JPS62149681A - Novel derivative of cephalosporin compound, production thereof and pharmaceutical composition containing said derivative - Google Patents

Abstract

NEW MATERIAL:A cephalosporin compound of formula I [R<1> is organic residue; R<2> is H or methoxy; n is 0 or 1; A is N of group of formula II or III constituting imidazolium ring; B is C of group of formula IV or V constituting imidazolium ring; R<3>-R<8> are H, (substituted) 1-12C alkyl, (substituted) 3-7C cycloalkyl, OH, etc.; X<-> is halogen or acid residue] having imidazolium ring substituted to the 3-site of cephem group. EXAMPLE:7-[ 2-( 2-t-Butoxycarbonyl )prop-2-oximino-2-(2-tritylaminothiazol-4-yl) acetamido]-3-[3-(2-propenyl-1-imidazoliomethyl]-3-cephem-1-oxide-4-car boxylic acid p-methoxybenzyl ester iodide. USE:Preventive and remedy for bacteriosis. PREPARATION:The compound formula VI (R<14> is H, metal, etc.) is made to react with the compound of formula VII and, if necessary, the reaction product is subjected to reduction, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to the general formula (1) having antibacterial activity (wherein R1 is an organic residue known in β-lactam antibiotics;
R2 represents a hydrogen atom or a methoxy group, n represents 0 or 1, A represents nitrogen of the following formula constituting the imigzolium ring, and B represents carbon of the following formula constituting the imigzolium ring.

R', R', R5, R'', R) and R11 are hydrogen atoms or substituted or unsubstituted C1-C12 alkyl groups, substituted or unsubstituted C2-CI2 furkynyl groups,
Substituted or unsubstituted benzyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted alkoxy group, substituted or unsubstituted amino group, substituted or unsubstituted carbamoyl group, substituted or unsubstituted ureido group, substituted or unsubstituted unsubstituted thiocarbamoyl group, hydroxyl group, halogen atom, mercap) mono-substituted, nitro group, cya/group, carboxyl group, cephem 3 position represented by ) (e means a halogen atom or acid residue, respectively) The present invention relates to novel cephalosporin compounds in which is substituted with an imigzolium ring, pharmaceutically acceptable salts thereof, methods for producing them, and pharmaceutical compositions containing them.

In the cephalosporin compound or its salts represented by the general formula (in which R', R2, Rco, nt A and B each have the same meanings as above), optical isomers due to the presence of asymmetric carbon atoms in the molecule Although one or more such stereoisomers may exist, such isomers are included within the scope of this invention.

The salts of the object compound (1) of the present invention include pharmaceutically acceptable salts, such as alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (calcium salts,
(magnesium salt, etc.), ammonium salt, organic amine salt (triethylamine salt, pyridine salt, etc.), inorganic acid addition salt (hydrochloride, hydrobromide, etc.), organic acid addition salt (formate, trichloroacetate, methanesulfone) salts with basic or acidic amino acids (arginine salts, aspartates, glutamates, etc.).

In the general formula (1) of the present invention, organic residues known in β-lactam antibiotics represented by R1 include, for example, a 4- to 6-membered heterocyclic ring (sulfur, nitrogen, and oxygen atoms are Examples include organic residues having 1 to 4 atoms).

Such organic residues include, for example, [wherein is an oxygen atom or a sulfur atom, R15 is an optionally substituted amino group, and R9 is hydrogen; methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Le
C3-C6 alkyl group such as rt-butyl; vinyl,
C2-C6 alkenyl groups such as propenyl, isopropynyl, phthynyl, imbutenyl, pentenyl, hexenyl; 02-C6 such as acetylenyl, propargyl, etc.
Furkynyl group; C3-C7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl group, C4-C7 such as cyclopentenyl, cyclohexynyl group
cycloalkenyl group; alkyl or alkenyl group substituted with chlorine, bromine, iodine or fluorine; alkyl group substituted with methylthio, ethylthio, propylthio group; alkyl group substituted with phenyl, benzyl group; chenyl, furyl, Heterocycle such as thiazolyl group; groups, preferably hydrogen, methyl,
It is ethyl. R12 is hydrogen or sodium, potassium or lithium, preferably a monovalent alkali metal such as sodium or potassium, a divalent alkaline earth metal such as calcium or magnesium, trimethylamine, triethylamine, methylamine, propylamine, N, Organic amine salts such as N-trimethylethanolamine, or lert-butyl, benzhydryl, 2,2,2-)lychloroethyl, p-methoxybenzyl, p-nitrobenzyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, diphenylmethane or It is a protecting group for carboxyl groups such as phenacyl)
].

Examples of organic residues represented by R1 include HR13 (wherein, D is an oxygen atom or a sulfur atom, R'5 is an optionally substituted amino7 group, and R'' is a lower alkyl group such as methyl, ethyl, C1-6 alkyl group such as propyl,
Examples of unsaturated lower alkyl groups include vinyl, flobenyl, impropenyl, butenyl, imbutenyl, pentenyl,
C2-6 unsaturated alkyl groups such as acetylenyl and propargyl, C3-7 cycloalkyl groups such as cyclopropyl, cyclobutyl, and cyclopentenyl as cycloalkyl groups, nicotine, isonicotine, chenyl, furyl, etc. as heterocycles, esterification Carboxyl group, halogen atom, nitro group that may be 1. A group represented by (amino 7 group, hydroxyl group, sia 7 group, substituted or unsubstituted phenyl group or benzyl group); (in the formula, R" has the same meaning as above), CH2- R+ is a substituted or unsubstituted aromatic An example of an organic residue having a group phenyl group is CH3.

etc. can be mentioned.

When R' is an organic residue having a substituted or unsubstituted alkyl group, examples thereof include F2CH3CH2-, H
OOCCHCH2S-CH2-.

’　　　　　NH2 CH,,C2H5 etc. can be mentioned.

When R1 is an organic residue having a substituted or unsubstituted alicyclic hydrocarbon group, examples thereof include NH2, NH2,
NH2 R2 is hydrogen or a methoxy group, R14 is a hydrogen atom, a metal atom such as sodium or potassium, an ester residue, a salt-forming cation, or an anion when COO- forms an intramolecular or molecular salt with a cation. Indicates electric charge. Examples of ester residues include lower alkyl such as methyl, ethyl,
propyl, inpropyl, butyl, isobutyl, ter
C1-6 alkyl groups such as t-butyl, halo-lower alkyl; 2.2.2-) substituted or unsubstituted phenylalkyl such as dichloroethyl; benol, 1-fumethoxybenzyl, trimethoxybennol, trimethoxydichloroben; Nor, p-nitrobenol, benzhydryl, etc., also diphenylmethyl, trityl, ditolylmethyl, phenyl-p-methoxyphenylmethyl,
Examples include carboxyl group-protecting groups such as a-p-methoxyphenylethyl, α-p-methoxyphenyl-β-trichloroethyl, α-nophenylethyl, trimethylsilyl, benzyloxymethyl or 7-enacyl.

R3-R6 are hydrogen atoms or substituted or unsubstituted C1-C1
As a straight chain or branched alkyl group of □, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t
Substituted or unsubstituted C2-C6 fulkenyl groups such as ert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decanyl, undecanyl, dodecanyl, etc., C2-C6 fulkynyl such as vinyl, allyl, impropenyl, butenyl and methallyl; Substituted or unsubstituted C1-C7 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.; lower alfxyl groups include C1-6 furfxyl, such as methoxy, ethoxy, propoxy, isopropoquine, and butoxy; Lower alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, and butylthio; lower alkanoyl groups include formyl, acetyl, propionyl, butyryl, and imbutyryl; halogens include chlorine, bromine, fluorine, and iodine; and alkyl Carbonyl groups include methylcarbonylmethyl, ethylcarbonylmethyl, methylcarbonylethyl, ethylcarbonylethyl, substituted or unsubstituted 7-enyl or benzyl groups, and substituents include phenol, aceto-7-emene, etc., and nitro groups, Examples include heterocycles such as amine 7 group, hydroxyl group, cyano group, carboxyl group, carbamoyl group, or chenyl group, furyl group, and pyridyl group, and these groups may also be substituted or polysubstituted.

The cephalosporin compound N) and its salts of the present invention can be produced by various methods, but the following two routes are preferred.

Synthetic route (1) (0)n CO2R'' (■) (■) (In the formula, R1 and R2 have the same meanings as above, R1'' is a hydrogen atom, a metal atom, an ester residue, a salt-forming cation, or a C
When OO- forms an intramolecular or extramolecular field with a cation pair, it exhibits an anionic charge. n means 0 or 1, and X represents a group that can be substituted with a substituted or unsubstituted imidazole compound. ) Compound (II) or a salt thereof can be produced by reacting Compound (■) or a reactive derivative having an amide 7 group or a salt thereof with Compound (l) or a reactive derivative having a carboxyl group or a salt thereof.Compound (■) ) and (Vl) include the same salts exemplified for compound (1). Examples of reactive derivatives at the amine 7 group of compound (■) include, for example, compound (■) and Silyl compounds [e.g.
silyl derivatives formed by reaction with [bis(trimethylsilyl)acetamide, trimethylsilyl chloride, etc.]; isocyanates; inthiocyanates;
Compound (■) and carbonyl compound [e.g., aldehydes such as acetaldehyde and benzaldehyde, acetone,
Examples include ship bases formed by reaction with ketones such as methyl ethyl ketone, and enamine-type tautomers thereof.

Examples of reactive derivatives at the carboxyl group of compound (■) include acid halides such as acid chlorides and acid bromides; substituted phosphoric acids, noalkyl phosphorous acids, sulfites, thiosulfates, sulfuric acids, alkyl carbonates, and organic carboxylic acids. Acid anhydrides and symmetrical acid anhydrides with acids such as; activated acid amides with imidazole, dimethylpyrazole, etc.; p-nitrophenyl ester, phenylthioester, carboxymethylthioester or N-hydroxypiperidine, N
Examples include active esters such as esters with N-hydroxy compounds such as -hydroxyphthalimide and N-hydroxyphthalimide.

Examples of the solvent used in this reaction include water,
Single or mixed solvents that do not adversely affect the reaction can be used, such as acetone, nooxane, acetonitrile, chloroform, methylene chloride, benzene, ethyl acetate, N,N-trimethylformamide, birinone, hexane, and the like. The reaction temperature is not particularly limited, but it is usually cooled or heated, preferably about 0 to 40°C.

This reaction can be carried out in the presence of an organic or inorganic base. Such bases include, for example, alkali metals such as lithium, sodium, potassium, calcium,
Alkaline earth metals such as magnesium, alkali metal hydroxides such as sodium hydroxide, alkali metal hydrides such as sodium hydride, alkaline earth metal hydrides such as calcium hydride, alkali metals such as +7um Examples include carbonates, alkali metal hydrogen carbonates such as potassium hydrogen carbonate, alkali metal alkoxides such as sodium ethoxide, trialkylamines such as triethylamine, and nitrogen-containing heterocyclic compounds such as pyridine, picoline, and quinoline.

Among these, it is preferable to use trialkylamines and nitrogen-containing heterocyclic compounds. The amount of the base to be used is not particularly limited, but it is usually 25 equivalents or less, preferably 0.25 to 4 equivalents, relative to compound (■).

In the above reaction, the ratio of compound (■) and compound (Vl) to be used is not particularly limited and can be appropriately selected from a wide range, but the ratio of the former to the latter is usually 1:5 to 5:1 (equivalent ratio).
, preferably 1:2 to 2:1.

When compound (Vl) is used in the form of a free acid or a salt thereof in this reaction, it is preferable to carry out the reaction in the presence of a condensing agent. As the condensing agent, carbodiimide compounds such as N,N'-dicyclohexylcarbodiimide, ketene imine compounds such as nophenylketene-N-cyclohexylimine, unsaturated alkyl ether compounds such as ethoxyacetylene and β-chlorovinylethyl ether, N-hydroxy Examples of sulfonic acid esters of benzotriazole derivatives (C, 1-(4-chlorobenzenesulfonyloxy)-6-chloro-IH-benzotriazole, etc.), trialkyl phosphite or triphenylphosphine and carbon tetrachloride, ethyl polyphosphate, trichloride The so-called Vilsmeier reagent (formed by the reaction of amide compounds such as N,N-methylformamide, N-methylformamide with halogen compounds such as thionyl chloride, phosphoryl chloride, and phosdene) ), etc.

The amount of the condensing agent used is usually 25 equivalents or less, preferably 0.25 to 4 equivalents, based on compound (■).

(○)n (II) (I[I)00
・1゛■ (In the formula, R'+ R2+ R co+ R"+ A, By
(Xe and Vn each have the same meaning as above) Next, when the 3-position of compound (II) is subjected to a substitution reaction with a substituted or unsubstituted imidazole (If), water, acetonitrile, methanol, acetone, In a single or mixed solvent such as N,N-methylformamide or tetrahydro7rane, using sodium carbonate, sodium bicarbonate or triethylamine as a base, or in the presence of propylene oxide, the reaction temperature is not particularly limited, but usually Under cooling or heating, preferably from 0°C
It is best to do this at about 40°C.

In compound (IV), does R1 or R'' have, for example, an amino protecting group or a carboxyl protecting group?
Alternatively, when n=1, compound (+) can be produced by subjecting the amino-protecting group and the carboxyl-protecting group to an elimination reaction or a reduction reaction, respectively. This elimination reaction and V reduction reaction can be carried out by conventional methods such as hydrolysis and reduction as shown below.

(b) Hydrolysis Hydrolysis is preferably carried out in the presence of an acid.

Suitable acids include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, and organic acids such as formic acid, trifluoroacetic acid, propionic acid, benzenesulfone M, and p-)luenesulfonic acid.

For hydrolysis, a single or mixed solvent that does not adversely affect the reaction, such as water, methanol, tetrahydro-7-alane, N,N-dimethylformamide, nooxane, benzene, hexane, etc., can be used. Moreover, when the above-mentioned acid is a liquid, this acid itself can be used as a solvent.

The reaction temperature for this hydrolysis is not particularly limited, but it is usually preferable to carry out the reaction under cooling or under heating.

(b) Reduction Reduction is carried out by conventional methods such as chemical reduction and catalytic reduction.

Chemical reducing agents include, for example, metals or metal compounds such as tin, zinc, iron, chromium monoride, chromium acetate, and formic acid,
Examples include those in combination with organic or inorganic acids such as acetic acid, trifluoroacetic acid, p-)luenesulfonic acid, hydrochloric acid, hydrobromic acid, and phosphorus tribromide.

The catalyst used in the catalytic reduction is, for example, a conventional catalyst containing heavy metals such as platinum, palladium, rhodium, nickel, copper, cobalt, and iron. Catalytic reduction usually involves water, methanol, N,N-dimethylformamide,
Single or mixed solvents that do not adversely affect the reaction, such as hexane, benzene, dioxane, etc., can be used.

Moreover, when the above-mentioned acid is a liquid, it can also be used as a solvent.

The reaction temperature of this catalytic reduction is not particularly limited, but it is usually preferable to carry out the reaction under cooling or heating.

Synthetic route (2) (0)n (wherein, R't R2+ R't R”l At B
+
It can be produced by reacting with compound (Vl), a reactive derivative at the carboxyl group, or a salt thereof.

Suitable salts of compounds (V) and (VI) include the same salts exemplified for compound (1).

Examples of reactive derivatives at the amine 7 group of compound (V) include the compound (■) in the synthetic route (1) described above.
The same things as mentioned above can be mentioned.

Examples of reactive derivatives at the carboxyl group of compound (Vl) include those mentioned above.

As the solvent used in this reaction, the same solvent as in the synthetic route (1) can be used. The reaction temperature is not particularly limited, but usually under cooling or heating,
Preferably, the temperature is about 0 to 40°C.

This reaction can be carried out in the presence of an organic or inorganic base. As the deceptive base, the above synthetic route (1
) can be used. The amount of the base to be used is not particularly limited, but it is usually 25 equivalents or less, preferably 0.25 to 4 equivalents, relative to compound (V).

In the above reaction, the ratio of compound (V) and compound (VI) to be used is not particularly limited and can be appropriately selected from a wide range, but the ratio of the former to the latter is usually 1:5 to 5:1 (equivalent ratio).
, preferably 1:2 to 2:1.

In this reaction, when the compound (l) is used in the form of a free acid or its salt, it is preferable to carry out the reaction in the presence of a condensing agent.
Something similar to that described in 1) can be used. The amount of the condensing agent used is usually 25 equivalents or less, preferably 0.25 to 4 equivalents, relative to compound (V).

In compound (■), R' or R3 is, for example, ami/
If a protecting group or a carboxyl protecting group is present, or if n=1, the compound (1
) can be manufactured. As this elimination reaction and 1/'' reduction reaction, a reaction similar to the above-described synthetic route (1) can be used.

Compound (1) of the present invention has high antibacterial activity and is useful as a preventive or therapeutic agent for bacterial infections.

When administering the compound (1) of the present invention and its salts for the purpose of prophylaxis and treatment, the compound (1) containing the compound as an active ingredient and containing an organic or inorganic solid or They are used in conventional formulations mixed with pharmaceutically acceptable carriers such as liquid excipients. The formulation may be in solid form such as tablets, granules, powders, capsules, or in liquid form such as solutions, suspensions, syrups, emulsions, lemonades, etc. If necessary, in the above formulations,
Auxiliary substances, stabilizers, lubricants and other customary additives, such as lactose, magnesium stearate, terracotta, sucrose, corn starch, talc, stearic acid, gelatin, agar, pectin, peanut oil, olive oil, cocoa butter. , ethylene glycol, etc. may be mixed.

The dosage of compound (1) is selected depending on the patient's age, condition, type of ailment, type of compound (I) to be administered, etc. Generally, doses of 1 to about 4000 τ per day, or even more, can be administered to a patient. For the treatment of pathogenic bacterial infections, the average dose of compound (1) per dose is approximately 5.
0mg, 100mg, 250mg, 500B, 10
Amounts of 00mg and 2QOOmg can be used.

(Example) Next, Examples and Test Examples of the present invention will be described below, but the present invention is not limited thereto.

In addition, in the following, Tr represents a trityl group and tBu represents a tertiary butyl group.

Example 1 7-7mi/-3-ri-4-romethyl-3-cephemu-4-carboxylic acid p-methoxybennorester p-)luenesulfonate (700+ag) in ethylene chloride (20m
l) Triethylamine (0,1
9ml) was added and stirred, and (Z)-2-
(2-7lyloxyimi/)-2-(2-1lythylami7thiazol-4-yl)acetic acid (600 mg) was added and stirred to form a homogeneous solution. Stir this solution under water cooling.
-Hydroxybenzotriazole (265111!?
), then dicyclohexylcarbodiimide (270 m
g) was added. The mixture was further stirred for 3 hours under water cooling. The mixture was passed through the mouth and the white solid was washed with a small amount of a7ton. Combine the oral performance and washing liquid
n even η colder h 0 .

It was eluted through a silica gel column with form-methanol (8:1 by volume). By collecting and then concentrating the product-containing eluate, ? -[2-(2-propenyloxyimino)-2-(2-)lythylami/thiazol-4-yl)acetamide]-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (syn isomer ) (900 mg) was obtained.

NMRδ ppm (CD CI,): 3.50 (2
H,s), 3.78(3H,s), 4.45(2)1
．． d, J = 12Hz).

4.58(2)1. d, J=5.511z), 4.9
8 (Ill, d, J = 5,0 Hz).

5.1-5.4(4H+m)+5.8-6.1(2H
, m), 6.7 (IH, 5) s7.08-7.84 (
20H, m), 8.13 (ill, s) Example 2 7-(2-(2-propenyloxyimino)-2-(2
-) dithylaminothiazol-4-yl)acetamide]-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxypencyl ester (syn isomer) (890
Sodium iodide (237 mg) and sodium carbonate (157 mg) are added to the acetone (50a+I) solution of B).
The mixture was heated to reflux for 1 hour while stirring. The mixture was cooled to room temperature, passed through the mouth, concentrated under reduced pressure, and the residue was dissolved in methylene chloride (50a+1) and washed with a 5% aqueous sodium thiosulfate solution (30a+1). The obtained organic phase was concentrated under reduced pressure to give 7-(: 2-(2-probenyloximi/)-2-(2-)ritylami7thiazol-4-yl)acetamide]-3-iodomethyl-3-cephem. -4-carboxylic acid p-methoxybennorester (syn isomer) (820 mg) was obtained.

NMRδ ppm (CD CL): 3.50 (21
1,n+), 3.82(311,s), 4.32(
2H,5)-4,70(211,d-J=5.5Hz)
, 4.90 (ltlzd-J=5,0Hz).

5.1-5.4 (411, u+), 5.8-6.1
(ZH, In), 6.7 (ltl, s).

7.08-7.84 (2011, In), 8.13
(llt, s) Example 3 ↑ 7-(2-(2-propenyloxyimino)-2-(2
-) ritylami7thiazol-4-yl)acetamide]-3-iodomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (syn isomer) (5,0
g) and methylene chloride (160 IIll) was added dropwise over 10 minutes with a solution of O''C cooling-chloroperbenzoic acid (1.5 g) in methylene chloride (40 ml) and stirred at the same temperature for 50 minutes. (After returning to room temperature, carbonate) l) Wash with rum aqueous solution, water and saturated brine, dehydrate with magnesium sulfate, and remove the solvent from the organic phase under reduced pressure. 2-propenyloxyimino)-
2-(2-)ditylaminothiazol-4-yl)acetamide]-3-iodomethyl-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl ester (syn isomer) (5.1 g) was obtained. Ta.

NMRδ ppm (CD C13): 3.54 (2
11,n+,), 3.78(3H,s), 4.41
(2Hym) w4.44 (ill, m), 4.73 (
:J, In)-4,97-5,42(211,m).

5.22 (2tl-s), 5.65-6.21 (2Lm
), 6.64 (III-s) + 7.08 (4H, m)
, 7.25 (161-s) Example 4 ↑ 7-(2-(2-propenyloxyimino)-2-(2
-) dithylaminothiazol-4-yl)acetamide]-3-iodomethyl-3-cephem-1-xyto-
4-Carboxylic acid p-methoxybenzyl ester (syn isomer) (0.5 g) was dissolved in a mixed solution of THF (5 ml) and chloroform (2.5 ml), and 1-(2-propenyl)-imidazole (64 , 8 mg). After the addition is complete, warm to room temperature and stir for an additional 3 hours.

After distilling off the solvent under reduced pressure, it was powdered with noethyl ether, purified using a silica gel column (chloroform-methanol volume ratio 8:1), and the target-containing eluate was collected and the solvent was distilled off to obtain 7- [2-(2-propenyloxyimino)-2-(2-)lythylamide/thiazole-4-
yl)acetamido)-3-(3-(2-propenyl)
-1-imigzoliomethyl]-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl ester.
Iodite (syn 51 body) (375, 1 mH) was obtained.

NMRδ ppIII (DMSO-d,): 3.
75 (21t, In), 3.80 (311, s),
4.60 (2H, In).

4, ss-5,47 (9Htm)t 5,60-6.3
0(311,l11)+6.81(1,Il,s)+
7.14 (4ft, m), 7.32 (15H9s)+
7.66 (211, +a), 8.74 (Ill, s)
, 8.94 (111, m).

9.06 (IH,s) Example 5 7-(2-(2-propenyloxyimino)-2-(2
-) dithylaminothiazol-4-yl)acetamide)-3-(3-(2-propenyl)-1-imigzoliomethyl]-3-cephem-1-oxyto-4-carboxylic acid p-methoxybennorester・Yogate (syn isomer) (359, SIIIg>) in acetone (20 ml)
Dissolved in and cooled to -40'C with dry ice-acene refrigerant.
The mixture was cooled to 100 mL, phosphorus tribromide (270 μm) was added dropwise, and the mixture was stirred for 1 hour. Under the same cooling, potash carbonate (500mg)
After adding the aqueous solution (3n+1) and warming it to room temperature, water (60u+l) was added and extracted twice with ethyl acetate (1,00ml). After dehydrating the organic phase with anhydrous magnesium sulfate, ethyl acetate was distilled off. By removing 7-(2-(2-
propenyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamide)-3-(3-(
2-propenyl)-1-imigzoliomethyl]-3-cephem-4-carboxylic acid ρ-methoxybenzyl ester yogate (syn isomer) (292,81+1[1)
I got it.

NMRδ ppm (DMS Ods): 3.5
0 (2H, s), 3.78 (3H, s), 4.56
(2H, m).

4.84(2H9m)-5,01-5,60(9H,1
1).

5.60-6.40 (3H, m), 6.72 (ill
, s), 7.15 (4H, m).

7.31 (15H, s), 7.62 (2H, m),
9.05 (IH, s).

9.20(IHls)-9,53(IH,m) Example 6 7-(2-(2-propenyloxyimino)-2-(2
-) dithylaminothiazol-4-yl)acetamide)-3-(3-(2-propenyl)-1-imigzoliomethyl]-3-cephem-4-calphone flip-methoxypencyl ester yogate (syn isomer) )(2
80+wg) was dissolved in an 80% aqueous acetic acid solution (3 ml), stirred at 35 to 40°C for 2 hours, and then lyophilized to remove the solvent. Diethyl ether was added to the residue and the precipitated powder was collected. ? -(2-(2-ami7thiazol-4-yl)-2-(2-probenyloxyimi/)acetamide)-3-[3-(2-propenyl)-1-imigzoliomethyl] = 3 -Cephem-4-carboxylic acid p-7 toxybenzyl ester yogate (syn 5%) (
209.2 mg) was obtained.

NMRδ ppm (DMSO-d,): 3.54
(2H, s), 3.76 (3H, s), 4.5
8(211,l11)-4,83(211,m),
5.0-5.54(9H,m)-5,81-6,35(
3H, m), 6.78 (IH, s), 6.83
(28, s).

7.13 (411, m), 7.68 (2H, n)t
9,22(IH,5)-9,63(IH,s) Example 7 7-(2-(2-7minothiazol-4-yl)-2-
(2-propenyloxyimino)acetamide)-3-
(3-(2-propenyl)-1-imigzoliomethyl)
-3-cephem-4-carboxylic acid p-methoxybenzyl ester yogate (syn isomer) (190 mg>) was added to methylene chloride (3 ml), trifluoroacetic acid (930 μl),
After stirring for 2 hours under water cooling in a mixed solvent consisting of m) and Ansor (650 μI), the solvent was distilled off under reduced pressure,
Diethyl ether (100 ml) was added to the residue to precipitate a powder. After taking this, it was neutralized with an aqueous solution of potassium carbonate and freeze-dried to obtain a yellow coarse powder. This was passed through a Sephadex LH-20 column (methanol) to obtain an eluate containing the desired content, and the solvent was distilled off under reduced pressure.
-(2-aminothiazol-4-yl)-2-(2-propenyloxyimino)acetyl)? )-3-(3-
(2-propenyl)-1-imigzoliomethyl]-3-
Cephem-4-carboxylate (68,4111g)
I got it.

NMRδ ppm (DMS OcL): 3.6
5 (2H, m), 4.57 (2■, UkeL 4.82 (
211, m).

5.01-5.5 (7H, m), 5.55-6.35
(3H, +a).

6.83(IHr!i)t 7,17(211*s)*
7,63(2Htm)+9.23(IH,s),9.
35 (IH, d, J = 8,0 Hz) Example 8 According to Example 4, 7-[2-(2-propenylokiniami/)-2-(2-)ditylami/thiazole-4-
yl) acetamido-3-iodomethyl-3-cephem-1-oxide-4-carboxylic acid p-methoxybennorester (syn isomer) (0.5 g) and 1-benzylimigzole (94.8 mg), 7-(2-(2
-propenyloxyimino>-2-(2-)ditylamido/thiazol-4-yl)acetamide)-3-(3-
Benzyl-1-imigzoliomethyl)-3-cephem-
1-Oxido-4-carboxylic acid p-nodoxybenzyl ester yogate (syn isomer) (418,3n+g
) was obtained.

NMRδ ppm (DMS Oda): 3.6
5 (2H, m), 3.28 (38, s), 4.56
(2)1. n+).

4.97 (IH, m), 5.01-5.60 (8H, m
).

5.51-6.30 (2H, +m), 6.80 (IH
, s), 7.12 (4H, n+).

7.32 (15H, s), 7.43 (5H, s),
7.62 (IH, s).

7.73 (IH, s), 8.73 (LH, s), 8.9
1 (IH, l11).

9.40 (IH, s) Example 9 According to Example 5.6 and V7, ? -(2-(2-probenyloximi/)-2-(2-)ditylami/thiazol-4-yl)acetamide]-3-(3-benzyl-1-imigzoliomethyl)-3-cephem -1-oxide-4-carboxylic acid p-methoxybenzyl ester
7 from Yogate (syn isomer) (408,3tng)
-(2-(2-7minoti7zol-4-yl)-2-(
2-propenylokinea) ≧ ノ) MaJ*L'?
:le)Q/M-,.

1-Imigzoliomethyl)-3-cephem-4-carboxylate (syn isomer) (37.2mlr) was obtained.

NMR6ppm (DMSO-d6): 3.47 (2
t(-m), 4.68 (2fltIIIL 4.80-
5.50 (5f1.n).

5.41(2)1. s), 5.60-6.23 (21
(, l11), 6.93(1)1. s).

7.37(51(,s), 7.67(2FItm)y
9.23(1)1. s) Example 10 ↑ According to Example 4, 7-[2-(2-probenyloximi/)-2-(2-)ditylamide/thiazole-4-
yl) acetamido-3-iodomethyl-3-cephem-1-oxyto-4-carboxylic acid p-methoxybennorester (syn isomer) (0.5 g) and 1 ter
j-1 Toxicitylupomethyl imiguzole (109,2m
Fi), from Methyl)-3-cephem-1
-Oxido-4-carboxylic acid p-methoxybennorester yogate (syn isomer) (447.4 mg) was obtained.

NMRδ ppm (DMS〇-d6): 2.97 (
911,s), 3.63(211,+n), 3.7
8 (3H, s).

4.07 (211, m), 4.86 (2H, s),
4.91-5.54 (7H, m).

5.70-6.35(2)1. m), 6.81(II
I, s), 7.17 (4H, m).

7.37 (15H, s), 7.22 (2H, m),
8.74 (ill, s).

8.83 (18, m), 9.12 (Iff, s) Example 11 According to Examples 5.6 and 7, 7-[2-(2-propenyloximi/)-2-(2- ) lytylaminothiazol-4-yl)acetamide]-3-(3-Lert
-butoxycarbomethyl-1-imigzoliomethyl)-
3-cephem-4-carboxylic acid p-methoxybenzyl ester Yogui V (syn isomer) (425.9 mg)
from, 7-(2-(2-ami/thiazol-4-yl)
-2-(2-probenyloxyimi7)acetamide)
-3-(3-carboxymethyl-1-imigzoliomethyl)-3-se7em-4-carboxylate (syn isomer) (50,3a+g) was obtained.

NMRδ ppm (DMS Oda): 3.5
0 (2tl, m), 4.70 (2H1m), 4.9
5-5.61 (7H, m) 15.67-6.41 (2H
,+o), 8.98(ill,s), 7.74(2
H,s).

9.21 (IH,s) Example 12 According to Example 4, 7-(2-(2-propenyloxyimino)-2-(2-)lythyl 7mi/thiazole-4-
yl) acetamido-3-iodomethyl-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl ester (syn isomer) (0.5 g) and 1-vinylimiguzole (57 μm), ? -(2-(2-probenyloximi/)-2-(2-)lythyl 7mi/thiazol-4-yl)acetamide) -3-(3-vinyl-1-imigzoliomethyl)-3- Cephem-1-oxy-4-carboxylic acid ρ dimethoxybenzyl yogate (syn isomer) (380 mg) was obtained.

NMRδ ppm (DMS Odi): 3.7
5 (2H1m), 3.80 (311,s), 4.60
(21(9m)-4,85-5,47(9tl,m),
7.32 (15 tl, s), 7.66 (21 (
, +n).

8.74 (ltl, s), 8.94 (18,+++
), 9.06(]tl,s) Example 13 According to Examples 5.6 and 7, 7-,[2-(2-probenyloximi/)-2-(2-)lythylamide 7 From ρ-methoxybenzyl yogate (syn isomer) (350 Ing) ,7-(2-(
2-Amino7thiazol-4-yl)-2-(2-probenyloxyimi7)acetamide)-3-(3-vinyl-1-imigzoliomethyl)-3-cephem-4-carboxylate (sin isomer) (29 mg) was obtained.

NMRδ nnn+ (DMSO-a,): 3
．． 75 (2H, +n), 4.60 (2H, m),
4.80-5.47 (9H, +n).

6.78 (IH, s), 6.83 (2H, s),
7.17 (2H, s).

9.23 (III, s), 9.35 (IH, d, J
=8,0llz) Example 14 ↑ According to Example 4, 7-(2-(2-propenyloxyimino)-2-(2-)ritylami7thiazole-4-
yl)acetamide]-3-iodomethyl~3-cephem-1-oxide-4-carboxylic acid p-methoxybennorester (syn isomer) (0,5!?) and 4-imiguzoleacet7-7-( 100 μm) to 7-(2
-(2-propenyloxyimino)-2-(2-tritylami7thiazol-4-yl)acetamide) -3
-(3-7setophenyl-1-imigzoliomethyl)-
3-cephem-1-oxide-4-carboxylic acid p-methoxybennor yogate (syn isomer) (330+n
g) was obtained.

NMRδ ppm (DMS Oda): 3.8
0 (3H, s), 3.75 (21'l, m), 4.
50 (211, m).

4.56 (2H, m), 5.0 (2H, +n), 5
．． 15 (4H, +n).

6.60 (IH, s), 7.32 (18tl, m).

9.30 (1t1.d, J = 8.0Hz) Example 15 According to Examples 5.6 and 7, 7-(2-(2-probenyloximi/)-2-(2-) dithylaminothiazol-4-yl)acetamide]-3-(3-acetophenyl-1-imigzoliomethyl)-3-cephem-1
-oxido-4-carboxylic acid p-methoxybenzyl yogate (syn isomer) (310n+g) to 7-(
2-(2-ami/thiazol-4-yl)-2-(2-
propenyloxyimino)acetamide]-3-(3-
aceto7en2/l, -1-imigzoliomethyl)-3-
6HMRδ ppm (DM S Ods) obtained (cephem-4-carboxylene) (53 mg): 3.
75 (211, +++), 4.50 (2!H, n+)
, 5.0 (2H, w).

5.50 (ill, m), 6.65 (IH, s), 7
．． 0 (2H9s).

9.06 (IH, d, J = 8.0 Hz) Example 16 According to Example 4, 7-(2-(2-propenyloxyimino)-2-(2-)ditylaminothiazole-4-
yl)acetamide]-3-iodomethyl-3-cephem-1-oxyto-4-carboxylic acid p-methoxybennorester (synte form) (0.5 g) and 4-imiguzoleacetate (88 μm) ) and from? -[:2-
(2-propenyloximi/)-2-(2-)ditylamifthiazol-4-yl9acetamide)-3-1
:3-(4-hydroxyphenyl)-1-imigzoliomethyl]-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl iodite C syn isomer (
310 mg) was obtained.

NMRδ 1) III (DMSO-d,i)
:3.80(3H,s), 3.75(2)1. m),
4.50(2)1. +n).

4.56 (2H, +++), 5.75-6.10 (4
11, m).

7.0-7.32 (1711, +n), 9.20 (i
ff, d, J = 8.0 flz) Example 17 According to Examples 5.6 and 7, 7-(2-(2-propenyloxyimino)-2-(2-tritylami/thiazol-4-yl) Acetamide]-3-C3-(4-hydroxyphenyl)-1-imigzoliomethyl]-3-
Cephem-1-oxide-4-carboxylic acid p-methoxybenzyl yogate (syn isomer) (290+ng)
Gara7-(2-(2-7mi/thiazol-4-yl)-
2-(2-probenyloxyimi7)acetamide)-
3-(3-(4-hydroxyphenyl)-1-imigzoliomethyl]-3-cephem-4-carboxylate (
Syn isomer) (53+ng) was obtained.

NMRδ ppm (DMSO-d6): 3.75 (
2H, +n), 4.50 (2H, +n), 4.56
(2H, m).

5.75-6.10 (41 (, m), 7.2 (611
, m).

9.20 (1,1!, dtJ=8,0Hz) Example 1
8 According to Example 4, ? -(2-(2-probenyloxyimi/)-2-(2-)ditylaminothiazole-4
-yl) acetamido-3-iodomethyl-3-cephem-1-oxyto-4-carboxylic acid p-methoxybenzyl ester (syn isomer) (0.5 g) and 1-provinylimigzole (58 μI). ,? −[2−(2
-propenyloxyimino)-2-(2-)lytylaminothiazol-4-yl)acetamide]-3-(3-
(2-propynyl)-1-imigzoliomethyl]-3-
Cephem-1-oxide-4-carboxylic acid p-methoxybenzyl yogate (syn isomer) (325 mg) was obtained.

NMRδ pp spear (DMSOds): 3.9-4.4
(Z)l,m), 4.6(2H,s).

4.85(1)1. d, J=5.0tlz), 5.
45 (IH, ship).

6.72(LH,s)=7.25(15H,5)t
9.45 (IH, +J, J=8.0Hz) Example 19 According to Examples 5.6 and 7, ? -(2-(2-propenyloximi/)-2-(2-)lythylami7thiazol-4-yl)acetamide]-3-[3-(2-propynyl)-1-imidazoliomethyl]-3-cephem From -1-oxide-4-carboxylic acid p-methoxybenzyl ioguide (syn isomer) (315ωg), 7-[
2-(2-7minothiazole-4-i/?)-2-(2
-7'robenyloximi/)acetamide)-3-(
3-(2-propynyl)-1-imigzoliomethyl]-
3-cephem-4-carboxylate (38u+g
) was obtained.

NMRδ pp signal (DMSO-d,): 3.9
-4.4 (211tm), 4.6 (2H, s).

4.85 (IH, d, J = 5,0 Hz), 5.45 (
ltl, l11)-8,72(IH,s), 7.10
(2H,s), 9.45(1)1. d, J'=8,0
Hz) Example 20 ↑ According to Example 4, 7-f"2-(2-probenyloximi/)-2-(2-)lythylamide/thiazol-4-yl)7cetamide]-3- 7-[2-(2-propylene) Benyloxyimi/)-2-(2-tritylaminothiazole)acetamide]-3-(3-(2-butenyl)
-1-Imidazoliomethylcou-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl yogate (syn isomer) (365 mg) was obtained.

NMRδppm (DMS Odg): 1.7
(3H, d, J=6.0), 3.9-4.4 (28,
m).

4.6 (2H, s), 4.85 (LH, d, J=5.
0Hz) + 5.45 (IH, n+).

6.72 (IH, s), 7.25 (15H, 5) = 9
．． 45 (IH, d, J = 8,0 Hz) Example 21 According to Examples 5.6 and 7, 7-(2-(2-propenyloxyimino)-2-(2-)rithylaminothiazole)acetamide )-3-(3-(2-butenyl)-
7-(2-(2-aminothiazol-4-yl)-2-(2 -probenyloximi/)acetamide]-3-[3-(2-butenyl-1-
Imigzoliomethyl]-3-cephem-4-carboxylate (syn isomer) (57 mg) was obtained.

NMRδ ppm (DMS〇-d6): 1.7 (3
H, d, J=6.0), 3.9-4.4 (211, 餉).

4.6 (2tl, s), 4.85 (Ill, d, J=
5. '0Hz), 5.45 (IH, m).

6.73 (IH, s), 7.10 (2H, s), 9
．． 45(ill, d, J=8.0)1z) Example 22 ↑ According to Example 4, 7-(2-(2-propenyloxyimino)-2-(2-)rithylaminothiazole-4-
yl) acetamido]-3-iodomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (syn isomer) (0.5 g),! -1-(3-butenyl)imidazole (68μI) and 7-(2-(2-propenyloxyimino)-2-(2-tritylami7thiazole)acetamide]-3-(3-(3-butenyl) -1-imigzoliomethyl]-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl yogate (syn isomer) (353 mg) was obtained.

NMRδ ppIII (DMS OdB): 2.2
8 (2H, m) = 3.85 (2H, m), 4.6 (
2H,s).

4.85 (10, d, J = 5.0 Hz), 5.45 (I
H, theory).

6.76 (IH, s), 7.25 (15H, s).

9.20 (ill, cl, J=8.0Hz) Example 23 According to Examples 5.6 and 7, ? -(2-(2-propenyloxyimino)-2-(2-)lythylami/thiazol-4-yl)acetamide]-3-(3-(3-butenyl)-1-imigzoliomethyl)-3-cephem −
p-methoxybenzyl 1-oxide-4-carboxylate
From Yogate (syn isomer) (348 mg), 7-(
2-(2aminothiazol-4-yl)-2-(2-propenyloxyimino)acetamide)-3-[3-(
3-Butenyl-1-imigzoliomethyl]-3-cephem-4-carboxylate (syn isomer) (51 mg)
I got it.

NMRδ ρpa+ (D M S Ods): 2.
28 (2H, l11), 3.85 (2H, +m), 4
．． 6 (2H, s).

4.85 (IH, d, J=5.01lz), 5.45
(IH, a+).

6.76 (IH, s), 7.01 (2H-s), 9
．． 20 (IH, d, J=8.0Hz) Example 24 According to Example 4, ? -[2-(2-probenyloxyimi/)-2-(2-)ditylaminothiazole-4-
yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylic acid p-methoxybennorester (synthetic form) (0.5g) 1-(3,4,4,)refluoro-3 -butenyl)imidazole (100 μm), ? -(2-(2-propenyloxyimino)-2
-(2-)ditylaminothiazol-4-yl)acetamide)-3-(3-3,4,4,-trifluoro-3
-butenyl)-1-imigzoliomethyl]-3-cephem-1-oxide-4-carboxylic acid p-methoxybennol yogate (syn isomer) (213 mg) was obtained.

NMRδ pp theory (DMSO-d,):
2.7-3.0 (21, m), 4.0 (211, m
), 4.6 (211,≦).

4.85 (LH, d, J=5,0Hz), 5.45
(ltl, a+).

6.70(11(,S), 7.30<1514.S
)? 9.30 (IH, d, J”8,0 Hz) Example 25 According to Examples 5.6 and 7, 7-(2-(2-probenyloximi/)-2-(2-) dithylaminothiazol-4-yl)acetamide]-3-(3-3,4,
4,-)Lifluoro-3-butenyl)imigzoliomethyl]-3-cephem-1-oxyto-4-carboxylic acid p
-Methoxybenzyl yogate (syn isomer) (20
0τll[l) to 7-[: 2-(2-7thiazol-4-yl)-2-(2-propenyloxyimino)acetamide]-3-[3-(3,4,4,-) [Lifluoro-3-butenyl)-1-imigzoliomethyl]
-3-cephem-4-carboxylate (syn isomer)
(21+eg) was obtained.

NMRδ ppm (DMSO-ds): 2.
7-3.0 (Zl(, m), 4.0 (2 old theory L
4.6(Zl(,5)−4,85(IH+dtJ=5,
0Hz) t 5.45 (IH, m).

6.70 (18, s), 7.10 (2H, 5) = 9.
32 (18, d, J=8,0FIz) Example 26 ↑ According to Example 4? -(2-(2-probenyloxyimi/)-2-(2-)lytylaminothiazole-4-
yl)acetamide]-3-iodomethyl-3-cephem-4-carvone fllp-methoxybenzyl ester (syn isomer) (0,5g>,!-1-methyl imiguzole (50 μm) to 7-(2- (2-7”robenyloxyimi/)-2-(2-)ditylaminothiazol-4-yl)acetamide]-3-(3-methyl-1-
imigzoliomethyl)-3-cephem-1-xyto-
4-carboxylic acid p-methoxybenzyl ester yogate (syn isomer) (336τllg) was obtained.

NMRδ ppm (DM S Od@L”3.
65 (211, m) t 3.73 (3H, s), 3.
85 (3 Fl, s).

4.64 (2H, m), 4.97 (ill, m),
5.0-5.50 (6 tl, m).

5.6-6.40(Zl(,m), 6.92(18,
s), 7.07 (4H, m).

7.31 (1511, s), 7.60 (2H, m),
8.80 (II, s) Example 27 According to Examples 5.6 and 7, 7-(2-(2-probenyloximi/)-2-(2-t')!-ruamino thiazol-4-yl)7cetamido]-3-(3-methyl-1-imigzoliomethyl)-3-3-cephem-
From 1-oxide-4-carboxylic acid p-methoxybennorester yogate (syn isomer) (300 mH) to
-(2-7'ropenyloxyimi/)acetamide]-
3-(3-Methyl-1-imigzoliomethyl)-3-cephem-4-carboxylate (syn isomer) (25,
IB) was obtained.

NMRδ ppa+ (D M S Ods): 3.
48 (2H, m), 3.85 (3H, s), 4.17
(2H, s).

4.90-5.50 (5H, 饋)t 5.86 (IHv
m) y5.70-6.40 (IH, m) - 7,65 (211, s), 9.10 (IH, s) Example 28 ↑ According to Example 4? -(2-(2-probenyloxyimi/)-2-(2-)lythylami7thiazole-4-
7 from acetamido-3-iodomethyl-3-cephem-1-oxyto-4-carboxylic acid p-methoxybenzyl ester (syn isomer) (0.5 g) and 1-butylimigzole (63 μm). -(2-(2-7"
lobenyloxyimino)-2-(2-)ditylaminothiazol-4-yl)acetamide)-3-(3-butyl-1-imigzoliomethyl)-3-cephem-1-
Oxide-4-carboxylic acid p-methoxybenzyl ester yogate (syn isomer) (310 mg) was obtained.

NMRδ pp theory (DMS Odi): 1.40
(9H, s), 1.8-2.11 (4FI, a+),
3.68 (3H, s).

4.8 (2O2m) + 5.1~5.6 (4H, m)
, 5.80 (IH, theory).

6.68 (IH, s), 7.25 (151 (, s),
9.4 (IHtdtJ=8,0Hz) Example 29 According to Examples 5.6 and 7, 7-(2-(2-flobenyloxyimino)-2-(2-)ditylaminothiazole-4 -yl)acetamide]-3-(3-butyl-
1-imidazoliomethyl)-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl ester from 7-(2
-(2-7minothiazol-4-yl)-2-(2-probenyloxyimi7)acetamide)-3-(3-butyl-1-imigzoliomethyl)-3-cephem-4-
(21 mg) was obtained.

NMRδppn (DMS Od6): 1.4
0 (9tl, s), 1.6-2.11 (4Lm),
3.68 (3H, s).

4.8 (211,111), 5.1-5.6 (411
tm)t 5.80 (Ill, m).

6.68 (LH, s), 7.10 (2H, s) = 9
．． 4 (IH, d, J = 8.0 Hz) Example 30 ↑ According to Example 4, 7-(2-(2-propenyloxyimino)-2-(2-)rityl 7-minothiazole-4-
yl) acetamido-3-iodomethyl-3-cephem-1-oxide-4-carboxylic acid ρ-methoxypencyl ester (syn isomer) (0.5 g) and 1-7 cetyl imiguzole (50 μl). -(2-(2-propenyloxyimino)-2-(2-)ditylaminothiazol-4-yl)acetamide) -3-(3-7
cetyl-1-imidazoliomethyl)-3-cephem-1
-Oxido-4-carboxylic acid p-methoxybenzyl ester yogate (syn isomer) (302 mg) was obtained.

NMRδ ppm (D M S○-d, -T F
A-d): 1.90 (3H9s), 3.5-3.
8 (211, l11), 4.8 (2H, m) t5.
1-5.6 (4H, m), 5.80 (IH, +a)
, 7.0 (III, sL7.25 (15H, s) Example 31 According to Examples 5.6 and 7, ?-[2-(2-Flobenyloxyimino)-2-(2-) Lythylamide/thiazol-4-yl)acetamide]-3-(3-7cetyl-1-imigzoliomethyl)-3-cephem-1-oxide-4-carboxylic acid p-methoxybennorester.
Iodite (syn isomer) (290B> to 7-(2
-(2-aminothiazol-4-yl)-2-(2-propenyloxyimino)acetamide)-3-(3-7
Cetyl-1-imigzoliomethyl-3-cephem-4-
Carboxylate (syn isomer) (24 mg) is obtained.

NMRδ ppm (DMSO-d@): 1.
90 (311, s), 3.5-3.8 (211, m)
, 4.8(211,+n).

5.1-5.6 (211, +n), 5.80 (IH,
m), 6.69 (IH, s).

7.20 (2H, s) t 9.4 (IH, d, J=8,
0llz) Example 32 ↑ According to Example 4, 7-[2-methoxyimino-2-(
2-) dithylaminothiazol-4-yl)acetamido-3-iodomethyl-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl ester (syn isomer) (0,6 g) and 1-(2- From propenylnoimidazole (79 mg), 7-[2-methoxyimino-2-(2-)ditylaminothiazol-4-yl)
Acetamide]-3-(3-(2-propenyl)-1-
imigzoliomethyl]-3-cephem-1-xyto-
4-carboxylic acid p-methoxybenzyl ester yogate (syn isomer) (390 mg) was obtained.

NMRδ ppm (CD CI: l): 3.7
7 (38, s), 4.0 (3H, s), 4.95 (
IH, d, J = 4Hz).

5.6-6.5 (2H, m), 6.65 (IH, 5)
−6,7−7,5(19FI,+)t 7,7(1[1
,s)-9,7(LH,s) Example 33 According to Examples 5.6 and 7, 7-(2-methoxyimino-2-(2-tritylaminothiazol-4-yl)
acetamido)-3-(3-(2-propenyl)-1-
imigzoliomethyl)-3-cephem-1-oxide-
From 4-carboxylic acid p-methoxybennorester yogate (syn isomer) (320B), ? −[2−(2
-aminothiazol-4-yl)-2-methoxyiminoacetamide)-3-(3-(2-propenyl)-1-
Imigzoliomethyl]-3-cephem-4-carboxylate (syn isomer) (26 mg) was obtained.

NMRδ ppIII (DMSO-ds): 3.
80 (38, s>, 4.48-8.25 (m8H),
6.65 (Ill, s).

7.1(2H,s)t 7.6(IH,s), 7.9
5 (IH, s).

9.25 (IH, s), 9.4 (Iff, d, J=8
,0Hz) Example 34 ↑ According to Example 4, ? -(2-(2-propenyloxyimino)-2-(2-)lytylaminothiazole-4-
7-(2-(2 -propenyloxyimino)-2-(2-tritylami/thiazol-4-yl)acetamide) -3-(1-imidazoliomethyl)-3-cephem-1-oxide-4-fj
Rubonic acid p-z toxybenzyl ester yogate (
Syn isomer) (250 mg) was obtained.

NMRδ ppm (DMS Ods): 3.8
0(3H,s), 4.95(IHtd, J=4.0I
(z).

5.50 (IH, n+), 6.70 (18, s),
6.80-7.75(20H,m)-9,40(IH,
d, J = 6.0 Hz) Example 35 According to Examples 5.6 and 7, 7-(2-(2-propenyloxyimino)-2-(2-)ditylaminothiazol-4-yl)acetamide 7-(2-(2- 7mi/thiazol-4-yl)-2-(2-probenyloxyimi7)acetamide) -3-(1-imigzoliomethyl)-3-cephem-4-carboxylate (syn isomer) ( 19+ag) was obtained.

NMRe pp Juku (DMS O-d,): 3.
80 (3H, s) t 4.95 (IH, d, J=4.0
Hz).

5.50 (IH, +++), 6.70 (18,s),
7.5(IH,5)-7,30(IH,s), 7.
70(LH,s)v 9.4(IH,d,J=6.0H
z) Example 36 ↑ According to Example 4, 7-[2-methoxyimi/-2-(
2-) dithylaminothiazol-4-yl)acetamide]-3-iodomethyl-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl ester (syn isomer) (0.6 g) and 1-brovinyl imiguzol (
88 mg) and 7-[2-methoxyimi/-2-(
2-) dithylaminothiazol-4-yl)7cetamido)-3-(3-(2-propynyl)-1-imigzoliomethyl)-3-cephem-1-oxyto-4-carboxylic acid p-methoxy Bennoresterne isomer) (330 mg) was obtained.

NMR δ ppn+ (C D C I *): 2
, 75 (IH, m), 3.75 (311, s), 4
．． 0(3H,s)-4,75(IH,d,J=3,OH
z), 4.8-5.5(6)1,m).

6, 0- 6.3 (IH-m), 6.70 (IHts)
+6, 8-7.75 (2011, n+), 9.8 (I
H,s) Example 37 According to Examples 5, 6 and 7, 7-[2-methoxyimi/-2-(2-)ditylaminothiazol-4-yl)
7cetamido]-3-(3-(2-propynyl)-1-
imigzoliomethyl]-3-cephem-1-oxide-
4-Carboxylic acid p-methoxybenzyl ester (syn isomer) (300II1g) from 7-(2-(2-7minothiazol-4-yl)-2-methoxyiminoacetamide]-3-[3-(2- Propynyl)-1-imigzoliomethyl]-3-cephem-4-carboxylate (syn isomer) (52 mg) was obtained.

NMR δ ppm (DMSO ds)
:3,80(3H,s), 4.75-5.25(5H
, m), 5.5 (IH, +6).

6, 65 (ILs), 7.1 (20,s), 7.6
5 (III, s).

7,95(ill,s), 9.35(IH,d,J=
8.0Hz), 9.45 (dish, s) Example 38 ↑ According to Example 4, 7-[2-methoxyimino-2-(
2-) Lithylaminothiazol-4-yl)acetamido-3-iodomethyl-3-cephem-1-oxide-4-carboxylic acid p-nodoxybennorester (syn isomer) (0,54 g) and 1-butylic acid Migzol (8
0mg) to 7-(2-methoxyimino-2-(2
-) dithylamide/thiazol-4-yl)acetamide) -3-(3-butyl-1-imidazoliomethyl)-
3-cephem-1-oxide-4-carboxylic acid p-methoxybennorester yogate (syn!L form)
(365 mg) was obtained.

NMRδ ppm (DMS Oda): 3.8
(3)1ts), 4.0(3I,s), 8.2
(IH, +n) t6.7 (111, s).

6.8-7.5 (19 fl, m), 7.75 (IH
,s), 9.7(ltl,s>Example 39 According to Examples 5.6 and 7, 7-[2-methoxyimino-2-(2-)lytylaminothiazol-4-yl)
From (acetamide)-3-(3-butyl-1-imidazoliomethyl)-3-cephem-1-oxyto-4-carboxylic acid p-methoxybenzyl ester yogate (syn isomer) (350n+g), 7-[ 2-aminothiazol-4-yl)-2-methoxyiminoacetamide)
-3-(3-butyl-1-imidazoliomethyl)-3
-cephem-4-carboxylate (syn isomer>(6
0g> was obtained.

NMRδ ppm (D M S Od6): 0.7
8-1.8 (9H, m), 3.75 (3H, 5)t
4.95 (IHtd, J = 4.0Hz>, 5.50 (I
t(,m).

6.70(1)1-s)-7,10(2Hts)*
7.70(Itlws)-8,0(1)1. s>, 9.
25 (IH, s), 9.4 (IH, d, J = 8,0Hz
) Example 40 ↑ According to Example 4, 7-[2-methoxyimino-2-(
2-tritylamide/thiazol-4-yl)acetamido-3-iodomethyl-3-cephem-1-oxyto-4-carboxylic acid ρ-methoxybendi/thiazol-4-yl)
(1,37g) and 1-methylimigusol (120μm
) to 7-[2-methoxyimino-2-(2-)lythylimiguzol-4-yl)acetamide]-3-(
3-Butyl-1-imigzoliomethyl)-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl ester yogate (syn isomer) (6501I+g
) was obtained.

NMRδ ppm (DMSO-d6): 3.
74(3H*s)-3,80(3■tsL 3,82(
311, s).

4.95 (IHtd, J=4,01(z), 5.75
(ill, m), 6.75(1)1. s) Example 41 According to Examples 5.6 and 7, 7-[2-methoxyimi/-2-(2-tritylamide/thiazole-
4-yl)acetamido]-3-(3-methyl-1-imigzoliomethyl)-3-cephem-1-xyto-4
- From carboxylic acid p-methoxybenzyl ester yogate (syn isomer) (600 mg)? -(2-(2
-7minothiazol=4-yl)-2-methoxyiminoacetamide]-3-(3-methyl-1-imigzoliomethyl)-3-cephem-4-carboxylate (42
g) was obtained.

NMRδ ppm (DMS Ods): 3.8
(3tl, s) = 5.0(ill, d, J = 4.0H
z), 5.6 (18, m).

6.7<1)1. s), 7.2(2H,s), 7.
7 (S, l1l), 7.9 (ILs).

9.2 (IH, s), 9.4 (III, d, J=8.
0IIz) Example 42 ↑ According to Example 4, 7-[2-methoxyimino-2-(
7- 2-methoxyimino-2-(2-tritylimidazol-4-yl)
acetamido]-3-(1-imidazo1nobutyl)-
3-cephem-1-oxide-4-carboxylic acid p-methoxypencyl ester yogate (syn isomer) (3
31 mg> was obtained.

NMRδ ppm (DMSO-ds): 3.80 (
3H, s), 4.95 (LH, d, J=4,0tlz
).

5.50 (IH, Ill>, 6.70 (ltl, s)
, 7.25 (15H, s).

7.30(IHws>, 7.70(111-s)-9,
4(ill, d+J=6.oIIz) Example 43 According to Examples 5.6 and 7, 7-[2-methoxyimino-2-(2-)lythylami7thiazol-4-yl)
Acetamide] -3-(1-imigzoliomethyl)-
3-cephem-1-oxyto-4-carboxylic acid p-methoxybenzyl ester yogate (syn isomer) (
320 mg) to 7-[2-7minothiazole-4-
yl)-2-methoxyiminoacetamide]-3-(1
-imidazoliomethyl)-3-cephem-4-carboxylate (syn isomer) (38 mg) was obtained.

NMRδ ppLl (DMS Oda): 3.80
(3H=s), 4.95 (111-d*J= 4,0H
z)t5.50(IH,m), 6.70(11(,s
), 6.80 (2■, S).

7.15 (IH, s), 7.30 (18, s),
7.70 (ift, s).

9.4 (1B, d, J=6,01lz) Example 44 ↑ 7- (2-(2-tert-butoxycarbonyl)prop-2-oximino-2-(2-)lytylaminothiazol-4-yl ) Acetamide]-3-iodomethyl-3-cephem-1-oxide-4-carboxylic acid p-
Methoxybennorester (syn isomer) (0.6g)
A solution of 1-(2-propenyl) dissolved in THF (5 ml) and chloroform (2.5 ml) was cooled to 0°C.
After adding imidazole (70 mg), warm and stir at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was powdered with diethyl ether (50 ml), and eluted with a silica sol column (chloroform dimethane, volume ratio 8:1) to give 7-(2-( 2-tert-butoxycarbonyl)prop-2-oximino-2-(2-)ditylamido/thiazol-4-yl)acetamide) -3-(
3-(2-propenyl)-1-imigzoliomethyl]-
3-cephem-1-oxyto-4-carboxylic acid p-methoxybennorester iodine (syn isomer) (4
12.2 mg) was obtained.

NMRδ ppm (DMSO-d6): 1.36 (
15H,s), 3.75(2L+n), 3.79(
3H,s).

4.83 (2H, Sho), 5.00 (IH, Sho L 5.
07-5.53 (6H, 111).

5.75-5.95 (2H-m), 6,73 (1) 1.
s), 7.18 (4H1m)? 7.23 (15H, s)
, 7.70 (211, m), 8.75 (Ill
, s).

9.23(1flta+)t 9,42(IH,s)
Example 45 According to Examples 5 and 6, 7-(2-(2-tert-
butoxycarbonyl)prop-2-oximino-2-
p-Methoxybenzyl (2-)ditylamide/thiazol-4-yl)acetamide)-3-(3-(2-propenyl)-1-imigzoliomethyl]-3-cephem-1-oxide-4-carboxylate From ester yogate (syn isomer) (400 mg), 7-(2-(2-7mi/thiazol-4-yl)-2-(2-Lert-butoxycarbonyl)prop-2-oxyiminoacetamide]- 3-[3-(2-propenyl-1-imigzoliomethyl]-3-cephem-4-carboxylic acid I]-methoxybenzyl ester yogate (syn isomer) (2
30 "fig)" was obtained.

NMRδ ppm (DMS Ods): 1.3
7 (9H, s), 1.49 (3H, s), 1.52
(311, s).

3.50 (2Hts), 3.76 (311, sL 4.
82 (2H++n).

4.90-5.52 (7H, aa), 5.72-6.
31 (211, m).

6.69 (IH, s>, 7.13 (48, +a),
7.22 (2H, 5) t7.66 (2H, m), 9.
21 (IH, s), 9.30 (IH, m) Example 46? -(2-(2-7minothiazol-4-yl)-2-
(2-tert-butoxycarbonyl)prop-2-oxyiminoacetamide)-3-(3-(2-propenyl-1-imigzoliomethyl)-3-cephem-4-carboxylic acid p-methoxybenzyl yogate ( Synisomer) (220 mg) was dissolved in methylene chloride (3 nl) and 7-nisole (2,2 ml), and fluoroacetic acid (3,1a+1) was added dropwise while cooling at 0°C.

After stirring at 0°C for 2 hours and then at 10°C for 4 hours, the solvent was distilled off under reduced pressure, and diethyl ether (50ml) was added to the residue to powder it, which was taken in the mouth and then neutralized with an aqueous potassium hydrogen carbonate solution. A yellow powder was obtained by freeze-drying. This was eluted with Sephadex LH-20 (meth/-l) to give a white powder of 7=+2-(2-7mi/thiazol-4-yl)-2-[potassium(2,2-dimethylacetate)]. ) Oxyiminoacetamide 1-3-[3-(2
-propenyl-1-imigzoliomethyl]-3-cephem-4-carboxylate (syn isomer) (53,2m
g) was obtained.

NMRδ ppm (DMSO-cl,): 1
．． 38 (3H, s), 1.43 (3H, s),
3.50 (2H, s).

4.83 (2tl, m), 4.91-5.60 (5
H,m)-5,75-6,37(2H,m), 6.
68 (IH, s) - 7,07 (2H, s).

7.58(IHts)t 7,48(IH,s),
9.46 (IH, s).

12.13 (IH, m) Example 47 ↑ According to Example 44? -(2-(2tert-butoxycarbonyl)prop-2-oximi/-2-(2
-)Ritylami7thiazol-4-yl)acetamide]-3-iodomethyl-3-cephem-1-xyto-
7-[2-(2tert-butoxycarbonyl)prop-2-oximi/-2- (2
-1 lytylami7thiazol-4-yl)acetamide)-3-(3-acetophenyl-1-imigzoliomethyl)-3-cephem-1-oxide-4-carboxylic acid p
-Methoxybenzyl ester φyogate (syn isomer) (340+ag) was obtained.

NMRl ppm (DMSOd6): 1.36 (
15H, s), 3.75 (2H, ai), 3.60
(3H, s).

4.83 (2H, m), 6.73 (LH, s), 7
．． 18(4H,m)-7,25(15H=s)-9,4
2 (IH, d, J = 8,0 Hz) Example 48 According to Examples 45 and 46, 7-(2-(2-ter
t-butoxycarbonyl)prop-2-oximi/-
2-(2-)ditylaminothiazol-4-yl)acetamide) -3-(3-acetophenyl-1-imigzoliomethyl)-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl ester・Yogate (
syn isomer) (330+ag), 7-12-(2-
aminothiazol-4-yl)-2-C potassium (2,
2-methylacetate)oxyimino]acetamide 1-3-(3-7cetophenyl-1-imigzoliomethyl)-3-cephem-4-carboxylate (syn isomer) (53+++ g) was obtained.

NMRδ ppo+ (D M S Od6): 3.
80 (3H, s) t 4.83 (2H, +*), 6.
69 (IH, s).

7.13 (2H, s), 7.66 (211, m),
9.30 (IH, d, J = 8,0 Hz) Example 49 According to Example 44, 7-(2-(2-tert-butoxycarbonyl)prop-2-oximino-2-(2
-) dithylaminothiazol-4-yl)acetamide]-3-iodomethyl-3-cephem-1-oxide-
4-Carboxylic acid p-methoxypencyl ester (syn isomer) (0.6 g) and 1-butylimigzole (80B
) from 7-(2-(2-tert-butoxycarbonyl)prop-2-oximino-2-(2-)lytylaminothi7zol-4-yl)acetamide) -3-
(3-Butyl-1-imigzoliomethyl)-3-cephem-1-oxide-4-carboxylic acid p-methoxybennorester yogate (syn isomer) (410+ag
) was obtained.

NMRδ ppm (CDCl2): 0.97 (3H
, m), 1.40 (9fl, s), 1.53 (6H
,s).

1.6-2.11 (411, m), 3.68 (3H
,s), 4.00(2H,s).

4.13 (2tl, ai), 4.97 (IH, d)
, 5.21(2H,5)-5,48(211,m)
, 6.22 (IH, ai), 6.52 (ltl, s
).

7.13 (48, m), 7.25 (15H, s),
7.26 (II, s).

9.72 (IH, s) Example 50 H3 According to Examples 45 and 46, 7-(2-(2-ter
L-butoxycarbonyl)prop-2-oximi/-
2-(2-)ditylaminothiazol-4-yl)acetamido)-3-(3-butyl-1-imigzoliomethyl)-3-cephem-1-oxide-4-carboxylic acid ρ
-Methoxybenzyl ester yogate (syn isomer) (385 mg>), 7-(2-(2-ami/thiazol-4-yl)-2-[potassium(2,2-methylacetate)oximi7]acetamide l-3-(3
-butyl-1-imigzoliomethyl)-3-cephem-
4-carboxylate (syn isomer) (51 mg) was obtained.

NMRδppm (DMS Odg): 0.8
5 (3H, m), 1.36 (3Hts), 1.40
(3H, s).

3.46 (・2tl, s), 4.12 (21, a+)
, 5.67 (111, m) - 6,64 (IH, s),
7.10 (2H, s), 7.64 (1j'14sL
-7,9(1)1ts)t 9,46(18
,s)t 11.95 (IH911) Example 51 ↑ According to Example 44, ? -(2-(2-tert-butoxycarbonyl)prop-2-oximino-2-(
2-) Dithylaminothiazol-4-yl)acetamide]-3-iodomethyl-3-cephem-1-oxide-4-carboxylic acid p-methoxybennorester (syn isomer) (0,6g>1 n-hexyl imidazole (80B), 7-(2-(2tert-butoxycarbonyl)prop-2-oximi/-2-(
2-Tritylaminothiazol-4-yl)acetamido)-3-(3-n-hexyl-1-imidazoliomethyl)-3-cephem-1-oxide-4-carboxylic acid p
-Methoxybenzyl ester yogate (syn isomer) (360 mg) was obtained.

NMRδ ppm (CD CI, ): 0.88 (3H
, m), 1.05-2.15 (8H, m), 1.39
(9H, s).

2.04(6)1. s), 3.76 (3H, s),
5.02 (IO, m).

5.43 (211, n), 6.14 (IH, m),
6.48 (IHts) t7.02 (4H, +n), 7
．． 24(15FI,s), 7.73(it(,s).

9.64 (IH, s) Example 52 According to Examples 45 and 46, 7-(2-(2-ter
t-butoxycarbonyl)probu-2-oximi/-
2-(2-)Ritylaminothiazol-4-yl)acetamide) -3-(3-n-hexyl-1-imidazoliomethyl)-3-cephem-1-oxyto-4-carboxylic acid p-methoxy Bennorester yogate (synthetic form) (345II1g) Togara 7-12-
(2-aminothiazol-4-yl)-2-(potassium(2,2-methylacetate)oximino)acetamide l-3-(3-n-hexyl-1-imigzoliomethyl)-3-cephem -4-carboxylate (syn isomer) (23 mg) was obtained.

NMRδ ppol (DMSOdg): 0.82 (
3)1. t, J=6.5)12), 4.08(2)
1. t,, J=6.5)12).

0.98-2.05 (48, m), 4.93 (IH,
d, J=5.0Hz).

1.34 (311, s), 5.63 (IH, cl, d
, J=5. OHz, J=8,0llz).

1.38(3)1. s), 6.64(1)1. s),
3.43(2)1. s).

7.07 (2H, s), 7.82 (ill, s),
7.92 (IH, s).

9.39 (IH, s), 11.75 (IHtd, J=
8,0Hz) Example 53 ↑ According to Example 44, ? -(2-(2-term-butoxycarbonyl)pro-2-oximino-2-<
2-) Dithylaminothiazol-4-yl)acetamide]-3-iodomethyl-3-sethyl-1-oxido-4-carboxylic acid p-methoxybennorester (syn-M) (0.5 g) 7-(2-(2-
tert-butoxycarbonyl)propbu-2-oxyimino-2-(2-)lythylamido/thiazol-4-yl)acetamide)-3-(3-n-dodecanyl-1-
imigzoliomethyl)-3-cephem-1-xyto-
4-carboxylic acid p-methoxybennorester iodite (syn isomer) (296II1 g) was obtained.

NMRδ ppm (DMSO-d,): 0.8
4 (3H, m), 0.9-2.3 (20H, m),
1.33 (911, s).

1.40 (6H, s), 3.60 (28, m), 3
．． 74 (3H9s) -4,96 (IH, +a), 5.
22 (2H, s); 5.84 (ill, a+).

6.73(ill,s), 7.25(15■*s)-
7,75 (IH-s) t8.07 (IH, m), 9.
01(IH,s) Example 54 According to Examples 45 and 46, 7-C2-(2-ter
t-butoxycarbonyl)prop-2-oximino-
2-(2-tritylaminothiazol-4-yl)acetamide)-3-(3-n-dodecanyl-1-imigzoliomethyl)-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl ester・7-(2-(
2-aminothiazol-4-yl)-2-(potassium (
2,2-dimethylacetate)oxyimino]acetamide l-3-(3-n-dodecanylate-1-imigzoliomethyl)-3-cephem-4-carboxylate (syn isomer) (31,5+g) was obtained. .

NMRδ ppm (D M S Od6): 0.84
(3H, n+), 0.96-2.05 (20H, m
), 1.35(3H,5)-1,40(3H,s)
= 3.50 (2H, s), 3.68 (2L+e).

4.93 (IH, 11), 4.98 (28, +*)
, 5.64 (1■9m).

6.65 (LH, s), 7.08 (2H+s)*
7.64 (IH, s).

7.95 (IH, s), 9.35 (1■, s),
11.50 (IH, m) Example 55 ↑ According to Example 44, 7-(2-(2-terdi-butoxycarbonyl)prop-2-oximino-2-(2
-) Lydylaminothiazol-4-yl)acetamide]-3-iodomethyl-3-cephem-1-oxide-
7-(2-(2t
ert-butoxycarbonyl)prop-2-oxyimino-2-(2-)lythylamide/thiazol-4-yl)
acetamido)-3-[3-(2-propynyl)-1-
imigzoliomethyl]-3-cephem-1-xyto-
4-carboxylic acid p-methoxybenzyl ester yogate (syn isomer) (294B) was obtained.

NMRδ ppm (CD CI3): 1.41 (9
H,s), 1.57(6,H,s), 3.89(3
H,s).

5.24 (2H, s), 6.40 (IH, m), 6.
57 (IH, s).

7.06(4)1. m), 7.28 (15H, s) Example 56 According to Examples 45 and 46, 7-(2-(2-Ler
t-butoxycarbonyl)prop-2-oximi/-
2-(2-)ritylami/thiazol-4-yl)acetamide)-3-(3-(2-propynyl)-1-imigzoliomethyl]-3-cephem-1-oxide-4-
7-(2-(2
-7mi/thiazol-4-yl)-2-(potassium(2
,2-dimethylacetate)oximi/]acetamido)-3-(3-(2-propynyl)-1-imigzoliomethyl]-3-cephem-4-carboxylate (syn isomer) (34.2 mg). Obtained.

NMRδ ppm (DMS Ods): 1.4
0 (3H, s), 1.45 (3H, s), 3.62
(2H, s).

3.72 (IH, spear L 4,50-5.45 (5H, m
), 5.32 (IH, Ya).

8.74 (11,s), 7.15 (2Hvs)y 7
,64(IHts)+7.96(IH,s), 9.1
5(LH,s), 11.88(11,m) Example 57 According to Example 44, 7[2(2tert-butoxycarbonyl)prop-2-oximino-2-(2-)lytylaminothi7zole-4 -yl)acetamide]-3
-iodomethyl-3-cephem-1-oxyto-4-carboxylic acid p-methoxybenzyl ester (syn isomer)
(0.6 g) and 1-benzylimiguzole (101 mg)
) to 7-(2-(2-tert-butoxycarbonyl)prop-2-oximino-2-(2-)ditylaminothiazol-4-yl)acetamide)-3-(
3-Benzyl-1-imigzoliomethyl]-3-cephem-1-oxide-4-carboxylic acid p-methoxybennorester iodite (syn isomer) (409 mg)
I got it.

NMRδ ppm (DMSO-d,): 1
36(15t(,s), 3.65(2H,+s),
3.73(3tl,5)-4,85~5.32(5
H, m), 5.42 (28, s), 5.72 (
IH, m) - 6,63 (IH, s) = 7.13 (4
H, a+), 7.28 (1511, s).

7.42(5t(,s), 7.71(21,m),
8.76<ILs)-9,23(IHtm)y
9.32 (IHts) Example 58 According to Examples 45 and 46, 7-(2-(2-ter
t-butoxycarbonyl)prop-2-oximi/-
2-(2-)ritylamide/thiazol-4-yl)acetamide) -3-(3-benzyl-1-imigzoliomethyl)-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl ester yogate (Syn isomer) (480 mg>), 7-i2-(2-7mi/thiazol-4-yl)-2-[potassium(2,2-dimethylacetate)oximino]acetamide l-3-
(3-benzyl-1-imigzoliomethyl)-3-cephem-4-carboxylate (syn isomer) (38,9
+g) was obtained.

NMRδ ppm (DMS Ods): 1.
34 (9Hts), 1.43 (6H,s), 3.5
0(21(,s).

5.45 (28, s), 5.68 (ill, m), 6.
72 (ill, s).

7.12 (211,s), 7.42 (511,s),
7.64(1)1. s).

8.03 (IH, s), 9.65 (ill, s),
12.01 (IH, m) Example 59 ↑ According to Example 44, 7-(2-(2-tert-butoxycarbonyl)prop-2-oximino-2-(
2-)Ritylaminothiazol-4-yl)acetamide]-3-iodomethyl-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl ester (syn isomer) (0.6 g) and 1-bennoyl Migzol (5
0 μm) to 7-(2-(2tert-butoxycarbonyl)prop-2-oxyimino-2-(2-)ditylami/thiazol-4-yl)acetamide)-3
-(3-Methyl-1-imigzoliomethyl]-3-cephem-1-oxide-4-carboxylic acid p-methoxypencyl ester yogate (syn isomer) (339 ng
) was obtained, NMRδ ppm (DMSOda): 1.36 (1
58,s), 3.70(2H,+s), 3.75(
3LsL3.83 (3H, s), 4.80-5.46
(5tl,m)-5,68([,++)-6,67(I
H,s), 7.22(15H,s), 8.28(1
)1. s).

9.08(II(,s), 9.23(LLm) Example 60 CH.

According to Examples 45 and 46, 7-(2-(2-ter
t-butoxycarbonyl)prop-2-oximi/-
2-(2-)ditylaminothiazol-4-yl)acetamido)-3-(3-methyl-1-imigzoliomethyl]-3-cephem-1-oxide-4-carboxylic acid p
-Methoxybenzyl ester yogate (syn isomer) (320 mg) to 7-i2-(2-aminothiazol-4-yl)-2-[carium(2,2-methylacetate)oxyimino]acetamide l-3 −(3
-Methyl-1-imigzoliomethyl)-3-cephem-
4-carboxylate (syn isomer) (50.9 mg)
I got it.

NMRδ ppm (DMSO-da): 1.
39(3N, s), 1.45(31(-s>-3,
48 (2H-s>.

4.84 (3Ls), 4.97 (1) 1. m),
4.99(2H,m)-5,73(1)11111)
g6.71 (ILs), 7.12 (2Hts)? 7.5
7 (ILs), 7.95 (IH, S), 9.48
(1)1. s).

12.06(1)1. m) Example 61 ↑ According to Example 44, 7 (2(2tert-butoxycarbonyl)prop-2-oximi/-2-(2-
tritylamide 7thiazol-4-yl)acetamide]
-3-iodomethyl-3-cephem-1-xyto-4
- from carboxylic acid p-methoxybenzyl ester (syn isomer) (0.5 g) and imidazole (50 μm),
7 [:2 (2tert-butoxycarbonyl)
Prop-2-oximino-2-(2-)lytylaminothiazol-4-yl)acetamide)-3-(1-imigzoliomethyl)-3-oxyimino-1-oxido-4
-Carboxylic acid p-methoxypencyl ester yogate (syn isomer) (2801I1 g) was obtained.

NMRδ ppm (DMSO-d@
): 1.34 (9H, s) = 1.42 (61'1ss
) + 3.53 (2H, m) - 3,75 (3H, s),
5.26 (2H, s) t 5,86 (18, m).

6.75 (IH, s), 7.09 (IH, s), 7
．． 26 (15H, s).

7.42 (IH, s), 7.60 (IH, s), 8.0
2(IHtm)*8.63(1)1. s) Example 62 According to Examples 45 and 46, 7-[2-(2-ter
t-butoxycarbonyl)prop-2-oximino-
2-(2-)lytylaminothi7zol-4-yl)acetamide) -3-(1-imigzoliomethyl)-3-
Cephem-1-oxide-4-carbon Rp-methoxybenzyl ester yogate (syn isomer) (27
0mg) to ? -(2-(2-7mi/thiazole-
4-yl)-2-(potassium (2,2-dimethylacetate)oxyimino]acetamide l-3-(1-imidazoliomethyl)-3-cephem-1-carboxylate (syn isomer) (30 mg) was obtained. Ta.

NMRδ ppm (DMSO-ds): 1.
36 (3H, s) = 1.41 (3H, s), 3.4
6 (28, s).

4.91(IHtm)t 5.50(1)1. l11)
, 6.67 (IH, s).

7.05 (2H=s), 7.20 (IH, s), 7.
61 (IH*s).

12.00 (IH, m) Example 63 According to Example 44, ? -(2-(2-tert-butoxycarbonyl)prop-2-oximino-2-(
2-) dithylaminothiazol-4-yl)acetamido-3-iodomethyl-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl ester (syn isomer) (0.5 g) and 1-methylbenzi From Migzol (71,3a+g), 7-[2-(2-tert
-butoxycarbonyl)prop-2-oximino-2
p -methoxybenzyl -(2-tritylaminothiazol-4-yl)acetamide)-3-(benz-3-N-methyl-1-imigzoliomethyl)-3-cephem-1-oxide-4-carboxylate Ester bioyogate (syn isomer) (294B) was obtained.

NMRδ ppm (DMSOds): 1.32 (9
H=s), 1.37(6H,s), 3.60(2H
, m).

3.69 (3Hts) t 3.80 (3Htm) t 4
．． 10 (3H, s).

5.22 (2H, s) = 5.45 (2H, s), 5
．． 86 (II, +m).

6.70<1)1. s)t 7,09(14tltm
) * Fu, 19 (15) 1. s).

8.60<1)1. s) Example 64 According to Examples 45 and 46, ? -(2-(2-ter
t-butoxycarbonyl)prop-2-oximino-
2-(2-)ditylaminothiazol-4-yl)acetamide)-3-(benz-3-N-methyl-1-imigzoliomethyl)-3-cephem-1-oxide-4-
From carboxylic acid p-7 toxypencyl ester iodite (syn isomer) (280 mg), ? -12-(2-
7minothiazol-4-yl)-2-(potassium(2,
2-dimethylacetate)oxyimino]acetamido)-3-(benz-3-N-methyl-1-imigzoliomethyl)-3-cephem-1-carboxylate (syn isomer) (12+sg) was obtained.

NMRδ ppm (DM S〇-d6): 1.4
1 (3H, s), 1.45 (38, s), 3.80
(3H, m) = 4.89 (IH, 111), 5.17
(2)1. ll1), 5.52 (IH, m).

6.72 (IH, s), 6.73-7.42 (2H,
io), 7.12 (211, s).

8.32 (18, s), 12.08 (IH, io) Example 65 ↑ According to Example 44, 7-(2(2-tert-butoxycarbonyl)prop-2-oximino-2-(2
-) dithylaminothiazol-4-yl)acetamide]-3-iodomethyl-3-cephem-1-xyto-
7 (2(2-Lert-butoxycarbonyl)prop-2-oximino-2-( 2-)Ritylami/thiazol-4-yl)7cetamido]-3-(benz-1-imidazoliomethyl)-3-cephem-1-oxyto-4-carvonerllp-methoxybenzyl ester yogate (syn isomer) 6HMRδ ppm (D M S Ods) obtained (354 mg): 1.
32 (9H=s), 1.37 (6H-s), 3.60 (
2H*aa).

3.89(3H,s)-4,96(1)1. m), 5
．． 22 (2H, s).

5.45 (211, s), 5.86 (IH, m),
8.70(lllts)y7.09(4H,m), 7
．． 19 (15H, s), 8.60 (LH, s) Example 6G According to Examples 45 and 46, 7-(2-(2-ter
t-butoxycarbonyl)prop-2-oximi/-
2-(2-)Ritylaminothiazol=4-yl)acetamide]-3-(benz-1-imigzoliomethyl)
-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl ester yogate (syn isomer) (
345 mg), potassium 7-i2-(2-aminothiazol-4-yl)-2-[potassium(2,2-dimethylacetate)oximi/]acetamide l-3-
(benr-1-imigzoliomethyl)-3-cephem-
4-carboxylate (syn isomer) (21.2 mg)
I got it.

NMRl ppm (DMSO-d6): 1.
41 (3H, s), 1.45 (3H, s), 3
．． 47 (2H, s).

4.89 (ILmL 5.17 (2H9m)y 5
．． 52 (LH-m).

6.72 (IH=s) -8,73~7.42 (2Htm
)-7,12(21LsL8.32(IH,s),
12.06 (IHIm) Example 67 ↑ According to Example 4, 7-[2-methoxyimino-2-(
2-) dithylaminothiazol-4-yl)acetamide]-3-iodomethyl-3-cephem-1-oxide-4-carboxylic acid p-methoxypencyl ester (syn isomer) (0.5 g) and 1-methylbenz From imiguzol (70II1g), 7-[2-methoxyimino-
2-(2-tritylaminothiazol-4-yl)acetamide]-3-(benz-3-N-methyl-1-imigzoliomethyl)-3-cephem-1-oxide-4-
Carboxylic acid p-methoxybenzyl ester yokeid (syn isomer) (285 mg) was obtained.

NMRδ ppm (DMS Oda): 3.8
0 (3H, m), 4.10 (3H, s), 4.90 (1
8, m).

5.2-5.6 (6H, m), 6.60 (IH, s)
.

7.0-7.3 (1511, s), 9.2 (IH, d
, J=8,0Hz) Example 68 According to Examples 5.6 and 7, 7-[2-methoxyimino-2-(2-)lythylami/thiazol-4-yl)
acetamido)-3-(benz-3-N-methyl-1-
imigzoliomethyl)-3-cephem-1-oxide-
From 4-carboxylic acid p-methoxybenzyl ester yogate (syn isomer) (279B), 7-(2-(2
-amino/thiazol-4-yl)-2-methoxyiminoacetamide) -3-(benz-3-N-methyl-1
-Imigzoliomethyl)-3-cephem-4-carboxylate (syn isomer) (20.5ml) was obtained.

NM・Rδ ppm (DM S Ods): 3.
80 (3H, a+), 4.10 (3FI, s), 4.
90 (LH, m).

5.2-5.8 (3Htm)t 6.80 (IH, 5)
t7.0 (2H, S), Fu, 8 (2Htm), 7
．． 8 (ILm).

9.2 (IH, d, J = 8.0 Hz) Example 69 ↑ According to Example 44, 7-(2-(2-tert-butoxycarbonyl)probu-2-oximino-2-(
2-) Lythyl 7minothy7zol-4-yl)acetamido-3-iodomethyl-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl ester (syn isomer) (0,6g> and 1-methyl- From 5-(2-)lythylami/)ethyl imiguzole (234B), 7
- (2-(2-tert-butoxycarbonyl)probu-2-oxyimino-2-(2-tritylami/thiazol-4-yl)acetamide)-3-(3-methyl-4-(27)lytylamino)ethyl- 1-Imigzoliomethyl]-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl ester yogate (syn isomer) (432 molg) was obtained.

NMRδ ppm (CD CL): 1.42 (9H
ts), 1.55 (6H, s), 2.30-2.9
2 (4H, +a).

3.70 (3flts), 3.80 (3H,s), 4
．． 02 (2B, s).

4.98(IH=a+)+5.21(2H-8)-5
,29(2H+m)+6.22(H,i), 6.57
(IH,s)* 7.12(4)1. m) +7.21-
7.43 (30H, s), 7.02-7.64 (4H,
m)? 9.17 (ILs) Example 70 According to Examples 43 and 44, 7-(2-(2-ter
(t-butoxycarbonyl)probut-2-oximino-
2-(2-)Ritylaminothiazol-4-yl)acetamido)-3-(3-methyl-4-(2-)rityl 7
mino)ethyl-1-imigzoliomethyl]-3-cephem-1-oxide-4-carboxylic acid p-methoxybennorester yogate (syn isomer) (400+eg
), 7-(2-(2-aminothiazol-4-yl)-2-(potassium(2,2-methylacetate)oximino)acetamide l-3-(3-methyl-4-yl)
(2-7minoethyl-1-imidazoliomethyl]-3-
Cephem-4-carboxylate (syn isomer) (59
, 4 mg) was obtained.

NMRδ ppm (DMSO-d, -TFA-d
): 1.56 (611, s), 2.53-3.31 (
4FI, m), 3.52 (2H, s).

3.82 (3H1s), 4.98 (LH, +11),
5.17(Zt(,+a).

5.91 (IH, m), 6.81 (IH, s), 7
．． 02 (20,s).

7.51 (28, s), 8.10 (IH, s) = 9
．． 17 (LHLs).

11.85 (IH, s) Example 71 7-phenylacetami1″-3-(3-(2-propenyl)-1-imigzoliomethyl]-3-cephem-4 was prepared by a known iminoether method. -7- obtained from calfone Mp-methquine benol ester (syn isomer)
7 minnow 3-[3-(2-propenyl)-1-imigzoliomethyl]-3-cephem-4-carboxylic acid (0,5
Bis(trimethylsilyl)7cetamide (4.8 g) was added to a suspension of 6 g) in dry ethyl acetate (20 ml), and the mixture was stirred at room temperature (solution A). On the other hand, phosphorus oxychloride (0
, 6g) was mixed with 2-propenyloxyimide/-2-(
2-7minothiazol-4-yl)acetic acid (syn isomer)
(0.53 g) and stirred for 20 minutes (solution B).

Next, drop B solution into A solution at -20℃, and then add it to -10℃.
Stir at ~-20'C for 1 hour and 30 minutes. To this reaction solution, ice water (30 ml) was added while cooling at -20°C to -30°C, and further ethyl acetate (50 ml) was added and stirred.
The precipitated insoluble matter is removed and the organic phase is separated. A saturated aqueous sodium bicarbonate solution is added to this organic phase to adjust the pH to 7.5, and the aqueous layer is separated and washed with methylene chloride. The aqueous layer was adjusted to pH 2 with 10% hydrochloric acid, the precipitate was collected, dried, and then dissolved in a 5% aqueous potassium hydrogen carbonate solution.
7-(2-(2) obtained in Example 7 in H-20(H2O)
-ami/thiazol-4-yl)-2-(2-prope7
quinimino)acetamido)-3-(3-(2-propenyl)-1-imigzoliomethyl]-3-cephem-4
- Same compound as carboxylate (syn isomer) (18
tl1g) was obtained.

Example 7Z 7- obtained by subjecting the compound obtained in Example 34 to reduction with phosphorus tribromide as in Example 7
(2-(2-propenyloxyimino>-2-(2-)
dithylaminothiazol-4-yl)acetamide)-
3-(1-imigzoliomethyl)-3-cephem-1-
Oxide-4-carboxylic acid p-methoxybennornisyl φyogate (syn isomer) (230111 g) was added to 7
Seven tonitrile (5 cranes 1) and chloroform (2,5+++
l), and propylene oxide (
After adding methyl iodide (2 ml) and stirring at room temperature for 18 hours, 7-(2-(
2-propenyloxyimino)-2-(2-)ditylamido/thiazol-4-yl)acetamide) -3-(
3-Methyl-1-imidazoliomethyl)-3-cephem-4-carboxylic acid p-methoxypencyl nisyl yogate (syn isomer) (205 mg>) was obtained.

NMRδ pp ring (DMSO-d,): 3.6
5 (20, +m), 3.73 (3H, s), 3.8
5 (3H, s).

4.64 (211, theory), 4.97 (11L+a),
5.0-5. '50 (8B, +o).

5.6-6.40 (2Hym), 6.92 (IH,s
), 7.07 (411, m).

7.31 (15tl, s) - 7,60 (Z) 1,111
), 8.80(1)1.9) Example 73 According to Example 6 and rj7, 7-(2-(2-propenyloxyimino)-2-(2-tritylaminothiazol-4-yl) 7-(2 -(2-7minothiazol-4-yl)-2-(2-propenyloxyimino)acetamide]-3-(3-methyl-1-imigzoliomethyl)-3-cephem-4-carboxylate (syn isomer ) (18 g) was obtained.

NMRδ ppIII (DMS Oda): 3.4
8 (2 + 1. L 3,85 (311, s) = 4.1
7 (211, s).

4.90-5.50 (5N, IrI), 5.86 (L
H, m).

5.70-6.40(ILmL 7,65(2H1s>
, 9.10 (IHLs) Example 74 7-(2-(2-probenyloximi/)-2-(2-)ritylami7thiazol-4-yl)acetamide]-3 obtained in Example 26 =(3-methyl-1
-Imigzoliomethyl)-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl ester yogate (2251 units) (400 mg) mixed with 7cetonitrile (31) and chloroform (1.5ml) Propylene oxide (0,5 so 1
), then methyl iodide (0.78 ml) was added and 1
After stirring at room temperature for 8 hours, the solvent and excess methyl iodide were distilled off under reduced pressure to give 7-(2-(2-propenyloxyimino)-2-(2-)ditylaminothiazole-4. -yl)acetamide)-3-(3-methyl-1-imigzoliomethyl)-3-cephem-1-oxyto-4-carboxylic acid monomethoxybenzyl ester Jogate (syn isomer) (363mg) I got it.

NMRδ ppm (DMSO-d,): 3.
65 (2H, +m), 3.73 (3H, s),
3.85 (6H, s).

4.64 (2H=IIl)! 4.97 (1) 11m
), 5.0 to 5.50 (6H, Ya).

5.6-6.40 (2H, m), 6.92 (ltl,
s), 7.07 (4H, m).

7.31 (1511, s), 7.60 (211, m)
, 8.80 (ILs) Example 75 According to Examples 5.6 and 7, ? -(2-(2-propenyloxyimino)-2-(2-)ditylaminothiazol-4-yl)acetamide]-3-(3-tumethyl-1-imigzoliomethyl)=3-cephem-1- Oxide-4-carboxylic acid p-methoxybenzyl ester
From Jogate (syn isomer) (350u+ir),
? -(2-(2-7minothiazol-4-yl)-2-
(2-7”Lopenyloxyimi7)acetamide)-3
-(3-Tmethyl-1-imigzoliomethyl)-3-cephem-4-carboxylate yogate (syn isomer) (18 mg) was obtained.

NMRδpp! n(DMS Oda): 3.48
(2H, m), 3-85 (6H, s), 4.17 (
2Hts)+4.90-5.50(5)1. +a),
5,86(1)I,m).

5.70-6.40 (189m), 7.65 (211,
s), 9.10 (IHts) Example 76 ↑ According to Example 44, 7-(2-(2-tert-butoxycarbonyl)prop-2-oximino-2-(
500 mg of 2-tritylaminothiazol-4-yl)acetamide]-3-iodomethyl-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl ester (syn isomer) and 1-vinylimidazole 68-
g, 7-(2-(2-tert-butoxycarbonyl)prop-2-oximino-2-(2-)ditylaminothiazol-4-yl)acetamide)-3-(
3-vinyl-1-imidazoliomethyl)-3-cephem-1-oxyto-4-carboxylic acid p-methoxypencyl yogate (syn isomer) 6H obtained 317.5B
MRδ ppa+ (CD CIs): 1.39 (9
tl, s), 1.55 (61Ls), 3.71 (3
H,s).

4.07 (211, m), 4.97 (1) I, d, J
=5,0tlz).

4.75-5.91 (41 (, m), 5.21 (Zt
(,s).

6.10 (IH, dd, J=5.0, 8.0Hz),
6.72 (ltl, s).

7.05 (4t1.dd, J=8.0,35,01lz
).

6.61-8.09 (5H, m), 7,25 (1511
,s), 9.68(+,)I,s) Example 77 According to Examples 45 and v46, ? -1:2-(2-te
rt-butoxycarbonyl)prop-2-oximi/
-2-(2-)ditylami/thiazol-4-yl)acetamide)-3-(3-vinyl-1-imigzoliomethyl)-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl ester・From 300 mg of yogate (syn isomer), 7-(2-(2-7minothiazol-4-yl)-2-[potassium(2,2-methylacetate)oximino]acetamide l-3-(3
-vinyl-1-imidazoliomethyl)-3-cephem-
25.9 mg of 4-carboxylate (syn isomer) was obtained.

N M Rδ ppIIl (D M S O-d6
): 1.38 (311,s), 1.44 (3tl,
s), 3.103.77 (2H, +n).

4.65-5.50 (4111m), 4.98 (IHt
dtJ” 5.0llz).

5.64(lfl, dd, J==5.0,8,0)Iz
), 6.75(ltl,s)+6.90-7.60
(III, m), 7.12 (IH, s), 7.
98 (1t1.s).

8.11 (IH, s), 9.70 (IH, s).

12.06 (IH9d, J=8.0)1z) Example 78 ↑ According to Example 44, 7-(2-(2-terL-butoxycarbonyl)prop-2-oximino-2-(
2-) dithylamide/thiazol-4-yl)acetamide]-3-iodomethyl-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl ester (syn isomer) from 500 mg and 1-cyclohexylimidazole 220 mg, 7-[2-(2-tert-butoxycarbonyl)prop-2-oximino-2-(2
-tritylamide/thiazol-4-yl)acetamide) -3-(3-cyclohexyl-1-imigzoliomethyl)-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl ester yogate (syn-X >185.8+ng of body weight was obtained.

NMRδ pp so (CD CI, ): 1.35 (9H
,s), 1.50(6H,s), 0.95-2.3
0 (IIH, +a).

3.73 (311, s), 4.08 (2H, m).

4.92 (111, d, J=5.0Hz), 5.17 (
2H+s).

5.0-5.92 (211, +n), 6.08 (If
t, dd, J=5.0, 8.01lz).

6.61 (1fl, s), 7.04 (4H, dd, J
=8.0,37.5Hz)-7,24(15H,s),
7.05-7.94 (4H, m), 9.65 (lt
l, s) Example 79 According to Examples 45 and 46, ? -(2-(2-jer
t-butoxycarbonyl)prop-2-oximino-
2-(2-)rityl 7minothiazol-4-yl)acetamide) -3-(3-cyclohexyl)-1-imigzoliomethyl]-3-cephem-1-oxide-4-
From 185 mg of carboxylic acid p-methoxybennorester yogate (2751 bodies), 7-12-(2-7
Mi/thiazol-4-yl)-2-(potassium(2,Z
-trimethylacetate)oxyimino]acetamide l
8.8111 g of -3-(3-cyclohexyl-1-imigzoliomethyl)-3-cephem-4-carboxylate (syn isomer) was obtained.

NMRδpp+e (DMSO-dg): 1
．． 41 (311,s), 1.44 (3H,s),
0.81-2.36 (11!Lm).

3.10-3.75(211,+a), 4.97(
IH, d, J = 5.0Hz) - 5,05 - 5,45 (2
)1. m), 5.50-5.85 (IFI, a+)
.

6.69 (IH, sL 7,10 (2H, S),
7.58(II(,s).

8.00 (III, s), 9.46 (Ill, s)
.

12.13 (IH, cl, J=8.01tz) Example 8
0 ↑ According to Example 44? -(2-(2tert-butoxycarbonyl)prop-2-oximi/-2-(2-
) lythylaminothiazol-4-yl) acetamido-3-iodomethyl-3-cephem-1-oxide-4
-Carboxylic acid p-methoxybennor ester (syn isomer) 350 mg and 1-(4-hydroxyphenyl)
From imidazole 65B, 7- (2-(2-ter
t-butoxycarbonyl)prop-2-oximi/-
2-(2-)rityl 7m7thiazol-4-yl)acetamide]-3-(3-(4-hydroxyphenyl)
-1-Imigzoliomethyl]-3-cephem-1-oxyto-4-carboxylic acid p-methoxypencyl ester.
Yogate (syn isomer) 160.9+g was obtained.

NMRδ ppm (CD CIs): 1.37 (9
H1s)-1,54(6H-s), 3.76(3H9s
)+4.13(211,m), 4.99(IH,d,
J=5.0Hz).

5.24 (211,s), 5.05-5.85 (2H
, m).

6.14 (IH=dd, J=5.0,8,01lz)-
6,63 (I11tsL7.07 (4H, dd, J=8
．． 0.37.5Hz).

6.65-8.10 (9H, m), 7.23 (15H
, s), 9.71 (IH, s) Example 81 According to Examples 45 and 46, 7-(2-(2-ter
t-butoxycarbonyl)prop-2-oximi/-
2-(2-)lythyl 7minothiazol-4-yl)acetamide)-3-[3-(4-hydroxyphenyl)
-1-imidazoliomethyl]-3-cephem-1-oxide-4-carboxylic acid p-7 toxybennorester.
Yogate (syn isomer) From 16On+g? -1
2-(2-7minothiazol-4-yl)-2-(potassium(2,2-methylacetate)oxyimino]acetamide)-3-(3-(4-hydroxyphenyl)-1-imigzoliomethyl)- 3-cephem-4-carboxylate (syn isomer) 9.0+aFI was obtained.

NMRδ pp+a (D M S Odg): 1.
39(3H+s)t 1.41(3H,s), 3.2
0-3.72 (2 tl, m).

4.95 (IH, d, J=5.0Hz), 5.05-
5.40 (2H, m).

5.47-5.84 (IH, m), 6.72 (IH,
s).

6.23-8.25 (911, m), 9.47 (I
H,s).

12.03(Ill,c(,J=8,0Hz)Example 8
2 ↑ According to Example 44, 7-(2-(2-tert-butoxycarbonyl)prop-2-oximino-2-(
2-) ritylamido/thiazol-4-yl)acetamido-3-iodomethyl-3-cephem-1-oxide-4-carboxylic acid p-methoxybennorester (syn isomer) 500 mg and 1-penzylbenzimiguzole IZ1+B from, 7-[2-(2-tert-butoxycarbonyl)prop-2-oximi/-2-(2
-) dithylaminothiazol-4-yl)acetamide)-3-(benz-3-N-bentrue-1-imigzoliomethyl)-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl ester yogate (Syn isomer) 288.5+H was obtained.

NMRδ ppLfi (CD CI*): 1.39 (9
H,s), 1.54(611,s), 3.74(3
11,5)=4.16(2H,m), 5.13(LH
, d, J=5.0Hz).

5.23(211,s), 6.10(2H,s)t
5.75 (2H, m).

6.11 (IH, dd, J=5.0, 8.0Hz).

7.02 (4H, dd, J” 8,0,42.5tlz
).

7.25(15!(,s), 7.37(5H,s),
6.70-8.10 (711, m) Example 83 According to Examples 45 and 46, 7-(2-(2-Ler
t-butoxycarbonyl)prop-2-oximino-
2-(2-tritylami7thiazol-4-yl)acetamide)-3-Cbenz-3-N-benzyl-1-imigzoliomethyl)-3-cephem-1-oxide-4
-Carboxylic acid p-methoxybennorester yogate (syn isomer) from 280mg? -(2-(2
-ami7thiazol-4-yl)-2-(potassium(2
,2-methylacetate)oximi/]acetamido)-3-(benz-3-N-benzyl-1-imigzoliomethyl)-3-cephem-4-carboxylate(
Synisomer) 30.1 mg was obtained.

N M Rl pp Kasu (D M S Ods): 1.
35 (3H, s), 1.40 (3H, s), 3
．． 08-3.78 (2H, m).

4.93 (18, cl, J=5,0Hz), 5.4
5 (2H, s).

5.77(2H9s)-5,46-5,82(IH-m
)* 6.66(IH-s)-6,85-8,50(9
H, a+), 7.07 (2H, s), 10.1
3 (IH, 5) - 11,84 (IH, d, J” 8,0
tlz) Example 84 ↑ According to Example 44? -(2-(2-jert-butoxycarbonyl)prop-2-oximino-2-(2
-tritylaminothiazol-4-yl)acetamido-3-iodomethyl-3-cephem-1-oxide-
4-carboxylic acid 1)-methoxybenzyl ester (syn isomer) 350 mg 1-(2-propynyl)penzimigsol 64 to g, 7-(2-(2
-Lert-butoxycarbonyl)prop-2-oxyimino-2-(2-)ditylaminothiazol-4-yl)acetamide]-3-[benz-3-N-(2-propynyl)-1-imigzoliomethyl ]-3-cephem-1-oxyto-4-carboxylic acid p-methoxybenzyl ester yogate (syn isomer) 209.1 mg
I got it.

NMRδ ppm (CD Clz): 1.38 (9
H,s), 1.52 (611,s).

2.47 (LH, t, J = 2.8Hz), 3.72 (
3H9s).

4.07 (211, m), 4.88 (211, d, J
=2.8)1z).

5.16(1)1. d, J=5.0H2), 5.25
(2H, S).

6.03 (21, +m), 6.23 (IH, dd, J
=5.0,8,0H2).

6.59 (LH, s), 7.01 (4H, dd, J=
8.0, 42.5Hz).

7.2.6 (15tl, s), 6.62-8.10 (
611, m), 10.31 (IH, s) Example 85 According to Examples 45 and 46, 7-(2-(2-ter
t-butoxycarbonyl)prop-2-oximi/-
2-(2-)Ritylaminothiazol-4-yl)acetamide)-3-[benz-3-N-(2-propynyl)-1-imigzoliomethyl]-3-cephem-1-oxide-4- Carboxylic acid p-methoxybenzyl ester yogate (syn isomer) From 217.6+B, 7
-(2-(2-7minoch7・/-ru4-il)-2-
(Potassium (2,2-dimethylacetate)oximi/]acetamide)-3-[benr-3-N-(2-propynyl)-1-imigzoliomethyl]-3-cephem-4-carboxylate (sin isomer) 36.5o+
6HMRδ ppm (DMSO-d
a): 1.38 (311, s), 1.42 (311
, s), 3.35-3.86 (211, a+).

4.96 (IH, d, J=5.0IIz), 5.05-
5.82 (5H, m).

6.67 (IH, s), 7.10 (2H, s), 6
．． 96-8.50 (4tl, +a).

10.06(IH,s), 11.17(11(,d,J
=8,0Hz) Example 86 ↑ According to Example 44, 7-[2-(2-tert-butoxycarbonyl)prop-2-oximino-2-(
2-tritylaminothiazol-4-yl)acetamido-3-iodomethyl-3-cephem-1-oxide-4-carboxylic acid p-methoxybennorester (syn J% compound) 500II1gto1 (2-methyl-2
- propenyl) from 100 mg of penzimigsol,
7-(2(2-tert-butoxycarbonyl)prop-2-oximino-2-(2-)lytylaminothiazol-4-yl)acetamide)-3-(benz-3
-N-(2-methyl-2-propenyl)-1-imigzoliomethyl]-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl ester (syn isomer) 2
68.9aig was obtained.

NMRδ pprn (CD C+3): 1.40 (91
1-s)-1,54(allys), 1.75(3H
,s).

2.76 (3H, s), 4.17 (2H, +a),
4.66 (2H, s).

4.85-5.40 (3H, m), 5.21 (2H,
s), 5.75 (2 fl, m).

6.20 (if, dd, J=5.0,8,0Hz),
6.59 (IH+s) + 7.02 (411, dd, J
=8.0,42,511z), 7.25(15H,s
).

6.70-8.15 (7H, +e) Example 87 According to Example 45 and 1/46, 7-(2-(2-te
rt-butoxycarbonyl)prop-2-oximi/
-2-(2-)Ritylaminothiazol-4-yl)acetamide)-3-[benz-3-N-(2-methyl-
Propenyl)-1-imigzoliomethyl]-3-cephem-1-oxyto-4-carboxylic acid p-methoxybennorester thiazol-4-yl)-
2-(potassium(2,2-dimethylacetate)oxyimino)acetamide l-3-(benz-3-N-(2
-propenyl)-1-imigzoliomethyl]-3-cephem-4-carboxylate (syn isomer) 30.8
I got a B.

NMRδ ppm (DMS Oda): 1.3
7 (3H9s) + 1.42 (3H9s), 2.24
(30, s) +3.32~3.75 (211, Zui L
4,55-5.25 (2ft, a+) - 4,95 (LH
, d, J=5.0Hz)+ 5.15(2H,5)+
5.42 (2H, s), 5.62 (lfl, dd,
J=5.0,8,0Hz)-6,67(ltl,s),
7.07 (2H, s), 6.81-8.46 (4
H, Ua).

9.99 (IH=s), 11.58 (IH, d, J
=8,0Hz) Example 88 ↑ According to Example 44, ? -(2-(2-tert-butoxycarbonyl)prop-2-oximino-2-(2
-)Ritylami7thiazol-4-yl)acetamide]-3-iodomethyl-3-cephem-1-oxide-
From 350 II g of 4-carboxylic acid p-methoxybenzyl ester (syn isomer) and 70 mg of 1-(3-butenyl)penzimigsol, 7(2(2tert-butoxycarbonyl)prop-2-oximino-2-(2 −
) lythylaminothiazol-4-yl)acetamide]
-3-[benz-3-N(3-butenyl)-1-imigzoliomethyl]-3-cephem-1-oxide-4-carboxylic acid p-methoxybennorester yogate (
214 mg of syn isomer) was obtained.

NMRδ ppm (CD Cl:l): 1.38 (
9H,s) = 1.52(6H,s).

2.72 (2H, q, J = 6.0Hz), 3.80 (
3)1. s).

4.14 (2tl, m), 4.48 (211,t, J
=6.0Hz).

5.20 (211,s) = 4.80-5.26 (3H
,w), 5.67(2Hzm)+5.70-6.20
(LH, +a), 6.17 (111, dd, J=5.
0,8.011z).

6.58 (IHLs), 7.02 (4H9dd-J=8
．． O+42.5Hz).

7.24 (15H, s), 6.75-8.08 (61
1, m), 10.6 (ill, s) Example 89 According to Examples 45 and 46, 7-(2-(2-ter
t-butoxycarbonyl)prop-2-oximino-
2-(2-)Ritylaminothiazol-4-yl)acetamido)-3-(benz-3-N-(2-butenyl)
-1-Imigzoliomethyl]-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl ester.
From 210 g of Yogate (syn isomer), 7-(2-
(2-7minothia'zol-4-yl)-2-(potassium(2,2-methylacetate)oximino]acetamide)+3-[benz-3-N-(3-butenyl)
-1-imigzoliomethyl]-3-cephem-4-carboxylate (syn isomer) 25.3B was obtained.

NMRδ ppm (DMS Oda): 1.
36 (3H, s), 1.41 (311, s).

2.66 (2H, q=J=6,0Hz), 3.30-
3.75 (2H, m).

4.58 (211,t, J=6.0Hz), 4.92
(IH, d, J=5,0Hz).

5.04 (2H, s), 5.25-6.22 (4H,
m), 6.67 (IH, s) + 7.07 (2H, s)
, 7.35-8.47 (4H, 111), 10.3
(111,5) 111.91 (IH, d, J= 8.0
Hz) Example 90 ↑ According to Example 44, ? -(2-(2-jert-butoxycarbonyl)prop-2-oximino-2-(2
-Tritylamide/thiazole)acetamide]-3-iodomethyl-3-cephem-1-oxide-4-carboxylic acid p-methoxybennorester (syn isomer) 3
50B and 71 mg of 1-butylbenzimiguzole, 7-(2-(2-Lert-butoxycarbonyl)probu-2-oximino-2-(2-)lythylami7thiazol-4-yl)acetamide)-3- (benz-3-N-butyl-1-imigzoliomethyl)-3-
Cephem-1-oxide-4-carboxylic acid p-methoxybennorester yogate (syn isomer) 198
10g was obtained.

NMRδ pp@(CD C13): 0.97(3
11,t, J=6.0Hz), 1.48(9H,s)
.

1.52 (6tl, s), 1.70-2.25 (4F
I, i*), 3.75 (3H, s).

4.18 (211, m), 4.40 (2Htt, J=
6.0Hz).

5.16 (111, d, J = 5.0 Hz), 5.22 (
2H9s).

5.72 (2H1+s), 6.17 (IH9dd, J=
5.0,8,0tlz)+6.58(III,s),
7.02 (4H, dd, J=8.0, 42.5Hz).

7.24 (15H, s), 6.65-8.20 (7H
, aA) Example 91 According to Example 45 and (/'46), 7-[2-(2-t
ert-butoxycarbonyl)prop-2-oximi/-2-C2-)lythylami7thiazol-4-yl)
acetamido)-3-(benz-3-N-butyl-1-
imidazoliomethyl)-3-cephem-1-xyto-
7-12-(2-
7mi/thiazol-4-yl)-2-(potassium(2,
2-methylacetate)oxyimino]acetamidony 3 (benz-3-N-butyl-1-imigzoliomethyl)-3-cephem-4-carboxylate (syn isomer) 24. Omg'Ii: Obtained.

NMRδ ppm (DMSO-ds): 0.
92 (3H2t, J=6.011z), 1.37 (31
1tsL1.41 (3tl, s), 1.27 (2H
, +6), 1.83 (2H, m).

3.15-3.75 (2H, m), 4.48 (2H
, t, J=6,0Hz)-4,93<IH+d, J=5
,0Hz),5.42(2Hts)-5,30-5,8
3(111,n), 6.67(111-s).

6.95-8.48 (4H, m), 7.07 (2H+
s), 10.00(LHLs)tll, 83(1!l,
cl, J = 8.0 Hz) Example 92 ↑ According to Example 44, 7-(2-(2tert-butoxycarbonyl)prop-2-oximino-2-(2-
) Lythyl 7-minothiazol-4-yl)acetamide]
-3-iodomethyl-3-cephem-1-oxide-4
-Carboxylic acid p-methoxybenzyl ester (syn J%
7- (2-(2-te)
rt-butoxycarbonyl)probu-2-oximi/
-2-(2-)Ritylaminothiazol-4-yl)acetamide]-3=[benz-3-N-(2-propenyl)-1-imigzoliomethyl]-3-cephem-1-
224.3+wg of xyto-4-carboxylic acid p-methoxybennorester yogate (synisomer) was obtained.

NMRδ pp theory (CD C+3): 1.40 (9H
ts) t 1,54 (61Ls), 3.66 (311
,5)+4.11(2H,m), 4,76(2tl,
d, J=6,3)1z).

5.02 (IHtdtJ=5.0Hz)t 5,23(
211, s).

5.05-6.14 (Zl(,m), 6.37-6.
70<4t(,+n).

6. 61 (ltl, s), 7.04 (4N, dd,
J = 8.0, 42.5Hz) = 7.26 (15H, s
), 6.65-8.15 (78, m) Example 93 According to Examples 45 and 46, 7-(2-(2-ter
t-butoxycarbonyl)prop-2-oximi7-
2-(2-tritylami7thiazol-4-yl)acetamide)-3-(benz-3-N-(2-propenyl)-1-imidazoliomethyl]-3-cephem-1-oxide-4-carboxylic acid p - From 200 g of methoxypencil ester yogate (syn isomer), 7-(2
-(2-aminothiazol-4-yl”)-2-(potassium(2,2-dimethylacetate)oxyimino]acetamide)-3-[benr-3-N-(2-propenyl)-1-imig Zoliomethyl]-3-cephem-4-
Carboxylate (syn isomer) 11.5LIF1 was obtained.

NMRδ ppm (DMSOds): 1.37 (3
11,s), 1.39(311,s), 3,1
．． 2-3.77<28. +n).

4.87 (211, d, J=6.0tlz), 4.
93 (IH,d,,I=5,01lz).

5.0:'-5.74 (3tl, +a), 5.40
(2tl, 5)-5,74-6,34 (IH, 111)
, 6.65 (IH, s).

6.41-8.46 (411, n), 7.10<2Ls
), 9.91(1)1. s).

11.90 (II (, d, J = 8.0 Hz) Example 94 ↑ According to Example 4, 7-[2-methoxyimi/-2-(
2-Tritylamide/thiazol-4-yl)acetamide]-3-iodomethyl-3-cephem-1-oxide-4-carboxylic acid p-methoxypencyl ester (syn isomer) 450mg 1-(2-propenyl)penzi From Miguzol 87 +a g, 7-[2-methoxyimi/-2-(2-tritylamide/thiazole-4-
yl)acetamide]-3-[benz-3-N-(2-
130 mg of p-methoxybenzyl propenyl-1-imigzoliomethyl]-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl ester Miedite (syn isomer) was obtained.

NMRδ ppIII (DMSO-d,): 3.
75(3)1. s), 3.80 (3H, s), 4.
1-4.3(2)1. +s).

4.45 (2H, s), 4.90-5.10 (2H,
a+), 5.22 (4H, s).

5.4s (zu, s), 5.5-5.65 (IH, l
11), 6.75 (ill, S).

7.25 (i5H,s), 9.20 (LH,s) Example 95 According to Examples 5, 6 and 7, 7-[2-methoxyimino-2-(2-)ditylaminothiazole-4 −il)
acetamido)-3-(benz-3-N-(2-propenyl)-1-imigzoliomethyl]-3-cephem-1
- from 120 mg of xyto-4-carboxylic acid p-methoxybenzyl ester yogate (syn isomer), 7
-(2-(2-7minothiazol-4-yl)-2-methoxyiminoacetamide)-3-(benz-3-N-
(2-propenyl)-1-imigzoliomethyl]-3-
Cephem-4-carboxylate (syn isomer) 17B
I got it.

NMRδ ppm (DMSO-d,): 3.
10-3.70 (2tl, m), 3.80 (3H1s
)-4,1~4,3(2)1. m), 4.40-4.
50 (2H, imported).

4.98 (2H1d, J=8.0Hz), 5.22
-5.45 (411, m).

6.75 (IH, s), 12.5 (IH, d, J=8
,0Hz) Example 96 ↑ According to Example 4, 7-(2-(2-probenyloximi/)-2-(2-)ditylamide/thiazole-4-
yl) acetamido-3-iodomethyl-3-cephem-1-oxyto-4-carboxylic acid p-methoxypencyl ester (syn isomer) 460mg 7- (2
-(2-probenyloxyimide/)-2-(2-)ditylamido/thiazol-4-yl)acetamide)-3-
140 mg of (benz-3-N-(2-propenyl)-1-imigzoliomethyl]-3-cephem-1-oxide-4-carboxylic acid p-methoxybennorester yogate (syn isomer) was obtained.

NMRδ ppm (DMS○-d6): 3.75 (
3H, s), 4.2-4.3 (4H, a+), 4,
45(2)1. s).

5.05~5.15 (411, spear L 5,22~5.4
5 (6H, n).

5.5-5.6 (211, m) = 6.75 (IH, s
).

7.08-7.15 (414, +a), 7.25 (1
5H,s), 9.20(Ift,s) Example 97 According to Examples 5, 6 and 7, 7-(2-(2-7"robenyloxyimino)-2-(2-)dityl aminothiazol-4-yl)acetamide]-3-[benz-3
-N-(2-propenyl)-1-imidazoliomethyl]
-3-cephem-1-oxide-4-carboxylic acid p-methoxybennorester iodite (syn isomer)
From 130B, 7-(2-(2-7minothiazole-4
-yl)-2-(2-probenyloxyimi7)acetamide]-3-[benz-3-N-(2-propenyl)
26 mg of -1-imidazoliomethyl]-3-cephem-4-carboxylate (syn isomer) was obtained.

NMRδ ppm (DMSO-d6): 3.
60-3.65 (2H, m), 4.2-4.3 (4H
, m).

4.45(2H=s)-5,05-5,15(4H*m
) t5.22-5.45 (4H, m), 5.5-5.6
(28,a+)*6.75(ILs>,12.5(LH
ld, J=8.0Hz>Example 98 ↑ According to Example 44? -(2-(2-tert-butoxycarbonyl)prop-2-oximi/-2-(2
-) dithylamide/thiazol-4-yl)acetamido-3-iodomethyl-3-cephem-1-oxide-
From 4-carvoneItlp-methoxybennorester (syn isomer) 502a+g and 1-(2-butenyl)penzimigsol 103■, 7-(2-(2-t
ert-butoxycarbonyl)prop-2-oximi/-2-(2-)ditylaminothiazol-4-yl)
acetamido]-3-[benz-3-N-(2-butenyl)-1-imigzoliomethyl]-3-cephem-1-
410 mg of oxybe-4-carboxylic acid p-methoxybennorester yogate (syn isomer) was obtained.

N M RI ppm+ (D M S Ods)
'.

1.34 (9H, s), 1.44 (3H, s) t 1
,7(3H,s>.

4.7-4.85 (3H, m), 5.30 (2H9s
)-5,5-5,9 (3H, m), 6.60 (IH,
s), 7.25 (15H, s).

9.20 (LH, s) Example 99 According to Examples 45 and 46, 7-(2-(2-ter
t-butoxycarbonyl)prop-2-oximino-
2-(2-)Ritylaminothiazol-4-yl)acetamido)-3-[benz-3-N-(2-butenyl)
-1-Imigzoliomethyl]-3-cephem-1-oxide-4-carboxylic acid p-714 dibenzyl ester.
Iodite (syn isomer) From 280+ag? -1
2-(2-7minothiazol-4-yl)-2-(potassium(2,2°-trimethylacetate)oxyimino)
acetamido)-3-[benz-3-N-(2-butenyl)-1-imigzoliomethyl]-3-cephem-1-
21.5 mg of carboxylate (syn isomer) was obtained.

NMRδ ppm (DMS Oda): 1.3
8 (311,s), 1.41 (311,s), 1.
7 (3tl, s).

4.7-4.85 (3H, m), 5.30 (2H, s
).

5.5-5.9(3H9m)-6,60(LH+s)+
9.80 (lfl-s).

12.50 (111, d, J=8,0Hz) Example 10
0 According to Example 44, 7-(2-(2-tert-butoxycarbonyl)prop-2-oximino-2-(
2-)Ritylami/thiazol-4-yl)acetamide]-3-iodomethyl-3-cephem-1-oxide-4-carboxylic acid p-methoxybenzyl ester (syn isomer) 502mg 1 (3-methyl-2-butenyl) ) from penzimigsol 111B, 7- (2-
(2-Lert-butoxycarbonyl)prop-2-oximino-2-(2-)ditylaminothiazole-4
-yl)acetamido)-3-(benz-3-N-(3
-methyl-2-butenyl)-1-imidazoliomethyl]
-3-cephem-1-oxyto-4-carboxylic acid p-methoxybenzyl ester yogate (syn isomer)
380 mg was obtained.

NMRδ ρpIIl (DMS Ods): 1.3
4 (9H, s), 1.39 (6H, s), 1.80
(6H, 5) = 4.7-4.85 (3Htm), 5.
30 (2H, s).

5.3-5.6 (2H, a+), 6.60 (IH, s
), 7.25 (15H, s).

9.20 (IH, s) Example 101 According to Examples 45 and 46, ? -(2-(2-ter
t-butoxycarbonyl)prop-2-oximi/-
2-(2-)Ritylami/thiazol-4-yl)acetamide)-3-[benz-3-N-(3-methyl-2
-butenyl)-1-imigzoliomethyl]-3-cephem-1-oxide-4-carboxylic acid p-7 toxybennorester iodite (syn isomer) From 260 mg, 7-(2-(2-aminothiazole) -4-yl)-
2-(potassium(2,2'-dimethylacetate)oxyimino)acetamide l-3-(benz-3-N-(
12.6 mg of 3-methyl-2-butenyl)-1-imigzoliomethyl]-3-cephem-1-carboxylate (syn isomer) was obtained.

NMRδ ppm (DMS Ods): 1.3
8 (6H, s), 1.80 (61, s), 4.7-4
．． 85 (3H, l).

5.30 (211, s), 5.3-5.6 (2H, m
), 6.60 (IH, s).

9.80 (IH, s), 12.50 (ltl, d, J
=8,01lz) Example 102 7-(2-(2-probenyloxyimi/)-2-(2-tritylami7thiazole-4-
yl)acetamide]-3-iodomethyl-3-cephem-4-carboxylic acid p-methoxybennorester (syn isomer) was dissolved in chloroform (600+o
l) and acetonitrile (), dissolved in a mixed solvent of 0,000 ml and cooled with water to dissolve 1-(2-propenyl)imidazole (
41°Ig). After the addition is complete, warm to room temperature and stir for an additional 4 hours. After distilling off the solvent under reduced pressure, it was purified using a silica gel column! l! (Chloroform-methanol, volume ratio 3:1)L By collecting the eluate containing the target product and distilling off the solvent, -yl)acetamido)-3-(3-(2-propenyl)-
268 g of 1-imigzoliomethyl]-3-cephem-4-carboxylic acid p-methoxybenzyl ester yogate (syn isomer) was obtained.

NMRδ ppIl (DMSO-d6): 3
．． 55 (211, s), 3.77 (3H, s).

4.58 (21!, d, J=5,0llz), 4.
87 (211, d, J=5,01lz).

4.98-5.60 (911, m), 5.62-6.3
5 (3H, m).

6.76 (IH, s), 7.12 (4H, dd, J
=8,0tlz, 32,511z).

7.32 (15H, s), 7.68 (IH, s),
7.75 (ill, s).

9.28 (III, s), 9.27 (ltl, s)
, 9,58(1)1. d, J = 8,0 Hz) In order to demonstrate the usefulness of the present compound (I) in dogs, the present compound -
) Test data on in vitro antibacterial activity for representative compounds are shown below.

Test: In vitro antibacterial activity test Compounds: A: Compound B of Example 7: Compound C of Example 15: Compound D of Example 17: Compound E of Example 19: Compound F of Example 73: Example 33 Compound G of Example 37: Compound H of Example 46: Compound I of Example 48: Compound J of Example 48: Compound L of Example 56: Compound M of Example 64: Compound of Example 77 Compound N: Compound 0 of Example 79: Compound P of Example 81: Compound Q of Example 83: Compound R of Example 85: Compound S of Example 87: Compound T of Example 89: Compound of Example 91 U: Compound V of Example 93: Compound W of Example 95: Compound X of Example 97: Compound Y of Example 99: Compound of Example 101 Test method In vitro antibacterial activity by the following 2x agar plate dilution method I asked for Each test bacterial species was cultured in susceptibility measurement broth for 20 hours.
．． 005n+1 was inoculated onto agar medium for susceptibility determination containing various concentrations of antibacterial agents, and after culturing at 37°C for 20 hours, the minimum inhibitory concentration (MIC) was measured in units of Ig/w l. The results are shown in Table 1.

Claims (10)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R^1 is an organic residue known in β-lactam antibiotics, and R^2 is a hydrogen atom or a methoxy group. where n indicates 0 or 1, A indicates nitrogen of the following formula constituting the imidazolium ring, ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼ B is imidazolium Indicates the carbon of the following formula that makes up the ring. ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲Mathematical formulas, chemical formulas,
There are tables etc. ▼ R^3, R^4, R^5, R^6, R^7 and R^8 are hydrogen atoms or substituted or unsubstituted C_1_ to C_
1_2 alkyl group, substituted or unsubstituted C_2_~
C_1_2 alkynyl group, substituted or unsubstituted benzyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted alkoxy group, substituted or unsubstituted amino group, substituted or unsubstituted carbamoyl group, substituted or unsubstituted A ureido group, substituted or unsubstituted thiocarbamoyl group, hydroxyl group, halogen atom, mercapto substitution, nitro group, cyano group, carboxyl group, X^
(■ means a halogen atom or an acid residue, respectively)
A cephalosporin compound in which the cephem 3-position is substituted with an imidazolium ring, and a pharmacologically acceptable salt thereof. (2) Claim 1 in which R^1 is an organic residue having a 4- to 6-membered heterocycle (containing 1 to 4 of each of sulfur, nitrogen, and oxygen atoms as constituent atoms) Cephalosporin compounds as described. (3) When R^1 is a constituent factor of ▲There is a mathematical formula, chemical formula, table, etc.▼ in the organic residue, R^3 is hydrogen,
Substituted or unsubstituted C_2 to C_6 straight chain or branched alkyl group, substituted or unsubstituted C_2 to C_6 straight chain or branched alkenyl group, substituted or unsubstituted C_2 to C_6 straight chain or branched alkynyl group, substituted or unsubstituted C_
3 to C_7 cycloalkyl group, substituted or unsubstituted C_
4-C_7 cycloalkenyl group or ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1^0 and R^1^1 are the same or different, hydrogen atom, methyl or ethyl group, R^1 ^2 is a hydrogen atom,
alkali metals, alkaline earth metals, organic amine bases, or ordinary protective groups for carboxyl groups) or substituted or unsubstituted 4- to 6-membered heterocycles (with sulfur, nitrogen, and oxygen atoms as their constituent atoms) The cephalosporin compound according to claim 1 or 2, wherein the cephalosporin compound is (4) When R^1 is an organic residue whose constituent factor is ▲There is a mathematical formula, chemical formula, table, etc.▼, R^1^3 is a substituted or unsubstituted saturated or unsaturated lower alkyl group, Claim 1, which is a cycloalkyl group, a heterocyclic group, a carboxyl group that may be esterified, a halogen atom, a nitro group, an amino group, a hydroxyl group, a cyano group, a substituted or unsubstituted phenyl group, or a benzyl group The cephalosporin compound according to item 1 or 2. (5) The cephalosporin compound according to claim 1, wherein R^1 is an organic residue having a substituted or unsubstituted aromatic phenyl group. (6) The cephalosporin compound according to claim 1, wherein R^1 is an organic residue having a substituted or unsubstituted alkyl group. (7) The cephalosporin compound according to claim 1, wherein R^1 is an organic residue having a substituted or unsubstituted alicyclic hydrocarbon group. (8) General formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R^1 and R^2 have the same meaning as above,
n is 0 or 1, R^1^4 is a hydrogen atom, a metal atom, an ester residue, a salt-forming cation, or an anionic charge when COO^- forms an intramolecular or extramolecular salt with a cation pair. show. X is a substituted or unsubstituted imidazole compound (
Compounds represented by the general formula (III) (which is a group such as a halogen atom or an acid residue that can be substituted by (B represents the same meaning as above) is reacted with a compound represented by the general formula (IV) ▲ There are numerical formulas, chemical formulas, tables, etc. ▼ (IV) (wherein R^1, R^2, R^3, R^1^4, A, B,
A cephalosporin compound or a salt thereof is obtained (X^ and n have the same meanings as above), and the cephalosporin compound or a salt thereof is further reduced or deprotected as necessary. General formula (I) characterized by being subjected to group reactions, etc. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1, R^2, R^3, n, A and B are respectively A method for producing a cephalosporin compound or a salt thereof, which has the same meaning as above. (9) General formula (V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) (In the formula, R^2, R^3, R^1^4, A, B, X^■ and n are respectively A cephalosporin compound represented by the general formula (VI) R^1 COOH (VI) (in which R^1 has the same meaning as above) is reacted to form the general formula (IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) (In the formula, R^1, R^2, R^3, R^4, A, B, X^
(2) and n have the same meanings as above) or their salts, and further reduce or deprotect the cephalosporin compound or its salts represented by general formula (IV) as necessary. General formula (I) ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R^1, R^2, R^3, n, A and B are respectively A method for producing a cephalosporin compound or a salt thereof, which has the same meaning as above. (10) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1, R^2, R^3, n, A, and B have the same meanings as above.) A prophylactic and therapeutic agent for bacterial infections containing a cephalosporin compound or a salt thereof.