JPS61165366A - Manufacture of lactam compound - Google Patents

Abstract

(57) [Abstract] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to enol derivatives, particularly those having the general formula
Rt is a hydrogen atom or an amino protecting group R+, l is a hydrogen atom or an acyl group AC, or l and R1!
are both divalent amino protecting groups, and R2 is a hydroxyl group or a carbonyl group in the formula, -C(=O
)- together with the group R to form a protected carboxyl group, and R□ is a hydrogen atom, a lower alkyl group or an optionally substituted α-phenyl-lower alkyl group 7 expressed as
β-Amino-3-cephem-3-ol-4-carboxylic acid and the 1-oxide of the 3-cephem compound represented by formula (IA), and the general formula (in which Rt, R1, R8, and R5 has the meaning given above) or the preparation of salts of these compounds having a salt-forming group.

The enol derivatives of the present invention are ethers of 3-cephem-3-ol or 2-cephem-3-ol compounds.

In the 2-cephem compound represented by formula (IB) having double viscosity at the 2.3-position, the optionally protected carboxyl group represented by 2C(=O)-Rt is α Preferably, it is an arrangement.

The amino protecting group R↑ is a group which can be substituted with a hydrogen atom, mainly an acyl group Acs, but also a triarylmethyl group, especially a trityl group, and an organosilyl or organostannyl group.

The group Ac, including the acyl group of the group R9, is mainly an acyl group of organic carboxylic acids having preferably up to 18 carbon atoms, in particular optionally substituted aliphatic, cycloaliphatic, alicyclic-aliphatic acyl groups of group, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acids (including formic acid) and of carbonic acid semi-derivatives.

Base R? The divalent amino-protecting group formed by the linkage of α-aminoacetic acid which preferably carries a substituent, e.g. an aromatic or heterocyclic group, in the α-position; is preferably an acyl group bonded to the nitrogen atom via a methylene group. The radicals 1 and l can also both be organic ylidene radicals having preferably up to 18 carbon atoms, such as aliphatic, cycloaliphatic, cycloaliphatic or araliphatic ylidene radicals.

The protected carboxyl group represented by the formula -C(=O)-R4 is mainly an esterified carboxyl group,
It can also be an anhydride group, a common mixed anhydride group or an optionally substituted carbamoyl or hydrazinocarbonyl group.

Therefore, the group Rt can be a hydroxyl group etherified with an organic group whose number of carbon atoms, which together with the group -C(=O)- form the esterified carboxyl group, is preferably up to 18. can. Such organic radicals include, for example, aliphatic, cycloaliphatic, cycloaliphatic, aromatic or araliphatic radicals, in particular optionally substituted hydrocarbon radicals of this type, as well as heterocyclic or heterocyclic radicals. It is a ring-aliphatic group.

MR8 can also be an organosilyloxy group or a hydroxyl group etherified with an organometallic group, such as the corresponding organostannyloxy group, in particular an optionally substituted hydrocarbon group having preferably up to 18 carbon atoms, such as an aliphatic group. It can also be a silyloxy or stannyloxy group substituted by 1 to 3 hydrocarbon radicals and optionally by a halogen atom, such as a chlorine atom.

The group R8 which together with the group -C(=O)- forms an anhydride group, mainly a mixed anhydride group, is, for example, a halogen atom, especially a chlorine atom, or an acyloxy group, the acyl group preferably being a carbon atom. is the corresponding group of an organic carboxylic acid having up to 18 atoms, such as an aliphatic, cycloaliphatic, cycloaliphatic, aromatic or araliphatic carboxylic acid or a carbonate derivative such as a carbonic acid half ester.

The group R8 which together with the group -C(=O)- forms a carbamoyl group is an optionally substituted amino group. This substituent is an optionally substituted monovalent or divalent hydrocarbon radical having preferably up to 18 carbon atoms, such as an optionally substituted monovalent or divalent hydrocarbon radical having up to 18 carbon atoms. aliphatic, cycloaliphatic,
cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, as well as corresponding heterocyclic or heterocyclic-aliphatic radicals having up to 18 carbon atoms and/or functional groups, e.g. hydroxyl groups, in particular free hydroxyl groups, also etherified or esterified hydroxyl groups (the etherified or esterified groups have, for example, the meanings given above and preferably have up to 18 carbon atoms) or acyl groups; Mainly carbon atoms, preferably 1
It is an acyl group of an organic carboxylic acid or carbonate derivative having up to 8 atoms.

In the substituted hydrazinocarbonyl group represented by the formula -C(=O)-R8, one or both nitrogen atoms may be substituted.

Substituents are mainly monovalent or divalent hydrocarbon radicals which can be substituted, preferably having up to 18 carbon atoms, such as monovalent, which can be substituted, having up to 18 carbon atoms. or divalent aliphatic, cycloaliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, as well as corresponding heterocyclic or heterocycloaliphatic radicals having up to 18 carbon atoms and (or ) Functional groups, such as acyl groups, may be mentioned, mainly acyl groups of organic carboxylic acids or carbonate derivatives having preferably up to 18 carbon atoms.

The general terms described herein have, for example, the following meanings. Aliphatic radicals (including the corresponding aliphatic radicals of organic carboxylic acids) as well as the corresponding ylidene radicals are monovalent or divalent aliphatic hydrocarbon radicals which may be substituted, in particular up to 7 carbon atoms, for example. Preferably, it is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or a lower alkylidene group which can have up to 4 groups. Such groups may optionally be substituted by functional groups, such as free or etherified or esterified hydroxyl or mercapto groups, such as lower alkoxy, lower alkenyloxy, lower alkylenedioxy groups. phenyloxy group or phenyl lower alkoxy group, lower alkylthio group, optionally substituted phenylthio group or phenyl lower alkylthio group, heterocyclylthio group or heterocyclyl lower alkylthio group, optionally substituted lower Alkoxycarbonyloxy group or lower alkanoyloxy group, or halogen atom, as well as oxo group, nitro group, optionally substituted amino group such as lower alkylamino group, di-lower alkylamino group, lower alkylene amino group, oxa-lower alkylene Amino groups or aza lower alkylene amino groups and acylamino groups such as lower alkanoylamino groups, lower alkoxycarbonylamino groups, halogeno lower alkoxycarbonylamino groups, optionally substituted phenyl lower alkoxycarbonylamino groups, optionally substituted Certain carbamoylamino, ureidocarbonylamino or guazininocarponylamino groups, as well as sulfoamino groups which may be present in the form of salts such as alkali metal salts, acyl groups such as amide groups, lower alkanoyl groups and benzoyl groups. , carboxyl groups which may be functionally modified, e.g. carboxyl groups in the form of salts, esterified carboxyl groups such as lower alkoxycarbonyl groups, N-lower alkyl- or N,N-di-lower alkyl-
An optionally substituted carbamoyl group such as a carbamoyl group, an optionally substituted ureidocarbonyl or guazininocarbonyl group, or a cyano group, an optionally functionally modified sulfo group for example a sulfamoyl group or a sulfo group in salt form,
or a phosphono group which may be O-mono- or o,o'-di-substituted (the substituent being, for example, an optionally substituted lower alkyl group, phenyl group or phenyl lower alkyl group, -Unsubstituted or 0-monosubstituted phosphono groups can be mono-, di- or polysubstituted (which can also be in the form of salts, such as alkali metal salts).

The divalent aliphatic group, including the aliphatic group of the divalent aliphatic carboxylic acid, is, for example, a lower alkylene group or a lower alkenylene group, which may be mono-substituted, di-substituted or substituted as the case may be. It can be polysubstituted and/or have heteroatoms such as oxygen, nitrogen or sulfur atoms interposed in the chain.

Alicyclic or cycloaliphatic groups (including corresponding cycloaliphatic or cycloaliphatic groups in organic carboxylic acids) and corresponding cycloaliphatic or cycloaliphatic ylidene groups are substituted. monocyclic or bicyclic alicyclic or alicyclic-aliphatic hydrocarbon groups, such as monocyclic, bicyclic or polycyclic cycloalkyl or cycloalkenyl groups, as well as cycloalkylidene groups, or a cycloalkyl- or cycloalkenyl-lower alkyl group or a mono-lower alkenyl group, further a cycloalkyl-lower alkylidene group or a cycloalkenyl-lower alkylidene group. In these radicals, cycloalkyl and cycloalkylidene have e.g. up to 12 ring carbon atoms, e.g. 3 to 8, preferably 3 to 6, and cycloalkenyl has e.g. up to 12 ring carbon atoms, e.g.
up to 8, for example 5 to 8, preferably 5 or 6, and with 1 or 2 double bonds, and the aliphatic part of the cycloaliphatic group has up to 7 carbon atoms, for example Preferably, there may be up to four. These cycloaliphatic or cycloaliphatic groups may be substituted if desired, for example by aliphatic hydrocarbon radicals, e.g. by the optionally substituted lower alkyl groups mentioned above or by e.g. They can be mono-, di- or polysubstituted with functional groups such as aliphatic hydrocarbon groups.

Aromatic groups (including the corresponding aromatic groups of carboxylic acids) are optionally substituted aromatic hydrocarbon groups, such as monocyclic, bicyclic or polycyclic aromatic hydrocarbon groups, in particular Phenyl groups and biphenylyl or naphthyl groups, which can optionally be mono-, di- or polysubstituted, such as the aforementioned aliphatic and cycloaliphatic hydrocarbon groups.

The divalent aromatic group of the aromatic carboxylic acid is especially 1.2-
Arylene radicals, especially 1,2-phenylene radicals, which can optionally be mono-, di- or polysubstituted, such as the aforementioned aliphatic and cycloaliphatic hydrocarbon radicals.

The above-mentioned araliphatic groups (including araliphatic groups in the corresponding carboxylic acids) and also araliphatic ylidene groups are e.g. optionally substituted araliphatic hydrocarbon groups,
For example, optionally substituted aliphatic hydrocarbon radicals carrying up to three optionally substituted monocyclic, bicyclic or polycyclic aromatic hydrocarbon radicals, especially phenyl-lower Alkyl or phenyl-lower alkenyl groups, as well as phenyl-lower alkynyl and also phenyl-lower alkylidene groups, and such groups have, for example, 1 to 3 phenyl groups and optionally contain, for example, the aliphatic and Like cycloaliphatic groups, they can be mono-, di- or polysubstituted in their aromatic and/or aliphatic parts.

Heterocyclic groups (including those in heterocyclic-aliphatic groups and the corresponding heterocyclic or heterocyclic-aliphatic groups in carboxylic acids) are particularly monocyclic and dicyclic groups with aromatic character.
Cyclic or polycyclic azacyclic, thiacyclic, oxacyclic,
Thiazacyclic, thiadiazacyclic, oxaazacyclic, diazacyclic, triazacyclic or tetraazacyclic groups and also corresponding partially or totally saturated heterocyclic groups of this type, Such groups can optionally be mono-, di- or polysubstituted, such as the cycloaliphatic groups mentioned above.

The aliphatic moiety in a heterocycloaliphatic radical has, for example, the meaning given to the corresponding cycloaliphatic or araliphatic radical.

The acyl group of the carbonate derivative is the acyl group of the corresponding half ester (the organic group of this ester group is an optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon group or heterocyclic group). aliphatic groups), especially the acyl groups of lower alkyl half esters of carbonic acid (which are e.g.
- or β-position) and acyl groups of lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl half esters of carbonic acid, which may be substituted in the organic group. . The acyl group of the carbonic acid half ester is further defined as the corresponding group of the lower alkyl half ester of carbonic acid, the lower alkyl part of which has a heterocyclic group, for example one of the aforementioned heterocyclic groups of aromatic character, Both alkyl groups and heterocyclic groups can be optionally substituted. Furthermore, the acyl group of the carbonate derivative can also be an optionally N-substituted carbamoyl group, such as an optionally halogenated N-lower alkylcarhamoyl group.

Etherified hydroxyl groups are mainly substituted.

lower alkoxy groups, the substituents of which are mainly free or functionally converted eg etherified or esterified hydroxyl groups, especially lower alkoxy groups or halogen atoms;
cycloalkyloxy or optionally substituted phenyloxy groups, as well as heterocyclyloxy or heterocyclyl lower alkoxy groups, in particular optionally substituted phenyl lower alkoxy groups.

Examples of amino groups that may be substituted include amino groups,
lower alkylamino group, di-lower alkylamino group, lower alkyleneamino group, oxa-lower alkyleneamino group,
thia lower alkylene amino group, aza lower alkylene amino group, hydroxyamino group, lower alkoxyamino group,
It is a lower alkanoyloxyamino group, a lower alkoxycarbonylamino group, or a lower alkanoylamino group.

The hydrazino group which may be substituted is, for example, a hydrazino group, a 2-lower alkylhydrazino group, a 2,2-di-lower alkylhydrazino group, a 2-lower alkoxycarbonylhydrazino group or a 2-lower alkanoylhydrazino group. be.

Examples of lower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tertiary-butyl, and n-pentyl, isopentyl, and n-hexyl groups. , isohexyl or n-heptyl; lower alkenyl groups can be, for example, vinyl, allyl, isopropenyl, 2- or 3-methallyl or 3-butenyl; lower alkynyl groups are, for example, It can be a propargyl group or a 2-butynyl group, and a lower alkylidene group can be, for example, an isopropylidene group or an isobutylidene group.

The lower alkylene group is, for example, 1.2-ethylene group, 1.2-ethylene group,
- or 1,3-propylene group, 1,4-butylene group,
The lower alkenylene group is, for example, a 1,2-ethenylene group or a 2-buten-1,4-ylene group. A lower alkylene group having an intervening heteroatom is, for example, an oxa-lower alkylene group such as 3-oxa-1,5-pentylene group, a thia-lower alkylene group such as 3-thia-1,5-bentylene group, or a 3-lower alkylene group such as 3-oxa-1,5-bentylene group. Alkyru 3-aza-1
, 5-benzene group e.g. 3-methyl-3-aza-1,
It is an aza lower alkylene group such as 5-pentyline group.

Cycloalkyl groups are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and adamantyl; cycloalkenyl groups are, for example, cyclopropenyl, 1-12
- or 3-cyclopentenyl group, 1-12- or 3
-cyclohexenyl group, 3-cycloheptenyl group or 1,4-cyclohexagenyl group, and the cycloalkylidene group is, for example, a cyclopentylidene group or a cyclohexylidene group. Cycloalkyl-lower alkyl or cycloalkyl-lower alkenyl groups are, for example, cyclopropyl, cyclobenthyl, cyclohexyl-
or cyclohebutyl-methyl group, -1, ■- or -
1,2-ethyl group, -1,1-1-1,2- or -1
, 3-propyl, -vinyl or -allyl, the cycloalkenyl-lower alkyl or cycloalkenyl-lower alkenyl group being, for example, 1-12- or 3-cyclopentenyl-11-12- or 3-cyclo hexenyl- or 1-12- or 3-cycloheptenyl-methyl group, -1,1- or -1,2-ethyl group, -1,1, -1,2- or -1,3-probyl group,
- vinyl group or monoallyl group. cycloalkyl
The lower alkylidene group is, for example, a 3-cyclohexenyl group or a methylene group.

The naphthyl group is a 1- or 2-naphthyl group, and the biphenylyl group is, for example, a 4-biphenylyl group.

Phenyl-lower alkyl or phenyl-lower alkenyl groups are, for example, benzyl, 1- or 2-phenylethyl, 1-12- or 3-phenylpropyl, diphenylmethyl, trityl, styryl or cinnamyl. A naphthyl-lower alkyl group such as (1)- or 2-naphthylmethyl group is a 1- or 2-naphthylmethyl group, and a phenyl-lower alkylidene group is, for example, a benzylidene group.

Heterocyclic radicals are in particular optionally substituted heterocyclic radicals with aromatic character, such as corresponding monocyclic monoazacyclic, monothiacyclic or monooxacyclic radicals, such as 2-
Pyryl group such as pyryl group and 3-pyryl group, 2-13-
or pyridyl groups and pyridinium groups such as 4-pyridyl groups, chenyl groups such as 2- or 3-chenyl groups, or furyl groups such as 2-furyl groups, bicyclic monoazacyclic, monooxacyclic or monothiacyclic groups. cyclic groups such as indolyl groups, such as 2- or 3-indolyl groups, 2
- or a quinolinyl group, such as a 4-quinolinyl group, 1-
isoquinolinyl group such as isoquinolinyl group, benzofuranyl group such as 2- or 3-benzofuranyl group or pentuchenyl group such as 2- or 3-benzochenyl group, monocyclic diazacyclic, triazacyclic, tetraazacyclic, Oxaazacyclic, thiazacyclic or thiadiazacyclic groups, e.g. imidazolyl groups such as 2-imidazolyl groups, pyrimidinyl groups such as 2- or 4-pyrimidinyl groups, 1,2.4-)lyazol-3-yl groups triazolyl group such as, tetrazolyl group such as 1- or 5-tetrazolyl group, oxasilyl group such as 2-oxasilyl group, isoxasilyl group such as 3- or 4-isoxasilyl group, 2-thiazolyl group a thiazolyl group such as a thiazolyl group, an isothiazolyl group such as a 3- or 4-isothiazolyl group, or a 1. 2.4- or 1.3.4-thiadiazolyl groups, or bicyclic diazacyclic, oxaazacyclic or thiazacyclic groups, such as benzimidazolyl groups such as 2-benzimidazolyl groups, 2-benzoxasilyl groups benzoxasilyl group such as or benzthiazolyl group such as 2-benzthiazolyl group. Corresponding partially or totally saturated groups are, for example, tetrahydrochenyl groups such as 2-tetrahydrochenyl groups, 2
- a tetrahydrofuryl group such as a tetrahydrofuryl group or a piperidyl group such as a 2- or 4-piperidyl group. Heterocyclic-aliphatic radicals are heterocyclic radicals, in particular lower alkyl or lower alkenyl radicals bearing the abovementioned radicals.

Said heterocyclic radicals include, for example, aliphatic or aromatic hydrocarbon radicals which may be substituted, in particular phenyl substituted by lower alkyl radicals such as methyl radicals or optionally by halogen atoms such as chlorine atoms. It can be substituted by groups such as phenyl or 4-chlorophenyl groups or by functional groups such as the aliphatic hydrocarbon groups mentioned above.

Lower alkoxy groups include, for example, methoxy, ethoxy, n
-propoxy group, isopropoxy group, n-butoxy group,
Isobutoxy group, 2nd butoxy group, tertiary butoxy group, n
-pentoxy group or tertiary pentoxy group. These groups may be substituted, for example halogeno-lower alkoxy, especially 2-halogeno-lower alkoxy, such as 2.2.2-trichloroethoxy, 2-chloro-12-bromo or 2-iodo-ethoxy. I can be there.

Lower alkenyloxy groups are, for example, vinyloxy or allyloxy groups, lower alkylenedioxy groups are, for example, methylenedioxy, ethylenedioxy or isopropylidenedioxy groups, and cycloalkoxy groups are, for example, cyclopentyloxy, cyclohexyloxy. or adamantyloxy group, the phenyl-lower alkoxy group being, for example, the benzyloxy group or the 1- or 2-phenylethoxy group, the diphenylmethoxy group or the 4,4'-dimethoxy-diphenylmethoxy group, and the heterocyclyl- An oxy group or a heterocyclyl lower alkoxy group is, for example, a pyridyl-lower alkoxy group such as a 2-pyridylmethoxy group, a furyl-lower alkoxy group such as a furfuryloxy group, or a 2-
It is a thenyl-lower alkoxy group such as a thenyloxy group.

Lower alkylthio groups are, for example, methylthio, ethylthio or n-butylthio, lower alkenylthio groups are, for example, allylthio groups, phenyl-lower alkylthio groups are, for example, benzylthio groups, and also heterocyclic groups or heterocyclic groups. -Mercapto groups etherified with aliphatic groups are in particular pyridylthio groups such as 4-pyridylthio, imidazolylthio, thiazolylthio groups such as 2-thiazolylthio, 1,2,4-thiadiazole-3
-ylthio group or 1.2.4- or 1.3.4-thiadiazolylthio group such as 1.3.4-thiadiazol-2-ylthio group or tetrazolylthio group such as 1-methyl-5-tetrazolylthio group. It is the basis.

Esterified hydroxyl groups are inter alia halogen atoms such as fluorine, chlorine, bromine or iodine atoms, and lower alkoxy, carbonyloxy groups such as methoxycarbonyloxy, ethoxycarbonyloxy or t-butyloxycarbonyloxy groups, 2-halogeno lower an alkoxycarbonyloxy group such as a 2,2.2-)lychlorethoxylponyloxy group, a 2-bromoethoxycarbonyloxy group or a 2-iodoethoxycarbonyloxy group, or an arylcarbonylmethoxycarbonyloxy group such as a phenacyloxycarbonyloxy group; be.

Lower alkoxycarbonyl groups are, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl or t-pentoxycarbonyl.

N-lower alkyl-carbamoyl group or N.

N-dilower alkyl-carbamoyl group is, for example, N-methylcarbamoyl group, N-ethylcarbamoyl group, N,N
-dimethylcarbamoyl group, N,N-diethylcarbamoyl group, while the N-lower alkylsulfamoyl group is, for example, N-methylsulfamoyl group or N,N-dimethylsulfamoyl group.

Carboxyl or sulfo groups in the form of alkali metal salts are, for example, carboxyl or sulfo groups in the form of sodium or potassium salts.

A lower alkylamino group or di-lower alkylamino group is, for example, a methylamino group, an ethylamino group, a dimethylamino group or a diethylamino group, a lower alkyleneamino group is, for example, a pyrrolidino group or a piperidino group, an oxa-lower alkyleneamino group is, for example, a morpholino group, a thia lower alkylene amino group is, for example, a thiomorpholino group, and an aza lower alkylene amino group is, for example, a piperazino group or a 4-methylpiperazino group.

Acylamino groups are in particular carbamoylamino groups, lower alkylcarbamoylamino groups such as methylcarbamoylamino groups, ureidocarbonylamino groups, guanidinocarbonylamino groups, lower alkoxycarbonylamino groups such as methoxycarbonylamino groups, ethoxycarbonylamino groups or t-butoxy carbonylamino group, 2
．． 2. Halogeno lower alkoxycarbonylamino group such as 2-trichloroethoxycarbonylamino group, 4-
Phenyl lower alkoxycarbonylamino groups such as methoxybenzyloxycarbonylamino groups, lower alkanoylamino groups such as acetylamino groups and propionylamino groups, as well as phthalimide groups or salts such as alkali metal or ammonium salts such as sodium salts. It is a sulfamino group that can be found in

Examples of lower alkanoyl groups include formyl group, acetyl group,
It is a propionyl group or a pivaloyl group.

〇-lower alkylphosphono group is, for example, 0-methyl- or 0-ethyl-phosphono group, and 0.0'-di-lower alkyl-phosphono group is, for example, 0,0'-dimethyl-phosphono group or 0,0' -diethyl-phosphono group, 0-phenyl lower alkyl-phosphono group is e.g. O-benzyl-phosphono group and 0-lower alkyl-O'-phenyl lower alkyl-phosphono group is e.g. It is.

The lower alkenyloxycarbonyl group is, for example, a vinyloxycarbonyl group, and the cycloalkoxycarbonyl group and the phenyl-lower alkoxycarbonyl group are, for example, an adamantyloxycarbonyl group, a benzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl group, a diphenylmethoxycarbonyl group. or α-4-biphenyl-α-methylethoxycarbonyl group. A lower alkoxycarbonyl group whose lower alkyl group has, for example, a monocyclic monoazacyclic, monooxacyclic or monothiacyclic group is a furyl-lower alkoxycarbonyl group such as furfuryloxycarbonyl or a 2-tenyl group. It is a chenyl-lower alkoxycarbonyl group such as an oxycarbonyl group.

The 2-lower alkylhydrazino group and the 2,2-di-lower alkylhydrazino group are, for example, a 2-methylhydrazino group or a 2,2-dimethylhydrazino group, and the 2-lower alkoxycarbonylhydrazino group is, for example, a 2-dimethylhydrazino group. -methoxycarbonylhydrazino group, 2-ethoxycarbonylhydrazino group or 2-t-butoxycarbonylhydrazino group, and the lower alkanoylhydrazino group is, for example, 2-acetylhydrazino group.

The acyl group Ac can be produced naturally or biosynthetically, semi-synthetically or totally synthetically, especially from 6-amino-penam-3-carboxylic acid compounds or 7-amino-3-cephem-4-carboxylic acid compounds. Preferably pharmacologically active N
- The number of carbon atoms contained in the acyl derivative is preferably 1
Acyl groups of up to 8 organic carboxylic acids or easily cleavable acyl groups, especially acyl groups of carbonate derivatives.

6-amino-penam-3-carboxylic acid compound or 7-
The acyl group Ac contained in the pharmacologically active N-acyl derivative of the amino-3-cephem-4-carboxylic acid compound is mainly represented by the formula [in this formula, n is 0 and RI is a hydrogen atom or substituted] optionally cycloaliphatic or aromatic hydrocarbon groups, optionally substituted and preferably aromatic heterocyclic groups, functionally modified e.g. esterified or etherified hydroxyl or mercapto groups; or an optionally substituted amino group, or n is 1, and RI is a hydrogen atom or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic, aromatic or aromatic aliphatic hydrocarbon radicals, optionally substituted heterocyclic radicals or heterocyclic-aliphatic radicals whose heterocyclic radicals preferably have aromatic character and/or have a quaternary nitrogen atom; hydroxyl or mercapto groups which may be functionally modified (preferably etherified or esterified), carboxyl groups which may be functionally modified, acyl groups, amino groups which may be substituted or is an amide group, and the groups R11 and R1 are both hydrogen atoms, or n is l, and RI is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic, aromatic or an araliphatic hydrocarbon group or an optionally substituted heterocyclic or heterocyclic-aliphatic group in which the heterocyclic group preferably has aromaticity, and R
1[ is a hydroxyl or mercapto group which may be functionally modified, e.g. esterified or etherified, e.g. a halogen atom, an amino group which may be substituted;
a carboxyl group or a sulfo group, which may be functionally modified, a phosphono group or an amide group, which may be 0-mono- or 0.0'-disubstituted, and R11 is a hydrogen atom; or n is l, the groups RI and R1 are each a functionally modified (preferably etherified or esterified) hydroxyl group or an optionally functionally modified carboxyl group, and RIM is a hydrogen atoms, or n is 1 and R
I is a hydrogen atom or an optionally substituted aliphatic group,
a cycloaliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon group, and R1 and R111 may both be substituted and bonded by a double bond to a carbon atom in the formula is an aliphatic, cycloaliphatic, cycloaliphatic, or araliphatic hydrocarbon group, or n is 1 and RI is an optionally substituted aliphatic, cycloaliphatic, an alicyclic-aliphatic, aromatic or araliphatic hydrocarbon group or a heterocyclic or heterocyclic-aliphatic group, the heterocyclic group of which may be substituted, preferably having aromatic character; RI [is optionally substituted aliphatic;
a cycloaliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon group, and Rm is a hydrogen atom or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic, aromatic group; or an aromatic aliphatic hydrocarbon group].

In the acyl group of formula (^) above, for example, n is O and RI is a hydrogen atom or a cycloalkyl group having 5 to 7 ring carbon atoms [this may also be an amino group, an acylamino group (the acyl The group is mainly an acyl group of a carbonic acid half ester such as a lower alkoxycarbonyl group, a 2-halogeno lower alkoxycarbonyl group or a phenyl lower alkoxycarbonyl group) or a sulfoamino group (which can be used in the form of a salt such as an alkali metal salt). may be substituted preferably in the 1-position by an optionally protected amino group such as ), optionally substituted phenyl, naphthyl or tetrahydronaphthyl group [ These are optionally preferably hydroxyl groups, lower alkoxy groups such as methoxy groups, acyloxy groups (the acyl groups being primarily carbonic acid half esters such as lower alkoxycarbonyl groups, 2-halogeno lower alkoxycarbonyl groups or phenyl lower alkoxycarbonyl groups). acyl group) and (
or) by a halogen atom such as a chlorine atom], a heterocyclic group which may be substituted (e.g. by a lower alkyl group such as a methyl group) and/or by a substituent e.g. [can be substituted by a phenyl group which may itself carry a halogen atom such as a chlorine atom], for example a 4-isoxacylyl group or an amino group (which amino group may be substituted with a substituent such as a chlorine atom). (preferably N-substituted by a lower alkyl group which may bear a halogen atom) or n is 1 and RI is a lower alkyl group (which in some cases is preferably N-substituted, such as a chlorine atom); protected by a halogen atom or by a phenyloxy group which may bear a halogen atom, such as a substituent such as a hydroxyl group, an acyloxy group (wherein the acyl group has the meaning given above) and/or a chlorine atom; may be substituted with an amino group and/or a carboxyl group which may be protected], e.g.
Silylation e.g. tri-lower alkylsilylated amino or acylamino groups such as trimethylsilylation, e.g. lower alkanoylamino, halogeno-lower alkanoylamino or phthaloyl-termino groups and/or silylation e.g. 3-amino-3- with an alkylsilylated carboxyl group or a carboxyl group esterified with, for example, a lower alkyl group, a 2-halogen lower alkyl group or a phenyl lower alkyl group such as a diphenylmethyl group. Carboxy-propyl, lower alkenyl, phenyl groups, which may optionally be further protected by substituents e.g. or with an amino lower alkyl group such as an aminomethyl group which may be acylated as in a phenyloxy group which may be substituted], an amino group which may be substituted by a substituent, e.g. a lower alkyl group such as a methyl group, or protected (e.g. acylated as above); Pyridyl groups, which may be substituted by aminomethyl groups, such as 4-pyridyl groups, pyridinium groups, such as 4-pyridinium groups, chenyl groups, such as 2-chenyl groups, furyl groups, such as 2-furyl groups, imidazolyl groups, such as l- an imidazolyl or tetrazolyl group, e.g. 1-tetrazolyl, or a lower alkoxy group which may be substituted, e.g. methoxy, phenyloxy; lower alkylthio groups such as n-butylthio groups or lower alkenylthio groups such as allylthio groups, substituents such as methyl groups, phenylthio group, pyridylthio group such as 4-pyridylthio group, 2-imidazolylthio group, 1,2.4-1-riazol-3-ylthio group, which can be substituted with a lower alkyl group such as 1.3. 4-) Liazol-2-ylthio group, 1,2.4-thiadiazole-3-
ylthio group, e.g. 5-methyl-1,2,4-thiadiazol-3-ylthio group, 1,3.4-thiadiazol-''-
2-ylthio groups, such as methyl-1,3,4-thiadiazol-2-ylthio groups or 5-tetrazolylthio groups, such as 1-methyl-5-tetrazolylthio groups, halogen atoms, especially chlorine or bromine atoms, if functionally modified certain carboxyl groups, e.g. lower alkoxycarbonyl groups such as methoxycarbonyl or ethoxycarbonyl groups, cyano groups or N-substituted carbamoyl groups which may be N-substituted with lower alkyl groups such as methyl groups or phenyl groups; , an optionally substituted lower alkanoyl group such as an acetyl or propionyl group, a benzoyl group or an azido group, and R [ and 8 are hydrogen atoms, or n is l and R
1 is a lower alkyl group, or a phenyl group or a 2-furyl group, which can be optionally substituted with a hydroxyl group and/or a halogen atom such as a chlorine atom, which can be acylated as described above. a furyl group such as a chenyl group such as a 2- or 3-chenyl group or an isothiazolyl group such as a 4-isothiazolyl group, and also a 1,4-cyclohexagenyl group;
R1 has an optionally protected or substituted amino group such as an amino group, an acylamino group such as a lower alkoxycarbonylamino group, a 2-halogeno lower alkoxycarbonylamino group, or a substituent such as a lower alkoxy group such as a methoxy group or a nitro group; phenyl lower alkoxycarbonylamino groups, such as t-butoxycarbonylamino, 2.2.2-trichloroethoxycarbonylamino, 4-methoxybenzyloxycarbonylamino or diphenylmethyloxycarbonylamino, arylsulfonylamino; groups such as 4-methylphenylsulfonylamino, tritylamino, arylthioamino, nitrophenylthioamino or tritylthioamino, such as 2-nitrophenylthioamino, or substituents such as ethoxycarbonyl, A 2-propylideneamino group which may have a lower alkanoyl group such as a lower alkoxycarbonyl group or an acetyl group, such as a 1-ethoxycarbonyl-2-propylideguamino group, or a substituted group such as a guazininocarbonylamino group. a carbamoylamino group, which may be in the form of a salt, such as an alkali metal salt;
A carboxyl group which can be in protected form such as an acydo group, a salt form such as an alkali metal salt or an esterified form (e.g. as a lower alkoxycarbonyl group such as a methoxycarbonyl group or an ethoxycarbonyl group) or a phenyloxycarbonyl group such as diphenylmethoxycarbonyl group)
, cyano groups, sulfo groups, hydroxyl groups which can be functionally modified [functionally modified hydroxyl groups are in particular acyloxy groups such as formyloxy groups, as well as lower alkoxycarbonyloxy groups, 2-halogeno lower alkoxycarbonyl groups] a phenyl lower alkoxycarbonyloxy group which may have an oxy group or a substituent (e.g. a lower alkoxy group such as a methoxy group or a nitro group), such as a t-butoxycarbonyloxy group, 2,2.
2-trichloroethoxycarbonyloxy group, 4-methoxybenzyloxycarbonyloxy group or diphenylmethoxycarbonyloxy group, or optionally substituted lower alkoxy group such as methoxy group or phenyloxy group], 〇-lower alkyl group or 0
．． a 0'-dilower alkyl-phosphono group, such as a 0-methylphosphono group or a 0,0'-dimethylphosphono group, or a halogen atom, such as a chlorine or bromine atom, and R11+ is a hydrogen atom, or n is 1; ,R
I and R1 are each a halogen atom, such as a bromine atom, or a lower alkoxycarbonyl group, such as a methoxycarbonyl group, and R is a hydrogen atom, or n is 1, and RI is optionally, for example, a phenyl group, a furyl group such as a 2-furyl group, a 2- or 3-chenyl group, which may be substituted with a hydroxyl group and/or a halogen atom such as a chlorine atom; a chenyl group such as or an isothiazolyl group such as a 4-isothiazolyl group, and also a 1,4-cyclohexagenyl group, R1 is optionally an aminomethyl group protected, for example as above, and R11 is is a hydrogen atom, or n is 1, and RI, R1[, and R11 are all lower alkyl groups, such as methyl groups.

Such an acyl group Ac is, for example, a formyl group, a cyclopentylcarbonyl group, an α-aminocyclopentylcarbonyl group, or an α-aminocyclohexylcarbonyl group [
This may be an amino group which may be substituted, for example a sulfamino group which may be in the form of a salt, or a chemical reduction such as zinc with an acidic agent such as trifluoroacetic acid or in the presence of an aqueous acetic acid solution. an amino group substituted with an acyl group (preferably Suitable acyl groups of carbonic acid half esters, such as lower alkoxycarbonyl groups such as t-butoxycarbonyl groups, 2,2.2-1-lychloroethoxycarbonyl groups, 2-bromoethoxycarbonyl groups or 2-iodoethoxycarbonyl groups; 2-halogeno lower alkoxycarbonyl groups such as 2-halogeno lower alkoxycarbonyl groups, arylcarbonyl methoxycarbonyl groups such as phenacyloxycarbonyl groups, phenyl lower alkoxycarbonyl groups which may have substituents e.g. lower alkoxy groups such as methoxy groups or nitro groups, e.g. by an N-lower alkylcarbamoyl group such as a 4-methoxybenzyloxycarbonyl group or a diphenylmethoxycarbonyl group, or a suitable acyl group of a carbonic hemiamide, such as a carbamoyl group or an N-substituted carbamoyl group, such as an N-methylcarbamoyl group, By the trityl group we can also add arylthio groups such as 2-nitrophenylthio groups, arylsulfonyl groups such as 4-methylphenylsulfonyl groups or 1-lower alkoxycarbonyl groups such as 1-ethoxycarbonyl-2-propylidene groups.
- having an amino group substituted by a propylidene group), 2.6-simethoxybenzoyl group, 5.6,
7.8-tetrahydronaphthoyl group, 2-methoxy-1
-naphthoyl group, 2-ethoxy-1-naphthoyl group, benzyloxycarbonyl group, hexahydrobenzyloxycarbonyl group, 5-methyl-3-phenyl-4-isoxasilyl-carbonyl group, 3- (2-chlorophenyl) -5-methyl-4-isoxasilylcarbonyl group, 3-(2,6-dichlorophenyl)-5-methyl-
4-isoxasilylcarbonyl group, 2-chloroethylaminocarbonyl group, acetyl group, propionyl group, butyryl group, pivaloyl group, hexanoyl group, octanoyl group, acrylyl group, crotonoyl group, 3-butenoyl group, 2-pentenoyl group, Methoxyacetyl group, butylthioacetyl group, allylthioacetyl group, methylthioacetyl group, chloroacetyl group, bromoacetyl group, dibromoacetyl group, 3-chloropropionyl group, 3-bromopropionyl group, aminoacetyl group or 5-amino -5-carboxy-valeryl groups [these may be substituted, e.g. by 1 or 2 acyl groups, e.g. lower alkanoyl or phthaloyl groups, which may be halogenated, such as acetyl or dichloroacetyl groups, as described above; amino groups and/or functionally in the form of salts such as sodium salts or esters such as lower alkyl esters such as methyl esters or ethyl esters or aryl lower alkyl esters such as diphenyl methyl esters. ], aminoacetyl group, carboxyacetyl group', methoxycarbonylacetyl group, ethoxycarbonylacetyl group, bis-methoxycarbonylacetyl group, N-phenylcarbamoylacetyl group, cyanoacetyl group group, α-cyanopropionyl group, 2-cyano-3,3-dimethylacrylyl group, phenylacetyl group, α-bromphenylacetyl group, α-acydophenylacetyl group, 3-chlorophenylacetyl group, 2- or 4-aminomethylphenylacetyl group (with an amino group which may be substituted, e.g. as described above), phenacylcarbonyl group,
Phenyloxyacetyl iF, 4-trifluoromethylphenyloxyacetyl group, benzyloxyacetyl group, phenylthioacetyl group, bromphenylthioacetyl group, 2-phenyloxypropionyl group, α-phenyloxyphenylacetyl group, α-methoxyphenyl Acetyl group, α-ethoxyphenylacetyl group, α-methoxy-3,4-dichlorophenylacetyl group, α-cyanophenylacetyl group, especially phenylglycyl group, 4-
Hydroxyphenylglycyl group, 3-chloro-4-hydroxyphenylglycyl group, 3,5-dichloro-4-hydroxyphenylglycyl group, α-amino-α-(1,
4-cyclohexagenyl)-acetyl group, α-amino-α-(1-cyclohexenyl)-acetyl group, α-aminomethyl-α-phenylacetyl group or α-hydroxyphenylacetyl group [in these groups, the presence The amino groups present may also be substituted, for example as mentioned above, and/or the aliphatic hydroxyl groups and/or phenolic hydroxyl groups present may be substituted, for example by suitable acyl groups, in particular formyl groups or ], or α-0-methylphosphono-phenylacetyl group or α-0,0′-dimethyl-phosphono-phenylacetyl group, and also benzylthioacetyl group, benzylthioacetyl group, etc. propionyl group, α-carboxyphenylacetyl group (which can optionally have a functionally modified carboxyl group, e.g. as mentioned above), 3-phenylpropionyl i, 3-(3-cyanophenyl)- propionyl groups, 4-(3-methoxyphenyl) to butyryl groups, 2-pyridylacetyl groups, 4-aminopyridinium acetyl groups (which can optionally carry amino groups substituted, for example, as described above), 2-thhenylacetyl group, 3-thhenylacetyl group, 2-tetrahydrothenylacetyl group, 2-furylacetyl group, 1-
imidazolylacetyl group, 1-tetrazolylacetyl group, α-carboxy-2-chenylacetyl group or α-
Carboxy-3-thhenylacetyl group (which can optionally have a functionally modified carboxyl group, e.g. as mentioned above), α-cyano-2-thhenylacetyl group, α-amino-α -(2-chenyl)-
Acetyl group, α-amino-α-(2-furyl)-acetyl group or α-amino-α-(4-isothiazolyl)-
acetyl groups (which may optionally carry substituted amino groups, e.g. as mentioned above), α-sulfophenylacetyl groups (which sulfo groups may optionally be functionally modified, e.g. the carboxyl groups mentioned above); 3-methyl-2-imidazolylthioacetyl group, 1.2.4-) lyazol-3-ylthioacetyl group, 1,3.4-) lyazol-2-y ruthioacetyl group 5-methyl-1,2,4-
They are a thiadiazol-3-ylthioacetyl group, a 5-methyl-1,3,4-thiadiazol-2-ylthioacetyl group, or a 1-methyl-5-tetrazolylthioacetyl group.

The acyl group Ac of the carbonate half-ester which is easily cleavable, especially the acyl group of the carbonate half-ester which can be cleaved by reduction, e.g. by treatment with a chemical reducing agent, or by acid treatment, e.g. by treatment with trifluoroacetic acid;
For example, lower alkoxycarbonyl radicals which are highly branched and/or aromatically substituted in the carbon atom in the α-position relative to the oxygen atom, or methoxycarbonyl radicals substituted with arylcarbonyl radicals, especially benzoyl radicals. or a lower alkoxycarbonyl group substituted with halogen in the β-position, such as t-butoxycarbonyl group, t-pentoxycarbonyl group, phenacyloxycarbonyl group, 2.2.2-trichloroethoxycarbonyl group or 2-iodo An ethoxycarbonyl group or a group that can be converted into a 2-coded ethoxycarbonyl group, such as a 2-chloroethoxycarbonyl group or a 2-coded ethoxycarbonyl group.
groups such as bromoethoxycarbonyl groups, and preferably polycyclic cycloalkoxycarbonyl groups such as adamantyloxycarbonyl groups, optionally substituted phenyl-lower arylcarbonyl groups, especially α-
a phenyl-lower alkoxycarbonyl group (preferably polysubstituted in the α-position), such as a diphenylmethoxycarbonyl group or an α-4-biphenylyl group;
α-methylethoxycarbonyl group or furyl-lower alkoxycarbonyl group, especially α-furyl-lower alkoxycarbonyl group, such as furfuryloxycarbonyl group.

The divalent acyl group formed by the groups R+ and I' is, for example, an acyl group of a lower alkanedicarboxylic acid or a lower alkenedicarboxylic acid, such as a succinyl group, or an acyl group of an O-arylene dicarboxylic acid such as a phthaloyl group. be.

Other divalent radicals formed by the radicals R+ and R1i+ can also carry, for example, substituents, such as phenyl or chenyl groups, which may be substituted, in particular in the 2-position, and optionally in the 4-position. 1 which can be mono- or di-substituted with a lower alkyl group such as a methyl group
-oxo-3-aza-1,4-butylene group, for example 4.
4-dimethyl-2-phenyl-1-oxo-3-aza-
It is a 1,4-butylene group.

The etherified hydroxyl group R8 together with the carbonyl group in the formula is preferably easily cleavable or easily converted into other functionally modified carboxyl groups, such as carbamoyl or hydrazinocarbonyl groups. It forms an esterified carboxyl group that can be esterified. Such groups RI7 are, for example, lower alkoxy groups such as methoxy, ethoxy, n-propoxy or isopropoxy, which are carbonyl/L
Together with 4, they form esterified carboxyl groups, which can be easily converted into free carboxyl groups or into other functionally modified carboxyl groups, especially in 2-cephem compounds.

The etherified hydroxyl group Re, which together with the group -C(=O)- forms an esterified carboxyl group which can be particularly easily split, has, for example, an atomic mass of 19 or more as a halogen atom. It is a 2-halogeno-lower alkoxy group. Such a group is the group -C(
=O)- together with esterified carboxyl groups or such which can be easily cleaved by treatment with zinc in the presence of a chemical reducing agent such as aqueous acetic acid under neutral or weakly acidic conditions. It forms an esterified carboxyl group that can be easily converted into a carboxyl group. Such groups are, for example, 2.2.2-) lychloroethoxy or 2-iodoethoxy, or 2-chloroethoxy or 2-bromoethoxy which can be easily converted into 2-iodoethoxy. .

Additionally, it can be easily treated with zinc in the presence of a chemical reducing agent such as aqueous acetic acid under neutral or weakly acidic conditions or by treatment with a suitable nucleophile such as sodium thiophenolate. The esterified carboxyl group that can be split is defined as i−c (=
The etherified hydroxyl group R8 formed together with 0)- is an arylcarbonylmethoxy group (the aryl group is in particular a phenyl group which may be substituted) and preferably a phenacyloxy group. .

Furthermore, the radical R can also be an arylmethoxy radical, in particular a monocyclic, preferably substituted aromatic hydrocarbon radical, in which case the -R radical is a monocyclic, preferably substituted, aromatic hydrocarbon radical.

Such groups together with the group -C(-0)- form an esterified carboxyl group which can be easily cleaved by radiation, preferably UV radiation, under neutral or acidic conditions. The aryl group in such an arylmethoxy group is particularly a lower alkoxyphenyl group such as a methoxyphenyl group [the methoxy group is mainly 3
-14- and (or) 5- position]
and/or a nitrophenyl group, with the nitro group preferably in the 2-position.

Such radicals are in particular lower alkoxy-1, such as methoxy-benzyloxy and/or nitro-benzyloxy radicals, principally 3- or 4-methoxybenzyloxy, 3,5-dimethoxybenzyloxy, 2-nitrobenzyl Oxy group or 4,5-dimethoxy-2-
It is a nitrobenzyloxy group.

Furthermore, the etherified hydroxyl group R8 forms together with the group -C(=O)- an esterified carboxyl group which can be easily cleaved under acidic conditions, e.g. by treatment with trifluoroacetic acid or formic acid. It can also be a group. Such radicals are primarily composed of hydrocarbon radicals, the methyl radicals of which may be substituted, in particular aliphatic or aromatic hydrocarbon radicals, such as polysubstituted lower alkyl radicals such as methyl radicals, and/or phenyl radicals. a methoxy group or its methyl monosubstituted by a carbocyclic aryl group having an electron-donating substituent or by an aromatic heterocyclic group having an oxygen or sulfur atom as a ring member; a methoxy group in which the group forms a ring member in a polycyclic aliphatic hydrocarbon group or a ring member occupying the α-position relative to the oxygen or sulfur atom in an oxacycloaliphatic or alicyclic group; .

Among polysubstituted methoxy groups of this type, preferred are t-lower alkoxy groups, such as 1-butyloxy or t-pentyloxy, optionally substituted diphenylmethoxy groups, such as diphenylmethoxy or 4, 4″-dimethoxy-diphenylmethoxy group,
Furthermore, the methoxy group is a 2-(4-biphenylyl)-2-propyloxy group, and the above-mentioned substituted ester group or heterocyclic group is, for example, a 4-methoxybenzyloxy group or a 3,4-dimethoxy group. α like benzyloxy group
-lower alkoxyphenyl-lower alkoxy group or 2
- a furfuryloxy group such as a furfuryloxy group. The polycyclic aliphatic hydrocarbon group having the methyl group of the methoxy group as a preferably tri-branched ring member is, for example, an adamantyl group such as a 1-adamantyl group, and the methyl group of the methoxy group is an adamantyl group such as a 1-adamantyl group. The above-mentioned oxa- or thia-cycloaliphatic groups having as ring members in the α-position relative to the atom or sulfur atom include, for example, 5 to 7 ring atoms.
2-oxa- or 2-thia lower alkylene or lower alkenylene groups having 2-oxa- or 2-thia, such as 2-tetrahydrofuryl, 2-tetrahydropyranyl or 2,3-
A dihydro-2-pyranyl group or a corresponding sulfur homologue.

Furthermore, the group R8 is an etherified hydroxyl group which together with the group -C(·0)- forms an esterified carboxyl group which can be cleaved by hydrolysis, e.g. under weakly basic or weakly acidic conditions. It can also be.

Such groups are preferably etherified hydroxyl groups such as 4-nitrophenyloxy or 2,4 which together with the group -C(=O)- form an activated ester group.
-nitrophenyloxy group such as dinitrophenyloxy group, nitrophenyl lower alkoxy group such as 4-nitrobenzyloxy group, 4-hydroxy-3,5-t
-Hydroxy-lower alkyl-benzyloxy groups such as -butyl-benzyloxy groups, polyhalogenophenyl groups such as 2.4.6-trichlorophenyloxy groups and 2.3,4.5.6-pentachlorophenyloxy groups. Oxy groups, as well as cyanomethoxy groups and acylaminomethoxy groups, such as phthaliminomethoxy or succinyliminomethoxy groups.

The group R8 also converts an esterified carboxyl group that can be split under hydrogenolysis conditions into a carbonyl 4-C(=O
)- can also be an etherified hydroxyl group, such as a benzyloxy group, 4
an α-phenyl lower alkoxy group which can be substituted with, for example, a lower alkoxy group or a nitro group, such as a -methoxybenzyloxy group or a 4-nitrobenzyloxy group.

In addition, the group octopus converts the esterified carboxyl group, which can be cleaved under physiological conditions, into the carbonyl group -C
Etherified hydroxyl groups formed together with (=O)-, mainly acyloxymethoxy groups (the acyl groups are, for example, groups of existing carboxylic acids, mainly of lower alkane carboxylic acids that may be substituted) or its acyloxymethyl moiety forming a lactone group). Such etherified hydroxyl groups include lower alkanoyloxymethoxy groups, such as acetyloxymethoxy or pivaloyloxymethoxy groups, amino-lower alkanoyloxymethoxy groups, especially alpha-amino-lower alkanoyloxymethoxy groups, such as glycyloxymethoxy. group, L-valyloxymethoxy group, L-leucyloxymethoxy group, and furthermore phthalidi and ruoxy groups.

R8 as a silyloxy group or stannyloxy group is preferably an aliphatic, alicyclic, aromatic or araliphatic hydrocarbon group which may be substituted as a substituent, such as a lower alkyl group, a halogeno-lower alkyl group, a cycloalkyl group , a phenyl group or a phenyl lower alkyl group, or a functional group which may be modified, such as an etherified hydroxyl group such as a lower alkoxy group or a halogen atom such as a chlorine atom, mainly a trimethylsilyloxy group, etc. A tri-lower alkylsilyloxy group, a halogeno-lower alkoxy-lower alkyl-silyl group such as a chloro-methoxy-methyl-silyl group, or a tri-lower alkylstannyloxy group such as a tri-n-butylstannyloxy group.

R as an acyloxy group which together with the group -C<=O>- preferably forms a mixed anhydride group which can be cleaved by hydrolysis, can be used, for example, with the acyl group of the organic carboxylic acid or carbonic acid derivative mentioned above. a lower alkanoyloxy group, such as an acetyloxy group, a piparyloxy group or a trichloroacetyloxy group, or a lower alkoxycarbonyl group, which may optionally be substituted in the α-position, preferably by a halogen atom such as a fluorine or chlorine atom; An oxy group is, for example, a methoxycarbonyloxy group or an ethoxycarbonyloxy group.

Furthermore, R8 as a group forming a carbamoyl group or a hydrazinocarbonyl group which may be substituted together with the group -C(=O)- is, for example, an amino group, a methylamine group or an ethylamino group. lower alkylamino groups, di-lower alkylamino groups such as dimethylamino and diethylamino groups, lower alkyleneamino groups such as pyrrolidino and piperidino groups, oxa-lower alkyleneamino groups such as morpholino groups, hydroxyamino groups, hydrazino groups; group, 2- such as 2-methylhydrazino group
A lower alkylhydrazino group or a 2,2-di-lower alkylhydrazino group such as a 2,2-dimethylhydrazino group.

The lower alkyl group R3 has up to 7 carbon atoms, preferably 4
and a methyl group, ethyl group, n-propyl group, hexyl group, or hebutyl group.

As α-phenyl-lower alkyl radicals R1 is in particular benzyl and diphenylmethyl, substituents on the phenyl nucleus being e.g. esterified or etherified hydroxyl groups, e.g. halogen atoms, e.g. fluorine, chlorine or bromine atoms, or a lower alkoxy group such as a methoxy group. Salts are suitable in particular of formulas (IA) and (IB) with acidic groups such as carboxyl, sulfo or phosphono groups.
), mainly metal salts or ammonium salts, for example salts of alkali metals or alkaline earth metals, such as salts of sodium, potassium, magnesium or calcium, as well as ammonium salts with ammonia or suitable organic amino acids. It is. Organic amines which can be used for the formation of salts are, in particular, aliphatic, cycloaliphatic, cycloaliphatic and araliphatic primary, secondary or tertiary monoamines, diamines or polyamines and heterocyclic bases. Such amines include lower alkyl amines such as triethylamine, 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri(2-hydroxyethyl)-amine.
hydroxy-lower alkyl amines such as -hydroxyethyl)-amine, basic aliphatic esters of carboxylic acids such as 4-aminobenzoic acid-2-diethylamino-ethyl ester, lower alkylene amines such as 1-ethylpiperidine, cycloalkylamines such as bicyclohexylamine or benzylamines such as N,N'-dibenzylethylenediamine and also bases of the pyridine type such as pyridine, collidine or quinoline. Compounds of formula (IA) and (IB) having a basic group can also be used as acid addition salts, such as bases, inorganic acids such as sulfuric acid or phosphoric acid, or suitable organic carboxylic acids or sulfonic acids, such as trifluoroacetic acid or p-toluenesulfone. Acid addition salts can be formed with acids. The compounds of formulas (IA) and (IB) having acidic and basic groups can also be in the form of internal salts, ie in the form of Zwitter ions. 1- of a compound of formula (IA) having a salt-forming group
Oxides can also form salts as described above.

The new compounds according to the invention exhibit pharmacologically valuable properties or can be used as intermediates for the production of compounds with such properties. In formula (IA), for example, R+ is the acyl group Ac present in the pharmacologically active N-acyl derivative of the 6β-amino-penam-3-carboxylic acid compound or the 7β-amino-3-cephem-4-carboxylic acid compound, and l is a hydrogen atom or R+ and RY are both preferably in the 2-position by an aromatic or heterocyclic group and in the 4-position preferably by two lower alkyl groups, such as for example a methyl group; represents a 1-oxo-3-aza-1,4-butylene group substituted by carbonyl, where R2 is a hydroxyl group or an esterified carboxyl group that can be easily cleaved under physiological conditions. an etherified hydroxyl group R8 forming together with the group R3 a lower alkyl group, and functional groups which may be present in RY as an acyl group such as an amino group, a carboxyl group, a hydroxyl group and (or ) Compounds in which the sulfo group is normally present in free form, or salts of such compounds with salt-forming groups, when administered parenterally and/or orally, may be used to treat microorganisms such as Durham-positive bacteria, e.g. Staphylococcus
aureus (Staphylococcus aure)
us), Strebricocus 0 pyrogenes (Strept.
ococcus Pyrogenes) and Diplococcus pneumoniae
(For example, in mice, about 0.001 to 0.02 g/
kg S, c, or P, o,) and Durham-negative bacteria such as N. coli (Escher
ichia coli)% Salmonella typhimurium, Shigella fl.
exneri), Talebcilla numoniae (Kl
ebsiellapneumoiae), Enterobacter cloacani (Enterobacter c.
loacae ), Proteus 0 vulgaris (Prot.
eus vulgaris), Proteus rettgeri and Proteus mirabilis
s ) (for example, about 0.001-0.s in mice).
(at a dose of 15 g/kg S, c, or P, 0°) and is effective with low toxicity, especially against penicillin-resistant bacteria. These new compounds can therefore be used, for example in the form of antibiotic preparations, for the treatment of corresponding infections.

1- of a compound of formula (IB) or a compound of formula (IA)
In the oxide, RY, RY, R2 and R3 have the formula (I
A) or in formula (IA) R3 has the same meaning as defined above and RY
and R1 are hydrogen atoms, or RY is the pharmacologically active N of the 6β-amino-penam-3-carboxylic acid compound or the 7β-amino-3-cephem-4-carboxylic acid compound.
- an amine protecting group different from the acyl group present in the acyl derivative and l is a hydrogen atom or both RY and l are preferably in the 2-position, e.g. by an aromatic group or a heterocyclic group; and a divalent amino protecting group different from the 1-oxo-3-aza-1,4-butylene group which is preferably substituted in the 4-position by two lower alkyl groups such as methyl groups and R2 is a hydroxyl group, or RY and l have the abovementioned meanings and R2 preferably forms a readily cleavable protected carboxyl group with the group -C(=O)-. The protected carboxyl group shall not be a physiologically cleavable carboxyl group) and such compounds in which R1 has the above meanings can be easily converted into the above pharmacologically active compounds, e.g. as follows: It is a valuable intermediate that can be used for various purposes.

The present invention particularly provides a compound in which 1 in formula (IA) is a hydrogen atom, 6β-amino-penam-3, or 7
Particularly pharmacologically active (e.g. highly active) N-acyl which can be prepared fermentatively (i.e. naturally occurring) or biosynthetically, semi-synthetically or totally synthetically of β-amino-3-cephem-4-carboxylic acid compounds. An acyl group present in the derivative, for example an acyl group of the above formula (^), for example one of the acyl groups of the above formula (^) (in this formula, R, R11, RIM and n mainly have the meanings mentioned above as preferred). ) and l is a hydrogen atom or RY and 1 are both 2-
1-oxo-3-aza-butylene substituted in the 4-position preferably by an aromatic or heterocyclic group, such as a phenyl group, and preferably by two lower alkyl groups, such as a methyl group, in the 4-position. and Rz is a hydroxyl group, a lower alkoxy group [which may optionally be substituted, preferably in the α-position, e.g. an aryloxy group, e.g.
- lower alkoxyphenyloxy groups such as methoxyphenyloxy, lower alkanoyloxy groups such as acetyloxy or pivaloyloxy, α-amino lower alkanoyloxy groups such as glycyloxy, L-valyloxy or L-leucyloxy; , an arylcarbonyl group such as a benzoyl group, or an optionally substituted aryl group such as a phenyl group, a lower alkoxyphenyl group such as a 4-methoxyphenyl group, a 4-
Nitrophenyl group or 4-
lower alkoxy groups, such as methoxy, ethoxy, n- A bis-phenyloxy-methoxy group which may be substituted with a lower alkoxy group, such as a pro-, isopropyloxy, n-butyloxy, 1-butyloxy or t-pentyloxy group, e.g. Bis-4-methoxyphenyloxy-methoxy group, lower alkanoyloxy-methoxy group such as acetyloxymethoxy group or pivaloyloxymethoxy group, α-amino lower alkanoyloxy-methoxy group such as glycyl group, oxymethoxy group, phenacyloxy group , a phenyl lower alkoxy group which may be substituted, in particular a 1-phenyl lower alkoxy group such as a phenylmethoxy group (such groups include, for example, substituents such as a lower alkoxy group such as a methoxy group, a nitro group or a phenyl group). may have 1 to 3 phenyl groups, which may be substituted with),
For example, benzyloxy group, 4-methoxyhensyloxy group, 2-biphenylyl-2-propyloxy group, 4-nitrobenzyloxy group, diphenylmethoxy group, 4,4
'-dimethoxy-diphenylmethoxy group or trityloxy group, or 2-halogeno lower alkoxy group, such as 2.2.2-)lychloroethoxy group, 2-chloroethoxy group, 2-bromoethoxy group or 2-iodoethoxy group; 2-phthalidyloxy group and acyloxy group (for example, lower alkoxycarbonyloxy group such as methoxycarbonyloxy group or ethoxycarbonyloxy group or lower alkanoyloxy group such as acetyloxy group or pivaloyloxy group), trimethylsilyl a tri-lower alkylsilyloxy group such as an oxy group, or an amino group or a hydrazino group (which may optionally be substituted by a lower alkyl group such as, for example, a methyl group or a hydroxyl group)
For example, an amino group, a lower alkylamino group such as a methylamino group, a di-lower alkylamino group such as a dimethylamino group, a hydrazino group, a 2-lower alkylhydrazino group such as a 2-methylhydrazino group, 2, 2,2-dilower alkylhydrazino, such as 2-dimethylhydrazino, or a hydroxyamino group, and R1 is a hydrogen atom, a lower alkoxy group, especially a methyl group, or a benzyl or diphenylmethyl group, e.g. (may be substituted with a halogen atom or lower alkoxy group)
cepham-3-one compounds, their 1-oxides and corresponding 2-cephem compounds of formula (IB) or salts of such compounds with salt-forming groups. In particular, the 3-cephem compounds of the formula (IA) and the corresponding 2-cephem compounds of the formula (IB) also contain the 1-oxide or salt-forming group of the 3-cephem compounds of the formula (IA). In the salts of these compounds, R? is a hydrogen atom, or an N-acyl derivative that can be produced by fermentation (i.e., naturally occurring) or biosynthetically of a 6β-amino-penam-3-carboxylic acid compound or a 7β-amino-3-cephem-4-carboxylic acid compound The acyl group present in
＾) (in this formula RI, RI[, R11 and n mainly have the meanings given above as preferred), for example a phenylacetyl group or a phenyloxyacetyl group which may be substituted with a hydroxyl group, and if For example, lower alkylthio or lower alkenylthio groups,
lower alkanoyl groups which may be substituted, for example by amino groups which may be acylated and/or by functionally altered carboxyl groups (e.g. carboxyl groups which may be esterified); Lower alkenoyl groups, such as 4-hydroxy-phenylacetyl, hexanoyl, octanoyl or n-butylthioacetyl groups, and especially 5-amino-5-carpoxyvaleryl groups, the amino and/or carboxyl groups being optionally protected and can be present, for example, as an acylamino group or an esterified carboxyl group], a phenylacetyl group or a phenyloxyacetyl group,
or the acyl group present in the highly active N-acyl derivative of the 6β-amino-penam-3-carboxylic acid compound or the 7β-amino-3-cephem-4-carboxylic acid compound, especially the group of formula (^) (this formula in which the formulas Rx, R1, Rfll and n mainly have the meanings given above as preferred), such as formyl group, 2-chloroethylcarbamoyl group, etc.
-halogenoethylcarbamoyl group, cyanoacetyl group,
Tetrazolyl groups such as phenylacetyl group, 2-thhenylacetyl group, but especially cycloaliphatic in the α-position,
cyclic groups such as aromatic or heterocyclic groups, mainly by monocyclic groups and functional groups mainly by amino groups, carboxyl groups,
an acetyl group substituted by a sulfo group or a hydroxyl group,
In particular, a phenylglycyl group, in which the phenyl group may optionally be protected, for example by a hydroxyl group, such as an acyloxy group, such as a lower alkoxycarbonyloxy group or a lower alkanoyloxy group, which may be substituted with halogen, and ( or) a phenyl group, such as a phenyl group, 3- or 4-, which can be substituted by a halogen atom, e.g. a chlorine atom.
hydroxy-13-chloro-4-hydroxy- or 3
, 5-dichloro-4-hydroxyphenyl group, the hydroxyl group of which can also be a protected e.g. acylated hydroxyl group, and the amino group optionally substituted and e.g. in the form of a salt. There may also be sulfoamino groups or substituted amino groups (e.g.
Substituents include trityl groups which can be cleaved by hydrolysis or predominantly acyl groups such as optionally substituted carbamoyl groups such as optionally substituted ureidocarbonyl groups such as ureidocarbonyl groups and N'-trichloromethylureidocarbonyl groups. or an optionally substituted guanidinocarbonyl group, such as a guanidinocarbonyl group, or a chemical reducing agent such as zinc or hydrogen contacted with an acid such as trifluoroacetic acid or in the presence of aqueous acetic acid. Acyl groups which can be cleaved or converted into such acyl groups when treated reductively with Alkoxycarbonyl groups, which may include, for example, t-butyloxycarbonyl group, 2,2,2-trichloroethyloxycarbonyl group, 2-chloroethoxycarbonyl group, 2-
a bromoethoxycarbonyl group, a 2-iodoethoxycarbonyl group, or a phenacyloxycarbonyl group, a phenyl lower alkoxycarbonyl group which may be lower alkoxy- or nitro-substituted, such as a 4-methoxybenzyloxycarbonyl group or a diphenylmethoxycarbonyl group, or acyl groups of carbonic acid hemiamides such as carbamoyl groups or N-methylcarbamoyl groups, and also arylthio groups or hanaryl lower alkylthio groups which are cleaved by nucleophilic agents such as hydrocyanic acid, mineral acid or thioacetamide, e.g. 2-nitrophenylthio or tritylthio groups, which can be cleaved by electrolytic reduction; -rusulfonyl groups, such as 4-methylphenylsulfonyl groups; or 1, which can be cleaved by acidic agents such as formic acid or aqueous inorganic acids, such as hydrochloric acid or phosphoric acid. -lower alkoxy carbonyl-2-propylidene group or 1-lower alkanoyl-2-propylidene group, such as I-ethoxycarbonyl-2-propylidene group], and further α-1,4-cyclohexagenyl-glycyl group,
α-(l-cyclohexenyl)-glycyl group, α-2-
or an α-thethylglycyl group such as an α-3-chenylglycyl group, an α-methylglycyl group such as an α-2-furylglycyl group,
Furylglycyl group, or α-isothiazolylglycyl group such as α-4-isothiazolyl-glycyl group (the amino group of these groups, for example, the phenylglycyl group, is substituted or protected as mentioned above) ),
Furthermore, α-carboxy-phenylacetyl group or α-
Carboxy-thhenylacetyl groups such as α-carboxy-2-thhenylacetyl groups (these may optionally be functionally modified carboxyl groups, e.g. in the form of salts such as the sodium salt or esters such as the methyl ester or ethyl ester) may have a carboxyl group in the form of a phenyl-lower alkyl ester, such as a phenyl-lower alkyl ester or diphenylmethyl ester) or an α-sulfo-phenylacetyl group (which may optionally have a functional group, such as the carboxyl group mentioned above). ), α-phosphono-1α-〇-methylphosphono or α-〇,0′
-dimethylphosphonophenylacetyl group, or α-
Hydroxy-phenylacetyl group [this is a functionally modified hydroxyl group, especially an acyloxy group (the acyl group can be treated with an acidic agent such as trifluoroacetic acid or treated with a chemical agent such as zinc in the presence of aqueous acetic acid). An acyl group which is preferably easily cleavable or convertible into such an acyl group when treated with a chemical reducing agent, preferably an acyl group of a carbonic acid half-ester, such as the halogen-substituted or benzoyl-substituted acyl groups mentioned above. lower alkoxycarbonyl groups, such as 2,2.2-trichloroethoxycarbonyl groups, 2-
a chloroethoxycarbonyl group, a 2-bromoethoxycarbonyl group, a 2-iodoethoxycarbonyl group, a t-butyloxycarbonyl group or a phenacyloxycarbonyl group, and a formyl group], and a 1-aminoxycarbonyl group. an aminomethylphenylacetyl group such as a hexylcarbonyl group, a 2- or 4-aminomethyl-phenylacetyl group, or a 4-
an amino-pyridinium acetyl group, such as an aminopyridinium acetyl group (which may also have a substituted amino group, e.g. as described above), or a 4-
a pyridylthioacetyl group, such as a pyridylthioacetyl group, and l is a hydrogen atom, or R? and R9 are 1-oxo-3-aza-, which may both have two lower alkyl groups such as methyl groups at the 4-position.
a 1,4-butylene group, which in the 2-position is preferably an optionally protected hydroxyl group, such as an acyloxy group, such as a lower alkoxycarbonyloxy group or a lower alkanoyloxy group, which may be substituted with halogen, and/or A phenyl group, such as a phenyl group, or a 3- or 4-hydroxy-13-chloro-4-hydroxy- or 3,5-dichloro-4-hydroxy-phenyl group ( The hydroxyl group can also be protected, e.g. acylated as above)
and R2 is a hydroxyl group, a lower alkoxy group, especially a highly branched lower alkoxy group in the α-position, such as an L-butoxy group, and also a methoxy or ethoxy group, a 2-halogeno lower alkoxy group. or 2.2.2-trichloroethoxy group, 2-iodoethoxy group or 2 that can be easily converted into this group.
- 1 to 3 phenyl groups which can be substituted with chloroethoxy or 2-bromoethoxy, phenacyloxy, lower alkoxy or nitro groups;
-Phenyl lower alkoxy group such as 4-methoxybenzyloxy group, 4-nitrobenzyloxy group, diphenylmethoxy group, 4,4'-dimethoxy-diphenylmethoxy group or trityloxy group, lower alkanoyloxymethoxy group such as acetyloxymethoxy group or pivaloyloxymethoxy group, α-amino lower alkanoyloxymethoxy group, e.g. glycyloxymethoxy group, 2
- a phthalidyloxymethoxy group, a lower alkoxycarbonyloxy group such as an ethoxycarbonyloxy group or a lower alkanoyloxy group such as an acetyloxy group, and also a tri-lower alkylsilyloxy group such as a trimethylsilyloxy group, and R1 is a hydrogen atom, a lower alkyl group in particular a methyl group, or a benzyl or diphenylmethyl group (which may optionally be substituted, for example with a halogen, chlorine or bromine atom, or with a lower alkoxy group, such as a methoxy group)
It is.

The present invention mainly relates to R1? is the formula Ra −(
X) m-CH-C-(B) h [In this formula, Ra is a phenyl group or a hydroxyphenyl group, such as a 3- or 4-hydroxyphenyl group, and further a hydroxy-chlorophenyl group, such as 3-chloro-4-
Hydroxyphenyl group or 3,5-dichloro-4-hydroxyphenyl group (in these groups, the hydroxyl group can be a lower alkoxycarbonyl group that can be halogenated, such as a t-butoxycarbonyl group or 2.2.2
- can be protected by an acyl group such as a trichloroethoxycarbonyl group), 2- or 3
- chenyl group such as chenyl group, pyridyl group such as 4-pyridyl group, aminopyridinium group such as 4-aminopyridinium group, furyl group such as 2-furyl group, isothiazolyl group such as 4-inchazolyl group group, a tetrazolyl group such as 1-tetrazolyl group or 1
．． 4-cyclohexagenyl group or l-cyclohexenyl group, X is an oxygen atom or a sulfur atom,
m is 0 or l, and Rb is a hydrogen atom, or if m is O, Rb is an amino group, a protected amino group such as an acylamino group such as an t-butoxycarbonylamino group. 2-halogeno lower alkoxycarbonylamino groups, such as 2.2.2-trichloroethoxycarbonylamino groups, 2-iodoethoxycarbonylamino groups or 2-bromoethoxycarbonylamino groups, which are highly branched at the - position. or a phenyl lower alkoxycarbonylamino group which may be lower alkoxy- or nitro-substituted, such as a 4-methoxyhensyloxycarbonylamino group or a diphenylmethoxycarbonylamino group, or a 3-guanylureido group, as well as a sulfamino group, trityl Amino group, arylthioamino group such as 2-nitrophenylthioamino group, arylsulfonylamino group such as 4-methylphenylsulfonylamino group or 1-lower alkoxycarbonyl-2-propylideneamino group such as 1-ethoxycarbonyl-2-
Propylidene amino groups, carboxyl groups or salts such as carboxyl groups in the form of alkali metal salts such as sodium salts, as well as protected carboxyl groups such as esterified carboxyl groups such as phenyl lower alkoxycarbonyl groups such as diphenylmethoxycarbonyl groups. groups, sulfo groups or salts, sulfo groups in the form of alkali metal salts, such as sodium salts, protected sulfo groups,
a hydroxyl group or a protected hydroxyl group, such as an acyloxy group, a lower alkoxycarbonyloxy group highly branched in the α-position, such as a t-butoxycarbonyloxy group;
2,2.2-) 2-halogen lower alkoxycarbonyloxy group such as lychloroethoxycarbonyloxy group, 2-iodoethoxycarbonyloxy group or 2-bromoethoxycarbonyloxy group, further formyloxy group, or 〇-lower an alkylphosphono group or o,
o'-dilower alkylphosphono group such as 0-methylphosphono group or 0.0'-dimethylphosphono group] or 5-amino-5-carboxyvaleryl group (such as acetylamino group) a lower alkanoylamino group such as a halogenated lower alkanoylamino group such as a dichloroacetylamino group, a henshylamino group or a phthaloylamino group, or an esterified carboxyl group such as a phenyl lower alkoxycarbonyl group such as a diphenylmethoxycarbonyl group. (in addition, Ra is a phenyl group,
When it is a hydroxyphenyl group, a hydroxy-chlorophenyl group or a pyridyl group, m is preferably 1, and Ra is a phenyl group, a hydroxyphenyl group, a hydroxy-chlorophenyl group, a chenyl group, a furyl group,
isothiazolyl group, 1,4-cyclohexagenyl group or 1-cyclohexenyl group, m is preferably 0 and Rh is not a hydrogen atom), RIi+ is a hydrogen atom, and R2 is mainly a hydroxyl group and Lower alkoxy groups Highly branched lower alkoxy groups, especially in the α-position, such as 1-butoxy, 2-halogeno-lower alkoxy groups, such as 2,2.2-trichloroethoxy, 2-iodoethoxy or 2-bromo a diphenylmethoxy group which may be substituted with an ethoxy group or a lower alkoxy group such as a methoxy group, e.g. a diphenylmethoxy group or a 4,4'-dimethoxy-diphenylmethoxy group, and also a tri-lower alkyl group such as a trimethylsilyloxy group. a silyloxy group, and R3 is a hydrogen atom, a lower alkyl group such as a methyl, ethyl or n-butyl group, and a benzyl or diphenylmethyl group (these groups optionally contain a halogen atom such as a chlorine atom or a bromine atom); 3-, which is an atom or a lower alkoxy group (optionally substituted with a methoxy group)
cephem-compounds, the 1-oxides of such 3-cephem compounds of formula (IA) and the corresponding 2-cephem compounds of formula (IB), or salts of such compounds with salt-forming groups, especially for pharmaceuticals. Non-toxic salt that can be used for
For example, an alkali metal salt such as a sodium salt, an alkaline earth metal salt such as a calcium salt, or an ammonium salt, including an amine salt, of a compound in which R2 is a hydroxyl group and has a free amino group in the acyl group of formula (B). It is related to.

Primarily 3-cephem compounds of the formula (IA) and corresponding 2-cephem compounds of the formula (IB) or the salts of such compounds with salt-forming groups can be used pharmaceutically, especially as mentioned in the preceding paragraph. In non-toxic salts, R? is a hydrogen atom or an acyl group of formula (B) (in this formula, Ra is a phenyl group, a hydroxyphenyl group such as 4-hydroxyphenyl group, a chenyl group such as 2- or 3-chenyl group, a 4-isothiazolyl group, or 1.4-cyclohexagenyl group or 1-cyclohexenyl group, X is an oxygen atom, m is 0 or 1, and Rb is a hydrogen atom or when m is 0 Rb is an amino group, a protected amino group such as an acylamino group, a lower alkoxycarbonylamino group highly branched at the α-position, such as a t-butoxycarbonylamino group;2.
2.2- trichloroethoxycarbonylamino group, 2
--? -2-halogeno-lower alkoxycarbonylamino groups, such as luponylamino groups or 2-bromoethoxycarbonylamino groups, or phenyl lower alkoxycarbonylamino groups, which may be lower alkoxy-substituted or nitro-substituted, e.g. 4-methoxybenzyloxy a carbonylamino group, or a hydroxyl group or a protected hydroxyl group, such as an acyloxy group, a lower alkoxycarbonyloxy group highly branched in the α-position, such as the t-butoxycarbonyloxy group, 2,2.2
-2-halogeno-lower alkoxycarbonyloxy, such as trichloroethoxycarbonyloxy, 2-iodoethoxycarbonyloxy or 2-bromoethoxycarbonyloxy, and also formyloxy) or 5-amino-5-carboxyvalene. a lyl group (whose amino and carboxyl groups may also be protected, such as an acylamino group, a lower alkanoylamino group such as an acetylamino group, a halogeno-lower alkanoylamino group such as a dichloroacetylamino group, a benzoylamino group) or as a phthaloylamino group or as an esterified carboxyl group, e.g. a phenyl lower alkoxycarbonyl group such as a diphenylmethoxycarbonyl group (where R
When a is a phenyl group or a hydroxyphenyl group, m is preferably l), R'i' is a hydrogen atom, R2 is mainly a hydroxyl group, and further a halogen atom at the 2-position, such as a chlorine atom or a bromine atom. or a lower alkoxy group which may be substituted with an iodine atom, especially a highly branched lower alkoxy group in the α-position, such as a t-butoxy group, a 2-halogeno-lower alkoxy group, such as 2.2.2
-) a lychloroethoxy group, a 2-iodoethoxy group or a 2-bromoethoxy group, or a diphenylmethoxy group, for example a diphenylmethoxy group, which may be substituted with a lower alkoxy group, such as a methoxy group;
．． 4'-dimethoxy-diphenylmethoxy group, or p
- a tri-lower alkyloxy group, such as a nitrobenzyloxy group, and also a trimethylsilyloxy group, and R1 is a hydrogen atom, a lower alkyl group, especially a methyl group,
A benzyl group or a diphenylmethyl group (optionally substituted with a halogen atom, such as a chlorine or bromine atom, or a lower alkoxy group, such as a methoxy group).

The present invention mainly focuses on 7β-(D-α-amino-α-Ra-
acetylamino)-3-lower alkoxy-3-cephem-4-carboxylic acid (Ra is a phenyl group, 4-hydroxyphenyl group, 2-chenyl group, 1,4-cyclohexagenyl group or 1-cyclohexenyl group) and lower alkoxy having up to 4 carbon atoms, such as ethoxy or n-butoxy, but mainly methoxy) and their inner salts, and especially 3-methoxy-7β-(D-α-phenyl- glycylamino)-3
= 3-Hydroxy-3-cephem-4-carboxylic acid compound useful as a method for producing cephem-4-carboxylic acid and its inner salt, and as an intermediate for producing a 3-lower alkoxy-3-cephem-4-carboxylic acid compound The company provides the manufacturing of These 3-lower alkoxy compounds, at the doses indicated, especially when administered orally, exhibit a marked antibiotic effect with low toxicity against Durham-positive and especially Durham-negative bacteria.

According to the method of the present invention, the compound represented by the general formula (IA), its 1-oxide, the compound represented by the general formula (B) and the salts of these compounds having a salt-forming group are prepared by the general formula [in this formula R ? is a hydrogen atom or an amino protecting group R+, and l is a hydrogen atom or an acyl group Ac, or R
? and l' are both divalent amino protecting groups, and R8 is a group that forms a protected carboxyl group together with the carbonyl group -C(=O)- in the formula; -N(Ra) (R list) is the 2nd or 37th amino group, Y is the group to be removed] By removing H-Y from the compound represented by The formula formed as [Kono formula-cR? and R2 and R8 and -N(R:)(Rshi)
has the same meaning as above, 2.3-position or 3.4
The amino group -N (R:) (R
2) is converted by solvolysis into the group =〇R3 (in which R8 is a hydrogen atom, a lower alkyl group or an optionally substituted α-phenyl-lower alkyl group), and optionally the formula (I A) or (I B
) In the obtained compound represented by the formula -〇 (=O
) changing the protected carboxyl group represented by -R8 to a free or other protected carboxyl group, and (or) optionally changing the α-phenyl-lower alkoxy group -0-R3 to a free hydroxyl group, and (or) converting the resulting free hydroxyl group -0-R, into a lower alkoxy group -0-R1, and (or) optionally converting the resulting compound into other compounds within the definition of the final product. and (or) optionally converting the compound with the salt-forming group obtained into a salt or converting the salt obtained into the free compound or other salt, and (or) optionally converting the obtained isomeric compound can be produced by separating a mixture of into individual isomers.

In the compound represented by formula (n), an amino group -N
(R:) (R:) can be in the trans-position (crotonic acid coordination) or in the cis-position (isocrotonic acid coordination) with respect to the carboxyl group.

In the starting compound represented by formula (■), the group Y to be removed is, for example, -5Ra group, -SO□-R5 group (bonded to thio group -8- by a sulfur atom), or -S
SOzRa group.

In the group represented by S Ra, R4 is 1 carbon atom
up to 5, preferably up to 9, optionally substituted aromatic heterocyclic groups containing at least one ring nitrogen atom and optionally other ring heteroatoms such as oxygen or sulfur atoms; and the group is connected to the thio group -8- by one ring carbon atom which is connected to the ring nitrogen atom by a double bond. Such groups are monocyclic or bicyclic and contain substituents such as lower alkyl groups such as methyl or ethyl groups, lower alkoxy groups such as methoxy or ethoxy groups,
It can be substituted with a halogen atom, such as a fluorine or chlorine atom, or an aryl group, such as a phenyl group.

Such a group R4 is, for example, a monocyclic five-membered thiaza ring group, thiatriaza ring group, oxadiaza ring group or oxatriaza ring group (these groups are aromatic groups), in particular an aromatic group. Family-based especially monocyclic 5-membered diaza ring group,
oxyaza ring groups and thiaza ring groups, and/or especially corresponding benzdiaza ring groups, benzoxyaza ring groups or benzthiaza ring groups, where the heterocyclic group moiety is a 5-membered ring and exhibits aromatic character. and the substitutable nitrogen atom in the group R4 may be substituted, for example, by a lower alkyl group. As such a group R1,
For example, 1-methyl-imidazol-2-yl group, 1,3
-thiazol-2-yl group, 1,3.4-thiadiazol-2-yl group, 1.3,4.5-thiatriazole-
2-yl group, 1,3-oxazol-2-yl group, 1,
3.4-oxadiazol-2-yl group, 1,3,4.
5-oxatriazol-2-yl, 2-quinolyl, 1-methyl-benzimidazol-2-yl, benzoxazol-2-yl and especially benzthiazol-2-yl. Furthermore, the group R4 can be an acyl group of an organic carboxylic acid or a thiocarboxylic acid, e.g.
up to 8, preferably up to 10, optionally substituted aliphatic, cycloaliphatic, araliphatic or aromatic acyl or thioacyl groups such as lower alkanoyl groups such as acetyl or propionyl groups , lower thioalkanoyl groups such as thioacetyl or thiopropionyl groups, cycloalkanecarbonyl groups such as cyclohexanecarbonyl groups, cycloalkanethiocarbonyl groups such as cyclohexanethiocarbonyl groups, benzoyl groups, thiobenzoyl groups, naphthylcarbonyl groups, naphthylthiocarbonyl groups, hetero Cyclic carbonyl or thiocarbonyl groups, such as 2-93- or 4-pyridylcarbonyl, 2- or 3-thenoyl, 2- or 3-furoyl, 2-13- or 4-pyridylthiocarbonyl, 2- or 3-thiothenoyl group, or 2
- or 3-thiofuroyl groups or substituted corresponding acyl or thioacyl groups, such as lower alkyl groups such as methyl groups, halogen atoms such as fluorine or chlorine atoms, lower alkoxy groups such as methoxy groups,
An aryl group such as a phenyl group, or an acyl or thioacyl group mono- or polysubstituted by an aryloxy group such as a phenoxy group.

In the radicals of the formulas -so, -R5 and -5-SO□-R3, the radical R3 is an optionally substituted, in particular aliphatic, cycloaliphatic group having up to 18 carbon atoms, preferably up to 10 carbon atoms. , an araliphatic or aromatic hydrocarbon group. Such radicals R6 may optionally be mono- or polysubstituted, for example by lower alkoxy groups such as methoxy, halogen atoms such as fluorine, chlorine or bromine, aryl groups such as phenyl, or aryloxy groups such as phenoxy. an alkyl group, in particular a lower alkyl group, such as a methyl or butyl group, an alkenyl group, such as an allyl or butenyl group, a cycloalkyl group, such as a cyclopentyl or cyclohexyl group, or a naphthyl group, or, in particular, an optional lower alkyl group. For example, a methyl group, a lower alkoxy group such as a methoxy group, a halogen atom such as a fluorine atom, a chlorine atom or a bromine atom, an aryl group such as a phenyl group,
Aryloxy groups, such as phenoxy groups, or phenyl groups, which may be mono- or polysubstituted by nitro groups, such as phenyl groups, 〇-1m- or preferably p-)lyl groups, 0-lm- or preferably p- tolyl, 0-lm- or preferably p-methoxyphenyl, 0-2m- or p-chlorophenyl, p-biphenylyl, p-phenoxyphenyl, p-nitrophenyl, or 1- or 2- It is a naphthyl group.

In the starting material represented by formula (n), R8 is -C
It is an etherified hydroxyl group that together with the group represented by (=O')- forms an esterified carboxyl group (which can be split under mild conditions), and in the carboxyl protecting group R8. If functional groups are present, they can be protected in a manner known per se in the same manner as described above. The group 8 can be, for example, a lower alkoxy group optionally substituted with a halogen atom, such as a methoxy group, a lower alkoxy group highly branched in the α-position, such as a tert-butoxy group, or two halogen atoms (a halogen atom). the atom is, for example, a chlorine, bromine or iodine atom), in particular a 2.2.2-) lychloroethoxy, 2-bromoethoxy or 2-iodoethoxy group; , or an optionally substituted 1-phenyl-lower alkoxy group such as a lower alkoxy group such as a methoxy group or a 1-phenyl-lower alkoxy group bearing a nitro group such as a benzyloxy group or a diphenylmethoxy group (these are optionally substituted as described above), e.g. benzyloxy group, 4-
methoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy groups, and also organic silyloxy or stannyloxy groups, such as tri-lower alkylsilyloxy groups, such as trimethylsilyloxy groups,
or a halogen atom, such as a chlorine atom. Preferably, in the starting material represented by formula (If), R? is an amino protecting group R + for example an acyl group Ac (if a free functional group such as an amino group, a hydroxyl group, a carboxyl group or a phosphono group is present in the group, the amino group can be protected by a method known per se as described above). Acyl group, trityl group,
It can be protected by a silyl or stannyl group as well as a substituted thio or sulfonyl group, and a hydroxyl carboxyl or phosphono group can be protected by an ether or ester group containing, for example, a silyl or stannyl group as described above. ) and RY
is a hydrogen atom.

In the 27th amino group -N(R) (R2), the substituent R
One of 2 and R2 is a hydrogen atom and the other is a carbon atom 1
Up to 8, especially up to 12 and preferably up to 7 aliphatic or cycloaliphatic hydrocarbon groups.

Aliphatic hydrocarbon groups 1 or R1 include, for example, optionally substituted alkyl groups, especially lower alkyl groups, such as substituents lower alkoxy groups, such as methoxy groups, lower alkylthio groups, such as methylthio groups, cycloalkyl groups, such as cyclohexyl. alkyl groups, especially lower alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl; group, hexyl group, 2-
They are ethoxyethyl group, 2-methylthioethyl group, cyclohexylmethyl group, benzyl group or chenylmethyl group. Examples of alicyclic hydrocarbon groups include optionally substituted cycloalkyl groups such as substituents, lower alkyl groups such as methyl groups, lower alkoxy groups such as methoxy groups, and lower alkylthio groups such as methylthio groups. , a cycloalkyl group such as a cyclohexyl group, an aryl group such as a phenyl group or a heterocyclic group such as a furyl group, such as a cyclopropyl group optionally substituted as above, a cyclopentyl group, It is a cyclohexyl group or a cycloheptyl group.

In the 37th amino group -N (R')(R''), the substituents R2 and RR are each one of the aliphatic or alicyclic hydrocarbons described above, and R2 and R2 are the same or or can be different groups, and the two substituents R and R2 together can be substituted by carbon-carbon bonds and by oxygen or sulfur atoms, or optionally substituted, e.g. by lower alkylation, e.g. by methyl The nitrogen atom may form a ring.

Suitable 37th amino groups -N (R:) (R2) include, for example, dimethylamino group, diethylamino group, N-methyl-ethylamino group, diisopropylamino group, N-methyl-isopropylamino group, dibutylamino group, N-
Methyl-isobutylamino group, dicyclopropylamino group, N-methyl-cyclopropylamino group, dicyclopentylamino group, N-methyl-cyclopentylamino group, dicyclohexylamino group, N-methyl-cyclohexylamino group, dibenzyl Amino group, N-methy7L/-
Benzylamino group, N-cyclopropyl-benzylamino group, 1-aziridinyl group, l-pyrrolidinyl group, 1-
Piperidyl group, I H-2,3,4,5゜6.7-xahydroazepinyl group, 4-morpholinyl group, 4-thiomorpholinyl group, 1-piperazinyl group or 4-methyl-
1-Piperazinyl.

According to the process of the invention, the cyclization reaction of a compound of formula (II) to obtain a compound of formula (III) can be carried out in a suitable inert solvent such as an aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. Hexane, cyclohexane, benzene or toluene, halogenated hydrocarbons such as methylene chloride, ethers such as di-lower alkyl ethers such as diethyl ether, di-lower alkoxy-lower alkanes such as dimethoxyethane, cyclic ethers such as dioxane or tetrahydrofuran, or aliphatics, in a cycloaliphatic or aromatic nitrile such as acetonitrile, or mixtures thereof, optionally in the presence of a moisture adsorbent such as dried molecular sieves, at room temperature or about 150°C.
Preferably, the reaction is carried out at a temperature of about 80-100° C., and optionally in an inert gas atmosphere, such as a nitrogen gas atmosphere.

The enamines of formula (I[ ) can be obtained.

In the enamine represented by formula (III) produced as an intermediate product, the double bond can be at the 2,3-position or the 3,4-position. Mixtures of the two isomers can also be obtained. If the water or the alcohol of the formula R, -OH is not completely removed during the cyclization reaction, the crude product obtained will also be of the formula (IA) or (
Some solvolysis products represented by IB) are present. Solvolysis can be inhibited by the presence of moisture adsorbents such as dry molecular sieves. Formula (IA
) or (IB) can be obtained directly by carrying out a cyclization reaction in the presence of an RaOH compound, particularly a lower alkanol.

Solvolysis of the resulting enamine of formula (III) is carried out using up to equimolar amounts of an organic or inorganic acid, such as a carboxylic acid, sulfonic acid or mineral acid, of water or an alcohol of formula R3-OH and, if appropriate, a catalyst. For example, formic acid, acetic acid,
Benzenesulfonic acid, methanesulfonic acid, p-)luenesulfone M, salt M, sulfuric acid or phosphoric acid from about -10°C to about 4
The addition is carried out at 0° C., preferably at room temperature.

In the cyclization reaction and solvolysis according to the method of the present invention,
Depending on the starting materials and reaction conditions, a single compound of formula (IA) or formula (IB), or formula (IA)
and a mixture of compounds represented by formula (IB) is obtained. The resulting mixture can be separated by methods known per se, for example by adsorption and fractional elution [chromatography (column) using a suitable adsorbent such as silica gel or aluminum oxide and an eluent. , paper or plate chromatography)
] and fractional crystallization, solvent distribution, etc.

The resulting compounds of formula (IA) and formula (IB) are suitable as intermediates for pharmacologically active end products and can be prepared by various additional methods known per se to such active end products. It can be turned into something.

Formula (I″A) or formula (IB
In the compound represented by ), the α-phenyl-lower alkyl group R3 can be easily split and replaced with a hydrogen atom. α may be substituted in some cases
-Phenyl-lower alkyl groups, such as benzyl or diphenylmethyl groups, can be synthesized by acidolysis, e.g. by treatment with suitable inorganic or organic acids such as hydrochloric acid, sulfuric acid, formic acid or especially trifluoroacetic acid, or by hydrogenolysis,
For example, cleavage can be effected by treatment with hydrogen atoms in the presence of a catalyst such as palladium.

The 3-hydroxy compounds obtained are primarily in the form of 3-cephems. The elimination of the α-phenyl-lower alkyl group R1 can optionally be carried out selectively, i.e. the carboxyl protecting group R
This can be done simultaneously without any separation.

Enol-ethers, that is, compounds represented by formula (IA) and/or formula (IB) in which R8 is a lower alkyl group, are compounds represented by formula (IA) or (IB).
can be obtained from a compound in which R3 is a hydrogen atom or a residue protecting a hydroxyl group, and when R3 is a residue protecting a hydroxyl group, replacing this group with a hydrogen atom and subsequently , obtained by etherifying free hydroxyl groups according to any method suitable for etherifying enol groups. Suitable etherification agents include diazo compounds of the formula % corresponding to the group R3, mainly optionally substituted diazo lower alkanes such as diazomethane, diazoethane or diazo-n-butane, and further substituted diazo-lower alkanes such as diazomethane, diazoethane or diazo-n-butane. It is preferred to use certain alpha-phenyldiazo lower alkanes such as phenyldiazomethane and diphenyldiazomethane.

These reactants can be dissolved in a suitable inert solvent such as an aliphatic solvent such as hexane, cyclohexane, benzene or toluene,
Cycloaliphatic or aromatic hydrocarbons, halogenated aliphatic hydrocarbons such as methylene chloride, lower alkanols such as methanol, ethanol or t-butanol, ethers such as di-lower alkyl ethers such as diethyl ether or tetrahydrofuran, in the presence of a cyclic ether such as dioxane or a solvent mixture thereof and with a diazo compound, cooled at room temperature or under slight heating, and if necessary in a sealed container and/or an inert gas such as nitrogen gas. Use under gas.

Furthermore, reactive esters of alcohols of the formula % (in which R1 is a lower alkyl group or an optionally substituted α-phenyl-lower alkyl group, such as a benzyl group or a diphenylmethyl group) By treatment, enol ethers of formula (IA) and/or formula (IB) can be produced.

Suitable esters are primarily strong inorganic or organic acids, such as mineral acids, such as hydrohalic acids, such as hydrochloric acid, hydrobromic acid or hydroiodic acid, halogenosulfuric acid, such as sulfuric acid or fluorosulfuric acid, or strong organic sulfonic acids, such as fluorine. lower alkanesulfonic acids which may be substituted with halogens, or aromatic sulfonic acids which may be substituted with lower alkyl groups such as methyl groups, halogen atoms such as bromine and/or nitro groups; Esters with benzenesulfonic acid, such as methanesulfonic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid. These etherifying agents are particularly di-lower alkyl sulfates such as dimethyl sulfate, and also lower alkyl fluorosulfates such as methyl fluorosulfate or lower alkyl methanesulfonates which may be halogen-substituted such as methyl trifluoromethanesulfonate. Esters are generally defined as solvents such as aliphatic, cycloaliphatic or aromatic hydrocarbons which may be halogenated such as chlorinated, ethers such as methylene chloride, dioxane or tetrahydrofuran, lower alkanols such as methanol or the like. Use in a mixture of In this case, suitable condensing agents such as carbonates or bicarbonates of alkali metals such as sodium or potassium (generally in the case of sulfuric esters) or organic bases such as N,N-diisopropyl-N-ethylamine, generally steric Preference is given to using hindered tri-lower alkyl amines (preferably in the case of halogenosulfuric acid lower alkyl esters or methanesulfonic acid lower alkyl esters which may be halogen-substituted). The reaction is operated cooled, at room temperature or under heat, for example from about -20 to 50°C, and if necessary in a sealed vessel and/or under an inert gas such as nitrogen.

The etherification reaction can be further promoted by a phase transfer catalyst. Phase transfer catalysts that can be used are quaternary phosphorus salts and especially quaternary ammonium salts, such as optionally substituted tetraalkylammonium halides, such as tetrabutylammonium chloride,
Bromide or iodite, or benzyl-triethylammonium chloride, used in catalytic or up to equimolar amounts. Any water-immiscible solvent can be used as the organic phase, such as optionally halogenated, e.g. chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbons, e.g. tri- or tetra-chloroethylene; di-, tri- or tetra-chloroethane, chlorobenzene, or especially carbon tetrachloride, or toluene or xylene. Alkali metal carbonates or bicarbonates, such as potassium carbonate or bicarbonate, sodium carbonate or bicarbonate, alkali metal phosphates, such as potassium phosphate, and alkali metal hydroxides, such as sodium hydroxide, are suitable as condensing agents. In the case of base-sensitive compounds, the pH value during etherification is approximately 7 and 8.5.
can be added to the reaction mixture so that the

Furthermore, the enol ether can be prepared by treatment with a compound having 2 to 3 etherified hydroxyl groups of the formula on the same aliphatic carbon atom, i.e. the corresponding acetal or orthoester, in the presence of an acidic agent. You can also make one.

Thus, geII+-lower alkoxy lower alkanes such as 2,2-dimethoxy-propane are used as etherification agents in the presence of a strong organic sulfonic acid such as p-1-luenesulfonic acid and in a suitable solvent such as methanol. strong inorganic acids such as sulfuric acid, or tri-lower alkyl orthoformates such as orthoformate toluethyl ester in the presence of lower alkanols or di-lower alkyl- or lower alkylene-sulfoxides such as dimethyl sulfoxide. or p-) can be used in the presence of a strong organic sulfonic acid such as luenesulfonic acid and in the presence of a suitable solvent such as a lower alkanol such as ethanol or an ether such as dioxane, such that R□ Formula (rA) and/or formula (which is a lower alkyl group such as a methyl group or an ethyl group)
The compound represented by IB) is obtained.

Furthermore, compounds represented by formulas (IA) and (or') (IB) (wherein R3 is a hydrogen atom) may be added to tri-R1-oxonium salts (so-called Meherwein salts) represented by the formula % formula % () or DiR30-rubenium salt or formula% expressed by the formula% formula% (in these formulas A○ is an anion of the acid and Hag
(○ is a halonium ion such as a bromonium ion) Enol ethers represented by formulas (IA) and (or ") (IB) are also obtained when treated with di-R3-halonium salts represented by: Such reactants are mainly tri-lower alkyloxonium salts, di-lower alkylhalonium salts or di-lower alkylhalonium salts,
- Particular mention may be made of the corresponding salts with complex fluorine-containing acids, such as the corresponding tetrafluoroborates, hexafluorophosphates, hexafluorophosphates or hexachloroantimonates. Such reactants are, for example, trimethyloxonium- or triethyloxonium-hexafluorantimonate, -hexachlorantimonate, -hexafluorophosphate or -tetrafluoroborate, dimethoxycarbenylam hexafluorophosphate. or dimethylbromonium-hexafluorantimonate. These etherifying agents are preferably carried out in an inert solvent such as an ether such as diethyl ether or tetrahydrofuran or a halogenated hydrocarbon such as methylene chloride or a mixture thereof, if necessary a base such as a preferably sterically hindered tri-lower alkylamines in the presence of an organic base such as N,N-diisopropyl-N-ethylamine and under cooling, room temperature or slight heating, e.g.
Used at 20-+50°C, if necessary in a sealed container and/or under an inert gas such as nitrogen.

Furthermore, compounds represented by formula (IA) and (or) formula (IB) in which formula R3 is a hydrogen atom can be added to an IR:I-) riazene compound substituted at the 3-position (i.e., a substituent -N=N Enol ethers of formulas (IA) and/or (IB) are also produced by treatment with compounds having -NH-R,. The substituent on the 3-nitrogen atom is an organic group bonded via a carbon atom, preferably a carbocyclic ring group, such as an optionally substituted phenyl group, such as a 4-methylphenyl group. It is a lower alkylphenyl group. Such triazene compounds include 3-aryl-1-lower alkyl-triazenes such as 3-(4-methylphenyl)-1-methyl-triazene, 3-(4-methylphenyl)-1-ethyl-
Triazene, 3-(4-methylphenyl)-1-n-propyl-triazene or 3-(4-methylphenyl)
-1-isopropyl-triazene, or 3-ori-1-(α-phenyl lower alkyl)-triazene, such as 1-benzyl-3-(4-methylphenyl)-triazene. These reactants are generally dissolved in an inert solvent such as a hydrocarbon which may be halogenated such as benzene or an ether or a solvent mixture and cooled, at room temperature or preferably at an elevated temperature, e.g.
00°C, if necessary in a sealed container and/or under an inert gas such as nitrogen.

Compounds in which -0R3 is a reactively esterified hydroxyl group in formulas (IA) and (IB) are converted into R, -OH (
wherein R1 is a lower alkyl group or an α-phenyl-lower alkyl group), formula (IA) and/or formula (I
The enol ether represented by B) can be obtained. Reactively esterified hydroxyl groups -OR, are in particular hydroxyl groups esterified with strong inorganic or organic acids.

Such acids include, for example, mineral acids, hydrochloric acids such as hydrochloric acid, hydrobromic acid or hydrocolic acid, and or sulfuric acid or halogenated sulfuric acids, such as fluorosulfuric acid, or preferably strong organic sulfonic acids such as acids of the formula % formula % (in which R6 has the same meaning as given in the group Y), such as lower alkanesulfonic acids, which may optionally be substituted by halogen atoms, such as fluorine atoms; ), or aromatic sulfonic acids such as benzenesulfonic acid (optionally substituted, e.g. by lower alkyl groups such as methyl groups, halogen atoms such as bromine atoms, and/or nitro groups), e.g. especially Methanesulfonic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid. The reaction with alcohols of the formula Rs OH is usually carried out in solvents such as optionally halogenated, e.g. chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbons such as benzene, toluene or methylene chloride, ethers. For example in dioxane or tetrahydrofuran, di-lower alkyl amides such as dimethylformamide or dimethylsulfoxide, etc., or in mixtures thereof, preferably with suitable condensing agents such as alkali metal carbonates or bicarbonates, such as sodium carbonate or bicarbonate. , potassium carbonate or bicarbonate, or in the presence of an organic base such as a normally sterically hindered tri-lower alkylamine such as triethylamine or N,N-diisopropyl-N-ethylamine. Warm it to about -20℃ to 50℃, for example.
in a sealed container if necessary, and/or
It is carried out in an inert gas atmosphere, for example, a nitrogen atmosphere.

In formula (IA) and/or formula (IB), -0
Compounds in which R1 is a reactively esterified hydroxyl group have already been disclosed in DE 2.408,686 and DE 2.408.698, and can also be obtained by the method of the present invention. It can be produced from compounds represented by formula (IA) and/or formula (IB) in which -0R3 is a free hydroxyl group in the same manner as the methods disclosed in the above-mentioned German publications.

For example, a sulfonic acid ester of a compound represented by formula (IA) and/or formula (IB) in which R3 is 13ow Rs is a compound represented by formula (IA) in which -0R1 is a free hydroxyl group.
) and (or) a compound represented by formula (IB),
It can be made by esterification with a reactively functionalized derivative of a sulfonic acid of the formula HOSOx Rs. 2〇〇-S that can be used
Reactive functional derivatives of sulfonic acid represented by O□-R3 include, for example, its reactive anhydrides, especially mixed anhydrides with hydrohalic acids, such as its chlorides, such as mesyl chloride and p-)luenesulfonic acid chloride. It is.

The esterification is preferably carried out in the presence of an organic tertiary nitrogen base such as pyridine, triethylamine or ethyl-diisopropylamine in a suitable inert solvent such as an aliphatic,
Cycloaliphatic or aromatic hydrocarbons, e.g. hexane, cyclohexane, benzene or toluene, halogenated aliphatic hydrocarbons such as methylene chloride, lower alkalis such as methanol, ethanol or t-butanol.
cooled, room temperature or slightly heated, i.e. in the presence of a di-lower alkyl ether such as diethyl ether or a cyclic ether such as tetrahydrofuran or dioxane or a solvent mixture thereof and depending on the reactivity of the esterifying agent, i.e. It is carried out at a temperature of -10°C to +50°C, if necessary in a sealed container and/or under an inert gas such as nitrogen gas. The resulting sulfonic ester can be isolated or further processed in the same reaction mixture.

In the process of the invention and the additional steps which may be carried out if desired, free functional groups which do not take part in the reaction in the starting materials or in the compounds obtained by the process of the invention may be removed, for example free amino groups. For example, by acylation, tritylation or silylation, free hydroxyl groups or mercapto groups can be converted by etherification or esterification, and free carboxyl groups can be converted by esterification, for example by esterification, including silylation. The groups can be temporarily protected by a method and, if desired, liberated individually or simultaneously after the end of the reaction by methods known per se. Therefore, preferably an amino group, a hydroxyl group, a carboxyl group or a phosphono group in R+ or Rb as an acyl group is replaced with an acylamino group such as the above-mentioned acylamino group such as 2,2
．． in the form of a 2-trichloroethoxycarbonylamino group, a 2-bromoethoxycarbonylamino group, a 4-methoxybenzyloxycarbonylamino group, a diphenylmethoxycarbonylamino group or a t-butoxycarbonylamino group, an aryl-ruthioamino group or an aryl lower alkylthio group. Amino groups, for example in the form of a 2-nitrophenylthioamino group, arylsulfonylamino groups, for example in the form of a 4-methylphenylsulfonylamino group, l-lower alkoxycarbonyl-2-propylideneamino groups, as mentioned above; Acyloxy groups, for example in the form of (-butoxycarbonyloxy, 2.2.2-)lychloroethoxycarbonyloxy or 2-bromoethoxycarbonyloxy groups, esterified carboxyl groups as mentioned above, such as diphenylmethoxycarbonyl groups. or a 0.0'-disubstituted phosphono group as described above, e.g.
in each case in the form of a di-lower alkylphosphono group and subsequently, optionally after conversion of the protecting group (e.g. a 2-bromoethoxycarbonyl group into a 2-iodoethoxycarbonyl group), by methods known per se. Depending on the type of protecting group, e.g. 2,2.2-)lychloroethoxycarbonylamino or 2-iodoethoxycarbonylamino, this can be treated with a suitable reducing agent such as zinc in the presence of aqueous acetic acid. , diphenylmethoxycarbonylamino groups and t-butoxycarbonylamino groups are treated with formic acid or trifluoroacetic acid, and arylthioamino groups and aryl lower alkylthioamino groups are treated with a nucleophilic agent such as sulfite. The sulfonylamino group is obtained by electrolytic reduction, the l-lower alkoxycarbonyl-2-propylideneamino group is treated with an aqueous inorganic acid solution, and the t-butoxycarbonyloxy group is treated with formic acid or trifluoroacetic acid. Process with 2
．． 2. The 2-trichloroethoxycarbonyloxy group is treated with a chemical reducing agent such as zinc in the presence of aqueous acetic acid, and the diphenylmethoxycarbonyl group is treated with formic acid or trifluoroacetic acid or hydrolyzed. The or 0,0'-disubstituted phosphono group can be partially cleaved, for example, if desired by treating it with an alkali metal halide.

Formula -C(=O)-R obtained by the method of the present invention
In the compounds of formula (IA) or formula (IB) with a particularly esterified carboxyl group, this can be converted into a free carboxyl group by methods known per se, for example depending on the nature of the group R8. can. Esterification, for example hydrolysis of lower alkyl groups, especially methyl or ethyl groups, or carboxyl groups esterified with benzyl groups (especially in 2-cephem compounds of formula (IB)) in a weakly basic medium. for example with an alkali metal or alkaline earth metal hydroxide or carbonate, such as sodium hydroxide or an aqueous solution of sodium hydroxide, preferably at a pH value of about 9 to 10 and optionally in the presence of lower alkanols. By doing so, it can be converted to a free carboxyl group.

A carboxyl group esterified with a suitable 2-halogeno lower alkyl group or arylcarbonylmethyl group can be reduced by a chemical reducing agent such as a metal such as zinc or a divalent chromium salt such as a chloride of divalent chromium. nascent hydrogen by treatment in the presence of a hydrogen donor such as an acid, primarily acetic acid or formic acid, or an alcohol (preferably with the addition of water). Let's divide,
and the carboxyl group esterified with the arylcarbonylmethyl group can be cleaved by treating it with a nucleophilic, preferably salt-forming, reagent such as sodium thiophenolate or sodium iodide. and a carboxyl group esterified with a suitable arylmethyl group, for example by irradiation [preferably the arylmethyl group is esterified in the 3-14- and/or 5-position with a lower alkoxy group and/or For example, if the benzyl group is substituted with a nitro group, use ultraviolet light of 290 mμ or less, and if the arylmethyl group is a benzyl group substituted with a nitro group at the 2-position, for example, 290 mμ or less.
using long wavelength ultraviolet light of mμ or more] can be split,
Carboxyl groups esterified with suitably substituted methyl groups such as t-butyl or diphenylmethyl may be treated with suitable acidic agents such as formic acid or trifluoroacetic acid, and in some cases with phenol or anisole. The active esterified carboxyl group and also the carboxyl group in anhydride form can be cleaved by treatment with nucleophilic compounds such as hydrochloric acid, aqueous sodium bicarbonate solution, etc. or an esterified carboxyl group that can be cleaved by treatment with an acidic or weakly basic aqueous agent such as an aqueous potassium phosphate buffer solution of pH about 7-9, and can also be hydrogenolyzed, e.g. It can be split by treatment with hydrogen in the presence of a noble metal catalyst such as a palladium catalyst.

Carboxyl groups which have been protected, for example by silylation or stannylation, can be liberated by conventional treatment, for example with water or alcohol.

The resulting compound represented by formula (IA) or formula (IB) can be prepared by a method known per se.
It can be changed to other compounds represented by IB).

In the compounds obtained, for example, amino protecting groups R+ or Ry, in particular easily cleavable acyl groups, can be cleaved off by methods known per se. For example, a highly branched lower alkoxycarbonyl group at the α-position, such as t-butoxycarbonyl group, can be prepared by treating it with trifluoroacetic acid or a 2,2.2-)lychloroethoxycarbonyl group. A 2-halogeno-lower alkoxycarbonyl group such as a 2-iodoethoxycarbonyl group or a phenacyloxycarbonyl group can be treated with a suitable reducing metal or corresponding metal compound such as zinc or
A divalent chromium compound such as a chloride or acetate of valent chromium, preferably in the presence of a hydrogen donor which together with this metal or metal compound forms nascent hydrogen, preferably hydrated acetic acid. can be split by processing in the presence of.

Furthermore, formula (IA) or formula (IB) (wherein formula -C
The carboxyl group represented by (=O) Rz is preferably protected by esterification, including silylation, for example with a suitable organosilicon halide or halogeno-tin(IV) compound such as trimethylchlorosilane or trimethylchlorosilane. In the resulting compound, the acyl group R? or R11 (free functional groups which may be present in this group are optionally protected) is treated with an imide-halide forming agent, the resulting imide-halide is reacted with alcohol and thus formed The iminoether can be cleaved by cleavage, and protected carboxyl groups, such as carboxyl groups protected with organosilyl groups, may become free during the reaction.

Imide-halide formers in which a halogen atom is bonded to an electrophilic central atom are especially acid halides, such as acid bromides and especially acid chlorides.

These are mainly acid halides of inorganic acids, especially phosphorus-containing acids, such as phosphorus oxyhalides, phosphorus trihalides and especially phosphorus pentahalides, such as phosphorus oxychloride,
phosphorus trichloride and mainly phosphorus pentachloride, as well as pyrocatekyl-phosphorus trichloride, and acid halides, especially chlorides, of sulfur-containing acids or carboxylic acids, such as thionyl chloride,
Phosgene or oxalyl chloride.

To react with one of the above imide-halide forming agents,
In general, suitable bases, especially organic bases, especially tertiary amines, such as tertiary aliphatic monoamines or diamines, such as tri-lower alkyl amines, such as trimethylamine, triethylamine or N,N-diisopropyl-N-ethyl-amine, and also N, N, N', N '-Tetra-lower alkyl-lower alkylene diamine e.g. N, N, N'
, N'-tetramethyl-1,5-benzenediamine or N,N,N',N'-tetramethyl-1,6-hexylene diamine, monocyclic or bicyclic monoamines or diamines such as N- Substituted (e.g. N-lower alkylated) alkylene amines, azaalkylene amines or oxaalkylene amines such as N-methylpiperidine or N-methylmorpholine, or 2,3.4,6
．． 7.8-hexahydropyrrolo(1,2-a)pyrimidine (i.e. diazabicyclononene, DBN) or tertiary aromatic amines such as di-lower alkylaniline such as N,N-dimethylaniline or especially tertiary hetero of aliphatic or aromatic hydrocarbons such as methylene chloride, which may preferably be halogenated (e.g. chlorinated), in the presence of a cyclic monocyclic or bicyclic base such as quinoline or isoquinoline, especially pyridine. The reaction is carried out in the presence of a solvent such as In this reaction, imide-
The halide former and the base can be used in approximately equimolar amounts, but the base can be used in excess or less than an equivalent amount, such as up to about 0.2 to 2 times or about 10 times excess;
In particular, an amount of about 3 to 5 times excess can also be used.

While cooling the reaction with the imide-halide forming agent,
For example, it is preferred to carry out the reaction at a temperature of about -50 to +lO<0>C, but the reaction can be carried out at higher temperatures, e.g. up to about 75<0>C, if the stability of the raw materials and the stability of the product permit higher temperatures. can.

The imide-halide product thus formed is generally not isolated, but is reacted with an alcohol, preferably in the presence of one of the bases mentioned, to give the iminoether. Alcohols include, for example, aliphatic or araliphatic alcohols;
In particular, lower alkanols which may be substituted, such as halogenated (e.g. chlorinated) or which additionally carry a hydroxyl group, such as ethanol, propatool or butanol, especially methanol, as well as 2,2,2-trichloroethanol. Suitable are 2-halogeno lower alkanols such as and 2-bromoethanol, and also optionally substituted phenyl-lower alkanols such as benzyl alcohol. The alcohol is generally used in excess, e.g. up to about 100 times excess, and the process is continued with cooling, e.g.
Preferably it is carried out at 10°C.

The iminoether product thus formed can advantageously be cleaved off without being isolated. The splitting of this iminoether can be achieved by treating it with an appropriate hydroxy compound.
This is preferably achieved by hydrolysis or even alcoholysis (which alcoholysis can be carried out following the formation of the iminoether using an excess of alcohol). Preference is given here to use water or a mixture of an organic solvent such as an alcohol, in particular a lower alkanol such as methanol, or an alcohol with water. This step is generally carried out in an acidic medium at a pH value of, for example, about 1 to 5, and this pH value is, if necessary, a solution of a basic agent, e.g. an aqueous alkali metal hydroxide such as sodium hydroxide or potassium hydroxide. Alternatively, acids can be adjusted by adding inorganic or organic acids such as hydrochloric acid, sulfuric acid, borohydride, trifluoroacetic acid or p-toluenesulfonic acid.

The three-step process for cleavage of the acyl group described above can be carried out without intermediate isolation of the imido-halide and iminoether intermediates, generally in an organic solvent inert towards these reactants, such as methylene chloride. It is advantageous to carry out the reaction in the presence of hydrocarbons, which may be present, and/or in an inert gas such as nitrogen gas.

If the imide-halide intermediate obtained by the above method is reacted with a carboxylic acid, especially a salt such as an alkali metal salt of a sterically hindered carboxylic acid, instead of reacting with an alcohol, in formula (IA) or (IB), R? and R.I.
A compound in which i+ and both are acyl groups is obtained.

Group R in formula (TA) or (IB)? and R1i' are both acyl groups, one of these groups, preferably the one with less steric hindrance, can be selectively removed, for example, by hydrolysis or amithrisis.

In the compound represented by formula (IA) or (IB), R? If and Rb together with their attached nitrogen atom represent a phthalimide group, this can be converted into a free amino group, for example, by hydraziturysis (ie, by treating such a compound with hydrazine).

Among the acyl radicals R+ of the acylamino groups in the compounds obtained by the process of the invention, for example the 5-amino-5-carboxy-valeryl group [the carboxyl group of which is removed, for example by esterification, in particular by the diphenylmethyl group and/or by the amino The group can also be protected, for example by acylation, in particular by an acyl group of an organic carboxylic acid, e.g. a halogeno-lower alkanoyl group such as dichloroacetyl group or a phthaloyl group], a nitrosylating agent such as nitrosyl chloride, benzenediazonium Carbocyclic allene-diazonium salts such as chlorides or N-halogen-amides or N-halogen-imides A reactant donating a positive halogen atom such as N-bromosuccinimide, preferably in a suitable solvent or solvent mixtures, such as nitro-lower alkanes or cyano-
treatment with lower alkanes in formic acid and mixing the reaction product with water or lower alkanols such as methanol, or with iR↑
The amino group in the 5-amino-5-carboxy-valeryl group as is unsubstituted and the carboxyl group is protected, for example by esterification, and RI! +
is preferably an acyl group, but can also be a hydrogen atom, by standing in a suitable solvent such as dioxane or a halogenated aliphatic hydrocarbon, for example methylene chloride, and if necessary in this way. The free or monoacylated amino compounds formed can be cleaved off by working up by methods known per se.

The formyl group R+ may also be removed by treatment with acidic agents such as p-)luenesulfonic acid or hydrochloric acid, weakly basic agents such as dilute ammonia or decarbonylating agents such as tris-(triphenylphosphine)-rhodium chloride. can.

A triarylmethyl group R+ such as a trityl group can be removed by treatment with an acidic agent such as an inorganic acid, such as hydrochloric acid.

In the compounds of formula (IA) or (IB), in which R? and l are hydrogen atoms, the free amino group is replaced in a manner known per se, for example by an acid such as a carboxylic acid or a reactive acid thereof. Acylation can be achieved by treatment with derivatives.

In the case of acylation with free acids (preferably the optional functional groups, e.g. the optional amino groups, are protected), suitable condensing agents commonly used, such as carbodiimides. For example, N,N'-diethyl-1N, N'-dipropyl-1N, N'-diisopropyl-1N.

N'-dicyclohexyl- or N-ethyl-N'-3
-dimethylaminopropyl-carbodiimide, suitable carbonyl compounds such as carbonylimidazole or isoxazolinium salts such as N-ethyl-5-phenyl-isoxazolinium-3'-sulfonate, and N-t-butyl-5-methyl -isoxazolinium verchlorate, or a suitable acylamino compound such as 2-ethoxy-I-ethoxycarbonyl-1,2-dishdroquinoline.

This condensation reaction is preferably carried out in an anhydrous reaction medium as described below, such as methylene chloride, dimethylformamide or acetonitrile.

In addition, the functional derivatives of acids used to form amides (if they have a functional group such as an amino group, it is preferable to protect this group) are mainly anhydrides of such acids. a mixed anhydride, preferably a mixed anhydride. Mixed anhydrides are, for example, anhydrides with inorganic acids, especially hydrohalic acids, i.e. the corresponding acid halides, such as acid chlorides or bromides, and also anhydrides with hydroazidic acid, i.e. the corresponding acid amide,
Anhydrides with phosphorus-containing acids such as phosphoric acid or phosphorous acid, sulfur-containing acids such as sulfuric acid or hydrocyanic acid. Other suitable anhydrides are e.g. anhydrides of organic acids e.g. with organic acids e.g. lower alkanecarboxylic acids such as lower alkane carboxylic acids which may be substituted with halogen atoms e.g. fluorine or chlorine atoms or with carbonic acids e.g. pivalic acid or trichloroacetic acid. half esters, especially lower alkyl half esters, such as ethyl half ester or isobutyl half ester, anhydrides or organic, especially aliphatic or aromatic sulfonic acids, such as
-) Anhydride with luenesulfonic acid.

Furthermore, intramolecular anhydrides such as ketenes such as diketene, isocyanates (i.e., intramolecular anhydrides of carbamic acid compounds), or intramolecular anhydrides of carboxylic acid compounds with carboxy-substituted hydroxyl or amino groups can be used as acylating agents. For example, mandelic acid-〇-carboxyanhydrite or the anhydride of 1-N-carboxyamino-cyclohexanecarboxylic acid can be used.

Other acid derivatives suitable for reaction with free amino groups include activated esters (if they carry functional groups it is generally preferred to keep them protected), such as lower vinyl alkanols. Esters with vinyl alcohols (i.e. enols), or aryl esters such as phenyl esters preferably substituted with e.g. a nitro group or a halogen atom such as chlorine, e.g. pentachlorophenyl ester, 4-nitrophenyl ester or 2.4- dinitrophenyl esters, heteroaromatic esters such as benztriazole esters, or diacylimino esters such as succinylimino esters and phthalyl imino esters.

Other acylated derivatives include, for example, substituted formimino derivatives of acids, such as substituted N,N-dimethylchloroformimino derivatives, or N-substituted N,N-diacyls, such as N,N-diacylated anilines. There is an amine.

For acylation with acid derivatives such as anhydrides or especially acid halides, acid binders such as organic bases such as organic amines such as tertiary amines such as tri-lower alkyl amines such as triethylamine, N, N-dimethyl bases of the N,N-dilower alkylaniline or pyridine type such as aniline, e.g. pyridine, inorganic bases e.g. alkali metal or alkaline earth metal hydroxides, carbonates or bicarbonates e.g. sodium, potassium or calcium hydroxides; The reaction can be carried out in the presence of carbonates, carbonates or bicarbonates, or oxiranes such as lower 1,2-alkylene oxides such as ethylene oxide or propylene oxide.

The above acylation may be carried out in aqueous or preferably non-aqueous solvents or solvent mixtures, such as N,N-di-lower alkylamides, carboxylic acid amides such as dimethylformamide, halogenated acids such as methylene chloride, carbon tetrachloride or chlorobenzene. hydrocarbons, ketones such as acetone, esters such as ethyl acetate or nitrites such as acetonitrile or mixtures thereof and if necessary at reduced or elevated temperature and/or non-containing substances such as nitrogen. It can be carried out under active gas.

In the above acylation reaction, formula (IA) or (IB
) (in this formula, R5 is a lower alkyl group or an optionally substituted α-phenyl lower alkyl group, such as a benzyl group or a diphenylmethyl group,
R3 has the meaning given above) and the formula -C(=O)'-RZ
(where R2 is a hydroxyl group) can be used in the form of a salt, for example an ammonium salt, for example with triethylamine, or a suitable organophosphorus halide, for example a lower alkyl- Phosphorus civalides or lower alkoxy-phosphorus civalides can also be used in the form of compounds with carboxyl groups protected by reaction with, for example, methyl-phosphorus dichloride, ethyl-phosphorus dibromide or methoxy-phosphorus dichloride. . In the acylated products obtained, the protected carboxyl groups can be liberated by methods known per se, for example by hydrolysis or alcoholysis as described above.

The acyl group has the formula (IA) or (IB) (in this formula R?
and l are both ylidene groups (this group is R? and R1)
is a hydrogen atom, for example by post-treatment with an aldehyde, such as an aliphatic, aromatic or araliphatic aldehyde), and the obtained It is also possible to introduce the acylated product by hydrolysis, preferably in a neutral or slightly acidic medium.

Alternatively, the acyl group can be introduced in steps. That is, for example, by introducing a halogeno-lower alkanoyl group, such as a bromoacetyl group, into a compound of formula (IA), i and (IB) having a free amino group, or by treating with a carbonic acid civalide, such as phosgene, to form a chlorocarbonyl group. and the N-(halogeno-lower alkanoyl)-amino compound or N-(halogenocarbonyl)-aminated gold compound thus obtained is treated with a suitable substituent such as a basic compound such as tetrazole, 2-mercapto. - Substituted N-lower alkanoylamino or N-hydroxycarbonyl by reaction with a thio compound such as 1-methyl-imidazole, a metal salt such as sodium azide or an alcohol such as a lower alkanol such as di-butanol. Amino compounds can be obtained.

In both reactant systems, free functional groups can be temporarily protected during the acylation reaction by known methods and, after the acylation, can be protected by methods known per se, such as those described above. It can be liberated.

Furthermore, it is also possible to acylate existing acyl groups by replacing them with other preferably sterically hindered acyl groups, for example by the methods described above.

In this case, the imidohalide compound is prepared, it is treated with a salt of an acid, and one of the acyl groups (generally the less sterically hindered acyl group) in the product thus obtained is removed by hydrolysis. It causes division.

Furthermore, for example, R in formula (IA) or (IB)
? R is a glycyl group, preferably substituted in the α-position, such as a phenylglycyl group, and RIil is a hydrogen atom, by reacting a compound with an aldehyde such as formaldehyde or a ketone, such as a lower alkanone such as acetone. ? and l together with these bonding nitrogen atoms are 5-oxo-1,3-
Formula (IA) representing a diaza-cyclopentyl group, which is preferably substituted in the 4-position and optionally substituted in the 2-position, or (
The compound IB) is obtained.

R in formula (IA) or (IB)? and in compounds where RIil is a hydrogen atom, by introducing a triarylmethyl group, for example by treatment with a reactive ester of triarylmethanol such as trityl chloride, preferably in the presence of a basic agent such as pyridine. The free amino group can also be protected.

Moreover, the amino group can also be protected by introducing a silyl group or stannyl group.

Such groups can be introduced by methods known per se, for example by using a suitable silylating agent, e.g. Lower alkyl-dihalogenosilanes or tri-lower alkylsilyl halides such as trimethylsilyl chloride or dimethyl-t-butylsilyl chloride (preferably these are used in the presence of a base such as pyridine)
or N-monolower alkylation, N.

N-(tri-lower alkyl-silyl)-amines which may be N-di-lower alkylated, N-)-ly lower alkylsilylated or N-lower alkyl-N-tri-lower alkylsilylated (e.g. British patents No. 1,07
3,530) or a silylated carboxylic acid amide such as bis-trimethylsilylacetamide, bis-trilower alkylsilyl-acetamide or trifluorosilylacetamide, or a suitable Stannylating agents such as bis-
Bis-(tri-lower alkyl-tin)-oxide such as (tri-n-butyl-tin)-oxide, tri-lower alkyl-tin hydroxide such as triethyl-tin-hydroxide, tri-lower alkyl-
Lower alkoxy-tin compounds, tetra-lower alkoxytin compounds or tetra-lower alkyltin compounds or tri-lower alkyltin halides such as tri-n-butyltin chloride (e.g. Dutch Special No. 67
Please refer to the specification of No./17107).

Formula -C(=0)-R obtained by the method of the present invention.

Formula (IA) or (IB) with a free carboxyl group of
In the compounds, this group can be converted into a protected carboxyl group by methods known per se.

That is, for example, treatment with a suitable diazo compound such as a diazo-lower alkane such as diazomethane or diazobutane or a phenyldiazo-lower alkane such as diphenyldiazomethane, if necessary in the presence of a Lewis acid such as boron trifluoride. or with an alcohol suitable for esterification in the presence of an esterifying agent such as a carbodiimide such as dicyclohexylcarbodiimide or carbonyldiimidazole, or N,N'
- with a disubstituted O- or S-substituted isourea or isothiourea, the O- and S-substituents being, for example, lower alkyl groups, in particular tert-butyl, phenyl lower alkyl or cycloalkyl groups; And then N-
or the N'-substituent is, for example, a lower alkyl group, in particular an isopropyl group, a cycloalkyl group or a phenyl group)
or other known suitable esterification methods such as reacting a salt of the acid with a reactive ester of an alcohol and a strong inorganic or organic sulfonic acid.

In addition, acid halides such as acid chlorides (which are made, for example, by treatment with oxalyl chloride), activated esters (which are made by treatment with N-hydroxy-nitrogen compounds such as, for example, N-hydroxy-succinimide), mixed anhydrides (which are produced using, for example, halogenoformic acid lower alkyl esters such as ethyl chloroformate or isobutyl chloroformate or halogenoacetic acid halides such as trichloroacetic acid chloride), It can be converted into an esterified carboxyl group by reaction with an alcohol, optionally in the presence of a base such as pyridine.

In the resulting compounds with an esterified group of the formula -C(=0)-Rz, this group can be changed to other esterified groups of the same formula, e.g.
A 2-chloroethoxycarbonyl group or a 2-bromoethoxycarbonyl group is treated with an iodine salt such as sodium iodide in the presence of a suitable solvent such as acetone to form a 2-chloroethoxycarbonyl group.
It can be changed to iodoethoxycarbonyl group.

The mixed anhydride is a group in formula (IA) or (IB) -
Compounds in which C(=O)-Rz is a free carboxyl group or preferably salts thereof, especially alkali metal salts such as sodium salts or ammonium salts such as triethylammonium salts, are combined with reactive derivatives of acids such as acid chlorides. It is produced by reacting with a halide or halogenoformic acid lower alkyl ester or lower alkanecarboxylic acid chloride.

In the compounds obtained by the process of the invention in which the group -C(=0)-R, is a free carboxyl group, this group can be converted into an optionally substituted carbamoyl group or a hydrazinocarbonyl group. In this case, preferably reactive functionally modified derivatives such as the aforementioned acid halides, generally esters such as the aforementioned activated esters or mixed anhydrides with the corresponding acids, including ammonia, hydroxylamine, etc. React with amine or hydrazine.

A carboxyl group protected with an organic silyl group or a stannyl group can be prepared by a method known per se, for example, by formula (IA).
or a compound in which R2 in (IB) is a hydroxyl group or a salt thereof, e.g. an alkali metal salt such as a sodium salt, is treated with a suitable silylating agent or stannylating agent, such as one of the above-mentioned silylating agents or stannylating agents. formed by For example, British Patent No. 1,073,530 or Dutch Patent No. 67/17
Please refer to the specification of No. 107.

Furthermore, modified functionalities such as substituted amino groups, acylated hydroxyl groups, esterified carboxyl groups or 0,0'-disubstituted phosphono groups in the groups R+, Rv and/or Rz The groups can be liberated by methods known per se, for example by the methods mentioned above, or free functionalities such as free amino, hydroxyl, carboxyl or phosphono groups in the radicals R+, l and/or RZ The groups can be functionally modified by methods known per se, for example by acylation, esterification or substitution reactions.

Thus, for example, an amino group can be converted to a sulfamino group by treatment with a trioxidized sulfur, preferably in the form of a complex with an organic base, such as a tri-lower alkylamine, such as triethylamine.

Furthermore, the reaction mixture obtained by the reaction of the acid addition salt of 4-guanyl semicarbatide and sodium nitrite,
The amino group can be converted into a 3-guanylureido group by reaction with a compound in which the amino protecting group R↑ in formula (IA) or (IB) is, for example, an optionally substituted glycyl group. Furthermore, if a compound with an aliphatically bonded halogen atom, such as a possibly substituted α-bromoacetyl group, is reacted with a phosphite such as a tri-lower alkyl phosphite compound, the corresponding phosphono compound can be obtained. It will be done.

The resulting compounds of formula (IA) and (IB) are converted into the 1-oxide of the corresponding 3-cephem compound of formula (IA) by oxidation with a suitable oxidizing agent, such as the oxidizing agent described below. be able to. The resulting 1-oxide of the 3-cephem compound represented by formula (IA) is reduced to the corresponding 3-cephem compound represented by formula (IA) by reducing with a suitable reducing agent, such as the reducing agent described below. be able to. In these reactions, it must be ensured that the free functional groups are protected if necessary and subsequently released again if desired.

The resulting cephem compounds can be isomerized. In this way, the obtained 2-cephem compound represented by formula (IB) or the obtained mixture of 2- and 3-cephem compounds is added to the 2-cephem compound represented by formula (IB) or the 2- and 3-cephem compound obtained. By isomerization of a mixture consisting of cephem compounds (in which the free functional groups can, if appropriate, be temporarily protected as described above), the corresponding compounds of formula (IA) are prepared. It can be converted into a 3-cephem compound. In this reaction,
For example, it is possible to use a 2-cephem compound in which the formula -C(=0)-Rv group in formula (IB) is a free or protected carboxyl group, and even if a protected carboxyl group is generated during the reaction. good.

The 2-cephem compound of formula (IB) can be converted to isomerism by treating it with a basic agent and isolating the corresponding 3-cephem compound of formula (IA) from the equilibrium mixture of 2- and 3-cephem compounds. can be converted into

Suitable isomerizing agents are, for example, organic nitrogen-containing bases, such as aromatic tertiary heterocyclic bases and predominantly tertiary aliphatic, azaalicyclic or araliphatic bases such as N,N,N-)dimethylamine, N , N-dimethyl-N-ethylamine, N,N
, N-1-ethylamine or N,N-diisopropyl-N-ethylamine, N-lower alkyl-azacycloalkanes such as N-methyl-piperidine or -Benzyl-
N-phenyl lower alkyl-N,N-lower alkyl-amines, such as N,N-dimethylamine, or mixtures thereof; pyridine-type bases, such as mixtures of pyridine and triethylamine, e.g. pyridine and N,N,N- )
It is a mixture with lower alkylamine. Furthermore, inorganic or organic salts of bases, especially salts of moderately strong or strong bases with weak acids, such as alkali metal salts of lower alkane carboxylic acids such as sodium acetate, triethylammonium acetate or N-methylpiperidine acetate; Ammonium salts as well as other similar bases or mixtures of such basic agents can also be used.

The isomerization with a basic agent as described above can be carried out, for example, in the presence of a derivative of a carboxylic acid suitable for the formation of a mixed anhydride, such as an anhydride or a halide of the carboxylic acid, for example using pyridine in the presence of acetic anhydride. can. In this case, solvents such as aliphatic, cycloaliphatic or aromatic hydrocarbons or solvent mixtures which may be halogenated, such as chlorinated, in an anhydrous medium (in which case the reaction conditions used as reactants) under cooling or heating, preferably at about -30 to +100° C.
Operate under an inert gas such as nitrogen and/or in a sealed container.

The 3-cephem compound of the formula (IA) thus produced can be converted to the 3-cephem compound of the formula (IB), which may still be present, by methods known per se, for example by adsorption and/or crystallization.
can be separated from the 2-cephem compound.

Alternatively, a 2-cephem compound of formula (IB) may be oxidized at the 1-position, optionally the 1-oxide of a 3-cephem compound of formula (IA) may be separated from the isomer mixture thus formed, and the 1-oxide of a 3-cephem compound of formula (IA) Isomerization can also be carried out by reducing the 1-oxide of the corresponding 3-cephem compound represented by

Suitable oxidizing agents for the 1-position oxidation of this 2-cephem compound include inorganic peracids, organic peracids, or hydrogen peroxides that have a low reduction potential (+1.5 volts) and are composed of nonmetallic elements. Mention may be made of acids whose constant is at least 10-5, especially in mixtures with organic carboxylic acids.Suitable inorganic peracids are periodic and persulfuric acids.Organic peracids include the corresponding percarboxylic and persulfonic acids. It can be used as such or it can be formed in the reaction using at least equivalent amounts of hydrogen peroxide and a carboxylic acid. Suitable peracids are, for example, peracid, peracetic acid, pertrifluoroacetic acid, permaleic acid, perbenzoic acid, monoperphthalic acid or p-toluene persulfonic acid.

Furthermore, the oxidation can be carried out with hydrogen peroxide containing a sufficient amount of an acid having a dissociation constant of at least 10@-5 as a catalyst. It is also possible to use this acid in lower concentrations, for example 1-2% or less, but in higher amounts. The effectiveness of this mixture depends primarily on the strength of the acid. Suitable mixtures are, for example, mixtures of hydrogen peroxide and acetic acid, perchloric acid or trifluoroacetic acid.

The above oxidation can be carried out in the presence of a suitable catalyst.
For example, oxidation with percarboxylic acids can be mediated by the presence of an acid with a dissociation constant of at least 10@-5, the effectiveness of which depends on its strength. Acids suitable as catalysts are, for example, acetic acid, perchloric acid and trifluoroacetic acid. Generally a small (equimolar amount of oxidizing agent, preferably about 10
~b Use a small excess amount. This oxidation is carried out under mild conditions, e.g. about -50 to +100°C, preferably about -10 to +40°C.
Perform at 0°C.

In addition, ozone is used to oxidize the 2-cephem compound to the 1-oxide of the corresponding 3-cephem compound, as well as an organic hypohalite compound such as a lower alkyl-hypochloride such as t-butylhypochloride. in an inert solvent, such as a hydrocarbon which may be halogenated, such as methylene chloride, and about -
10 to +30°C), periodic salt compounds, such as periodic salts of alkali metals, such as potassium periodine, preferably at a pH of about 6 and at about -10 to +30°C in an aqueous medium. (used), iodobenzene dichloride (which is dissolved in an aqueous medium, preferably in the presence of an organic base such as pyridine and cooled, for example from about -20 to 0
°C) or other oxidizing agents suitable for converting thio groups to sulfoxide groups.

The 1-oxide of the 3-cephem compound of formula (IA) thus obtained, especially R? , l and R2 have the preferred meanings given above, in which the group R? , R1) and/or R2 can be changed, split or introduced into other groups within the scope of their definition. In addition, the isomer α-
The mixture of 1-oxide and β-1-oxide can be separated, for example by chromatography.

The 1-oxide of the 3-cephem compound of formula (IA) can be reduced by methods known per se, if necessary in the presence of an activating agent, by treatment with a reducing agent. Examples of reducing agents include: Catalytically activated hydrogen (using a noble metal catalyst such as palladium, platinum or rhodium, optionally supported on a suitable support such as charcoal or barium sulfate), reducing soot, iron, copper or manganese cations [in the form of the corresponding inorganic or organic compounds or complexes, e.g. as tin(II) chloride, butide, acetate or formate;
) as chlorides, sulphates, oxalates or succinates; as chlorides, benzoates or oxides of copper(I); or as chlorides, sulphates, acetates or oxides of manganese(n); or as a complex with ethylenediaminetetraacetic acid or nidololtriacetic acid], the reducing dithionite anion, iodine anion or iron(n) cyanide anion (using their corresponding inorganic or organic salts) alkali metal salts such as sodium dithionite, potassium dithionite, sodium iodide, potassium iodide, sodium ferrocyanide or potassium ferrocyanide or corresponding acids such as hydroiodic acid. ), reducing trivalent inorganic or organophosphorus compounds such as phosphines, as well as esters of phosphinic acid, phosphonic acid or diphosphorous acid,
Amides and halides, as well as phosphorus and sulfur compounds corresponding to these phosphorus and oxygen compounds (the organic groups of these compounds are mainly aliphatic, aromatic or araliphatic groups, such as lower alkyl groups that may be substituted, phenyl groups or phenyl lower alkyl group), such as triphenylphosphine, tri-n-butylphosphine, methyl diphenylphosphinate, diphenylchlorophosphine, phenyldichlorophosphine, benzene phosphonite dimethyl ester, butane methyl phosphonite, phosphorous acid Triphenyl ester, phosphorous acid trimethyl ester, phosphorus trichloride, phosphorus tribromide, and other reducing halogenosilane compounds (these have at least one hydrogen atom bonded to a silicon atom and also contain a chlorine atom, a bromine atom, etc.) or halogen atoms such as iodine atoms, organic groups such as aliphatic or aromatic groups such as optionally substituted lower alkyl groups or phenyl groups), such as chlorosilane, bromosilane, di- or trichloro silanes, di- or tolylbromosilanes, diphenylchlorosilanes, dimethylchlorosilanes, and other reducing quaternary chlormethylene-iminium salts, especially the corresponding chlorides or bromides, substituted by lene or lower alkyl groups. ), for example N-chlormethylene-N, N-diethyliminium chloride or N-chlormethylene-pyrrolidinium chloride, and cobalt chloride (n
complex metal hydrides such as sodium hydride in the presence of a suitable activating agent such as borane, as well as borane dichloride.

For use with the above-mentioned reducing agents which themselves are non-Lewis acidic, i.e. primarily with dithionite reducing agents, iodine reducing agents, iron(II) cyanide reducing agents or halogen-free trivalent phosphorus reducing agents. Activators which can be added to or in the case of catalytic reduction include, in particular, /'t halides of organic carboxylic acids and sulfonic acids, as well as sulfur, lido, chloride, whose secondary hydrolysis constant is the same as or higher than that of benzoyl chloride. acetic acid chloride, pivalic acid chloride, 4-methoxybenzoic acid chloride, 4-cyanobenzoic acid chloride, p-)luenesulfonic acid chloride,
Methanesulfonyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, phenyldichlorophosphine, benzenephosphonite chloride, dimethylchlorosilane or trichlorosilane, as well as a suitable acid such as trifluoroacetic anhydride. Anhydrides, or cyclic sultones such as ethanesultone, 1,3-propanesultone, 1,4-butanesultone or 1. 3-hexane sultone is mentioned.

Preferably, the above reduction reaction is carried out in a solvent or a mixture thereof; the choice of solvent depends primarily on the solubility of the raw materials and the type of reducing agent. Thus, for example, catalytic reduction uses lower alkane carboxylic acids or their esters, such as acetic acid and ethyl acetate, and chemical reducing agents use aliphatic, cycloaliphatic, aromatic, which may be substituted, such as halogenated or nitrated. or araliphatic hydrocarbons such as benzene, methylene chloride, chloroform or nitromethane, suitable acid derivatives such as lower alkanecarboxylic acid esters such as ethyl acetate, lower alkanonitriles such as acetonitrile, amides of inorganic or organic acids such as dimethylformamide or Hexamethyl phosphoric acid amide, ethers such as diethyl ether, tetrahydrofuran or dioxane, ketones such as acetone or sulfones, especially aliphatic sulfones such as dimethyl sulfone or tetramethylene sulfone, are used; these solvents are preferably free from water. The reaction is generally carried out at temperatures of about -20 DEG to +100 DEG C., but the reaction can be carried out at lower temperatures if very reactive activators are used.

In the 3-cephem compound represented by the formula (rA) thus obtained, the group R? , R1) and/or RZ are other groups 1. R1? Or it can be changed to R2.

Salts of compounds represented by formulas (IA) and (IB) are produced by methods known per se.

That is, salts of such compounds with acidic groups can be prepared by treatment with metal compounds such as alkali metal salts of the appropriate carboxylic acids, such as the sodium salt of α-ethylcaproic acid, or with ammonia or with suitable organic amines. can be generated. For this purpose, it is preferred to use the salt-forming agent in stoichiometric or slightly excess amounts. In addition, formulas (IA) and (IB) having a basic group
The acid addition salts of the compounds of formulas (IA) and (IB) can be prepared by conventional methods, for example, the internal salts of the compounds of formulas (IA) and (IB) with acids or salts can be prepared by, for example, weakly Produced by neutralization with base or treatment with liquid ion exchange agents. Salts of the 1-oxides of compounds of formula (IA) with salt-forming groups can be made by similar methods.

The salt can be converted into the free compound by conventional methods. For example, metal and ammonium salts can be converted to the free compounds by treatment with a suitable acid, and acid addition salts can be converted into the free compounds, for example by treatment with a suitable basic agent.

The isomer mixture obtained can be separated by methods known per se, for example by fractional crystallization of the mixture of diastereoisomers, adsorption chromatography (column chromatography or thin layer chromatography) or other suitable separation methods. Can be separated into isomers. The obtained racemate is treated by a conventional method, if appropriate, after introducing a suitable salt-forming group, for example, to form a diastereomer salt mixture with an optically active salt-forming agent, and this mixture is divided into each diastereomer. by separating into diastereomeric salts and converting the thus separated diastereomeric salts into the free compounds, or by fractional crystallization from an optically active solvent.
Can be divided into individual enantiomers.

The present invention also includes embodiments in which compounds produced as intermediates in the process are used as raw materials and the remaining process steps are carried out or the process is interrupted at any stage. Furthermore, the raw materials can be used in the form of derivatives or generated during the reaction.

Note that the raw materials and reaction conditions are preferably selected so as to obtain the compounds listed above as particularly preferred.

In the starting material represented by formula (n), the group to be removed Y
is preferably a group represented by the formula -3ow Rs (in which R1 has the meaning given above, but is particularly the group given as preferred above).

Compared to the prior art, the process according to the invention starts from inexpensive and particularly readily available starting materials, such as 1-oxide, and the intermediate products required in the process according to the invention are produced in high yields. It is particularly excellent in that it is manufactured in In particular, the method of the present invention also provides a method for converting the compound represented by formula (1) in which R1 is a hydrogen atom into a hydroxyl-protecting group R
3 can be manufactured directly without splitting.

The starting material represented by formula (n) used in the present invention is:
For example, it can be created according to the following chemical equation.

Below margin 01 near, 0, l
Takashi Takashi
The starting compounds of formula (IV) are known and can be prepared by known methods.

Compounds of formula (Va) are also known and made by the method described in Dutch Patent No. 72108671.

Formulas (■a), (■b), (■C), (IIa), (Ir
b) and (Inc) (in these formulas, R?, l, Re and Y have the meanings given in formula (II) above), and processes for their preparation are also contemplated for the purpose of the present invention. be.

The compound represented by formula (vb) can be obtained by reacting the compound represented by formula (IV) with a sulfinic acid represented by formula Hsog-Rs or a sulfonyl cyanide represented by formula N=c-soz-R5. I can do it. The compound represented by the formula (rVc) has the formula HS Sow
It can be obtained from the compound represented by formula (IV) by reaction with thiosulfonic acid represented by Rs. The reaction is carried out in an inert solvent or solvent mixture, for example with an optionally halogenated, e.g. chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. pentane, hexane,
Cyclohexane, benzene, toluene, methylene chloride,
Chloroform or chlorobenzene, aliphatic, cycloaliphatic or aromatic alcohols such as lower alkanols such as methanol or ethanol, cyclohexanol or phenol, polyhydroxy compounds such as polyhydroxyalkanes such as dihydroxy-lower alkanes such as ethylene glycol or propylene glycol, lower ketones For example, it is carried out in acetone or methyl ethyl ketone, ether-like solvents such as diethyl ether, dioxane or tetrahydrofuran, lower carboxylic amides such as dimethylformamide or dimethyl acetamide, lower alkyl sulfoxides such as dimethyl sulfoxide, or mixtures thereof.

The reaction is carried out at room temperature or preferably at an elevated temperature, eg the boiling point of the solvent used, optionally under an inert gas, eg nitrogen gas.

The reaction with the sulfonyl cyanide represented by N=c SOx Rs can be accelerated by adding a compound that supplies a halogen anion. Suitable compounds supplying halogen anions are, for example, quaternary ammonium halides, especially chlorides and bromides, such as tetra-lower alkyl-ammonium halides (optionally substituted in the lower alkyl group, e.g. aryl (may be mono- or polysubstituted by groups such as phenyl groups), such as tetraethylammonium chloride or bromide,
or benzyltriethylammonium chloride or bromide. The compound providing the halogen anion is added in an amount of about 1 to 50 mole %, preferably about 2 to 5 mole %.

Compounds represented by formulas (Vb) and (Vc) also have
A compound represented by formula (IV) and 2M"(-50□-
R2), a heavy metal salt of sulfinic acid or 2M'' (-S-5ow-Rs)n (where M is a heavy metal cation and n represents the valence of this cation)
It can also be produced by reaction with a polymeric metal salt of thiosulfonic acid represented by: Suitable heavy metal salts of sulfinic or thiosulfonic acids have the formula M''(S
As the heavy metal cation M'', which has a larger solubility product in the reaction medium used than the heavy metal compound represented by copper, mercury,
It is a monovalent or divalent cation of silver and tin, and Cu
+ + and Ag'' are particularly preferred.

The heavy metal salts of sulfinic acids or heavy metal salts of thiosulfonic acids can be used in that form and in situ during the reaction process to form sulfinic acids of the formula 5R (hRs or 2〇-5-SO!-R, thiosulfonic acids or their soluble salts, e.g. alkali metal salts such as sodium salts, and heavy metal salts (the solubility product of which is greater than the heavy metal salts of sulfinic acids or heavy metal salts of thiosulfonic acids formed), e.g. nitric acid, acetic acid. or heavy metal salts of sulfuric acid, such as silver nitrate, mercury(If)-diacetic acid or copper(II) sulfate, or soluble chlorides such as tin(II chloride).
・It can also be produced from dihydrate salt.

A compound represented by formula (Va) and a heavy metal salt of sulfinic acid represented by formula M"(-5(h-Rs)- or a heavy metal salt of thiosulfonic acid represented by formula P.(-S-5Oz-Rs)- The reaction with the salt can be carried out in an inert organic solvent, in water or in a solvent mixture consisting of water and a water-miscible solvent. Inert organic solvents include, for example, aliphatic, cycloaliphatic or aromatic solvents. hydrocarbons such as pentane, hexane, cyclohexane, benzene, toluene or xylene, aliphatic, cycloaliphatic or aromatic alcohols such as lower alkanols such as methanol or ethanol, cyclohexanol or phenol,
Polyhydroxy compounds such as polyhydroxyalkanes such as dihydroxy-lower alkanes such as ethylene glycol or propylene glycol, carboxylic acid esters such as carboxylic acid lower alkyl esters such as ethyl acetate, lower ketones such as acetone or methyl ethyl ketone, ether-like solvents such as dioxane or tetrahydrofuran, or Ethers such as dimethoxyethane, lower carboxylic acid amides such as dimethylformamide or lower alkyl nitriles such as acetonitrile, lower alkyl sulfoxides such as dimethyl sulfoxide. The reaction usually proceeds more rapidly in water or especially in a mixture of water and said solvent (including emulsions) than in organic solvents alone.

The reaction temperature is usually room temperature, but can be lower to slow the reaction, higher to accelerate the reaction, i.e. up to the boiling point of the solvent used, and the reaction can be carried out at normal pressure or It can be done with high pressure.

In the resulting compound represented by formula (V), the group R?
, Rl Mataha R+, and others (7) R? ,RY*
ta can be changed to R8, and in that case a similar reaction can be used.

In the second and third or 2a steps, converting the compound of formula (V) into a compound of formula (■) by oxidative degradation from the methylene group to the oxo group, converting the methylene group of the compound of formula In order to perform oxidative splitting while forming an oxo group, it is preferable to perform treatment with ozone to generate an ozone compound. In this case, ozone is generally used as a solvent such as lower alkanols such as alcohols such as methanol or ethanol, lower alkanones such as ketones such as acetone, aliphatic, cycloaliphatic or aromatic hydrocarbons which may be halogenated, such as chlorinated It is used in a solvent mixture, including a halogenated lower alkane such as methylene or carbon tetrachloride, or an aqueous mixture and under cooling or slight heating, e.g., from about -90 to +40°C.

The oscinide of the formula (VIa) thus obtained as an intermediate, optionally without isolation, and analogously to the conversion of the compound of the formula (Va) into the compounds of the formulas (Vb) and (Vc). , 2M" (-SORs)- or 2M" (-
5SOz Rs), by reaction with a heavy metal salt of thiosulfonic acid represented by formula (■b) or (Vlc)
It can be converted into a compound represented by

A compound represented by formula (■) can be obtained by subjecting the oscinide represented by formula (V) to reductive splitting in the third step. In this case, catalytically activated hydrogen, e.g. hydrogen in the presence of a heavy metal hydrogenation catalyst such as a nickel or palladium catalyst (preferably supported on a suitable support such as calcium carbonate or charcoal), or a chemical zinc in the presence of a hydrogen donor such as an acid such as acetic acid or an alcohol such as a lower alkanol;
Reducing inorganic salts such as hydrogen donors such as alkali metal iodides such as sodium iodide or formic acid in the presence of acids such as acetic acid, reducing sulfide compounds such as dimethyl sulfide, etc. Reducing organophosphorus compounds such as di-lower alkyl sulfides, phosphines (which may carry optionally substituted aliphatic or aromatic hydrocarbon groups) such as tri-n-butylphosphine; tri-lower alkyl phosphines such as tri-lower alkyl phosphines or triphenylphosphine; phosphites having aliphatic hydrocarbon groups as substituents which may be further substituted; e.g. (generally in the form of the corresponding alcohol addition compound) or phosphite triamides with optionally substituted aliphatic hydrocarbon groups as substituents, such as hexamethyl phosphite triamide; Alkyl phosphite triamides (which are preferably in the form of methanol adducts) or tetracyanoethylene can be used.

The generally unisolated oscinides mentioned above are cleaved under the conditions customarily employed for their preparation, ie in the presence of a suitable solvent or solvent mixture and by cooling or slight heating.

The enol compound represented by formula (■) can also exist in a tautomeric keto form.

The enol compound represented by formula (■a) is represented by formula (Va)
Similarly to the conversion of the compound into the compound of formula (Vb) or (Vc), the heavy metal salt of sulfinic acid represented by 2M"(-5O□-R5)
) can be converted into a compound represented by formula (■b) or (■C) by reaction with a heavy metal salt of thiosulfonic acid represented by formula (■b) or (■C), respectively.

In the resulting compound represented by formula (■), the groups R, R1? Or R8 can be converted to another group R? in the same manner as the reaction suitable for the conversion of these groups in the compound represented by formula (iA) or (IB). , l or R8.

In the fourth step, the obtained enol compound represented by formula (■) is converted into a compound represented by formula (■) by esterification.

In order to prepare a sulfonic acid ester represented by the formula (■), a compound represented by the formula (■) is converted into a compound represented by the formula HOSow.
Esterification with a reactive functional derivative of sulfonic acid represented by Rs (where R3 has the same meaning as given to R2 in the group Y).

Within the meaning given to the group Rs, these two groups may be the same or different groups in the compound of formula (■).

The reactive functional derivatives of sulfonic acids of the formula HOSot Rs which are used include, for example, their reactive anhydrides, especially heat-of-mixture with hydrohalic acids, hydrates, e.g. their chlorides, e.g. mesyl chloride and p-). It is luenesulfonic acid chloride.

The esterification is preferably carried out in the presence of an organic tertiary nitrogen base such as pyridine, triethylamine or ethyl-diisopropylamine, in a suitable inert solvent such as an aliphatic, cycloaliphatic or aromatic hydrocarbon such as hexane, cyclohexane, benzene or toluene, Halogenated aliphatic hydrocarbons such as methylene chloride, or ethers such as di-lower alkyl ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran or dioxane, or in a solvent mixture, and depending on the activity of the esterifying agent, cooled, at room temperature or slightly temperature, i.e. about -10~
It is carried out at a temperature of +50° C. and also optionally in a sealed container and/or under an inert gas, for example nitrogen gas.

The resulting sulfonic ester of formula (■) can be isolated or further reacted in the same reaction mixture.

The compound represented by formula (■a) can be obtained by converting a sulfinic acid represented by Heavy metal salt or 2M” (-S SOz Rs
) can be converted into a compound represented by formula (■b) or (■C) by reaction with a heavy metal salt of thiosulfonic acid represented by formula (■b) or (■C), respectively.

In the resulting compound represented by formula (■), the group R?
, RV Mataha R: cat, formula (I A) * Taha (
Analogously to the reactions suitable for the transformation of these groups in compounds of IB), other groups R=7, l or R8
can be changed to

In the fifth step, the resulting sulfonic acid ester represented by formula (■) is treated with a primary or secondary amine represented by formula can be converted into a compound that

Amination can be carried out using suitable inert solvents, such as aliphatic, cycloaliphatic or aromatic hydrocarbons such as hexane-cyclohexane, benzene or toluene, halogenated aliphatic hydrocarbons such as methylene chloride, or ethers such as di-lower alkyl ethers such as diethyl an ether, or a cyclic ether such as tetrahydrofuran or dioxane, or in a solvent mixture, and at a temperature of from about -10"C to 50"C, preferably from about 0"C to 20"C, depending on the group -OSO2Rs and the activity of the amine used. If necessary, the reaction is carried out in a sealed container and/or in an inert gas such as nitrogen gas.

In step 5a, a compound represented by formula (■) is
A salt of a primary or secondary amine of the formula H-N (R') (R14), such as a hydrochloric acid addition salt, in the presence of a tertiary base, such as pyridine, in a suitable solvent such as a lower alcohol such as absolute ethanol, about Compounds of formula (II) can also be prepared by treatment at temperatures of 20 to 100°C, preferably about 40 to 60°C.

The compound of formula (Ila) is a heavy metal salt of a sulfinic acid represented by 2M''(-5Ox Rs)11, similar to the conversion of a compound of formula (Va) to a compound of formula (Vb) or (Vc). Or 2M” (-5Sow Rs)
By reacting the thiosulfonic acid represented by the formula with a heavy metal salt, it can be converted into a compound represented by the formula (■b) or (■C), respectively.

In the resulting compound represented by formula (■), the group R1
? , R7 or R can now be converted to other groups R? in analogy to the reactions suitable for the transformation of these groups in compounds of formula (IA) or (IB). , l or R8.

The pharmacologically useful compounds according to the invention can be prepared, for example, by combining a pharmaceutically effective amount of the active substance with an inorganic or organic solid or liquid pharmaceutically useful carrier suitable for enteral or parenteral administration. Alternatively, it can be used in the production of pharmaceutical preparations containing the mixture. Therefore, this active substance is combined with diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine and lubricants such as silica, talc, stearates such as stearic acid or calcium stearate and/or polyethylene. Use tablets or gelatin capsules containing glycol. For tablets, binders such as magnesium aluminum silicate, starches such as corn starch, wheat starch, rice starch or arrowroot starch, gelatin, tragacanth,
Methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone and if desired disintegrants such as starch, agar, alginic acid or sodium alginate, or effervescent mixtures and (
or) adsorbents, dyes, flavors and sweeteners. Furthermore, these new pharmacologically active compounds can be used in the form of injectable, eg intravenous, formulations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, which can be prepared, for example, from a vacuum lyophilized formulation containing the active substance alone or together with a carrier such as mannitol, prior to administration. It is prepared in These pharmaceutical preparations can be sterilized and/or contain auxiliary agents such as preservatives, stabilizers/wetting agents and/or emulsifiers, solubilizers, salts to adjust the osmotic pressure and/or buffers. . These pharmaceutical preparations can be prepared by methods known per se, such as conventional mixing, granulation, tabletting,
prepared by the method of dissolving or vacuum freeze-drying and containing the active substance in an amount of about 0.1 to 100%, especially about 1 to 50% (up to 100% for vacuum freeze-dried products) and optionally other substances. It can contain pharmacologically valuable substances.

In this specification, organic groups indicated as lower have up to 7 carbon atoms, preferably up to 4 carbon atoms, unless otherwise specified. Acyl groups are those having up to 20 carbon atoms, preferably up to 12 and primarily up to 7 carbon atoms.

Next, the present invention will be explained in more detail with reference to Examples, in which the temperature unit is Celsius. The cephem compounds described in the examples below have the toniR-configuration at the 6- and 7-positions, and the azetidinone compounds described in the examples below have the R-configuration at the 3- and 4-positions.

Example 1 Isocrotonic acid corresponding to 2-(4-(p-)luenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-(1-pyrrolidyl)-croton Hp-nitrobenzyl ester A solution of 160 mg (0.23 mmol) of a mixture consisting of
Heat with silica gel, toluene/ethyl acetate 1:1) until undetectable. Remove the heating bath and add 7β-phenoxyacetamide-3-pyrrolidino-cephem-4-
p-)luenesulfonic acid (approximately 0.23 mmol) was added to the reaction mixture containing carboxylic acid p-nitrobenzyl ester.
And water 0.2mJ! and stir the mixture for an additional 2 hours at room temperature. The reaction mixture is diluted with benzene, washed with water, dried over sodium sulphate and evaporated in vacuo. The residue is triturated with diethyl ether at 0°C to give blue-yellow 7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester.

Infrared absorption spectrum (methylene chloride): 2.9
5 i3.3; 5.6; 5.75; (sh)
; 5.9 ; 5.95 (sh) ; 6.55
Characteristic hand at i 7.45, 8.15 and 8.3μ, NMR spectrum (deuterochloroform); δp
pm; 3.4 (2H, 2, J = 17Hz)
; 4.57 (2H, s); 5.06 (IH, d; J
= 5Hz); 5.35 (2H, q, J = 14H
z) ; 5.7 (L H, dd.

J=5.10Hz); 6.8~8.4 (10H
, c) and 11.4 (L H, br, s,).

The starting material can be produced as follows.

(a) 6-funinoxyacetamidopenicillanic acid 1β-
A solution of 36.6 g (0.1 mol) of oxide, 11.1 ml (0.11 mol) of triethylamine and 23.8 g (0.11 mol) of p-nitrohensylbromide in 200 ml of dimethylformamide was prepared. Stir at room temperature for 4 hours under nitrogen atmosphere. The reaction solution is then poured into ice water 1.5β, the precipitate is filtered, dried and recrystallized twice from ethyl acetate/methylene chloride. Colorless crystalline 6-phethoxyacetamidopenicillanic acid p-nitrobenzyl ester 1β-oxide is 179-180
Melts at °C.

(b) 5.01 g (10
mmol) and 1.67 g of 2-mercaptobenzthiazole
A solution of (10 mmol) in 110 i of dry toluene is boiled under reflux for 4 hours under a nitrogen atmosphere. This solution was concentrated by distillation to about 25 ml and the ether was concentrated to about 10 ml.
Dilute with 0 wll. Recrystallization of the separated product from methylene chloride/ether yields p-nitro 2-(4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyric acid. A benzyl ester is obtained, with a melting point of 138-141'C.

(C) 2-(4-(benzthiazol-2-yl-dithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyric acid p-nitrobenzyl varnish 3.25 g (5.0 mmol) ) in acetone/water 9:1 (v/v) 200 mj! Add 1.06 g of finely powdered silver nitrate to the dissolved solution. Immediately after that, add 890 mj of sodium p-toluenesulfinate (
A solution of 5 mmol) in 100 mf of the same solvent mixture as above is added over 1.0 min. A blue-yellow precipitate forms immediately. After stirring for 1 hour at room temperature, the mixture is filtered and Celite is added.

The filtrate is diluted with water and extracted twice with ether. The combined ethereal extracts were dried over sodium sulfate and concentrated to give a blue-yellow solid, 2-(4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl)-3. -methylenebutyric acid p-nitropencyl ester is obtained.

Thin layer chromatography (silica gel, toluene/acetic acid x-
F-R2: 1): Rf value = 0.24; Infrared absorption spectrum (in CH2Cf Z): 3.90
．． 5゜56.5.70.5.87.6, 23.6.53
．． 6.66.7.40.7.50.8.10.8.72
．． Characteristic bands at 9.25 and 10.95μ.

This product can be used in the next reaction without further purification.

The same compound as above can also be prepared by the following method.

(c-i) Acetone/water 9:1 (v/v) 20
0ml! 2- (4-(benzthiazole-2-
In a solution of 3.25 g (5.0 mmol) of p-nitrobenzyl 3-methylenebutyrate, p.
-) Luensulfine am 1.58 g (1.2 eq.) is added dropwise over a period of 10 minutes. This suspension was mixed at room temperature for 1
Stir for a period of time, filter and proceed as described in Example 1 (C). 2-[4=(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl-3-methylenebutyric acid p-nitrobenzyl ester is obtained quantitatively.

When combined, a colorless precipitate is obtained. The product is dried in vacuo for 24 hours.

(c-ii) 2-(4-(benzthiazol-2-yldithio)-
3-phenoxyacetamide-2-oxoazetidine-
1-yl]-3-methylenebutyric acid p-nitrohensyl ester and copper p-toluenesulfinate (I
[) 1.87g (2 equivalents) and Karademo 2- (
4-(p-Toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3
-methylenebutyric acid p-nitrohensyl ester can be obtained quantitatively.

Di-p-toluenesulfinic acid 1m (11) Obtained by combining copper halosulfate and sodium p-toluenesulfinate (2 equivalents) in water. After filtration, the salt is dried in vacuo at 60°C for 1z hours.

(c-iii) In a similar manner to (c-i) of Example 1,
2-[4-(Benzthiazol-2-yldithio)-3
-Phenoxyacetamide-2-oxoazetidine-1
-yl2-3-methylenebutyric acid p-nitrobenzyl ester 130+wg and p-)tin luenesulfinate (I
I) 85 mg (2 equivalents) and 2- (4-
(p-)Luensulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl-3-methylenebutyric acid p-nitrobenzyl ester can be obtained.

Tin di-p-1-luenesulfinate (Il) is tin chloride (
Obtained by reacting n) (2H20) with sodium p-toluenesulfinate in water.

After filtering and washing with water, the salt was stored in vacuum for about 12 hours.
Dry at 0-60°C.

(c-iv) Similar to (c-i) of Example 1, 2-C4-(
Benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl23
-methylenebutyric acid p-nitrobenzyl ester 130n+
g and mercury(II) di-p-toluenesulfinate 10
2 mg (2 equivalents) of 2-(4-(p-toluenesulfonylthio)=3-phenoxyacetamido-2-oxoazetidin-1-yl-3-methylenebutyric acid p-nitrobenzyl ester) can be obtained even from 2 mg (2 equivalents).

p-)Toluenesulfinic acid water SM (II) c'; Obtained by reacting vinegar t'l water SR (■) and sodium p-toluenesulfinate in water. After filtering and washing with water, the salt is dried in vacuo at 50-60° C. for about 12 hours.

(c-v) 10 mj of 1,2-dimethoxyethane (or dioxane)! 6-Funinoxyacetamidobenicillanic acid p-nitrohendylaceteno'1β-oxide 5
A solution of 17 mg (1,02 mmol) and 187 mg (1,2 mmol) of p-toluenesulfinic acid was heated under reflux for 4.5 hours in the presence of 3.5 g of 3A molecular sieves and under a nitrogen atmosphere, and then Then, 308 mg (1,98 mmol) of p-1-luenesulfinic acid dissolved in 2 tails of 1,2-dimethoxyethane was further added in 5 portions at 45 minute intervals. After 4.5 hours, the reaction mixture was reduced to 5%
Pour into 100 mji of strong aqueous sodium bicarbonate solution and extract with ethyl acetate. The combined organic phases are washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated. Chromatography of the residue with silica gel thin layer chromatography (toluene/ethyl acetate 2:1) yields 2-[4-p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3- Methylene butyric acid p-nitrohensyl ester is obtained.

(c-vi) peroxide-free dry dioxane 2 m/
250 mg of 6-funinoxyacetamidopenicillanic acid p-nitrobenzyl ester 1β-oxide
, 5 mmol) and p-toluenesulfonyl cyanide 110
A mixture of 5 mg (0.022 mmol) of benzyl-toluethylammonium chloride and 5 mg (0.022 mmol) of benzyl-toluethylammonium chloride is stirred at 110 DEG C. for 4.5 hours under an argon atmosphere. The solvent is removed under vacuum and the residual yellow oil is chromatographed on acid-washed silica gel. 30 in toluene
Elution with % ethyl acetate yields 2-(4-(p-toluenesulfonylthio)-3-phenoxyacetamide-2-
Oxoazetidin-1-yl)-3-methylene e1M6
Rp-nitrobenzyl ester is obtained.

(c-vi) p- in 1 ml of pure dioxane
Toluenesulfonylanide L10+++g (0,61
mmol) and tetraethylammonium bromide 4.5
mg (0.021 mmol) is stirred for 30 minutes at 110° C. under an argon atmosphere. Then dioxane l
250 mg of 6-funinoxyacetamidopenicillanic acid p-nitrobenzyl ester 1β-oxide in ll16
(0.5 mmol) is added and the resulting solution is stirred at 110° C. for 4 hours under an argon atmosphere. The solvent is removed in vacuo, the crude product is dissolved in ethyl acetate and the solution is washed with water and saturated aqueous sodium chloride solution. The organic phase is dried with magnesium sulfate and the solvent is removed in vacuo to give the crude 2-(4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylenebutyric acid p -Nitrobenzyl ester is obtained.

(d) 2-(4-(
p-Toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl-3-methylenebutyric acid p-nitrobenzyl ester 1.92 g
, 0 mmol) of ozone is passed through the solution at -78° C. for 33 minutes. Immediately thereafter, excess ozone is removed with a stream of nitrogen (-78°C, 15 min), dimethyl sulfide 2.2n+j! (10 eq.) and warm the solution to room temperature. After standing for 5 hours, the solvent is evaporated in vacuo and the remaining colorless oil is taken up in 100 ml of benzene.

The benzene solution was added to 501 Il of a saturated sodium chloride solution.
Wash three times, dry over magnesium sulfate, and concentrate to dryness in vacuo. Recrystallizing the residue from toluene yields 2-[4-(p-toluenesulfonylthio)-3-
Phenoxyacetamide-2-oxoazetidine-1-
]-3-hydroxycrotonic acid p-nitrobenzyl ester is obtained. The melting point is 159-160°C.

(d-i) Crude 2-( obtained in (c-vi) of Example 1
4-(p-)luenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl23
- Methylenebutyric acid p-nitrobenzyl ester is dissolved in 20 mA of methyl acetate and ozonated at -70°C. Ozonation is carried out until no starting material is detected by thin layer chromatography. A stream of nitrogen is then passed through the solution and the solution is warmed to 0-5°C. A solution of 300++ g of sodium bisulfite in 5 ml of water is added and the mixture is stirred for about 5 minutes until no more ocinide can be detected on the potassium iodide/starch paper. The mixture is diluted with ethyl acetate, the aqueous phase is separated, the organic phase is washed with water, dried over magnesium sulphate and freed from the solvent in vacuo. The crude product was dissolved in 3m7i of methylene chloride and 15aj! of toluene. Add. Filter the precipitate and evaporate the filtrate in vacuo. Recrystallization of the residue from methanol yields 2-C4-(p-toluenesulfonylthio)-3-phenoxyacetamide-2-
Oxyazetidin-1-yl-3-hydroxycrotonic acid p-nitrobenzyl ester is obtained. The melting point is 1
The temperature is 59-160°C.

tel 2-(4-(p-
Toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl2-3-hydroxycrotonic acid p-nitrobenzyl ester 641 mg
A solution of (1 mmol) was cooled to -10°C in an acetone/ice bath and 285+wg of p-toluenesulfonyl chloride was added.
(1.5 mmol) is added and the mixture is stirred under a nitrogen atmosphere for about 5 hours until no starting material can be detected anymore by thin layer chromatography (silica gel: toluene/ethyl acetate 1:1). Add 50 mj of benzene to the reaction solution! diluted with water, washed with water, water-cooled 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. Blue-yellow 2-(4-(p-)luenesulfonylthio)-3-phenoxyacetamide-2-
Oxoazetidin-1-yl)-3-p-toluenesulfonyloxy-crotonic acid p-nitrobenzyl ester is obtained, which is sufficiently pure for further processing.

Infrared absorption spectrum (methylene chloride): Characteristic bands are 5.6; 5, 8 G 5.9; 6.55 i 7.
45 i 8.55 and 8.75μ; NMR spectrum (deuterochloroform): δppn+: 2
．． 4 (6H, s); 2.45 (3H, s)
;4.4 (2H, q, J=15Hz);5.3
(2H.

s); 5.3 (I H, dd, J = 5.
10Hz); 5.8 (IHd; J=5Hz) and 6.6-8.4 (18H,c).

(fl 2-[ in 2 m7 of dry tetrahydrofuran!
4-<p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl)-3
-p-) A solution of 80 mg (0.1 mmol) of luenesulfonyloxy-crotonic acid p-nitrobenzyl ester and 0.0175 ml (0.21 mmol) of pyrrolidine was heated under a nitrogen atmosphere for about 1 hour until the starting material was thin layer chromatographed. (Silica gel: toluene/ethyl acetate 1:
Stir until it can no longer be detected in step 1). The reaction mixture is diluted with 10 ml of benzene, washed twice with 5 ml of saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. Thin layer chromatography of the residue on silica gel in 1:1 toluene/ethyl acetate yields colorless 2-
(4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl)
A mixture is obtained consisting of -3-(1-pyrrolidyl)-crotonic acid p-nitrobenzyl ester and its corresponding isocrotonic ester. Infrared absorption spectrum (
methylene chloride): 5.6 i 5.95; 6
．． Characteristic bands at 55, 7.45 and 8.75μ;
NMR spectrum (deuterochloroform): δp
pm: 1.6-2.2 and 3.0-3.8 (
8H, c); 2.0B and 2.27 (3H,
s); 2°38 and 2.39 (3H, s)
; 4.42 (2H, q.

J=15Hz); 4.8-6.0 (4H, c) and 6.6-8.4 (14H, c).

The same compound can also be prepared as follows.

(fi) 2-C4- in dry methylene chloride S tel
(p-Toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl2-3-hydroxycrotonic acid p-nitrobenzyl ester 256
A solution of 0.4 mmol of triethylamine cooled to -10 °C was added with 0.1115 ml of triethylamine under a nitrogen atmosphere.
(0.8 mmol) and then 0.8 mmol of methanesulfonyl chloride.
062mj? (0.8 mmol). After 1 hour, 0.104+++j of freshly distilled pyrrolidine!
(1.24 mmol) is added and the mixture is stirred for a further 2 hours at -10°C. Add 20 mf of methylene chloride to the reaction solution.
Wash 3 times with 15 ml of water, dry over sodium sulfate and evaporate in vacuo. The residue was triturated with diethyl ether to give a blue-yellow 2-(4-(p-)luenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-(1-pyrrolidyl)-crotonic acid p. A mixture consisting of -nitrobenzyl ester and its corresponding isocrotonic acid p-nitrobenzyl ester is obtained, which can be used as such in the next step. (IR spectrum two characteristic bands 5.
6.5.95.6.55.7.45 and 8.75μ).

The methanesulfonic acid ester formed as an intermediate product can be isolated or prepared as follows.

(f-ii) 2-(4-(
p-1ruenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxycrotonic acid p-nitrohensyl ester 128n
A solution of +g (0.2 mmol) cooled to -10°C was added with 0.042 ml (0.3 mmol) of triethylamine under a nitrogen atmosphere.
mmol) and methanesulfonyl chloride 0.017mf
(0.22 mmol) and the mixture is stirred for 30 minutes at the same temperature. The reaction mixture was diluted with methylene chloride 1
Dilute with 0 ml of saturated aqueous sodium chloride solution 10I11
7! Wash three times with water, dry over sodium sulfate and evaporate in vacuo. 2-(4-(p-)luenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl-3-methanesulfonyloxy-crotonic acid p-nitrobenzyl ester Remains containing tonic acid ester are unstable. Although it cannot be purified by chromatography, it is sufficiently pure to be used in the following steps, such as (fi) in Example 1.

Infrared absorption spectrum (methylene chloride): 5,55 i
5.7; 5.8; 6.55; 7.4
5 i 8.55 and 8,75μ characteristic band,
NMR spectrum (deuterochloroform: δI)
)III 7 2.37 (3 H.s);2
, 39 and 2.5 (3 H, s); 3.1
2 and 3.27 ( 3 H, s); 4.39 and 4.41 (2 H, s); 5.2 (I H
dd, J -5.10Hz); 5.25 (2
H, s); 5, 88 and 5.95 (IH,
d. J = 5Hz) and 6,6~8.4 (1 5
H, c).

Example 2 2-(4-(p-1-luenesulfonylthio)
-3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-(N-methylcyclohexylamino)-crotonic acid p-nitrobenzyl ester and the corresponding isocrotonic ester 148 mg
(0.2 mmol) in 3 ml of dry acetonitrile
The solution dissolved in
Heat until the starting material is no longer detectable by thin layer chromatography (silica gel, toluene/ethyl acetate 1:1). The heating bath was removed, and 38 mg (0.2 mmol) of p-)luenesulfonic acid and about 0.2 mj of water were added to the reaction mixture.
! and stir the mixture for an additional 2 hours at room temperature. The reaction mixture is diluted with benzene, washed with water, dried over sodium sulphate and evaporated in vacuo.

The residue was triturated with diethyl ether at 0°C to give a blue-yellow color 7.
β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester is obtained.

Infrared absorption spectrum (methylene chloride): 2.95; 3
, 3; 5.6; 5.75 (sh);
5.9; 5.95 (sh); 6.55.

7, 45; characteristic band i at 8.15 and 8.3μ
NMR spectrum (deuterochloroform); δp
pm: 3, 4 (zH. q. J= 1 7Hz
) ; 4.57 (2H,s) ; 5,06 (
IH, d, J=5Hz); 5.35
(2H, d.

J=14Hz); 5.7 (IH, dd, J=5.10
Hz); 6.8-8.4 (10H, c
) and 11.4 (I Hl br+ s.).

The starting material can be produced as follows.

diacetamido-2-oxoazetidin-1-yl)-
N-methyl-
N-cyclohexylamine 0.056 mj2 (0,42
mmol) is added and the mixture is stirred for a further approximately 2 hours at room temperature until starting material can no longer be detected by thin layer chromatography (silica gel: toluene/ethyl acetate 1:l). The reaction solution is diluted with benzene, washed several times with water, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on 10 g of acid-washed silica gel with benzene/ethyl acetate 3:1. 2- (4-(p-toluenesulfonylthio)-3-phenoxyacetamide-2-
A mixture of oxoazetidin-1-yl]-3-(N-methylcyclohexylamino)-croton 61 p-nitrobenzyl ester and its corresponding isocrotonic acid ester is obtained as a blue-yellow oil. Infrared absorption spectrum (methylene chloride): 2.95; 3.
Characteristic bands at 4; 5.6; 5.8; 6.55; 7.4 and 8.75μ.

Example 3 By the method described in Example 1, 2-(4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl-3-cyclohexylamino-crotonic acid p-nitrobenzyl ester and its equivalents) 7β-phenoxyacetamido-3-cyclohexylamino-cephem-4-carboxylic acid p-nitrobenzyl ester (
2- and 3-cephem derivative mixture) and from it 7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester.

The starting material can be produced as follows.

(a) 2-(4-(p-)luenesulfonylthio)-3- dissolved in 2 tsl of dry tetrahydrofuran.
Phenoxyacetamide-2-oxoazetidine-1-
yl)-3-p-)luenesulfonyloxy-crotonic acid p-nitrobenzyl ester 160 mg (0.2
cyclohexylamine (mol) solution under nitrogen atmosphere
．． 0577 ml (0.5 mmol) and stirred the mixture for 1 hour at room temperature. The reaction solution is diluted with benzene, washed with water, dried over sodium sulfate and evaporated in vacuo. Consisting of 2-(4-(p-)luenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl-3-cyclohexylamino-crotonic acid p-nitro67dyl ester and its corresponding isocrotonic acid ester The residue containing the mixture can be used in the following step without purification. Infrared absorption spectrum (methylene chloride): 2.9; 3.4; 5, 6
i 5.9; 6.0; 6.25; 6.5
Characteristic hand i NMR spectrum (deuterochloroform): δppm: 1.8-2.0 (11H,c) at 5; 7.45; 8.10 and 8.75μ
2.02 (3H, s); 2.35 (3H, s
); 4.43 (2H, s); 4.95 (IHdd,
J~5.10Hz); 5.1? (2H,s
); 5.80 (IH, d, J=5Hz) and 6.
6-9.2 (15H, c).

Example 4 (a) 7β-phenoxyacetamide-3-hydroxy-3-cephem- in 10 mA' of dry chloroform
4-carboxylic acid p-nitrobenzyl ester 485mg
An ethereal diazomethane solution 3IIl (0.5 mol, 1.5 equivalents) is added to the solution, which has been dissolved and cooled to 0° C., over about 10 minutes. The blue-yellow solution was stirred for 1 hour at 0°C and flushed with nitrogen to remove excess diazomethane.
Concentrate in vacuo. If the residue is recrystallized from methylene chloride, 7β phenoxyacetamido-3-methoxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester is obtained. The melting point is 140.5-142°C.

The same compound can be obtained by phase transfer catalysis as follows.

(a-i) 7β-phenoxyacetamido-3-hydroxy-3 in 25+w6 carbon tetrachloride and 21 ml water
- A suspension of 4.85 g of cephem-4-carboxylic acid p-nitrobenzyl ester was continuously mixed with 3.0 g of potassium bicarbonate and 3.8 g of dimethyl sulfate while stirring vigorously at 20°C.
m/ and 1.93 g of tetrabutylammonium bromide. The mixture is stirred vigorously for 4 hours at 20°C.

Water 50II+7! After diluting with water, the mixture is extracted twice with 50 mf of methylene chloride. Evaporation of the extracts, drying over sulfate and recrystallization of the residue from methylene chloride/diethyl ether yields 7β-phenoxyacetamide-3-
Methoxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester is obtained. Melting point 140.5-142℃
.

tb+ methanol/tetrahydrofuran 1:1 2
7β-phenoxyacetamide-3- dissolved in ml
A solution of 250 mg (0.5 mmol) of methoxy-3-cephem-4-carvone 61p-nitrobenzyl ester was prepared in a 5% vanadium/charcoal mixture in the same solvent 21 (this mixture was prehydrogenated for 1 h at atmospheric pressure). ) and the reaction mixture is hydrogenated at room temperature and under atmospheric pressure for 3 hours.

Approximately 90% of the theoretical amount of hydrogen is taken up here.

The catalyst is filtered and the filtrate is evaporated to dryness in vacuo.

The residue is methylene chloride Iom/! Take it inside and add 10n+ of 50% sodium bicarbonate aqueous solution! ! Extract twice. The combined bicarbonate extracts are neutralized with dilute hydrochloric acid at Q"c and extracted three times with 10 mJ of methylene chloride. The organic phase is dried over sodium sulfate and the solvent is removed in vacuo. Chloroform/pentane. When crystallized from the residue, 7β-phenoxyacetamide-3-methoxy-3-cephem-4
- A carboxylic acid is obtained. The melting point is 173-174°C.

(C1 2.55 g (7 mmol) of 7β-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid in 1 m/m of anhydrous methylene chloride and N.

N-dimethylaniline 2.9 tail (22.4m
0.7 n of dimethyl-dichlorosilane in suspension with
+j2 (5.7 mmol) is added at 20° C. under nitrogen atmosphere and the mixture is stirred for 30 minutes at the same temperature. The clear solution thus obtained was cooled to -20°C and the solid 5
1.6 g (7.7 mmol) of phosphorus chloride are added and the mixture is stirred for 30 minutes. I chilled it in advance (-
20°C) N,N-dimethylaniline O09mj! (
7 mmol) n-butanol 0.9 ml! , at the same temperature for 2-3 minutes, then quickly add 10 m# of pre-chilled (-20°C) n-butanol, then let the mixture cool at -20°C for 20 minutes and cool. Stir for 10 minutes without stirring. Add 0.4 mA of water at about -10°C and store the mixture in a water bath (0°C) for about 100 mA.
After stirring for a minute, 11 ml of dioxane was added, and after stirring for a further 10 minutes at 0°C, about 4.5 mA of tri-n-butylamine (the sample diluted with water was at a constant pH) was added.
(until it shows a value of 3.5). After stirring for 1 hour at 0° C., the precipitate is filtered and washed with dioxane to recrystallize the water/dioxane. 7β-amino-3 thus obtained
-Methoxy-cef-3-em-4-carboxylic hydrochloride dioxanate has a melting point of 300°C or higher. Thin layer chromatography: Rf value = 0.17 (silica gel; system, n-butanol/carbon tetrachloride/methanol/formic acid/water, 30:
40:20:5:5).

(c-i) Anhydrous methylene chloride (distilled over PzOs) 47
11.75 g of 93% 7β-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid in mA
(equivalent to 10.93 g of 100%) and 13.4 mj of N,N-dimethylaniline! (12,73 g) was heated to +20°C under a nitrogen atmosphere with 3.6 mj of dimethyldichlorosilane! (3.87 g) and then stir the mixture for 30 minutes at the same temperature. Cool the clear solution to -18"C (-19°C), add 8 g of solid phosphoric pentachloride, and raise the internal temperature to -10°C.
After stirring in a 20°C bath for 30 minutes, the clear solution was mixed with n-butanol (cooled to -20°C) over about 7 minutes.
Add dropwise to a mixture of anhydrous, dried over silica >41 mA and 4.4 mA (4,18 g) of dimethylaniline.

The internal temperature rises to -8°C. The mixture was initially mixed with 120
C. bath followed by a water bath (0.degree. C.) for an additional 30 minutes, the internal temperature finally reaches -10.degree. At that temperature, 47 mj of dioxane and 1.6 mj of water! Add the mixture dropwise (required time: approximately 5 minutes). The product then gradually precipitates out.

After stirring for another 10 minutes, about 9.5 n/! of tri-n-butylamine! dropwise over about 1 hour (first 3
ml during the first 5 minutes) and maintain the pH value of the mixture between 2.2 and 2.4 in a water bath. The product is then filtered, followed by about 30 ml of dioxane and then about 15 n/! of methichloride! If you wash it little by little with
-Carboxylic hydrochloride dioxanate is obtained. The melting point is 300°C or higher. Ultraviolet absorption spectrum (0,1β
in sodium bicarbonate): λmax = 270 mμ (ε
=7,600) i Infrared absorption spectrum (Nujol): 5.62; 5.80; 5.88; 6.
26; 6.55; 7.03: 7.45;
7.72 ;7.96 i 8・14i8.26 i
8.45; 8°64 i 8.97; 9.2
9; characteristic bands at 10.40 and 11.47 mμ; [α] tube = +134° ±1° (C = 1i0.5N
sodium bicarbonate solution).

The zwitterion of 7β-amino-3-methoxy-cef-3-em-4-carboxylic acid can be obtained from the pH sanate with 20% water solubility of the hydrochloride dioxanate obtained above. If filtered and dried, the melting point of the zwitterion is 30.
The temperature is 0°C or higher. Ultraviolet absorption spectrum (in 0,IN sodium bicarbonate solution) λmax = 270 nm (ε
=7,600).

Thin layer chromatography: Rf identified as Rf value of hydrochloride
Value (silica gel, above system); [α] = +232°±
1° (C=1; 0.5N sodium bicarbonate solution).

fdl of 7β-amino-3-methoxy-cef-3-em-4-carboxylic hydrochloride dioxane) 1 g (2,82 mmol) in 20 mz dry methylene chloride. !
L. Add 1.65 earl of bis-(trimethylsilyl)-acetamide to the suspension at room temperature under nitrogen atmosphere. 4
After 0 min, the bright solution was cooled to 0 °C and 900 mg of solid D-α-phenylglycylic acid chloride hydrochloride (4,37
mmol) is added. After 5 minutes, propylene oxide 0.1
ml (10 mmol) is added. The suspension was then stirred at 0° C. for 1 hour under a nitrogen atmosphere, after which 0.5111 ffi of methanol was added and 7β-(D-α-phenylglycylamino)-3-methoxy-cef-3-em-
The 4-carboxylic hydrochloride salt precipitates as crystals. The hydrochloride salt is filtered, dissolved in 9 ml of water and the pH value of the solution is adjusted to 4.6 with IN sodium hydroxide solution.

Precipitated 7β-(D-α-phenylglycylamino)-
The dihydrate of the inner salt of 3-methoxy-ceph-3-em-4-carboxylic acid is filtered, washed with acetone and diethyl ether and dried. Melting point: 174-176°C (with decomposition). [α] 萱=+132° (c=0.714;0
．． IN hydrochloric acid); thin layer chromatography (silica gel)
: Rf (+!0.18 (system, n-butanol/acetic acid/water, 67:10:23). Ultraviolet absorption spectrum (
0,IN in aqueous sodium bicarbonate solution) λIIIax =
269μ (ε=7.000) i Infrared absorption spectrum (in mineral oil): characteristic hand at 5.72.5.94.6.23 and 6.60μ.

(d-i) 7β-amino- in methylene chloride lo#If
N,N-bis-(trimethylsilyl)-acetamide 1 was added to a suspension of 993+++ g (4.32 mmol) of 3-methoxy-cef-3-em-4-carboxylic acid (internal salt).
．． 37+wj! (5.6 mmol) is added and the mixture is stirred at room temperature for 45 minutes under nitrogen atmosphere. The clear solution is cooled to 0° C. and 111 g (5.4 mmol) of D-α-phenylglycylic acid tuchloride hydrochloride are added. After 5 hours, 0.4r*It (5.6 mmol) of propylene oxide is added. The suspension is then stirred for 1 hour at 0° C. under a nitrogen atmosphere before 0.6 mf of methanol is added. 7β-(D-α-phenylglycylamino) precipitates
-3-Methoxy-ceph-3-em-4-carboxylate was filtered and added with 15 mj of water at 0°C! and the pH of the solution
Adjust the value to about 4 with 5IIIL of IN sodium hydroxide. When the solution is warmed to room temperature and the pH of the solution is adjusted to about 4.8 with triethylamine, 7β-(D-α-phenylglycylamide)-3-methoxy-cef-3-em-4-carboxylic acid is converted to dihydrochloride. It precipitates in the form of hydrate.

Example 5 2-(4-(p-)luenesulfonylthio)=3-phenoxyacetamido-3-oxoazetidin-1-yl)-3-(1-pyrrolidyl)-crotonic acid diphenylmethyl ester and the corresponding isocrotonic ester A solution of 158.2 g (0.2 mol) of a mixture consisting of :1) until it becomes undetectable. Remove the heating bath and
The reaction mixture containing -phenoxyacetamido-3-pyrrolidino-cephem-4-carboxylic acid diphenylmethyl ester is treated with 12200 ml of 0.1 N HC and stirred for a further 3 hours at room temperature. The reaction mixture is evaporated to dryness in vacuo.

The residue is taken up in ethyl acetate and washed successively with dilute sulfuric acid, water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried over sodium sulfate. The solution is evaporated in vacuo and the crude 7β-phenoxyacetamide-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester is purified by column chromatography (silica gel; toluene/ethyl acetate, 4:1). Thin layer chromatography: Rf (!0.24 (silica gel; toluene/ethyl acetate, 1:1).

The product obtained can be further processed as follows.

(i) The resulting 7β-phenoxyacetamide-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester is taken up in methanol and treated at 0° C. with an excess of an ethereal solution of diazomethane. After a reaction time of 5 min, the solution is completely concentrated and the oily residue is subjected to thin layer chromatography on silica gel (toluene/ethyl acetate, 3:1), when the silica gel with Rf = 0.19 is extracted with ethyl acetate. 7β-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid diphenylmethyl ester is obtained. Melting point 120°C (from ether). Infrared absorption spectrum (in CHCl3)
; 3310.1775.1700.1690 and 1600cse-'.

(ii) Similarly to (a-i) of Example 4, the obtained 7β-
Phenoxyacetamide-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester was prepared by a phase transfer method using dimethyl sulfate and potassium bicarbonate.
It can be converted to phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid diphenylmethyl ester.

(iii) Methylene chloride 5n+j! 7β-phenoxyacetamido-3-methoxy-cef-3-em-4 in
-carboxylic acid diphenylmethyl ester 2.0 g (
0.87 ml of anisole was added to a solution of 3.78 mmol), the mixture was cooled to 0°C, and 1 liter of trifluoroacetic acid was added.
．． Add 2ml and leave for 1 hour. The reaction mixture is concentrated in vacuo and the residue is recrystallized from acetone/ether. 7β-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid is obtained. Melting point is 17
0°C (with decomposition).

The starting material can be produced as follows.

(a) 6-fethoxyacetamidopenicillanic acid 1β-
100 g (27.3 mol) of oxide and 50 g of dioxane
0m+1 and diphenylmethyldiazomethane 58.4g (
30 mmol), 6-funinoxyacetamidopenicillanic acid diphenylmethyl ester 1β-oxide is obtained after about 2 hours. Melting point 144-146°C (ethyl acetate/petroleum ether).

(b) 6-fethoxyacetamidopenicillanic acid diphenylmethyl ester 1 as in Example 1 (bJ)
292 g (55 mmol) of β-oxide and 99 g (59.5 mmol) of 2-mercaptobenzthiazole
- (4-(benzthiazol-2-yldithio)-3
-Phenoxyacetamide-2-oxoazetidine-1
-Il2-3-methylenebutyric acid diphenylmethyl ester is obtained. Melting point: 140-141°C (toluene/ether).

In the same manner as in (C) of CC1 Example 1, ethyl acetate 50II
(7) 2-(4-(benzthiazol-2-yldithio)-3-phenoxyacetamide-2-oxoazetidin-1-ylgo-3-methylenebutyric acid diphenylmethyl ester 10 g (14° 7 mmol) in IN) Fine powder p -Silver toluenesulfinate 4.92g (24,9
8 mmol) and 2-(4-(
p-)luenesulfonyl-thio)-3-phenoxyacetamide-2=oxoazetidin-1-ylgo-3-methylenebutyric acid diphenylmethyl ester is obtained.

Rf value = 0.28 (silica gel, toluene/ethyl acetate, 3:1), infrared absorption spectrum (CHCl, ):
1782.1740.1695.1340 and 11
50C11-'.

(d) Methylene chloride l in the same manner as (dl) in Example 1.
2-(4-(p-1-luenesulfonylthio)) in l
10.8 g (16.2 mmol) of -3-phenoxyacetamide-2-oxoazetidin-1-ylgo-3-methylenebutyric acid diphenylmethyl ester and 1.0 g (16.2 mmol) of osone.
1 equivalent gives 2-(4-(p-)luenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl-3-hydroxycrotonic acid diphenylmethyl ester. The melting point is 142-143℃ (
from ether/pentane).

[e) 2- in 500 vall of dry methylene chloride
A solution of 134.4 g (0.2 mol) of C4-(p-1-luenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl-3-hydroxycrotonic acid diphenylmethyl ester cooled to -10°C was Triethylamine 34.8ml (0
, 25 mol) and then methanesulfonyl chloride 24.5 mol)
ml (0.25 mol). After 20 minutes, 47 nil (0.55 mol) of freshly distilled pyrrolidine is introduced and the mixture is stirred at -10° C. for a further 2.5 hours. The reaction solution is washed three times with 1501 ml of water, dried over sodium sulfate and evaporated in vacuo. When the residue is dried to form a foam, a blue-yellow color of 2-(4-(p-)luenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-(1-pyrrolidyl)-crotonate diphenyl is obtained. A mixture of the methyl ester and its corresponding isocrotonic acid diphenylmethyl ester is obtained, which can be used as such in the next step.

Example 6 1.16 g of 7β-amino-3-methoxy-cef-3-em-4-carboxylic hydrochloride dioxanate (
3 mmol) and bis-(trimethylsilyl)-acetamide 1.5*j! (6.2 mmol), and then the reaction product and (a) D-α-amino-(
2-chenyl)-acetic acid chloride hydrochloride 765mg (3
, 6 mmol), 7β-[D-α-amino-α-(2-thenyl)-acetylaminoco-3-methoxy-3-cephem-4-carboxylic acid is reacted with Obtainable. Melting point 140°C (with decomposition).

Single layer chromatography (identified with silica gel, iodine)
: Rf ~0.22 (system, n-butanol/acetic acid/
water, 67:10:23) and Rf~0.53 (system, isopropanol/formic acid/water, 77:4:19); UV absorption spectrum: λmax = 235 mμ (ε = 11.
400) and λ shoulder = 272 r@μ(ε=6.10
0) (0,IN in hydrochloric acid), and λmax” 23
8 taμ (ε = 11,800) and λ shoulder = 267
+wμ(ε=6.500) (in aqueous sodium bicarbonate solution).

(bl also D-α-amino-(1,4-cyclohexagenyl)-acetic acid chloride hydrochloride 940 mg (4,
7β-CD-α-amino-
α-(1,4-cyclohexagenyl)-acetylaminoco-3-methoxy-3-cephem-4-carboxylic acid can be obtained in the form of an inner salt. Melting point: 170°C (with decomposition).

Thin layer chromatography (identified with silica gel, iodine)
: Rf ~0.19 (system, n-butanol/acetic acid/
water, 67:10:23) and Rf~0.58 (system, isopropanol/formic acid/water, 77:4:19); UV absorption spectrum: λmax = 267 mμ (ε = 6,3
00) (0,IN in hydrochloric acid), λwax = 268m
μ (ε = 6.600) (0, IN aqueous sodium bicarbonate solution), [α] = 188° ± 1° (c = 1.06
i0. IN hydrochloric acid).

(C) Also, if 800 mg (3.6 mmol) of D-α-amino-4-hydroxyphenylacetic acid chloride hydrochloride is reacted with 7β-[D-α-amino-α-(4-hydroxyphenyl)-acetyl Aminoco-3-methoxy-3-cephem-4-carboxylic acid can be obtained in the form of an inner salt. Melting point 243-244.5°C (sintering begins at 231°C) (accompanied by decomposition). Thin layer chromatography (identified with silica gel, iodine): Rf-0,24 (
system, n-butanol/acetic acid/water, 67:10:
23) and Rf~0.57 (system, isopropanol/
Formic acid/water, 77:4:19); Ultraviolet absorption spectrum:
λIIIax = 228 mμ (ε = 12,000) and 271 mμ (ε = 6.900) (0,I N
in hydrochloric acid], and λwax = 227 mμ (ε = 10
, 500) and λ shoulder = 262 tag (ε = 8.0
00) (0,IN in aqueous sodium bicarbonate solution), (
CM) W=+165° ±1'(c=1.3;
0. IN hydrochloric acid).

Example 7 6 g (10,24 m
mol) of crystalline 3-morpholino-7β-phenoxyacetamide-3-cephem-4-carboxylic acid diphenylmethyl ester solution and 2011It of methanol were added to 0.
2 N HCj? 100 mA' and stir vigorously to form an emulsion. After the reaction is completed (approximately 48
time) the organic phase is separated, dried and the solvent removed in vacuo. Thus, very pure 3-
A white foam is obtained consisting of hydroxy-7β-phenoxyacetamido-3-cephem-4-carboxylic acid-diphenylmethyl ester.

The starting material can be produced as follows. 1.
107.5 g (151.1 mmol) of 2-(4-(p-toluenesulfonylthio)) in methylene chloride of 62
-3-phenoxyacetamido-2-oxoazetidin-1-yl2-3-hydroxy-carboxylic acid-diphenylmethyl ester solution at -10°C.
mj2 (374.4 mmol) of methanesulfonyl chloride are added dropwise and 52.2 ml (374.4 mmol) of methanesulfonyl chloride are added dropwise.
mol) of triethylamine. After 30 minutes, -10
750 mmol of morpholine are slowly added dropwise at 0.degree. C. and stirred for a further 3 hours at -10.degree. 25
Wash twice with 0w+1 0.2N HCl and saturated NaCl solution, dry the organic phase over sodium sulfate, filter, concentrate the filtrate thoroughly, add 650 ml of methanol,
Generates crystals. Thus, 2-(4-(p-1 luenesulfonylthio)-3-phenoxyacetamide-
2-oxyazetidin-1-yl)-3-(1-morpholinyl)-crotonic acid-diphenylmethyl ester,
A crystalline mixture consisting of the corresponding incrotonic ester (
Melting point 111-114°C, decomposition).

400 tag of acetonitrile (basic A g , 0
74.1 g (0.1 mol) of 2-
(4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl)-
A solution of 3-(1-morpholinyl)-crotonic acid-diphenylmethyl ester is heated under reflux for 7 hours. After this, the solvent is thoroughly removed in vacuo, followed by the addition of cold methanol. From this an almost colorless 3-morpholino-7β-phenoxyacetamide-3-cephem-4-carboxylic acid diphenylmethyl ester having a melting point of 167-169° C. is crystallized.

Example 8゜Crystalline 3-piperidino-7β-phenoxyacetamide-3-cephem-4-carboxylic acid-diphenylmethyl ester to 3-hydroxy-7β-phenoxyacetamide-3-cephem-4-carboxylic acid -diphenyl methyl ester is obtained.

The starting material can be obtained as follows.

11', 1g C in 100+w/dry acetonitrile
15 mmol) of 2-(4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-(1-piperidinyl)-crotonic acid diphenylmethyl ester for 5.5 hours. Heat to reflux. This solution was concentrated and mixed with 100 tell of dry, cold methanol, thus giving a melting point of 184-
Pure 3-piperidino-7β-phenoxyacetamide-3-cephem-4-carboxylic acid diphenylmethyl ester is crystallized at 188° C. (decomposition).

Example 9 To a solution of 10 mg (0.017 mmol) of 7β-phenoxyacetamido-3-(1-morpholinyl)-3-cephem-4-carboxylic acid diphenylmethyl ester in 5 ml of methylene chloride was added 5N salt Mltml. Add dropwise. The reaction mixture is stirred for 30 minutes at room temperature.

The aqueous phase is removed, the organic phase is mixed with water, dried over sodium sulphate and evaporated. Thus 7β-phenoxyacetamide-3-hydroxy-3-cephem-4
-Carboxylic acid-diphenylmethyl ester is obtained. IR
-Spectrum (in methylene chloride): 3410
, 2925-2850 , 1780 , 1690 , 1
600, 1510, 1490.

1360, 1220 and 1200 (has specific absorption bands at J-').

The starting material is obtained as follows.

a) 25mj! of methylene chloride (6.83 g (1
0 mmol) of 2-(4-(benzthiazol-2-yl-dithio)-3-phenoxyacetamide-2-oxoazetidin-1-yl-3-hydroxycrotonic acid-diphenylmethyl ester) was cooled to 20°C. , 0.971 tj' (12,5 mmol) of methanesulfonyl chloride and then 1.74 rall
(12.5 mmol) of triethylamine. The reaction mixture was cooled to -20°C for 1.5 hours and
Add 9 tal (27.5 mmol) of morpholine.

The reaction mixture is cooled to −15° C. for an additional hour and then warmed to room temperature. Add this mixture to 50IIIl
diluted with methylene chloride and diluted with 40 ml of 2N) ICf.
and then washed three times with saturated saline.

The organic phase is dried over sodium sulphate and evaporated. The crude product was dissolved in toluene/ethyl acetate (9:1°3=1.1=1) using 400 g of silica gel (Merck).
) and obtain 2-[4-benzthiazol-2-yl]-3-phenoxyacetamido-2-oxoazetidin-1-yl-3-(l-morpholinyl)-crotonic acid-diphenylmethyl ester. .

b) 100a+g (0,13
3 mmol) of 2-(4-(benzthiazol-2-yl-dithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-(1-morpholinyl)
-Crotonic acid-diphenylmethyl ester solution
Heat to 70°C for an hour. The solution is evaporated, the residue is dissolved in methylene chloride and diluted with methanol. The methylene chloride is slowly removed in vacuo and the product is crystallized from residual methanol. Thus, melting point 1
7β-phenoxyacetamide-3- at 72-173°C
(1-morpholinyl)-3-cephem-4-carboxylic acid-diphenylmethyl ester is obtained.

Example 10゜Crystals of 3-pyrrolidino-7β-phenoxyacetamide-3-cephem-4-1cephem-4 were prepared in the same manner as in Example 9.
-Carboxylic acid-diphenylmethyl ester is obtained.

The starting material is obtained as follows.

14.5 g (20 m
mol) of 2-(4-(p-toluenesulfonylthio)
-3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-(1-pyrrolidinyl)-crotonic acid-diphenylmethyl ester solution at 80°C until no starting material is visible on thin layer chromatography. Heat. The solvent was thoroughly removed in vacuo and replaced with 1001 dry cold methanol, thus producing 3-pyrrolidino-7β-phenoxyacetamide-3-cephem-4-carboxylic acid-diphenylmethyl ester with a melting point of 190-194°C. to crystallize.

Example 11 The following compounds can be prepared in a similar manner from the corresponding starting materials.

7β-phenylacetamido-3-hydroxy-3-cephem-4-carboxylic acid-diphenylmethyl ester,
IR-spectrum (in CHzCNz): 2.95, 5
．． 61, 5.77, 5.85, 5.95, 6.
7β-amino-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester, IR-spectrum (in cozczz): 5.58, 5.77 (
shoulder), with bands at 6.02 and 6,22μ; 7β
-[D-α-tert-butyloxycarbonylamino-α-phenylacetylamino]-3-hydroxy-3
-Cephem-4-carboxylic acid-diphenylmethyl ester, IR-spectrum (in CHzCNz): 2.
94, 3.40, 5.62, 5.77.

Has bands at 5.75, 5.95, 6.21 and 6.88μ; 7β-[D-α-tert-butyloxycarbonylamino-α-(4-hydroxyphenyl)-acetylamino-to-3-hydroxy -3-cephem-4-carbomethydiphenylmedyl ester, ultraviolet absorption spectrum (in 95% aqueous ethanol): λmax = 284
tsp (a = 5.100), infrared absorption spectrum (in methylene chloride): 5.59, 5.
83 (shoulder), 5.88, 6.18 and 6.67μ
has a specific band; 7β-[D-α-tert-butyloxycarbonylamino-α-(2-chenyl)-acetylamino2-3-
Hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester, UV absorption spectrum (in 95% aqueous ethanol) λmax = 283 mμ (ε = 5.
300), infrared absorption spectrum (in methylene chloride): 5.59, 5.87, 6.19 and 6
．． 7β-[D-α-tert 7′-tyloxycarbonylamino-α-(3-chenyl)-acetylamino-3-hydroxy-3-cephem-4-carboxylic acid-diphenylmethyl ester with a specific band at 66μ; , ultraviolet absorption spectrum (95%
in aqueous ethanol): λ+WaX=283111μ(ε
= 5.300 >, Infrared absorption spectrum (in methylene chloride): 5.59, 5.87, 6.19
and has a specific absorption at 6.66μ; Methyl ester, ultraviolet mi yield spectrum (in 95% aqueous ethanol): λ1IIax = 28311μ (ε =
5.300'), infrared absorption spectrum (in methylene chloride): 5.59, 5.8? , 6.
with specific bands at 19 and 6.66μ;

7β-[D-α-tert-7'Tyloxycarbonylamino-α-(4-isothiazolyl)-acetylamino-3-hydroxy-3-cephem-4-carboxylic acid-diphenylmethyl ester, ultraviolet absorption spectrum (
(in 95% aqueous ethanol): λ++ax = 250
tmμ(ε−12,000) and 280−μ(ε=5
．． 800), infrared absorption spectrum (in methylene chloride)
: 5.59, 5.87, 6.19 and 6.6
Has a specific band at 6μ; 7β-[D-α-ter t-butyloxycarbonylamino-α-(1,4-cyclohexagenyl)-acetylamino-3-hydroxy-3-cephem-4-carboxylic acid -Diphenylmethyl ester, IR-spectrum (C)l (1, medium) 3380.17B0°1690
, 1610, 1590 and 1470>-'; 7β-(2-chenyl)-acetylamino-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester, ultraviolet absorption spectrum (95% aqueous ethanol Medium): λtaax = 280 mμ (ε = 5.10
0”), infrared absorption spectrum (in methylene chloride)
: 5.5B, 5.82 (shoulder), 5.8
B, with specific bands at 6.17 and 6.67μ; 7β-(l-tetrazolyl)-acetylamino-3
-Hydroxy-3-cephem-4-carboxylic acid-diphenylmethyl ester, UV absorption spec: 5.59
7β-(4-pyridylthio)-acetylamino-3-hydroxy-3-cephem-4-carboxylic acid-diphenylmethyl ester, with specific bands at , 5.87, 6.19 and 6.66μ; External absorption spectrum (in 95% aqueous ethanol): λn+ax = 283-μ, infrared absorption spectrum (in methylene chloride): 5.59, 5.
83 (shoulder), 5.88, 6.18 and 6.67
Has a specific band for μ; 7β-(4-aminopyridinium-acetylamino)-
3-Hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester, ultraviolet absorption spectrum (95%
(in aqueous ethanol): λS+aX=282111μ, infrared absorption spectrum (in methylene chloride): 5.
7β-[D-α-(2,2,2-trichloroethoxycarbonyloxy)-α-phenyl-acetylaminoco-
3-Hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester, s external absorption spectrum (95%
(in aqueous ethanol): λmax-284 mμ, infrared absorption spectrum (in methylene chloride) 5.59, 5.
It has specific bands at 87, 6.19 and 6.66μ.

Furthermore, the following corresponding compounds in which the 3-hydroxyl group is etherified can be produced.

3-Methoxy-7β-phenylacetamido-3-cephem-4-carboxylic acid-diphenylmethyl ester, I
R-spectrum (in cozclz): 2.94, 5.
63, 5.83, 5.94, 6.26 and 6.6
Has a band at 6μ; 3-methoxy-7β-amino-3-cephem-4-carboxylic acid-diphenylmethyl ester (and its salt), I
R-spectrum (in dioxane) 2.87, 5.62
and has a band at 6.26μ; 3-methoxy-7β
-Phenylacetylamino-3-cephem-4-carboxylic acid (or its salt), IR-spectrum (C1hC12
Z Medium”): 3.03, 5.60.

Has bands at 5.74, 5.92, 6.24 and 6.67μ; 3-methoxy-7β-(D-α-tert, butyloxycarbonylamino-α-phenylacetyl-amino)
-3-cephem-4-carboxylic acid-diphenylmethyl ester, melting point 162-163°C (diethyl ether); 3-methoxy-7β-(D-α-phenylglycyl-amino)-3-cephem-4-carboxylic acid (or its salt)
, melting point 174-176°C (decomposition); 2-n-butyloxy-7β-phenylacetyl-amino-3-cephem-
4-Carboxylic acid-diphenylmethyl ester, melting point 16
8-170°C (from CH2Cl2/diethyl ether); 3-n-butyloxy-7β-(D-at-tert
-Butyloxycarbonylamino-α-phenyl-acetylamino)-3-cephem-4-carboxylic acid-diphenylmethyl ester, IR-spectrum (C)! ,+l
Z medium): 2.8B, 5.63, 5.84
(shoulder).

It has bands at 5.88, 6.26 and 6.71μ: 3 = n-butyloxy-7β-(D-α-phenylacetate)
3-methoxy-7β-phenylacetylamino-3-cephem-4-carboxylic acid (or its salt), melting point 141-142°C (acetone/diethyl ether); Methyl ester, melting point 171
~174°C (from CIICjl,/hexane); 3-ethoxy-7β-(D-α-ter t-butyloxycarbonylamino-α-phenyl-acetyl-amino)-
3-cephem-4-carboxylic acid-diphenylmethyl ester, IR-spectrum (CHZ (1, medium)?
2.96, 5.64, 5.90, 6.28 and 6
．． Has a band at 73μ; 3-ethoxy-7β-(D-α-phenylglycylamino)-3-cephem-4-carboxylic acid (or salt thereof)
, Ul-spectrum (0,1M Na) in lcOi solution)
:λtsax = 263 mμ (ε=5.500)
;3-benzyloxy-7β-(D-α-terL
-butyloxycarbonylamino-α-phenyl-acetyl-amino)-3-cephem-4-carboxylic acid-diphenylmethyl ester, JR-spectrum (CHICj
22): 2.96, 5.63, 5.88
, has bands at 6.26 and 6.72μ; 3-benzyloxy-7β-(D-α-phenylglycylamino)-3-cephem-4-carboxylic acid (or its salt), UV-spectrum ( 0, INNaHCO, in solution): λmax = 266 m p (ε = 6.500
); 7β-(5-benzoylamino-5-diphenylmethoxycarbonyl-valerylamino)-3-methoxy-3-cephem-4-carboxylic acid-diphenylmethyl ester, IR-spectrum (CH2Cl.

Medium”): 5.65, 5.7B, 6.03
and has a band at 6.64μ; 7β-(D-α-ter t-butyloxycarbonylamino-α-phenylacetyl-amino)-3-methoxy-3-cephem-4-carboxylic acid or its salt, IR-
Spectrum (in CHZC12z): 3.00°5.
Has bands at 64, 5.92, 6.25 and 6.72μ; 7β-(D-α-tert-butyloxycarbonylamino-α-(2-chenyl)-acetylaminoco-3
-Methoxy-3-cephem-4-carboxylic acid-diphenylmethyl ester, IR-spectrum (C11□(1,
Medium): 2.94, 5.62, 5.85, 6.
Has bands at 26 and 6.72μ; 7β-[D-α-ter t-butyloxycarbonylamino-α-(1,4-cyclohexagenyl)-acetylaminoco-3-methoxy-3-cephem-4 -Carboxylic acid-diphenylmethyl ester, IR-spectrum (in CH2CIZ): 2.96, 5.64° 5.86, 5.90 (shoulder), 6.27 and 6
．． 7β-[D-α-amino-α-(1-cyclohexene-
1-yl)-acetylaminoco-3-methoxy-3-cephem-4-carboxylic acid or salt thereof; 7β-[D-α-
tert-butyloxycarbonylamino-α-(4-
Hydroxyphenyl)-acetyl-aminoco-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester, IR-spectrum (CHzCj!z)
: 2.83, 2.96.

5.64, 5.86, 5.91 (shoulder), 6.2
3, has bands at 6.28, 6.65 and 6.72μ; 7β-[D-α-amino-α-(4-hydroxyphenyl)-acetylaminoco-3-methoxy-3-cephem-4- Carboxylic acid (or salt thereof), melting point 180°C (decomposed);

Claims (1)

[Claims] 1. The following formula (VII), ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (VII) [In the formula, R^a_1 is a hydrogen atom or an amino protecting group R^
A_1 and R^b_1 is a hydrogen atom or an acyl group Ac, or R^a_1 and R^b_1 are both divalent amino protecting groups, and R^A_2
is a group forming a protected carboxyl group together with the carbonyl group -C(=O)-, and Y is the group to be removed] or the following formula (VIII) ▲ There are mathematical formulas, chemical formulas, tables, etc.▼(VIII) (In the formula, R^a_1, R^b_1, R^A_1, and Y
have the same meaning as above and R_5 is an optionally substituted in particular aliphatic, cycloaliphatic, araliphatic or aromatic hydrocarbon radical of up to 18 carbon atoms) A sulfonic acid ester of a compound with the formula HN(R^a_4)(R^b_4) [wherein -N(R^a_4)(R^b_4) shall be a secondary or tertiary amino group]. A compound of the following formula (II ), ▲Mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, R^a_1, R^b_1, R^A_2, Y, and -N(R^a_4) (R^b_4) are the same as above. A method for producing a compound represented by: