JPH0246594B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides enol derivatives, particularly those of the general formula (In this 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 ₂ are both divalent amino protecting groups, and R ₂ is a hydroxyl group. or a carbonyl group in the formula, a group R ^A ₂ which together with -C(=O)- forms a protected carboxyl group, and R ₃ is a hydrogen atom, a lower alkyl group or 7β-amino-3-cephem-3-ol-4-carboxylic acid represented by α-phenyl-lower alkyl group which may be substituted by 1-oxide, and the general formula (In this formula, R ^a ₁ , R ^b ₂ , R ₂ and R ₃ have the meanings given above.) Regarding the manufacturing method.

The enol derivative of the present invention is 3-cephem-3
-ol or ether of 2-cephem-3-ol compound.

In the 2-cephem compound represented by formula (B) having a double bond at the 2,3-position, the formula -C
The optionally protected carboxyl group represented by (=O) _-R2 is preferably in the alpha configuration.

Amino protecting groups (R ^A ₁ ) are groups which can be substituted with hydrogen atoms, mainly acyl groups (Ac), but also triarylmethyl groups, especially trityl groups, and organosilyl or organostannyl groups. Acyl groups (Ac), including the acyl group R ^b ₁ , are mainly acyl groups of organic carboxylic acids having preferably up to 18 carbon atoms, especially aliphatic and alicyclic groups which may be substituted. acyl groups of formula, cycloaliphatic, aromatic, araliphatic, heterocyclic or heterocycloaliphatic carboxylic acids (including formic acid), as well as acyl groups of carbonic acid semi-derivatives.

The divalent amino protecting group formed by the linkage of the groups R ^a ₁ and R ^b ₁ is in particular a divalent acyl group of an organic dicarboxylic acid having preferably up to 18 carbon atoms, mainly an aliphatic group. or a diacyl group of an aromatic dicarboxylic acid, and an α-aminoacetic acid which preferably has a substituent such as an aromatic or heterocyclic group in the α-position (the amino group of this aminoacetic acid preferably has a substituent such as a methyl group). The acyl group preferably has two lower alkyl groups (bonded to the nitrogen atom via a methylene group). Also, the group R ^a ₁ and
R ^b ₁ can also be an organic ylidene group having preferably up to 18 carbon atoms in both cases, such as an aliphatic, cycloaliphatic, cycloaliphatic or araliphatic ylidene group.

The protected carboxyl group of the formula -C(=O)-R ^A2 is primarily an esterified carboxyl group _, but may also be an anhydride group, a common mixed anhydride group or a substituted It can also be a carbamoyl group or a hydrazinocarbonyl group.

Thus, the group R ^A ₂ is a hydroxyl group etherified with an organic group, preferably up to 18 carbon atoms, forming the carboxyl group esterified with the group -C(=O)-. can be. 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.

The radical R ^A ₂ 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 having preferably up to 18 carbon atoms. The radicals can also be, for example, silyloxy or stannyloxy radicals substituted by 1 to 3 aliphatic hydrocarbon radicals and optionally by halogen atoms, such as chlorine atoms.

The group R ^A ₂ 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, where the acyl group is Organic carboxylic acids preferably having up to 18 carbon atoms, such as aliphatic, cycloaliphatic,
Cycloaliphatic - the corresponding group of an aliphatic, aromatic or araliphatic carboxylic acid or a carbonic acid semi-derivative, such as a carbonic acid half-ester.

The group R ^A ₂ which together with the group -C(=O)- forms a carbamoyl group is an optionally substituted amino group. The substituent is an optionally substituted monovalent or divalent hydrocarbon group having preferably up to 18 carbon atoms, e.g.
optionally substituted monovalent or divalent aliphatic, cycloaliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals having up to 18 carbon atoms; Corresponding heterocyclic or heterocyclic-aliphatic groups and/or functional groups, such as hydroxyl groups, in particular free hydroxyl groups, which can be functionally modified, as well as etherified or esterified hydroxyl groups (such as etherified or esterified hydroxyl groups) or an esterified group (e.g. having the abovementioned meaning and preferably having up to 18 carbon atoms) or an acyl group, mainly an acyl group of an organic carboxylic acid or carbonic acid semi-derivative, preferably having up to 18 carbon atoms. It is.

In _the substituted hydrazinocarbonyl group represented by the formula -C(=O) ^-RA2 , one or both of the nitrogen atoms may be substituted.

Substituents are mainly monovalent or divalent hydrocarbon radicals having preferably up to 18 carbon atoms, which may be substituted, such as substituted hydrocarbon radicals having up to 18 carbon atoms. monovalent or divalent aliphatic, cycloaliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, as well as corresponding heterocyclic or heterocycloaliphatic groups having up to 18 carbon atoms. Groups and/or functional groups such as acyl groups are mentioned, mainly acyl groups of organic carboxylic acids or carbonic acid semi-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 alkyl group, or a lower alkylidene group which can have up to 4 groups. Such groups may optionally be provided with functional groups, such as free or etherified or esterified hydroxyl or mercapto groups, such as lower alkoxy, lower alkenyloxy, lower alkylenedioxy, substituted phenyloxy group or phenyl lower alkoxy group, lower alkylthio group, phenylthio group or phenyl lower alkylthio group that may be substituted, heterocyclylthio group or heterocyclyl lower alkylthio group, if substituted a lower alkoxycarbonyloxy group or lower alkanoyloxy group, or a halogen atom,
Furthermore, oxo groups, nitro groups, optionally substituted amino groups such as lower alkylamino groups, di-lower alkylamino groups, lower alkylene amino groups, oxa lower alkylene amino groups or aza lower alkylene amino groups and acylamino groups such as lower alkanoyl Amino group, lower alkoxycarbonylamino group, halogeno lower alkoxycarbonylamino group, optionally substituted phenyl lower alkoxycarbonylamino group, optionally substituted carbamoylamino group, ureidocarbonylamino group or guazininocarbonyl Amino groups, as well as sulphoamino 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, optionally substituted carbamoyl groups such as N-lower alkyl- or N,N-di-lower alkyl-carbamoyl groups. , further optionally substituted ureidocarbonyl group or guazininocarbonyl group,
or a cyano group, a sulfo group which may be functionally modified, such as a sulfamoyl group or a sulfo group in salt form, or an O-mono- or O,
A phosphono group which may be O'-di-substituted (the substituent being an optionally substituted lower alkyl group, phenyl group or phenyl lower alkyl group, which is O-unsubstituted or O-mono-substituted) The substituted phosphono group can also be in the form of a salt, such as an alkali metal salt).
Can be di- or polysubstituted.

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. can be substituted or polysubstituted and (or)
Heteroatoms such as oxygen, nitrogen or sulfur atoms can be interposed in the chain.

Alicyclic or cycloaliphatic groups (including corresponding cycloaliphatic or cycloaliphatic groups in organic carboxylic acids) and corresponding cycloaliphatic or cycloaliphatic groups
An aliphatic ylidene group is an optionally substituted monocyclic or bicyclic alicyclic or alicyclic-aliphatic hydrocarbon group, such as a monocyclic, bicyclic or polycyclic cycloalkyl group or a cycloaliphatic hydrocarbon group. Alkenyl group, further cycloalkylidene group, or cycloalkyl group
or a cycloalkenyl-lower alkyl group or a -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 e.g. has up to 12 ring carbon atoms, e.g. 3-8
carbon atoms, e.g. 5 to 8, preferably 5 or 6, and one or two double bonds, and the aliphatic part of the cycloaliphatic group has up to e.g. 7 carbon atoms, Preferably, it can have up to four. These alicyclic groups or alicyclic groups-
Aliphatic groups may be substituted if desired, for example by aliphatic hydrocarbon groups which may be substituted, e.g. by the optionally substituted lower alkyl groups mentioned above or by e.g. can be mono-, di- or polysubstituted with functional groups such as.

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 may optionally be mono-, di- or polysubstituted, such as the aforementioned aliphatic and cycloaliphatic hydrocarbon groups.

Divalent aromatic radicals of aromatic carboxylic acids are in particular 1,2-arylene radicals, in particular 1,2-phenylene radicals, which may optionally be combined, such as the aliphatic and cycloaliphatic hydrocarbon radicals mentioned above. They can be mono-, di- or polysubstituted.

Said araliphatic groups (including araliphatic groups in the corresponding carboxylic acids) and/or araliphatic ylidene groups may be substituted, e.g. optionally substituted aliphatic hydrocarbon radicals having up to three monocyclic, bicyclic or polycyclic aromatic hydrocarbon radicals, especially phenyl-lower alkyl radicals or phenyl-lower alkenyl radicals; and phenyl-lower alkynyl groups and also phenyl-lower alkylidene groups, and such groups include, for example, phenyl groups 1-
3 and can optionally be mono-, di- or polysubstituted in its aromatic and/or aliphatic parts, such as the aliphatic and cycloaliphatic groups mentioned above. .

Heterocyclic groups (in heterocyclic-aliphatic groups,
and the corresponding heterocyclic or heterocyclic-aliphatic groups in the carboxylic acids) are particularly monocyclic, bicyclic or polycyclic azacyclic, thiacyclic, oxacyclic groups of aromatic character. thiazacyclic, thiadiazacyclic, oxaazacyclic, diazacyclic, triazacyclic or tetraazacyclic radicals and also corresponding partially or wholly saturated heterocyclic radicals of this type, , such groups may optionally be monosubstituted, such as for example the alicyclic groups mentioned above,
Can be di- or polysubstituted.
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 carbonic acid semi-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 heterocycle). aliphatic groups), especially the acyl groups of lower alkyl half esters of carbonic acid (which are e.g.
Preference is given to acyl groups of lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl half esters of carbonic acid which may be substituted in position) and which may be substituted in the organic group. The acyl group of the carbonic acid half-ester is furthermore the corresponding group of the lower alkyl half-ester of carbonic acid, the lower alkyl part of which carries a heterocyclic group, for example one of said heterocyclic groups of aromatic character, Both the lower alkyl and heterocyclic groups can be optionally substituted. Furthermore, the acyl group of the carbonic acid semi-derivative can also be an optionally N-substituted carbamoyl group, such as an optionally halogenated N-lower alkylcarbamoyl group.

Etherified hydroxyl groups are primarily lower alkoxy groups which may be substituted (the substituents being mainly free or functionally converted e.g. etherified or esterified hydroxyl groups, in particular lower alkoxy groups or halogen atoms). ), furthermore lower alkenyloxy groups, cycloalkyloxy groups or optionally substituted phenyloxy groups, as well as heterocyclyloxy groups or heterocyclyl lower alkoxy groups, in particular optionally substituted phenyl lower alkoxy groups. It is.

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

Examples of the hydrazino group which may be substituted include hydrazino group, 2-lower alkylhydrazino group, 2,2-di-lower alkylhydrazino group, 2-
lower alkoxycarbonylhydrazino group or 2
-A lower alkanoylhydrazino group.

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

Lower alkylene groups include, for example, 1,2-ethylene, 1,2- or 1,3-propylene, 1,
4-butylene group, 1,5-pentylene group or 1,6-hexylene group, and the lower alkenylene group is, for example, 1,2-ethenylene group or 2-
It is a butene-1,4-ylene group. Lower alkylene groups with intervening heteroatoms are, for example, 3-oxa-
an oxa-lower alkylene group such as a 1,5-pentylene group, a thia-lower alkylene group such as a 3-thia-1,5-pentylene group, or a 3-lower alkyl-3-aza-1,5-pentylene group, e.g. ―
It is an aza lower alkylene group such as methyl-3-aza-1,5-pentylene group.

The cycloalkyl group is, for example, a cyclopropyl group,
cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and adamantyl; cycloalkenyl is, for example, cyclopropenyl, 1-, 2- or 3-cyclopentenyl, 1-, 2- or 3-cyclohexenyl group, 3-cycloheptenyl group or 1,4
-cyclohexadienyl group, and the cycloalkylidene group is, for example, a cyclopentylidene group or a cyclohexylidene group. cycloalkyl
Lower alkenyl groups are, for example, cyclopropyl-, cyclopentyl-, cyclohexyl- or cycloheptyl-methyl groups, -1,1- or -1,2
-ethyl group, -1,1-, -1,2- or -
1,3-propyl group, -vinyl group or -allyl group, and the cycloalkenyl-lower alkyl group or cycloalkenyl-lower alkenyl group is, for example, 1-, 2- or 3-cyclopentenyl-,
1-, 2- or 3-cyclohexenyl- or 1-, 2- or 3-cycloheptenyl-methyl group, -1,1- or -1,2-ethyl group, -
It is a 1,1, -1,2- or -1,3-propyl group, -vinyl group or -allyl group. The cycloalkyl-lower alkylidene group is, for example, 3-cyclohexenyl or 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-, 2- or 3-phenylpropyl, diphenylmethyl, trityl, styryl or cinnamyl. hand,
A naphthyl-lower alkyl group such as a 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 heterocyclic radicals which may be substituted with aromatic character, such as corresponding monocyclic monoazacyclic, monothiacyclic or monooxacyclic radicals, such as 2-pyryl or 3- Pyryl groups such as pyryl groups, pyridyl groups and pyridinium groups such as 2-, 3- or 4-pyridyl groups, 2
- or a thienyl group such as a 3-thienyl group or a furyl group such as a 2-furyl group, a bicyclic monoazacyclic, monooxacyclic or monothiacyclic group such as an indolyl group such as a 2- or 3-indolyl group a quinolinyl group such as a 2- or 4-quinolinyl group, an isoquinolinyl group such as a 1-isoquinolinyl group, a benzofuranyl group such as a 2- or 3-benzofuranyl group, or a 2- or 3-quinolinyl group;
-benzothienyl group, such as benzothienyl group,
monocyclic diazacyclic, triazacyclic, tetraazacyclic, oxaazacyclic, thiazacyclic or thiadiazacyclic groups, such as imidazolyl groups such as 2-imidazolyl groups, 2- or 4-pyrimidinyl groups; pyrimidinyl group, triazolyl group such as 1,2,4-triazol-3-yl group, 1-
or a tetrazolyl group such as 5-tetrazolyl group, oxazolyl group such as 2-oxazolyl group, isoxazolyl group such as 3- or 4-isoxazolyl group, thiazolyl group such as 2-thiazolyl group, 3- or 4-isothiazolyl group. an isothiazolyl group, such as a 1,2,4-
a 1,2,4- or 1,3,4-thiadiazolyl group, such as a thiadiazol-3-yl group or a 1,3,4-thiadiazol-2-yl group;
a cyclic diazacyclic, oxaazacyclic or thiazacyclic group such as a benzimidazolyl group such as a 2-benzimidazolyl group, a benzoxazolyl group such as a 2-benzoxazolyl group or a 2-benzthiazolyl group; It is a benzthiazolyl group. Corresponding partially or totally saturated groups are, for example, tetrahydrothienyl groups such as 2-tetrahydrothienyl groups, tetrahydrofuryl groups such as 2-tetrahydrofuryl groups or piperidyl groups such as 2- or 4-piperidyl groups. It is. Heterocyclic-aliphatic radicals are heterocyclic radicals, especially lower alkyl radicals or lower alkenyl radicals bearing the aforementioned radicals. Said heterocyclic radicals are for example aliphatic or aromatic hydrocarbon radicals which may be substituted, in particular by lower alkyl radicals such as methyl radicals or optionally by halogen atoms such as chlorine atoms. Substituted phenyl groups can be substituted, for example by phenyl or 4-chlorophenyl groups, or by functional groups, such as for example the aliphatic hydrocarbon groups mentioned above.

Lower alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n
-butoxy group, isobutoxy group, sec-butoxy group, tertiary-butoxy group, n-pentoxy group or tertiary-pentoxy group. These groups are, for example, halogeno-lower alkoxy groups, in particular 2-halogeno-lower alkoxy groups, such as 2,2,2-trichloroethoxy, 2-chloro, 2-bromo or 2-
It can be substituted, such as an iodo-ethoxy group. 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 an adamantyloxy group, the phenyl-lower alkoxy group being, for example, a benzyloxy group or a 1- or 2-phenylethoxy group, a diphenylmethoxy group or a 4,4'-dimethoxy-diphenylmethoxy group, and a hetero A cyclyl-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 thienyl-lower alkoxy group such as thenyloxy group.

Lower alkylthio groups are, for example, methylthio, ethylthio or n-butylthio, lower alkenylthio groups are, for example, allylthio, phenyl-lower alkylthio groups are, for example, benzylthio, and heterocyclic groups or heterocyclic -Mercapto groups etherified with aliphatic groups are especially pyridylthio groups such as 4-pyridylthio groups,
Imidazolylthio group, thiazolylthio group such as 2-thiazolylthio group, 1,2,4- or 1- ,3,4-thiadiazolylthio group or 1-
A tetrazolylthio group such as methyl-5-tetrazolylthio group.

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, 2-halogeno-lower alkoxycarbonyloxy groups such as 2,2,2-trichloroethoxycarbonyloxy, 2-bromo An ethoxycarbonyloxy group or a 2-iodoethoxycarbonyloxy group, or an arylcarbonylmethoxycarbonyloxy group such as a phenacyloxycarbonyloxy group.

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-di-lower alkyl-carbamoyl group.
-Methylcarbamoyl group, N-ethylcarbamoyl group, N,N-dimethylcarbamoyl group, N,N
-diethylcarbamoyl group, and the N-lower alkylsulfamoyl group is, for example, N-methylsulfamoyl group or N,N-dimethylsulfamoyl group.

A carboxyl or sulfo group in the form of an alkali metal salt is, for example, a carboxyl or sulfo group in the form of a sodium or potassium salt.

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 alkyleneamino group is, for example, a thiomorpholino group, and an aza-lower alkyleneamino 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,
Halogeno lower alkoxycarbonylamino groups such as 2,2-trichloroethoxycarbonylamino groups, phenyl lower alkoxycarbonylamino groups such as 4-methoxybenzyloxycarbonylamino groups, lower alkanoylamino groups such as acetylamino groups and propionylamino groups. groups, and also phthalimide groups or sulphoamino groups which can be in the form of salts such as alkali metal salts such as sodium salts or ammonium salts.

Lower alkanoyl groups are, for example, formyl, acetyl, propionyl or pivaloyl.

O-lower alkyl-phosphono groups are, for example, O-methyl- or O-ethyl-phosphono groups, O,
O′-di-lower alkyl group-phosphono group is, for example, O,
O'-dimethyl-phosphono group or O,O'-diethyl-phosphono group, O-phenyl lower alkyl-
A phosphono group is, for example, an O-benzyl-phosphono group and an O-lower alkyl-O'-phenyl lower alkyl-phosphono group is, for example, an O-methyl-O'-benzyl-phosphono group.

A lower alkenyloxycarbonyl group is, for example, a vinyloxycarbonyl group, and a cycloalkoxycarbonyl group and a 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. The lower alkyl group is, for example, a monocyclic monoazacyclic group,
A lower alkoxycarbonyl group having a monooxacyclic or monothiacyclic group is, for example, a furyl-lower alkoxycarbonyl group such as a furfuryloxycarbonyl group or a thienyl-lower alkoxycarbonyl group such as a 2-thenyloxycarbonyl group. It is.

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

The acyl group Ac is especially 6-amino-penam-3-
Carbon atoms contained in preferably pharmacologically active N-acyl derivatives of carboxylic acid compounds or 7-amino-3-cephem-4-carboxylic acid compounds that are naturally occurring or can be prepared by biosynthesis, semi-synthesis or total synthesis. The number of is preferably up to 18 acyl groups of organic carboxylic acids or easily cleavable acyl groups, especially acyl groups of carbonic acid semi-derivatives.

The acyl group Ac contained in the pharmacologically active N-acyl derivatives of 6-amino-penam-3-carboxylic acid compounds or 7-amino-3-cefem-4-carboxylic acid compounds mainly has the formula [In this formula, n is 0 and R is a hydrogen atom or an optionally substituted alicyclic or aromatic hydrocarbon group, an optionally substituted heterocyclic ring preferably having aromatic character. a formula group, a functionally modified hydroxyl or mercapto group, for example an esterified or etherified group, or an optionally substituted amino group, or n is 1
and R〓 is a hydrogen atom or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon group, and the heterocyclic group is preferably aromatic. optionally substituted heterocyclic or heterocyclic-aliphatic radicals having a quaternary nitrogen atom and/or a quaternary nitrogen atom, functionally modified (preferably etherified or esterified); a hydroxyl or mercapto group which may be present, a carboxyl group which may be functionally modified, an acyl group, an amino group which may be substituted or an amide group, and the groups R〓 and R〓
and are both hydrogen atoms, or n is 1, and R is an optionally substituted aliphatic group,
cycloaliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals or heterocyclic or heterocyclic-aliphatic radicals in which the heterocyclic radicals may be substituted, preferably having aromatic character; and R〓 is a hydroxyl or mercapto group which may be functionally modified, e.g. esterified or etherified, such as a halogen atom, an amino group which may be substituted, or a functionally modified a carboxyl group or a sulfo group, a phosphono group or an amide group which may be O-mono-substituted or O,O′-disubstituted, and R〓 is a hydrogen atom, or n is 1; The groups R〓 and R〓 are each a functionally modified (preferably etherified or esterified) hydroxyl group or a carboxyl group which may be modified with a functional group, and R〓 is a hydrogen atom. , or n is 1, R〓 is a hydrogen atom or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon group, and R〓 is R〓
is an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon group which may be substituted with both and which is bonded to a carbon atom in the formula by a double bond. or n is 1;
R〓 is aliphatic, alicyclic, which may be substituted,
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; R〓 is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon group, and
R is a hydrogen atom or an optionally substituted aliphatic, alicyclic, alicyclic-aliphatic, aromatic or araliphatic hydrocarbon group.

In the acyl group of formula (A) above, for example, n is 0 and R is a hydrogen atom or a cycloalkyl group having 5 to 7 ring carbon atoms [this may be an amino group, an acylamino group, as the case may be]. , (the acyl group is mainly the 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 is an acyl group such as an alkali metal salt). optionally substituted phenyl group, naphthyl, which can be substituted preferably in the 1-position by an optionally protected amino group, such as (which can also be in the form of a salt) group or tetrahydronaphthyl group [which in some cases is preferably a hydroxyl group, a lower alkoxy group such as a methoxy group, an acyloxy group (the acyl group being primarily a lower alkoxycarbonyl group, a 2-halogeno lower alkoxycarbonyl group or a phenyl lower alkoxy group) an acyl group of a carbonic acid half-ester, such as a carbonyl group) and (or) can be substituted by a halogen atom, such as a chlorine atom],
Heterocyclic groups which may be substituted (e.g. by lower alkyl groups such as methyl and/or phenyl which may themselves carry a substituent e.g. a halogen atom such as a chlorine atom) [can be substituted by a group]
For example, a 4-isoxazolyl group or an amino group (which amino group is preferably N-substituted, for example by a lower alkyl group which may carry a substituent, for example a halogen atom, such as a chlorine atom) , or n is 1 and R〓 is a lower alkyl group [which optionally preferably has a halogen atom such as a chlorine atom] or a substituent such as a hydroxyl group, an acyloxy group (the acyl group being an amino group and/or which may be protected by a phenyloxy group, which may bear a halogen atom such as a chlorine atom;
amino groups which may be substituted by carboxyl groups], e.g. amino groups which may be protected and/or carboxyl groups [e.g. silylated tri-lower alkylsilylated amino groups such as trimethylsilylated or an acylamino group such as a lower alkanoylamino group, a halogeno lower alkanoylamino group or a phthaloylamino group and/or a carboxyl group which has been silylated, e.g. tri-lower alkylsilylated, e.g. trimethylsilylated, or an esterified e.g. lower alkyl group, a 3-amino-3-carboxy-propyl group, a lower alkenyl group, a phenyl group [which is optionally is a substituent such as a hydroxyl group which can be acylated as described above and/or
by a halogen atom such as a chlorine atom, further protected e.g. by an amino lower alkyl group such as an aminomethyl group which may be acylated as described above, or acylated e.g. as described above. by a hydroxyl group which may carry a hydroxyl group and/or by a phenyloxy group which may bear a halogen atom such as a chlorine atom], by a substituent such as a lower alkyl group such as a methyl group. a pyridyl group, for example a 4-pyridyl group, a pyridinium group, for example a 4-pyridinium group, which may be substituted by an amino group or an aminomethyl group, which may be protected or protected (e.g. acylated as above) or by an aminomethyl group. , thienyl group such as 2-thienyl group, furyl group such as 2-furyl group, imidazolyl group such as 1
-imidazolyl or tetrazolyl group, e.g. 1
- a tetrazolyl group or a lower alkoxy group which may be substituted, such as a methoxy group, a phenyloxy group [which may contain substituents, such as a protected hydroxyl group and (or ) can be substituted by a halogen atom such as a chlorine atom], a lower alkylthio group such as an n-butylthio group or a lower alkenylthio group such as an allylthio group, a substituent substituted with a lower alkyl group such as a methyl group phenylthio group, pyridylthio group such as 4-pyridylthio group, 2-imidazolylthio group, 1,2,4-triazol-3-ylthio group, such as 1,3,4-triazol-2-ylthio group, which can be , 1,2,4-thiadiazol-3-ylthio group such as 5-methyl-
1,2,4-thiadiazol-3-ylthio group,
1,3,4-thiadiazol-2-ylthio group such as methyl-1,3,4-thiadiazole-2-
ylthio or 5-tetrazolylthio groups, such as the 1-methyl-5-tetrazolylthio group, halogen atoms, especially chlorine or bromine atoms, carboxyl groups which may be functionally modified, such as lower alkoxy groups such as methoxycarbonyl and ethoxycarbonyl groups. Carbonyl group, cyano group or N-
A carbamoyl group which may be N-substituted, for example a lower alkyl group such as a methyl group or a phenyl group, a lower alkanoyl group which may be substituted, such as an acetyl or propionyl group, a benzoyl group or an azido group; and
R〓 and R〓 are hydrogen atoms, or n is 1
and R〓 is a lower alkyl group, or a phenyl group which may optionally be substituted with a hydroxyl group and/or a halogen atom, such as a chlorine atom, which may be acylated, e.g. as described above. group, a furyl group such as 2-furyl group, 2
- or a thienyl group such as a 3-thienyl group or an isothiazolyl group such as a 4-isothiazolyl group, and also a 1,4-cyclohexadienyl group, where R〓 is an optionally protected or substituted amino group, e.g. Amino groups, acylamino groups such as lower alkoxycarbonylamino groups, 2-halogeno lower alkoxycarbonylamino groups or phenyl lower alkoxycarbonylamino groups which may carry substituents such as lower alkoxy groups such as methoxy groups or nitro groups, e.g. t-butoxycarbonylamino group, 2,2,2-
trichloroethoxycarbonylamino group, 4-methoxybenzyloxycarbonylamino group or diphenylmethyloxycarbonylamino group, arylsulfonylamino group such as 4-methylphenylsulfonylamino group, tritylamino group, arylthioamino group such as 2-nitrophe 2 which can have a nitrophenylthioamino group or a tritylthioamino group such as a nylthioamino group, or a substituent such as a lower alkylcarbonyl group such as an ethoxycarbonyl group or a lower alkanoyl group such as an acetyl group. - a propylideneamino group, for example a 1-ethoxycarbonyl-2-propylideneamino group, or an optionally substituted carbamoylamino group, such as a guazininocarbonylamino group, or in the form of a salt, such as an alkali metal salt; sulfamino group, which can be
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 as a phenyloxycarbonyl group, such as diphenylmethoxycarbonyl group), a cyano group, a sulfo group, a hydroxyl group that can be functionally modified [the functionally modified hydroxyl group is in particular a formyl group] Acyloxy groups such as oxy groups as well as lower alkoxycarbonyloxy groups, 2-halogeno lower alkoxy carbonyloxy groups or phenyl lower alkoxy which may have substituents (e.g. lower alkoxy groups such as methoxy groups or nitro groups) Carbonyloxy group, such as t-butoxycarbonyloxy group, 2,2,2-
trichloroethoxycarbonyloxy group, 4-methoxybenzyloxycarbonyloxy group or diphenylmethoxycarbonyloxy group, or an optionally substituted lower alkoxy group such as methoxy group or phenyloxy group],
an O-lower alkyl group or an O,O'-dilower alkyl-phosphono group, such as an O-methylphosphono group or an O,O'-dimethylphosphono group, or a halogen atom, such as a chlorine or bromine atom, and R〓 is a hydrogen atom or n is 1;
R〓 and R〓 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 R〓 is, as the case may be, e.g. A phenyl group, a furyl group such as a 2-furyl group, a 2- or a thienyl group such as a 3-thienyl group or an isothiazolyl group such as a 4-isothiazolyl group, and also a 1,4-cyclohexadienyl group, where R〓 is optionally a protected amino group, e.g. is a methyl group and
R〓 is a hydrogen atom, or n is 1, and R〓, R〓, and R〓 are all lower alkyl groups, such as methyl groups.

Such acyl group Ac is, for example, formyl group,
cyclopentylcarbonyl group, α-aminocyclopentylcarbonyl group or α-aminocyclohexylcarbonyl group [which may be a substituted amino group, e.g. an acyl group which can be easily cleaved preferably by hydrolysis or by treatment reductively with a chemical reducing agent such as zinc or with hydrogen contacted with an agent or for example in the presence of aqueous acetic acid; An amino group substituted with an acyl group that can be converted into an acyl group (preferably an appropriate acyl group of a carbonic acid half ester, such as a lower alkoxycarbonyl group such as t-butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group) a 2-halogeno-lower alkoxycarbonyl group such as a 2-bromoethoxycarbonyl group or a 2-iodoethoxycarbonyl group, an arylcarbonylmethoxycarbonyl group such as a phenacyloxycarbonyl group, a substituent such as a lower alkoxy group such as a methoxy group; or a phenyl lower alkoxycarbonyl group which may bear a nitro group, such as a 4-methoxybenzyloxycarbonyl group or a diphenylmethoxycarbonyl group, or a suitable acyl group of a carbonic acid hemiamide, such as a carbamoyl group or an N-substituted carbamoyl group. groups such as N-methylcarbamoyl
- by a lower alkylcarbamoyl group, by a trityl group, and also by an arylthio group such as a 2-nitrophenylthio group, an arylsulfonyl group such as a 4-methylphenylsulfonyl group or a 1-ethoxycarbonyl-2 -1-lower alkoxycarbonyl-2- such as propylidene group
having an amino group substituted with a propylidene group], 2,6-dimethoxybenzoyl 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-isoxazolyl-carbonyl group, 3-(2-chlorophenyl)
-5-methyl-4-isoxazolylcarbonyl group, 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolylcarbonyl group, 2-
Chlorethylaminocarbonyl 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 group [these include, for example, 1 to 2 acyl groups, e.g. or amino groups which may be substituted by lower alkanoyl or phthaloyl groups, which may be halogenated, such as dichloroacetyl groups, and/or functionally in the form of salts, such as sodium salts. or esters with carboxyl groups which can be converted into lower alkyl esters such as methyl esters and ethyl esters or aryl lower alkyl esters such as diphenyl methyl esters], acydoacetyl groups, carboxyacetyl groups. , methoxycarbonylacetyl group, ethoxycarbonylacetyl group, bis-methoxycarbonylacetyl group, N-phenylcarbamoylacetyl group, cyanoacetyl 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 (which may be substituted, e.g. as described above) (having an amino group), phenacylcarbonyl group, phenyloxyacetyl group, 4-trifluoromethylphenyloxyacetyl group, benzyloxyacetyl group, phenylthioacetyl group,
Bromphenylthioacetyl group, 2-phenyloxypropionyl group, α-phenyloxyphenylacetyl group, α-methoxyphenylacetyl group, α-ethoxyphenylacetyl group, α-methoxy-3,4-dichloromethane lorphenylacetyl 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-cyclohexadienyl)-acetyl group, α-amino-α-
(1-cyclohexenyl)-acetyl group, α-aminomethyl-α-phenylacetyl group or α-
Hydroxyphenylacetyl group [In these groups, the amino group present may also be substituted, for example as described above, and/or the aliphatic hydroxyl group and/or phenolic hydroxyl group present may be substituted with an amino group. It may likewise be protected, for example, by a suitable acyl group, in particular a formyl group or an acyl group of carbonic acid half esters], or an α-O-methylphosphono-phenylacetyl group or an α-O,O'-dimethyl-phosphono- -phenylacetyl groups, as well as benzylthioacetyl, benzylthiopropionyl, α-carboxyphenylacetyl groups (which can optionally carry functionally modified carboxyl groups, e.g. as mentioned above) ), 3-phenylpropionyl group, 3-(3-cyanophenyl)-propionyl group, 4-(3-methoxyphenyl)-butyryl group, 2-pyridylacetyl group, 4-aminopyridinium acetyl group (in some cases 2-thienylacetyl group, 3-thienylacetyl group, 2-tetrahydrothienyl acetyl group, 2-furylacetyl group, 1-imidazolylacetyl group. , 1-tetrazolylacetyl group, α
-carboxy-2-thienyl acetyl group or α
-carboxy-3-thienylacetyl groups (these can optionally have functionally modified carboxyl groups, e.g. as mentioned above),
α-cyano-2-thienyl acetyl group, α-amino-α-(2-thienyl)-acetyl group, α-amino-α-(2-furyl)-acetyl group or α
-amino-α-(4-isothiazolyl)-acetyl group (these can optionally carry amino groups substituted, for example as above), α
-sulfophenylacetyl group (the sulfo group can optionally be a functionally modified sulfo group, such as the carboxyl group mentioned above), 3-methyl-2-imidazolylthioacetyl group, 1 , 2,4-triazol-3-ylthioacetyl group, 1,3,4-triazol-2-ylthioacetyl group 5-methyl-1,2,4-thiadiazol-3-ylthioacetyl group, 5-methyl -1,3,4-thiadiazol-2-ylthioacetyl group or 1-methyl-5-tetrazolylthioacetyl group.

The acyl group Ac of a carbonic acid half ester which is easily cleavable, in particular the acyl group Ac of a carbonic acid half ester, which can be cleaved by reduction e.g. treatment with a chemical reducing agent or by acid treatment e.g. trifluoroacetic acid, e.g. lower alkoxycarbonyl radicals which are highly branched and/or aromatically substituted in the carbon atom 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 at the β-position, such as a t-butoxycarbonyl group, a t-pentoxycarbonyl group, a phenacyloxycarbonyl group, 2,
2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl or groups convertible into 2-iodoethoxycarbonyl, such as 2-chloroethoxycarbonyl or 2-bromoethoxycarbonyl, and preferably Polycyclic cycloalkoxycarbonyl groups, such as adamantyloxycarbonyl groups,
an optionally substituted phenyl-lower alkoxycarbonyl group, especially an α-phenyl-lower alkoxycarbonyl group (preferably polysubstituted in the α-position), such as a diphenylmethoxycarbonyl group or an α-4- biphenylyl-α-methylethoxycarbonyl group, or furyl-lower alkoxycarbonyl group especially α-
Furyl - lower alkoxycarbonyl group, for example furfuryloxycarbonyl group.

The divalent acyl group formed by the groups R ^A ₁ and R ^b ₁ is, for example, an acyl group of a lower alkanedicarboxylic acid or a lower alkenedicarboxylic acid, such as a succinyl group, or an O-arylene dicarboxylic acid group such as a phthaloyl group. It is an acyl group.

Other divalent radicals formed by the radicals R ^A ₁ and R ^b ₁ may also have, for example, a substituent in the 2-position, such as a phenyl or thienyl group, which may be substituted and optionally 1-oxo-3-aza-1,4-butylene radicals, which may even be mono- or di-substituted in the 4-position with lower alkyl groups such as methyl radicals, e.g. 4,4-dimethyl-2 -Phenyl-1-oxo-3-aza-1,4
-Butylene group.

The etherified hydroxyl group R ^A ₂ is preferably a readily cleavable or other functionally modified carboxyl group (e.g. a carbamoyl group or a hydrazinocarbonyl group) whenever a carbonyl group in the formula It forms an esterified carboxyl group that can be easily converted into Such groups R ^A ₂ are, for example, methoxy, ethoxy,
A lower alkoxy group such as an n-propoxy group or an isopropoxy group, which together with a carbonyl group forms an esterified carboxyl group. can be converted into a free carboxyl group or into other functionally altered carboxyl groups.

The etherified hydroxyl group R ^A ₀ forming an esterified carboxyl group which can be particularly easily split with the group C-(=O)- is, for example, a halogen atom with an atomic weight of 19 or more. It is a 2-halogeno-lower alkoxy group with Such groups, along with the group -C(=O)-, are easily cleaved by treatment with zinc in the presence of a chemical reducing agent such as aqueous acetic acid under neutral or slightly acidic conditions. or an esterified carboxyl group that can be easily converted into such a group. Such groups are, for example, 2,2,2
-trichloroethoxy group or 2-iodoethoxy group, or 2-chloroethoxy group or 2-chloroethoxy group that can be easily converted into 2-iodoethoxy group
-Bromethoxy group.

Additionally, by treatment with zinc in the presence of a chemical reducing agent such as aqueous acetic acid, also under neutral or weakly acidic conditions, or by treatment with a suitable nucleophilic agent such as sodium thiophenolate. As the etherified hydroxyl group R ^A ₂ which forms an esterified carboxyl group which can be easily split with the group -C(=O)-, an arylcarbonylmethoxy group ( Aryl is in particular phenyl, which may be substituted) and preferably phenacyloxy.

Furthermore, the radical R ^A ₂ can also be an arylmethoxy radical, the aryl group of which is in particular a monocyclic, preferably substituted, aromatic hydrocarbon radical.
Such groups are based on esterified carboxyl groups that can be easily cleaved under neutral or acidic conditions by irradiation, preferably by UV irradiation.
It is always formed as C(=O)-. The aryl group in such an arylmethoxy group is in particular a lower alkoxyphenyl group, such as a methoxyphenyl group, the methoxy group being primarily in the 3-, 4- and/or 5-position and/or especially a nitrophenyl group, the nitro group preferably being in the 2-position;
It is. Such groups are especially lower alkoxy,
For example, methoxy-benzyloxy and/or nitro-benzyloxy groups, primarily 3- or 4-methoxybenzyloxy, 3,5-dimethoxybenzyloxy, 2-nitrobenzyloxy or 4,5-dimethoxy-2 -Nitrobenzyloxy group.

Furthermore, the etherified hydroxyl group R ^A ₂ can be replaced by an esterified carboxyl group, which can be easily cleaved under acidic conditions, e.g. by treatment with trifluoroacetic acid or formic acid, as a group -C(=O)-. It can also be a group formed in Such groups are mainly composed of hydrocarbon groups, in particular aliphatic or aromatic hydrocarbon groups, the methyl group of which may be substituted, e.g. by lower alkyl groups such as the methyl group and/or by phenyl groups. methoxy radicals which are substituted or monosubstituted by carbocyclic aryl radicals bearing electron-donating substituents or by aromatic heterocyclic radicals having oxygen or sulfur atoms as ring members; or the methyl 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 oxaalicyclic or alicyclic group. This is a methoxy group.

Preferred among this type of polysubstituted methoxy groups are t-lower alkoxy groups such as t-
butyloxy group or t-pentyloxy group, optionally substituted diphenylmethoxy group,
For example, diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, and also 2-(4
-biphenyl)-2-propyloxy group,
The above-mentioned methoxy group with a substituted aryl group or heterocyclic group is an α-lower alkoxyphenyl-lower alkoxy group such as a 4-methoxybenzyloxy group or a 3,4-dimethoxybenzyloxy group, or a 2-fluor Furfuryloxy group such as furyloxy group. The polycyclic aliphatic hydrocarbon group having the methyl group of the methoxy group as a preferably three-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-alicyclic group having as a ring member α-position relative to the oxygen or sulfur atom is, for example, a 2-oxa- or 2-thia-lower alkylene group having 5 to 7 ring atoms. or lower alkenylene groups, such as 2-tetrahydrofuryl, 2-tetrahydropyranyl or 2,3-dihydro-2
- a pyranyl group or a corresponding sulfur homologue.

Furthermore, the group R ^A ₂ represents an esterified carboxyl group which can be cleaved by hydrolysis, e.g. under weakly basic or acidic conditions.
It can also be an etherified hydroxyl group formed together with -. Such groups are preferably etherified hydroxyl groups, such as 4-nitrophenyloxy or 2,4-dinitro groups, which form an activated ester group together with the group -C(=O)-. Nitrophenyloxy group such as phenyloxy group, nitrophenyl lower alkoxy group such as 4-nitrobenzyloxy group, hydroxy-lower alkyl group such as 4-hydroxy-3,5-t-butyl-benzyloxy group benzyloxy groups, polyhalogenophenyloxy groups such as 2,4,6-trichlorophenyloxy groups and 2,3,4,5,6-pentachlorophenyloxy groups, as well as cyanomethoxy groups and acylaminomethoxy groups. Examples include phthaliminomethoxy or succinyliminomethoxy groups.

It is also possible that the group R ^A ₂ is an etherified hydroxyl group which together with the carbonyl group -C(=O)- forms an esterified carboxyl group which can be split under hydrogenolysis conditions. This is, for example, an α-phenyl lower alkoxy group which can be substituted with a lower alkoxy group or a nitro group, such as, for example, a benzyloxy group, a 4-methoxybenzyloxy group or a 4-nitrobenzyloxy group.

The group R ^A ₂ is also an etherified hydroxyl group which together with the carbonyl group -C(=O)- forms an esterified carboxyl group which can be split under physiological conditions, mainly an acyloxymethoxy group, the acyl group being for example the group of an organic carboxylic acid, primarily a lower alkane carboxylic acid which may be substituted, or the acyloxymethyl moiety forming a lactone group; You can do something. Such etherified hydroxyl groups include lower alkanoyloxymethoxy groups such as acetyloxymethoxy or pivaloyloxymethoxy groups, amino-lower alkanoyloxymethoxy groups, especially α-amino-lower alkanoyloxymethoxy groups such as glycyloxymethoxy group, L-valyloxymethoxy group, L
-Leucyloxymethoxy group, and furthermore, phthalidyloxy group.

R ^A ₂ as a silyloxy or stannyloxy group is preferably an optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon group such as a lower alkyl group, a halogeno-lower alkyl group, a cyclo an alkyl 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 trimethylsilyloxy tri-lower alkylsilyloxy groups such as halogeno-lower alkoxy groups such as chloro-methoxy-methyl-silyl groups;
A lower alkyl-silyl group or a tri-lower alkylstannyloxy group such as a tri-n-butylstannyloxy group.

R ^A ₂ as an acyloxy group which together with the group -C(=O)- preferably forms a mixed anhydride group which can be cleaved by hydrolysis, is for example A lower alkanoyloxy group, such as an acetyloxy group, carrying an acyl group of the derivative, which may optionally be substituted, preferably in the α-position, by a halogen atom, such as a fluorine atom or a chlorine atom. , pivalyloxy group or trichloroacetyloxy group or lower alkoxycarbonyloxy group such as methoxycarbonyloxy group or ethoxycarbonyloxy group.

Furthermore, a carbamoyl group or a hydrazinocarbonyl group which may be substituted with a group -C (=
R ^A ₂ as a group formed together with O)- is, for example, an amino group, a lower alkylamino group such as a methylamino group or an ethylamino group, or a di-lower alkyl group such as a dimethylamino group or a diethylamino group. Amino group, lower alkylene amino group such as pyrrolidino group or piperidino group, oxa lower alkylene amino group such as morpholino group, 2-lower alkylhydrazino group such as hydroxyamino group, hydrazino group, 2-methylhydrazino group or 2,
2,2-di-lower alkyl group hydrazino group such as 2-dimethylhydrazino group.

The lower alkyl group R ₃ has up to 7, preferably up to 4 carbon atoms and is methyl, ethyl, n-propyl, hexyl or heptyl.

R ₃ is α-phenyl-lower alkyl group,
Particularly benzyl and diphenylmethyl groups, substituents of the phenyl nucleus being, for example, esterified or etherified hydroxyl groups, such as halogen atoms, such as fluorine, chlorine or bromine atoms, or lower alkoxy groups, such as methoxy groups.
Salts are suitable in particular of formulas (A) and (
Salts of the compounds of B), principally metal 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 with ammonia or suitable organic amino acids. It's salt. 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, hydroxy-lower alkyl amines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, 4-amino Basic aliphatic esters of carboxylic acids such as benzoic acid-2-diethylamino-ethyl ester, lower alkylene amines such as 1-ethylpiperidine, cycloalkylamines such as bicyclohexylamine or N,N′-
benzylamines such as dibenzylethylenediamine and also pyridine type bases such as pyridine, collidine or quinoline. Compounds of formulas (A) and (B) 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. Compounds of formulas (A) and (B) having an acidic group and a basic group can also be in the form of internal salts, ie, in the form of zipper ions. 1-oxides of compounds of formula (A) that have salt-forming groups 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 (A), for example, R ^A ₁ is a 6β-amino-penam-3-carboxylic acid compound or a 7β-amino-3-cephem-4
- Acyl group Ac present in pharmacologically active N-acyl derivatives of carboxylic acid compounds, and R ^b ₁ is a hydrogen atom or R ^A ₁ and R ^b ₁ are both 2-
1-oxo-3-aza- substituted in the 4-position preferably by an aromatic or heterocyclic group and in the 4-position preferably by two lower alkyl groups, such as methyl groups;
Represents a 1,4-butylene group, R ₂ is a hydroxyl group or etherification, in which an esterified carboxyl group that can be easily cleaved under physiological conditions is formed with the carbonyl group. the hydroxyl group R ^A ₂ and R ₃ is a lower alkyl group, and the functional groups that may be present in R ^a ₁ as an acyl group, such as amino, carboxyl, hydroxyl and/or sulfo groups, are usually free. Compounds such as those present in the form of ), Streplicoccus
Streptococcus Pyrogenes and Diplococcus pneumoniae
pneumoniae) (e.g. approximately 0.001 to 0.02 in mice)
g/KgS.c. or Po) and Gram-negative bacteria such as Escherichia coli.
coli), Salmonella typhimurium, Shigella flexneri, Klebsiella pneumoiae, Enterobacter cloacae,
Proteus vulgaris,
Proteus rettgeri and Proteus mirabilis
mirabilis) (e.g. approximately 0.001 to 0.15 in mice)
g/KgS.c. or Po), it 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.

In the compound of formula (B) or the 1-oxide of the compound of formula (A), R ^a ₁ , R ^b ₁ , R ₂ and R ₃ have the same meanings as defined above in relation to formula (A). or in formula (A), R ₃ has the same meaning as above, and R ^a ₁ and R ^b ₁ are hydrogen atoms,
or R ^a ₁ is a 6β-amino-penam-3-carboxylic acid compound or 7β-amino-3-cephem-4
- an amino protecting group different from the acyl group present in the pharmacologically active N-acyl derivatives of carboxylic acid compounds and R ^b ₁ is a hydrogen atom or R ^a ₁ and R ^b ₁
and in both the 2-position, preferably by an aromatic or heterocyclic group and in the 4-
a divalent oxy-protecting group different from a 1-oxo-3-aza-1,4-butylene group substituted in position preferably by two lower alkyl groups such as a methyl group and R ₂ is a hydroxyl group,
or a group R in which R ^a ₁ and R ^b ₁ have the above meanings and R ₂ preferably forms an easily cleavable protected carboxyl group with the group -C(=O)-; ^A ₂ (provided that the protected carboxyl group is not a physiologically cleavable carboxyl group), and R ₃ has the above meaning, can be easily described in the above pharmacological formulations, e.g. It is a valuable intermediate that can be converted into active compounds.

The present invention particularly provides that R ^a ₁ in formula (A) is a hydrogen atom, a 6β-amino-penam-3-carboxylic acid compound, or a 7β-amino-3-cephem-4
- acyl groups present in particularly pharmacologically active (e.g. highly active) N-acyl derivatives which can be prepared fermentatively (i.e. naturally occurring) or biosynthetically, semi-synthetically or totally synthetically of carboxylic acid compounds, e.g. Acyl group of formula (A) For example, one of the acyl groups of formula (A) above
and
R ^b ₁ is a hydrogen atom or R ^a ₁ and R ^b ₁ are both in the 2-position preferably by an aromatic or heterocyclic group such as a phenyl group and 4
1 substituted in the - position preferably by two lower alkyl groups, such as for example methyl groups;
-oxo-3-aza-butylene group, and
R ₂ is a hydroxyl group, a lower alkoxy group [which may optionally be substituted, preferably in the α-position, for example by an optionally substituted aryloxy group, e.g. a lower alkoxyphenyloxy group such as the 4-methoxyphenyloxy group; groups, lower alkanoyloxy groups such as acetyloxy or pivaloyloxy, α-amino lower alkanoyloxy groups such as glycyloxy, L-valyloxy or L-leucyloxy, arylcarbonyl groups such as benzoyl, or substituted or by β- a lower alkoxy group, such as a methoxy group, which may be mono- or polysubstituted in position by a halogen atom, such as a chlorine atom, a bromine atom or an iodine atom;
Bis-phenyloxy, which can be substituted with a lower alkoxy group such as ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, 1-butyloxy or t-pentyloxy, or a lower alkoxy group. methoxy groups such as bis-4-methoxyphenyloxy-methoxy groups, lower alkanoyloxy-methoxy groups such as acetyloxymethoxy or pivaloyloxymethoxy groups, α-amino lower alkanoyloxy-methoxy groups such as glycyl oxymethoxy groups, phenyloxy groups, phenyl lower alkoxy groups which may be substituted, especially 1-phenyl lower alkoxy groups such as phenylmethoxy groups (such groups include, for example, substituents such as lower alkoxy groups such as methoxy groups, nitro groups). or may have 1 to 3 phenyl groups which may be substituted with phenyl groups), such as benzyloxy group, 4-methoxybenzyloxy 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-trichloroethoxy group, 2-chloroethoxy group, 2-bromoethoxy group or 2-iodoethoxy group], as well as 2-phthalidyloxy group and acyloxy group (for example, lower alkoxycarbonyloxy group such as methoxycarbonyloxy group or ethoxycarbonyloxy group or acetyloxy group) a lower alkanoyloxy group such as a pivaloyloxy group), a tri-lower alkylsilyloxy group such as a trimethylsilyloxy group, or an amino group or a hydrazino group (which may in some cases be a lower alkyl group such as 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-
a 2-lower alkylhydrazino group such as a methylhydrazino group, a 2,2-dilower alkylhydrazino group such as a 2,2-dimethylhydrazino group, or a hydroxyamino group, and R ₃ is a hydrogen atom, Cefam-3-one compounds which are lower aralkyl groups, especially methyl groups, or benzene or diphenylmethyl groups (which may be substituted, for example, with halogen atoms or lower alkoxy groups), their 1-oxides and formula (B) or the salts of such compounds with a salt-forming group. In particular, 3-cephem-compounds of formula (A) and the corresponding 2-cephem compounds of formula (B)
In the cefem compound and the 1-oxide of the 3-cefem compound of formula (A) or the salt of these compounds having a salt-forming group, R ^a ₁ is mainly a hydrogen atom or 6β-amino-penam-3-carboxylic acid. Acyl groups depending on the compound or N-acyl derivatives which can be produced by fermentation (i.e. naturally occurring) or biosynthetically of the 7β-amino-3-cephem-4-carboxylic acid compound, especially the group of formula (A) In this formula, R〓, R〓, R〓 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 further optionally Thus, for example, lower alkylthio or lower alkenylthio groups, substituted, e.g. amino groups which may be acylated and/or functionally modified carboxyl groups (e.g. carboxyl groups which may be esterified) ), such as 4-hydroxy-phenylacetyl, hexanoyl, octanoyl or n-butylthioacetyl and especially 5-amino-5- a carboxy-valeryl group, the amino and/or carboxyl groups of which are optionally protected and can be present, for example, as an acylamino group or an esterified carboxyl group; a phenylacetyl group or a phenyl group; is an oxyacetyl 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 (A) (in this formula Formula R〓, R〓, R〓
and n mainly have the meanings given above as preferred), for example formyl group, 2-halogenoethylcarbamoyl group such as 2-chloroethylcarbamoyl group, cyanoacetyl group, phenylacetyl group, 2-thienylacetyl group tetrazolyl groups such as, but especially in the α-position cyclic groups such as alicyclic, aromatic or heterocyclic groups and functional groups mainly by monocyclic groups, mainly amino groups, carboxyl groups, an acetyl group substituted by a sulfo group or a hydroxyl group, in particular a phenylglycyl group (the phenyl group in this group may optionally be, for example, a protected hydroxyl group, e.g. an acyloxy group, which may be substituted with a halogen); Phenyl groups, such as phenyl groups, which can be substituted by lower alkoxycarbonyloxy or lower alkanoyloxy groups and/or by halogen atoms, such as chlorine atoms, 3
- or a 4-hydroxy-, 3-chloro-4-hydroxy- or 3,5-dichloro-4-hydroxyphenyl group (the hydroxyl group can also be a protected eg acylated hydroxyl group) and an amino The radicals may optionally be substituted and may be in the form of salts, for example, sulphoamino groups or substituted amino groups (for example, as substituents, trityl groups or primarily acyl groups which can be cleaved by hydrolysis). For example, an optionally substituted carbamoyl group, an optionally substituted ureidocarbonyl group, such as a ureidocarbonyl group or an N'-trichloromethylureidocarbonyl group, or a substituted ureidocarbonyl group, such as a guanidinocarbonyl group. Some guanidinocarbonyl groups, or when treated reductively with acids such as trifluoroacetic acid or with chemical reducing agents such as zinc or contacted hydrogen in the presence of aqueous acetic acid or by hydrolysis or an acyl group which can be converted into such an acyl group, preferably a suitable acyl group of a carbonic acid half ester, such as an alkoxycarbonyl group which may be halogen-substituted or benzoyl-substituted, such as t-butyloxy. Carbonyl group, 2,2,2-trichloroethyloxycarbonyl group, 2-chloroethoxycarbonyl group, 2-bromoethoxycarbonyl group, 2-
iodoethoxycarbonyl group, or phenacyloxycarbonyl group, phenyl lower alkoxycarbonyl group which may be lower alkoxy- or nitro-substituted, such as 4-methoxybenzyloxycarbonyl group or diphenylmethoxycarbonyl group, or carbamoyl group or N- Acyl groups of carbonic acid hemiamides such as methylcarbamoyl groups, and also arylthio groups or aryl lower alkylthio groups which are cleaved by nucleophilic agents such as hydrocyanic acid, sulfite or thioacetamide, such as 2-nitrophenylthio or a tritylthio group, an arylsulfonyl group that can be cleaved by electroreduction, such as a 4-methylphenylsulfonyl group, or a 1-lower alkoxycarbonyl-2- group that can be cleaved with an acidic agent such as formic acid or an aqueous inorganic acid, such as hydrochloric acid or phosphoric acid. a propylidene group or a 1-lower alkanoyl-2-propylidene group, such as a 1-ethoxycarbonyl-2-propylidene group], and further α-1,4-
Cyclohexadienyl-glycyl group, α-(1-
cyclohexenyl)-glycyl group, α-thiethylglycyl group such as α-2- or α-3-thienylglycyl group, α-furylglycyl group such as α-2-furylglycyl group, or α-4-isothiazolyl-glycyl group. such as the α-isothiazolylglycyl group (the amino group of these groups can be substituted or protected, e.g. the phenylglycyl group mentioned above), and also the α-carboxy-phenylacetyl group. or an α-carboxy-thienylacetyl group, such as an α-carboxy-2-thienylacetyl group (which may optionally be a functionally modified carboxyl group, for example in the form of a salt such as the sodium salt or an ester such as the methyl ester or ethyl may have carboxyl groups in the form of lower alkyl esters such as esters or phenyl-lower alkyl esters such as diphenylmethyl ester) or α-sulfo-phenylacetyl groups (which may in some cases For example, it may have a functionally modified sulfo group like the above carboxyl group),
α-phosphono-, α-O-methylphosphono- or α-O,O′-dimethylphosphono-phenylacetyl group, or α-hydroxy-phenylacetyl group [this is a functionally modified hydroxyl group, especially An acyloxy group, which is preferably easily cleavable when treated with an acidic agent such as trifluoroacetic acid or with a chemical cyclizing agent such as zinc in the presence of aqueous acetic acid. An acyl group or an acyl group convertible into such an acyl group, preferably an acyl group of a carbonic acid half ester, such as a lower alkoxycarbonyl group which can be halogen-substituted or benzoyl-substituted, such as those mentioned above, e.g. 2,2,2 - trichloroethoxycarbonyl group, 2-chloroethoxycarbonyl group, 2-bromoethoxycarbonyl group, 2-iodoethoxycarbonyl group, t-butyloxycarbonyl group or phenacyloxycarbonyl group, and also formyl group). ], and amino-pyridinium acetyl groups such as 1-amino-cyclohexylcarbonyl groups, aminomethylphenylacetyl groups such as 2- or 4-aminomethyl-phenylacetyl groups, or 4-aminopyridinium acetyl groups. or a pyridylthioacetyl group such as a 4-pyridylthioacetyl group, and R ^b ₁ is a hydrogen atom; Alternatively, R ^a ₁ and R ^b ₁ are both 1-oxo-3-aza-1,4-butylene groups that may have two lower alkyl groups such as methyl groups at the 4-position [this is 2 - position, preferably by 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 by a halogen atom such as a chlorine atom. phenyl groups which may be substituted, such as phenyl groups, or 3- or 4-hydroxy-, 3-chloro-
4-hydroxy- or 3,5-dichloro-4-
a hydroxy-phenyl group, the hydroxyl group of which can also be protected, e.g. acylated as described above], and
R ₂ is a hydroxyl group, a lower alkoxy group, especially a highly branched lower alkoxy group in the α-position, such as a t-butoxy group, and also a methoxy or ethoxy group, 2
-halogeno lower alkoxy group or 2,2,2-
a phenyl group which can be substituted with a trichloroethoxy group, a 2-iodoethoxy group or a 2-chloroethoxy group or a 2-bromoethoxy group that can be easily converted into this group, a phenacyloxy group, a lower alkoxy group or a nitro group; 1~
1-phenyl lower alkoxy group having three atoms, 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 such as glycyloxymethoxy group, 2-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 R ₃ is a hydrogen atom, a lower alkyl group, especially a methyl group; or a benzyl or diphenylmethyl group, which may be optionally substituted, for example with a halogen, chlorine or bromine atom, or with a lower alkoxy group, such as a methoxy group.

The present invention mainly relates to formula A in which R ^a ₁ is the formula [In this formula, Ra is a phenyl group or a hydroxyphenyl group, such as a 3- or 4-hydroxyphenyl group, and a hydroxy-chlorophenyl group, such as a 3-chloro-4-hydroxyphenyl group or a 3,5-dichloro-4-hydroxy phenyl group (in these groups, the hydroxyl group is a lower alkoxycarbonyl group that can be halogenated, such as a t-butoxycarbonyl group or a 2,2,2
- can be protected by an acyl group such as a trichloroethoxycarbonyl group), 2
- or a thienyl group such as a 3-thienyl group, a pyridyl group such as a 4-pyridyl group, an aminopyridinium group such as a 4-aminopyridinium group, a furyl group such as a 2-furyl group, or a 4-isothiazolyl group. isothiazolyl group such as, tetrazolyl group such as 1-tetrazolyl group or 1,4
- cyclohexadienyl group or 1-cyclohexenyl group, X is an oxygen atom or a sulfur atom, m is 0 or 1, and Rb is a hydrogen atom, or if m is 0,
Rb is an amino group, a protected amino group such as an acylamino group, a highly branched lower alkoxycarbonylamino group at the α-position such as t-butoxycarbonylamino group, a 2,2,2-trichloroethoxycarbonylamino group, 2-halogeno lower alkoxycarbonylamino groups such as 2-iodoethoxycarbonylamino or 2-bromoethoxycarbonylamino groups, or phenyl lower alkoxycarbonylamino groups which may be lower alkoxy- or nitro-substituted, e.g. 4-methoxy benzyloxycarbonylamino group or diphenylmethoxycarbonylamino group, or 3-guanylureido group, as well as sulfamino group, tritylamino group, arylthioamino group such as 2-nitrophenylthioamino group,
An arylsulfonylamino group such as a 4-methylphenylsulfonylamino group or a 1-lower alkoxycarbonyl-2-propylideneamino group such as a 1-ethoxycarbonyl-2-propylideneamino group, a carboxy group or a salt such as an alkali such as a sodium salt. Carboxyl groups in the form of metal salts, as well as protected carboxyl groups such as esterified carboxyl groups such as phenyl lower alkoxycarbonyl groups such as diphenylmethoxycarbonyl groups, sulfo groups or salts such as alkali metal salts such as sodium salts. a sulfo group, a protected sulfo group, a hydroxyl group or a protected hydroxyl group such as an acyloxy group such as a t-
A highly branched lower alkoxycarbonyloxy group at the α-position such as butoxycarbonyloxy group, 2,2,2-trichloroethoxycarbonyloxy group, 2-iodoethoxycarbonyloxy group or 2-bromoethoxycarbonyloxy group. 2-halogen lower alkoxycarbonyloxy group, further formyloxy group, or O-
an acyl group represented by a lower alkylphosphono group or an O,O'-dilower alkylphosphono group, such as an O-methylphosphono group or an O,O'-dimethylphosphono group, or a 5-amino-5-carboxyvaleryl group; group (its amino group and/or
The carboxyl group can also be protected, for example 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 a phthaloylamino group, or an esterified carboxyl group, for example a phenyl lower alkoxycarbonyl group such as a diphenylmethoxycarbonyl group (where 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 thienyl group, a furyl group, an isothiazolyl group,
When it is a 1,4-cyclohexadienyl group or a 1-cyclohexenyl group, m is 0 and Rb
is preferably not a hydrogen atom), R ^b ₁ is a hydrogen atom and R ₂ is mainly a hydroxyl group and a lower alkoxy group, especially a highly branched lower alkoxy group in the α-position, such as a t-butoxy group, a 2-halogen -lower alkoxy groups such as 2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy groups, or diphenylmethoxy groups which may be substituted with lower alkoxy groups such as methoxy groups, e.g. a diphenylmethoxy group or a 4,4'-dimethoxy-diphenylmethoxy group, as well as a tri-lower alkylsilyloxy group such as a trimethylsilyloxy group, and
R ₃ is a hydrogen atom, a lower alkyl group such as a methyl group,
3- which is an ethyl or n-butyl group, as well as a benzyl or diphenylmethyl group (these groups may optionally be substituted with a halogen atom, such as a chlorine or bromine atom, or a lower alkoxy group, such as a methoxy group); Cefm
compounds, such 1-oxides of 3-cephem compounds of formula (A) and corresponding 2-cepheme compounds of formula (B), or salts of such compounds with salt-forming groups, especially for pharmaceutical use. Non-toxic salts that can be used, for example alkali metal salts such as sodium salts, alkaline earth metal salts such as calcium salts of compounds in which R ₂ is a hydroxyl group and have a free amino group in the acyl group of formula (B). Ammonium salts, including salts or amine salts.

Primarily 3-cephem compounds of formula (A) and corresponding 2-cepheme compounds of formula (B) or the salts of such compounds with salt-forming groups, especially those mentioned in the preceding paragraph, can be used pharmaceutically. In the non-toxic salt, R ^a ₁ 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, 2
- or thienyl group, such as 3-thienyl group, 4
- isothiazolyl group or 1,4-cyclohexadienyl group or 1-cyclohexenyl group, X is an oxygen atom, m is 0 or 1, and Rb is a hydrogen atom or m is 0
, Rb is an amino group, a protected amino group, such as an acylamino group, a lower alkoxycarbonylamino group highly branched in the α-position, such as a t-butoxycarbonylamino group, 2,
a 2-halogeno lower alkoxycarbonylamino group, such as a 2,2-trichloroethoxycarbonylamino group, a 2-iodoethoxycarbonylamino group or a 2-bromoethoxycarbonylamino group, or which may be lower alkoxy-substituted or nitro-substituted; Phenyl lower alkoxycarbonylamino group, such as 4-methoxybenzyloxycarbonylamino group, or hydroxyl group or protected hydroxyl group, such as acyloxy group, such as t-
A highly branched lower alkoxycarbonyloxy group in the α-position such as butoxycarbonyloxy group, 2,2,2-trichloroethoxycarbonyloxy group, 2-iodoethoxycarbonyloxy group or 2-bromoethoxycarbonyloxy group. 2-halogeno lower alkoxycarbonyloxy groups such as 2-halogeno lower alkoxycarbonyloxy groups, further formyloxy groups) or 5-amino-5-carboxyvaleryl groups (the amino and carboxyl groups of which can also be protected, such as acylamino groups such as acetyl lower alkanoylamino groups such as amino groups,
(can be present as a halogeno lower alkanoylamino group, such as a dichloroacetylamino group, a benzoylamino group or a phthaloylamino group, or as an esterified carboxyl group, e.g. a phenyl lower alkoxycarbonyl group, such as a diphenylmethoxycarbonyl group) (Note that when Ra is a phenyl group or a hydroxyphenyl group, m is preferably 1), R ^b ₁
is a hydrogen atom, R ₂ is primarily a hydroxyl group, and also a lower alkoxy group which may be substituted in the 2-position by a halogen atom, such as a chlorine atom, a bromine atom or an iodine atom, especially highly branched in the α-position. Lower alkoxy groups such as t-butoxy group, 2-
Halogeno-lower alkoxy group e.g. 2,2,2-
a trichloroethoxy group, a 2-iodoethoxy group or a 2-bromoethoxy group, or a diphenylmethoxy group, which may be substituted with a lower alkoxy group such as, for example, a methoxy group, such as a diphenylmethoxy group or a 4,4'-dimethoxy group; - diphenylmethoxy, or p-nitrobenzyloxy, and also tri-lower alkyloxy, such as trimethylsilyloxy, and R ₃ is a hydrogen atom, a lower alkyl group such as especially a methyl, benzyl or diphenylmethyl group (if may be 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 phenyl group, 4-hydroxyphenyl group, 2-thienyl group, 1,4-cyclohexadienyl group or 1-
cyclohexenyl 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-cephem-4-carboxylic acid and its inner salt production method, and intermediate for producing 3-lower alkoxy-3-cepheme-4-carboxylic acid compound The present invention provides the production of a 3-hydroxy-3-cephem-4-carboxylic acid compound that is useful as a body. These 3-lower alkoxy compounds exhibit, at the abovementioned doses, especially when administered orally, a marked antibiotic action with low toxicity against Gram-positive and especially Gram-negative bacteria.

According to the method of the present invention, a compound represented by general formula (A), its 1-oxide, general formula (B)
Compounds represented by and salts of those compounds having a salt-forming group are represented by the general formula [In this formula, R ^a ₁ is a hydrogen atom or an amino protecting group R ^A ₁
where 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 carbonyl group -C in the formula.
It is a group that forms a protected carboxyl group when combined with (=O)-, and the group -N(R ^a ₄ ) (R ^b ₄ )
is a secondary or tertiary amino group, and Y is a group to be removed] A formula formed as an intermediate product by removing H--Y from a compound represented by [In this formula, R ^a ₁ , R ^b ₁ , R ^A ₂ and -N(R ^a ₄ ) (R ^b ₄ ) have the same meanings as above, and the 2,3-position or the 3,4-position
- can have a double bond at the amino group -N in enamine represented by
(R ^a ₄ )(R ^b ₄ ) is solvolyzed to form a group -OR ₃ (in this formula, R ₃ is a hydrogen atom, a lower alkyl group, or an optionally substituted α-phenyl-lower alkyl group). and optionally formula (A) or (
B) In the resulting compound represented by formula -C
Converting the protected carboxyl group represented by (=O)-R ^A ₂ to a free or other protected carboxyl group and/or optionally converting the α-phenyl-lower alkoxy group -O-R ₃ into a free hydroxyl group and/or convert the resulting free hydroxyl group -O-R ₃ into a lower alkoxy group -O-R 3 and (or) optionally convert the obtained free hydroxyl group -O-R ₃ within the definition of the final product. converting the resulting compound into another compound and/or optionally converting the resulting compound with a salt-forming group into a salt or converting the resulting salt into the free compound or other salt; It can be produced by separating a mixture of isomeric compounds obtained by the method into individual isomers.

In the compound represented by the formula (), the amino group -N(R ^a ₄ )(R ^b ₄ ) is the same as the carboxyl group.
It can be in the trans-position (crotonic acid coordination) or in the cis-position (isocrotonic acid coordination).

In the starting compound of formula (), the group Y to be removed is, for example, -S-R ₄ group, -SO ₂ -R ₅ group (bonded to thio group -S- by a sulfur atom), or -S- _SO2 - _R5 groups.

In the group represented by -S-R ₄ , R ₄ has up to 15 carbon atoms, preferably up to 9 carbon atoms, and contains at least one ring nitrogen atom and optionally other ring heteroatoms such as oxygen or sulfur atoms. an aromatic heterocyclic group which may be substituted with a thio group -S- by one ring carbon atom which is bonded to the ring nitrogen atom by a double bond. It is assumed that Such groups are monocyclic or bicyclic and contain substituents such as lower alkyl groups such as methyl or ethyl, lower alkoxy groups such as methoxy or ethoxy, fluorine or chlorine atoms. can be substituted with a halogen atom, such as, or an aryl group, such as a phenyl group.

Such a group R ₄ is, for example, a monocyclic 5-membered ring,
Thiaza ring group, thiatriaza ring group, oxadiaza ring group or oxatriaza ring group (these groups are aromatic groups), especially aromatic, especially monocyclic five-membered diaza ring group, oxyaza ring group cyclic groups and thiaza cyclic groups, and/or especially corresponding benzdiaza cyclic groups, benzoxyaza cyclic groups or benzthiaza cyclic groups in which the heterocyclic moiety is a 5-membered ring and exhibits aromatic character. Yes, base
The substitutable nitrogen atom in R ₄ may be substituted, for example, by a lower alkyl group. Examples of such a group R ₄ include 1-methyl-imidazol-2-yl group, 1,3-thiazol-2-yl group,
yl group, 1,3,4-thiadiazol-2-yl group, 1,3,4,5-thiatriazol-2-yl group, 1,3-oxazol-2-yl group, 1,
3,4-oxadiazol-2-yl group, 1,
3,4,5-oxatriazol-2-yl group,
2-quinolyl, 1-methyl-benzimidazol-2-yl, benzoxazol-2-yl and especially benzthiazol-2-yl. Furthermore, the group R ₄ can be an acyl group of an organic carboxylic acid or a thiocarboxylic acid, such as an optionally substituted aliphatic, cycloaliphatic, araliphatic group having up to 18 carbon atoms, preferably up to 10 carbon atoms. 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 group, benzoyl group, thiobenzoyl group, naphthylcarbonyl group,
Naphthylthiocarbonyl group, heterocyclic carbonyl group or thiocarbonyl group such as 2-, 3- or 4-pyridylcarbonyl group, 2- or 3-thenoyl group, 2- or 3-furoyl group, 2-, 3-
- or 4-pyridylthiocarbonyl group, 2- or 3-thiothenoyl group, or 2- or 3-
a thiofuroyl group or a substituted corresponding acyl or thioacyl group such as a lower alkyl group such as a methyl group, a halogen atom such as a fluorine or chlorine atom, a lower alkoxy group such as a methoxy group, an aryl group such as a phenyl group, or an aryl group; Oxy groups are, for example, acyl or thioacyl groups mono- or polysubstituted by phenoxy groups.

In the radicals of the formulas _-SO2 - _R5 and -S- _SO2 - _R5 , the radical _R5 is an optionally substituted in particular aliphatic group having up to 18 carbon atoms, preferably up to 10; It is an alicyclic, araliphatic or aromatic hydrocarbon group. As such a group _R5 ,
Optionally, for example, lower alkoxy groups such as methoxy, halogen atoms such as fluorine, chlorine or bromine, aryl groups such as phenyl,
or an aryloxy group, such as an alkyl group which may be mono- or polysubstituted, such as a phenoxy group, especially 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 group. or a cyclohexyl group, or a naphthyl group, or especially optionally a lower alkyl group such as 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, an aryloxy group such as Phenoxy group or phenyl group which may be mono- or polysubstituted by nitro group, e.g. phenyl group, o-, m-
or preferably p-tolyl group, o-, m- or preferably p-tolyl group, o-, m- or preferably p-methoxyphenyl group, o-, m- or p-chlorophenyl group, p-biphenylyl p-phenoxyphenyl group, p-nitrophenyl group, or 1- or 2-naphthyl group.

In the starting material represented by formula (), R ^A ₂
is an etherified hydroxyl group which together with a group represented by -C(=O)- forms an esterified carboxyl group (which can be split under mild conditions); protecting group
If a functional group is present in R ^A ₂ it can be protected in a manner known per se in the same manner as described above. The radical R ^A ₂ 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 is, for example, a chlorine atom, a bromine atom or an iodine atom), especially 2,2,2
- a trichloroethoxy group, a 2-bromoethoxy group or a 2-iodoethoxy group, or an optionally substituted 1-phenyl group - a lower alkoxy group such as a lower alkoxy group such as a methoxy group or a nitro group; 1-
phenyl-lower alkoxy groups, such as benzyloxy or diphenylmethoxy groups, which may be optionally substituted as described above;
For example, benzyloxy, 4-methoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy groups, and also organic silyloxy or stannyloxy groups, such as tri- A lower alkylsilyloxy group such as a trimethylsilyloxy group, or a halogen atom such as a chlorine atom. Preferably, in the starting material represented by formula (), R ^a ₁ is an amino-protecting group R ^A ₁ such as an acyl group Ac (in which a free functional group such as an amino group, a hydroxyl group, a carboxyl group or a phosphono group is present). If so, the amino group can be protected by methods known per se with an acyl, trityl, silyl or stannyl group as well as a substituted thio or sulfonyl group, as described above, and a hydroxyl, carboxyl or sulfonyl group. The phosphono group can be protected, for example, by an ether or ester group, including a silyl or stannyl group as described above), and R ^b ₁ is a hydrogen atom.

In the secondary amino group -N(R ^a ₄ )(R ^b ₄ ), one hydrogen atom of the substituents R ^a ₄ and R ^b ₄ and the other has up to 18 carbon atoms, especially up to 12 carbon atoms, and preferably is 7
up to 3 aliphatic or cycloaliphatic hydrocarbon groups.

Aliphatic hydrocarbon radicals R ^a ₄ or R ^b ₄ 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, cyclo Alkyl groups such as cyclohexyl, aryl groups such as phenyl or heterocyclic groups such as thienyl, especially lower alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, These are isobutyl group, pentyl group, hexyl group, 2-ethoxyethyl group, 2-methylthioethyl group, cyclohexylmethyl group, benzyl group, or thienylmethyl group. Alicyclic hydrocarbon groups R ^a ₄ or R ^b ₄ include, for example, optionally substituted cycloalkyl groups such as substituents, lower alkyl groups such as methyl groups, lower alkoxy groups such as methoxy groups, lower alkylthio groups, etc. For example, a cycloalkyl group substituted by a methylthio group, 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 cyclopropyl optionally substituted as above. group, cyclopentyl group, cyclohexyl group or cycloheptyl group.

In the tertiary amino group -N(R ^a ₄ )(R ^b ₄ ), the substituents R ^a ₄ and R ^b ₄ are each one of the aliphatic or alicyclic hydrocarbons described above, and R ^a ₄ and
R ^b ₄ can be the same or different groups, and the two substituents R ^a ₄ and R ^b ₄ are always connected by a carbon-carbon bond and by an oxygen atom or A ring can be formed by a sulfur atom or by a nitrogen atom which is optionally substituted, eg lower alkylated, eg methylated.

Suitable tertiary amino groups -N(R ^a ₄ ) (R ^b ₄ ) 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 group, N-methyl-cyclopentylamino group, dicyclohexylamino group, N-methyl-cyclohexylamino group, dibenzylamino group, N-methyl-benzylamino group, N-cyclopropyl-benzylamino group, 1-aziridinyl group, 1 -pyrrolidinyl group, 1-piperidyl group, 1H-2,3,4,
5,6,7-xahydroazepinyl group, 4-morpholinyl group, 4-thiomorpholinyl group, 1-piperazinyl group or 4-methyl-1-piperazinyl group.

According to the method of the present invention, the cyclization reaction of the compound of formula () to obtain the compound of formula () is carried out in a suitable inert solvent such as an aliphatic solvent,
Cycloaliphatic or aromatic hydrocarbons such as 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 For example dioxane or tetrahydrofuran, or aliphatic,
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,
It is carried out at room temperature or at a temperature of about 150°C, preferably at about 80-100°C, and optionally in an inert gas atmosphere, such as nitrogen gas.

The enamine of formula () formed by the cyclization reaction can optionally be isolated as a crude product, or can be solvolyzed in the same reaction solution to form the enamine of formula (A) or (B). compound can be obtained. In the enamine represented by the formula () produced as an intermediate product, 2
The double bond can be in the 2,3- or 3,4-position. Mixtures of the two isomers can also be obtained. If water or the alcohol of the formula R ₃ -OH is not completely removed during the cyclization reaction, the crude product obtained also already contains some solvolysis product of the formula (A) or (B). include. Solvolysis can be inhibited by the presence of moisture adsorbents such as dry molecular sieves. The compound represented by formula (A) or (B) can be obtained directly by carrying out a cyclization reaction in the presence of an R ₃ -OH compound, particularly a lower alkanol.

Solvolysis of the resulting enamine of the formula () is carried out using up to equimolar amounts of an organic or inorganic acid, such as a carboxylic acid, a sulfonic acid or a mineral acid, of water or an alcohol of the formula R ₃ -OH and, if appropriate, a catalyst. For example, formic acid, acetic acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid,
This is done by adding sulfuric or phosphoric acid at about -10°C to about 40°C, preferably at room temperature.

In the cyclization reaction and solvolysis according to the method of the present invention, a single compound of formula (A) or formula (B) or a compound of formula (A) and formula (B) may be used, depending on the starting materials and reaction conditions. A mixture of compounds 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 partitioning, etc.

The resulting compounds of formula (A) and formula (B) are pharmacologically active and suitable as intermediates for the final products, and such activity can be determined by various additional methods known per se. can be converted into the final product.

In the compound represented by formula (A) or formula (B) obtained by the method of the present invention, the α-phenyl-lower alkyl group R ₃ is easily split,
Can be replaced with a hydrogen atom. Optionally substituted α-phenyl-lower alkyl groups, such as benzyl or diphenylmethyl groups, can be subjected to acidolysis, for example by treatment with suitable inorganic or organic acids such as hydrochloric acid, sulfuric acid, formic acid or especially trifluoroacetic acid, or The splitting can be effected by hydrogenolysis, for example by treatment with hydrogen atoms in the presence of a catalyst such as palladium. The obtained 3-hydroxy compound is mainly 3-
It is in the form of Cefem. The removal of the α-phenyl-lower alkyl group R ₃ can optionally be carried out selectively, i.e. without simultaneous separation of the carboxyl protecting group R ^A ₂ .
It can be carried out.

Enol-ethers, that is, compounds represented by formula (A) and/or formula (B) in which R ₃ is a lower alkyl group, are compounds in which R ₃ is a hydrogen atom or a hydroxyl group in formula (A) or (B). If R ₃ is a residue protecting a hydroxyl group, substitution of this group with a hydrogen atom and subsequent etherification of the enol group can be obtained from a compound that is a protecting residue. It is obtained by etherification of free hydroxyl groups according to any suitable method. Suitable etherification agents include diazo compounds of the formula R ₃ -N ₂ corresponding to the radical R ₃ , mainly optionally substituted diazo lower alkanes such as diazomethane, diazoethane or diazo-n-butane, which may also be substituted. Preference is given to using α-phenyl-diazo lower alkanes which may be present, such as phenyldiazomethane or diphenyldiazomethane. These reactants are mixed with 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, lower alkanols such as methanol, ethanol or t-butanol, ethers such as di-lower alkyl ethers such as diethyl ether or cyclic ethers such as tetrahydrofuran or dioxane; It is used in the presence of a solvent mixture and with the diazo compound cooled, at room temperature or under slight heating, if necessary in a sealed container and/or under an inert gas such as nitrogen gas.

Furthermore, reactive esters of alcohols of the formula R ₃ -OH, in which R ₃ is a lower alkyl group or an optionally substituted α-phenyl-lower alkyl group, such as a benzyl group or a diphenylmethyl group. By processing the formula (A) and (or)
Enol ether represented by formula (B) 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 fluoric acid. lower alkanesulfonic acids which may be substituted with halogens such as, 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 acids such as methanesulfonic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid. These etherifying agents are particularly di-lower alkyl sulfates such as dimethyl sulfate, furthermore 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, generally steric, such as N,N-diisopropyl-N-ethylamine, are used. 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). Cooling this reaction,
Operate at room temperature or under heat, for example from about -20 to 50°C, and if necessary in a sealed container 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 iodide, 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, they can be added to the reaction mixture such that the PH value is between about 7 and 8.5 during the etherification. Furthermore, by treatment in the presence of an acidic agent with a compound having 2 to 3 etherified hydroxyl groups of the formula R ₃ -O- on the same aliphatic carbon atom, i.e. the corresponding acetal or orthoester. Therefore, enol ether can also be made.
Therefore, a gem-lower alkoxy-lower alkane such as 2,2-dimethoxy-propane is used as an etherifying agent in the presence of a strong organic sulfonic acid such as p-toluenesulfonic acid and in a suitable solvent such as methanol. orthoformic acid tri-lower alkyl esters such as orthoformic acid toluethyl ester in the presence of a strong inorganic acid such as sulfuric acid or It can be used in the presence of a strong organic sulfonic acid such as p-toluenesulfonic 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 ₃ is a methyl group. Alternatively, compounds represented by formula (A) and/or formula (B) which are lower alkyl groups such as ethyl group can be obtained.

Furthermore, formula (A) and (or) (B)
A compound represented by (where R ₃ is a hydrogen atom) is a tri-R ₃ -oxonium salt (so-called Meherwein salt) represented by the formula (R ₃ ) ₃ O A or a tri-R 3 -oxonium salt (so-called Meherwein salt) of the formula (R ₃ O) ₂ CH A A di-R ₃ O-carbenium salt or a di-R 3 O-carbenium salt of the formula (R ₃ ) ₂ Hal A (where A is an acid anion and
(Hal is a halonium ion such as a bromonium ion) Also when treated with a di-R ₃ -halonium salt represented by
The enol ether represented by is obtained. Such reactants are mainly tri-lower alkyloxonium salts, di-lower alkoxycarbenium salts or di-lower alkylhalonium salts, in particular the corresponding salts with complex fluorine-containing acids, such as the corresponding tetrafluoroborates. , hexafluorophosphate,
Mention may be made of hexafluorantimonate or hexachlorantimonate. Such reactants are, for example, trimethyloxonium- or triethyloxonium-hexafluorantimonate, -hexachloroantimonate, -hexafluorophosphate or -tetrafluoroborate, dimethoxycarbenium 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 such as N,N-diisopropyl-N-
in the presence of an organic base such as ethylamine and cooled, at room temperature or under slight heating e.g. about -20 to +50°C, if necessary in a sealed container and/or under an inert gas such as nitrogen. Use below.

Furthermore, a compound represented by formula (A) and/or formula (B) in which formula R ₃ is a hydrogen atom can be substituted with a 1-R ₃ -triazene compound substituted at the 3-position (i.e., a substituent -N= A compound with the _formula (
Enol ethers represented by A) and/or (B) are produced. The substituent on the 3-nitrogen atom is an organic group bonded via a carbon atom, preferably a carbocyclic aryl group, such as an optionally substituted phenyl group, such as a lower alkyl phenyl group such as a 4-methylphenyl group. It is the basis. Such triazene compounds are 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
-Aryl-1-(α-phenyl lower alkyl)
-Triazene, for example 1-benzyl-3-(4-methylphenyl)-triazene. These reactants are generally mixed 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.
Use at 100°C, if necessary in a sealed container and/or under an inert gas such as nitrogen.

Compounds in which -OR ₃ is a reactively esterified hydroxyl group in formulas (A) and (B),
R ₃ −OH (where R ₃ is a lower alkyl group or α-
phenyl - a lower alkyl group) can also be reacted with an alcohol of the formula (
Enol ethers of formula A) and/or formula (B) can be obtained. Reactively esterified hydroxyl groups -OR ₃ are in particular hydroxyl groups esterified with strong inorganic or organic acids. Such acids include, for example, mineral acids, hydrohalic acids such as hydrochloric acid, hydrobromic acid or hydroiodic acid, and or sulfuric acid or halogenated sulfuric acids, such as fluorosulfuric acid, or preferably strong organic sulfonic acids such as those of the formula HO -SO ₂ -R ₅ (in which R ₅ has the same meaning as given in the group Y), such as lower alkanesulfonic acids, which may optionally be substituted by a halogen atom, such as a fluorine atom; aromatic sulfonic acids such as benzenesulfonic acid (optionally lower alkyl groups such as methyl groups, halogen atoms such as bromine atoms,
and/or substituted by nitro groups), such as in particular methanesulfonic acid,
Trifluoromethanesulfonic acid or p-toluenesulfonic acid. The reaction with alcohols of the formula R ₃ -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, etc. for example in dioxane or tetrahydrofuran, di-lower alkyl amides such as dimethylformamide or dimethyl sulfoxide, etc., or in mixtures thereof, preferably in a suitable condensing agent such as an alkali metal carbonate or bicarbonate, such as carbonic acid or bicarbonate. in the presence of sodium, potassium carbonate or bicarbonate, or an organic base such as a usually sterically hindered tri-lower alkylamine such as triethylamine or N,N-diisopropyl-N-
Performed in the presence of ethylamine. Furthermore, the reaction is carried out cooled, at room temperature or at elevated temperatures, e.g. from about -20 DEG C. to 50 DEG C., if necessary in a sealed container, and/or in an inert gas atmosphere, e.g. nitrogen atmosphere.

Compounds in which -OR ₃ is a reactively esterified hydroxyl group in formula (A) and (or) formula (B) have already been disclosed in German Patent Publication No. 2408686 and German Patent Publication No. 2408698, Furthermore, formula (A ₎ and (or) formula (
It can be produced from the compound represented by B) in a similar manner to the methods disclosed in the above-mentioned German publications.

For example, the sulfonic acid ester of the compound represented by formula (A) and/or formula (B) in which R ₃ is -SO ₂ -R ₅ is a compound represented by formula (A) and () in which -OR ₃ is a free hydroxyl group. or) by esterifying a compound of formula (B) with a reactively functionalized derivative of a sulfonic acid of formula HO- _SO2 - _R5 . Reactive functional derivatives of sulfonic acids of the formula HO- _SO2 - _R5 which can be used are, for example, their reactive anhydrides, especially mixed anhydrides with hydrohalic acids, such as their chlorides, e.g. Mesyl chloride and p-toluenesulfonic 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 halogenated aliphatic hydrocarbons such as toluene, methylene chloride, lower alkanols such as methanol, ethanol or t-butanol, ethers such as di-lower alkyl ethers such as diethyl ether or cyclic ethers such as tetrahydrofuran or dioxane. or in the presence of a solvent mixture thereof and depending on the reactivity of the esterifying agent, cooled, at room temperature or slightly heated, i.e. at temperatures of about -10°C to +50°C, and 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 participate in the reaction in the raw materials or in the compounds obtained by the process of the invention may be removed, for example free amino A free hydroxyl group or mercapto group can be modified by esterification, for example by etherification or esterification, and a free carboxyl group can be modified by esterification, including silylation. It is therefore possible to temporarily protect them beforehand by methods known per se and, after the end of the reaction, to liberate the groups individually or simultaneously, if desired, by methods known per se. Thus, preferably an amino group in R ^A ₁ or R ^b ₁ eg as an acyl group,
A hydroxyl group, a carboxyl group or a phosphono group may be replaced with an acylamino group such as 2,2,2, etc.
-Trichloroethoxycarbonylamino group, 2-
An arylthioamino group or an aryl lower alkylthioamino group, for example 2-nitrophenylthioamino, in the form of a bromoethoxycarbonylamino, 4-methoxybenzyloxycarbonylamino, diphenylmethoxycarbonylamino or t-butoxycarbonylamino group. in the form of an arylsulfonylamino group, for example a 4-methylphenylsulfonylamino group, in the form of a 1-lower alkoxycarbonyl-2-propylideneamino group, an acyloxy group as mentioned above, for example t-butoxycarbonyloxy; in the form of a 2,2,2-trichloroethoxycarbonyloxy group or a 2-bromoethoxycarbonyloxy group, an esterified carboxyl group as described above, such as a diphenylmethoxycarbonyl group, or an O , O′-disubstituted phosphono group such as O,O′-dimethylphosphono group
protection in the form of a di-lower alkylphosphono group and, optionally, subsequent conversion of the protecting group (e.g. a 2-bromoethoxycarbonyl group into a 2-bromoethoxycarbonyl group).
2,2,2-trichloroethoxycarbonylamino or 2-iodoethoxycarbonylamino groups by methods known per se and depending on the nature of the protecting group. Diphenylmethoxycarbonylamino groups and t-butoxycarbonylamino groups are treated with a suitable reducing agent such as zinc in the presence of aqueous acetic acid, arylthioamino groups and arylthioamino groups are treated with formic acid or trifluoroacetic acid. Lower alkylthioamino groups are treated with a nucleophilic agent such as sulfite, arylsulfonylamino groups are treated with electrolytic reduction, and 1-lower alkoxycarbonyl-2-propylidene amino groups are treated with an inorganic acid aqueous solution. The t-butoxycarbonyloxy group is treated with formic acid or trifluoroacetic acid, and the 2,2,2-trichloroethoxycarbonyloxy group is treated with chemical reduction such as zinc in the presence of aqueous acetic acid. Diphenylmethoxycarbonyl groups are treated with formic acid or trifluoroacetic acid or hydrolyzed, or O,O′-disubstituted phosphono groups are treated with an alkali metal halide. For example, it can be partially split if desired.

Formula -C(=O)- obtained by the method of the present invention
Protection of R ^A ₂ In particular, in compounds of formula (A) or formula (B) having an esterified carboxyl group, this can be protected by methods known per se, for example depending on the nature of the group R ^A ₂ . , can be converted into a free carboxyl group. Esterification, for example, hydrolysis of lower alkyl groups, especially methyl or ethyl groups, or carboxyl groups esterified with benzyl groups (particularly in 2-cephem compounds of formula (B)) in a weakly basic medium. eg alkali metal or alkaline earth metal hydroxides or carbonates, 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. can be converted into a free carboxyl group by treatment with
A carboxyl group esterified with a suitable 2-halogeno-lower alkyl group or an 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. hydrogen carriers capable of producing nascent hydrogen by the metal, such as acids, primarily acetic acid or formic acid, or alcohols (preferably to which water is added)
The carboxyl group esterified with an arylcarbonylmethyl group can be cleaved by treatment in the presence of a nucleophilic salt such as sodium thiophenolate or sodium iodide. A carboxyl group esterified with a suitable arylmethyl group can be cleaved by treatment with a forming reagent, and a carboxyl group esterified with a suitable arylmethyl group can be cleaved, for example by irradiation [preferably the arylmethyl group is 3-, For example, if a benzyl group is substituted in the 4- and/or 5-position by a lower alkoxy group and/or a nitro group, use UV radiation below 290 mμ, and if the arylmethyl group is substituted in the 2-position, for example, A benzyl group substituted by a nitro group can be cleaved using long-wavelength ultraviolet light of 290 mμ or more], and an appropriately substituted methyl group such as a t-butyl group or a diphenylmethyl group can be used to cleave the ester. The converted carboxyl group can be cleaved by treating it with a suitable acidic agent such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound such as phenol or anisole. The active esterified carboxyl group and also the carboxyl group in the anhydride form can be hydrolyzed with e.g. hydrochloric acid, an aqueous sodium bicarbonate solution or pH approx. 7-9.
Esterified carboxyl groups can be cleaved by treatment with acidic or weakly basic aqueous agents such as aqueous potassium phosphate buffers, and can also be hydrogenolyzed. can be split by treatment with hydrogen in the presence of noble metal catalysts.

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

The resulting compound represented by formula (A) or formula (B) can be prepared by a method known per se.
A) or other compounds represented by formula (B).

In the resulting compound, for example, an amino protecting group
R ^A ₁ or R ^b ₁ , especially easily cleavable acyl groups, can be cleaved off by methods known per se. For example, a lower alkoxycarbonyl group highly branched at the α-position, such as a t-butoxycarbonyl group, can be prepared by treating it with trifluoroacetic acid, such as a 2,2,2-trichloroethoxycarbonyl group or a 2- A 2-halogeno-lower alkoxycarbonyl group such as the iodoethoxycarbonyl group or a phenacyloxycarbonyl group is treated with a suitable reducing metal or a corresponding metal compound such as a divalent chloride or acetate of zinc or divalent chromium. by treatment with a chromium compound, advantageously in the presence of a hydrogen donor such as to produce nascent hydrogen together with the metal or metal compound, preferably in the presence of hydrous acetic acid. , can be divided.

Furthermore, formula (A) or formula (B) (where,
The carboxyl group of the formula -C(=O) _-R2 is preferably protected by esterification including silylation, for example by a suitable organosilicon or tin halide (IV). In the resulting compound represented by the acyl group R ^a ₁ or R ^b ₂ (preferably a carboxyl group protected by reaction with e.g. trimethylchlorosilane or tri-n-butyl-tin chloride) Free functional groups that may be present in this group are optionally protected)
can be cleaved by treating with an imido-halide forming agent, reacting the resulting imido-halide with an alcohol and cleaving the iminoether thus formed, which is protected with a protected carboxyl group, e.g. an organosilyl group. The carboxyl group 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,
For example, phosphorus oxychloride, phosphorus trichloride and mainly 5
Phosphorus chloride, and pyrocatekyl-trichloride,
and acid halides, especially chlorides, of sulfur-containing acids or carboxylic acids, such as thionyl chloride, phosgene or oxalyl chloride.

For reaction with one of the above imide-halide formers, a suitable base, especially an organic base, especially a tertiary amine such as a tertiary aliphatic monoamine or a diamine such as a tri-lower alkyl amine such as trimethylamine, triethylamine or N,N
-diisopropyl-N-ethyl-amine, also N,N,N',N'-tetra-lower alkyl-lower alkylene diamine such as N,N,N',N'-tetramethyl-1,5-pentylene diamine 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-hexahydro-pyrrolo[1,2-a] pyrimidine (i.e. diazabicyclononene, DBN) or a tertiary aromatic amine such as a di-lower alkylaniline such as N,N-dimethylaniline or especially a tertiary heterocyclic monocyclic or bicyclic base such as quinoline or isoquinoline, Preferably halogenated (e.g. chlorinated), especially in the presence of pyridine
The reaction is carried out in the presence of a solvent such as an aliphatic or aromatic hydrocarbon, such as methylene chloride. In this reaction, the imide-halide forming agent and the base can be used in approximately equimolar amounts, but the base can be used in excess or in less than an equivalent amount, such as in an excess of about 0.2 to 2 times or about 10 times. It may also be used in amounts up to, especially about a 3- to 5-fold excess.

This reaction with the imide-halide forming agent is preferably carried out with cooling, e.g. between about -50 and +10°C, but at higher temperatures if the stability of the raw materials and the stability of the product permit higher temperatures. For example, it is also possible to carry out the reaction at temperatures up to about 75°C.

The imidohalide 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 hydroxyl groups, such as ethanol, propanol or butanol, in particular methanol,
as well as 2,2,2-trichloroethanol and 2
2-halogeno lower alkanols, such as -bromoethanol, and also optionally substituted phenyl-lower alkanols, such as benzyl alcohol, are suitable. The alcohol is generally used in excess, for example up to about 100 times excess, and the process is preferably carried out with cooling, for example at about -50 to +10°C.

The iminoether product thus formed can advantageously be cleaved off without being isolated. This splitting of the imino ether is achieved by treatment with a suitable hydroxy compound, preferably by hydrolysis or further alcoholysis (the formation of the iminoether is followed by removal of an excess amount 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 the PH value is adjusted, if necessary, by a basic agent such as an aqueous solution of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide. or acids such as hydrochloric acid, sulfuric acid, fluoroboric acid,
It can be adjusted by adding inorganic or organic acids such as trifluoroacetic acid or p-toluenesulfonic acid.

The three-step process for cleavage of the acyl groups 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, during halogenation. It is advantageous to carry out the reaction in the presence of a hydrocarbon, 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 salt of a carboxylic acid, especially a sterically hindered carboxylic acid, such as an alkali metal salt, instead of with an alcohol, formula (IA) or (IB ) in which both R ^a ₁ and R ^b ₁ are acyl groups is obtained.

Groups R ^a ₁ and R ^b ₁ in formula (A) or (B)
In compounds where both are acyl groups,
One of these groups, preferably the less sterically hindered group, can be selectively removed, for example by hydrolysis or aminolysis.

In the compound represented by formula (A) or (B), when R ^a ₁ and R ^b ₁ together with the nitrogen atom to which they are bonded represent a phthalimide group, this can be prepared by, for example, hydrazinolysis (i.e. , by treating such compounds with hydrazine).

Among the acyl groups R ^A ₁ of the acylamino group in the compound obtained by the method of the present invention, for example, the 5-amino-5-carboxy-valeryl group [the carboxyl group can be converted, for example, by esterification, in particular by diphenylmethyl group]. and/or the amino group may be protected, for example by acylation, in particular by an acyl group of an organic carboxylic acid, such as a halogeno-lower alkanoyl group such as dichloroacetyl group or a phthaloyl group. Nitrosylating agents such as nitrosyl chloride, carbocyclic allenes such as benzenediazonium chloride
Diazonium salts 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 mixture, such as a nitro-lower alkane or a cyano −
A lower alkane is treated in formic acid and the reaction product is mixed with water or a compound with a hydroxyl group such as a lower alkanol such as methanol, or 5-amino-5 as the group R ^A ₁ If the amino group in the -carboxy-valeryl group is unsubstituted and the carboxy group is protected, e.g. by esterification, and R ^b ₁ is preferably an acyl group but can also be a hydrogen atom, , dioxane or a halogenated aliphatic hydrocarbon, for example methylene chloride, and, if necessary, the free or monoacylated amino compound thus formed by methods known per se. It can be split by post-processing.

The formyl group R ^A ₁ can be prepared by treatment with acidic agents such as p-toluenesulfonic acid or hydrochloric acid, weakly basic agents such as dilute ammonia or decarbonylating agents such as tris-(triphenylphosphine)-rhodium chloride. It can also be removed.

Triarylmethyl group R ^A ₁ such as trityl group
can be removed by treatment with an acidic agent such as an inorganic acid, such as hydrochloric acid.

Formula (A) or (B) (in this formula R ^a ₁
and R ^b ₁ is a hydrogen atom),
Free amino groups can be substituted in a manner known per se, for example acylated by treatment with acids such as carboxylic acids or reactive acid derivatives thereof.

In the case of acylation with free acids (preferably the optional functional groups, e.g. the optional amino groups, are protected), commonly used suitable condensing agents such as carposiimide can be used. For example, N,N'-diethyl-, N,N'-dipropyl-, N,N'-diisopropyl-, N,
N'-dicyclohexyl- or N-ethyl-
N'-3-dimethylaminopropyl-carposiimide, 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 perchlorate, or a suitable acylamino compound such as 2-ethoxy-1-ethoxycarbonyl-1,2
- Use dihydroquinoline.

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, e.g. acid chlorides or bromides, and also anhydrides with hydroazidic acid, e.g. acids or anhydrides with phosphorous acid, sulfur-containing acids such as sulfuric acid or hydrocyanic acid. Other suitable anhydrides are e.g. anhydrides with organic acids e.g. lower alkanecarboxylic acids such as lower alkane carboxylic acids which may be substituted with halogen atoms such as fluorine or chlorine atoms or carbonic acids. half esters, especially with lower alkyl half esters, such as ethyl half ester and isobutyl half ester, or anhydrides with organic, especially aliphatic or aromatic sulfonic acids, such as p-toluenesulfonic acid.

Furthermore, intramolecular anhydrides such as ketenes such as diketenes, isocyanates (i.e. intramolecular anhydrides of carbamic acid compounds), as acylating agents;
Alternatively, an intramolecular anhydride of a carboxylic acid compound having a carboxy-substituted hydroxyl or amino group, such as mandelic acid-O-carboxyanhydride or 1-N-carboxyamino-cyclohexanecarboxylic acid anhydride, 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- such as N,N-diacylated anilines.
There are substituted N,N-diacylamines.

For acylation with acid derivatives such as anhydrides or especially acid halides, an acid binder such as an organic base such as an organic amine such as a tertiary ammonium such as a tri-lower alkylamine such as triethylamine,
bases of the N,N-dilower alkylaniline or pyridine type such as N,N-dimethylaniline, e.g. pyridine, inorganic bases e.g. alkali metal or alkaline earth metal hydroxides, carbonates or bicarbonates e.g. sodium, potassium; or in the presence of calcium hydroxide, carbonate or bicarbonate, or an oxirane, such as a lower 1,2-alkylene oxide 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 solvents such as methylene chloride, carbon tetrachloride or chlorobenzene. hydrocarbons, ketones such as acetone, esters such as ethyl acetate or nitriles 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 (A) or (B) (in which R ₃ is a lower alkyl group or an optionally substituted α-phenyl lower alkyl group such as a benzyl group or a diphenylmethyl group) is used. and R ₂ has the meaning given above) and a free compound of the formula -C(=O)-R ₂ where R ₂ is a hydroxyl group. Compounds having a carboxy group can be used in the form of salts, for example with ammonium salts, for example with triethylamine, or with suitable organophosphorus halides, such as lower alkyl-phosphorus dihalides or lower alkoxy-phosphorus dihalides, such as methyl. It is also possible to use the type of compounds with a protected carboxy group by reaction with -phosphorus dichloride, ethyl-phosphorus dibromide or methoxy-phosphorus dichloride. In the acylated products obtained, the protected carboxy groups can be liberated by methods known per se, for example by hydrolysis or alcoholysis as described above.

The acyl group is represented by the formula (A) or (B) [in this formula, R ^a ₁ and R ^b ₁ are both ylidene groups (this group is R ^a ₁
and compounds in which R ^b ₁ is a hydrogen atom can also be introduced by after-treatment with an aldehyde, such as an aliphatic, aromatic or araliphatic aldehyde, for example, according to the method described above. It can also be introduced by acylation and hydrolysis of the acylated product obtained, preferably in a neutral or weakly acidic medium.

Moreover, the acyl group can also be introduced in steps. That is, for example, by introducing a halogeno-lower alkanoyl group, such as a bromoacetyl group, into compounds of formulas (A) and (B) having a free amino group, or by treating with a carbonic acid dihalide, such as phosgene, to form a halogenoyl group such as a chlorocarbonyl group. Introducing a carbonyl group and thus obtaining N
The -(halogeno-lower alkanoyl)-amino compound or the N-(halogenocarbonyl)-amino compound is replaced with a suitable substituent such as a basic compound such as tetrazole, a thio compound such as 2-mercapto-1-methyl-imidazole, an azide Substituted N-lower alkanoylamino or N-hydroxycarbonylamino compounds can be obtained by reaction with metal salts such as sodium chloride or alcohols such as lower alkanols such as t-butanol.

In both reactant systems, the free functional group is
During the acylation reaction, they can be temporarily protected by known methods and, after acylation, liberated by methods known per se, such as the methods described above.

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 in the product thus obtained (generally the less sterically hindered acyl group) is subjected to hydrolysis. It causes them to divide.

Further, for example, compounds in which R ^a ₁ in formula (A) or (B) is a glycyl group preferably substituted in the α-position, such as a phenylglycyl group, and R ^b ₁ is a hydrogen atom, may be combined with an aldehyde such as formaldehyde. or by reacting with a lower alkanone such as a ketone, e.g. acetone, R ^a ₁ and R ^b ₁ both together with their bonded nitrogen atoms form a 5-oxo-1,3-diaza-cyclopentyl group. Compounds of formula (A) or (B) are obtained which are preferably substituted in the 4-position and optionally substituted in the 2-position.

In compounds in which R ^a ₁ and R ^b ₁ of formula (A) or (B) are hydrogen atoms, for example, 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 by treatment with to introduce a triarylmethyl group.

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 suitable silylating agents, e.g. treatment with 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 with N-mono-lower alkylation,
N, which may be N,N-di-lower alkylated, N-tri-lower alkylsilylated or N-lower alkyl-N-tri-lower alkylsilylated
-(tri-lower alkyl-silyl)-amines (see e.g. specification of GB 1073530) or silylated carunamides e.g. bis-tri-lower alkyls such as bis-trimethylsilyl-acetamide. treatment with silyl-acetamide or trifluorosilylacetamide or with a suitable stanylating agent 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 Patent Application No.
67/17107).

Formula -C(=O)- obtained by the method of the present invention
In compounds of formula (A) or (B) with a free carboxyl group of R ₂ , this group can be converted into a protected carboxyl group by methods known per se. That is, for example, by treating 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 esterification agent such as a carpodiimide or carbonyldiimidazole, such as dicyclohexylcarpodiimide, or with an alcohol suitable for esterification, or with an N,N′-disubstituted O- or S-substituted with urea or isothiourea (the O- and S-substituents are, for example, lower alkyl groups, especially tert-butyl, phenyl lower alkyl or cycloalkyl groups, and the N- or N'-substituents are For example, lower alkyl groups, especially isopropyl, cycloalkyl or phenyl groups), or other known suitable salts thereof, are reacted with reactive esters of alcohols and strong inorganic acids or strong organic sulfonic acids. The ester can be obtained by a suitable esterification method. Furthermore, acid halides such as acid chlorides (which are made, for example, by treatment with oxalyl chloride), activated esters (which are made, for example, by treatment with N-
N-hydroxy-nitrogen compounds such as hydroxy-succinoimides) or mixed anhydrides (which are produced using lower alkyl halogenoformates such as ethyl chloroformate or isobutyl chloroformate or trichloroacetic acid chloride) (produced using halogenoacetic acid halides such as halogenacetic acid halides) can be converted into esterified carboxy groups by reacting with an alcohol, optionally in the presence of a base such as pyridine.

In the resulting compounds having an esterified group of the formula -C(=O) _-R2 , this group can be changed to another esterified group of the same formula. For example, a 2-chloroethoxycarbonyl group or a 2-bromoethoxycarbonyl group can be converted to a 2-iodoethoxycarbonyl group by treatment with an iodine salt such as sodium iodide in the presence of a suitable solvent such as acetone. can.

Mixed anhydrides are compounds in which the group -C(=O) _-R2 in formula (A) or (B) is a free carboxyl group or preferably a salt thereof, especially an alkali metal salt such as a sodium salt or a triethylammonium salt. Such ammonium salts are prepared by reacting such ammonium salts with reactive derivatives of acids such as halides such as acid chlorides or halogenoformic acid lower alkyl esters or lower alkanecarboxylic acid chlorides.

Group -C(=O)- obtained by the method of the present invention
In compounds where R ₂ is a free carboxyl group,
This group can be converted to an optionally substituted carbamoyl or 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, a compound in which R ₂ in formula (A) or (B) is a hydroxyl group, or a salt thereof such as an alkali metal salt such as a sodium salt. It is formed by treating the salt with a suitable silylating or stannylating agent, such as one of the silylating or stannylating agents described above. For example, British patent no.
1073530 or Dutch Patent No. 67/17107.

Furthermore, substituted amino groups, acylated hydroxyl groups in the groups R ^A ₁ , R ^b ₁ and/or R ₂ ,
Esterified carboxyl group or 0,0′-
Modified functional groups such as di-substituted phosphono groups can be liberated by methods known per se, for example by the methods described above, or can be added to the groups R ^A ₁ , R ^b ₁ and (or ) functional modification of free functional groups such as free amino, hydroxyl, carboxyl or phosphono groups in R ₂ by methods known per se, for example by acylation, esterification or substitution reactions; Can be done. Thus, for example, an amino group can be converted into 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 with sodium nitrite is treated with a reaction mixture in which the amino protecting group R ^A ₁ in formula (A) or (B) is substituted, for example. The amino group can be converted to a 3-guanylureido group by reacting with a compound that is optionally a glycyl group. Additionally, aliphatically bonded halogen atoms may be substituted e.g.
Reacting a compound with a bromoacetyl group with a phosphite such as a tri-lower alkyl phosphite compound yields the corresponding phosphono compound.

The resulting compounds represented by formulas (A) and (B) can be oxidized with a suitable oxidizing agent, such as the oxidizing agent described below, to obtain the 1-oxide of the corresponding 3-cephem compound represented by formula (A). can be changed to The resulting 1-oxide of the 3-cephem compound represented by formula (A) is reduced to the corresponding 3-cephem compound represented by formula (A) 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 cefem compound can be isomerized. In this way, the obtained 2-cephem compound represented by formula (B) or the obtained 2-cephem compound
A mixture of - and 3-cephem compounds is prepared by formula (
B) 2-cephem compound or 2-
and 3-cephem compounds (in which the free functional groups can, if appropriate, be temporarily protected as described above), to obtain compounds of formula (A). Equivalent to 3
-Can be converted into cefem compounds. In this reaction, for example, in formula (B), formula -C
2-cephem compounds in which the (=O)-R ₂ group is a free or protected carboxyl group can be used, and protected carboxyl groups may also be generated during the reaction.

The 2-cephem compound of formula (B) is prepared by treating it with a basic group and from the equilibrium mixture of 2- and 3-cepheme compounds the corresponding 3-cepheme compound of formula (A) is prepared.
By isolating the cefem compound, it can be isomerized.

Suitable isomerizing agents are, for example, organic nitrogen-containing bases such as aromatic tertiary heterocyclic bases and mainly tertiary aliphatic, azaalicyclic or araliphatic bases such as N,N,N-trimethylamine, N,N N,N,N-tri-lower alkylamines such as dimethyl-N-ethylamine, N,N,N-triethylamine or N,N-diisopropyl-N-ethylamine, N-lower alkyls such as N-methyl-piperidine. - an azacycloalkane or an N-phenyl lower alkyl-N,N-lower alkyl-amine, such as N-benzyl-N,N-dimethylamine, or a mixture thereof; a pyridine-type base, such as a mixture of pyridine and triethylamine; For example, a mixture of pyridine and N,N,N-trilower 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) (at the same time a liquid base can also be used as a solvent), if necessary under cooling or heating, preferably about -
Operate at 30 to +100°C, under an inert gas such as nitrogen and/or in a sealed container.

The 3-cephem compound of formula (A) thus produced is removed from the 2-cephem compound of formula (B), which may still be present, by methods known per se, for example by adsorption and/or crystallization. Can be separated.

In addition, the 2-cephem compound of formula (B) can be
oxidation in position, optionally separating the 1-oxide of the 3-cephem compound of formula (A) from the isomer mixture thus formed and removing the 1-oxide of the corresponding 3-cepheme compound of formula (A). Isomerization can also be achieved by reducing the oxide.

An oxidizing agent suitable for oxidizing the 1-position of this 2-cephem compound has a reduction potential of at least +1.5
Mention may be made of inorganic peracids, organic peracids or mixtures of hydrogen peroxide with acids, in particular organic carboxylic acids, having a dissociation constant of at least 10 ^-5 and consisting of non-metallic elements. Suitable inorganic peracids are periodic acid and persulfuric acid. Organic peracids are the corresponding percarboxylic and persulfonic acids, which can be used as such or can be formed in situ using at least equivalents of hydrogen peroxide and carboxylic acid. In this case, for example, when acetic acid is used as a solvent, it is suitable to use a large excess of 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. Lower concentrations of this acid, such as 1-2% or less, but higher amounts can also be used. 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, at least an equimolar amount of oxidizing agent is used, preferably a small excess of about 10-20%. This oxidation is carried out under mild conditions, for example at about -50 to +100°C, preferably about -10 to +40°C.

Additionally, ozone is used to oxidize the 2-cephem compound to form the 1-oxide of the corresponding 3-cepheme compound, and organic hypohalite ester compounds such as lower alkyl-hypochlorite such as t-butyl hypochlorite are used. (in an inert solvent such as a possibly halogenated hydrocarbon such as methylene chloride and from about -10 to +
30°C), periodate compounds such as alkali metal periodates such as potassium periodate (preferably used in an aqueous medium at a pH of about 6 and between about -10 and +30 ), iodobenzene dichloride (used in an aqueous medium, preferably in the presence of an organic base such as pyridine and cooled, e.g. at about -20 to 0°C), or converting a thio group to a sulfoxide group. This can be done using other suitable oxidizing agents.

In the 1-oxide of the 3-cephem compound of formula (A) thus obtained, especially in the compound in which R ^a ₁ , R ^b ₁ and R ₂ have the above-mentioned preferred meanings, the groups R ^a ₁ , R ^b ₁
and/or R ₂ can be changed, cleaved or introduced into other groups within the scope of its definition. In addition, the isomers α-1-oxide and β-
The mixture with 1-oxide can be separated, for example by chromatography.

The 1-oxide of the 3-cephem compound of formula (A) can be reduced by methods known per se by treatment with a reducing agent, if necessary in the presence of an activator. Examples of reducing agents include: Catalytically activated hydrogen (palladium,
noble metal catalysts such as platinum or rhodium, optionally supported on a suitable support such as charcoal or barium sulfate), reducing tin, iron, copper or manganese cations (these may be combined with inorganic or in the form of organic corresponding compounds or complexes, such as tin () as chloride, fluoride, acetate or formate; iron () as chloride, sulphate, oxalate or succinate; , as the chloride, benzoate or oxide of copper (), or as the chloride, sulfate, acetate or oxide of manganese (), or as a complex with e.g. ethylenediaminetetraacetic acid or nitroltriacetic acid] , reducing dithionite, iodine or iron cyanide () anions in the form of their corresponding inorganic or organic salts, e.g. sodium dithionite, potassium dithionite,
(used in the form of an alkali metal salt such as sodium iodide, potassium iodide, sodium ferrocyanide or potassium ferrocyanide or a corresponding acid such as hydroiodic acid), a reducing trivalent inorganic or organophosphorus compound, e.g. Phosphine, as well as esters, amides, and halides of phosphinous acid, phosphonous acid, or diphosphorous acid, and phosphorus/sulfur compounds corresponding to these phosphorus/oxygen compounds (the organic groups of these compounds are mainly aliphatic,
aromatic or araliphatic groups such as optionally substituted lower alkyl groups, phenyl groups or phenyl lower alkyl groups), such as triphenylphosphine, tri-n-butylphosphine,
Methyl diphenylphosphinate, diphenylchlorphosphine, phenyldichlorphosphine,
Benzene phosphonate dimethyl ester, butane phosphonate methyl ester, phosphite triphenyl ester, phosphite trimethyl ester, phosphorus trichloride, phosphorus tribromide, and other reducing halogenosilane compounds (these are having at least one hydrogen atom attached and furthermore halogen atoms such as chlorine, bromine or iodine, organic groups such as aliphatic or aromatic groups such as optionally substituted lower alkyl or phenyl groups; ), such as chlorosilane, bromosilane, di- or tri-
chlorosilane, di- or tri-bromosilane,
Diphenylchlorosilane, dimethylchlorosilane and other reducing quaternary chlormethylene-iminium salts, especially the corresponding chlorides or bromides, in which the iminium group is a divalent organic group or two monovalent organic groups, e.g. N-chlormethylene-N,N-diethyliminium chloride or N-chlormethylene-pyrrolidinium chloride, and Complex metal hydrides such as boron, as well as borane dichloride, of sodium hydride in the presence of a suitable activator such as cobalt chloride ().

Used in conjunction with the above reducing agents which themselves are non-Lewis acidic, i.e. mainly with dithionite reducing agents, iodine reducing agents, iron cyanide reducing agents or halogen-free trivalent phosphorus reducing agents. Activators added in any case or in the case of catalytic reduction are in particular halides of organic carboxylic acids and sulfonic acids, and also sulfur, phosphorus or silica whose secondary hydrolysis constant is the same or higher than that of benzoyl chloride. Elemental halides such as phosgene,
Oxalyl chloride, acetic acid chloride or bromide, chloroacetic acid chloride, pivalic acid chloride, 4-methoxybenzoic acid chloride, 4-cyanobenzoic acid chloride, p-toluenesulfonic acid chloride, methanesulfonic acid chloride, thionyl chloride, phosphorus oxychloride, 3 1 , 3-propanesultone, 1,4-butanesultone or 1,3
-Hexane sultone.

Preferably, the above reduction reaction is carried out in a solvent or a mixture thereof. The choice of solvent depends primarily on the solubility and reducing nature of the raw materials. Thus, for example, catalytic reduction uses lower alkanecarboxylic acids or their esters such as acetic acid and ethyl acetate, and chemical reducing agents use aliphatic, cycloaliphatic, aromatic, which may be substituted, e.g. 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 phosphoramide, 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. Generally about −20
It is carried out at ~+100°C, but the reaction can be carried out at lower temperatures if very reactive activators are used.

In the 3-cephem compound represented by formula (A) thus obtained, the groups R ^a ₁ , R ^b ₁ and/or R ₂ are replaced by the other groups R ^a ₁ , R ^b ₁ or
Can be changed to _R2 .

Salts of compounds represented by formulas (A) and (B) are produced by methods known per se.
Thus, salts of such compounds with acidic groups can be prepared by treatment with metal compounds such as the 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 (A) and (B) having a basic group
Acid addition salts of the compounds are obtained in conventional manner, for example by treatment with an acid or a suitable anion exchanger. Intramolecular salts of compounds of formulas (A) and (B) having a salt-forming amino group and a free carboxyl group can be prepared by neutralizing the salts, such as their acid addition salts, with, for example, a weak base, to their isoelectric point. Or produced by treatment with a liquid ion exchanger. Salts of the 1-oxides of compounds of formula (A) having 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 resulting isomer mixture may be subjected to methods known per se, such as fractional crystallization of the mixture of diastereoisomers, adsorption chromatography (column chromatography or thin layer chromatography) or other methods. The individual isomers can be separated by appropriate separation methods. The obtained racemate is treated by a conventional method, if appropriate, after introducing a suitable salt-forming group, for example, to form a diastereomeric salt mixture with an optically active salt-forming agent, and this mixture is mixed with each Separation into the individual enantiomers can be achieved by partitioning into diastereomeric salts and converting the diastereomeric salts thus separated into the free compounds, or by fractional crystallization from optically active solvents.

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 mentioned above as particularly preferred.

In the starting material represented by the formula (), the group Y to be removed is of the formula -SO ₂ -R ₅ (in this formula, R ₅ has the meaning given above, but is particularly the group given as preferred above) ) is preferable.

Compared to the prior art, the process according to the invention uses inexpensive and particularly easily available starting materials, such as penicillin G or V obtained in particular by fermentation.
It is particularly advantageous to start from the 1-oxide of 6-aminopenicillanic acid and the 1-oxide of 6-aminopenicillanic acid, and that the intermediate products required in the process according to the invention are prepared in high yields. In particular, the method of the invention also applies to formulas () in which R ₃ is a hydrogen atom:
The compound represented by can be directly produced without splitting the hydroxyl protecting group _R3 .

The starting material represented by the formula () used in the present invention can be prepared, for example, according to the following chemical equation.

The starting compounds of formula () are known and can be prepared by known methods.

Compounds of formula (a) are also known and made by the method described in Dutch Patent No. 72/08671.

Formulas (a), (b), (c), (a), (b
)
and (c) (in these formulas, R ^a ₁ , R ^b ₁ , R ^A ₂ , and Y have the meanings given in the above formula ()), and their production methods are also covered by the present invention. It is a purpose.

The compound represented by formula (b) is produced by the reaction of a compound represented by formula () with a sulfinic acid represented by the formula _HSO2 - _R5 or a sulfonyl cyanide represented by the formula N≡C- _SO2 - _R5 . It can be obtained by The compound represented by formula (c) is
It can be obtained from a compound of formula () by reaction with thiosulfonic acid of formula H-S- _SO2 - _R5 . 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 phenols, polyhydroxy compounds such as polyhydroxy alkanes 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, naoxane 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 a sulfonyl cyanide of the formula N≡C- _SO2 - _R5 can be accelerated by adding a compound that supplies a halogen anion. Suitable compounds supplying halogen anions include, 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),
For example, 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 of formula (b) and (c) also include compounds of formula () and compounds of formula M ⁿ⁺
( ^-SO2 - _R5 ) _o or the heavy metal salt of sulfuric acid with the formula Mn ⁺ ( ^-S - _SO2 - _R5 ) _o (where M is a heavy metal cation and _n is an atom of this cation. It can also be produced by reaction with a heavy metal salt of thiosulfonic acid represented by the following formula: Suitable heavy metal salts of sulfinic or thiosulfonic acids are those which have a greater solubility product in the reaction medium used than the heavy metal compound of the formula M ⁿ⁺ (-S-R ₄ ) _o formed during the reaction. It is.
As the heavy metal cation M ⁿ⁺ , those that produce particularly poorly soluble sulfides are suitable. For example, monovalent or divalent cations of copper, mercury, silver and tin, with Cu ⁺⁺ and Ag ⁺ being 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 SHO ₂ -R ₅ or of the formula H-S-SO ₂ -R. ₅ or a soluble salt thereof, such as an alkali metal salt such as the sodium salt, and a heavy metal salt (the solubility product of which is greater than the heavy metal salt of the sulfinic acid or the heavy metal salt of the thiosulfonic acid formed), such as nitric acid, heavy metal salts of acetic acid or sulfuric acid,
It can also be produced, for example, from silver nitrate, mercury()-diacetic acid or copper sulfate(), or from soluble chlorides such as tin()chloride dihydrate.

A compound represented by formula (a) and a compound represented by formula M ⁿ⁺
The reaction with the heavy metal salt of sulfinic acid of the formula ( ^-SO2 _{- R5} ) _o or the heavy metal salt of thiosulfonic acid of the formula ^Mn+ ( ^-S - _SO2 - _R5 ) _o is 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 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 phenols, 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 polyethers such as dimethoxyethane, lower carboxylic 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 (), the group R ^a ₁ , R ^b ₂ or R ^A ₁ is replaced with another R ^a ₁ , R ^b ₁ or R ^A ₂
, and in that case the expression (
Similar reactions to those described above for the transformation of these groups in compounds of formula A) or formula (B) can be used.

In the second and third or 2a stages, the formula ()
To convert the compound represented by the formula into the compound represented by the formula () by oxidative degradation from the methylene group to the oxo group, and to oxidatively split the methylene group of the compound of the formula while forming the 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 halogeno-lower alkane such as methylene or carbon tetrachloride, or an aqueous mixture and under cooling or slight heating, e.g., from about -90°C to +40°C.

The ozonide of the formula (a) thus obtained as an intermediate, optionally without isolation, and analogously to the conversion of the compound of the formula (a) into the compounds of the formulas (b) and (c). ,formula
_{The formula} ^{( b _ _} _{_ _ _} ) or (c).

The compound represented by the formula () can be obtained by subjecting the ozonide represented by the formula () to ring element 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 Reducing agents such as heavy metal alloys or heavy metal amalgams, reducing heavy metals such as hydrogen donors such as zinc in the presence of acids such as acetic acid or alcohols such as lower alkanols, reducing inorganic salts such as hydrogen donors such as acetic acid, etc. alkali metal iodides such as sodium iodide or reducing organic compounds such as formic acid, reducing sulfide compounds such as di-lower alkyl sulfides such as dimethyl sulfide, phosphine, etc. Reducing organophosphorus compounds, which may carry optionally substituted aliphatic or aromatic hydrocarbon groups, e.g. tri-lower alkylphosphine such as tri-n-butylphosphine; Triarylphosphines such as triphenylphosphine, phosphites bearing an aliphatic hydrocarbon group which may be further substituted, e.g. trilower alkyl phosphites such as trimethylphosphite (this is generally (in the form of corresponding alcohol adducts) or phosphite triamides bearing optionally substituted aliphatic hydrocarbon groups as substituents, e.g. hexa-lower alkyl phosphite triamides, such as hexamethyl phosphite triamide; (which is preferably in the form of a methanol adduct) or tetracyanoethylene can be used. The generally unisolated ozonide mentioned above is cleaved under the conditions normally employed for its preparation, ie in the presence of a suitable solvent or solvent mixture and upon cooling or slight heating.

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

Enol compounds of formula (a) can be converted into compounds of formula (b) or (c) as well as compounds of formula Mn ⁺ ( ^-SO2 _{- R5} ) _o. Heavy metal salts of sulfinic acid or formula M ⁿ⁺
By reacting thiosulfonic acid represented by ( ^-SO2 _{- R5} ) with a heavy metal salt, it can be converted into a compound represented by formula (b) or (c), respectively.

In the resulting compound of formula (), the groups R ^a ₁ , R ^b ₁ or R ^A ₂ can be reacted similarly to the reactions suitable for the transformation of these groups in compounds of formula (A) or (B). , another group R ^a ₁ ,
It can be changed to R ^b ₁ or R ^A ₂ .

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

In order to make a sulfonic acid ester represented by the formula (), a compound represented by the formula () is converted into a sulfonic acid ester represented by the formula ().
Esterification with a reactive functional derivative of sulfonic acid represented by HO- _SO2 - _R5 (where _R5 has the same meaning as given to _R5 in group Y).

Within the meaning given to the radical R ₅ ,
These two groups may be the same or different groups in the compound represented by formula ().

The reactive functional derivatives of sulfonic acids of the formula HO-SO ₂ -R ₅ used are, for example, their reactive anhydrides, especially mixed anhydrides with hydrohalic acids, such as their chlorides, such as mesyl chloride. It is p-toluenesulfonic acid chloride.

The esterification is preferably carried out using organic tertiary nitrogen bases such as pyridine, triethylamine or ethyl-
In the presence of diisopropylamine, a suitable inert solvent such as an aliphatic, cycloaliphatic or aromatic hydrocarbon such as hexane, cyclohexane, benzene or toluene, a halogenated aliphatic hydrocarbon such as methylene chloride, or an ether such as a di-lower alkyl ether for example diethyl ether, cyclic ethers such as tetrahydrofuran or dioxane, or in a solvent mixture and depending on the activity of the esterification agent, cooled, at room temperature or slightly warmed,
ie at a temperature of about -10 DEG to +50 DEG C. and optionally also in a sealed container and/or under an inert gas, such as 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) is represented by formula (a)
Similar to the conversion of compounds of formulas (b) and (c) into compounds with formulas (b) and (c), heavy metal salts of sulfinic acid of formula M ⁿ⁺ ( ^- SO ₂ − R ₅ ) _o or of formula M ⁿ⁺ ( ⁻ S−
By reaction with a heavy metal salt of thiosulfonic acid represented by _SO2 - _R5 ), it can be converted into a compound represented by formula (b) or (c), respectively.

In the resulting compound of formula (), the groups R ^a ₁ , R ^b ₁ or R ^A ₂ can be reacted similarly to the reactions suitable for the transformation of these groups in compounds of formula (A) or (B). , another group R ^a ₁ ,
It can be changed to R ^b ₁ or R ^A ₂ .

In the fifth step, the resulting sulfonic acid ester represented by the formula () is converted into the formula H-N(R ^a ₄ )(R ^b ₄ )
By treating with a primary or secondary amine represented by formula (2), it can be converted to a compound represented by formula ().

Amination is carried out using 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, or cyclic ethers such as tetrahydrofuran or dioxane, or in solvent mixtures, and depending on the group -O-SO ₂ -R ₅ and the activity of the amine used, from about -10°C to 50℃
It is preferably carried out at a temperature of about 0 DEG C. to 20 DEG C., optionally in a sealed container and/or under an inert gas such as nitrogen gas.

In step 5a, a compound represented by formula () is added to a first compound represented by formula H-N(R ^a ₄ )(R ^b ₄ ).
or by salts of secondary amines, such as hydrochloric acid addition salts,
in the presence of a third base such as pyridine, in a suitable solvent such as a lower alcohol such as absolute ethanol,
Compounds of formula () can also be prepared by processing at temperatures of about 20-100°C, preferably about 40-60°C.

The compound represented by formula (a) is represented by formula (a)
Similarly to the conversion of compounds of formula (b) or (c) into compounds of formula (b) or (c), heavy metal salts of sulfinic acid of formula M ⁿ⁺ ( ^- SO ₂ − R ₅ ) _o or of formula M ⁿ⁺ ( ⁻ S− SO ₂
-R ₅ ) can be converted into a compound represented by formula (b) or (c), respectively, by reaction with a heavy metal salt of thiosulfonic acid.

In the resulting compound of formula (), the groups R ^a ₁ , R ^b ₁ or R ^A ₂ can be reacted similarly to the reactions suitable for the transformation of these groups in compounds of formula (A) or (B). , another group R ^a ₁ ,
It can be changed to R ^b ₁ or R ^A ₂ .

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. It can be used in the production of pharmaceutical preparations containing or mixed with. The active substance may therefore be combined with diluents such as lactose, glucose, sucrose, mannite, sorbitate, cellulose and/or glycine and lubricants such as silica, talc, stearates such as stearic acid or calcium stearate and/or ) Use tablets or gelatin capsules containing polyethylene 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, crushed Agents such as starch,
agar, alginic acid or sodium alginate,
or may contain 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 administered, for example, from vacuum lyophilized formulations containing the active substance alone or together with a carrier such as mannite. Prepared beforehand. These pharmaceutical preparations are sterilized and/or auxiliary agents such as preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers,
Salts and/or buffers may be included to adjust the osmotic pressure. These pharmaceutical preparations are prepared by methods known per se, for example by customary mixing, granulating, tabletting, dissolving or vacuum freeze-drying methods, and contain from about 0.1 to 100% of the active substance, especially about 1
~50% (up to 100% for the vacuum lyophilizate) and can optionally contain other pharmacologically valuable substances.

In addition, in this specification, unless otherwise defined, organic groups indicated as lower have up to 7 carbon atoms,
Preferably it has up to four. Acyl groups are those having up to 20, 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, where the temperature is expressed in degrees Celsius. The cefem compounds described in the examples below have R-configurations at the 6- and 7-positions, and the azetidinone compounds described in the examples below have R-configurations at the 3- and 4-positions.
Has a configuration.

Example 1 2-[4-(p-toluenesulfonylthio)-3
-Phenoxyacetamido-2-oxoazetidin-1-yl]-3-(1-pyrrolidyl)-crotonic acid p-nitrobenzyl ester and the corresponding isocrotonic acid ester 160 mg
(0.23 mmol) in 3 ml of dry acetonitrile at 80°C under a nitrogen atmosphere for approximately 4 hours until the starting material could no longer be detected by thin layer chromatography (silica gel, toluene/ethyl acetate 1:1). Heat. Remove the heating bath and add 7β-phenoxyacetamide-3-pyrrolidino-cephem-4.
- p-toluenesulfonic acid (approximately
0.23 mmol) and 0.2 ml of water are added and the mixture is stirred for a further 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 DEG C. to give blue-yellow 7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester.

Infrared absorption spectrum (methylene chloride):
2.95; 3.3; 5.6; 5.75; (sh); 5.9; 5.95 (sh);
Characteristic bands at 6.55; 7.45; 8.15 and 8.3μ, NMR
Spectrum (deuterochloroform); δppm;
3.4 (2H, 2, J = 17Hz); 4.57 (2H, s); 5.06
(1H, d; J=5Hz); 5.35 (2H, q, J=14
Hz); 5.7 (1H, dd, J=5.10Hz); 6.8-8.4 (10H,
c) and 11.4 (1H, br.s.).

The starting material can be produced as follows.

(a) 6-phenoxyacetamidopenicillanic acid
A solution of 36.6 g (0.1 mol) of 1β-oxide, 11.1 ml (0.11 mol) of triethylamine and 23.8 g (0.11 mol) of p-nitrobenzyl bromide in 200 ml of dimethylformamide is stirred at room temperature for 4 hours under a nitrogen atmosphere. Next, pour the reaction solution into ice water.
1.5, filter the precipitate, dry and recrystallize twice from ethyl acetate/methylene chloride. Colorless crystalline 6-phenoxyacetamidopenicillanic acid p-nitrobenzyl ester 1β
-The oxide melts at 179-180°C.

(b) 6-phenoxyacetamidopenicillanic acid p
-Nitrobenzyl ester 1β-oxide 5.01g
(10 mmol) and 1.67 g (10 mmol) of 2-mercaptobenzthiazole in 110 ml of dry toluene is boiled under reflux for 4 hours under a nitrogen atmosphere. The solution is concentrated by distillation to about 25 ml and diluted with about 100 ml of ether. Recrystallization of the separated product from methylene chloride/ether yields p-2-[4-(benzthiazol-2-yldithio)-3-phenocyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyric acid. A nitrobenzyl ester is obtained. Melting point is 138-141°C.

(c) 2-[4-(Benzthiazol-2-yl-dithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-
p-nitrobenzyl butyrate 3.25g (5.0mmol)
Add 1.06 g of finely powdered silver nitrate to a solution of 200 ml of acetone/water 9:1 (v/v).
Immediately thereafter, 890 mg (5 mmol) of sodium p-toluenesulfinate was added to the same solvent mixture as above.
Add the 100ml solution over 10 minutes.
A blue-yellow precipitate forms immediately. Stir for 1 hour at room temperature, then filter the mixture and add Celite. 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-phenoxyacetamide-2-oxoazetidine-1- [yl]-3-methylenebutyric acid p-nitrobenzyl ester is obtained.

Thin layer chromatography (silica gel, toluene/ethyl acetate 2:1): Rf value = 0.24; infrared absorption spectrum (in _CH2Cl2 ): 3.90, _5.56 ,
5.70, 5.87, 6.23, 6.53, 6.66, 7.40, 7.50,
Characteristic bands at 8.10, 8.72, 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-) 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3- in 200 ml of acetone/water 9:1 (v/v). 1.58 g of silver p-toluenesulfinate in a solution of 3.25 g (5.0 mmol) of p-nitrobenzyl methylenebutyrate
(1.2 eq.) dropwise over 10 minutes. The suspension is stirred for 1 hour at room temperature, filtered and further worked up 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.

Silver p-toluenesulfinate can be obtained as a colorless precipitate by combining equimolar amounts of silver nitrate and sodium p-toluenesulfinate. Dry the product in vacuo for 24 hours.

(c-) By the same method as (c-) in Example 1,
3.25 g of 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylenebutyric acid p-nitrobenzyl ester and di-p-toluenesulfinic acid Copper () 1.87g
(2 equivalents) and 2-[4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]
-3-methylenebutyric acid p-nitrobenzyl ester can be obtained quantitatively.

Copper di-p-toluenesulfinate (2) is obtained by combining copper sulfate and sodium p-toluenesulfinate (2 equivalents) in water. After filtration, the salt is dried in vacuo at 60° C. for 12 hours.

(c-) In the same manner as (c-) in Example 1, 2-
[4-(Benzthiazol-2-yldithio)
-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylenebutyric acid p-nitrobenzyl ester 130 mg and di-p
-85 mg (2 equivalents) of tin toluenesulfinate (2-[4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-
Methylene butyric acid p-nitrobenzyl ester can be obtained.

Tin di-p-toluenesulfinate (2) is obtained by reacting tin chloride ( _2H2O ) 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-) Similar to (c-) in Example 1, 2-[4-
(benzthiazol-2-yldithio)-3-
130 mg of p-nitrobenzyl phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylenebutyric acid and 102 mg (2 equivalents) of mercuric di-p-toluenesulfinate ()
Tokarademo 2-[4-(p-toluenesulfonylthio)-3-phenoxyacetamide-2
-oxoazetidin-1-yl]-3-methylenebutyric acid p-nitrobenzyl ester can be obtained. Mercury di-p-toluenesulfinate (2) is obtained by reacting mercury diacetate (2) and sodium p-toluenesulfinate in water. After filtering and washing with water, the salt is dried in a vacuum at 50-60°C for about 12 hours.

(c-) 6-phenoxyacetamidopenicillanic acid p-nitrobenzyl ester in 10 ml of 1,2-dimethoxyethane (or dioxane)
A solution of 517 mg (1.02 mmol) of 1β-oxide and 187 mg (1.2 mmol) of p-toluenesulfuric 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, Next, 308 mg of p-toluenesulfuric acid dissolved in 2 ml of 1,2-dimethoxyethane
(1.98 mmol) was further added in 5 portions at 45 minute intervals. After 4.5 hours, the reaction mixture was poured into 100 ml of 5% strength aqueous sodium bicarbonate solution.
Extract with ethyl acetate. The combined organic phases are then 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-1yl]-3. −
Methylene butyric acid p-nitrobenzyl ester is obtained.

(c‐) 2 ml of dry peroxide-free dioxane
250 mg (0.5 mmol) of 6-phenoxyacetamidopenicillanic acid p-nitrobenzyl ester 1β-oxide, 110 mg (0.61 mmol) of p-toluenesulfonyl cyanide, and 5 mg of benzyl-toluethylammonium chloride.
(0.022 mol) is stirred at 110 °C for 4.5 h under an argon atmosphere. The solution is removed under vacuum and the residual yellow oil is chromatographed on acid-washed silica gel. 30 in toluene
Elution with % ethyl acetate gives 2-[4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-methylenebutyric acid p-nitrobenzyl ester.

(c‐) 110 mg (0.61 mmol) of p-toluenesulfonylanide and 4.5 mg of tetraethylammonium bromide in 1 ml of pure dioxane.
(0.021 mmol) was stirred at 110 °C for 30 min under an argon atmosphere. Then 6-phenoxyacetamidopenicillanic acid p-nitrobenzyl ester 1β in 1 ml of dioxane
A suspension of 250 mg (0.5 mmol) of -oxide is added and the resulting solution is stirred at 110° C. for 4 hours under an argon atmosphere. The solution 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. Dry the organic phase with magnesium sulfate and remove the solvent in vacuo to obtain the crude 2-[4-(p-
Toluenesulfonylthio)-3-phenoxyacetamide-2-oxoazetidine-1-
yl]-3-methylenebutyric acid p-nitrobenzyl ester is obtained.

(d) 2-[4-[p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]- in 30 ml of dry methyl acetate.
3-methylenebutyric acid p-nitrobenzyl ester
1.1 equivalents of ozone are passed through a solution of 1.92 g (3.0 mmol) at −78° C. over a period of 33 minutes. Immediately thereafter, excess ozone is removed with a stream of nitrogen (-78°C, 15 minutes). Add 2.2 ml (10 equivalents) of dimethyl sulfide 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. Wash the benzene solution three times with 50 ml of saturated sodium chloride solution,
Dry over magnesium sulfate and concentrate to dryness in vacuo. If the residue is recrystallized from toluene, 2-[4-(p-toluenesulfonylthio)
-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxycrotonic acid p-nitrobenzyl ester is obtained.
Melting point is 159-160°C.

(d-) Purified 2- obtained in (c-) of Example 1
[4-(p-toluenesulfonylthio)-3-
Phenoxyacetamido-2-oxoazetidin-1-l]-3-methylenebutyric acid p-nitrobenzyl ester is dissolved in 20 ml 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. 5ml water
Add a solution of 300mg of sodium bisulfite in
The mixture is stirred for about 5 minutes until no more ozonide 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 is dissolved in 3 ml of methylene chloride and 15 ml of toluene are added. Filter the precipitate,
Evaporate the filtrate in vacuo. Recrystallization of the residue from methanol yields 2-[4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-
3-hydroxycrotonic acid p-nitrobenzyl ester is obtained. Melting point is 159-160°C.

(e) 2-[4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3 in 5 ml of dry pyridine.
A solution of 641 mg (1 mmol) of -hydroxycrotonic acid p-nitrobenzyl ester was cooled to -10°C in an acetone/ice bath, 285 mg (1.5 mmol) of p-toluenesulfonyl chloride was added, and the mixture was heated under a nitrogen atmosphere. Stir for about 5 hours until starting material can no longer be detected by thin layer chromatography (silica gel: toluene/ethyl acetate 1:1). The reaction solution is diluted with 50 ml of benzene, washed with water, ice-cold 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. blue yellow 2-
[4-(p-Toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-p-toluenesulfonyloxy-crotonic acid p-nitrobenzyl ester is obtained, which can be used in subsequent steps. It is sufficiently pure. Infrared absorption spectrum (methylene chloride): Characteristic bands are 5.6; 5.8; 5.9; 6.55; 7.45;
8.55 and 8.75μ; NMR spectrum (deuterochloroform): δppm: 2.4 (6H, s); 2.45
(3H, s); 4.4 (2H, q, J=15Hz); 5.3 (2H,
s); 5.3 (1H, dd, J = 5.10Hz); 5.8 (1Hd; J
= 5 Hz) and 6.6-8.4 (18H, c).

(f) 2-[4- in 2 ml of dry tetrahydrofuran
(p-Toluenesulfonylthio)-3-phenoxyacetamide-2-oxoazetidine-1-
yl]-3-p-toluenesulfonyloxy-
Crotonic acid p-nitrobenzyl ester 80mg
(0.1 mmol) and pyrrolidine 0.0175 ml
(0.21 mmol) is stirred under a nitrogen atmosphere for about 1 hour until no starting material can be detected any longer by thin layer chromatography (silica gel: toluene/ethyl acetate 1:1). 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 with 1:1 toluene/ethyl acetate yields colorless 2-[4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]. -3-
A mixture is obtained consisting of (1-pyrrolidyl)-crotonic acid p-nitrobenzyl ester and its corresponding isocrotonic ester. Infrared absorption spectrum (methylene chloride): 5.6; 5.95;
6.55; Characteristic bands at 7.45 and 8.75μ; NMR spectrum (deuterochloroform); δppm:
1.6-2.2 and 3.0-3.8 (8H, c); 2.08 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.

(f‐) 2-[4-(p
-Toluenesulfonylthio)-3-phenoxyacetamide-2-oxoazetidine-1
A solution of 256 mg (0.4 mmol) of p-nitrobenzyl]-3-hydroxycrotonic acid, cooled to -10°C, was mixed with 0.1115 ml (0.8 mmol) of triethylamine and then 0.062 ml (0.062 ml) of methanesulfonyl chloride ( 0.8mmol)
Process with. After 1 hour, 0.104 ml (1.24 mmol) of freshly distilled pyrrolidine is added and the mixture is stirred for a further 2 hours at -10°C. The reaction solution is diluted with 20 ml of methylene chloride, washed three times with 15 ml of water, dried over sodium sulfate and evaporated in vacuo. The residue is triturated with diethyl ether to give blue-yellow 2-[4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3.
A mixture consisting of -(1-pyrrolidyl)-crotonic acid p-nitrobenzyl ester and its corresponding isocrotonic acid p-nitrobenzyl ester is obtained, which can be used as such in the next step. (IR spectrum: 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‐) 2-[4-(p
-Toluenesulfonylthio)-3-phenoxyacetamide-2-oxoazetidine-1
A solution of 128 mg (0.2 mmol) of p-nitrobenzyl]-3-hydroxycrotonic acid cooled to -10°C was mixed with 0.042 ml (0.3 mmol) of triethylamine and 0.017 ml (0.22 mmol) of methanesulfonichloride under a nitrogen atmosphere. mmol) and stir the mixture at the same temperature for 30 minutes. The reaction mixture is diluted with 10 ml of methylene chloride, washed three times with 10 ml of saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. 2-[4-(p-toluenesulfonylthio)-3-phenoxyacetamide-
The residue containing 2-oxoazetidin-1-yl]-3-methanesulfonyloxy-crotonic acid p-nitrobenzyl ester and its corresponding isocrotonic acid ester cannot be purified by chromatography as it is unstable; It is sufficiently pure to be used in the following steps [e.g. (f-) in Example 1].

Infrared absorption spectrum (methylene chloride):
5.55; 5.7; 5.8; 6.55; 7.45; 8.55 and 8.75μ
Characteristic band; NMR spectrum (deuterochloroform: δppm: 2.37 (3H, s);
2.39 and 2.5 (3H, s); 3.12 and 3.27
(3H, s); 4.39 and 4.41 (2H, s); 5.2
(1H dd, J=5.10Hz); 5.25 (2H, s); 5.88
and 5.95 (1H, d, J = 5Hz) and 6.6~
8.4 (15H, c).

Example 2 2-[4-(p-toluenesulfonylthio)-3
-Phenoxyacetamido-2-oxoazetidin-1-yl]-3-(N-methylcyclohexylamino)-crotonic acid p-nitrobenzyl ester and the corresponding isocrotonic acid ester (148 mg (0.2 mmol)) were dried. The solution in 3 ml of acetonitrile is heated under a nitrogen atmosphere at 80° C. for about 4 hours until the starting material can no longer be detected by thin layer chromatography (silica gel, toluene/ethyl acetate 1:1). Remove the heating bath and add 38 mg of p-toluenesulfonic acid to the reaction mixture.
(0.2 mmol) and about 0.2 ml of water are added and the mixture is stirred for a further 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 DEG C. to give blue-yellow 7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester.

Infrared absorption spectrum (methylene chloride):
2.95; 3.3; 5.6; 5.75 (sh); 5.9; 5.95 (sh); 6.55
，
7.45; Characteristic bands at 8.15 and 8.3μ; NMR spectrum (deuterochloroform); δppm: 3.4
(zH, q, J=17Hz); 4.57 (2H, s); 5.06 (1H,
d, J=5Hz); 5.35 (2H, d, J=14Hz); 5.7
(1H, dd, J=5, 10Hz); 6.8~8.4 (10H, c)
and 11.4 (1H, br, s).

The starting material can be produced as follows.

2-[4-(p) in 2 ml of dry tetrahydrofuran
-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]
-3-Toluenesulfonyloxy-crotonic acid p-nitrobenzyl ester (160 mg (0.2 mmol)) was added to a solution of N-
Methyl-N-cyclohexylamine 0.056ml
(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 1:1). The reaction solution is diluted with benzene, washed several times with water, dried over sodium sulfate and evaporated in vacuo. The residue is benzene/
Chromatograph on 10 g of acid-washed silica gel with 3:1 ethyl acetate. 2-[4-(p-toluenesulfonylthio)-3-phenoxyacetamide-
A mixture of 2-oxoazetidin-1-yl]-3-(N-methylcyclohexylamino)-crotonic acid p-nitrobenzyl ester and its corresponding isocrotonic acid ester is obtained as a blue-yellow oil. Infrared absorption spectrum (methylene chloride): 2.95; 3.4; 5.6; 5.8; 6.55; 7.4 and 8.75μ
on the characteristic band.

Example 3 By the method described in Example 1, 2-[4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-
Starting from cyclohexylamino-crotonic acid p-nitrobenzyl ester and its corresponding isocrotonic acid ester, 7β-phenoxyacetamido-3-cyclohexylamino-cephem-
4-Carboxylic acid p-nitrobenzyl ester (2
- and 3-cefem derivative mixture),
and then 7β-phenoxyacetamide-
3-Hydroxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester can be produced.

The starting material can be manufactured as follows.

(a) 2 dissolved in 2 ml of dry tetrahydrofuran
-[4-(p-toluenesulfonylthio)-3-
A solution of 160 mg (0.2 mmol) of p-nitrobenzyl phenoxyacetamido-2-oxoazetidin-1-yl]-3-p-toluenesulfonyloxy-crotonic acid was added to 0.0577 ml (0.5 mmol) of cyclohexylamine under a nitrogen atmosphere. ) and stir the mixture for 1 hour at room temperature. The reaction solution was diluted with benzene, washed with water,
Dry over sodium sulfate and evaporate in vacuo. 2-[4-(p-toluenesulfonylthio)
-3-Phenoxyacetamido-2-oxoazetidin-1-yl]-3-cyclohexylamino-crotonic acid p-nitrobenzyl ester and its corresponding isocrotonic acid ester The residue containing the mixture is not purified and subjected to the following steps. It can be used for. Infrared absorption spectrum (methylene chloride): 2.9; 3.4; 5.6; 5.9; 6.0;
Characteristic bands at 6.25; 6.55; 7.45; 8.10 and 8.75μ; NMR spectrum (deuterochloroform); δppm: 1.8-2.0 (11H, c) 2.02 (3H,
s); 2.35 (3H, s); 4.43 (2H, s); 4.95 (1H
dd, J=5.10Hz); 5.17 (2H, s); 5.80 (1H,
d, J = 5 Hz)) and 6.6-9.2 (15H, c).

Example 4 (a) 7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester in 10 ml of dry chloroform.
Dissolve 485 mg of ethereal diazomethane in a solution cooled to 0°C and add 3 ml of ethereal diazomethane solution (0.5 mol, 1.5 equivalents).
Add for about 10 minutes. The blue-yellow solution is stirred for 1 hour at 0° C., flushed with nitrogen to remove excess diazomethane, and concentrated in vacuo. If the residue is recrystallized from methylene chloride, 7β
Phenoxyacetamide-3-methoxy-3-
Cefem-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-) 7β-Phenoxyacetamide-3-hydroxy-3 in 25 ml of carbon tetrachloride and 27 ml of water.
- A suspension of 4.85 g of cefem-4-carboxylic acid p-nitrobenzyl ester was continuously stirred vigorously at 20°C with 3.0 g of potassium bicarbonate.
and treated with 3.8 ml of dimethyl sulfate and 1.93 g of tetrabutylammonium bromide. The mixture is stirred vigorously for 4 hours at 20°C. water 50
After diluting with ml, the mixture was diluted with methylene chloride.
Extract twice with 50 ml. Evaporation of the extracts, drying over sulfate, and recrystallization of the residue from methylene chloride/diethyl ether yielded 7β-phenoxyacetamido-3-methoxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester. can get. Melting point 140.5-142℃.

(b) methanol/tetrahydrofuran 1:1 2
A solution of 250 mg (0.5 mmol) of 7β-phenoxyacetamido-3-methoxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester dissolved in 2 ml of the same solvent was added to a mixture of 5% panadium/charcoal in 2 ml of the same solvent. (This mixture is 1
The reaction mixture is hydrogenated for 3 hours at room temperature and under atmospheric pressure. 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 taken up in 10 ml of methylene chloride and extracted twice with 10 ml of 50% aqueous sodium bicarbonate solution. The combined bicarbonate extracts are made neutral with dilute hydrochloric acid at 0°C and extracted three times with 10 ml of methylene chloride. The organic phase is dried over sodium sulfate and freed from the solvent in vacuo. Crystallization from chloroform/pentane yields 7β-phenoxyacetamide-3 from the residue.
-Methoxy-3-cephem-4-carboxylic acid is obtained. Melting point is 173-174°C.

(c) 2.55 g (7 mmol) of 7β-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid in 11 ml of anhydrous methylene chloride and N,N-
0.7 ml (5.7 mmol) of dimethyl-dichlorosilane are added to the suspension with 2.9 ml (22.4 mmol) of dimethylaniline at 20 DEG C. under a nitrogen atmosphere, and the mixture is then stirred for 30 minutes at the same temperature. The clear solution thus obtained is cooled to -20 DEG C., 1.6 g (7.7 mmol) of solid phosphorus pentachloride are added and the mixture is stirred for 30 minutes. Pre-chilled (-20℃) N,N-dimethylaniline 0.9
ml (7 mmol) and n-butanol 0.9 ml at the same temperature over 2-3 minutes, followed by pre-chilled (-20°C) n-butanol.
Immediately add 10 ml and then heat the mixture to −20°C.
Stir for 20 minutes and then 10 minutes without cooling. 0.4 ml of water was added at about -10°C, the mixture was stirred in an ice bath (0°C) for about 10 minutes, then 11 ml of dioxane was added, and after stirring for another 10 minutes at 0°C, the tri-n- Butylamine approx. 4.5
ml (until the sample diluted with water shows a constant pH 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 thus obtained
-amino-3-methoxy-cef-3-em-4
-The melting point of carboxylic hydrochloride dioxanate is
The temperature is 300℃ or higher. Thin layer chromatography: Rf value = 0.17 (silica gel; system, n-butanol/4
Carbon chloride/methanol/formic acid/water, 30:40:
20:5:5).

(c‐) 47 ml of anhydrous methylene chloride (distilled over P ₂ O ₅ )
93% 7β-phenoxyacetamide-3 in
-Methoxy-cef-3-em-4-carboxylic acid 11.75g (equivalent to 10.93g of 100%) and N,N-
The suspension with 13.4 ml (12.73 g) of dimethylaniline is treated with 3.6 ml (3.87 g) of dimethyldichlorosilane at +20° C. under nitrogen atmosphere, and the mixture is then stirred for 30 minutes at the same temperature. Cool the now clear solution to -18°C (-19°C),
Add 7.8g of solid phosphorus pentachloride and bring the internal temperature to -
Raise to 10℃. After stirring for 30 minutes in a -20°C bath, the clear solution was stirred for about 7 minutes.
47 ml of n-butanol (anhydrous, dried on a rack) cooled to 20°C and 4.4 ml of dimethylaniline
ml (4.18 g) dropwise. Internal temperature rises to -8°C. The mixture was initially −
Stirring in a 20°C bath followed by an ice bath (0°C) for a further 30 minutes brings the internal temperature to a final -10°C. 47ml of dioxane and 1.6ml of water at the same temperature
Add the mixture dropwise (required time: approximately 5 minutes).
The product then gradually precipitates out. After stirring for an additional 10 minutes, the PH value of the mixture was brought to 2.2-2 in an ice bath by adding approximately 9.5 ml of tri-n-butylamine dropwise over approximately 1 hour (the first 3 ml was added during the first 5 minutes). Adjust between 2.4 and keep that value. The product is then filtered and washed with about 30 ml of dioxane and then with about 15 ml of methylene chloride to obtain crystalline 7β-amino-
3-Methoxy-cef-3-em-4-carboxylic hydrochloride dioxanate is obtained. Melting point is over 300℃. Ultraviolet absorption spectrum (in 0.1n sodium bicarbonate): λmax=270mμ
(ε=7600); Infrared absorption spectrum (nujiol): 5.62; 5.80; 5.88; 6.26; 6.55;
7.03; 7.45; 7.72; 7.96; 8.14; 8.26; 8.45;
Characteristic bands at 8.64; 8.97; 9.29; 10.40 and 11.47 mμ; [α] ²⁰ _D = +134° ± 1° (c = 1; 0.5N
sodium bicarbonate solution).

7β-amino-3-methoxy-cef-3-
The zwitterion of em-4-carboxylic acid is obtained by treating the 20% aqueous solubility of the hydrochloride dioxanate obtained above with 2N sodium hydroxide until the pH value becomes 4.1 (isoelectric point). can be obtained from. If filtered and dried, the melting point of the zwitterion is 300.
℃ or higher. Ultraviolet absorption spectrum (in 0.1N sodium bicarbonate solution) λmax=
270nm (ε=7600). Thin layer chromatography: Rf value identified as Rf value of hydrochloride (silica gel,
(above system); [α] ²⁰ _D = +232° ± 1° (c = 1;
0.5N sodium bicarbonate solution).

(d) 7β-amino-3 in 20 ml of dry methylene chloride
-methoxy-cef-3-em-4-carboxylic hydrochloride dioxanate in a suspension of 1 g (2.82 mmol) of bis-(trimethylsilyl)-acetamide.
Add 1.65 ml at room temperature under nitrogen atmosphere. After 40 minutes, the clear solution was cooled to 0°C and 900 mg of solid D-α-phenylglycylic acid chloride hydrochloride was added.
(4.37 mmol) is added. After 5 minutes, 0.7 ml (10 mmol) of propylene oxide is added. The suspension was then stirred at 0°C for 1 hour under a nitrogen atmosphere, after which 0.5 ml of methanol was added and 7β-(D
-α-phenylglycylamino)-3-methoxy-cef-3-em-4-carboxylic hydrochloride is precipitated as crystals. Filter the hydrochloride and add 9 ml of water.
and adjust the PH value of the solution to 4.6 with 1N sodium hydroxide solution. Precipitated 7β-(D-α
-Phenylglycylamino)-3-methoxy-
The dihydrate of the inner salt of cef-3-m-4-carboxylic acid is filtered, washed with acetone and diethyl ether, and dried. Melting point: 174-176°C (with decomposition). [α] ²⁰ _D = +132° (c = 0.714; in 0.1N hydrochloric acid); Thin layer chromatography (silica gel); Rf
Value 0.18 (system, n-butanol/acetic acid/water, 67:
10:23). Ultraviolet absorption spectrum (in 0.1N sodium bicarbonate aqueous solution) λmax = 269μ (ε =
7000); Infrared absorption spectrum (in mineral oil):
Characteristic bands at 5.72, 5.94, 6.23 and 6.60μ.

(d-) 7β-Amino-3- in 10 ml of methylene chloride
To a suspension of 993 mg (4.32 mmol) of methoxy-cef-3-em-4-carboxylic acid (inner salt) was added 1.37 ml (5.6 mmol) of N,N-bis-(trimethylsilyl)-acetamide, and the mixture Stir at room temperature for 45 min under nitrogen atmosphere. The clear solution was cooled to 0°C and 1.11 g (5.4 m
mol). Propylene oxide after 5 minutes
Add 0.4ml (5.6mmol). The suspension is then stirred for 1 hour at 0° C. under a nitrogen atmosphere, and then 0.6 ml of methanol is added. precipitate
7β-(D-α-phenylglycylamino)-
The 3-methoxy-ceph-3-em-4-carboxylic acid salt is filtered and dissolved in 15 ml of water at 0 DEG C., and the pH value of the solution is adjusted to about 4 with 5 ml of 1N sodium hydroxide. Warming the solution to room temperature and adjusting the pH of the solution to about 4.8 with triethylamine yields 7β-(D-α-phenylglycylamide).
-3-Methoxy-cef-3-em-4-carboxylic acid precipitates out in the form of a dihydrate.

Example 5 2-[4-(p-toluenesulfonylthio)-3
-Phenoxyacetamido-3-oxoazetidin-1-yl]-3-(1-pyrrolidyl)-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid ester (158.2 g (0.2 mol)) in 1500 ml of dry acetonitrile. The solution is heated at 80° C. under a nitrogen atmosphere for about 5 hours until the starting material can no longer be detected by thin layer chromatography (silica gel, toluene/ethyl acetate 1:1). The heating bath was removed and the reaction mixture containing 7β-phenoxyacetamide-3-pyrrolidino-cephem-4-carboxylic acid diphenylmethyl ester was treated with 200 ml of 0.1 NCl and stirred for a further 3 hours at room temperature. The reaction mixture is evaporated to dryness in vacuo.

Take up the residue in ethyl acetate and dilute sulfuric acid,
Wash successively with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dry over sodium sulfate. Evaporate the solution in vacuo to obtain 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 value 0.24 (silica gel; toluene/ethyl acetate, 1:1).

The product obtained can be further processed as follows.

(i) Obtained 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 minutes, the solution is completely concentrated and the oily residue is chromatographed on thin layer silica gel (toluene/ethyl acetate, 3:1). Extraction of silica gel with Rf=0.19 with ethyl acetate yields 7β-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid diphenylmethyl ester.
Melting point 120°C (from ether). Infrared absorption spectrum (in _CHCl3 ); 3310, 1775, 1700, 1690 and 1600 cm ^-1 .

(ii) Similarly to Example 4 (a-), the obtained 7β-
Phenoxyacetamido-3-hydroxy-3
-Cefem-4-carboxylic acid diphenylmethyl ester is converted to 7β-phenoxyacetamide-3-methoxy-cef-3-em-4-carboxylic acid diphenylmethyl ester by a phase transition method using dimethyl sulfate and potassium bicarbonate. It can be changed.

(iii) 7β-phenoxyacetamido-3-methoxy-cef-3-em-4 in 5 ml of methylene chloride.
-Carboxylic acid diphenyl methyl ester 2.0g
Add 0.87 ml of anisole to a solution of (3.78 mmol), cool the mixture to 0°C, add 1.2 ml of trifluoroacetic acid, and leave for 1 hour. The reaction mixture is concentrated in vacuo and the residue is recrystallized from acetone/ether. 7β-Phenoxyacetamide-3-methoxy-cef-3-em-4
- A carboxylic acid is obtained. Melting point is 170°C (with decomposition).

The starting material can be produced as follows.

(a) 6-phenoxyacetamidopenicillanic acid
1β-oxide 100g (27.3mol) and dioxane
500ml and 58.4g of diphenylmethyldiazomethane
(30 mmol), 6-phenoxyacetamidopenicillanic acid diphenylmethyl ester 1β-oxide is obtained after about 2 hours. Melting point 144-146°C (ethyl acetate/petroleum ether).

(b) In the same manner as in Example 1 (b), 292 g (55 mmol) of 6-phenoxyacetamidopenicillanic acid diphenylmethyl ester 1β-oxide and 2-
99 g (59.5 mmol) of mercaptobenzthiazole and 2-[4-(benzthiazole-2)
-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3
-methyleneacetic acid diphenylmethyl ester is obtained. Melting point 140-141°C (from toluene/ether).

(c) 2-[4-(Benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3- in 50 ml of ethyl acetate as in Example 1 (c). 10 g (14.7 mmol) of methylene butyric acid diphenyl methyl ester and finely powdered silver p-toluenesulfinate
4.92g (24.98mmol) was stirred at room temperature for 7 hours to obtain 2-[4-(p-toluenesulfonyl-
thio)-3-phenoxyacetamide-2-
Oxoazetidin-1-yl]-3-methylenebutyric acid diphenylmethyl ester is obtained. Rf value = 0.28 (silica gel, toluene/ethyl acetate, 3:1), infrared absorption spectrum (CHCl ₃ ): 1782, 1740, 1695, 1340 and
1150cm ^-1 .

(d) Same as Example 1 (d), methylene chloride 1
10.8 g (16.2 m
mol) and 1.1 equivalents of ozone to 2-[4-(p
-Toluenesulfonylthio)-3-phenoxyacetamide-2-oxoazetidine-1
-yl]-3-hydroxycrotonic acid diphenylmethyl ester is obtained. Melting point is 142
~143°C (from ether/pentane).

(e) 2-[4-(p) in 500 ml of dry methylene chloride
-Toluenesulfonylthio)-3-phenoxyacetamide-2-oxoazetidine-1
-yl]-3-hydroxycrotonic acid diphenylmethyl ester 134.4 g (0.2 mol) of -10
The solution cooled to 0.degree. C. is treated under a nitrogen atmosphere with 34.8 ml (0.25 mol) of triethylamine and then with 24.5 ml (0.25 mol) of methanesulfonyl chloride. After 20 minutes, freshly distilled pyrrolidine
47 ml (0.55 mol) and the mixture -10
Stir for another 2 1/2 hours at ℃. Pour the reaction solution into water.
Wash 3 times with 150 ml, dry over sodium sulfate and evaporate in vacuo. When the residue is dried to form a foam, a blue-yellow 2-[4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-
A mixture consisting of (1-pyrrolidyl)-crotonic acid diphenylmethyl 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 (3 mmol) of 7β-amino-3-methoxy-cef-3-em-4-carboxylic hydrochloride dioxanate obtainable by the method of the invention in a similar manner to Example 4 (d). and 1.5 ml (6.2 mmol) of bis-(trimethylsilyl)-acetamide, and then the reaction product and (a) 765 mg (3.6 mmol) of D-α-amino-(2-thienyl)-acetic acid chloride hydrochloride 7β-[D-α-amino-α-(2-thienyl)]
-acetylamino]-3-methoxy-3-cephem-4-carboxylic acid can be obtained in the form of an inner salt. Melting point 140℃ (with decomposition). Thin layer chromatography (silica gel, identified with 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 = 11400) and λ shoulder = 272 mμ (ε = 6100) [ in 0.1N hydrochloric acid], and λmax = 238μ (ε = 11800) and λ shoulder =
267 mμ (ε = 6500) [in aqueous sodium bicarbonate solution].

(b) Also D-α-amino-(1,4-cyclohexadienyl)-acetic chloride hydrochloride 940 mg
(4.5 mmol), 7β-[D-α-
Amino-α-(1,4-cyclohexadienyl)-
Acetylamino]-3-methoxy-3-cephem-4-carboxylic acid can be obtained in the form of an inner salt. Melting point 170℃ (with decomposition). Thin layer chromatography (silica gel, identified with 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 = 6300) [in 0.1N hydrochloric acid], λmax = 268 mμ (ε = 6600) [0.1N sodium bicarbonate aqueous solution], [α] ²⁰ _D = +88° ± 1° (c =
1.06; 0.1N hydrochloric acid).

(c) Furthermore, 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)-acetylamino]-3
-Methoxy-3-cephem-4-carboxylic acid can be obtained in the form of an inner salt. Melting point 243~
244.5℃ (sintering starts at 231℃) (with decomposition). Thin layer chromatography (silica gel, identified with 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: λmax=228mμ (ε=
12000) and 271 mμ (ε = 6900) [in 0.1N hydrochloric acid], and λmax = 227 mμ (ε = 10500) and λ shoulder = 262 mμ (ε = 8000) [in 0.1N aqueous sodium bicarbonate solution], [α] ²⁰ _D =+165°±1°(c=
1.3; 0.1N hydrochloric acid).

Example 7 6 g (10.24 mmol) of crystal 3- in 100 ml of CH ₂ Cl ₂
Morpholino-7β-phenoxyacetamide-3
- Cefem-4-carboxylic acid-diphenyl methyl ester solution and 20 ml of methanol.
Mix with 100 ml of 0.2NHCl and stir vigorously to form an emulsion. After completion of reaction (about 48 hours)
The organic phase is separated, dried and the solvent removed in vacuo. Thus, a very pure 3 with a melting point of 87-79°C
-Hydroxy-7β-phenoxyacetamide-
A white foam is obtained consisting of 3-cephem-4-carboxylic acid-diphenylmethyl ester.

The starting material can be produced as follows. 107.5 g (151.1 mmol) in 1.6 methylene chloride
2-[4-(p-toluenesulfonylthio)-3
-Phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-carboxylic acid-
29.2 ml (374.4 mmol) of methanesulfonyl chloride are added dropwise to the solution of diphenyl methyl ester at −10° C. and 52.2 ml (374.4 mmol) of triethylamine are added. After 30 minutes, 750 mmol of morpholine was slowly added dropwise at -10°C.
It is then stirred for an additional 3 hours at -10°C.
Washed twice with 250 ml of 0.2NHCl and saturated NaCl solution, dried the organic phase over sodium sulfate, filtered and
Concentrate the filtrate sufficiently, add 650ml of methanol,
Generates crystals. Thus, 2-[4-(p-
Toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-
A crystalline mixture of 3-(1-morpholinyl)-crotonic acid-diphenylmethyl ester and the corresponding isocrotonic ester (melting point 111 DEG -114 DEG C., decomposed) is separated.

74.1 g (0.1 mol) of 2-[4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]- in 400 ml of acetonitrile (dried over basic Al ₂ O ₃ ) 3-
A solution of (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 melting point 167 to 169
Almost colorless 3-morpholino-7β-phenoxyacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester is crystallized at .

Example 8 In the same manner as in Example 7, crystal 3-piperidino-7β
-Phenoxyacetamide-3-cephem-4-
3- from carboxylic acid diphenyl methyl ester
Hydroxy-7β-phenoxyacetamide-3
-Cefem-4-carboxylic acid-diphenylmethyl ester is obtained.

The starting material can be obtained as follows.

11.1 g [15 mmol] in 100 ml dry acetonitrile
2-[4-(p-toluenesulfonylthio)-3
-Phenoxyacetamido-2-oxoazetidin-1-yl]-3-(1-piperidinyl)-crotonic acid-diphenylmethyl ester is heated under reflux for 5.5 hours. This solution was concentrated and mixed with 100 ml of dry cold methanol, thus melting point
Pure 3-piperidino-7β- at 184-188℃ (decomposition)
Phenoxyacetamide-3-cephem-4-carboxylic acid-diphenylmethyl ester is crystallized.

Example 9 10 mg (0.017 mmol) in 5 ml methylene chloride
1 ml of 5N hydrochloric acid is added dropwise to a solution of 7β-phenoxyacetamido-3-(1-morpholinyl)-3-cephem-4-carboxylic acid-diphenylmethyl ester. The reaction mixture is stirred for 30 minutes at room temperature. removing the aqueous phase and mixing the organic phase with water;
Dry over sodium sulfate and evaporate. Thus 7β-phenoxyacetamide-3
-Hydroxy-3-cefem-4-carboxylic acid-
Diphenyl methyl ester is obtained. IR-spectrum (in methylene chloride): 3410, 2925-2850,
1780, 1690, 1600, 1510, 1490, 1360, 1220 and
It has a specific absorption band at 1200cm ^-1 .

The starting material is obtained as follows.

(a) 6.83 g (10 mmol) of 2 in 25 ml of methylene chloride
-[4-(Benzthiazol-2-yl-dithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxycrotonic acid-diphenylmethyl ester at -20°C
The cooled solution was added with 0.971 ml (12.5 mmol) of methanesulfonyl chloride and then 1.74 ml
(12.5 mmol) of triethylamine.
The reaction mixture was cooled to −20°C for 1.5 h and then
Add 2.39 ml (27.5 mmol) of morpholine.
The reaction mixture is cooled to −15° C. for an additional hour and then warmed to room temperature. Dilute this mixture with 50ml of methylene chloride and add 40ml of
Wash once with 2NHCl and three times with saturated saline. The organic phase is dried over sodium sulphate and evaporated. The crude product was chromatographed on 400 g of silica gel (Mel) with toluene/ethyl acetate (9:1, 3:1, 1:1) and 2-[4-benzthiazol-2-yl] -3-Phenoxyacetamido-2-oxoazetidin-1-yl-3-(1
-morpholinyl)-crotonic acid-diphenylmethyl ester is obtained.

(b) 100 mg (0.133 mmol) in 5 ml dry toluene
A solution of 2-[4-(benzthiazol-2-yl-dithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-(1-morpholinyl)-crotonic acid-diphenylmethyl ester Heat to 70°C for 24 hours. 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, the melting point
7β-Phenoxyacetamide at 172-173℃
3-(1-morpholinyl)-3-cephem-4-
Carboxylic acid-diphenylmethyl ester is obtained.

Example 10 In the same manner as in Example 9, crystal 3-pyrrolidino-7β
-Phenoxyacetamide-3-cephem-4-
3- from carboxylic acid diphenyl methyl ester
Hydroxy-7β-phenoxyacetamide-3
-Cefem-4-carboxylic acid-diphenylmethyl ester is obtained.

The starting material is obtained as follows.

14.5g (20mmol) in 150ml dry acetonitrile
2-[4-(p-toluenesulfonylthio)-3
-Phenoxyacetamido-2-oxoazetidin-1-yl]-3-(1-pyrrolidinyl)-crotonic acid-diphenyl methyl ester solution was heated to 80°C until no starting material was visible on thin layer chromatography. Heat it up. The solvent was thoroughly removed in vacuo and replaced with 100 ml of dry, cold methanol, thus producing 3-pyrrolidino-7β-phenoxyacetamide-3-3-pyrrolidino-7β-phenoxyacetamide-3- with a melting point of 190-194°C.
Cefem-4-carboxylic acid-diphenylmethyl ester is crystallized.

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 _CH2Cl2 ):
Has bands at 2.95, 5.61, 5.77, 5.85, 5.95, 6.21 and 6.87μ; 7β-amino-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester,
IR-spectrum (in _CH2Cl2 ): 5.58 _, 5.77 (shoulder),
Has 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 CH ₂ Cl ₂ ): 2.94, 3.40, 5.62, 5.77, 5.75,
Has bands at 5.95, 6.21 and 6.88μ; 7β-[D-α-tert-butyloxycarbonylamino-α-(4-hydroxyphenyl)-acetylamino]-3-hydroxy-3-cephem-4
-Carboxylic acid-diphenyl methyl ester, ultraviolet absorption spectrum (in 95% aqueous ethanol):
λmax=284mμ (ε=5.100), Infrared absorption spectrum (in methylene chloride): 5.59, 5.83 (shoulder), 5.88,
Has specific bands at 6.18 and 6.67μ; 7β-[D-α-tert-butyloxycarbonylamino-α-(2-thienyl)-acetylamino]
-3-Hydroxy-3-cephem-4-carboxylic acid-diphenylmethyl ester, ultraviolet absorption spectrum (in 95% aqueous ethanol) λmax = 283 mμ
(ε=5.300), UV absorption spectrum (in methylene chloride): with specific bands at 5.59, 5.87, 6.19 and 6.66μ; 7β-[D-α-tert-butyloxycarbonylamino-α-(3-thienyl )-acetylamino]
-3-Hydroxy-3-cephem-4-carboxylic acid-diphenylmethyl ester, ultraviolet absorption spectrum (in 95% aqueous ethanol): λmax=
283 mμ (ε = 5.300), infrared absorption spectrum (in methylene chloride): with specific absorption at 5.59, 5.87, 6.19 and 6.66μ; 7β-[D-α-tere-butyloxycarbonylamino-α-(2- Furyl)-acetylamino]-
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): with specific bands at 5.59, 5.87, 6.19 and 6.66μ; )-acetylamino]-3-hydroxy-3-cephem-4-carboxylic acid-diphenylmethyl ester, UV absorption spectrum (in 95% aqueous ethanol): λmax
= 250 mμ (ε = 12.000) and 280 mμ (ε = 5.800),
Infrared absorption spectrum (in methylene chloride): 5.59,
Has specific bands at 5.87, 6.19 and 6.66μ; 7β-[D-α-tert-butyloxycarbonylamino-α-(1,4-cyclohexadienyl)-
acetylamino]-3-hydroxy-3-cephem-4-carboxylic acid-diphenylmethyl ester, IR-spectrum (in _CHCl3 ) 3380, 1780,
Has bands at 1690, 1610, 1590 and 1470 cm ^-1 ; 7β-(2-thienyl)-acetylamino-3-
Hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester, ultraviolet absorption spectrum (in 95% aqueous ethanol): λmax = 280 mμ (ε =
7β-(1-tetrazolyl)-acetylamino-
3-Hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester, ultraviolet absorption spectrum (in 95% aqueous ethanol): λmax = 282 mμ,
Infrared absorption spectrum (in methylene chloride): 5.59,
Has specific bands at 5.87, 6.19 and 6.66μ; 7β-(4-pyridylthio)-acetylamino-
3-Hydroxy-3-cephem-4-carboxylic acid-diphenylmethyl ester, ultraviolet absorption spectrum (in 95% aqueous ethanol): λmax = 283 mμ,
Infrared absorption spectrum (in methylene chloride): 5.59,
Has specific bands at 5.83 (shoulder), 5.88, 6.18 and 6.67μ; 7β-(4-aminopyridinium-acetylamino)-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester, UV absorption Spectrum (in 95% aqueous ethanol): λmax=
282 mμ, infrared absorption spectrum (in methylene chloride): with specific bands at 5.59, 5.87, 6.19 and 6.66μ; 7β-[D-α-(2,2,2-trichloroethoxycarbonyloxy)-α-phenyl- Acetylamino]-3-hydroxy-3-cephem-4
-Carboxylic acid-diphenyl methyl ester, ultraviolet absorption spectrum (in 95% aqueous ethanol):
λmax = 284 mμ, with specific bands at 5.59, 5.87, 6.19 and 6.66μ in the infrared absorption spectrum (in methylene chloride).

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

3-Methoxy-7β-phenylacetamide-
3-Cefem-4-carboxylic acid-diphenylmethyl ester, IR-spectrum ( _{in CH2Cl2} ):
Has bands at 2.94, 5.63, 5.83, 5.94, 6.26 and 6.66μ; 3-methoxy-7β-amino-3-cepheme-
4-Carboxylic acid-diphenylmethyl ester (and its salts), IR-spectrum (in dioxane)
Has bands at 2.87, 5.62 and 6.26μ; 3-methoxy-7β-phenylacetamino-
3-cephem-4-carboxylic acid (or its salt),
IR-spectrum (in _CH2Cl2 ): 3.03, 5.60 _, 5.74,
Has bands at 5.92, 6.24 and 6.60μ; 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 salt thereof), melting point 174-176°C (decomposition) ;2-n
-Butyloxy-7β-phenylacetyl-amino-3-cephem-4-carboxylic acid-diphenylmethyl ester, melting point 168-170°C (from _CH2Cl2 / _diethyl ether); 3-n-butyloxy-7β-( D-α-tert-
Butyloxycarbonylamino-α-phenyl-
acetylamino)-3-cephem-4-carboxylic acid-diphenylmethyl ester, IR-spectrum ( _{in CH2Cl2} ): 2.88, 5.63, 5.84 (shoulder), 5.88,
Has bands at 6.26 and 6.71μ; 3-n-butyloxy-7β-(D-α-phenylglycyl-amino)-3-cephem-4-carboxylic acid (or its salt), melting point 141-142°C (acetone/diethyl ether); 3-methoxy-7β-phenylacetamino-
3-cephem-4-carboxylic acid methyl ester, mp 171-174°C (from CH ₂ Cl ₂ /hexane); 3-ethoxy-7β-(D-α-tert-butyloxycarbonylamino-α-phenyl-acetyl -amino)-3-cephem-4-carboxylic acid-diphenylmethyl ester, IR _- spectrum (in _CH2Cl2 ): bands at 2.96, 5.64, 5.90, 6.28 and 6.73μ; 3-ethoxy-7β- (D-α-phenylglycyl-amino)-3-cephem-4-carboxylic acid (or its salt), UI-spectrum (0.1M NaHCO ₃
in solution): λmax = 263 mμ (ε = 5.500); 3-benzyloxy-7β-(D-α-tert-butyloxycarbonylamino-α-phenyl-acetyl-amino)-3-cephem-4-carboxylic acid- Diphenyl methyl ester, IR-spectrum (CH ₂ Cl ₂
Medium): Bands at 2.96, 5.63, 5.88, 6.26 and 6.72μ; 3-benzyloxy-7β-(D-α-phenylglycylamino)-3-cephem-4-carboxylic acid (or its salt), UI −Spectrum (0.1N
7β-(5-benzoylamino-5-diphenylmethoxycarbonyl-valerylamino)-3 _- methoxy-3-cephem-4-carboxylic acid-diphenylmethyl ester , IR-spectrum (CH ₂ Cl ₂
7β-(D-α-tert-butyloxycarbonylamino-α-phenylacetyl-amino)-3-
Methoxy-3 _- cephem-4-carboxylic acid or its salts, IR-spectrum (in _CH2Cl2 ): 3.00, 5.64,
Has bands at 5.92, 6.25 and 6.72μ; 7β-(D-α-tert-butyloxycarbonylamino-α-(2-thienyl)-acetylamino)
_{7β- [} D- α-tert-butyloxycarbonylamino-α-(1,4-cyclohexadienyl)-
acetylamino]-3-methoxy-3-cephem-4-carboxylic acid-diphenylmethyl ester,
IR-spectrum (in _CH2Cl2 ): 2.96, 5.64, _5.86 ,
Has bands at 5.90 (shoulder), 6.27 and 6.73μ; 7β-[D-α-amino-α-(1-cyclohexen-1-yl)-acetylamino]-3-methoxy-3-cephem-4-carvone Acid or its salt; 7β-[D-α-tert-butyloxycarbonylamino-α-(4-hydroxyphenyl)-acetyl-amino]-3-methoxy-3-cephem-4
-Carboxylic acid-diphenyl methyl ester, IR
-Spectrum (CH ₂ Cl ₂ ): 2.83, 2.96, 5.64,
Has bands at 5.86, 5.91 (shoulder), 6.23, 6, 28, 6.65 and 6.72μ; 7β-[D-α-amino-α-(4-hydroxyphenyl)-acetylamino]-3-methoxy-3
-Cefem-4-carboxylic acid (or its salt), melting point 180°C (decomposition); 7β-[D-α-tert-butyloxycarbonylamino-α-(4-isothiazolyl)-acetyl-
Amino]-3-methoxy-3-cephem-4-carboxylic acid-diphenylmethyl ester, IR-spectrum ( _{in CH2Cl2} ): 2.94, 5.65, 5.71 (shoulder),
It has bands at 5.88, 6.28 and 6.73μ.

Claims (1)

[Claims] First-order equation (), [In the formula, R ^a ₁ is a hydrogen atom or an amino protecting group, and R ^b ₁ is a hydrogen atom or an acyl group,
Alternatively, R ^a ₁ and R ^b ₁ are both divalent amino protecting groups, and R ^A ₂ is a carbonyl group -C(=O)
- together with a group forming a protected carboxyl group, the group -N(R ^a ₄ )(R ^b ₄ ) is a secondary or tertiary amino group, and Y is a leaving group. ] The following formula (), characterized in that the compound is cyclized by removing H-Y from the compound represented by [Wherein R ^a ₁ , R ^b ₁ , R ^A ₂ , and -N(R ^a ₄ )(R ^b ₄ ) have the same meanings as above] A method for producing a compound represented by the following.