JPH0526795B2 - - Google Patents

Description

[Detailed description of the invention]

This invention is useful as an antibacterial substance with the general formula: [In the formula, R ¹ is an amino group or a protected amino group; R ² is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cyclo(lower) alkyl group, or Cyclo (lower) alkenyl group; R ³ is lower alkylamino group, N- (lower) alkanoyl (lower) alkylamino group, di (lower)
Alkylamino group, sulfo (lower) alkylamino group, hydroxy (lower) alkylamino group, N
-(lower)alkanoylhydroxy(lower)alkylamino group, alkanoyloxy(lower)alkyl group, alkenoyloxy(lower)alkyl group, loweralkoxy(lower)alkoxy(lower)
Alkyl group, di(lower)alkylamino(lower)
Alkyl group, lower alkylthio (lower) alkyl group, lower alkylthio group, lower alkoxy group, lower alkoxy (lower) alkoxy group, hydroxy (lower) alkoxy group, lower alkanesulfonyl (lower) alkyl group, hydroxy (lower) alkylthio group, di(lower)alkylamino(lower)alkylthio group, tetrazolyl group, tetrazolylthio group, tetrazolylthio(lower)alkyl group or dihydrotriazinylthio(lower)alkyl group substituted with oxo, hydroxy and lower alkyl; R ⁴ is a hydrogen atom or a lower alkyl group, or R ¹ has the same meaning as above; R ² is an ethyl group; R ³ is a methoxymethyl group; R ₄ is a hydrogen atom]; The present invention relates to salts thereof, methods for producing them, and agents for preventing and treating bacterial infections. The novel cefem compound [] of this invention can be produced by various methods shown in the following reaction formula. [In the formula, R ¹ , R ² , R ³ and R ⁴ have the same meanings as before; R ⁵ has the formula:

[Formula] (wherein R ³ and R ⁴ have the same meanings as before); R ^3a is an N-(lower) alkanoyl(lower) alkylamino group or an N-(lower ) Alkanoylhydroxy (lower) alkylamino group; R ^3b is a lower alkylamino group or hydroxy (lower) alkylamino group; R ⁶ is a protected carboxy group; X means an acid residue]. Among the raw material compounds of this invention, compound [] is a new compound and can be produced by the production method shown in the following reaction formula. [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁶ and X each have the same meaning as before]. Some of the compounds [] can be produced by the production method shown in the following reaction formula. [In the formula, R ² has the same meaning as before, Z means a protected carboxy group, and Y means a halogen.] Target compounds [], [a] and [b] and starting compounds [], [], [], [a],
〔〕,〔〕,〔〕,〔〕,〔〕and〔
]
For the above, the target compound and starting compound include syn isomer, anti isomer, and mixtures thereof. For example, the target compound []
The syn isomer has the formula: [In the formula, R ¹ and R ² each have the same meaning as before]
refers to one geometric isomer having a partial structure of the formula: [In the formula, R ¹ and R ² have the same meanings as above] means the other geometric isomer having the partial structure. Regarding the target compounds and starting compounds other than compound [], the syn isomer and anti isomer can be explained in the same manner as the geometric isomer explained for compound []. Suitable salts of the target compound [] are conventional non-toxic salts, such as metal salts such as alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts and magnesium salts;
Ammonium salts, such as trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, organic base salts such as N,N'-dibenzylethylenediamine salts, such as acetates, maleates, tartrates, methanesulfonates. , organic acid salts such as benzenesulfonate, formate, toluenesulfonate, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, or for example arginine, Examples include salts with amino acids such as aspartic acid and glutamic acid. In the foregoing and following descriptions of this specification, pertinent examples and explanations of various definitions falling within the scope of this invention are set forth in detail below. "Lower" means 1 to 1 carbon atom unless otherwise specified.
It means a group having 6 members. A suitable “protected amino” for R ¹ is:
Examples include amino groups substituted with conventional protecting groups such as acylamino or al(lower) alkyl which may have at least one substituent such as benzyl or trityl. Suitable acyl groups and suitable acyl moieties in "acylamino", "acyloxy" and "acyloxy(lower)alkyl" include carbamoyl, aliphatic acyl groups and acyl groups containing aromatic or heterocycles. Preferable examples of the acyl group include carbamoyl; for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl,
Alkanoyls having 1 to 18 carbon atoms such as succinyl, pivaloyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl; Acryloyl, methacryloyl, crotonoyl, isocrotonoyl, pentenoyl, hexenoyl, heptenoyl, dodecenoyl, tetradecenoyl, hexadecenoyl, oleoyl,
Alkenoyl having 3 to 20 carbon atoms such as elaidyl; e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl lower alkoxycarbonyl having 2 to 7 carbon atoms such as; lower alkanesulfonyl such as mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl; arenesulfonyl such as benzenesulfonyl, tosyl; for example benzoyl, toluoyl, Aroyl such as xyloyl, naphthoyl, phthaloyl, indancarbonyl; Al(lower) alkanoyl such as phenyl acetyl, phenylpropionyl; Al(lower) alkoxycarbonyl such as benzyloxycarbonyl, phenethyloxycarbonyl, etc. . The acyl moiety may have at least one substituent such as halogen (eg, chlorine, bromine, fluorine, and iodine), lower alkanoyl, and the like. Suitable "alkanoyl" moieties in the "alkanoyloxy(lower)alkyl group" include those described above for the acyl group. Suitable "alkenoyl" moieties in the "alkenoyloxy(lower)alkyl group" include those described for the acyl group above. The "(lower)alkanoyl" moiety in "N-(lower)alkanoyl(lower)alkylamino group" and "N-(lower)alkanoylhydroxy(lower)alkylamino group" includes those explained for the above-mentioned acyl group. carbon atom 1~
One example is one having 6 pieces. Suitable "lower alkyl" and "lower alkylamino", "N-(lower)alkanoyl(lower)alkylamino", "di(lower)alkylamino",
"Sulfo(lower)alkylamino", "Hydroxy(lower)alkylamino", "N-(lower)alkanoylhydroxy(lower)alkylamino group", "Hydroxy(lower)alkylthio", "Di(lower)alkylamino( (lower)alkylthio”, “acyloxy(lower)alkyl”, “lower alkoxy(lower)alkoxy(lower)alkyl”, “di(lower)
"alkylamino (lower) alkyl", "lower alkylthio (lower) alkyl", "lower alkylthio",
"Lower alkanesulfonyl (lower) alkyl" and "tetrazolylthio (lower) alkyl group",
and “Dihydrotriazinylthio (lower) substituted with oxo, hydroxy and lower alkyl
Preferred "lower alkyl moieties" in "alkyl groups" are alkyls having 1 to 6 carbon atoms, examples of which are methyl, ethyl, propyl,
Examples include isopropyl, butyl, isobutyl, tertiary butyl, pentyl, tertiary pentyl, hexyl, etc., and preferably alkyl having 1 to 4 carbon atoms. Suitable "lower alkenyl" has 2 to 6 carbon atoms, examples of which include vinyl, allyl, isopropenyl, 1-propenyl, 2-butenyl, 3-pentenyl, etc., but preferably carbon It has 2 to 4 atoms. Suitable "lower alkynyls" are those having 2 to 6 carbon atoms, examples include ethynyl,
Examples include 2-propenyl, 2-butynyl, 3-pentynyl, 3-hexynyl, etc., and preferably one having 2 to 4 carbon atoms. The above-mentioned "lower alkyl group", "lower alkenyl group" and "lower alkynyl group" may be substituted with 1 to 3 carboxy groups. Suitable "cyclo(lower)alkyl" has 3 to 6 carbon atoms, and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., but preferably has 5 to 6 carbon atoms.
It has 6 pieces. Suitable "cyclo(lower) alkenyl" has 3 to 6 carbon atoms, and includes cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc., and preferably has 5 to 6 carbon atoms. It is. Preferred "lower alkoxy" moieties in "lower alkoxy" and "lower alkoxy (lower) alkoxy (lower) alkyl", "lower alkoxy (lower) alkoxy" and "hydroxy (lower) alkoxy" include methoxy, ethoxy , propoxy, isopropoxy, butoxy, tertiary butoxy, pentyloxy, hexyloxy and the like, preferably having 1 to 3 carbon atoms. "Lower alkanesulfonyl (lower) alkyl"
Suitable "lower alkanesulfonyl" moieties include those exemplified for the "acyl group" above. Suitable "tetrazolyl group" and "tetrazolylthio group" and "tetrazolylthio (lower)
Suitable "tetrazolyl" moieties in "alkyl groups" include, for example, 1H-tetrazolyl, 2H-
Examples include tetrazolyl. Suitable ^R5 examples include acyloxy, azide,
Examples include acid residues such as halogens (eg, chlorine, bromine, iodine or fluorine), and the acyl moiety of "acyloxy" includes the same as those exemplified above. Suitable examples of X include the above acid residues. Suitable "halogens" include chlorine, bromine, fluorine or iodine. Suitable "protected carboxy" includes esterified carboxy, such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester. , pentyl ester, tertiary pentyl ester, hexyl ester, heptyl ester, octyl ester, nonyl ester,
Alkyl esters such as decyl ester, undecyl ester, dodecyl ester, and hexadecyl ester; Lower alkenyl esters such as vinyl ester and allyl ester; Lower alkynyl esters such as ethynyl ester and propynyl ester; For example, 2-iodoethyl ester, 2,
Mono (or di or tri) halo (lower) alkyl esters such as 2,2-trichloroethyl ester; for example acetoxymethyl ester, propionyloxymethyl ester, 1-acetoxypropyl ester, valeryloxymethyl ester,
Lower alkanoyloxy (lower) alkyl esters such as pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1-acetoxyethyl ester, 2-propionyloxyethyl ester, 1-isobutyryloxyethyl ester; for example, mesylmethyl ester, Lower alkanesulfonyl (lower) alkyl esters such as 2-mesylethyl ester; e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, diphenylmethyl ester, bis(methoxyphenyl) Methyl ester, 3,4-
dimethoxybenzyl ester, 4-hydroxy-
1 such as 3,5-ditertiary butylbenzyl ester
Al (lower) alkyl esters, examples of which include phenyl (lower) alkyl esters optionally substituted with one or more suitable substituents; such as methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, ethoxycarbonyloxyethyl Lower alkoxycarbonyloxy (lower) alkyl esters optionally substituted with azide, such as esters; heterocyclic esters, preferably benzotetrahydrofuryl esters optionally substituted with an oxo group, more preferably phthalidyl esters; e.g. Aroyloxy (lower) alkyl esters such as benzoyloxymethyl ester, benzoyloxyethyl ester, toluoyloxyethyl ester; e.g. phenyl ester, tolyl ester, tertiary butyl phenyl ester, xylyl ester, mesityl ester, cumenyl ester Examples include aryl esters which may have one or more suitable substituents. Preferred examples of "protected carboxy" include lower alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, or, for example, benzyloxycarbonyl, phenethyloxycarbonyl, trityloxy Al(lower) alkoxycarbonyl such as carbonyl and diphenylmethoxycarbonyl are mentioned. Preferred embodiments of the target compound [] are as follows. Preferred embodiments of R ¹ are amino; preferred embodiments of R ² are lower alkyl, carboxy(lower) alkyl, lower alkynyl, cyclo(lower) alkyl, cyclo-lower alkenyl or lower alkenyl; preferred embodiments of R ³ are the above-mentioned as defined; a preferred embodiment of R ⁴ is hydrogen or lower alkyl; or a preferred embodiment of R ¹ is amino; a preferred embodiment of R ² is ethyl; a preferred embodiment of R ³ is methoxymethyl ; A preferred embodiment of R ⁴ is hydrogen. The method for producing the object compound of the present invention will be explained in detail below. Method 1 The target compound [ ] or its salts can be produced by reacting the compound [ ] or its salts with the compound [ ] or its salts. As the compound [] and suitable salts of the compound [], the same salts as those exemplified for the compound [] can be mentioned. This reaction may be carried out in a solvent such as water, phosphate buffer, phosphoric acid, acetone, chloroform, acetonitrile, nitrobenzene, methylene chloride, ethylene chloride, formamide, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran, dimethyl sulfoxide. Although any solvent can be used as long as it does not adversely affect the reaction, it is preferable to carry out the reaction in a polar solvent. The hydrophilic solvent in the above solvent may be used in combination with water. The reaction is preferably carried out in a near-neutral medium. When compound [] is used in free form, the reaction is carried out with a base,
Inorganic bases such as alkali metal hydroxides, alkali metal carbonates, alkali metal hydrogen carbonates,
It is desirable to carry out the reaction in the presence of an organic base such as a trialkylamine. The reaction temperature is not particularly limited, and the reaction is usually carried out at room temperature, with or without heating. This reaction is preferably carried out in the presence of an alkali metal halide such as sodium iodide or potassium iodide, an alkali metal thiocyanate such as sodium thiocyanate or potassium thiocyanate. Method 2 The target compound [b] or its salts can be produced by subjecting the compound [a] or its salts to an amino-protecting group elimination reaction. Suitable salts for compounds [a] and [b] include the same salts as exemplified for compound []. This elimination reaction involves hydrolysis; reduction; reacting the compound [ ] whose protecting group is an acyl group with an iminohalogenating agent, then reacting with an iminoetherifying agent, and if necessary, subsequently hydrolyzing the product. It is carried out according to conventional methods such as the method described in . Examples of the hydrolysis method include methods using acids, bases, hydrazine, and the like. These methods may be selected depending on the type of protecting group to be removed. Among these methods, hydrolysis using acid is
For example, substituted or unsubstituted alkoxycarbonyl such as tertiary pentyloxycarbonyl, tertiary butoxycarbonyl, alkanoyl such as formyl, cycloalkoxycarbonyl, substituted or unsubstituted aral such as benzyloxycarbonyl, substituted benzyloxycarbonyl, etc. It is one of the common and preferred methods for removing protecting groups such as koxycarbonyl, eg, alkyl (lower) alkyl such as benzyl and trityl. Suitable acids include organic or inorganic acids such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, and preferred acids include formic acid, trifluoroacetic acid, hydrochloric acid, etc. be. The acid to be used in the reaction is appropriately selected depending on the type of protecting group to be removed. If the elimination reaction is carried out using an acid, a solvent may or may not be present. Suitable solvents include conventional organic solvents, water or mixtures thereof. When using trifluoroacetic acid, it is desirable to carry out the elimination reaction in the presence of anisole. Hydrolysis with hydrazine is commonly applied to remove protecting groups such as succinyl or phthaloyl. Base hydrolysis is preferably applied to eliminate acyl groups, such as haloalkanoyls such as dichloroacetyl, trifluoroacetyl, etc. Examples of suitable bases include, for example, sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, e.g. magnesium carbonate, calcium carbonate, etc. alkaline earth metal carbonates, e.g. sodium bicarbonate,
Alkali metal bicarbonate such as potassium bicarbonate,
For example, alkali metal acetates such as sodium acetate and potassium acetate, alkaline earth metal phosphates such as magnesium phosphate and calcium phosphate, alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate, etc. Inorganic bases such as, for example, trialkylamines such as trimethylamine, triethylamine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5
- Organic bases such as diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane, 1,5-diazabicyclo[5,4,0]undecene-5, etc. can be mentioned.
Hydrolysis with bases is often carried out in water, customary organic solvents or mixtures thereof. In the protecting group, the acyl group can usually be removed by the above hydrolysis or other conventional hydrolysis. When the acyl group is halogen-substituted alkoxycarbonyl or 8-quinolyloxycarbonyl, these acyl groups are removed by treatment with heavy metals such as copper, zinc, etc. Elimination by reduction is usually carried out for example by haloalkoxycarbonyl, such as trichloroethoxycarbonyl,
For example, it is applied to the removal of protecting groups such as benzyloxycarbonyl, substituted or unsubstituted aralkoxycarbonyl such as substituted benzyloxycarbonyl, and 2-pyridylmethoxycarbonyl. Examples of suitable reduction methods include reduction with an alkali metal borohydride such as sodium borohydride. The reaction temperature is not particularly limited and is appropriately selected depending on the type of amino protecting group and the type of the above-mentioned elimination method, but this reaction is preferably carried out under cooling, at room temperature, or under mild conditions with slight warming. It will be held in In this reaction, the case where the protected amino group of R ¹ is converted into a free amino group during the above-mentioned elimination reaction process or during the post-treatment process of the reaction product mixture is also included within the scope. Method 3 Compound [] or its salts are compound []
can be produced by subjecting it to an elimination reaction of the carboxy protecting group. This reaction can be carried out by conventional methods such as hydrolysis or reduction. When the protecting group is an ester, it can be removed by hydrolysis. Hydrolysis is preferably carried out in the presence of a base or acid. Suitable bases include, for example, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, their hydroxides or carbonates or bicarbonates, trialkylamines such as trimethylamine and triethylamine, picoline, 1,5-diazabicyclo[4,
Inorganic and organic bases such as 3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane, 1,8-diazabicyclo[5,4,0]undecene-7, etc. It will be done. Suitable acids include, for example, organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, etc., and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc. If trifluoroacetic acid is used, the reaction is preferably carried out in the presence of anisole. The reaction is usually carried out in water, alcohols such as methanol and ethanol, and mixtures thereof, but can be carried out in any other solvent that does not adversely affect the reaction.
Liquid bases or acids can also be used as solvents. Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or heating. Reduction is preferably applied to remove protecting groups such as 4-nitrobenzyl, 2-iodoethyl, 2,2,2-trichloroethyl and the like. Examples of reduction methods that can be applied to the elimination reaction include the use of metals such as zinc or zinc amalgam, or salts of chromium compounds such as chromium chloride and chromium acetate, and organic acids such as acetic acid, propionic acid, and hydrochloric acid. or reduction using combinations with inorganic acids; and conventional catalytic reductions under conventional metal catalysts, such as palladium on carbon. The production of the raw material compound [] will be explained in detail below. Manufacturing method 1 Compound [] or its salts are compound []
Alternatively, it can be produced by reacting the compound [] or a reactive derivative at its amino group or a salt thereof with a reactive derivative at its carboxy group or a salt thereof. This reaction can be carried out by a conventional method used for the acylation reaction at the 7-amino position of a cephalosporin compound. Manufacturing method 2 The compound [] or its salts are the compound []
Alternatively, it can be produced by oxidizing its salts. A suitable oxidizing agent used in this reaction is the -S- group in the cephalosporin compound.

All oxidizing agents that can oxidize the group [Formula] may be mentioned, and examples thereof include hydrogen peroxide, peroxides such as 3-chloroperbenzoic acid, and the like. The reaction is usually carried out in a solvent such as methylene chloride, but any solvent can be used as long as it does not adversely affect the reaction. Although the reaction temperature is not particularly limited, the reaction is preferably carried out under cooling or at room temperature. Production method 3 Compound [] can be produced by reacting compound [] with compound [] or its salts. This reaction can be carried out according to Method 1. Production method 4 Compound [] can be produced by reducing compound []. This reduction in cephalosporin compounds

This can be carried out in the presence of a conventional reducing agent capable of reducing the group ##STR1## to the group -S-, for example a phosphorus halide such as a phosphorus trihalide such as phosphorus trichloride. The production of compound [a] will be explained in detail below. Production method 5 The compound [] or its salts can be produced by halogenating the compound [] or its salts. Examples of the compound [] and suitable salts of the compound [] include the acid addition salts exemplified for the compound []. This reaction can be carried out by reacting the compound [ ] or its salt with a halogenating agent. Suitable halogenating agents used in this reaction include halogens (e.g. chlorine, bromine, fluorine or iodine), e.g. N-chlorosuccinimide,
N-halogenated succinimides such as N-bromosuccinimide, e.g. hypochlorous acid, hypohalous acids such as hypobromous acid, e.g. isocyanuric chloride,
Examples include halogenated isocyanuric acids such as brominated isocyanuric acid. The reaction is usually carried out in a solvent that does not adversely affect the reaction, such as an ether, an alcohol such as methanol or ethanol, or a mixture thereof. Although the reaction temperature is not particularly limited, the reaction is usually carried out in a range from cooling to room temperature. Manufacturing method 6 The compound [] or its salts are the compound []
] or its salts can be produced by subjecting it to an elimination reaction of the carboxy protecting group. This elimination reaction can be carried out according to method 3. Production method 7 Compound [a] or its salts are compound [a] or its salts.
] or its salts include thiocyanic acid (HSCN)
It can be produced by reacting with a salt of As suitable salts for compound [] and [a], the same salts as exemplified for compound [] can be used. Suitable salts of thiocyanic acid include metal salts such as alkali metal salts such as sodium salts and potassium salts, salts with organic tertiary bases such as trimethylamine, triethylamine, dimethylaniline, and the like. This reaction is usually carried out in a solvent that does not adversely affect the reaction, such as a hydrophilic solvent such as an alcohol such as methanol or ethanol. The reaction temperature is not particularly limited, and is usually carried out in the range of cooling to room temperature. The compounds thus obtained according to Methods 1 to 3 above can be converted into salts by conventional methods. The object compounds of this invention [ ] exhibit high antibacterial activity and inhibit the growth of numerous microorganisms, including Gram-positive and Gram-negative pathogens. When using the target compound [ ] as a medicine,
It may also be used in the form of pharmaceutically acceptable salts. When administered for therapeutic purposes, the cefem compounds of this invention [ ] or salts thereof may be administered in a pharmaceutically acceptable medium, such as an organic or inorganic solid or liquid suitable for oral, parenteral or topical administration. It is used in the form of a preparation mixed with excipients. Such preparations include solid preparations such as capsules, tablets, granules, ointments, and suppositories, and liquid preparations such as solutions, suspensions, and emulsions. Furthermore, if desired, adjuvants may be added to the formulation.
Stabilizers, wetting or emulsifying agents, buffering agents, and other conventional additives may also be included. Although the dosage of the active compound will vary depending on the age and condition of the patient, average single doses of the compounds of this invention are approximately 50 mg, 100 mg, and 250 mg.
Amounts of 500 mg and 500 mg are effective in treating infections caused by many pathogenic bacteria. Generally, daily doses of 1 mg to about 1000 mg or more may be administered. Next, in order to demonstrate the usefulness of the target compound [], test data regarding the antibacterial activity of representative compounds according to the present invention will be shown. Test method In vitro antibacterial activity was determined by the agar plate dilution method described below. Trypticase soy broth (bacteria count 10 ⁸
A loopful of each test strain, cultured overnight in 100 ml/ml), was inoculated onto heart infusion agar (HI-agar). This medium contained antibacterial agents at various concentrations, and the minimum inhibitory concentration (MIC) was measured after culturing at 37°C for 20 hours. (Unit: μg/
ml) Test compound (1) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(3-methylamino-1-pyridiniomethyl)- 3-Cefem-4-carboxylate (syn isomer) (2) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(3 -dimethylamino-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (3) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazole-3- yl)acetamido]-3-(3-methoxy-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer)

[Table] The present invention will be explained below with reference to Production Examples and Examples. Manufacturing example 1 N between isonitrosomalonic acid dimethyl ester (12.25g) and diethyl sulfate (14.32g),
To the mixture in N-dimethylformamide (12 ml),
Triethylamine (9.39 g) was added dropwise with stirring at 30 to 40°C, and stirring was continued at the same temperature for an additional 1.5 hours. The mixture was diluted with methylene chloride (45 ml) and water (30 ml) and the organic layer was separated, washed with 5% aqueous potassium carbonate and water, dried over magnesium sulphate and evaporated to dryness to give an oily residue ( 11.5g) was obtained. This residue was distilled under reduced pressure (5 mmHg) to obtain ethoxyiminomalonate dimethyl ester (5.5 g). Boiling point 85-105°C (5mmHg). IR (Film): 3000, 2970, 1755, 1730, 1610
cm ^-1 NMR (CDCl ₃ , δ): 1.30 (3H, t, J = 7Hz),
3.83 (6H, s), 4.32 (2H, q, J = 7Hz) A mixture of ethoxyiminomalonic acid dimethyl ester (57.4 g) and concentrated aqueous ammonia (50 ml) in methanol (150 ml) was stirred at room temperature for 2.5 hours. The mixture was adjusted to pH 4 with concentrated hydrochloric acid under cooling, and concentrated under reduced pressure to 70 ml. The aqueous solution was left in the refrigerator for 1 hour, the precipitate formed was collected, washed with cold water, and dried.
g) was obtained. Melting point 68-71℃. IR (Nujiyor): 3450, 3300, 3200, 1740,
1680, 1660, 1600 cm ^-1 NMR (DMSO-d ₆ , δ): 1.28 (3H, t, J = 7
Hz), 3.83 (3H, s), 4.28 (2H, q, J=7Hz),
7.70 (2H, broad s) Meyerbein reagent (triethyloxonium)
2-carbamoyl-2- Ethoxyiminoacetic acid methyl ester (syn isomer, 2.6 g) was added and the mixture was stirred at room temperature for 18 min.
Stir for hours. The reaction mixture was cooled in an ice bath and triethylamine (3 g) was added thereto followed by water (20 ml). The organic layer was separated, dried over magnesium sulfate, and then evaporated to dryness to give crude 3-imino-3-ethoxy-2-ethoxyiminopropionic acid methyl ester (syn isomer) (5.0
g) was obtained as an oil. A methanol (25 ml) solution of the crude 3-imino-3-ethoxy-2-ethoxyiminopropionic acid methyl ester (syn isomer) (5.0 g) obtained above and ammonium chloride (802 mg) was added at room temperature.
After stirring for an hour, the residue obtained by evaporation to dryness was triturated in ethyl acetate to obtain 2-amidino-2-ethoxyiminoacetic acid methyl ester hydrochloride (syn isomer).
(1.75g) was obtained. Melting point 138-140℃ (decomposition). IR (Nujiyor): 2600, 2490, 1740, 1680,
1595cm ^-1 NMR (DMSO-d ₆ , δ): 1.33 (3H, t, J = 7
Hz), 3.90 (3H, s), 4.45 (2H, q, J = 7Hz) A solution of 2-amidino-2-ethoxyiminoacetic acid methyl ester hydrochloride (syn isomer) (12.6 g) in methanol (300 ml) was added with an ether solution of hypozinclic acid (90 ml) [10% aqueous solution of sodium hypochlorite ( 100 ml) and prepared from 3N hydrochloric acid (60 ml) in diethyl ether (100 ml)] in an ice bath at 0-5°C.
The solution was added dropwise with stirring while cooling to , and stirred for an additional 30 minutes at the same temperature. Triethylamine (14 g) was added dropwise to the reaction mixture at the same temperature and the mixture was evaporated to dryness. The residue was triturated in cold water (150 ml) and
Stir in an ice bath for 30 minutes. The generated precipitate was collected, washed with cold water, and then dried to obtain 2-( ^N2 -chloro)amidino-2-ethoxyiminoacetic acid methyl ester (syn isomer) (7.2 g). melting point 38
−40℃. IR (Nujiyor): 3470, 3350, 1750, 1635,
1600, 1560, 1030, 840cm ^-1 NMR (CD ₃ OD, δ): 1.23 (3H, t, J = 7Hz),
3.76 (3H, s), 4.20 (2H, q, J = 7Hz) (6) 2-(N ² -chloro)amidino-2-ethoxyiminoacetic acid methyl ester (syn isomer) (6.0
A suspension of g) in 1N aqueous sodium hydroxide solution (30ml) was stirred at room temperature for 1 hour. The solution was cooled in an ice bath, acidified with 6N hydrochloric acid (5.5 ml),
Extracted twice with ethyl acetate (30ml). The extract was dried and evaporated to dryness, and the residue was triturated in a mixed solvent of diisopropyl ether and petroleum ether to give 2-( ^N2 -chloro)amidino-2-ethoxyiminoacetic acid (syn isomer) (5.0 g) was obtained.
Melting point 125-126°C (decomposition). IR (Nujiyor): 3480, 3370, 2800-2200,
1740, 1620, 1600, 1380, 1040, 970, 820cm ^-1 NMR (CD ₃ OD, δ): 1.30 (3H, t, J = 7
Hz), 4.25 (2H, q, J = 7Hz) (7) 2-(N ² -chloro)amidino-2-ethoxyimino was added to a methanol (40 ml) solution of potassium thiocyanate (970 mg) and triethylamine (1.2 g). Acetic acid (syn isomer) (2.13 g) was added under stirring while cooling to -5 to 0<0>C in an ice-salt bath. The mixture was stirred at the same temperature for 30 minutes and left in the refrigerator overnight. The mixture was evaporated to dryness,
The residue was dissolved in water (10 ml), adjusted to pH 1.5 with 3N hydrochloric acid, and extracted with ethyl acetate. The extract was dried over magnesium sulfate, evaporated to dryness, and triturated in diisopropyl ether to give 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (sinyl). isomer)
(1.67g) was obtained. Melting point 164-165°C (decomposition). Production example 2 Phosphorus pentachloride (54.6g) in methylene chloride (500ml)
2-ethoxyimino-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (54.0 g) was added with stirring while cooling to -20°C. The mixture was stirred at -15 to -12°C for 30 minutes and at -5°C for 2 hours. Diisopropyl ether (500 ml) was added to the mixture containing the precipitate of the target compound at -5°C, and the mixture was incubated at -5 to 10°C.
Stir for 30 minutes. The generated precipitate was collected, washed with diisopropyl ether, and dried to give 2-
Ethoxyimino-2-(5-amino-1,2,4
-thiadiazol-3-yl)acetyl chloride hydrochloride (syn isomer) (6.017 g) was obtained. melting point
125-127℃ (decomposition). IR (nujiol): 1785, 1625, 1055 cm ^-1 Elemental analysis: C ₆ H ₈ O ₂ N ₄ SCl ₂ as C H N S Cl Calculated value: 26.57 2.95 20.66 11.81 26.20 Experimental value: 26.13 2.99 20.49 11.77 26.41 Manufacture Example 3 To a solution of 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride (27 g) in methylene chloride (300 ml) was added N,
N-dimethylaniline (36.2 g) was heated at 5°C in an ice bath.
was added while cooling. To this solution was added 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetyl chloride hydrochloride (syn isomer) (16.2 g) in portions at a temperature below 11°C. and the mixture was stirred for 45 minutes at 5°C. The reaction mixture was diluted with a mixed solvent of methylene chloride (100 ml) and water (200 ml), and the pH was adjusted to 2 with 1N hydrochloric acid.
The organic layer was separated, washed with water, dried over magnesium sulfate, and evaporated to dryness. The residue was triturated in diethyl ether to give 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-chloromethyl-3-cephem-4. -Carboxylic acid diphenyl methyl ester (syn isomer) (32.4 g) was obtained.
Melting point 120-125℃ (decomposition). IR (Nujiyor): 3300, 3150, 1780, 1725,
1675, 1625, 1530, 1495 cm ^-1 NMR (DMSO-d ₆ , δ): 1.28 (3H, t, J = 7
Hz), 3.68 (2H, broad s), 4.23 (2H, q,
J = 7Hz), 4.47 (2H, s), 5.27 (1H, d, J =
5Hz), 5.97 (1H, 2d, J=5 and 8Hz), 7.0
(1H, s), 7.2-7.7 (10H, m), 8.17 (2H, broad s), 9.62 (1H, d, J = 8Hz) Production example 4 7-[2-ethoxyimino-2-(5-amino −
1,2,4-thiadiazol-3-yl)acetamide]-3-chloromethyl-3-cephem-4
- In a cold mixed solvent solution of carboxylic acid diphenyl methyl ester (syn isomer) (10 g) in methylene chloride (100 ml) and acetic acid (10 ml), 30% hydrogen peroxide (1.84 ml) and sodium tungstate (0.3
g) was added. The mixture was stirred in an ice bath for 45 minutes and then poured into diethyl ether (300ml). Take the precipitate,
Washing with diethyl ether gave 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-chloromethyl-3-cephem-4-carboxylic acid. Diphenyl methyl ester-1-oxide (syn isomer) (8.9 g) was obtained. Melting point 150-155℃ (decomposition). IR (Nujiyor): 3280, 3170, 1785, 1723,
1667, 1628, 1530 cm ^-1 NMR (DMSO-d ₆ , δ): 1.30 (3H, t, J = 7
Hz), 3.90 (2H, broad s), 4.23 (2H, q,
J=7Hz), 4.58 (2H, broad s), 5.12 (1H,
d, J=5Hz), 6.10 (1H, 2d, J=5 and 8
Hz), 7.02 (1H, s), 7.20-7.73 (10H, m), 8.15
(2H, broad s), 9.00 (1H, d, J=8Hz) Production example 5 7-[2-ethoxyimino-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetamide]-3-chloromethyl-3-cephem-4
A mixture of -carboxylic acid diphenyl methyl ester-1-oxide (syn isomer) (3g) and 3-dimethylaminopyridine (0.7g) in tetrahydrofuran (20ml) was stirred at 48-50°C for 2.5 hours.
The generated precipitate was taken, washed with tetrahydrofuran, dried, and 7-[2-ethoxyimino-2
-(5-amino-1,2,4-thiadiazole-
3-yl)acetamido]-3-(3-dimethylamino-1-pyridiniomethyl)-3-cephem-
4-Carboxylic acid diphenylmethyl ester-1-
Oxide chloride (syn isomer) (3.18 g) was obtained. Melting point 120-130℃ (decomposition). IR (Nujiyor): 3250, 1800, 1720, 1670,
1620, 1580, 1525 cm ^-1 NMR (DMSO-d ₆ , δ): 1.17 (3H, t, J = 7
Hz), 3.00 (6H, s), 3.90 (2H, m), 4.18 (2H,
q, J = 7Hz), 5.22 (1H, d, J = 4Hz), 5.50
(2H, m), 6.10 (1H, dd, J=4 and 8Hz),
6.94 (1H, s), 7.35 (10H, m), 7.70 (2H, m),
8.03 (2H, m), 8.22 (2H, m), 9.03 (1H, d, J
=8Hz) Production example 6 7-[2-ethoxyimino-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetamide]-3-(3-dimethylamino-1-pyridiniomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester-1-oxide chloride (syn isomer ) (3.12g) and N,N-dimethylaniline (1.01g) in acetonitrile (31ml)
Phosphorus trichloride (1.14 g) was added dropwise to the mixture while stirring while cooling in an ice-salt bath, and the mixture was further stirred for 1.5 hours under the same conditions. Diethyl ether (200ml) was added to the reaction mixture and stirred for 30 minutes. The generated precipitate was collected, washed with diethyl ether, and dried to give 7-[2-ethoxyimino-2-
(5-amino-1,2,4-thiadiazole-3
-yl)acetamido]-3-(3-dimethylamino-1-pyridiniomethyl)-3-cephem-4
-Carboxylic acid diphenylmethyl ester chloride (syn isomer) (2.96 g) was obtained. Melting point 97~107
°C (decomposition). IR (Film): 1780, 1740, 1680, 1620, 1580,
1525cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.25 (3H, t,
J=7Hz), 3.10 (6H, s), 3.67 (2H, m), 4.19
(2H, q, J = 7Hz), 5.37 (1H, d, J = 5
Hz), 5.5 (2H, m), 6.07 (1H, d, J=5Hz),
7.00 (1H, s), 7.45 (10H, m), 7.67~8.15 (3H,
m), 8.22 (1H, m) Production Example 7 A solution of hexadecanoyl chloride (25.2 g) in tetrahydrofuran (80 ml) was added to a solution of 4-hydroxymethylpyridine (10.02 g) and triethylamine (9.27 g) in tetrahydrofuran (100 ml). was added dropwise with stirring while cooling in an ice bath, and the mixture was further stirred at the same temperature for 1 hour. The formed precipitate was separated and the liquid was evaporated to dryness. The residue was dissolved in diethyl ether, washed with water, dried over magnesium sulfate and evaporated to dryness. Pour the residue into silica gel (250
g) It was purified by column chromatography and eluted with a methylene chloride-ethyl acetate mixed solvent to obtain 4-hexadecanoyloxymethylpyridine (14.3 g). NMR (CDCl ₃ , δ): 0.88 (3H, m), 1.28 (26H,
m), 2.39 (2H, t, J=7Hz), 5.07 (2H, s),
7.15 (2H, m), 8.50 (2H, m) Production Example 8 The following compound was obtained according to the method of Production Example 7. (1) 4-Dodecanoyloxymethylpyridine (oil) IR (film): 1745, 1610, 1570, 1465,
1420, 1380, 1360, 1240, 1160, 1115, 1075,
1050cm ^-1 NMR (CCl ₄ , δ): 0.88 (3H, m), 1.27 (18H,
m), 2.33 (2H, t, J=6Hz), 5.02 (2H,
s), 7.10 (2H, m), 8.45 (2H, m) (2) 4-(3-hexadecanoyloxypropyl)
Pyridine, melting point 37-40°C. IR (Nujiol): 1730, 1605, 1175 cm ^-1 (3) 4-oleoyloxymethylpyridine (oil) IR (Film): 3020, 2950, 2870, 1746,
1608cm ^-1 Production Example 9 3-aminopyridine (2.82g) and sodium hydroxymethanesulfonate monohydrate (9.12g)
A mixture of and in water (40ml) was stirred at 80°C for 1.5 hours. The solution was concentrated to form a precipitate and allowed to stand for several hours. The generated precipitate was collected, washed with ethanol, and then dried to obtain sodium 3-pyridylaminomethanesulfonate (3.71 g). melting point
211-220℃. IR (Nujiyor): 3600, 3530, 3250, 3200,
1640, 1590, 1490 cm ^-1 NMR (DMSO-d ₆ , δ): 4.05 (2H, d, J = 6
Hz), 6.30 (1H, t, J=6Hz), 7.05 (2H, m),
7.74 (1H, m), 8.10 (1H, m) Production example 10 A solution of 3-bromopyridine (S5.10g), ethanolamine (34.89g) and copper sulfate (2.90g) in water (140ml) was mixed with stirring for 5 minutes. Refluxed for an hour. The reaction mixture was washed with chloroform and the aqueous layer was separated. An aqueous solution of potassium carbonate (22 g) was added to the aqueous layer, and the mixture was then saturated with sodium chloride and extracted with a mixed solvent of chloroform and ethanol (1:1). The extract was evaporated to dryness, and the residue was subjected to column chromatography on silica gel (200 g) and eluted with a mixed solvent of chloroform and ethanol (5:1). Fractions containing the target compound were collected and evaporated to dryness to give 3-(2-hydroxyethyl)aminopyridine (5.96 g) as an oil. IR (Film): 3500-3050, 2950, 2850, 1590,
1515, 1490, 1460, 1420, 1380, 1330, 1305,
1250, 1190, 1140, 1070, 1050, 800, 710 cm ^-1 NMR (CCl ₄ + CDCl ₃ , δ): 3.13 (2H, t, J =
5Hz), 3.73 (2H, t, J = 5Hz), 4.89 (2H, broad s), 6.85 (2H, m), 7.77 (2H, m) Production example 11 Formic acid (5.02g) and acetic anhydride (11.14g) The mixture was stirred at 40-45°C for 30 minutes and then cooled in an ice bath. A solution of 3-(2-hydroxyethyl)aminopyridine (5.80 g) in tetrahydrofuran (20 ml) was added to the cold mixed anhydride under stirring while cooling in an ice bath, and the mixture was further stirred at room temperature for 2 hours.
The mixture was distilled to recover tetrahydrofuran and poured into water (100ml). The mixture was adjusted to pH 6-7 with sodium bicarbonate and extracted with methylene chloride. The extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and evaporated to dryness to give 3-[N-(2-formyloxyethyl)formamide]pyridine (7.47 g) as an oil. IR (Film): 3075, 2975, 2910, 1725, 1700
~1655, 1585, 1490, 1435, 1415, 1355, 1295,
1230, 1190-1160, 1110, 1030, 940, 815, 715
cm ^-1 NMR (CDCl ₃ , δ): 4.23 (4H, m), 7.50 (2H,
m), 7.93 (1H, s), 8.35 (1H, s), 8.53 (2H,
m) Production example 12 3-[N-(2-formyloxyethyl)formamide]pyridine (7.01 g) and sodium bicarbonate (3.04 g) in tetrahydrofuran (60 ml)
and water (110 ml) in a mixed solvent of 45-46
The mixture was stirred at ℃ for 8 hours. The reaction mixture was extracted with a mixed solvent of chloroform and ethanol (1:1),
The extract was evaporated to dryness. The residue was dissolved in a mixed solvent of chloroform and ethanol (4:1) and subjected to silica gel (150 g) column chromatography. Fractions containing the target compound were collected by elution with the same solvent and evaporated to dryness to give 3-[N-(2-hydroxyethyl)formamide]pyridine (4.60 g) as an oil. IR (Film): 3600-3050, 3000, 2950, 2900,
1700〜1650, 1585, 1490, 1430, 1350, 1290,
1190, 1080-1050, 870, 810, 710 cm ^-1 NMR (CDCl ₃ , δ): 3.84 (5H, m), 7.50 (2H,
m), 8.31 (1H, s), 8.45 (2H, m) Example 1 3-(N-methylformamide)-pyridine (3.26 g), sodium iodide (21.58 g), phosphoric acid (0.71 g), water (3 ml) and acetonitrile (9 ml) and acetonitrile (9 ml)
A mixture of 7-[2-ethoxyimino-2-(5-amino-
Sodium 1,2,4-thiadiazol-3-yl)acetamide]cephalosporanate (syn isomer) (5.90 g) was added. Mixture at 70-72℃
After stirring for 1.5 hours, it was diluted with water (30ml). Cool the aqueous solution, adjust the pH to 3 with 6N hydrochloric acid, and adjust the pH to 150 with water.
diluted to ml. The aqueous solution was washed five times with a mixed solvent of chloroform and ethanol (2:1) (100 ml) and concentrated under reduced pressure to 200 ml. Separate the insoluble matter and pour the liquid into a nonionic adsorption resin “Diaion”.
HP-20” (trademark, manufactured by Mitsubishi Chemical Industries, Ltd.) (200ml)
It was subjected to column chromatography using . After washing the column with water, it was eluted with 10% aqueous methanol. The eluate containing the target compound was collected, methanol was recovered by distillation under reduced pressure, and the residue was freeze-dried.
-[2-ethoxyimino-2(5-amino-1,
2,4-thiadiazol-3-yl)acetamide]-3-[3-(N-methylformamide)-1-
Pyridiniomethyl]-3-cephem-4-carboxylate (syn isomer) (3.14 g) was obtained. Melting point 120-127°C (decomposition). IR (Nujiyor): 3250, 3150, 1770, 1670,
1610, 1590, 1510cm ^-1 NMR (D ₂ O, δ): 1.29 (3H, t, J = 7Hz),
3.19 and 3.73 (2H, ABq, J = 18Hz), 3.37 and 3.50 (3H, s), 4.32 (2H, q, J = 7Hz),
5.28 (1H, d, J = 5Hz), 5.30 and 5.70 (2H,
ABq, J=14Hz), 5.87 (1H, d, J=5Hz),
8.10 (1H, m), 8.4-9.0 (3H, m), 9.33 (1H,
m) Example 2 According to the method of Example 1, the following compound was obtained. (1) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(3-methylamino-1-pyridiniomethyl)-3-cephem- 4-carboxylate (syn isomer), melting point 149-157°C
(Disassembly). IR (Nujiyor): 3250, 3050, 1770, 1660,
1610, 1530cm ^-1 (2) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(4-dodecanoyloxymethyl-1- (pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), melting point
111.5-118.0℃ (decomposition). IR (Nujiyor): 3300, 1770, 1730, 1670,
1640, 1610, 1570, 1520 cm ^-1 NMR (d ₆ -DMSO + D ₂ O, δ): 0.85 (3H,
m), 1.25 (21H, m), 2.40 (2H, m), 3.40
(2H, m), 4.15 (2H, q, J = 7Hz), 4.80~
5.93 (4H, m), 5.07 (1H, d, J=5Hz),
5.71 (1H, d, J = 5Hz), 8.00 (2H, d, J =
6 Hz), 9.22 (2H, d, J = 6 Hz) (3) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(4 -hexadecanoyloxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer),
Melting point 121-130℃ (decomposition). IR (Nujiyor): 3300, 3150, 1770, 1670,
1640, 1610, 1570, 1520 cm ^-1 NMR (d ₆ -DMSO + D ₂ O, δ): 0.82 (3H,
m), 1.21 (29H, m), 2.35 (2H, m), 3.42
(2H, m), 4.15 (2H, q, J=7Hz), 5.05
(1H, d, J=5Hz), 5.2~5.6 (2H, m),
5.40 (2H, s), 5.70 (1H, d, J=5Hz),
8.02 (2H, d, J = 6Hz), 9.28 (2H, d, J =
6Hz) (4) Sodium 7-[2-ethoxyimino-2
-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(3-sulfonatomethylamino-1-pyridiniomethyl)-
3-Cefem-4-carboxylate (syn isomer), melting point 161-169°C (decomposed). IR (Nujiyor): 3350, 3300, 1760, 1660,
1640, 1610, 1530 cm ^-1 (5) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(3-dimethylamino-1-
pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), melting point 129-138°C
(Disassembly). IR (Nujiyor): 3300, 1775, 1660, 1620,
1580, 1530cm ^-1 (6) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[3-(2-hydroxyethyl)amino -1-pyridiniomethyl]-3-cephem-4-carboxylate (syn isomer),
Melting point 141-150℃ (decomposition). IR (Nujiyor): 3300, 1770, 1660, 1610,
1530cm ^-1 (7) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-[3-{N-(2-hydroxyethyl) Formamide}-1-pyridiniomethyl]-3-cephem-4-carboxylate (syn isomer), mp 147-155°C (decomposition). IR (Nujiyor): 3250, 1770, 1670, 1610,
1530, 1510cm ^-1 NMR (D ₂ O, δ): 1.36 (3H, t, J = 7Hz),
3.30 and 3.73 (2H, ABq, J=18Hz), 3.70~
4.30 (4H, m), 4.39 (2H, q, J=7Hz),
5.35 (1H, d, J = 5Hz), 5.43 and 5.70
(2H, ABq, J=14Hz), 5.95 (1H, d, J=
5Hz), 8.69 (1H, s), 8.80~8.85 (2H, m),
8.95 (1H, d, J = 6Hz), 9.37 (1H, s) (8) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]- 3-[4-(3-hexadecanoyloxypropyl)-1-pyridiniomethyl]-
3-Cefem-4-carboxylate (syn isomer), melting point 140-150°C (decomposed). IR (Nujiyor): 3300, 1775, 1725, 1670,
1640, 1610, 1525 cm ^-1 NMR (DMSO-d ₆ + D ₂ O, δ): 0.87 (3H, t,
J=5Hz), 1.25 (31H, m), 1.75~2.40 (2H,
m), 2.67-3.23 (2H, m), 3.56 (2H, m),
3.80~4.40 (4H, m), 5.03 (1H, d, J=5
Hz), 4.9-5.7 (2H, m), 5.83 (1H, d, J=
5Hz), 7.98 (2H, d, J = 7Hz), 9.22 (2H,
d, J = 7Hz) (9) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(4-oleoyloxymethyl-1 -pyridiniomethyl)-3-cephem-
4-carboxylate (syn isomer), melting point 106
~116℃ (decomposition). IR (Nujiyor): 3300, 1770, 1670, 1640,
1610, 1520 cm ^-1 NMR (DMSO-d ₆ + D ₂ O, δ): 0.84 (3H, t,
J=5Hz), 1.25 (25H, m), 1.95 (4H, m),
2.41 (2H, m), 3.60 (2H, m), 4.15 (2H, q,
J=7Hz), 4.9-5.8 (6H, m), 5.07 (1H, d,
J=5Hz), 5.72 (1H, d, J=5Hz), 8.04
(2H, d, J = 6 Hz), 9.27 (2H, d, J = 6
Hz) Example 3 7-[2-ethoxyimino-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetamide]-3-[3-(N-methylformamide)-
To a suspension of 1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (2.75 g) in methanol (27.5 ml) was added concentrated hydrochloric acid (1.39 ml) and the mixture was stirred for 75 minutes. The solvent was evaporated and the residue was triturated in acetone. The obtained powder was suspended in water (70 ml), adjusted to pH 4-5 with an aqueous sodium bicarbonate solution, and subjected to column chromatography using a nonionic adsorption resin "Diaion HP-20" (100 ml). . After washing the column with water, it was eluted with 15% aqueous isopropyl alcohol. The eluate containing the target compound was collected, distilled under reduced pressure to recover isopropyl alcohol, and the residue was freeze-dried to obtain 7-[2-ethoxyimino-2-(5-
Amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(3-methylamino-1
-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (1.41 g) was obtained.
Melting point 149-157°C (decomposition). IR (Nujiyor): 3250, 3050, 1770, 1660,
1610, 1530 cm ^-1 NMR (DMSO-d ₆ + D ₂ O, δ): 1.22 (3H, t,
J=7Hz), 2.79 (3H, s), 3.05 and 3.57 (2H,
ABq, J=18Hz), 4.15 (2H, q, J=7Hz),
5.05 (1H, d, J = 5Hz), 5.08 and 5.55 (2H,
ABq, J=14Hz), 5.70 (1H, d, J=5Hz),
7.65 (2H, m), 8.40 (1H, m), 8.60 (1H, broad s) Example 4 The following compound was obtained according to the method of Example 3. 7-[2-ethoxyimino-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetamide]-3-[3-(2-hydroxyethyl)amino-1-pyridiniomethyl]-3-cephem-
4-carboxylate (syn isomer), melting point 141~
150℃ (decomposition). IR (Nujiyor): 3300, 1770, 1660, 1610,
1530cm ^-1 NMR (D ₂ O, δ): 1.30 (3H, t, J = 7Hz),
3.44 (2H, t, J=5Hz), 3.23 and 3.80 (2H,
ABq, J=18Hz), 3.80 (2H, t, J=5Hz),
4.33 (2H, q, J = 7Hz), 5.28 (1H, d, J = 5
Hz), 5.15 and 5.43 (2H, ABq, J=15Hz),
5.88 (1H, d, J=5Hz), 7.65 (2H, m), 7.97
~8.30 (2H, m) Example 5 7-[2-ethoxyimino-2-(5-amino-
0.42 g ) and anisole (1 ml) in trifluoroacetic acid (3.5 ml) was stirred for 15 minutes while cooling in an ice bath. The mixture was poured into diisopropyl ether (10ml) and the formed precipitate was collected. This powder was dissolved in water and subjected to column chromatography using a nonionic adsorption resin "Diaion HP-20" (10 ml). After washing the column with water, it was eluted with 30% aqueous methanol. The eluate containing the target compound was collected, methanol was recovered by distillation under reduced pressure, and the residue was freeze-dried to obtain 7-[2-ethoxyimino-2-(5-amino-1,2,4-
Thiadiazol-3-yl)acetamide]-3
-(3-dimethylamino-1-pyridiniomethyl)
-3-Cefem-4-carboxylate (syn isomer) (0.12 g) was obtained. Melting point 129-138°C (decomposition). IR (Nujiyor): 3300, 1775, 1660, 1620,
1580, 1530cm ^-1 NMR (D ₂ O, δ): 1.30 (3H, t, J = 7Hz),
3.03 (6H, s), 3.20 and 3.60 (2H, ABq, J=
18Hz), 4.32 (2H, q, J = 7Hz), 5.26 (1H, d,
J = 5Hz), 5.17 and 5.43 (2H, ABq, J = 16
Hz), 5.83 (1H, d, J=5Hz), 7.65 (2H, m),
8.00 (1H, m), 8.19 (1H, m) Example 6 According to the method of Example 5, the following compound was obtained. (1) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-[3-(N-methylformamide)-1-pyridiniomethyl]- 3-Cefem-4-carboxylate (syn isomer), melting point
120-127℃ (decomposition). IR (Nujiyor): 3250, 3150, 1770, 1670,
1610, 1590, 1510 cm ^-1 (2) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(3-methylamino-1- pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), melting point 149-157°C
(Disassembly). IR (Nujiyor): 3250, 3050, 1770, 1660,
1610, 1530cm ^-1 (3) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(4-dodecanoyloxymethyl-1- (pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), melting point
111.5-118.0℃ (decomposition). IR (Nujiyor): 3300, 1770, 1730, 1670,
1640, 1610, 1570, 1520 ^{cm -1} (4) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-hexadodecanoyl oxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer),
Melting point 121-130℃ (decomposition). IR (Nujiyor): 3300, 3150, 1770, 1670,
1640, 1610, 1570, 1520cm ^-1 (5) Sodium 7-[2-ethoxyimino-2
-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(3-sulfonatomethylamino-1-pyridiniomethyl)-
3-Cefem-4-carboxylate (syn isomer), melting point 161-169°C (decomposed). IR (Nujiyor): 3350, 3300, 1760, 1660,
1640, 1610, 1530 cm ^-1 (6) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-[3-(2-hydroxyethyl ) amino-1-pyridiniomethyl]-3-cephem-4-carboxylate (syn isomer),
Melting point 141-150℃ (decomposition). IR (Nujiyor): 3300, 1770, 1660, 1610,
1530cm ^-1 (7) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-[3-{N-(2-hydroxyethyl) Formamide}-1-pyridiniomethyl]-3-cephem-4-carboxylate (syn isomer), mp 147-155°C (decomposition). IR (Nujiyor): 3250, 1770, 1670, 1610,
1530, 1510 cm ^-1 (8) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-[4-(3-hexadecanoyloxy) propyl)-1-pyridiniomethyl]-
3-Cefem-4-carboxylate (syn isomer), melting point 140-150°C (decomposed). IR (Nujiyor): 3300, 1775, 1725, 1670,
1640, 1610, 1525 cm ^-1 (9) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(4-oleoyloxymethyl- 1-pyridiniomethyl)-3-cephem-
4-carboxylate (syn isomer), melting point 106
~116℃ (decomposition). IR (Nujiyor): 3300, 1770, 1670, 1640,
1610, 1520 cm ^-1 Example 13 According to the method of Example 7, the following compound was obtained. (1) 4-tetradecanoyloxymethylpyridine (oil). IR (Film): 2910, 2850, 1740, 1606,
1560, 1460, 1405, 1160cm ^-1 NMR (DMSO-d ₆ , δ): 0.7-1.9 (25H, m),
2.1~2.5 (2H, m), 5.12 (2H, s), 7.3 (2H,
m), 8.5 (2H, m) (2) 3-hexadecanoyloxymethylpyridine (oil). IR (Film): 2950, 2860, 1740, 1580,
1470, 1430, 1380, 1350, 1230, 1160, 1120,
1030cm ^-1 NMR (DMSO-d ₆ , δ): 0.7-1.7 (29H, m),
2.35 (2H, t, J=7Hz), 5.12 (2H, s),
7.36 (1H, m), 7.75 (1H, m), 8.50 (2H, m) (3) 4-Octadecanoyloxymethylpyridine (semi-solid). IR (Nujiyor): 1740, 1605, 1560, 1415,
1160cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 0.7-1.9
(33H, m), 2.1~2.6 (2H, m), 5.05 (2H,
s), 7.15 (2H, m), 8.50 (2H, m) Example 14 7-[2-methoxyimino-2-(5-amino-
7
-[2-methoxyimino-2-(5-amino-1,
Sodium 2,4-thiadiazol-3-yl)acetamide]cephalosporanate (syn isomer) was obtained. Melting point 185-190℃ (decomposition). IR (Nujiyor): 3150, 1765, 1745, 1670,
1550, 1400, 1355, 1290, 1250, 1055 cm ^-1 Example 7 The following compounds were obtained according to the above examples. (1) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(3-methoxymethyl-1-
pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), melting point 138-146°C
(Disassembly). IR (Nujiyor): 3250, 3150, 1770, 1670,
1610, 1530, 1340, 1280, 1230, 1190, 1140cm
^-1 NMR (D ₂ O, δ): 1.30 (3H, t, J = 7Hz),
3.47 (3H, s), 3.20 and 3.66 (2H, ABq, J
= 18Hz), 4.33 (2H, q, J = 7Hz), 4.73 (2H,
s), 5.28 (1H, d, J=5Hz), 5.34 and
5.63 (2H, ABq, J = 14Hz), 5.88 (1H, d, J
=5Hz), 8.15 (1H, m), 8.51 (1H, m), 8.90
(2H, m) (2) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-[3-(N,N-dimethylamino methyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate (syn isomer),
Melting point 145.5-155.5℃ (decomposition). IR (Nujiyor): 3300, 3150, 2700, 1770,
1660, 1610, 1520, 1350, 1290, 1145, 1060,
1030cm ^-1 NMR (D ₂ O, δ): 1.33 (3H, t, J = 7Hz),
3.00 (6H, s), 3.33 and 3.77 (2H, ABq, J
= 18Hz), 4.35 (2H, q, J = 7Hz), 4.60 (2H,
s), 5.32 (1H, d, J=5Hz), 5.43 and
5.67 (2H, ABq, J = 14Hz), 5.88 (1H, d, J
=5Hz), 8.24 (1H, m), 8.78 (1H, m), 9.17
(2H, m) (3) 7-[2-cyclopentyloxyimino-2
-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-[4-(1H-
Tetrazol-5-yl)-1-pyridiniomethyl]-3-cephem-4-carboxylate (syn isomer), mp 181.5-190°C (decomposed). IR (Nujiyor): 3300, 1775, 1670, 1640,
1530, 1400, 1350, 1210, 1160, 1060, 1000cm
⁻¹ NMR (D ₂ O + NaHCO ₃ , δ): 1.1−1.9 (8H,
m), 3.25 and 3.70 (2H, ABq, J=18Hz),
5.30 (1H, d, J = 5Hz), 5.33 and 5.67
(2H, ABq, J=15Hz), 5.84 (1H, d, J=
5Hz), 8.37 (2H, d, J = 6Hz), 8.98 (2H,
d, J=6Hz) (4) 7-[2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-
Thiadiazol-3-yl)acetamide]-
3-[4-(1H-tetrazol-5-yl)-1
-pyridiniomethyl]-3-cephem-4-carboxylate (syn isomer), melting point 165-174
°C (decomposition). IR (Nujiyor): 3300, 1770, 1670, 1635,
1530, 1210, 1160, 1110, 1060, 1030, 1010cm
⁻¹ NMR (D ₂ O + NaHCO ₃ , δ): 1.6−2.5 (4H,
m), 3.28 and 3.68 (2H, ABq, J=18Hz),
5.12−6.20 (5H, m), 5.30 (1H, d, J=5
Hz), 5.88 (1H, d, J = 5Hz), 8.37 (2H, d,
J = 6 Hz), 8.98 (2H, d, J = 6 Hz) (5) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3- (3-methylthiomethyl-1
-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), melting point 150-153
°C (decomposition). IR (Nujiyor): 3300, 3150, 1770, 1660,
1640−1610, 1530, 1280, 1140, 1060, 1040cm
^-1 NMR (D ₂ O, δ): 1.33 (3H, t, J = 7Hz),
2.03 (3H, s), 3.35 and 3.85 (2H, ABq, J
= 18Hz), 3.97 (2H, s), 4.43 (2H, q, J =
7Hz), 5.40 (1H, d, J=5Hz), 5.45 and
5.92 (2H, ABq, J = 14Hz), 5.95 (1H, d, J
= 5Hz), 7.93-8.27 (1H, m), 8.62 (1H, broad d, J = 8Hz), 8.87 (1H, d, J =
5Hz), 8.92(1H,s) (6) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(4-methylthio-1 -pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), m.p. 167-171°C (decomposed). IR (Nujiyor): 3650-3100, 1770, 1660,
1620, 1530, 1490, 1280, 1170, 1100, 1030cm
^-1 NMR (D ₂ O + DCl, δ): 1.32 (3H, t, J =
7Hz), 2.70 (3H, s), 3.33 and 3.83 (2H,
ABq, J=18Hz), 4.40 (2H, q, J=7Hz),
5.37 (1H, d, J = 5Hz), 5.23 and 5.70
(2H, ABq, J=14Hz), 5.95 (1H, d, J=
5Hz), 7.80 (2H, d, J = 7Hz), 8.57 (2H,
d, J = 7Hz) (7) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(3-methoxy-1-pyridiniomethyl) -3-Cefem-4-carboxylate (syn isomer), melting point 137.5-145°C (decomposed). IR (Nujiyor): 3250, 3150, 1770, 1665,
1610, 1530, 1510, 1290, 1240, 1180, 1150,
1110, 1040cm ^-1 NMR (D ₂ O, δ): 1.22 (3H, t, J = 7Hz),
3.15 and 3.58 (2H, ABq, J=18Hz), 3.94
(3H, s), 4.26 (2H, q, J=7Hz), 5.22
(1H, d, J=5Hz), 5.22 and 5.50 (2H,
ABq, J=14Hz), 5.82 (1H, d, J=5Hz),
8.0 (2H, m), 8.57 (2H, m) (8) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-[4 -(1H-tetrazole-
5-yl)-1-pyridiniomethyl]-3-cephem-4-carboxylate (syn isomer),
Melting point 182-187°C (decomposition). IR (Nujiyor): 3300, 3150, 1775, 1665,
1635, 1520, 1150, 1030 cm ^-1 NMR (D ₂ O + NaHCO ₃ , δ): 1.30 (3H, t,
J = 7Hz), 3.32 and 3.75 (2H, ABq, J =
18Hz), 4.30 (2H, q, J = 7Hz), 5.38 (1H,
d, J=5Hz), 5.33 and 5.62 (2H, ABq,
J=14Hz), 5.97 (1H, d, J=5Hz), 8.35
(2H, d, J = 6 Hz), 8.93 (2H, d, J = 6
Hz) (9) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-[3-(1H-tetrazole-
5-yl)-1-pyridiniomethyl]-3-cephem-4-carboxylate (syn isomer),
Melting point 176-181°C (decomposition). IR (Nujiyor): 3290, 3150, 1770, 1665,
1605, 1520, 1150, 1030 cm ^-1 NMR (D ₂ O + NaHCO ₃ , δ): 1.28 (3H, t,
J = 7Hz), 3.42 and 3.80 (2H, ABq, J =
18Hz), 4.30 (2H, q, J = 7Hz), 5.32 (1H,
d, J=5Hz), 5.50 and 5.80 (2H, ABq,
J=14Hz), 5.97 (1H, d, J=5Hz), 8.0−
8.3 (1H, m), 8.8−9.5 (2H, m), 9.5 (1H, broad s) (10) 7-[2-(2-propynyloxyimino)-
2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-[4-(1H
-tetrazol-5-yl)-1-pyridiniomethyl]-3-cephem-4-carboxylate (syn isomer), mp 165-175°C (decomposed). IR (Nujiyor): 3250, 1770, 1670, 1635,
1530, 1150, 1010 cm ^-1 NMR (DMSO-d ₃ , δ): 3.2-3.8 (2H, m),
3.5 (1H, m), 4.7 (2H, m), 5.18 (1H, d, J
= 5Hz), 5.2-5.7 (2H, m), 5.89 (1H, dd,
J = 5 and 8Hz), 8.10 (2H, broad
s), 8.52 (2H, d, J=6Hz), 8.88 (2H, d,
J = 6 Hz), 9.63 (1H, d, J = 8 Hz) (11) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3- (3-Mesylmethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), melting point 155-158°C
(Disassembly). IR (Nujiyor): 3300, 3150, 1770, 1660,
1610, 1530cm ^-1 NMR (D ₂ O, δ), 1.30 (3H, t, J = 7Hz),
3.18 (3H, s), 3.15 and 3.70 (2H, ABq, J
= 18Hz), 4.35 (2H, q, J = 7Hz), 4.87 (2H,
s), 5.28 (1H, d, J=5Hz), 5.33 and
5.68 (2H, ABq, J = 14Hz), 5.90 (1H, d, J
= 5Hz), 8.0-8.3 (1H, m), 8.65 (1H, broad d, J = 7Hz), 9.0-9.3 (1H, m),
9.30 (1H, s) (12) 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(4-hexadecanoyloxymethyl- 1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer),
Melting point 143-148°C (decomposition). IR (Nujiyor): 3270, 3150, 1770, 1750,
1730, 1670, 1640, 1610, 1520, 1145, 1135cm
⁻¹ NMR (DMSO−d ₆ +D ₂ O, δ): 0.85 (3H, t,
J=5Hz), 1.0-1.9 (27H, m), 2.1-2.5 (2H,
m), 3.1-3.7 (2H, m), 3.87 (3H, s), 5.07
(1H, d, J=5Hz), 5.1−5.7 (2H, m),
5.40 (2H, broad s), 5.5-5.8 (1H, m),
8.10 (2H, m), 9.40 (2H, m) (13) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(4 -tetradecanoyloxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer),
Melting point 149-154°C (decomposition). IR (Nujiyor): 3260, 3150, 1770, 1670,
1640, 1610, 1525, 1150, 1035 cm ^-1 NMR (DMSO-d ₆ + D ₂ O, δ): 0.84 (3H, t,
J = 5Hz), 1.3-1.7 (25H, m), 2.1-2.7 (2H,
m), 3.20 and 3.58 (2H, ABq, J=18Hz),
4.14 (2H, q, J = 7Hz), 5.08 (1H, d, J =
5Hz), 5.1-5.7 (4H, m), 5.73 (1H, d, J
= 5Hz), 8.07 (2H, d, J = 6Hz), 9.41 (2H,
d, J = 6Hz) (14) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(4-octadecanoyloxymethyl- 1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer),
Melting point 151-156°C (decomposition). IR (Nujiyor): 3300, 3150, 1770, 1750,
1670, 1640, 1610, 1520 cm ^-1 NMR (DMSO-d ₆ + D ₂ O, δ): 0.85 (3H, t,
J = 5Hz), 1.0-1.9 (33H, m), 2.1-2.5 (2H,
m), 3.30 and 3.68 (2H, ABq, J=18Hz),
4.14 (2H, d, J = 7Hz), 5.06 (1H, d, J =
5Hz), 5.0-5.8 (4H, m), 5.70 (1H, d, J
= 5Hz), 8.07 (2H, d, J = 6Hz), 9.43 (2H,
d, J = 6 Hz) (15) 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(4-oleoyloxymethyl-1 -pyridiniomethyl)-3-cephem-
4-carboxylate (syn isomer), melting point 123
~131℃ (decomposition). IR (Nujiyor): 3300, 1770, 1670, 1640,
1610, 1570, 1525 cm ^-1 NMR (DMSO-d ₆ + D ₂ O, δ): 0.80 (3H, t,
J = 5Hz), 1.18 (22H, m), 1.6-2.4 (6H,
m), 3.0-3.7 (2H, m), 3.80 (3H, s), 4.90
-5.85 (6H, m), 5.06 (1H, d, J=5Hz),
5.71 (1H, d, J=5Hz), 8.02 (2H, m),
9.18 (2H, m) (16) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(3-hexadecanoyloxymethyl- 1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer),
Melting point 137-146°C (decomposition). IR (Nujiyor): 3300, 3150, 1770, 1670,
1610, 1520, 1510 cm ^-1 NMR (DMSO-d ₆ + D ₂ O, δ): 0.82 (3H, t,
J=6Hz), 1.2 (29H, m), 2.32 (2H, m),
3.50 (2H, m), 4.15 (2H, q, J=7Hz), 4.9
-5.9 (4H, m), 5.06 (1H, d, J=5Hz),
5.72 (1H, d, J=5Hz), 8.13 (1H, m),
8.50 (1H, m), 9.30 (2H, m) (17) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-[3 -(1H-tetrazone-
5-ylthiomethyl)-1-pyridiniomethyl]
-3-Cefem-4-carboxylate (syn isomer), melting point 151-160°C (decomposed). IR (Nujiyor): 3250, 3150, 1775, 1670,
1620, 1525, 1140, 1030 cm ^-1 NMR (D ₂ O + NaHCO ₃ , δ): 1.27 (3H, t,
J = 7Hz), 2.97 and 3.40 (2H, ABq, J =
18Hz), 4.32 (2H, q, J = 7Hz), 4.35 (2H,
s), 5.27 and 5.50 (2H, ABq, J=14Hz),
5.28 (1H, d, J = 5Hz), 5.88 (1H, d, J =
5Hz), 7.90 (1H, dd, J=6 and 8Hz),
8.40 (1H, d, J = 8Hz), 8.75 (2H, m) (18) 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide] -3-[4-(1H-tetrazon-5-yl)-1-pyridiniomethyl]-3
- Cefem-4-carboxylate (syn isomer), melting point 183-188°C (decomposed). IR (Nujiyor): 3300, 3180, 1775, 1680,
1640, 1530, 1155, 1070, 1020 cm ^-1 NMR (D ₂ O + NaHCO ₃ , δ): 3.30 and 3.73
(2H, ABq, J=18Hz), 4.5−5.1 (2H, m),
5.0−6.3 (5H, m), 5.35 (1H, d, J=5Hz),
5.94 (1H, d, J = 5Hz), 8.22 (1H, d, J =
6Hz), 9.02 (2H, d, J = 6Hz) Production example 15 3-chloromethylpyridine hydrochloride (54.87g)
A mixture of and thiosemicarbazide (27.68g) in methanol (280ml) was refluxed for 3.5 hours. After cooling, the mixture was diluted with methanol (220ml) and the solution was poured into isopropyl alcohol (3) under stirring. The generated precipitate was collected, washed with methanol, and dried to give 3-(3-pyridylmethyl)isothiosemicarbazide. Dihydrochloride (58
g) was obtained. Melting point 143-145℃. A solution of sodium nitrite (3.45 g) in water (25 ml) was added to a solution of the product thus obtained (12.75 g) in 100 ml of water.
The mixture was added dropwise with stirring at 10-20° C. while cooling in an ice solution, and then 10% hydrochloric acid (20 ml) was added. mixture
After stirring for 40 min at 10-20 °C. The pH was adjusted to 4.5 with an aqueous sodium hydrogen carbonate solution. The solution was evaporated to dryness and the residue was extracted with ethanol. The extract was evaporated to dryness and the residue was triturated in acetone to give 3-
(1H-tetrazol-5-ylthiomethyl)pyridine (10.44 g) was obtained as a crude product. IR (Nujiyor): 2400−2300, 1605, 1570−
1550, 1430, 1330, 1050, 1040 cm ^-1 NMR (D ₂ O, δ): 4.30 (2H, s), 7.50 (1H,
dd, J=5 and 8Hz), 8.10 (1H, m), 8.38
(2H, m) The crude product was recrystallized from acetonitrile to obtain lobular crystals. Melting point 141.5-144.0℃. Example 8 To a stirred mixture of 4-methoxypyridine (4.4 g), sodium iodide (36 g), phosphoric acid (1.2 g), water (6 ml) and acetonitrile (18 ml) was added 7- imino-2-(5-
Sodium amino-1,2,4-thiadiazol-3-yl)acetamide]cephalosporanate (syn isomer) (11.0 g) was added at 65°C and the mixture was stirred at 68-70°C for 2.5 hours. The reaction mixture was poured into water (300ml), adjusted to pH 3.2 with 3N hydrochloric acid, and filtered. The liquid was subjected to column chromatography using a nonionic adsorption resin "Diaion HP-20" (300 ml). The column was washed with water (1) and then eluted with 30% aqueous methanol (700ml).
The eluate was concentrated under reduced pressure to a weight of 17 g, and N,N
-Dissolved in dimethylformamide (17ml). This solution was poured into acetone (200 ml) with stirring, and the resulting precipitate was collected, washed with acetone, and dissolved again in warm water (100 ml). After separating the insoluble matter,
Pass the liquid through a tower filled with acidic alumina (38g), and weigh the
It was concentrated under reduced pressure to 5.5 g and dissolved in N,N-dimethylformamide (5 ml). The solution was poured into acetone (100 ml) with stirring, the resulting precipitate was collected, washed with acetone, and dried to give 7-[2-methoxyimino-2-(5-amino-1,2,4 -thiadiazol-3-yl)acetamide]-3-(4-methoxy-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (2.5 g) was obtained. Melting point 180~185℃
(Disassembly). IR (Nujiyor): 3300, 1760, 1670, 1640,
1610, 1560, 1520 cm ^-1 NMR (D ₂ O + CD ₃ OD, δ): 3.27 and 3.67
(2H, ABq, J=18Hz), 4.12 (3H, s), 4.20
(3H, s), 5.28 (1H, d, J = 4Hz), 5.17 and 5.47 (2H, ABq, J = 14Hz), 5.93 (1H, d, J
= 4Hz), 7.57 (2H, d, J = 7Gz), 8.83 (2H,
d, J=7Hz) Example 9 The following compound was obtained according to the above example. (1) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(4-methoxy-1-pyridiniomethyl)-3-cephem-4 - Carboxylate (syn isomer), melting point 195-200°C (decomposed). IR (Nujiyor): 3300, 1770, 1670, 1630,
1590, 1560 cm ^-1 NMR (D ₂ O + DCl, δ): 1.30 (3H, t, J =
7Hz), 3.40 and 3.73 (2H, ABq, J=18
Hz), 4.17 (3H, s), 4.42 (2H, q, J=7
Hz), 5.27 and 5.63 (2H, ABq, J=14Hz),
5.33 (1H, d, J = 4Hz), 5.90 (1H, d, J =
4Hz), 7.50 (2H, d, J=8Hz), 8.70 (2H,
d, J=8Hz) (2) 7-[2-(2-propynyloxyimino)-
2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(4-methoxy-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), melting point
185-190℃ (decomposition). IR (Nujiyor): 3250, 1770, 1740, 1640,
1570, 1520cm ^-1 NMR (D ₂ O + DCl, δ): 3.08 (1H, t, J =
2Hz), 3.43 and 3.73 (2H, ABq, J=18
Hz), 4.17 (3H, s), 5.37 (1H, d, J=4
Hz), 5.40 (2H, d, J=2Hz), 5.55 and
5.67 (2H, ABq, J = 14Hz), 5.93 (1H, d, J
= 4Hz), 7.53 (2H, d, J = 7Hz), 8.73 (2H,
d, J = 7Hz) (3) 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(4-methoxy-1-
pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), melting point 180-185°C
(Disassembly). IR (Nujiyor): 3300, 1780, 1660, 1640,
1620, 1570, 1520cm ^-1 NMR (D ₂ O, δ): 3.20 and 3.57 (2H, ABq,
J=18Hz), 4.10 (3H, s), 4.5−4.8 (2H,
m), 5.1−5.7 (5H, m), 5.85 (1H, d, J=
4Hz), 5.76-6.17 (1H, m), 7.45 (2H, d,
J = 7 Hz), 8.68 (2H, d, J = 7 Hz) (4) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3- (4-Ethoxy-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), m.p. 150-155°C (decomposition). IR (Nujiyor): 3350, 3250, 3150, 1770,
1670, 1633, 1610, 1555, 1515 cm ^-1 NMR (D ₂ O, δ): 1.30 (3H, t, J = 7Hz),
1.47 (3H, t, J = 7Hz), 3.23 and 3.63
(2H, ABq, J=18Hz), 4.33 (2H, q, J=
7Hz), 4.42 (2H, q, J = 7Hz), 5.27 (1H,
d, J=4Hz), 5.18 and 5.35 (2H, ABq,
J=14Hz), 5.87 (1H, d, J=4Hz), 7.42
(2H, d, J=7Hz), 8.68 (2H, d, J=7
Hz) (5) 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(3-methyl-4-methoxy-1-pyridiniomethyl) -3-CEFM-4
-Carboxylate (syn isomer), melting point 140~
145℃ (decomposition). IR (Nujiyor): 3250, 3150, 1770, 1660,
1635, 1610, 1515, 1490cm ^-1 NMR (CD ₃ OD + D ₂ O, δ): 2.30 (3H, s),
3.15 and 3.62 (2H, ABq, J=18Hz), 4.03
(3H, s), 4.18 (3H, s), 5.20 (1H, d, J
= 4Hz), 5.12 and 5.45 (2H, ABq, J = 14
Hz), 5.87 (1H, d, J = 4Hz), 7.50 (1H, d,
J = 7Hz), 8.72 (1H, s), 8.83 (1H, d, J
=7Hz) (6) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(3-methyl-4-methoxy-1-pyridiniomethyl )-3-CEFEM-4
-Carboxylate (syn isomer), melting point 155~
160℃ (decomposition). IR (Nujiyor): 3250, 3150, 1770, 1665,
1630, 1610, 1515, 1490 cm ^-1 NMR (D ₂ O, δ): 1.32 (3H, t, J = 7Hz),
2.28 (3H, s), 3.20 and 3.62 (2H, ABq, J
= 18Hz), 4.15 (3H, s), 4.35 (2H, q, J =
7Hz), 5.15 and 5.32 (2H, ABq, J=14
Hz), 5.28 (1H, d, J = 4Hz), 5.87 (1H, d,
J=4Hz), 7.43 (1H, d, J=7Hz), 8.50
(1H, s), 8.62 (1H, d, J = 7Hz) (7) 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3 -(4-Methylthio-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), mp 170-175°C (decomposed). IR (Nujiyor): 3300, 3160, 1770, 1670,
1625, 1545, 1530, 1490 cm ^-1 NMR (D ₂ O + CD ₃ OD, δ): 2.70 (3H, s),
3.18 and 3.60 (2H, ABq, J=18Hz), 4.03
(3H, s), 5.22 (1H, d, J = 5Hz), 5.13 and 5.42 (2H, ABq, J = 14Hz), 5.85 (1H,
d, J = 5Hz), 7.78 (2H, d, J = 7Hz),
8.65 (2H, d, J = 7Hz) (8) 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(4-methylthio -1
-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), melting point 155-163
°C (decomposition). IR (Nujiyor): 3300, 1770, 1670, 1620,
1530, 1490 cm ^-1 NMR (DMSO-d ₆ , δ): 2.70 (3H, s), 3.08
and 3.52 (2H, ABq, J=18Hz), 4.62 (2H,
d, J=5Hz), 5.03 and 5.47 (2H, ABq,
J=14Hz), 5.04 (1H, d, J=5Hz), 5.2−
6.2 (4H, m), 7.93 (2H, d, J=6Hz), 8.17
(2H, broad s), 9.10 (2H, d, J=6
Hz), 9.49 (1H, d, J = 8Hz) (9) 7-[2-carboxymethoxyimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamido]-3-(4-methylthio-1-pyridiniomethyl)-3-cephem-
4-carboxylate (syn isomer), melting point 168
~177℃ (decomposition). IR (Nujiyor): 3300, 1770, 1670, 1625,
1520, 1490 cm ^-1 NMR (DMSO-d ₆ + D ₂ O, δ): 2.70 (3H,
s), 3.10 and 3.57 (2H, ABq, J=17Hz),
5.10 (1H, d, J = 5Hz), 5.03 and 5.47
(2H, ABq, J=14Hz), 5.77 (1H, d, J=
5Hz), 7.87 (2H, d, J = 7Hz), 8.88 (2H,
d, J = 7Hz) (10) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-[4-(2-methoxyethoxy) Methyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer),
Melting point 132-140℃ (decomposition). IR (Nujiyor): 3250, 1775, 1670, 1640,
1570, 1530cm ^-1 NMR (D ₂ O, δ): 1.27 (3H, t, J = 7Hz),
3.37 (3H, s), 3.20 and 3.63 (2H, ABq, J
= 18Hz), 3.74 (3H, m), 4.31 (2H, q, J =
7Hz), 4.90 (2H, s), 5.25 (1H, d, J=5
Hz), 5.30 and 5.57 (2H, ABq, J=14Hz),
5.85 (1H, d, J = 5Hz), 8.01 (2H, d, J =
7Hz), 8.89 (2H, d, J = 7Hz) (11) 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-[4 -(2-methoxyethoxy)methyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer),
Melting point 127-134°C (decomposition). IR (Nujiyor): 3250, 1770, 1660, 1640,
1610, 1530 cm ^-1 NMR (D ₂ O, δ): 3.40 (3H, s), 3.22 and
3.63 (2H, ABq, J=18Hz), 3.75 (3H, broad s), 4.05 (3H, s), 4.91 (2H, s), 5.26
(1H, d, J=5Hz), 5.30 and 5.57 (2H,
ABq, J=15Hz), 5.87 (1H, d, J=5Hz),
8.03 (2H, d, J = 7Hz), 8.90 (2H, d, J =
7Hz) (12) 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(2-methoxyethoxy)methyl-1 -Pyridiniomethyl]-
3-cephem-4-carboxylate (syn isomer), melting point 140-146°C (decomposed). IR (Nujiyor): 3250, 1770, 1670, 1640,
1610, 1530 cm ^-1 NMR (D ₂ O, δ): 3.43 (3H, s), 3.27 and
3.67 (2H, ABq, J=18Hz), 3.80 (4H, broad s), 4.95 (2H, s), 4.8-5.0 (2H, m),
5.0−5.6 (2H, m), 5.23 (1H, d, J=5Hz),
5.27 and 5.50 (2H, ABq, J=14Hz), 5.92
(1H, d, J=5Hz), 5.9−6.1 (1H, m),
8.10 (2H, d, J = 7Hz), 8.95 (2H, d, J =
7Hz) (13) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-[4-(1H-tetrazole-
5-ylthiomethyl)-1-pyridiniomethyl]
-3-Cefem-4-carboxylate (syn isomer), melting point 165-172°C (decomposed). IR (Nujiyor): 3300, 3180, 1770, 1660,
1635, 1520cm ^-1 NMR (D ₂ O + NaHCO ₃ , δ): 1.27 (3H, t,
J=7Hz), 3.10 and 3.55 (2H, ABq, J=
18Hz), 4.30 (2H, q, J = 7Hz), 4.70 (2H,
s), 5.25 (1H, d, J=5Hz), 5.23 and
5.50 (2H, ABq, J = 14Hz), 5.87 (1H, d, J
= 5Hz), 7.79 (2H, d, J = 7Hz), 8.74 (2H,
d, J=7Hz) (14) 7-[2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-
Thiadiazol-3-yl)acetamide]-
3-[4-(1H-tetrazol-5-ylthiomethyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate (syn isomer), mp 173-180°C (decomposed). IR (Nujiyor): 3300, 3150, 3050, 1770,
1660, 1630, 1530cm ^-1 NMR (D ₂ O + NaHCO ₃ , δ): 1.70−2.60 (4H,
m), 3.08 and 3.57 (2H, ABq, J=17Hz),
4.73 (2H, s), 4.88-5.75 (3H, m), 5.27
(1H, d, J=5Hz), 5.88 (1H, d, J=5
Hz), 5.75-6.35 (2H, m), 7.88 (2H, d, J
= 6 Hz), 8.81 (2H, d, J = 6 Hz) (15) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-[ 4-(1H-tetrazole-
5-ylthio)-1-pyridiniomethyl]-3-
Cefem-4-carboxylate (syn isomer), melting point 166-173°C (decomposed). IR (Nujiyor): 3300, 3150, 1770, 1660,
1620, 1530, 1490 cm ^-1 NMR (D ₂ O + NaHCO ₃ , δ): 1.32 (3H, t,
J = 7Hz), 3.33 and 3.67 (2H, ABq, J =
18Hz), 4.36 (2H, q, J=7Hz), 5.23 and
5.50 (2H, ABq, J = 14Hz), 5.32 (1H, d, J
= 5Hz), 5.94 (1H, d, J = 5Hz), 7.57 (2H,
d, J = 7 Hz), 8.67 (2H, d, J = 7 Hz) (16) 7-[2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-
Thiadiazol-3-yl)acetamide]-
3-[4-(1H-tetrazol-5-ylthio)
-1-pyridiniomethyl]-3-cephem-4
-Carboxylate (syn isomer), melting point 164 ~
171℃ (decomposition). IR (Nujiyor): 3300, 3150, 1770, 1670,
1620, 1530, 1490 cm ^-1 NMR (D ₂ O + NaHCO ₃ , δ): 1.80−2.60 (4H,
m), 2.8-3.8 (2H, m), 5.10-5.65 (3H, m),
5.1−5.9 (4H, m), 5.30 (1H, d, J=5Hz),
5.90 (1H, d, J=5Hz), 6.15 (1H, m),
7.58 (2H, d, J = 7Hz), 8.70 (2H, d, J =
7Hz) (17) 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(1H-tetrazol-5-yl) -1-pyridiniomethyl]-3
- Cefem-4-carboxylate (syn isomer), melting point 151-160°C (decomposed). IR (Nujiyor): 3300, 1770, 1670, 1640,
1525cm ^-1 NMR (D ₂ O + NaHCO ₃ , δ): 3.30 and 3.70
(2H, ABq, J=18Hz), 4.5−4.8 (2H, m),
5.0−6.2 (7H, m), 8.37 (2H, d, J=6Hz),
8.95 (2H, d, J = 6Hz) (18) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-[4-(2 -methoxyethoxy)-1-pyridiniomethyl]-3-cephem-
4-carboxylate (syn isomer), melting point 150
~155℃ (decomposition). IR (Nujiyor): 3350, 3250, 3110, 1770,
1660, 1630, 1610, 1560, 1515 cm ^-1 NMR (D ₂ O, δ): 1.32 (3H, t, J = 7Hz),
3.45 (3H, s), 3.23 and 3.63 (2H, ABq, J
= 18Hz), 3.77-4.07 (2H, m), 4.33 (2H, q,
J = 7Hz), 4.4-4.7 (2H, m), 5.30 (1H, d,
J = 5Hz), 5.22 and 5.37 (2H, ABq, J =
14Hz), 5.88 (1H, d, J = 5Hz), 7.50 (2H,
d, J = 7 Hz), 8.75 (2H, d, J = 7 Hz) (19) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]- 3-[4-(2-hydroxyethoxy)-1-pyridiniomethyl]-3-cephem-4-carboxylate (syn isomer), melting point
160-165℃ (decomposition). IR (Nujiyor): 3360, 3250, 3160, 1770,
1660, 1635, 1610, 1560, 1520 cm ^-1 NMR (D ₂ O, δ): 1.30 (3H, t, J = 7Hz),
3.20 and 3.58 (2H, ABq, J=18Hz), 3.98
(2H, t, J = 4Hz), 4.28 (2H, q, J = 7
Hz), 4.40 (2H, t, J = 4Hz), 5.22 (1H, d,
J = 4Hz), 5.12 and 5.30 (2H, ABq, J =
14Hz), 5.80 (1H, d, J = 4Hz), 7.40 (2H,
d, J = 7 Hz), 8.60 (2H, d, J = 7 Hz) (20) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]- 3-[4-(2-methyl-5-oxo-6-hydroxy-2,5-dihydro-
1,2,4-triazin-3-yl)thiomethyl-1-pyridiniomethyl]-3-cephem-
4-carboxylate (syn isomer), melting point 195
~197℃ (decomposition). IR (Nujiyor): 3300, 3180, 1773, 1665,
1655, 1635, 1610, 1510 cm ^-1 NMR (D ₂ O, δ): 1.28 (3H, t, J = 7Hz),
3.16 and 3.58 (2H, ABq, J=18Hz), 3.66
(3H, s), 4.30 (2H, q, J=7Hz), 5.22
(1H, d, J=5Hz), 5.28 and 5.47 (2H,
ABq, J=14Hz), 5.83 (1H, d, J=5Hz),
8.10 (2H, d, J = 7Hz), 8.82 (2H, d, J =
7Hz) (21) 7-[2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4
-thiadiazol-3-yl)acetamide]
-3-[4-(2-methyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-1-pyridiniomethyl]-3-cephem-4- Carboxylate (syn isomer), melting point 168-173°C (decomposition). IR (Nujiyor): 3300, 3150, 1770, 1635,
1510cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.6-2.6 (4H,
m), 3.58 (3H, s), 3.2-3.9 (2H, m), 5.1-
6.1 (7H, m), 8.1 (2H, m), 8.8 (2H, m) (22) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)
Acetamide]-3-(4-methoxymethyl-1
-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), melting point 145-153
°C (decomposition). IR (Nujiyor): 3300, 1775, 1670, 1640,
1610, 1570, 1530cm ^-1 NMR (D ₂ O, δ): 1.30 (3H, t, J = 7Hz),
3.50 (3H, s), 3.23 and 3.63 (2H, ABq, J
= 18Hz), 4.32 (2H, q, J = 7Hz), 4.83 (2H,
s), 5.28 (1H, d, J=5Hz), 5.32 and
5.57 (2H, ABq, J = 14Hz), 5.88 (1H, d, J
= 5Hz), 8.00 (2H, d, J = 7Hz), 8.90 (2H,
d, J = 7 Hz) Production Example 16 4-chloropyridine (42.7 g) was added dropwise to a solution of sodium metal (9.96 g) in 2-methoxyethanol (100 ml) while stirring while heating to 140-145°C. After the addition was completed, the mixture was stirred at 135°C for an additional hour. The mixture was cooled to -15°C and dry ice (5.6g) was added to it. The mixture was warmed to 45°C and then left at room temperature. The generated precipitate was separated and washed with diisopropyl ether. The liquid and washing liquid were combined and evaporated to dryness. The remaining oil was distilled to give 4-(2-methoxyethoxy)pyridine (42.3g). Boiling point 98-106℃ (6mmH
g). NMR ( _CDCl3O , δ): 3.42 (3H, s), 3.57−
3.90 (2H, m), 4.03-4.30 (2H, m), 6.82 (2H,
d, J = 6 Hz), 8.60 (2H, d, J = 6 Hz) Production example 17 4-chloropyridine (39.6
g) was added in portions while stirring at 120 to 130°C, and after the addition was complete, the mixture was further stirred at 130°C for 1 hour. The mixture was cooled to -15°C and dry ice (5.2g) was added to it. The mixture was warmed to 45°C and left at room temperature. The generated precipitate was separated and washed with diisopropyl ether. The liquid and washing liquid were combined and evaporated to dryness. The remaining oil was distilled to give 4-(2-hydroxyethoxy)pyridine (9 g). Boiling point 138~145℃ (5~6mmH)
g). The oil solidified and was recrystallized from ethyl acetate. Melting point 113-115°C (decomposition). NMR (DMSO-d ₆ + D ₂ O, δ): 3.82 (2H, t,
J = 5Hz), 4.17 (2H, t, J = 5Hz), 7.02 (2H,
d, J = 6Hz), 8.42 (2H, d, J = 6Hz) Production example 18 2-methyl-3-mercapto-5-oxo-6
-Hydroxy-2,5-dihydro-1,2,4-
A mixture of triazine (15.91g), 4-chloromethylpyridine hydrochloride (19.68g) and sodium bicarbonate (33.6g) in water (500ml) was stirred at 45°C for 2 hours. Cool the mixture to 10 °C and PH with 6N hydrochloric acid.
Adjusted to 6.2. The generated precipitate was collected, washed with water and acetone, and dried to give 2-methyl-
3-(4-pyridylmethylthio)-5-oxo-6
-Hydroxy-2,5-dihydro-1,2,4-
Triazine (17.2g) was obtained. Melting point 219-222℃
(Disassembly). IR (Nujiyor): 3480, 3400, 1700, 1630,
1605, 1500cm ^-1 NMR (DMSO-d ₆ + D ₂ O, δ): 3.63 (3H, s),
4.43 (2H, s), 7.3-7.6 (2H, m), 8.4-8.6 (2H,
m) Production Example 19 A solution of 4-chloromethylpyridine hydrochloride (22.5 g) in 2-methoxyethanol (150 ml) was added to a solution of sodium metal (7.57 g) in 2-methoxyethanol (135 ml) in an ice-salt bath. It was added dropwise while stirring while cooling. The mixture was stirred at 65° C. for 45 minutes and then evaporated to dryness under reduced pressure. Add the residue to water (500ml)
This solution was extracted with chloroform.
The extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated to dryness. The remaining oil was distilled to give 4-(2-methoxyethoxymethyl)pyridine (21.56 g). boiling point 98
~101°C (3-3.5mmHg). NMR (CDCl ₃ O, δ): 3.42 (3H, s), 3.66 (4H,
s), 4.63 (2H, s), 7.33 (2H, m), 8.63 (2H,
m) Production example 20 (1) 4-chloromethylpyridine hydrochloride (0.82g)
A mixture of and thiosemicarbazide (0.46 g) in methanol (6 ml) was refluxed for 2 hours. The mixture was poured into isopropyl alcohol (60 ml) with vigorous stirring, and the precipitate formed was collected, washed with isopropyl alcohol, dried, and 3-(4-pyridylmethyl)isothiosemicarbazide dihydrochloride. (0.75g) was obtained. Melting point 185-188℃ (decomposition). IR (Nujiyor): 3250, 3100, 2650, 1640,
1630, 1610, 1590, 1520, 1505 cm ^-1 (2) 3-(4-pyridylmethyl)isothiosemicarbazide dihydrochloride (25.5 g) in water (180 ml)
Add sodium nitrite (8.97 g) to the solution (50
ml) solution at 10-20°C while cooling in an ice-salt bath.
It was added dropwise while stirring. Add 10% hydrochloric acid to the reaction mixture
It was added dropwise while stirring at 12-13°C. This solution was adjusted to pH 4.7 with an aqueous sodium hydrogen carbonate solution and evaporated to dryness. Ethanol was added to the residue and insoluble materials were separated. The liquid was evaporated to dryness to give a dark brown oil which was mixed with a solution of anhydrous sodium acetate (4.15g) in methanol (250ml). The mixture was evaporated to dryness and the residue was triturated in diethyl ether to give the sodium salt of 5-(4-pyridylmethylthio)tetrazole (8.61 g).
was used in the next reaction without further purification. The sodium salt aqueous solution was adjusted to pH 4 with an aqueous sodium bicarbonate solution, salted out, and extracted with tetrahydrofuran. The extract was dried over magnesium sulfate and evaporated to dryness. The residue was dissolved in ethanol, and insoluble materials were separated. The liquid was evaporated to dryness, and the residue was recrystallized from diethyl ether to give 5-
(4-pyridylmethylthio)tetrazole was obtained. Melting point 131-138°C (decomposition). IR (Nujiyor): 2450, 1940, 1610, 1510cm ^-
1 NMR (D ₂ O + NaHCO ₃ , δ): 4.27 (2H, s),
7.33 (2H, d, J = 5Hz), 8.45 (2H, d, J =
5Hz) Production Example 21 A mixture of 4-chloropyridine hydrochloride (7.25g), 5-mercapto-1H-tetrazole (4.93g) and triethylamine (14.64g) in dimethylformamide (120ml) was stirred at 82-85°C for 1 hour. and then cooled in an ice bath. The formed precipitate was separated and the liquid was mixed with water (60 ml). This aqueous solution was adjusted to pH 2 with 2N hydrochloric acid and evaporated to dryness under reduced pressure. The residue was triturated in chloroform (300ml) and
The generated precipitate was collected and washed with the same solvent. Ethanol (650 ml) was added to this precipitate to separate insoluble matter. The liquid was evaporated to dryness to give 4-(1H-
Tetrazol-5-ylthio)pyridine (4.03
g) was obtained. Melting point 159-161°C (decomposition). IR (Nujiyor): 3080, 2750-2300, 1630,
1610, 1510cm ^-1 NMR (D ₂ O, δ): 7.70 (2H, d, J = 7Hz),
8.55 (2H, d, J = 7Hz) Production example 22 (1) 3-Mercaptopyridine Hexachlorostanaate and 2-hydroxyethyl bromide are reacted in a conventional manner to produce 3-(2-hydroxyethylthio)pyridine (oil). I got it. IR (Film): 3250, 2940, 2860, 1575,
1565, 1470, 1410, 1110, 1070, 1045, 1020,
795cm ^-1 NMR (d ₆ -acetone, δ): 3.17 (2H, t, J
= 7Hz), 3.75 (2H, t, J = 7Hz), 7.27 (1H,
m), 7.80 (1H, m), 8.38 (1H, dd, J = 2 and 6Hz), 8.55 (1H, d, J = 2Hz) (2) 3-mercaptopyridine hexachlorostanaate and 2-dimethylaminoethyl chloride were reacted in a conventional manner to obtain 3-(2-dimethylaminoethylthio)pyridine (oil). IR (Film): 3400, 3020, 2950, 2930,
2850, 2800, 2760, 1560, 1460, 1400, 1365cm
⁻¹ NMR (CDCl ₃ O, δ): 2.23 (6H, broad
s), 2.37-2.70 (2H, m), 2.87-3.20 (2H,
m), 7.0-7.33 (1H, m), 7.53-7.80 (1H,
m), 8.30-8.50 (1H, m), 8.57 (1H, d, J
= 2 Hz) Example 10 The following compound was obtained in the same manner as in the above example. (1) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-[3-(2-hydroxyethylthio)-1-pyridiniomethyl] -3-Cefem-4-carboxylate (syn isomer), m.
p.158-163℃ (decomposition). IR (Nujiyor): 3300, 3150, 1770, 1660,
1610, 1530, 1350, 1285, 1160, 1060, 1040cm
⁻¹ NMR (DCl+D ₂ O, δ): 1.33 (3H, t, J=
7Hz), 3.37 and 3.85 (2H, ABq, J=18
Hz), 3.35 (2H, t, J=6Hz), 3.87 (2H, t,
J = 6Hz), 4.47 (2H, q, J = 7Hz), 5.37 and 5.85 (2H, ABq, J = 14Hz), 5.38 (1H,
d, J=5Hz), 5.90 (1H, d, J=5Hz),
7.83-8.17 (1H, m), 8.40-8.93 (3H, m) (2) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]- 3-[3-(2-dimethylaminoethylthio)-1-pyridiniomethyl]-3-cephem-4-carboxylate (syn isomer),
mp105-110℃ (decomposition). IR (Nujiyor): 3300, 2690, 2350, 1770,
1665, 1610, 1525 cm ^-1 NMR (D ₂ O, δ): 1.32 (3H, t, J = 7Hz),
2.95 (6H, s), 3.53 (4H, s), 3.30 and 3.72
(2H, ABq, J=18Hz), 4.35 (2H, q, J=
7Hz), 5.32 (1H, d, J=5Hz), 5.28 and
5.60 (2H, ABq, J = 14Hz), 5.85 (1H, d, J
=5Hz), 7.87-8.17 (1H, m), 8.40-8.65
(1H, m), 8.73-8.93 (1H, m), 9.17 (1H,
d, J=2Hz)

Claims (1)

[Claims] 1. General formula: [In the formula, R ¹ is an amino group or a protected amino group; R ² is a lower alkyl group optionally substituted with a carboxy group, a lower alkenyl group, a lower alkynyl group, a cyclo(lower) alkyl group, or a cyclo(lower) ) alkenyl group; R ³ is lower alkylamino group, N-(lower) alkanoyl (lower) alkylamino group, di(lower)
Alkylamino group, sulfo (lower) alkylamino group, hydroxy (lower) alkylamino group, N
-(lower)alkanoylhydroxy(lower)alkylamino group, alkanoyloxy(lower)alkyl group, alkenoyloxy(lower)alkyl group, loweralkoxy(lower)alkoxy(lower)
Alkyl group, di(lower)alkylamino(lower)
Alkyl group, lower alkylthio (lower) alkyl group, lower alkylthio group, lower alkoxy group, lower alkoxy (lower) alkoxy group, hydroxy (lower) alkoxy group, lower alkanesulfonyl (lower) alkyl group, hydroxy (lower) alkylthio group, di(lower)alkylamino(lower)alkylthio group, tetrazolyl group, tetrazolylthio group, tetrazolylthio(lower)alkyl group or dihydrotriazinylthio(lower)alkyl group substituted with oxo, hydroxy and lower alkyl; R ⁴ is a hydrogen atom or a lower alkyl group, or R ¹ has the same meaning as before; R ² is an ethyl group; R ³ is a methoxymethyl group; R ₄ is a hydrogen atom] and The salts.