JPH02275886A - Cephalosporin compound and its production - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is (protected) amino; R<2> is (substituted) heterocyclic ring group having 1 to 3 O or S atoms; R<3> is (protected) carboxyl; R<4> is nucleophilic compound residue; R<5> is (protected) carboxyl or COO<->]. EXAMPLE:Sodium 7beta-{(Z)-2-(aminothiazol-4-yl)-2-[(2-furyl)(carboxy)- methyloxyimino]acetamido}-3-[(1-quinolinio)methyl]-3-cephem-4-carboxyl ate. USE:An antimicrobial agent against Gram-positive and Gram-negative bacterial and additive for animal feeds. PREPARATION:An oxyiminoacetic acid compound expressed by formula II [R<11> is (protected) amino; R<31> is (protected) carboxyl] is condensed with a 7- aminocephalosporin compound expressed by formula III [R<51> is (protected) carboxyl or COO<->].

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention provides novel cephalocarbon R''-C with excellent antibacterial activity.
I-R3(1) (However, R1 is an amino group or a protected amino group, R2
is a substituted or unsubstituted heteromonocyclic group having 1 to 3 heteroatoms selected from oxygen atoms and sulfur atoms, R3 is a carboxyl group or a protected carboxyl group, R4 is a nucleophilic compound residue, R5 represents a carboxyl group, a protected carboxyl group, or a group represented by COO-. ) The novel cephalosporin compound (I) of the present invention or a salt thereof has excellent antibacterial activity against a wide variety of microorganisms including Durum-positive bacteria and Durum-negative bacteria, and is a useful pharmaceutical compound as an antibacterial agent. For example, the target compound (1) can be used as a therapeutic agent for various infectious diseases caused by the above-mentioned Durum-positive bacteria and Durum-negative bacteria, as a chemotherapeutic agent for mammals including humans, or as an additive for animal feed.

Specific examples of the object compound of the present invention include -i in formula (1), in which the nucleophilic compound residue represented by R4 is a pyridinio group which may have one substituent acetoxy group; quinolinio group; isoquinolinio group; 2
, 3-cyclopentanopyridinio group, 5,6,7.8-
Tetrahydroquinolinio group; Phenanthrizinio group; Substituted thiacylinio group; Substituted tetrazolylthio group or formula s5
'-R6, where R6 is a lower alkenyl group; a lower alkyl group that may have a substituent; a phenyl group that may have a substituent; or a nitrogen-containing heterocyclic group. Examples include compounds.

Among these, a preferred specific example of the substituted pyridinio group is a pyridinio group having 1 to 3 substituents selected from an amino group, a lower alkyl group, a lower alkoxy group, a carbamoyl group, and a phenyl group (e.g., 3-amino-2- Methylpyridinio group, 5-amino 3-methoxypyridinio group, 3-
Preferred specific examples of the substituted quinolinio group include a quinolinio group substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom (e.g., a 4- or 6-chloroquinolinio group, Preferred specific examples of the substituted thiacylinio group (6-fluoroquinolinio group, 3 or 6-bromoquinolinio group, 4 or 6-methylquinolinio group, 6-medoxyquinolinio group), substituted thiacylinio group or substituted tetrazolylthio group include lower alkyl-substituted thiacylinio group (e.g. , 4-methylthiacylinio group) or lower alkyl-substituted tetrazolylthio group (e.g., 1-methyltetrazol-5-ylthio group), and R6
Among the groups represented by, preferred specific examples of substituted lower alkyl groups, substituted phenyl groups, and nitrogen-containing heterocyclic groups include lower alkylthio groups, phenyl groups, phenyl groups substituted with hydroxyl groups, thiocarbamoyl groups, and N-lower A lower alkyl group having a substituent selected from alkylthiocarbamoyl groups (e.g., methylthiomethyl group, thiocarbamoylmethyl group, thiocarbamoylpropyl group, N-methylthiocarbamoylmethyl group, benzyl group, 3,4-dihydroxyphenethyl group), hydroxyl group and a phenyl group having a substituent selected from amino groups (for example, 4-hydroxyphenyl group, 3.4-dihydroxyphenyl group, 3-amino-4-hydroxyphenyl group), and 2-oxo-pyrrolidinyl group.

In addition, other specific examples of the object compound of the present application include -soft formula (
In 1), R1 is an amino group, R3 is a carboxyl group, and r2s is a carboxyl group or -000-
Examples include compounds that are groups represented by:

More preferred target compounds N) include compounds in which R2 is a furyl group or a thienyl group.

A still more preferable target compound is one in which R4 is a quinolinio group, a 6-chloroquinolinio group, or a formula -SR)-R
' and R4 is a thiocarbamoylmethyl group, 3,4-dihydroxyphenyl group, or 3,4-dihydroxyphenethyl group.

In addition, in the object compound (1) of the present invention, when R1 is a protected amino group, various protecting groups commonly used in the field of peptide synthetic chemistry can be used as the protecting group for this amino group. can. Examples of such protecting groups include lower alkanoyl groups such as formyl, acetyl, and pivaloyl; mono-, di-, or trihalogen groups such as chloroacetyl and trifluoroacetyl;
Lower alkanoyl group; lower alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl group, tert, -butoxycarbonyl group; substituted or unsubstituted benzyloxycarbonyl group such as benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group;
Substituted or unsubstituted phenyl lower alkyl groups such as benzyl group, p-methoxybenzyl group, and 3,4-dimethoxybenzyl group; di- or triphenyl lower alkyl groups such as benzhydryl group and trityl group, and the like.

On the other hand, when R3 and R5 are protected carboxyl groups, it is preferable to use an iN group that can be removed by conventional treatments such as hydrolysis, acid treatment, and reduction as the protecting group for the carboxyl groups. Examples of such protecting groups include lower alkyl groups such as methyl, ethyl, tert, and -7'-thyl groups; substituted or unsubstituted phenyl lower alkyl groups such as benzyl L, p-methoxybenzyl, and p-nitrobenzyl; Groups include benzhydryl groups, tri-lower alkylsilyl groups such as trimethylsilyl groups, and the like.

In addition, the partial structure represented by the formula % in the present invention is represented by the formula (Z)- unless otherwise specified.
Isomers shall mean geometric isomers represented by ([E)-isomers, or mixtures thereof. However, when used as a medicine, the target compound (1) of the present invention has particularly excellent biological properties when the oximino group is in the (Z)-configuration.

According to the present invention, the target compound (1) or a pharmacologically acceptable salt thereof is (A)-soft formula% (wherein R is an amino group or a protected amino group, R3
1 is a carboxyl group or a protected carboxyl group, R
2 has the same meaning as above. ), a salt thereof, or a reactive derivative thereof and the general formula (where XI is a reactive residue, R2, R11, I?ff+
and R5I have the same meanings as above. ), or a cephalosporin compound represented by (V) or a salt thereof is reacted with a nucleophilic compound (V) or a salt thereof, or
or (C)-soft formula (wherein, R5I is a carboxyl group, a protected carboxyl group, or a group represented by -000-, and R4 has the same meaning as above); A cephalosporin compound or a salt thereof represented by (B)-soft formula (wherein R11, R4 and R5I have the same meanings as above) and a general formula (however, Z is a reactive Residues R2 and R31 have the same meanings as above.) or a salt thereof is condensed, and (D)
If R11 is a protected amino group and/or R31 and/or R5I are protected carboxyl groups, the protecting groups are optionally removed, and (E) the product is optionally further modified to improve its pharmacologically acceptable properties. It can be produced by making it into a salt that can be used.

The nucleophilic compound (V) which is a raw material compound of the present invention includes acetic acid, pyridine, pyridine having a substituent (for example,
pyridine having 1 to 3 substituents selected from a lower alkyl group, a lower alkoxy group, an amino group, a carbamoyl group, and a phenyl group), quinoline, a quinoline having a substituent (e.g., a lower alkyl group, a lower alkoxy group, or a halogen quinoline having an atom as a substituent), isoquinoline, 2,3-cyclopentanopyridine, 5,67.8
-Tetrahydroquinoline, phenanthridine, lower alkyl group-substituted thiazole, (substituted tetrazolyl)thiol, or compounds represented by formula 5()-R' (wherein R6 has the same meaning as above), etc. The nuclear compound (V) may be used in the above reaction as its salt (eg, mineral acid salt, alkali metal salt).

In addition, the raw material compounds (II) and (III) (
As the salts of rV), (Vl) and (■), both conventional inorganic salts and organic amine salts can be suitably used.

Compounds (■), (III), (IV), (Vl) and (
In (ii), R1 is a protected amine group and R31,
When R5I is a protected carboxyl group, any of the groups explained as protecting groups for R1, R2 and R5 can be used as these protecting groups.

In the reaction of step (A), the condensation reaction between the free oxyiminoacetic acid compound (II) and the 7-amine cephalosvorin compound (I[[) is carried out in an appropriate solvent in the presence of a dehydrating agent. be able to. Examples of dehydrating agents include:
Any conventional dehydrating agent can be used, such as dicyclohexylcarbodiimide, phosphorus oxychloride, thionyl chloride, oxalyl chloride, or Willsmeier's reagent prepared from dimethylformamide and phosphorus oxychloride, oxalic chloride, phosgene, or thionyl chloride. can. As the solvent, for example, dioxane, tetrahydrofuran, acetonitrile, methylene chloride, chloroform, pyridine, ethanol, water, or a mixture thereof can be suitably used.

This reaction proceeds suitably under cooling to room temperature.

In addition, the condensation reaction between reactive derivatives of oximinoacetic acid compounds (If) (e.g. acid anhydrides, mixed acid anhydrides, activated esters, etc.) and 7-amine cephalosvorin compounds (■) or its salts can be carried out using deoxidizing agents. The reaction, which can be carried out in the presence or absence of , can be carried out in the same solvent as above,
In addition, as a deoxidizing agent, alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogen carbonate, trialkylamine,
The reaction, in which N,N-dialkylaniline, pyridine, etc. can be suitably used, proceeds suitably under cooling to room temperature.

In the reaction of step (B), the starting compound (■) can be a compound whose reactive residue XI is, for example, a carbamoyloxy group, a lower alkanoyloxy group, a halogen atom, etc. The reaction can be suitably carried out in a solvent at room temperature to elevated temperatures. Examples of reaction solvents include water, hydrophilic organic solvents (e.g. dimethylformamide, dimethylacetamide, dioxane, acetone, alcohol, acetonitrile, dimethylsulfonate). oxide, tetrahydrofuran, etc.) or a mixed solution thereof can be suitably used. This reaction is preferably carried out at pH 2 to 8, particularly pH 5 to 8. If desired, in order to improve the reactivity, alkali metal halides, alkali metal thiocyanates, trialkylsilyl trihalogenomethanesulfonates, , an alkali metal hydrogencarbonate, a quaternary ammonium salt having a surfactant effect (for example, tri-lower alkylbefurylammonium halide), or a phosphate buffer solution may be added.

In the reaction of step (C), the raw material compound (■) has a reaction residue Z such as a hydroxyl group, a halogen atom,
The cotton blending reaction in which a compound having an alkylsulfonyl group, an arylsulfonyl group, etc. can be used can be carried out in a suitable solvent in the presence of a dehydrating agent or a deoxidizing agent. Examples of the dehydrating agent include a combination of azodicarboxylic acid di-lower alkyl ester such as azodicarboxylic acid diethyl ester, azodicarboxylic acid dimethyl ester, and azodicarboxylic acid diisopropyl ester, and a phosphine compound such as triphenylphosphine and diphenylmethylphosphine. As the deoxidizing agent, alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogen carbonate, trialkylamine, N,
N-dialkylaniline, pyridine, etc. can be suitably used. As the solvent, for example, dimethylformamide, dimethyl sulfoxide, dioxane, tetrahydrofuran, ether, benzene, toluene, chloroform, methylene chloride, acetonitrile, or a mixture thereof can be suitably used.
~proceeds suitably at room temperature.

In the target compound thus obtained, when the R eye is a protected amino group and/or pal and/or R8I is a protected carboxyl group, the protecting group may be removed if desired. Removal can be carried out according to conventional methods, for example, by hydrolysis, solvolysis, acid treatment, reduction, etc. depending on the type of protecting group, or by an appropriate combination of these.

The object compound (1) of the present invention or a salt thereof is a compound of the genus Enterococcus (for example,
Enterococcus fuecalis (n, faecal)
is)), Staphylococcus (Staphy Io)
coccus) (e.g., Staphylococcus aureus (S, aureus), Staphylococcus aureus)
Epidermizois (S, epidermidis)
, Talebsiella genus (e.g., Talebsiella pneumoniae (K, pneumonia)
ae)), the genus MorBanella (e.g. Morganella morganii (M, +norgani)
i) Citrobacter genus (e.g. Citrobacter).

C. freundit and Pseudomonas genera (e.g. P. aeruginosa)
), etc., and exhibits excellent antibacterial activity against both Durham-positive and Durham-negative bacteria.

For example, the 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-[(S)(2-furyl)(
Carboxy)methyloxyimino]acetamide l-3-
[(1-quinolinio)methyl]-3-cephemu 4-carboxylate sodium salt of Enterococcus faecalis (E, faecalis) CN-478,
Morganella morganii (M, morganii) 65
01. Talebsiella pneumoniae (K, pneum)
The antibacterial activity against C. oniae) 5038 and Citrobacter freundii (C. freundii) GN-346 is 4 times or more superior to that of cefdasidime.

Furthermore, 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-[(2-thienyl)(carboxy)methyloxyimino]acetamide)-3-[(1
-thiocarbamoylmethyl-4-pyridinio)thiomethyl]-3-cephemu 4-carboxylate sodium salt, 7β-[(Z)-2-(2-aminothiazole-
4-yl)-2-[(2-furyl)(carboxy)methyloxyimino]acetamide)-3-[(1-thiocarbamoylmethyl-4-pyridinio)thiomethyl)-3
-Cephem-4-carboxylate sodium salt and 7θ-[(Z)-2-(2-aminothiazol-4-yl)-2-[(2-furyl)(carboxy)methyloxyimino]acetamide)-3 -The antibacterial activity of [(6-chloro-1-quinolinio)methyl]-3-cephemu 4-carboxylate sodium salt against Staphylococcus aureus (S, aureus) 209P JC-1 is also more than 4 times that of ceftazidime. Are better.

Furthermore, the 7β-[(Z)-2-(,2-aminothiazol-4-yl)-2-[(2-furyl)(carboxy)methyloxyimino)acetamide)-3-[
[1-(3,4-dihydroxyphenyl)-4-pyridinio]thiomethyl)-3-cephem-4-carboxylate sodium salt and 7β-[(Z)-2-(2-aminothiazol-4-yl) -2- [(2-Frill)(
carboxy)methyloxyimino]acetamide)-3[
(1-(3,4-dihydroxyphenethyl)-4-pyridinio]thiomethyl)-3-cephem-4-carboxylate sodium salt is 322 times more effective against Pseudomonas aeruginosa (P, aeruginosa) 35R than ceftazidime. It shows excellent antibacterial activity.

In addition, the target compound (N or a salt thereof) is a compound of the genus Escherichia (e.g., Escherichia coli CE, coli), Proteus (Pro t
eus) genera (e.g. Proteus reteigeri (r',
re Ltger i)), Enterobacter (E
nterobacter) genus (e.g., Enterobacter aerogenes (E, aerogeneS), Enterobacter cloacae (E, cloacae))
, Serratia genus (e.g., Serratia marcescens (S, marcescens)
s)), or Shigella (
Shige'l Ia) genus, Salmonella
It also exhibits excellent antibacterial activity against bacteria belonging to the genus Ella. Furthermore, since the target compound (1) or its salt is well absorbed by biological tissue and its therapeutic effect lasts for a long time, it is effective against various bacterial infections including Staphylococcus aureus and Pseudomonas aeruginosa. It shows excellent defensive effect against. Furthermore, the target compound (I) or a salt thereof is characterized by good stability against various β-lactamase producing bacteria. In addition, the target compound N
) or its salts have low toxicity and exhibit high safety as pharmaceuticals.

The object compound (1) of the present invention can be used for pharmaceutical purposes either in free form or in the form of a pharmacologically acceptable salt. Such pharmacologically acceptable salts include, for example, non-toxic metal salts such as sodium salts, potassium salts, calcium salts, magnesium salts, aluminum salts; trialkylamines (e.g. triethylamine), pyridine, ethanolamine, 1-ly Salts with non-maternal amines such as ethanolamine and dicyclohexylamine; Salts with inorganic acids such as hydrochloric acid, sulfuric acid and hydrobromic acid; Salts with organic acids such as oxalic acid and tartaric acid; Glycine, lysine, arginine, asparagine Examples include addition salts with acids and amino acids such as glutamic acid. Further, the salt of the target compound (1) is in the form of a salt with a resin formed from, for example, a polystyrene resin containing an amino group, a quaternary amine group, or a sulfonic acid group, or a resin containing a carboxyl group, such as a polyacrylic acid resin. Good too. Furthermore, 11 may be a metal such as iron or copper or an ammonium salt such as ammonium chloride. Therefore, the object compound (1) of the present invention and its salts should be interpreted to include any of its inner salts, adducts, complexes, solvates, hydrates, etc.

The object compound (1) of the present invention or a salt thereof can be administered orally or parenterally (e.g., intravenously, intramuscularly, subcutaneously), and can be administered in the form of tablets, granules, etc. by conventional methods.
It can be used as appropriate pharmaceutical preparations such as capsules, powders, and injections.

The dosage of the object compound (1) of the present invention or its salt is:
Depending on the method of administration, age, weight, condition of the patient, and type of disease being treated, it is usually about 2 to 2 doses per day.
00 mg/kg, particularly preferably about 5 to 40 mg/kg.

Further, in the present invention, the formulas in the target compound (1), the starting compound (IT), (■) and (■) (where * represents that the carbon atom is an asymmetric carbon atom, R2,
R3 and R31 have the same meanings as above. ) There are optically active forms based on the partial structure shown below, and the present invention includes both these optically active forms and racemic forms.

In addition, the raw material thiazuryl acetic acid derivative (If) of the method of the present invention
is a new compound, for example - soft type (however, -CO□Y
is a carboxyl group or a protected carboxyl group, R
11 has the same meaning as above. ) and the compound (■) to form a compound represented by the general formula % (however, the symbols have the same meanings as above), or the compound (■) and the N-hydroxy Phthalimide is reacted with an alkali metal salt to form a compound represented by the following formula (however, the symbols have the same meanings as above), and the compound (X) is treated with lower alkylhydrazine to form the general formula (X): The symbols have the same meanings as above.), and the compound (IXI) is reacted with a glyoxylic acid compound represented by -soft formula (the symbols have the same meanings as above) to form the compound (IXI). ), and then, if desired, the protecting group can be removed.

The reaction between compound (■) and compound (■) can be carried out in the same manner as in step (C) for producing the target compound. The reaction between compound (■) and the alkali metal salt of N-hydroxyphthalimide is preferably carried out in a suitable solvent (eg, dimethylformamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, or a mixture thereof) under cooling. The treatment of compound (X) with a lower alkylhydrazine (e.g., methylhydrazine) can be carried out using a suitable solvent (e.g., methylene chloride, chloroform, acetonitrile, tetrahydrofuran, and a mixture thereof).
It can be carried out under medium cooling. Compound (XI) and (
The reaction with
Among them, it is preferable to carry out the reaction in the presence or absence of a base (eg, alkali metal bicarbonate, alkali metal carbonate, alkali metal hydroxide) for p II clause 11 under cooling to heating. Removal of the protecting group from the compound (IX) thus obtained can be carried out by hydrolysis, solvolysis, acid treatment, reduction, etc., depending on the type of the protecting group, or by an appropriate combination of these.

Example 1 (1) 7-amitsef 70 suboranic acid (0.65g)
Add 1.3~bis(trimethylsilyl)urea (t, +7g) to a suspension of 1.3~bis(trimethylsilyl)urea (t, +7g) in acetonitrile (6ml) under water cooling, and stir at room temperature for 4 hours (the resulting solution is referred to as Solution A'').Meanwhile, 2-(2-tritylaminothiazol-4-yl)-2-[(2-thienyl) (tar
t,-butyloxycarbonyl)methyloxyimino]
Acetic acid (1,25 g) 1-hydroxybenzotriazole (0,3 g) and dicyclohexylcarbodiimide (0
, 45 g) in dimethylformamide (6 ml) is stirred at room temperature for 1.5 hours (the resulting suspension is referred to as "suspension B 11"). Solution A is ice-cooled under a stream of argon and this After dropping Suspension B into the solution, the mixture is stirred at room temperature for 22 hours. The mixture is poured into ice water and extracted with ethyl acetate. The extract is washed with brine, dried, and the solvent is distilled off under reduced pressure.

The residue was dissolved in tetrahydrofuran (20 ml), diphenyldiazomethane (1.15 g) was added, and the mixture was stirred at room temperature for 2 hours. The mixture is poured into ice water and extracted with ethyl acetate. The extract is washed with aqueous sodium bicarbonate and brine, dried, and then the solvent is distilled off under reduced pressure. By purifying the residue with silica gel chromatography (solvent: hexane-ethyl acetate-chloroform), 7β-[(Z)-
2-(2-)ditylaminothiazol-4-yl)-2
-[(2-thienyl) (tert, -butyloxycarbonyl)methyloxyimino]acetamido)cephalosporanic acid diphenylmethyl ester (0.85 g)
It is obtained as a pale Rr colored powder.

IR1/c+a-': 32B0. 179
0. 1730. 1680M5 (III/Z):
1046 (Mfl”) (2) Main island (0,82
Water (1 ml) was added dropwise to a solution of g) in formic acid (4 ml), and the mixture was stirred at room temperature for 1.5 hours. The mixture is filtered and the filtrate is concentrated under reduced pressure to remove the solvent. Anisole on the residue (5m
After cooling with water, add trifluoroacetic acid (5 ml) and stir at room temperature for 4 hours. The mixture is concentrated under reduced pressure to remove the solvent. The residue is triturated with isopropyl ether and filtered. Dissolve this powder in sodium bicarbonate water and use nonionic adsorption resin (product name: Diaion IIP-).
Purify by column chromatography (eluent, water) packed with 20, manufactured by Mitsubishi Kasei Co., Ltd., hereinafter referred to as IIP-20). After collecting and concentrating the fractions containing the target product,
By freeze-drying, 7β-[(Z)-2-(2-
Aminothiazol-4-yl)-2-[(2-thienyl)(carboxy)methyloxyimino]acetamido)cephalosporanic acid disodium salt (0.31 g, yield 64%) is obtained as a colorless powder.

m, p, > 150°C (decomposed) IRνcm −': 3340. 3200. L
760. 1600MS (m/z): 626 (
MH"") NMR (020) δ: 2. IH311
, s), 3.21 (III, d, J = 1811
z) 3.54 (III, d, J = 1811z),
4.70 (IH, d, J = 1211z).

4.89 (111, d, J= 12112), 5.
09 (IH, d, J = 4.811z).

5.72 (III, d, J = 4.811z), 5
．． 77 (III, s), 7.04 (LH.

s), 7.07 (ill, d, d, J= 5.4.
3. ll1z), 7.25 (Ill, d.

J= 3.1Hz), 7.48(IH, dd, J=
5.4. fHz) Example 2 Phosphorous oxychloride (0.73 g) and methylene chloride (3 ml) were sequentially added to dimethylformamide (0.57 g) under an argon stream and water cooling, and after stirring at room temperature for 1 hour -60
Cool to °C. Add 2-(2-)ditylaminothiazol-4-yl)-2-[(2-furyl) to this mixture.
(diphenylmethyloxycarbonyl)methyloxyimino)acetic acid (247g) in methylene chloride (25ml)
Add the solution dropwise and stir for 50 minutes at -60 to -55°C (resulting solution is referred to as "reaction@A"). On the other hand, add 7 ml of bis(trimethylsilyl)acetamide (3.85 ml).
- Amitusephalosborane acid (1.42 g) was added to a suspension of methylene chloride (15 ml) under an argon atmosphere and water-cooled, and the mixture was stirred at room temperature for 40 minutes (the resulting solution was referred to as "reaction solution B t+"). Reaction solution A was cooled to -60°C, reaction solution B was added dropwise to this solution, and then the reaction solution was heated at -60 to -30°C for 2.5 hours.
Stir for an hour. After the reaction, the mixture was poured into ice water and extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off to give 7β-[(Z)-2-(2-)lytylaminothiazol-4-yl)-2-[(2-furyl)(diphenylmethyloxycarbonyl ) Methyloxyimino)acetamido)cephalosporanic acid (3.37 g) is obtained as crude product.

(2) This crude product (3.37g) was mixed with formic acid (45ml).
While cooling with water, add water (5 ml) and stir at room temperature for 6 hours. After the reaction, water (5 ml) is added to the mixture, insoluble materials are filtered off, and the filtrate is concentrated to remove the solvent. Ethanol was added to the residue, the precipitate was collected by filtration, washed with ether, and dried to give 7β-[(Z)-2-(2-aminothiazol-4-yl')-2-[(2-furyl ) (carboxy)methyloxyimino]acetamido)cephalosporanic acid (1.58 g, yield 84%) is obtained as a pale yellow powder.

m, p, >150"C (decomposition) lRvcm -': 3300. 3200. 2
200-2800 1770M5 (III/z):
566 (Mll"") NMR (DMSO-di) δ
: 2.03 (311,s), 3.24-3.80
(4i1゜m), 4.67 and 4.69 (111, d
X2. J = 13.711z and 12,7112)
, 4.99 and 5.00 (ltl, d X2.J=
12.711z and 13.711z), 5.07 and 5.12 (ill, d X2.J, 4.911z and 4.9Hz), 5.62 and 5.65 (Ill,
5x2).

5.75 and 5.79 (Ill, dX2.J=4.
911z and 4.9JIz) 6.50 (III, rM)
, 6.58(1)1. m), 6.80 and 5.82
(Ill.

5X2), 7.71 (Ill, s), 9.54
(Ill, d, J = 7.811z) Main island disodium salt: I, p, >160°C (decomposition) MS (n+/z); 610 (Mll”) Example 3 (1) 2-(2 -tritylaminothiazol-4yl)-2-C(S)-(2-furyl)(diphenylmethyloxycarbonyl)methyloxyimino]acetic acid (64
1■) and 7-aminocephalosporanic acid (413■)
By treating in the same manner as in Example 2-(1), 7β
-[(Z)-2-(2-tritylaminothiazole-4
-yl)-2-[(S)-(2-furyl)(diphenylmethyloxycarbonyl)methyloxyimino)acetamido)cephalosporanic acid (727 µ, yield 84%) is obtained.

m, p, 188-189°C (decomposition) [α) o
+19.7° (C=1.0, chloroform) (2)
Example 2-
By processing in the same manner as (2), 7β-[(Z)-
2-(2-aminothiazol-4yl)-2-[(S)
-(2-furyl)(carboxy)methyloxyimino]
Acetamide) cephalosporanic acid (454) is obtained as a pale yellow powder.

m, p, > 150°C (decomposition) 1630, 1220. 1020. 750MS (m
/z): 566 (M1 yen, 309.154.13
7NMR (DMSO-d,) δ: 2.04 (3H, s
), 2.9 to 3.80 (211+11zO), 4.
67 (Ill, d, J=12.711z), 4.98
(III, d, J=12.711z), 5.07(I
II, d, J=5.411z), 5.59 (III,
s).

5.77 (111, dd, J=4.9, 7.811z)
, 6.49 (III, dd, J=2°0.3.411
z), 6.5-6.6 (III, n+), 6.80
(411,s), 7.1~7.3 (2111m)+
7.6~7.7 (1'll, m), 9.5~9゜6
(LH,m) Example 4 (1) 2-(2-1-ditylaminothiazole-4
-yl)-2,-[(R)-(2-furyl)(diphenylmethyloxycarbonyl)methyloxyim/)if
f (721 mg) and 7-aminocephalosporanic acid (
463■) in the same manner as in Example 2-(1) to obtain 7β-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-[(R)-(2- Frill) (
Diphenylmethyloxycarbonyl)methyloxyimino]acetamido)cephalosporanic acid (912 mg, yield 94%) is obtained.

m, p, 151-153°C (decomposition) (2) Ice crystals (
900 mg) and 98% formic acid (10d) in Example 2-(2
), 7β-[(Z)-2-
(2-aminothiazol-4-yl)-2-[(R)-
(2-furyl)(carboxy)methyloxyimino)acetamido)cephalosporanic acid (570 mg) is obtained as a pale yellow powder.

m, p, > 150°C (decomposition) 1630.1230, 1030.750M5 (n+/z
): 566 (Mll”), 506.44
2. 167, 154NMR (mouth MSO-da)
δ: 2.04 (311,s), 3.0~3
．． 60 (I11+HzO, m), 3.6 (III,
d, J=18.111z), 4.69(III, d
, J=12.711z), 5.00 (Ill,
d, J=12.7+1z), 5.12(ill, d
, J=4.911z), 5.63(Ill,s
), 5.77 (III, dd, J-4, 9, 7, 8
11z), 6.49 (III, dd, J=1.7,
3.2Hz), 6.59 (Ill, d, J=3.4
11z), 6.79 (III, s), 7.1
~7.3 (211, m), 7.6 ~ 7.7 (III, m
), 9.57 (III, d, J = 7.8 Hz).

13.0-14.0 (211,brm) Example 5 2-(2-1 lythylaminothiazol-4-yl)-2
-[(3-thienyl)(diphenylmethyloxycarbonyl)methyloxyimino)acetic acid (4,12 g) and 7
-Aminocephalosporanic acid (2.29g) in Example 2
- Process in the same way as (1) to obtain 7β-[(Z)-2-(2
-tritylaminothiazol-4-yl)-2-[(3
-thienyl) (diphenylmethyloxycarbonyl) methyloxyimino] acetamide) cephalosporanic acid (
6.07 g) are obtained as crude product.

After treating the ice crystals in the same manner as in Example 2-(2), the residue is dissolved in water and sodium bicarbonate water, and purified by HP-20 column chromatography (eluent: water and 5% methanol water). After collecting and concentrating the fractions containing the target product, the residue was lyophilized to obtain 7β-[(Z)
-(2-aminothiazol-4-yl)-2-[(3-
thienyl)(carboxy)methyloxyimino]acetamido)cephalosporanic acid disodium salt (2,39
g, yield 76%) as a pale yellow powder.

i, p, > 150°C (decomposition) MS (m/z): 648 (MNa”), 626 (M
ll”) NMR (Il, 0) δ: 2.106 and 2.
114 (311,5X2), 3.23 (111,d,
J = 1811z), 3.54 and 3.55 (III
, dX2. J=1311z and 1811z), 4.7
0 and 4.73 (III, dX2.J = 12112 and 1311z), 4.87 and 4.88 (IH, dx2
．． J=12112 and 1311z), 5.095 and 5.101(ill, dX2°J=4.411z and 4
．． 911z), 5.64 (III, brs), 5.
73 and 5.76 (Ill, dX2.J-4,411z
and 4.911z), 7.03(Ill,s),
7.22 (III, dd J= 4.9, 1.511z
), 7.45 (IIt, dd J= 4.9.2.
911z), 7.54 (Ill, m) Example 6 2-(2-tritylaminothiazol-4-yl)-2
-[(3-furyl)(diphenylmethyloxycarbonyl)methyloxyimino)acetic acid (5,08g) and 7-
Example 2- Aminocephalosporanic acid (2,87 g)
By processing in the same manner as in (1), 7β-[(Z)-
2-(2-)lythylaminothiazol-4-yl)-2
-[(3furyl)(diphenylmethyloxycarbonyl)methyloxyimino)acetamido)cephalosporanic acid (9.29 g) is obtained as a crude product.

After treating ice crystals in the same manner as in Example 2-(2), HP-20
Purify by column chromatography (eluent: water and 20% methanol/water). After collecting and concentrating the fractions containing the target product, the residue is freeze-dried to obtain 7β.
-[(Z)-2-(2-aminothiazol-4-yl)
-2-[(3-furyl)(carboxy)methyloxyimino)acetamido)cephalosporanic acid disodium salt (273 g, yield 63%) is obtained as a pale yellow powder.

m, p,: 189-190°C (decomposition) MS
(m/z):632(MNa”)NMR(0,0)δ:
2.10 (311,s), 3.29 (III
, d, J= 18.111z), 3.59 and 3.
60 (Ill, d X2.J-18, 111z and J=
18.111z), 4.71(III, d, J=1
2.711z), 4.89 (III.

d, J=12.711z), 5.13 and 5.15(
III, d X2. J=4°9flz and 4.911z
), 5.53 and 5.54 (III, s X 2
).

5.76 and 5.80 (111, dX2.J-4,91
1z and 4.911z), 6.58 (III, d, J
=111z), 7.04(111,s), 7.
51 (III.

t), 7.67 (111, d) Example 7 (1) (R)-2-furyl-2-hydroxyacetic acid diphenyl methyl ester (0,31 g), 7β-[(Z)
-2-(2-)ditylaminothiazol-4-yl)-
Azodicarboxylic acid diethyl ester (2-hydroxyiminoacetamide) was added to a solution of cephalosporanic acid diphenylmethyl ester (0.85 g) and triphenylphosphine (0.39 g) in tetrahydrofuran (15 d).
0.24 μm) was added dropwise under an argon atmosphere at -60°C. After stirring at the same temperature for 30 minutes, the mixture was stirred at room temperature for 20 hours.

The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: ethyl acetate-hexane) to give 7β-[(Z)-2-(2-1-ditylaminothiazol-4-yl)- 2-[(S)(2-furyl)(diphenylmethyloxycarbonyl)methyloxyimino]acetamido)cephalosporanic acid diphenylmethyl ester (0.3 g) is obtained as a pale yellow powder.

ga, p,: 110-113 °C (decomposition) (2) Honjima (0.28 g) and 98% formic acid (5d) were prepared in Example 2-(
By processing in the same manner as in 2), 7β-[(Z)-2-
(2-aminothiazol-4-yl) -2-[(S)
-(2-furyl)(carboxy)methyloxyimino]acetamido)cephalosporanic acid (0.13 g) is obtained as a pale yellow powder.

The physicochemical properties of the main island matched those of the specimen obtained in Example 3-(2).

Example 8 7β-amino-3-[(1-quinolinio)methyl)-3
-Cephem-4-carboxylate (034g) in water (
Triethylamine (1.8 ml) was added dropwise to a suspension of 2.2 ml) and ethanol (35 ml) at -20 to 15°C, and the mixture was stirred for 10 minutes at the same temperature (the resulting solution is referred to as "reaction solution A"). ).

On the other hand, (Z)-2-(2-tritylaminothiazole-
4-yl)-2-[(S)-(2-furyl)(diphenylmethyloxycarbonyl)methyloxyimino]acetic acid (0,72 g) in dimethylacetamide (1,5d) and methylene chloride (1,5ml) ) to the solution, -25 to -20°
Add phosphorus oxychloride (0,37d) dropwise at C to -10~
Stir at -5°C for 5 minutes and at -40°C for 30 minutes (the resulting solution is referred to as Reaction Solution B 11)0 Reaction Solution A
was added to reaction solution B, stirred at -35 to -25°C for 30 minutes, and then dissolved in water. The mixture was extracted with methylene chloride, the extract was washed with water, and the solvent was distilled off after drying to obtain crude 7β-[(Z)-2-()ditylaminothiazole-4.
-yl)-2-[(S)-(2-furyl)(diphenylmethyloxycarbonyl)methyloxyimino)acetamide)-3-[(1quinolinio)methyl]-3-cephemu 4-carboxylate (1,0g ) was obtained as a pale yellow solid. This product was dissolved in formic acid (12d), and water (3d) was dissolved in formic acid (12d).
) and stir at room temperature for 14 hours. Filter the precipitate,
Wash with 80% formic acid. The filtrate and washing liquid are combined and concentrated under reduced pressure, and aqueous acetonitrile is added to the residue. After adjusting the pH to about 8 with saturated sodium bicarbonate water and distilling off acetonitrile, the aqueous layer is purified by HP-20 column chromatography (eluent: water-20% methanol water). 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-[(S)-(2- Furyl)(carboxy)methyloxyimino)acetamide)-3-[(1-quinolinio)methyl)-3-cephem-4-carboxylate sodium salt (265■) is obtained as a pale yellow powder.

m, p, >170°C (decomposition) MS (m/z): 679 (MNa”), 657 (Ml
1, 484,309.177°139,119 NMR (D, O) δ: 2.88 (III, d, J=
17.111z), 3.37(III, d, J=1
8.611z), 5.12 (1!I, d, J=4.
911z), 5.62 (III, s), 5.7
6 (Ill, d, J-4, 4! Iz), 5.86 (
III, d, J=15.111z), 5.95(1
11, d, J=, 16.111z), 6.19(I
II, dd, J=2.0.3.411z), 6.4
8 (III, d, J = 3.411z), 6.98 (
III, s).

7.29 (III, d, J=1.0Hz), 7.9
-8.1 (211, m), 8.1-8.3 (111
, ++), 8.41 (Ill, d, J=8.311
z), 8.51 (III, d, J=9.311z)
, 9.19 (Ill, d, J=8.311z),
9.27 (III.

d, J=5.911z) Example 9 7β-amino-3-[(1-pyridinio)methyl)-3
-cephem-4-carboxylate (096 g) in methylene chloride (5 ml) and acetonitrile (5++i)
The suspension was cooled to -10°C, and 26 ml of bis(trimethylsilyl) was added dropwise to the t8 solution, followed by stirring at -10 to -5°C for 2 hours (the resulting solution was referred to as "reaction solution A").

On the other hand, dimethylformamide (0.26 g) was mixed with phosphorus oxychloride (0.34 g) in methylene chloride (2 ml).
) The solution was added dropwise while stirring with water cooling, and after stirring at room temperature for 50 minutes,
Cool to -60°C. To this solution was added 2-(2-tritylaminothiazol-4-yl)-2-[(2-thienyl) (tert.-butyloxycarbonyl)methyloxyimino]acetic acid (1.25 g) in methylene chloride (8 ml). Add the solution dropwise and stir at -60"C for 50 minutes (the resulting solution is referred to as reaction solution B++). Add reaction solution A to reaction solution B at -60"C, and stir at -60"C for 50 minutes.
After stirring at -20°C for 50 minutes, water was added to terminate the reaction, and the mixture was extracted with methylene chloride. After washing the extract with water and drying, the solvent is distilled off, and the residue is pulverized with ether and filtered. Dissolve this powder (lOg) in formic acid (6a+1), add water (1.5 ml) while cooling with water, stir at room temperature for 1.5 hours, and then filter. The filtrate was concentrated under reduced pressure, trifluoroacetic acid (5n+1) and anisole (5 ml) were added to the residue, and the mixture was stirred at room temperature for 4 hours. Add ether to the mixture and filter the resulting powder. This powder is dissolved in water and sodium bicarbonate water, and purified by HP-20 column chromatography (eluent: water).

7β-[(Z)-2- (2
-aminothiazol-4-yl)-2-((2-thienyl)(carboxy)methyloxyimino)acetamide)-3-((1-pyridinio)methyl]-3-cephemu 4-carboxylate sodium salt (0. 3
g) is obtained as a pale yellow powder.

m. p. >150'C (decomposition) NMR (DzO
) δ: 2.92 (Ill, d, J = 1811z
), 3.52 (Ill, d.

J= 1811z), 5.16(ill,d,J
= 4.911z), 5.26(III, d.

J = 1411z), 5.56 (III, d, J
= 141! z), 5.76 (III, m).

5,76(ill,s), 6.9HIIl,dd)
, 6.99(Ill,s), 7.19(III
, m), 7.33 (III, dd), 8.09
(211, t), 8.58 (211, tJ= 7
．． 811z), 8.94(211,d,J=5
．． 9Hz) Example IO (1) 7β-amino-3-[(1-methyl-IH-tetrazol-5-yl)thiomethyl]-3-cephemu 4
-Carboxylic acid (0.79g) in methylene chloride (7mt)
Bis(trimethylsilyl)acetamide (2.1
4 ml) was soaked in water-cooling and stirred at room temperature for 1 hour (the resulting solution is referred to as reaction solution A').Meanwhile, dimethylformamide (026 g) was mixed with phosphorus oxychloride (0.3 g) and stirred at room temperature for 1 hour.
A solution of 4g) of methylene chloride (1n+1) was added dropwise to the mixture while stirring with water cooling, and after stirring at room temperature for 50 minutes, the mixture was cooled to -60°C.

Add 2-(2-)lytylaminothiazol-4-yl)-2-[(2-thienyl) (tert.butyloxycarbonyl)methyloxyimino]acetic acid (1.
A solution of 25 g) in methylene chloride (9 ml) was added dropwise at -60°C and stirred for 1 hour at the same temperature (the resulting solution is referred to as "Reaction Solution B"). Reaction Solution A was changed to Reaction Solution B. Dropwise at -60°C, then 1,5 times at -60 to -20'C.
Stir for an hour. Add water to the mixture and extract with chloroform. Wash the extract with water, dry it, and then evaporate the solvent under reduced pressure.
The residue was dissolved in tetrahydrofuran (20 ml), diphenyldiazomethane (12 g) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel chromatography (solvent: hexane-ethyl acetate) to obtain 7β-[(Z)-2
-(2-)ditylaminothiazol-4-yl)-2-
[(2-thienyl) (tert, -butyloxycarbonyl)methyloxyimino]acetamide)-3-[
(1-Methyl-IH-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester (0.96 g) is obtained as a powder.

MS (a+/z): 11l102('') (2) Dissolve Honjima (0.88 g) in formic acid (8aI), add water (21) under water cooling, and stir at room temperature for 2 hours. Filter the insoluble matter. The filtrate is concentrated under reduced pressure to remove the solvent.The residue (
Anisole (5aI) and trifluoroacetic acid (5ail) were added to 0.76 g) under water cooling, and after stirring at room temperature for 4 hours, the solvent was distilled off under reduced pressure. Add hexane to the residue and filter the resulting powder. This powder is dissolved in water and sodium bicarbonate water, and purified by HP-20 column chromatography (eluent: water). By collecting the fractions containing the target substance, concentrating them, and freeze-drying them, 7β
-[(Z)-2-(2-aminothiazol-4-yl)
-2-[(2-thienyl)(carboxy)methyloxyimino]acetamide)-3-[(1-methyl-IH-tetrazol-5-yl)thiomethyl)-3-cephem-
4-carboxylic acid disodium salt (0.25 g) is obtained as a pale yellow powder.

Soku, p, >180°C (decomposition) MS (m/z): 6B2 (Mll”) NMR
(D!0) δ: 3.25 (111, d, J-1811
z), 3.62 and 3°64(1)f, dX2. J-
18Hz and 18Hz), 4.00 and 4°02 (I
H, dX2. J-1311z and 13112), 4.
02 and 4゜03 (311,5X2), 4.29 and 4.32 (01,d X2.J-1311z and 131
1z) , 5.05 and 5.06 (III, d X2
．． J-4,911z and 4.911z), 5.65
and 5.68 (III, d X2.J=4.9Hz and 4.911z), 5.78 (III, s), 7.0
3 (211, m), 7.24 (111, d), 7
．． 46(III, d) Example 11 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-[(2-thienyl)(carboxy)methyloxyimino]acetamide)cephalosboranic acid・Disodium salt (0.94 g), 5-formylamino-3-methoxypyridine (069 g) and sodium iodide (2
, 25 g) in water (20 ml) at 80°C and stirred at the same temperature for 50 minutes under an argon stream. After cooling, the mixture was purified by HP-20 column chromatography (eluent: water and 15% methanol aqueous solution), and the solvent was distilled off under reduced pressure. By freeze-drying the residue, 7β-[(Z
)-2-(2-aminothiazol-4-yl)-2-[
(2-thienyl)(carboxy)methyloxyimino)
acetamido)-3-[(5-formylamino-3-methoxy-1-pyridinio)methyl]-3-cephem-4-
Sodium carboxylate salt (0.51 g) obtained as pale yellow powder (0.51 g) in 5% hydrochloric acid (6
aI)g The suspension is stirred at 4°C for 50 minutes and then cooled.

The mixture was made alkaline with sodium bicarbonate water and HP
-20 column chromatography (eluent: 10% methanol aqueous solution). By collecting the fractions containing the target substance, concentrating them, and freeze-drying them, 7β
-[(Z)-2-(2-aminothiazol-4-yl)
-2-[(2-thienyl)(carboxy)methyloxyimino]acetamide)-3-[(5-amino-3-methoxy-1-pyridinio)methyl]-3-cephem-4-
The sodium carboxylate salt (0.35 g) is obtained as a pale yellow powder.

Heel, p, >150'C (decomposition) MS (a+/z): 66B (Mll'') NMR (
D, 0) δ: 2.75 and 2.84 (III, d
2. J-1811z and 1811z), 3.42 and 3.47 (III, d X2.J.

1811z and 1811z), 3.89 and 3.90
31! , s X2), 4.92 and 4.94 (111
, dX2. J-1511z and 1511z), 5.3
5 and 5.37 (111, dX2.J = 1511z and 1511z), 5.68. and 5.70 (Ill,
dX2. J=4.9112 and 4.9Hz), 5.
76 (III, s), 6.88 (1!I, m).

6.93 and 6.95 (III, s, X2), 7
．． 18 (211, m).

7.33 (III, dd), 7.87 (211, m
) Example 12 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-[(2-furyl)(carboxy)methyloxyimino)acetamide)cephalosporanic acid disodium salt and 3 -Formylamino-2-methylpyridine was treated in the same manner as in Example 11 to produce 7β-[(Z
) -2-(2-aminothiazol-4-yl)-2-
[(2-furyl)(carboxy)methyloxyimino]
acetamide) -3-[(3-amino-2-methyl-1
-pyridinio)methylgo 3-cephem-4-carboxylate sodium salt is obtained.

m, p, > 200°C (decomposed) IRVcm −': 3360. 3200 (Sh)
, 1770°1610 (br) MS (m/z): 65B (MNatsu NMR (Dlo
) δ: 2.55 (3) 1. s), 2.87 and 2.
89 (lIl, dX2.J= 1811z and 1811
2), 3.27 and 3.29 (111, d X2.J
-18Hz and 18Hz), 5.12(Ill, d
.

J-4,911z), 5.30(ill,brd),
5.5H111, d, J-16fiz), 5.6
1 and 5.63 (111,5X2), 5.74 and 5
．． 77 (III, d X2.J-4, 911z and 4.
911z), 6.32-6.37(III, m),
6.50 and 6.53 (III, dX2.J・2.9
11z and 3.411z), 7.02 (III,
s), 7.43 (Ill, s), 7.55-7
．． 61 (Ill, m), 7.71 (III, d, J=7
．． 311z), 8.07 (IO,d, J-5,91
1z) Example 13 (1) Under an argon stream, trimethylsilyltrifluoromethanesulfonate (1,4d) was added to a solution of quinoline (1,1 g) in methylene chloride (10 ml), stirred at room temperature for 10 minutes, and 7β-[ (Z)-2-(tritylaminothiazol-4-yl)-2-[(S)-(2-furyl)(diphenylmethyloxycarbonyl)methyloxyimino)acetamido)cephalosporanic acid (974
After adding (2), the mixture was further stirred at room temperature for 7 hours. The solvent was distilled off, ether and water were added to the residue, and after stirring, the supernatant was removed. Water was added to the residue, the precipitate was collected by filtration, washed, and dried under reduced pressure to give 7β-[(Z)-2-()ditylaminothiazol-4-yl)-2-[(S)-( 2
-furyl)(diphenylmethyloxycarbonyl)methyloxyimino)acetamide)-3-[(1mquinolinio)methylgo 3-cephem-4-carboxylate(
630 mg) as a pale yellow powder.

m, p, 143-145℃ (decomposition) MS (m/z
): 101043(”)(2) Main island (1.04g)
Add water (3d) to a solution of formic acid (12m) and prepare 12m at room temperature.
Stir for an hour. The precipitate is filtered off and washed with 80% formic acid. The filtrate and washing liquid are combined and concentrated under reduced pressure, and aqueous acetonitrile is added to the residue. pl with sodium bicarbonate water
+ about 8, and after distilling off the acetonitrile, the aqueous layer was heated to HP-2.
0 column chromatography (? Eluate: water - 20%
Purify with methanol/water). By collecting fractions containing the target substance, concentrating them, and freeze-drying the residue,
7β-[(Z)-2-(2-aminothiazol-4-yl)-2-[(S)-(2-furyl)(carboxy)methyloxyimino]acetamide)-3-[(1-quinolinio) Methylgo 3-cephem-4-carboxylate sodium salt (265 .mu.) is obtained as a pale yellow powder.

The physicochemical properties of the main island were consistent with the specimen obtained in Example 8.

Example 14 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-[(2-furyl)(carboxy)methyloxyimino)acetamide)cephalosporanic acid disodium salt (0, 85g), quinoline (0.90g) and sodium iodide (210g) were dissolved in a mixture of water (15d) and acetonitrile (5mA), and acetic acid was added dropwise to p.
Let H be 65. After stirring the mixture at 80° C. for 1 hour under a stream of argon, the solvent was distilled off. Adjust the pH to 8.2 with an aqueous sodium hydrogen carbonate solution, and purify by HP-20 column chromatography (eluent: water to 20% methanol aqueous solution). 7β-[(Z)-2-(
2-aminothiazol-4-yl)-2-[(2-furyl)(carboxy)methyloxyimino]acetamide)
-3-[(1-quinolinio)methyl]-3-cephemu 4-carboxylate sodium salt (0.19 g) is obtained as a pale yellow powder.

m, p, > 200″C (decomposition) MS (ta/z): 679 (MNa, 657
(Mll NMR (DtO) δ: 2.83 and 2.8
6 (III, d X2.J= 1811z and 1811
z), 3.30 and 3.35 (Ill, d X2.J
.

18Hz and 18112), 5.09 and 5.10 (
10,d x2゜J□ 4.9112 and 4.9Hz)
, 5.56 and 5.61 (ltl, 5X2), 5.
73 and 5.74 (III, d X2.J-4, 911
z and 4.9Hz), 5.87(ill, d, J-1
511z), 5.92 (III, d, J-1511
z), 6.13 and 6.19 (111, dd X2
．． J, 3°4.2.0IIz and 3.4.2.0Hz)
, 6.38 and 6.48 (IH, dX2.J-3,
411z and 3.411z), 6.94(III, s
), 7.29 (III, d, J-2,011z),
7.99-8.51 (511, n+).

9.17 (III, d, J-8, 311z), 9.
25 (Ill, d, J = 5.911z) Example 15 Under an argon atmosphere, trimethylsilyltrifluoromethanesulfonate (1,4d) was added to a solution of 6-chloroquinoline (1°45g) in methylene chloride (10d), Stir for 10 minutes at room temperature and add 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-[(2-furyl)(carboxy)methyloxyimino)]acetamido)cephalosporanic acid (0 , 59 g) and stirred under reflux for 4 hours. The precipitate was filtered, the solvent was distilled off, and water (5ate)
and acetonitrile (lOd) and left at room temperature for 20 minutes. After adjusting the pH to 118 with sodium bicarbonate water and distilling off acetonitrile, the aqueous layer is purified by HP-20 carom chromatography (solvent: water and 5-30% methanol). 7β-[(Z)-
2-(2-aminothiazol-4-yl)-2-[(2
-furyl)(carboxy)methylogiciimino]acetamide)-3-[(6-chloro-1-quinolinio)methyl]-3-cephemu 4-carboxylate sodium salt (300 µ) is obtained as a pale yellow powder.

m, p, 206-210℃ (decomposition) 1770 (s
h), 1610(br)MS (m/z):
550 (MNa”-6-ionxin.

528 (Ml Do-6-1 Or1 Kihan) NMR (DtO
) δ: 2.87 and 2.88 (III, dX2.J
-1811z and 1811z), 3.34 and 3.4
0(IIl, dX2.J=1811z and 1B+12
), 5.11 and 5.14 (III, dX2゜J-
4,911z and 4.9Hz), 5.58 and 5.6
3()II, 5X2), 5.74 and 5.75(II
I, dX2. J-4,9112 and 4.911z),
5.88 (211,brs), 6.21 and 6.2
6 (IH, a+X2), 6.44 and 6.51 (I
H, dx2. J-3,411z and 3.41(z),
6.91 and 6.92 (ill, 5X2).

7.36 (III, m), 8.12-8.23 (2
11, m), 8.40 (III, d, J・2.01
1z), 8.50 and 8.52 (ill, dX2
．． J・9.311z and 9・,311z), 9.09
(III, d, J-8, 811z).

9.26 (III, d, J-5,411z).

Examples 16-38 7β-[(Z)-2-(2-aminothiazo-/L/-4
Example 14 or Example 1
By treating in the same manner as in 5, the compounds listed in Table 1 below are obtained.

Table 1 (However, compound (IA) has a Z configuration, * represents that the carbon atom is an asymmetric carbon atom, and (S) in the table
and (R) represent the configuration of the isosymmetric carbon atoms in the compound.) Example 39 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-[(2-thienyl)( Carboxy)methyloxyimino)acetamide)cephalosporanic acid disodium salt (0.81g), 1-[(thiocarbamoyl)
Methyl]-4-thiopyridone (0.24gL) A mixture of sodium iodide (18g), acetonitrile (10ml) and water (12ml) was heated at 65-70°C under an argon atmosphere.
Stir for 4 hours. The mixture is concentrated under reduced pressure to remove the solvent, and the residue is made alkaline with aqueous sodium bicarbonate. The mixture is purified by HP-20 column chromatography (eluent: 10-20% methanol aqueous solution), and the first, middle, and last parts of the desired fraction are concentrated under reduced pressure. By freeze-drying each product, 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-[(2-thienyl)
(carboxy)methyloxyimino]acetamide)-3
- [α-isomer, mixture of α and β-isomers and β-isomer of (1-(thiocarbamoylmethyl)-4-pyridiniocothiomethyl)-3-cefmu 4-carboxylate sodium salt Get each.

Enil static yield: 0.1g m, p, 180-183'C (decomposition) MS (m/
z): 72B (Ml”) NMR (D!0) δ:
3.25 (III, d, J= 1711z), 3.
53 (III, d.

J=1711z), 4.25(2H,s), 5.
08 (Ill, d, J = 4.4Hz) 5.36 (21
1, s), 5.64 (III, d, J = 4.411
z), 5.79 (III.

s), 6.93 (1tLs), 7.00 (IH,t
), 7.22 (IH, d, J=3112), 7.4
1 (111, d, J-4, 411z), 7.81 (2
H, d, J-, 811z), 8.24 (21%+d+
J=16.811z)α and ゛°human yield; 0.25g m, p, >170'C (decomposition) MS (*/z): 728 (MH") NMR (
D, 0) δ: 3.1B and 3.25 (III, d
2. J-18112 and 1811, 3.48 and 3
．． 53 (III, d X2.J= 1711z and 17
Hz), 4.25 (2H, s), 5.05 and 5.
08 (Ill, dX2.J-4, 4Hz and 4.411
2), 5.37 (2H, s), 5.60 and 5.6
3 (III, d X2.J-4,411z and 4.41
1z), 5.76 and 5.79 (111,s X2)
, 6.93 and 6.94 (11t, a X2).

6.99 (18, dd), 7.20 (10, dd)
, 7.40 (IH, dd), 7°82 (211
, d), 8.25 (211, a+) "υ1 raw yield: 0,05 g Steel, p, >170 °C (decomposed) MS (1/Z): 728 (Mllo) NMR (
D! O) δ: 3.1B (IH, d, J-1811z
), 3.48 (111, d.

J-1711z), 4.25<2tLs), 5
．． 05 (LH, d, J-4, 41iz) 5.37 (21
1,s), 5.60(111,d, J-4,411
z), 5.76 (III.

s), 6.94 (111, s), 6.98 (I
H, t), 7.19 (111, d, J-3,411
z), 7.39 (111, d, J-4,911z)
, 7.82 (2H, d, J-6, 1Hz), 8
．． 27 (211, d, J-6, 111z) Example 40 Sodium hydrogen carbonate (0,24 g) in water (15 m + 1)
7β-[(Z)-2-(2-aminothiazole-
4-yl)-2-[(2-furyl)(carboxy)methyloxyimino]acetamido)cephalosporanic acid (0
, 79 g), acetonitrile (15 ml), l-benzyl-4-thiopyridone (0.38 g) and sodium iodide (2.10 g) and stirred. The mixture was adjusted to pH 6°2 with acetic acid, then heated at 65-70°C under an argon stream.
Stir for 7 hours. The mixture is concentrated, the solvent is distilled off, the insoluble matter is filtered off, and the filtrate is further concentrated. The residue was adjusted to pH 8 with sodium hydrogen carbonate, purified by HP-20 column chromatography (eluent: 820-30% methanol water), the solvent was distilled off under reduced pressure, and lyophilized to give 7β-[(Z )-2-(2-aminothiazole-4-
yl)-2-[(2-furyl)(carboxy)methyloxyimino]acetamide)-3-[(1-benzyl-4
-pyridinio)thiomethylgo 3-cephem-4-carboxylate sodium salt (0.48 g) is obtained as a powder.

m, p, > 170°C (decomposition) MS (m/z): 751 (MNa''), 72
9 (Mll'')NMR(010)δ: 3.
23 and 3.25 (III, d X2.J-1711z
and 17Hz), 3.51 and 3.54 (IH, d
X2. J-1711z and 17Hz), 4.20(
111, d, J-1411z), 4.27 and 4.3
0 (111, dX2.J-14Hz and 1411z),
5.01 and 5.03 (111, dX2.J-4,9
11z and 4.4Hz), 5.57-5.63 (48
, m), 6.37 (III, a+), 6.48
(III, m), 6.94 (III, s).

7.44(611,brs), 7.8021(,brd
), 8.46 (211, d, J-7゜3 II z
) Example 41 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-(:(2-thienyl)(carboxy)methyloxyimino]acetamido)cephalosporanic acid and 1
-Methyl-2-thiopyridone was treated in the same manner as in Example 40 to obtain 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-[(2-thienyl)(carboxy)methyl oxyimino]acetamide) -3-[
(1-Methyl-2-pyridinio)thiomethyl go 3-cephem-4-carboxylate sodium salt is obtained.

Cocoon, p, 180-190℃ (decomposition) J-3,41
12), 7.48(III, d, J-4,91!z
), 7.68 (III, t).

7.89 (LH, d, J-8,811z), 8.
28 (IH, m), 8.64 (IH, d, J-6,
3Hz) Examples 42-60 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-[(thienyl or furyl)(carboxy)
By treating methyloxyimino)acetamido)cephalosporanic acid and the pyridone compound in the same manner as in Example 39 or 40, the following compounds listed in Table 2 are obtained.

MS(II/Z): 669(Mll”)NM
R(D!0)δ: 3.27 and 3.29 (III,
dX2. J-17,3Hz and 1711z), &,
56 and 3. ．． 5B(Ill, dX2. J-17,
312 and 1711z), 4.25 (111,d,
J-13,711z), 4.41(IH, d, J-1
3,7Hz), 5.05 and 5.06 (Ill, d
x2, J-4゜411z and 4.411z), 5.6
4 and 5.67 (Ill, d X2°J = 4.4Hz and 4.411z), 5.78 (III, s), 7.
0H111, s), 7.06 (III, d, d, J-4
,911z, J-3,4[1z), 7.23(II
I, d.

Table 2 (However, compound (1-B) has Z configuration.) Reference example 1 (1) N-hydroxyphthalimide potassium salt (31
, 1 g) of dimethylformamide (2501) was cooled to below O'C under an argon stream, and 2
-Fromo 2-(2-thienyl)acetic acid tert-butyl ester (33.0 g) in dimethylformamide (50 m
l) After dropping the solution at 4°C or below, stir at the same temperature for 1 hour. The mixture was poured into ice water and extracted with ethyl acetate. The extract is washed with sodium bicarbonate solution and water, and dried. After filtering the solution, the solvent is distilled off under reduced pressure to obtain 2.
Phthalimidoxy-2-(2-thienyl)acetic acid tert-butyl ester (41.4 g, 97% yield) is obtained as a tan oil.

MS (m/z): 286 (M”-
C41LO) (2) A solution of the main island (41.3 g) in methylene chloride (3001111) was cooled to -50°C under an argon stream, and after dropping methylhydrazine (5.3 g) to this solution, the temperature was reduced to -50°C to 0°C. for 1 hour, then at 0-5°C for 2 hours.
Stir for 0 minutes. The mixture is filtered, and the filtrate is washed with ice water and dried. After filtering the solution, the solvent is distilled off under reduced pressure. The residue was purified by silica gel chromatography (solvent: hexane-
2-aminooxy-2-(2-thienyl)acetic acid tert-butyl ester (2-aminooxy-2-(2-thienyl)acetate)
4.5 g (93% yield) is obtained as a pale yellow oil.

MS (m/z): 197 (M''-32
) (3) Honjima (127B) and 2-tritylaminothiazol-4-yl-glyoxylic acid (200 mg)' were dissolved in acetonitrile (2 ml) and tetrahydrofuran (11
) and water (2,6111), and the pH of this solution was adjusted to 5. After the temperature was reduced to 0, the mixture was stirred at room temperature for 22 hours. Pour the mixture with sodium bicarbonate water.
After reaching H7.85, the solvent was distilled off under reduced pressure. The residue was adjusted to pH 1.98 with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with brine, dried, and the solvent is distilled off. By treating the residue with isopropyl ether, 2-
(2-tritylaminothiazol-4-yl)-2-[
(2-thienyl) (tart, -butoxycarbonyl)methyloxyimino]acetic acid (256B, yield 89%
) is obtained as a powder.

MS (m/z): 626 (Mlji) Reference Example 2 (1) Ether (100 ml) of (2-furyl)glyoxylic acid (7 g) Add diphenyldiazomethane (
19.4 g) and stirred at room temperature for 2 days. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (solvent: hexane-ethyl acetate) to give (2-furyl)glyoxylic acid diphenylmethyl ester (14.7 g, yield 96%) as a pale yellow color. Obtained as crystals.

, p, 33~34°C IRνc+w −': l'/3υ, lt)'
/UMS (m/z): 167 (PhzCIi (2
) Tetrahydrofuran (24a+) of the main island (10,2g)
1) - Cool a water (0.6ml) mixture to -15°C, add sodium borohydride (1°0g) to this solution,
Stir for 20 minutes at -15 to -10°C. A mixture of ice water (50 ml) and ethyl acetate (50+11 l) was added to the mixture, and the mixture was adjusted to 114 with an aqueous oxalic acid solution. Separate the ethyl acetate solution and extract the aqueous layer with ethyl acetate. The ethyl acetate solutions were combined, washed with sodium bicarbonate water and water, dried, and then the solvent was distilled off under reduced pressure to obtain 2-(2-furyl)-2-hydroxyacetic acid diphenylmethyl ester (
10g, yield 97%) as crystals.

Face, p, 87-88°C IRv cm -': 3450,3410,
1740.1600MS (m/z): 30B (
M') (3) - (a) Main island (0,71 g) and calcium carbonate (0,5 g) in tetrahydrofuran (5 m
l) Add phosphorus tribromide (1.01 g) dropwise to the suspension under water cooling, and stir at the same temperature for 40 minutes. Filter the mixture and add 2
N aqueous sodium hydroxide (7 ml) and ethyl acetate (7 ml)
Add 1) and make alkaline with sodium bicarbonate water. Separate the ethyl acetate solution and extract the aqueous layer with ethyl acetate. The ethyl acetate solutions were combined, washed with brine, dried, and then the solvent was distilled off under reduced pressure to obtain 2-(2-furyl)-2-bromoacetic acid diphenylmethyl ester (0,8
5 g, yield 92%) as a crude oil. A solution of this crude product (0.85 g) in dimethylformamide (21) was added to N-hydroxyphthalimide potassium salt (0.60 g).
Add dropwise to a suspension of g) in dimethylformamide (8 ml) at O'C under an argon stream. Thereafter, the treatment was carried out in the same manner as in Reference Example 1-(1), and the residue was purified by silica gel column chromatography (solvent: hexane-ethyl acetate) to obtain 2-(2-furyl)-2-(phthalimidoxy).
Acetic acid diphenylmethyl ester (0.58 g) is obtained as colorless crystals.

Kasu, p, 142-144℃ IRv cm -': 1790.1760.1
740MS (w/z); 167 (PhzCll)
(b) Suspension of 2-(2-furyl)-2-hydroxyacetic acid diphenylmethyl ester (3,08 g), N-hydroxyphthalimide (2,69 g) and triphenylphosphine (3,93 g) in tetrahydrofuran (50 m) After cooling to -55"C and dropping azodicarboxylic acid diethyl ester (2.61g) to this suspension, the temperature was -55~0".
Stir at C for 3.5 hours. The mixture is passed through the mouth, and the oral solution is concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (solvent: hexane-ethyl acetate) to give 2-(2-furyl)-2-(phthalimidooxy)acetic acid diphenylmethyl ester (2.87 g).
The physical constants of one product obtained as colorless crystals (yield: 63%) were completely inferior to the standard product obtained in (a) above.

(4) A solution of Honjima (0.45 g) in methylene chloride (2 ml) was cooled to -50°C under an argon stream, and after adding methylhydrazine (53 μl) to this solution, Reference Example 1-(2
), 2-(2-frill)-
2-Aminooxyacetic acid diphenylmethyl ester (0,
30 g (92% yield) are obtained as a pale yellow oil.

MS(a+/z): 324 (Mll')(
5) Honjima (1,46 g) and 2-tritylaminothiazol-4-yl-glyoxylic acid (1°74 g) were dissolved in acetonitrile (6 ml) and tetrahydrofuran (16y+).
I) and water (6 ml), Reference Example 1-(3
), 2-(2-)ditylaminothiazol-4-yl)-2-[(2-furyl)(
Diphenylmethyloxycarbonyl)methyloxyimino]acetic acid (2.46 g, yield 81%) is obtained as crystals.

Crab, p, 142-143°C (decomposition) 1650.16
00 M5 (m/z): 720 (Mldo) Reference Example 3 (1) Thiophene-3-acetic acid (56.9g), selenium dioxide (66.6g), dioxane (500d), acetic acid (
35d), a mixture of water (10 m) is refluxed under stirring for 24 hours and then filtered. Concentrate the filtrate and add ethyl acetate (700111) to the residue.

Insoluble materials are filtered off, the filtrate is dried, and the solvent is distilled off.

The residue was dissolved in tetrahydrofuran (12), diphenyldiazomethane (103 g) was added over 30 minutes under water cooling, and the mixture was stirred at room temperature for 1 hour and then filtered. Concentrate the filtrate;
(3-thienyl)glyoxylic acid diphenylmethyl ester (88,1
g, yield 68%).

a+, p, 63-64°C (2) Main island (20g) of tetrahydrofuran (12Od
)-water (5 tnl) mixture was cooled to -25°C, sodium borohydride (2.35 g) was added to this solution,
After stirring at -25 to -5°C for 30 minutes, Reference Example 2-(2)
By treating in the same manner as 2-(3-thienyl)-
2-hydroxyacetic acid diphenylmethyl ester (19,
5 g, yield 97%).

m, p, 93-96 °C (3) Main island (16,3 g), N-hydroxyphthalimide (13,5 g), triphenylphosphine (19,7
g) and azodicarboxylic acid diethyl ester (13,1
By treating the tetrahydrofuran (250rd) solution of g) in the same manner as in Reference Example 2-(3)-(b),
2-(3-thienyl)-2-(phthalimidoxy)acetic acid diphenylmethyl ester (17.8 g, yield 76%)
).

m, p, 120-121.5°C (4) A methylene chloride (254) solution of the main island (3,83 g) and methylhydrazine (0,46rn1) were prepared in Reference Example 1.
- By treating in the same manner as in (2), 2-aminooxy-2-(3-thienyl)acetic acid diphenylmethyl ester (2,77 g) is quantitatively obtained.

(5) By treating Honjima (13.0 g) and 2-tritylaminothiazol-4-yl-glyoxylic acid (14°5 g) in the same manner as in Reference Example 1-(3), 2-(
2-) dithylaminothiazol-4-yl) -2-
[(3-thienyl)(diphenylmethyloxycarbonyl)methyloxyimino]acetic acid (22.1 g, yield 86
%).

Cabinet, p, 149-151°C MS (s+/z): 736 (Mll'') Reference Example 4 (1) Dimethyl sulfoxide (6Od
) in sodium hydride (63% oil dispersion, 7.7 g)
was added, heated at 70-75°C for 45 minutes, and then cooled. Tetrahydrofuran (50d) was added, and furan-3-carboxylic acid methyl ester (10.6g) was added at 0-3°C.
A solution of in tetrahydrofuran (40d) is added dropwise. The reaction mixture was incubated at 2°C to room temperature for 1. After stirring for 5 hours, acetic acid (15d) was added under cooling, and the solvent was distilled off under reduced pressure.

Acetic anhydride (160m) and sodium acetate (15m) were added to the residue.
g) and reflux for 30 minutes. The solvent was distilled off, ethyl acetate was added to the residue, and insoluble materials were filtered off. The filtrate and washings are concentrated to remove the solvent. The residue (oil) was dissolved in methanol (200d) and lithium hydroxide (6g) in water (
20 ml) suspension and stirred at room temperature for 1 hour. The mixture was adjusted to pH 1-2 with concentrated hydrochloric acid while cooling with water, and then the solvent was distilled off under reduced pressure. The residue was suspended in ether (200d) and methanol (50d), to which diphenyldiazomethane (14g) was added over 1 hour and stirred at room temperature for 2 hours.The reaction product was concentrated and ethyl acetate and water were added. Afterwards, separate the ethyl acetate layer. Water stone is extracted with ethyl acetate, combined with the ethyl acetate layer, washed with water, dried, and then distilled off.

The residue was purified by silica gel column chromatography (solvent: hexane-ethyl acetate) to obtain 2-(3
-Furyl)-2-hydroxyacetic acid diphenylmethyl ester (3.65 g) is obtained.

ta, p, 94-96°C (2) Main island (4,2 g), N-hydroxyphthalimide (3,67 g), ) liphenylphosphine (5,36 g
) and azodicarboxylic acid diethyl ester (3,56g
) in tetrahydrofuran (70I11) as Reference Example 2.
-(3)-(b) By processing in the same way as 2-(
3-furyl)-2-(phthalimidooxy)acetic acid diphenylmethyl ester (482 g, yield 78%) is obtained.

116-117.5 °C (3) Main island (
4.75 g) of methylene chloride (3 od) and methylhydrazine (0.56 d) were treated in the same manner as in Reference Example 1-(2) to obtain 2-a.minooxy-2-(3-
furyl) acetic acid diphenylmethyl ester (3.69g,
yield of 99%) is obtained quantitatively.

(4) By treating Honjima (3.32 g) and 2-tritylaminothiazol-4-yl-glyoxylic acid (14°5 g) in the same manner as in Reference Example 1-(3), 2-(2
-tritylaminothiazol-4-yl)-2-[(3
-Furyl)(diphenylmethyloxycarbonyl)methyloxyimino)acetic acid (5.15 g, yield 77%) is obtained.

Thought, p, 161-162℃ If(y ca+ -': 3240,3110
．． 3G60.3030,1750.1700M5(n+
/z): 720 (Mll"") Reference Example 5 (1) (R)-2-furyl-2-hydroxyacetic acid (57
1 mg, prepared from brucine salt) of tetrahydrofuran (
A tetrahydrofuran solution (5d) of diphenyldiazomethane (820 ml) was added dropwise to the 10 mil) solution under water cooling. After stirring for 15 hours at room temperature, the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography, and further recrystallized from a mixed solvent of isopropyl ether-n-hexane to obtain (R)-2-furyl-2. -Hydroxyacetic acid diphenylmethyl ester (950mg).

P, 99-101°C [α) D 23.0'' (C=1.0, chloroform) , S), the following compound is obtained.

(2) (S)-2-(2-furyl)-2-(phthalimidoxy)acetic acid diphenylmethyl ester m, p,
114-115°C [α)”+ +88.9° (C=1.0, chloroform) (3) (S)-2-(2-furyl)-2-aminooxyacetic acid diphenylmethyl ester m, p, 76-77°C (4) 2-(2-)Ritylaminothiazol-4-yl)-2-[(S)-(2-furyl)(diphenylmethyloxycarbonyl)methyloxyimino)acetic acid m, p, 155-156°C (decomposition) [α)”o
+21.6° (C-0,97, chloroform) Reference Example 6 (1) A solution of 2-furyl-2-hydroxyacetic acid diphenylmethyl ester (3,06 g) and pyridine (235 g) in tetrahydrofuran (50 d) was added under water cooling. ,(S)
-1-(2-naphthylsulfonyl)pyrrolidine-2-carboxylic acid chloride (482g) in tetrahydrofuran (
15d) Add the solution dropwise and after stirring for 1 hour, remove the solvent under reduced pressure.

Add brine to the residue under water cooling, and add 20 od of ethyl acetate.
) After extraction, wash and dry. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography, crystallized from ether, and recrystallized from a mixed solvent of ethyl acetate and isopropyl ether to give 2-(2S)-(2-
Furyl)-2-[(2S)-1-(2-naphthylsulfonyl)pyrrolidine-2-carbonyloxy)acetic acid diphenylmethyl ester (2.40 g) is obtained as colorless crystals.

Seagull, p, 145-146°C (2) Main island (238■) in tetrahydrofuran (5m)
and methanol (51 dl) and catalytically reduced in the presence of palladium black (20 dl) at room temperature and normal pressure. 2-(2S)-(2-
furyl) -2-[(23)-1-(2-naphthylsulfonyl)pyrrolidine-2-carbonyloxy)acetic acid (2
09 mg).

2300, 1760-1730. 1330. 11
50. To a solution of 750 (3) Honjima (1.54 g) in tetrahydrofuran (24 d) is added 5% sodium hydroxide solution (7.5 d) under water cooling, and the mixture is stirred for 2.5 hours. After concentration under reduced pressure, add water and wash with ether. After concentrating the aqueous layer under reduced pressure, it is treated with a strongly acidic ion exchange resin (40d), and the eluate is concentrated under reduced pressure and cooled on ice. The precipitate was removed from the filter side, the filtrate was distilled off under reduced pressure, and (S)-2-furyl-2-hydroxyacetic acid (4
84 mg).

(4) By esterifying Honjima (484■) in the same manner as in Reference Example 5-(1), (S)-2-furyl-2-hydroxyacetic acid diphenylmethyl ester (829 mg,
Yield: 86%) is obtained as colorless needle crystals.

m, p, 101-103'C Honjima is treated in the same manner as the corresponding (R,S) bodies described in Reference Example 2-(3)-b, (4) and (5) to obtain the following compound.

(5) (R)-2-(2-furyl')-2-(phthalimidoxy)acetic acid diphenylmethyl ester m, p,
115-116°C (6) (R) -2-(2-furyl)-2-aminooxyacetic acid diphenylmethyl ester m, p, 68-70°C (7) 2-(2-tritylaminothiazole-4- yl)-2-[(R)-(2-furyl)(diphenylmethyloxycarbonyl)methyloxyimino)acetic acid sardine, p, 145-146°C (decomposition) Reference Example 7 Under argon stream, 7-aminocephalosporan Acid (2,
72 g) and quinoline (5,81 g) of methylene chloride (
55IR1) Trimethylsilyltrifluoromethanesulfonate (8,7d) is added dropwise to the suspension and stirred at room temperature for 4 hours. The solvent was distilled off and water (10I!11) was added to the residue.
and prepare by HP-20 column chromatography (eluent: water). Collect the fractions containing the target product, add sodium bicarbonate water, and adjust the pH to 6.0-6.
5, and after concentration, it is purified by HP-20 column chromatography (eluent: water and 20-30% methanol water). Fractions containing the target product are collected, concentrated, and lyophilized to obtain 7-amino-3-(1-quinolinio)methyl-3-cephem-4-carboxylate (
1.54 g) is obtained as a pale yellow powder.

m, p, ~140°C (decomposition) Reference example day (1) 18.72 g of chelidonic acid, 15.58 g of 4-aminoveratrol and 100 m of dimethyl sulfoxide were
After heating to 60-170"C, the solvent is distilled off. Add chloroform to the residue, extract with diluted hydrochloric acid, make the extract alkaline, and re-extract with chloroform. Wash the extract,
After drying, the solvent was distilled off, chloroform-ethyl acetate was added to the residue, and the crystals were collected by filtration to obtain 16.38 g of 1-(3,4-dimethoxyphenyl)-4-pyridone.

m, p, 168-170'C (2) 8.0 g of the product from (1) above was mixed with methylene chloride 10
After cooling, 17.38 g of boron tribromide was added dropwise. After stirring at the same temperature and room temperature, the mixture is cooled again, methanol is added to the residue, and the solvent is distilled off. The residue was recrystallized from methanol-ethyl acetate to obtain 9.40 g of 1-(3,4-dihydroxyphenyl)-4-hydroxypyridinium bromide.

m, p, 260-265°C (decomposition) (3) above (2
), 10.1 g of acetic anhydride, and 100 g of pyridine were stirred at room temperature, and the solvent was distilled off. The residue was dissolved in chloroform, washed with water, dried, and the solvent was distilled off. Ethyl acetate-hexane was added to the residue, and the precipitated crystals were collected by filtration.
-(3,4-diacetoxyphenyl)-4-pyridone 7
．． Obtain 0.6g.

Chicken, p, 162-165°C (4) Heat 7.0 g of the product from (3) above, 120 g of dimethoxyethane solution, and 30 ml of pyridine, and then add Lawesson's reagent [2,4-bis(4-methoxyphenyl )
-1,3-dithia-2,4-diphosphethane-2,4-
5.92 g of disulfide) was added, the solvent was distilled off from the refluxing reaction solution, and the residue was purified by silica gel chromatography.
The product is washed with ethyl acetate to obtain 4.67 g of 1-(3,4-diacetoxyphenyl)-4-thiopyridone.

1 m, f), 193-196°C (5) 0.50 g of the product from (4) above, 4 m of water, 6 d of methanol, and 0.35 g of sodium bicarbonate are stirred under an argon stream. Hydrochloric acid was added to the reaction solution, the solvent was distilled off, the residue was purified by silica gel chromatography, and the product was washed with ethyl acetate to obtain 1-(3,4-dihydroxyphenyl).
0.30 g of -4-thiopyridone is obtained.

m, p, 259-261°C (decomposition) The following compounds are obtained by treating the corresponding raw material compounds in the same manner as in (1) to (5) above.

(i) 1-(3,4-dihydroxyphenethyl)-4-
Thiopyridone m, p, 220-223°C (ii) 1 (4-hydroxyphenyl)-4
-Thiopyridone Reference Example 9 Dissolve 4-chloropyridine hydrochloride (7.5 g) in water,
This solution is made alkaline with an aqueous sodium bicarbonate solution and extracted with methylene chloride. After drying the extract, the solvent is distilled off under reduced pressure. Benzyl bromide (10,3
g) and stirred at room temperature for 2 hours. Add ether to the mixture and filter the precipitate. Dissolve the precipitate in water and add 18
Add % sodium mercaptan (8 ml). The precipitate was filtered and purified by silica gel column chromatography to obtain 1-benzyl-4-thiopyridone (3,
54 g) is obtained.

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (However, R^1 is an amino group or a protected amino group, R
^2 is a substituted or unsubstituted heteromonocyclic group having 1 to 3 heteroatoms selected from oxygen atoms and sulfur atoms, R
^3 is a carboxyl group or a protected carboxyl group,
R^4 is a nucleophilic compound residue, R^5 is a carboxyl group,
Represents a protected carboxyl group or a group represented by -COO^-. ) A cephalosporin compound or a pharmacologically acceptable salt thereof. (2) The nucleophilic compound residue represented by R^4 is an acetoxy group; a pyridinio group that may have a substituent; a quinolinio group that may have a substituent: an isoquinolinio group; 2
, 3-cyclopentanopyridinio group, 5,6,7,8-
A tetrahydroquinolinio group; a phenanthridinio group; a substituted thiazolinio group; a substituted tetrazolylthio group or a group represented by the formula ▲There are numerical formulas, chemical formulas, tables, etc.▼, and R
^6 is a lower alkenyl group; a lower alkyl group that may have a substituent; a phenyl group that may have a substituent;
or a nitrogen-containing heterocyclic group. (3) The nucleophilic compound residue represented by R^4 has an acetoxy group; a pyridinio group; a pyridinio group having 1 to 3 substituents selected from an amino group, a lower alkyl group, a lower alkoxy group, a carbamoyl group, and a phenyl group; Group; Quinolinio group; Quinolinio group substituted with a lower alkyl group, lower alkoxy group or halogen atom; Isoquinolinio group; 2
,3-cyclopentanopyridinio group; 5,6,7,8-
A tetrahydroquinolinio group; a phenanthridinio group; a lower alkyl-substituted thiazolinio group; a lower alkyl-substituted tetrazolylthio group or a group represented by the formula ▲There are numerical formulas, chemical formulas, tables, etc.▼, and R^6 is a lower alkenyl group ;
Lower alkyl group; lower alkyl group having a substituent selected from lower alkylthio group, phenyl group, phenyl group substituted with hydroxyl group, thiocarbamoyl group and N-lower alkylthiocarbamoyl group; lower alkyl group having substituent selected from hydroxyl group and amino group The compound according to claim (2), which has a phenyl group or a 2-oxo-pyrrolidinyl group. (4) R^4 is an acetoxy group, a pyridinio group, a 3-amino-2-methylpyridinio group, a 5-amino-3-methoxypyridinio group, a 3-carbamoylpyridinio group, a 4-
Phenylpyridinio group, quinolinio group, 4 or 6-chloroquinolinio group, 6-fluoroquinolinio group, 3 or 6
-bromoquinolinio group, 4 or 6-methylquinolinio group, 6-methoxyquinolinio group, isoquinolinio group, 2,
3-cyclopentanopyridinio group, 5,6,7,8-tetrahydroquinolinio group, phenanthridinio group, 1-
Methyltetrazol-5-ylthio group, 4-methylthiazolinio group, or a group represented by the formula ▲Mathematical formula, chemical formula, table, etc.▼, where R^6 is a propenyl group, methyl group, methylthiomethyl group, thiocarbamoylmethyl group , thiocarbamoylpropyl group, N-methylthiocarbamoylmethyl group, benzyl group, 3,4-dihydroxyphenethyl group,
4-hydroxyphenyl group, 3,4-dihydroxyphenyl group, 3-amino-4-hydroxyphenyl group or 2
The compound according to claim (3), which is an -oxo-pyrrolidinyl group. (5) The compound according to claims (1) to (4), wherein R^1 is an amino group, R^3 is a carboxyl group, and R^5 is a carboxyl group or a group represented by -COO^-. . (6) Claim in which R^2 is a furyl group or a thienyl group (
Compounds described in 1) to (5). (7) R^4 is a quinolinio group, 6-chloroquinolinio group, or a group represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, and R^6 is a thiocarbamoylmethyl group, 3,4-dihydroxyphenyl group, or 3 , 4-dihydroxyphenethyl group. (8) 7β-{(Z)-2-(aminothiazole-4-
yl)-2-[(2-furyl)(carboxy)methyloxyimino]acetamide}-3-[(1-quinolinio)
Methyl]-3-cephem-4-carboxylate sodium salt (9) 7β-{(Z)-2-(aminothiazole-4-
yl)-2-[(S)-(2-furyl)(carboxy)
Methyloxyimino]acetamide}-3-[(1-quinolinio)methyl]-3-cephem-4-carboxylate sodium salt (10) 7β-{(Z)-2-(aminothiazol-4-yl)- 2-[(2-furyl)(carboxy)methyloxyimino]acetamide}-3-[
(6-chloro-1-quinolinio)methyl]-3-cephem-4-carboxylate sodium salt (11) 7β-{(Z)-2-(aminothiazole-4
-yl)-2-[(S)-(2-furyl)(carboxy)methyloxyimino]acetamide}-3-[(6-chloro-1-quinolinio)methyl]-3-cephem-4-
Carboxylate sodium salt (12) (A) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (II) (However, R^1^1 is an amino group or a protected amino group, R^3^1 is carboxyl group or protected carboxyl group, R^2 is 1 selected from oxygen atom and sulfur atom
Represents a substituted or unsubstituted heteromonocyclic group having ~3 heteroatoms. ) Oximinoacetic acid compounds, salts thereof, or reactive derivatives thereof, and general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (III) (However, R^5^1 is a carboxyl group, a protected carboxyl group, or - The group represented by COO^-, R^4 represents a nucleophilic compound residue.) is condensed with a 7-aminocephalosporin compound or a salt thereof, or (B) general formula ▲ mathematical formula, chemical formula , tables, etc.▼(IV) (However, X^1 is a reactive residue, R^2, R^1^1, R
^3^1 and R^5^1 have the same meanings as above. ), or a cephalosporin compound represented by (V) or a salt thereof is reacted with a nucleophilic compound (V) or a salt thereof, or
or (C) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VI) (However, R^1^1, R^4 and R^5^1 have the same meanings as above.) Sporin compound or its salt and general formula▲Mathematical formula, chemical formula, table, etc.▼(VII) (However, Z is a reactive residue, and R^2 and R^3^1 have the same meaning as above.) (D)
R^1^1 is a protected amino group and/or R^3
When ^1 and/or R^5^1 is a protected carboxyl group, the protecting group is optionally removed, and (E) the product is optionally further converted into a pharmaceutically acceptable salt thereof. There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (I) (where R^1 is an amino group or a protected amino group, R
^3 is a carboxyl group or a protected carboxyl group,
R^5 is a carboxyl group, a protected carboxyl group or -COO^-, and R^2 and R^4 have the same meanings as above. ) A method for producing a cephalosporin compound or a pharmacologically acceptable salt thereof. (13) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R^1^1 is an amino group or a protected amino group, and R^2 is 1 to 3 atoms selected from oxygen atoms and sulfur atoms. Thiazolyl acetic acid derivatives or their salt.