JPS604191A - Novel cephalosporin compound - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is H or carboxyl-protecting group; R<2> is group of formula II (R<6> is H, alkyl, aryl, etc.; R<7> is alkyl, aryl, heterocyclic group, etc.), etc.; R<3> is H or alkoxy; R<4> is H or amino; A is methylene or group of formula III (R<8> is H, alkyl, alkenyl, aryl, heterocyclic group, etc.)] or its salt. EXAMPLE:7-[2-( 2-Aminothiazol-4-yl )-2-( syn )-methoxyiminoacetamido]-3-(methanesulfonamido)methyl-DELTA<3>-cephem- 4-carboxylic acid. USE:beta-Lactamase-resistant antibacterial agent. PREPARATION:The objective compound can be prepared e.g. by reacting the 7- amino-3-(substituted methyl)cephemcarboxylic acid of formula IV [R<17> is (substituted) amino] with the carboxylic acid-containing thiazole derivative of formula V.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel cephalosporins, specifically cephalosporins represented by the general formula and salts thereof.

Therefore, the object of the present invention is to have a broad antibacterial spectrum, exhibit excellent antibacterial activity against Durham-positive bacteria and Gram-negative bacteria, and be stable against β-lactamases produced by bacteria. The object of the present invention is to provide a novel cephalosporin and its salts, which have excellent therapeutic properties for human and animal diseases both orally and parenterally.

The cephalosporins of the present invention have a heterocyclic group represented by the formula -N-8O*R" (Formula 6 (in the formula, -W has the above-mentioned meaning) at the 3-position echinmethylene group of the cephem ring. Its characteristic lies in the way it is connected.

The present invention will be further explained in detail below.

In this specification, unless otherwise specified, alkyl refers to C1-+4 alkyl, such as methyl, ethyl,
n-propyl, inglovir, D-butyl, imbutyl, 5ea-butyl, tert-phthyl, pentyl, hexyl, heftyl, octyl, dodecyl or lauryl; alkoxy means 10-alkyl having an alkyl group as defined above; ;Lower alkyl means C1-S alkyl, such as methyl, ethyl, carpropyl, improvil, n-butyl, isobutyl, 5ee-butyl,
tart-butyl or pentyl]Lower alkoxy means 10-lower alkyl having a lower alkyl group as defined above]Acyl means -I! [Acyloxy] refers to the acyl group defined above [f-0-acyl] Alkylthio refers to -S-alkyl having an alkyl group as defined above; alkenyl refers to C-10 alkenyl, tatoeha, hinyl, allyl, 1so-7'ropenyl, 2-pentenyl or butenyl, etc. means C8~u+7/'quinyl, such as ethynyl or 2-provinyl AI] cycloalkyl/l
/ Toha, Cs~7 cycloalkyl, Ritoe i? Aryl is, for example, phenyl, naphthyl or indanyl. Tearyloxy refers to 10-aryl having an aryl group as defined above; Aralkyl refers to, for example, benzyl, phenethyl, 4-methylbenzyl or naphthylmethyl; Aralkyloxy refers to A -0-aralkyl group having an aralkyl group as defined in , pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, inthiazolyl,
oxacylyl, inoxasilyl, thiadiazolyl, oxadiazolyl, thiatriazolyl, oxatriazolyl, triazolyl, tetrazolyl, pyridyl, 3-(2
-Methyl-4-pyrrolinyl), 3-(4-?” Lorini A
/), N-(methylpiperidinyl), pyridazinyl, quinolyl, 7-enazinyl, 1,6-penzodioxalanyl, benzolyl, pentuchenyl, penzoxazolyl, benzothiazolyl or tamarinyl, etc.; heterocyclic alkyl means a group consisting of a heterocyclic group and an alkyl group as defined above] A halogen atom means, for example, fluorine,
Compare the amounts of chlorine, bromine, or iodine atoms, respectively.

In each general formula in this specification, R1 is a hydrogen atom or a carboxyl group-protecting group, and the carboxyl group-protecting group is one commonly used in the field of penicillin and cephalosporin compounds. can be mentioned.

Protective groups for these carboxyl groups include ester-forming groups that can be eliminated by treatment under catalytic reduction, chemical reduction, or other mild conditions, or ester-forming groups that can be easily eliminated in vivo, or water or alcohol. Examples thereof include an organic silyl group, an organic phosphorus group, an organic tin group, etc., which are easily eliminated by treatment with a chemical compound, and various other known ester-type groups.

Among these types of protecting groups, preferable protecting groups include the following.

(a) Alkyl group.

(b) At least one of the substituents is norogen, nitro, carbalkoxy, acyl, alkoxy, oxo, cyano, cycloalkyl, aryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, 5-alkyl-2-oxy-1 , 6-cyoxylv-4-yl, 1-indanyl, 2-indanyl, furyl, pyridyl, 4-imidazolyl, 7talimide, succinimide, acetidino, aziridino, pyrrolidino, piperidino, morpholino, thiomorpholino, N-lower alkyl biverazino , pyrrolyl, pyrazolyl, thiazolyl, inthiazolyl, oxasilyl, inoxasilyl, thiadiazolyl, oxadiazolyl, thiatriazolyl, oxatriazolyl, triazolyl, tetra-lazolyl, pyridyl, quinolyl, phenazinyl, bensif 1
Nor.

Pentuchenyl, pentuthiazolyl, pentuthiazolyl, coumarinyl, 225-dimethylpyrrolidino, 1.4.
5.6-Titrahydropyrimidinyl, 4-methylpiperidino, 2,6-dimethylpiperidino, 5-(2-methy/
l/-4-pyrrolinyl), 5-(4-pyrrolinyl), N
-(methylpiperidino, TI/), 1,3-penzodioxalanyl, alkylamino, dialkylamino, acyloxy, acylthio, acylamino, dialkylaminocarbonyl, alkoxycarbonylamino, aralkyne, aryloxy, aralkyloxy, cycloalkyloxy , cycloalkenyloxy, heterocyclicoxy, alkoxycarbonyloxy, alkenyloxycarbonyloxy, aryloxycarbonyloxy, aralkyloxycarbonyloxy, polycyclic oxycarbonyloxy, alkenyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, cyclo Substituted lower alkyl groups which are alkyloxycarbonyl, cycloalkenyloxycarbonyl, heterocyclic oxycarbonyl, alkylanilino or alkylanilino substituted with halogen, lower alkyl or lower alkoxy.

(c) Cycloalkyl group: lower alkyl-substituted cycloalkyl or (2,2-dilower alkyl-13-dioxo-/l/-4-yl)methyl group.

←) Alkenyl group.

Rhinoceros) Alkynyl group.

(f) A phenyl group or a substituted phenyl group in which the substituent is at least one substituent arbitrarily selected from the substituents exemplified in (b) above, or a group represented by the formula or a substituted derivative thereof (the substituent is (
b)), or a group represented by the formula or a substituted derivative thereof (the substituent is selected from the substituents exemplified above (
An aryl group arbitrarily selected from the substituents exemplified in b).

(I) An aralkyl group such as benzyl or a substituted benzyl group in which the substituent is at least one substituent arbitrarily selected from the substituents exemplified in (b) above.

(g) A substituted heterocyclic group in which the heterocyclic group or substituent is at least one substituent arbitrarily selected from the substituents exemplified above (Cff+).

Alicyclic indanyl, alicyclic phthalidyl or their substituted derivatives whose substituent is methyl or halogen, alicyclic tetrahydronaphthyl or their substituted derivatives whose substituent is methyl or halogen, trityl, cholesteryl, bicyclo(4,, 4, O] Decyl.

09 Alicyclophthalidylidene lower alkyl groups or substituted derivatives thereof, wherein the substituent is a halogen or a lower alkyl group.

The carboxyl group protecting groups exemplified above are representative examples,
In addition to these, protecting groups described in the following documents can be arbitrarily selected.

U.S. Patent No. 499,909, 5.57'3,296
No. and No. 5,641,018; West German Patent Publication No. 2.
No. 301,014, No. 4255.287 and 2.5
'34105.

Among these, preferred carboxyl group protecting groups include, for example, 5-lower alkyl-2-oxy-1,5-
Dioxol-4-i has one low R alkyl group, acyloxyalkyl group, acylthioalkyl group, 7-talidyl group,
Examples include groups that are easily eliminated in vivo, such as an indanyl group, a phenyl group, a phthalidylidene lower alkyl group with or without a substituent, or a group represented by the following formula.

2-oxo-1,6-dioxol-4-yl-methyl, 5-ethyl-2-oxy-1,5-dioxyl-4
-yl-methyl, 5-n-propyl-2-oxo-1,
5-lower alkyl-2-oxo-1,6-cyoxy-4-yl-methyl group such as 6-dioxy-4-yl-methyl group] acetoxymethyl, bivaloy-yvyl-xymethyl, propionyloxymethyl, butyryloxymethyl, [Acyloxyalkyl groups such as imbutyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 1-acetoxy-n-propyl, 1-pivaloyloxyethyl, 1-pivaloyloxy-n-propyl] acetylthiomethyl, pivaloylthiomethyl, benzoylthiomethyl, p-chlorobenzoylthiomethyl, 1
-acetylthioethyl, 1-pivaloylthioethyl, 1
- Acylthioalkyl groups such as pensoylthioethyl and 1-(p-chlorobenzoylthio)ethyl groups iAlkoxymethyl groups such as methoxymethyl, ethoxymethyl, D-proboxymethyl, impropoxymethyl, and n-butyloxymethyl groups [Group] methoxycarbonyloxymethyl,
Ethoxycarbonyloxymethyl, n-proboxycarbonyloxymethyl, impropoxycarbonyloxymethyl, n-butyloxycarbonyloxymethyl,
tart-butyloxycarbonyloxymethyl, 1-
Alkoxycarbonyl groups such as methoxycarbonyloxymethyl, 1-ethoxycarbonyloxy-ethyl, 1-n-flopoxycarbonyloxy-ethyl, 1-improboxycarbonyloxy-ethyl, and 1-n-7' thyloxycarbonyloxy-ethyl groups. Oxy-alkyl group i Alkoxycarbonylmenal group such as methoxycarbonylmethyl, ethoxycarbonylmethyl group; Phthalidyl group; Indanyl group; Phenyl group;
Examples include 7tallydylidene alkyl groups such as 2-(6-chlorophtallycylidene)-ethyl, 2-(6-medoxyphtallydylidene)-ethyl, and the like.

Furthermore, R3 is represented by the formula -N-sotR' (wherein, R6 is hydrogen R
R' represents a 6° atom or an optionally substituted alkyl, aryl or aralkyl group, and R' represents an optionally substituted alkyl, aryl, aralkyl or heterocyclic group. ) or a sulfonyl group, together with a halogen atom, nitro, cyano, amino, carboxyl, carbamoyl, sulfo or sulfamoyl group, or an optionally substituted alkyl, aralkyl, aryl, Forming a 5- or 6-membered ring optionally substituted with alkenyl, alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl group is 126-thiadiazine-1
1-Dioxyno” be-2-yl group, tetrahydro-12-thiazine-1,
1-dioxide-2-yl group, inthiazolidine-1,
Examples include 1-dioxid-2-yl group, 1.2.5-thiadiazolin-1,1-dioxid-2-yl group, and the like.

Furthermore, substituents for the various groups mentioned above include halogen atoms, alkyl groups, aralkyl%, aryl groups, alknyl groups, hydroxyl groups, oxo groups, alkoxy groups, alkylthio groups, nitro groups, cyano groups, and amino groups. group, acyl group, acyloxy group, carboxyl group, carbamoyl group, sulfo group, sulfamoyl group; alkylamino group represented by -NH-alkyl; -N/A/J
JL/ ＼A7. Ya2. dialkylamino group represented by acylamino group represented by 1-N-acyl; Al 1-koxycarbonyl group represented by -C-O~alkyl; aralkyl group such as acetylmethyl, probionylmethyl; aminomethyl, aminoethyl Aminoalkyl groups such as; N-methylaminomethyl,
N-alkylaminoalkyl groups such as N-methylaminoethyl; N,N-dialkylaminoalkyl groups such as N,N-dimethylaminomethyl, N,N-dimethylaminoethyl; hydroxyalkyl groups such as 3-hydroxymethyl and hydroxyethyl; ;Hydroxyiminoalkyl group i such as hydroxyiminomethyl, hydroxyiminoethyl
AJboxyalkyl groups such as methoxymethyl, methoxyethyl, ethoxymethyl, and ethoxyethyl i Carboxyalkyl groups such as carboxymethyl and carboxyethyl i Alcokyne carbonyls such as methoxy7 carbonylmethyl, methoxycarbonylethyl, ethoxycarbonylmethyl, and ethoxycarbonylethyl Alkyl groups; aralkyloxycarbonylalkyl groups such as benzyloxycarbonylmethyl and benzyloxycarbonylethyl; sulfoalkyl groups such as sulfomethyl and sulfonyl groups; sulfamoylalkyl groups such as sulfamoylmethyl and sulfamoylethyl; carbamoyl Examples include carbamoylalkyl groups such as methyl and carbamoylethyl; carbamoylalkenyl groups such as carbamoylallyl; and he-hydroxycarbamoylalkyl groups such as N-hydroxycarbamoylmethyl and koji-hydroxycarbamoylethyl; various groups include one or more of these groups. It may be substituted with a substituent. Furthermore, among these substituents, hydroxyl groups, amino groups, carboxyl groups, etc. may be protected with suitable protecting groups commonly used in the field.

Here, the hydroxyl-protecting group includes all groups that can normally be used as hydroxyl-protecting groups, such as tetrahydropyranyl, tetrahydrofuranyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-7'romo Benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 5,
4-dimethoxypenzyloxycarponi/l/, 4-(
phenylaso)benzyloxycarbonyl, 4-(4-
methoxyethyl aso)benzyloxycarbonyl, te
rt-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, improboxycarbonyl, diphenylmethoxycarbonyl, 2.2,2-toIJchloroethoxycarbonyl, 2.2,2-trifuromoethoxy7carbonyl, 2-furfuryloxycarbonyl , 1-adamantyloxycarbonyl, 1-cyclopropylethoxycarbonyl, 8-quinolyloxycarbonyl, formyl, acetyl, (mono-, di-, )! J-) Chloroacetyl, benzoyl or trifluoroacetyl/l/fl
Which acyl group can be eliminated] Methanesulfonyl, ethanesulfonyl, alkylsulfonyl group phenylsulfonyl, toluenesulfonyl group 17) Arylsulfonyl group and benzyl group, trityl group, methoxymethyl group, 0-nitrophenylsulfenyl group , 2,4-dinitrophenylsulfenyl group.

Furthermore, the protecting group for an amine group includes all groups that can be normally used as a protecting group for an amino group, such as trichloroethoxycarbonyl, +1 furomoethoxycarboninopebenzyloxycarponyl, P-1 luenesulfonyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, (mono-, di-z)li-)taloloacetyl, trifluoroacetyl, porumyl, Lert L-amyloxycarbonyl, tert-f) # deer) L/; f! 2/l/, p-methoxybenzyloxycarbonyl, 5,4-dimethoxybenzyloxycarbonyl, 4-(phenylaso)benzyloxycarbonyl, 4-(4-methoxycarnylaso)befuryloxycarbonyl, pyridine-1-oxide -2-yl-methoxycarbonyl, 2-furyloxycarbonyl, cyphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, improboxycarbonyl, 1-cyclopropylethoxycarbonyl, 7taloyl, succinyl, 1-7 damantyloxycarbonyl,
Easily eliminated acyl groups such as 8-quinolyloxycarbonyl itrityl, 0-nitrophenylsulfenyl/l/
, 2,4-cy=)lophenylsulfenyl, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene,
6-hydroxy-4-pyridylmethylene, 1-methoxycarbonyl-2-propylidene, 1-ethoxycarbonyl-2-propylidene, 6-ethoxycarbonyl-2-
butylidene, 1-acetyl-2-propylidene, 1-benzoyl-2-glopylidene, 1-(N-(2-me)xyphenyl)carbamoyl]-2-7-ropylidene,
1'-(N-(4-methoxyphenyl)carbamoyl]
- Easily leaving groups such as -2-glopylidene, 2-ethoxycarbonylcyclohexylitine, 2-nitoxycarbonylcyclobentritene, 2-acetylcyclohexylidene, 625-dimethyl-5-oxonclohexylidene, and di- or tri- Examples include protecting groups for amino groups such as alkylsilyl groups.

Next, the carboxyl group-protecting group refers to all groups that can be used as normal carboxyl group-protecting groups, such as methyl, ethyl, n-propyl, Improvil% tart-butyl, n-butyl, benzyl , diphenylmethyl, to-17tyl, p-nitrobenzyl, p-
Methoxybenzyl, benzoylmethyl, acetylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methanesulfonylbenzoylmethyl, 7talimidomethyl, trichloroethyl, 1,1-dimethyA
/ 70 biru, acetylmethyl, propionyloxymethyl, hivaloyloxymethyl, 1,1-dimethyl-2
-propenyl, 3-methyl-3-butenyl, succinimi, tomethyl, 1-cyclopropylethyl, methylthiomethyl, phenylthiomethyl, dimethylaminomethyl,
Examples include groups such as quinolin-1-oxid-2-yl-methyl, pyridin-1-oxid-2-yl-methyl, and bis(,-methoxyphenyl)methyl; Examples include cases where the group is protected, and cases where the carboxyl group is protected with a silyl compound such as dimethylchlorosilane, as described in JP-A-46-7075 and Dutch Publication No. 7105259.

Further, R'' means a hydrogen atom or an optionally preserved amino group, and examples of protecting groups for such amine groups include:
Many groups commonly used in the fields of penicillins and cephalosporins are mentioned, and specifically, all the protecting groups for amino groups described for R'' are mentioned.

-Person- is a group of the formula -CHl- or a group of the formula -C-) OH' [wherein R' is a hydrogen atom or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, ara and 110 are the same or different and represent a hydroxyl, alkyl, aralkyl, aryl, alkoxy, aralkyloxy or aryloxy group; ] means.

Here, examples of the hydroxyl group-protecting group include the hydroxyl group-protecting groups described for W. Furthermore, substituents for the various groups shown above include halogen atoms, oxo groups, cyano groups, hydroxyl groups, alkoxy groups, amino groups, alkylamino groups, dialkylamino groups, double broken groups, or - NHCOB" or the formula -S, on +4 B" in the formula \OR+ 1 has the above meaning, and R14, Hr@ and Rlo are the same or different and represent a hydrogen atom, alkyl, aralkyl
or represents an aryl group. ) The various groups shown above may be substituted with one or more of these substituents. Among these substituents, the hydroxyl group and the amine group may be protected with the hydroxyl group and amino group protecting groups described for R1, respectively.

Next, the oxime represented by -0- includes AR, anti isomers, and mixtures thereof, all of which are included in the present invention.

When R1 is an optionally protected amino group, tautomers exist as shown in the following balanced formula, and these tautomers are also included in the present invention.

In the above formula, the protecting group for the imino group of R6' includes groups normally used in the field of penicillin and cephalosporin, and specifically, one of the protecting groups for the amine group explained for R1. Groups similar to the valence groups can be mentioned.

Examples of the salts of the compound of general formula [1] include salts with basic groups or acidic groups that are conventionally known in the field of penicillin and cephalosporin compounds. Salts with such basic groups include, for example, salts with mineral acids such as hydrochloric acid, nitric acid or sulfuric acid; oxalic acid, succinic acid;
Salts with organic carboxylic acids such as formic acid, trichloroacetic acid or trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluene-2-sulfonic acid, toluene-4-sulfonic acid, mesitylenesulfonic acid (
2,4,6-)limethylbenzenesulfonic acid), naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid,
Phenylmethanesulfonic acid, benzene-1,3-disulfonic acid, toluene-3,5-disulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-226-disulfonic acid, naphthalene-2,7-disulfonic acid, benzene- 1,3,5-trisulfonic acid, benzene-1,2,4
-) with sulfonic acids such as disulfonic acid, naphthalene-1,3,5-trisulfonic acid, and as salts with acidic groups, for example salts with alkali metals such as sodium or potassium salts such as calcium or magnesium. [Salts with alkaline earth metals] Ammonium salt ipropylene, Sibenzi A/7, N-benzyl-β-7enethylamine, 1-enamine, N-dipenzylethylenediamine, triethylamine, trimethylamine, triethylamine Butylamine, pyridine, dimethylaniline,
Salts with nitrogen-containing organic bases such as N-methylpiperidine, N-methylmorpholine, diethylamine, and dicitalohexylamine can be mentioned.

Furthermore, the present invention includes all optical isomers and racemates of the cephalosporin of general formula [1] and its salts, as well as all crystal forms and hydrates.

More specifically, among the compounds of general formula [1], preferable examples are oxime bodies in which -Am is represented by the formula -〇-, among which I Δ□・, syn isomers, and is a hydrogen atom or an alkyl group, in particular a methyl group, an ethyl group or an alkyl group substituted with R'', each of the formula -CH!coon' (wherein R1 has the meaning given above); The following groups are mentioned.

Next, as a preferable example of q for R1, when an elementary atom or a lower alkyl group is used, and R' is a lower group, 1.2.6-thiadiazine-1,1- which may be substituted
Dioxide-2-yl group is mentioned.

Among the compounds of general formula [1], some representative compounds exhibit antibacterial activity.

Antibacterial action (Table 1) Japanese Society of Chemotherapy Standard Method [(CHEMOTHEIIAP
Y) Volume 2!1, pages 1-2 (1975)], H
H
It was inoculated into an earth Inphalon agar medium (manufactured by Eiken Kagaku Co., Ltd.), and after culturing at 67°C for 20 hours, the presence or absence of bacterial growth was observed, and the minimum concentration at which bacterial growth was inhibited was defined as the MIC (μm). However, the extenuating amount of inoculation was 104 pieces/gray) (1o' pieces/m).

The test compounds are as follows.

Prisoner 7-[2-(2-aminothiazol-4-yl)-
2-(syn)-methoxyiminoacetamide]-3-(
xr, 5-dimethyl-2,6-thiadiazine-1,1
-dioxide-2-y/I/)methyl-Δ3-cephem-4carboxylic acid trifluoroacetate (Bl 7-(2-(2-aminothiazol-4-yl)-2-(syn)-methoxyimino Acetamide]-5
-(methanesulfonamido)methyl-Δ°-cephemu 4-carboxylic acid trifluoroacetate (C1'7-(2-(2-aminothiazol-4-yl)-2-(syn)-carboxymethoxyiminoacetamide ]-3-(3,5-dimethyl-1,2,6-thiadiazin-1,1-dioxid-2-yl)methyl-Δ1
- Formate salt of cephemu 4-carboxylic acid.

Next, a method for producing the compound of the present invention will be explained.

The compound of the present invention can be produced, for example, by the method shown below.

Hereinafter, when explaining in detail, HIY is an amino group, and groups such as HIY are also included in the present invention. And R+6. B.I.D.

Organic residues that do not participate in the reaction in BH, F and 111 include organic residues known in the art, such as aliphatic residues with or without substituents, alicyclic residues, aromatic residues. residue, araliphatic residue, heterocyclic residue,
Examples include acyl groups, and specific examples include the following groups.

+11 Aliphatic residues: for example, alkyl groups such as methyl, ethyl, propyl, n-butyl, isobutyl, pentyl, i alkenyl groups such as vinyl, propenyl, butenyl.

(2) Alicyclic residues: For example, cyfuranone groups such as cyclopentyl, cyclohexyl, and cycloheptylnato; cycloalkenyl groups such as cytalobentenyl and cyclohexenyl.

(3) Aromatic residues: for example, aryl groups such as phenyl and naphthyl.

(4) Aroaliphatic residues: for example, aralkyl groups such as benzyl and 7enethyl.

(5) Heterocyclic residues: For example, pyrrolidinyl, piperazinyl, furyl, chenyl, hyloryl, pyrazolyl, oxacylyl, thiazolyl, pyridyl, imidazolyl, quinolyl, benzothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, etc. , nitrogen or sulfur atoms).

(6) Acyl group: An acyl group derived from an organic carboxylic acid, such organic carboxylic acids include, for example, aliphatic carboxylic acid, alicyclic carboxylic acid, alicyclic aliphatic carboxylic acid; Aromatic substituted aliphatic carboxylic acids, aromatic oxyaliphatic carboxylic acids, aromatic thioaliphatic carboxylic acids, heteroaromatics in which an aromatic residue or a heterocyclic group is bonded to a carboxylic acid with or without an oxygen or sulfur atom Ring-substituted aliphatic carboxylic acid, heterocyclic oxyaliphatic carboxylic acid, heterocyclic thioaliphatic carboxylic acid i Oxygen in the carbonyl group,
Examples include organic carboxylic acids to which an aromatic residue, aliphatic residue, or alicyclic residue is bonded via a nitrogen or sulfur atom, such as aromatic carboxylic acids, heteroaromatic carboxylic acids, and the like.

Here, examples of aliphatic carboxylic acids include formic acid, acetic acid, propionic acid, butanoic acid, isobutanoic acid, pentanoic acid, methoxyacetic acid, methylthioacetic acid, acrylic acid, crotonic acid, etc., and examples of alicyclic carboxylic acids include cyclohexane. Examples of the alicyclic aliphatic carboxylic acids include cyclopentane acetic acid, cyclohexane acetic acid, cyclohexane propionic acid, and cyclohexadiene acetic acid.

Further, aromatic residues in the above-mentioned organic carboxylic acids include phenyl, naphthyl, etc., and further examples of the above-mentioned heterocyclic groups include furan, thio7e/, virol,
Pyrazole, imidazole, triazole, thiazole, inthiazole, oxazole, inoxazole,
Examples include residues of heterocyclic compounds containing one or more heteroatoms in the ring, such as thiadiazole, oxadiazole, thiatriazole, oxatriazole, tetrazole, benzoxazole, and benziflav.

The groups constituting these organic carboxylic acids include, for example, a halogen atom, a hydroxyl group, a protected hydroxyl group, an alkyl group, an alkoxy group, an acyl group, a nitro group, an amino group, a protected amino group, and a carboxyl group. It may be further substituted with a substituent such as a group or a protected carboxyl group.

In addition, examples of the acyloxy and carnocumyloxy groups of R'" include acetoxy, probionyloxy, and alkanoyloxy groups such as butyryloxy; alkenoyloxy groups such as acryloyloxy;
aroyloxy groups such as hendiyloxy or naphthoyloxy and carbamoyloxy groups,
These are halogen atoms, nitro groups, amino groups, alkyl groups, alkoxy groups, and alkylthio groups.

It may be substituted with one or more substituents such as an acyloxy group, an acylamino group, a hydroyl group, a carbalkoxysulfamoyl group, an aryol group, and a carbamoyloxy group.

In the above-mentioned substitution of R6, the hydroxyl group, amine group, carboxyl group, etc. may be protected with commonly used protecting groups, and the protecting groups are specifically explained for R2. Examples include protecting groups for hydroxyl groups, amine groups, and carboxyl groups.

(a) Three-position conversion reaction The compound of general formula [1] or its salt is treated with a sulfonamide of general formula [g] or a heterocyclic compound of general formula [■b] or 7-substituted or unsubstituted amino-3-substituted methylcephemcarboxylic acids of the general formula LIV) are obtained by reacting the salts thereof and, if desired, removing the protecting group or protecting or converting the carboxyl group into a salt. or its salts can be produced with good yield and high purity through industrially easy operations.

Furthermore, if desired, the substituent at the 7-position amino group can be removed by a conventional method to obtain a 7-unsubstituted amine.

According to this method, not only Δ“-cephem compounds but also Δ
A '-cephem compound can also be used, and when a Δ'-cephem compound is used, the -cephem compound obtained after the reaction can be converted into a Δ1-cephem compound.

Moreover, not only compounds where 〉z is 〉S, but also compounds where 〉2 is 〉S→
Compounds which are O can also be used as starting materials, in which case 〉→0 can be converted to >S during the reaction or in the after-treatment step.

In addition, when the sulfonamides of the general formula [■a] or the heterocyclic compounds of the general formula Llb] used as reaction reagents in this reaction have a basic group or an acidic group as a substituent, if necessary, may be subjected to the reaction in the form of their respective salts, and in that case, the salts in the basic group or the salts in the acidic group may be the same basic salts as explained for the salts of the compound of general formula [J]. salts on groups or acidic groups.

In addition, salts of the compound of general formula (113 and or an acidic group.Salts of the compound of general formula CI] may be isolated beforehand and used, or may be prepared in-system.

The acid or acid complex used in this reaction includes, for example, a protonic acid, a Lewis acid, or a Lewis acid complex. Examples of protonic acids include sulfuric acids, sulfonic acids, or super strong acids (super strong acid means an acid stronger than 100% sulfuric acid, and some of the above-mentioned sulfuric acids and sulfonic acids can also be used), More specifically, sulfuric acids such as sulfuric acid, chlorosulfuric acid, and fluorosulfuric acid; alkyl (mono- or di)sulfonic acids such as methanesulfonic acid and trifluoromethanesulfonic acid; Sulfonic acids such as (mono-, di- or g!J-) sulfonic acid i
Perchloric acid, magic acid (FSO Ju H-8bFg), F
SOs HhsFa, CF island5onH5bFi,
Examples include super strong acids such as HF BF island and H@804 So field.

Furthermore, examples of the Lewis acid include boron trifluoride. In addition, examples of complex compounds of Lewis acids include dialkyl ether complex salts of boron trifluoride and diethyl ether, di-n-propylether, di-n-ster ether, etc., ethylamine, n-7'robylamine, Examples include amine complexes with p-butylamine, triethanolamine, etc., carbonaceous ester complexes with ethyl formate, ethyl acetate, etc., fatty acid complexes with acetic acid, propionic acid, etc., nitrile complexes with acetonitrile, propionitrile, etc. .

In addition, it is preferable to use an organic solvent in this reaction, and examples of organic solvents that can be used include all organic solvents that are inert to the reaction, such as nitroalkanes such as nitromethane, nitroethane, nitropropanato, formic acid, acetic acid, Organic carboxylic acids such as trifluoroacetic acid, dichloroacetic acid, propionic acid, acetone, methyl ethyl ketone,
Ketones such as methyl isobutyl ketone; ethers such as diethyl ether, diimpropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, anisole, dimethyl selenium; ethynope formate, diethyl carbonate, methyl acetate, ethyl acetate, ethyl chloroacetate, butyl acetate Nitriles such as acetonitrile and butyronitrile, halogenated hydrocarbons such as methylene chloride, chloroform, and 1,2-citaloloethane, sulfolanes such as nusulfolane, and mixtures of two or more of these solvents. It may also be used as

Moreover, a complex compound formed by these organic solvents and a Lewis acid can also be used as a solvent.

The amount of the acid or acid complex compound to be used may be at least the equivalent molar amount to the compound of general formula [11] or its salt, and can be increased or decreased as appropriate depending on the individual case. In particular, 2
It is preferable to use an amount of 1 to 10 times the molar amount. When using an acid complex compound, it can itself be used as a solvent,
A mixture of two or more types of complex compounds may be used.

In addition, the amount of the sulbonamide of the general formula [g] or the heterocyclic compound of the general formula [Ib] or their salts used as a reaction reagent in this reaction is equivalent to the amount of the compound of the general formula CI] or its salt. The amount may be at least 1 mole, and it is particularly preferable to use 10 to 5.0 moles/amount.

This reaction is usually carried out at a temperature of D to 80°C and is completed in several minutes to several tens of hours.

If moisture is present in the reaction system, undesirable side reactions such as lactonization of the raw material or product and cleavage of the β-lactam ring may occur, so it is desirable to maintain the reaction system in an anhydrous state. To meet this condition, a suitable dehydrating agent is added to the reaction system, such as a phosphorus compound such as phosphorus pentoxide, polyphosphoric acid, phosphorus pentachloride, phosphorus trichloride, or phosphorus oxychloride; or O-bis(trimethylsilyl)acetamide. , trimethylsilylacetamide, trimethylchlorosilane, dimethyldichlorosilane, etc.; organic acid chlorides such as acetylchloride, p-)luenesulfonyl chloride; acid anhydrides such as acetic anhydride and trifluoroacetic anhydride; anhydrous magnesium sulfate; , anhydrous calcium chloride, molecular sheets, calcium carbide, and other inorganic desiccants may be added.

General formula in which R'' represents a carboxyl protecting group [If the old compound is used as a raw material, a compound of the corresponding general formula [1■] in which R1 is a hydrogen atom may be obtained by post-reaction treatment; If desired, the protecting group is removed by a conventional method,
It is also possible to obtain compounds of the general formula LIV:] in which R' is a hydrogen atom.

General formula C1 used as a reaction reagent in this reaction
,] or the multicyclic compound of the general formula [1b] or their salts, when the substituent thereof is substituted with a hydroxyl group, an amino group, a carboxyl group, etc., in carrying out this reaction, The desired compound can be obtained by protecting these groups with the same protecting group as explained for V and subjecting them to a conventional elimination reaction after completion of the reaction.

Further, in the compound of general formula LIV, if desired, a carboxyl group can be retained or a salt can be obtained according to a conventional method, and the desired compound can also be obtained. Also, Bl? The compound of general formula [1v] in which is an amino group can be prepared by a conventional method,
It can be a reactive derivative of the amino group as described below.

←) To the compound of the general formula [1'V] obtained by the acylation reaction method, or its reactive derivative at the amino group, or a salt thereof, the general formula [V], [■], [■], [1] or (
If a compound of XI) or a reactive derivative at the carboxyl group or a salt thereof is reacted, a compound of general formula Ll), (XI, [)D, [su] or [citrus] or a salt thereof can be obtained. .

Also, the general formula [v], [■], [, Vj], [■], (
IXI, [X], [Xl), (XI), 1 Mataha [X1
v] Salts of the compound include salts with a basic group or acidic group, and these salts include salts with the same basic group or acidic group as explained for the salts of the compound of general formula [1]. It will be done.

Examples of reactive derivatives at the amino group of the compound of general formula (IVI) include incyanate, general formula [■]
Silyl derivatives, phosphorus or tin compounds produced by the reaction of compounds or their salts with phosphorus compounds such as silylated PCI such as bis(trimethylsilyl)acetamide, trimethylsilylacetamide, and trimethylsilyl chloride, or tin compounds such as (C4He) and l5nCffr. All substances frequently used in acylation reactions, such as derivatives, are included.

General formula EV), [■], [t1], Cven: ] Sunri &
Examples of reactive derivatives at the carboxyl group of the compound of i (Xl) include acid halides, acid anhydrides, mixed acid anhydrides, active acid amides, active esters, and general formulas LVI, (Vl), [ i], [food] or shi
Examples include reactive derivatives of the compound I) and Vilsmeier's reagent. Examples of mixed acid anhydrides include mixed acid anhydrides with carbonic acid monoalkyl esters such as carbonic acid monoethyl ester and carbonic acid monoimbutyl ester, and lower alkanoic acids which may be substituted with halogens such as pivalic acid and trichloroacetic acid. Mixed acid anhydrides with and the like are used. As the active acid amide, for example, N-acylsaccharin, N-acylimidazole, N-acylbenzoylamide, N N'-dicyclohexyl-N-acylurea, N-acylsulfonamide, etc. are used. Next, as the active ester, for example, cyanomethyl ester, substituted phenyl ester, substituted benzyl ester, and substituted thenyl ester are used.

In addition, as a reactive derivative with Vilsmeier reagent, °C
Acid amides such as N, N-dimethylformamide, N, N-dimethylacetamide, phosgene, thionyl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride, phosphorus pentachloride, trichlormethyl chloroformate, Examples include derivatives reactive with Vilsmeier's reagent obtained by the action of a halogenating agent such as oxalyl chloride.

General formula [v], (VIA, (■), [■] or cxi
] When using each compound in the form of a free acid or salt, a suitable condensing agent is used.

Such condensing agents include, for example:) N,N/-disubstituted carbodiimides such as N-dicyclohexylcarbodiimide;) azolide compounds such as N'-thionyldiimidazole iN-ethoxycarbonyl-2-ethoxy- Dehydrating agents for 122-hydroxyquinoline, phosphorus oxychloride, and alkoxyacetylenato; 2-halogenpyridinium salts such as 2-talolopyridinicum methyl iodide and 2-fluoropyridinium methyl iosite are used.

This acylation reaction is generally carried out in a suitable solvent - with or without a base. As a solvent, e.g.
Halogenated hydrocarbons such as chloroform and methylene chloride; x-thyl compounds 5N such as tetrahydro7rane and dioxane, N-dimethylformamide, N,N-dimethylacetamide, acetone, water, and mixtures thereof can be used. Examples of bases include inorganic bases such as alkali hydroxide, alkali hydrogen carbonate, alkali carbonate, and acetate; Examples include organic bases such as tertiary amines or secondary amines such as dicyclohexylamine and diethylamine.

In addition, the compound of the general formula (IX) or the salt thereof that can be derived from the compound of the general formula [1m] or [1b] or the salt thereof of the present invention can also be created as the following j5.

Using a compound of the general formula (In or its salts), the general formula [
To obtain the compound or its salts, 4-halogen-
3-oxybutyryl halide and the compound of general formula (rV) or a salt thereof may be reacted according to a conventional method.For this reaction conditions and operations, conditions and operations known in the art can be applied. , the salts of the compound of the general formula [3] can be easily obtained according to a conventional method, and the salts include the same basic group or acidic group as explained above for the salt of the compound of the general formula [summer]. The resulting compound of general formula (1) or the salts of Sagi may be isolated and purified by a conventional method, but may also be used in the next reaction without being isolated.

In addition, the amount of the compound of the general formula EV), [V]'), [■], [■] or the reactive derivative or salt thereof in the carboxyl group is determined according to the general formula (IV).
Usually about 1 to several mol each is preferably used per 1 mol of the compound, its reactive derivative at the amino group, or a salt thereof.

These reactions are usually carried out at -50 to 40°C and are completed in 10 minutes to 48 hours.

In addition, in this acylation reaction, the introduction and removal of a protecting group and the conversion to a salt can be carried out according to conventional methods to convert it into the corresponding target compound.

General formula [1], (DD, EX
), (Xl] or (XJV), or their salts can be isolated and purified by known means. It can also be used as a raw material for the next reaction without separating it.

(c) Nitronization reaction Next, in order to obtain the compound of general formula (X) or its salts from the compound of general formula (IX) or its salts, the general formula (
The compound of IX) or its salt is reacted with a nitrifying agent.

This reaction is usually carried out in a solvent, such as water,
Acetic acid, benzene, methanol, ethanol, tetrahydrofuran, and other solvents inert to the reaction can be used.

Preferred examples of nitrifying agents include nitric acid and its derivatives, such as nitrosyl chloride, nitrosyl bromide and other nitrosyl halides; alkali metal salts of nitrite such as sodium nitrite and potassium nitrite; i. Examples include hentyl nitrate tx and (D nitrite alkyl ester).

When a salt of nitrous acid is used as a nitrifying agent, it is preferable to react K in the presence of an inorganic or organic acid such as hydrochloric acid, sulfuric acid, formic acid, or acetic acid. When a nitrite alkyl ester is used as a nitrifying agent, it is preferably carried out in the presence of a strong base such as an alkali metal alkoxide.

The reaction is generally carried out at -15 to 30°C, and from 10 minutes to 10 minutes.
Complete in time. In addition, the salts of the compound of general formula [X] can be easily obtained according to conventional methods, and the salts include the same basic group or acidic group as explained for the salt of the compound of general formula [1]. Examples include salt. Furthermore, the introduction and removal of a protecting group can be carried out according to a conventional method to convert the compound into the corresponding target compound.

The compound of general formula [x] or its salt obtained in this way may be isolated and purified by a conventional method, but it can also be used in the next reaction without being isolated.

) etherification reaction and vosborylation reaction;
Compounds of general formula [X] or salts thereof ρ, etc. of general formula [X]
I] or its salts, the general formula (Xl
or a salt thereof is subjected to an etherification reaction or a phosphorylation reaction.

This etherification reaction and bosborylation reaction were carried out in JP-A No. 5
It can be carried out by conventional methods such as etherification reaction and phosphorylation reaction described in JP-A No. 3-137988, JP-A-55-105689, JP-A-55-149295, and the like.

For example, the alkylation reaction can be carried out according to conventional methods. The reaction is generally carried out at -20 to 60°C and is completed in 5 minutes to 10 hours.

Any solvent may be used as long as it does not inhibit this reaction, such as tetrahydrofuran, dioxane, methanol, ethanol, chloroborum, [methylene chloride,
Ethyl acetate, butyl acetate, N,N-dimethylformamide, NN-dimethylacetanomide, water, etc., or a mixture of stiff straws, etc. are used.

Examples of the alkylating agent include methyl iodide, methyl bromide, ethyl iodide, lower alkyl bromide such as ethyl bromide, dimethyl sulfate, diethyl sulfate, diazomethane, diazoethane, or methyl p-)luenesulfonate. is used. When using alkylating agents other than diazomethane and diazoethane, alkylating agents such as alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, triethylamine, pyridine, dimethylaniline, etc. Generally carried out in the presence of a base.

In addition, salts of the compound of the general formula [su] can be easily obtained according to conventional methods, and the salts include the same basic group or acidic group as explained for the salt of the compound of the general formula [l]. Salt is an example.

Furthermore, the introduction and removal of a protecting group can be carried out according to a conventional method to convert the compound into the corresponding target compound.

The compound of the general formula CM or its salts obtained in this way may be isolated and purified by a conventional method, but it can also be used in the next reaction without being isolated.

(This ring-closing reaction) Next, each compound of the general formula [IX], CX) or [■] or a salt thereof is reacted with a thioborumamide or thiourea of the general formula [■], resulting in the reaction of the general formula ( Compounds of Ia:l or (xb':l) or salts thereof are obtained.

This reaction is usually carried out in a solvent. Any solvent may be used as long as it does not inhibit this reaction, such as water, methanol, ethanol, acetone, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyridone, etc. A mixed solvent of two or more of these is used.

Although it is not particularly necessary to add a deoxidizing agent, the reaction may proceed smoothly if the deoxidizing agent is added in an amount within a range that does not change the cephalosporin skeleton. The deoxidizers used in this reaction include alkali metal hydroxide, alkali metal hydrogen carbonate, triethylamine, pyridine, N, N-
Mention may be made of inorganic or organic bases such as dimethylaniline.

The reaction is generally carried out at a temperature in the range of 0 to 100°C. Usually, 1 to several equivalents of thioformamide or thioureas are used per 1 equivalent of the compound of general formula (IXI, [X] or (Xl) or a salt thereof. The reaction time is usually 1 ~48 hours, preferably 1 to 10 hours.

In addition, in this ring-closing reaction, the introduction and removal of a protecting group and the conversion to a salt can be carried out according to conventional methods to convert it into the corresponding target compound.

The target compounds of the general formula [Ia] or [:xb:] or salts thereof of the present invention obtained as above are as follows:
It can be isolated by conventional methods.

(to) Oxime formation reaction A compound of the general formula (XIV: or a salt thereof) is reacted with the general formula [
By reacting the compound of XVI or its salt, a compound of general formula [from] or its salt can be obtained.

Examples of the salts of the compound of general formula The reaction is carried out in an active solvent or a mixed solvent thereof, and the reaction is usually carried out at a temperature of 0 to 100°C, preferably 10 to 100°C.
It is carried out at a temperature of 50°C and is completed in 10 minutes to 48 hours.

For 1 equivalent of the compound of general formula [Yu] or its salt,
One to several equivalents of the compound of the general formula [XVI or its salts are used.

The salts of the compound of general formula [Xv] can be used unreacted as they are; Alkali earth metals such as magnesium carbonate and calcium carbonate] Alkali metals of hydrogen carbonates such as sodium bicarbonate and potassium bicarbonate Phosphorus such as magnesium myphosphate and calcium phosphate Acid alkaline earth metal] Inorganic bases such as alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate, or alkali metal acetates such as sodium acetate and potassium acetate Trialkylamines such as metrimethylamine and triethylamine 5 Picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4,3,0] -]
The reaction can also be carried out in the presence of an organic base such as 5-nonene, 1,4-diazabicycloC2,2,2]octane, and 1,5-diazabicyclo[5,4,O]-7-undecene.

In the oximation reaction of mata and co, the introduction and removal of a protecting group and the conversion to a salt can be carried out according to conventional methods, and the reaction can be converted to the corresponding target compound. The compound of general formula [1] of the present invention or its salts obtained as described above can be isolated by a conventional method.

Next, the compound of the general formula [1v] in which B is alkoxy or a salt thereof can be obtained by a method known per se, for example, the Organic Synthesis Association Journal, Vol. 55, No. 7, pp. 563-574 (1977).
General formula C in which R" is a hydrogen atom based on the method described in
IV: It can be synthesized using the compound or its salt.

Compounds of the general formula [xIv] in which R1 is alkoxy or salts thereof can be prepared by methods known per se, for example, the methods described in JP-A-54-24888 and JP-A-54-103889. Based on the general formula [ ]], ], (Ib], (X
I), [x], 0ffl -1: f,: C [XJV
: Can be synthesized using the compounds of 1 or their salts.

The compound of general formula [1] or its salts obtained as above can be used in the treatment and prevention of bacterial infections in the form of free acid, non-toxic salt or physiologically acceptable ester. It is preferable to apply parenteral administration methods in the form of free acids or non-toxic salts, or oral administration methods in the form of physiologically acceptable esters. In that case, the dosage forms normally applied to cephalosborin drugs, such as tablets, capsules, powders, granules, fine granules, syrups, injections (including infusions), and suppositories, may be used. Just adjust the shape. When preparing the above drugs, if necessary, for example, starch, lactose,
Excipients such as sugar, calcium phosphate, calcium carbonate; binders such as gum arabic, starch, crystalline cellulose, carboxymethyl cellulose, hydroxypropyl cellulose; lubricants such as talc, magnesium stearate, and carboxymethyl calcium, talc, etc. Diluents and/or additives such as disintegrants may also be used.

In addition, when administering the compound of general formula [1] or its salts, the dosage, frequency of administration, and administration method can be selected as appropriate depending on the symptoms, but in general, the same amount of about 50
~5,000 μl may be administered orally or parenterally about 1 to 4 times a day.

Next, the present invention will be explained with reference to reference examples and examples, but the present invention is not limited to these examples.

Reference example 1 7 in 50 m of sulfolane solution containing 13.69 boron trifluoride
- Amitusephalosboranic acid (abbreviated as 7'-ACA under DL) 15.69 and methanesulfonamide 4
．． After adding and dissolving 75 g, react at room temperature for 4 hours. After the reaction is completed, the reaction solution is cooled with water and mixed with 25OJ of methanol.
Then, 158 g of pyridine is added dropwise.

If the precipitation tool is removed, thoroughly washed with methanol, and then dried, 7-amino-
6-(methanesulfonamido)methyl-Δ8-cephemu-4-carboxylic acid7. a sy (yield 511%)
get.

I R(KB r ) ♂' t l″C==0179
0p 161 DhMR (cps cooD) δ value is, 26 (3H, s, -can le 5.90 (2H, bl, Cm -H).

4.55 (2 horses b % s; L□-) no 5.49 (2H
, C.-H, Cl-H) The following compound was obtained in the same manner.

o7-Amino-3-[(p-chlorobenzenesulfonamido)methyl]-Δ1-cephemu 4-carboxylic acid Melting point: 197-199°C (decomposition) -1ν IB (KBr) scratch; C-01790,161ONMM
CF (C00D) δ value; 3.80 (2H, @, CI-If).

5.35 (2H, 8, Cl-H, C7-H).

Reference Example 2 (1) Sulfolane solution 10 containing boron trifluoride 2Z12
7-ACA27.2Sl and 5,5-dimethyl-1,2,<i-thiadiazine-1,1-dioxide 1 at 0d
After adding and dissolving 6.0 g, react at room temperature for 4 hours. After stirring, soak the anti-WrW in methanol 500 ml while cooling with water.
d, and then 31.6 g of pyridine are added dropwise. If the precipitation tool is taken, thoroughly washed with methanol and dried, 7-amino-3-(3,5-dimethyl-1゜2.
Crude crystals of 6-thiadiazin-1,1-dioxid-2-yl)methyl-cephem-4-carboxylic acid 30.
s g (yield 82.0%).

In the same manner, crude crystals of the following compound were obtained.

o7-amino-3-(N-methylmethanesulfonamido)methyl-Δ8-cephemu-4-carboxylic acid 07-amino-3-(1,2,(S-thiadiazine-1)
1-dioxid-2-yl)methyl-cephemu 4
-carboxylic acid 07-amino-6-(tetrahydro-1,2-thiazin-1,1-dioxid-2-yl)methyl-Δ3-cephemu-4-carboxylic acid 07-amino-3-(5-methyl-inthiazolidine) -1,1-dioxide-2-yl)
Methyl-Δ3-cephemu-4-carphonic acid +21 fl
300 dK of 7-amino-3-(3,5-dimetatool) obtained in + was suspended, and p-toluenesulfonic acid/p-toluenesulfonic acid was added to this.
12.3g of monohydrate = 71%. Then, 46.97 g of diphenyldiazomethane was gradually added, and the mixture was allowed to react at room temperature for 15 minutes.

After the reaction is completed, the solvent is distilled off under reduced pressure, and 600 d of ethyl acetate and 300 V of water are added to the resulting residue, and the pH is adjusted to 7 by adding sodium hydrogen carbonate. After removing insoluble matter from P, the organic layer is separated, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to column chromatography (Wako silica gel c=200.
When purified with eluent; benzene:ethyl acetate = 3:1), diphenylmethyl-
7-amino-5-(5,-5-dimethypv-1,2,6
-Thiadiazin-1,1-dioxid-2-yl)methyl-cephem-4-carboxylate 20, s
y (yield 47.2%).

I 11 (KB r ) Country p C-01780p
172 DNMR (CDCim) δ value; 1,90 (3H,@, -C&).

2.22 (3H, 11, -〇Hi).

! 1.44 (2H, bs, c, =)i).

4-7 s (I H7at J = s Hz, c
@-u)y4.92(IH,d, J=5H1,CW
-H).

7.03 (IH, i, -CH/').

\7.23-170 (10I(+m+ -@X2) Compounds shown in Table 2 were obtained in the same manner.

(diphenylmethyl-7-amino-3-(5,5-dimethyl-1,2,6-thiadiazin-1,1-dioxide-2-yl)methyl-Δ1-cephemu 4-carboxylate 1 obtained in 31+21 Trifluoroacetic acid 5
Dissolve in a mixed solvent of 2 ml of M and anisole and react at room temperature for 2 hours. After the reaction is completed, the solvent is distilled off under reduced pressure, and diethyl ether is added to the residue to obtain crystals. If thoroughly washed with diethyl ether and dried, the melting point is 1.
7-Amino-s-(5
,5-dimethyl=1,2.6-thiadiazine-1,1-
Dioxide-2-y) l/) Trifluorome' acid salt of methyl-Δ1-cephemu-4-carboxylic acid 0.79 y
(yield 878%).

IR(KBr) CI+';'C=0 1780
．． 171 ONMR (CFm GOOD) δ value] 2.44 ((SH, l, -CH Otori x 2).

164 (2H, bs, Cm-n).

5. 54 (2H, bl, S; L, , ).

5.65 (2) I7 b a, Ca-I(, Ct H
)7625 (1% B7 > H) In the same manner, the compounds shown in Table 6 were obtained.

Example 1 +1+ 2 (2-tert-amyloxycarboxamitothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid 3.159 was dissolved in N,N-dimethylacetamide 51.5111Z and heated at -10°C. Then, phosphorus oxychloride t625' was added dropwise to the mixture, and the mixture was allowed to react at -5 to D°C for 1 hour.

Then, diphenylmethyl=7-amino~3-
(3,5-dimethyl-1,2,6-thiadiazine-1
, 1-dioxide-2-i/L/) methyl-Δ5-cephemu 4-carboxylate (538 g) was added, -5 to 0
Incubate at ℃ for 1 hour. After the reaction is completed, the reaction solution is introduced into a mixed solvent of 100 d of ethyl acetate and 100 g of water, and the pH is adjusted to 6.5 by adding 9 mouthfuls of sodium hydrogen carbonate. Then, the organic layer is separated, dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and diethyl ether is added to the residue to obtain one crystal, which shows a melting point of 145-146°C (decomposition). diphenylmethyl = 7-(2(2-tar
t-Amyloxycarboxamitothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-5
-(3,5-dimethyl-1,2,S-thiadiazine-1
1-dioxid-2-yl) methyl-Δ1-cephemu 4-carboxylate 6,85 y (yield 82.0%
).

IB(KBr) cr+' 7 vC=0 1790
1750685 NMR (CDCl, l) δ value i 0.85 (3H, J =7 HZJ CCHe'
Ml) 7 summer 179 (2H, q, J=7Hz, -r-CH,,CH
HI387 (5H,a,-Cl).

2.26 (5H1s, -cH, le 3.48 (2H, be, cm -H).

4.05 (3H, B, -0CHR).

5-08 (21 (, b m, Sy cloud) 75.16 (1
H, d, J=5Hz 0s-H:)pays(1H,
s, > n).

6.19 (IH, dd, J=5Hz, J=8Hz,
Ct H).

7.01 (1) Ibeiri).

114' (1F4a, CHgu).

131-7.62 (10) I, m, -@X2).

8.14 (11% d, J=8Hz, -CONH-
).

9! 45 (1% sp CON H) Similarly,
The compounds shown in Table 4 were obtained.

[Diphenylmethyl obtained in 21+11=7-(2(
2tert-amyloxycarboxamitothiazole-
4-yl)-2-(syn)-methoxyiminoacetamide]-5-(s,5-1dimethyl-1,2,6-thiadiazin-1,1-dioxid-2-yl)methylome 1
-cephem-4-carboxylate 5.09 F) I
J fluoroacetic acid 25aj and anisole 10111t
Dissolve in a mixed solvent of and react at room temperature for 2 hours.

After the reaction is completed, the solvent is distilled off under reduced pressure, and diethyl ether is added to the residue to collect crystals.

If thoroughly washed with diethyl ether and dried, the melting point is 148.
7-[2-(2-aminothiazol-4-yl-2-(syn)-methoxyiminoacetamide]-s-(!1,5-dimethyl-1.2.6
-Thiadiazin-11-dioxid-2-yl)methyl-Δ8-cephemu-4-carboxylic acid trifluoroacetate! Obtain 1.60 $1 (yield: $90.0%).

In(KBr) x';'C=01780.1710
~163ONMia-nMso) δ value] 2.21 (3H,i, -CHI).

2-29 (5% 87 CH Hatake).

3.45 (2 horses b sp C* H) p! 1.94 (
3H,a, -0CR++).

5.05 (2 Hp b l, 8; -methoxyiminoacetamide]-3-(3,5-dimethyl-1,2,6
2 g of trifluoroacetate of -thiadiazin-11-dioxid-2-yl)methyl-Δ1-cephemu-4-carboxylic acid was dissolved in 10 d of N,N-dimethylacetamide, and 1,8-diazabiditalo(5, 4,0
) Add 086 g of -7-undecene and 109 g of bivaloyloxymethyl iodide, and heat at -10 to 0°C for 50
Let it react for a minute. After the reaction is complete, the reaction solution is diluted with 3Q ethyl acetate.
iu and 6Q ml of water into a mixed bath medium. The organic layer is then separated, washed with 3Qm of water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and diethyl ether was added to the residue to obtain crystalline P, which had a melting point of 1.
Pivaloyloxymethyl 7-(2-(2-aminothiazol-4-yl)-2 exhibiting 16-118°C (decomposition)
-(syn)-methoxyiminoacedeamide)-3-(3
,5-dimethyl-1,2,6-thiadiazine-1,1-
dioxide-2-yl)methyl-Δ1-cephemu-4-
1.42 g of carboxylate (yield 7 tO%) is obtained.

IR(KBr) 0117 C=0 1780.174
5.167 ONMR (CDCIM) δ value] 1.24 (9 horses 87 -C (CHl) Hatake).

2.2 s (6H, 11, -CHI x 2).

5.47 (2H, ba, c, -H).

397 (RoH, m, OCH Tan).

5.16 (3H, be, s≧, , Cg H) J5
．． 85 (148,>-H).

5.96 (5H, ba, -OCH snow 0-7. cy-
H, -NH neglect).

6-75 (IH, m petori).

8.41 (IJa, J=8Hz, -CoNH-) Similarly, the following compound was obtained.

0 pivaloyloxymethyl = 7-, L2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide)-3-(5-methyl-isothiazolidine-1,1-dioky Carboxylate melting point; 112-116°C (decomposed) In(KBr) am';'C=01780.17
50.1675tuH(cDctx)δ value] 1.23(9H,s,-c(cHs)s);1i9(3
H, d, J=7Hz, 〉CM-C3,).

3.65 (2H, bB, C1-H).

4, o5(s x, 8.-0CHJ, ”:) cI
i, ).

5.18 (IIi, d, J=5Hz, t, -H)
.

s, so~6.3q (srr, m, -0CHt07
C, -H, -NHJ).

6.73 (IH, Yogo H).

8.29 (IH, d, J=8Hz -CONH-)
Example 3 (0.955' of 11 diketene was dissolved in 10 d of anhydrous methylene chloride)
1.819 bromine was added dropwise at -60°C, and -3
React for 30 minutes at 0 to -20'C. Then this anti-F
[diphenylmethyl=7-amino-3-(3,5-dimethyl-1,2,6-thiadiazin-1-1-dioxide-2-yl)methyl-Δ1-cephemu 4-carboxylate 50 and N, N-dimethylaniline 338
-30 to -2 into a 5 ml solution of anhydrous methylene chloride containing 2
Add dropwise at 0°C. After dropping, the mixture was allowed to react at -20 to -10°C for 1 hour. After the reaction is completed, the solvent is distilled off under reduced pressure, 80 ml of ethyl acetate and 80 ml of water are added to the residue, and the organic layer is separated. After washing with 3Qd of water, it is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was subjected to column talomagography (Wako silica gel C
-200. When purified with [eluent] chloroform), diphenylmethy/I/
=7-(4-promo 3-oxybutyramide)-5-
<5,5-dimethyl-1,2,6-thiadiazine-1,
1-dioxid-2-yl)methyl-cephem-4
-carboxylate s, soy' (yield 84.5%).

IR(KBr) a++';I'C=01775.1
720.1680°64O NMR (dg-DMSO) δ value 1 2A4 (311,a,-CHx).

2.21 (3H, l, -CHl).

3.55 (4H, bB, c, -H, -COCHIC
O-).

451 (2Hl tit B r cH, CO) 15
08 (2% b sp SQn, )/s, 6o(u
+, a, J=5H1,CM-H).

5.? 4(H(, dd, J=5HE, J=8Hz pie H)/6A5(1■(convex)-H).

7.09 (IH, a, -CH\Lua, 1 s ~ 7.87 (10'H, m, -@X2)
.

-9,32(IH,d, J=8Hz -eONH-
) + 21 fl + diphenylmethyl = 7-(
4~Bromo-3-oxybutylamide)-! l-(many 5
-dimethylthi226-thiadiazin-1,1-dioxido-2-yl)methyl-Δ8-cephemu-4-carboxylate) 5.05"& water containing 0.54 Sl of sodium nitrite dissolved in 25 d of acetic acid and distilled under ice. 2 red solution was added dropwise and allowed to react at room temperature for 2 hours. After the reaction was completed, the reaction solution was introduced into 200 ml of water, and the precipitated crystals were collected, thoroughly washed with water, and then dried. The crystals were then dried. was dissolved in chloroborum and subjected to column chromatography (Wako silica gel C
Diphenylmethyl = 7 has a melting point of 138-141°C (decomposition) when purified with -200° eluent; chloroform).
-(4-promo 2-hydrothousandiimino-6-oxybutylamide)-X-(3,5-dimethyl-1,2,6-
Thiadiazine-1,1-dioxide-2-i/I/) methylome 8-cephem-4-carboxyle) 3.1
79 (yield 61.0%) is obtained.

I R(KB r ) 0I p c==o 1 7
85y1725Noro9O NMR (di-DMSO) δ value: 2.18 (Fu, s, -CH).

2.24 (3H7s, CHa)7 3.54 (2 bow BL, C meeting-■).

4.72 (2H, bi, BrCHmCO-).

s-09 (2H, bSJ, ;L, &), *5.36
(IH,a,J=5H1,CI-H).

6.10 (I H, d dJJ = 5 HZ) J-8
Hzs Cy H) J6.14 (IH, s, %H).

109 (1% 17 CHgu).

7.22-7.99 (10H, m, →X2).

9.65(1)i, d, J=8Hz, -CONH-
) tl 3-3 ” (I HJs, OH) (3) (2
] Diphenylmethyl-7-(4promo 2-
Hydroxyimino-3-oxobutyramide)-3-(
2.0 g of 5,5-dimethyl-1,2,6-thiadiazin-1-1dioxido-2-yl)methyl-g-cephem-4-carboxylate was dissolved in 20 MIC of methanol, and the diethyl ether of diazomethane was heated at 0 to 5°C. Add the solution slowly and react at the same temperature for 30 minutes. After the reaction is completed, the solvent is distilled off under reduced pressure after confirming that diazomethane has disappeared. The resulting residue was then purified by column chromatography (Wako silica gel C-200, eluent: toluene:ethyl acetate = 3:1) to give a melting point of 145-1.
48°C (decomposition) Diphenylmethyl = 7-(4-7
'Romo2-(syn)-methoxyimino-3-oxobutyramide)-3-(3,5-dimethylol2,6-thiadiazin-1,1-dioxid-2-yl)methyl-
(-cephem-4-carpoxyle) 1.12 y
(yield 54.9%).

IR(KBr) tt+';'C=0 1780 1
720 no 67O N jLR (diDMSO) δ value; 2.13 (3H, l, -CHs)/2.20 (3H
,8,-C&).

5.50 (2H, b town Cm H)y s, q3 (S horse sp - OC mountain).

4.0B, 4.66 (2H, ABQ, J=5Hz,
BrCLCO-).

5.03 (2Hp b 87”>-).

Suni 5.26 (IH, d, J-5Hz, C5-H).

5.85 (IH, dd, J=5H!, J=8Hz,
Cv-H).

6.07 (IH, s, >H).

7.02 (IH, m, -ca〈).

7.10 to 7.77 (10H, m, R→X 2).

975 (I H, dp J Mi8 Hzp -CON
H) (4) Diphenylmethyl obtained in (3) = 7-
(4-furomo2-(syn)-methoxyimino-6-oxobutyramide)-3-(3,5-dimethyl-1,2
,,6-thiadiazin-1,1-dioxid-2-yl)methyl-cephem-4-carboxylate 1. O
F and 15g of thiourea are dissolved in 5g of N,N-dimethylacetamide and reacted at room temperature for 2 hours. After completion of the reaction, the reaction solution was introduced into a mixed solvent of ethyl acetate 2011j and water 201, and the pH was adjusted by adding sodium hydrogen carbonate.
Adjust to 7.0. Then, separate the organic layer and add 2Qag of water.
After washing with water and drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Add diethyl ether to the residue and collect the crystals to obtain diphenylmethyl-7-[2-(2-aminothiazol-4-yl)-2-(syn)-, which has a melting point of 145-148°C (decomposition). Methoxyiminoacetamide]-3-(!+,5-dimethyl-1,21.S-thiadiazin-1)1-dioxid-2-yl)methyl-
0.679 of Δ3-cephemu 4-carboxylate (691% yield) is obtained.

1R(KBr) an'; IC=0 1780.1
720.167ONMB (ds DMSO) δ value; 2.18 (3H,S,-CH,).

Z 24 (5Hz m, r CHs )y149(2
Le bsy C-H).

Otsu96 (6 horses, OCHa)y 5.12 (2 skill b 8 -).

Mushi558 (I Hp % J Ka5 HZT Cs”
), +/s-09 (11'v d dt J ~5
Hz* J ~8 Hj, Ct-H).

615 (I HJ sp>il 6.96 (1% @, : entered).

7.12 (1B, l, -cu<).

7.22-7.92 (10H, rIIJ-@X2).

9.94 (IH, a, J-8H!, -CONH-) (
51 (diphenylmethyl obtained in 41 = 7-(2-(
2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-5-(3,5-dimethyl-1,2,6-thiadiazine-1,1-dioxide-2
-yl)methyl-Δ5-cephemu-4-carboxylene) 0.59 is dissolved in a mixed solvent of 2.5 m of trifluoro#acid and 1 d of trifluoroacid, and reacted at room temperature for 1 hour. After the reaction, the solvent is distilled off under reduced pressure and diethyl ether is added to the residue to obtain crystalline P, which has a melting point of 148~
7-42-(2-aminothiazol-4-yv)-2-(syn)-methoxyiminoacetamide ml-3-(3,5-dimethyl-1°2) showing 150°C (decomposition)
．． 6-thiadiazin-1,1-dioxide-2-yl)
0.4151 (yield: 89.1%) of trifluoroacetate of methyl-Δ8-cephemu-4-carboxylic acid is obtained. The physical properties (IR and NMR) of this compound are as shown in Example 1-1.
21 was the same as what I got.

Example 4 +112-(2-formamidothiazol-4-yl)
Glyoxylic acid was suspended in N,N-dimethylacetamide 5, Oaijlc, and phosphorus oxychloride was dissolved at -20°C.
812 was added dropwise and reacted at the same temperature for 2 hours. Then diphenylmethyl=7-amino-3-(3,5-dimethyl-1,2,6-thiadiazine-1,1-dioxide-2
-yl)methyl-cephem-4-carboxylate)
Anhydrous methylene chloride solution containing 2.4551 12111
7 was added dropwise at -30 to -20°C, and 1 was added at -20 to -10°C.
Allow time to react. After the reaction was completed, the solvent was distilled off under reduced pressure.
Ethyl acetate 50#11 and water 50ml were added to the residue,
Add sodium bicarbonate to adjust pH to 7.0. Then, insoluble matters were removed, and the organic layer was separated, washed with 5 oav of water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (Wako silica gel C-200
．． If purified with elution YL (chloroform), the melting point was 141.
~143°C (decomposition) diphenylmethyl-7-(2
-(2-fort-amidothiazol-4-yl)-glyoxylamide)-3-(5,5-dimethyl-1,2゜6
-thiadiazine-1,1-dioxide-2-i/I/)
Methyl-Δ3-cephemu-4-carboxylate 2.2
79 (yield 68.8%) is obtained.

I l'l (KBr) Cll t C±0 17
80.1720.1665NMR(da DMSO)δ
Value; 2.19 (3H, @, -CHm).

2.23 (3H, I, -CHfi).

3.51 (2H, M, Cm-H) ~ 5.41 (I
H, d, J=5HL, c, -H).

6.02 (IH, dd, J=5Hz J=8HI,
cy-n).

6.13 (IH, ΣH)2 7.09(IH,l,-CH().

127-78 B (10H, mt - ■ x 2).

8.65 (1 horse 8).

8.76(IH,s) 10.13(IH,d,, J =8Hz, -CONH
-)(21(diphenylmethyl-7- obtained in 11)
2-(2-borumamidothiazol-4-yl)-glyoxylamide)-5-(5,5-dimethyl-1,2,
, 6-thiadiazin-1,1-dioxide-2-yl)
Methyl-cefemu 4-carboxylate 0.89
is dissolved in 4d of NjN-dimethylacetamide, 0.14P of methoxyamine hydrochloride is added under water cooling, and the mixture is reacted at room temperature for 3 hours. After the reaction is completed, the reaction solution is diluted with ethyl acetate for 20 minutes.
ml and water, and the organic layer was separated, washed with 20 ml of water, and dried over anhydrous magnesium sulfate. Then, the solvent is distilled off under reduced pressure, diethyl ether is added to the residue, and the crystals are collected.
Diphenylmethyl = 7-(2-(
2-formamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamide)-5-(3,5-dimethyl-126-thiadiazine-11-dioxide-2
-yl)methyl-Δ5-cephemu 4-carboxylate 0.651 (yield 78.5%) is obtained.

IB(KBr)ilJ'C-01780
71720, 1685 NMR (ds-DMSO) δ value 5 2.06 (5H, Lee-OH port).

2-15 (3Hllip L Hs) J6.4o
(2H/ b a , C2n) p5.8B (5H, B,
-0CHI).

4.93 (2H, bay, )-box-).

5.20 (IH, d, J=5Hz, CI-H).

5.93 (IH, da, J=5Hz, J=8Hz,
C7-H).

5.94 (1H, B)\H).

690 (I H,ey CH< ),? 7.03-7
．． 66 (11 Tokitotsu x 2).

8.48 (IH, 8, HCO-).

9.76 (IH, d, J=8HE, -CONn-).

12.66 (1 horse, -CONH-) (diphenylmethyl obtained in 31121 = 7-(2-
(2-formamidothiazol-4-yl-2-(syn)-methoxyiminoacetamide)-3-(3,5-dimethyl-1,2,6-thiadiazin-1,1-dioxido-2-yl)methyl- Δ1-cephemu 4-carboxylate α6 was dissolved in methanol 5d, and concentrated hydrochloric acid 0
Add 33d and react at 35-40°C for 2 hours. After the reaction, the reaction solution was mixed with 201t of ethyl acetate and 20Rt of water.
into a mixed solvent, add sodium hydrogen carbonate and p
Adjust to H6.0. Then, separate the organic layer and add 20 d of water.
After washing with water, dry with anhydrous magnesium sulfate.

The solvent is distilled off under reduced pressure, and diethyl ether is added to the residue to obtain one crystal, which has a melting point of 145-148°C (decomposition).
Diphenylmethyl = 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide)-3-(45-dimethyl-1,2,6-thiadiazine-1,1 -dioxide-2-yl)methyl-
Δ1-cephemu 4-carboxylate 0.4 B y
(yield 82.8%). Furthermore, the physical properties of this compound (I
R and NMR) were consistent with those obtained in Example 3-(4).

Example 5 1.61 of +112-(2-tritylaminothiazol-4-yl)-2-(syn)-tart-butoxycarbonylmethoxyiminoacetic acid was dissolved in 8.01 of NN-nodimethylacetamide and the mixture was heated at -10°C. 0.479 g of phosphorus oxychloride is added dropwise and reacted at -5 to 0°C for 1 hour. Then diphenylmethyl=7-amino-3
-(5,5-dimethyl-2,2,6-thiadiazine-1
, 1-dioxid-2-yl)methyl-Δ8-cephemu-4-carboxylene) 1.58 F was added, and 0 to 5
Incubate at ℃ for 2 hours. After the reaction was completed, the reaction solution was introduced into a mixed solvent of 5 Q ml of ethyl acetate and 5 Q ml of water,
The organic layer is separated, washed with 30 ml of water, and then dried over anhydrous magnesium sulfate.

Then, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (Aiko Silica Gel C-2oo, 'f8-tL).
; When purified with benzene:ethyl acetate-5=1), diphenylmethyl-7 has a melting point of 123-125°C (decomposition).
-[2-(2-)lytylaminothiazol-4-yl)
-2-(syn)-tert-butoxycarbonylmethoxyiminoacetamide]-6-(35-dimethyl-1
,2,6-thiadiazine=1,1-dioxid-2-yl)methyl-Δ3-cefemu 4-carboxylate 2
-1051 (yield 6Z1%) is obtained.

IR(KBr) cm, pC=01790.17
30. 168ONMB (ds DMSO) δ value] 145 (9Hz s,' (C”s)m).

2.15 (3H,8,-C&).

2.2s (3H, S, -CHI).

3.4s (2n, be, CI-H).

4.65 (2H, ba, -OCH!Go-).

5.07 (2N(,bll,8)-knee).

5.32 (IH, d, J=5HK, C5-H).

5.94 (IH, dd, J=5Hz, J=8Hz, C
7-T().

6.1s (I H7IIt >H)/6.94 (1 horse 8).

108 (I H, +1) J l 22~l 90 (25Hp mp # ×5)
p9.03 (11B; -NH<).

9.72 (IH, d, J=8Hz, -CONH-) (2
Diphenylmethyl obtained in 1+11=7-[2-(2
-) dithylaminothiazol-4-yl)-2-(syn)-tert-butoxycarbonylmethoxyiminoacetamide]-3-(3,5-dimethyl-1,2,6-
Thiadiazin-1,1-dioxid-2-yl)methyl-Δ3-cephemu-4-carboxyle) 2. OS
+ i Dissolve in a mixed solvent of 10 Il of trifluoroacetic acid and 4a of anisole and react at room temperature for 1 hour.

After the reaction is completed, the solvent is distilled off under reduced pressure, and diethyl ether is added to the residue to collect crystals. Next, add this crystal to 5
0% formic acid water+? Dissolve in Fj20m, 40-5
React at 0°C for 1 hour. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was mixed with l\F acid ether to obtain crystals. If thoroughly washed with ethyl acetate and dried, the melting point will be 186~
189℃ (decomposition) 7-(2-42-aminothiazol-4-yl)-2-(syn)-carboxymethoxyimino "acetamido" -3-(3,5-dimethyl-1°2.6- Thiadiazine-1,1-dioxide-
The formate salt of 2-yl)methyl-Δ3-cephemu-4-carboxylic acid is obtained (yield 86.8%).

I n (KB r ) cm p c-=tt 17
75 17301675 1650! NMR (da DMSO) δ value; 2.20 (F)I, a, -CHI).

2.25 (3H, s, CHs).

3.41 (,2H, bB, C*-H).

4.69'(2H, ha, -0CHjCO-).

5.09 (2H, bs, so).

5.24 (II% d p J = 5 HZ/C
a-H) p5.91 (I H, dd, J=5H1,
J=10HI, c, -n).

615 (1H7s, ~H).

7.04 (IH, a, ”, 几).

q, 75 (1H, d, J=10H1, -CONH-)
Example 6 1 g of fil 2 (2tart-amyloxycarboxamitothiazol-4-yl)acetic acid is dissolved in 201 Lt of anhydrous methylene chloride, 041 L of N-methylmorpholine is added, and the mixture is cooled to -30°C. Next, ethyl chlorocarbonate 0422 was added and the reaction was carried out at -30 to 20°C for 1 hour. 198 g of -2-yl)methyl-Δ3-cephemu 4-carboxylate is added and reacted at -10 to 0°C for 2 hours. After the reaction is complete, the solvent is distilled off under reduced pressure, and 30μ of ethyl acetate and 50M of water are added to the residue to separate the organic layer.
Add water 3Q+j again, add hydrogen carbonate, and adjust the pH to 7.0. The organic layer is separated, dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, diethyl ether is added to the residue, and the crystals are collected to give diphenyl having a melting point of 147-149°C (decomposed) Methyl = 7
, (2(2-tert-amyloxycarboxamitothiazol-4-yl)-acetamido)-3-(3
,5-dimethyl-1,2,6-thiadiazidi7-1,1-
263 methyl dioxide-2-yl-cefemu 4-carboxylate (yield: 80.1%) was obtained.

111(KBr)LM; C=01780.1720.
167ONMR (d-DMSO) δ value; 2.16 (3H7sp-cHa).

2.24 (3I series-CHM).

549 (2% b 8. C proverb-H).

3.65 (2H, bst'; stop) no 5.07 (2H, bl, s horse).

5.31 (IH, d, J-5Hz, CI-H).

5, q e (I H/ aap J = s a zt
J = a H$7”? H)y6.17 (1 horse 1?
>a) j l 01 (1% my CHgu).

7.10 (IH, I, large).

726-7.92 (10H, m, -@X2).

9.22 (I H, % J = 8 Hz CON
H) +21 +diphenylmethyl obtained in 11 = 7-
[2(2-tert-amyloxycarboxamitothiazo-JL/-4-yl)-acetamide]-3-(3,
5-dimethyl-1,2,,6-thiadiacycin-1-dioxide-2-yl)methyl-Δ'-cef! A
-4-carboxylate 1.09 to trifluoroacetic acid 5
Dissolve in a mixed solvent of Rt and anisole 2d and react at room temperature for 2 hours. After the reaction is complete, the solvent is distilled off under reduced pressure, the residue is mixed with diethyl ether, and one crystal is taken, which shows a melting point of 155-157°C (decomposition).7-(2-
(2-aminethiazol-4-yl)-acetamide]
-3-(5,5-dimethy/l/-1,2,6-thiadiazin-1,1-dioxid-2-yl)methyl-Δ1-
Cephemu 4-carboxylic acid trifluoro6F acid tmo
, 6a9 (yield 86.1%) is obtained.

IR (KBr) cs+, C=0 1775 171
01670 1 63 O NMn (d-DMSO) δ value; 2.29 (3H,1,-CHI).

2j 6 (5H74, CH++).

5.51 (2 liters b ~ CI-) 1).

5-25 (2I% b st >, a-)t5.34
(IH, d, J=5Hz, CI-H).

5.95 (IH, dd, J=5Hz, J=8Hz, C?
-H).

6.27(1H2s,')-H).

6.82 (1, ma-.

9, 40 (I H, d, Jm8Hz, -CONH
-) Patent Applicant: Toyama Chemical Industry Co., Ltd. Continued from page 1 0 Inventor: Yu Saiyo 7-52 Oizumi Nakacho, Toyama City

Claims (1)

[Claims] (1) Cephalosporin and its salts represented by the general formula. +21 1" is a hydrogen atom, Claim No. (11)
Cephalosporins and their salts as described in Section. The cephalosporin and its salts according to claim 11 or (2), wherein (31R' is a hydrogen atom). Claims (1) to 3, wherein (41R' is an aba) group
(3) The cephalosporin and its salts according to any one of the items. It has a meaning. ) The cephalosporin and its salts according to any one of claims (1) to (4). t6) B' is an optionally substituted alkyl group; ￥fClaim No. 1
) to (6) The cephalosporous phosphorus and its salts as described in item 1. It is a columnar body, and B1 has the meaning described above. ) The cephalosporin and its salts according to any one of claims (1) to (6). It has meaning. ) Claim No. (
The cephalosporin and its salts according to any one of items 1) to (8). The cephalosporin/and its salts according to claim (9), wherein uG R,' is a hydrogen atom or an optionally substituted alkyl group. The cephalosporin and its salts according to claim (9) or CLG, wherein αυ RW is an optionally substituted alkyl or aryl group. has. ) Claims H1 to (8)
) A cephalosporin and its salts as described in any of the above. The cephalosporin and its salts according to claim 1, wherein 03B2 is an optionally substituted 1,2,6-thiadiazin-1,1-dioxido-2-yl group. 04R8 optionally substituted tetrahydro-12-
The cephalosporin and salts thereof according to claim U, which are thiazin-11-dioxide-2-yl groups. Cephalosporins and salts thereof according to claim U, wherein (15Fl'' is an optionally substituted inthiazolidin-1,1-dioxid-2-yl group. IJ(57-(2-(2 -aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide)-3
-(methanesulfonamido)methyl-Δ5-cephemu-4-carboxylic acid, an ester thereof, or a salt thereof. 0η 7-(2-(2-aminothiazol-4-yl)
-2-(syn)-methoxyiminoacetamide)-3-
(3,5-dimethyl-1,2,6-thiadiazine-11
-dioxido-2-yl)methyl-Δ8-cephemu 4
- The compound according to claim (2), which is a carboxylic acid, an ester thereof, or a salt thereof. Decoy 7-[2-(2-aminothiazol-4-yl)-
2-(syn)-methoxyiminoacetamide]-3-(
The compound according to claim 14, which is an ester of tetrahydro-1,2-thiazin-1,1-dioxid-2-yl)methylome-8-cephem-4-carboxylic acid, or a salt thereof. α1 7-[2-(2-aminothiazol-4-yl)
-2-(syn)-methoxyiminoacetamide]-3-
(5-Methyl-isothiazolidin-1,1-dioxide-2-yl)methyl-Δ1-cehumu-4-carbon a
- The compound according to claim 09, which is an ester thereof or a salt thereof. ■ 7-42-(2-aminothiazol-4-yl)-
2-(syn)-carboxymethoxyiminoacetamide]-5-(3,5-dimethy/l/-1,2,6-thiadiazine-1,1-dioxido-2-y/l/)methyl-Δ1-cephemu 4-carboxylic acid, an ester thereof or a salt thereof;