solution. The resulting solution was stirred overnight. The reaction solution was added to ethyl acetate. The produced precipitate was collected by filtration to obtain 1.65 g of a yellow powder.

10 ml of anisole was added to the powder, and then, under ice-cooling, 11.7 ml of trifluoroacetic acid was added dropwise over 30 minutes with stirring, and further stirred for 1 hour 30 minutes. Isopropyl ether was added to the reaction solution and the resulting precipitate was collected by filtration. The precipitate was suspended in 4.5 ml of water, and the suspension was adjusted to pH 7 by addition of sodium acetate. The insoluble matter was removed by filtration and the filtrate was purified by reverse phase silica gel column chromatography to give two kinds of isomers (relative to the nitrogen atom of pyrrolidine) of the title compound as follows.

Isomer (7-1) 96mg

Isomer (7-2) 207 mg

Example 8

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- ( 4R-hydroxy-2S-hydroxymethyl-1-pyrrolidinio) -1-methyl-1-propen-1-yl] -3-cepem-4-carboxylate

700 mg of the compound prepared in Experiment 4 was dissolved in 4 ml of acetone, and a solution of 89 mg of N-methyl-trans-4-hydroxy-L-prolinol dissolved in 2 ml of acetone was added thereto, and the resulting solution was overnight. Stirred. The reaction solution was added to 100 ml of ethyl ether, and the resultant precipitate was collected by filtration to obtain 700 mg of a yellow powder.

4.5 ml of anisole was added to the powder, and 5.3 ml of trifluoroacetic acid was added dropwise over 30 minutes while stirring under ice cooling, followed by further stirring for 1 hour 30 minutes. 50 ml of isopropyl ether was added to the reaction solution, and the resulting precipitate was collected by filtration. The precipitate was then suspended in 30 ml of water. In this suspension, sodium acetate was added to adjust pH to 7. Insoluble matter was removed by filtration and the filtrate was purified by reverse phase silica gel column chromatography to give 92 mg of the target compound.

Example 9

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- ( 1-carbamoylmethyl-3-hydroxy-1-pyrrolidinio) -1-propen-1-yl] -3-cepem-4-carboxylate

1.0 g of the compound prepared in Experimental Example 4 was dissolved in 4 ml of dimethylformamide, and a solution of 186 mg of N-carbamoylmethyl-3-hydroxypyrrolidine dissolved in 2 ml of dimethylformamide was added thereto. The resulting solution was stirred overnight. The reaction solution was added to 200 ml of ethyl ether. The produced precipitate was collected by filtration to give 970 mg of a yellow powder.

9.0 ml of anisole was added to the powder, and then 10.6 ml of trifluoroacetic acid was added dropwise over 30 minutes while stirring under ice cooling. The mixture was further stirred for 1 hour 30 minutes. 80 ml of isopropyl ether was added to the reaction solution, and the resulting precipitate was collected by filtration. The precipitate was suspended in 50 ml of water. Sodium acetate was added to this suspension to adjust to pH 7. Insoluble material was removed by filtration and the filtrate was purified by reversed-phase silica gel column chromatography to find isomers of each type of the title compound (relative to the nitrogen atom and the carbon atom at the 3-position of the pyrrolidine, high pressure liquid chromatography Four kinds of phases) were obtained as follows.

71 mg (two kinds of mixtures) of isomer (9-1)

70 mg of an isomer (9-2) (single substance)

54 mg of isomers (9-3) (single substance)

Example 10

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- ( 1-methyl-4-sulfo-1-piperazinio) -1-propen-1-yl] -3-cepem-4-carboxylate

2.0 g of the compound prepared in Experiment 4 was added to a mixed solution containing 718 mg of 4-methylpiperazino sulfonic acid sulfate, 2 ml of N-methyl-N- (trimethylsilyl) trifluoroacetamide, and 6 ml of dimethylformamide, The resulting solution was stirred overnight. 2 ml of methanol was added to the reaction solution, and the insoluble matter was removed by filtration. The filtrate was added to a mixed solution containing 50 ml of ethyl acetate and 50 ml of ethyl ether, and the resulting precipitate was collected by filtration to give 1.79 g of a yellow powder.

10.9 ml of anisole was added to this powder, and 12.7 ml of trifluoroacetic acid was added dropwise over 30 minutes while stirring under ice cooling. The resulting solution was further stirred for 1 hour 30 minutes. 100 ml of isopropyl ether was added to the reaction solution, and the resulting precipitate was collected by filtration. The precipitate was suspended in 4.5 ml of water, and the suspension was adjusted to pH 7 by addition of sodium acetate. The insoluble material was filtered off and the filtrate was purified by reverse phase silica gel column chromatography to afford 50 mg of the desired product.

Example 11

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- ( 1-carbamoylmethyl-4-hydroxy-1-piperidinio) -1-propen-1-yl] -3-cepem-4-carboxylate

1.0 g of the compound prepared in Experimental Example 4 was dissolved in 9 ml of acetone, and 206 mg of N-carbamoylmethyl-4-hydroxypiperidine was added thereto. The solution was stirred overnight. The reaction solution was added to 100 ml of a mixed solution containing ethyl ether and isopropyl ether (2: 1), and the resulting precipitate was collected by filtration to obtain 1.0 g of a yellow powder.

9.0 ml of anisole was added to the powder, 10.6 ml of trifluoroacetic acid was added dropwise over 30 minutes while stirring under ice-cooling, and the resulting solution was further stirred for 1 hour and 30 minutes. 80 ml of isopropyl ether was added to the reaction solution, and the resulting precipitate was collected by filtration. The precipitate was suspended in 5 ml of water, and the suspension was adjusted to pH 7.0 by addition of sodium acetate. The insoluble material was filtered off and the filtrate was purified by reverse phase silica gel column chromatography to give 166 mg of the desired product.

Example 12

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- ( 5-aza-1-methyl-2,8-dioxabicyclo [3.3.1] nona-5-io))-1-propen-1-yl) -3-cepem-4-carboxylate

The compound prepared in Experimental Example 4 was dissolved in 10 ml of dimethylformamide, and 800 mg of 5-aza-1-methyl-2,8-dioxabicyclo [3.3.1] nonane was added thereto. The resulting solution was stirred for 20 minutes. The reaction solution was diluted with 25 ml of ethyl acetate and the solution was added to ethyl ether to give 3.85 g of a brown precipitate.

The precipitate was dissolved in 23 ml of anisole and 26 ml of trifluoroacetic acid was added thereto under ice cooling. The solution was stirred at the same temperature for 30 minutes. Ethyl ether was added to the reaction solution and the resulting precipitate was collected by filtration. The precipitate was suspended in 40 ml of water, and the suspension was adjusted to pH 7.0 by addition of sodium acetate. The insoluble material was filtered off and the filtrate was filtered by reversed phase silica gel column chromatography to give 408 mg of the desired product.

In the same manner as described in Example 1-12, the following Example 13-113 compound was prepared.

Because of the ammonia phase on A, a plurality of isomers can be produced. When isolating isolates, each yield is shown separately for each isomer.

The following abbreviations were used.

Boc: t-butoxy carbonyl group

tBu: t-butyl group

Bh: Mercedes Benz Drilling Machine

Tr: Trityl

Example 114

7β- [2- (5-amino-1,2,4-diadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- ( Dimethylcarbamoylmethylammonio) -1-propen-1-yl] -3-cefe-4-carboxylate

500 mg of the compound of Experimental Example 6 was dissolved in a mixed solution of 10 ml of ethyl acetate and 10 ml of ethyl ether. 160 mg of dimethylglycine amide was added to the solution, followed by reaction stirring at room temperature for 30 minutes. Isopropyl ether was added to the reaction solution. The produced precipitate was collected by filtration and dried to obtain 400 mg of a tan powder.

The powder was stirred under ice cooling in a mixed solution of 5 ml of trifluoroacetic acid and 4.5 ml of anisole for 1 hour. Ethyl ether was added to the reaction solution, and the resulting precipitate was collected by filtration and then washed with ethyl ether. This precipitate was suspended in 5 ml of water, and then sodium acetate was added to adjust the pH of the suspension to 5.5-6.5. The insoluble material was filtered off and the filtrate was purified by reverse phase silica gel column chromatography to afford 55 mg of the desired product.

In the same manner as described in Example 114, the compounds of the following Examples 115-117 were produced.

Experimental Example 7

[Synthesis of Raw Material Compounds]

p-methoxybenzyl 7β- [2- (5-tritylamino) -1,2,4-thiadiazol-3-yl)-(Z) -2-2,2,2-trifluoroethyloxy Mino acetamido] -3-[(Z) -3-chloro-1-propen-1-yl] -3-cefe-4-carboxylate

The mixed solution consisting of 0.247 ml of dimethylformamide and 3 ml of tetrahydrofuran was cooled to -10 ° C, 0.297 ml of phosphorus oxychloride was added thereto, and stirred for 40 minutes while cooling with ice. In the resulting solution, 2- (5-tritylamino-1,2,4-thiazoldiazol-3-yl- (Z) -2- (2,2,2-trifluoroethyl) oxyaminoacetic acid 1.36 4 ml of g tetrahydrofuran solution was added, followed by further stirring at this temperature for 1 hour The resulting reaction solution was cooled to −20 ° C. with p-methoxybenzyl 7β-amino-3-[(Z) -3 -Chloro-1-propen-1-yl] -3-cepem-4-carboxylate hydrochloride 1.145 g, 2.09 g N- (trimethylsilyl) acetamide and 10 ml ethyl acetate were added to a mixed solution, followed by 1 The temperature was raised to 0 ° C. with stirring for hours, after which ethyl acetate was added to the reaction solution, which was washed with water and dried over anhydrous sodium sulfate, the solvent was evaporated and the residue was purified by silica gel column chromatography. 1.43 g of product was obtained.

Example 118

7β- [2- (5-amino) -1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- (Carbamoylmethyldimethylammonio) -1-propen-1-yl] -3-cepem-4-carboxylate

500 mg of the compound obtained in Experiment 4 was dissolved in a mixed solution consisting of 3 ml of methol and 1 ml of dimethylformamide, and 71.3 mg of N, N-dimethylglycineamide was added thereto while cooling with ice, followed by stirring overnight at room temperature. The resulting reaction solution was added to a mixed solution of 50 ml of ethyl acetate and 50 ml of ethyl ether, and the resulting precipitate was collected by filtration and dried to give 382 mg of a yellow powder.

This powder was added to a mixed solution of 2.7 ml of trifluoroacetic acid and 2.3 ml of anisole, followed by stirring for 2 hours with ice cooling. The reaction solution was added to a mixed solution of 25 ml of ethyl ether and 25 ml of isopropyl ether, and the resulting precipitate was collected by filtration and washed with ethyl ether. The precipitate thus obtained was suspended in 4.5 ml of water, then sodium acetate was added to adjust the pH of the resulting suspension to 5.5 to 6.5, and the insoluble material was filtered off. The filtrate was purified by reverse phase silica gel column chromatography to give 94 mg of the desired product.

Example 119

7β- [2- (5-amino) -1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- (1-methyl-4-sulfamoyl-1-piperazio) -1-propen-1-yl] -3-cepem-4-carboxylate

500 mg of the compound obtained in Experimental Example 4 was dissolved in a mixed solution consisting of 3 ml of methanol and 1 ml of dimethylformamide, and 116 mg of N-sulfamonyl-N'-methylpyrazine was added thereto while cooling with ice, followed by stirring at room temperature overnight. The reaction solution was added to a mixed solution of 50 ml of ethyl acetate and 50 ml of ethyl ether, and the resulting precipitate was collected by filtration and dried to give 402 mg of a yellow powder.

This powder was added to a mixed solution of 2.7 ml of trifluoroacetic acid and 2.5 ml of anisole, and stirred for 2 hours while cooling with ice. The reaction solution was added to a mixed solution of 25 ml of ethyl ether and 25 ml of isopropyl ether, and the resulting precipitate was collected by filtration and washed with ethyl ether. The resulting precipitate was suspended in 4.5 ml of water, then sodium acetate was added to adjust the pH of the resulting suspension to 5.5-6.5, and the insoluble material was filtered off. The filtrate was purified by reverse phase silica gel column chromatography to give 58 mg of the desired product.

Example 120

7β- [2- (5-amino) -1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- [(1,3,4-oxadiazol-2-yl) methyldimethylammonio] -1-propen-1-yl] -3-cepem-4-carboxylate

500 mg of the compound obtained in Experiment 4 was dissolved in a mixed solution of 1 ml of methanol and 4.8 ml of ethyl acetate, and then 1 ml of ethyl acetate solution of 88.8 mg of 2-dimethylaminomethyl-1,3,4-oxadiazole was added thereto. It was added while cooling with ice, and stirred overnight at room temperature. The resulting reaction solution was added to a mixed solution of 50 ml of ethyl acetate and 50 ml of ethyl ether, and then the resulting precipitate was collected by filtration and dried to give 443 mg of a yellow powder.

This powder was added to a mixed solution of 3.1 ml of trifluoroacetic acid and 2.7 ml of anisole, followed by stirring for 2 hours under ice cooling. The resulting reaction solution was added to a mixed solution of 25 ml of ethyl ether and 25 ml of isopropyl ether, and the resulting precipitate was collected by filtration and washed with ethyl ether. The precipitate thus obtained was suspended in 4.5 ml of water, and then sodium acetate was added to adjust the pH of the resulting suspension to 5.5 to 6.5, and the insoluble matter was removed by filtration. The filtrate was purified by reverse phase silica gel column chromatography to give 92 mg of the desired product.

Example 121

7β- [2- (5-amino) -1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- (1-methyl-4-carbamoyl-1-piperazinio) -1-propen-1-yl] -3-cepem-4-carboxylate

After dissolving 500 mg of the compound obtained in Experimental Example 4 in a mixed solvent consisting of 3 ml of methanol and 1 ml of dimethylformamide, 100 mg of 2-methyl-N'-carbamoylpiperazine was added thereto while cooling with ice, followed by stirring at room temperature overnight. I was. The resulting reaction solution was added to a mixed solution of 50 ml of ethyl acetate and 30 ml of ethyl ether, and then the resulting precipitate was collected by filtration and dried to give 425 mg of a yellow powder.

This powder was added to a mixed solution of 3.0 ml of trifluoroacetic acid and 2.6 ml of anisole, followed by stirring for 2 hours under ice cooling. The resulting reaction solution was added to a mixed solution of 25 ml of ethyl ether and 25 ml of isopropyl ether, and the resulting precipitate was collected by filtration and washed with ethyl ether. The precipitate thus obtained was suspended in 4.5 ml of water, and then sodium acetate was added to adjust the pH of the resulting suspension to 5.5 to 6.5, and the insoluble matter was removed by filtration. The filtrate was purified by reverse phase silica gel column chromatography to give 107 mg of the desired product.

Example 122

7β- [2- (5-amino) -1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- (1,2-dimethyl-1-pyrazolidinio) -1-propen-1-yl] -3-cepem-4-carboxylate (isomers A and B)

783 mg of the compound obtained in Experiment 4 was dissolved in a mixed solution of 1.5 ml of methanol and 7.1 ml of ethyl acetate, and then, 1.5 ml of an ethyl acetate solution of 103 mg of N, N'-dimethylpyrazolidine was added thereto while ice-cooling. The mixture was stirred overnight at room temperature. The resulting reaction solution was added to a mixed solution of 50 ml of ethyl acetate and 50 ml of ethyl ether, and the resulting precipitate was collected by filtration and dried to give 631 mg of a yellow powder.

This powder was added to a mixed solution of 4.5 ml of trifluoroacetic acid and 3.8 ml of anisole, followed by stirring for 2 hours under ice cooling. The resulting reaction solution was added to a mixed solution of 25 ml of ethyl ether and 25 ml of isopropyl ether, and the resulting precipitate was collected by filtration and washed with ethyl ether. The precipitate thus obtained was suspended in 4.5 ml of water, and then sodium acetate was added to adjust the pH of the resulting suspension to 5.5 to 6.5, and the insoluble matter was removed by filtration. The filtrate was purified by reverse phase silica gel column chromatography to obtain 37 mg of the desired isomer A and 27 mg of the isomer B.

Example 123

7β- [2- (5-amino) -1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- (1-methyl-4-formimidoyl-1-piperazinio) -1-propen-1-yl] -3-cepem-4-carboxylate hydrochloride

750 mg of the compound obtained in Experimental Example 4 was dissolved in a mixed solution of 4.5 ml of methanol and 1.5 ml of dimethylformamide, and then added thereto while cooling with 158 mg of N-methyl-N'-formimidoylpiperazine hydrochloride, at room temperature. Stir overnight. The resulting reaction solution was added to a mixed solution of 50 ml of ethyl acetate and 30 ml of ethyl ether, and then the resulting precipitate was collected by filtration and dried to give 485 mg of a yellow powder.

This powder was added to a mixed solution of 3.4 ml of trifluoroacetic acid and 3.0 ml of anisole, followed by stirring for 2 hours under ice cooling. The resulting reaction solution was added to a mixed solution of 25 ml of ethyl ether and 25 ml of isopropyl ether, and the resulting precipitate was collected by filtration and washed with ethyl ether. The precipitate thus obtained was suspended in 4.0 ml of water, and then the insoluble matter was removed by filtration. The filtrate was purified by reverse phase silica gel column chromatography to give 58 mg of the desired product.

In the same manner as in Examples 118 to 123, the compounds of Examples 124 to 140 were synthesized as follows.

Example 124

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- ( 1-methyl-1-piperazinio) -1-propen-1-yl] -3-cepem-4-carboxylate

After reacting 750 mg of the compound obtained in Experiment 4 with 116 μl of N-methylpiperazine, the protecting group was removed to obtain 16 mg of the desired product.

Example 125

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- ( 4-carboxypyridinio) -1-propen-1-yl] -3-cepem-4-carboxylate

After reacting 750 mg of the compound obtained in Experimental Example 4 with 198 mg of isnicotinic acid, the protecting group was removed to obtain 143 mg of the desired product.

Example 126

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- ( 1-methylpyrrolidinio) -1-propen-1-yl] -3-cefe-4-carboxylate

After 500 mg of the compound obtained in Experiment 4 was reacted with 55.8 μl of N-methyl pyrrolidine, the protecting group was removed to obtain 21 mg of the desired product.

Example 127

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- ( 4-carbamoylpyridinio) -1-propen-1-yl] -3-cepem-4-carboxylate

After 500 mg of the compound obtained in Experiment 4 was reacted with 131 mg of 4-carbamoylpyridine, the protecting group was removed to obtain 42 mg of the desired product.

Example 128

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- ( Trimethylammonio) -1-propen-1-yl] -3-cefe-4-carboxylate

500 mg of the compound obtained in Experiment 4 was reacted with trimethylamine (then, 57 mg of trimethylamine hydrochloride when neutralized), and then the protecting group was removed to obtain 79 mg of the target product.

Example 129

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- ( 1,4-diazabicyclo [2,2,2] octane-1io) -1-propen-1-yl] -3-cepem-4-carboxylate

After 500 mg of the compound obtained in Experiment 4 was reacted with 72 mg of 1.4-diazabicyclo [2,2,2] octane, the protecting group was removed to obtain 61 mg of the desired product.

Example 130

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- ( 1,5-diazabicyclo [3,3,0] octane1-io) -1-propen-1-yl] -3-cepem-4-carboxylate

After 500 mg of the compound obtained in Experiment 4 was reacted with 120 mg of 1,5-diazabicyclo [3,3,0] oxane, the protecting group was removed to obtain 32 mg of the desired product.

Example 131

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- ( 4-methyl-4-thiomorpholine-1,1-dioxide-4-io) -1-propen-1-yl] -3-cepem-4-carboxylate

After 250 mg of the compound obtained in Experiment 4 was reacted with 52 mg of 4-methylthiomorpholine-1,1-dioxide, the protecting group was removed to obtain 17 mg of the desired product.

Example 132

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- ( 1,4-dimethyl-1-piperazinio) -1-propen-1-yl] -3-cepem-4-carboxylate

After 500 mg of the compound obtained in Experiment 4 was reacted with 94 μl of 1,4-dimethylpiperazine, a protecting group was removed to obtain 35 mg of the desired product.

Example 133

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- ( 2-aminoethyl) dimethylammonio] -1-propen-1-yl] -3-cepem-4-carboxylate

After reacting 750 mg of the compound obtained in Experimental Example 4 with 115 µl of N, N-dimethylethylenediamine, the protecting group was removed to obtain 15 mg of the desired product.

Example 134

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- [ (Tetrazol-5-yl) methyldimethylammonio] -1-propen-1-yl] -3-cepem-4-carboxylate

After 500 mg of the compound obtained in Experiment 4 was reacted with 150 mg of 5-dimethylaminomethyltetrazole, the protecting group was removed to obtain 37 mg of the desired product.

Example 135

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- ( 3-sulphopyridinio) -1-propen-1-yl] -3-cepem-4-carboxylate

After reacting 750 mg of the compound obtained in Experiment 4 with 384 mg of 3-pyridinesulfonic acid, the protecting group was removed to obtain 68 mg of the desired product.

Example 136

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- [ (2-dimethylaminoethyl) dimethylammonio] -1-propen-1-yl] -3-cepem-4-carboxylate

After 500 mg of the compound obtained in Experimental Example 4 was reacted with 105 µl of N, N, N ', N'-tetramethylethylenediamine, the protecting group was removed to obtain 22 mg of the desired product.

Example 137

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- [ (2-oxopropyl) dimethylammonio] -1-propen-1-yl] -3-cepem-4-carboxylate

After 500 mg of the compound obtained in Experimental Example 4 was reacted with 80 µl of (dimethylamino) acetone, the protecting group was removed to obtain 60 mg of the desired product.

Example 138

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- ( 4-carbamoylquinuclidinio) -1-propen-1-yl] -3-cefe-4-carboxylate

After 500 mg of the compound obtained in Experiment 4 was reacted with 107.6 mg of 4-carbamoylquinuclidin, the protecting group was removed to obtain 77 mg of the desired product.

Example 139

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- [ 1-methyl-2- (2-hydroxyethyl) pyrrolidinio])-1-propen-1-yl] -3-cepem-4-carboxylate (isomers A and B)

500 mg of the compound obtained in Experimental Example 4 was reacted with 83.8 mg of 1-methyl-2- (2-hydroxyethyl) pyrrolidine, and then the protecting group was removed to obtain 24 mg of the isomer A and 26 mg of the isomer B.

Example 140

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- ( 4-carboxymethylpyridinio) -1-propen-1-yl] -3-cepem-4-carboxylate

After 500 mg of the compound obtained in Experiment 4 was reacted with 280 mg of 4-pyridylacetic acid hydrochloride, the protecting group was removed to obtain 5 mg of the desired product.

Example 141

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- ( 1,4,4-trimethyl-1-piperazinio) -1-propen-1-yl] -3-cepem-4-carboxylate

After 1.0 g of the compound obtained in Experiment 4 was suspended in 100 ml of ethyl ether, 189 µl of 1,4-dimethylpiperazine, 40 ml of ethyl acetate solution was added dropwise and stirred overnight. The resulting precipitate was collected by filtration, which was further reprecipitated in tetrahydrofuran / ethyl acetate and then washed with ethyl acetate to give 492 mg of a yellow powder. This was dissolved in 2 ml of dichloromethane and then added thereto while ice-cooled with 4 ml of methyl iodide, followed by stirring overnight at the same temperature. The reaction solution was put in ethyl acetate and the resulting precipitate was collected by filtration to give 190 mg of a tan powder.

This powder was added to a mixed solution of 1.35 ml of trifluoroacetic acid and 1.16 ml of anisole, followed by stirring for 2 hours under ice cooling. The resulting reaction solution was added to a mixed solution of 25 ml of ethyl ether and 25 ml of isopropyl ether, and the resulting precipitate was collected by filtration and washed with ethyl ether. The soak thus obtained was suspended in 4.5 mg of water, and then the insoluble matter was removed by filtration. The filtrate was purified by reverse phase silica gel column chromatography to give 23 mg of the desired product.

Example 142

7β- [2- (5-amino-1, 2,4-thiadiazol-3-yl)-(Z) -2- (2,2,2-trifluoroethyl) oxyimino acetamido]- 3-[(E) -3- (carbamoylmethyldimethylammonio) -1-propen-1-yl] -3-cepem-4-carboxylate

After dissolving 1.43 g of the compound obtained in Experimental Example 4 in 20 ml of acetone, 0.927 g of sodium iodide was added thereto with ice cooling, followed by stirring at the same temperature for 10 minutes and then at room temperature for 30 minutes. The solvent was evaporated and ethyl acetate was added to the resulting residue, which was washed with dilute sodium thiosulfate and saturated brine and then dried by addition of sodium sulfate. After evaporation of the brine, the residue was dissolved in 40 ml of ethyl acetate. 237 mg of dimethylglycineamide was then added to the resulting solution and stirred at room temperature for 1 hour. After isopropyl ether was added to the resulting solution, the resulting precipitate was collected by filtration to give 1.07 g of a tan powder.

This powder was added to a mixed solution of 8 ml of trifluoroacetic acid and 6 ml of anisole, followed by stirring for 1 hour under ice cooling. The resulting reaction solution was added ethyl ether, and the resulting precipitate was collected by filtration. After the precipitate was suspended in 10 ml of water, sodium acetate was added to adjust the pH of the resulting suspension to 5.5-6.5, and the insoluble material was removed by filtration. The filtrate was purified by reverse phase silica gel column chromatography to give 268 mg of the desired product.

Physical data list

Example 143

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyimino acetamido] -3-[(E) -3- [ Tras (2-hydroxyethyl) ammonio] -1-propen-1-yl] -3-cepem-4-carboxylate

400 mg of the compound obtained in Experiment 4 was dissolved in 4 ml of ethyl acetate, and then 96 mg of triethanolamine in 4 ml of ethyl acetate was added thereto. The resulting solution was stirred at rt for 6 h. 24 ml of diisopropyl ether was added to the reaction solution, and the resulting precipitate was collected by filtration. This precipitate was added to 4.5 ml of a mixed solution of trifluoroacetic acid and anisole (1: 1) under ice cooling. The mixture was stirred at rt for 1 h 30 min. 18 ml of diisopropyl ether was added to the reaction solution. The resulting precipitate was collected by filtration and washed with diisopropyl ether. This precipitate was suspended in 3 ml of water, and sodium acetate was added thereto to adjust the pH of the resulting solution to 6. After the inert material was removed by filtration, the filtrate was purified by reverse phase silica gel column chromatography to give 17 mg of the desired product.

Example 144

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- [Bis (2-hydroxyethyl) methylammonio] -1-propen-1-yl] -3-cepem-4-carboxylate

In the same manner as in Experimental Example 143, after 500 mg of the compound prepared in Experiment 4 was reacted with 150 mg of N-methyldiethanolamine, a protecting group was removed to obtain 15 mg of the target product.

Example 143

2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z) -2-cyanomethoxyiminoacetic acid

8.00 g of N-cyanomethoxyphthalimide was suspended in 50 ml of ethanol, and then 1.93 ml of hydrazine monohydrate was added at room temperature. The resulting mixture was stirred for 1 hour 45 minutes. Then saturated brine and ethyl ether were added thereto. The mixture was made basic by addition of concentrated ammonia water and then extracted with ethyl ether. The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was then distilled off.

To the residue was added 350 ml of methanol and 650 g of 2- (5-tritylamino-1,2,4-thiadiazol-3-yl) glyoxylic acid, and the resulting mixture was stirred at room temperature for 1 hour. After distilling off the solvent, the residue was dissolved in ethyl acetate and then washed with 0.1N hydrochloric acid followed by saturated brine. After drying the organic layer through anhydrous sodium sulfate, the solvent was distilled off and 7.64g of the target compound was obtained.

Example 9

[Synthesis of raw compound]

p-methoxybenzyl 7β- [2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z) -2-cyanomethoxyiminoacetateamido] -3- [ (Z) -3-chloro-1-propen-1-yl] -3-cepem-4-carboxylate

After 1.51 ml of dimethylformamide and 18 ml of tetrahydrofuran were cooled to -10 ° C, 1.82 ml of phosphoryl chloride was added thereto. The resulting mixture was stirred for 40 minutes under ice cooling. Then a solution of 7.64 g of the compound of Experimental Example 8, dissolved in 24 ml of tetrahydrofuran was added thereto, and the resulting mixture was further stirred at the same temperature for 1 hour.

p-methoxybenzyl 7β-amino-3-[(Z) -3-chloro-1-propen-1-yl] -3-cef-4-carboxylate hydrochloride 6.00 g, N-trimethylsilylacetamide 12.8 g and 60 ml of ethyl acetate were cooled to -25 ° C. Then, after adding the reaction mixture described above thereto, the temperature was raised to 0 ° C. while stirring the resulting mixture for 40 minutes. The solution mixture was extracted with mg of ethyl acetate, and then the organic layer was washed with saturated brine and dried using anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain 7.80 g of the target compound.

Example 10

[Synthesis of raw compound]

p-methoxy benzyl 7β- [2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z) -2-cyanomethoxyiminoacetamido] -3- [(E) -3-iodine-1-propen-1-yl] -3-cepem-4-carboxylate

To a solution of 7.80 g of the compound of Example 9 dissolved in 120 ml of acetone, 6.9 g of sodium iodide was added under ice cooling. The resulting mixture was stirred for 10 minutes more then 1 hour 30 minutes at room temperature. After distilling off the solvent, the residue was extracted using ethyl acetate. The extract was washed with dilute aqueous sodium thiosulfate solution followed by saturated brine and then dried over anhydrous sodium sulfate. The solution was concentrated and then added dropwise to a mixture of isopropyl ether and ethyl ether. The resultant precipitate was filtered to give 6.50 g of the target compound.

Example 145

7β- [2-5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-cyanomethoxyiminoacetamido] -3-[(E) -3- [ (1S-carbamoyl-2-hydroxyethyl) dimethylammonio] -1-propen-1-yl] -3-cepem-4-carboxylate

1.0 g of the compound of Experimental Example 10 was dissolved in 2 ml of dimethylformamide, and then 210 mg of (1S-carbamoyl-2-hydroxyethyl) dimethylamine was added thereto at room temperature. The resulting pig mixture was stirred for 1 hour, and diluted by adding 10 ml of ethyl acetate thereto. The resulting solution was added dropwise to 100 ml of ethyl ether to obtain 710 mg of brown precipitate.

This precipitate was stirred in a mixture of 6 ml of anisole and 6.4 ml of trifluoroacetic acid under ice cooling for 1 hour. Ethyl ether was then added to the reaction mixture to give 430 mg of a brown precipitate. The precipitate was suspended in 10 ml of water, and then the pH of the suspension obtained by adding sodium acetate was adjusted to 7.0. After filtering the insoluble material, the filtrate was purified by reverse phase silica gel column chromatography to obtain 50 mg of the target compound. Got it.

Example 146

7β- [2-5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-cyanomethoxyiminoacetamido] -3-[(E) -3- [ (1-methyl-2R-hydroxymethyl-4R-hydroxy-1-pyrrolidinio) -1-propen-1-yl] -3-cefe-4-carboxylate

1.0 g of the compound of Experimental Example 10 was dissolved in a mixture of 10 ml of ethyl acetate and 8 ml of ethyl ether. Then, 167 mg of N-methyl-4R-hydroxy-D-prolinol was added thereto, and the resulting mixture was stirred overnight. The reaction mixture was added to 100 ml of ethyl ether, and the resulting precipitate was filtered to give 840 mg of yellow powder.

After 6m of anisole was added to the powder, 8 ml of trifluoroacetic acid was added dropwise to the resulting mixture for 30 minutes under ice cooling. The reaction mixture was then stirred for another 1 hour 30 minutes. After 100 ml of ethyl ether was added to the reaction mixture, the resulting precipitate was filtered and suspended in 4 ml of water. To this was added sodium acetate to adjust the pH of the resulting suspension to 7.0. After insoluble material was filtered off, the filtrate was purified by reverse phase silica gel column chromatography to give 24 mg of the target compound.

In the same manner as in Examples 145 and 146, the compounds of Examples 147-154 below were obtained.

If a plurality of isomers were produced according to Ammoniagi A, the yields of the isomers are shown respectively.

Physical data list

Example 155

7β- [2-5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-cyanomethoxyiminoacetamido] -3-[(E) -3-- Carbamoylmethyldimethylammonio) -1-propen-1-yl] -3-cefe-4-carboxylate

After 64 mg of dimethylglycinamide was added to a solution of 390 mg of the compound of Experimental Example 10 dissolved in 15 ml of ethyl acetate, the mixture was stirred at room temperature for 1 hour. After adding ethyl ether to this reaction solution, the resulting precipitate was filtered and dried to give 260 mg of a tan powder.

A mixture of 2 ml of trifluoroacetic acid and 1.5 ml of anisole was added to the powder and then stirred for 1 hour under ice-cooled conditions. After addition of ethyl ether to the resulting solution, the resulting precipitate was filtered off and washed with ethyl ether. This precipitate was suspended in 5 ml of water and the pH of this suspension was adjusted to 5.5-6.5, after which the insoluble material was filtered off. The filtrate was purified by reverse phase chromatography to give 37 mg of the target substance.

Example 156

7β- [2-5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-cyanomethoxyiminoacetamido] -3-[(E) -3- ( 1-methyl-4-sulfamoyl-1-piperazinio) -1-propen-1-yl] -3-cepem-4-carboxylate

500 mg of the compound of Experimental Example 10 was dissolved in a mixture of 5 ml of dichloromethane and 1 ml of methanol, and then 145 mg of N-sulfamoyl-N'-methylpiperazine was added thereto, and all of them were stirred at room temperature for 4 hours. . After the resulting solution was concentrated, ethyl ether was added thereto. The resulting precipitate was filtered and dried to give 420 mg of a tan powder.

A mixture of 3.5 ml of trifluoroacetic acid and 3 ml of anisole was added to the powder, which was all stirred for 1 hour. After addition of ethyl ether to the resulting solution, the resulting precipitate was filtered off and washed with ethyl ether. The precipitate was suspended in 5 ml of water and the pH of this suspension was adjusted to 5.5-6.5, after which the insoluble material was filtered off. The solution was purified by reverse phase chromatography to give 39 mg of the target substance.

Example 157

7β- [2-5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-cyanomethoxyiminoacetamido] -3-[(E) -3- ( 1,4-diazabicyclo [2,2,2] octane-1-io) -1-propen-1-yl] -3-cepem-4-carboxylate

500 g of the compound of Experimental Example 10 was dissolved in a mixture of 6 ml of ethyl acetate and 0.5 ml of methanol, and then 90 mg of 1,4-diazabicyclo [2,2,2] octane was added thereto, followed by stirring at room temperature for 20 minutes. I was. After addition of ethyl ether to the resulting solution. The resulting precipitate was filtered and dried to give 330 mg of a tan powder.

A mixture of 3 ml of trifluoroacetic acid and 2.5 ml of anisole was added to the powder, which was all stirred for 1 hour under ice-cooled conditions. After addition of ethyl ether to the resulting solution, the resulting precipitate was filtered off and washed with ethyl ether. The precipitate was suspended in 5 ml of water and the pH of this suspension was adjusted to 5.5-6.5, after which the insoluble material was filtered off. The solution was purified by reverse phase chromatography to give 48 mg of the target substance.

In the same manner as in Examples 155 to 157, the compounds of Examples 158 to 161 were obtained.

Example 158

7β- [2-5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-cyanomethoxyiminoacetamido] -3-[(E) -3- ( 4-carbamoylpyridinio) -1-propen-1-yl] -3-cepem-4-carboxylate

After 600 mg of the compound of Experimental Example 10 was reacted with 235 mg of 4-carbamylpyridine, the protecting group was removed to obtain 37 mg of the target substance.

Example 159

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-cyanomethoxyiminoacetamido] -3-[(E) -3- (1,3,4-oxadiazol-2-yl) methyldimethylammonio] -1-propen-1-yl] -3-cepem-4-carboxylate

After 600 mg of the compound of Experimental Example 10 was reacted with 163 mg of 2-dimethylaminomethyl-1,3,4-oxadiazole, the protecting group was removed to obtain 54 mg of the target substance.

Example 160

7β- [2-5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-cyanomethoxyiminoacetamido] -3-[(E) -3- ( 1,2-dimethyl-1-piperazinio) -1-propen-1-yl] -3-cepem-4-carboxylate (isomers A and B)

After reacting 510 mg of the compound of Experimental Example 10 with 0.4 ml of 1,2-dimethylpyrazolidine, the protecting group was removed to obtain 20 mg of the desired isomer A and 20 mg of the isomer B.

Example 161

7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-cyanomethoxyiminoacetamido] -3-[(E) -3- (1,5-diazabicyclo [3,3,0] octane-1-io) -1-propen-1-yl] -3-cepem-4-carboxylate

After reacting 600 mg of the compound of Experimental Example 10 with 220 mg of 1,5-diazabicyclo [3,3,0] octane, the protecting group was removed to obtain 39 mg of the target substance.

Experimental Example 11

[Synthesis of raw compound]

2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetic acid chloride hydrochloride

395 mg of phosphorus pentachloride was dissolved in 2.9 ml of dichloromethane and then cooled to -5 ° C. 627 mg of the compound of Experimental Example 2 was added to this solution, and the mixture was stirred for 2 and a half hours at the same temperature as above. The reaction solution was added to a mixture of 9.4 ml of n-hexane and 9.4 ml of n-octane. The resulting crystalline material was collected by filtration and washed with n-octane to give 325 mg of the desired product.

Melting point: 139 ° -140 ° C. (decomposition).

Mass spectrum (m / e): M ⁺ . 480 ( ³⁵ Cl), 482 ( ³⁷ Cl)

Infrared Absorption Spectrum (cm ^-1 , Newsol): 1795, 1780, 1740, 1630

NMR spectrum (δ, DMSO-d ₆ ): 5.79 (2H, d, J = 54 Hz), 7.31 (15H, s), 10.09 (1H, s).

Experimental Example 12

[Synthesis of raw compound]

2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetic acid ethyl ester

2.00 g of the compound of Experimental Example 1 was stirred in trifluoro acetic acid at room temperature for 30 minutes. After distilling off the solvent, the residue was purified by silica gel column chromatography to give 405 mg of the desired product.

Melting point: 172 ° -173 °.

Infrared Absorption Spectrum (cm ^-1 , Newsol): 1730, 1615

NMR spectrum (δ, DMSO-d ₆ ): 1.28 (3H, t, J = 7.0 Hz), 4.34 (2H, q, J = 7.0 Hz), 5.83 (2H, d, J = 54.5 Hz), 8.27 (2H , brs).

Experimental Example 13

[Synthesis of raw compound]

2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetic acid

200 mg of the compound of Experimental Example 12 was suspended in a mixture of 6 ml of ethanol and 2 ml of water, and then 1.75 ml of 1N sodium hydroxide aqueous solution was added thereto, and the mixture was stirred at 60 ° C for 1 hour. After distilling ethanol from the reaction solution, the pH of the solution was adjusted to 2 using 1N hydrochloric acid. The resulting solution was purified by Dia-Ion 5P207 [trademark of nonionic adsorption resin manufactured by Mitsubishi Chemical Industries, Ltd.] to obtain 30 mg of the desired product.

Infrared Absorption Spectrum (cm ^-1 , Newsol): 1720, 1620

NMR spectrum (δ, DMSO-d ₆ ): 5.74 (2H, d, J = 55 Hz), 8.24 (2H, br).

Experimental Example 14

[Synthesis of raw compound]

p-methoxybenzyl 7β-[-(5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3- [ (Z) -3-chloro-1-propen-1-yl] -3-cepem-4-carboxylate

In a mixture of 37 ml of ethyl acetate, 5 ml of tetrahydrofuran and 15.7 ml of dichloromethane, 8.17 g of N- (trimethylsilyl) acetamide and p-methoxybenzyl 7β-amino-3-[(Z) -3-chloro-1-prop The latter material was dissolved by adding 3.33 g of phen-1-yl] -3-cef-4-carboxylate hydrochloride. After cooling the solution to −20 ° C., 3.80 g of the compound of Experimental Example 11 was added thereto and stirred at 10 ° C. for 1 hour. After adding 500 ml of ethyl acetate to the reaction solution, the mixture was washed successively with water, saturated aqueous sodium bicarbonate solution, 1N hydrochloric acid and saturated brine, and then dried by adding anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain 4.33 g of the desired product.

The infrared absorption spectrum and NMR spectrum of the obtained product were consistent with Experimental Example 3 above.

Experimental Example 15

[Synthesis of raw compound]

2-cyano-2-fluoromethoxyiminoacetamide

After dissolving 22.6 g of 2-cyano-2-hydroxyaminoacetamide in 100 ml of dimethyl sulfoxide, 55.2 g of potassium carbonate was then added thereto while stirring at room temperature, and the solution was further stirred for 20 minutes. To this solution was then added 27 g of fluorobromometal dissolved in 20 ml of dimethylformamide, then the solution was stirred at room temperature for 20 minutes and then cooled. The reaction solution was added to 1 liter of ice water, and then extracted twice using 150 ml of ethyl acetate. The organic layer was washed twice with saturated brine, dried by adding anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was washed with ethyl ether and dried to give 14.4 g of the desired product.

Melting Point: 124 ° -125 ℃

Infrared Absorption Spectrum (cm ^-1 , Newsol): 3410, 3290, 3150, 1690, 1590

NMR spectrum (δ, DMSO-d ₆ ): 5.94 (2H, d, J = 54.0 Hz), 7.85-9.40 (2H, b).

Experimental Example 16

[Synthesis of raw compound]

2-fluoromethoxyiminopropanedinitrile

A mixture containing 14.0 g of the compound prepared in Experiment 15, 15 ml of acetonitrile, 15 g of sodium chloride, and 14 ml of phosphoryl chloride was reacted under reflux for 2 hours. 5 ml of phosphoryl chloride was added to the mixture, and all of them were reacted for 2 hours. After the reaction solution was cooled, it was added to 200 ml of ice water and stirred at room temperature for 1 hour. This solution was extracted twice using 50 ml of methylene chloride. The extract was washed with 5% aqueous sodium bicarbonate solution and saturated brine, and then dried by adding anhydrous magnesium sulfate. After distilling off the solution, the resulting oily product was distilled off under reduced pressure to give 9.1 g of a colorless oily target product.

Boiling Point: 69 ° -70 ℃ / 25mmHg

NMR spectrum (δ, CDCl ₃ ): 5.85 (2H, d, J = 52.0 Hz).

Experimental Example 17

[Synthesis of raw compound]

2-cyano-2-fluoromethoxyiminoacetamines

The mixed solution containing 50 ml of 28% ammonia water, 8 g of ammonium chloride and 50 ml of ethanol was cooled to -5 ° C, and then 9.1 g of the compound prepared in Experimental Example 16 was added thereto under stirring, followed by further 3 hours at the same temperature. Stirred. 100 ml of water was added to the reaction solution. This solution was extracted three times using 50 ml of methylene chloride. The extract was dried by adding anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was washed with ethyl ether and dried to give 3.4 g of the desired product.

Some of the product was dissolved in ethanol and then added dropwise with glacial acetic acid. The resulting precipitate was collected by filtration, washed with ethanol and dried to obtain an acetate of the target compound. The data showing the physical properties of this acetate salt are as follows.

Melting Point: 125 ° -127 ℃

Infrared Absorption Spectrum (cm ^-1 , Newsol): 3200, 1670, 1570

NMR spectrum (δ, DMSO-d ₆ ): 1.90 (3H, s), 5.95 (2H, d, J = 54.0 Hz), 7.40 (3H, b).

Experimental Example 18

[Synthesis of raw compound]

2- (5-amino-1,2,4-thiadiazol-3-yl)-(E) -2-fluoromethoxyiminoacetonitrile

3.0 g of the compound prepared in Experimental Example 17 was dissolved in 50 ml of methanol, and 4.2 g of triethylamine was added thereto. After cooling the solution to −5 ° C., 3.5 g of bromine was added dropwise thereto. A solution of 2.1 g of potassium thiocyanate dissolved in methanol was then added dropwise at a temperature of -3 ° C to -5 ° C, and then the solution was stirred at the same temperature for 2 hours. The resulting precipitate was recovered by filtration and washed with water and methanol. The precipitate was then recrystallized using acetone to give 3.4 g of the desired product.

Melting point: 236 ° -238 ° C.

Infrared Absorption Spectrum (cm ^-1 , Newsol): 3450, 3250, 3075, 1610, 1520

NMR spectrum (δ, DMSO-d ₆ ): 6.02 (2H, d, J = 54.0 Hz), 8.32 (2H, b).

Experimental Example 19

Synthesis of Raw Compound

2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetamide

To a solution of 0.23 g of sodium hydroxide dissolved in 18 ml of water, 7.4 ml of 35% aqueous hydrogen peroxide solution was added. To this, 2.0 g of the compound prepared in Experimental Example 18 was added while stirring at room temperature. The mixture was further stirred for 8 hours at a temperature of 25 ° to 30 ° C. The precipitate deposited was collected by filtration, washed with water and acetone, and dried to obtain 1.3 g of the desired product.

Melting point: 210 ° -211 ° C.

Infrared Absorption Spectrum (cm ^-1 , Newsol): 3450, 3260, 3180, 1690, 1610

NMR spectrum (δ, DMSO-d ₆ ): 5.73 (2H, d, J = 55.0 Hz), 7.69 (2H, br), 7.98 (1H, br), 8.10 (1H, br).

Experimental Example 20

2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxy iminoacetic acid

A mixture containing 1.1 g of the compound prepared in Experimental Example 19 and 10 ml of a 2N sodium hydroxide aqueous solution was stirred at 50 ° C. for 5 hours. The reaction mixture was cooled, adjusted to ph 1.0 by adding concentrated hydrochloric acid, and then extracted three times using 20 ml of ethyl acetate. Anhydrous magnesium sulfate was added to the extract, dried and the solvent was distilled off. The residue was washed with isopropyl ether to give 0.8 g of crude product. The crude product was purified by reverse phase silica gel column chromatography to afford 0.4 g of the desired product.

The infrared absorption spectrum and NMR spectrum of this product were the same as those in Experimental Example 13.

Example 162

[Production of Injection]

10 g of the compound prepared in Example 1 was dissolved in 50 ml of distilled water. The solution was divided and polymerized to contain 5 ml of solution in each vial. This solution was lyophilized to obtain an injection.

Example 163

[Production of Injection]

10 g of the compound prepared in Example 151 was dissolved in 50 ml of distilled water. The solution was divided and injected to contain 5 ml per vial. This solution was lyophilized to obtain an injection.

Acute toxicity and antimicrobial activity of the compounds according to the invention were determined by the following method.

(1) Acute Toxicity in Bird Rats

Compounds of the present invention dissolved in physiological saline were administered intravenously to five 6 week old, male ICR rats. As a result, all of the acute monounsities of the compounds prepared in the following examples were 2 g / kg or more.

Example number

1, 2-1, 2-2, 3-1. 3-2, 5, 6-1, 6-2, 7-1, 7-2, 9-1, 9-2, 9-3, 10, 11, 12, 13-1, 13-2, 96, 121, 137, 145, 146, 150, 151, 154 and 155

(2) antimicrobial activity (MIC)

MIC (µg / ml) was measured by agar dilution method [Chemotherapy (Japan), Vol. 29, pp. 76-79 (see 1981) .Bacterial strain overnight culture in Mueller-Hinton broth. Water was diluted to a final concentration of about 10 ⁶ CFU / ml and 5 μl of each bacterial suspension was dropped onto a Mueller-Hinton agar plate containing a 2-fold dilution of the antibody, which was incubated at 37 ° C. for 18 hours. , MIC was measured.

As a control, CAZ (Sephatazidim) and CTM (Cellosis) were selected.

Antimicrobial activity list

3. Antimicrobial Activity (MIC)

A comparative test of antimicrobial activity was conducted between a compound of the present invention having the following general formula and a corresponding control compound wherein R ₁ is a methyl group. The measurement of MIC is the same as the method described in the said item. The results are shown in the table below.

Claims (1)

Quinoline carboxylic acid derivative represented by the following general formula [I], and its physiologically acceptable salt. Wherein R ¹ is hydrogen, alkyl, or substituted or unsubstituted phenyl, R ² is hydrogen or alkyl, R ³ is hydrogen, halogen, or alkoxy.