JPH04234891A - New cephem compound and salt thereof - Google Patents

Abstract

PURPOSE:To obtain a new cephem compound (salt) containing pyrazolio group, effective for treating infectious diseases with pathogenic bacteria, useful as an antimicrobial agent having much more excellent effects than existing cephem- based compounds, having high antimicrobial activity. CONSTITUTION:A 7beta-substituted amino-3-substituted-3-cephem-4-carboxylic acid ester shown by formula I(R<5> is protected amino group; R<6> is protected carboxyl group; Y is eliminable group) is reacted with a 1-substituted-oxypropyl-5- substituted-aminopyrazole shown by formula II [R<3> is (protected)amino; R<4> is (protected)hydroxypropyl] and deprotected to give a 73b-amino-3(1-substituted- pyrazolio)methyl-3-cephem-4-carboxylic acid shown by formula III, which is reacted with a 5-aminothiadiazole derivative shown by formula IV [R<1> is (protected)amino; R<2> is H or organic group; Z is N or CH] to give the objective new cephem compound (salt) shown by formula V.

Description

[Detailed description of the invention]

0001

FIELD OF INDUSTRIAL APPLICATION This invention relates to a novel cephem compound having high antibacterial activity and is used in the medical field.

0002

BACKGROUND OF THE INVENTION Although many cephem compounds are known, the cephem compound represented by the following general formula [I] of the present invention is not known.

0003

[Problems to be Solved by the Invention] Many cephem compounds that have antibacterial activity and are useful as pharmaceuticals are known.
This invention was made with the intention of developing even better medicines.

0004

[Means for Solving the Problems] The target cephem compounds and salts thereof are novel and can be represented by the following general formula [I]. [wherein R1 is an amino group or a protected amino group, R
2 is hydrogen or an organic group, R3 is an amino group or a protected amino group, R4 is a hydroxypropyl group, a protected hydroxypropyl group, an isopropyl group, a lower alkoxy (lower) alkyl group, a halo (lower) alkyl group, a carboxy (lower) alkyl group, protected carboxy (lower) alkyl group, carbamoyl (lower) alkyl group, amino (lower) alkyl group or protected amino (lower) alkyl group, Z means N or CH, respectively. However, when R4 means a hydroxypropyl group or a protected hydroxypropyl group, Z means N. ]

One point to note is that the pyrazolio moiety of compound [I] can exist in a tautomeric form, and such tautomeric equilibrium can be represented by the following formula. (In the formula, R3 and R4 each have the same meaning as before). Although all of the above tautomerisms are included within the scope of the present invention, in this specification, the target compound [I] will be represented by one expression of the pyrazolio group of formula (A) for convenience.

The cephem compound [I] of the present invention can be produced by the production method shown in the following reaction formula.

[0007]

[0008]

[In the formula, R1 and R2, R3, R4 and Z each have the same meaning as before, and Y each represents a leaving group]

[0010] In the foregoing and following description of this specification, preferred examples and explanations of various definitions falling within the scope of this invention are set forth in detail below. The term lower is used to include groups having 1 to 6 carbon atoms, unless otherwise specified.

Suitable "protecting groups" for the "protected amino group" include, for example, lower alkanoyl groups such as formyl, acetyl, propionyl, pivaloyl, and hexanoyl;
For example, mono (or di or tri) halo (lower) alkanoyl groups such as chloroacetyl, bromoacetyl, dichloroacetyl, trifluoroacetyl, etc., such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tertiary butoxycarbonyl, tertiary pentyl Lower alkoxycarbonyl groups such as oxycarbonyl and hexyloxycarbonyl, carbamoyl groups, such as aroyl groups such as benzoyl, toluoyl, and naphthoyl; al(lower) alkanoyl groups such as phenylacetyl and phenylpropionyl, such as phenoxycarbonyl and naphthyloxy; Aryloxycarbonyl groups such as carbonyl, aryloxy(lower)alkanoyl groups such as phenoxyacetyl, phenoxypropionyl, arylglyoxyloyl groups such as phenylglyoxyloyl, naphthylglyoxyloyl, such as benzyloxycarbonyl, phenethyloxycarbonyl , p-nitrobenzyloxycarbonyl, which may bear suitable substituents; substituted or unsubstituted alkylidene groups, such as benzylidene, hydroxybenzylidene, e.g. benzyl; , phenethyl, benzhydryl, trityl, etc., mono (or di or tri) phenyl (lower) alkyl groups, etc., and preferred among them are lower alkanoyl groups or carbamoyl groups. , more preferably C1 to C
4-alkanoyl group or carbamoyl group.

Suitable "lower alkoxy (lower) alkyl groups" as well as "halo (lower) alkyl groups", "carboxy (lower) alkyl groups", "protected carboxy (lower) alkyl groups"
Suitable "lower alkyl moieties" of "lower) alkyl group", "carbamoyl (lower) alkyl group", "amino (lower) alkyl group" and "protected amino (lower) alkyl group" include methyl, ethyl, Propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl,
Examples include straight chain alkyl or branched chain alkyl such as hexyl, among which preferred are C1-
Examples include C4 alkyl groups.

[0013] Preferred examples of the "protected carboxy group" in the "protected carboxy (lower) alkyl group" include esterified carboxyl groups, and specific examples of the ester moiety of the esterified carboxy group include: For example, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary ester, which may have a suitable substituent.
Lower alkyl esters such as butyl ester, pentyl ester, tertiary pentyl ester, hexyl ester, 1-cyclopropyl ester, examples thereof include acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, isobutyryl Lower alkanoyloxy (lower) such as oxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 1-acetoxyethyl ester, 1-propionyloxyethyl ester, 2-propionyloxyethyl ester, hexanoyloxymethyl ester Alkyl esters, e.g. lower alkanesulfonyl (lower) alkyl esters such as 2-mesylethyl ester, or e.g. 2-iodoethyl ester, 2,
Mono (or di or tri) halo (lower) alkyl esters such as 2,2-trichloroethyl ester; lower alkenyl esters such as vinyl esters, allyl esters; lower alkynyl esters such as ethynyl ester, propynyl ester; e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(3-methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5- Al(
lower) alkyl ester; e.g. phenyl ester, 4
-chlorophenyl ester, tolyl ester, 4-tertiary
Examples include aryl esters which may have appropriate substituents, such as butylphenyl ester, xylyl ester, mesityl ester, and cumenyl ester.

Preferred examples of the "protected hydroxy group" in the "protected hydroxypropyl group" include an acyloxy group and the like. Suitable "acyl moieties" of the "acyloxy group" include lower alkanoyl groups such as formyl, acetyl, propionyl, hexanoyl, pivaloyl, etc., mono(or di- or tri)halo(lower ) Alkanoyl groups, such as lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, tertiary butoxycarbonyl, tertiary pentyloxycarbonyl, and hexyloxycarbonyl.

Suitable "organic groups" include lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, neopentyl, tertiary pentyl, hexyl, etc., such as chloromethyl, Mono(or di- or tri)halo(lower)alkyl groups such as dichloromethyl, trichloromethyl, bromomethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoroethyl, trifluoroethyl, e.g. vinyl, 1-propenyl, allyl, 1-methylallyl , 1-
or 2- or 3-butenyl, 1- or 2- or 3- or 4-pentenyl, 1- or 2- or 3-
or lower alkenyl groups such as 4- or 5-hexenyl, e.g. ethynyl, 1-propynyl, propargyl, 1
- lower alkynyl groups such as methylpropargyl, 1- or 2- or 3-butynyl, 1- or 2- or 3- or 4-pentynyl, 1- or 2- or 3- or 4- or 5-hexynyl, e.g. formyl; , acyl groups such as lower alkanoyl groups such as acetyl, propionyl, hexanoyl, pivaloyl, cyclo(lower)alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aryl groups such as phenyl, naphthyl, etc., such as benzyl, phenethyl. , an al(lower)alkyl group such as a phenyl(lower)alkyl group such as phenylpropyl, a carboxy(lower)alkyl group where the lower alkyl moiety is as exemplified above,
Examples include protected carboxy (lower) alkyl groups such as esterified carboxy which can be hydrolyzed in vivo.

Suitable "leaving groups" include, for example, chlorine,
Examples include halogens such as bromine and iodine, sulfonyloxy groups such as benzenesulfonyloxy, tosyloxy and mesyloxy, and acyloxy groups such as lower alkanoyloxy groups such as acetyloxy and propionyloxy.

Suitable salts of the target compound [I] include pharmaceutically acceptable salts, especially commonly used non-toxic salts,
Metal salts such as alkali metal salts such as sodium salts, potassium salts and alkaline earth metal salts such as calcium salts, magnesium salts, ammonium salts such as triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, N, Organic salts such as N'-dibenzylethylenediamine salts, such as hydrochlorides, hydrobromides,
Inorganic acid salts such as sulfates and phosphates, such as formates, acetates,
Organic acid salts such as trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, P-toluenesulfonate, salts with amino acids such as arginine salt, aspartate, glutamate, etc. Can be mentioned.

The method for producing the target compound [I] will be explained in detail below. Production method 1 Target compound [I] or a salt thereof can be produced by reacting compound [II] or a salt thereof with compound [III] or a salt thereof. Suitable salts for compounds [II] and [III] include those exemplified for compound [I]. The reaction is usually carried out in a conventional solvent such as water, an alcohol such as methanol or ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, or pyridine. However, the reaction can be carried out in any other organic solvent as long as it does not adversely affect the reaction. These conventional solvents may be used in mixtures with water. In this reaction, the compound [I
II] in the free form or in the form of its salts, N,N'-dicyclohexylcarbodiimide;N-cyclohexyl-N'-morpholinoethylcarbodiimide;N-cyclohexyl-N'-(4-diethylaminocyclohexyl)Carbodiimide;N,N'-diethylcarbodiimide,N,N'-diisopropylcarbodiimide;N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;N,N'-carbonylbis-(2-
methylimidazole);pentamethyleneketene-N-cyclohexylimine;diphenylketene-N-cyclohexylimine;ethoxyacetylene; 1-alkoxy-
1-chloroethylene; trialkyl phosphite; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride; lower alkyl haloformates such as ethyl chloroformate and isopropyl chloroformate; triphenylphosphine ;2-ethyl-7-hydroxybenzisoxazolium salt;2-ethyl-5-
(m-sulfophenyl) isoxazolium hydroxide inner salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; N,
N-dimethylformamide and thionyl chloride, phosgene,
Preferably, the reaction is carried out in the presence of a conventional condensing agent, such as the so-called Vilsmeier reagent prepared by reaction with trichloromethyl chloroformate, phosphorus oxychloride, and the like. The reaction can also be carried out in the presence of inorganic or organic bases such as alkali metal bicarbonates, tri(lower)alkylamines, pyridine, N-(lower)alkylmorpholines, N,N-di(lower)alkylbenzylamines, etc. A reaction may also be carried out. Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or humidification.

Production method 2 The target compound [Ib] or a salt thereof can be produced by subjecting compound [Ia] or a salt thereof to an elimination reaction of the carboxy protecting group. This reaction can be carried out by conventional methods such as hydrolysis, reduction, etc. Hydrolysis is preferably carried out in the presence of a base or an acid (including a Lewis acid). Suitable bases include, for example, alkali metals such as sodium and potassium, e.g. magnesium,
alkaline earth metals such as calcium, their hydroxides or carbonates or bicarbonates, e.g. trimethylamine;
Trialkylamines such as triethylamine, picoline,
1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1
, 8-diazabicyclo[5.4.0]undec-7-ene, and the like. Suitable acids include, for example, formic acid, acetic acid, propionic acid,
Examples include organic acids such as trichloroacetic acid and trifluoroacetic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, and hydrogen bromide. For example, desorption using a Lewis acid such as a trihaloacetic acid such as trichloroacetic acid, trifluoroacetic acid, etc. is preferably carried out in the presence of a cation scavenger such as anisole, phenol, etc. The reaction is usually carried out in a solvent such as water, an alcohol such as methanol or ethanol, methylene chloride, tetrahydrofuran, or a mixture thereof, but the reaction may be carried out in any other solvent that does not adversely affect the reaction. It can be carried out. 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 methods that can be applied to this elimination reaction include chemical reduction and catalytic reduction. Suitable reducing agents used in the chemical reduction are metals such as tin, zinc, iron or metal compounds such as chromium chloride, chromium acetate, etc., and for example formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluene. It is a combination with organic or inorganic acids such as sulfonic acid, hydrochloric acid, and hydrobromic acid. Suitable catalysts used for catalytic reduction are:
For example, platinum catalysts such as platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc., such as palladium sponge, palladium black, palladium oxide, palladium-carbon, colloidal palladium, palladium-barium sulfate, palladium-barium carbonate, etc. Palladium catalysts such as reduced nickel, nickel oxide, Raney nickel, etc., reduced cobalt, cobalt catalysts such as Raney cobalt, reduced iron, iron catalysts such as Raney iron, e.g. reduced copper, Raney copper, etc. , commonly used copper catalysts such as Ullmann's copper, etc. Reduction is usually done with water, methanol, ethanol,
It is carried out in customary solvents which do not adversely affect the reaction, such as propanol, N,N-dimethylformamide, or mixtures thereof. Furthermore, when the above-mentioned acids used for chemical reduction are in the form of solutions, they can also be used as solvents. Furthermore, in addition to the above-mentioned solvents, suitable solvents used for catalytic reduction include diethyl ether,
Mention may be made of customary solvents such as dioxane, tetrahydrofuran, etc. or mixtures thereof. The reaction temperature for this reduction is not particularly limited, but the reaction is usually carried out under cooling or heating.

Production method 3 The target compound [I] or its salt can be produced by reacting compound [VII] or its salt with compound [V] or its salt. Compound [V] and [
For suitable salts of [VII], refer to those exemplified for compound [I]. The reaction is carried out in solvents such as water, phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzene, methylene chloride, ethylene chloride, formamide, N,N-dimethylformamide, methanol, ethanol, diethyl ether, tetrahydrofuran, dimethyl sulfoxide. However, the reaction can be carried out in any other solvent as long as it does not adversely affect the reaction, and it is preferable to carry out the reaction in a strongly polar solvent. In the solvent, hydrophilic solvents may be used as a mixture with water. When compound [V] is a liquid, it can also be used as a solvent. The reaction is preferably carried out in the presence of a base such as an inorganic base such as an alkali metal hydroxide, an alkali metal carbonate or an alkali metal hydrogen carbonate, or an organic base such as a trialkylamine. Although the reaction temperature is not particularly limited, the reaction is usually carried out at room temperature, under heating, or under heating. This reaction is preferably carried out in the presence of an alkali metal halide such as sodium iodide or potassium iodide, or an alkali metal thiocyanate salt such as sodium thiocyanate or potassium thiocyanate.

Production method 4 The target compound [Id] or a salt thereof can be produced by subjecting the compound [Ic] or a salt thereof to an amino-protecting group elimination reaction. This reaction can be carried out according to conventional methods such as hydrolysis. Hydrolysis is based on
Alternatively, it is preferable to carry out the reaction in the presence of an acid (including a Lewis acid). Suitable bases include, for example, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, hydroxides or carbonates or bicarbonates of these metals, trialkylamines such as trimethylamine and triethylamine, Picoline, 1,5-
diazabicyclo[4.3.0]non-5-ene, 1,4
- Inorganic and organic bases such as diazabicyclo[2.2.2]octane, 1,8-dizabicyclo[5.4.0]undec-7-ene, and the like. Suitable acids include organic acids such as formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, and the like. Desorption using a Lewis acid such as a trihaloacetic acid such as trichloroacetic acid, trifluoroacetic acid, etc. is preferably carried out in the presence of a cation scavenger such as anisole, phenol, etc. The reaction is usually carried out in a solvent such as water, an alcohol such as methanol or ethanol, methylene chloride, tetrahydrofuran, or a mixture thereof, but it can also be carried out in any other solvent that does not adversely affect the reaction. It can be performed. 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.

The starting material compound [II] can be prepared by the following production method A.
and B.

(wherein R3, R4 and Y have the same meanings as before, R5 is a protected amino group, R6 is a protected carboxy group,

[0024] For suitable protecting groups for the "protected amino group" of R5, refer to those exemplified above.
Preferred examples include substituted or unsubstituted al(lower) compounds such as benzylidene and hydroxybenzylidene.
Examples include alkylidene groups, such as lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, tertiary butoxycarbonyl, tertiary pentyloxycarbonyl, and hexyloxycarbonyl. Regarding the suitable "protected carboxy group" of R6, refer to those exemplified above, and preferable ones include al(( (lower) alkoxycarbonyl group. Suitable "anions" include formate,
Acetate, trifluoroacetate, maleate (m
aleate), tartrate, methanesulfonate,
Examples include benzene sulfonate, torunine sulfonate, chloride, bromide, iodide, sulfate, phosphate, and the like.

Processes A and B for producing the starting material compound [II] will be explained in detail below. Production method A-■ Compound [VI] or a salt thereof can be produced by reacting compound [IV] or a salt thereof with compound [V] or a salt thereof. This reaction can be carried out in the same manner as in Production Method 3, and therefore the description of Production Method 3 may be referred to for the reagents to be used and reaction conditions such as solvent and reaction temperature. Examples include those derived by conventional methods.

Production method A-■ Compound [II] or a salt thereof can be produced by subjecting compound [VI] or a salt thereof to an elimination reaction of the amino protecting group of R5 and the carboxy protecting group of R6. can. This reaction can be carried out according to conventional methods such as hydrolysis. Hydrolysis is preferably carried out in the presence of a base or acid (including Lewis acids). Suitable bases include, for example, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, hydroxides or carbonates or bicarbonates of these metals, trialkylamines such as trimethylamine and triethylamine, Picoline, 1,5-diazabicyclo [4.
3.0] non-5-ene, 1,4-diazabicyclo[2
．． 2.2] octane, 1,8-diazabicyclo[5.4
．． 0] undec-7-ene and the like and organic bases. Suitable acids include, for example, formic acid,
Organic acids such as acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid and the like and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride and hydrogen bromide are mentioned. Desorption using a Lewis acid such as a trihaloacetic acid such as trichloroacetic acid, trifluoroacetic acid, etc. is preferably carried out in the presence of a cation scavenger such as anisole, phenol, etc. The reaction is usually carried out in a solvent such as water, an alcohol such as methanol or ethanol, methylene chloride, tetrahydrofuran, or a mixture thereof, but it can also be carried out in any other solvent that does not adversely affect the reaction. It can be performed. 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.

Production method B It can be produced by subjecting it to a protective group elimination reaction. This reaction can be carried out in the same manner as in the above-mentioned production method A-2, and therefore, the explanation of production method A-2 can be referred to regarding the reagents to be used and reaction conditions such as solvent and reaction temperature.

For therapeutic administration, the object compound [I] of the present invention and its salts may be administered in organic or inorganic solid or liquid excipients suitable for oral, parenteral and topical administration. The compounds can be used in the form of conventional pharmaceutical preparations containing them as active ingredients in admixture with pharmaceutically acceptable carriers. Pharmaceutical preparations may be in solid form such as capsules, tablets, granules, or powders;
It may be in liquid form such as a solution, suspension, syrup, emulsion, lemonade, etc. If necessary, auxiliaries, stabilizers, wetting agents and other commonly used lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, Pectin, fallen raw oil, olive oil,
Additives such as cocoa butter, ethylene glycol, etc. may also be included. The dosage of compound [I] varies depending on the patient's age, condition, type of disease, type of compound applied, etc. Generally, patients are given 1 mg to about 40 mg per day.
00 mg or more may be administered. The object compound [I] of this invention is used in the treatment of pathogenic bacterial infections at an average single dose of about 50 mg, 100 mg, 250 mg, and 500 mg.
, 1000mg, 2000mg may be used.

The present invention will be explained in more detail below with reference to production examples and examples. Production Example 1 Methyl acrylate (43.34 ml) is added to 5-aminopyrazole (30 g) at room temperature with stirring. 90% of the mixture
Stir at ℃ for 1 hour. The reaction mixture is cooled and the solvent is distilled off under reduced pressure. The residue (66 g) is subjected to column chromatography using silica gel (3 l), eluting with ethyl acetate. Fractions containing the target compound were collected and the solvent was distilled off under reduced pressure to obtain 5-amino-1-(2-methoxycarbonylethyl)pyrazole (10.7 g). IR (neat): 3340, 3200, 1720, 1
560, 1440, 1220 cm-1 NMR (DMSO-d6, δ): 2.75 (t, 2H,
J=7Hz), 3.60 (s, 3H), 4.06 (t,
2H, J=7Hz), 5.08 (s, 2H), 5.25
(d, 1H, J=2Hz), 7.00 (d, 1H, J=
2Hz)

Production Example 2 5-Amino-1-(2-methoxycarbonylethyl)pyrazole (10.7g) was dissolved in tetrahydrofuran (80ml).
l) Pour the solution into lithium aluminum hydride (7.20g)
The mixture was added dropwise to a suspension of the solution in tetrahydrofuran (120 ml) under ice-cooling and stirring. After stirring the mixture for 2 hours, sodium fluoride (31.87 g) is added to it. Mixture at 0-5℃
Cool in an ice bath and add water (10.26 ml) dropwise. Insoluble matter is filtered off, and the solvent of the filtrate is distilled off under reduced pressure to obtain 5-amino-1-(3-hydroxypropyl)pyrazole. IR (Nujol): 3300, 3150, 1640,
1550, 1070, 1020, 740cm-1NMR
(DMSO-d6, δ): 1.81 (quintet,
2H, J=6Hz), 3.40(t, 2H, J=6Hz
), 3.89 (t, 2H, J=6Hz), 4.55 (s
, 1H), 5.01 (s, 2H), 5.24 (d, 1H
, J=2Hz), 6.99 (d, 1H, J=2Hz)

Production Example 3 5-Amino-1-(3-hydroxypropyl)pyrazole (5.3 g) was added to a mixture of acetic anhydride (8.86 ml) and formic acid (7.08 ml) under ice cooling. The mixture is stirred at room temperature for 2 hours. The reaction mixture was poured into ice water (30 ml).
, ethyl acetate (30 ml) and tetrahydrofuran (
60 ml) and pH it with an aqueous potassium carbonate solution.
Adjust to 7. The organic layer is separated and dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and the solvent of the filtrate was distilled off under reduced pressure to obtain 1-(3-formyloxypropyl).
-5-formylaminopyrazole is obtained. IR (Nujol): 3200, 1700, 1660,
1550, 1200, 1160, 890, 790cm-
1 NMR (DMSO-d6, δ): 2.05 (quint
et, 2H, J=6Hz), 4.07(t, 4H, J=
6Hz), 6.25 (d, 1H, J=2Hz), 7.3
3 (d, 1H, J=2Hz), 8.14 (s, 1H),
8.21 (s, 1H)

Production Example 4 A suspension of 5-amino-4-ethoxycarbonyl-1-ethoxycarbonylmethylpyrazole (95 g) in a 4N aqueous sodium hydroxide solution (295 ml) was refluxed for 1 hour. The reaction solution was cooled in an ice bath and adjusted to pH 2.5 with concentrated hydrochloric acid, and the white powder produced was collected by filtration, washed with ice water, dried over phosphorus pentoxide under reduced pressure, and 5-amino-4-carboxy-1 -Carboxymethylpyrazole (76.5g) is obtained. IR (Nujol): 3450, 3325, 3200,
1650,1600 cm-1 NMR (DMSO-d6, δ): 4.69 (2H, s)
, 6.24 (2H, brs), 7.39 (1H, s)

Production Example 5 5-amino-4-carboxy-1-carboxymethylpyrazole (75 g) was dissolved in cyclohexanol (225 ml).
) Reflux the suspension for 30 minutes. The reaction mixture was cooled to room temperature, the resulting precipitate was collected by filtration, washed with diisopropyl ether, dried over phosphorus pentoxide under reduced pressure, and 5-amino-1
-Carboxymethylpyrazole (46.9g) is obtained. IR (Nujol): 3320, 3170, 1640,
1590 cm-1 NMR (DMSO-d6, δ): 4.61 (2H.s)
, 5.23 (1H, d, J = 3Hz), 7.01 (1H
, d, J=3Hz)

Production Example 6 5-Amino-1-carboxymethylpyrazole (26g
) in methanol (260 ml) was added thionyl chloride (6
7.6 ml) was added dropwise at -10°C. Mixture at room temperature
Stir for an hour. The solvent is distilled off from the reaction mixture. Pour the residue into diisopropyl ether. The precipitate formed is collected by filtration, washed with diisopropyl ether and dried over phosphorus pentoxide under reduced pressure. The resulting powder is added to a mixture of ethyl acetate and water and the pH is adjusted to 7 with aqueous sodium bicarbonate solution. The organic layer is separated and the aqueous layer is extracted three times with tetrahydrofuran. The organic layers are combined, dried over magnesium sulfate, and the solvent is distilled off to obtain 5-amino-1-methoxycarbonylmethylpyrazole (24.9 g). IR (Nujol): 3395, 3180, 1740,
1638, 1555, 1510 cm-1NMR (D
MSO-d6, δ): 3.65 (3H, s), 5.16
(2H, s), 5.65 (1H, d, J=3Hz), 7
．． 89 (1H, d, J=3Hz), 8.03-9.27
(2H, brs)

Production Example 7 To a solution of 5-amino-1-methoxycarbonylmethylpyrazole (8 g) in methanol (40 ml) was added 28% aqueous ammonia (36 ml) at room temperature. Stir the mixture for 1 hour. The solvent is distilled off from the reaction mixture. The residue was recrystallized from ethanol, the crystals were collected by filtration, and 5-amino-1
-Carbamoylmethylpyrazole (3.1 g) is obtained. Further, the solvent of the filtrate was distilled off to obtain 5-amino-1-carbamoylmethylpyrazole (3.62 g) as crystals. IR (Nujol): 3360, 3080, 1685,
1610-1650, 1560 cm-1NMR (D
MSO-d6, δ): 4.45 (2H, s), 5.08
(2H, brs), 5.25 (1H, d, J=2Hz)
, 7.02 (1H, d, J = 2Hz), 7.13 (2H
,brs)

Production Example 8 Acetic anhydride (8.75 ml) and formic acid (4.43 ml)
The mixture is stirred at room temperature for 40 minutes. Mixture in ice bath
Cool to <0>C and add 5-amino-1-carbamoylmethylpyrazole (6.5g) to it. Cool the mixture on ice 3
Stir for an hour. The solvent is distilled off from the reaction mixture to precipitate crystals. Add diisopropyl ether to the crystals,
Stir for 2 hours and collect by filtration to obtain 5-formylamino-1-carbamoylmethylpyrazole (7.52 g). IR (Nujol): 3360, 3270, 3160,
1690, 1640, 1560 cm-1NMR (D
MSO-d6, δ): 4.68 (2H, s), 6.31
(1H, s), 7.20 (1H, brs), 7.33 (
2H, brs), 8.20 (1H, s), 10.33 (
1H,brs)

Production Example 9 The following compound was obtained in the same manner as in Production Example 8. 5-formylamino-1-carboxymethylpyrazole. IR (Nujol): 1680, 1580, 1530
cm-1 NMR (DMSO-d6, δ): 4.78 (2H, s)
, 6.25 (1H, s), 7.25 (1H, s), 8.
11 (1H, s), 10.6 (1H, brs) Production Example 1
0 hexafluoropropenediethylamine (69.04g
) in tetrahydrofuran (280 ml) was mixed with 1-(2
-hydroxyethyl)-5-formylaminopyrazole (40 g) in tetrahydrofuran (200 ml) while stirring. The mixture is stirred at room temperature for 5 hours. The reaction mixture is added to a mixture of brine and tetrahydrofuran, and the pH is adjusted to 7 with aqueous sodium bicarbonate. The separated organic layer is dried with magnesium sulfate. Magnesium sulfate was filtered off, and the solvent of the filtrate was distilled off under reduced pressure to obtain 1-(2-fluoroethyl)-5-formylaminopyrazole (13.83 g). IR (Nujol): 3210, 1660, 1180,
850,760 cm-1 NMR (CDCl3, δ): 4.16 (t, 1H, J=
7Hz), 4.3-4.6 (m, 2H), 4.95 (t
, 1H, J=7Hz), 6.1 to 6.3 (m, 1H),
7.36 (d, 1H, J=3Hz), 8.20 (s, 1
H), 10.25 (s, 1H)

Production Example 11 1-carbamoylmethyl-5-aminopyrazole (1g
) is added to a suspension of lithium aluminum hydride (1.08 g) in tetrahydrofuran (20 ml) while stirring under ice cooling. The mixture is stirred for 4 hours and sodium fluoride (4.80 g) is added to it. Place the mixture in an ice bath from 0 to
Cool to 5° C. and add water (1.54 ml) dropwise to it. Insoluble materials were filtered off, the solvent was distilled off under reduced pressure, and 1-(2-
(aminoethyl)-5-aminopyrazole (520mg)
get. NMR (DMSO-d6, δ): 2.80 (t, 2H,
J=6Hz), 3.43(brs, 2H), 3.80(
t, 2H, J=6Hz), 5.13 (s, 2H) 5.2
5 (d, 1H, J = 3Hz), 7.00 (d, 1H, J
=3Hz)

Production Example 12 The following compound was obtained using 1-(2-aminoethyl)-5-aminopyrazole in the same manner as in Production Example 3. 1-(2-
(formylaminoethyl)-5-formylaminopyrazole. IR (Nujol): 3280, 1700, 1660,
1640, 1550 cm-1 NMR (DMSO-d6, δ): 3.50 (t, 2H,
J=6Hz), 4.10 (t, 2H, J=6Hz), 6.0~6.3(m, 1H
), 7.36 (d, 1H, J=3Hz), 7.95 (s, 1H), 8
．． 23(s,1H) Production Example 13 A solution of potassium carbonate (105.98 g) in water (300 ml) was mixed with 2-(ethoxymethylene)-2-cyano-acetic acid ethyl ester (100 g) and isopropylhydrazine sulfate (132.25 g). ) into a solution of benzene (1.2 l). The mixture is stirred at room temperature for 4 hours. The reaction mixture is filtered and the filtrate is evaporated under reduced pressure. Ethanol (500 ml) is added to the residue and the solution is refluxed for 3 hours. The solvent of the solution was distilled off under reduced pressure, and 4-ethoxycarbonyl-1-isopropyl-5-aminopyrazole (10
3.5 g) is obtained. IR (neat): 3450, 3350, 1680, 1
620, 1550, 1310, 1230, 1120cm
-1 NMR (CDCl3, δ): 1.20 (t, 3H, J=
7Hz), 1.40 (d, 6H, J=7Hz), 4, 2
0 (q, 2H, J = 7Hz), 4.0 to 4.4 (m, 1
H), 5.06 (brs, 2H), 7.56 (s, 1H
)

Production Example 14 A 4N aqueous sodium hydroxide solution (260 ml) of 4-ethoxycarbonyl-1-isopropyl-5-aminopyrazole (103.5 g) was refluxed for 2 hours, and the pH was adjusted to 3 with concentrated hydrochloric acid.
．． Adjust to 5. The formed precipitate was collected by filtration and 4-carboxy-1-isopropyl-5-aminopyrazole (80.
5g). IR (Nujo1): 3400, 3300, 3200,
1660, 1620, 1540, 1320, 1230,
960 cm-1 NMR (DMSO-d6, δ): 1.29 (d, 6H,
J=6.5Hz), 4.36~4.50(m, 1H),
6.15 (s, 2H), 7.44 (s, 1H), 11.
7(s, 1H) Production Example 15 A suspension of 4-carboxy-1-isopropyl-5-aminopyrazole (0.25 g) in diphenyl ether (1 ml) is stirred at 160 to 165°C for 2 hours. The solution is subjected to column chromatography using silica gel (10 ml) and eluted with ethyl acetate. Fractions containing the desired product were combined and concentrated under reduced pressure to obtain 1-isopropyl-5-aminopyrazole (0.125 g). IR (Nujol): 3300, 3150, 1640,
1540, 1500, 930, 730 cm-1NMR (
DMSO-d6, δ): 1.30 (d, 6H, J=7H
z), 4.35 (m, 1H), 4.98 (s, 2H),
5.23 (d, 1H, 3Hz), 7.00 (d, 1H,
J=3Hz)

Production Example 16 The following compound was obtained in the same manner as in Production Example 8. 5-formylamino-1-isopropylpyrazole. NMR (CDCl3; δ): 1.47 and 1.50 (
each d, 6H, J=7Hz), 4.2 to 4.7
(m, 1H), 6.0-6.3 (m, 1H), 7.43
(d, 1H, J=3Hz), 8.28 (s, 1H), 8
．． 88 (brs, 1H) Production Example 17 4-ethoxycarbonyl-1-(2-hydroxyethyl)-5-aminopyrazole (100 g) and triethylamine (104.95 ml) in dichloromethane (50 g)
0ml) solution, add methanesulfonyl chloride (42.74m
1) while stirring under ice-cooling. The mixture is stirred at room temperature for 3 hours. The reaction mixture was poured into ice water (250 ml),
Adjust the pH to 7. The separated organic layer is washed with 1N hydrochloric acid and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the solvent of the filtrate was distilled off under reduced pressure to give 4-ethoxycarbonyl-1-(2-methanesulfonyloxyethyl)-
5-aminopyrazole is obtained. IR (Nujol): 3320, 1650, 1540,
1300, 1160, 1000, 790, 780cm-
1 NMR (DMSO-d6, δ): 1.24 (t, 3H,
J=7,0Hz), 3.08(s, 3H), 4.16(
q, 2H, J = 7,0Hz), 4.26 (t, 2H, J
=5,1Hz),4.48(t,2H,J=5,1Hz
), 6.37 (s, 2H), 7.51 (s, 1H)

0
Production Example 18 4-ethoxycarbonyl-1-(2-methanesulfonyloxyethyl)-5-aminopyrazole (50 g) was mixed with methanol (250 ml) and tetrahydrofuran (3
Add sodium methoxide to the solution (00 ml) while stirring under ice cooling. The mixture is stirred at 40° C. for 2 hours. The reaction mixture is filtered and the filtrate is evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel and eluted with ethyl acetate. Fractions containing the target product were combined and concentrated under reduced pressure to give 4-ethoxycarbonyl-1-(2
-methoxyethyl)-5-aminopyrazole and 4-
Methoxycarbonyl-1-(2-methoxyethyl)-5
-Aminopyrazole (20.3g, 3:5) is obtained. 4
-ethoxycarbonyl-1-(2-methoxyethyl)-
5-aminopyrazole and 4-methoxycarbonyl-
Mixture of 1-(2-methoxyethyl)-5-aminopyrazole IR (neat): 3450, 3330, 1680, 1
620,1540,1110,780cm-14-methoxycarbonyl-1-(2-methoxyethyl)-5-aminopyrazole NMR (CDCl3, δ): 3.35(
s, 3H), 3.68 (t, 2H, J=6Hz), 3.
78 (s, 3H), 413 (t, 2H, J=6Hz),
5.40 (brs, 2H), 7.53 (s, 1H) 4-ethoxycarbonyl-1-(2-methoxyethyl)
-5-Aminopyrazole NMR (CDCl3, δ): 1
．． 34 (t, 3H, J=7Hz), 3.35 (s, 3H
), 3.68 (t, 2H, J=6Hz), 4.13 (t
, 2H, J=6Hz), 4.23(q, 2H, J=7H
z), 5.40 (brs, 2H), 7.53 (s, 1H
)

Production Example 19 4-ethoxycarbonyl-1-(2-methoxyethyl)
-5-Aminopyrazole and 4-methoxycarbonyl-1-(2-methoxyethyl)-5-aminopyrazole were treated in the same manner as in Production Example 14 to obtain the following compound 4
-Carboxy-1-(2-methoxyethyl)-5-aminopyrazole. IR (Nujol): 3440, 3300, 1650,
1630, 1320, 1220, 950cm-1NMR
(DMSO-d6, δ): 3.25 (s, 3H), 3.
63 (t, 2H, J=6Hz), 4.06 (t, 2H,
J=6Hz), 6.09(s, 2H), 7.40(s,
1H) Production Example 20 The following compound was obtained in the same manner as in Production Example 15. 1-(2-
methoxyethyl)-5-aminopyrazole. IR (neat): 3350, 3200, 1630, 1
560, 1120, 930, 750 cm-1 NMR (D
MSO-d6, δ): 3.23 (s, 3H), 3.56
(t, 2H, J=6Hz), 4.06 (t, 2H, J=
6Hz), 4.98 (s, 2H), 5.23 (d, 1H
, J=3Hz), 6.98 (d, 1H, J=3Hz) Production Example 21 The following compound was obtained in the same manner as in Production Example 8. 5-formylamino-1-(2-methoxyethyl)pyrazole. IR (neat): 3250, 1690, 1550, 1
100,770 cm-1 NMR (DMSO-d6, δ): 3.33 (s, 3H)
, 3.64 (t, 2H, J=6Hz), 4.17 (t,
2H, J=6Hz), 6.1 to 6.3 (m, 1H), 7
．． 32 (d, 1H, J=3Hz), 8.20 (s, 1H
)

Production Example 22 Benzhydryl 7β-tertiary-butoxycarbonylamino-3-chloromethyl-3-cephem-4-carboxylate (
5.87 g) was dissolved in N,N-dimethylformamide (5.8
7 ml) with stirring. It was followed by sodium iodide (1.71 g) and then 1-(3-formyloxypropyl)-5-formylaminopyrazole (6.74 g).
Add. The mixture is stirred at room temperature for 24 hours. The reaction mixture is poured into a mixture of ethyl acetate (230 ml) and ice water (115 ml). Separate the organic layer, wash with brine,
Dry with magnesium sulfate. The magnesium sulfate is filtered off, and the solvent is distilled off under reduced pressure to 60 ml. The residue was triturated with diisopropyl ether (500 ml) to give 7β-tert-butoxycarbonylamino-3-[3-formylamino-2-(3-formyloxypropyl)-1-pyrazolio]methyl-3-cephem-4- Benzhydryl iodide carboxylic acid is obtained. NMR (DMSO-d6, δ): 1.43 (s, 9H)
, 2.06 (quintet, 2H, J=6Hz), 3
．． 46 (brs, 2H), 4.06 (t, 2H, J=6
Hz), 4.08 (t, 2H, J=6Hz), 5.16
(d, 1H, J=5Hz), 5.40 (s, 2H), 5
．． 60 (dd, 1H, J=8Hz, 5Hz), 7.97
(s, 1H), 8.20 (d, 1H, J=3Hz), 8
．． 50 (s, 1H)

Production Example 23 The following compound was obtained in the same manner as in Production Example 22. (1) 7β-tertiary butoxycarbonylamino-3-[
3-formylamino-2(2-methoxyethyl)-1-
pyrazolio]methyl-3-cephem-4-carboxylic acid benzhydryl iodide. IR (Nujol): 1770, 1150, 690cm
-1 NMR (DMSO-d6, δ): 1.41 (s, 9H)
, 3.19 (s, 3H), 3.38 (brs, 2H),
3.62 (t, 2H, J=5.5Hz), 4.18 (t
,2H,J=5.5Hz),5,14(d,1H,J=
5Hz), 5.33 and 5.55 (ABq, 2H, J
= 15Hz), 5.65 (dd, 1H, J = 5Hz, 8
Hz), 6.92 (s, 1H), 7.0-7.6 (m,
10H), 7.06 (d, 1H, J=3Hz), 8.2
6 (d, 1H, J = 8Hz), 8.29 (d, 1H, J
=3Hz),8.51(s,1H)(2)7β-tertiary-butoxycarbonylamino-3-(3-formylamino-2-isopropyl-1-pyrazolio)methyl-3-cephem-4-carboxylic acid Benzhydryl iodide. NMR (DMSO-d6, δ): 1.33 (d, 6H,
J=7Hz), 1.45(s, 9H), 3.35(br
s, 2H), 4.2-4.5 (m, 1H), 5.17 (
d, 1H, J=5Hz), 5.40 (s, 2H), 5.
60 (dd, 1H, J=8Hz, J=5Hz), 6.9
2 (s, 1H), 7.03 (d, 1H, J=3Hz),
7,1-7,6 (m, 10H), 7.95 (d, 1H,
J = 8Hz), 8.23 (d, 1H, J = 3Hz), 8
．． 50 (s, 1H)

(3) 7β-tertiary butoxycarbonylamino-3-[3-formylamino-2-(2-formylaminoethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylic acid benzhydryl iodide . IR (Nujol): 1780, 1720, 1250,
1160,700 cm-1 NMR (DMSO-d6, δ): 1.43 (s, 9H)
, 3.46 (brs, 2H), 3.60 (t, 2H, J
= 6Hz), 4.06 (t, 2H, J = 6Hz), 5.
16 (d, 1H, J=5Hz), 5.36 (brs, 2
H), 5.55 (dd, 1H, J=8Hz, 5Hz),
6.90 (s, 1H), 6.96 (d, 1H, J=3H
z), 7.0-7.5 (m, 10H), 8.22 (d,
1H, J = 3Hz) (4) 7β-tertiary butoxycarbonylamino-3-[
3-formylamino-2-(2-fluoroethyl)-1
-pyrazolio]methyl-3-cephem-4-carboxylic acid benzhydryl iodide. IR (Nujol): 1780, 1710, 1250,
1160,700cm-1 NMR (DMSO-d6, δ): 1.40 (s, 9H)
, 3.35 (brs, 2H), 4.0-4.65 (m,
3H), 4.7-5.0 (m, 1H), 5.15 (d,
1H, J=5Hz), 5.35 (s, 2H), 5.55
(dd, 1H, J=8Hz, 5Hz), 6.89(s,
1H), 7.03 (d, 1H, J=3Hz), 7.1~
7.6 (m, 10H), 7.95 (d, 1H, J=8H
z), 8.20 (s, 1H), 8.30 (d, 1H, J
=3Hz)

(5) 7β-tertiary-butoxycarbonylamino-3-(2-carboxymethyl-3-formyl-amino-1-pyrazolio)methyl-3-cephem-4-carboxylic acid benzhydryl iodide. (6) 7β-tertiary butoxycarbonylamino-3-(
2-Carbamoylmethyl-3-formylamino-1-pyrazolio)methyl-3-cephem-4-carboxylic acid benzhydryl iodide. IR (Nujol): 1780, 1705-1720
cm-1 NMR (DMSO-d6, δ): 1.42 (9H, s)
, 3.10-3.87 (2H, m), 4.90-5.7
3 (6H, m), 6.83-8.10 (16H, m),
11.7 (1H, brs)

Production Example 24 7β-tertiary-butoxycarbonylamino-3-[3-formylamino-2-(3-formyloxypropyl)-
1-pyrazolio]methyl-3-cephem-4-carboxylic acid benzhydryl iodide (6.50 g) is added to a solution of anisole (6.5 ml) in methylene chloride (19.5 ml). The mixture is cooled to 0-5°C in an ice bath and trifluoroacetic acid (13 ml) is added dropwise to it. The mixture is stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (100
ml) and diisopropyl ether (100 ml) to give 7β-amino-3-[3-formylamino-2-(3-formyloxypropyl)-1-pyrazolio]methyl-3-cephem-4-carboxy. The di(trifluoroacetic acid) salt of Lato is obtained. IR (Nujol): 1780, 1700cm-1NM
R (DMSO-d6, δ): 2.06 (quintet
, 2H, J=6Hz), 3.50(brs, 2H), 4
．． 06 (t, 4H, J=6Hz), 5.23 (m, 2H
), 5.46 (s, 2H), 7.04 (d, 1H, J=
3Hz), 8.12 (s, 1H), 8.34 (d, 1H
, J=3Hz), 8.53(s, 1H)

Production Example 25 The following compound was obtained in the same manner as in Production Example 24. (1) 7β-amino-3-[3-formylamino-2-
(2-methoxymethyl)-1-pyrazolio]methyl-3
- Di(trifluoroacetic acid) salt of cephem-4-carboxylate. IR (Nujol): 1780, 1670, 1200,
720cm-1 NMR (DMSO-d6, δ): 3.23 (s, 3H)
, 3.56 (brs, 2H), 3.65 (t, 2H, J
=5.5Hz), 4.20(5,2H, J=5.5Hz
), 5.30 (m, 2H), 5.50 (s, 2H), 7
．． 10 (d, 1H, J = 3Hz), 8.34 (d, 1H
, J=3Hz), 8.54(s, 1H) (2) 7β-amino-3-(3-formylamino-2-isopropyl-
Di(trifluoroacetic acid) salt of 1-pyrazolio)methyl-3-cephem-4-carboxylate. IR (Nujol): 1780, 1660, 1560,
1200, 1130, 720 cm-1 NMR (DMSO-d6, δ): 1.57 (d, 6H,
J=7Hz), 3.50 (brs, 2H), 4.2~4
．． 5 (m, 1H), 5.05 (m, 1H), 5.20 (
s, 2H), 5.50 (m, 1H), 7.05 (d, 1
H, J = 3Hz), 8.26 (d, 1H, J = 3Hz)
,8.50(s,1H) (3)7β-amino-3-[3-formylamino-2-
Di(trifluoroacetic acid) salt of (2-formylaminoethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate. IR (Nujol): 1780, 1660, 1200c
m-1 NMR (DMSO-d6, δ): 3.50 (brs, 2
H), 3.60 (t, 2H, J=6Hz), 4.00 (
t, 2H, J=6Hz), 5.26 (m, 2H), 5.
46 (s, 2H), 7.03 (d, 1H, J=3Hz)
, 7.93 (s, 1H), 8.20 (s, 1H), 8.
30 (d, 1H, J = 3Hz) (4) 7β-amino-3-[3-formylamino-2-
(2-fluoroethyl)-1-pyrazolio]methyl-3
- Di(trifluoroacetic acid) salt of cephem-4-carboxylate. IR (Nujol): 1790, 1680, 1200,
1140,730 cm-1 NMR (DMSO-d6, δ): 3.50 (brs, 2
H), 4-4.6 (m, 3H), 5.0 (m, 1H),
5.23 (m, 2H), 5.45 (s, 2H), 7.1
0 (d, 1H, J = 3Hz), 8.37 (d, 1H, J
=3Hz), 8.56(s, 1H)

(5) Di(trifluoroacetic acid) salt of 7β-amino-3-(2-carboxymethyl-3-formylamino-1-pyrazolio)methyl-3-cephem-4-carboxylate. IR (Nujol): 3400, 1770, 1670
cm-1 (6) 7β-amino-3-(2-carbamoylmethyl-
Di(trifluoroacetic acid) salt of 3-formylamino-1-pyrazolio)methyl-3-cephem-4-carboxylate.

Production Example 26 7β-amino-3-(2-carboxymethyl-3-formylamino-1-pyrazolio)methyl-3-cephem-
Di(trifluoroacetic acid) salt of 4-carboxylate (6
．． 7 g) in methanol (34 ml), add concentrated hydrochloric acid (3
．． 4 ml). The mixture is stirred at room temperature for 2 hours. The reaction mixture is triturated dropwise into ethyl acetate (340 ml). The powder was collected by filtration, washed with diisopropyl ether, dried over phosphorus pentoxide under reduced pressure, and 7β-amino-3-(2
-Carboxymethyl-3-amino-1-pyrazolio)methyl-3-cephem-4-carboxylate trihydrochloride (4.5 g) is obtained. NMR (D2O-NaHCO3, δ): 3.23, 3.
54 (2H, ABQ, J=18Hz, 28Hz), 4.
80-5.60 (6H, m), 6.02 (1H, d, J
= 3Hz), 7.98 (1H, d, J = 3Hz)

00
52 Production Example 27 The following compound was obtained in the same manner as Production Example 26. (1) 7β-amino-3-[3-amino-2-(2-methoxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate trihydrochloride. IR (Nujol): 3350, 1780, 1700,
1640, 1220, 1110, 720cm-1NMR
(DMSO-d6, δ): 3.20 (s, 3H), 3.
56 (brs, 2H), 3.60 (t, 2H, J=5.
5Hz), 4.16 (t, 2H, J=5.5Hz), 5
．． 23 (s, 2H), 5.30 (m, 2H), 5.92
(d, 1H, J=3Hz), 8.10 (d, 1H, J=
3Hz) (2) 7β-amino-3-(3-amino-2-isopropyl-1-pyrazolio)methyl-3-cephem-4-carboxylate trihydrochloride. IR (Nujol): 3300, 1780, 1640,
1200 cm-1 NMR (DMSO-d6, δ): 1.46 (d, 6H,
J=7Hz), 3.2~3.5 (m, 2H), 4.2~
4.5 (m, 1H), 5.06 (m, 1H), 5.20
(brs, 2H), 5.33 (m, 1H), 5.90 (
d, 1H, J=3Hz), 7.40(brs, 2H),
8.12 (d, 1H, J = 3Hz) (3) 7β-amino-3-[3-amino-2-(2-fluoroethyl)-1
-pyrazolio]methyl-3-cephem-4-carboxylate trihydrochloride. IR (Nujol): 3300, 1780, 1630,
1580, 1220, 720 cm-1 NMR (DMSO-d6, δ): 3.30-3.60 (
m, 2H), 4.0 to 4.6 (m, 3H), 4.7 to 5
．． 0 (m, 1H), 5.0-5.3 (m, 4H), 5.
93 (d, 1H, J = 3Hz), 7.75 (brs, 2
H), 8.12 (d, 1H, J = 3Hz) (4) 7β-
Amino-3-(2-carbamoylmethyl-3-amino-
1-pyrazolio)methyl-3-cephem-4-carboxylate trihydrochloride. IR (Nujol): 1780, 1680, 1630,
1580 cm-1 NMR (D2O, δ): 3.07-3.73 (2H, m
), 4.83-5.63 (6H, m), 6.01 (1H
, d, J=3Hz), 7.98(1H, d, J=3Hz
)

Production Example 28 7β-amino-3-[3-formylamino-2-(3-
formyloxypropyl)-1-pyrazolio]methyl-
Di(trifluoroacetic acid) salt of 3-cephem-4-carboxylate (5.30 g) was added to methanol (31.8 ml).
). Concentrated hydrochloric acid is added dropwise to it with stirring at room temperature. Stir the mixture for 3 hours. The reaction mixture was triturated with ethyl acetate (400 ml) to give 7β-amino-3-[3-amino-2-(3-hydroxypropyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate trihydrochloride. get. IR (Nujol): 3300, 1780, 1630,
1580, 1220 cm-1 NMR (DMSO-d6, δ): 1.60-2.00 (
m, 2H), 3.30-3.60 (m, 4H), 3.6
5-3.83 (m, 2H), 5.23 (m, 2H), 5
．． 30 (brs, 2H), 5.92 (d, 1H, J=3
Hz), 8.14 (d, 1H, J=3Hz)

0054
] Production Example 29 7β-amino-3-[2-(2-fluoroethyl)-3
-amino-1-pyrazolio]methyl-3-cephem-4
- A solution of carboxylate trihydrochloride in water (48.8 ml) was applied to a large-pore nonionic adsorption resin “Diaion HP-20”.
(trademark: manufactured by Mitsubishi Kasei Corporation) and eluted with water. Collect fractions containing the target product, and add isopropyl alcohol (500 ml) under ice-cooling. The mixture was stirred at the same temperature for 2 hours, the resulting precipitate was collected by filtration, and 7β-amino-3-[2-(2-fluoroethyl)
-3-amino-1-pyrazolio]methyl-3-cephem-4-ruboxylate hydrochloride (7.3 g) is obtained as crystals. mp: 178-183℃ (decomposition) Elemental analysis (%) C13H17ClFN5O3S
・Calculated value as 1.5H2O: C 38.57, H 4.98, Cl
8.76, F 4.69, N17.30, S 7.
92 actual value: C 38.75, H 4.89, Cl
8.85, F 4.23, N17.10, S
8.27IR (Nujol): 3350, 1780, 1
635,1580 cm NMR (DMSO-d6, δ): 3.14 and 3.3
3 (2H, ABq, J=17.8Hz), 4.16~4
．． 95 (4H, m), 4.87 (1H, d, J = 5.1
Hz), 5.03 (1H, d, J=5.1Hz), 5.
15 (2H, brs), 5.91 (1H, d, J=3.
3Hz), 7.74 (2H, brs), 8.13 (1H
, d, J=3.3Hz)

Example 1 7β-amino-3-[3-amino-2-(3-hydroxypropyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate trihydrochloride (800 mg) and N- (trimethylsilyl)acetamide (2.27g
) in methylene chloride (16 ml) was added (Z)-2-(5
-amino-1,2,4-thiadiazol-3-yl)-
2-(1-carboxy-1-methylethoxyimino)acetic acid methanesulfonic anhydride (729 mg) in an ice bath from 0 to
Add at 5°C. The mixture is stirred at room temperature for 2 hours. The reaction mixture is triturated with diethyl ether (240 ml). The precipitate is filtered and dried over phosphorus pentoxide under reduced pressure. Pour the powder into water (30 ml) and adjust the pH to 2 with 1N hydrochloric acid. The aqueous solution is applied to the large-pore nonionic adsorption resin “Diaion HP-”.
20 (trademark: manufactured by Mitsubishi Chemical Industries, Ltd.) and eluted with a 10% aqueous isopropyl alcohol solution. The fractions containing the target product are combined and the isopropyl alcohol is distilled off under reduced pressure. The residue was lyophilized to give 7β-[(Z)-2-(5-amino-1,2,4
-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamide]-3-[
3-amino-2-(3-hydroxypropyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate is obtained. IR (Nujol): 3320, 1770, 1640c
m-1 NMR (D2O, δ): 1.52 (s, 6H), 1.9
3(quinted, 2H, J=6Hz), 3.10(
d, 1H, J=18Hz), 3.33(d, 1H, J=
18Hz), 3.56 (t, 2H, J=6Hz), 4.
23 (t, 2H, J=6Hz), 5.07 (brs, 2
H), 5.17 (d, 1H, J = 5Hz), 5.80 (
d, 1H, J=5Hz), 5.91(d, 1H, J=3
Hz), 7.82 (d, 1H, J=3Hz)

0056
Example 2 The following compound was obtained in the same manner as in Example 1. (1) 7β-[(Z)-2-(2-aminothiazole-
4-yl)-2-methoxyiminoacetamide]-3-
[3-Amino-2-(2-methoxythiethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate. IR (Nujol): 1770, 1610, 1030,
730 cm-1 NMR (D2O, δ): 3.10 and 3.46 (AB
q, 2H, J=18Hz), 3.36(s, 3H), 3
．． 73 (t, 2H, J=6Hz), 4.36 (t, 2H
, J=6Hz), 5.12 (brs, 2H), 5.22
(d, 1H, J=5Hz), 5.80 (d, 1H, J=
5Hz), 5.96 (d, 1H, J=3Hz), 6.9
7 (s, 1H), 7.86 (d, 1H, J=3Hz) (
2) 7β-[(Z)-2-(5-amino-1,2,4-
Thiadiazol-3-yl)-2-(1-carboxy-
1-methylethoxyimino)acetamide]-3-(3
-amino-2-isopropyl-1-pyrazoliothomethyl) 3-cephem-4-carboxylate. IR (Nujol): 3300, 1780, 1640,
1580cm-1 18Hz), 4.2-4.5 (m, 1H), 5.15 (
s, 2H), 5.22 (d, 1H, J=5Hz), 5.
80 (d, 1H, J=5Hz), 5.92 (d, 1H,
J = 3Hz), 7.80 (d, 1H, J = 3Hz)

0
(3) 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-(3-amino-2-isopropyl-1-pyrazolio)methyl-3 -Cephem-4-carboxylate. IR (Nujol): 3300, 1770, 1600,
1040,720cm-1 NMR (D2O, δ): 1.50 (d, 6H, J=7H
z), 3.00 and 3.30 (ABq, 2H, J=1
8Hz), 4.00(s, 3H), 4.2-4.6(m
, 1H), 5.10 (brs, 2H), 5.20 (d,
1H, J=5Hz), 5.77(d,1H,J=5Hz
), 5.90 (d, 1H, J=3Hz), 6.96 (s
, 1H), 7.80, (d, 1H, J=3Hz) (4)
7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-amino-2-isopropyl-1-pyrazolio)methyl -3-cephem-4-carboxylate. IR (Nujol): 3300, 3150, 1760,
1600, 1040 cm-1 NMR (D2O, δ): 1.53 (d, 6H, J=7H
z), 3.03 and (ABq, 2H, J=18Hz)
, 4.06 (s, 3H), 4.2-4.5 (m, 1H)
, 5.10 (brs, 2H), 5.20 (d, 1H, J
= 5Hz), 5.81 (d, 1H, J = 5Hz), 5.
90 (d, 1H, J=3Hz), 7.80 (d, 1H,
J=3Hz) (5) 7β-[(Z)-2-(2-aminothiazole-
4-yl)-2-methoxyiminoacetamide]-3-
(3-amino-2-(2-fluoroethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate. IR (Nujol): 3300, 1760, 1600,
1030,720cm-1 3.10 and 3.43 (ABq, 2H, J=18Hz
), 4.00 (s, 3H), 4.46 (m, 2H), 5
．． 0 (m, 2H), 5.10 (s, 2H), 5.20 (
d, 1H, J=5Hz), 5.80(d, 1H, J=5
Hz), 5.96 (d, 1H, J=3Hz), 6.96
(s, 1H), 7.89 (d, 1H, J=3Hz) (6
)7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-[3-amino-2-(2-fluoroethyl) -1-pyrazolio]methyl-3-cephem-4-carboxylate. IR (Nujol): 3300, 1770, 1600,
1040,720 cm-1 NMR (D2O, δ): 3.06 and 3.40 (AB
q, J=18Hz, 2H), 4.06 (s.3H), 4
．． 45 (m, 2H), 5.0 (m, 2H), 5.10 (
brs, 2H), 5.18 (d, 1H, J=5Hz),
5.80 (d, 1H, J=5Hz), 5.95 (d, 1
H, J = 3Hz), 7.87 (d, 1H, J = 3Hz)

(7) 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1
-carboxy-1-methylethoxyimino)acetamide]-3-[3-amino-2-(2-fluoroethyl)
-1-pyrazolio]methyl-3-cephem-4-carboxylate. IR (Nujol): 3300, 1770, 1600,
1580cm-1 NMR (D2O, δ): 1.50 (s, 6H), 3.0
6 and 3.40 (ABq, J=18Hz), 4.35
~4.50 (m, 2H), 4.9 ~ 5.0 (m, 2H)
, 5.10 (s, 2H), 5.20 (d, 1H, J=6
Hz), 5.80 (d, 1H, J=6Hz), 5.95
(d, 1H, J=3Hz), 7.88 (d, 1H, J=
3Hz) (8) 7β-[(Z)-2-(5-amino-1,2,4
-thiadiazol-3-yl)-2-allyloxyiminoacetamide]-3-[3-amino-2-(2-fluoroethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate. IR (Nujol): 3300, 1760, 1580,
1010,710 cm-1 NMR (DMSO-d62, δ): 2.80 and 3.
23 (ABq, 2H, J=18Hz), 4.2-4.8
(m, 5H), 4.8-5.0 (m, 5H), 5.65
(dd, 1H, J=8Hz, 5Hz), 5.0 to 6.2
(m, 1H), 5.83 (d, 1H, J=3Hz), 7
．． 50 (brs, 2H), 8.10 (brs, 2H),
8.15 (d, 1H, J=3Hz), 9.45 (d, 1
H, J=8Hz)

(9) 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-(2-carboxymethyl-3-amino-1
-pyrazolio)methyl-3-cephem-4-carboxylate. NMR (D2O, δ): 3.00, 3.45 (2H, A
Bq, J = 18Hz, 40Hz), 3.78 (3H, s
), 4.70 (2H, s), 4.78-5.33 (3H
, m), 5.77 (1H, d,, J=5Hz), 5.9
9 (1H, d, J=3Hz), 7.07 (1H, s),
7.97 (1H, d, J = 3Hz) (10)7β-[(
Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-methyl-1-carboxy)ethoxyiminoacetamide]-3-(2-carbamoylmethyl-3-amino -1-pyrazolio)methyl-3-cephem-4-carboxylate. IR (Nujol): 3300, 3150, 1770,
1630-1660 cm-1 NMR (D2O-NaHCO3, δ): 1.52 (6H
, s), 2.98, 3.40 (2H, ABq, J=18
Hz, 38Hz), 4.83-5.33 (5H, m),
5.84 (1H, d, J = 5Hz), 5.95 (1H,
d, J = 3Hz), 7.92 (1H, d, J = 3Hz) (11) 7β-[(Z)-2-(5-amino-1,2,
4-thiadiazol-3-yl)-2-allyloxyiminoacetamide]-3-(2-carboxymethyl-3
-amino-1-pyrazolio)methyl-3-cephem-4
-Carboxylates. IR (Nujol): 3250, 1760, 1580~
1670, 1520 cm-1 NMR (D2O-NAHCO3, δ): 3.12, 3.
47 (2H, ABq, J=18Hz, 30Hz), 4.
77 (2H, s), 4.87-5.50 (7H, m),
5.73-6.23 (1H, m), 5.84 (1H, d
, J=5Hz), 5.93 (1H, d, J=3Hz),
7.83 (1H, d, J=3Hz)

(12
)7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1
-methylethoxyimino)acetamide]-3-(2-
Carboxymethyl-3-amino-1-pyrazolio)methyl-3-cephem-4-carboxylate. IR (Nujol): 1830, 1620-1670,
1520 cm-1 NMR (D2O-NaHCO3, δ): 1.57 (6H
, s), 3.12, 3.47 (2H, ABq, J=18
Hz, 30Hz), 4.70 (2H, s), 4.50~
5.10 (2H, m), 5.21 (1H, d, J = 5H
z), 5.86 (1H, d, J = 5Hz), 5.96 (
1H, d, J = 3Hz), 7.86 (1H, d, J = 3
Hz) (13) 7β-[(Z)-2-(2-formylaminothiazol-4-yl)-2-methoxyiminoacetamide]-3-(2-carbamoylmethyl-3-amino-1
-pyrazolio)methyl-3-cephem-4-carboxylate. (14) 7β-[(Z)-2-(5-amino-
1,2,4-thiadiazol-3-yl)-2-(1-
tert-butoxycarbonyl-1-methylethoxyimino)acetamide]-3-[3-formylamino-2-(
2-formylaminoethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate. IR (Nujol): 1780, 1710, 1660,
1140, 1040 cm-1 NMR (DMSO-d6, δ): 1.43 (brs, 1
5H), 3.45 (brs, 2H), 3.60 (t, 2
H, J=6Hz), 4.40 (t, 2H, J=6Hz)
, 5.17 (d, 1H, J=6Hz), 5.36 (br
s, 2H), 5.85 (dd, 1H, J=5Hz, 8H
z), 6.97 (d, 1H, J=3Hz), 7.90(
s, 1H), 8.06 (sM, 1H), 8.21 (d,
1H, J=3Hz), 9.36(d,1H,J=8Hz
)

(15) 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3-[3-amino-2-
(2-fluoroethyl)-1-pyrazolio]methyl-3
-Cephem-4-carboxylate. IR (Nujol): 3300, 1765, 1600,
1040,720cm-1 NMR (DMSO-d6+D20,δ): 1.23(t
, 3H, J=7.0Hz), 2.85 and 3.22(
ABq, 2H, J=17.3Hz), 4.16(q, 2
H, J=7.0Hz), 4.4-4.9 (m, 4H),
5.01 (d, 1H, J = 4.9Hz), 5.12 (b
rs, 2H), 5.65 (d, 1H, J=4.9Hz)
, 5.87 (d, 1H, J = 3.2Hz), 8.18 (
d, 1H, J=3.2Hz)

(16) 7β
-[(Z)-2-(2-aminothiazol-4-yl)
-2-cyclopentyloxyiminoacetamide] -3
-[2-(2-fluoroethyl)-3-amino-1-pyrazolio]methyl-3-cephem-4-carboxylate. IR (Nujol): 1770, 1660, 1600c
m-1 NMR (DMSO-d6, δ): 1.30 to 1.93 (
8H, m), 2.83 and 3.23 (2H, ABq,
J=18Hz), 4.33 (1H, brs), 4.87
(1H, brs), 4.62 (1H, brs), 4.7
5-4.97 (2H, m), 5.00 (1H, d, J=
5Hz), 5.10 (2H, brs), 5.57 (1H
, dd, J=5.8Hz), 5.83(1H, d, J=
3Hz), 6.64 (1H, s), 7.14 (2H, b
rs), 7.53 (2H, brs), 8.15 (1H,
d, J=3Hz), 9.36 (1H, d, J=8Hz)

(17) 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetamide]-3-[2-(2-fluoroethyl)-3
-amino-1-pyrazolio]methyl-3-cephem-4
-Carboxylates. IR (Nujol): 1770, 1590-1650c
m-1 NMR (DMSO-d6, δ): 2.84 and 3.2
3 (2H, ABq, J=17Hz), 4.57 (1H,
d, J=5Hz), 4.49 (1H, brs), 4.7
3 (2H, brs), 4.89 (1H, brs), 5.
03 (1H, d, J = 5Hz), 5.13 (2H, br
s), 5.18-5.35 (2H, m), 5.62 (1
H, dd, J = 5.8Hz), 5.86 (1H, d, J
=3Hz), 5.87-6.05 (1H, m), 6.7
0 (1H, s), 7.24 (2H, brs), 7.57
(2H, brs), 8.19 (H, d, J=3Hz),
9.58 (1H, d, J=8Hz)

Example 3 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino) Acetamide]
-3-[3-formylamino-2-(2-formylaminoethyl)-1-pyrazolio]methyl-3-cephem-
4-carboxylate (1.78 g) was dissolved in methanol (1
1 ml). Concentrated hydrochloric acid (0.89 ml) was added dropwise thereto with stirring at room temperature. Stir the mixture for 3 hours. The reaction mixture was triturated with ethyl acetate (150 ml) and 7β
-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamide]-3
-[3-amino-2-(2-aminoethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate tetrahydrochloride is obtained. IR (Nujol): 1770, 1710, 1620,
1140cm-1 NMR (DMSO-d6, δ): 1.41 (s, 9H)
, 1.47 (s, 6H), 3.50 (brs, 2H),
3.63 (t, 2H, J=6Hz), 4.20 (t, 2H
H, J=6Hz), 5.10 (brs, 2H), 5.2
2 (d, 1H, J=5Hz), 5.85 (dd, 1H,
J=5Hz, 8Hz), 5.90(d, 1H, J=3H
z), 7.85 (d, 1H, J=3Hz), 9.36(
d, 1H, J=8Hz)

Example 4 7β-[(Z)-2-(2-formylaminothiazol-4-yl)-2-methoxyiminoacetamide]-3
-(2-Carbamoylmethyl-3-amino-1-pyrazolio)methyl-3-cephem-4-carboxylate in the same manner as in Example 3 to obtain the following compound. 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]3-(2-carbamoylmethyl-3-amino-1-pyrazolio)methyl-3-cephem-4- Carboxylate. IR (Nujol): 3300, 3160, 1760,
1580-1660, 1520cm-1NMR (D2O
, δ): 3.00 and 3.41 (2H, ABq, J=
18Hz), 3.98 (3H, s), 4.97 and 5
．． 50 (2H, ABq, J=18Hz), 5.10 (2
H, s), 5.16 (1H, d, J=5Hz), 5.8
0 (1H, d, J = 5Hz), 5.97 (1H, d, J
=3Hz), 6.99 (1H, s), 7.92 (1H,
d, J=3Hz)

Example 5 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino) Acetamide]
-3-[3-amino-2-(2-aminoethyl)-1-
pyrazolio]methyl-3-cephem-4-carboxylate tetrahydrochloride (1.488 g) in anisole (1.4
88 ml) solution, add trifluoroacetic acid (4.464 ml)
) while stirring under ice-cooling. The mixture is stirred at room temperature for 3 hours. The reaction mixture is triturated with ethyl acetate (250 ml). The precipitate is filtered and dried over phosphorus pentoxide under reduced pressure. Pour the powder into water (20 ml) and adjust the pH to 2 with saturated aqueous sodium bicarbonate solution. The aqueous solution was subjected to column chromatography using a large-pore nonionic adsorption resin "Diaion HP-20" (30 ml) and eluted with a 10% aqueous isopropyl alcohol solution. The fractions containing the target product are combined and the isopropyl alcohol is distilled off under reduced pressure. The residue was lyophilized to yield 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1
-carboxy-1-methylethoxyimino)acetamide]-3-[3-amino-2-(2-aminoethyl)-
1-pyrazolio]methyl-3-cephem-4-carboxylate is obtained. IR (Nujol): 3300, 1750, 1560c
m-1 NMR (D2O, δ): 1.56 (s, 6H), 3.0
0 and 3.50 (ABq, 2H, J=18Hz), 3
．． 40 (t, 2H, J=6Hz), 4.36 (t, 2H
, J=6Hz), 5.00 and 5.30(ABq,2
H, J = 15Hz), 5.25 (d, 1H, J = 5Hz
), 5.82 (d, 1H, J=5Hz), 5.99 (d
, 1H, J=3Hz), 7.93(d, 1H, J=3H
z)

Example 6 7β-amino-3-[2-(2-fluoroethyl)-3
-amino-1-pyrazolio]methyl-3-cephem-4
- Carboxylate hydrochloride (1.0 g) in water (10 m
l) and tetrahydrofuran (20 ml) was adjusted to pH 7.0 with a saturated aqueous solution of sodium hydrogen carbonate,
(Z)-2-(2-aminothiazol-4-yl)-2
-acetoxyiminoacetyl chloride hydrochloride (1.2
3g) at room temperature. The mixture is stirred for 2 hours while maintaining pH 7.0 with 20% aqueous potassium carbonate solution. Tetrahydrofuran was distilled off, and methanol (20 ml) was added to the residue.
) and ammonium chloride (0.425g), and
Adjust the pH to 8.0 with 0% aqueous potassium carbonate solution. The mixture is stirred at room temperature for 2 hours. Methanol was distilled off from the reaction mixture, and the residue was adjusted to pH 3.0 with 1N hydrochloric acid. The solution is transferred to the large-pore nonionic adsorption resin "Diaion HP-20".
(30 ml) and eluted with 5% isopropyl alcohol aqueous solution. Fractions containing the target product were combined, the isopropyl alcohol was distilled off, and lyophilized to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3- [2-(2-fluoroethyl)-3
-amino-1-pyrazolio]methyl-3-cephem-4
-carboxylate (0.63 g) is obtained. IR (Nujol): 1770, 1590-1670c
m-1 NMR (DMSO-d6, δ): 2.85 and 3.2
3 (2H, ABq, J=17Hz), 4.40-5.0
4 (4H, m), 5.03 (1H, d, J=5Hz),
5.12 (2H, brs), 5.65 (1H, dd, J
=5.8Hz), 5.86 (1H, d, 3Hz), 6.
63 (1H, s), 7.13 (2H, brs), 7.5
7 (2H, brs), 8.18 (1H, d, J=3Hz
), 9.41 (1H, d, J = 8Hz), 11.40 (
1H,brs)

Claims (1)

[Claims] Claim 1: General formula [wherein R1 is an amino group or a protected amino group, R
2 is hydrogen or an organic group, R3 is an amino group or a protected amino group, R4 is a hydroxypropyl group, a protected hydroxypropyl group, an isopropyl group, a lower alkoxy (lower) alkyl group, a halo (lower) alkyl group, a carboxy (lower) alkyl group, protected carboxy (lower) alkyl group, carbamoyl (lower) alkyl group, amino (lower) alkyl group or protected amino (lower) alkyl group, Z means N or CH, respectively. However, when R4 means a hydroxypropyl group or a protected hydroxypropyl group, Z means N. ] A novel cephem compound and its salt.